Psoriatic and Reactive Arthritis: A Companion to Rheumatology

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PSORIATIC AND REACTIVE ARTHRITIS A COMPANION TO RHEUMATOLOGY Copyright © 2007 by Mosby, Inc., an affiliate of Elsevier Inc.

ISBN-13: 978-0-323-03622-1 ISBN-10: 0-323-03622-8

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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. Library of Congress Cataloging-in-Publication Data Psoriatic and reactive arthritis: a companion to rheumatology / [edited by] Christopher T. Ritchlin, Oliver FitzGerald.–1st ed. p. ; cm. Includes bibliographical references and index. ISBN 0-323-03622-8 1. Psoriatic arthritis. 2. Infectious arthritis. I. Ritchlin, Christopher T. II. FitzGerald, Oliver. [DNLM: 1. Arthritis, Psoriatic. 2. Arthritis, Reactive. WE 344 P9734 2007] RC931.P76P75 2007 616.7’227–dc22 2006050135

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To our patients and mentors

Contributors

Firas Alkassab, MD Clinical Fellow, Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas Spectrum of Reactive Arthritis Dominique Baeten, MD, PhD Associate Professor of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Synovial Immunopathology in Spondyloarthropathy Juergen Braun, MD Professor, Ruhr University, Bochum; Medical Director, Rheumazentrum Ruhrgebiet, Herne, Germany Imaging in Reactive Arthritis Antoni Chan, MB ChB, MRCP ARC Clinical Research Fellow, Nuffield Orthopaedic Centre and MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom Genetics of Reactive Arthritis Daniel O. Clegg, MD Professor of Medicine; Chief, Division of Rheumatology; and Harold J., Ardella T., and Helen T. Stevenson Presidential Chair in Rheumatology, University of Utah School of Medicine; Chief, Rheumatology Section, Salt Lake City Veterans Affairs Medical Center, Salt Lake City, Utah Management of Reactive Arthritis Filip De Keyser, MD, PhD Professor of Rheumatology, Department of Rheumatology, University Hospital Ghent, Ghent, Belgium Enteric Infections and Arthritis; Natural History, Prognosis, Socioeconomic Aspects, and Quality of Life

Stephanie Diamantis, MD Fellow, Mount Sinai School of Medicine, New York, New York Dermatologic Management of Psoriasis James T. Elder, MD, PhD Professor, Department of Dermatology, University of Michigan Medical School; Physician, University of Michigan Health System and Ann Arbor Veterans Administration, Ann Arbor, Michigan Psoriasis: Etiopathogenesis Luis R. Espinoza, MD Professor and Chief, Section of Rheumatology, Department of Internal Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana Historical Aspects of the Disease Ursula Fearon, PhD Newman Fellow, University College Dublin; Senior Scientist, St. Vincent’s University Hospital, Dublin, Ireland Angiogenesis in Psoriasis and Psoriatic Arthritis Oliver FitzGerald, MD, FRCP Consultant Rheumatologist and Newman Clinical Research Professor, St. Vincent’s Hospital and Conway Institute, University College Dublin, Dublin, Ireland Pathogenesis of Psoriatic Arthritis Tracy M. Frech, MD Rheumatology Fellow, University of Utah School of Medicine, Salt Lake City, Utah Management of Reactive Arthritis

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CONTRIBUTORS

Dafna D. Gladman, MD, FRCPC Professor of Medicine, University of Toronto Faculty of Medicine; Senior Scientist, Division of Outcomes and Population Health, Toronto Western Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada Clinical Features of Psoriatic Arthritis Johann E. Gudjonsson, MD, PhD Resident/Research Fellow, Department of Dermatology, University of Michigan Medical School; Resident, Department of Dermatology, University of Michigan Health System, Ann Arbor, Michigan Psoriasis: Etiopathogenesis Shahir Hamdulay, BSc, MRCP Specialist Registrar, Department of Rheumatology, Hammersmith Campus, Imperial College School of Medicine, London, United Kingdom Outcomes in Reactive Arthritis Philip S. Helliwell, MD, PhD Senior Lecturer in Rheumatology, University of Leeds, Leeds; Attending Physician, Bradford Teaching Hospitals NHS Trust, Bradford, West Yorkshire, United Kingdom Natural History, Prognosis, and Socioeconomic Aspects of Psoriatic Arthritis Robert D. Inman, MD Professor of Medicine and Immunology, University of Toronto Faculty of Medicine; Senior Scientist, Consultant, and Rheumatologist, Toronto Western Hospital, Toronto, Ontario, Canada Chlamydia-Induced Arthritis

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Gabrielle H. Kingsley, MB ChB, PhD, FRCP Reader in Rheumatology, King’s College London; Consultant Rheumatologist, University Hospital Lewisham, London, United Kingdom Historical Aspects of Reactive Arthritis Elli Kruithof, MD, PhD Physician, Department of Rheumatology, University Hospital Ghent, Ghent, Belgium Synovial Immunopathology in Spondyloarthropathy Mark Lebwohl, MD Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine, New York, New York Dermatologic Management of Psoriasis Marjatta Leirisalo-Repo, MD Professor of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Kasarmikatu, Finland Epidemiology of Reactive Arthritis Dennis McGonagle, PhD, FRCPI Academic Unit of Musculoskeletal Diseases, Chapel Allerton Hospital, University of Leeds, Leeds; Consultant Rheumatologist, Calderdale Royal Hospital, Halifax, West Yorkshire, United Kingdom Imaging in Psoriatic Arthritis Neil McHugh, MB ChB, FRCP Consultant Rheumatologist, Royal National Hospital for Rheumatic Diseases, Bath, United Kingdom Clinical Outcome Measures in Psoriatic Arthritis

David John Kane, PhD, MB BCh, MRCPI Honorary Senior Lecturer, Newcastle University, Northumbria Division, Newcastle upon Tyne, England; Consultant Rheumatologist, Adelaide & Heath Hospital, Dublin, Ireland Imaging in Psoriatic Arthritis

Philip Mease, MD Clinical Professor, University of Washington School of Medicine; Head, Seattle Rheumatology Associates; Chief, Rheumatology Clinical Research, Swedish Hospital Medical Center, Seattle, Washington Management of Psoriatic Arthritis: Biologic Agents in Psoriatic Arthritis

Arthur Kavanaugh, MD Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, School of Medicine, La Jolla, California Clinical Outcome Measures in Psoriatic Arthritis

Herman Mielants, MD, PhD Professor of Rheumatology, Ghent University; Head, Department of Rheumatology, University Hospital Ghent, Ghent, Belgium Enteric Infections and Arthritis

Andrew Keat, MD, FRCP Consultant Physician and Rheumatologist, Northwick Park Hospital, Harrow, Middlesex, United Kingdom Outcomes in Reactive Arthritis

Peter Nash, MD Director, Rheumatology Research Unit, Department of Medicine, University of Queensland, Queensland, Australia Management of Psoriatic Arthritis: Traditional DiseaseModifying Antirheumatic Drug Therapies for Psoriatic Arthritis

Proton Rahman, MD, MSc, FRCPC Professor of Medicine, Memorial University of Newfoundland Faculty of Medicine; Staff Rheumatologist, St. Clare’s Mercy Hospital, St. John’s, Newfoundland, Canada Epidemiology of Psoriatic Arthritis John D. Reveille, MD Director, Division of Rheumatology, University of Texas Health Science Center at Houston, Houston, Texas Spectrum of Reactive Arthritis Christopher T. Ritchlin, MD Associate Professor of Medicine, University of Rochester School of Medicine and Dentistry; Director, Clinical Immunology Research Center, Allergy, Immunology, and Rheumatology Division, University of Rochester Medical Center, Rochester, New York Pathogenesis of Psoriatic Arthritis Eric Ruderman, MD Associate Professor of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine; Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois Natural History, Prognosis, and Socioeconomic Aspects of Psoriatic Arthritis David L. Scott, MD, BSc, FRCP Professor of Clinical Rheumatology, King’s College London and King’s College Hospital Trust, London, United Kingdom Historical Aspects of Reactive Arthritis Joachim Sieper, MD Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany Pathogenesis of Reactive Arthritis

Ai Lyn Tan, MRCP Specialist Registrar in Rheumatology, Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, United Kingdom Imaging in Psoriatic Arthritis

Contributors

Finbar D. O’Shea, MB, MRCPI Research Fellow, Spondylitis Clinic, Toronto Western Hospital, Toronto, Ontario, Canada Chlamydia-Induced Arthritis

William J. Taylor, MB ChB, FRACP, FAFRM Senior Lecturer, Department of Medicine, Wellington School of Medicine and Health Sciences, University of Otago; Consultant Rheumatologist, Hutt Valley District Health Board, Wellington, New Zealand Diagnostic Criteria of Psoriatic Arthritis Auli Toivanen, MD Professor of Medicine Emerita, Turku University, Turku, Finland Clinical Picture and Diagnostic Criteria of Reactive Arthritis Bert Vander Cruyssen, MD, PhD Department of Rheumatology, University Hospital Ghent, Ghent, Belgium Natural History, Prognosis, Socioeconomic Aspects, and Quality of Life Douglas J. Veale, MD, FRCPI, FRCP (Lon) University College Dublin; Consultant, St. Vincent’s University Hospital, Dublin, Ireland Angiogenesis in Psoriasis and Psoriatic Arthritis Robert Winchester, MD Professor of Medicine, Pediatrics, and Pathology, Columbia University College of Physicians and Surgeons, New York, New York Genetics of Psoriatic Arthritis Paul Wordsworth, PhD Professor of Clinical Rheumatology, University of Oxford; Honorary Consultant in Rheumatology, Nuffield Orthopaedic Centre, Oxford, United Kingdom Genetics of Reactive Arthritis

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Foreword

Psoriatic and reactive arthritis, long-neglected though valued siblings, have assumed their rightful places at the arthropathy family table. The chairs were shifted as the clinical criteria were affirmed, outcomes better appreciated, and pathophysiologic mechanisms more clearly understood. This altered status is, in many ways, due to previous scientific contributions from the esteemed authors of this excellent book. There are two sections. In the section that addresses psoriatic arthritis, Espinoza outlines interesting historical misunderstandings, summarizes current thinking, and surmises on future directions. The distinctive epidemiology and novel genetic associations are eloquently detailed by Rahman and Winchester, respectively. Gudjonsson and Elder, Ritchlin and FitzGerald, and Veale and Fearon each elucidate current knowledge of pivotal pathophysiologic mechanisms. Gladman; Taylor; Helliwell and Ruderman; Kavanaugh and McHugh; and Kane, Tan, and McGonagle separately describe the clinical features, natural history and outcomes, diagnostic criteria, and emerging imaging modalities. Finally, Mease and Nash summarize therapeutic advances in the use of targeted therapies for arthritis, and Diamantis and Lebwohl outline a systematic, evidence-based approach to the management of psoriasis of the skin.

The section on reactive arthritis is similarly structured. Scott and Kingsley discuss the historical aspects, while Leirisalo-Repo and Chan and Wordsworth describe the epidemiologic and genetic characteristics. Insightful discussions of selected pathophysiologic mechanisms are provided by De Keyser and Mielants, O’Shea and Inman, Kruithof and Baeten, and Sieper. The spectrum of clinical features and diagnostic criteria, natural history and prognosis, outcome measures, and imaging modalities is elegantly outlined by Toivanen and Reveille and Alkassab, Vander Cruyssen and De Keyser, Keat and Hamdulay, and Braun, respectively. Finally, Frech and Clegg summarize the evidence for employing both traditional and novel therapeutic approaches. As with other categories of inflammatory arthritis, there is still much to learn about psoriatic and reactive arthritis, and further therapeutic advances are eagerly awaited. This timely volume provides a comprehensive outline of our collected knowledge as it currently stands in the early twenty-first century. Barry Bresnihan, MD Dublin, Ireland

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Preface

It is instructive to note that less than 50 years have passed since psoriatic and reactive arthritis were recognized as distinct forms of joint disease and not “atypical” variants of rheumatoid arthritis. Despite this recognition, both reactive arthritis, originally labeled Reiter’s syndrome, and psoriatic arthritis have languished in relative obscurity. Clinical studies of these disorders were hampered by a striking heterogeneity in disease manifestations and course coupled with the absence of a defining marker such as rheumatoid factor or HLA B27. Moreover, investigations of disease mechanisms were relatively rare compared with the prodigious efforts made by those studying rheumatoid arthritis. Over the past several years, significant advances have taken place in the classification and treatment of psoriatic arthritis. These advances are due in large part to the development of effective biologic agents and improved clinical trial design and implementation. In parallel, mechanistic investigations based on tissue analysis, genetic studies, and novel imaging modalities have provided new insights into disease pathogenesis. In reactive arthritis, the recognition of the role of the innate immune response combined with improved epidemiologic methods and pathogen detection holds great promise for increased understanding and

improved treatment for this disorder in the near future. The topics of psoriatic and reactive arthritis are usually covered in both medicine and rheumatology texts, but in-depth presentations have been precluded by space considerations and a dearth of new information. The marked increase in new knowledge from both a scientific and clinical perspective, however, has kindled great interest in these diseases. Thus, we thought it appropriate to provide an authoritative and comprehensive volume to serve as a resource for health care professionals and biomedical scientists. The material for this text has been provided by investigators and clinicians from around the world in order to provide a truly global perspective. The style and format of the book are the same as the user-friendly and easily accessible parent textbook, Rheumatology. It is our sincere hope and expectation that this resource will contribute to improved care for patients and spark scientific investigators to focus attention on these two fascinating inflammatory disorders. Christopher T. Ritchlin Oliver FitzGerald

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PSORIATIC ARTHRITIS

1

Epidemiology of Psoriatic Arthritis Proton Rahman

HISTORICAL PERSPECTIVE The first widely cited depiction of arthritis associated with psoriasis was reported by Alibert in the early 1800s.1 Despite recognition of this association, there was a longstanding impression that psoriatic arthritis (PsA) was a variant of rheumatoid arthritis (RA). It was not until the emergence of epidemiologic studies that PsA surfaced as a unique disease entity separate from RA, and it was recognized as a specific rheumatic entity by the American Rheumatology Association in 1964.2 This, in part, was due to population studies demonstrating an increased frequency of inflammatory arthritis among patients with psoriasis and an increased prevalence of arthritis among patients with psoriasis. The prevalence of psoriasis in subjects with arthritis was found to be 2.6% to 7.0%, whereas the prevalence of psoriasis in the general population was estimated as 0.1% to 2.8%.3,4 On the other hand, the prevalence of arthritis in subjects with psoriasis varies from 7% to 25% and the prevalence of arthritis in the general population is estimated as 2% to 3%.3,4 Historically, the rheumatoid factor further defined PsA, as subjects with PsA tended to be seronegative. It is now apparent that 10% to 15% of patients with PsA are in fact seropositive for rheumatoid factors, albeit in a low titer.3 The entity of PsA is now well characterized and encompasses unique clinical features including distinct patterns of peripheral joint involvement, periarticular manifestations, and axial involvement.3 The delineation of PsA and RA is validated by responses to concomitant human immunodeficiency virus infections, as symptoms of PsA worsen5 and symptoms attributable to RA improve.6 Furthermore, the genetic epidemiology of these two inflammatory arthropathies appear to be distinct as noted by multiple disease-specific associations within and more recently outside the major histocompatibility complex region (e.g., association of PTPN22 and seropositive RA).7

EPIDEMIOLOGY There is a paucity of well-designed population-based studies that have estimated the prevalence and inci-

dence of PsA. There is also a wide range in the reported prevalence and incidence rates of PsA related, in part, to the lack of a widely accepted classification or diagnostic criteria. Until recently, there were seven classification schemes proposed for PsA, six of which were based on clinical experience.8 Historically, the most widely cited classification criteria were developed by Wright and Moll.9

Prevalence The reported prevalence of PsA varies from 0.056% to 0.28%, and PsA affects men and women equally.10-13 The most recent population-based study, by Gelfand and colleagues, reported a PsA prevalence of 0.25% (95% confidence interval [CI]: 0.18%, 0.31%).10 This prevalence was estimated in a U.S. population by randomly interviewing 27,220 subjects.10 Cases were defined as patients who reported a physician diagnosis of psoriasis and PsA. In this survey, 601 subjects stated that they had psoriasis and 71 had PsA. The prevalence of PsA in Gelfand’s study was substantially higher than that calculated using the Rochester Epidemiological Project computerized medical system. In the latter study, Shbeeb and associates screened the records of all Olmsted County residents with a diagnosis consistent with psoriasis or PsA over a 10-year period.11 This screening identified 1844 patients with a diagnosis of psoriasis, of whom 1056 had the diagnosis of psoriasis confirmed by a dermatologist. Among these individuals, 66 cases of PsA were identified, resulting in a prevalence of PsA of 0.1% (95% CI: 0.081% to 0.121%). Kay and coauthors carried out a similar study and determined the prevalence of PsA in northeast England by evaluating records from six general practices.12 One practice was used for the pilot study (5842 individuals) and five practices were used for the main study (29,348 individuals). A questionnaire, which was validated in the pilot study, was used to identify inflammatory arthritis in patients with psoriasis. Data determined from this evaluation showed that 81 of 772 psoriasis subjects had inflammatory arthritis, with a crude prevalence of 0.28%.

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EPIDEMIOLOGY OF PSORIATIC ARTHRITIS

In another population-based study, Alamanos and colleagues investigated the frequency and distribution of PsA in a defined area of northwest Greece with a population of 500,000.13 All inpatient and outpatient PsA cases, diagnosed using the European Spondyloarthropathy Study Group criteria and referred from rheumatology clinics in two hospitals, were identified over a 9-year period. The age-adjusted prevalence of PsA in this study was 0.056%.

Incidence The reported incidence of PsA has varied from 3 to 23 per 100,000.10-15 From the Rochester Epidemiological Project, the average age- and sex-adjusted incidence rate was 6.59 per 100,000 U.S. population (95% CI: 4.99 to 8.19). Alamanos and co-workers from northern Greece reported an age-adjusted mean incidence rate of 3.02 per 100,000. No difference was noted between males and females in the latter study, and the peak incidence was observed between 45 and 64 years. Savolainen and colleagues systematically collected data on a population of 87,000 inhabitants of Kuopio, Finland.14 PsA was diagnosed as peripheral arthritis with psoriasis in the absence of rheumatoid factor– positive polyarthritis or spondylitis with psoriasis. Sixteen new cases of PsA were identified, resulting in a mean incidence rate of 23 per 100,000. Furthermore, Soderlin and coauthors performed a prospective population-based study on the annual incidence of early arthritis in Kronoberg County in southern Sweden.15 The patients were referred from primary health care centers to the rheumatology department in the central hospital or to private clinics participating in the study. Additional hospital records were checked. The patients were registered as incident cases if the onset of the joint inflammation was between May 1, 1999 and May 1, 2000. In total, 11 patients presented with PsA, corresponding to an annual incidence of 8 per 100,000 for PsA.

Prevalence of Psoriatic Arthritis among Psoriasis Subjects

2

The estimated prevalence of inflammatory arthritis among patients with psoriasis has varied widely from 6% to 42%.4 Historically, however, a value of 7% to 10% for the prevalence of inflammatory arthritis in psoriasis patients was most often cited.4 The U.S. study by Gelfand and colleagues noted a self-reported incidence of inflammatory arthritis of 11% (95% CI: 9% to 14%). This may be an underestimate as the diagnosis of psoriasis is often overlooked because it may not be in direct view of patients and physicians (such as scalp, buttocks). Also, there is a lower level of tenderness of inflammatory arthritis among PsA patients. Thus, ideally, patients with psoriasis should be carefully examined and questioned specifically about peripheral and

axial inflammatory symptoms. Two European studies that included assessments by dermatologists and rheumatologists from outpatient clinics estimated a prevalence of inflammatory arthritis of 30% and 31% in patients with psoriasis.16,17 These estimates are similar to those reported in the mid-1980s by Scarpa and coauthors, who noted the prevalence of inflammatory arthritis to be 30%.18

Pattern of Inflammatory Arthritis and Psoriasis Moll and Wright described five clinical patterns of PsA and estimated the frequency of these subgroups on the basis of their own clinical observations.19 The five clinical patterns and their estimated frequencies are (1) “classical” PsA confined to distal interphalangeal (DIP) joints of the hands and feet (5%), (2) arthritis mutilans with sacroiliitis (5%), (3) symmetric polyarthritis indistinguishable from RA (15%), (4) asymmetric oligoarthritis (70%), and (5) spondyloarthropathy (15%). Subsequent reports validated these subgroups; however, there is considerable overlap and evolution of these subgroups.20 At present, there is an ongoing debate about the most prevalent subgroup of PsA (most acknowledge that the polyarticular variant is probably the most frequent) and the existence of pure DIP involvement. These issues are addressed in detail in Chapter 3. The majority of patients with PsA have the classical form of psoriasis vulgaris, although pustular psoriasis and erythredema have also been reported.3 In approximately 70% of cases, psoriasis precedes the onset of arthritis, but the interval in between is extremely variable. In approximately 15% of cases, arthritis precedes the onset of psoriasis. In another 15% of cases, the psoriasis and inflammatory arthritis are diagnosed together. There appears to be no clear relationship between the extent of psoriasis and the severity of inflammatory arthritis.4

Genetic Epidemiology of Psoriatic Arthritis Moll and Wright estimated the strength of familial clustering of PsA.19 Evaluation of the first- and seconddegree relatives of 88 consecutive PsA probands showed that 12.5% had at least one relative with confirmed PsA. Of the 181 first-degree relatives assessed, 10 relatives had PsA, including 5 siblings. Thus, the overall prevalence of PsA among first-degree relatives was 5.5%. Using the calculated prevalence of PsA in the United Kingdom population of 0.1%, the risk for affected first-degree relatives (λ1) is 55, a heritability substantially greater than those obtained for psoriasis.21 In the mid-1980s, Henseler and Christophers noted that type I psoriasis, defined by the onset of psoriasis prior to age 40, had a stronger genetic basis (defined by

affected mother.25 Interestingly, a linkage study in PsA noted significant linkage only when assessing the transmission of alleles of paternal origin.26 In summary, the exact prevalence and incidence of PsA are not known. There is a large variance in the reported prevalence and incidence rates of PsA, in part because of a lack of widely accepted diagnostic criteria. When the Classification of Psoriatic Arthritis (CASPAR) group arrives at a valid set of diagnostic-classification criteria, a proper prospective epidemiologic study may provide better estimates regarding the epidemiology of PsA.

References

a family history of psoriasis) and exhibited stronger human leukocyte antigen (HLA) associations.22 Two independent groups noted a similar trend for PsA when PsA was stratified according to the age of onset of psoriasis.23,24 PsA patients with early-onset psoriasis (onset of psoriasis prior to age 40) were more likely to have a family history of psoriasis and PsA and exhibited differential expression of HLA antigens. A parent-of-origin effect has also been demonstrated in PsA as there appears to be a greater proportion of PsA probands with an affected father than with an

REFERENCES 1. Alibert JL. Précis Théoretique et Pratique sur les Maladies de la Peau. Paris: Caille et Ravier, 1818, p 21. 2. Blumberg BS, Bunim JJ, Calkins E, et al. Nomenclature and classification of arthritis and rheumatism (tentative) accepted by the American Rheumatism Association. Bull Rheum Dis 1964;14:339-340. 3. Gladman DD, Antoni C, Mease P, et al. Psoriatic arthritis: Epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64 (Suppl 2):ii14-ii17. 4. Gladman DD. Psoriatic arthritis. In: Gordon K, Ruderman E (eds). Psoriasis and Psoriatic Arthritis. Berlin: Springer-Verlag, 2005, pp 57-65. 5. Arnett FC, Reveille JD, Duvic M. Psoriasis and psoriatic arthritis associated with human immunodeficiency virus infection. Rheum Dis Clin North Am 1991;17:59-78. 6. Kaye BR. Rheumatologic manifestations of infection with human immunodeficiency virus (HIV). Ann Intern Med 1989;111:158-167. 7. Gregersen PK. Gaining insight into PTPN22 and autoimmunity. Nat Genet 2005;37:1300-1302. 8. Helliwell PS, Taylor WJ. Classification and diagnostic criteria for psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl 2): ii3-ii8. 9. Wright V, Moll JMH. Psoriatic arthritis. In: Wright V, Moll JMH (eds). Seronegative Polyarthritis. Amsterdam: North Holland, 1976, pp 169-223. 10. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 2005;53:573. 11. Shbeeb M, Uramoto KM, Gibson LE, et al. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 19821991. J Rheumatol 2000;27:1247-1250. 12. Kay LJ, Parry-James JE, Walker DJ. The prevalence and impact of psoriasis and psoriatic arthritis in the primary care population in North East England. Arthritis Rheum 1999;42:S299. 13. Alamanos Y, Papadopoulos NG, Voulgari PV, et al. Epidemiology of psoriatic arthritis in northwest Greece, 19822001. J Rheumatol 2003;30:2641-2644. 14. Savolainen E, Kaipiainen-Seppanen O, Kroger L, Luosujarvi R. Total incidence and distribution of inflammatory joint diseases

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in a defined population: Results from the Kuopio 2000 arthritis survey. J Rheumatol 2003;30:2460-2468. Soderlin MK, Borjesson O, Kautiainen H, et al. Annual incidence of inflammatory joint diseases in a population based study in southern Sweden. Ann Rheum Dis 2002;61:911-915. Zachariae H. Prevalence of joint disease in patients with psoriasis: Implications for therapy. Am J Clin Dermatol 2003;4:441447. Brockbank JE, Schentag C, Rosen C, Gladman DD. Psoriatic arthritis (PsA) is common among patients with psoriasis and family medical clinic attendees [abstract]. Arthritis Rheum 2001;44 (Suppl 9):S94. Scarpa R, Oriente P, Pucino A, et al. Psoriatic arthritis in psoriasis patients. Br J Rheumatol 1984;23:246-250. Moll JM, Wright V. Familial occurrence of PsA. Ann Rheum Dis 1973;32:181-201. Jones SM, Armas JB, Cohen MG, et al. Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-839. Rahman P, Elder JT. Genetic epidemiology of psoriasis and psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl II): ii37-ii39. Henseler T, Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985;13:450-456. Rahman P, Gladman DD, Schentag CT. Immunogenetic profile of patients with psoriatic arthritis varies according to the age at onset of psoriasis. Arthritis Rheum 1999;42:822-823. Fernandez-Sueiro JL, Willisch A, Pinto J, et al. Clinical features of psoriatic arthritis according to the type of cutaneous psoriasis. Arthritis Rheum 2005;52:S216. Rahman P, Gladman DD, Schentag C, Petronis A. Excessive paternal transmission in psoriatic arthritis. Arthritis Rheum 1999;42:1228-1231. Karason A, Gudjonsson JE, Upmanyu R, et al. A susceptibility gene for psoriatic arthritis maps to chromosome 16p: Evidence for imprinting. Am J Hum Genet 2003;72:125-131.

3

PSORIATIC ARTHRITIS

2

Historical Aspects of the Disease Luis R. Espinoza

Study of the history of psoriatic arthritis (PsA) from ancient times through the present millennium is hampered by the lack of well-defined diagnostic and classification criteria. Considerable evidence gathered in the past several years, however, supports the concept that both psoriasis and PsA are old disorders that may have afflicted humans since the beginning of history.

THE PAST

Psoriasis

4

It has long been recognized that psoriasis, rather than Hansen’s disease or leprosy, accounted for most cases of biblical leprosy.1,2 In fact, in a description of a leper’s pool excavated in the Roman baths at Hammat Gader near the Sea of Galilee, it was noted that the principal problem treated there in the third century AD was most likely psoriasis and not Hansen’s disease.3 The word for leprosy in Hebrew was zaraath, and lepers were considered unclean and were subject to regulation and segregation from the normal population.4,5 It is now well accepted that the term included a variety of dermatologic disorders including psoriasis. An often quoted passage in the Old Testament attests to the antiquity of this disorder: Naaman, captain of the hosts of the King of Syria, on the advice of Elisha, washed seven times in the Jordan to rid himself of zaraath.4 This was thought by Russell6 to be psoriasis, although Hebra7 suggested that it might have been scabies. The term psoriasis derives from the Greek psora, meaning itch. The ancient Greek writers divided cutaneous diseases into three classes: psora, lepra, and leichen.5 Generally, moist pustular ulcerated conditions were called psora; scaly conditions, lepra; and tuberculous conditions, leichen. It is highly likely that psoriasis was known to the ancients as a form of lepra. The term elephantiasis graecorum was used by the Greeks to denote leprosy. Further, confusion and mistakes in the terminology used to recognize these two conditions—leprosy and psoriasis—were introduced in the Middle Ages when Arabic texts were translated into Latin. The translators confused lepra graecorum with elephantiasis graecorum, thus giving the erroneous impression that all scaly conditions of the skin

were due to leprosy. In order to circumvent this anomaly, the term lepra arabum was introduced to describe leprosy, but it took several hundred years before these two disorders were distinguished from each other. It has been suggested that during the Middle Ages thousands of psoriasis patients received the same drastic treatment as real lepers, who were forced to carry a bell or clapper to warn the healthy from their path, wore a special dress, were not allowed to talk above a whisper to a healthy person, and could not touch anyone with their hands or eat with anybody other than a leper. In addition, during the reign of Philip the Fair of France in 1313, many were executed by burning at the stake.8 Aurelius Cornelius Celsus (25 BC to AD 45), in his “De ra medice” during the reign of Emperor Tiberius, was probably the first to describe psoriasis as we know it today, although Hippocrates years earlier had used the term psora to indicate a scaly rash localized on the face and genitals.9,10 Galen (AD 133 to 200) was credited by Willan as the first to use the word psoriasis, but there is agreement among authors that what he described may have actually been seborrheic dermatitis. It is intriguing and fascinating to consider a report by Jasaliq, a Persian physician, in the eighth century AD, describing and differentiating psoriasis from leprosy. In addition, the effective use of psychotherapy has been discussed.11 The lack of distinction between leprosy or Hansen’s disease and other dermatitides and psoriasis in the West lasted until the beginning of the 18th century. At that time an Englishman, Robert Willan (1757 to 1813), considered the founder of modern dermatology, provided an accurate description of psoriasis.12 Willan, however, called it lepra and described another skin condition that he named psoriasis. Other authors, including Turner in 1826, Plumbe in 1827, and Gilbert in 1840, realized that Willan’s lepra and psoriasis were the same disorder. In 1841 Hebra dropped the term lepra, and he is credited with the precise definition of psoriasis.12-16 Wilson in 1863 and subsequently Fox in 1871 agreed with Hebra’s definition, and in 1872 Milton unsuccessfully recommended omission of the word psoriasis.17-19 Thus, the term psoriasis as we

Psoriatic Arthritis More recent evidence also provides support for the concept that PsA was present in ancient times. The earliest report on PsA in antiquity in the Old World dates back to a sixth-century site in North Africa.23 Cases of seronegative arthritis from ancient Judea have also been described, but insufficient lesions were described to differentiate further among this group of disorders.24 Dieppe and Rogers25 in 1989 described a likely case of PsA from medieval England. The same group had previously described the presence of PsA in a study of 400 skeletons from archeological excavations in England. They found three skeletons with erosive peripheral arthritis. One of the cases was a 13thcentury man who was buried with the knees flexed (at a time when this was not a burial custom) and with evidence of widespread arthritis. Radiographic findings included ankylosis of interphalangeal joints and erosive “cup-and-pencil” deformities affecting distal as

well as proximal joints, all of which strongly support an underlying diagnosis of PsA.2 More compelling evidence for the existence of PsA in ancient times comes from the report by Zias and Mitchell.26 These investigators described the presence of PsA in a fifth-century Judean desert monastery. The monastery of Martyrius, uncovered in 1983 by the Israel Antiquities Authority, had been built in the fifth century AD and destroyed during the Persian invasion of AD 614. A common mass grave was discovered beneath the mosaic floor of one of the chapels that was dedicated to an important historical figure in the monastic order named Paulus and bore the Greek inscription “Tomb of Paulus, priest and archimandrite.” Epigraphic and literary evidence indicates that the tombstone was from the late fifth or early sixth century. In the ensuing years, an additional eight males and one female were interred in the chamber. The skeletal remains recovered from the tomb of Paulus represent the commingled bones from nine adult males and one adult female. Despite constraints posed by the commingling of the remains along with the erosive pathology found, the investigators were able to study the skeletal material by macroscopic observation and by radiographic imaging including scanning electron microscopy. Their analysis showed that three individuals were affected with a seronegative arthritis characterized by severe erosive articular changes, enthesopathy at tendon insertions, and ossification of ligaments and tendons to produce spurs and ankylosis of joints. Involvement of distal interphalangeal as well as proximal and middle interphalangeal, metatarsal, and tarsal bones was also found. Axial skeleton with cervical and thoracic vertebrae fusion and syndesmophyte formation and unilateral sacroiliac joint fusion were also present. The authors concluded that two of the affected individuals exhibited findings characteristic of PsA—arthritis mutilans—and the third showed less widespread erosive lesions consistent with oligoarticular PsA or reactive arthritis. These findings in a Judean desert monastery are of extreme interest and importance because they provide a link with the concept that psoriasis was one, if not the most common, disorder included under the umbrella of biblical leprosy. It was a regular practice during the Byzantine period (fourth to seventh centuries) to house afflicted individuals diagnosed as having “biblical leprosy” in special facilities such as monasteries built for their care. The presence of these three individuals provides further support for the presence of psoriasis and PsA in these facilities built to house cases of biblical leprosy. More modern references to PsA began to appear in the 17th century in a text written by Fray Felipe Colombo and published by the Royal Printing House

The Past

know it today received full recognition just over 125 years ago, although as recently as close to 60 years ago, 1946, it was suggested that this disorder be called Willan’s syndrome or the Willan-Plumbe syndrome in recognition of the original describers. The clinical spectrum of psoriasis has remained unchanged over the past 150 years, with many clinicians contributing to this endeavor. Many notable clinical and histopathologic features of psoriasis were described in the second half of the 18th century, including the Koebner phenomenon, Auspitz phenomenon, and the Munro microabscess.20,21,22 As reported by Waisman,20 Koebner in 1872 at a presentation to the Silesian Society for National Culture presented a case in which 5 or 6 years after the appearance of an isolated plaque of psoriasis, various traumatic events on remote parts of the body (excoriations from horseback riding, suppuration from lymphadenitis, horse bite, and, finally, tattoos) evoked outbreaks of psoriasis in the patient, at first exactly in the shape of the injured skin and later by general extension. Heinrich Auspitz, a medical student at the time, described the clinical phenomenon that bears his name—capillary bleeding after lifting the scabs off psoriatic plaques. It should be noted, however, that others, including Hebra and Devergie, had previously recognized and reported this observation. To Auspitz’s credit, he also first described acantholysis.21 William John Munro in 1899 described the abscess that he regarded as “la lésion primitive du psoriasis,” although L. Kopytowski in 1895 had reported a similar finding in a Polish journal. Kopytowski’s paper, however, had not been translated into any other language, and there is no evidence that Munro was aware of the publication.22

5

HISTORICAL ASPECTS OF THE DISEASE

6

of Madrid in 1674.27 The book narrates the life of Fray Pedro de Urraca, a Mercedarian monk who lived in Peru for over 40 years and is still worshipped and venerated in the country. He was afflicted by a severe cutaneous and deforming arthritic condition affecting both peripheral and axial joints, consistent with PsA. It is well accepted, however, that the first description of the association between psoriasis and arthritis was made by the great French physician Baron Jean Louis Alibert in 1818.28 Unfortunately, his description in Précis Théorique et Pratique sur les Maladies de la Peau reflects the confusion regarding the identity of psoriasis at that time and, therefore, describes arthritis in association with “lepra squammeuse,” following the customary practice in those days of classifying psoriasis as a form of leprosy. His original description of this association, however, has been criticized as being too vague and superficial to warrant much credit.29 In the mid-19th century several case reports of PsA were published, including those of Rayner (1825), Gilbert (1839), and Cazenave (1941).30 In 1948 Devergie first suggested a common pathogenetic pathway for cutaneous and articular involvement, and in 1980 Ernest Bazin introduced the term psoriasis arthritique, but this term described a variety of psoriasis and not an association with arthropathy.31,32 Charles Bourdillon, in his doctoral thesis of 1888, “Psoriasis et arthropathies,” reviewed 36 cases of psoriasis with rheumatic complaints, in 20 of which he was personally involved.33 Some of these descriptions are consistent with PsA. In the 1930s, several case reports of a small series of patients with PsA, such as that of Jeghers and Robinson, the 26 cases reported by Dawson and Tyson, and the 50 patients reported by Weissenback (1938), strengthened the association.33-35 Philip S. Hench (1935), a Nobel Prize winner in medicine for his work on the use of corticosteroids in RA, pointed out the unusual fact that arthritis in the presence of psoriasis affects distal interphalangeal joints frequently.36 All of these reports solidified the concept of PsA as a distinct entity. However, strong opposition to this concept came from several investigators including Brocq, Margolis, Romanus, and Gribble.37-40 Walter Bauer, a renowned and powerful American rheumatologist, professor at Harvard Medical School, staff physician at the Massachusetts General Hospital, and president of the Rheumatism Association (now American College of Rheumatology), argued in 1939 that “to date there is little justification for considering these patients as suffering from a distinct disease entity.”41,42 Beginning in the 1940s, several events led to the decision in 1964 to classify PsA as a distinct entity. These events included the discovery of the rheumatoid factor by Waaler43; the demonstration that a number of

forms of inflammatory arthritis were rheumatoid factor negative, including PsA; and the results from several large, well-conducted surveys involving large numbers of patients, such as those by Vilanova and Pinol, Coste and associates, and Leczinsky, Baker, and Wright, who introduced the term psoriatic arthritis. The decision to classify PsA as a distinct entity was reached by a committee from the American Rheumatism Association, under the chairmanship of Baruch S. Blumberg, also a Nobel Prize winner for his work on Australian antigen.44-53

THE PRESENT: PSORIATIC ARTHRITIS

Is Psoriatic Arthritis a Distinct Disorder? As noted previously, opposition to this concept remains, and it is based on a number of factors including the lack of validated, standardized diagnostic and classification criteria. Some of these concerns are being addressed now and are discussed later in this chapter. There are established positions regarding the status of PsA. First, PsA can be explained by the chance occurrence of two relatively common disorders, psoriasis, occurring in 1% to 2% of the general population, and a specific form of arthritis such as RA or ankylosing spondylitis. Second, psoriasis is associated with a distinct clinical or pathologic type of arthritis, or the presence of psoriasis increases susceptibility to certain specific types of arthritis; and third, psoriasis has a quantitative influence on polyarthritis.54 Cats suggested that there is no causal connection between psoriasis and chronic polyarthritis. Psoriasis and chronic polyarthritis occur together only by chance. It could be that there is a constitutional, perhaps hereditary, tendency in certain individuals and families for the development of both diseases. In certain cases, chronic polyarthritis may be modified by the presence of psoriasis.41,50,53-55 Over the past 25 to 30 years, however, considerable evidence based on epidemiologic, immunogenetic, and radiologic studies has been gathered in support of the concept that PsA is a separate disorder, especially from RA. An overview of the major highlights that have occurred in PsA in the past 30 years follows. A more in-depth discussion is the subject of the next several chapters in this book.

Epidemiologic Studies Population-based and clinic-based epidemiologic surveys conducted independently by several investigators have established that (1) psoriasis is significantly associated with an inflammatory arthropathy, (2) the arthritis is often clinically and radiologically different from RA, and (3) the majority of patients with psoriasis and arthritis are rarely positive for rheumatoid

Synovial Membrane: Histopathology The histopathologic characteristics of the psoriatic synovium appear to be distinct. Early studies suggested that the inflammatory changes observed in psoriatic synovium were similar to those seen in RA. A number of authors, however, beginning in the 1960s, began to publish observations supporting certain differences in psoriatic synovium compared with RA synovium. Our studies published in 1982 clearly demonstrated unique histopathologic features in psoriatic synovium.58 Both light and electron microscopic studies confirmed the presence of distinct findings in psoriatic synovium— especially in the blood vessels, mainly in capillaries and arterioles, and to a much lesser degree in venules. These changes were characterized by prominent endothelial cells with dilated rough endoplasmic reticulum and marked intracellular edema. In addition, the basement membrane of most capillaries and arterioles exhibited a variable degree of thickening. My deepest appreciation is due to Professor Ralph Schumacher from the University of Pennsylvania, who provided invaluable assistance in the interpretation of the observed electron microscopic changes. These initial observations have been confirmed and also described in the psoriatic skin and nail fold capillaries, suggesting a common link.59-61 More recent work from different laboratories has established the role of angiogenic growth factors including transforming growth factor α, platelet-derived growth factor, and vascular endothelial growth factor in the pathogenesis of the vascular changes seen in psoriatic skin and synovium.62-65 Other growth factors have also been shown to play a role in the pathogenesis of PsA.

Immunopathology of the Synovium The immunopathology of psoriasis and PsA has been clearly delineated.66-68 A number of investigators from both sides of the Atlantic Ocean have contributed to this endeavor, including Winchester, Ritchlin, Veale, and Fitzgerald. Findings in both skin and synovium can be summarized as follows. The inflammatory cellular infiltrate is predominately in a perivascular distribution, although cells may migrate to the lining layer of the joints or the epidermis. CD4+ cells are the most significant lymphocytes in the tissues, although CD8+ cells and B lymphocytes are also present. Access to the joints by T cells occurs first by binding to activated endothelial cells through cell adhesion molecules expressed on their surface. These adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) are regulated in both skin and synovium.69,70,71,72 In addition, elegant and clever studies performed by

Ritchlin and colleagues have shown that the receptor activator of nuclear factor–κB ligand (RANKL)-RANK signaling pathway may be altered in the psoriatic joint and participate in the development of the erosive joint damage seen in this disorder.73

Genetic Studies Genetic studies of both psoriasis and PsA have played an important role in solidifying the concept of PsA as a distinct disorder, particularly separate from RA.74-79 The complex, multifactorial genetic transmission of psoriasis and PsA was recognized through the study of large populations, study of families including twin studies, and over the past 30 years by studies of the association of the disease with genes of the major histocompatibility complex region. Genome-wide scan studies have also identified a number of genes located in different chromosomes that may contribute to disease susceptibility. Certain class I human leukocyte antigens including HLA-B13, HLA-B17 and its split HLA-B57, and HLA-Cw6 have been shown to be associated with psoriasis, and others such as HLAB38, HLA-B39, and HLA-B27 are associated with peripheral PsA and psoriatic spondylitis, respectively. These findings provide a strong argument in favor of the distinctiveness of PsA compared with RA, in which class II human leukocyte antigen HLA-DR4 is highly prevalent.

The Present: Psoriatic Arthritis

factor.48 To this, we can now also add that most PsA patients as opposed to RA patients seldom exhibit antibodies to cyclic citrullinated peptide (anti-CCP).56,57

Etiologic Aspects An aspect of both psoriasis and PsA that needs to be clearly elucidated is the etiologic trigger or triggers underlying their causation. Autoimmune mechanisms are thought to play an important role, but the nature of the antigenic trigger has not been defined.80 In addition, infectious microorganisms have long been considered to play an important role, and a number of microbial agents, particularly streptococcus, have been considered potential etiologic agents.81 More recent work from a long-time PsA researcher, Vasey, and colleagues has provided further support for a role of streptococcal antigens in the etiopathogenesis of PsA.82 Of greater relevance and interest is the known association of human immunodeficiency virus (HIV) infection with both psoriasis and PsA. HIV can trigger de novo or exacerbate both clinical disorders.83,84 All of these observations strengthened the potential role of infectious microorganisms in the etiology of psoriasis and PsA. However, further studies are needed to delineate the precise roles of microorganisms in the etiology of these disorders.

Clinical Characteristics A better understanding of the clinical course and prognosis of PsA has resulted from the longitudinal studies

7

HISTORICAL ASPECTS OF THE DISEASE

in a large cohort of PsA patients performed by Gladman and associates.85-90 Gladman and her group have shown conclusively that approximately 20% of patients with PsA have a severe and debilitating form of arthritis. Furthermore, they have identified a series of clinical and laboratory parameters associated with a poor prognosis. They have also shown that when observed longitudinally for over 20 years, approximately 18% of PsA patients reached remission. Studies on quality of life and function in PsA from their group have shown that patients with PsA exhibit reduced quality of life as measured by lower scores on the Medical Outcomes Study 36-Item Short Form Survey (SF-36) and also reduced function by Health Assessment Questionnaire (HAQ) scores, which is comparable to that seen in patients with RA. They have also provided evidence of increased mortality risk in their PsA population followed prospectively for over 15 years. They were able to characterize certain prognostic indicators of death such as an elevated erythrocyte sedimentation rate and radiologic changes at initial presentation, evidence of previously active and severe disease as manifested by the prior use of medication. Causes of death in PsA were similar to those in the general population, that is, cardiovascular, respiratory, and malignancy.91

Advances in Therapy

8

Significant developments have occurred in the therapeutic management of PsA in the past two to three decades. Efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and of disease-modifying antirheumatic drugs (DMARDs) including biologic agents has been clearly documented. It has been shown conclusively that most patients with PsA exhibiting mild joint involvement can be safely and effectively managed with cyclooxygenase 1 (COX-1) and COX-2 NSAIDs. PsA patients exhibiting a more severely erosive disease should be treated with DMARDs. Despite the lack of randomized clinical trials on the use of DMARDs in PsA, a number of studies on PsA have proved the efficacy and safety of conventional DMARDs such as methotrexate, cyclosporine A, and sulfasalazine alone or in combination.92-95 The largest impact regarding efficacy in PsA has been achieved with the use of tumor necrosis factor α (TNF-α) inhibition. Large prospective randomized controlled studies with the three available TNF-α inhibitors—etanercept, infliximab, and adalimumab—have shown their effectiveness and relative safety in PsA. More important, these agents resulted in remission in a large proportion of PsA patients and ameliorated the radiologic progression of joint damage.96-98

Two other biologic agents, efalizumab and alefacept, specifically developed through better understanding of the fundamental mechanisms in the biology of psoriasis and PsA, have been introduced in our therapeutic armamentarium. Efalizumab, a monoclonal antibody, binds to the CD11a α subunit of leukocyte function antigen 1 (LFA-1) and inhibits binding of T cells to endothelial cells, prevents activation of T cells, and inhibits T cell trafficking into the dermis.99 Alefacept is a fully human fusion protein consisting of the first extracellular domain of LFA-3 fused to the hinge segment and constant regions of immunoglobulin G1 (IgG1). Alefacept binds to the CDR receptor on T cells, thus blocking their natural interaction with LFA-3 on antigen-presenting cells and thereby inhibiting the antigen-dependent activation of T cells. It also induces a selective apoptosis of the memory T cells. Both agents have also been shown to be effective in PsA but not to the same degree as in psoriasis or when compared with TNF-α inhibitors.99,100

THE FUTURE The past 25 to 30 years have seen significant progress in our understanding of the basic pathogenetic mechanisms operating in both psoriasis and PsA. There remains, however, a great deal to understand in the etiopathogenesis of these disorders. A significant development has occurred in the past few years that may have a positive impact in PsA over the next several years. This has been the formation of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). This organization includes most leaders in PsA research and was the brainchild of Phillip Helliwell, a disciple of Verna Wright, a pioneer in the study of PsA. Their research agenda reflects areas of concern or interest in PsA. One of the first topics already discussed has been the development of classification criteria for PsA. This has been an area of urgent need to establish once and for all criteria that allow differentiation from other arthritides, especially RA.101 The task of establishing defining criteria has been completed and presented at peer review meetings. A full manuscript has been prepared for publication. Other issues that will be studied in the immediate future include clinical assessment of skin and joint involvement including both peripheral and axial joints. Functional, radiologic, quality of life, histologic, and immunohistochemical changes and immunogenetic and clinical trial assessments are on the research agenda and most likely will yield important information on this distinctive arthropathy.102,103

1. Hulse EV. The nature of biblical “leprosy” and the use of alternative medical terms in modern translations of the Bible. Palest Explor Q 1975;107:87-105. 2. Rogers J, Watt I, Dieppe P. Arthritis in Saxon and mediaeval skeletons. Br Med J 1981;283:1668-1670. 3. Hirschfeld Y, Solar G. Sumptuous Roman baths uncovered near the Sea of Galilee. Bibl Archeol Rev 1984;10(6):22-40. 4. Meenan FOC. A note on the history of psoriasis. Ir J Med Sci 1955;351:141-142. 5. Glickman FS. Lepra, psora, psoriasis. J Am Acad Dermatol 1986;14:863-866. 6. Russel B. Psoriasis. Practitioner 1950;164:197-204. 7. Hebra F. On Diseases of the Skin. NSS Vol 11. London, 1868. 8. Bechet PE. Psoriasis, a brief historical review. Arch Dermatol Syph 1936;33:327-334. 9. Fry L. Psoriasis. Br J Dermatol 1988;119:445-461. 10. Holubar K. Psoriasis—100 years ago. Dermatologica 1990;180:1-4. 11. Shafii M, Shafii SL. Exploratory psychotherapy in the treatment of psoriasis. Arch Gen Psychiatry 1979;36:1242-1245. 12. Willan R. On Cutaneous Diseases. London: Johnsen, 1798. 13. Zampieri A. Notes on history of psoriasis. Acta Derm Venereol Suppl (Stockh) 1994;186:58-59. 14. Turner D. De Morbis Cutaneis, 3rd ed. London: Bonwicke, Walthoe, Wilkin and Ward, 1726. 15. Plumbe S. Practical Treatise on Diseases of the Skin. London: Underwood, 1827. 16. Gilbert CM. Traité Pratique des Maladies Spéciales de la Peau, 2nd ed. Paris: Germer-Bailliere, 1840, p 323. 17. Wilson E. Diseases of the Skin. Philadelphia: Blanchard and Lea, 1863, pp XII-XIII. 18. Fox T. Skin Diseases: Their Description, Pathology, Diagnosis, and Treatment. New York: William Wood, 1871, pp 123-129. 19. Milton JL. Diseases of the Skin. London: Robert Hardwicke, 1872. 20. Waisman M. Historical note: Koebner on the isomorphic phenomenon. Arch Dermatol 1981;117:415. 21. Holubar K. Remembering Heinrich Auspitz. Am J Dermatopathol 1986;8:83-85. 22. Johnson A. William John Munro (1863-1908). Am J Dermatopathol 1983;5:477-478. 23. Kilgore L, Jurmain R. Possible psoriatic arthritis in a skeleton from Carthage, Tunisia. Sixteenth Annual Meeting of the Paleopathology Association, San Diego, California, 1989. 24. Bloom RA, Smith P. On the antiquity of the seronegative spondyloarthropathies: Evidence from ancient Judea. Skeletal Radiol 1992;21:111-114. 25. Dieppe P, Rogers JM. Skeletal paleopathology of rheumatic disorders. In: McCarty DJ (ed). Arthritis and Allied Conditions, 11th ed. Philadelphia: Lea & Febiger, 1989, pp 8-15. 26. Zias J, Mitchell P. Psoriatic arthritis in a fifth-century Judean desert monastery. Am J Phys Anthropol 1996;101:491-502. 27. Castillo-Ojugas A, Hernandez IR. Description of psoriatic arthropathy in the 17th century. Arthritis Rheum 1982;32: 812-813. 28. Alibert JL. Précis Théorique et Pratique sur les Maladies de la Peau. Paris: Caille et Ravier, 1818, p 21. 29. Benedek TG, Rodnan GP. A brief history of the rheumatic diseases. Bull Rheum Dis 1982;32:59-68. 30. Eccles JT, Wright V. The history and epidemiologic definition of psoriatic arthritis as a distinct entity. In: Gerber LH, Espinoza LR (eds). Psoriatic Arthritis. New York: Grune & Stratton, 1985, pp 1-8. 31. Scarpa R, Biondi Oriente C, Oriente P. The classification of psoriatic arthritis: What will happen in the future? J Am Acad Dermatol 1997;36:78-83. 32. Bazin P. Leçons Théoretiques et Cliniques sur les Afflections Cutanées de Nature Arthritique et Arthreux. Paris: Delahaye, 1860, pp 154-161. 33. Bourdillon C. Psoriasis et Arthropathies. M.D. thesis, University of Paris, 1888.

34. Dawson MH, Tyson TL. Psoriasis arthropathia with observations on certain features common to psoriasis and rheumatoid arthritis. Trans Assoc Am Physicians 1938;53:303-309. 35. Weissenback R-J. Le psoriasis arthropathique. Arch Dermatol Syph 1938;10:13. 36. Hench PS. Arthropathia psoriatica—Presentation of a case. Proc Mayo Clin 1927;2:89. 37. Brocq L. Quelques réflexions sur l’étiologie du psoriasis à propos de récentes publications Americaines. Ann Dermatol Syph 1910;1:56-83. 38. Margolis HM. Arthritis and Allied Disorders. New York: Hoeber, 1941, p 125. 39. Romanus T. Psoriasis from a prognostic and hereditary point of view. Acta Derm Venereol (Stockh) 1945;26 (Suppl 12): 6-137. 40. Gribble M de G. Rheumatoid arthritis and psoriasis. Ann Rheum Dis 1955;14:198-207. 41. Bauer W. The diagnosis of the various arthritides. N Engl J Med 1939;221:524-533. 42. Bauer W, Bennett GA, Zeller JW. The pathology of joint lesions in patients with psoriasis and arthritis. Trans Assoc Am Physicians 1941:56:349-352. 43. Waaler F. On the occurrence of a factor in human serum actuating the specific agglutination of sheep blood corpuscles. Acta Pathol Microbiol Scand 1940;17:172-178. 44. Vilanova X, Pinol J. Psoriasis arthropathica. Rheumatism 1951;7:197-208. 45. Coste F, Francon R, Touraine R, et al. Polyarthrite psoriasique. Rev Rhum (Mal Osteoartic) 1958;25:75-84. 46. Leczinsky CG. The incidence of arthropathy in a 10 year series of psoriasis cases. Acta Dermato Ken 1948; 28:483-487. 47. Wright V. Psoriasis and arthritis. Ann Rheum Dis 1956;15: 348-356. 48. Wright V. Rheumatism and psoriasis. A re-evaluation. Am J Med 1959;27:454-462. 49. Wright V, Reed WB. The link between Reiter’s syndrome and psoriatic arthritis. Ann Rheum Dis 1964;23:12-21. 50. Baker H. Epidemiological aspects of psoriasis and arthritis. Br J Dermatol 1966;78:249-261. 51. Blumberg BS, Bunin JJ, Calkins E, et al. ARA nomenclature and classification of arthritis and rheumatism (tentative). Arthritis Rheum 1964;7:93-97. 52. Vasey FB, Espinoza LR. Psoriatic arthropathy. In: Calin A (ed). Spondyloarthropathies. New York: Grune & Stratton, 1984, pp 151-185. 53. Moll JMH. Psoriatic arthritis. Br J Rheumatol 1984;23:241-245. 54. Cats A. Psoriasis and arthritis. In: Farber EM, Cox AJ (eds). Psoriasis. Proceedings of the First International Symposium. Stanford, Calif: Stanford University Press, 1971, pp. 127-136. 55. O’Neill T, Silman AJ. Historical background and epidemiology. Baillieres Clin Rheumatol 1994;8:245-261. 56. Korendowych E, Owen P, Ravindran J, et al. The clinical and genetic associations of anti-cyclic citrullinated peptide antibodies in psoriatic arthritis. Rheumatology (Oxford) 2005;44:1056-1060. 57. Bogliolo L, Alpini C, Caporali R, et al. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J. Rheumatol 2005;32:511-515. 58. Espinoza LR, Vasey FB, Espinoza CG, et al. Vascular changes in psoriatic synovium: A light and electron microscopic study. Arthritis Rheum 1982;25:677-684. 59. Braverman IM, Yen A. Ultrastructure of the capillary loops in the dermal papillae of psoriasis. J Invest Dermatol 1977;68:53-60. 60. Reece RJ, Canete JD, Parsons WJ, et al. Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum 1999;42:1481-1484. 61. Fiocco U, Cozzi L, Chieco-Bianchi F, et al. Vascular changes in psoriatic knee joint synovitis. J Rheumatol 2001;28:2480-2486. 62. Creamer D, Jaggar R, Allen M, et al. Overexpression of the angiogenic factor platelet-derived endothelial cell growth

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10

factor/thymidine phosphorylase in psoriatic epidermis. Br J Dermatol 1997;137:851-855. Fearon U, Reece R, Smith J, et al. Synovial cytokine and growth factor regulation of MMPs/TIMPs: Implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients. Ann NY Acad Sci 1999;878:19-21. Fearon U, Veale DJ. Pathogenesis of psoriatic arthritis. Clin Exp Dermatol 2001;26:333-337. Veale DJ, Ritchlin C, Fitzgerald O. Immunopathology of psoriasis and psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl II):ii26-ii29. Espinoza LR, Aguilar JL, Espinoza CG, et al. Fibroblast function in psoriatic arthritis I. Alteration of cell kinetics and growth factor responses. J Rheumatol 1994;21:1502-1506. Espinoza LR, Aguilar JL, Espinoza CG, et al. Fibroblast function in psoriatic arthritis. II. Increased production of GF and cytokines. J Rheumatol 1994;21:1507-1511. Ritchlin C, Haas-Smith SA, Hicks D. Patterns of cytokine production in psoriatic synovium. J Rheumatol 1998;25: 1544-1552. Costello P, Bresnihan B, O’Farrelly C, Fitzgerald O. Predominance of CD8+ T lymphocytes in psoriatic arthritis. J Rheumatol 1999;26:1117-1124. Costello P, Winchester RJ, Curran SA, et al. Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions appear antigen driven. J Immunol 2001;166: 2878-2886. Veale DJ, Rogers S, Fitzgerald O. Immunolocalization of adhesion molecules in psoriatic arthritis, psoriatic and normal skin. Br J Dermatol 1995;132:32-38. Pitzalis C, Cauli A, Pipitone N, et al. Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 1996;39:137-145. Ritchlin CT, Haas-Smith SA, Li P, et al. Mechanisms of TNF-alpha and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003;111:821-831. Espinoza LR, Bombardier C, Gaylord SW, et al. Histocompatibility studies in psoriasis vulgaris. Family studies. J Rheumatol 1980;7:445-452. Espinoza LR, Vasey FB, Oh JH, et al. Association between HLA-BW38 and peripheral psoriatic arthritis. Arthritis Rheum 1978;21:72-75. Espinoza LR, Vasey FB, Gaylord SW, et al. Histocompatibility typing in the seronegative spondyloarthropathies. A survey. Semin Arthritis Rheum 1982;11:375-381. Rahman P, Bartlett S, Siannis F, et al. CARD15: A pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 2003;73:677-81. Tomfohrde J, Silverman A, Barnes R, et al. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 1994;264:1141-1145. Rahman P, Elder JT. Genetic epidemiology of psoriasis and psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl II):ii37-ii39. Bowcock AM. Understanding the pathogenesis of psoriasis, psoriatic arthritis, and autoimmunity via a fusion of molecular genetics and immunology. Immunol Res 2005;32:45-56. Vasey FB, Deitz C, Fenske NA, et al. Possible involvement of group A streptococci in the pathogenesis of psoriatic arthritis. J Rheumatol 1982;9:719-722. Wang Q, Vasey FB, Mahfood JP, et al. V2 regions of 16S ribosomal RNA used as a molecular marker for the species identification of streptococci in peripheral blood and synovial fluid from patients with psoriatic arthritis. Arthritis Rheum 1999;42:2055-2059.

83. Espinoza LR, Berman A, Vasey FB, et al. Psoriatic arthritis and acquired immunodeficiency syndrome. Arthritis Rheum 1988;31:1034-1040. 84. Njobvu P, McGill P, Kerr H, et al. Spondyloarthropathy and human immunodeficiency virus infection in Zambia. J Rheumatol 1998;25:1553-1559. 85. Gladman DD, Shuckett R, Russell ML, et al. Psoriatic arthritis— An analysis of 220 patients. Q J Med 1987;62:127-141. 86. Gladman DD, Stafford-Brady F, Chang CH, et al. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J Rheumatol 1990;17:809-812. 87. Gladman DD, Farewell VT. Progression in psoriatic arthritis: Role of time varying clinical indicators. J Rheumatol 1999;26:2409-2413. 88. Gladman DD, Farewell VT, Kopciuk K, Cook RJ. HLA markers and progression in psoriatic arthritis. J Rheumatol 1998;25:730-733. 89. Gladman DD, Ng Tung Hing E, Schentag CT, Cook R. Remission in psoriatic arthritis. J Rheumatol 2001;28:1045-1048. 90. Husted J, Gladman DD, Long JA, et al. Validating the SF-36 health questionnaire in patients with psoriatic arthritis. J Rheumatol 1997;24:511-517. 91. Gladman DD, Farewell VT, Wong K, Husted J. Mortality studies in psoriatic arthritis. Results from a single outpatient center. II. Prognostic indicators for death. Arthritis Rheum 1998;41: 1103-1110. 92. Prasad R, Gladman DD. Current and investigational treatment of psoriatic arthritis. Expert Opin Investig Drugs 2004;13: 139-150. 93. Willkens RF, Williams HJ, Ward JR, et al. Randomized doubleblind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984;27:376-381. 94. Cuellar ML, Espinoza LR. Methotrexate use in psoriasis and psoriatic arthritis. Rheum Dis Clin North Am 1997;23:797-809. 95. Salvarani C, Macchioni P, Olivieri I, et al. A comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis. J Rheumatol 2001;28: 2274-2282. 96. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: A randomised trial. Lancet 2000;356:385-390. 97. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis. Results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2005;52:1227-1236. 98. Chew AL, Bennett A, Smith CH, et al. Successful treatment of severe psoriasis and psoriatic arthritis with adalimumab. Br J Dermatol 2004;151:492-496. 99. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T cell modulator, efalizumab, for plaque psoriasis. N Eng J Med 2003;349:2004-2013. 100. Kraan MC, van Kuijk AW, Dinant HJ, et al. Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 2002;46:2776-2784. 101. Helliwell PS, Taylor WJ. Classification and diagnostic criteria for psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl II) ii3-ii8. 102. Gladman DD. Discussion: Clinical features, epidemiology, classification criteria, and quality of life in psoriasis and psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl II):ii24-ii25. 103. McGonagle D. Imaging the joint and enthesis: Insights into pathogenesis of psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl II):ii58-ii60.

PSORIATIC ARTHRITIS

3

Clinical Features of Psoriatic Arthritis Dafna D. Gladman

PSORIASIS Psoriasis is an inflammatory skin disease affecting 1% to 3% of the population.1,2 Psoriasis may develop at any age, but there are peaks in the age of onset in the teens, at age 30, and at age 50.3 There are several phenotypes of psoriasis, including plaque psoriasis or psoriasis vulgaris (Fig. 3-1), guttate psoriasis, pustular psoriasis, flexural psoriasis, and erythroderma. By far the commonest form of psoriasis is psoriasis vulgaris, which most commonly involves the extensor surface of the elbows and knees but may also affect the scalp, the trunk, and the extremities. Flexural psoriasis affects the groin, anal folds, and other flexural areas. Guttate psoriasis tends to develop at a younger age of onset and be associated with a preceding infection, usually streptococcal.3 Guttate psoriasis arises with small lesions that resemble teardrops but can be extensive. The most serious form of psoriasis is the erythrodermic form, which covers large parts of the body and may be life threatening as it is associated with loss of nutrients, fever, and significant morbidity. Psoriasis has been described as two types depending on the age of onset. Patients with early-onset psoriasis (younger than age 40) tend to have more severe disease, with a familial history, and their disease tends to be associated with the human leukocyte antigen HLAC*0602.4,5 Patients with late-onset psoriasis tend to have milder disease and the disease tends to be sporadic.1 In addition to the inflammatory lesion in the skin, nail lesions occur in almost half the patients with psoriasis.6 Nail lesions include pits, onycholysis, and ridges (Fig. 3-2). Psoriasis has important implications for the psychological and social well-being of its sufferers.7 It is associated with impaired quality of life. Generic instruments such as the 36-Item Short Form Survey (SF-36) have shown that the impact of psoriasis on quality of life was worse than that of hypertension, diabetes, and myocardial infarction. Skin disease–specific instruments such as the Dermatology Life Quality Index (DLQI) have also shown the significant effect of psoriasis. Psoriasis-specific instruments such as the

psoriasis disability index, the psoriasis disability scale, and the psoriasis quality of life instrument have been particularly responsive to changes in psoriasis disease activity.

SYNOVITIS The exact prevalence of psoriatic arthritis among patients with psoriasis is unknown. Prevalence rates have varied from 6% in a population-based study in the Mayo Clinic8 to 42% in an outpatient clinic in South Africa.9 A population survey suggests that the prevalence of psoriatic arthritis among patients with psoriasis varies with the severity of the psoriasis. Overall, 11% of individuals with psoriasis had psoriatic arthritis, but with more severe psoriasis (>30% involvement) the number rose to 56%.10 Although this study may suggest that psoriatic arthritis is more common in patients with worse psoriasis, this is not borne out in clinical experience. First, psoriatic arthritis arises before the obvious diagnosis of psoriasis in 15% of the patients (Table 3-1). In these patients, it is the pattern of arthritis described subsequently that leads the clinician to make the appropriate diagnosis. At times, the diagnosis becomes obvious only after the recognition of the presence of psoriasis. In therapeutic clinical trials in psoriatic arthritis, the degree of psoriasis is much lower than that recorded in clinical trials in psoriasis. There is no relationship between the degree of skin involvement and the severity of psoriatic arthritis. An analysis of 221 patients who participated in the sulfasalazine multicenter trial revealed no correlation between skin and joint severity.11 A smaller study of 70 patients with psoriatic arthritis showed no correlation between skin and joint manifestations overall, although there was a trend in those who presented with skin and joint manifestations simultaneously.12 Among patients participating in a large prospective longitudinal cohort, only 35% of the patients reported that skin and joint manifestations flared at the same time.13 Psoriatic arthritis arises with symptoms and signs of inflammation. Thus, patients complain of joint pain, stiffness, and often associated redness of the affected

11

CLINICAL FEATURES OF PSORIATIC ARTHRITIS

Figure 3-1. Psoriasis vulgaris. See also Color Plate.

Figure 3-2. Psoriatic nail lesions. See also Color Plate.

joints. However, it should be noted that patients with psoriatic arthritis demonstrate a lower level of tenderness than patients with rheumatoid arthritis.14 Some patients may therefore develop joint deformities without having complained of any pain at all. On the other hand, the synovitis of psoriatic arthritis may be intense with purplish discoloration over the affected joint. Psoriatic arthritis may affect any joint. Joints most commonly affected early in the course of the disease are the joints of the hands and feet (Table 3-2). Wright and Moll described five clinical presentations in psoriatic arthritis (Fig. 3-3).15 The distal pat-

tern, in which the distal interphalangeal (DIP) joints are primarily involved, is considered typical for psoriatic arthritis and was originally documented in 5% of the patients (see Fig. 3-3A). It has been described in 0% to 12% of patients in subsequent series (see Table 3-1). Some investigators did not identify isolated distal joint disease in any of their patients, but others included DIP joint involvement with other patterns. The most common pattern seen by Wright and Moll was oligoarticular, in which up to four joints are involved, often in an asymmetric distribution (see Fig. 3-3B). This pattern may be the most common at

TABLE 3-1 CHARACTERISTICS OF PATIENTS INCLUDED IN LARGE SERIES (>100 PATIENTS) Feature

Roberts44 (1976)

No. of patients

168

Kammer45 (1979) 100

M/F

67/101

47/53

Age of onset (yr)

36-45

33-45

Disease duration

?

?

Oligoarthritis(%)

53

54

Scarpa46 (1989)

220

138

104/116 37 9 yr 14 †

Torre-Alonso47 (1991) 180

Veale48 (1994)

Jones49 (1994)

100

100

Kane50 (2003) 129

71/67

99/81

59/41

43/57

68/61

40

39

34

37.6

40

?

?

13

37

4 yr

12 yr

43

26

9 mo 40

Polyarthritis (%)

54*

25

56

33

35

33

63

60

Distal (%)

17

?

12

9

0

16

1

NA‡

Back alone (%)

5

21

2

44§

7

4

6

0

Mutilans (%)

5

?

16

1

4

2

4

0

?

?

27

?

20

15

6

17

16

30

17

?

15

?

18

?

Sacroiliitis (%) Joints before skin (%)

*Includes patients with only distal joints involved. †

Includes patients with back involvement.

‡

Distal interphalangeal joint involvement in 39% of patients.

§

12

Gladman13 (1987)

Includes patients with peripheral arthritis.

?, unspecified; M/F, male/female.

onset of psoriatic arthritis but is clearly not the most common in established disease (see Table 3-1). Polyarticular involvement is more common in psoriatic arthritis than previously appreciated (see Fig. 3-3C). Even among patients with early psoriatic arthritis, the polyarticular pattern was more common than the oligoarticular one.16 Although many patients present with symmetrical arthritis, indistinguishable from rheumatoid arthritis, at least 50% of the patients have an asymmetric distribution. However, Helliwell and colleagues17 have demonstrated that symmetry is a function of the number of joints involved. The most typical pattern of psoriatic arthritis is arthritis mutilans—a very destructive form of arthritis associated with flail joints and fused joints (see Fig. 3-3D). This

Synovitis

Figure 3-3. Patterns of psoriatic arthritis. A, Distal joint disease. B, Oligoarthritis. C, Polyarthritis. D, Arthritis mutilans. A-D, See also Color Plate.

13

TABLE 3-2 JOINT DISTRIBUTION AT FIRST VISIT AMONG 124 PSORIATIC ARTHRITIS PATIENTS SEEN WITHIN 12 MONTHS OF DIAGNOSIS FROM THE UNIVERSITY OF TORONTO PSORIATIC ARTHRITIS CLINIC Actively Inflamed Joints (%)

Clinical Damage (%)

Hands

71

10

Feet

64

8

Knees

33

1

Elbows/shoulders

32

1

Wrists

31

2

Ankles

17

0

9

1

Hips

CLINICAL FEATURES OF PSORIATIC ARTHRITIS

14

pattern was described in 5% of the original cohort15; however, it seems that with time more patients develop destructive arthritis and arthritis mutilans may affect as many as 20% of the patients.18 The last pattern described by Wright and Moll is predominant spondyloarthritis (see Fig. 3-3E). Isolated spinal disease occurs in 2% to 4% of patients with psoriatic arthritis. Spondyloarthritis associated with peripheral arthritis occurs in 40% to 70% of the patients, depending on whether or not radiographs are taken.19 Just like the peripheral arthritis in psoriatic arthritis, the spinal disease is not as symptomatic and severe as that of idiopathic ankylosing spondylitis.20

The patterns recorded in patients with psoriatic arthritis may vary over time. Variation has been noted by a number of investigators.11,16,21 This may have affected the varied distribution of patterns among reported series. The observation also highlights the importance of performing radiographic evaluation in patients with psoriatic arthritis. Radiographic changes may be noticed without any clinical complaints, particularly when it comes to sacroiliitis, spondylitis, or enthesitis. The presence of polyarticular involvement, whether at baseline or during follow-up, is an important prognostic indicator for disease progression in patients with psoriatic arthritis.22-24 The number of actively inflamed joints at each visit is an independent risk factor for progression of clinical damage. The presence of erosions is also an indicator of further progression of both clinical and radiologic damage. A feature typical of psoriatic arthritis is dactylitis, also termed “sausage digit,” which is an inflammation of the whole digit (Fig. 3-4). Dactylitis probably results from inflammation in both tendons and joints,25 although magnetic resonance imaging studies suggested that the major component is tenosynovitis.26,27 Dactylitis affects the feet more commonly than the hands. In a study of 537 patients with psoriatic arthritis observed prospectively, 260 (48%) had at least one episode of dactylitis and 33.5% had dactylitis at presentation to clinic.28 A similar frequency (29%) was documented in the early psoriatic arthritis cohort from Dublin.13 Digits with dactylitis had more radiographic progression than those without dactylitis, suggesting that dactylitis is a prognostic indicator for more severe disease in psoriatic arthritis.19 Salvarani and colleagues argued that isolated dactylitis and enthesitis should be considered a manifestation of psoriatic arthritis. They identified 14 patients out of a total of 401 patients

Figure 3-3 E, Psoriatic spondylitis.

Figure 3-4. Dactylitis. See also Color Plate.

tar fascia insertion. Other sites include the insertion of the patellar tendon, the iliac crest, and the insertion of the rotator cuff. Clinically, enthesitis arises with pain at the insertion site, occasionally with swelling (Fig. 3-5). These areas may develop spurs that can be detected radiologically. Often spurs are detected without preceding clinical evidence of inflammation. Falsetti and coworkers32 used ultrasonography to detect calcaneal lesions in patients with rheumatoid arthritis,158 osteoarthritis,56 erosive osteoarthritis,209 and psoriatic arthritis125 and in healthy control subjects50; Achilles tendonitis was present in 8% of their patients with psoriatic arthritis compared with 2% of patients with rheumatoid arthritis but in none of the patients with osteoarthritis. Plantar calcaneal lesions were more common among patients with inflammatory arthritis compared with osteoarthritis, but there was no significant difference between psoriatic arthritis (37%) and rheumatoid arthritis (25%).

ENTHESOPATHY

Iritis or uveitis occurs in about 7% to 18% of patients with psoriatic arthritis.13,33 Uveitis in psoriatic arthritis is more likely to be bilateral and is usually, although not exclusively, associated with the presence of spondylitis. It tends to develop more insidiously than the uveitis of ankylosing spondylitis.32,34 Urethritis occurs in patients with psoriatic arthritis. It is indistinguishable from the urethritis described in patients with ankylosing spondylitis or reactive arthritis.35 Heart involvement is not common in psoriatic arthritis. However, patients with psoriatic arthritis may have cardiac abnormalities similar to those seen in the other spondyloarthropathies.34 Bowel symptoms, particularly diarrhea, are common among patients with psoriatic arthritis. However, these may be due to medications taken by patients with psoriatic arthritis. In a study of 64 patients with psoriatic arthritis in which ileocolonoscopy was carried out, 16% of the patients had inflammatory gut lesions. These were more common among patients with psoriatic spondylitis.36 It is not clear whether any of the patients had clinical symptoms of bowel disease, nor is it clear whether medications contributed to the gut inflammation. In a study of 15 patients with psoriatic arthritis who did not have any symptoms and were not taking any medications that would induce bowel inflammation, Scarpa and coauthors37 demonstrated microscopic inflammatory changes in all patients, although 6 had macroscopically normal mucosa. Of 103 unselected patients with psoriatic arthritis studied by Williamson and associates,38 4 (3.9%) had biopsyproven inflammatory bowel disease compared with a

Enthesitis, inflammation at tendon insertion into bone, is a feature common to all spondyloarthropathies, occurs commonly in psoriatic arthritis, and may arise as an isolated feature.28 Indeed, in a controlled cohort study enthesitis occurred significantly more frequently among patients with psoriatic arthritis than control subjects (3.5% versus 0.2%, P = .001). The sites most commonly affected are the Achilles insertion and plan-

Figure 3-5. Enthesitis.

Extra-articular Manifestations

observed in three Italian rheumatology clinics who presented with psoriasis and these isolated features. Ten of the 14 patients had dactylitis. Dactylitis did not occur in any of 483 control patients without psoriasis or spondyloarthritis.29 Olivieri and associates30 underscored the importance of having baseline radiographs in patients with suspected psoriatic arthritis and dactylitis. They presented a patient with a remote history of dactylitis that was confirmed on radiographs taken at the time. Aside from the presence of psoriasis and nail lesions, dactylitis was the only clinical feature that distinguished patients with psoriatic arthritis from patients with other types of inflammatory arthritis in a study aimed at deriving classification criteria for psoriatic arthritis.31 Tenosynovitis, inflammation of the tendon sheath, may occur without the development of dactylitis. It may affect the Achilles tendon or the plantar fascia but may also affect the digital tendons. It arises with pain and swelling of the affected tendon and may be associated with tendon nodules.

EXTRA-ARTICULAR MANIFESTATIONS

15

CLINICAL FEATURES OF PSORIATIC ARTHRITIS

prevalence of 0.4% of inflammatory bowel disease in the general population in the United Kingdom. It is difficult to know whether these are cases of inflammatory bowel disease with psoriasis and peripheral arthritis or whether they reflect true bowel involvement in psoriatic arthritis. Distal limb edema has been described as a feature of psoriatic arthritis.39 In a case-control study of 183 consecutive outpatients with psoriatic arthritis and 366 control subjects without spondyloarthropathies, distal extremity swelling with pitting edema was recorded in 39 of the 183 (21%) patients with psoriatic arthritis and in 18 of the 366 (4.9%) control subjects (P < .0001). Patients with pitting edema more commonly demonstrated enthesitis and had a lower disease duration than those without pitting edema. This feature was infrequently seen among patients observed prospectively at the University of Toronto psoriatic arthritis clinic, where only 4 of 680 patients were noted to have distal limb edema (Fig. 3-6).

DIFFERENTIATING PSORIATIC ARTHRITIS FROM OTHER FORMS OF INFLAMMATORY ARTHRITIS As an inflammatory arthritis, psoriatic arthritis must be differentiated from rheumatoid arthritis on the one hand and from other spondyloarthridites on the other. Psoriatic arthritis may be distinguished from rheumatoid arthritis by the presence of distal joint involvement, which occurs in approximately 50% of the patients. Inflammatory DIP joint involvement is uncommon in rheumatoid arthritis. Patients with psoriatic arthritis have been found to be less tender than those with rheumatoid arthritis, both on the most clinically affected joint and on fibromyalgia tender points and control points.14 In addition, the affected joints in

16

Figure 3-6. Distal limb edema. See also Color Plate.

patients with psoriatic arthritis tend to have a purplish discoloration, which is uncommon among patients with rheumatoid arthritis.40 The presence of this discoloration over the affected joint requires differentiation from crystal-induced arthritis. The latter is often associated with periarticular inflammation, and if joint aspiration is performed the presence of crystals helps make the correct diagnosis. The absence of rheumatoid nodules as well as other extra-articular features common to rheumatoid arthritis among patients with psoriatic arthritis and the presence of extra-articular manifestations common to spondyloarthritis among patients with psoriatic arthritis also help differentiate the two conditions. The presence of spondylitis and sacroiliitis is another differentiating feature between psoriatic arthritis and rheumatoid arthritis. Differentiating psoriatic arthritis from other spondyloarthropathies may be difficult. However, psoriatic spondylitis is associated with peripheral arthritis more commonly than other forms of spondylitis.34 It tends to occur at a later age and be less painful and less restrictive than ankylosing spondylitis.41 Patients with psoriatic spondylitis tend to have peripheral arthritis as described previously, with only 2% to 4% having isolated spondylitis. HLA-B*27 occurs more commonly among patients with ankylosing spondylitis that those with psoriatic arthritis, whereas HLA-B*13, *16, *38, and *39 occur more commonly among patients with psoriatic arthritis.35

BONE DISEASE

Extra Bone Formation Typical radiographic changes among patients with psoriatic arthritis include erosions, which can be at the joint margin as seen in rheumatoid arthritis but may be slightly away from the margin, reflecting insertion of capsule and tendon into bone. Erosions may develop at all affected sites. Because distal joint disease is common among patients with psoriatic arthritis, DIP joints are commonly affected. In some patients with psoriatic arthritis the erosions may be large, leading to the typical pencil-in-cup change associated with arthritis mutilans (Fig. 3-7). Other typical lesions include lysis of distal tufts (Fig. 3-8) and at times lysis of a whole phalanx (Fig. 3-9). Although erosive disease is common, developing in 67% of the patients by the time they present to a specialty clinic,13,18 another typical feature is that of bone formation. Extra bone formation may occur at tendon insertions, not only in areas of enthesitis but also at the proximal and DIP joints as well as along the shaft of phalanges and other bones (see Fig. 3-9). When this occurs along the tibia and fibula, the extra bone formation resembles that of hypertrophic osteoarthropathy. Extra

References

Figure 3-7. Typical pencil-in-cup change associated with arthritis mutilans.

Figure 3-9. Lysis of a whole phalanx.

Osteoporosis

Figure 3-8. Lysis of distal tufts.

bone formation was found to be an important feature differentiating psoriatic arthritis from other inflammatory forms of arthritis in the Classification of Psoriatic Arthritis (CASPAR) study.31

The characteristic new bone formation that is seen commonly in patients with psoriatic arthritis has been thought to be protective against bone loss; therefore, systemic osteoporosis has not been a recognized complication of this disease. However, studies indicate that osteoporosis is common among patients with psoriatic arthritis. Cooper and colleagues, however, found a significant reduction in distal forearm bone mineral density in 20 patients with psoriatic arthritis compared with control subjects by single-photon absorptiometry.42 Frediani and associates43 assessed bone mineral density by dual-energy x-ray absorptiometry and heel ultrasonography in 186 patients with psoriatic arthritis and found that total body, lumbar spine, and femoral neck bone mineral density and heel stiffness were significantly reduced in patients with psoriatic arthritis compared with control subjects regardless of age, sex, or menopausal status.

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3. Mallbris L, Larsson P, Bergqvist S, et al. Psoriasis phenotype at disease onset: Clinical characterization of 400 adult cases. J Invest Dermatol 2005;124:499-504. 4. Gladman DD, Cheung C, Michener G, et al. HLA C-locus alleles in psoriatic arthritis. Hum Immunol 1999;60: 259-261.

17

CLINICAL FEATURES OF PSORIATIC ARTHRITIS

18

5. Guojonsson JE, Karason A, Antonsdottir AA, et al. HLA-Cw6positive and HLA-Cw6-negative patients with psoriasis vulgaris have distinct clinical features. J Invest Dermatol 2002;118: 362-365. 6. Gladman DD, Anhorn KB, Schachter RK, et al. HLA antigens in psoriatic arthritis. J Rheumatol 1986;13:586-592. 7. Feldman SR, Rapp SR. Quality of life. Psoriasis. In: Gordon KG, Ruderman EM (eds). Psoriasis and Psoriatic Arthritis. An Integrated Approach. Berlin: Springer-Verlag, 2005, pp 109-117. 8. Shbeeb MI, Uramoto KM, Gibson WW, et al. The epidemiology of psoriatic arthritis in Olmstead County 1982-91. J Rheumatol 2000;27:1247-1250. 9. Gladman DD. Psoriatic arthritis. Baillieres Clin Rheumatol 1995;9:319-329. 10. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 2005;53:573. 11. Jones SM, Armas JB, Cohen MG, et al. Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-839. 12. Cohen MR, Reda DJ, Clegg DO. Baseline relationships between psoriasis and psoriatic arthritis: Analysis of 221 patients with active psoriatic arthritis. J Rheumatol 1999;26:1752-1756. 13. Gladman DD, Shuckett R, Russell ML, et al. Psoriatic arthritis— Clinical and laboratory analysis of 220 patients. Q J Med 1987;62:127-141. 14. Buskila D, Langevitz P, Gladman DD, et al. Patients with rheumatoid arthritis are more tender than those with psoriatic arthritis. J Rheumatol 1992;19:1115-1119. 15. Wright V, Moll JMH. Psoriatic arthritis. In: Seronegative Polyarthritis. Amsterdam: North Holland, 1976, pp 169-223. 16. Kane D, Stafford L, Bresnihan B, et al. A prospective, clinical and radiological study of early psoriatic arthritis: An early synovitis clinic experience Rheumatology (Oxford) 2003;42: 1460-1468. 17. Helliwell PS, Hetthen J, Sokoll K, et al. Joint symmetry in early and late rheumatoid and psoriatic arthritis: Comparison with a mathematical model. Arthritis Rheum 2000;43:865-871. 18. Gladman DD. The natural history of psoriatic arthritis. Baillieres Clin Rheumatol 1994;8:379-394. 19. Battistone MJ, Manaster BJ, Reda DJ, et al. The prevalence of sacroiliitis in psoriatic arthritis: New perspectives from a large, multicenter cohort. A Department of Veterans Affairs Cooperative Study. Skeletal Radiol 1999;28:196-201. 20. Gladman DD, Helliwell P, Mease PJ, et al. Assessment of patients with psoriatic arthritis. A review of currently available measures. Arthritis Rheum 2004;50:24-35. 21. Khan M, Schentag C, Gladman D. Clinical and radiological changes during psoriatic arthritis disease progression: Working toward classification criteria. J Rheumatol 2003;30:1022-1026. 22. Gladman DD, Farewell VT. Progression in psoriatic arthritis: Role of time varying clinical indicators. J Rheumatol 1999;26: 2409-2413. 23. Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, et al. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis 2003;62:68-70. 24. McHugh NJ, Balachrishnan C, Jones SM. Progression of peripheral joint disease in psoriatic arthritis: A 5-yr prospective study. Rheumatology (Oxford) 2003;42:778-783. 25. Kane D, Greaney T, Bresnihan B, et al. Ultrasonography in the diagnosis and management of psoriatic dactylitis. J Rheumatol 1999;26:1746-1751. 26. Olivieri I, Barozzi I, Favaro L, et al. Dactylitis in patients with seronegative spondyloarthropathy: Assessment by ultrasonography and magnetic resonance imaging. Arthritis Rheum 1996;39:1524-1528. 27. Olivieri I, Barozzi I, Pierro A, et al. Toe dactylitis in patients with spondyloarthropathy: Assessment by magnetic resonance imaging. J Rheumatol 1997;24:926-930.

28. Brockbank J, Stein M, Schentag CT, et al. Characteristics of dactylitis in psoriatic arthritis (PsA). Ann Rheum Dis 2005;62:188-190. 29. Salvarani C, Cantini F, Olivieri I, et al. Isolated peripheral enthesitis and/or dactylitis: A subset of psoriatic arthritis. J Rheumatol 1997;24:1106-1110. 30. Olivieri I, Montaruli M, Scarano E, et al. Usefulness of plain film radiography in the diagnosis of dactylitis by history-taking. J Rheumatol 2005;32:1379. 31. Taylor WJ, Helliwell PS, Gladman DD, et al. A validation of current classification criteria for the diagnosis of psoriatic arthritis—Preliminary results of the CASPAR study. Ann Rheum Dis 2005;64 (Suppl III):107. 32. Falsetti P, Frediani B, Fioravanti A, et al. Sonographic study of calcaneal entheses in erosive osteoarthritis, nodal osteoarthritis, rheumatoid arthritis and psoriatic arthritis. Scand J Rheumatol 2003;32:229-234. 33. Queiro R, Torre JC, Belzunegui J, et al. Clinical features and predictive factors in psoriatic arthritis–related uveitis. Semin Arthritis Rheum 2002;31:264-270. 34. Paiva ES, Macaluso DC, Edwards A, et al. Characterisation of uveitis in patients with psoriatic arthritis. Ann Rheum Dis 2000;59:67-70. 35. Gladman DD. Clinical aspects of spondyloarthropathies. Am J Med Sci 1998;316:234-238. 36. Schatteman L, Mielants H, Verys EM, et al. Gut inflammation in psoriatic arthritis: A prospective ileocolonoscopic study. J Rheumatol 1995;22:680-683. 37. Scarpa R, Manguso F, D’Arienzo A, et al. Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms. J Rheumatol 2000;27:1241-1246. 38. Williamson L, Dockerty JL, Dalbeth N, et al. Gastrointestinal disease and psoriatic arthritis. J Rheumatol 2004;31: 1469-1470. 39. Cantini F, Salvarani C, Olivieri I, et al. Distal extremity swelling with pitting edema in psoriatic arthritis: A case-control study. Clin Exp Rheumatol 2001;19:291-296. 40. Jajic J. Blue-coloured skin over involved joints in psoriatic arthritis. Clin Rheumatol 2001;20:304-305. 41. Gladman DD, Brubacher B, Buskila D, et al. Differences in the expression of spondyloarthropathy: A comparison between ankylosing spondylitis and psoriatic arthritis. Genetic and gender effects. Clin Invest Med 1993;16:1-7. 42. Cooper C, Poll V, McLaren M, et al. Alterations in appendicular skeletal mass in patients with rheumatoid, psoriatic, and osteoarthropathy. Ann Rheum Dis 1988;47:481-484. 43. Frediani B, Allegri A, Falsetti P, et al. Bone mineral density in patients with psoriatic arthritis. J Rheumatol 2001;28:138-143. 44. Roberts ME, Wright V, Hill AG, Mehra AC. Psoriatic arthritis. Follow-up study. Ann Rheum Dis 1976;35:206-212. 45. Kammer GM, Soter NA, Gibson DJ, Schur PH. Psoriatic arthritis: A clinical, immunologic and HLA study of 100 patients. Semin Arthritis Rheum 1979;9:75-97. 46. Scarpa R, Pucino A, Iocco M, et al. The management of 138 psoriatic arthritic patients. Acta Derm Venereol Suppl (Stockh) 1989;146:199-200. 47. Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, et al. Psoriatic arthritis (PA): A clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991 Aug;30(4): 245-250. 48. Veale D, Rogers S, Fitzgerald O. Classification of clinical subsets in psoriatic arthritis. Br J Rheumatol 1994;33:133-138. 49. Jones SM, Armas JB, Cohen MG, et al. Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-839. 50. Kane D, Stafford L, Bresnihan B, FitzGerald O. A prospective, clinical and radiological study of early psoriatic arthritis: An early synovitis clinic experience. Rheumatology (Oxford) 2003;42:1460-1468. Epub 2003 Oct 1.

PSORIATIC ARTHRITIS

4

Diagnostic Criteria of Psoriatic Arthritis William J. Taylor

Until the pioneering work of Wright1 and Baker and colleagues,2 an inflammatory arthritis occurring in the presence of psoriasis was thought to represent rheumatoid arthritis (RA) occurring coincidentally with psoriasis. The discovery of rheumatoid factor in the serum provided an important tool that helped categorization of polyarthritis, but the distinction between RA and psoriatic arthritis (PsA) was achieved primarily on clinical and radiologic grounds. Wright described the frequent involvement of distal interphalangeal (DIP) joints with erosion and absorption of the terminal phalanges, coexisting sacroiliitis, involvement of the proximal interphalangeal (PIP) joints of the toes, and a characteristic mutilating arthritis with reduction in bone stock particularly in the digits.3 The American Rheumatism Association adopted PsA as a distinct clinical entity, including it in a classification of rheumatic diseases for the first time in 1964.4 However, the inclusive Moll and Wright criteria published more than 30 years5 ago may fail to recognize adequately the possibility that psoriasis can exist independently of coexistent arthropathies. Defining PsA as the co-occurrence of an inflammatory arthritis and psoriasis is likely to overidentify such individuals. For instance, the presence of psoriasis alone barely characterizes patients with early arthritis in a clearly distinctive clinical way.6 In this study of early arthritis, patients with psoriasis were more likely to be male and to be rheumatoid factor (RF) negative and there was a trend toward more DIP joint disease, but in other respects the clinical pattern of the arthritis was similar and may have been due to the presence or absence of RF rather than psoriasis. Despite clinical, radiologic, and familial evidence supporting PsA as a distinct disease entity, controversy still exists about which patients to include within this disease group. Some authors have even questioned whether PsA is a separate disease, suggesting that psoriasis merely modifies the expression of preexisting RA.7 The concept of diagnostic or classification criteria is more problematic than it would first appear.

Essentially, such criteria attempt to mimic as closely as possible a “gold standard” test for the disease. Such a gold standard rarely exists for rheumatic diseases, and PsA is no exception. In the absence of a gold standard test or pathognomonic feature, diagnostic criteria must attempt to mimic expert clinical diagnosis. Ideally, the standard of diagnosis should also incorporate longitudinal follow-up and panel of expert consensus rather than relying upon a single clinician’s opinion at a single time point.8 Such rigorous standards have rarely been met for classification studies. In the case of PsA, Symmons and coauthors9 showed that expert clinicians do have different thresholds for making a diagnosis of PsA in patients with nonclassical disease presentations. Using a statistical technique of latent class analysis and diagnostic simulations of a variety of paper-patients, it was possible to identify three classes of patients: definite disease, definite nondisease, and a class of possible disease. Furthermore, it was possible to classify the 15 rheumatologist participants as “high diagnosers” or “low diagnosers” depending on their behavior with respect to the possible disease class of patient. Even in the ideal situation, it is unlikely that any validated criteria will be perfect, that is, display 100% sensitivity and 100% specificity. There will always be an error rate expressed mathematically as the false-positive rate (the proportion of nondisease subjects who fulfill classification criteria) and the false-negative rate (the proportion of disease subjects who do not fulfill classification criteria). In groups of subjects in whom the prevalence of the disease is known, one can make a statement about the probability of having the disease given fulfillment of the criteria (positive predictive value) or of having the disease given nonfulfillment of the criteria (negative predictive value). Of course, these probabilistic statements are of limited usefulness in the individual patient. After all, the individual patient either has the disease or does not. It is only with groups of patients that test performance characteristics such as specificity or sensitivity have real meaning.

19

DIAGNOSTIC CRITERIA OF PSORIATIC ARTHRITIS

It is important to underline this: classification criteria (or any other diagnostic test) must be interpreted in the clinical context. It is not necessary, or always helpful, for classification criteria to be used to make the diagnosis for an individual patient. For example, a patient with glomerulonephritis, hypocomplementemia, and antibodies to double-stranded DNA may be diagnosed appropriately with lupus without fulfilling the 1982 classification criteria.10 And a patient with arthritis, positive antinuclear antibody test, proteinuria, dry eyes and mouth, mouth ulcers, and positive SSA and SSB tests may be diagnosed appropriately with Sjögren’s syndrome despite fulfilling criteria for lupus. The primary role for diagnostic or classification criteria is to identify groups of patients who have the same disorder, usually for the purpose of epidemiology or clinical studies. Because physicians may vary in their diagnostic bias, a standard case definition using validated criteria for entry into a clinical study (rather than physician diagnosis) makes the interpretation of the study and comparison with other studies much more straightforward. Classification criteria may have some useful teaching role, highlighting the key features that lead experts to a particular diagnosis. Nonetheless, it must be emphasized that obsessive adherence to criteria for making individual diagnoses is a fundamental error. Unfortunately for clinical research in PsA, validated criteria such as those developed for RA11 do not yet exist for PsA. A number of authors have suggested classification criteria, and the content of these is summarized in Table 4-1. None of these have been widely adopted. Apart from the criteria of Fournié, these suggestions represent theoretical notions of the nature of PsA and have not, until recently, been empirically evaluated. Yet the development of new therapies, particularly biologic therapies, has highlighted this deficiency12 and made the need for such criteria and for standardized outcome and response criteria more urgent. There are now two studies that have examined the accuracy of different diagnostic criteria.13 The Classification of Psoriatic Arthritis (CASPAR) study represents a major advance in classification criteria for PsA, incorporating data on over 1000 patients by 30 rheumatologists in 13 countries.14 Some of the information from this study is discussed in this chapter, but before discussing these studies, it is worthwhile reviewing some of the background in more detail.

THE MOLL AND WRIGHT CRITERIA AND SPECIFIC FEATURES OF PSORIATIC ARTHRITIS

Moll and Wright Criteria 20

The original diagnostic criteria of Moll and Wright5 are the simplest and the most frequently used in

current studies. The criteria of Moll and Wright are as follows: ●

● ●

An inflammatory arthritis (peripheral arthritis and/or sacroiliitis or spondylitis) The presence of psoriasis The (usual) absence of serologic tests for RF

The original criteria were designed to be sensitive without being too specific, but it is possible that Moll and Wright were using other features of the disease to make their diagnosis. As a consequence of omitting from the criteria what would now be regarded as characteristic features of PsA, it is possible that many of the patients included in later series have seronegative RA with coincidental psoriasis. In addition, some of the features emphasized by Moll and Wright do not endure further scrutiny, and these will be discussed briefly.

Rheumatoid Factor and Antibodies to Cyclic Citrullinated Peptide Gladman and colleagues argued that there is no reason to insist on seronegativity for RF as RF is found to be positive in many people unaffected by arthritis, particularly if they have a chronic inflammatory disorder such as psoriasis. In fact, 12% of cases in their original series were seropositive for RF but the authors were careful to exclude patients who displayed other characteristic signs of RA such as nodules or extra-articular involvement.18 It may also be possible to separate seronegative RA from PsA by the use of other more specific autoantibody assays, particularly antifillagrin antibodies. One such antibody, anti-cyclic citrullinated peptide (CCP), has shown much higher specificity for RA than immunoglobulin M RF.22 Unfortunately, absence of anti-CCP has not been found to be much more specific in PsA than absence of RF. In a study by Korendowych and colleagues, anti-CCP was found in 5.6% of patients with PsA and RF in 8.7%.23 In most of these CCP-positive patients, typical radiologic features of PsA (new bone formation, DIP disease, and sacroiliitis) were observed. Antibodies to CCP were found in 15.7% of patients with PsA in another study compared with RF in 17.9%.24 In both studies, anti-CCP was associated with more severe and erosive disease, suggesting that this antibody is a useful marker for disease severity but is not better than RF in discriminating between PsA and RA. In the CASPAR study, 7.6% of the PsA cohort had anti-CCP and 4.6% had RF. In the multivariate analysis, only a negative test for RF remained an independent predictor for the diagnosis of PsA.

✓

✓

✓

Fournié21

✓

✓

✓

✓

✓

✓

✓

✓

From Taylor WJ. The epidemiology of psoriatic arthritis. Curr Opin Rheumatol 2002;14:98-103.

DIP, distal interphalangeal; ESSG, European Spondyloarthropathy Study Group; HLA, human leukocyte antigen; RF, rheumatoid factor.

✓

✓

✓

✓

✓

Dactylitis

✓

✓

✓

✓

X-ray Features

✓

HLA

✓

✓

✓

Evidence of Skin Disease

✓

✓

✓

McGonagle20

ESSG19

Gladman

✓

✓

Clinical Enthesitis

✓

✓

✓

18

Vasey and Espinoza17

✓

Clinical Spondylitis

✓

✓

✓

16

Clinical Sacroiliitis

✓

✓

✓

Moll and Wright5

Bennett

Inflammatory Arthritis

RF Negative

TABLE 4-1 MAIN CHARACTERISTICS OF PROPOSED CLASSIFICATION CRITERIA FOR THE DIAGNOSIS OF PSORIATIC ARTHRITIS15

✓

✓

Family History of Psoriasis

DIP involvement

DIP involvement and rare associated conditions

Asymmetric lower limb pattern

Excluding other defined diseases

DIP disease

DIP disease, absence of nodules, asymmetry, synovial tissue and fluid analysis

Other Features

The Moll and Wright Criteria and Specific Features of Psoriatic Arthritis

21

DIAGNOSTIC CRITERIA OF PSORIATIC ARTHRITIS

Joint Symmetry

Asymmetric syndesmophytes Paravertebral ossification More frequent involvement of cervical spine

●

The Presence of Psoriasis

Dactylitis

A further problem with distinguishing PsA from other arthropathies, in particular RA, is the almost universal mandatory criterion of the presence of psoriasis. The pitfalls associated with this can be summarized as follows: ●

●

●

●

Psoriasis is a common skin disease, occurring in about 3% of the North European population. Although human leukocyte antigen (HLA) studies suggest different associations with psoriasis and RA, the diseases are not mutually exclusive and by chance alone some cases of RA have coincidental psoriasis. Psoriasis may precede, occur simultaneously with, or follow the onset of arthritis. In the last case the patient may be mistakenly diagnosed as having an inflammatory arthritis other than PsA. Psoriasis may be present but may be hidden or may be misdiagnosed (by rheumatologists).26 Psoriasis may be apparent only in the natal cleft or some other hidden area such as under the breasts, around the umbilicus, or in the hairline. The psoriasis may be evident only in the nails. In the true absence of psoriasis, a positive family history in a first-degree relative may be of equal importance from a diagnostic point of view.27

Spinal Involvement In addition to peripheral arthritis, people with psoriasis are more likely to develop an inflammatory spinal disease similar to ankylosing spondylitis (AS). The inflammatory spinal disease may be radiologically indistinguishable from AS but may differ from the classical disease in several respects. These differences were originally described by McEwen and colleagues28 and, in part, later confirmed by Helliwell and associates.29 The features more often seen in association with psoriasis (and reactive arthritis) can be summarized as follows: 22

●

One of the clinical characteristics not explicit in the Moll and Wright criteria but nevertheless emphasized in the accompanying papers was the asymmetry of the disease, particularly in the oligoarthritis subgroup. However, a definition of symmetry was not provided. A study that used a strict definition of symmetry demonstrated that symmetry is not an inherent and distinctive feature of PsA but a function of the number of joints involved.25 The fact that early PsA and late PsA have fewer joints involved than RA clinically accounts for the asymmetry of this disease.

● ●

Asymmetric sacroiliitis Nonmarginal syndesmophytes

●

In fact, the later study by Helliwell and others found paravertebral ossification to be so rare as to be of little value in discrimination, and the predominance of cervical spine involvement was a result of a relative sparing of the lumbar spine in psoriatic spondylitis. De Vlam and co-workers suggested a possible mechanism for the nonmarginal syndesmophytes that is related to less frequent involvement of the zygapophyseal joint.30

Dactylitis received little emphasis in early studies of PsA, yet in longitudinal research it is a common feature, seen in 48% of patients.31 It is a feature of a new mouse model of PsA,32 can be a marker for PsA without skin disease,33 and is not observed in RA.34 Although dactylitis can occur in other spondyloarthropathies, sarcoidosis, sickle-cell disease, and tuberculosis, it is a feature worth considering for any PsA classification criteria. In the CASPAR study, dactylitis was observed in 54% of cases of PsA.14

Radiographic Features Wright’s early writing discounted peripheral radio graphic features of PsA as being sufficiently different from those of RA to be useful as diagnostic criteria. However, the seminal paper by Avila and coauthors35 clearly showed that features such as juxta-articular new bone formation, joint osteolysis, and phalangeal periostitis were excellent markers of PsA. In the study by Fournié and colleagues, the presence of any one of Avila’s features was highly associated with PsA.21 In the CASPAR study, it was confirmed that such radiographic features were highly specific for PsA but generally too infrequent to be good diagnostic tests. Table 4-2 shows the frequency, sensitivity, and specificity of several peripheral radiographic features. Of these, only juxta-articular new bone formation (Fig.4-1A) was independently associated with PsA in a multivariate logistic regression analysis.

OTHER DIAGNOSTIC CRITERIA O’Neill and Silman36 noted that the classification of PsA poses methodologic difficulties: the spectrum of clinical disease is wide, the disease is relapsing and remitting, prevalence of disease is low, and methods for ascertaining past arthritis and psoriasis would need to be found. In their review of existing classification criteria, it was noted that all are derived theoretically rather than from analysis of patients’ data. Furthermore, three of the criteria sets are not especially feasible, as they

Frequency, N

Univariate Analysis Sensitivity (%)

Specificity (%)

74

11.9

97.0

DIP erosive disease

170

61.9

89.0

Juxta-articular new bone formation

116

18.7

95.4

Joint osteolysis

102

12.6

91.5

Ray involvement

37

6.1

98.6

Tuft osteolysis

22

4.3

100.0

230

31.0

83.0

Feature Interphalangeal bony ankylosis

Any peripheral x-ray feature

Other Diagnostic Criteria

TABLE 4-2 DISCRIMINANT VALUE OF PERIPHERAL X-RAY FEATURES FROM THE CASPAR STUDY

CASPAR, Classification of Psoriatic Arthritis; DIP, distal interphalangeal.

require either synovial fluid analysis or biopsy, HLA typing, or specialized imaging techniques. In an attempt to make the diagnostic criteria for PsA more specific, Bennett proposed a new set of classification criteria in 1979.16 The new criteria combined the clinical features unique to PsA together with characteristic radiologic features. In addition, two criteria, one based on synovial fluid analysis and the other based on synovial histology, were included. Despite the inclusion of radiographic, synovial fluid, and synovial

B

A

Figure 4-1. Juxta-articular new bone formation (A) and tuft osteolysis (B) in a patient with psoriatic arthritis.

biopsy items, it is still possible to diagnose PsA on clinical grounds alone (Table 4-3). These criteria were not validated using patients’ data and have not been used in prospective studies in the complete format because of the difficulty of obtaining complete data. Vasey and Espinoza (Table 4-4) simplified the Bennett rule, recognizing that there are two principal manifestations of PsA17 and only two criteria are required—psoriasis and one manifestation of either peripheral joint disease or spinal disease. The European Spondyloarthropathy Study Group (ESSG) derived classification criteria from consecutive patients with rheumatologist-diagnosed spondyloarthropathy and control patients with other rheumatic diseases.19 Although the intention of the criteria was the diagnostic classification of the spondyloarthropathy group as a whole, particular types of spondyloarthropathy can be identified from the published classification criteria, including PsA (Table 4-5). For the first time, it was possible for PsA to be classified in the absence of psoriasis if a family history of psoriasis was present. McGonagle and co-workers (Table 4-6) have proposed a definition of PsA based on enthesopathy.37 There is a significant problem with evaluating the original McGonagle criteria set because of the magnetic resonance imaging (MRI) requirements. It is unlikely that MRI would be practical for epidemiologic studies or clinical trials. It is also likely that the MRI appearances in well-established disease would show features of both enthesopathy and synovitis so that the discriminant value of this feature would be markedly attenuated. In established disease, it has been suggested that plain radiographic evidence of enthesopathy might be more useful (D McGonagle, personal communication). As the first proper attempt to define and validate criteria from actual patients’ data, the study by Fournié and colleagues21 represented an important step (Table 4-7).

23

DIAGNOSTIC CRITERIA OF PSORIATIC ARTHRITIS

TABLE 4-3 CRITERIA PROPOSED BY BENNETT Mandatory Clinically apparent psoriasis (skin or nails) Pain and soft tissue swelling and/or limitation of motion in at least one joint observed by a physician for 6 weeks or longer Supportive Pain and soft tissue swelling and/or limitation of motion in one or more other joints observed by a physician Presence of an inflammatory arthritis in distal interphalangeal joint. Specific exclusions: Bouchard’s or Heberden’s nodes Presence of “sausage” fingers or toes An asymmetric distribution of arthritis in the hands and feet Absence of subcutaneous nodules A negative test for rheumatoid factor in the serum An inflammatory synovial fluid with a normal or increased C3 or C4 level and an absence of infection (including acid-fast bacilli) and crystals of monosodium urate or pyrophosphate A synovial biopsy showing hypertrophy of the synovial lining with a predominant mononuclear cell infiltration and an absence of granuloma or tumor Peripheral radiographs showing erosive arthritis of small joints with a relative lack of osteoporosis. Specific exclusion: erosive osteoarthritis Axial radiographs showing any of the following: sacroiliitis, syndesmophytes, paravertebral ossification Definite psoriatic arthritis (PsA): mandatory plus 6 supportive. Probable PsA: mandatory plus 4 supportive. Possible PsA: mandatory plus 2 supportive. From Bennett RM. Psoriatic arthritis. In: McCarty DJ (ed). Arthritis and Related Conditions, 9th ed. Philadelphia: Lea & Febiger, 1979, p 645.

24

The items and weighting were selected using discriminant function and logistic regression analysis. The data were derived from a population of patients diagnosed by rheumatologists from a single clinic as having PsA, AS, and RA. A score of 11 points is required for the diagnosis of PsA (sensitivity 95%, specificity 98%, LR+ 47.5) and, although the criteria include HLA data, it is possible to attain this threshold on clinical data alone. Further validation would be required if the HLA criteria were omitted. However, there are a number of limitations with this research. The problem of case selection is a central issue of classification studies. Prospective, consecutive identification of all patients with physician-diagnosed (or other gold standard) disease is important to avoid selection bias. The study by Fournié was retrospective in design. Choice of gold standard is also problematic where no pathologic benchmark exists. The usual practice is to identify patients with expert (rheumatologist)-diagnosed disease. This may be problematic in single-center studies where local diagnostic practice could differ from that at other centers. Finally, the statistical method of logistic regression to define the classification rule exclusively has significant problems. In particular, it makes it possible to define patients with

disease in ways that were never actually observed. For example, the rule requires a score of 11 to diagnose PsA; the presence of a family history of psoriasis (score 3), RF negativity (score 4), and HLA-B17 (score 6) results in a score beyond the threshold of diagnosis for PsA, yet the patient has neither psoriasis nor arthritis. A recursive partitioning technique such as classification and regression tree (CART)38 or serial partitioning analysis (SPAN)39 may be more likely to result in robust data-derived criteria.

Direct Comparison of the Accuracy of Different Criteria Two studies have sought to identify the best performing classification criteria. We found in a retrospective study using data from clinical records and existing radiographs in 343 patients with PsA and 156 with RA that the criteria of Vasey and Espinoza had the best combination of specificity, sensitivity, and feasibility, although there was not a statistically significant difference between Vasey, Gladman, and McGonagle (Fig. 4-2).13 The CASPAR study also found that the criteria of Vasey and Espinoza performed best of all the currently proposed classification criteria.14 This study was

TABLE 4-6 MODIFIED MCGONAGLE CRITERIA Psoriasis or family history of psoriasis

Criteria I plus one from either criteria II or III Criteria I: Psoriatic skin or nail involvement Criteria II: Peripheral pattern 1. Pain and soft tissue swelling with or without limitation of movement of the distal interphalangeal joint for over 4 weeks 2. Pain and soft tissue swelling with or without limitation of motion of the peripheral joints involved in an asymmetric peripheral pattern for over 4 weeks. This includes a sausage digit. 3. Symmetrical peripheral arthritis for over 4 weeks in the absence of rheumatoid factor or subcutaneous nodules 4. Pencil-in-cup deformity, whittling of terminal phalanges, fluffy periostitis, and bony ankylosis

Plus any one of: Clinical inflammatory enthesitis Radiographic enthesitis (replaces magnetic resonance imaging evidence of enthesitis) DIP disease Sacroiliitis/spinal inflammation Uncommon arthropathies (SAPHO, spondylodiscitis, arthritis mutilans, onycho-pachydermo-periostitis, chronic multifocal recurrent osteomyelitis) Dactylitis Monoarthritis Oligoarthritis (four or less swollen joints)

Criteria III: Central pattern

DIP, distal interphalangeal; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis.

1. Spinal pain and stiffness with the restriction of motion present for over 4 weeks

From McGonagle D, Conaghan PG, Emery P. Psoriatic arthritis. A unified concept twenty years on. Arthritis Rheum 1999;42:1080-1086.

2. Grade 2 symmetrical sacroiliitis according to the New York criteria 3. Grade 3 or 4 unilateral sacroiliitis From Vasey F, Espinoza LR. Psoriatic arthropathy. In: Calin A (ed). Spondyloarthropathies. Orlando, Fla: Grune & Stratton, 1984, pp 151-185.

conducted across 13 countries and involved more than 1000 patients. Patients with other inflammatory arthritis were control subjects—these included RA (70% of controls), AS, undifferentiated arthritis, and a smaller number of other diseases. Using items derived from two different statistical techniques (classification and

Other Diagnostic Criteria

TABLE 4-4 CRITERIA PROPOSED BY VASEY AND ESPINOZA

regression tree, logistic regression), new criteria were derived that had very high specificity but slightly less sensitivity than the Vasey and Espinoza criteria. The features identified as the most discriminating between PsA and controls were psoriasis itself (current, history, or family history), dactylitis (current or history), TABLE 4-7 CRITERIA OF FOURNIÉ (PSORIATIC ARTHRITIS ≥ 11 POINTS) Psoriasis antedating or concomitant with joint symptom onset—6 points Family history of psoriasis (if criterion 1 negative) or psoriasis postdating joint symptom onset—3 points Arthritis of a DIP joint—3 points

TABLE 4-5 MODIFIED EUROPEAN SPONDYLOARTHROPATHY STUDY GROUP (ESSG) CRITERIA FOR PSORIATIC ARTHRITIS Inflammatory spinal pain OR

Inflammatory involvement of cervical and thoracic spine— 3 points Asymmetric monarthritis or oligoarthritis—1 point Buttock pain, heel pain, spontaneous anterior chest wall pain, or diffuse inflammatory pain in the entheses—2 points

AND

Radiologic criterion (any one present): erosion DIP, osteolysis, ankylosis, juxta-articular periostitis, phalangeal tuft resorption—5 points

One or more of the following:

HLA-B16 (38,39) or B17—6 points

Synovitis (either asymmetric or predominantly lower limb)

Positive family history of psoriasis

Negative RF—4 points

Psoriasis

DIP, distal interphalangeal; HLA, human leukocyte antigen; RF, rheumatoid factor;

From Dougados M, van der Linden S, Juhlin R, et al. The European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathy. Arthritis Rheum 1991;34: 1218-1227.

From Fournié B, Crognier L, Arnaud C, et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev Rhum Engl Ed 1999;66:446-456.

25

DIAGNOSTIC CRITERIA OF PSORIATIC ARTHRITIS

Sensitivity

Specificity

Proportion classified

1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 Moll and Wright

Vasey and Espinoza

Bennett

ESSG

Gladman McGonagle

Fournié

Figure 4-2. Comparison of different criteria. ESSG, European Spondyloarthropathy Study Group. (Data from Taylor WJ, Marchesoni A, Arreghini M, et al. A comparison of the performance characteristics of classification criteria for the diagnosis of psoriatic arthritis. Semin Arthritis Rheum 2004;34:575-584.)

negative test for RF, radiographic juxta-articular new bone formation, and psoriatic nail dystrophy. The CASPAR criteria are shown in Table 4-8. It must be remembered that all subjects (cases and controls) had established inflammatory articular disease (arthri-

tis, spondylitis, or enthesitis), and this feature was taken for granted when the new criteria were constructed. It is possible for subjects to be classified with PsA if they are positive for RF or do not have psoriasis as long as other characteristic features are present.

TABLE 4-8 THE CLASSIFICATION OF PSORIATIC ARTHRITIS (CASPAR) CRITERIA Inflammatory articular disease (joint, spine, or entheseal) With 3 or more points from the following: 1. Evidence of psoriasis (one of a, b, c)

(a) Current psoriasis*

Psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologist

(b) Personal history of psoriasis

A history of psoriasis that may be obtained from patient, family doctor, dermatologist, rheumatologist, or other qualified health care provider

(c) Family history of psoriasis

A history of psoriasis in a first- or second-degree relative according to patient’s report

2. Psoriatic nail dystrophy

Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis observed on current physical examination

3. A negative test for rheumatoid factor

By any method except latex but preferably by ELISA or nephelometry, according to the local laboratory reference range

4. Dactylitis (one of a, b)

(a) Current

Swelling of an entire digit

(b) History

A history of dactylitis recorded by a rheumatologist

5. Radiologic evidence of juxta-articular new bone formation

Ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of hand or foot

Specificity 0.987, sensitivity 0.914. * Current psoriasis scores 2, whereas all other items score 1. ELISA, enzyme-linked immunosorbent assay.

26

From Taylor WJ, Gladman DD, Helliwell PS, et al. Classification criteria for psoriatic arthritis: New criteria from a large international study. Arthritis Rheum 2006; 54:2665-2673.

It is hoped that the CASPAR criteria will become the standard for defining case definition for clinical studies, especially intervention studies, of PsA. At the very least, this will provide a uniform starting point for interpreting the results of clinical studies and comparison across different studies. Nonetheless, there are still a number of classification issues that need to be resolved by further work. Foremost among these is the problem of classifying early disease. At present, there is no clear way of distinguishing recent-onset undifferentiated arthritis destined to become PsA as opposed to some other inflammatory arthritis. It may be that MRI will be helpful to identify entheseal disease40 or sacroiliitis,41 but at present this whole area is still very much a research question. With better understanding of the pathophysiology of PsA, it may be possible to identify more clear-cut distinguishing features.

Second, the application of any of the proposed criteria in general population settings for epidemiologic purposes needs to wait until the criteria have been properly tested in the population. It is likely that the CASPAR criteria will retain high specificity in a general population setting, but it may be more useful that criteria have high sensitivity in this situation. Finally, the application of criteria for regulatory purposes (e.g., funding of expensive biologic treatment) must be approached carefully. Logically, the entry criteria for the studies that showed benefit of such intervention should be the starting point for considering access criteria by regulatory authorities. How any new criteria should be applied in this situation is unclear. It may be necessary for pivotal trial data to be reexamined to see how many of the participants would have fulfilled new classification criteria.

References

FUTURE PROSPECTS

REFERENCES 1. Wright V. Rheumatism and psoriasis: A re-evaluation. Am J Med 1959;27:454-462. 2. Baker H, Golding DN, Thompson M. Psoriasis and arthritis. Ann Intern Med 1963;58:909-925. 3. Wright V. Psoriatic arthritis. A comparative study of rheumatoid arthritis, psoriasis and arthritis associated with psoriasis. Ann Rheum Dis 1959;80:65-73. 4. Blumberg BS, Bunim JJ, Calkins E, et al. ARA nomenclature and classification of arthritis and rheumatism (tentative). Arthritis Rheum 1964;7:93-97. 5. Moll JMH, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3:55-78. 6. Harrison BJ, Silman AJ, Barrett EM, et al. Presence of psoriasis does not influence the presentation or short-term outcome of patients with early inflammatory polyarthritis. J Rheumatol 1997;24:1744-1749. 7. Cats A. Is psoriatic arthritis an entity? In: Brooks PM, York JR (eds). Rheumatology—85. Proceedings of the XVIth International Congress of Rheumatology; 1985. Sydney: Elsevier Science Publishers, 1985, pp 295-301. 8. Fries JF, Hochberg MC, Medsger TA Jr, et al. Criteria for rheumatic disease. Different types and different functions. The American College of Rheumatology Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1994;37:454-462. 9. Symmons D, Lunt M, Watkins G, et al. Developing classification criteria for peripheral joint psoriatic arthritis. Step I. Establishing whether the rheumatologist’s opinion on the diagnosis can be used as the “gold standard.” J Rheumatol 2006;33:552-557. 10. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-1277. 11. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-324. 12. Taylor WJ, Helliwell PS. Case definition of psoriatic arthritis [letter]. Lancet 2000;356:2095. 13. Taylor WJ, Marchesoni A, Arreghini M, et al. A comparison of the performance characteristics of classification criteria for the diagnosis of psoriatic arthritis. Semin Arthritis Rheum 2004;34:575-584.

14. Taylor WJ, Gladman DD, Helliwell PS, et al. Classification criteria for psoriatic arthritis: New criteria from a large international study. Arthritis Rheum 2006;54:2665-2673. 15. Taylor WJ. The epidemiology of psoriatic arthritis. Curr Opin Rheumatol 2002;14:98-103. 16. Bennett RM. Psoriatic arthritis. In: McCarty DJ (ed). Arthritis and Related Conditions, 9th ed. Philadelphia: Lea & Febiger, 1979, p 645. 17. Vasey F, Espinoza LR. Psoriatic arthropathy. In: Calin A (ed). Spondyloarthropathies. Orlando, Fla: Grune & Stratton, 1984, pp 151-185. 18. Gladman DD, Shuckett R, Russell ML, et al. Psoriatic arthritis— An analysis of 220 patients. Q J Med 1987;238:127-141. 19. Dougados M, van der Linden S, Juhlin R, et al. The European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathy. Arthritis Rheum 1991;34:1218-1227. 20. McGonagle D, Conaghan PG, Emery P. Psoriatic arthritis: A unified concept twenty years on. Arthritis Rheum 1999;42:1080-1086. 21. Fournié B, Crognier L, Arnaud C, et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev Rhum Engl Ed 1999;66:446-456. 22. Bizzaro N, Mazzanti G, Tonutti E, et al. Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin Chem 2001;47:1089-1093. 23. Korendowych E, Brown S, Jones S, et al. Anti-cyclic citrullinated peptide antibody testing in patients with psoriatic arthritis (abstract). Rheumatology 2002;41(Suppl 1):115. 24. Bogliolo L, Alpini C, Caporali R, et al. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J Rheumatol 2005;32: 511-515. 25. Helliwell PS, Hetthen J, Sokoll K, et al. Joint symmetry in early and late rheumatoid and psoriatic arthritis: Comparison with a mathematical model. Arthritis Rheum 2000;43:865-871. 26. Gorter S, van der Heijde DM, van der Linden S, et al. Psoriatic arthritis: Performance of rheumatologists in daily practice. Ann Rheum Dis 2002;61:219-224. 27. Moll JMH, Wright V. Familial occurrence of psoriatic arthritis. Ann Rheum Dis 1973;32:181-201. 28. McEwen C, DiTata D, Lingg C, et al. Ankylosing spondylitis and spondylitis accompanying ulcerative colitis, regional enteritis,

27

DIAGNOSTIC CRITERIA OF PSORIATIC ARTHRITIS

28

29.

30.

31.

32.

33.

psoriasis and Reiter’s disease. A comparative study. Arthritis Rheum 1971;14:291-318. Helliwell PS, Hickling P, Wright V. Do the radiological changes of classic ankylosing spondylitis differ from the changes found in the spondylitis associated with inflammatory bowel disease, psoriasis, and reactive arthritis? Ann Rheum Dis 1998;57: 135-140. de Vlam K, Mielants H, Verstaete KL, Veys EM. The zygapophyseal joint determines morphology of the enthesophyte. J Rheumatol 2000;27:1732-1739. Brockbank JE, Stein M, Schentag CT, Gladman DD. Dactylitis in psoriatic arthritis: A marker for disease severity? Ann Rheum Dis 2005;64:188-190. Lories RJ, Matthys P, de Vlam K, et al. Ankylosing enthesitis, dactylitis, and onychoperiostitis in male DBA/1 mice: A model of psoriatic arthritis. Ann Rheum Dis 2004;63:595-598. Scarpa R, Cosentini E, Manguso F, et al. Clinical and genetic aspects of psoriatic arthritis “sine psoriasis.” J Rheumatol 2003;30:2638-2640.

34. Rothschild BM, Pingitore C, Eaton M. Dactylitis: Implications for clinical practice. Semin Arthritis Rheum 1998;28:41-47. 35. Avila R, Pugh DG, Slocumb CH, Winkleman RK. Psoriatic arthritis: A roentgenologic study. Radiology 1960;75:691-701. 36. O’Neill T, Silman AJ. Psoriatic arthritis. Historical background and epidemiology. Baillieres Clin Rheumatol 1994;8:245-261. 37. McGonagle D, Conaghan PG, Emery P. Psoriatic arthritis. A unified concept twenty years on. Arthritis Rheum 1999;42:1080-1086. 38. Breiman L, Friedman JH, Olshen RA, Stone JS. Classification and Regression Trees. Belmont, Calif: Wadsworth, 1984. 39. Marshall RJ. The use of classification and regression trees in clinical epidemiology. J Clin Epidemiol 2001;54:603-609. 40. McGonagle D, Gibbon W, O’Connor P, et al. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis Rheum 1998;41:694-700. 41. Williamson L, Dockerty JL, Dalbeth N, et al. Clinical assessment of sacroiliitis and HLA-B27 are poor predictors of sacroiliitis diagnosed by magnetic resonance imaging in psoriatic arthritis. Rheumatology (Oxford) 2004;43:85-88.

PSORIATIC ARTHRITIS

5

Natural History, Prognosis, and Socioeconomic Aspects of Psoriatic Arthritis Philip S. Helliwell and Eric Ruderman

Psoriatic arthritis (PsA) is a heterogeneous disease. Clinical manifestations vary from a mild, slightly troublesome oligoarthritis to a severe, mutilating polyarticular form. The diverse clinical manifestations make single-statement predictions of outcome impossible. Further, people affected often have two diseases to cope with—the skin and the joints—and the severity of each of these may be quite different. Most of the early work on PsA was performed by Verna Wright, and his initial papers and those from his team slightly later suggested that, on the whole, PsA was a less severe form of arthritis than rheumatoid arthritis.1 Wright acknowledged, however, that in some people the disease followed a particularly aggressive and deforming course. Further clinical studies have challenged the assertion that this is a benign disease compared with rheumatoid arthritis.2 Methodologic differences may have accounted for some of these differences. For example, in comparative studies, cases should be appropriately matched with comparator conditions, something that was not always apparent in earlier studies. Another example, in longitudinal studies, would be the importance of maximizing follow-up—milder cases may be more likely to default, thus skewing the results toward a more severe outcome. It is also worth noting that almost all the published studies on outcome in PsA have been carried out on secondary or tertiary care populations, which are likely to represent the more severe cases and are more likely to receive the most treatment in order to control their disease. Inevitably, the outcome of all cases, including those in the community who either do not consult or are not referred, remains largely unknown. This chapter attempts to synthesize the clinical research that has contributed to our knowledge of PsA, given the preceding contradictions and methodologic problems. A large proportion of this research has been conducted by Dafna Gladman and colleagues in Toronto, Canada, where a PsA clinic and database have been established since 1978. Paramount among other

investigators, this team have been able to carry out longitudinal studies on sufficiently large numbers of people to give meaningful results; the significant contribution of this team is acknowledged. We are entering a period of unprecedented treatment activity in PsA—new drugs, including the biologics, not only are much more effective against skin and joint manifestations but also have encouraged further research into the condition. Earlier, more aggressive treatment may have a significant beneficial effect on the natural and treated course of this disease.

NATURAL HISTORY Obtaining accurate information on natural history is difficult in the context of clinical studies—once identified, people want treatment. Those not seeking treatment, in whom the natural course can be observed, are likely to have a milder form of the disease. Nevertheless, clinical experience would suggest, and some publications would support, the contention that up to a third of patients with PsA either have a mild, minimally progressive disease that requires only symptomatic treatment or have an oligoarticular disease limited to a few affected joints. The former group include those with arthralgia and lowgrade inflammation; sometimes only a “cold” swollen knee is observed over many years with little progression to joint damage. Nevertheless, oligoarticular disease can be very disabling; one or two dactylitic digits on a dominant hand and a severe enthesopathy at the Achilles insertion can limit both manual tasks and mobility.

Mild, Nonprogressive Disease Wright, in his original series, identified two populations of patients—a group in whom the onset of the disease was severe but who made a complete and lasting recovery and a more severe progressive group.1 Although no exact figures were given, Wright stated that cases with mild disability outnumbered those with severe disabil-

29

NATURAL HISTORY, PROGNOSIS, AND SOCIOECONOMIC ASPECTS OF PSORIATIC ARTHRITIS

ity. Further, 74% of the total group had few, mildly affected, joints at presentation. These observations were confirmed in a later paper looking at radiologic changes.3 The initial cohort of patients collected by Wright in Leeds was later reviewed by Roberts and colleagues and the largely benign nature of the condition restated: 78% of a group of 178 patients were classified as “mild” with only 11% of this group deteriorating over a follow-up period of more than 10 years.4 Later studies, particularly those from Toronto, have also hinted at a milder, nonprogressive, oligoarticular group. For example, the first complete series published by Gladman and coauthors included a large nonerosive group.5 Subsequent series have looked at progression of damage and identified a group of 33% to 36% of patients who had no evidence of damaged joints at either presentation or follow-up.6,7 A similar proportion of patients—28%—remained without disability over a 10-year period.8 An earlier study looking at remission in PsA, using rather exacting criteria of no inflamed joints over three consecutive visits, found that 18% of 391 patients fulfilled these criteria in an 18-year period; just over half of these subsequently relapsed, however.9 As mentioned previously, community-based data are usually not available but a report from the United States provided some indication of the burden of disease in this community.10 The cohort was identified from health records covering the entire local population and data were available over a 9-year period. Despite the large population (124,277), numbers of cases were small at 66 and corresponding prevalence and incidence figures were low. Only 10 of this largely oligoarticular group were treated with disease-modifying antirheumatic drugs (DMARDs), and only 8% developed erosions in the hands.

Progressive Deforming Arthritis

30

Wright reported a group of patients who developed a severely deforming arthritis, termed arthritis mutilans, with osteolysis of the digits, polyarticular involvement, and frequent spinal involvement.11 Subsequent reports have also described this most severe form of PsA, which results in marked disability.12,13 Affected individuals often have flail digits in both hands and feet, resulting in the main en lorgnette deformity described by Wright. Fortunately, this distinctive subgroup represents only a small proportion of affected people, rarely more than 5% of the total. Between the mild, nonprogressive forms and the severe arthritis mutilans, there is a predominantly polyarticular group in which progressive deformity and damage are slow but persistent. These people slowly accrue damaged joints and become progressively more disabled, as demonstrated by several cross-sectional surveys.14,15 Longitudinal surveys, particularly from the

Toronto group, have confirmed this. Other longitudinal studies, from England and Finland, have provided mixed results. In a tertiary referral center in Droitwich, England, a small series of 40 patients were observed for an average of 8 years: 58% experienced improved functional ability during this period and the mean number of active joints at final assessment was two.16 In a referral center in Tampere, Finland, a small cohort of 14 patients was observed for 3 years—most had functional improvement but all progressed radiologically and only 2 patients were in remission at the final assessment.17

Spinal Disease The prevalence and progression of spondylitis in PsA remain controversial. The prevalence depends to some extent on the method used to identify spinal involvement. If symptoms and signs of inflammatory spinal pain are used the prevalence is 40%, but if plain radiography of the sacroiliac joints is used the prevalence is 25%. However, clinical tests of sacroiliac joint involvement are insensitive—Williamson and colleagues demonstrated poor sensitivity (38%) and specificity (67%) of clinical tests for sacroiliac involvement compared with magnetic resonance imaging.18 In contrast, both Khan19 and Williamson18 and their colleagues have demonstrated a high prevalence of asymptomatic spinal involvement in PsA. Furthermore, and colleagues confirmed that changes consistent with inflammatory spondylitis can occur in PsA in the absence of radiologic sacroiliitis, an important observation in the context of the modified New York criteria for the classification of ankylosing spondylitis that require evidence of radiologic damage.20 A further study from the Toronto group has demonstrated radiologic progression of spinal disease in the absence of clinical progression (as indicated by symptoms and spinal movements) over a mean follow-up period of 57 months—clearly, symptomatic and disease-modifying treatment in this cohort did not prevent progression of the disease.21 Across this spectrum of manifestations and severity, it is obviously of importance to the clinician to predict the course and outcome, given the first presentation. This is addressed in the following section. It should be noted that this review does not cover the new-onset, human immunodeficiency virus (HIV)-associated PsA, which clearly has a separate prognosis.

PROGNOSTIC FACTORS It is possible to obtain some idea of the factors associated with a more severe outcome by looking at a cohort of people and comparing the clinical and disease-associated features between subgroups defined by outcome. However, better quality data are obtained by performing longitudinal studies, although the useful-

Cross-Sectional Studies Roberts and coauthors, reporting on the cohort of patients established by Wright, divided the group up into three: an arthropathy indistinguishable from rheumatoid arthritis, a distal interphalangeal predominant group, and a more severe deforming group.4 Although there were only eight patients in the deforming group, features at onset that appeared to be more common in this group were an acute onset with systemic features, onset before the age of 20, and spinal involvement. Kammer and associates divided their cohort into an asymmetric oligoarthritis group, a symmetric polyarthritis group, and a spinal group.22 The polyarticular group was more likely to progress and more likely to have nail involvement, although 25% of an oligoarticular group developed chronic persistent arthritis. Gladman and colleagues, in their 1987 paper, found that 40% of their series of 220 patients had deforming progressive arthritis.5 However, Jones and others23 reported that the outcome did not depend on the mode of onset of the arthritis, although most (63%) of their cases had polyarthritis at later review, in contrast to the 25% who had a polyarticular onset.

Longitudinal Studies In longitudinal studies, significant polyarticular inflammation at onset predicts outcome in terms of joint damage. This was demonstrated in Toronto, reviewing the course of 305 patients over a 14-year period.6 The best predictors on univariate analysis were more than five inflamed joints, more than five joints with effusions, an erythrocyte sedimentation rate (ESR) greater than 30, and more than two previous antiarthritic medications. In a multivariate model, joint effusions together with ESR and number of previous medications were the significant predictor variables. Interestingly, previous use of steroid was also an indicator of progression and is probably a surrogate for high disease activity. In an extension of this study, published in 1999, the significant variables in the final model included the number of actively inflamed joints (odds ratio = 1.04), functional class (1.5), damage index (2.23), high number of DMARDs used (1.83), and use of steroids (1.89).24 Two factors were protective: male sex and initial ESR less than 15. A further study, published in 2005, reported the predictors of disability as measured by the Health Assessment Questionnaire (HAQ).8 Of 341 patients in the database, mostly with polyarthritis, 28% remained unchanged with no disability over a 10-year

period. A predictor of deterioration was, again, the number of inflamed joints (relative risk [RR] 1.03), and male sex once again appeared to be protective (RR 0.54). Two other longitudinal series have shown similar results. Kane and co-workers, studying an inception cohort in an early arthritis clinic, found that patients were more likely to be in remission at 2 years if they had an oligoarticular onset.25 In a Spanish group, once again, the predictors for the development of erosions were, on univariate statistics, a polyarticular onset but additionally were female sex, distal interphalangeal involvement, presence of the human leukocyte antigen HLA-B27, and a high HAQ score.12 However, in a multivariate model, only polyarticular disease was a significant predictor. These studies are reassuring. In the clinic it is appropriate to treat the patients with the most severe disease most aggressively. Therefore, those with polyarticular disease who are not functioning well are targeted for early and intensive therapy—further work is required to test the efficacy of this practice given that the polyarticular subgroup incorporates a wide range of severity. Because the patients destined to develop arthritis mutilans are almost certainly in this group, it will be of interest to see whether an aggressive treatment strategy will eliminate this devastating condition. One other longitudinal series is notable. The Norfolk early arthritis register is an inception cohort study of all cases of inflammatory arthritis presenting to primary care in a defined geographic area. When reporting the results of this cohort, no assumptions are made about disease classification, and an abstract has detailed the 5-year outcome of a group of people with inflammatory arthritis (more than two inflamed joints for more than 4 weeks) both with (n = 79) and without (n = 755) psoriasis.26 At 5 years, the only significant difference between the two groups, after adjustment for age and DMARD use, and restricting the psoriasis group to those who were seronegative for rheumatoid factor, was a lower Larsen score in the erosive psoriasis group. In this context, it is worth noting that other studies have demonstrated lower damage scores for PsA compared with rheumatoid arthritis, despite equivalent disability scores.14

Prognostic Factors

ness of these depends on the extent and the quality of the data collected at the outset. Stored serum and DNA samples are invaluable as new concepts emerge during the course of the study.

Other Clinical Prognostic Factors Dactylitis, one of the hallmark clinical features of PsA, represents inflammation in articular and soft tissues of a digit. It is present in about 30% of cases of PsA at some time and is associated with marked disability, particularly when present in the hand. Brockbank and coauthors have reported that dactylitic digits are more likely to develop progressive radiologic changes than nondactylitic digits, thus making dactylitis a severity marker for PsA.27 A nonacute form of dactylitis,

31

NATURAL HISTORY, PROGNOSIS, AND SOCIOECONOMIC ASPECTS OF PSORIATIC ARTHRITIS

32

possibly residual change following an acute episode, can be distinguished from acute, painful dactylitis— the clinical significance and pathophysiology of this have yet to be determined. Nail disease has sometimes emerged in cross-sectional studies as associated with severe disease, and this has been confirmed in a study reporting the development of a new instrument to quantify nail involvement.28 A Psoriatic Nail Severity Score (PNSS) of more than 16 was associated with more hospital admissions for psoriasis and greater radiologic progression of the arthritis. Although only a few patients with established PsA have clinical and radiologic hip involvement, those with arthritis of this joint are often very disabled and require early arthroplasty. Early hip involvement is typical of ankylosing spondylitis, but a series from the Mayo Clinic has shown that cases of PsA with hip disease are significantly younger at onset (29 years versus 40 years of age) and are more likely to have spondylitis.29

Human Leukocyte Antigen Studies Genetic factors have been associated with different subgroups of PsA and, in rheumatoid arthritis, certain HLA haplotypes are associated with disease severity and susceptibility, so it seems reasonable to seek such predictors in PsA. Espinoza and colleagues30 first reported an association between HLA-Bw38 and peripheral polyarthritis (the subgroup most likely to progress), and this was later confirmed in a larger series from Toronto.31 In fact, the Toronto group also found a higher prevalence of HLA-DR4 in the polyarticular subgroup, provided distal interphalangeal joints were not involved. The role of HLA antigens in predicting disease progression was studied in a further two papers from Toronto.7,32 In this model, 276 patients who had HLA typing were observed for 14 years; progression of joint damage was used to assess the relationship between HLA factors and outcome. During the course of the study, 88 patients did not progress. Progression was predicted by the following HLA antigens: combination of HLA-B27 and HLA-DR7 (RR 2.47), DQw3 (RR 1.63), and HLAB39 (RR 7.05). The association of DQw3 with DR7 was, however, protective (RR 0.54). This model was confirmed and extended 3 years later by the addition of another 16 patients; the model again includes HLAB39 providing risk for progression in early stages, HLA-B27 in the presence of HLA-DR7 providing risk for progression at all times, and DQw3 providing increased risk in the absence of DR7 and, in the presence of DR7, protection. Another HLA antigen, B22, was found to be protective (RR 0.19). In a later Swedish study, these results were not confirmed.33 In a cross-sectional study of 88 patients,

HLA-B37 and HLA-B62 were associated with joint destruction and HLA-A3 was inversely associated with erosion or deformity. However, in a multivariate model, none of the HLA antigens were significant, the only significant variables predicting destruction being distal interphalangeal involvement and a polyarticular pattern. Finally, emerging data on cytokine polymorphisms suggest that erosive disease, and by inference the worst prognostic groups, is associated with certain tumor necrosis factor (TNF) subtypes. Balding and colleagues looked at 147 patients with PsA and compared them with 389 healthy control subjects.34 Fifty-one of the PsA patients had sequential radiographs to assess the progression of erosive disease. TNF-α −308 and TNF-β +252 were associated with erosive disease and progression of erosions. However, there was no increase in any of the pro-inflammatory genotypes in PsA overall.

MORBIDITY: EXTRA-ARTICULAR DISEASE, DISABILITY, AND QUALITY OF LIFE

Extra-articular Disease It is appropriate to consider the dermatologic aspects of the disease as an extra-articular feature. Early studies suggested that the worst skin disease was associated with the worst arthritis, but more recent studies have not supported this. It is possible to witness a severe mutilating arthropathy in the presence of minor skin and nail changes. Further, skin severity scores at presentation do not predict progression.8 However, one report demonstrated a decline in function and quality of life with increasing skin severity scores.14 Such comments are to be taken in the context of secondary care referral centers, which may be studying a biased population. Further, it is possible that, in predominant articular disease, treatment of the joints is of benefit to the skin, thus obfuscating this relationship. Nevertheless, the dermatologic component of this disease is important to the patient as it provides a very public manifestation of the affliction. Skin disease has been shown to contribute to disability and poor quality of life in PsA (see later).

Other Extra-articular Complications Unlike those in rheumatoid arthritis, significant extraarticular manifestations of this disease do not occur. Nevertheless, there is a growing literature on the increased cardiovascular morbidity and mortality in PsA and there are reports of left ventricular dysfunction. A small study from Turkey using echocardiography has reported abnormal left ventricular end-diastolic and systolic parameters compared with control subjects.35 However, only 14 of 21 patients had definite PsA at the time of the study, the other 7 having

Disability and Quality of Life Although the World Health Organization has introduced a new system for quantifying and describing health status, the International Classification of Functioning, Disability and Health, ICF (http://www3. who.int/icf/icftemplate.cfm), the available data in relationship to PsA are related to the old system, where impairment is related to disability and handicap. Health-related quality of life is a related concept, traditionally measured in rheumatology by the 36-Item Short Form Survey (SF-36)38 and in Europe by the EuroQoL.39 Sokoll and Helliwell compared impairment, function, and quality of life in a series of 50 patients with PsA and a sample of patients with rheumatoid arthritis matched for age and duration of disease.14 Impairment, as measured by radiologic damage score, was greater in the rheumatoid arthritis group, but both disability and quality of life were similarly impaired in both groups. Patients graded for severity of skin disease showed a decline in function and quality of life with increasing severity of skin disease. A similar study was reported at virtually the same time by the Toronto group, who compared disability (as measured by the HAQ) and quality of life (as measured by the SF-36) in 107 patients with PsA and 43 patients with rheumatoid arthritis.15 Patients with rheumatoid arthritis had markedly higher HAQ disability index scores (mean 1.11) than the PsA patients (mean 0.58). On the domains of the SF-36, patients with rheumatoid arthritis had significantly less vitality, worse physical functioning, and more role limitations attributed to physical functioning. In the same study, the SF-36 domains of bodily pain and general perception of health were equivalent between the groups. After adjustment for age, sex, and disease duration (the groups were not matched for these variables) only the vitality domain of the SF-36 remained to separate the two groups. In contrast to the Leeds study, there was no correlation between skin severity (as measured by the psoriasis area and severity index) and quality of life.

MORTALITY Early studies suggested that PsA was a relatively mild arthropathy and, by implication, that there was little morbidity and no increase in mortality in this condition. One of the first studies documenting this was the follow-up study of Wright’s original cohort, reported by Roberts and colleagues in 1976.4 They noted 18

deaths over a period of more than 10 years but no ageand sex-adjusted mortality ratios were calculated, so it is hard to know how this cohort fared relative to the general population. However, there were two points of interest. First, there was one death related to treatment and, second, there were eight deaths related to cardiovascular disease. Both of these are of interest—the first because the aggressive use of relatively toxic pharmaceuticals inevitably results in some severe adverse reactions and the second because of the growing recognition that people with inflammatory diseases are susceptible to more cardiovascular morbidity and mortality, as has been demonstrated in rheumatoid arthritis and psoriasis.40,41 Further follow-up studies of mortality from the Toronto group have confirmed an increase in cardiovascular mortality but also highlighted increased mortality from respiratory diseases and injuries or poisoning, the latter particularly in men.42 In this study, 290 patients were followed up on the Toronto database and 53 deaths were reported. All-cause mortality was increased in this study, with a standardized mortality ratio (SMR) of 1.59 for men and 1.65 for women, suggesting 59% and 65% increases in mortality relative to the general population, respectively, during the period of follow-up. The SMR for cardiovascular diseases was 1.33 (not significant), respiratory diseases 5.05, neoplasms 0.73 (not significant), and injuries or poisoning 3.54. There were a few cases of liver cirrhosis, often a worry with people with PsA, where methotrexate is used in the context of higher than average alcohol intake. However, none of the deaths could be attributable to methotrexate therapy. In a later report, the same group examined prognostic indicators for death. Recognizing that there was a small number of deaths, the poor prognostic indicators were, at presentation, prior DMARD medication use (RR 1.84), radiologic damage (RR 3.03), and an elevated ESR (RR 3.49).43 The pattern of arthritis was not a prognostic indicator of mortality in this study. The higher mortality related to cardiovascular diseases was confirmed in a literature review published by Peters and coauthors.44 This group concluded that in PsA there is an increase in cardiovascular morbidity (see earlier) and mortality related in part to an increase in conventional risk factors and also factors such as decreased physical activity and systemic inflammation. Finally, the community-based study by Shbeeb and colleagues did not find any increase in mortality in their series, observed over a 19-year period.10 However, numbers were small at 66 and most (91%) had oligoarticular disease. Only 10 patients had taken DMARDs. This study, alone among those of other referral-based populations, has indicated that the total disease burden in the community may not be as bad as

Mortality

arthralgia only. These results need confirmation in a larger series. There are case reports of secondary amyloidosis in association with PsA, as would be expected in this chronic inflammatory disease.36,37

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the hospital surveys indicate. A number of criticisms were made of the Shbeeb study at the time45; the truth probably lies somewhere between what has been reported from community and referral centers.

SOCIOECONOMIC FACTORS As PsA has gained recognition as a completely separate entity from rheumatoid arthritis, a number of studies have begun to examine the impact that this disease has on patients’ function, and some, as described previously, have distinguished it from the impact of RA. Data on the effect of PsA on employment and disability, however, remain limited.

Disability and Function The HAQ and several modifications have been used to assess function in rheumatoid arthritis since they were first developed at Stanford in the 1980s.46 Although these questionnaires were designed to measure function in rheumatoid arthritis, their utility and validity have now been examined in a number of other types of arthritis, including PsA. Interestingly, although the HAQ correlates well with other measures of function in PsA, such as grip strength and functional class, it correlates less well with measurements of disease severity.47 One potential explanation for this is the impact of skin disease, a unique element of PsA that is not present in rheumatoid arthritis, on perceptions of disease severity. In an assessment of a modified version of the HAQ that included questions related to functional issues with psoriasis, however, the addition of questions related to skin did not significantly change the HAQ score.48 Another unique feature of PsA is the varying presentation of joint involvement. In a Spanish cohort of PsA patients with spondyloarthropathy, those with polyarticular peripheral arthritis had worse HAQ scores than those with oligoarticular peripheral arthritis or pure axial disease.49 Functional assessments in PsA patients that do not adequately distinguish between presentations of joint disease may fail to give an accurate picture of function in some patients. Additional measures of function have also been tested and validated in PsA patients. Both the Arthritis Impact Measurement Scales (AIMS) and the expanded AIMS2, which assess pain, physical function, and psychosocial function, have been demonstrated to be valid in PsA.50,51 The psychosocial scales in these instruments correlated less well with standard clinical measures than the other scales. This may relate to psychosocial aspects of the skin disease in psoriasis that are not well captured in PsA outcome measures. Interestingly, given the frequency of depression associated with psoriasis, the AIMS depression scale showed some correlation with function.

Other data, however, suggest that joint symptoms may have a unique impact on quality of life in PsA. In a comparison of psoriasis and atopic dermatitis in Sweden, both were found to have significant, and comparable, impacts on quality of life, and patients with PsA reported significantly worse quality of life than those with either skin disease.52 In the United States, a survey conducted by the Psoriasis Foundation found that 39% of those contacted with PsA reported that the disease was a large problem in their everyday life, compared with just 12% of those with psoriasis.53 Regardless of the relative contributions of skin and joint disease to quality of life and disability in PsA, there have historically been few data demonstrating that treatment can have a significant impact. Studies with TNF antagonist therapies, however, have demonstrated that these therapies produce improvements in HAQ scores that are significantly larger than those seen with placebo.54-56

Work Disability With respect to more definitive outcomes regarding disability in PsA, such as work disability, there are, as yet, limited data available. A prospective study of newonset inflammatory arthritis in Finland, which included only 13 patients with PsA, found that 69% of them were working at 8-year follow-up, compared with 36% of those with RA.57 In a large study of employment in German patients with rheumatologic diseases, PsA patients were only slightly less likely to be employed than the general population (standardized employment ratio of 0.92 relative to the general population) and more likely to be employed than those with RA.58 As might be expected, disease duration greater than 10 years and lower educational level were associated with a decreased likelihood of employment within diagnoses in this study.

Costs of Care Data regarding costs of care for PsA are also limited. An analysis of direct and indirect costs associated with psoriasis found that costs increased with the severity of the skin disease, although this study did not account for the presence of arthritis.59 A more recent study of direct costs of care for psoriasis and PsA reported a U.S. estimate of $649.6 million in 1997 dollars.60 This was lower than previous estimates, perhaps because of lower rates of hospitalization, and, again, this analysis did not specifically account for the presence of arthritis.

CONCLUSIONS Although early reports suggested that PsA was, with the exception of arthritis mutilans, a relatively mild arthritis, later studies have challenged this view.

disease. The socioeconomic impact of the disease has not been widely studied but, by reference to studies in rheumatoid arthritis, is likely to be significant in terms of both work and home. Further studies are clearly needed to define the true impact of PsA on disability and participation as well as to sort out the unique contributions of skin and joint disease to these effects.

References

There is no doubt that this arthropathy can manifest as a progressive disabling disease with consequences as severe as those of rheumatoid arthritis. Further, these patients manifest increased mortality, mainly related to cardiovascular disease. Despite this, there is a proportion of patients who have relatively mild disease and who do not develop significant disability; these are more likely to be men with oligoarticular

REFERENCES 1. Wright V. Psoriasis and arthritis. Ann Rheum Dis 1956;15:348-356. 2. Gladman DD, Stafford-Brady F, Chang C-H. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J Rheum 1990;17:809-812. 3. Wright V. Psoriatic arthritis: A comparative study of rheumatoid arthritis and arthritis associated with psoriasis. Ann Rheum Dis 1961;20:123. 4. Roberts MET, Wright V, Hill AGS, Mehra AC. Psoriatic arthritis: Follow-up study. Ann Rheum Dis 1976;35:206-212. 5. Gladman DD, Shuckett R, Russell ML, et al. Psoriatic arthritis (PSA)—An analysis of 220 patients. Q J Med 1987;238:127-141. 6. Gladman DD, Farewell VT, Nadeau C. Clinical indicators of progression in psoriatic arthritis: Multivariate relative risk model. J Rheumatol 1995;22:675-679. 7. Gladman DD, Farewell VT, Kopciuk KA, Cook RJ. HLA markers and progression in psoriatic arthritis. J Rheumatol 1998;25: 730-733. 8. Husted JA, Tom BD, Farewell VT, et al. Description and prediction of physical functional disability in psoriatic arthritis: A longitudinal analysis using a Markov model approach. Arthritis Rheum 2005;53:404-409. 9. Gladman DD, Hing EN, Schentag CT, Cook RJ. Remission in psoriatic arthritis. J Rheumatol 2001;28:1045-1048. 10. Shbeeb M, Uramoto K, Gibson L, et al. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA 1982-1991. J Rheumatol 2000;27:1247-1250. 11. Wright V. Rheumatism and psoriasis: A re-evaluation. Am J Med 1959;27:454-462. 12. Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, LopezLagunas I. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis 2003;62:68-70. 13. Helliwell P, Marchesoni A, Peters M, et al. A re-evaluation of the osteoarticular manifestations of psoriasis. Br J Rheumatol 1991;30:339-345. 14. Sokoll KB, Helliwell PS. Comparison of disability and quality of life in rheumatoid and psoriatic arthritis. J Rheumatol 2001;28:1842-1846. 15. Husted JA, Gladman D, Farewell VT, Cook RJ. Health related quality of life of patients with psoriatic arthritis: A comparison of patients with rheumatoid arthritis. Arthritis Rheum 2001;45:151-158. 16. Coulton BL, Thomson K, Symmons DPM, Popert AJ. Outcome in patients hospitalised for psoriatic arthritis. Clin Rheumatol 1989;8:261-265. 17. Nissila M, Isomaki H, Kaarela K, et al. Prognosis of inflammatory joint diseases. Scand J Rheumatol 1983;12:33-38. 18. Williamson L, Dockerty JL, Dalbeth N, et al. Clinical assessment of sacroiliitis and HLA-B27 are poor predictors of sacroiliitis diagnosed by magnetic resonance imaging in psoriatic arthritis. Rheumatology (Oxford) 2004;43:85-88. 19. Khan M, Schentag C, Gladman DD. Clinical and radiological changes during psoriatic arthritis disease progression. J Rheumatol 2003;30:1022-1026. 20. Van Der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. Arthritis Rheum 1984;27:361. 21. Hanly JG, Russell ML, Gladman DD. Psoriatic spondyloarthropathy: A long term prospective study. Ann Rheum Dis 1988;47:386-393.

22. Kammer GM, Sotar NA, Gibson DJ. Psoriatic arthritis: A clinical, immunologic and HLA study of 100 patients. Semin Arthritis Rheum 1979;9:513-518. 23. Jones SM, Armas JB, Cohen MG, et al. Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-839. 24. Gladman DD, Farewell VT. Progression in psoriatic arthritis: Role of time varying clinical indicators. J Rheumatol 1999;26:2409-2413. 25. Kane D, Stafford L, Bresnihan B, Fitzgerald O. A classification study of clinical subsets in an inception cohort of early psoriatic peripheral arthritis—`DIP or not DIP revisited.’ Rheumatology (Oxford) 2003;42:1469-1476. 26. Morgan C, Lunt M, Bunn D, et al. Similar outcome at 5 years in inflammatory arthritis patients with and without psoriasis. Arthritis Rheum 2005;52 (Abstract Supplement). 27. Brockbank JE, Stein M, Schentag CT, Gladman DD. Dactylitis in psoriatic arthritis: A marker for disease severity? Ann Rheum Dis 2005;64:188-190. 28. Williamson L, Dalbeth N, Dockerty JL, et al. Extended report: Nail disease in psoriatic arthritis—Clinically important, potentially treatable and often overlooked. Rheumatology (Oxford) 2004;43:790-794. 29. Michet C, Mason T, Mazlumzadeh M. Hip joint disease in psoriatic arthritis: Risk factors and natural history. Ann Rheum Dis 2005;64:1068-1070. 30. Espinoza LR, Vasey FB, Oh JH, et al. Association between HLABW38 and peripheral psoriatic arthritis. Arthritis Rheum 1978;21:72-75. 31. Gladman DD, Anhorn KAB, Schachter RK, Mervart H. HLA antigens in psoriatic arthritis. J Rheum 1986;13:586-592. 32. Gladman DD, Farewell VT. The role of HLA antigens as indicators of disease progression in psoriatic arthritis. Multivariate relative risk model. Arthritis Rheum 1995;38:845-850. 33. Alenius GM, Jidell E, Nordmark L, Rantapaa DS. Disease manifestations and HLA antigens in psoriatic arthritis in northern Sweden. Clin Rheumatol 2002;21:357-362. 34. Balding J, Kane D, Livingstone W, et al. Cytokine gene polymorphisms—Association with psoriatic arthritis susceptibility and severity. Arthritis Rheum 2003;48:1408-1413. 35. Saricaoglu H, Gullulu S, Bulbul BE, et al. Echocardiographic findings in subjects with psoriatic arthropathy. J Eur Acad Dermatol Venereol 2003;17:414-417. 36. Qureshi MSA, Sandle GI, Kelly JK, Fox H. Amyloidosis complicating psoriatic arthritis. Br Med J 1977;3:302. 37. Taylor R, Morgan JM, Davie RM. Renal amyloidosis secondary to psoriatic arthritis. Br J Clin Pract 1981;35:410-411. 38. Ware J, Snow K, Kosinski M, Gandek B. SF36 health Survey Manual and Interpretation Guide. Boston: New England Medical Centre, Health Institute, 1993. 39. Kind P, Dolan P, Gudex C, Williams A. Variations in population health status: Results from a United Kingdom national questionnaire. BMJ 1998;316:736-741. 40. Mallbris L, Akre O, Granath F, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol 2004;19:225-230. 41. Van Dournum S, McColl G, Wicks I. Accelerated atherosclerosis—An extra-articular feature of rheumatoid arthritis. Arthritis Rheum 2002;46:862-873.

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42. Wong K, Gladman DD, Husted J, et al. Mortality studies in psoriatic arthritis: Results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum 1997;40:1868-1872. 43. Gladman DD, Farewell VT, Wong K, Husted J. Mortality studies in psoriatic arthritis: Results from a single outpatient center. II. Prognostic indicators for death. Arthritis Rheum 1998;41:11031110. 44. Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum 2004;34:585-592. 45. Veale D. The epidemiology of psoriatic arthritis. Fact or fiction? J Rheumatol 2000;27:1105-1106. 46. Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: The health assessment questionnaire, disability and pain scales. J Rheumatol 1982;9:789-793. 47. Blackmore MG, Gladman DD, Husted JA, et al. Measuring health status in psoriatic arthritis: The Health Assessment Questionnaire and its modification. J Rheumatol 1995;22:886893. 48. Husted JA, Gladman DD, Long JA, Farewell VT. A modified version of the Health Assessment Questionnaire (HAQ) for psoriatic arthritis. Clin Exp Rheumatol 1995;13:439-443. 49. Queiro R, Sarasqueta C, Torre JC, et al. Comparative analysis of psoriatic spondyloarthropathy between men and women. Rheumatol Int 2001;21:66-68. 50. Duffy CM, Watanabe Duffy KN, Gladman DD, et al. The utility of the arthritis impact measurement scales for patients with psoriatic arthritis. J Rheumatol 1992;19:1727-1732. 51. Husted J, Gladman DD, Long JA, Farewell VT. Relationship of the Arthritis Impact Measurement Scales to changes in articular

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status and functional performance in patients with psoriatic arthritis. J Rheumatol 1996;23:1932-1937. Lundberg L, Johannesson M, Silverdahl M, et al. Health-related quality of life in patients with psoriasis and atopic dermatitis measured with SF-36, DLQI and a subjective measure of disease activity. Acta Derm Venereol 2000;80:430-434. Gelfand JM, Gladman DD, Mease P, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 2005;53:573. Kavanaugh A, Antoni C, Krueger GG, et al. Infliximab improves health-related quality of life and physical function in patients with psoriatic arthritis. Ann Rheum Dis 2006;65:471-477. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264-2272. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebocontrolled trial. Arthritis Rheum 2005;52:3279-3289. Kaarela K, Lehtinen K, Luukkainen R. Work capacity of patients with inflammatory joint diseases. An eight-year follow-up study. Scand J Rheumatol 1987;16:403-406. Mau W, Listing J, Huscher D, et al. Employment across chronic inflammatory rheumatic diseases and comparison with the general population. J Rheumatol 2005;32:721-728. Feldman SR, Fleischer AB Jr, Reboussin DM, et al. The economic impact of psoriasis increases with psoriasis severity. J Am Acad Dermatol 1997;37:564-569. Javitz HS, Ward MM, Farber E, et al. The direct cost of care for psoriasis and psoriatic arthritis in the United States. J Am Acad Dermatol 2002;46:850-860.

PSORIATIC ARTHRITIS

6

Psoriasis: Etiopathogenesis Johann E. Gudjonsson and James T. Elder

Psoriasis vulgaris is a common inflammatory and hyperproliferative skin disease, affecting about 2% of Americans at an estimated cost of $1.6 billion to $3.2 billion annually.1 This disease strikes early in life, as the majority of the 150,000 new U.S. cases annually are diagnosed in individuals younger than 30 years of age, and 10,000 of these individuals are younger than 10 years.2 The cutaneous manifestations of psoriasis are unpleasant and obvious, with a negative impact on quality of life.3 Moreover, up to 40% of patients develop psoriatic arthritis (PsA), and in 5% of psoriatic patients the arthritis is severe and deforming.4 Psoriasis is characterized by complex alterations in epidermal growth and differentiation; multiple biochemical, immunologic, inflammatory, and vascular abnormalities; and a poorly understood relationship to nervous system function.5,6 It has been estimated that only about 10% of basal keratinocytes are cycling in normal skin, whereas this value rises to 100% in lesional psoriatic skin.7 Because of striking similarities to wound healing, this altered pattern of epidermal differentiation has been termed regenerative maturation8 and is an excellent marker for therapeutic response in psoriasis.9 Psoriasis was widely considered to be a primary disorder of keratinocytes until the early 1980s, when an important role for immunologic activation became apparent with the discovery that the T cell–specific immunosuppressant cyclosporine A was highly effective against psoriasis.10 In the following, we briefly review the evidence that psoriasis is genetic and review research advances in this area. We then proceed to summarize our current understanding of the immunology of psoriasis, concluding with a model of psoriasis pathogenesis that integrates the genetics and the immunology of this fascinating disease.

GENETICS That psoriasis has a genetic basis has been appreciated for nearly 100 years.11 However, as Gunnar Lomholt lamented in 1963, “That psoriasis is genetically conditioned is beyond doubt. But when the mode of inheri-

tance appears to have been almost demonstrated, it again slips out of the fetters of fixed rules!”12 Over the years, based on some very large pedigrees and population surveys, single-gene recessive, two-gene recessive, and dominant with reduced penetrance models have been suggested. In more recent years, the multifactorial model (i.e., multiple genes and environmental factors) has gained favor in the field. Analysis of the population-based studies of Lomholt12 and Hellgren13 utilizing Risch’s method of recurrence risk analysis14 demonstrated that λr − 1, the excess recurrence risk for relatives of degree r, dropped by a factor of 6 to 7 as r increased from 1 to 2, as opposed to the factor of 2 predicted for monogenic disorders. Thus, involvement of more than two genes is implicated.15 The multiplicity of candidate loci identified by genome scans in the past decade16-23 further supports the concept that psoriasis is polygenic. Twin studies have consistently found less than perfect concordance for psoriasis in identical twins, which was 73% in the United States, 60% in Denmark, and 35% in Australia.24-26 This variability suggests a role for environmental or stochastic factors, or both. Because the Tcell receptor and immunoglobulin system are generated by DNA recombination during development and are then selected by the individual’s major histocompatibility complex (MHC), there are random effects of repertoire selection within the individual that are not germline but also are not environmental. However, one would not expect these recombination events to vary in a geographic way. Given the apparent latitudinal gradient in monozygotic concordance and the clear therapeutic benefits of ultraviolet (UV) light in psoriasis, it has been speculated that UV light exposure might be a major environmental factor interacting with genetic factors in psoriasis.27 Another recognized environmental factor is streptococcal throat infections.28 The prevalence of Streptococcus pyogenes throat infections peaks at age 20 at approximately 25%, and the age-specific prevalence of infection closely parallels that of psoriasis, particularly the guttate subtype.29,30 Interestingly, twin studies have indicated that many of the clinical features observed in psoriasis are also

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determined by genetic factors.18,19 Age at onset is believed to be one such clinical variable reflective of genetic heterogeneity. Henseler and Christophers30 have defined a subset of “type I” psoriasis, characterized by early age at onset (younger than 40 years) and the presence of human leukocyte antigen (HLA) associations. This subset, which is commonly referred to as early-onset psoriasis, has a much stronger tendency for familial aggregation.27 Despite multiple genome-wide linkage studies, only one locus, PSORS1, has been consistently identified.31 However, identification of the PSORS1 gene has been hampered by the existence of extensive linkage disequilibrium in the class I region of the MHC. Through a combination of genomic resequencing and ancestral recombinant haplotype analysis, it was shown that HLA-Cw6 is the disease allele at the PSORS1 locus.32 Despite the clear importance of HLA-Cw6 in the pathogenesis of psoriasis, only about 10% of HLACw6 carriers develop guttate or chronic plaque psoriasis, and the gene-specific recurrence risk in siblings (λs) is estimated as 1.6 for PSORS133 as opposed to an overall λs of 5 to 10.27 This implies that PSORS1 accounts for less than 50% of the familial clustering observed in psoriasis, and it is highly likely that additional, non-MHC genes are involved as well. Despite identification of at least 18 susceptibility loci outside the MHC region,34 many of these loci have not yet been replicated in independent studies. Among these, the PSORS2 (17q24-q25), PSORS5 (3q21), and PSORS9 (4q28-31) loci show the strongest evidence for reproducibility. To date, four independent studies17,20,35,36 have provided confirmatory evidence (P < .01) in support of the original report of linkage to PSORS2,37 and another study reached P = .05.38 Although it has been reported that genetic variations influencing the expression of the SLC9A341, NAT9 or RAPTOR gene, or both, may account for the PSORS2 locus,39 others have been unable to confirm these findings.40,41 Reports of two large families linked to this locus35,37 underscore the possibility that more than one susceptibility gene may reside at PSORS2—one carrying a common disease allele with low penetrance and the other carrying one or more rare alleles with high penetrance. Another region of recent replication is PSORS5.42,43 In this case, the replication is based on association, rather than linkage. The implicated gene, SLC12A8, shares protein homology with a large family of cation-chloride–coupled transporters of unknown function. However, this gene is not detectably expressed in normal skin, nor is it overexpressed in psoriasis.42 Moreover, no disease-associated coding variations in the gene have yet been identified.40,42 PSORS9 was originally identified in a Chinese Han population.44 However, it had also been found at a less

significant p value (P < .08) in each of four other genome-wide linkage scans. When a meta-analysis of these studies was performed, only PSORS1 and PSORS9 emerged as significant.45 Other, less well replicated areas of biologic interest include PSORS4 (1q21.3), located in the epidermal differentiation complex, and PSORS8 (16q12-q13), which overlaps with a known susceptibility gene for Crohn’s disease (CARD15) and has been implicated in PsA. Readers interested in additional details on psoriasis genetics are referred to excellent reviews.31,46,47

IMMUNOLOGY The discovery that HLA-Cw6 is a major disease allele in psoriasis32 further strengthens an impressive body of evidence supporting the immunopathogenesis of this disease. In the following, we consider the multiple cellular participants in the pathogenesis of psoriasis, followed by a description of the cytokine network and a summarization of the evidence that psoriasis is an autoimmune disease.

Lymphoid Cells T Cells

A direct role for T cells was suggested in 1983,48 and it was first reported in 1984 that the eruption of psoriatic skin lesions coincided with epidermal influx and activation of T cells.49 Subsequent research demonstrated that resolution of psoriatic lesions during phototherapy was preceded by depletion of T cells, particularly from the epidermis.50 In 1986, cyclosporine A was confirmed in controlled trials to be highly effective in psoriasis,51,52 and this effect was demonstrated to be primarily through blockade of T cells rather than keratinocytes.53 Later studies using other T-cell–selective agents showed similar efficacy54-56 and provided the first direct evidence that T cells can induce reactive hyperplasia in epidermal keratinocytes as depletion of T cells from skin lesions induced clinical and histopathologic remission of psoriasis.57 The key role of T cells in psoriasis was conclusively demonstrated in 1996 when psoriatic lesions were induced by injecting stimulated autologous T cells into uninvolved psoriatic skin transplanted onto severe combined immunodeficiency (SCID) mice.58 Likewise, psoriasis has been triggered or cured by bone marrow transplantation, depending upon whether the donor or the host was psoriatic.59,60 Available data indicate, furthermore, that psoriasis is an antigen-driven disease rather than mediated by superantigens, as clonal populations of both CD4+ and CD8+ T cells have consistently been identified in psoriatic lesions.61-64 Thus, a substantial body of evidence has been generated during the past 20 years in support of the concept that psoriasis is

Natural Killer Cells Natural killer (NK) cells are major producers of interferon γ (IFN-γ) and serve as a bridge between innate and acquired immunity. NK and natural killer–T (NKT) cells are present in psoriasis lesions as shown by staining with NK surface markers,67,68 but further work is needed to confirm their precise identities and role in the pathogenesis of psoriasis. HLA-C has been functionally implicated in the regulation of killer immunoglobulin-like receptors (KIRs), which can either inhibit or stimulate NK cells. KIR genes have been associated with psoriasis69,70 and with PsA.71,72 Inhibitory KIR genes interact with a dimorphic allotype (Asn80/Lys80) present on HLA-C molecules to negatively regulate NK cell activation.73 The HLA ligands for the inhibitory receptor KIR2DL1 carry Lys80 at HLA-C, whereas the HLA ligands for another inhibitory receptor, KIR2DL2/3, carry Asn80 at HLAC. HLA-C is a group 2 ligand, recognizing KIR2DL1 and expressing Lys80. However, a number of other HLA-C alleles also belong to group 2, including HLACw2, 4, 5, 15, and 17, among others. Thus, it is not straightforward to explain effects of HLA-Cw6 in psoriasis on the basis of KIR recognition alone. Indeed, in one study, although HLA-Cw6 conferred risk for PsA, it was actually found to have a protective effect when its cognate inhibitory receptor, KIR2DL1, was present.71 Carrington and colleagues proposed a model predicting that susceptibility to PsA is determined by the overall balance of activating and inhibitory composite genotypes.74

Regulatory T Cells Relatively little information exists about the role of regulatory T cells (T-reg cells) in psoriasis. A study of the CD4+ CD25+ T-reg subset in psoriasis demonstrated impaired inhibitory function and failure to suppress effector T-cell proliferation.75 As dysregulation of T-regs can lead to abnormal or exaggerated responses against self-antigens, these findings provide additional evidence in support of an autoimmune etiology of the disease. This can also explain why psoriasis can worsen dramatically in human immunodeficiency virus (HIV)infected individuals with relatively few circulating CD4+ T cells.76 It has been shown that CD4+CD25+ T-regs restrict memory CD8+ T-cell responses as depletion of this regulatory subset is associated with at least 10-fold expansion77 and activity78 of the CD8+ T-cell population. Interestingly, HIV-associated psoriasis is strongly

associated with HLA-Cw6.79 Thus, the exacerbation observed in HIV-positive psoriasis patients might, at least in part, be due to depletion or dysregulation of Tregs and subsequent enhancement in the activity of CD8+ T cells. Predictably, if CD4+ T cells can both stimulate and restrain the CD8+ T-cell responses, a near depletion of the CD4+ T-cell population, as happens in full-blown acquired immunodeficiency syndrome (AIDS), should be associated with remission of psoriasis.80,81

Immunology

mediated by activated antigen-specific T cells,65 with a T helper 1 (Th1)-dominated cytokine profile.66 Consistent with this, there is virtually no evidence for B-cell involvement or antibody-mediated processes in psoriasis.

Myeloid Cells Besides infiltration of T cells, psoriatic lesions are characterized by infiltration of various subtypes of leukocytes, including neutrophils, which are quite variably expressed in psoriasis lesions from different patients. Dendritic cells form another major class of leukocytes that is found in increased abundance in psoriatic skin lesions.6 Various subsets of dendritic cells have been defined, and many of these are found within psoriatic lesions.82 These cells are able to take up not only extracellular antigens for presentation to T cells but also intracellular antigens from adjacent cell types, in a process called cross-presentation.83 Langerhans cells, which are considered as one type of immature dendritic cells (iDC), are resident in normal epidermis but their number is usually decreased in psoriatic lesions.82 Although this subset has a well-defined role in other skin diseases such as contact dermatitis,84 its role in psoriasis is still unclear. Dermal dendritic cells, identified initially by strong expression of MHC class II or factor XIIIa, can be considered another type of iDC that is similar to interstitial-myeloid iDCs found in other tissues.85 Psoriasis lesions show a marked increase of these cells.82 Furthermore, a very similar, if not the same, dendritic cell subset, termed inflammatory dendritic epidermal cells, is also increased in the epidermis of active lesions.86 These cells can be further stimulated to become mature dendritic cells (mDCs) that have potent immunostimulatory capacity for T lymphocytes. Another type of dendritic cell termed plasmacytoid dendritic cell (pDC) is greatly increased in psoriatic skin.82 Although pDCs are a minor dendritic cell subset in skin lesions, they have the ability, if activated, to produce large amounts of interferon α (IFN-α).87 These cells have been shown to infiltrate the skin of psoriatic patients and become activated to produce IFN-α.88 Interestingly, inhibition of pDCs prevented the T-cell–dependent development of psoriasis in a xenograft mouse model.88 Although pDCs have been thought to be poor presenters of antigens to T cells, they regulate inflammation and link innate with adaptive immunity.87 The type 1 interferons, including IFNα, affect T-cell function by inducing early activation,

39

PSORIASIS: ETIOPATHOGENESIS

long-term T-cell survival, Th1 differentiation, and production of the type 2 interferon, IFN-γ.87 Furthermore, IFN-α can upregulate both class I and class II MHC molecules on the surface of dendritic cells and can induce efficient uptake and cross-presentation of antigens.89 Finally, macrophages are known to be scattered just under the basement membrane of psoriatic lesions,90 where they may be involved in generating fenestrations in the epidermal basement membrane.91

mation by promoting the development of a separate CD4+ T-cell subset characterized by IL-17 production.109 These cytokines, along with other chemokines and growth factors such as transforming growth factor α,110 vascular endothelial growth factor (VEGF),94 and amphiregulin,111 create a complex network of positive and negative feedback cycles between the main cellular players—the T cells, keratinocytes, and dendritic cells—with resulting formation and maintenance of psoriatic lesions (Fig. 6-1).

Keratinocytes, Fibroblasts, and Endothelial Cells

Extracellular Matrix Environment

One of the main cellular players in the immunologic network that occurs in psoriasis and is surprisingly often ignored is the keratinocyte itself. Besides producing a multiplicity of growth factors, some of which may have some immune functions, keratinocytes are a major contributor to epidermal cytokine production.92 Many of these cytokines are produced by keratinocytes either constitutively or upon induction by various stimuli. Such production has multiple consequences for the migration of inflammatory cells, modification of the inflammatory and cytokine network, and keratinocyte proliferation and differentiation processes.92 Considerable evidence supports the concept that lesional psoriatic epidermis is engaged in an alternative pathway of keratinocyte differentiation (regenerative maturation), which is activated in wound healing8 and in response to immunologic stimulation in psoriasis.93 Other cell types, such as endothelial cells and fibroblasts, are also likely to participate in the pathogenesis of psoriasis. Endothelial cells are activated in psoriasis and actively participate in controlling the flux of leukocytes into psoriatic tissue.94-96 Fibroblasts support keratinocyte proliferation in a paracrine manner,97 a process that is exaggerated in psoriasis.98

Cytokine Network

40

How the local activation of T cells results in hyperproliferation of keratinocytes is incompletely understood. T-cell clones isolated from psoriatic skin lesions are able to promote keratinocyte proliferation in an IFNγ–dependent manner,99 but IFN-γ by itself has an antiproliferative effect on cultured keratinocytes.100 Other cytokines highly upregulated in psoriasis include tumor necrosis factor α,101 interleukin 6 (IL6),102 IL-8,103 IL-15,104 IL-17,105 and IL-18.106 The relative importance of IL-12 and IL-23 in psoriasis has been debated, as previous studies implicating IL-12 in psoriasis used antibodies that bound their common p40 subunit. Subsequent studies have shown that both of these cytokines are expressed and upregulated in psoriasis.107 However, IL-23 is thought to be more important in psoriasis108 as it supports chronic inflam-

The extracellular matrix environment plays a major role in wound healing and may also play a major role in psoriasis. The presence of fenestrations in the epidermal basement membrane has been suggested to result in leakage of fibronectin into the epidermal compartment.112,113 Normally, α5 integrin receptors for fibronectin are only weakly expressed in normal unwounded skin, and α2 and α3 integrins (receptors for collagen and laminin-5) are confined to the basal layer. In uninvolved psoriatic skin, α5, but not α3, integrin expression is upregulated,113 suggestive of an early role for fibronectin in psoriasis. In lesional psoriatic skin (and in healing wounds), α3β1 integrins are expressed in suprabasal keratinocytes, and forced expression of β1 integrin in the suprabasal compartment results in epidermal hyperplasia.114 Glycosaminoglycans and their proteoglycans play a wide range of roles in host defense,115 and these would also be predicted to gain access to the epidermal compartment through basement membrane fenestrations in psoriasis. Heparan sulfate binds a wide variety of cytokines and growth factors, including IFN-γ, granulocyte-macrophage colony-stimulating factor, IL-8, and amphiregulin, influencing their spatial distribution and biologic activity. Hyaluronan interacts with CD44 to promote leukocyte recruitment, and lowmolecular-weight hyaluronans have been shown to activate toll-like receptor 4, resulting in dendritic cell maturation and the release of pro-inflammatory cytokines.116 Thus, the extracellular matrix appears to be critically involved in multiple aspects of psoriasis immunology and the epidermal response.

PSORIASIS AS AN AUTOIMMUNE DISEASE: INTEGRATING GENETICS AND IMMUNOLOGY Acute guttate psoriasis is often self-limiting and may reflect an abnormal immune reaction to streptococcal throat infection. Chronic plaque psoriasis, however, behaves like most autoimmune diseases, being characterized by a chronic but fluctuating inflammatory process. Given that the major role of MHC molecules is to present antigens to T cells, the discovery of HLA-

TNFα IL-18

IL-8

TNFα

IFNγ TNFα

KCs IL-15

IL-17

CD8+ IL-23 DCs

IL-2

CD4+ Th17

IL-12

IL-2

IL-15

CD4

+

IL-12

Figure 6-1. The cytokine network in psoriasis is mainly characterized by T helper 1 (Th1) cytokines such as interferon γ (IFN-γ), interleukin 23 (IL-23), and tumor necrosis factor α (TNF-α). IL-23 is thought to induce generation of specific subset of CD4+ T cells named Th17 and is characterized by IL-17 production. This subset has been found to be pathogenic in two other prototypical Th1 diseases, experimental autoimmune encephalomyelitis and type II collagen-induced arthritis.147 Interestingly IFN-γ inhibits the generation of these cells, whereas IL-23 is stimulatory.147 Other major cytokine producers in the lesional skin are dendritic cells (DCs), CD4+ and CD8+ T cells, and keratinocytes. IFN-γ and TNF-α induce keratinocytes to produce IL-7, IL-8, IL-12, IL-15, IL-18, and TNF-α besides a multitude of other cytokines, chemokines, and growth factors, including amphiregulin (AREG) and transforming growth factor-α (TGFα). IL-18 acts on DCs synergistically with IL-12 to increase further the production of IFN-γ. IL-7 and IL-15 are important for the proliferation and homeostatic maintenance of the CD8+ T cells. IL-17 synergizes with IFN-γ to elicit further production of pro-inflammatory cytokines by the keratinocytes. These and other cytokines, chemokines, and growth factors create a network of highly complex positive and negative feedback cycles that maintain the lesional inflammatory activity.

Cw6 as the major disease allele at PSORS132 provides a major new impetus to focus research efforts on understanding precisely how the immune system is dysregulated in psoriasis. The predominance of oligoclonal CD8+ T cells in lesional epidermis64 suggest that specific antigens rather than superantigens drive the pathogenic process. HLA-Cw6 seems well suited for a role in this process, as HLA-C presents peptide antigens to CD8+ T cells and CD8+ T cells constitute at least 80% of the T cells in the epidermis of psoriatic lesions.117 HLA-Cw6 homozygotes have a 2.5-fold higher risk of psoriasis than heterozygotes without having more severe disease. This outcome would be expected if the density of HLA-Cw6 molecules on the surface of antigen-presenting cells (APCs/DCs) determined, together with the local concentration of relevant neoantigen, the probability of exceeding the threshold for breakage of tolerance leading to an “all or none” process of T-cell activation.117 Furthermore, the CD4+ T cells in stable psoriasis lesions are also likely to be oligoclonal,61-64 further supporting the concept that chronic psoriasis is an antigen-driven disease. Psoriasis (particularly its guttate variant) has long been known to be triggered by streptococcal pharyngi-

tis,28 and associations between guttate psoriasis and HLA-Cw6 are extremely strong.118 Streptococcal tonsillitis is the only infection shown to trigger psoriasis in a prospective cohort study.28 Interestingly, streptococcal skin infections such as erysipelas, impetigo, and cellulitis generally do not seem to trigger psoriasis, suggesting a critical role for the tonsils. The tonsils are a part of the mucosal lymphoid system but have several unique features. It is the only mucosal lymphoid organ that is lined by stratified squamous epithelium, it does not have any afferent lymphatics, and skin-homing T cells have been identified and isolated from the tonsils.119 Thus, this lymphoid tissue can be thought of as being on the boundary of the cutaneous and mucosal surfaces and can probably function as a generator of skin-homing cross-reactive T cells in psoriasis. It has been postulated that psoriasis is mediated by T cells that cross-react with epitopes that are common to streptococcal M proteins and the keratins that are upregulated in psoriatic lesions (keratin 16 [K16] and keratin 17 [K17]).65 M proteins are a virulence factor of β-hemolytic streptococci and over 80 serotypes are known, reflecting considerable variability in the protein sequence of these proteins.120 In contrast to

Psoriasis as an Autoimmune Disease: Integrating Genetics and Immunology

IL-20 AREG

TGFα

41

PSORIASIS: ETIOPATHOGENESIS

42

findings in rheumatic fever, no specific M protein is associated with guttate psoriasis. However, all M proteins have a conserved amino acid sequence, and this conserved region has considerable homology to keratins, particularly K16 and K17.121-123 These keratins are usually expressed only at low levels or not at all in normal skin but are upregulated during inflammation or trauma. Consistent with this hypothesis, skin-homing (cutaneous lymphocyte antigen–positive, CLA+) CD8+ T cells in HLA-Cw6–positive patients have been shown to respond to peptide sequences present in both K16 and K17 keratins and M proteins, but nonpsoriatic HLA-Cw6–positive control subjects responded only to peptides from the M protein.124 These data strongly support the concept that psoriasis is an autoimmune disease, even though there is little evidence for immune-mediated tissue damage (with the exception of joint disease in PsA). Instead, a major consequence of autoimmunity in psoriasis appears to be activation of the epidermal regenerative maturation program. With influx of these cross-reactive cells into the skin, they are able to recognize cross-reactive antigens in the binding pocket of HLA-Cw6 on the keratinocytes themselves and induce local release of cytokines with subsequent local inflammation. This response would be more characteristic for the skin lesions we know of as guttate psoriasis rather than chronic plaque psoriasis. For the lesions to evolve into classical chronic plaque lesions, generation of a self-sustaining number of autoreactive T cells probably needs to occur (Fig. 6-2). As keratins are intracellular proteins expressed by keratinocytes and as keratinocytes are not effective antigen-presenting cells for naïve or even resting memory T cells,125 this model necessitates that the putative autoantigens derived from K16 and K17 must be taken up by dendritic cells in order to trigger T-cell responses. It has been recognized for many years that psoriatic lesions are characterized by a large increase in the number and activation levels of dendritic cells.126 Dendritic cells have been shown to “sample” intracellular proteins from adjacent living cells in a process known as cross-presentation.83 Dendritic cells are particularly efficient in their ability to cross-present antigens and are the only cells that can cross-present antigens to CD8+ T cells.127 Because this cross-priming event is dependent upon support of activated CD4+ T cells,128 the model posits that presentation of self-peptides to activated CD4 T cells in the context of HLA class II is also important for the functional maturation of cross-presenting dendritic cells. Indeed, epitopes of K17 predicted to bind to HLA-DRB1*07 (which is often found in cis to HLA-Cw6 on extended MHC haplotypes) were found to stimulate proliferation and IFN-γ production in T cells from psoriatic patients but not from control subjects.129 CD4+ T-cell support is also necessary for maintaining CD8+ effector T-cell function.130

Once activated, the CD8+ T cells induce further maturation and Th1 polarization of the dendritic cell population.131 Thus, a self-sustained cycle continuously generating new autoreactive T cells is established (Fig. 6-3). These keratin-reactive CD8+ T cells would then directly recognize keratin peptides on the surface of keratinocytes in the context of HLA-Cw6. Consistent with this model, at least 80% of epidermal T cells in psoriatic lesions are CD8+ and most of these are in contact with keratinocytes. In contrast, CD4+ T cells are found in contact with dendritic cells.65 Although the classical outcome of such an interaction in the context of viral infection would be cytolysis of virus-infected keratinocytes by cytotoxic T cells, frank cytolysis is not a prominent feature of the psoriatic epidermal response. Nickoloff and colleagues have suggested that the psoriatic keratinocyte is resistant to apoptosis because of precocious differentiation in the context of the regenerative maturation program.132 Alternatively, it is not clear whether epidermal CD8+ T cells possess the full complement of cytotoxic effectors. Thus, lesional psoriatic skin manifested less perforin and granzyme B than lesional atopic epidermis,133 although levels of these cytotoxic effectors were higher in psoriatic than in normal epidermis.133,134 Krueger and colleagues have proposed that epidermal hyperplasia may be triggered by sublethal injury of keratinocytes by αEβ7-positive CD8+ T cells that recognize E-cadherin.135 Whatever the mechanism, interaction of CD8+ T cells and keratinocytes would lead to production of growth factors, chemokines, and cytokines by keratinocytes and dendritic cells, promoting keratinocyte proliferation, angiogenesis, and further chemotaxis of inflammatory and immune cells into the epidermis. It is interesting that guttate psoriasis is a self-limited process and only one third to one half of these patients later develop chronic plaque psoriasis.136 This indicates that there are potent mechanisms to prevent generation of autoreactive T cells. It has been shown that the generation of autoreactive T cells requires persistently high expression of the target antigen in order to overcome the network of regulatory events that normally lead to cessation of immune responses when the pathogen has been cleared.137,138 Dysfunction of T-reg cells, as mentioned earlier, would significantly lower that threshold. Clearly, K16 and K17 fulfill this requirement, as they are strongly overexpressed in psoriatic lesions as well as in healing wounds8,139-141 but not in normal skin, thereby meeting the definition of neoantigens. K16 and K17 have long been recognized as two components of the regenerative maturation response, which is activated in wound healing140 and in psoriasis.142 However, these keratins need not be the only neoantigens relevant to psoriasis. Interestingly, many of the genes undergoing upregulation in regen-

Psoriasis as an Autoimmune Disease: Integrating Genetics and Immunology

Figure 6-2. Normal dermis and epidermis contain resting dendritic antigen-presenting cells (dendritic cells [DCs]) as well as resting memory (RM) T cells in surveillance mode. In the context of streptococcal pharyngitis, β-hemolytic streptococci carrying one of many different M proteins enter or are taken up by DCs, where streptococcal peptides are presented to naïve T cells in the context of HLA-Cw6. Due to the unique properties of the tonsils, skin-homing CD4 and CD8 memory T cells are generated. Components of the regenerative maturation (RM) program of epidermal differentiation, such as keratins K16 and K17 and other neoantigens, designated “X,” are induced by local trauma or stress (Koebner phenomenon). Homologies between streptococcal M proteins and these RM-related neoantigens then lead to reactivation of these strep-reactive T cells in the skin. Most dermal T cells are CD4+ and are found in contact with dermal DCs, whereas most epidermal T cells are CD8+ and are found in contact with keratinocytes (KCs). Interaction of dermal CD4 cells with resting dermal DCs results in “licensing” and activation of the DCs to activate T cells against self-antigens presented in the context of both HLA class I (HLA-Cw6) and class II (often but not always HLA-DR7). Epidermal CD8 cells may be further stimulated by activated upper dermal and epidermal DCs but primarily recognize HLA-Cw6 expressed by KCs. Rather than cytolysis (the classical outcome of this interaction), this recognition sustains the RM program, resulting in epidermal hyperplasia, chemokine production, and sustained production of neoantigens. APC, antigen-presenting cell; CSA, cyclosporin A; HLA, human leukocyte antigen; IFN, interferon; IL-12, interleukin 12; K16, keratin 16; PMN, polymorphonuclear neutrophil; TCR, T-cell receptor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

erative maturation of the skin are located in the epidermal differentiation complex (PSORS4, 1q21.3), where linkage and disease association with psoriasis have been reported.19,143-145 Many of these genes are among the most highly overexpressed genes in psoriasis, as assessed by global gene expression analysis.146 Perhaps peptides derived from proteins other than K16 and K17 will prove to interact with HLA alleles other than HLA-C, thereby providing an explanation for the

approximately one third of white psoriatics and two thirds of Asian psoriatics who do not carry HLA-Cw6. This model integrates the genetic finding of direct involvement of HLA-Cw6 in psoriasis32 with immunologic evidence for increased reactivity to K17 peptides in Cw6-positive psoriatic patients. However, it is important to keep in mind that this model envisions the interaction of HLA-Cw6 with keratin peptides as one way to trigger a complex and multifaceted

43

PSORIASIS: ETIOPATHOGENESIS

GUTTATE PSORIASIS

CHRONIC PLAQUE PSORIASIS Auto-reactive CD4+ Auto-reactive CD8+

Tonsils

Lymph nodes

Skin

Strep CD4+ Strep CD8+ Self-limited

mDC carrying neoantigens Sustained

Figure 6-3. Schematic presentation of the processes thought to be involved in the generation of guttate psoriasis and chronic plaque psoriasis. In guttate psoriasis or exacerbation of chronic plaque psoriasis after streptococcal throat infection, it is envisaged that streptococcus-specific T cells migrate from the tonsils into the skin, where the specific T cells recognize cross-reactive antigens derived from keratinocytes with a resulting eruption of guttate psoriasis. If effective crosspresentation does not occur, the disease process is self-limited, whereas effective cross-presentation results in generation and recruitment of autoreactive T cells that recirculate between lymph nodes and the skin lesions. mDC, mature dendritic cell.

response, which could have a multiplicity of additional genetic and environmental inputs. Whether this model can eventually account for most or all psoriasis, rather than just its guttate variant and its evolution into chronic plaque disease, remains to be determined.

role of HLA-Cw6 as one of the main pathogenic genes in psoriasis, published data indicate that CD8+ T cells may play a major role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8+ T cells is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. Although this response is likely to be initially based on responses against cross-reactive self-peptides presented in the context of HLA-Cw6, the reaction may be sustained by breakage of tolerance, a phenomenon that is promoted by strong induction of a target antigen that is not usually well or widely expressed (neoantigen). Such neoantigens might be expressed during cutaneous wound healing or inflammatory response. In contrast, the dermal T-cell infiltrate of psoriatic lesions is largely composed of CD4+ cells. It is likely that CD4+ T-cells are essential for initiating and maintaining the pathogenic process, particularly the newly defined Th17 subset, but that cross-primed autoreactive CD8+ T-cells are the main effector cells responding to neoantigens presented by HLA-Cw6 on the surface of keratinocytes. Furthermore, the CD8+T-cells may be involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4+ and CD8+ T-cells, keratinocytes, and dendritic cells. These interactions create a complex cytokine network with further involvement of other immune cell subsets and activation of a wound healing program in keratinocytes, all of which are probably important in the maintenance, modification, and resolution of psoriasis.

CONCLUSIONS SUMMARY Psoriasis is a common chronic inflammatory and hyperproliferative skin disease characterized by complex and striking alterations in epidermal growth and differentiation. Up to 40% of patients also have an associated arthritis. The disease has a strong but complex genetic background with concordance up to 70% in monozygotic twins. Consistent with the newly defined

Psoriasis is a highly complex genetic and immunologic disease. Although several aspects of the pathogenic mechanisms are still incompletely understood, the genetic unraveling of the disease, as has already begun, will lead to far greater understanding of the initiation, maintenance, and resolution of the disease with eventual development of more effective therapeutic measures.

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chronic myelogenous leukemia: Case report and review of the literature. Am J Hematol 2002;71:41-44. Gardembas-Pain M, Ifrah N, Foussard C, et al. Psoriasis after allogeneic bone marrow transplantation [letter]. Arch Dermatol 1990;126:1523. Chang JC, Smith LR, Froning KJ, et al. CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes. Proc Natl Acad Sci USA 1994;91: 9282-9286. Prinz JC, Vollmer S, Boehncke WH, et al. Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris. Eur J Immunol 1999;29:3360-3368. Vollmer S, Menssen A, Prinz JC. Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: Evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. J Invest Dermatol 2001;117:1296-1301. Lin WJ, Norris DA, Achziger M, et al. Oligoclonal expansion of intraepidermal T cells in psoriasis skin lesions. J Invest Dermatol 2001;117:1546-1553. Valdimarsson H, Baker BS, Jonsdottir I, et al. Psoriasis: A Tcell–mediated autoimmune disease induced by streptococcal superantigens? Immunol Today 1995;16:145-149. Schlaak J, Buslau M, Jochum W, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994;102:145-149. Ferenczi K, Burack L, Pope M, et al. CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: Blood and skin comparisons by flow cytometry. J Autoimmun 2000;14:63-78. Bonish B, Jullien D, Dutronc Y, et al. Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells. J Immunol 2000;165:4076-4085. Suzuki Y, Hamamoto Y, Ogasawara Y, et al. Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris. J Invest Dermatol 2004;122:1133-1136. Holm SJ, Sakuraba K, Mallbris L, et al. Distinct HLA-C/KIR genotype profile associates with guttate psoriasis. J Invest Dermatol 2005;125:721-730. Martin MP, Nelson G, Lee JH, et al. Cutting edge: Susceptibility to psoriatic arthritis: Influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol 2002;169:2818-2822. Williams F, Meenagh A, Sleator C, et al. Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis. Hum Immunol 2005;66: 836-841. Long EO, Rajagopalan S. HLA class I recognition by killer cell Iglike receptors. Semin Immunol 2000;12:101-108. Nelson GW, Martin MP, Gladman D, et al. Cutting edge: Heterozygote advantage in autoimmune disease: Hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 2004;173:4273-4276. Sugiyama H, Gyulai R, Toichi E, et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: Mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005;174:164-173. Myskowski PL, Ahkami R. Dermatologic complications of HIV infection. Med Clin North Am 1996;80:1415-1435. Kursar M, Bonhagen K, Fensterle J, et al. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J Exp Med 2002;196:1585-1592. Ribeiro RM, Mohri H, Ho DD, Perelson AS. In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted? Proc Natl Acad Sci USA 2002;99:15572-15577. Mallon E, Young D, Bunce M, et al. HLA-Cw*0602 and HIV-associated psoriasis. Br J Dermatol 1998;139:527-533. Obuch ML, Maurer TA, Becker B, Berger TG. Psoriasis and human immunodeficiency virus infection. J Am Acad Dermatol 1992;27:667-673. Colebunders R, Blot K, Mertens V, Dockx P. Psoriasis regression in terminal AIDS. Lancet 1992;339:1110.

82. Wollenberg A, Wagner M, Gunther S, et al. Plasmacytoid dendritic cells: A new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 2002;119:1096-1102. 83. Heath WR, Belz GT, Behrens GM, et al. Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev 2004;199:9-26. 84. Kripke ML, Munn CG, Jeevan A, et al. Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization. J Immunol 1990;145:2833-2838. 85. Nestle FO, Zheng XG, Thompson CB, et al. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J Immunol 1993;151:6535-6545. 86. Wollenberg A, Kraft S, Hanau D, Bieber T. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol 1996;106:446-453. 87. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol 2004;5:1219-1226. 88. Nestle FO, Conrad C, Tun-Kyi A, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005;202:135-143. 89. Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol 2003;4:1009-1015. 90. Boehncke WH, Wortmann S, Kaufmann R, et al. A subset of macrophages located along the basement membrane (“lining cells”) is a characteristic histopathological feature of psoriasis. Am J Dermatopathol 1995;17:139-144. 91. Pinkus H, Nehregan AH. The primary histologic lesion of seborrheic dermatitis and psoriasis. J Invest Dermatol 1966;46:109-116. 92. Grone A. Keratinocytes and cytokines. Vet Immunol Immunopathol 2002;88:1-12. 93. Krueger JG, Wolfe JT, Nabeya RT, et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. J Exp Med 1995;182:2057-2068. 94. Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 1994; 180:1141-1146. 95. Xia YP, Li B, Hylton D, et al. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 2003;102:161-168. 96. Creamer D, Allen MH, Sousa A, et al. Localization of endothelial proliferation and microvascular expansion in active plaque psoriasis. Br J Dermatol 1997;136:859-865. 97. Szabowski A, Maas-Szabowski N, Andrecht S, et al. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 2000;103:745-755. 98. Saiag P, Coulomb B, Lebreton C, et al. Psoriatic fibroblasts induce hyperproliferation of normal keratinocytes in a skin equivalent model in vitro. Science 1985;230:669-672. 99. Prinz JC, Gross B, Vollmer S, et al. T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol 1994;24:593-598. 100. Nickoloff BJ, Mitra RS, Elder JT, et al. Decreased growth inhibition by recombinant gamma interferon is associated with increased transforming growth factor-alpha production in keratinocytes cultured from psoriatic lesions. Br J Dermatol 1989;121:161-174. 101. Ettehadi P, Greaves MW, Wallach D, et al. Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96:146-151. 102. Grossman RM, Krueger J, Yourish D, et al. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA 1989;86:6367-6371. 103. Degiulio R, Montemartini C, Mazzone A, et al. Increased levels of leukotriene B4 and interleukin-8 in psoriatic skin. Ann NY Acad Sci 1993;685:614-617. 104. Ruckert R, Lindner G, Bulfone-Paus S, Paus R. High-dose proinflammatory cytokines induce apoptosis of hair bulb keratinocytes in vivo. Br J Dermatol 2000;143:1036-1039. 105. Teunissen MB, Koomen CW, de Waal Malefyt R, et al. Interleukin-17 and interferon-gamma synergize in the

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enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 1998;111:645-649. Ohta Y, Hamada Y, Katsuoka K. Expression of IL-18 in psoriasis. Arch Dermatol Res 2001;293:334-342. Piskin G, Tursen U, Sylva-Steenland RM, et al. Clinical improvement in chronic plaque-type psoriasis lesions after narrowband UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducers—IL-12, IL-18 and IL-23. Exp Dermatol 2004;13:764-772. Bowcock AM, Krueger JG. Getting under the skin: The immunogenetics of psoriasis. Nat Rev Immunol 2005;5:699-711. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003;198:1951-1957. Elder JT, Fisher GJ, Lindquist PB, et al. Overexpression of transforming growth factor alpha in psoriatic epidermis. Science 1989;243:811-814. Piepkorn M. Overexpression of amphiregulin, a major autocrine growth factor for cultured human keratinocytes, in hyperproliferative skin diseases. Am J Dermatopathol 1996;18:165-171. Fyrand O. Studies on fibronectin in the skin. II. Indirect immunofluorescence studies in psoriasis vulgaris. Arch Dermatol Res 1979;266:33-41. Bata-Csorgo Z, Cooper KD, Ting KM, et al. Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis. J Clin Invest 1998;101:1509-1518. Carroll JM, Romero MR, Watt FM. Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis. Cell 1995;83:957-968. Taylor KR, Gallo RL. Glycosaminoglycans and their proteoglycans: Host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 2006;20:9-22. Termeer C, Benedix F, Sleeman J, et al. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 2002;195:99-111. Gudjonsson JE, Johnston A, Sigmundsdottir H, Valdimarsson H. Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol 2004;135:1-8. Mallon E, Bunce M, Savoie H, et al. HLA-C and guttate psoriasis. Br J Dermatol 2000;143:1177-1182. Perry M, Whyte A. Immunology of the tonsils. Immunol Today 1998;19:414-421. Fischetti VA. Streptococcal M protein. Sci Am 1991;264(6):58-65. Sigmundsdottir H, Sigurgeirsson B, Troye-Blomberg M, et al. Circulating T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human epidermal keratins. Scand J Immunol 1997;45:688-697. Gudmundsdottir AS, Sigmundsdottir H, Sigurgeirsson B, et al. Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis? Clin Exp Immunol 1999;117: 580-586. McFadden J, Valdimarsson H, Fry L. Cross-reactivity between streptococcal M surface antigen and human skin. Br J Dermatol 1991;125:443-447. Johnston A, Gudjonsson JE, Sigmundsdottir H, et al. Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8+ T cells. Clin Exp Immunol 2004;138:83-93. Nickoloff BJ, Mitra RS, Green J, et al. Accessory cell function of keratinocytes for superantigens. Dependence on lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. J Immunol 1993;150:2148-2159. Baadsgaard O, Gupta AK, Taylor RS, et al. Psoriatic epidermal cells demonstrate increased numbers and function of nonLangerhans antigen-presenting cells. J Invest Dermatol 1989;92:190-195.

47

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7

Pathogenesis of Psoriatic Arthritis Christopher T. Ritchlin and Oliver FitzGerald

Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis (Ps). Such a simple definition fails to capture the complexity and spectrum of the skin and joint manifestations characteristic of this disorder. Patients present with a diversity of manifestations that differ markedly from the clinical features that are characteristic of rheumatoid arthritis (RA). These manifestations include asymmetric joint involvement, axial disease, enthesitis, dactylitis, and nail disease. Moreover, mounting evidence supports the concept that novel disease mechanisms, distinct from those identified in RA, underlie susceptibility and progression in PsA. Until recently, these mechanisms remained unknown, but research performed over the past several years has provided new insights and perspectives on disease pathogenesis. In this chapter, the genetic and environmental factors that are associated with PsA are discussed and a comprehensive review of the alterations that take place in Ps skin, synovium, bone, cartilage, and entheses is presented. In addition, seminal observations derived from animal models are highlighted and incorporated into a working disease model of Ps skin and joint disease.

GENETIC FACTORS

48

As reviewed in detail in Chapters 1 and 9, several genetic loci have been implicated in the predisposition to Ps and PsA, with the strongest effect residing within the major histocompatibility complex (MHC). Earlier association studies in Ps focused attention on human leukocyte antigen HLA-Cw6, in addition to HLA-B13 and B17 (B57) and the class II allele, HLA-DR7. These associations reflect the strong linkage disequilibrium between HLA-Cw6 and HLA-B57 and HLA-Cw6 and HLA-B13, which extends into the MHC class II region.1 In individuals with PsA, the association with HLA-Cw6 is slightly weaker than in Ps. A smaller proportion of cases have an association with HLA-B27, chiefly in patients with predominant spinal disease. Other reports noted an association with HLA-B38 and B39, as well as with other alleles in linkage disequilibrium.2 These findings have been interpreted to suggest that the MHC association with Ps lies close to the HLA-C region and the association with the articular

manifestations more likely lies in or close to the HLAB region. However, it should be emphasized that the great majority of these studies have been made in cases or families ascertained by the presence of Ps. Thus, to dissect out disease associations specific to arthritis, two separate cohorts of Ps patients (with and without arthritis) must be characterized and genotyped. Moreover, a third prevalent and purely musculoskeletal phenotype of arthritis, enthesitis, and spondylitis without detectable Ps, termed undifferentiated spondyloarthropathy, has not received much attention. Despite considerable effort being made to identify the genetic basis for susceptibility to Ps, the basis of the development of the PsA phenotype remains largely unknown. Increasing evidence suggests that an additional or distinct genetic contribution outside the MHC loci is responsible for the development of PsA, and considerable work is required to understand this contribution further.

ENVIRONMENTAL FACTORS As genetic analyses have identified potential key target chromosomal regions, intriguing but incomplete data implicate a role for trauma, stress, and infection in the etiologic pathway of Ps and PsA. The Koebner phenomenon, described as Ps lesions arising at sites of trauma, has been reported in 24% to 52% of Ps patients.3,4 The development of PsA following trauma to a joint, with the suggested name of the deep Koebner phenomenon, has also been reported in the Toronto longitudinal observational cohort where 50 of 203 (24.6%) patients reported a traumatic event prior to the diagnosis of PsA.5 In another study, 8% of patients with PsA compared with less than 2% of RA patients reported some form of trauma in the 3 months before arthritis was noted.6 Subclinical trauma may also contribute to distal interphalangeal arthritis, dactylitis, and enthesitis, although this relationship has not been formally studied.7 It is also important to note that a history of trauma has been reported in only a minority of PsA patients. In addition to trauma, a variety of events have been associated with the onset of PsA, including recent sur-

CELLULAR IMMUNOPATHOLOGY The key pathologic events in PsA take place in the skin, synovium, and entheseal tissues as well as in the cartilage and bone. Although the skin and synovial pathobiology has been well described, only a few studies have focused on entheseal pathology. In relation to cartilage and bone, Fassbender noted that inflammation in psoriatic synovium was similar to that observed in the rheumatoid joint.16 In the phalanges outside the capsule, however, he described focal loss of proteoglycan that presumably is the result of enzymatic events related to adjacent skin disease. More recent studies (reviewed later) demonstrated the presence of osteo-

clasts at the cartilage-pannus junction and high numbers of circulating osteoclast precursors in the circulation of PsA patients. Detailed studies similar to those performed in RA on the synovium-cartilage-bone interface could well yield valuable information regarding joint destruction in PsA.

Psoriatic Plaque The immunopathology of the skin is reviewed in detail in Chapter 6. Involved Ps skin is characterized by epidermal hyperplasia, mononuclear leukocytes in the papillary dermis, neutrophils in the stratum corneum, and an increase in various subsets of dendritic cells.17 Interestingly, CD8+ T cells are the T cells chiefly found in the epidermis; dermal T cells are a mixture of CD4+ and CD8+. Most T cells in skin lesions express the addressin cutaneous lymphocyte antigen (CLA), in contrast to both circulating T cells and indeed those found in the inflamed synovium in PsA.18 Finally, vascular changes are also prominent in Ps with impressive growth and dilation of superficial blood vessels. This is reflected by the expression of proangiogenic molecules such as vascular endothelial growth factor (VEGF) and angiopoietins (reviewed in Chapter 8).

Cellular Immunopathology

gery, therapeutic abortion, myocardial infarction, thrombophlebitis, and phosphoric ester poisoning.8 Documentation of a prior acute event was reported in 9% of PsA patients compared with only 1% of those with RA. A common factor in these acute events is psychological stress.7 The role of psychological distress in the initiation of psoriatic joint inflammation has not been systematically examined, but such an association may exist. A link between stress and exacerbation of Ps has been published, although once again this association is not based on strong scientific or clinical evidence.9 A pathophysiologic link between infection and both Ps and PsA has been proposed on the basis of clinical and laboratory observations. A strikingly high association between guttate Ps and preceding streptococcal pharyngitis and tonsillitis exists in children.10 The association between streptococcal superantigens and Ps was demonstrated by the isolation of streptococcal pyogenic exotoxin serotype C–producing (SPEC- or scarlet fever type C–producing) group A streptococcus from the oropharynx of patients with acute guttate Ps and the presence of increased numbers of Vβ2expressing T cells in the lesional skin.11 In addition, noninvolved skin from psoriatic patients grafted onto immunodeficient mice can be induced to develop into psoriatic lesions by repeated injection with autologous superantigen (SAg)-treated immunocytes.12 The association between gram-positive infection and PsA was suggested by high levels of circulating antibodies to microbial peptidoglycans and elevated levels of group A streptococcus 16S RNA in PsA peripheral blood.13,14 Both streptococcal and staphylococcal superantigens promote inflammation and upregulation of keratinocyte tumor necrosis factor (TNF) in noninvolved psoriatic skin but not in other inflammatory dermatoses.15 These data underscore the potential importance of this novel immune pathway in Ps, although additional studies are required to elucidate the role of superantigens in synovial inflammation.

Synovium A number of early studies of synovial pathology in PsA highlighted the presence of prominent and striking vascular changes.19 In the first study that compared PsA and RA synovial tissue, quantitative immunopathologic analysis confirmed these prominent vascular changes and found that vessel number was significantly increased in PsA.20 Lining layer hyperplasia was less marked in PsA and fewer macrophages were seen trafficking into the synovium and out to the lining layer. Interestingly, the number of T lymphocytes and their subsets and the number of B cells were similar to the frequency found in RA (Fig. 7-1B). Although neutrophil infiltration was not assessed, this study further examined adhesion molecule expression in the two subgroups of patients and found E-selectin expression to be considerably reduced in PsA. Although some of the preceding observations have been disputed, the prominent vascularity and lymphocytic infiltration and the lack of lining layer hyperplasia are consistent findings that have been confirmed in a number of studies.21,22 Indeed, the important role of the vasculature in PsA synovium has been further underscored by studies that demonstrated increased perivascular expression of a number of diverse proteins. These proteins include members of the S100 protein family, myeloid-related protein (MRP) 8 and MRP14, which have a number of diverse roles including neutrophil extension, chemoattraction, and the induction of adhesion molecule expression.23 In one

49

PATHOGENESIS OF PSORIATIC ARTHRITIS

50

Figure 7-1. Psoriatic arthritis synovial tissue stained for (A) tumor necrosis factor α, (B) CD4+ T cells, (C) vascular endothelial growth factor, and (D) myeloid-related protein 8/14.23 See also Color Plate.

A

B

C

D

study, MRP8, MRP14, and MRP8/MRP14 expression was increased in the sublining layer of PsA patients, particularly in perivascular regions, compared with that in RA and other spondyloarthropathy (SpA) patients, suggesting a central role of MRP proteins in transendothelial migration of leukocytes in PsA (see Fig. 7-1D).24 Using oligonucleotide microarray analysis, MRP8 /MRP14 was shown to induce a thrombogenic, inflammatory response in human microvascular endothelial cells by increasing the transcription of proinflammatory chemokines and adhesion molecules and by decreasing the expression of cell junction proteins and molecules involved in monolayer integrity. This suggests an important role for these proteins in initiating distinct inflammatory reactions in vascular endothelium.25 Other proteins prominently expressed at the vascular endothelium in PsA include the corticotropin-related hormone (CRH) receptor 126 and Flt-1–positive neutrophils (O FitzGerald, unpublished observations). CRH signaling, through the CRH receptor subtype R1α, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation.26 The role of Flt-1–positive neutrophils is not yet understood, but it is possible that they traffic preferentially into the inflamed synovial tissue. Overall, these studies provide a framework to understand better the origin of prominent blood vessels in PsA pathogenesis perhaps most elegantly demonstrated by the large numbers of tortuous and dilated blood vessels observed through an arthroscopic view of psoriatic joints.27

In a number of papers, Dominique Baeten’s group has compared the synovial immunopathologic features in patients with SpA, including PsA, with those seen in RA. Using a semiquantitative scoring system, the authors identified a number of features characteristic of the SpA group as a whole and the PsA subgroup alone.28 Increased vascularity, higher neutrophil numbers, and a higher number of infiltrating CD163+ macrophages, a marker of mature tissue macrophages, reliably distinguished SpA from RA. Interestingly, no significant differences were seen between oligoarticular and polyarticular PsA. The authors concluded that the synovitis in PsA, both oligo- and polyarticular, resembles SpA more than RA. These observations have a number of important implications. First, the synovitis in PsA shows features similar to those in other SpA patients, both ankylosing spondylitis and undifferentiated SpA. Second, the interesting additional observation of an increase in neutrophil infiltration in PsA is consistent both with the well-described neutrophil infiltration seen in Ps skin and with the observation of Flt-1–positive neutrophils in PsA synovium. It is clear that the role of the neutrophil in both Ps and PsA requires further study. Finally, the finding that the synovial immunohistologic features of oligo- and polyarticular types of PsA are not different and that they are both more like those of other SpA patients than RA patients answers an important question: is polyarticular PsA really RA in disguise but with coincidental Ps? Indeed, McGonagle and colleagues have proposed an alternative classification of PsA based on entheseal involvement. In this

Angiogenesis Prominent new vessel formation (angiogenesis) characterizes both the involved skin and the inflamed synovium in Ps and PsA. This feature is fully reviewed in Chapter 8. An interaction of key growth factors closely regulate the angiogenic process, including TNF-α, transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), angiopoietins (ANG-1, ANG2), and VEGF. Skin and synovial expression of these growth factors has been described (see Fig. 7-1C). As this expression is found at an early stage of inflammation, it may represent a primary event in PsA as opposed to a reaction or response to hypoxia. In considering any overall pathogenesis for Ps and PsA, it is critical that this feature be taken into account. One possibility is that there is a genetic predisposition to endothelial activation that results in both new vessel formation and increased cellular trafficking. A candidate genetic study or a search for polymorphisms in proangiogenic proteins or adhesion molecules would seem a reasonable approach.

Enthesis In a number of papers, Benjamin and colleagues have carefully described the anatomy of the normal enthesis.30,31 This work might usefully be extended to patients with enthesitis as there has been little published in the area. Laloux and coauthors nicely described the immunopathologic features of the enthesis in patients undergoing joint replacement surgery with SpA, including PsA, and compared with RA.32 Numbers of patients were small in this study, but there was a consistent increase in CD8+ T-cell expression at the enthesis in PsA patients as compared with RA. Ultrasound-guided biopsy of five sites of acute enthesitis in early SpA also confirmed an inflammatory response with increased vascularity and cellular, predominantly macrophage infiltration.33 These findings are consistent with the well-described association of PsA with HLA class I antigens. They are also consistent with the previously described dominance of activated and mature CD8+ T cells in PsA

synovial fluid samples as compared with RA.34 On the basis of magnetic resonance imaging studies, McGonagle and colleagues suggested that much of PsA pathophysiology is centered on the “enthesis organ,” whereas it is centered on the synovium in RA.29 It is certainly attractive to suggest that enthesis-derived antigens might trigger an immune response in the adjacent synovial tissue. To date, evidence for this hypothesis has not been found, although it is clearly an area for future study. A search for candidate antigens common to the enthesis and the skin might be informative.

CYTOKINES, METALLOPROTEINASES, AND CARTILAGE DESTRUCTION

Cytokines The imbalance of inflammatory and anti-inflammatory cytokines in the rheumatoid joint is a pivotal factor responsible for the chronic inflammatory response and subsequent joint destruction.35,36 Investigators from several laboratories have reported the presence of T helper 1 (Th1) cytokines, interleukin 2 (IL-2), and interferon-γ (IFN-γ). The pro-inflammatory cytokines TNF-α and IL-1 are also strongly expressed in rheumatoid synovium, tipping the balance toward cellular activation, synovial hyperplasia, and subsequent cartilage degradation and bone resorption. Synovial explant tissues obtained from Ps joints produce higher levels of the Th1 cytokine IL-2 and IFN-γ protein than explants similarly cultured from osteoarthritis and RA patients.37 In contrast, IL-4 and IL-5 were not identified in psoriatic explants but IL-10 was highly expressed in synovium but not skin in tissues examined from individual patients. This Th1 profile has been observed in Ps plaques.38 The cytokines IL-1β and TNF-α were also released by Ps synovial explants in high concentrations. A similar pattern of cytokine production in PsA synovium was shown using immunohistochemical techniques.22 In addition, expression of nuclear factor NF-κB (p65) was similar in the lining layer in RA and PsA but lower in psoriatic than rheumatoid sublining tissues. Notably, staining for the innate cytokines TNF and IL-15 was highest in the psoriatic synovial lining layer with lower levels of expression noted in the subsynovium. Another innate cytokine, 1L-18, was also present in Ps synovial tissue.39 TNF-α is a multifunctional cytokine that promotes joint inflammation by multiple mechanisms.40 Released predominantly by cells of the monocyte/macrophage lineage, TNF-α can induce lymphocyte and neutrophil migration into the synovium, promote release of matrixdegrading metalloproteinases, enhance the secretion of other pro-inflammatory cytokines (IL-1, IL-6, IL-8), and potentiate osteoclastic bone resorption.41 TNF-α binds to two distinct but structurally similar receptors, p55 and

Cytokines, Metalloproteinases, and Cartilage Destruction

classification, patients with predominant synovitis and Ps would be grouped with RA.29 The results in Kruithof’s paper, however, suggest that this proposed classification is not appropriate.28 Although Kruithof’s results indicate that PsA belongs to the SpA family, these data do not indicate that all peripheral joint SpA is the same. The relatively unique clinical, genetic, and radiologic features that are associated with PsA suggest an altogether different clinical entity. At the very least, the joint disease in PsA is modified by the presence of Ps to produce a form of SpA with easily distinguished clinical features.

51

PATHOGENESIS OF PSORIATIC ARTHRITIS

p75. These receptors, located on the surface of many cells, can be cleaved to circulate as soluble molecules capable of attenuating the pro-inflammatory actions of TNF-α.42-45 TNF levels are elevated in psoriatic skin, synovium, and joint fluid of patients with PsA.37,46 Several lines of evidence support the concept that TNF-α is an important cytokine in the psoriatic joint. TNF-α transgenic mice exhibit extensive bone destruction similar to that observed in some PsA patients. In a study of 129 patients with early PsA, patients with erosions were significantly more likely to have the TNF-α-308 A allele, an allele associated with high TNF production.47 As mentioned earlier, immunohistochemical studies demonstrated marked upregulation of TNF-α in the psoriatic synovial membrane (see Fig. 7-1A). Furthermore, histopathologic analysis of synovial specimens from SpA patients (four of eight with PsA) treated with the anti-TNF monoclonal antibody infliximab revealed decreased vascularity, synovial lining thickness, and mononuclear cell infiltration following therapy.48,49 In another study, a significant reduction in the quantity of infiltrating macrophages, the CD31+ vascular area, αvβ3+ neovessels/Ulex europaeus agglutinin+ vessels, VEGF and its receptor kinase insert domain receptor KDR/flk-1 (VEGF receptor 2), and stromal cell–derived factor 1 (SDF-1)+ vessels in PsA synovium was noted after 8 weeks (three infusions) of infliximab treatment.50

Metalloproteinases and Cartilage Destruction

52

Radiographs of psoriatic joints often reveal cartilage loss manifested as joint space narrowing.51 As with RA, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were identified in the lining and sublining layers of psoriatic synovial membranes.52,53 In particular, immunohistochemical studies revealed that MMP-9 localized to blood vessel walls and MMP-1, MMP-2, MMP-3, and both TIMPs 1 and 2 showed a cellular and interstitial staining pattern in the synovial lining. MMP-3 serum levels exhibited a marked and rapid decrease after successful anti-TNF therapy, raising the possibility that this molecule may serve as a biomarker. In another study, similar levels of MMP-1 and MMP-3 messenger RNA were detected in rheumatoid and psoriatic synovial tissue despite the fact that the RA patients exhibited more erosions on plain radiographs.54 Furthermore, the elevated ratio of MMPs to TIMP-1 in the synovial tissue favored cartilage degradation, although the expression of MMPs was not significantly elevated at the cartilagepannus junction compared with other sites. These reports show that MMPs are upregulated in psoriatic synovium but their precise functions remain to be

defined. On the basis of their tissue localization, it is conceivable that they participate in vascular remodeling and cartilage destruction.

BONE REMODELING IN PSORIATIC ARTHRITIS

Bone Resorption Radiographs of PsA joints can also reveal markedly altered bone remodeling in the form of tuft resorption, large eccentric erosions, and pencil-in-cup deformities along with features of new bone formation such as periostitis and bone ankylosis.55 With regard to bone resorption, psoriatic joint biopsies demonstrate large multinucleated osteoclasts in deep resorption pits at the bone-pannus junction.56 Studies of adjuvantinduced and collagen-induced arthritis in the Lewis rat indicate that osteoclast formation begins in the earliest stages of arthritis.57 Osteoclasts were found in two locations in the first stages of arthritis—at the junction of the synovial membrane and the periosteum and in vascular channels traversing the cortical bone beneath the articular cartilage. As the synovitis progresses, large numbers of osteoclast precursors (OCPs) infiltrated the inflamed synovial membrane in these rat models. Osteoclastogenesis (differentiation of monocytes into osteoclasts) is a contact-dependent process directed by osteoblasts and stromal cells in the bone marrow.58 These cells release two different signals necessary for differentiation of an OCP derived from the CD14+ monocyte population into an osteoclast. The first, macrophage colony-stimulating factor (M-CSF), and the second, receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, bind to RANK on the surface of OCP and osteoclasts.59 This ligand-receptor interaction stimulates proliferation and differentiation of OCP and activation of osteoclasts. Because permissive quantities of M-CSF are constitutively expressed in the bone microenvironment, it has been proposed that the relative expression of RANKL and its natural antagonist osteoprotegerin (OPG) ultimately controls osteoclastogenesis.60 Interestingly, RANKL is also expressed by infiltrating T cells and synovial fibroblastoid cells in the synovial lining of inflamed joints.61 In psoriatic synovial tissues, marked upregulation of RANKL protein and low expression of OPG were detected in the adjacent synovial lining (Fig. 7-2). Osteoclasts were also noted in cutting cones traversing the subchondral bone, supporting a bidirectional attack on the bone in psoriatic joints. In addition, OCPs, derived from circulating CD14+ monocytes, were markedly elevated in the peripheral blood of PsA patients compared with healthy control subjects.56 Treatment of PsA patients with anti-TNF agents

B

C

D

significantly decreased the level of circulating OCP, thus supporting a central role for TNF-α in the generation of this precursor population.

New Bone Formation The mechanisms responsible for new bone formation in the psoriatic joint are poorly understood. TGF-β and VEGF may be pivotal in this process because TGF-β is strongly expressed in synovial tissues isolated from patients with ankylosing spondylitis and synergizes with VEGF to induce bone formation in animal models.62,63 Lories and colleagues showed that bone morphogenetic proteins (BMPs) 2 and 7 are upregulated in regions of pathologic new bone formation.64 The same investigators demonstrated that the expression of phosphorylated Smad 1 and Smad 5, important molecules in the downstream BMP signaling pathway, was markedly increased in regions of new bone formation taken from the calcaneus in a patient with Achilles tendonitis and periostitis. These studies provide evidence that potential mediators of ankylosis and periostitis in the psoriatic enthesis and joint include BMP molecules and possibly VEGF and TGF-β.

ACQUIRED VERSUS INNATE IMMUNE RESPONSE IN PSORIASIS AND PSORIATIC ARTHRITIS As hyperkeratotic scales and epidermal hyperplasia are the characteristic pathologic features of Ps, for many years it was hypothesized that Ps is a primary disorder of keratinization. The focus changed in the 1980s when the T-cell hypothesis began to emerge and Ps was considered a type 1 T cell–associated disease. In PsA, a

Figure 7-2. Receptor activator of NFκB ligand (RANKL) and osteoprotegerin (OPG) expression in psoriatic arthritis (PsA) synovium. A representative synovial membrane from a PsA patient stained with antiRANKL antibody (A), anti-OPG antibody (B), secondary antibody only (C), and hematoxylin and eosin (D) are shown photographed at ×20. Of note is the intense RANKL staining of synovial lining cells and the OPG staining restricted to the endothelial cells below the synovial lining. See also Color Plate. (From Kane D, Jensen LE, Grehan S, et al. Quantitation of metalloproteinase gene expression in rheumatoid and psoriatic arthritis synovial tissue distal and proximal to the cartilagepannus junction. J Rheumatol 2004;31:1274-1280.)

CD8+ T cell–mediated mechanism of disease was proposed.65 A number of studies in both Ps and PsA have analyzed T-cell receptor (TCR) usage with a view to identifying clonal expansion.65-68 T-cell clonality has indeed been identified; however, to date, the identification of a specific antigen or superantigen that can trigger this T-cell expansion has eluded investigators. The pendulum has swung back to the keratinocyte as studies from animal models (discussed in “Animal Models of Psoriatic Arthritis”) have indicated that the primary event in the clinical expression of the Ps lesion is suppression of a key transcription factor, JunB, in the epidermis that results in overproduction of chemokines and subsequent cellular infiltration. With the success of TNF-α inhibiting strategies in both Ps and PsA, the role of the innate immune response has also come into focus. In this section, the evident interplay between the innate and acquired elements of the immune response in Ps and PsA is reviewed. It is likely that both arms are intimately involved in disease pathogenesis, and a greater understanding of their roles and interactions is required.

Acquired versus Innate Immune Response in Psoriasis and Psoriatic Arthritis

A

Acquired Immune Response T cells, B cells, and plasma cells are the key cellular elements of the acquired immune response, with antibody formation the consequence of humoral activation.

T Cells in Psoriasis The T lymphocytes observed in lesional psoriatic skin express markers for an activated and mature phenotype.69 The CD4+ and CD8+ T cells are fairly equally distributed in the dermis, and CD8+ T cells predominate

53

PATHOGENESIS OF PSORIATIC ARTHRITIS

in the epidermis. A number of studies have confirmed that these T cells produce more type 1 than type 2 cytokines, including IFN-γ.70 With the assumption that T cells are antigen driven, Chang and colleagues examined the TCR repertoire in psoriatic epidermal cells and showed preferential TCR usage of BV3 and BV13.1 in the CD8+ but not in the CD4+ T-cell population.71 Tassiulas and associates analyzed nonseparated T-cell infiltrates and showed that several homologous amino acid motifs were present in the skin and synovium among and between PsA patients.67 This preferential TCR usage supports the concept of T-cell expansion in response to antigens or superantigens. A number of candidates have been suggested, including streptococcal superantigens, keratins 13 and 17, stratum corneum autoantigen, and human papillomavirus 5.17 To date, support for these specific antigens as triggers for T-cell clonal expansion has not been forthcoming.

T Cells in Psoriatic Arthritis

54

Previous studies have confirmed that there are large numbers of T cells in both synovial fluid and synovium in PsA.34,72 Whereas CD4+ T cells predominate in the inflamed synovium, CD8+ T cells are dominant in synovial fluid and in the subchondral bone beneath the enthesis. These cells are activated (HLADR+) and mature (CD45RO+) and they express Th1 cytokines, including upregulation of IFN-γ,73 a pattern also observed in psoriatic plaques. Analyses of synovial fluid and synovium revealed clonal expansion of T cells with preferential TCR usage particularly in the CD8+ population. 65,66 Three main populations of T cells were identified that reflected the presence of distinct immunologic mechanisms in active synovitis. The dominant population consisted of expanded polyclonal CD4 T cells, presumably attracted by chemokines. This population was greatly reduced in the synovium following methotrexate therapy. A second, smaller, and more complex population consisted of moderately expanded CD4 or CD8 lineage clones located only in the inflamed synovium or active joint fluid, or both, with minimal or no expansion of the blood precursor pool. These clones did not persist in the synovium during methotrexate treatment and appeared to be bystander clones. The third, least common population was composed of greatly expanded CD8 lineage clones that were also highly expanded in blood and joint fluid. These clones persisted during methotrexate therapy and showed evidence of antigen drive. One of these driver clones was specific for an Epstein-Barr virus (EBV) peptide, and to date, evidence for antigen-specific responses that are not EBV related has not been shown.

B Cells, Plasma Cells, and Antibody Formation in Psoriasis and Psoriatic Arthritis Previous studies have identified B cells and plasma cells in inflamed psoriatic plaques and synovial membranes.74 Occasional focal B-cell aggregates are present in synovial tissue, and indeed B-cell numbers are similar to those seen in RA.72 The exact role of these B cells is unknown. They may be involved in antigen presentation or they may be bystanders with no specific function in the inflammatory response. The finding of new bone formation adjacent to B-cell infiltrates in the bone marrow of mice with adjuvant arthritis raises the possibility that they may have a reparative function.75 Ps and PsA are certainly not typically associated with autoantibody formation, although some antibodies have been described. Low levels of rheumatoid factor positivity are seen in some patients with PsA, the significance of which is uncertain. In the absence of a diagnostic test for PsA, the presence of rheumatoid factor only serves to confuse diagnosis, particularly in patients with symmetrical joint disease. Anti-CCP antibodies are also occasionally seen in PsA. In one study, 7 (5.6%) of 126 patients with PsA were positive for anti-CCP antibodies, compared with 0% of control subjects and 97% of 40 patients with seropositive RA.76 The presence of anti-CCP antibodies in PsA was significantly associated with the HLA-DRB1 shared epitope (P < .005).

Innate Immune Response The innate immune response acts as a rapid response system largely developed for detecting an infective agent. The key cellular components of the innate immune response include keratinocytes and dendritic cells, neutrophils, monocytes/macrophages, and natural killer (NK) or natural killer T (NKT) cells. The main effector proteins include Toll-like receptors (TLRs), components of the complement system, cytokines (TNF-α, IFN-γ, IL-1, IL-6, IL-12, IL-15, IL18), and chemokines (IL-8). In the following, some of these cells and effector proteins are reviewed with a specific reference to what is known in Ps and PsA.

Keratinocytes The role of keratinocytes in Ps pathogenesis is reviewed elsewhere. It is important to point out that keratinocytes can function as pro-inflammatory cells, produce cytokines and chemokines, and thus contribute to the developing lesion.17 Indeed, it has been proposed that keratinocyte hyperplasia represents an exaggerated innate immune response.77 The finding that epidermal deletion of the transcription factors JunB and c-Jun can generate a Ps and arthritis phenotype in a murine model demonstrates that keratinocyte activation is the key perturbation.78 The development

Dendritic Cells, Monocytes, and Macrophages Activated, plasmacytoid, and monocytoid dendritic cells are increased in Ps dermis and may be an important source of TNF-α.79 Interestingly, gene expression analysis comparing involved and uninvolved Ps skin has shown dendritic cell activation markers in uninvolved skin.80 These dendritic cells may thus be primed to be triggered by a number of diverse stimuli. A recent study has described the dendritic cell phenotype in blood and synovial compartments in PsA compared with RA.80a Significantly reduced numbers of circulating myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) were found in both RA and PsA compared with controls. The mDC and pDC subsets were detected in higher numbers in synovial fluid but exhibited an immature phenotype. PsA synovial membrane contains both mDC and pDC subsets distributed in particular adjacent to lymphocytic aggregates. Monocytes and macrophages are found in inflamed skin and synovial tissue in increased numbers compared with normal tissue. In comparison with RA, however, macrophage numbers were reduced in both the lining and sublining layers.72 The high levels of TNF noted in the synovium and synovial fluid are probably released by activated monocytes in the joint and the peripheral blood.

Neutrophils The accumulation of neutrophils in Ps skin and the formation of microabscesses (of Munro) have long been described histologically.81 These microabscesses can enlarge, leading to the classical pustule formation observed in the pustular phenotype. It is only more recently that the presence of neutrophils in the inflamed PsA synovium has received attention. As reviewed previously, higher neutrophil numbers were observed in SpA synovial tissues, in contrast to RA, where only a few neutrophils are observed.28

Natural Killer and Natural Killer T Cells NK cells are thought to be the principal cell population responsible for recognizing self-antigens, ensuring integrity of the host through recognition of altered MHC class I expression—a frequent consequence of chronic infection. Control of NK cell activity is provided principally by inhibitory signals from cell surface receptors (NKRs), which are also involved in the regulation of CD8+ populations. NK cells, through their ability to lyse self-cells, could be directly involved in tissue destruction in the joints of PsA patients or exacerbate T cell–mediated pathology through production of cytokines. NKT

cells are another potentially autoreactive population. They lyse cells in both a T and NK cell manner, are activated by glycolipid antigen presented by CD1 molecules, have a restricted TCR repertoire, accumulate in specific sites, and produce both Th1 and Th2 cytokines.82 It has been suggested that NKT cells are an important immunoregulatory population involved in control of autoimmune disease. Studies in Ps and PsA have largely concentrated on conventional CD4+/C8+ T cells, and little is known about NK or NKT cell populations. Both NK and NKT cells have been described in increased numbers in Ps plaques.83 Following antipsoriatic therapies, CD3+CD56+ cells increased, suggesting an active role in the development of Th1-mediated autoimmunity. Circulating Vα24+ Vβ11+ NKT cell numbers are reduced in Ps patients,84 and further studies using a severe combined immunodeficiency (SCID) mouse model have demonstrated that T cells bearing NKRs can directly provoke a Th1-mediated response to create psoriatic plaques.85 We have carried out a number of preliminary studies on NK/NKT cell populations in matched blood and synovial fluid mononuclear cells from PsA patients. Initial results suggest that NK/NKT cells may be important in perpetuating the inflammatory response in PsA. Interestingly, the data also support the reduction in Vα24+ Vβ11+ NKT cell numbers previously seen in Ps blood (O FitzGerald, unpublished data). NK cell activity is partially controlled through interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their respective HLA class I ligands. In one study, subjects with activating KIR2DS1 or KIR2DS2 genes, or both, were susceptible to the development of PsA but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, were missing.86 Furthermore, it has been shown in a number of studies that the gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris.87-89 All of these studies serve to emphasize the potential importance of NK cells in Ps and PsA pathogenesis with susceptibility to disease perhaps determined by the overall balance of activating and inhibitory composite KIRHLA genotypes.90

Acquired versus Innate Immune Response in Psoriasis and Psoriatic Arthritis

of the acquired immune response with expansion of T-cell subsets may well be a secondary event.

Toll-like Receptors The innate immune response is mediated by a family of molecules called TLRs that are expressed by many of the cells previously mentioned. Up to 10 TLRs have now been described, and each TLR can detect a broad class of disease-causing agents. For example, gramnegative bacteria–derived lipopolysaccharide (LPS) is detected by TLR4. After recognition of LPS, TLR4 activation signals a number of intracellular pathways that

55

PATHOGENESIS OF PSORIATIC ARTHRITIS

in turn result in activation of NF-κB and pro-inflammatory cytokine production. TLR expression in Ps and normal skin has been studied.91 TLR1 and TLR2 were upregulated in the upper epidermis while expression of TLR5 was reduced. More recently, TLR2 and TLR4 expression was studied in patients with SpA including PsA before and after anti-TNF therapy.92 Expression of TLR4, but not TLR2, was increased on peripheral blood mononuclear cells from patients with SpA, whereas both TLRs were increased in RA patients. Infliximab reduced TLR2 and TLR4 expression, leading to lower levels than in control subjects. In inflamed synovium, the expression of both TLRs was significantly higher in patients with SpA than in those with RA or osteoarthritis. Paralleling the systemic effect, TLRs in synovium were downregulated following TNF blockade. This suggests an important role for TLR engagement in SpA and provides additional clues regarding the mechanism of action as well as the potential side effects of TNF-α blockade.

Cytokines As reviewed earlier, upregulation of pro-inflammatory cytokine expression has been described in both inflamed skin and synovial tissue. These cytokines, including TNF-α, IL-1, IL-6, IL-12, IL-15, and IL-18 are all key cytokine components of the innate immune response. Both protein expression and gene expression have been shown to be downregulated by methotrexate therapy.73 In particular, the success of TNF-inhibiting

strategies in the treatment of both skin and joint disease emphasizes the importance of these cytokines in disease expression.

Chemokines Although there have been only a few studies of chemokine expression in Ps and PsA, upregulation of IL-8 has been well established.79 In addition, IL-8 gene expression was significantly reduced in synovial tissue following methotrexate therapy.73 The cutaneous T cell–attracting chemokine CTACK/CCL27 is a pivotal chemokine in mediating the migration of lymphocytes into the skin, through the binding to the chemokine receptor CCR10. CCL27 is continuously expressed by keratinocytes but is highly upregulated in inflammatory skin diseases such as Ps. In addition, CCL27 can be induced in cultured keratinocytes by TNF-α and NF-κΒ activation.93

ANIMAL MODELS OF PSORIATIC ARTHRITIS Formerly, the absence of a reliable animal model hindered research in Ps and PsA. Research with rodent models over the past several years, however, has provided novel insights into the mechanisms that drive psoriatic skin and joint inflammation (Table 7-1). The finding that an inducible epidermal deletion of JunB and c-Jun yielded a murine phenotype with features of both Ps and inflammatory arthritis has generated new models regarding the pathogenesis of PsA.78 c-Jun and JunB are transcription factors that

TABLE 7-1 ANIMAL MODELS WITH SKIN AND JOINT INFLAMMATION Author

Species

Genetic Alteration

Phenotype

Zenz et al78

Mouse

Inducible epidermal deletion of JunB and c-Jun

Psoriasiform skin lesions, erosive arthritis with periostitis

Hammer et al98

Rat

HLA-B27/β2 transgene

Psoriasiform skin lesions, peripheral arthritis, gut and nail lesion

Khare et al99

Mouse

β2-Microglobulin knockout

Paw swelling, joint ankylosis, nail changes

Bardos et al94

Mouse

Lack endogenous MHC class II molecules

Psoriasiform skin lesions, resorption of distal phalanges, nail changes

Rothschild102

Baboon

None

30% of baboons exhibit radiographic changes similar to those in PsA

Lories et al97

Mouse, DBA/1 strain

None

Ankylosing enthesitis, dactylitis, onychoperiostitis

Cook et al103

Mouse, FVB/ NCrIBR strain

Amphiregulin expression under control of INV-AR

Psoriasiform skin lesions, mild knee synovitis

HLA, human leukocyte antigen; MHC, major histocompatibility complex; PsA, psoriatic arthritis.

56

MHC background genes. Although these models do not fully mimic the phenotype observed in humans with PsA, they suggest that alteration of MHC expression combined with microbial interactions may play a critical role in the pathogenesis of skin and joint disease. Spondyloarthropathies have been identified in a variety of primate and nonprimate species. In baboons, the prevalence of spondyloarthritis reaches 30%.100 The distribution of erosive disease and axial joint involvement in Old World primates is quite characteristic of that noted in human PsA.101 Thus, these mammals may be a more appropriate animal model for deciphering mechanisms of disease in PsA.

SUMMARY AND PROPOSED MODEL FOR PSORIATIC ARTHRITIS IMMUNOPATHOGENESIS Taken together, the evidence suggests that trauma or infection in a genetically susceptible individual may favor development of Ps and PsA and that the initial inciting event takes place in the skin (Table 7-2). This event, possibly initiated by altered gene activation programs in keratinocytes or NK cells, induces chemokine expression and recruitment of inflammatory cells of the innate and of the acquired immune system into the dermis. A second step occurs in some genetically susceptible Ps patients that triggers activation of T cells, which home to a highly vascularized synovium. In the setting of high levels of systemic TNF, osteoclastogenesis takes place in the subchondral bone. OCPs enter the synovium through channels emanating from the bone and blood vessels in the inflamed synovium, where they encounter RANKL expressed on synoviocytes and a microenvironment with low expression of OPG. The hyperplastic synovial membrane is transformed into an aggressively invasive pannus. Inflammation also induces increased signaling in the BMP pathway and subsequent new bone formation that is largely centered in the entheses. In addition, MMPs released by synovial lining cells degrade cartilage and engage in blood vessel remodeling. Presumably, perpetual release of pro-inflammatory cytokines, particularly TNF, leads to persistent synovitis, enthesitis, and progressive matrix degradation. The events that underlie axial inflammation have not been elucidated. Future studies focused on pathogenetic factors that link inflammation in the joint and skin coupled with genetic analyses of large populations will undoubtedly provide new mechanistic insights and uncover novel therapeutic targets.

Summary and Proposed Model for Psoriatic Arthritis Immunopathogenesis

are components of the activator protein 1 (AP-1) complex. Inducible deletion of JunB and c-Jun resulted in the development of psoriasiform lesions on the scalp and tail and also inflammatory erosive arthritis with periostitis in all the mice. The authors demonstrated that soon after inducible deletion, chemokine production increased in the skin and this was followed by influx of granulocytes and macrophages. It is of interest that before the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the Ps susceptibility region PSORS4 and previously shown to be strongly expressed in diseased tissue were induced in mutant keratinocytes both in vivo and in vitro. Development of arthritis required the presence of functional B and T cells and signaling through the TNFR1 receptor, and Ps was still present in mice without lymphocytes or TNF signaling. Thus, abrogation of epidermal AP1 proteins was sufficient to initiate skin and joint disease in affected mice. Moreover, the joint disease was remarkably similar to that seen in PsA. Transgenic mice lacking endogenous MHC class II molecules spontaneously developed extensive resorption of distal phalangeal bones along with pitting and frequent loss of nails and hyperkeratosis and parakeratosis.94 These mice did not manifest arthritis in other peripheral joints or in the axial skeleton. Moreover, the skin findings were localized to the affected toes. Of note, joint involvement was not described in any of the Ps rodent models.85,95,96 Involvement of the distal joints was also reported in aging male DBA/1 mice from different litters that were caged together (four to six mice per cage) at the age of 12 weeks.97 Hind paws showed clinical signs of arthritis and nail abnormalities. Pathologic examination revealed dactylitis characterized by diffuse neutrophil infiltration in 6 of 50 paws examined. Onychoperiostitis with progressive destruction of the nail bed and the underlying distal phalanx was seen in 5 of 50 paws examined. Two other models of spontaneously developing arthritis have been described in rodents transgenic for HLA-B27 class I molecules. The HLA-B27/Β2 microglobulin transgenic rat developed gut lesions, peripheral mild nonerosive arthritis, psoriasiform skin lesions, alopecia, and nail lesions, but no thickening or shortening of the distal joints was reported.98 When the transgenic rats were raised in a germ-free environment, they developed the skin lesions but no gut or joint inflammation. Likewise, paw swelling, joint ankyloses, nail changes, and hair loss developed in transgenic mice lacking β2-microglobulin.99 In these mice, the disease frequency was highly influenced by non-

57

PATHOGENESIS OF PSORIATIC ARTHRITIS

TABLE 7-2 A PARADIGM OF DISEASE PATHOGENESIS IN PSORIATIC ARTHRITIS Stage

Pathobiology

Clinical Phenotype

Environmental Factors

Precutaneous

Altered expression of JunB, TNF-α, TLRs, or KIR genes

None

Infection

Cutaneous

Chemokine upregulation in epidermis with influx of neutrophils and mononuclear cells

Psoriatic plaque

Infection

Trauma

Trauma Development of hyperkeratosis, acanthosis, Munro’s abscesses Pre-arthritis

Stress

Systemic overproduction of TNF

None

Trauma

OCPs and OC accumulate in bone

None

Trauma

Synovial hyperplasia with influx of T lymphocytes, monocytes, and OCPs

Synovitis

Infection

Inflammation of tendon, ligament insertions

Enthesitis

Stress, trauma

Osteoclastogenesis in the bone and synovium

Erosive arthritis

Bone resorption, cartilage degradation, and tenosynovitis

Joint deformities

Inflammation activates BMP signaling pathway and new bone formation

Ankylosis periostitis

Angiogenesis in the synovium Influx of neutrophils and activated T cells home to joint Arthritis

Trauma

BMP, bone morphogenetic protein; KIR, killer immunoglobulin-like receptor; OC, osteoclast; OCP, osteoclast precursor; TLR, Toll-like receptor; TNF, tumor necrosis factor

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1. Schmitt-Egenolf ME, Eiermann TH, Boehncke WH, et al. Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6-B57DRB1*0701-DQA1*0201-DQB1*0303: A population- and familybased study. J Invest Dermatol 1996;106:711-714. 2. Gladman DD, Farewell VT. The role of HLA antigens as indicators of disease progression in psoriatic arthritis. Multivariate relative risk model. Arthritis Rheum 1995;38:845-850. 3. Stankler L. An experimental investigation on the site of skin damage inducing the Koebner reaction in psoriasis. Br J Dermatol 1969;81:534-535. 4. Melski JW, Bernhard JD, Stern RS. The Koebner (isomorphic) response in psoriasis. Associations with early age at onset and multiple previous therapies. Arch Dermatol 1983;119:655-659. 5. Langevitz P, Buskila D, Gladman DD. Psoriatic arthritis precipitated by physical trauma. J Rheumatol 1990;17:695-697. 6. Scarpa R, Del Puente A, di Girolamo C, et al. Interplay between environmental factors, articular involvement, and HLA-B27 in patients with psoriatic arthritis. Ann Rheum Dis 1992;51:78-79. 7. Bruce IN, Silman AJ. The aetiology of psoriatic arthritis. Rheumatology (Oxford) 2001;40:363-366. 8. Punzi L, Pianon M, Bertazzolo N, et al. Clinical, laboratory and immunogenetic aspects of post-traumatic psoriatic arthritis: A study of 25 patients. Clin Exp Rheumatol 1998;16:277-281. 9. Gupta MA, Gupta AK. The Psoriasis Life Stress Inventory: A preliminary index of psoriasis-related stress. Acta Derm Venereol 1995;75:240-243. 10. Rasmussen JE. The relationship between infection with group A beta hemolytic streptococci and the development of psoriasis. Pediatr Infect Dis J 2000;19:153-154.

11. Leung DY, Travers JB, Giorno R, et al. Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest 1995;96:2106-2112. 12. Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996;98:1878-1887. 13. Rahman MU, Ahmed S, Schumacher HR, Zeiger AR. High levels of antipeptidoglycan antibodies in psoriatic and other seronegative arthritides. J Rheumatol 1990;17:621-625. 14. Vasey FB, Deitz C, Fenske NA, et al. Possible involvement of group A streptococci in the pathogenesis of psoriatic arthritis. J Rheumatol 1982;9:719-722. 15. Travers JB, Hamid QA, Norris DA, et al. Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis. J Clin Invest 1999;104:1181-1189. 16. Fassbender HG. Extra-articular processes in osteoarthropathia psoriatica. Arch Orthop Trauma Surg 1979;95:37-46. 17. Bos JD, de Rie MA, Teunissen MB, Piskin G. Psoriasis: Dysregulation of innate immunity. Br J Dermatol 2005;152:1098-1107. 18. Pitzalis C, Cauli A, Pipitone N, et al. Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 1996;39:137-145. 19. Espinoza LR, Vasey FB, Espinoza CG, et al. Vascular changes in psoriatic synovium. A light and electron microscopic study. Arthritis Rheum 1982;25:677-684. 20. Veale D, Yanni G, Rogers S, et al. Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 1993;36:893-900.

44. Smith MD, Roberts-Thomson PJ. Lymphocyte surface marker expression in rheumatic diseases: Evidence for prior activation of lymphocytes in vivo. Ann Rheum Dis 1990;49:81-87. 45. Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993;151:1548-1561. 46. Partsch G, Steiner G, Leeb BF, et al. Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol 1997;24:518-523. 47. Balding J, Kane D, Livingstone W, et al. Cytokine gene polymorphisms: Association with psoriatic arthritis susceptibility and severity. Arthritis Rheum 2003;48:1408-1413. 48. Baeten D, Kruithof E, Van den Bosch F, et al. Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: Histologic findings in eight patients from an open-label pilot study. Arthritis Rheum 2001;44:186-195. 49. Kruithof E, De Rycke L, Roth J, et al. Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies. Arthritis Rheum 2005;52:3898-3909. 50. Canete JD, Pablos JL, Sanmarti R, et al. Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis. Arthritis Rheum 2004;50:1636-1641. 51. Resnick D. Psoriatic arthritis. In: Resnick D (ed). Bone and Joint Imaging. Philadelphia: WB Saunders, 1989, pp 320-329. 52. Ribbens C, Martin y Porras M, Franchimont N, et al. Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: Relationship with synovitis and steroid treatment. Ann Rheum Dis 2002;61:161-166. 53. Vandooren B, Kruitof E, Yu DT, et al. Matrix metalloproteinases and their inhibitors are involved in peripheral synovitis and downregulated by TNF blockade in spondyloarthropathy. Arthritis Rheum 2004;50:2942-2953. 54. Kane D, Jensen LE, Grehan S, et al. Quantitation of metalloproteinase gene expression in rheumatoid and psoriatic arthritis synovial tissue distal and proximal to the cartilage-pannus junction. J Rheumatol 2004;31:1274-1280. 55. Resnick D. Psoriatic arthritis. In: Resnick D, Niwayama G, Diagnosis of Bone and Joint Disorders, 2nd ed. Philadelphia: WB Saunders, 1988, pp 1171-1198. 56. Ritchlin CT, Haas-Smith SA, Li P, et al. Mechanisms of TNFalpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003;111:821-831. 57. Schett G, Stolina M, Bolon B, et al. Analysis of the kinetics of osteoclastogenesis in arthritic rats. Arthritis Rheum 2005;52:3192-3201. 58. Suda T, Takahashi N, Udagawa N, et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999;20:345-357. 59. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-176. 60. Hofbauer LC, Heufelder AE. The role of osteoprotegerin and receptor activator of nuclear factor kappaB ligand in the pathogenesis and treatment of rheumatoid arthritis. Arthritis Rheum 2001;44:253-259. 61. Udagawa N, Kotake S, Kamatani N, et al. The molecular mechanism of osteoclastogenesis in rheumatoid arthritis. Arthritis Res 2002;4:281-289. 62. Braun J, Bollow M, Neure L, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995;38:499-505. 63. Peng H, Wright V, Usas A, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein—4. J Clin Invest 2002;110:751-759. 64. Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest 2005;115:1571-1579. Epub 2005 May 12. 65. Costello PJ, Winchester RJ, Curran SA, et al. Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions that appear antigen driven. J Immunol 2001;166:2878-2886.

References

21. Kraan MC, Haringman JJ, Post WJ, et al. Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology (Oxford) 1999;38:1074-1080. 22. Danning CL, Illei GG, Hitchon C, et al. Macrophage-derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheum 2000;43:1244-1256. 23. Rambotti MG, Giambanco I, Spreca A, Donato R. S100B and S100A1 proteins in bovine retina: Their calcium-dependent stimulation of a membrane-bound guanylate cyclase activity as investigated by ultracytochemistry. Neuroscience 1999;92:1089-1101. 24. Kane D, Roth J, Frosch M, et al. Increased perivascular synovial membrane expression of myeloid-related proteins in psoriatic arthritis. Arthritis Rheum 2003;48:1676-1685. 25. Viemann D, Strey A, Janning A, et al. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood 2005;105:2955-2962. 26. McEvoy AN, Bresnihan B, FitzGerald O, Murphy EP. Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1 alpha corticotropin-releasing hormone receptor. Arthritis Rheum 2001;44:1761-1767. 27. Reece RJ, Canete JD, Parsons WJ, et al. Distinct vascular patterns in the synovitis of psoriatic, reactive and rheumatoid arthritis. Arthritis Rheum 1999;42:1481-1485. 28. Kruithof E, Baeten D, De Rycke L, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005;7:R569-R580. 29. McGonagle D, Conaghan PG, Emery P. Psoriatic arthritis: A unified concept twenty years on. Arthritis Rheum 1999;42: 1080-1086. 30. Benjamin M, Ralphs JR. Fibrocartilage in tendons and ligaments—An adaptation to compressive load. J Anat 1998;193:481-494. 31. Benjamin M, McGonagle D. The anatomical basis for disease localisation in seronegative spondyloarthropathy at entheses and related sites. J Anat 2001;199:503-526. 32. Laloux LV, Allain M-C, Martin J, et al. Immunohistological study of enthesis in spondyloarthropathies: Comparison in rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 2001;60: 316-321. 33. McGonagle D, Marzo-Ortega H, O’Connor P, et al. Histological assessment of the early enthesitis lesion in spondyloarthropathy. Ann Rheum Dis 2002;61:534-537. 34. Costello P, Bresnihan B, O’Farrelly C, FitzGerald O. Predominance of CD8+ T lymphocytes in psoriatic arthritis. J Rheumatol 1999;26:1117-1124. 35. Vervoordeldonk MJ, Tak PP. Cytokines in rheumatoid arthritis. Curr Rheumatol Rep 2002;4:208-217. 36. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-916. 37. Ritchlin C, Haas-Smith SA, Hicks D, et al. Patterns of cytokine production in psoriatic synovium. J Rheumatol 1998;25:1544-1552. 38. Austin LM, Ozawa M, Kikuchi T, et al. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: A type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999;113:752-759. 39. Rooney T, Murphy E, Benito M, et al. Synovial tissue interleukin18 expression and the response to treatment in patients with inflammatory arthritis. Ann Rheum Dis 2004;63:1393-1398. 40. Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem 1991;266:7313-7316. 41. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med 1996;334:1717-1725. 42. Brennan FM, Feldmann M. Cytokines in autoimmunity. Curr Opin Immunol 1992;4:754-759. 43. Saxne T, Palladino MA Jr, Heinegard D, et al. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 1988;31:1041-1045.

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66. Curran SA, FitzGerald OM, Costello PJ, et al. Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognzing autoantigens. J Immunol. 2004;172:1935-1944. 67. Tassiulas I, Duncan SR, Centola M, et al. Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis. Hum Immunol 1999;60:479-491. 68. Curran SA, FitzGerald OM, Costello PJ, et al. Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens. J Immunol 2004;172:1935-1944. 69. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005;352:1899-1912. 70. Piskin G, Koomen CW, Picavet D, et al. Ultraviolet-B irradiation decreases IFN-gamma and increases IL-4 expression in psoriatic lesional skin in situ and in cultured dermal T cells derived from these lesions. Exp Dermatol 2003;12:172-180. 71. Chang JC, Smith LR, Froning KJ, et al. CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes. Proc Natl Acad Sci USA 1994;91:9282-9286. 72. Veale DY, Rogers G, Barnes S, et al. Reduced synovial membrane ELAM-1 expression, macrophage numbers and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 1993;36:893-900. 73. Kane D, Gogarty M, O’Leary J, et al. Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum 2004;50:3286-3295. 74. Veale DJ, Barnes L, Rogers S, FitzGerald O. Immunohistochemical markers for arthritis in psoriasis. Ann Rheum Dis 1994;53:450-454. 75. Görtz B, Hayer S, Redlich K, et al. Arthritis induces lymphocytic bone marrow inflammation and endosteal bone formation. J Bone Miner Res 2004;19:990-1000. 76. Korendowych E, Owen P, Ravindran J, et al. The clinical and genetic associations of anti-cyclic citrullinated peptide antibodies in psoriatic arthritis. Rheumatology (Oxford) 2005;44: 1056-1060. 77. Nickoloff BJ, Schroder JM, von den Driesch P, et al. Is psoriasis a T-cell disease? Exp Dermatol 2000;9:359-375. 78. Zenz R, Eferl R, Kenner L, et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 2005;437:369-375. 79. Nickoloff BJ, Karabin GD, Barker JN, et al. Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol 1991;138:129-140. 80. Zhou X, Krueger JG, Kao MC, et al. Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol Genomics 2003;13:69-78. 80a. Jongbloed SL, Lebre MC, Fraser AR, et al. Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis. Arthritis Res Ther 2005;8:R15. 81. Habif T. Psoriasis and other papulosquamous diseases. In: Habif T (ed). Clinical Dermatology, 3rd ed. St Louis: Mosby, 1996, pp 190-235. 82. Wilson SB, Delovitch TL. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 2003;3:211-222. 83. Cameron AL, Kirby B, Fei W, Griffiths CE. Natural killer and natural killer-T cells in psoriasis. Arch Dermatol Res 2002;294:363-369. 84. van der Vliet HJ, von Blomberg BM, Nishi N, et al. Circulating V(alpha24+) Vbeta11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin Immunol 2001;100:144-148.

85. Nickoloff BJ, Bonish B, Huang BB, Porcelli SA. Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J Dermatol Sci 2000;24:212-225. 86. Martin MP, Nelson G, Lee JH, et al. Cutting edge: susceptibility to psoriatic arthritis: Influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol 2002;169:2818-2822. 87. Suzuki Y, Hamamoto Y, Ogasawara Y, et al. Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris. J Invest Dermatol 2004;122:1133-1136. 88. Luszczek W, Manczak M, Cislo M, et al. Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris. Hum Immunol 2004;65:758-766. 89. Williams F, Meenagh A, Sleator C, et al. Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis. Hum Immunol 2005;66:836-841. 90. Nelson GW, Martin MP, Gladman D, et al. Cutting edge: Heterozygote advantage in autoimmune disease: Hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 2004;173:4273-4276. 91. Baker BS, Ovigne JM, Powles AV, et al. Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: Modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol 2003;148:670-679. 92. De Rycke L, Vandooren B, Kruithof E, et al. Tumor necrosis factor alpha blockade treatment down-modulates the increased systemic and local expression of toll-like receptor 2 and tolllike receptor 4 in spondylarthropathy. Arthritis Rheum 2005;52:2146-2158. 93. Vestergaard C, Johansen C, Otkjaer K, et al. Tumor necrosis factor-alpha-induced CTACK/CCL27 (cutaneous T-cell–attracting chemokine) production in keratinocytes is controlled by nuclear factor kappaB. Cytokine 2005;29:49-55. 94. Bardos T, Zhang J, Mikecz K, et al. Mice lacking endogenous major histocompatibility complex class II develop arthritis resembling psoriatic arthritis at an advanced age. Arthritis Rheum 2002;46:2465-2475. 95. Nickoloff BJ. Characterization of lymphocyte-dependent angiogenesis using a SCID mouse:human skin model of psoriasis. J Investig Dermatol Symp Proc 2000;5:67-73. 96. Hong K, Chu A, Ludviksson BR, et al. IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol 1999;162: 7480-7491. 97. Lories RJ, Matthys P, de Vlam K, et al. Ankylosing enthesitis, dactylitis, and onychoperiostitis in male DBA/1 mice: A model of psoriatic arthritis. Ann Rheum Dis 2004;63:595-598. 98. Yanagisawa H, Richardson JA, Taurog JD, Hammer RE. Characterization of psoriasiform and alopecic skin lesions in HLA-B27 transgenic rats. Am J Pathol 1995;147:955-964. 99. Khare SD, Luthra HS, David CS. Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: A model of human spondyloarthropathies. J Exp Med 1995;182:1153-1158. 100. Rothschild BM, Woods RJ. Spondyloarthropathy in gorillas. Semin Arthritis Rheum 1989;18:267-276. 101. Rothschild BM, Woods RJ. Erosive arthritis and spondyloarthropathy in Old World primates. Am J Phys Anthropol 1992;88:389-400. 102. Rothschild BM. Primate spondyloarthropathy. Curr Rheumatol Rep 2005;7:173-181. 103. Cook PW, Brown JR, Cornell KA, Pittelkow MR. Suprabasal expression of human amphiregulin in the epidermis of transgenic mice induces a severe, early-onset, psoriasis-like skin pathology: Expression of amphiregulin in the basal epidermis is also associated with synovitis. Exp Dermatol 2004;13: 347-356.

PSORIATIC ARTHRITIS

8

Angiogenesis in Psoriasis and Psoriatic Arthritis Douglas J. Veale and Ursula Fearon

Psoriasis is a common dermatosis characterized by hyperkeratosis often occurring in plaques on the elbows and knees and in the scalp. Psoriatic arthritis (PsA), characterized by specific patterns of joint involvement, negative rheumatoid factor, and associated psoriasis, develops in 10% to 40% of patients. Features of dactylitis, enthesitis, and nail dystrophy, predominantly pitting and onycholysis, are also commonly noted (67% to 90% of patients with PsA).1,2 Indeed nail dystrophy and distal interphalangeal (DIP) joint arthritis are significantly associated.2,3 Patterns of polyarticular or oligoarticular arthritis account for 90% of cases, with the former pattern somewhat more common.4 Common clinical features of PsA with psoriasis are as follows: ● ●

●

Up to 40% of patients with psoriasis develop PsA. PsA is characterized by inflammation of key sites outside the joints including nail beds, entheses, and uveal tract. PsA of the DIP joints is significantly associated with nail dystrophy.

Elongated and tortuous blood vessels were observed in psoriatic skin by Braverman and colleagues in the 1970s.5,6 Nail fold capillary changes were also found in PsA patients by capillaroscopy.7 A study of patients with DIP arthritis with and without nail disease described quantitative vascular morphologic abnormalities,8 suggesting a primary vascular pathogenesis of both psoriasis and PsA. The pattern of blood vessel growth in skin may predict the spread of the psoriatic plaque, suggesting that angiogenesis is a primary pathogenic event.9 Abnormal vascularity was first described in PsA synovial membrane (SM) on immunohistologic analysis of biopsies.10 Subsequently, synovial blood vessel morphology was examined by direct macroscopic visualization using needle arthroscopy.11 The vascular morphologic pattern of PsA SM is identical to that described in both the skin and the nail fold capillaries of patients with psoriasis.

Cytokines such as tumor necrosis factor α (TNF-α) and vascular endothelial growth factor (VEGF) are markedly increased in psoriatic skin, synovial fluid, and SM of patients with PsA.12-14 Expression of angiopoietins (ANGs), a family of vascular growth factors, and their receptor Tie2 co-localize with VEGF in the skin and SM of patients with psoriasis and PsA (Fig. 8-1) in a perivascular distribution.15,16 Expression of VEGF and ANGs appear at an early stage in the skin and arthritic SM and may represent a primary event as opposed to a response to hypoxia. In vitro studies suggest that TNF-α directly regulates the Tie2 signaling pathway, leading to differential regulation of ANG-1 and ANG-2 angiogenic effects on vascular survival and maintenance.17 Angiogenesis, new blood vessel formation by proliferation of endothelial cells (ECs) from sprouting capillaries,17 is crucial for normal development and tumor progression and in pathologic inflammatory diseases. VEGF is a main “on” switch, acting early in vascular morphogenesis, stimulating EC proliferation and migration. ANG-1 and ANG-2 compete to bind the receptor tyrosine kinase (Tie2) downstream of VEGF. Binding of ANG-1 and Tie2 induces stabilization of maturing vessels, and an ANG-1 knockout mouse is embryo lethal. ANG-2 in the presence of abundant VEGF, however, stimulates vessel invasion and blocks maturation and stabilization.18 ANG-2 causes vessels to remain in a plastic state, maintaining a response to VEGF that results in vascular remodeling, increasing capillary diameter, and new blood vessel sprouting; ANG-2 in the absence of VEGF results in vessel regression. Pericyte recruitment further leads to stabilization of a mature blood vessel, which becomes less VEGF dependent, and ANG-1 binding to Tie2 also leads to stabilization of a mature vessel. Angiogenesis appears to be a primary event in psoriasis and in PsA. New vessels advance through the connective tissue of the synovium and the dermal papillae of the skin supporting the proliferating tissue. In 1999, we first described a distinct pattern of blood vessel growth in the joints of patients with PsA compared with those with rheumatoid arthritis. PsA is characterized by

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of VEGF and ANG-2 in an animal model of glioma tumor tissue. Conventional disease-modifying antirheumatic drugs including methotrexate and cyclosporin and the new TNF inhibitors both show a potential antiangiogenic effect. Common vascular features of psoriasis and PsA are as follows: ●

●

Figure 8-1. CD31 immunohistochemical staining of a synovial tissue section in early psoriatic arthritis showing numerous vessels with positive (brown) staining (×25). See also Color Plate.

long, bushy, tortuous vessels with little or no branching (Fig. 8-2), whereas rheumatoid arthritis is characterized by straight vessels with regular branching, reflecting a different pathogenesis and outcome.19 In subsequent studies, expression of VEGF, ANG-2, and matrix metalloproteinase 9 was co-localized with differential vascular patterns and decreased EC apoptosis.20 The role of angiogenesis in the pathophysiology of psoriasis and PsA is important as antiangiogenic strategies may prove a useful therapeutic approach; the potential for inhibition of these pathways is supported by tumor biology studies.21 In 1999, Benjamin and colleagues demonstrated inhibition of vascular growth and even regression of some vessels through inhibition

62

Figure 8-2. Macroscopic assessment of blood vessel morphology in the psoriatic joint at arthroscopy: tortuous, elongated, or bushy vessels. See also Color Plate.

●

Abnormal vascular lesions in the skin, nails, and joints are similar. Dilated, bushy vessels in the dermis, the nail fold capillaries, and the SM are found in active disease and diminish after successful therapy. Perivascular expression of angiogenic growth factors and their receptors occurs in both psoriatic skin and PsA synovium.

ANGIOGENESIS—A POTENTIAL THERAPEUTIC TARGET IN PSORIASIS AND PSORIATIC ARTHRITIS If angiogenesis and expression of vascular growth factors are primary and early events in the inflammatory process in psoriasis and PsA, do they offer a novel target for therapy? The focus of these studies has been on the mechanisms of growth factor regulation, receptor activation, and signal transduction pathways. Upregulation of VEGF may occur in response to a number of stimuli, such as hypoxia, which is thought to be important in the inflamed joint. Evidence suggests that insulin-like growth factor II (IGF-II) may be critical in the regulation of angiogenesis.22 IGF-II is highly overexpressed in psoriatic skin and in studies of psoriatic keratinocytes it stimulated VEGF production by the tyrosine kinase pathways, whereas the protein kinase C pathway appeared to regulate negatively IGFmediated VEGF expression. Angiogenic cytokines, including TNF-α and IL-18, are also overexpressed in psoriatic skin and in the inflamed joint; the latter has been shown to use similar signaling pathways.23 A compound has been developed targeting kinase activity to block VEGF receptor 2 (VEGFR2) in a tumor model demonstrating reduction of angiogenesis and tumor growth.24 Pyrazine-pyridine biheteroaryl is a novel VEGFR2 inhibitor. It has shown potent inhibition of VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation, and it appears to be selective against HUVECs, human aortic smooth muscle cells, and MRC5 lung fibroblasts. The Tie2 receptor appears to be central to angiogenesis; as previously outlined, ANG-1 and ANG-2 compete for Tie2 binding, resulting in differential signaling downstream. Voskas and coauthors examined temporal expression of Tie2 in a double-transgenic mouse model using a tetracycline switch.25 The transgenic

NOVEL ANTIANGIOGENIC THERAPEUTIC STRATEGIES IN PSORIASIS AND PSORIATIC ARTHRITIS A number of novel drugs target specific angiogenic molecules, and a number of small clinical trials have been published that examine the role of anti-TNF therapy in psoriasis and PsA with specific reference to an effect on expression of vascular growth factors and their receptors. SU5416 is a selective inhibitor of the tyrosine kinase activity of VEGF receptor Flk-1/KDR. It has been shown to inhibit angiogenesis in vitro in cancer cells28 and is currently in clinical trials in advanced malignancy.29 In addition, endostatin and angiostatin (endogenous inhibitors) and TNP-470, which target the proliferating ECs, are being evaluated. Recombinant endostatin and angiostatin have both been reported to be well tolerated but with limited efficacy in phase I cancer trials.30,31

Established Drugs That May Inhibit Angiogenesis in Psoriasis and Psoriatic Arthritis Low-dose infliximab therapy, in combination with stable methotrexate, has been shown to deactivate the endothelium and reduce angiogenesis in psoriatic skin and synovium.32 In this study, 11 patients with mild active psoriasis and PsA received infliximab by intravenous

infusion (3 mg/kg) at baseline and weeks 2, 6, 14, and 22 while continuing a stable methotrexate dose (5 to 20 mg per week). Immunohistochemical analysis of the skin and synovium revealed reduction in blood vessel numbers, αvβ3 integrin, and adhesion molecule expression. A trend was also observed toward reduced VEGF expression, but this may reflect the small number of subjects in this study. In a similar study, nine patients with active PsA received infliximab in addition to methotrexate. In the synovium, a reduction in staining for CD31, αvβ3, VEGF, VEGFR2, and ANG-2 was observed. The authors concluded that the pattern of reduced VEGF/ANG-2 expression suggests vascular regression as a potential mechanism of anti-TNF therapy. We have concluded an open study of 16 patients with moderate to severe psoriasis and associated PsA who received infliximab infusions (3 to 5 mg/kg) at baseline and 2 and 6 weeks.16 Infliximab produced a significant reduction in protein expression of ANG-2, VEGF, and Tie2 along with a decrease in messenger RNA expression of Tie2, which paralleled significant reductions in the clinical PASI and Disease Activity Score in 28 joints (DAS28) scores at week 12. The data from these three studies suggest that infliximab has significant antiangiogenic effects, which may represent a critical mechanism of action of this drug in psoriasis and PsA. Pioglitazone is a novel peroxisome proliferator–activated receptor γ (PPARγ) agonist developed for diabetes that has shown some activity in the treatment of PsA.33 Pioglitazone has shown some antiangiogenic effects in in vitro and in vivo models. In a small clinical trial, 10 patients with at least two tender and swollen joints despite stable therapy with nonsteroidal anti-inflammatory drugs were enrolled. Pioglitazone at a daily dose of 60 mg was administered. The primary end point was the Psoriatic Arthritis Response Criterion (PsARC); secondary end points included a 20% improvement in American College of Rheumatology response criteria (ACR20) and PASI in patients with more than 2% skin involvement. Patients were evaluated at baseline and after 12 weeks. Sixty percent met PsARC, 50% met ACR20, and the mean percentage reduction in PASI was 38%, with a clinically meaningful PASI 50 response in two of six patients. Three patients had to be withdrawn from the study because of inefficacy and side effects. Major side effects were edema of the lower extremities and weight gain. The authors concluded that treatment with the PPARγ ligand agonist appears to be promising, although its use might be limited by its side effects.

Novel Antiangiogenic Therapeutic Strategies in Psoriasis and Psoriatic Arthritis

animals exhibited skin disease resembling human psoriasis, with features such as inflammatory infiltrate, dermal angiogenesis, and epidermal hyperplasia that persisted in the adult mice. Complete resolution, however occurred when the Tie2 receptor was suppressed through the tetracycline switch, suggesting a fundamental role for Tie2 signaling in the development of both pathologic and clinical features in this animal model. Cyclosporine treatment, used in humans for both psoriasis and PsA, was also noted to result in improvement of the skin lesions in these mice, further supporting the psoriasis-like disease in these animals. PsA patients with an incomplete response to methotrexate were randomly allocated to receive placebo or cyclosporine in addition to methotrexate.26 Joint count, C-reactive protein, and the Psoriasis Area and Severity Index (PASI) improved significantly; however, synovitis as detected by high-resolution ultrasonography (HRUS) significantly decreased in the methotrexate-cyclosporine compared with the placebo group. Joint vascularity visualized directly at arthroscopy correlates well with synovitis detected by HRUS within the same joint27 and therefore may provide a valid surrogate. The results in this trial therefore suggest that cyclosporine reduces vascularity of the joint as well as the skin in patients with PsA or psoriasis.

SUMMARY Angiogenesis is an early and central process in chronic inflammatory conditions such as psoriasis and PsA that results in an abnormal vascular pattern clinically

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apparent in the skin, nail folds, and joints. The evidence for angiogenesis as a common pathogenic pathway in the skin and joints is compelling. There are a number of important steps in the angiogenic process, from activation and proliferation of ECs through vessel sprouting, branching, and stabilization of the mature vessel. The process is complex and regulation includes critical growth factors, VEGF, and angiopoietins among others, that may themselves be modulated by cytokines, namely TNF; they in turn act on specific receptors, resulting in downstream molecular events. Each of these steps

provides a potential target for therapeutic modulation with drugs, some currently available, such as cyclosporine and the TNF blocking agents, others under development, such as the novel pioglitazone, endostatin, and angiostatin.

ACKNOWLEDGMENTS We are grateful to the Health Research Board of Ireland and the Science Foundation of Ireland for their funding.

REFERENCES 1. Scarpa R, Oriente P, Pucino A, et al. Psoriatic arthritis in psoriatic patients. Br J Rheumatol 1984;23:246-250. 2. Jones S, Armas JB, Cohen MG, et al. Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-839. 3. Wright V, Roberts MC, Hill AG. Dermatological manifestations in psoriatic arthritis: A follow-up study. Acta Derm Venereol 1979;59:235-240. 4. Veale D, Rogers S, Fitzgerald O. Classification of clinical subsets in psoriatic arthritis. Br J Rheumatol 1994;33:133-138. 5. Braverman IY, Yen A. Microcirculation in psoriatic skin. J Invest Dermatol 1974;2:493-502. 6. Braverman IY, Yen A. Ultrastructure of the capillary loops in the dermal papillae of psoriasis. J Invest Dermatol 1977;68:53-60. 7. Zaric DW, Worm AM, Stahl D, Clemmensen OJ. Capillary microscopy of the nailfold in psoriatic and rheumatoid arthritis. Scand J Rheumatol 1981;10:249-252. 8. Bhushan MM, Moore T, Herrick AL, Griffiths CE. Nailfold video capillaroscopy in psoriasis. Br J Dermatol 2000;142:1171-1176. 9. Hull SG, Goodfield M, Wood EJ, Cunliffe WJ. Active and inactive edges of psoriatic plaques: Identification by tracing and investigation by laser-Doppler flowmetry and immunocytochemical techniques. J Invest Dermatol 1989;92:782-785. 10. Veale DJ, Yanni G, Rogers S, et al. Reduced synovial membrane ELAM-1 expression, macrophage numbers and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 1993;36:893-900. 11. Ritchlin C, Haas-Smith SA, Hicks D, et al. Patterns of cytokine production in psoriatic synovium. J Rheumatol 1998;25:1544-1552. 12. Creamer DJ, Jaggar R, Allen M, et al. Overexpression of the angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase in psoriatic epidermis. Br J Dermatol 1997;137:851-855. 13. Fraser A, Fearon U, Billinghurst RC, et al. Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: Relationship to mediators of systemic and local inflammation. Arthritis Rheum 2003;48:3085-3095. 14. Fearon U, Reece R, Smith J, et al. Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients. Ann NY Acad Sci 1999;878:619-621. 15. Fearon U, Griosios K, Fraser A, et al. Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol 2003;30:260-268. 16. Markham T, Mullan R, Golden-Mason K, et al. Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy. J Am Acad Dermatol 2006;54:1003-1012. 17. DeBusk LM, Chen Y, Nishishita T, et al. Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alphainduced angiogenesis in rheumatoid arthritis. Arthritis Rheum 2003;48:2461-2471. 18. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284:1994-1998. 19. Reece RC, Canete JD, Parsons WJ, et al. Distinct vascular patterns in the synovitis of psoriatic, reactive and rheumatoid arthritis. Arthritis Rheum 1999;42:1481-1485.

20. Fraser A, Fearon U, Reece R, et al. Matrix metalloproteinase 9, apoptosis, and vascular morphology in early arthritis. Arthritis Rheum 2001;44:2024-2028. 21. Benjamin LE, Golijanin D, Itin A, et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999;103:159-165. 22. Kim HJ, Kim TY. Regulation of vascular endothelial growth factor expression by insulin-like growth factor-II in human keratinocytes, differential involvement of mitogen-activated protein kinases and feedback inhibition of protein kinase C. Br J Dermatol 2005;152:418-425. 23. Morel JCM, Park CC, Zhu K, et al. Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin18-induced vascular cell adhesion molecule-1 expression. J Biol Chem 2002;277:34679-34691. 24. Kuo GH, Wang A, Emanuel S, et al. Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors. J Med Chem 2005;24:1886-1900. 25. Voskas D, Jones N, Van Slyke P, et al. A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice. Am J Pathol 2005;166:843-855. 26. Fraser AD, van Kuijk AW, Westhovens R, et al. A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus cyclosporin in patients with active psoriatic arthritis. Ann Rheum Dis 2005;64:859-864. 27. Karim Z, Wakefield RJ, Quinn M, et al. Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: A comparison with arthroscopy and clinical examination. Arthritis Rheum 2004;50:387-394. 28. Strieth S, Echhorn ME, Sutter A, et al. Antiangiogenic combination tumor therapy blocking alpha(v)-integrins and VEGFreceptor-2 increases therapeutic effects in vivo. Int J Cancer 2006;119:423-431. 29. Hoff PM, Wolff RA, Bogaard K, et al. A phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma. Jpn J Clin Oncol 2006;36:100103. 30. Beerepoot LV, Witteveen FO, Groeneweger G, et al. Recombinant human angiostatin by twice-daily subcutaneous injection in advanced cancer: A pharmacokinetic and long-term safety study. Clin Cancer Res 2003;9:4025-4033. 31. Thomas JP, Arzoomanian RZ, Alberti D, et al. Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2003;21:223-231. 32. Goedkoop AY, Kraan MC, Picavet DI, et al. Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy. Arthritis Res Ther 2004;6:R326-R334. 33. Bongartz T, Coras B, Vogt T, et al. Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: An open-label pilot study. Rheumatology (Oxford) 2005;44:126129.

PSORIATIC ARTHRITIS

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Genetics of Psoriatic Arthritis Robert Winchester

IMPORTANCE OF IDENTIFYING SUSCEPTIBILITY GENES AND FACTORS THAT LIMIT ATTAINMENT OF THIS GOAL The identification of the genes responsible for the molecular basis of the development of psoriatic arthritis (PsA) should facilitate identifying pathways of inflammation and injury operating in the mechanism of PsA pathogenesis, developing drugs that should interdict targets in these pathways of injury, precisely diagnosing the presence of the disease for both clinical and epidemiologic purposes, clarifying the relationship between PsA and psoriasis (Ps), characterizing particular environmental factors that contribute to the development of the disease, and dividing patients into subsets by predicting disease severity and therapeutic response. However, the current knowledge about the genetic basis of PsA has major limitations that greatly impede attaining these goals. This state of affairs is summarized in the statement by Bruce and Silman: “PsA remains an intriguing and poorly understood condition.”1 I critically review aspects of the recent advances in the genetics of PsA and attempt to place this knowledge in context by identifying questions and problems that need to be addressed to facilitate further progress in the understanding of this disease.

Background Delineating the molecular basis of susceptibility to PsA is based on four mutually supporting and consistent, but still incomplete, sets of information.

1. Precise definition of the clinical phenotype: The currently acceptable phenotypes of PsA range from the classical syndrome of enthesitis, spondylitis, and onychodystrophy accompanying inflammatory peripheral arthritis that develops in an individual with Ps to much less distinctive forms of joint involvement including isolated symmetrical synovitis that occur in individuals with Ps, a form of arthritis not easily distinguishable from rheumatoid arthritis (RA), in which Ps is an incidental finding.2

2. Epidemiologic data that clearly demonstrate the existence of PsA but neither precisely define the disorder nor discriminate it from related entities. Among those presenting with various types of inflammatory arthritis, the prevalence of Ps is 4.5% to 5.3% compared with 1.5% to 3% in the general population, and conversely the prevalence of inflammatory arthritis is 15% to 20% in those with Ps, whereas in the general population it is about 2%.3,4 3. Familial aggregation: the classical studies of Moll and Wright in 1973 established the presence of an inherited predisposition to develop PsA and distinguished this disease from other entities.5 Among 88 probands with PsA, 12.5% had at least one first- or second-degree relative with confirmed PsA. Of the 181 first-degree relatives assessed, 10 had PsA, prevalence 5.5%. However, the pattern of inheritance of PsA does not segregate as a simple mendelian trait, implying that PsA is a genetically complex disease that arises through the interaction of alleles of multiple genes that may in turn interact with environmental effects. As is the case in other complex diseases, it is likely that the individual effect of a given gene is relatively small. 4. Knowledge supporting an autoimmune pathogenesis of PsA implicates the adaptive immune system and receptors of the innate immune response in immune recognition. Based on this evidence, one can sketch an overall scheme of pathogenesis (Fig. 9-1), which suggests categories of candidate genes. Interestingly, in comparison with other forms of inflammatory arthritis such as RA, the lack of identified autoantibodies and the observation that the disease progresses in the setting of advanced acquired immune deficiency syndrome emphasize that distinct elements operate in PsA pathogenesis and that CD4 T cells and B cells are not critically involved. They direct attention to more central roles played by the memory-effector subset of CD8 T cells and by natural killer (NK) cells. The first candidate genes to be explored were

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Microorganism, inflammation, trauma?

HLA genes + unknown genes

Initiates T-cell response

Define T cell repertoire susceptibility

Tolerance broken?

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Induction of stress glands

Enlarged Triggering repertoire of NK cells and of effector, effector/memory autoreactive T-cell T cells in response blood and skin

those regulating the adaptive immune response. Principal among these were the extremely polymorphic human leukocyte antigen (HLA) alleles that control the nature of the peptides presented to T cells in different individuals. The products of these genes operate during development to select the T-cell repertoires that define immunologic self and again operate to present pathogen-derived peptides during an adaptive immune response. HLA was the first candidate gene to be validated in PsA through the identification by Brewerton and colleagues of an increased frequency of HLA-B27 in the subset of those with PsA who develop spondylitis.6 Although associations of particular HLA alleles with PsA are intricate and not fully delineated, the importance of class I major histocompatibility complex (MHC) alleles is consistent with a primary role of CD8 T cells and NK cells in disease pathogenesis, suggesting that PsA is one of the few MHC class I–associated autoimmune diseases.

Shortcomings

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There appear to be two major shortcomings in our knowledge that thwart further progress. The first is that the diagnosis of PsA is syndromic in that it is based on a set of diagnostic or classification criteria, as discussed elsewhere in this volume. These criteria are undergoing progressive refinement, but currently there are concerns, strongly supported by an examination of reports on PsA genetics, that the criteria remain incompletely validated for distinguishing PsA from forms of synovitis such as seronegative RA that occur

Cytokine release, tissue injury, and altered differentiation program

Figure 9-1. A hypothetical scheme of events in psoriatic arthritis (PsA) pathogenesis that can be used to generate candidate genes for study. The development of PsA is separated into five stages. The first is the establishment of a T-cell repertoire that can respond to the inciting antigen. The second involves an initial provocative stimulus that breaks tolerance and results in T-cell expansion. The third stage reflects expansion of the T-cell clones in response to autoantigenic drive and their maturation to memory-effector T cells. The fourth stage involves induction of stress and injury ligands on target tissues and the response of natural killer (NK) cells and effector T cells to these ligands. The final stage is one of target cell and tissue injury by the innate and adaptive immune elements. HLA, human leukocyte antigen.

coincidently in an individual with Ps. Bruce and Silman stated that “Clinically, PsA remains difficult to define and it may be impossible at the clinical level to distinguish the co-occurrence of two common disorders that may modify each other from a common syndrome.”1 Obviously, there is no difficulty in the diagnosis of PsA when a patient exhibits the classical complex of enthesitis, distal interphalangeal joint involvement, onychodystrophy, and spondylitis in the setting of extensive plaque Ps. But there is uncertainty in diagnosis when a patient with Ps has only symmetrical metacarpophalangeal synovitis. Indeed, it has been argued that enthesitis is the characteristic manifestation of PsA.7 The challenge remains of distinguishing coincident arthritis in an individual with Ps from PsA because an incorrectly ascertained individual degrades the ability to identify the underlying genotype of those with true PsA. The second problem affecting work in this field is the genetic complexity of the human race and the potential for the presence of different susceptibility alleles in different racial and ethnic subsets. Studies, for example, in Crohn’s disease and RA, have revealed that some of the newly identified susceptibility genes responsible for the development of the autoimmune process are not shared by all ethnic groups, and indeed alleles that are definitively associated with susceptibility in one ethnic group are not even present in another. In addition, because the genetic contribution of some alleles may be small, this necessitates careful control of the study subject’s racial antecedents in “melting pot” situations, such as are found in North America, to identify the susceptibility genes and especially to avoid ethnic strat-

GENETIC STRUCTURE OF PSORIATIC ARTHRITIS AND THE RELATIONSHIP OF PSORIASIS TO PSORIATIC ARTHRITIS Although a relationship between Ps and PsA is indisputable, the nature of this relationship remains less than completely understood. Rahman and Elder8 and Barton9 have thoughtfully and instructively reviewed from somewhat contrasting perspectives the interrelationship between the two diseases and the crispness with which PsA is defined. Three different general models are proposed to help in examining the clinical and genetic data, with each model based on a differing genetic nature and relationship of Ps and PsA. To varying extents, each model is consistent with some of the available data. Model I considers Ps as a disease distinct from PsA, with separate susceptibility factors but with psoriasiform skin manifestation common to each. In PsA, the

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Figure 9-2. An example of a twogeneration pedigree illustrating three individuals affected with psoriatic arthritis, the proband, her brother, and a paternal uncle. There are no other affected family members. The proband bears the HLA-B*570101-Cw*0602 haplotype. (Courtesy of O FitzGerald et al.)

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penetrance of the joint manifestations is independent from that of the skin disease, leading to some individuals who manifest only skin disease and some with only joint disease, resembling the entity of undifferentiated spondyloarthritis (USpA) or “PsA sine psoriasis.” This model would account for the numerous large kindreds with multiple cases of Ps without any instances of PsA, as well as kindreds in which PsA and Ps are segregated in the same kindred or kindreds in which only PsA is identified (Fig. 9-2). The prediction of this model is that case series ascertained by the presence of Ps in the proband will be genetically heterogeneous, but case series ascertained by the presence of PsA will share certain susceptibility genes and all PsA will be genetically distinct from Ps. A variation on model I of complete genetic heterogeneity, model IA, postulates two separate diseases but with the addition that both parent diseases may be associated with arthritis; the Ps form is characterized by skin disease that is much more penetrant than joint disease, and in the second form joint disease is more penetrant than skin disease and may appear as USpA. The prediction of this model is that case series ascertained by the presence of either Ps or PsA in the proband will be genetically heterogeneous but there will be two subsets of Ps and PsA that each share a set of different susceptibility genes. Model II postulates that the genetic determinants of skin disease and of the enthesitis-arthritis complex of joint disease are independent but that the presence of the genetic determinants for either Ps or PsA lowers the threshold for the development of the other. Here, the entity of USpA or PsA sine psoriasis would be the designation of the parent joint disease, and PsA would occur when both the Ps and USpA genotypes were present. This model would account for the presence of USpA, a rheumatic disease with a prevalence approximately that of PsA, where the joint findings are indistinguishable from those found in PsA. The interaction

ification between cases and controls. It would appear that studies of comparable numbers of subjects performed in ethnically more homogeneous populations may have enhanced power to identify responsible genes because they minimize the potential for ethnic stratification. These points are particularly relevant to the comparison of the genetic elements responsible for Ps versus PsA, where a major question is the relationship of the two diseases, their genetic complexity, and whether there are genes that contribute only to Ps susceptibility or to PsA susceptibility. Unfortunately, there are very few studies in which a cohort of Ps and a cohort of PsA have been independently ascertained in the same population. This approach appears necessary to address these two shortcomings properly and allow cross validation of results. Selection of the subset of individuals with arthritis from a cohort ascertained by the presence of Ps is of interest, but this is not equivalent to a cohort of probands ascertained as PsA.

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between the two processes postulated to lower the threshold for both skin and joint disease would also account for the prevalence of PsA in epidemiologic studies. The prediction of this model is that case series ascertained by the presence of Ps in the proband will be genetically heterogeneous but case series ascertained by the presence of PsA will be homogeneous and share only a portion of these genes with those of Ps. Model III postulates that Ps is the parent disease, with PsA envisioned as a subset of Ps, perhaps in the sense of being a more severe phenotype that develops because of a greater dose of the same susceptibility genes or from an environmental factor. The additional genetic or environmental factors would be postulated to account for the development of the inflammatory arthritis that would be seen only in the setting of the Ps susceptibility genes. The prediction of this model is that case series ascertained by the presence of Ps in the proband will be genetically homogeneous and case series ascertained by the presence of PsA will also be homogeneous, completely overlap those of Ps, and perhaps be distinguished by additional genes. This model dominated the first quarter century of research on this question. Here, USpA would be a separate disease entity.

FORMAL GENETICS OF PSORIATIC ARTHRITIS

Familial Aggregation and Mode of Inheritance

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The classical studies of Moll and Wright in 1973 established the central phenotype of PsA and the presence of an inherited predisposition to develop the disease.5 Among 88 probands that fulfilled their criteria for PsA, 12.5% had at least one first- or second-degree relative who also met these criteria, with a prevalence of 5.5% among 181 first-degree relatives. Rahman and Elder8 reanalyzed these data and estimated the magnitude of the genetic contribution for PsA from the relative proportion of disease in the first-degree relatives compared with the prevalence of disease in the general population using the λR formulation by Risch.10 They assumed the estimated prevalence of PsA to be 0.1% and calculated the risk λR for first-degree relatives to be 55. Even assuming a higher prevalence of PsA in the population of 0.3%, the λR would decrease only to 18. Also, Moll and Wright found that the prevalence of Ps among first-degree relatives of probands with PsA was 19-fold that in the general population. Supporting these λR values, in a more recent study Myers and colleagues11 observed essentially similar findings, where the recurrence risk for Ps and PsA within sibships was studied in 80 index cases and 112 siblings. The concordance rate among sibs for all types of PsA was 14% including enthesitis and for Ps 21%. If enthesitis is

excluded, the resulting values resemble the frequency of affected sibs observed by Moll and Wright, who did not include enthesitis in their criteria. Sixteen affected sib pairs were found of which only four exhibited the same pattern of joint involvement, emphasizing the predominant clinical discordance of affected sibs for patterns of joint involvement and suggesting that clinical patterns of joint involvement might not be under genetic control. The most frequent pattern seen was joint involvement identical to that in RA. The most common symptom in affected siblings was enthesitis. Interestingly, the current knowledge of the genes involved in susceptibility to PsA in no way accounts for these high λR values. These λR values for PsA are notably higher than found in Ps, where the first-degree relative λR values are 4 to 10. This difference of λR between Ps and PsA indicates that PsA is not a simple genetic subset of Ps, assuming the ascertainment of Ps and PsA is comparable. However, apart from these studies, there have been few detailed examinations of the formal genetics of PsA. This is an area that requires additional study in different populations with comparisons between series of index cases of Ps without arthritis and index cases of PsA ascertained in the same population. Pedigrees provide the information that defines the mode of inheritance. Figure 9-3 contains representative pedigrees obtained from probands in a homogeneous Irish population ascertained with the presence of classical PsA. The mode of inheritance in these families is not compatible with a classical mendelian pattern but appears multigenic and is generally consistent with either dominant inheritance and reduced penetrance or recessive inheritance of common alleles also with reduced penetrance.

Penetrance The concordance of disease between monozygotic twins provides a measure of the penetrance of the susceptibility to develop the disease in question because these twins are identical in terms of their germline composition of genes. Ps has a concordance rate of 50% to 70% among monozygotic twins.12,13 This is a value in the upper range typically found in other autoimmune diseases. The interpretation of why penetrance in Ps or other autoimmune diseases is less than 100% indicates that inheritance of susceptibility genes in the germline is necessary but not sufficient to account for the disease. However, the converse, that there is an effect of the environment, is not necessarily implied because there are central events in the development of the adaptive and innate immune system that depend on stochastic interactions during development that are not germline encoded, such as generation of the T-cell and B-cell antigen specific clonal

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Figure 9-3. Three pedigrees illustrating varying patterns of inheritance of psoriasis (Ps) (quarter-filled symbols) or psoriatic arthritis (PsA) (half-filled symbols). A, A simplex situation in which no other family member is affected by Ps or PsA. Although this case appears sporadic, the individual bears the HLA-B*270502-Cw*010201 haplotype and could be explained by a recessive pattern of inheritance. B, A three-generation one depicting a father affected with Ps and three of his children affected with PsA. A child of the son affected with PsA has Ps. This suggests a dominant pattern of inheritance. The proband also bears the HLA-B*270502-Cw*010201 haplotype. C, A multiplex three-generation family where a mother affected with PsA has three children affected with PsA and two children with Ps. One of the affected daughters is the parent of three children affected with Ps and one child affected with PsA. The proband is a human leukocyte antigen (HLA) homozygote but lacks known susceptibility alleles. This pedigree suggests a dominant pattern of inheritance. (Courtesy of O FitzGerald et al.)

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receptor repertoire, that specify recognition properties of the lymphocyte and the expression of particular NK cell receptors on NK cells. Inexplicably, there have been no large-scale studies of twin concordance in PsA. It is likely that data similar to those of Ps with analogous implications will be obtained in PsA. On the basis of the higher ratios of λR calculated for PsA described earlier, the concordance rates for identical twins with PsA should well exceed those observed for Ps.

Simplex (Sporadic) versus Multiplex (Familial) Psoriatic Arthritis When an index case is found to have a positive family history, the pattern of the disease is designated “multiplex” or “familial.” In one comprehensive study of probands ascertained to have PsA,14 221 of 371 patients (60%) had no family history of PsA, Ps, or arthritis, and these pedigrees are designated “simplex” or “sporadic.” One hundred fifty patients had a family history positive for either PsA or Ps and were multiplex. The term sporadic may not be quite helpful and indeed may be a misnomer if it is misconstrued to imply that there is no genetic basis for disease in these instances. It is important to determine whether multiplex PsA and simplex (sporadic) PsA are the same disease, with the differences between the two explained by the number of susceptibility genes segregating in the family combined with penetrance, or whether these are genetically different forms of the disease. Interestingly, there is some evidence that the clinical and genetic features of disease differ between multiplex and simplex pedigrees. The study by Rahman and associates14 found that the multiplex group had an earlier age of onset of Ps (P = .001) and inflammatory arthritis (P = .001) and that the mean number of actively inflamed joints was

higher in the simplex group (P = .035), along with a higher frequency of rheumatoid factor positivity (P = .04), although the latter associations did not survive correction for multiple comparisons. These data suggest that a difference exists between the two forms of PsA and raise the question of whether each could be the consequence of different susceptibility genes with PsA subdivisible into two forms, in which case some multiplex families would result from the presence of genes not found in simplex PsA. However, the somewhat paradoxical combination of earlier age of onset and milder, rather than more severe, disease in individuals from multiplex families and the presence of rheumatoid factor raises the possibility that the ascertainment of additional family members might be influenced by the presence of one or more affected family members, leading to a lowering of the threshold for recognizing subsequent affected individuals with milder disease or at an earlier age with a contribution from the familial introspection that the presence of a disease engenders in certain families. The conclusive demonstration of genetic complexity requires that different alleles are shown to be responsible for multiplex and simplex forms of the disease or that the simplex form lacks susceptibility genes.

PSORIASIS—SUSCEPTIBILITY MAPS TO CANDIDATE GENES TELOMERIC TO HLA-B (HLA-C?) Because the identification of the genetic basis of Ps has progressed more rapidly than in PsA, the status in Ps is first briefly reviewed as background. An extensive line of investigation has clearly localized a major susceptibility gene for Ps to the class I region of the MHC on chromosome 6p at or near HLA-C (Fig. 9-4).

PSORS1C2 PSORS1C1 POU5F1 LOG442199

CDSN TCF19 HCG27 31,190 Telomere

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MICB BAT1 LTA 31,590

31,670kB Centromere

Figure 9-4. The region of chromosome 6p21 around human leukocyte antigen HLA-C and HLA-B in the major histocompatibility complex that is of primary interest in psoriasis and psoriatic arthritis. The numbering of the nucleotides constituting the sixth chromosome begins at the telomere of 6p, to the left. The numbers are in units of 1000 nucleotides (1 kB). The approximate location and size of the genes of interest are noted above the axis with the symbol for the gene. The HLA-A locus is not illustrated and is 1326 kB to the left of HLA-C. The region from HLA-C to CDSN is the probable location of PSORS1. The genes centromeric to HLA-B are more concerned with regulating innate immune responsiveness. 88 kB separate HLA-C from HLA-B. 49.5 kB separate HLAB from MICA. 83 kB separate MICA from MICB. The remainder of the class III region and the class II region are to the right of TNF. The data are selected from the National Center for Biotechnology Information website: Entrez Gene (http://www.ncbi.nlm.nih.gov/ entrez).

TABLE 9-1 THE MORE COMMON HAPLOTYPES THAT EXHIBIT LINKAGE DISEQUILIBRIUM IN HEALTHY EURO PEAN WHITES Haplotype

Haplotype Frequencies Europe (n = 1595)

0201/1302/0602

0.008

2402/1302/0602

0.002

3001/1302/0602

0.007 0.017

0201/2705/0102

0.004

0301/2705/0102

0.003

1101/2705/0102

0.002

3201/2705/0102

0.002 0.011

0201/2705/0202

0.005 0.005

0101/3701/0602

0.008

0201/3701/0602

0.003 0.011

0201/3801/1203

0.004

2601/3801/1203

0.006

Psoriasis—Susceptibility Maps to Candidate Genes Telomeric to HLA-B (HLA-C?)

Although still incompletely defined, this locus has been designated PSORS1. HLA alleles were early candidate genes in a disease considered to have an autoimmune pathogenesis. However, the MHC is the most gene-rich region of the genome and also the site of genes with by far the greatest numbers of alleles. Many of the alleles of different loci exhibit marked linkage disequilibrium, a situation where particular alleles of different loci are found together on the same haplotype significantly more frequently than would be expected by chance, assuming equal crossing over. Linkage disequilibrium may extend over many hundreds of thousands of base pairs and reflects founder effects or selection. The wealth of genes, alleles, and linkage disequilibrium makes it very difficult to identify which gene within a haplotype is responsible for an association. Delineation of Ps susceptibility began with extensive association studies, reviewed by Henseler and coauthors,15 that implicated several HLA-B locus alleles (see Fig. 9-4). HLA-B57 (a split of the older still B17 antigen), HLA-B37, and HLA-B13 were first identified. HLA-B27 was also found in a small proportion of those with Ps and was preferentially associated with pustular Ps.16 Subsequently, a stronger association was found with more telomeric genes,17 especially with the Cw6 allele of the HLA-C locus,18 currently designated HLA-Cw*0602. The HLA-C locus is 88.4 kb telomeric to HLA-B (see Fig. 9-4). HLA-C is a particularly interesting member of the MHC. Evolutionarily, only the chimpanzee possesses HLA-C alleles equivalent to those of humans; moreover, the HLA-C molecules have extensive roles in regulating NK and effector cell reactivity by interacting with particular killer cell immunoglobulin-like receptors (KIRs), molecules that act as either inhibitory or stimulatory receptors.19,20 The alternative forms of HLA molecules were referred to as “antigens” in the earlier terminology when the allelic specificities were detected by imprecise serologic techniques. Alleles of the HLA-B and HLA-C loci are now determined by various molecular biologic methods, such as DNA sequence-based typing. Because there are over 750 HLA-B alleles and well over 200 HLA-C alleles, the current terminology to represent specific alleles is usually a four- or five-digit number preceded by an asterisk. HLA-Cw*0602 alleles in whites are in strong linkage disequilibrium with each of the HLA-B locus alleles, such as HLA-B57 (HLA-B*5701) and HLA-B13 (HLA-B*1302), that were associated with susceptibility to Ps, suggesting that HLA-Cw*0602 drives the disease susceptibility. The common relevant haplotypes that exhibit linkage disequilibrium with alleles of interest are illustrated in Table 9-1. As expected, linkage studies with Ps using dense microsatellite maps have confirmed the importance of

0.01 0201/3901/1203

0.002 0.002

0201/3906/0702

0.002

2402/3906/0702

0.003 0.005

0101/5701/0602

0.019

0201/5701/0602

0.008

0301/5701/0602

0.002

2402/5701/0602

0.002 0.031

The table summarizes the more common haplotypes that exhibit linkage disequilibrium in healthy European whites and contain alleles relevant to psoriatic arthritis (PsA) susceptibility. The data are selected from the National Center for Biotechnology Information website: dbMHC, IHWG anthropology project (http://www.ncbi.nlm.nih.gov/projects/mhc/ihwg.cgi). The haplotypes are grouped according to the presence of common human leukocyte antigen HLA-B and HLA-C alleles. The HLA-A alleles of each HLA-B–HLA-C haplotype sometimes exhibit limited divergence from each other, accounted for by the distance of 1.3 million bases between HLA-A and HLA-C. The frequency of each haplotype is listed in terms of the fractional representation of each for a haploid chromosome. These presumptive PsA susceptibility haplotypes sum to a frequency of 0.092 (9.2%) of a total of 1.0. Note that this allele or haplotype frequency is not the phenotype or population frequency used in the remainder of this chapter that is based on the frequency of the allele among diploid individuals, which would add to 200%.

71

GENETICS OF PSORIATIC ARTHRITIS

alleles in the MHC class I region in most populations studied.21,22 Whether or not PSORS1 is HLA-Cw*0602 or another linked gene is still a matter of inquiry. It has been suggested that the true susceptibility locus may not be HLA-C itself but an allele of another gene in linkage disequilibrium with HLA-Cw*0602 located within a 60-kb region telomeric to the HLA-C locus (see Fig. 9-4).23 The region in the haplotypes bearing HLA-B57 and HLA-B13 that are telomeric to the HLAB locus that begin with HLA-C is common to each of these haplotypes in whites, and the region beginning with HLA-C almost certainly harbors the PSORS1 susceptibility gene. There are several interesting potential candidate genes in this region of the MHC, including those identified in the Human Genome Project, including corneodesmosin, CDSN, 160 kb telomeric to HLA-C24 and HCR.25 However, the extreme linkage disequilibrium in this region of the MHC with the HLA-Cw*0602 alleles within the white and Asian populations makes resolution of this question difficult. Other groups using single-nucleotide polymorphism (SNP) mapping technology place the susceptibility locus at or nearer HLA-C, such as in the study by Veal and co-workers.26 In addition, studies on the relevance of the KIR alleles to Ps, discussed in more detail subsequently, direct attention to the HLA-C locus itself.27,28

Stratification within Psoriasis

72

Two main types of psoriasis vulgaris have been proposed, mainly on the basis of bimodal distribution of the age at onset and inheritance: type I with onset before or at the age of 40 years, characterized by positive family history and frequent association with HLACw*0602, and type II with onset after the age of 40, negative family history, and a normal frequency of HLA-Cw*0602.29 In support of this stratification, HLA-Cw*0602–positive patients have an earlier onset of Ps than HLA-Cw*0602–negative patients.30-32 Among 369 patients, 67% were HLA-Cw6 positive with a mean age of 17.2 years at onset of skin disease, compared with 24.5 years in the Cw6-negative group. Gudjonsson and colleagues33 also found earlier disease onset and enhanced relative risk among HLA-Cw*0602 homozygous patients compared with heterozygous Ps patients. However, the homozygous patients did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes, or frequency of arthritis but had more extensive plaques and more severe disease. PSORS1 is clearly located telomeric to HLA-B, perhaps in HLA-C, or is again situated just telomeric to this locus. It appears to act to increase the penetrance of the trait of developing Ps, presumably through epistatic interactions. However, PSORS1 is certainly not the whole story of

Ps susceptibility as it does not well explain development of disease in individuals without family histories and there are highly multiplex families that do not have HLA-Cw*0602 haplotypes.34

CANDIDATE GENES IN PSORIATIC ARTHRITIS

Human Leukocyte Antigen Alleles In comparison with Ps, the role of HLA alleles in determining susceptibility to PsA is less conclusively etched and seemingly more intricate.13 Association studies with candidate genes with PsA began with the identification by Brewerton and colleagues of a significantly increased frequency of HLA-B27 in individuals with PsA,6 and this finding was extensively confirmed.35-38 Because of the previously identified association of HLA-B27 with ankylosing spondylitis and the presence of spondylitis in PsA, the HLA-B locus HLA-B27 was certainly an interesting candidate allele. There is considerable heterogeneity in the reported frequency of HLA-B27 in PsA, ranging from 39% in Taiwan36 to 17% to 34% in different studies from northern Spain,37,39,40 20% in Great Britain,38,41 4% in Israel,42 and series in which HLA-B27 was not detected.43 Molecular typing of the alleles that encode the HLAB27 antigen has revealed 24 different alleles in this family.44,45 Some alleles are rare or the specific property of certain ethnic groups, and two alleles are not associated with susceptibility to develop ankylosing spondylitis.44,45 HLA-B*27052 is the most common allele found in more northern white and Asian populations, where its population frequency is notably elevated. Where it was studied, the molecularly defined subtypes of HLAB27 found in PsA followed the frequency of the various HLA-B27 alleles in the population and predominantly consisted of HLA-B*27052.37 In contrast, in Ps, HLAB27 alleles contribute only minimally to susceptibility.16 Studies comparing the frequency of molecularly defined HLA-B*27052 in Ps versus PsA cohorts in the same ethnic population are distinctly rare, although this is clearly an important question, the answer to which bears directly on the alternative models that describe the potential relationship between Ps and PsA. HLA-B39 and to a lesser extent HLA-B38 (both splits of the specificity termed HLA-B16 in the very old nomenclature) have been identified as elevated in PsA in multiple independent studies but with divergence between different reports, in part because of the differences in ethnic distribution. HLA-B*3801 differs from HLA-B*3901 in that the former bears a strong ligand for the KIR3DL1 NK cell receptor and the latter is nonreactive. Espinoza and coauthors46 first identified an increased frequency of HLA-B38 in those with peripheral arthritis. Murray and associates43 found HLA-B38 in 23.1% of PsA, 6.8% of Ps, and 4.0% of a control

.00159; and not significantly increased in a Jewish population.47 Because the frequency of HLA-C*0602 in the Israeli population is slightly higher than in other white populations, it is likely that the reduced frequency of HLA-C*0602 in this PsA cohort is not due to the decrease of this allele in the sample and will be highly informative. Unfortunately, there was no parallel Ps cohort available with which to compare these results to confirm that a genetically different subset was being identified. Indeed, to emphasize the heterogeneity of results in this area, HLA-Cw6 was not found to be significantly elevated in a British series of juvenile-onset PsA, where one would have anticipated a notable increase of this allele.39 Also at odds with the reports of elevated frequencies of HLA-Cw6 in PsA that are similar to the frequency of this allele in Ps found in some series59 is the nonsignificant trend showing that PsA is more common among Ps patients who lack HLA-Cw6 than those having HLA-Cw6.60 Candidate genes telomeric to HLA-C have been studied in PsA that have previously been explored as candidates for PSORS1 in studies on Ps, and they include PSORS1C1 (Ps susceptibility 1 candidate 1) and PSORS1C2 located just proximal to CDSN, itself located approximately 150 kb from HLA-C (see Fig. 94). Rahman and coauthors61 examined the frequency of alleles of PSORS1C1, also termed SEEK1, and found that the frequency of the minor SEEK1(T) allele in subjects with PsA and control subjects was 48.5% and 32.4%, respectively (odds ratio [OR] = 2.0; P = .017), in a Newfoundland population and only slightly but not significantly elevated in an Ontario population, 46.5% and 38.0%, respectively (OR = 1.4; P = .16). This association appears secondary to linkage disequilibrium between SEEK1 and HLA-Cw*0602 and suggests that further exploration in the telomeric direction for susceptibility alleles in this HLA-Cw*0602 haplotype may not yield much information. Given that PsA susceptibility is associated to some degree with HLA-B and HLA-C locus alleles, it would be anticipated that members of affected sibling pairs should share these alleles on the same haplotype. A study of haplotype sharing among affected sibling pairs of individuals with PsA revealed that among 182 siblings of probands affected with PsA, 46 sibs were affected by PsA, 48 by Ps, and 88 were unaffected.62 The sharing of 2, 1, and 0 haplotypes for the PsAaffected sibling pairs was 14, 27, and 5, respectively, expected 11.5, 23, 11.5 (P = .04), whereas there was no significant haplotype sharing for the Ps-PsA–affected sibling pairs. The 8/46 increase among PsA concordant sib pairs is a slight one of 17.4%, with the balance of the sib pairs concordant for disease but discordant for HLA haplotypes. Perhaps the most intriguing finding in this study is that the extent of increased sharing

Candidate Genes in Psoriatic Arthritis

population. However, HLA-B38 is often found as a component of the HLA-A*2601-B*3801-DRB1*0402 haplotype present in elevated frequency among Israelis and others in northeastern Asia. Indeed, in the report by Murray and others each of the alleles in this haplotype was increased in the PsA population. Gonzalez and co-workers studied a Jewish population to address the possibility of ethnic stratification between patients and control group to account for these HLA associations and found in this more ethnically heterogeneous sample that there was no significant increase in any element of the HLA-B38 haplotype in PsA cases when a control was drawn that matched the ethnic composition of the population of patients.47 However, although the frequency of HLA-B38 in control subjects was 21% it was still slightly elevated, to 40%, among PsA patients, suggesting that HLA-B38 should not be totally excluded as a susceptibility allele. Ethnic stratification between disease sample and control appears to explain a portion but not all of the results in earlier studies that highlighted an increase in frequency of HLA-B38 in those with PsA. This question of HLAB38 as a determinant of PsA susceptibility requires further study. In contrast, the frequency of serologically determined HLA-B39 has been more consistently found elevated in those with PsA in various populations.13,48,49 The family of HLA-B39 alleles is much larger and includes alleles that encode two subfamilies of molecules, the principal alleles of which are HLAB*3901 and B*3906. These two molecules differ from one another in their peptide binding properties, primarily at the C terminus of the peptide. Molecular typing of the alleles composing the HLA-B39 has not been reported in PsA and is needed to resolve which of the classes of HLA-B39 alleles are associated with susceptibility. In terms of HLA-B–HLA-C haplotypes, the HLA-B27, HLA-B38, or HLA-B39 alleles are found in linkage disequilibrium with various HLA-Cw alleles, but none are in linkage disequilibrium with HLACw*0602 (see Table 9-1). PsA is also associated with an elevated frequency of HLA-Cw6, as first reported in a study using serologic techniques by Murray and colleagues,43 where it was identified in 34.6% of PsA, 50% of Ps, and 13.5% of a control population. This observation has been extensively confirmed.48,50-55 However, the frequency of HLA-Cw6 exhibited considerable heterogeneity among these series, making it difficult to draw firm conclusions regarding the difference in frequency of this allele, if any, between Ps and PsA. For example, the frequency in PsA of molecularly typed HLA-C*0602 allele versus control is 34% versus 18%, P < .0156; 40% versus 26%, P < .0557; 56% PsA in Poland versus 18.7% controls58; 60% in northern Spain versus 17%, P
3 swollen and tender joints and moderate or worse global assessments at baseline). The primary outcome measure was the PsARC, a composite score derived for PsA that has subsequently been incorporated into a number of clinical trials in PsA (Table 12-1). The duration of disease averaged 12 years, and males who were veterans of military service predominated. Significant improvement in the primary outcome measure was noted (PsARC 57.8% sulphasalazine vs 44.6% placebo) but not in the individual measures. Secondary outcome measures and laboratory measures failed to reach significance, apart from reduction in erythrocyte sedimentation rate, and these included indices for enthesopathy, dactylitis, and spondylitis. Longitudinal analysis added significance to patient global assessment. Response was seen by 4 weeks for most measures, but maximum difference from placebo took 28 weeks or longer. At baseline, mean percentage body surface area of psoriatic rash was 12%, and sulphasalazine produced a significant reduction in rash compared with placebo, but the confidence intervals were wide. Withdrawal rates were in the 22% to 32% range predominantly for nonserious adverse effects. The remainder of the sulphasalazine studies8-14 were small, contained 30 to 112 patients, and were of 6 to 12 months duration. Study designs included open-label, placebo controlled, and inclusion of PsA subjects as part a larger spondyloarthropathy trial. Dropout rates were high (26%-44%), and the most common adverse effects were rash and gastrointestinal

97

58 50

50 % response

MANAGEMENT OF PSORIATIC ARTHRITIS

60 44.6

40 30

30 20 10

6.6

7.8

SZP (13)

FUM (48)

0 LEF (29)

SZP (7)

MYC (49)

CHLO (16)

Figure 12-1. Placebo response rates in PsA trials. CHLO, chloroquine; FUM, fumarate; LEF, leflunomide; MYC, Mycobacterium; SZP, sulphasalazine.

TABLE 12-1 PSORIASIS ARTHRITIS RESPONSE CRITERIA (PsARC) 1. Patient self-assessment (improvement = decrease by 1 category) 2. Physician assessment (worsening = increase by 1 category) 3. Joint tenderness score (improvement = decrease by 30%) 4. Joint swelling score (worsening = increase by 30%) Treatment response is defined as improvement in at least 2 of 4 measures, one of which must include joint tenderness or swelling and no worsening in any of the measures. Modified from Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondyloarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42:2325–2329.

intolerance. A significant number of patients discontinued drug because of lack of efficacy. Decreases in erythrocyte sedimentation rate, pain, duration of morning stiffness, and peripheral joint tenderness and swelling were noted in some subjects. Articular indices showed limited improvement, and the effect on psoriasis was variable. The benefit of sulphasalazine appears to be confined to peripheral arthritis, with no significant anti-inflammatory effects on axial disease. These findings are similar to those reported for the effects of sulphasalazine on spinal disease in ankylosing spondylitis.7 Sulphasalazine failed to retard radiographic progression at 2 years in an open-label study when compared with controls, most of whom were not on DMARD therapy.14

Methotrexate 98

Methotrexate has been used since 1951 for the treatment of psoriasis. In 1964, in the first double-blind, placebo-controlled study, 21 patients who had active skin disease and peripheral arthritis15 received par-

enteral methotrexate (1 to 3 mg/kg * 3 doses at 10-day intervals) or placebo with an observation period of approximately 3 months. Significant improvement in joint tenderness and joint range of motion, extent of skin involvement, and erythrocyte sedimentation rate was seen. The majority of patients experienced a recurrence of skin and joint disease within 1 to 4 months after methotrexate was discontinued. Adverse effects were common: gastrointestinal 76%, leukopenia 33%, and two deaths. In the only randomized, double-blind, placebo-controlled trial of oral low-dose pulse methotrexate therapy,16 37 patients received 7.5 to 15 mg/week methotrexate or placebo for 12 weeks. Significance was shown for physician global assessment only, but no more than 16 patients received active drug and 50% of the patients finished the trial on 7.5 mg of methotrexate per week. At these doses no significant effect on rash was observed, and there were no safety issues. In a 24-month study involving 38 patients, methotrexate-treated patients did not show any improvement in radiographic progression compared with that of matched clinic controls.17 Whether the use of methotrexate in psoriasis and PsA results in more frequent or severe hepatotoxicity than that experienced in RA is unknown. A retrospective study of 104 patients followed over 2 decades did not suggest increased toxicity.18 General consensus regarding the indications for liver biopsy, either pretreatment or at specified intervals during treatment, has not been achieved, and the debate continues with considerable variation between dermatologic and rheumatologic recommendations.19 Despite the absence of evidence, methotrexate is widely used in treating PsA. Indeed, failure to respond to methotrexate therapy is a requirement of many regulatory authorities for reimbursing anti-TNF therapy. Definitive evidence to support or refute the efficacy of methotrexate in treating PsA is awaited, and a placebocontrolled trial is presently under way in the United Kingdom. More can be gleaned from the placebo arms of trials of biologic agents, in which background methotrexate use was allowed (these patients had active disease, as defined by three to five or more tender and swollen joints despite stable therapy). For example, in the Alefecept (LFA3-Ig) trial,20 62 subjects in the placebo arm were taking methotrexate (44% for less than 6 months prior). They demonstrated American College of Rheumatology (ACR) 20, 50, and 70 responses of 23%, 10%, and 7%, respectively. The skin scores in these patients were Psoriasis Area Severity Index (PASI) 50 and 75 responses of 31% and 24%, respectively. The subjects on methotrexate alone had few adverse events: 2 of 146 patients experienced temporary and reversible elevation of liver function test results higher than three times the upper limit of the normal range. These values normalized, and the patients were able to continue in the trial

Oral and Parenteral Gold Limited studies exist that test the efficacy of gold compounds. In a 6-month double-blind, placebo-controlled study of auranofin (6 mg/day) involving 238 patients, the auranofin-treated group showed significant improvement in physician’s global assessment and occupational/daily function scores compared with that in the placebo group, but with no significant difference in morning stiffness or joint tenderness/swelling scores.21 The rate of withdrawal from auranofin because of adverse drug reactions was 10%. An uncontrolled study involving 14 patients treated with injectable gold showed either remission or improvement (50% reduction in number of inflamed joints) in 71% of the patients.22 Toxicity was similar to that observed with parenteral gold in RA. A double-blind comparison of auranofin (6 mg/day), intramuscular gold sodium thiomalate (50 mg/wk), and placebo showed significant improvement in the Ritchie articular index, the visual analog pain score, and the erythrocyte sedimentation rate over 24 weeks in the parenteral gold group, but no significant difference in the auranofin group as compared with the placebo group.23 Radiographic disease progression was not prevented in a small controlled 2-year study of parenteral gold. Neither significant flare nor improvement in cutaneous psoriasis with oral or parenteral gold has been observed. When comparisons are made retrospectively24 as well as prospectively25 between patients on gold and methotrexate therapy, PsA patients treated with methotrexate are nine times more likely to respond and five times less likely to discontinue therapy than patients on gold. The mean duration of treatment survival was 6 months in PsA patients on gold compared with 16 months in patients on methotrexate.

Leflunomide Leflunomide is an isoxazole derivative and selective pyrimidine synthesis inhibitor that blocks dihydroorotate dehydrogenase and targets activated T cells that lack a salvage pathway.26 A small pilot, open-label study of six patients with psoriatic polyarthritis showed a significant decrease in the C-reactive protein as well as in the tender and swollen joint count, although not in the extent of psoriasis, after 3 months of therapy.27 Another open-label study conducted in 12 patients with polyarticular PsA who had failed at least one DMARD confirmed the clinical efficacy of leflunomide in the 8 patients available for 2-year follow-up.28 Psoriasis improved in two thirds of the patients.

These promising results led to a randomized doubleblind, placebo-controlled study of 6 months’ duration in 188 patients with active PsA (>3 tender and swollen joints) and active psoriasis (>3% body surface area).29 More than half of the patients had been inadequately controlled by prior DMARD therapy, including methotrexate. Dropouts were high in the treatment phase, perhaps because of requirements to cease all topical and DMARD therapies before enrollment (lack of efficacy dropouts were 19.8% in the leflunomide group compared with 35.9% in the placebo group). At 24 weeks 59% of patients in the leflunomide group met the primary efficacy endpoint (PsARC) compared with 29.7% in the placebo-treated patients. The ACR 20 response was 36.3% in the subjects on leflunomide compared with 20% in the placebo arm. For both of these outcome measures, all individual elements showed significant benefit over placebo. The PASI score improved significantly in 24% of the patients on leflunomide but none of the subjects on placebo, PASI 50 and PASI 75 scores being 30.4% and 17.4%, respectively, in those treated with leflunomide and 18.9% and 7.8%, respectively, in those treated with placebo. Target lesion response was also significant, with 48.4% (leflunomide) versus 25.6% (placebo). There were significant improvements in quality of life and function scores in patients taking leflunomide compared with those on placebo, both for arthritis and for rash as measured by Health Assessment Questionnaire (HAQ) and Dermatology Life Quality Index (DLQI). Treatment was relatively well tolerated, with adverse effects in keeping with the large RA experience and with no unexpected psoriasis-related toxicity seen. Treatment-related dropouts included 10.4% of the leflunomide group and 2.2% of those treated with placebo. Diarrhea, elevated alanine transaminase (ALT), and tiredness/lethargy were seen more frequently in the leflunomide group. Although 12 patients had ALT elevations (5 in placebo), only 2 were above three times the upper limit of the normal range leading to withdrawal; elevations for the remaining patients normalized with dosage adjustment. No radiologic assessments were made in this trial, so it is unknown what effect this drug has on radiologic progression in PsA.

Conventional Disease-Modifying Antirheumatic Drugs

without treatment change. It is anticipated that we will learn more about the efficacy and safety of methotrexate in future trials that examine earlier disease and in combination biologic therapy studies with monotherapy arms compared with combinations as seen in RA studies.

Azathioprine and 6-Mercaptopurine Both azathioprine and its derivative, 6-mercaptopurine, are purine analogs that have been used to treat psoriasis and PsA. Although favorable results have been reported, the study populations are small and no placebo-controlled data are available. Eleven of 13 patients treated with 6-mercaptopurine (20 to 50 mg/kg/day) showed improvement in both joint and skin disease within 3 weeks of initiation of therapy, and maintenance of this improvement on a dose of 1 mg/kg/day was observed with minimal adverse

99

MANAGEMENT OF PSORIATIC ARTHRITIS

effects.30 A 12-month double-blind, crossover study of azathioprine (3 mg/kg/day) in six patients reported moderate or marked joint improvement in all six patients and cutaneous improvement in four; however, the dose of azathioprine had to be reduced in five patients because of leukopenia.31 In view of the known toxicity of these agents, appropriate monitoring is mandatory. Issues of long-term toxicity and skin malignancy in other settings raise concerns about long-term safety of these agents in PsA.

Cyclosporine A Cyclosporine A (CyA) is effective in treating psoriasis, and benefit in PsA has been examined in a number of case reports and open-label studies.32,33 Marked improvements in joint and skin disease have been described with CyA doses that range from 2 to 6 mg/kg/day. Nephrotoxicity in the studies overall led to 6% discontinuation. A prospective controlled trial compared CyA (3 mg/kg/day) with methotrexate (7.5 mg weekly) in 35 PsA patients treated over a 1-year period. The data suggested equivalent efficacy in both groups, although combined withdrawals due to lack of efficacy and toxicity were greater in the subjects on CyA.34 In a more recent trial, 72 patients with active PsA (>3 tender and swollen joints) despite stable methotrexate therapy (mean 16 mg/week) were randomized to combination CyA therapy (mean 2.25-2.4 mg/kg/day) or placebo over 12 months of follow-up. Significant improvements in joint counts, reduction in C-reactive protein levels, and improvements in PASI were demonstrated in subjects randomized to CyA. Minor elevations in creatinine were noted in the CyA subjects, and 11% experienced serious adverse effects. Radiologic progression was examined using the Larsen score, and no significant difference in radiographic progression was achieved.33 Certainly, the balance of efficacy and toxicity of CyA, particularly as monotherapy in PsA, needs further evaluation.

Antimalarial Agents

100

Concerns that antimalarial drugs, particularly quinacrine, may have an adverse effect on psoriasis have limited their use in treating PsA. A review of 50 PsA patients treated with hydroxychloroquine showed no worsening of psoriasis.35 In one open-label study, 32 clinic patients treated with chloroquine were compared with clinic patients not using DMARD therapy. Six subjects had an exacerbation of psoriasis, as did an equal number of control patients, and 75% of subjects on chloroquine had a greater than 30% reduction in active joint count.36 Further prospective, controlled trials are required to assess the safety and efficacy of these agents.

D-Penicillamine Anecdotal and limited information exists for D-penicillamine in the treatment of PsA. Eleven patients were randomized to an initial phase consisting of treatment with either D-penicillamine or placebo for 4 months, followed by 4 months of treatment with D-penicillamine for all patients. The maximum dose of D-penicillamine was 750 mg/day, and no unusual toxicity was observed. No efficacy measure attained statistically significant improvement.37 Despite inadequate data regarding treatment, more efficacious choices exist.

Colchicine Colchicine interferes with neutrophil chemotaxis. A pilot study showed that 11 of 22 patients treated with colchicine (0.02 mg/kg/day) had significant cutaneous clearing and 4 of 8 patients with arthralgias were symptomatically improved.38 A 16-week double-blind, crossover study of 15 patients compared colchicine, 1.5 mg/day, with placebo.39 All measures including Ritchie Index, grip strength, pain scores, and physician assessment were significantly better with colchicine treatment than with placebo. Psoriasis was unaffected. Two patients dropped out because of gastrointestinal disturbance, and five others had diarrhea requiring dose adjustment. Larger studies of longer duration are needed to establish any role of colchicine in the management of PsA. Hyperuricemia and gout, common in PsA, were not documented in this study.

Retinoids Etretinate, a vitamin A derivative, is the most commonly used retinoid in the treatment of psoriasis, and initial experience with this agent in PsA suggests that is has a beneficial effect. In one recent pilot study, 40 patients treated with etretinate (50 mg/day) for a mean of 21.9 weeks experienced significant improvement in the number of tender joints, the duration of morning stiffness, and the erythrocyte sedimentation rate.40 Maximal improvement for most efficacy measurements was seen at between 12 and 16 weeks. Mucocutaneous reactions consisting of dried and cracked lips, mouth soreness, and nosebleeds were seen in the preponderance of patients (39 of 40) and required cessation of treatment in 9 patients. Other relatively frequent adverse effects were alopecia, hyperlipidemia, myalgias, and elevated transaminase levels. Etretinate is a teratogen and should not be used in women of child-bearing potential.

MISCELLANEOUS AGENTS Other agents41-49 that have been reported to have activity in PsA include mycophenolate mofetil, fumarate, Mycobacterium vaccae, interferon gamma, somatostatin, heliotherapy, photochemotherapy with psoralen plus ultraviolet A (PUVA), bromocriptine,

CONCLUSION Clinical trial evidence to guide the use of traditional DMARD therapy is disappointing, but despite this some regulatory authorities mandate the failure of salazopyrine, methotrexate, or leflunomide therapies as a requirement for allowing reimbursement for

anti-TNF therapy in PsA. Adequately powered trials of therapy stratified for subsets of disease; examination of treatments in early disease; and the efficacy of combination therapy in clinical trials that incorporate validated outcome measures, including assessment of radiologic progression, are all urgently needed. The emergence of the biologic agents has been accompanied by improved clinical trial design and implementation in both psoriasis and PsA. As we move forward, clinical studies that include important domains and validated instruments will allow us to learn more about the efficacy and safety of traditional DMARDs for the treatment of skin and joint inflammation in PsA.

References

cimetidine, fumaric acid, 2-chlorodeoxyadenosine, parenteral nitrogen mustard, peptide T, radiation synovectomy with yttrium 90, dietary supplements, and total lymph node irradiation. Further study is needed to define what role, if any, these regimens might have in patient management.

REFERENCES 1. Rahman P, Nguyen E, Cheung C, et al. Comparison of radiological severity in psoriatic arthritis and rheumatoid arthritis. J Rheumatol 2001;28:1041-1044. 2. Husted JA, Gladman DD, Farewell VT, Cook RJ. Health-related quality of life of patients with psoriatic arthritis: A comparison with patients with rheumatoid arthritis. Arthritis Care Res 2001;45:151-158. 3. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis & Rheumatism Council Low Dose Glucocorticoid study group. New Engl J Med 1995;333:142-146. 4. Maksymowych W, Inman R, Stone M, et al. The Spondyloarthritis Research Consortium of Canada (SPARCC) Canadian Rheumatology Association Consensus on the Use of Anti–Tumor Necrosis Factor α–Directed Therapies in the Treatment of Spondyloarthritis. J Rheumatol 2003;30:1356-1363. 5. Hilliquin P, Gregoir C, Menkes CJ. [Value of pulse methylprednisolone in polyarticular forms of psoriatic rheumatism. ] Rev Rhum Mal Osteoartic 1992;59:160-161. In French. 6. Baker H, Ryan TJ. Generalized pustular psoriasis. A clinical and epidemiological study of 104 cases. Br J Dermatol 1968;80: 771–793. 7. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42:2325–2329. 8. Farr M, Kitas GD, Waterhouse L, et al. Sulphasalazine in psoriatic arthritis: A double-blind placebo-controlled study. Br J Rheumatol 1990;29:46. 9. Seideman P. Sulphasalazine treatment of psoriatic arthritis. Rheumatology 1990;29:491-492. 10. Gupta AK, Grober JS, Hamilton TA, et al. Sulfasalazine therapy for psoriatic arthritis: A double-blind, placebo-controlled trial. J Rheumatol 1995;22:894-898. 11. Fraser SM, Hopkins R, Hunter JA, et al. Sulphasalazine in the management of psoriatic arthritis. J Rheumatol 1993;32: 923-925. 12. Dougados M, van der Linden S, Leirisalo-Repo M, et al. Sulfasalazine in the treatment of spondyloarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995;38:618-627. 13. Combe B, Goupille P, Kuntz JL, et al. Sulphasalazine in psoriatic arthritis: A randomised, multicentre, placebo-controlled study. J Rheumatol 1996;35:664-668. 14. Rahman P, Gladman DD, Cook RJ, et al. The use of sulfasalazine in psoriatic arthritis: a clinical experience. J Rheumatol 1998;25:1957-1961. 15. Black RL, O’Brien WM, Van Scott EJ, et al. Methotrexate therapy in psoriatic arthritis. JAMA 1964;189:141.

16. Willkens RF, Williams HJ, Ward JR, et al. Randomized, doubleblind, placebo-controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984;27:376. 17. Abu-Shakra M, Gladman DD, Thorne JC, et al. Long-term methotrexate therapy in psoriatic arthritis: Clinical and radiological outcome. J Rheumatol 1995;22:241–245. 18. Wollina U, Stander K, Barta U. Toxicity of methotrexate treatment in psoriasis and psoriatic arthritis—short- and long-term toxicity in 104 patients. Clin Rheumatol. 2001;20: 406-410. 19. Pioro M, Cash J. Treatment of refractory psoriatic arthritis. Rheumatic Disease Clinics of North Am 1995;21:129-148. 20. Mease P, Gladman D, Keystone E. Alefecept in combination with methotrexate for the treatment of psoriatic arthritis. Arthritis Rheum 2006;54:1638-1645. 21. Carette S, Calin A, McCafferty JP, et al. A double-blind placebocontrolled study of auranofin in patients with psoriatic arthritis. Arthritis Rheum 1989;32:158. 22. Dorwart BB, Gall EP, Schumacher HR, et al. Chrysotherapy in psoriatic arthritis. Arthritis Rheum 1978;21:513. 23. Palit J, Hill J, Capell HA, et al. A multicentre double-blind comparison of auranofin, intramuscular gold thiomalate and placebo in patients with psoriatic arthritis. Br J Rheumatol 1990;29:280. 24. Espinoza LR, Zakraqui L, Espinoza CG, et al. Psoriatic arthritis: Clinical response and side effects to methotrexate therapy. J Rheumatol 1992;19:872. 25. Dorwart BB, Gall EP, Schumacher HR, Krauser RE. Chrysotherapy in psoriatic arthritis. Efficacy and toxicity compared to rheumatoid arthritis. Arthritis Rheum 1978;21:513-515. 26. Fox RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 1999;93: 198-208. 27. Manguso F, Oriente A, Peluso R, Oriente P. Leflunomide in psoriatic polyarthritis: an Italian pilot study. Arthritis Rheum 2001;44(9S):S92. 28. Liang GC, Barr WG. Long-term follow-up of the use of leflunomide in recalcitrant psoriatic arthritis and psoriasis. Arthritis Rheum 2001;44(9S):S121. 29. Kaltwasser J, Nash P, Gladman D, et al. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis. Arthritis Rheum 2004;50:1939-1950. 30. Baum J, Hurd E, Lewis D, et al. Treatment of psoriatic arthritis with 6-mercaptopurine. Arthritis Rheum 1973;16:139. 31. Levy J, Paulus HE, Barnett EV, et al. A double-blind controlled evaluation of azathioprine treatment in rheumatoid arthritis and psoriatic arthritis. Arthritis Rheum 1972;15:116. 32. Olivieri I, Salvarani C, Cantini F, et al. Therapy with cyclosporine in psoriatic arthritis. Semin Arthritis Rheum 1997;27:36-43.

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33. Fraser A, van Kuijk A, Westhovens R, et al. A randomised double-blind placebo-controlled multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis. Ann Rheum Dis 2005; 64:859-864. 34. Spadaro A, Riccieri V, Sili-Scavalli A, et al. Comparison of cyclosporin A and methotrexate in the treatment of psoriatic arthritis: A one-year prospective study. Clin Exp Rheumatol 1995;13:589-593. 35. Kammer G, Sotar N, Gibson D, Schur P. Psoriatic arthritis : A clinical immunologic and HLA study of 100 patients. Semin Arthritis Rheum 1979;9:75-95. 36. Gladman DD, Blake R, Brubacher B, et al. Chloroquine therapy in psoriatic arthritis. J Rheumatol 1992;19:1724-1726. 37. Price R, Gibson T. D-penicillamine and psoriatic arthritis. Br J Rheumatol 1986;25:228. 38. Seideman P, Fjellner B, Johannesson A. Psoriatic arthritis treated with oral colchicine. J Rheumatol 1987;14:777. 39. Wahba A, Cohen H. Therapeutic trials with oral colchicine in psoriasis. Acta Derm Venereol (Stockh) 1980;60:515. 40. Klinkhoff AV, Gertner E, Chalmers A, et al. Pilot study of etretinate in psoriatic arthritis. J Rheumatol 1989;16:789. 41. Goupille P, Soutif D, Valat J. Treatment of psoriatic arthropathy. Semin Arthritis Rheum 1992;21:109.

42. Wilfert J, Honigsmann H, Steiner G. Treatment of psoriatic arthritis by extracorporeal photochemotherapy. Br J Dermatol 1990;122:225. 43. Matucci-Cerinic M, Lotti T, Cappugi P, et al. Somatostatin treatment of psoriatic arthritis. Int J Dermatol 1988;27:56. 44. Fierlbeck G, Rassner G. Treatment of psoriasis and psoriatic arthritis with interferon gamma. J Invest Dermatol 1990;95:138S. 45. O’Connell PG, Gerber LH, Digiovanna JJ, et al. Arthritis in patients with psoriasis treated with gamma-interferon. J Rheumatol 1992;19:80. 46. Huckins D, Felson DT, Holick M. Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: A pilot study. Arthritis Rheum 1990;33:1723. 47. Vahlquist C, Larsson M, Ernerudh J, et al. Treatment of psoriatic arthritis with extracorporeal photochemotherapy and conventional psoralen-ultraviolet A irradiation. Arthritis Rheum 1996;39:1519-1523. 48. Peeters AJ, Dijkmans BA, van der Schroeff JG. Fumaric acid therapy for psoriatic arthritis. A randomized, double-blind, placebocontrolled study. Br J Rheumatol 1992;31:502-504. 49. Dalbeth N, Yeoman S, Dockerty J, et al. A randomized placebocontrolled trial of delipidated deglycolipidated Mycobacterium vacae as immunotherapy for psoriatic arhritis. Ann Rheum Dis 2004;63:718-722.

Biologic Agents in Psoriatic Arthritis Philip Mease

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Our growing understanding of key mechanisms in the pathogenesis of chronic autoimmune diseases has led to the development of targeted therapies that can alter those pathways, thus modulating and inhibiting inflammation. Research, originally performed in animal models, has led to the development of bioengineered immunologic proteins produced in mammalian cell lines that can act in a variety of ways. Such actions include binding pro-inflammatory cytokines and thus inhibiting their ability to interact with cellular receptors and activate cells or binding directly to cellular receptors, thus inhibiting their function. There are a number of types of such compounds. Some of the first such compounds developed have been chimeric monoclonal antibodies, in which the fixed part is composed of human protein and the variable portion is composed of murine (mouse) protein. Newer forms are humanized (with a mixture of human and murine components in the variable region) or fully human. Theoretically, a human construct has less chance of promoting development of neutralizing antibodies that may contribute to administration reactions or to diminishment of effect. An alternative formulation is that of a soluble receptor fusion protein. All biologic agents developed thus far are delivered parenterally, either intravenously or by subcutaneous or intramuscular administration. There has been some initial investigation into intra-articular administration, either of the biologic agents themselves or of vectors containing the gene for the therapeutic protein, for

supplemental or more targeted effect. Although there was initial concern that parenteral administration would reduce patients’ acceptance, this mode of delivery has been fairly readily accepted by patients, especially given the significant positive results achieved with these compounds. It has been typical for these compounds to be first tested in patients with rheumatoid arthritis (RA), and sometimes psoriasis, prior to being tested in psoriatic arthritis (PsA) because of its lesser frequency. Many of the outcome measures employed in PsA clinical trials are also derived from their original use in RA and psoriasis studies. Similarly, our experience with the safety and tolerability of these compounds is also derived from a larger prior experience, especially in RA. Production and development of biologic agents are complex and costly. Thus, it has become increasingly imperative that the classification, staging, and treatment outcome measurement of PsA are accurate (see Chapter 11) to ensure that patients are appropriately treated and that health care resources are utilized wisely. Also, because these agents have proved to be highly effective in controlling symptoms and signs of disease activity, improving function and quality of life, and inhibiting disease activity, it has become important to assess the total impact of this improvement not only on the individual but also on society (e.g., reduction of work loss, increase in participation in family and community activities) in order to provide an accurate cost-benefit analysis of therapy.

TUMOR NECROSIS FACTOR-α INHIBITORS The pro-inflammatory cytokine TNF-α has been shown to be a central pro-inflammatory molecule in immunologically mediated diseases, including both rheumatologic and dermatologic diseases.3 TNF-α is significantly increased in the synovial tissue, synovial fluid, serum, and skin of patients with PsA and psoriasis.4-11 As discussed in preceding chapters (see Chapters 6 and 7), TNF-α underlies a variety of immunopathogenic processes in psoriasis and PsA, including stimulation of cells such as macrophages to produce additional pro-inflammatory cytokines, endothelial cells to generate adhesion molecules that attract inflammatory cells to sites of inflammation, fibroblasts and chondrocytes to produce metalloproteinases that thin cartilage, osteoclast precursor cells to mature into activated osteoclasts that destroy bone, and keratinocytes to proliferate, contributing to skin plaque development and sustainment.12-19

Etanercept Etanercept is a soluble TNF-α receptor fusion protein. It is approved for treatment of RA, PsA, ankylosing spondylitis, juvenile arthritis, and psoriasis. It is administered subcutaneously, either 25 mg twice per week or 50 mg once per week, for RA and PsA. For psoriasis, the starting dose is often 50 mg twice per week for 3 months, followed by a taper to 50 mg once per week.20 Approval of this agent in PsA was based on two placebo-controlled trials. A single-center trial conducted by Mease and colleagues (n = 60) examined the use of etanercept in PsA patients with inadequate response to other systemic therapies.21 Most patients had polyarticular disease, with an average 20-year history of psoriasis and a 9-year history of PsA. Patients taking methotrexate (MTX) were allowed to continue this medication and were randomly allocated equally to etanercept or placebo. Because nearly half of the patients were taking MTX, this created a four-arm trial, assessing the effect of the study drug with or without an MTX background. In addition, low-dose prednisone and nonsteroidal anti-inflammatory

drugs (NSAIDs) were allowed. The study was placebo controlled for 3 months, followed by 6 months of open-label observation. The principal outcome measure was one used in a previous sulfasalazine trial,22 which was named the Psoriatic Arthritis Response Criteria (PsARC) for the purpose of this and subsequent studies. To achieve response, a patient must show at least 30% improvement in tender or swollen joint count and improvement of patient’s or physician’s global assessment (or both). Secondary end points included the proportion of patients meeting American College of Rheumatology ACR50/70 criteria23 at 12 weeks and improvement in the Psoriasis Area and Severity Index (PASI)24 of patients with more than 3% body surface area involved with plaque psoriasis. Of patients treated with etanercept, 87% achieved PsARC, compared with 23% of patients treated with placebo (P < .0001). In addition, ACR20/50/70 were achieved by 73%, 50%, and 13% of etanercept patients, respectively, compared with 13%, 3%, and 0% of placebo patients (P = .015). Median improvement in PASI was 46% for etanercept patients compared with 9% for placebo patients (P = .0032). Within 12 weeks, 10 patients (34%) receiving etanercept achieved disability index scores of 0 (no disability) compared with one patient (3%) receiving placebo, as measured by the Health Assessment Questionnaire (HAQ).25 There was no discernible difference in outcome for patients receiving concomitant MTX. During the open-label phase of the study, patients who initially received placebo rapidly achieved PsARC and ACR scores similar to those of patients who initially received etanercept.26 Radiographic data were not collected for this study. In a second multicenter, placebo-controlled study of similar design, patients with PsA (n = 205) were randomly assigned to receive either placebo or etanercept at 25 mg subcutaneously twice weekly for 24 weeks.27 ACR20 at 12 weeks was chosen as the primary end point for this study. This was achieved by 59% of etanercept patients, compared with 15% of placebo patients (P < .0001). PsARC was achieved by 72% and 31% (P < .001), respectively. Skin lesions of patients receiving etanercept improved significantly. At 24 weeks, 40% of patients receiving etanercept achieved “clear” or “minimal” scores in the dermatologist’s static global assessment, compared with 19% of patients receiving placebo (P = .001). PASI 75 occurred in 23% of etanercept patients versus 3% of placebo patients (P = .001), whereas PASI 50 occurred in 47% and 18%, respectively (P < .001). Significant improvements in function as measured by the HAQ and quality of life as measured

Tumor Necrosis Factor-α Inhibitors

In this chapter, we review the efficacy and safety of the biologic agents currently approved for the treatment of PsA as well as those in development. These include the anti–tumor necrosis factor α (TNF-α) compounds, etanercept, infliximab, and adalimumab; the so-called costimulatory blockade agents, alefacept and efalizumab; and other emerging agents. The reader is also referred to reviews of this subject.1,2

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104

by the 36-Item Short Form Survey (SF-36) were demonstrated. For the first time in patients with PsA, inhibition of radiographic disease progression was demonstrated, as measured radiographically by the modified Sharp method, including distal interphalangeal (DIP) and carpometacarpal joints. At 12 months, disease progression was inhibited in etanercept patients (−0.03 unit) compared with worsening in placebo patients (+1.00 unit) (P = .0001). Specific clinical features of PsA, such as periostitis and pencil-in-cup deformity, did not show statistically significant change in either group during the study, consistent with being more fixed features of established disease. Two years after initiation of this study, persistent control of disease activity was demonstrated. One hundred sixty-one patients continued in open label. Of patients originally randomly allocated to etanercept, 64% maintained an ACR20 response, whereas 63% of those originally randomly allocated to placebo did so. A PASI 75 response was maintained by 38% of all evaluable patients throughout the period of observation. One hundred forty-one patients completed baseline and end point radiography. Inhibition of radiographic progression endured for the patients in the original etanercept group and was also achieved by the original placebo patients, now on open label.28 Throughout the course of the study, the drug was generally safe and well tolerated. During the placebocontrolled phase of the study, infections were seen at an equal level in the etanercept and placebo groups and were predominantly mild to moderate in nature. Mild injection site reactions, transient in nature, were seen more frequently in the etanercept group. The therapy continued to be generally safe and well tolerated through the period of open-label observation. No new type of adverse effect occurred in the PsA trials that had not been seen in the RA trials with etanercept.20 On the basis of these trials, etanercept has now been approved for PsA in multiple countries and is utilized widely. Approval in psoriasis patients without arthritis has followed based on a series of trials with a large number of patients with more severe degrees of skin disease, thus establishing a record of efficacy and safety.29, 30 Unlike the experience in RA, where varying dose above 25 mg twice a week did not seem to affect the disease response significantly,31 a dose response has been seen in the treatment of psoriasis. In a trial involving 672 patients, 59% of patients receiving an etanercept dose of 50 mg twice a week achieved a PASI 75 response at 24 weeks, whereas 44% did so at a dose of 25 mg twice a week. The majority of patients

achieved a PASI 50 response with the 25 mg twiceweekly dose, considered by most to be an adequate response.

Infliximab Infliximab is a chimeric monoclonal anti–TNF-α antibody that binds to both membrane-bound and soluble TNF-α. It is approved for treatment of RA, PsA, psoriasis, ankylosing spondylitis, and Crohn’s disease. It is administered intravenously; initially at baseline, 2 weeks, and then 6 weeks. This is typically followed by infusions every 8 weeks. The usual starting dose is 3 mg/kg, although dosage and frequency may be adjusted up to 10 mg/kg to achieve optimal benefit.32 Efficacy of infliximab in PsA has been established by two major placebo-controlled trials (IMPACT and IMPACT II), in which the drug was administered at 5 mg/kg. In the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT, n = 104),33 background use of disease-modifying antirheumatic drugs (DMARDs) was elective. After 16 weeks, patients assigned to the placebo group crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50. An ACR20 response was selected as the primary end point. ACR20 was achieved by 65% of infliximab patients and 10% of placebo patients (P < .001). ACR50/70 data were 46% and 29% in infliximab patients, compared with 0% in placebo patients (P < .001). Concomitant use of DMARDs had no significant effect on ACR20 at week 16. PsARC response was seen in 75% of infliximab-treated patients, compared with 21% of placebo patients. Enthesitis was measured by palpation of the Achilles tendon and plantar fascia insertion sites, and dactylitis was considered present or absent. Significant improvement occurred in both domains. Improvement in dactylitis from baseline to week 16 was shown by 85% of the infliximab group, compared with 29% of the placebo group (P < .001). The Disease Activity Score (DAS) 28, as used in RA trials, was employed. Mean improvement in DAS 28 was shown by 46% of infliximab patients, compared with 2.8% of placebo patients (P < .001). Skin responses were rapid and significant. At 16 weeks, of patients with a baseline PASI of 2.5 or higher, a PASI 75 response was achieved by 68% of infliximab and 0% of placebo patients (P < .001). The mean HAQ score improved for infliximab patients from 1.2 at baseline to 0.6 at week 16. For PsA, the degree of change in HAQ considered to be clinically meaningful is 0.3.34 No change in score was seen with patients receiving placebo (P < .001). All measures of disease activity and physical function remained

87% in ACR20 responders and 74% in ACR20 nonresponders, suggesting that infliximab can be effective in treating skin symptoms even in those whose joints do not improve significantly.36 As in the previous trial, there were significant improvements in physical function as measured by the HAQ as well as quality of life as measured by both the physical and mental scales of the SF-36. As with other anti-TNF agents, radiographic progression was shown to be inhibited in the infliximab arm at 24 weeks, demonstrating −0.7 units of the modified van der Heijde–Sharp score versus an advancement of 0.82 units in the placebo group (P < .001). At week 54, in open label, the original infliximab group showed a mean change of −0.94 from baseline and the placebo group showed a mean change of 0.53.36a

Tumor Necrosis Factor-α Inhibitors

improved at 50 weeks in the infliximab group, and improvements were similarly rapidly achieved by the original placebo group during the open-label portion of the study.33 Radiographic data for hands and feet were analyzed according to the van der Heijde–Sharp method modified for PsA (including the DIPs). These showed no disease progression in both groups over 50 weeks, as expected because of the short duration of placebo treatment (14 weeks). On the basis of the degree of x-ray damage at baseline and duration of disease, the annual damage progression rate was estimated and shown to be reduced in all patients, indicating that even delayed treatment with infliximab after 14 weeks inhibited radiographic progression of PsA. IMPACT II was a larger (n = 200) phase III trial of infliximab in PsA.35 Patients receiving MTX, oral corticosteroid (equivalent to less than 10 mg/day prednisone), or NSAIDs, or a combination, were allowed to continue the medication; however, other DMARDs were excluded. As in other PsA trials, topical agents and light therapy were not allowed. Patients received either infliximab or placebo 5 mg/kg at weeks 0, 2, and 6, with a maintenance dose at 14 and 22 weeks. Patients receiving either placebo or infliximab who had less than 10% improvement from baseline entered early escape at weeks 16, 18, and 22. ACR20 was the primary end point for this study, with PsARC and PASI scores as secondary end points. At week 14, an ACR20 response was seen in 58% of infliximab patients and 11% of placebo patients (P < .001).35 Response occurred as early as week 2 and was maintained throughout the study. ACR50/70 was achieved by 36% and 15% of patients receiving infliximab, compared with 3% and 1% of patients receiving placebo (P < .001). This percentage continued to increase for both groups through week 24 but more significantly for infliximab patients: 41%/27% and 4%/2%, respectively (P < .001). At week 14, 77% of patients receiving infliximab had improved PsARC scores, compared with 27% of patients receiving placebo. Presence of dactylitis decreased in the infliximab group (from 41% to 18%) compared with the placebo group (from 40% to 30%) (P = .025). Likewise, the incidence of enthesitis decreased in the infliximab group (from 42% to 22%) compared with the placebo group (from 35% to 34%) (P = .016). Skin response to infliximab was evident at week 2 and was maintained throughout week 24. The proportion of patients achieving PASI 75 at week 14 was 64% in those receiving infliximab and 2% in those receiving placebo (P < .001). The median PASI response in evaluable, infliximab-treated patients was

Adalimumab Adalimumab is a fully human anti–TNF-α monoclonal antibody administered subcutaneously, 40 mg, typically every other week, although it can be used weekly.37-40 It is approved for treatment of RA and PsA.41 Efficacy in PsA was first demonstrated in an open-label trial (n = 15).42 A larger, placebo-controlled study (n = 313), Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), was then conducted to confirm the safety and efficacy of this agent.43 Stratification was based on background MTX, utilized by nearly 50%. Low-dose prednisone and NSAIDs were allowed, and topical agents and light therapy were prohibited. Patients were administered subcutaneous injections of either placebo or 40 mg adalimumab every other week for 24 weeks. Patients who had less than a 20% decrease in swollen and tender joint counts by week 12 could receive rescue therapy with corticosteroids or DMARDs. The primary end points for this study were ACR20 at week 12 and change in modified total Sharp score (TSS) of hands and feet at week 24. Patients treated with adalimumab achieved significantly higher ACR response rates than patients receiving placebo. This response developed rapidly, with initial response observed at week 2. At 24 weeks, ACR20/50/70 response rates were 57%, 39%, and 23%, respectively, for patients receiving adalimumab compared with 15%, 6%, and 1% of patients receiving placebo (P < .001). This response rate did not differ between patients taking adalimumab in combination with MTX and those taking adalimumab alone. Outcomes for all seven individual ACR components were significantly better in the adalimumab group. PsARC response rate at week 24 was 60% for the treatment group and 23% for the placebo group. Although mean improvement in

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enthesitis and dactylitis was greater for patients receiving adalimumab, these results were not statistically significant. Patients receiving adalimumab showed a significant reduction in the extent of psoriasis. At week 24, PASI 50/75/90 responses were 75%, 59%, and 42%, respectively, for patients receiving adalimumab and 12%, 1%, and 0% for those receiving placebo (all P values < .001). A significant difference in these scores was observed as early as week 4 and through week 24. In addition, 67% of adalimumab-treated patients achieved “clear” or “almost clear” ratings of lesions by the physician’s global assessment of psoriasis, compared with 20% of patients receiving placebo (P < .001). Disability improved significantly for patients receiving adalimumab. Mean change in the HAQ Disability Index was −0.4 for adalimumab patients compared with −0.1 for placebo patients (P < .001) from week 12 through week 24. At 24 weeks, the mean change in the physical component of the SF-36 was 9.3 for the treatment group and 1.4 for the placebo group. The mental component of this score showed no statistically significant difference in change between the two groups. Radiographic progression of disease was significantly inhibited by adalimumab. Mean change in TSS at week 24 was −0.2 for patients receiving adalimumab and 1.0 for patients receiving placebo (P < .001). Similarly, mean change in erosion scores was 0.0 for the adalimumab patients and 0.6 for placebo patients. Mean change in joint space narrowing score was −0.2 for adalimumab patients and 0.4 for placebo patients. There was no significant progression of joint space widening, gross osteolysis, subluxation, pencil-in-cup deformity, juxta-articular periostitis, shaft periostitis, or phalangeal tuft resorption in either the adalimumab or placebo group. A second confirmatory trial of 100 PsA patients in whom DMARD therapy failed also showed significantly improved ACR scores in the adalimumabtreated group.44

Safety of Anti–Tumor Necrosis Factor-α Agents Data from studies of etanercept, infliximab, and adalimumab in PsA do not demonstrate new or different safety and tolerability issues compared with those seen in the larger experience with these compounds in RA. There has been little direct comparison of biologic agents with traditional DMARDs; however, data suggest that biologic agents are safer and better tolerated.1 The following adverse effects are rare but can be significant.

Administration Reactions 106

Because biologic agents are parenterally administered, administration reactions can occur. Approximately

one third of patients self-administering subcutaneous injections of etanercept experience mild and temporary injection site reactions.20,45,46 These reactions are less frequent with adalimumab.46,47 It is usually advisable to infuse infliximab over 2 hours.48 Infusion reactions are uncommon and typically mild and may include hypotension, fever, chills, rash, nausea, and headache. These effects often dissipate if the infusion is slowed. Some patients may be helped by comedication with acetaminophen, steroids, or antihistamines. In some cases, reactions such as bronchospasm or anaphylaxis can be significant. In this case, the infusion should be stopped and medical treatment instituted.32,49,50

Infection As these are immunomodulatory agents, the normal immunologic reaction to infection may be altered; thus, there needs to be surveillance for infection. Although data from RA studies show that the background rate of infection for patients treated with anti–TNF-α agents is no higher than for patients treated with placebo,45,51-56 it is nevertheless important to monitor patients closely and to stop anti–TNF-α therapy if serious infection (e.g., pneumonia, cellulitis, or urinary tract infection) arises. Similarly, if the patient presents with symptoms and fever that are difficult to explain, it is important to investigate for occult infection. Patients with chronic comorbid conditions such as diabetes, sinus conditions, or emphysema have a higher risk for infection, and extra caution should be employed when using these agents in patients with these conditions. Animal studies show that TNF-α protects against opportunistic infections, such as tuberculosis (TB), histoplasmosis, or coccidioidomycosis.50,57 Although these infections are rare with anti–TNF-α therapy, they have been seen with each of the TNF inhibitors.58 It is required practice with infliximab and adalimumab to perform a tuberculin skin test before instituting anti–TNF-α therapy, and it is advisable to do so with etanercept. If the skin test is positive, anti-TB treatment should be given before beginning anti–TNF-α agents. It is important to be aware that some instances of TB that have occurred during anti–TNF-α therapy have been extrapulmonary. Thus, clinicians should be alert to the possibility that unusual focal symptoms, lymphadenopathy, and fever of unknown origin in a patient with a normal chest radiograph could represent TB.59,60

Other Possible Effects

Multiple Sclerosis A small number of patients have developed a multiple sclerosis (MS) or MS-like condition or have had

Malignancy Patients with RA have a two to eight times higher risk for lymphoma than the general population.63 Further, when lymphoma risk was assessed in relation to severity of RA, it was noted that the standardized incidence ratio (SIR) was 26-fold greater in RA patients with severe disease.64 In one study, ankylosing spondylitis was noted to be associated with a higher prevalence of lymphoma,65 which was not noted, however, in a different study.66 The prevalence is increased in patients with psoriasis.67 The prevalence for patients with PsA is unknown. Lymphoma has occurred in increased frequency in clinical trials with anti–TNF-α agents in RA,20,32,41,68 but the frequency has fallen within the range of SIR for RA patients in general; therefore, it is not known whether its occurrence correlates with therapy or the underlying disease or whether it is unrelated to either treatment or disease. In RA, the prevalence of cancer in general (e.g., colon, breast, prostate) is not elevated above that in the general population, nor is there increased prevalence in clinical trials of anti-TNF medications.20,32,41 Congestive Heart Failure Concern has been raised about the possible association of use of anti-TNF medicines and development or worsening of congestive heart failure (CHF) both in RA69 and in trials of these agents in CHF,70 the latter studied because of the awareness that TNF-α can be significantly increased in CHF. Thus, it is not advised to use these medicines in patients with severe CHF. However, other studies have supported the possibility that there may be a lower incidence of CHF and other forms of cardiovascular disease in patients treated with anti-TNF medications, possibly because of the salutary effects of inflammation inhibition on cardiovascular disease development in RA.70,71 Drug-Induced Lupus A small number or patients have developed a lupus-like syndrome, characterized by such features as rash, arthralgias, and positive antinuclear antibody (ANA) or DNA antibody, that resolves when the biologic agent is

withdrawn.45,72-75 It is known that ANA or DNA antibodies can both appear and disappear while a patient is undergoing anti-TNF therapy, without any associated clinical symptoms, and the mere appearance of these does not necessarily warrant cessation of therapy. Drug-Induced Psoriasis There have been a few reports of psoriasis, usually of the palmar-plantar pustular variant, developing in patients being treated with anti-TNF medicines, including patients with no history of psoriasis, that has resolved with cessation of the medication.75a

Other Biologic Agents

exacerbation of established MS during treatment with anti–TNF-α agents.45,61,62 In some cases, the condition has improved upon withdrawal of the anti-TNF medication. Although it is possible that in some instances the development of MS may be coincidental, it is recommended to avoid use of the medicines in patients with MS, withdraw them if MS develops, and pursue appropriate investigation if concerning neurologic symptoms develop.

Immunogenicity Because biologic agents are proteins, antibodies may develop against them, especially the chimeric form. These antibodies are often of no clinical significance but occasionally may be neutralizing. It was suggested that when infliximab was given intermittently in Crohn’s disease, diminished efficacy and increased frequency of infusion reaction were correlated with such neutralizing antibodies.76 Neutralizing antibodies arise less often if infliximab is given concomitantly with MTX.32 Hematologic and Hepatic There have been rare reports of diminished white blood cell counts or aplasia in patients treated with anti-TNF medications, often in the context of concomitant use of other immunomodulatory agents.20,32,41 Transient elevations of liver function tests have been noted and rarely more serious liver reactions have occurred, usually in the context of concomitant therapy with an agent such as MTX but rarely with antiTNF monotherapy.20,32,41 Because of the extreme rarity of these findings, there is no recommendation for routine laboratory monitoring specific to the antiTNF medications.

OTHER BIOLOGIC AGENTS Other biologic agents being developed for use in RA or psoriasis have been or eventually will be assessed for use in PsA. These agents target different key cells or cellular messengers (cytokines) in the inflammatory process. Those currently being tested for efficacy in PsA include costimulatory blockade agents that inhibit T cells by blocking the second signal of T-cell activation. The first signal is the major histocompatibility complex on the antigen-presenting cell interacting with the T-cell receptor. There are several second signals that can also be modulated.

Alefacept Alefacept is a fully human fusion protein that binds to the CD2 receptor on the T cell and either blocks

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interaction with leukocyte function–associated antigen (LFA) 3 on the antigen-presenting cell or attracts natural killer cells to CD45RO+ T cells, causing their apoptosis.77 It is approved for treatment of psoriasis.78,79 Alefacept is administered weekly as a 15-mg intramuscular injection in a 12-weeks-on, 12-weeksoff regimen. This regimen is used partly to allow recovery of CD4 counts, which must be monitored during therapy. Despite depletion of CD4 cells, however, no increased risk of infection has been seen in psoriasis trials.78,79 A small (n = 11) open-label trial of this compound in PsA showed that more than one half of patients achieved an ACR20 response and a decrease of CD4, CD8, and CD68 cells in the synovial lining.77 A placebo-controlled trial (n = 185) showed that the combination of alefacept and MTX provides significant clinical improvement in patients with PsA.80 Patients given a 12-week course of alefacept and MTX had significantly greater response rates in both arthritis (ACR20) and psoriasis (PASI 50) than patients given placebo-MTX. An incremental improvement in ACR20 response during the treatment-free phase indicates that the response to alefacept continued even when the drug was not being administered. Radiographic assessment did not, however, show a statistically significant difference between the treatment and placebo arms.

Efalizumab Efalizumab is a humanized antibody to the CD11 subunit of LFA-1 that inhibits the interaction of LFA1 and intercellular adhesion molecule 1 (ICAM-1). It interferes with the activation of T lymphocytes and migration of lymphocytes from the circulation to the site of inflammation. It is administered subcutaneously once per week and is approved for use in psoriasis.81 In a 12-week trial of efalizumab in patients with PsA, 28% of patients achieved an ACR20 response versus 19% in the placebo group (P = .2717).82 Because this difference was not statistically significant, a formal approval in PsA is not being sought at this time.

Abatacept

108

Abatacept is a recombinant human fusion protein composed of the extracellular domain of human CTLA4 and a fragment of the Fc domain of human immunoglobulin G1. It binds to the CD80/86 receptor on an antigenpresenting cell, thus blocking the second signal activation of the CD28 receptor on the T cell. This agent is administered intravenously once per month. Abatacept has been approved for use in RA,83 and a phase II trial for use in psoriasis has been conducted.84 It is possible that further assessment of this drug will be conducted for PsA.

Other Potential Treatments Several cytokine inhibitors are being tested or could potentially be tested in PsA. A pilot trial of an anti–interleukin 15 (IL-15) compound, for example, has shown efficacy in PsA.85 In addition, a trial is under way to assess the efficacy and safety of an IL-1 antagonist, anakinra, in PsA.85a A monoclonal antibody to the IL-6 receptor (MRA) is in phase III development for the treatment of RA and is likely to be tested in PsA.86 In psoriasis, a humanized antibody to the α subunit (CD25) of the IL-2 receptor that blocks IL-2 binding to the T-cell receptor has been tried, but some loss of efficacy was noted over time.87,88 Several inhibitors of IL12 are being evaluated in psoriasis with good success (C Leonardi, personal communication) and are likely to be assessed in PsA. It is anticipated that inhibitors of IL-18 will also be studied. Pioglitazone is a ligand for peroxisome proliferator–activated receptor γ (PPARγ). It was originally developed to treat diabetes and was extended to PsA because of observations that it led to inhibition of angiogenesis and downregulation of proinflammatory cytokines.89 In an uncontrolled trial of pioglitazone administered orally, 60% of patients met PsARC criteria and 50% achieved an ACR20 response after 12 weeks.90 This agent may be beneficial for treating PsA, but its efficacy must be evaluated in a controlled study. Conversely, anti-inflammatory cytokines may also be effective in PsA and other conditions. For example, a recombinant human IL-11 has been utilized in psoriasis with preliminary clinical and histologic benefit.91 Similarly, a recombinant IL-10 agent has demonstrated preliminary benefit in psoriasis.88,92 However, a controlled study of this agent in patients with PsA showed benefit in the skin but not in joints.93 A monoclonal antibody to CD3, a component of the T-cell receptor complex huOKT3γ1, also demonstrated some benefit in PsA, although issues such as transient T-cell depletion and mild cytokine release symptoms have been noted.94 A fuller understanding of the safety profile of these agents awaits larger controlled trials.

BIOLOGIC AGENTS AND INFLAMMATION As clinicians, we invariably see patients with disorders comorbid to PsA. Indeed, ongoing research continues to elucidate the role of the inflammatory process in numerous physical and mental health conditions in addition to direct impact on the musculoskeletal system and skin, such as cardiovascular disease (CVD), osteoporosis, and clinical depression. Patients may be

Cardiovascular Disease The incidence of CVD in patients with RA is 30% to 60% higher than in patients with osteoarthritis or in the general population.95 This increased risk was initially linked to increased disability in RA; however, studies that control for traditional risk factors and for comorbidity have found that the risk for CVD still remains significantly greater in patients with RA.96,97 At a cellular and cytokine level, inflammatory processes are now known to contribute to the development of coronary disease; thus, the link between the pathophysiologic process in RA and accelerated atherosclerosis is being examined.98-102 It is hypothesized that inflammation may be a key element in the development of atherosclerotic CVD.103 As previously mentioned, a large observational study of RA patients suggested that there may be a lower incidence of CVD in patients treated with antiTNF medications.70 Two further studies of infliximab reported improvement in arterial endothelial function in patients with RA,104,105 although another study (n = 10) found arterial vasoconstriction, increased high-density lipoprotein, and increased arterial wall shear stress in RA patients taking anti–TNF-α medication.106 There has been little research on the risk of CVD in PsA. An analysis of patients enrolled in managed care organizations in the United States suggested increased co-occurrence of CVD with both RA and PsA and a similar disease burden between RA and PsA.107 Biomarkers known to be associated with cardiovascular risk were reduced in a PsA trial with an anti-TNF agent, onercept.108 Although data regarding the role of inflammation in CVD are emerging, it is logical to remain aware of this current research when administering biologic agents to PsA patients who also have, or are at risk for, CVD.

Osteoporosis RA and spondyloarthropathies (SpAs) are risk factors for generalized osteoporosis109-111 in addition to the known bone erosive changes that occur in joints in inflammatory arthritis. Analysis of a large PsA cohort suggested that bone density changes, when adjusted for weight, were similar in PsA and RA patients.112 Studies of infliximab have shown that this agent decreased the biochemical markers of osteoporosis in patients with RA113 and increased bone mineral density (BMD) in patients who had RA without osteo-

porosis.114 Studies in patients with SpA show that both etanercept and infliximab increase BMD in patients with active disease115-118 by decreasing bone resorption.116 Thus, in addition to the potential benefits of treating this comorbidity with antiosteoporosis agents such as bisphosphonates, there is increasing evidence that control of inflammation can be beneficial.

Conclusions

concomitantly using medicine for these conditions, such as statins, bisphosphonates, and antidepressants. It is useful, therefore, to consider briefly the role of inflammation in these conditions and the possible effect of biologic agents.

Clinical Depression Depression and related conditions, such as sleep disturbance and fatigue, are common comorbidities in patients with inflammatory arthritis and psoriasis. Multiple factors contribute, including chronic pain, sleep disturbance, embarrassment about unsightly skin lesions, loss of normal work and social function, and diminished self-esteem. This state, in turn, may contribute to further loss of function, social withdrawal, sexual dysfunction, anhedonia, and so forth. Biologic factors that may contribute include cytokine-neuroreceptor interactions, which are being explored in the field of psychoneuroimmunology.119-121 Antidepressant therapy as well as psychological counseling can improve depression. In a phase III trial of etanercept in psoriasis, there was significantly greater improvement of measures of depression and fatigue in the etanercept patients than patients in the placebo group. This could reflect the patients’ response to improvement of psoriasis; it is unknown whether there was a more direct influence of cytokine modulation on the biochemical elements of depression.122

CONCLUSIONS The development of biologic agents that modulate specific targets in the inflammatory process of autoimmune disease represents a significant advance in our ability to control disease activity and inhibit progressive structural damage. In PsA, these agents have demonstrated effectiveness in multiple domains: joints, enthesis, skin, bone, and quality of life and function. As a result of their effectiveness, many patients have been able to regain a relatively normal life. Patients have generally adapted well to their parenteral administration. With proper precautions about such issues as infection, they are reasonably safe and well tolerated in balance with the severity of the disease and cost of its impact on the individual, the family, and society. There is substantial evidence of the effectiveness of the anti-TNF medications. For patients who do not respond adequately to these agents, other biologic agents are being developed and studied in PsA in order to broaden our ability to treat the majority of patients effectively.

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110

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84. Abrams JR, Lebwohl M, Guzzo C. CTLA4Ig-mediated blockade of T cell co-stimulation in patients with psoriasis vulgaris. J Clin Invest 1999;103:1243-1252. 85. McInnes IB, Gracie JA. Interleukin-15: A new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol 2004;4:392-397. 85a. Gibb A, Gogarty M, Veale D, et al. Efficacy of anakinara (Kineret) in psoriatic arthritis, a clinical and immunohistological study. Ann Rheum Dis 2006;65(Suppl 3);216. 86. Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the IL-6 receptor antagonist tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arth Rheum 2006;54:2817-2829. 87. Krueger JG, Walters IB, Miyazawa M, et al. Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis. J Am Acad Dermatol 2000;43: 448-458. 88. Jung JH, Kavanaugh A. Other biologic therapy. In: Gordon KB, Ruderman EM (eds). Psoriasis and Psoriatic Arthritis: An Integrated Approach. Heidelberg: Springer-Verlag, 2005, pp 223-234. 89. Mease PJ. Recent advances in the management of psoriatic arthritis. Curr Opin Rheumatol 2004;16:366-370. 90. Bongartz T, Coras B, Vogt T, et al. Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: An open-label pilot study. Rheumatology (Oxford) 2005; 44:126-129. 91. Trepicchio WL, Ozawa M, Walters IB, et al. Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest 1999;104:1527-1537. 92. Reich K, Garbe C, Blaschke V, et al. Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8/CXCR2 pathway and normalization of keratinocyte maturation. J Invest Dermatol 2001;116:319-329. 93. McInnes IB, Illei GG, Danning CL, et al. IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis. J Immunol 2001;167:4075-4082. 94. Utset TO, Auger JA, Peace D, et al. Modified anti-CD3 therapy in psoriatic arthritis: A phase I/II clinical trial. J Rheumatol 2002;29:1907-1913. 95. Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 2003;30:1196-1202. 96. Navarro-Cano G, del Rincon I, Pogosian S, et al. Association of mortality with disease severity in rheumatoid arthritis, independent of comorbidity. Arthritis Rheum 2003;48: 2425-2433. 97. del Rincon ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737-2745. 98. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population-based cohort study. Arthritis Rheum 2005;52:402-411. 99. Nielen MM, van Schaardenburg D, Reesink HW, et al. Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis. Arthritis Rheum 2004;50:2423-2427. 100. Bergholm R, Leirisalo-Repo M, Vehkavaara S, et al. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler Thromb Vasc Biol 2002;22:1637-1641.

101. Yildiz M, Soy M, Kurum T, Ozbay G. Increased pulse wave velocity and shortened pulse wave propagation time in young patients with rheumatoid arthritis. Can J Cardiol 2004;20: 1097-1100. 102. Klocke R, Cockroft JR, Taylor GJ, et al. Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rheumatoid arthritis. Ann Rheum Dis 2003;62: 414-418. 103. Ford DE, Erlinger TP. Depression and C-reactive protein in US adults: Data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2004;164: 1010-1014. 104. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, et al. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum 2004;15:447-450. 105. Hurlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106: 2184-2187. 106. Irace C, Marcuso G, Fiaschi E, et al. Effect of anti–TNF-alpha therapy on arterial diameter and wall shear stress and HDL cholesterol. Atherosclerosis 2004;177:113-118. 107. Han C, Robinson D, Hackett M, et al. Co-occurrences of selected cardiovascular disease and risk factors in patients with rheumatoid arthritis and psoriatic arthritis. Ann Rheum Dis 2005;64 (Suppl 3):108. 108. Sattar N, Crompton P, Cherry L, et al. Effects of inflammatory suppression with onercept on vascular risk factors in psoriatic arthritis: Double-blind placebo-controlled study. Arthritis Rheum 2005;52 (Suppl 9):S561. 109. Marzo-Ortega H, Mc Gonagle D, Haugeberg G, et al. Bone mineral density improvement in spondyloarthropathy after treatment with etanercept. Ann Reum Dis 2003;62:1020-1021. 110. Romas E, Gillespie MT, Martin TJ. Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 2002;30:340-346. 111. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995;332:305-311. 112. Reddy S, Anandarajaha A, Reed G, et al. Comparative analysis of disease activity, radiographic features, and bone density in psoriatic and rheumatoid arthritis. Arthritis Rheum 2005;52 (Suppl 9):S640. 113. Di Munno O, Delle Sedie A, Rossini M, et al. Disease-modifying antirheumatic drugs and bone mass in rheumatoid arthritis. Clin Exp Rheumatol 2005;23:137-144. 114. Lange U, Teichmann J, Muller-Ladner U, et al. Increase in bone mineral density of patients with rheumatoid arthritis treated with anti–TNF-alpha antibody: A prospective openlabel pilot study. Rheumatology (Oxford) 2005;44: 1546-1548. 115. Allali F, Breban M, Porcher R, et al. Increase in bone mineral density of patients with spondyloarthropathy treated with anti-tumour necrosis factor alpha. Ann Rheum Dis 2003;62: 347-349. 116. Briot K, Garnero P, Le Henanff A, et al. Body weight, body composition, and bone turnover changes in patients with spondyloarthropathy receiving anti-tumour necrosis factor (alpha) treatment. Ann Rheum Dis 2005;64:1137-1140. 117. Domis E, Reban M, Dougados M. Infliximab in spondylarthropathy influence on bone density. Clin Exp Rheumatol 2002;20 (Suppl 28):S185-S186. 118. Marzo-Ortega H, McGonagle D, Haugeberg G, et al. Bone mineral density improvement in spondyloarthropathy after treatment with etanercept. Ann Rheum Dis 2003;62: 1020-1021.

121. Hayley S, Merali Z, Anisman H. Stress and cytokine-elicited neuroendocrine and neurotransmitter sensitization: Implications for depressive illness. Stress 2003;6:19-32. 122. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebo-controlled randomised phase III trial. Lancet 2006;367:29-35.

References

119. Anisman H, Hayley S, Turrin N, et al. Cytokines as a stressor: Implications for depressive illness. Int J Neuropsychopharmacol 2002;5:357-373. 120. Dunn AJ, Swiergiel AH, de Beaurepaire R. Cytokines as mediators of depression: What can we learn from animal studies? Neurosci Biobehav Rev 2005;29:891-909.

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13

Dermatologic Management of Psoriasis Stephanie Diamantis and Mark Lebwohl

TREATMENT OF PSORIASIS OF THE SKIN

114

Psoriasis is a chronic inflammatory disease that affects 1% to 3% of people in the United States.1 The different morphologic forms of psoriasis include plaque (most common), guttate, inverse, erythrodermic, pustular, and impetigo.2 In addition, psoriatic arthritis occurs in 7% to 31% of patients with psoriasis.3 The etiology of psoriasis has an immunologic basis, and both hereditary and environmental factors may exacerbate the condition.4 Evidence suggests that T lymphocytes are key mediators in the disease process. Activated CD4+ and CD8+ T cells in the dermis initiate keratinocyte hyperproliferation and abnormal differentiation in the epidermis, resulting in the characteristic psoriatic lesions.5 The T cells that play a key role in the pathophysiology of psoriasis become activated through a complex pathway that ends in cytokine production and cellular proliferation. Initially, an antigen-presenting cell (APC), usually a Langerhans cell in the skin, presents an antigen to the T-cell receptor (TCR) in the context of the major histocompatibility complex (MHC). In order to allow this interaction, the T cell must transiently but sufficiently bind to the APC. Binding is accomplished through the interaction of lymphocyte function–associated antigen type 1 (LFA-1) and CD2 on T cells to intercellular adhesion molecule 1 (ICAM1) and LFA-3 on APCs. At this point, CD40 on the APC interacts with an upregulated CD40 ligand on the T lymphocyte, and costimulatory molecules interact (CD28/CD86/CD2 on T cells and CD80/CD28/LFA-3 on APCs), which results in T cell activation. In summary, a T lymphocyte needs two signals to become activated, a primary signal involving the TCR and MHC and a secondary signal involving several costimulatory molecules.4,6,7 After activation, T lymphocytes must migrate into the skin, where they participate in local inflammatory processes. Many interactions take place that allow the T cells to bind to and then traverse the endothelium. First, the T cells “roll” along the endothelium, slowing down in preparation for exiting the vessel, a process

mediated by the T cell’s cutaneous lymphocyte antigen (CLA) and LFA-1. These molecules bind to special adhesion molecules on endothelial cells, E-selectin and ICAM-1, allowing the T cells to bind to vessel walls and migrate into the epidermis and dermis.4,7 After lymphocytes migrate into the skin, reexposure to antigen reactivates memory T cells, setting in motion a cascade of events that result in the production of pro-inflammatory cytokines (a T helper 1 [Th1] response). T cells, depending on their subtype, can produce cytokines that result in either a Th2 or Th1 response. Th1 lymphocytes produce interleukin 2 (IL-2) and interferon γ (IFN-γ) and are instrumental in cell-mediated immunity. Psoriatic plaques have high levels of Th1 cytokines; in particular, high levels of IL2 and IFN-γ stimulate the production of tumor necrosis factor α (TNF-α) and other chemokines, which regulate the migration and action of additional inflammatory cells in the skin responsible for the formation and maintenance of the psoriatic plaque.7 The activated T lymphocytes perpetuate the local immune response and induce keratinocyte hyperproliferation.8 At this time, no cure exists for psoriasis, and the goals of current therapies are to relieve symptoms and improve quality of life while minimizing adverse effects (Table 13-1). The type of treatment for psoriasis is determined by the extent of the patient’s body affected by the disease and the amount of debilitation. Topical therapy is a good treatment option if less than 5% of a patient’s body is involved and functions of daily living are not severely impaired by the disease. Topical corticosteroids, calcipotriol, and tazarotene are all effective. Involvement of certain areas of the body (scalp, face, intertriginous areas, palms, and soles) may require treatment with a combination of agents to minimize toxicity. When 5% to 10% of a patient’s body is affected, phototherapy and systemic medications often provide greater relief either as monotherapies or in combination with the topical agents.2 When greater than 10% of a patient’s body is affected or the disease is extremely debilitating, systemic therapies such as methotrexate, cyclosporine, acitretin, or biologic agents are appropriate.2

Topical Treatments Corticosteroids Anthralin/tar Calcipotriene Retinoids Phototherapy Ultraviolet B (UVB) Narrowband ultraviolet B (NBUVB) Psoralen plus ultraviolet A (PUVA) Systemic Treatments Methotrexate Cyclosporine Retinoids Other Biologic Treatments Alefacept Efalizumab Etanercept Infliximab

psoriasis and those in whom most other therapies have failed. Etanercept, infliximab, and adalimumab have been shown to prevent joint damage in patients with psoriatic arthritis. Because of the chronic nature of the disease and the serious adverse effects that can occur from the therapies available, treatment models such as combination, sequential, and rotational therapy have been developed to minimize toxicity while maximizing benefits. Combination therapy uses varying combinations of topical, systemic, and phototherapeutic methods in order to achieve the greatest therapeutic effect with the least cumulative toxicity from each treatment. The most common combinations are systemic retinoids and ultraviolet B (UVB) or psoralen plus ultraviolet A (PUVA), methotrexate and cyclosporine, and PUVA and UVB.9 Sequential therapy is a concept in which treatment begins with a potent drug that induces a rapid response (i.e., cyclosporine), and, after the initial response, a safer drug is introduced as a transition to maintenance therapy.2 Finally, rotational therapy minimizes toxicity by rotating three to four different treatments, thereby allowing patients to have an extended break from each therapy.10 Because biologic therapies are not associated with dose-related major organ toxicity, the need to rotate to other treatments is less pressing.

Topical Therapies

TABLE 13-1 TREATMENT OF PSORIASIS OF THE SKIN

Adalimumab

TOPICAL THERAPIES The introduction of biologic agents, such as alefacept, efalizumab, and etanercept, has provided additional treatment options for physicians. The biologic agents act as immunomodulators that reduce or eliminate the pathogenic effect of T lymphocytes implicated in the pathophysiology of psoriasis.6 Three biologic agents are currently approved for treatment of psoriasis (alefacept, efalizumab, and etanercept), and two others (infliximab and adalimumab) are effective for psoriasis but are not approved specifically for its treatment. These biologic agents are safer than other systemic therapies, but they tend to be expensive. Therefore, insurance coverage and the cost of treatment may dictate management. Furthermore, different groups of patients have different indications for the use of biologics. For example, patients with psoriatic arthritis can benefit from treatment with a TNF blocker such as etanercept. If patients have an insurance plan that does not have outpatient medication coverage, alefacept and infliximab are appropriate choices because they are administered in the office. Patients’ preference may also guide the physician to choose one biologic over another. Efalizumab and etanercept can be self-administered at home. Alefacept is administered in the office once weekly for a total of 12 weeks. Infliximab is effective for the sickest patients, including those with erythrodermic

Corticosteroids Corticosteroids are the most common topical therapy used by dermatologists to treat the cutaneous lesions of psoriasis. Corticosteroids are available in a range of potencies and vehicles, making them useful in many different circumstances. Potencies range from class 7 (e.g, 1% hydrocortisone) to the superpotent class 1 (e.g, clobetasol propionate), and they are chosen on the basis of disease severity and location.11 Rarely, medium and superpotent corticosteroids have caused suppression of the hypothalamic-pituitary-adrenal axis.12 More commonly, cutaneous side effects such as the development of striae and telangiectasias, atrophy of the skin, and skin fragility limit the use of corticosteroids. The face and intertriginous areas are most susceptible to these cutaneous side effects. Tachyphylaxis is the other major concern with the use of topical corticosteroids as steroids tend to lose their therapeutic effects after a period of constant treatment. However, pulse therapy (treatment with periods of rest) can help combat tachyphylaxis.11

Anthralin and Tars Tar regimens are appropriate for patients with chronic plaque, scalp, or palmoplantar psoriasis.13 Historically, coal tar was used in the context of the Goeckerman

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regimen for the treatment of severe psoriasis. This intensive regimen required patients to be hospitalized for weeks as they underwent treatments with coal tar and ultraviolet radiation. Although it was extremely effective, the course of therapy had serious drawbacks. Treatments were malodorous and caused staining, contact dermatitis, atrophy, telangiectasia, and occasionally the development of pustular psoriasis.13 In time, other treatments were developed that were less time intensive and had fewer adverse effects.11 Anthralin is another useful therapy that was once widely employed but is losing favor because of more tolerable and effective treatment options. Anthralin can be irritating and may stain the skin, clothing, or household items upon application; however, new methods of application have been developed that make anthralin more user friendly. Micanol, 1% anthralin in a heat-sensitive vehicle, minimizes staining of fabrics. Also, the addition of triethanolamine to the treatment regimen reduces cutaneous staining and irritation. Application of higher concentrations of anthralin for shorter time periods may also lessen adverse effects.11

Calcipotriene Calcipotriene, a vitamin D3 analogue, is available as an ointment, cream, and solution. Its efficacy is similar to that of class 2 topical corticosteroids.11 A synergistic effect is present when calcipotriene and superpotent corticosteroids are combined, and the side effects secondary to steroid use are diminished because of less frequent steroid application.14 Beneficial effects have also been observed when calcipotriene is combined with UVB or PUVA; however, calcipotriene must be applied after UVA exposure because UVA can inactivate calcipotriene.11 The most frequent side effect related to the use of calcipotriene is contact dermatitis, especially when the compound is applied to the face or intertriginous areas. Concomitant use of a steroid cream may prevent the development of irritation. Rare instances of hypercalcemia have been reported in patients using calcipotriene for lesions that cover a substantial amount of body surface; this side effect can be avoided if patients use less than 100 g per week.11

Retinoids

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Tazarotene, one of the first topical preparations of retinoid, reduces keratinocyte hyperproliferation and inflammation characteristic of psoriatic lesions. Tazarotene has been studied in 0.05% and 0.1% concentrations and is used as a gel or cream.11 This particular retinoid is effective as a monotherapy for chronic plaque psoriasis and is well tolerated by patients.15 The most common dose-dependent side effect associated with tazarotene therapy is local irritation.11

Topical retinoids are particularly effective when used in combination with topical corticosteroids. Patients have a greater therapeutic response and decreased local irritation secondary to tazarotene as well as decreased epidermal and dermal atrophy from topical steroid use. Tazarotene can also be combined with UVB to achieve faster and more complete remissions, but patients are more susceptible to burning following UVB therapy. To prevent UVB-induced erythema, the starting dose of UVB light must be reduced when UVB is combined with tazarotene.11

PHOTOTHERAPY

Ultraviolet B Of the different phototherapeutic modalities, UVB is the most commonly prescribed.11 This modality is effective for patients with mild to moderate disease, and dosing is based on the patient’s skin type or tendency to burn.16 Often, UVB is used in combination with other methods to yield faster and more complete results. When UVB therapy is combined with calcipotriene or tazarotene, the result is more complete remission; however, topical corticosteroids may actually decrease remission time. The disadvantages of combining UVB with other therapies include the increased risk of photosensitivity and the possibility of diminished length of remission.11 UVB is also impressively effective in combination with systemic medications, such as retinoids or methotrexate. Patients notice dramatic improvement in psoriatic lesions as well as a reduction in the side effects of the systemic medications. When UVB is combined with systemic retinoids (such as acitretin), patients need fewer UV treatments, which lessens the cumulative dose of UVB and decreases their chance of developing skin cancer. Systemic doses of retinoids are also reduced, resulting in a decrease of retinoid-associated side effects.11 It is postulated that pretreatment with retinoids allows a greater therapeutic effect because the retinoids cause epidermal thinning, thus increasing the penetration of UV light.16 Patients with extremely thick plaques can be pretreated with methotrexate, which results in thinning of the plaques and increased susceptibility to UVB treatments.16

Narrowband Ultraviolet B Narrowband UVB uses the spectrum of light that is most effective for the treatment of psoriasis. This therapy is more effective than traditional broadband UVB but is not as effective as PUVA. A good response can be obtained with 15 to 20 treatments (at a frequency of 3 to 5 treatments per week).16

PUVA is one of the most effective treatments available for plaque psoriasis, providing a complete response and long duration of remission.11 This modality is especially useful in patients with dark skin.16 A compound called 8-methoxypsoralen (8-MOP) is ingested orally 2 hours before UVA treatment. As a result of UVA treatment, pyrimidine dimers are formed and DNA cross-linking occurs. Therapeutic effects are evident after six or eight treatments.16 Side effects of ingestion of 8-MOP include nausea and gastrointestinal distress. These symptoms can be reduced if 8-MOP is ingested with food; psoralen baths are also available in some instances to avoid gastrointestinal interaction altogether. However, 8-MOP may be variably absorbed systemically, creating inconsistent levels of the compound in the blood.16 UVA irradiation may cause burning, which is most evident 24 hours after irradiation. Patients are also at risk for the development of PUVA lentigines, squamous cell carcinoma (SCC), and malignant melanoma.11 SCC becomes a significant risk when patients receive more than 260 PUVA treatments, and melanoma risk increases after 250 sessions.11,17 Notably, males have an 11-fold increased risk for genital SCC, and adequate genital shielding is necessary.11 PUVA has been studied in combination with other treatments with the goal of reducing the total number of PUVA treatments and thereby decreasing the risk of malignancy. PUVA plus calcipotriene results in quicker clearance of lesions with lower cumulative doses of PUVA, and the effects of oral retinoids are also additive with the effects of PUVA. Combinations with methotrexate and UVB are useful in patients who are not responding to monotherapy with either agent.11

SYSTEMIC THERAPIES

Methotrexate Methotrexate (MTX) acts by inhibiting dihydrofolate reductase, an enzyme responsible for converting folic acid to other compounds that act as cofactors in many biochemical reactions. It has been used to treat acute lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, breast cancer, lung cancer, and many other malignancies.18 MTX is also an extremely effective treatment that can be used in the long term in patients with moderate to severe plaque psoriasis, pustular and erythrodermic psoriasis, and psoriatic arthritis. MTX is usually indicated if more than 20% of the body’s surface area is affected, bodily functioning is impaired (as in palmar or plantar psoriasis), or the patient is not responsive to UVB phototherapy, PUVA, or retinoids.19 MTX is the least expensive systemic medication and is often prescribed if a patient has financial constraints.

Although MTX is very effective, it has serious side effects and therefore requires close monitoring. Bone marrow and liver toxicities are the most important short- and long-term adverse effects, respectively. Other toxicities include oral mucositis, nausea, macrocytic anemia, cough, dyspnea, and increased risk for lymphoma. Folic acid supplementation may help alleviate nausea and prevent anemia. When therapy is initiated, a complete blood count (CBC) is checked every week and then monthly as the patient reaches a maintenance dose. Liver function tests, blood urea nitrogen (BUN), and creatinine levels are checked every 1 or 2 months. In addition, a liver biopsy is recommended after a cumulative dose of 1 to 1.5 g in healthy patients and within 2 to 4 months of treatment in patients with risk factors for liver disease such as hepatitis, cirrhosis, history of excessive alcohol use, persistently elevated liver function tests, or family history of liver disease. MTX is teratogenic and must be avoided in patients who are pregnant or may become pregnant within several months after discontinuing therapy. Many drugs many increase the toxicity of MTX, including (but not limited to) nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, salicylates, and ethanol.20

Systemic Therapies

Psoralen plus Ultraviolet A

Cyclosporine Cyclosporine was initially used in transplant patients to prevent graft rejection and is now approved for the treatment of psoriasis. Cyclosporine interferes with Tcell signal transduction and prevents T-cell activation and cytokine production.18 Cyclosporine can be prescribed if a patient is acutely ill and it is desirable to obtain a rapid response to treatment. Because of kidney toxicity, cyclosporine’s use is limited to 1 year. Important adverse effects include dose-dependent renal toxicity and hypertension; consequently, cyclosporine should not be used in patients with uncontrolled hypertension or renal dysfunction. Hyperlipidemia, gastrointestinal symptoms, hypertrichosis, gingival hypertrophy, and keratosis pilaris have been attributed to cyclosporine use.18,20 Also, cyclosporine suppresses the immune system and should not be used in patients with active infection or malignancy. Laboratory monitoring includes monthly blood pressure, BUN, creatinine, CBC, liver function tests, lipids, magnesium, uric acid, and potassium.20 Cyclosporine has not been found to be teratogenic. Drugs that induce or inhibit cytochrome P450 3A can affect the metabolism of cyclosporine and must be prescribed with caution.18

Retinoids Three systemic retinoids are effective as therapies for psoriasis. Isotretinoin has been extremely successful in

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treating pustular psoriasis, although it has few applications for other forms of psoriasis. Etretinate and acitretin are especially effective in the treatment of pustular and erythrodermic psoriasis as well as plaque psoriasis. However, etretinate is no longer used because of its extremely long half-life. Acitretin is now the retinoid of choice and can be used as a monotherapy (most effective in pustular or erythrodermic psoriasis) or in combination with other treatment modalities (for guttate and plaque psoriasis).20 Retinoids are highly teratogenic; therefore, women of reproductive age are not given a retinoid regimen if they plan to become pregnant within 3 years of therapy. Retinoids are otherwise generally quite safe, but at higher doses mucocutaneous side effects (conjunctivitis, dry skin, hair loss, and abnormal nail plate development) and systemic side effects (hyperlipidemia, pseudotumor cerebri, liver toxicity) may occur. Patients require regular monitoring while taking retinoids; liver function tests, cholesterol and triglyceride levels, CBC and platelet counts, BUN, creatinine, and urinalysis are routinely assessed. Also, female patients of reproductive age are required to have a monthly pregnancy test.20 Retinoids are especially effective in combination with PUVA and UVB. Patients with disease unresponsive to retinoid monotherapy are pretreated with systemic retinoids 1 to 2 weeks before initiating phototherapy. These patients have remarkable resolution of their disease and require fewer phototherapy sessions and lower doses of retinoids. Because of the synergistic effect achieved when these modalities are combined, patients experience greater treatment effect with fewer side effects.21

Other

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Tacrolimus (FK506) is an immunosuppressive drug that diminishes T-cell activation and induces remission of psoriasis. Patients can experience diarrhea, paresthesias, insomnia, hypertension, nephrotoxicity, and immunosuppression when taking this drug. Because of systemic side effects, blood pressure, BUN, creatinine, chemistry, and CBC must be monitored.20 Mycophenolate mofetil is another immunomodulatory drug. Mycophenolate mofetil is converted to mycophenolic acid, a compound that inhibits inosine monophosphate dehydrogenase. This inhibition results in dysfunctional lymphocytes.18 Mycophenolate mofetil has been used to prevent transplant rejection and control inflammatory and autoimmune disorders and is another alternative for controlling psoriasis. Mycophenolate mofetil is especially useful in combination with cyclosporine and is often employed as an additional measure of control when cyclosporine is being tapered or in patients with resistant disease.

Because of mycophenolate mofetil’s immunosuppressive nature, caution must be used in patients with malignancy or active infection. A CBC and differential must be followed for patients taking this drug.20 Hydroxyurea is an inhibitor of DNA synthesis and is used to treat chronic myelogenous leukemia, acute myelogenous leukemia, polycythemia vera, and sickle cell disease.18 Hydroxyurea is quite effective for psoriasis but is not always well tolerated; more than half of the patients treated with this drug experience serious adverse effects and must be seen regularly.20 The development of leg ulcers is a disturbing cutaneous side effect, and systemic effects include bone marrow toxicity, leukopenia, thrombocytopenia, megaloblastic anemia, and rarely hepatotoxicity.20 6-Thioguanine is an immunosuppressive drug that is structurally similar to the purines. It interferes with purine biosynthesis and DNA replication and is generally used to treat leukemia but also induces remission of psoriasis. Laboratory monitoring is required every 2 weeks because of the risk of bone marrow suppression and liver toxicity.18,20 Other systemic therapies effective in some patients include sulfasalazine, azathioprine, thiazolidinediones, calcitriol, colchicine, dapsone, and propylthiouracil.18,20

BIOLOGIC THERAPIES

Alefacept This biologic agent was created by fusing the terminal aspect of LFA-3 (a molecule found on APCs and ligand for CD2) with the Fc portion of human immunoglobulin G1 (IgG1). Normally, the interaction between LFA-3 and CD2 serves as a costimulatory signal that is important in the T-lymphocyte activation pathway. Alefacept (Amevive, Biogen, Cambridge, MA) acts on T cells in two different ways. First, it blocks T-cell activation by competitively inhibiting the interaction between LFA-3 and CD2. Furthermore, alefacept mediates the interaction between natural killer cells and memory effector T cells and induces apoptosis of the memory T cells, thereby limiting T-cell activation. Because memory T cells have increased expression of CD2, they are more susceptible to apoptosis; consequently, circulating levels of these cells are diminished.4 Alefacept is appropriate for patients with moderate to severe psoriasis, patients who have not had a good response to other therapies, and patients who have comorbid illnesses that may preclude other systemic treatments.6 Clinical trials have shown that patients with moderate to severe psoriasis can respond well to alefacept.22-24 Alefacept therapy has resulted in significant clinical improvement, as measured by a reduction in the psoriasis area and severity index (PASI).22,23 A clinical

Efalizumab Efalizumab (Raptiva, anti-CD11a, Genentech), a humanized monoclonal IgG1 antibody, targets the CD11a subunit of LFA-1.4 Efalizumab acts by blocking the interaction between LFA-1 and ICAM-1, subsequently inhibiting signal transduction required for Tlymphocyte activation, T-cell migration into the skin, and T-cell adhesion to keratinocytes.25 Efalizumab is approved for the treatment of chronic plaque psoriasis and has been shown to be effective in treating moderate to severe cases.8 Because efalizumab targets multiple steps in the psoriasis disease process, it is an extremely effective therapeutic option in patients with moderate to severe psoriasis. Subjects treated with efalizumab have greater clearance of their disease and report improved quality of life.26 Moreover, the clinical improvements occur as early as week 4 of treatment.1,27 Histologic evidence of disease improvement is also apparent in patients treated with efalizumab; epidermal thickness is decreased and the number of CD3+ T cells in the skin biopsy is reduced.1 Overall, efalizumab is well tolerated. Patients may experience mild acute adverse effects (headache, fever, chills, nausea), which usually resolve after one or two injections.1,26,27 The absolute lymphocyte, eosinophil, and total white blood cell counts may increase transiently during treatment but return to normal after discontinuation of therapy.1,27 Efalizumab does not appear to increase the rate of infection or development of malignancy after treatment.1 When the

treatment time is extended from 12 to 24 weeks, patients experience sustained clinical improvement; notably, the average time to relapse is 84 days after the last dose of efalizumab.27 Some subjects exhibited an exacerbation of their disease at the end of the dosing period, and therefore it has been suggested that patients change to other therapies when discontinuing efalizumab.25

Biologic Therapies

response can be detected 2 weeks after the first dose, and the improvement continues even after the last dose (mean maximal reduction of disease severity is 8 weeks after the last dose).23 Adverse effects are mild and transient, consisting of dizziness, nausea, chills, and cough. No serious infections have been reported, and minimal immunogenicity exists. Thus far, patients treated with alefacept do not have an increased risk for malignancy; nor do they have blunted responses to immunizations.6 After discontinuation of treatment, no flaring or rebound of disease has been noted.22,23 The median duration of response to alefacept therapy is 7 months (after one 12-week course), with some patients sustaining their response up to 18 months without further treatment.23,24 CD4 levels must be checked before treatment is started and weekly thereafter. The drug should be stopped if CD4 counts fall below 250 cells/μL but may be restarted as soon as CD4 levels increase. If patients do not respond to the first 12-week course of therapy, a second course may be started after a 12-week drug-free interval.4 Patients most likely to benefit from a second course of therapy are those who have improved during the first course but are not yet completely clear of the disease.6

Etanercept Etanercept (Enbrel, Amgen, Thousand Oaks, CA) is a biologic agent that has been approved for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriatic arthritis.28,29 Etanercept is a dimeric fusion protein, composed of the extracellular domain of the TNF-α receptor and the Fc portion of human IgG1. It acts as an inhibitor of TNF-α by binding to TNF-α receptor molecules and preventing their interaction with cell surface TNF-α, therefore interfering with signal transduction and the production of pro-inflammatory cytokines.28 In addition to being effective for rheumatoid arthritis and psoriatic arthritis, etanercept has been shown to improve the cutaneous lesions of psoriasis.29 In psoriatic arthritis, etanercept can be used as a monotherapy or combined with MTX. When used as a monotherapy, etanercept also inhibits radiographic progression of disease.30 Patients with cutaneous psoriasis have a significant clinical response, and they show a continued response with longer treatment periods. Etanercept acts quickly; some patients see improvement by week 2 of treatment.29 Treatment with etanercept is associated with less than a 2% rate of immunogenicity, but cases of positive antinuclear antibody titers and reversible druginduced lupus have been reported.28 Mild to moderate injection site reactions (erythema, pruritus, pain, swelling) may occur, mostly within the first month of treatment. Rare cases of serious infection and sepsis have been linked with the use of etanercept. Also, one should consider testing for tuberculosis before initiating therapy even though testing is not mandated by the Food and Drug Administration (FDA).28 Caution should be used in patients with congestive heart failure because the possibility that TNF-α blockers worsen heart failure has been raised.28 The drug should be avoided in patients with demyelinating disease, which can be exacerbated by TNF-α blockers.28 Etanercept can be administered subcutaneously by the patient at home and requires no laboratory monitoring. This drug may also be a good option in pregnancy; animal studies so far have not shown the agent to be teratogenic.28

Infliximab Infliximab (Remicade, Centocor, Malvern, PA) is a chimeric monoclonal antibody with human constant

119

DERMATOLOGIC MANAGEMENT OF PSORIASIS

and murine variable regions that binds with high affinity to TNF-α. Infliximab binds both free and transmembrane TNF-α molecules and interferes with its pro-inflammatory activity; in addition, the drug lyses cells with transmembrane TNF-α.28 Infliximab is FDA-approved for treatment of rheumatoid arthritis and Crohn’s disease but not for psoriasis.31 However, a high proportion of patients treated with infliximab for their psoriasis achieve rapid and complete clearance of their disease, similar to the response observed with cyclosporine therapy.31 After three initial infusions, patients treated with infliximab show dramatic improvement compared with those receiving placebo.31,32 Patients typically respond to treatment within 2 weeks and have a maximal response 10 weeks after the initial infusion. The response can be maintained as long as 6 months after the initial three infusions with no other intervention.32 Notably, patients responded more quickly and to a greater degree with infliximab therapy than with the other biologics.32 The development of antibodies against infliximab is a concern, and concomitant MTX is administered to prevent neutralizing antibody formation.28 Patients administered infliximab on regular maintenance regimens are less likely to develop antibodies than those who use the drug intermittently. Infliximab is administered as an intravenous infusion over 2 to 3 hours every 4 to 8 weeks. Because of the possibility of serious infusion reactions (dyspnea, flushing, urticaria, hypotension, headache), patients must be monitored in a medical setting following the

infusion.33 In addition, the FDA requires screening for tuberculosis in potential candidates for infliximab therapy. This biologic agent is contraindicated in patients with moderate to severe congestive heart failure (New York Heart Association class III and IV). A reversible lupus-like syndrome has also been reported in study patients receiving infliximab for rheumatoid arthritis and Crohn’s disease. As with most other immunosuppressive therapies, risk of serious infection and sepsis exists with this drug.33

Adalimumab Adalimumab (Humira, Abbott Laboratories, Abbott, IL) is a monoclonal antibody with anti–TNF-α properties. Thus far, it has been approved for treatment of rheumatoid arthritis and may be used alone or with MTX to treat psoriasis and psoriatic arthritis.4,34 Studies have shown that adalimumab is well tolerated, but additional long-term clinical trials are necessary to characterize its safety. As with other immunomodulatory therapies, adalimumab should not be administered to patients with active infections. Also, tuberculin skin testing is recommended before initiating therapy with adalimumab because of the risk of reactivating latent tuberculosis.4,34 Other adverse events noted with the use of anti-TNF agents include the development of antinuclear antibodies, increased risk of malignancy, and exacerbation of demyelinating disease. Although clinical trials are ongoing for adalimumab, it shows promise as a safe and effective treatment for psoriasis.

REFERENCES

120

1. Papp K, Bissonnette R, Krueger JG, et al. The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. J Am Acad Dermatol 2001;45:665-674. 2. Lebwohl MG. Psoriasis. In: Lebwohl MG, Heymann WR, Warren R (eds). Treatment of Skin Disease: Comprehensive Therapeutic Strategies. New York: Mosby, 2002, pp 533-543. 3. Ruderman EM, Tambar S. Psoriatic arthritis: Prevalence, diagnosis, and review of therapy for the dermatologist. Dermatol Clin 2004;22:477-486. 4. Kormeili T, Lowe NJ, Yamauchi PS. Psoriasis: Immunopathogenesis and evolving immunomodulators and systemic therapies; U.S. experiences. Br J Dermatol 2004;151: 3-15. 5. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002;46:1-23. 6. Krueger GG, Callis KP. Development and use of alefacept to treat psoriasis. J Am Acad Dermatol 2003;49:S87-S97. 7. Mehlis SL, Gordon KB. The immunology of psoriasis and biologic immunotherapy. J Am Acad Dermatol 2003;49:S44-S50. 8. Jullien D, Prinz JC, Langley RGB, et al. T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva): Mechanisms of action. Dermatology 2004;208: 297-306. 9. Lebwohl M, Menter A, Koo J, et al. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol 2004;50: 416-430.

10. Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993;28:454-459. 11. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and phototherapy. J Am Acad Dermatol 2001;45:487-498. 12. Gilbertson EO, Spellman MC, Piacquadio DJ, et al. Super potent topical corticosteroid use associated with adrenal suppression: Clinical considerations. J Am Acad Dermatol 1998;38:318-321. 13. Thami GP, Sarkar R. Coal tar: Past, present and future. Clin Exp Dermatol 2002;27:99-103. 14. Lebwohl M, Siskin, SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 1996;35:268-269. 15. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: Vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol 1997;37:85-92. 16. Zanolli M. Phototherapy treatment of psoriasis today. J Am Acad Dermatol 2003;49:S78-S86. 17. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997;336:1041-1045. 18. Yamauchi PS, Rizk D, Kormeili T, et al. Current systemic therapies for psoriasis: Where are we now? J Am Acad Dermatol 2003;49:S66-S77.

27. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted Tcell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003;349:2004-2013. 28. Goffe B, Cather JC. Etanercept: An overview. J Am Acad Dermatol 2003;49:S105-S111. 29. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;349:2014-2022. 30. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis. Arthritis Rheum 2004;50:2264-2272. 31. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomized trial. Lancet 2001;357:1842-1847. 32. Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2004;51:534-542. 33. Gottlieb AB. Infliximab for psoriasis. J Am Acad Dermatol 2003;49:S112-S117. 34. Patel T, Gordon KB. Adalimumab: Efficacy and safety in psoriasis and rheumatoid arthritis. Dermatol Ther 2004;17:427-431.

References

19. Roenigk HH, Auerbach R, Maibach H, et al. Methotrexate in psoriasis: Consensus conference. J Am Acad Dermatol 1998;38: 478-485. 20. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001;45:649-661. 21. Lebwohl M. Acitretin for psoriasis therapy: Dosing, adverse events, and therapeutic options. J Am Acad Dermatol 1999;41:S22-S24. 22. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248-255. 23. Krueger GG, Papp KA, Stough DB, et al. A randomized, doubleblind, placebo-controlled phase III study evaluating the efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47:821-833. 24. Feldman SR, Menter A, Koo JY. Improved health-related quality of life following a randomized controlled trial of alefacept treatment in patients with chronic plaque psoriasis. Br J Dermatol 2004;150:317-326. 25. Leonardi CL. Efalizumab: An overview. J Am Acad Dermatol 2003;49:S98-S104. 26. Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis. JAMA 2003;290:3073-3080.

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14

Epidemiology of Reactive Arthritis Marjatta Leirisalo-Repo

DEFINITION Reactive arthritis is a member of the spondyloarthritides, which share several features in common.1 The patients have monoarthritis or oligoarthritis with or without inflammatory back symptoms. Extra-articular inflammatory symptoms also characterize the diseases. In addition to reactive arthritis, the diagnostic subgroups in the spondyloarthritis family include arthritis associated with inflammatory bowel disease, psoriasis arthritis, some forms of juvenile-onset arthritis, and ankylosing spondylitis. These diseases share a strong association with a genetic marker, human leukocyte antigen HLA-B27, absence of rheumatoid factor, tendency to family aggregation, and, frequently, extra-articular symptoms. A broad definition for reactive arthritis is joint inflammation that develops soon after or during infection elsewhere in the body but in which the microorganism cannot be recovered from the joint. It has been shown that the infectious pathogens can persist in the host, and indeed antigens of the triggering microbe can be isolated from the synovial fluid or synovial tissue of affected joints. Furthermore, there is evidence of a living organism (bacterial DNA and RNA) in the infected joints, as reviewed by Hill Gaston and Lillicrap.2 The best evidence for the presence of a viable organism in the joint has been presented for Chlamydia trachomatis. Despite the identification of links to infectious agents, no consensus on classification and diagnostic criteria for reactive arthritis has been achieved.3,4 Therefore, studies of reactive arthritis from different countries are difficult to compare. This has especially hindered our understanding of the epidemiology of reactive arthritis.

BACTERIAL INFECTIONS AND MUSCULOSKELETAL SYMPTOMS Enteric infections caused by gram-negative microbes are associated with a risk of reactive arthritis in about 1% to 15% of the patients. The classical microbes with this association include Yersinia, Salmonella, Shigella,

Campylobacter, and also Clostridium difficile, although less frequently. Chlamydia trachomatis is by far the most common cause of urethritis and of reactive arthritis following urethritis. The role of the other microbes (Neisseria gonorrhoeae, Mycoplasma genitalium, and Ureaplasma urealyticum) in the etiology of urethritis and subsequent reactive arthritis is not settled.5,6 Chlamydia pneumoniae has been implicated as the triggering organism in about 10% of patients with reactive arthritis.7,8 In about 60% of patients with reactive arthritis, evidence of previous infection can be detected either by serology or by cultures from urogenital or stool samples.9,10 In other cases, the role of infection is less distinct. Bacteria that reside in the normal gut flora (such as Escherichia coli or Klebsiella) are usually not linked to reactive arthritis. However, we have observed a patient with recurrent attacks of reactive arthritis that were preceded by urinary tract infections caused by E. coli.11 Also, Locht and Krogfelt have reported probable reactive arthritis in 6% of patients with gastroenteritis caused by enterotoxic E. coli.12 The list of potential triggering infections in reactive arthritis is gradually increasing (Table 14-1).

EPIDEMIOLOGY OF REACTIVE ARTHRITIS There is only limited information on the incidence and prevalence of reactive arthritis. The data depend on the presence of triggering infections in the community and the background genetic susceptibility in the population (HLA-B27) as well as on the diagnostic criteria (if any) applied in the diagnosis of reactive arthritis.

Prevalence of Infection in the Population The prevalence of infections capable of triggering reactive arthritis in different populations is poorly documented. On the basis of the presence of antibodies in healthy populations, infection as the cause of acute joint symptoms have been suggested to play a role in 9% to 18% of patients with inflammatory joint disease of less than 6 months’ duration.13,14 These figures are applicable only in the Western world, where background rates of infection related to gastrointestinal

123

EPIDEMIOLOGY OF REACTIVE ARTHRITIS

TABLE 14-1 MICROBIAL INFECTIONS ASSOCIATED WITH THE DEVELOPMENT OF REACTIVE ARTHRITIS

Country

Enteric bacteria Salmonella Shigella

Yersinia

1978

27

14

13

Norway

1994

10

5

5

S. sonnei

Finland

2000

10

7

3

Y. enterocolitica (especially O:3 and O:9)

Sweden

2002

28

18

1

C. jejuni

Chlamydia trachomatis Ureaplasma urealyticum (?)

From Isomaki H, Raunio J, von Essen R, Hameenkorpi R. Incidence of inflammatory rheumatic diseases in Finland. Scand J Rheumatol 1978;7:188-192; Kvien TK, Glennas A, Melby K, et al. Reactive arthritis: Incidence, triggering agents and clinical presentation. J Rheumatol 1994;21:115-122; Soderlin MK, Borjesson O, Kautiainen H, et al. Annual incidence of inflammatory joint diseases in a population based study in southern Sweden. Ann Rheum Dis 2002;61:911-915; Savolainen E, Kaipiainen-Seppanen O, Kroger L, Luosujarvi R. Total incidence and distribution of inflammatory joint diseases in a defined population: Results from the Kuopio 2000 arthritis survey. J Rheumatol 2003;30:2460-2468.

β-Hemolytic streptococcus (?) Chlamydia pneumoniae

Recently confirmed species/serovars.

pathogens are low. Microbial contamination of drinking water is a common problem and a major source of microbial pathogens in the developing world,15 where about half of the asymptomatic subjects can carry enteric pathogens in the stools.15 Interestingly, in a prevalence study in a rural population in western India, no cases of well-defined reactive arthritis were observed in the population of 4092 adults examined.16

Population-Based Studies on the Epidemiology of Reactive Arthritis Enteric infections capable of triggering reactive arthritis traditionally cause outbreaks, whereas Chlamydia trachomatis infection is endemic. Therefore, incidence figures are easier to obtain in reactive arthritis that arises during outbreaks of gastrointestinal diseases. There are only few population-based studies on the annual incidence of reactive arthritis, most from Scandinavia. The total incidence has been estimated to be 10 to 30 per 100,000 (Table 14-2).17-20 A community-based epidemiologic study from Norway found Chlamydia trachomatis and enterobacteria played an equal etiologic role.18 A similar incidence and spectrum were reported from Sweden.19 These studies showed that at the population level, reactive arthritis is mild19,21 and has a good prognosis.21

Hospital Series of Reactive Arthritis 124

Enteric Urogenital

Finland

Mycoplasma genitalium (?)

*

Total

S. flexneri

Clostridium difficile

Bacteria causing upper respiratory infection

Incidence/100,000

S. dysenteriae*

C. coli*

Bacteria causing urethritis

Year

Various serovars

Y. pseudotuberculosis Campylobacter

TABLE 14-2 ANNUAL INCIDENCE OF REACTIVE ARTHRITIS ACCORDING TO FOCUS OF INFECTION

The evidence in favor of an infectious trigger in acute arthritis is usually based on data from patients treated

at hospitals or outpatient departments for acute or prolonged joint pain. Reactive arthritis is present in about 10% of those presenting at early synovitis clinics.17,22 On the basis of a large hospital series of Yersinia-induced reactive arthritis from two countries, we reported a high frequency of HLA-B27 (80% to 90%) and frequent extra-articular features.23 A prolonged course of arthritis or recurrent acute arthritis was relatively common and associated with HLA-B27. Although no large analysis of the distribution of the background infections in patients with reactive arthritis has been made, it seems evident from the data outlined previously that the most frequent triggering infections are Yersinia and Chlamydia trachomatis.22,24 Salmonella was not mentioned25 or was only occasionally described as a triggering infection.23,24 In more recent reports, Salmonella10,26 and Shigella27 are more frequent etiologic agents.

Single-Source Outbreaks Most cases of reactive arthritis arise sporadically. Single-source epidemics, which give better information about the spectrum and severity of the diseases, have been published in association with Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter jejuni, Shigella flexneri (Table 14-3), and Salmonella enterica (Table 14-4). However, these results are also dependent on the response rate, how the clinical information was collected (only questionnaire or by personal interview), and whether the patients were clinically assessed. The results show that the frequency of reactive arthritis varies greatly among these studies (from 0% to 21%).

Study Type

Subjects Responding to Q (%)

Reference

Infective Agent

Subjects in the Outbreak, n

Reactive Arthritis (%)

Frequency of HLA-B27

35

Shigella

602

Hospital

—

1.5

NA

36

Shigella sonnei

184

Q + CE

80

0

NA

36

Shigella flexneri 2a

636

Q + CE

86

1.5

2/3

36

Shigella flexneri 1b

709

Q + CE

65

1.5

3/3

37

C. jejuni

347

Hospital

—

0.7

0/1

38

C. jejuni

106

Q + CE

81

1.8

1/1

33

C. jejuni/coli

330

Q

15

0.4

NA

39

Y. enterocolitica

117

H

—

0

NA

40

Y. pseudotuberculosis III

NA

Hospital

—

21

3/4

41

Y. pseudotuberculosis I

NA

Hospital

—

3

1/1

42

Y. pseudotuberculosis I

74

Q

80

0

NA

Epidemiology of Reactive Arthritis

TABLE 14-3 REACTIVE ARTHRITIS IN SHIGELLA, YERSINIA, AND CAMPYLOBACTER OUTBREAK COHORTS

C, Campylobacter; NA, not available; Q, questionnaire; Q + CE, questionnaire followed by clinical examination; Y., Yersinia.

The frequency of HLA-B27, although different between studies, is usually considerably lower than in hospital series.

Use of Survey Programs of Enteric Pathogens in the Epidemiology of Reactive Arthritis Epidemiologic studies can reliably be performed in patients with enteric infections and in countries with good collaboration between rheumatologists and nationwide laboratory registers of pathogenic microbial isolations. For example, Campylobacter has recently become one of the most important infections to cause gastroenteritis in the Western world, such as in Finland.28 By applying epidemiologic methods, it was determined that, in Finland, Campylobacter-induced reactive arthritis was frequent, with an annual incidence of 4.3 per 100,000. The disease is usually mild, oligoarticular or polyarticular, and at the population level there is no increased frequency of HLA-B27. 29 Similar results were also reported during a single outbreak of Campylobacter jejuni infection in Finland.30 In both of these studies, the patients were identified and clinical diagnosis was confirmed by a detailed questionnaire, often supplemented by clinical examination. In California, the Foodborne Diseases Active Surveillance Network (FoodNet), covering a population of 2.2 million, collects laboratory-confirmed

infections with enteric pathogens. In 1998 to 1999, 1454 infections were reported, of which 52% were due to Campylobacter, 22% due to Salmonella, 15% due to Shigella, 2% due to E. coli O157:H7, and 2% due to Yersinia.31 Using a posted questionnaire (response rate 43%), newly developed musculoskeletal symptoms were reported by 2.1% of the subjects.31 They were associated with Campylobacter (nine cases), Salmonella (two cases) and Shigella (one case). Recent data suggest that Campylobacter might be the leading cause for infectious-triggered musculoskeletal diseases in New Zealand. During the years 1988 to 2002, there was a slight or no increase in the reported infection rate due to Salmonella and Shigella but a greater than fourfold increase in the number of reported Campylobacter infections.32 At the same time, the number of patients discharged annually from hospitals with the diagnosis of Reiter’s disease or with postdysenteric arthropathy was consistently at a very low level, in contrast to the patents with unspecified infective arthritis (a rise from 16 to 384) and other inflammatory spondylopathies (from near 0 to 11 to 16). This rapid increase suggests a possible role for Campylobacter infections in arthritis in New Zealand. Campylobacter is a common inhabitant of natural water reservoirs, and it is known to cause diarrheal outbreaks. An outbreak of Campylobacter infection related to unchlorinated drinking water in northern

125

EPIDEMIOLOGY OF REACTIVE ARTHRITIS

TABLE 14-4 REACTIVE ARTHRITIS IN VARIOUS SALMONELLA ENTERICA OUTBREAK COHORTS Subjects in the Outbreak, n

Study Type

Subjects Responding to Q (%)

Reactive Arthritis (%)

Frequency of HLA-B27

Reference

Serovar

43

Typhimurium

330

Hospital

37

Typhimurium

448

Hospital

44

Typhimurium

473

Q + CE

72

45

Heidelberg

83

Q + CE

92

46

Enteritidis

126

Q

90

47

Enteritidis

88

Q + CE

39

9.1

2/8 (25%)

48

4,5;12:b:-

272

Q + CE

90

6.9

3/13 (31%)

49

Typhimurium

919

Q + CE

35

1.2-4.6

3/5 (60%)

50

Typhimurium

423

Q + CE

97

6.4

6/27 (22%)

51

Bovis-morbificans

210

Q + CE

91

11.5

10/22 (45%)

52

Typhimurium

849

Q + CE

50

4.5

2/19 (10%)

53

Enteritidis

423

Q

60

29

54

Typhimurium

78

Q + CE

81

8

2/4 (50%)

55

Typhimurium

493

Q

57

15

5/30 (17%)

3.9

9/13 (69%)

1.8

3/8 (38%)

7.3

4/11 (36%)

7.2

0/6 (0%)

15

NA

NA

NA, not available; Q, questionnaire; Q + CE, questionnaire followed by clinical examination.

Norway led to a diarrheal illness in about 15% of the population. Of the infected patients, 21% reported joint pain and 9% reported joint swelling.33 Shigella is a rare disease in the Western world and also in Finland. In a vast majority of cases, it is imported. We published the results of nationwide screening of patients with reactive arthritis in association with culture-positive Shigella infection. Reactive arthritis occurred in 7% of the patients, with annual incidence of 1.3 per 100,000.34

The frequency of HLA-B27 was slightly higher (36%) than that in the normal Finnish population (14%). Contrary to previous reports, besides the classical Shigella flexneri, Shigella sonnei and Shigella dysenteriae were shown to be associated with acute reactive arthritis. These results highlight the advantage of populationbased studies, which avoids the problem of selection bias. This bias favors inclusion of only the most severe cases who ultimately are referred to rheumatologists.

REFERENCES

126

1. Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227. 2. Hill Gaston JS, Lillicrap MS. Arthritis associated with enteric infection. Best Pract Res Clin Rheumatol 2003;17:219-239. 3. Sieper J, Braun J. Problems and advances in the diagnosis of reactive arthritis. J Rheumatol 1999;26:1222-1224. 4. Braun J, Kingsley G, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000;27:2185-2192. 5. Taylor-Robinson D, Gilroy CB, Thomas BJ, Hay PE. Mycoplasma genitalium in chronic non-gonococcal urethritis. Int J STD AIDS 2004;15:21-25. 6. Galadari I, Galadari H. Nonspecific urethritis and reactive arthritis. Clin Dermatol 2004;22:469-475.

7. Braun J, Laitko S, Treharne J, et al. Chlamydia pneumoniae—A new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 1994;53:100-105. 8. Hannu T, Puolakkainen M, Leirisalo-Repo M. Chlamydia pneumoniae as a triggering infection in reactive arthritis. Rheumatology (Oxford) 1999;38:411-414. 9. Keat A. Reiter’s syndrome and reactive arthritis in perspective. N Engl J Med 1983;309:1606-1615. 10. Fendler C, Laitko S, Sorensen H, et al. Frequency of triggering bacteria in patients with reactive arthritis and undifferentiated oligoarthritis and the relative importance of the tests used for diagnosis. Ann Rheum Dis 2001;60:337-343. 11. Laasila K, Leirisalo-Repo M. Recurrent reactive arthritis associated with urinary tract infection by Escherichia coli. J Rheumatol 1999;26:2277-2279. 12. Locht H, Krogfelt KA. Comparison of rheumatological and gastrointestinal symptoms after infection with Campylobacter jejuni/coli and enterotoxigenic Escherichia coli. Ann Rheum Dis 2002;61:448-452.

35. Noer HR. An “experimental” epidemic of Reiter’s syndrome. JAMA 1966;198:693-698. 36. Simon DG, Kaslow RA, Rosenbaum J, et al. Reiter’s syndrome following epidemic shigellosis. J Rheumatol 1981;8:969-973. 37. Eastmond CJ. Gram-negative bacteria and B27 disease. Br J Rheumatol 1983;22 (4 Suppl 2):67-74. 38. Bremell T, Bjelle A, Svedhem A. Rheumatic symptoms following an outbreak of campylobacter enteritis: A five year follow up. Ann Rheum Dis 1991;50:934-938. 39. Lindholm H, Visakorpi R. Late complications after a Yersinia enterocolitica epidemic: A follow up study. Ann Rheum Dis 1991;50:694-696. 40. Tertti R, Granfors K, Lehtonen OP, et al. An outbreak of Yersinia pseudotuberculosis infection. J Infect Dis 1984;149:245-250. 41. Tertti R, Vuento R, Mikkola P, et al. Clinical manifestations of Yersinia pseudotuberculosis infection in children. Eur J Clin Microbiol Infect Dis 1989;8:587-591. 42. Press N, Fyfe M, Bowie W, Kelly M. Clinical and microbiological follow-up of an outbreak of Yersinia pseudotuberculosis serotype Ib. Scand J Infect Dis 2001;33:523-526. 43. Hakansson U, Eitrem R, Low B, Winblad S. HLA-antigen b27 in cases with joint affections in an outbreak of salmonellosis. Scand J Infect Dis 1976;8:245-248. 44. Inman RD, Johnston ME, Hodge M, et al. Postdysenteric reactive arthritis. A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31:1377-1383. 45. Thomson GT, Chiu B, De Rubeis D, et al. Immunoepidemiology of post-Salmonella reactive arthritis in a cohort of women. Clin Immunol Immunopathol 1992;64:227-232. 46. Locht H, Kihlstrom E, Lindstrom FD. Reactive arthritis after Salmonella among medical doctors—Study of an outbreak. J Rheumatol 1993;20:845-848. 47. Thomson GT, Alfa M, Orr K, et al Secretory immune response and clinical sequelae of Salmonella infection in a point source cohort. J Rheumatol 1994;21:132-137. 48. Mattila L, Leirisalo-Repo M, Koskimies S, et al. Reactive arthritis following an outbreak of Salmonella infection in Finland. Br J Rheumatol 1994;33:1136-1141. 49. Samuel MP, Zwillich SH, Thomson GT, et al. Fast food arthritis— A clinico-pathologic study of post-Salmonella reactive arthritis. J Rheumatol 1995;22:1947-1952. 50. Thomson GT, DeRubeis DA, Hodge MA, et al. Post-Salmonella reactive arthritis: Late clinical sequelae in a point source cohort. Am J Med 1995;98:13-21. 51. Mattila L, Leirisalo-Repo M, Pelkonen P, et al. Reactive arthritis following an outbreak of Salmonella Bovismorbificans infection. J Infect 1998;36:289-295. 52. McColl GJ, Diviney MB, Holdsworth RF, et al. HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella typhimurium. Aust NZ J Med 2000;30:28-32. 53. Dworkin MS, Shoemaker PC, Goldoft MJ, Kobayashi JM. Reactive arthritis and Reiter’s syndrome following an outbreak of gastroenteritis caused by Salmonella enteritidis. Clin Infect Dis 2001;33:1010-1014. 54. Hannu T, Mattila L, Siitonen A, Leirisalo-Repo M. Reactive arthritis following an outbreak of Salmonella typhimurium phage type 193 infection. Ann Rheum Dis 2002;61:264-266. 55. Lee AT, Hall RG, Pile KD. Reactive joint symptoms following an outbreak of Salmonella typhimurium phage type 135a. J Rheumatol 2005;32:524-527.

References

13. Granfors K, Isomaki H, von Essen R, et al. Yersinia antibodies in inflammatory joint diseases. Clin Exp Rheumatol 1983;1:215-218. 14. Maki-Ikola O, Viljanen MK, Tiitinen S, et al. Antibodies to arthritis-associated microbes in inflammatory joint diseases. Rheumatol Int 1991;10:231-234. 15. Ashbolt NJ. Microbial contamination of drinking water and disease outcomes in developing regions. Toxicology 2004;198:229-238. 16. Chopra A, Patil J, Billempelly V, et al. Prevalence of rheumatic diseases in a rural population in western India: A WHO-ILAR COPCORD Study. J Assoc Physicians India 2001;49:240-246. 17. Isomaki H, Raunio J, von Essen R, Hameenkorpi R. Incidence of inflammatory rheumatic diseases in Finland. Scand J Rheumatol 1978;7:188-192. 18. Kvien TK, Glennas A, Melby K, et al. Reactive arthritis: Incidence, triggering agents and clinical presentation. J Rheumatol 1994;21:115-122. 19. Soderlin MK, Borjesson O, Kautiainen H, et al. Annual incidence of inflammatory joint diseases in a population based study in southern Sweden. Ann Rheum Dis 2002;61:911-915. 20. Savolainen E, Kaipiainen-Seppanen O, Kroger L, Luosujarvi R. Total incidence and distribution of inflammatory joint diseases in a defined population: Results from the Kuopio 2000 arthritis survey. J Rheumatol 2003;30:2460-2468. 21. Glennas A, Kvien TK, Melby K, et al. Reactive arthritis: A favorable 2 year course and outcome, independent of triggering agent and HLA-B27. J Rheumatol 1994;21:2274-2280. 22. Hulsemann JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol 1995;13:37-43. 23. Leirisalo M, Skylv G, Kousa M, et al. Followup study on patients with Reiter’s disease and reactive arthritis, with special reference to HLA-B27. Arthritis Rheum 1982;25:249-259. 24. Valtonen VV, Leirisalo M, Pentikainen PJ, et al. Triggering infections in reactive arthritis. Ann Rheum Dis 1985;44:399-405. 25. Bengtsson A, Ahlstrand C, Lindstrom FD, Kihlstrom E. Bacteriological findings in 25 patients with Reiter’s syndrome (reactive arthritis). Scand J Rheumatol 1983;12:157-160. 26. Locht H, Molbak K, Krogfelt KA. High frequency of reactive joint symptoms after an outbreak of Salmonella enteritidis. J Rheumatol 2002;29:767-771. 27. Sieper J, Braun J, Wu P, et al. The possible role of Shigella in sporadic enteric reactive arthritis. Br J Rheumatol 1993;32:582-585. 28. Rautelin H, Hanninen ML. Campylobacters: The most common bacterial enteropathogens in the Nordic countries. Ann Med 2000;32:440-445. 29. Hannu T, Mattila L, Rautelin H, et al. Campylobacter-triggered reactive arthritis: A population-based study. Rheumatology (Oxford) 2002;41:312-318. 30. Hannu T, Kauppi M, Tuomala M, et al. Reactive arthritis following an outbreak of Campylobacter jejuni infection. J Rheumatol 2004;31:528-530. 31. Rees JR, Pannier MA, McNees A, et al. Persistent diarrhea, arthritis, and other complications of enteric infections: A pilot survey based on California FoodNet surveillance, 1998-1999. Clin Infect Dis 2004;38 (Suppl 3):S311-S317. 32. Lake R, Baker M, Nichol C, Garrett N. Lack of association between long-term illness and infectious intestinal disease in New Zealand. NZ Med J 2004;117:U893. 33. Melby KK, Svendby JG, Eggebo T, et al. Outbreak of Campylobacter infection in a subartic community. Eur J Clin Microbiol Infect Dis 2000;19:542-544. 34. Hannu T, Mattila L, Siitonen A, Leirisalo-Repo M. Reactive arthritis attributable to Shigella infection: A clinical and epidemiological nation-wide study. Ann Rheum Dis 2005;64:594-598.

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15

Historical Aspects of Reactive Arthritis David L. Scott and Gabrielle H. Kingsley

BACKGROUND

128

The history of seronegative arthritis cannot be traced along a simple time line. Our present view of these diseases differs greatly from perspectives of previous generations. As history is written retrospectively, there can never be a single correct opinion, only different interpretations of incomplete data. Several authors have contributed reviews in this area dealing with reactive arthritis1 and psoriatic arthritis.2,3 There is always uncertainty about when history ends and current affairs begin. We have closed our historical review in 1973 with the ground-breaking description of an association between reactive arthritis and human leukocyte antigen HLA-B27.

erosions of peripheral joints, particularly the terminal interphalangeal joints. Reactive arthritis has a more recent provenance. One possible early example of reactive arthritis was the Renaissance artist Benvenuto Cellini, who admitted in his autobiography to contracting a sexually transmitted disease and arthritis, which may have been reactive arthritis.7 There have been suggestions that Columbus may also have had reactive arthritis, although this is very speculative.8,9 The first clear description of arthritis associated with venereal disease was given by Swediaur, initially in French (1798)10 and available in an English translation only in 1819. Swediaur wrote that “sometimes after blennorrhagica there is swelling of the knee, sometimes both knees and calcaneum.”

EARLY DESCRIPTIONS OF SERONEGATIVE ARTHRITIS

REACTIVE ARTHRITIS IN THE NINETEENTH CENTURY

It is most rational to consider the earliest history of reactive arthritis in relation to seronegative arthritis as a whole, and at least some components of this symptom complex appear to be diseases of antiquity. The evidence is strongest for ankylosing spondylitis. This disease was present in ancient Egypt and has been identified in mummified remains. There is good evidence that at least three pharaohs, including Rameses II (“The Great,” 1290 to 1221 BC) and his son Merenptah,4 had ankylosing spondylitis. However, an important caveat is that it can be difficult to distinguish ankylosing spondylitis from diffuse idiopathic skeletal hyperostosis.5 There is intriguing evidence for psoriatic arthritis also being an ancient disease from studies of skeletal remains in early Christian society. The fifth century AD Byzantine monastery of Martyrius in the Judean Desert east of Jerusalem is thought to be a place where lepers and those with similar disfiguring diseases such as psoriasis were looked after out of charity. Zias and Mitchell6 found features suggesting psoriatic arthritis in three skeletons they examined from the tomb of Paulus at the monastery. Characteristic features included sacroiliac and intervertebral joint fusion with

In the early 19th century, many common diseases were first described, including reactive arthritis associated with venereal disease. At this time the term gonorrhea did not have the specific diagnostic connotation that it has today, and there was not a clear distinction between gonococcal and nonspecific urethritis. The best early report is Brodie’s description in 1818 of six cases of urethritis, arthritis, and conjunctivitis, the classical triad of reactive arthritis.11 His first patient is particularly interesting. He described “a man aged 45 who had gonorrhea in June 1817 followed by pain in the feet and purulent inflammation of the eyes. His left knee swelled and later his right knee, elbow and shoulder were affected. By August 1817 there was a gradual improvement.” Between 1818 and 1836 there were 13 published reports of cases resembling reactive arthritis identified by Storey and Scott (Table 15-1).1 By 1836 Thomson was able to comment that “the character of the disease is well known and should not be confused with direct gonorrheal infection,”11a suggesting a greater understanding of the differentiation of various types of sexually acquired diseases. The relationship between arthritis associated with definite gonorrhea and arthritis related to nonspecific

Source Brodie

Year 1818

Cases 6

Details Five cases described in detail with urethritis, eye inflammation, and arthritis. Sixth case mentioned briefly

Astley Cooper

1823

2

Detailed report of an American with gonococcal infections, inflammation of eyes, and rheumatism of joints

St. Thomas’s Hospital

1823

1

Blacksmith with gonococcal infection who developed inflammation of both eyes and widespread arthritis

Lawrence

1825

3

Mainly eye involvement associated with urethritis and arthritis

Thomson

1836

1

Recurrent urethritis and arthritis with some eye inflammation

From Storey GO, Scott DL. Arthritis associated with venereal disease in nineteenth century London. Clin Rheumatol 1998;17:500-504.

urethritis (mainly shown to be due to Chlamydia trachomatis in later work) was unclear until the discovery of the gonococcus by Neisser in 1879.12 Although this made it possible to resolve accurately the differences between reactive arthritis and joint problems attributable to gonococcal infection, reports from the time indicate that there was still confusion between recurrent attacks of gonococcus-induced arthritis and what modern rheumatologists would classify as chronic reactive arthritis.13 Interestingly, irrespective of its exact cause, venereal disease–associated arthritis was common; at the London Hospital from 1895 to 1900 patients with arthritis were classified into only three groups: rheumatism (meaning rheumatic fever), rheumatoid arthritis, and “gonorrheal rheumatism.” There were 2133 admissions for arthritis during these years; the majority (91%) were due to rheumatic fever and the remainder were distributed between rheumatoid arthritis (5%) and gonorrheal rheumatism (3%). It is noteworthy that sexually acquired arthritis had a frequency similar to that of rheumatoid arthritis, but whereas rheumatoid arthritis was seen equally in men and women, sexually acquired arthritis was five times commoner in males. It is important to note, however, that women are probably underrepresented in these series because they were less likely to seek hospital care. Several reviews in the late 19th century dealt with the triad of arthritis, urethritis, and conjunctivitis. In 1866 Tixier described 14 cases,14 although he regarded eye involvement as rare. In 1872 Bond15 reported a series of patients from London, noting that such arthritis involved 10% of 300 patients with venereal disease. Although the condition was rare in women, he gave two female examples, one a prostitute and the other a married women with constitutional symptoms, pain in the heels, effusions into the knees, inflamed sclera, and urethral discharge. In those times much emphasis was placed on describing the clinical features and making deductions on the basis of such observations.

Reactive Arthritis in the Early Twentieth Century

TABLE 15-1 CASE OF REACTIVE ARTHRITIS REPORTED BETWEEN 1818 AND 1836

Interestingly, Bond observed that arthritis “Often occurs quite independently of the acute urethral inflammation called gonorrhoea, as well as of any gouty or rheumatic predisposition; but it is dependent on a local condition of the urethra.” In 1878 Potter16 reviewed 20 cases from St. Thomas’s Hospital including one woman. He described involvement of the tendo Achillis, sole of the foot, and the back.

REACTIVE ARTHRITIS IN THE EARLY TWENTIETH CENTURY In 1916, two French physicians, Noel Fiessinger, a microbiologist, and Edgar Leroy, a military physician, described four cases of what they termed conjunctivourethro-synovial syndrome occurring 10 to 20 days after diarrhea.17 These patients formed part of an extensive study of a gastroenteritis epidemic studied in a military hospital in the Somme during World War I. The cases were classified as bacillary dysentery with stool culture evidence of Shigella, Salmonella, or Yersinia. Joint aspiration showed an inflammatory synovial fluid with many polymorphs but negative cultures. This paper was the first to note that in some patients with urethritis, arthritis, and conjunctivitis, the disease was triggered by gastroenteritis. Recognition that other cases were due to chlamydial nonspecific urethritis had to wait for a better understanding of the role of these agents in human disease in the mid-1960s.18 The same year, Hans Reiter reported the case of a young officer serving at the Balkan front who developed, 7 days after acute diarrhea, an illness that was characterized by arthritis, urethritis, and bilateral conjunctivitis.19 He found from venous blood culture an unknown bacterium that was considered to be a spirochete. Consequently, the disease was called spirochaetosis arthritica.

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HISTORICAL ASPECTS OF REACTIVE ARTHRITIS

The etiology of the syndrome was correctly attributed to postinfectious bacillary dysentery by Fiessinger and Leroy, and they also gave a more detailed description of several cases; in contrast, it was incorrectly attributed to spirochaetosis arthritica by Reiter, who reported only a single case. Nevertheless, for many years the medical literature and textbooks in German and English adopted the term “Reiter’s syndrome.” His was considered the first report and was the most frequently cited paper, as if the 19th century contributions had never happened. After Reiter was feted for many years as the man behind the syndrome, his role has been questioned in recent years for three reasons. The first is that there is more than ample evidence that Hans Reiter was a Nazi war criminal; as well as being an anti-Semite and a strong proponent of the Nazi eugenics philosophy, he was personally responsible for atrocities that violated the precepts of ethics and professionalism.20,21 Reiter’s reputation is thus so tainted that the medical community should no longer afford him recognition. A second reason for withdrawing recognition is that, as described previously, many other investigators accurately described a reactive cutaneoarthropathy in papers that antedate Reiter’s work by many years. Finally, the only novel aspect of Reiter’s paper was his incorrect attribution of the syndrome to a spirochete. In contrast, the virtually simultaneous paper by Fiessinger and Leroy clearly described the association with dysentery and the added microbiologic identification of enteric bacteria such as Shigella.17 This French description is therefore the first to establish clearly the association of enteric bacterial infection with reactive arthritis. In 1969, Ahvonen and colleagues22 described the concept of reactive arthritis as an arthritis that is “associated with infection elsewhere in the body but the microbe is not present in the joint.” This was in contradistinction to the other main form of infectionrelated arthritis, septic arthritis, in which the joint lesion results primarily from the presence of replicating organisms. The term “reactive arthritis” is now generally recommended in place of Reiter’s syndrome, although more recent advances, described elsewhere in this volume, require modification of Ahvonen’s original concept to include arthritides where the microbe or microbial molecules are present in the joint but not in a rapidly replicating form that directly induces arthritis.

REACTIVE ARTHRITIS AND THE EVOLVING CONCEPT OF SERONEGATIVE SPONDYLOARTHOPATHIES A major 20th century landmark in the understanding of reactive arthritis came with the recognition that 130

the seronegative spondyloarthropathies, reactive arthritis, psoriatic arthritis, and ankylosing spondylitis, shared many clinical and pathologic similarities but were entirely separate diseases from rheumatoid arthritis.23,24 Ankylosing spondylitis was also first recognized in the 19th century in reports from Brodie (1841), Strümpell (1897), Marie (1898), and von Bechterew (1893); this literature was reviewed by O’Connell in 1956.25 The availability of radiography in the 20th century allowed recognition of the characteristic sacroiliitis, and this was described comprehensively by Buckley in 1931.26 Despite these reports, ankylosing spondylitis was firmly differentiated from rheumatoid arthritis clinically only in the second half of the 20th century23 and pathologically in the Heberden oration of 1970.24 The first suggestion of a link between psoriasis and arthritis has been attributed to Alibert in 1818.27 It was not until 1860 that Bazin introduced the term psoriasis arthritique.28 In 1888, Bourdillon29 described 34 patients with psoriasis and arthritis, and he is credited with being the first clinician to identify the characteristic involvement of the distal interphalangeal joints in psoriatic arthritis. Between the late 1950s and the mid-1970s, Verna Wright wrote several key papers that changed perceptions of seronegative arthritis. This work culminated in the concept of the seronegative spondyloarthropathies. His sequential studies started in 1956 with a clinical description of psoriasis and arthritis.30 Soon after, with John Moll, he introduced the subdivision of psoriatic arthritis into five types31 ranging from oligoarticular to arthritis mutilans; this has remained the dominant classification of psoriatic arthritis for the past 30 years. Almost by chance, Wright then noted a close interrelationship of psoriatic arthritis and Reiter’s syndrome.32 This led him and John Moll, in a landmark paper from 1974,33 to link together ankylosing spondylitis, Reiter’s disease, and psoriatic arthritis under the general title of the “seronegative spondyloarthropathies.” This paper, a complex mixture of analyses of previous reports, assessments of single cases and family groups, and other studies undertaken in Leeds, described the defining features of seronegative spondyloarthropathies. These were a negative test for rheumatoid factor, absence of subcutaneous nodules, inflammatory peripheral arthritis, radiologic sacroiliitis, clinical overlap among the group members, and familial aggregation. Although the initial classification included Behçet’s syndrome and Whipple’s disease, modern views have excluded these, leaving

Inflammatory Arthropathies Ankylosing spondylitis

Predominant Feature Axial involvement

Psoriatic spondyloarthritis

Psoriasis, nail changes

Inflammatory bowel disease–related spondyloarthritis

Colitis

Reactive spondyloarthritis

Conjunctivitis/uveitis, urethritis

Undifferentiated spondyloarthritis

Characteristic symptoms, no specific features

From Nash P, Mease PJ, Braun J, van der Heijde D. Seronegative spondyloarthropathies: To lump or split? Ann Rheum Dis 2005;64 (Suppl 2):9-13.

the four key diseases, together with an undifferentiated component, at the center of the seronegative classification34 as shown in Table 15-2.

UNDERSTANDING REACTIVE ARTHRITIS PATHOGENESIS In the 1960s and early 1970s, the two strands still thought to be the major contributors to the pathogenesis of reactive arthritis were initially clearly elucidated. These were, first, a genetic factor, in the shape of HLAB27, and, second, the mechanism by which infectious diseases such as dysentery and nonspecific urethritis induced arthritis. As an extension of their previous clinical studies, Wright and his colleagues had identified the familial clustering of seronegative spondyloarthritis.35 This observational work created an opening for more definitive genetic research. Brewerton and others were able to show that much of the genetic contribution in the seronegative arthropathies was explained by links to HLA-B27.36-39 Brewerton and colleagues found HLA-B27 in 96% of patients with ankylosing spondylitis but only 7% of the general population. They also found it in 25 of 33 patients with Reiter’s disease (76%), in 3 of 33 patients with nonspecific urethritis, and in 2 of 33 control subjects. There was also an excess of HLA-B27 in psoriatic arthritis and seronegative arthritis associated with colitis. Brewerton’s research was self-evidently an idea for its time, as shown by two parallel reports from North America on ankylosing spondylitis40 and Denmark on Reiter’s syndrome.41

The final analysis of the mechanisms by which infection induces synovitis in reactive arthritis is still under way and is the subject of other chapters in this book. However, two studies in the mid-20th century made some contribution in opening up this field. The first study, from the United States,18 cultured synovial fluid, synovium, urethral swabs, and conjunctival swabs from 16 patients with reactive arthritis. Chlamydia trachomatis (then known as Bedsonia) was not identified in control subjects but was found in five patients, of whom four had positive synovium, two had positive urethral swabs, and one had a positive conjunctival swab. Further supporting the pathogenetic link between infection and arthritis, Ahvonen and colleagues showed that Yersinia reactive arthritis, a major problem in Scandinavia, was associated with elevation of anti-Yersinia antibodies in the serum.22

Acknowledgment

TABLE 15-2 CURRENT VIEWS ON SPECTRUM OF SPONDYLOARTHROPATHIES

CONCLUSIONS One lesson from history should be to avoid eponyms. There are many claimants to the first description of reactive arthritis, including Brodie in 1818, Bond in 1872, Fiessinger and Leroy in 1916, and Reiter in 1916. Such a surfeit of claimants suggests that no one merits the eponym and that the disorder should simply be termed reactive arthritis, one member of the class of seronegative arthritis. A second thought is the variable frequency of reactive arthritis. Its description in 1818 may have been only chance but may have been an end result of the prolonged Napoleonic wars. The disease not only resurfaced in World War I but also was probably more common in the 1950s and 1960s after World War II. Now that we are in a period of social stability in the West, the disease, particularly the sexually transmitted variety, seems much rarer, suggesting that there are many unexpected medical consequences of hostilities and social instability. A final lesson is that everyone forgets the past and focuses on the present. Consequently, we all ignore contributions of earlier generations and live mainly for the present moment. Although many old ideas are best discarded, some contain fascinating insights and should not just be cast aside.

ACKNOWLEDGMENT This chapter has relied on previous work undertaken by Dr G Storey, a retired rheumatologist from Hackney Hospital, and a predecessor of one of us (DLS); we are indebted to his help and many contributions. 131

HISTORICAL ASPECTS OF REACTIVE ARTHRITIS

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REFERENCES 1. Storey GO, Scott DL. Arthritis associated with venereal disease in nineteenth century London. Clin Rheumatol 1998;17: 500-504. 2. Scarpa R, Biondi Oriente C, Oriente P. The classification of psoriatic arthritis: What will happen in the future? J Am Acad Dermatol 1997;36:78-83. 3. O’Neill T, Silman AJ. Psoriatic arthritis. Historical background and epidemiology. Baillieres Clin Rheumatol 1994;8:245-261. 4. Feldtkeller E, Lemmel EM, Russell AS. Ankylosing spondylitis in the pharaohs of ancient Egypt. Rheumatol Int 2003;23:1-5. 5. Rogers J, Watt I, Dieppe P. Palaeopathology of spinal osteophytosis, vertebral ankylosis, ankylosing spondylitis, and vertebral hyperostosis. Ann Rheum Dis 1985;44:113-120. 6. Zias J, Mitchell P. Psoriatic arthritis in a fifth-century Judean Desert monastery. Am J Phys Anthropol 1996;101:491-502. 7. Anderson B. Did Benvenuto Cellini (1500-1571) have Reiter’s disease? Sex Transm Dis 1989;16:47-48. 8. Allison DJ. Christopher Columbus: First case of Reiter’s disease in the Old World? Lancet 1980;2:1309. 9. Anonymous. Columbus: Was it Reiter’s disease? Lancet 1981;1:94. 10. Swediaur FS. Traité complet sur les symptômes des maladies syphilitiques. Paris: F.J. Baudouin, 1798, p 156. 11. Brodie B. Pathological Researchers Respecting the Diseases of Joints, 1st ed. London: Longman, 1818. 11a. North London Hospital. Gonorrhoeal rheumatism. Lancet 1836; 27:61. 12. Neisser ALS. Die Mikrokokken der Gonorrhoe. Dtsch Med Wochenschr 1882;8:279-283. 13. Société Francaise de Dermatologie et de Syphilographie Report. Lancet 1895;2:1610. 14. Tixier H. Thesis: Formes du rheumatism de la blenorrhagic. Paris, 1866. 15. Bond T. On gonorrhœal or urethral rheumatism. Lancet 1872;99:395-396. 16. Potter H. Gonorrhoeal Rheumatism. London: Spottiswoode, 1878. 17. Fiessinger N, Leroy E. Contribution a l’étude d’une dysenterie dans la Somme. Bull Soc Med Hop Paris 1916;40: 2030-2069. 18. Schachter J, Barnes MG, Jones JP, et al. Isolation of bedsoniae from the joints of patients with Reiter’s syndrome. Proc Soc Exp Biol Med 1966;122:283-285. 19. Reiter H. Uber eine bisher unerkannte Spirochiiteninjektion (Spirochaetosis arthritica). Dtsch Med Wochenschr 1916;42:1535-1536. 20. Wallace DJ, Weisman M. Should a war criminal be rewarded with eponymous distinction? The double life of Hans Reiter (1881-1969). J Clin Rheumatol 2000;6:49-54.

21. Panush RS, Paraschiv D, Dorff RE. The tainted legacy of Hans Reiter. Semin Arthritis Rheum 2003;32:231-236. 22. Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 1969;15: 232-253. 23. Graham W. Is rheumatoid arthritis a separate entity? Arthritis Rheum 1960;3:88-90. 24. Ball J. Enthesopathy of rheumatoid and ankylosing spondylitis. Ann Rheum Dis 1971;30:213-223. 25. O’Connell D. Ankylosing spondylitis. The literature up to the close of the nineteenth century. Ann Rheum Dis 1956;15: 119-123. 26. Buckley CW. Spondylitis deformans. Br Med J 1931;1:1108-1112. 27. Alibert JL. Précis théorique et pratique sur les maladies de la peau. Paris: Caille et Ravier, 1818, p 21. 28. Bazin P. Leçons théoretiques et cliniques sur les affections cutanées de nature arthritique et arthreux. Paris: Delahaye, 1860, pp 154-161. 29. Bourdillon C. Psoriasis et arthropathies. MD thesis, University of Paris, 1888. 30. Wright V. Psoriasis and arthritis. Ann Rheum Dis 1956;15: 348-356. 31. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3:55-78. 32. Wright V, Reed WB. The link between Reiter’s syndrome and psoriatic arthritis. Ann Rheum Dis 1964;23:12-21. 33. Moll JM, Haslock I, Macrae IF, Wright V. Associations between ankylosing spondylitis, psoriatic arthritis, Reiter’s disease, the intestinal arthropathies, and Behçet’s syndrome. Medicine (Baltimore) 1974;53:343-364. 34. Nash P, Mease PJ, Braun J, van der Heijde D. Seronegative spondyloarthropathies: To lump or split? Ann Rheum Dis 2005;64 (Suppl 2):9-13. 35. Moll JM, Wright V. Familial occurrence of psoriatic arthritis. Ann Rheum Dis 1973;32:181-201. 36. Brewerton DA. Discovery: HLA and disease. Curr Opin Rheumatol 2003;15:369-373. 37. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973;1:904-907. 38. Brewerton DA, Caffrey M, Nicholls A, et al. HL-A 27 and arthropathies associated with ulcerative colitis and psoriasis. Lancet 1974;1:956-958. 39. Brewerton DA, Caffrey M, Nicholls A, et al. Reiter’s disease and HL-A 27. Lancet 1973;2:996-998. 40. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973;288:704-706. 41. Zachariae H, Hjertshoj A, Kissmeyer-Nielsen F. Reiter’s disease and HL-A 27. Lancet 1973;2:565-566.

REACTIVE ARTHRITIS

16

Clinical Picture and Diagnostic Criteria of Reactive Arthritis Auli Toivanen

The clinical entity of reactive arthritis (ReA) has been known for a long time. A classical case was presented by Hans Reiter in 1916.1 The disease was thereafter called Reiter’s disease and described as a triad of arthritis, urethritis, and conjunctivitis. The term reactive arthritis has, however, been taken in common use and actually illustrates better the fact that immunopathologic processes are a key element in the pathogenesis. Extensive research regarding the epidemiology, pathogenesis, clinical features, and treatment has been carried out. ReA typically affects young adults, males and females with equal frequency. It is rather commonly seen not only in rheumatologic but also in general practice. A proper diagnosis is sometimes difficult to make because often only some of the typical manifestations are present. ReA can manifest with minor arthralgia as the only symptom, or it can be a severely debilitating and painful condition. At present, no generally accepted diagnostic criteria are available, but on the basis of careful history, clinical findings, and serologic studies a diagnosis can be made with reasonable certainty.

CLINICAL HISTORY For a patient with ReA, the onset may be very sudden or come on over a short period of time. In most instances the previously quite healthy patient seeks medical attention for a sudden unexpected swelling and pain of a joint, with no previous trauma. Because the susceptibility to ReA is genetically mediated, as illustrated by the strong association with human leukocyte antigen HLA-B27, family history may reveal that relatives have had a similar disease. It may also turn out that during the few preceding days or weeks the patient has had some abdominal discomfort, diarrhea, or symptoms of urogenital or upper respiratory tract infection. Further, especially in those cases triggered by an enteric infection, other close contacts of the patient may also have had signs of gastroenteritis. It must be kept in mind that the signs and symptoms of the triggering infection may have been mild or may have passed unnoticed. Typically, at the time of arthritis,

the symptoms of the triggering infection have already vanished.

GENERAL SYMPTOMS Although joint inflammation is the leading symptom, it must be understood that ReA is truly a systemic disease. Taking into account the pathogenetic process, which involves an immunologic reaction activated by the triggering microbe, this is quite understandable. Thus, the disease may affect many organs, and the clinical features vary from patient to patient.2 ReA is caused by several different infections. Mostly they affect the mucosal surfaces of the gastrointestinal tract, the urogenital organs, or the respiratory tract.3 At the initial stage of the disease, the corresponding manifestations such as diarrhea or urogenital infection are seen, as pointed out earlier. More rarely, the patient may have had an infection of the upper respiratory tract or even a lung infection. It must be emphasized, however, that the initial triggering infection may be mild or pass unnoticed. The severity of the resulting ReA is not related to the severity of illness caused by the triggering infection. The development of ReA may occur few days or even a couple of weeks after the initial triggering infection. Initially, the most commonly seen systemic symptoms are malaise, fever, and fatigue.

JOINT SYMPTOMS Typically, an asymmetric monoarthritis or oligoarthritis, affecting the large joints of the lower limbs, is seen. Yet any joint, such as the wrists or even the small joints of the feet and the hands, may be affected, giving rise to a suspicion of rheumatoid arthritis. The joints can be quite swollen, painful, hot, and red. At the initial stage, the joint fluid may contain an abundance of polymorphonuclear leukocytes, and differentiation from true septic arthritis may be almost impossible.4 Back pain and stiffness occur frequently. The arthritis may be so severe that the patient is bedridden and helpless. In these cases, muscle wasting may be prominent and requires attention in the treatment. On the other hand, mild arthralgia may be the only symptom.

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CLINICAL PICTURE AND DIAGNOSTIC CRITERIA OF REACTIVE ARTHRITIS

In addition to arthritis, enthesopathy (inflammation at ligament, tendon, or joint capsule attachment sites) or tenosynovitis or both are often seen and revealed by pain on palpation at the sites of involvement. Plantar fasciitis, bursitis of the ankle region, or Achilles tendinitis may also restrict movement. Osteitis and hyperostosis are occasionally seen. ReA has a strong tendency to relapse, and a chronic course is not uncommon. In these cases, the joint symptoms resemble those during the original attack. There is a tendency to develop chronic back pain and stiffness as well as sacroiliitis, and transition to true ankylosing spondylitis may take place. The resulting disease is, however, usually rather mild. The natural history and prognosis of ReA are discussed in detail in Chapter 18.

SKIN AND MUCOUS MEMBRANE SYMPTOMS Interesting clinical features of ReA are keratoderma blennorrhagicum, pustulosis palmoplantaris, and nail dystrophies. These lesions are practically indistinguishable from psoriasis both macroscopically and microscopically. Erythema nodosum is occasionally seen, but it is not a typical feature of ReA, and its presence is not associated with HLA-B27. Oral lesions have not received much attention, although painless shiny patches on the palate, tongue, and mucosa on the lips and cheeks and erythema on the soft palate, uvula, and the tonsillar region were described as part of the clinical picture by Wright and Moll.5 The mucous membranes of the urogenital tract may show various inflammatory lesions such as circinate balanitis, prostatitis, or sterile cystitis. In female patients, cervicitis or salpingo-oophoritis may pass unnoticed but give rise to later infertility.6 This fact has occasionally caused some confusion because mucosal infections are frequently the triggering factor in ReA. Yet later, a sterile inflammation at the same site may be a manifestation of the clinical entity. It is worthwhile to point out that questions have been raised about whether some triggering microbes, such as chlamydiae, might persist somewhere in the urogenital organs. If that were the case, it would speak in favor of long-lasting antibiotic therapy for their elimination. So far, the question is open.

GASTROINTESTINAL MANIFESTATIONS

134

Ileocolonoscopic studies have demonstrated both macroscopic and microscopic lesions closely resembling ulcerative colitis or Crohn’s disease in patients with ReA, even in the absence of clinical symptoms.7-10 It appears, furthermore, that the severity of the intestinal lesions and arthritis are correlated.

Regarding the mucosal lesions discussed above, these findings have also given rise to confusion. In ReA, intestinal pathogens are common triggering factors, and yet ReA may be associated with inflammatory bowel diseases. It is natural that if the intestinal epithelial barrier is broken by, for example, ulcerative colitis or Crohn’s disease, the intestinal microbes or their components have rather free access to the blood circulation or the mesenteric lymph nodes and can initiate an immunologic cascade that contributes to pathogenesis. On the other hand, the disease itself can cause mucosal damage via mechanisms that are similar to those seen on the skin or other epithelial surfaces. There are a few reports indicating that the triggering microbes, such as Yersinia, might be demonstrable on the intestinal epithelium during active ReA, but those observations have not been extensively confirmed.11

OCULAR LESIONS Eye inflammation is considered part of the classical triad in ReA. The most common manifestation is acute anterior uveitis (iritis). Other inflammatory eye conditions may also occur, such as sterile conjunctivitis, keratitis, or episcleritis. Considering the systemic character of the disease, it is surprising that the ocular lesions most commonly affect only one eye, although bilateral lesions may occasionally be seen. The patient experiences redness, photophobia, increased lacrimation, or decreased vision. It must be emphasized that careful ophthalmologic examination, including use of a slit lamp, is necessary to confirm the diagnosis or to exclude ocular lesions, even when the symptoms are mild. If the lesions are left untreated at an early stage, permanent and irreversible damage to the vision may follow. Eye inflammation has a strong tendency to recur even years after the initial attack.

VISCERAL MANIFESTATIONS Although ReA is a truly systemic disease, visceral manifestations are not a prominent part of the clinical picture. Occasionally the heart is affected, and then conduction disturbances or valvulitis is seen. Typical carditis as seen in rheumatic fever is unusual in ReA. Aseptic pyuria, proteinuria, and microhematuria are seen in about 50% of patients with ReA. Severe glomerulonephritis and permanent kidney damage are rare (Table 16-1).

LABORATORY FINDINGS Even if the history and the clinical picture in typical cases suggest the diagnosis, confirmation of ReA requires laboratory investigations.

General symptoms Symptoms of the locomotor system

Malaise, fever, fatigue Arthralgia, arthritis Enthesopathy, tendinitis, tenosynovitis Hyperostosis

Skin and mucous membrane symptoms

Keratoderma blennorrhagicum, pustulosis palmoplantaris, other psoriasis-like manifestations Nail dystrophies Oral buccal lesions

Urogenital manifestations

Circinate balanitis, sterile urethritis and cystitis, prostatitis Cervicitis, salpingo-oophoritis

Intestinal manifestations

Inflammatory bowel lesions

Ocular manifestations

Sterile conjunctivitis, iritis, episcleritis, keratitis

Visceral manifestations

Carditis, nephritis

The erythrocyte sedimentation ratio and C-reactive protein values are usually elevated. In the acute phase the peripheral blood shows marked leukocytosis. Later and in more chronic cases, these values are mostly within normal limits. Tests for rheumatoid factor are usually negative. Urinalysis should be carried out repeatedly in order to detect aseptic pyuria, hematuria, or proteinuria. Also, renal function tests such as serum creatinine or blood urea nitrogen should be performed. The same holds true for liver function tests such as γ-glutamyltransferase or serum alanine aminotransferase. To rule out cardiac abnormalities, electrocardiograms are necessary. Synovial fluid samples should always be obtained, if possible, to exclude septic or crystal-related conditions. Gram stain and bacterial culture should be carried out. By definition, no bacteria are demonstrable in ReA. In research studies, various immunologic methods and polymerase chain reaction (PCR) techniques are used to search for bacterial components in the synovial fluid or synovial tissue, but they are not applicable in everyday clinical practice. Microscopy under polarized light to exclude gout or pseudogout is necessary, as well as serum urate determination. Synovial biopsy is not of diagnostic value because the inflammation is nonspecific. A word of caution is necessary. At the very early stage of ReA, the clinical features as well as the laboratory findings, including marked leukocytosis with predominantly granulocytes in the synovial fluid, may mimic true septic arthritis.4,12 Within a few days the neutrophil predominance in ReA shifts to a lymphocytosis. Thus, differentiation between these two conditions may be problematic at an early stage, as discussed in more detail later (Table 16-2).

Microbiologic and Serologic Investigations

TABLE 16-1 CLINICAL MANIFESTATIONS OF REACTIVE ARTHRITIS

MICROBIOLOGIC AND SEROLOGIC INVESTIGATIONS Microbiologic and serologic investigations are of critical value in the diagnosis. All efforts should be made to isolate the triggering microbe from the throat, urogenital tract, or feces. PCR assays for Chlamydia using the first voided urine sample has proved practical. Isolation of Yersinia requires special incubation, whereas other intestinal pathogens such as salmonellae are demonstrable using routine culture conditions. At the time of clinical manifestation of ReA, efforts to isolate the triggering microbe are usually not productive. Therefore, serology is of major importance.

TABLE 16-2 RECOMMENDED LABORATORY TESTS FOR THE DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF REACTIVE ARTHRITIS Erythrocyte sedimentation rate, C-reactive protein Peripheral blood picture including differential cell count Rheumatoid factor determination Serum uric acid determination Liver function tests Serum creatinine or blood urea nitrogen Urinalysis Synovial fluid analysis: cell counts, search for crystals, Gram stain, and bacterial cultures Electrocardiography

135

CLINICAL PICTURE AND DIAGNOSTIC CRITERIA OF REACTIVE ARTHRITIS

Antibodies against the most common causative agents such as Yersinia, Salmonella, Campylobacter, Chlamydia, Neisseria gonorrhoeae, Borrelia burgdorferi, and β-hemolytic streptococci should be determined and followed. In ReA the antibodies of immunoglobulin class are typically elevated and persist for a long period. Because they are not readily detected by agglutination, other methods such as enzyme immunoassays should be used. The serologic response may be slow, and in order to detect rising titers, repeated determinations are advisable. Depending on the history, antibodies against various viruses may yield a specific diagnosis. Because several different microbes may give rise to ReA, negative serology does not rule out the diagnosis. Determination of the HLA-B27 is advisable. It may support the diagnosis even if it is well known that not all HLA-B27–positive persons develop ReA even after a suitable triggering infection and some negative persons do. It has been suggested that there exist two forms of ReA, one associated and the other not associated with HLA-B27.3 Anyway, positivity for B27 is one factor for the diagnosis and indicates a greater risk for chronic development and recurrences, calling for more intensive treatment and later prophylaxis against triggering infections (Table 16-3).

OTHER INVESTIGATIONS Because ileocolonoscopic studies have indicated that subclinical inflammatory bowel inflammation may be associated with ReA.7-9 A central question is whether

TABLE 16-3 MICROBIOLOGIC AND SEROLOGIC STUDIES RECOMMENDED Search for triggering microbe Bacterial culture of throat samples for isolation of streptococci Stool cultures, including special incubation for isolation of Yersinia Polymerase chain reaction using first voided urine sample to demonstrate chlamydial DNA Gram stain and bacterial culture of synovial fluid Serology for demonstration of antibodies against streptococci, Yersinia, Salmonella, Campylobacter, Chlamydia, Neisseria gonorrhoeae, Borrelia burgdorferi Determination of human leukocyte antigen HLA-B27

136

an ileocolonoscopy should be carried out. This may be problematic and cannot be recommended as a routine procedure. A few studies using scintigraphy with radiolabeled leukocytes to detect inflammatory areas in the bowel have been reported, but they are not useful in routine clinical work. Regarding radiographic examinations, the reader is referred to Chapter 24. As pointed out earlier, if the patient has ocular symptoms, a complete ophthalmologic evaluation and a slit lamp examination must be carried out.

DIFFERENTIAL DIAGNOSIS At presentation, the most important question is whether the patient has true bacterial infection of the joint or ReA. In the initial phase, these two conditions may be clinically indistinguishable. Also, the laboratory investigations may yield confusing results, including marked granulocytosis in the joint fluid.12 In such a case it is necessary to proceed with “empiric” antibiotic therapy that will be guided by the clinical setting. Another clinically important problem may be to differentiate ReA from erysipelas, especially when the joint inflammation is intense. In these cases it is also necessary to proceed with antibiotic treatment after joint fluid has been obtained for culture. Gout or pseudogout may resemble ReA, but a careful history combined with an analysis of crystals in the joint fluid and serum urate determination should clarify the situation in most instances. Occasionally, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis can resemble ReA, and follow-up may be required to establish the definitive diagnosis. It should be kept in mind that ReA may, with time, progress to ankylosing spondylitis.

PROBLEMS REGARDING THE DIAGNOSTIC CRITERIA Several efforts have been made to establish reliable and clinically useful diagnostic criteria.13-16 These criteria would greatly facilitate clinical research, especially for studies that focus on treatment. Unfortunately, at present no “gold standard” for the diagnosis of ReA is available.17-19 In large part, this stems from the diversity of clinical features and the multiplicity of triggering infectious agents. In everyday clinical practice, however, a careful clinical history, examination, and an appropriate laboratory work-up yield the correct diagnosis in most instances.

1. Reiter H. Ueber eine bisher unerkannte Spirochäteninfektion (Spirochaetosis arthritica). Dtsch Med Wochenschr 1916;42:1535-1536. 2. Toivanen A, Toivanen P. Reactive arthritis. Best Pract Res Clin Rheumatol 2004;18:689-703. 3. Toivanen P, Toivanen A. Two forms of reactive arthritis? Ann Rheum Dis 1999;58:737-741. 4. Toivanen P, Toivanen A. Bacterial or reactive arthritis? Rheumatol Eur 1995;24 (Suppl 2):253-255. 5. Wright V, Moll JMH. Reiter’s disease. In: Wright V, Moll JMH (eds). Seronegative Polyarthritis. Amsterdam: North-Holland, 1976, pp 237-269. 6. Yli-Kerttula UI, Vilppula AH. Reactive salpingitis. In: Toivanen A, Toivanen P (eds). Reactive Arthritis. Boca Raton, Fla: CRC Press, 1988, pp 125-131. 7. De Vos M, Cuvelier C, Mielants H, et al. Ileocolonoscopy in seronegative spondyloarthropathy. Gastroenterology 1989;96:339-344. 8. Leirisalo-Repo M, Turunen U, Stenman S, et al. High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum 1994;37:23-31. 9. Mielants H, Veys EM. The gut and reactive arthritis. Rheumatol Eur 1995;24:9-11. 10. Mielants H, De Vos M, Veys EM. Clinical aspects of enterogenic arthropathies. Rheumatol Eur 1997;26:6-10. 11. Hoogkamp-Korstanje JA, de Koning J, Heesemann J, et al. Influence of antibiotics on IgA and IgG response and persistence of Yersinia enterocolitica in patients with Yersinia-associated spondylarthropathy. Infection 1992;20:53-57.

12. Kortekangas P, Aro HT, Tuominen J, Toivanen A. Synovial fluid leukocytosis in bacterial arthritis vs. reactive arthritis and rheumatoid arthritis in the adult knee. Scand J Rheumatol 1992;21:283-288. 13. Amor B. Reiter’s syndrome and reactive arthritis. Clin Rheumatol 1983;2:315-319. 14. Dougados M, van der Linden S, Juhlin R, et al, Group TESS. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227. 15. Pacheco-Tena C, Burgos-Vargas R, Vázquez-Mellado J, et al. A proposal for the classification of patients for clinic and experimental studies on reactive arthritis. J Rheumatol 1999;26: 1338-1346. 16. Hülsemann JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol 1999; 13:37-43. 17. Braun J, Kingsley G, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000;27:2185-2192. 18. Toivanen A, Toivanen P. Reactive arthritis. Curr Opin Rheumatol 2000;12:300-305. 19. Sieper J, Rudwaleit M, Braun J, van der Heijde D. Diagnosing reactive arthritis: Role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 2002;46:319-327.

References

REFERENCES

137

REACTIVE ARTHRITIS

17

Spectrum of Reactive Arthritis John D. Reveille and Firas Alkassab

138

Reactive arthritis (ReA), previously known by the eponym Reiter’s syndrome, refers to a constellation of articular, entheseal, mucocutaneous, and ocular symptoms occurring after a urethral or enteric infection. It falls within the family of spondyloarthritides, a group of disorders characterized by predominantly asymmetric lower extremity or axial arthritis in association with a spectrum of mucocutaneous, ocular, urogenital, or enteric symptoms and a tendency toward familial aggregation and association with human leukocyte antigen HLA-B27. ReA provides perhaps the best example of the interaction of genes and the environment, and as such it was the subject of a great deal of excitement and investigation in the 1970s and 1980s. Unfortunately, with changes in the classification of this disorder, recognition of the limited utility of genetic (i.e., HLA-B27) testing, and falling prevalences in developed countries, related in part to changes in sexual mores attributed to the human immunodeficiency virus (HIV) epidemic and perhaps to better public health measures, the impact of ReA has fallen considerably, as has the focus it previously had. Nevertheless, the lessons it teaches remain a model for other rheumatic diseases today. This chapter summarizes where the work on this disorder has taken us, from a pathophysiologic, epidemiologic, clinical, and treatment point of view. Changes in laboratory approaches and in treatment promise to redefine our concept of ReA in the near future.

Dr. Reiter’s association with the atrocities associated with the Third Reich and the obvious fact that his description was not the first have led to the suggestion that this term be retired3 in favor of the physiologically more accurate term reactive arthritis, originally coined by Ahvonen and colleagues in 1969.4 Many patients with ReA do not fulfill the classical triad described by Reiter and others.5 At one point the term incomplete Reiter’s syndrome was proposed.5 However, with the development of the European Spondyloarthropathy Study Group (ESSG) classification criteria for spondyloarthritis in 1991,6 this term is now rarely used in favor of the terms reactive arthritis and undifferentiated spondyloarthritis. Historical outbreaks of ReA have underscored the potential impact of this disease. Perhaps the best known was the appearance of ReA in 344 Finnish patients after an epidemic of Shigella flexneri dysentery in 150,000 patients in 1944.1 Other well-described outbreaks include the one after a shipboard epidemic of S. flexneri dysentery among American sailors on the USS Kitty Hawk in 1962,7 and another among Toronto policemen in an outbreak of Salmonella typhimurium in 1987.8 The largest outbreak of S. typhimurium dysentery in the United States occurred among Chicago residents in 1985,9 although, probably because of the litigation associated therewith, a substantiated estimate of the frequency of associated ReA has not been forthcoming.

HISTORICAL BACKGROUND

DIAGNOSTIC AND CLASSIFICATION CRITERIA

The occurrence of arthritis following a dysenteric infection was first described in the fifth century by Galen. Stoll described arthritis following both urethritis and dysentery in soldiers of the Continental Army during the American Revolutionary War,1 and numerous cases of postdysenteric arthritis were reported in Europe in the 19th century. Even the triad of conjunctivitis, urethritis, and arthritis was reported years before Hans Reiter published his classical case in 1916,2 for which the term Reiter’s syndrome was coined and applied until only recently. However, the realization of

Preliminary criteria were proposed over 25 years ago for Reiter’s syndrome (now called ReA), that require the presence of “peripheral arthritis for at least 1 month’s duration occurring in association with urethritis and/or cervicitis.”10 However, given that the urethritis and cervicitis can be frequently missed,5 these criteria are rarely utilized any more. More recently, at the Third International Workshop on Reactive Arthritis, a new working definition was proposed: (1) an acute inflammatory arthritis, inflammatory low back pain, or enthesitis; and (2) evidence of an

Group

Ankylosing Spondylitis (%)

Reactive Arthritis (%)

Psoriatic Arthritis (%)

Spondyloarthritis (%)

NHANES (1973)*

0.4-1.0*

NA

NA

NA

Netherlands (1983)

0.1

NA

NA

NA

Olmstead County, MN

0.129

NA

0.1

NA

Berlin, Germany (1998)

0.9

NA

NA

1.9

Brittany, France

NA

NA

NA

0.47

†

‡

Northwest Greece

0.03

2.3 /0.6

0.57

NA

Norway (non-Sami)

1.1-1.4

NA

NA

NA

Azores

0.61

NA

NA

1.6

Sami

1.8

NA

0.23

NA

Siberia/Alaska

1.6

NA

“Rare”

4.5

Taiwan

0.19-0.4

NA

NA

NA

China

0.26

NA

NA

NA

Thailand

NA

NA

NA

0.12

*

Epidemiology

TABLE 17-1 WORLDWIDE PREVALENCE (PERCENT) OF REACTIVE ARTHRITIS AND OTHER TYPES OF SPONDYLOARTHRITIS

Radiographic sacroiliitis only.

†

1980-1983.

‡

1989-1992.

NA, not available; NHANES, National Health and Nutrition Examination Survey.

infection preceding this condition by 4 to 8 weeks.11 These criteria are still being validated. Most of the components of ReA fall under the ESSG criteria, accounting for the application of the term undifferentiated spondyloarthritis when an antecedent infection is not documented.

EPIDEMIOLOGY The frequency of ReA varies according to the population frequency of HLA-B27 and the presence of potential infectious triggers.12 In the groups with the highest frequencies of B27, the highest frequencies of ReA have been reported (Table 17-1), such as in the Navajos in Arizona and the Eskimos in Alaska and Siberia.13,14 With changes in sexual mores related in part to the HIV epidemic and perhaps with more effective public health measures and sanitation, the prevalence of ReA appears to be on the decrease in many developed countries.15 In a study comparing the prevalence of ReA in Greek army personnel between 1980 and 1983 (before knowledge of HIV infection was widespread) versus between 1989 and 1992, the prevalence fell from 2.3% to 0.6%.15 One report from Rochester, Minnesota from the pre-HIV era stated an incidence of 3.5 per 100,000 for males younger than 50 between 1950 and 198016; however, the lack of more recent studies in the United States does

not permit speculation that the prevalence is decreasing there. Older studies among Native American groups have shown frequencies of 3 per 1000 population in Navajos13 and between 2 and 10 per 1000 in Alaskan Yupik and Inupiat Eskimos,14 two groups known to have a high frequency of HLA-B27. Among Asians, ReA appears to be much less common.17-19 An epidemiologic study of 21,750 soldiers in the Chinese army found 106 cases of spondyloarthritis, with an overall prevalence of 4.87 per thousand, including 46 cases of ankylosing spondylitis (AS), 52 cases of undifferentiated spondyloarthritis (prevalence rates of 2.11 per thousand and 2.39 per thousand, respectively) but only 7 cases of ReA (prevalence 0.3 per thousand). The HIV pandemic has complicated the prevalence of ReA considerably. After initial reports that the frequency of ReA might be increased in the setting of advanced HIV infection,20-22 this was instead attributed to behaviors that heightened the risk for both infections known to trigger ReA and HIV infection.23 However, there were few reports of African patients with spondyloarthritis from Africa prior to the 1980s, although more recent case series show this now to be one of the most frequent types of arthritis encountered in sub-Saharan Africa.24 Of note, the prevalence of ReA in one large cohort of 8632 white, black, and Hispanic

139

SPECTRUM OF REACTIVE ARTHRITIS

HIV-positive outpatients in Houston, Texas seen between 1994 and 2002 was 0.21%.24

PATHOGENESIS

Genetic Predisposition Familial aggregation in spondyloarthropathy (SpA) and ReA has long been recognized,25-28 as has the tendency for these diseases to “breed true” within families; that is, both axial skeletal involvement and peripheral joint disease tend to cluster separately in individual kindreds.26 The association of HLA-B27 with ReA has been known for over 32 years.29,30 This association has been seen in nearly all ethnic groups,31-33 except in African Americans34,35 and Africans,36 where a high proportion of patients are HLA-B27 negative. Approximately 70% of patients with ReA have HLAB27.29-33 In HIV-associated ReA, similar prevalences are observed,37 except in Africans.24 HLA-B27 does not confer susceptibility to the initial triggering infections in ReA but does correlate with ReA chronicity.38 One early study suggested that HLA-B27–negative patients with ReA were more likely to have HLA-B7 cross-reactive group (CREG) antigens (HLA-B7, B40, B42, B55 and B56),39 but this has not been confirmed. Efforts at implicating HLA-C and HLA-DR genes have been confounded by their linkage disequilibrium with HLA-B27.40,41 Despite one study in ReA suggesting an association with transporters associated with antigen processing (TAP) alleles,42 subsequent studies showed that the polymorphism of human TAP does not affect the translocated repertoire of HLA-B27 ligands and is therefore unlikely to play a decisive role in the development of HLA-B27–associated disease.43 Hence, that a subsequent analysis in Spanish patients with AS failed to show a role for TAP alleles in pathogenesis is not surprising.44

The Role of HLA-B27 in Reactive Arthritis Pathogenesis The exact mechanism underlying the effect of HLAB27 on disease susceptibility still has not been determined. Four different theories for the role of HLA-B27 in influencing susceptibility to spondyloarthritis have been proposed (Fig. 17-1):

140

1. As a major histocompatibility complex class I protein, HLA-B27 has the classical function of presenting endogenous (i.e., viral, bacterial, tumor) peptides that have been degraded intracellularly in proteasomes to the α:β T-cell antigen receptor on cytotoxic (CD8+) T lymphocytes. However, in addition to their classical antigen-presenting role, HLA class I proteins (and the peptides presented therein) are recognized by members of the killer immunoglobulin receptor (KIR) family on natural killer

(NK) cells. The HLA-B27 heavy chain is transcribed off ribosomes in macrophages and retained in the endoplasmic reticulum by the molecular chaperone calnexin and ERp57, the latter a protein disulfide isomerase that reduces and oxidizes disulfide bonds (see Fig. 17-1).45 Then it is folded into its tertiary structure and bound to β2-microglobulin, after which calnexin releases the complex and it becomes associated with calreticulin, which in turn chaperones the formation of the peptide loading onto the complex of heavy chain, β2-microglobulin, and antigenic peptide through the TAP proteins and tapasin. Then the trimolecular peptide complex (HLA-B27 heavy chain, β2-microglobulin, and peptide) travels to the cell surface, where the antigenic peptide is presented either to the α:β T-cell receptor on CD8+ T lymphocytes or to the KIR receptor on NK cells. Thus, the arthritogenic peptide hypothesis suggests that ReA or other spondyloarthritis results from the ability of HLA-B27 to bind a unique set of antigenic peptides, either bacterial or self-derived. Disease results from an HLAB27–restricted cytotoxic T-cell response to this peptide (or these peptides) found only in joints and other affected tissues (see Fig. 17-1). Such a peptide could be bound and presented by all disease-associated HLA-B27 subtypes but not by other HLA class I molecules. Evidence for this hypothesis comes from the identification of HLA-B27–restricted peptides from the Chlamydia trachomatis proteome,46 as well as from molecular mimicry between endogenous B27 peptides and environmental antigens.47-49 Data suggest that the differential association of HLA-B27 subtypes with spondyloarthritis is more likely related to differentially bound peptides than to altered antigenicity of shared ligands.50,51 The strongest evidence against this theory is that a specific “arthritogenic peptide” has yet to be demonstrated in either ReA or other types of spondyloarthritis. 2. A unique property of HLA-B27 is that free heavy chains of HLA-B27 can reach the cell surface in the absence of β2-microglobulin and maintain their peptide-binding groove in vitro.52 Alternative recognition of different forms of HLA-B27 by leukocyte receptors could influence the function of cells from both innate and adaptive immune systems and may indicate a role for various leukocyte populations in spondyloarthritis. However, this pathway does not always proceed as smoothly. Self-association is a unique property of the HLA-B27 molecule. HLA-B27 heavy chains can form homodimers in vitro that are dependent on disulfide binding through their cysteine-67 residues in the extracellular α1 domain.53-55 This occurs as a result of B27 mis-

Pathogenesis

CD4 positive T lymphocyte CD8 positive T lymphocyte

Natural killer (NK) cell αβ T cell receptor

KIR receptor (b2)

(a2)

Free B27 HLA-class II heavy (DR, DQ, DP) chain presenting HLA-B27 HLA-B27: β2 microglobulin: peptide peptide trimolecular complex

Endoplasmic reticulum

BiP

BiP

BiP

BiP

HLA-B27 homodimers at cell surface (a2) Golgi

ERAD UPR

(b) B27 misfolding, homodimerization B27 heavy chain (HC)

HLA-B27: β2m: peptide trimolecular (a1) complex transported to the cell surface via the Golgi apparatus

(b1) B27 folding, assembly and loading of peptide

B27 HC folding

β2 microglobulin (β2m) loading

ERp57

Tapasin Peptide loading

Macrophage

HC Ribosome

(a)

Calnexin

Viral, bacterial or tumor protein

Calreticulin BiP

β2m

Proteolytic degradation within proteasome

TAP 1,2 Peptide fragments

Figure 17-1. Unique intracellular and extracellular functions of HLA-B27 that may affect susceptibility to spondyloarthritis. Four theories exist of how HLA-B27 can influence disease susceptibility. (a) The HLA-B27 heavy chain is transcribed off ribosomes in macrophages and is retained in the endoplasmic reticulum (ER) by the molecular chaperone calnexin and ERp57, a protein disulfide isomerase that reduces and oxidizes disulfide bonds. Then it is folded into its tertiary structure and bound to β2-microglobulin; after that calnexin releases the complex and it is associated with calreticulin, which in turn chaperones the formation of the peptide loading onto the complex of heavy chain, β2-microglobulin, and antigenic peptide, through the transporters associated with antigen processing (TAP) proteins and tapasin. Thence the trimolecular peptide complex (HLA-B27 heavy chain, β2-microglobulin, and peptide) (a1) travels through the Golgi apparatus to the cell surface, where (a2) the antigenic peptide is presented either to the α:β T-cell receptor on CD8+ T lymphocytes or to the killer immunoglobulin receptor (KIR) on natural killer (NK) cells. Alternatively, (b) the HLA-B27 heavy chain misfolds in the ER, forming B27 homodimers and other misfoldings, where either (b1) it undergoes ER-associated degradation (ERAD) or accumulates there, causing a pro-inflammatory unfolded protein stress response (UPR), or (b2) the B27 homodimers migrate to the cell surface, where they either become antigenic themselves or present peptide to receptors on other inflammatory cells; (c) intracellular impairment of peptide processing or loading into HLA-B27 by viruses or intracellular bacteria causes a selective impairment of the immune response; or (d) either the trimolecular complex presents processed peptide to the α:β T-cell receptor on CD4+ T lymphocytes, or free HLA-B27 heavy chains or HLA-B27 homodimers are recognized as antigenic by the T-cell receptor, or processed antigenic fragments of HLA-B27 are presented to the T-cell receptor of CD4+ T lymphocytes.

folding within the endoplasmic reticulum, and the accumulation of misfolded protein may result in a proinflammatory intracellular stress response. Protein misfolding affects cell function through the activation of a pro-inflammatory unfolded protein response.53 Alternatively, HLA-B27 homodimers

migrate to the cell surface, where they either become antigenic themselves or present peptide to receptors on other inflammatory cells,56 especially when the cell’s antigen-presenting function is impaired. 3. Intracellular impairment of peptide processing or loading into HLA-B27 by viruses or intracellular

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SPECTRUM OF REACTIVE ARTHRITIS

bacteria can cause a selective impairment of the immune response. Alteration of intracellular invasion or killing of arthritogenic organisms may contribute to the cellular basis for ReA, but the molecular basis of the bactericidal pathways in synoviocytes has not been fully resolved. HLAB27–positive U937 cells kill Salmonella less efficiently than controls and show upregulated production of interleukin 10 and to a lesser extent tumor necrosis factor (TNF) α. HLA-B27–associated modulation of cytokine response profiles may have importance in the pathogenesis of ReA.57-59 4. Finally, HLA-B27 may serve as an autoantigen. HLA-B27 itself (or peptides derived therefrom) can also act as autoantigens, where either the trimolecular complex presents processed peptide to the α:β Tcell receptor on CD4+ T lymphocytes, free HLA-B27 heavy chains or HLA-B27 homodimers themselves are recognized as antigenic by the T-cell receptor, or processed antigenic fragments of HLA-B27 are presented to the T-cell receptor of CD4+ T lymphocytes, either by itself or through presentation by HLA-class II (DR, DQ, and DP) heterodimers.60 In previous years, amino acid homology between HLA-B27 and microbes triggering ReA supported the concept of molecular mimicry, such as has been described for an outer membrane protein YadA of Yersinia enterocolitica that shares a linear tetrapeptide with HLA B27, a cationic outer membrane protein OmpH of S. typhimurium, a hexapeptide of Klebsiella pneumoniae nitrogenase, and a pentapeptide shared by an S. flexneri protein and HLA-B27.61,62

Infectious Triggers

142

The most frequent type of ReA in developed countries follows urogenital infections with C. trachomatis (endemic ReA).4 Males are much more commonly affected than females after chlamydial infection. It is noteworthy that Chlamydia pneumoniae has been implicated in up to 10% of patients with ReA in some series63,64 Postdysenteric or “epidemic” ReA usually follows conditions associated with dietary contamination with various Shigella and Salmonella (especially typhimurium and enteritidis), Campylobacter jejuni and Campylobacter fetus, and, in Europe, Y. enterocolitica species. In postdysenteric ReA, the male-female prevalence is equal. Microorganisms implicated in ReA share common biologic features: (1) they can invade mucosal surfaces and replicate intracellularly and (2) they contain lipopolysaccharide in their outer membrane. Of particular note, antigens from Salmonella, Yersinia, and Chlamydia have been found in synovial tissues and fluids of patients with ReA,65 often many years after the

initial infection. Although only bacterial fragments of the enteric pathogens have been found, evidence for viable C. trachomatis and even C. pneumoniae has been demonstrated in several studies.65,66 Chlamydia and other organisms have also been reported in the joints of healthy individuals, thus questioning the pathogenic significance of these findings.67 Other data, however, support the likelihood that bacterial persistence plays an important role in ReA, including the finding of specific immunoglobulin A antibodies and synovial T-cell proliferation to the initiating infectious agent.46,68 Whether recurrent infection plays a role in ReA chronicity is not clear. Animal models of ReA suggest that this is so, as exposure of splenocytes from HLAB27–positive transgenic rats to Chlamydia in vitro resulted in the induction of cytotoxic T lymphocytes that lysed HLA-B27 target cells.69 This has not been proved in humans in vivo, however.

CLINICAL MANIFESTATIONS As already noted, the classical triad of arthritis, urethritis, and conjunctivitis, representing what was formerly known as Reiter’s syndrome, is a presenting feature of only a minority of patients with ReA (only a third of the cases in some series).5 In ReA, the clinical features are now viewed more as a spectrum ranging from the classical triad to undifferentiated spondyloarthritis. In fact, the manifestations vary among patients, depending on the genetic makeup, the triggering event, and the sequential immunologic reaction.

Presentation Typically, the features start 1 to 4 weeks after a triggering event, frequently identified as an enteric or urogenital infection, but often the event passes unnoticed without specific symptoms. The syndrome starts with constitutional symptoms such as fatigue, malaise, and fever and then is typically manifested by asymmetric, additive lower extremity oligoarticular inflammatory arthritis along with an array of different extra-articular features (see later).

Musculoskeletal System The main categories of involvement are peripheral arthritis, axial arthritis, and enthesitis.

Peripheral Arthritis The pattern is usually oligoarticular or monoarticular and asymmetric. A sterile inflammatory, additive arthritis of the lower extremity large weight-bearing joints is the typical presentation. It affects most notably the knees, ankles, and occasionally hips, resulting in

Ocular Involvement

Sacroiliitis and spondylitis are less common than peripheral arthritis but are well recognized. As in other types of spondyloarthritis, the presentation is inflammatory low back pain that is typically worse with rest and better with activity and nonsteroidal anti-inflammatory drugs (NSAIDs). Unilateral and bilateral sacroiliac involvements have been described, and spondylitis is similar to that observed in AS, although ankylosis remains uncommon and is seen only in severe cases.

The ocular involvement associated with ReA is of particular interest. In general, ReA is associated with chronic recurrent ocular inflammation, and systemic therapy (including immunosuppressive treatment) is typically required to control the ocular inflammation and to prevent progressive visual loss. The most frequent ocular manifestation is acute anterior uveitis (iritis). It is usually unilateral and causes severe pain, photophobia, blurry vision, and erythema. It is frequently associated with HLA-B27 positivity and tends to follow a chronic recurrent course. Although anterior uveitis is most typical, posterior chamber involvement (posterior uveitis) is well described and can have more devastating sequelae. Because it is more commonly silent when occurring alone, patients with ReA should be observed at intervals by an ophthalmologist. Long-term complications can include cataracts, cystoid macular edema, papillitis, and glaucoma.71 Conjunctivitis may be unilateral or bilateral and is usually an early feature manifesting with irritation, erythema, and lacrimation. It is usually associated with a sterile discharge unless a superimposed infection occurs because of eye rubbing. It can be severe and occasionally progress to episcleritis, scleritis, or keratitis.

Enthesitis

Other Features

Axial Involvement

Enthesitis refers to involvement of insertions of tendons and ligaments into the periosteum. It is seen in all types of spondyloarthritis, especially in ReA. The most commonly affected sites are the Achilles tendon and plantar fascia insertions, although the symphysis pubis, iliac crest, ischial tuberosity, greater trochanters, and thoracic cage ribs are also clinically considered sites for enthesitis. The pain is inflammatory and can be associated with swelling and erythema that responds to NSAIDs or anti-TNF blockers.

Mucocutaneous Involvement ReA can arise with skin rashes that can be difficult to distinguish from those of psoriatic arthritis.37 Two rather typical manifestations of ReA are circinate balanitis and keratoderma blennorrhagica. Circinate balanitis70 is an ulcerative mucosal lesion over the glans or shaft of penis that is demarcated by a serpiginous erythematous border. The lesion is usually painless and sterile unless a superimposed infection occurs. Keratoderma blennorrhagica is seen on the soles or palms of affected individuals. It is manifested as a painless desquamative psoriatic-like papulosquamous eruption and is sometimes referred to as pustulosis palmoplantaris. Oral lesions have been described as shallow, painless ulcers or patches on the palate and tongue or mucositis of the soft palate and uvula.

Clinical Manifestations

marked limitation of the patient’s mobility due to pain. Upper extremity involvement is encountered not uncommonly and includes the shoulders, elbows, and wrists. Dactylitis occurs in the toes or fingers, resulting in the “sausage” digits, which represent inflammation not only of the interphalangeal joints of the hands and feet but also of the surrounding soft tissue structures including the tendons and subcutaneous tissue. Occasionally, the arthritis is polyarticular in a rheumatoid-like picture, making it difficult to distinguish from rheumatoid arthritis. The clinical context, extraarticular features, and laboratory data differentiate them in such cases.

Cardiac involvement is uncommon, but aortic valvular insufficiency, conduction abnormalities, and even complete heart block related to carditis have been reported as in AS.72,73 Although renal involvement is mainly described in the context of the urogenital triggering infectious process, sterile pyuria in conjunction with proteinuria and microscopic hematuria are sometimes encountered, although documentation of glomerulonephritis is rarely described. Progression to significant renal impairment is not a typical feature of ReA. Gastrointestinal involvement is also described in the context of a dysenteric triggering event. However, patients frequently complain of vague abdominal pains in the prodromal phase of the disease, and some may even undergo laparotomy only to find lymphadenitis.

Radiographic Findings In the acute phase, juxta-articular osteoporosis and soft tissue edema may be all that is present, with an intact unremarkable joint space. However, when arthritis becomes more evident and chronic, marginal erosions associated with periosteal reactive bone proliferation (a characteristic observed in seronegative SpA as a group known as periostitis) ensue. Similar changes are observed in enthesitis, where periostitis with fluffy bone reactivation and spur formation are seen on radiographs. When axial involvement is present for long time, erosive disease may appear on radi-

143

SPECTRUM OF REACTIVE ARTHRITIS

ographs with sacroiliitis or spondylitis, or both, in a manner similar to that in AS. An irregular joint line, erosions, and subcortical sclerosis are characteristic findings in sacroiliac involvement. Ankylosis develops in severe cases. Magnetic resonance imaging (MRI) has been employed not only in the diagnosis of early sacroiliitis74 but also in demonstrating enthesitis,75 where striking enhancement of tendon sheath insertion into the periosteum, especially in the subchondral bone, is seen and improves with effective treatment. Ultrasound demonstration of tendon thickening and periosteal reaction that accompany enthesitis is finding its way into clinical practice,76 although standardization of reading and concerns about interrater variability need to be addressed further.

LABORATORY FINDINGS The erythrocyte sedimentation rate and C-reactive protein are usually elevated and correlate with the degree of inflammation and disease activity.77 Arthrocentesis with synovial fluid analysis is recommended, especially at diagnosis and in monoarthritic presentations, to rule out septic and crystal-induced arthritis. The synovial fluid is usually inflammatory in nature, but Gram stain and cultures fail to show any organisms. As discussed earlier, synovial biopsies may provide indirect evidence of infection, but this practice has not found its way into the routine management of ReA. Urinalysis with microscopic analysis of the sediment must be performed, looking for aseptic pyuria that results from urethritis, and routine liver and renal function tests are recommended to uncover any coexisting abnormalities that would affect management options. The serum rheumatoid factor and anti–cyclic citrullinated peptide (CCP) antibodies are usually negative. HLA-B27 typing is not useful in the diagnosis for the patient presenting with classical symptoms or in determining prognosis, although it can be a useful diagnostic aid in the patient presenting with nonclassical symptoms (such as a young patient with lower extremity oligoarthritis or inflammatory back pain without confirmatory mucocutaneous, ocular, or radiographic features).

where I see patients with a painful lower extremity arthritis, urethritis, and enthesis and classical mucocutaneous lesions of ReA without any known antecedent dysenteric infection. His wife asked if his disease could have been sexually acquired. Not having seen the couple previously or having at that point documentation of the triggering microorganism and not wanting to make the man’s discomfort worse, I only replied, “possibly so, although this disease can be triggered by nonvenereal infections also.” I did explain that if a chlamydial infection was documented, she would also have to be treated (because they never returned for follow-up, the latter was not possible). Clarification of the diagnosis is necessary to begin effective treatment and to avoid subjecting the patient to inappropriate or ineffective regimens that can be costly if not frankly dangerous. It is also important at the outset to emphasize the overall good prognosis of ReA and to have the patient avoid situations where reinfections with a causative microorganism occurs (by using condoms and avoiding risky dietary habits), although the efficacy of this is controversial.

Physical Therapy Physical therapy has a well-established place in the treatment of AS, although no data exist on ReA.78,79

Nonsteroidal Anti-inflammatory Drugs Nonsteroidal anti-inflammatory agents are a mainstay in the treatment of spondyloarthritis (Table 17-2). Although no one NSAID has been found to be superior in the treatment of ReA, many clinicians classically have utilized indomethacin. However, whatever TABLE 17-2 TREATMENT OF REACTIVE ARTHRITIS General Education Physiotherapy NSAIDs Antibiotics If any role at all, in Chlamydial-triggered reactive arthritis DMARDs Sulfasalazine

MANAGEMENT

General

144

Methotrexate Anti-TNF blockers

Counseling and Education of Patients

Etanercept

Informing and educating a patient of the diagnosis of ReA can be a difficult challenge, especially with the potential social stigma of venereal infection. I (JDR) remember seeing a young traveling salesman for the first time in the emergency department of a hospital

Infliximab Adalimumab DMARD, disease-modifying antirheumatic drug; NSAID, nonsteroidal anti-inflammatory drug; TNF, tumor necrosis factor.

Antibiotics Early data suggested that a 3-month course of antibiotics in the acute phase after disease onset had a beneficial effect on the course of ReA, specifically in those with C. trachomatis–triggered ReA but not in other patients.80 Long-term follow-up data, however, suggest that tetracycline treatment did not change the natural history of the disease.81 In another study, a 3-month course of ciprofloxacin in the acute phase was found to have a beneficial effect on the long-term prognosis.82 In yet another, prolonged treatment with azithromycin was found to be ineffective in ReA.83 Thus, the place for antibiotic treatment of ReA is by no means clear.

Disease-Modifying Antirheumatic Drugs Sulfasalazine in doses of 2 to 3 g daily has been well studied and found to be effective in treating the peripheral arthritis associated with ReA.84-86 An ameliorative effect on enthesitis and axial disease has not been shown, however. The most prominent side effects include dyspepsia, nausea, vomiting, and allergic reactions to the drug. The rare occurrence of bone marrow suppression mandates periodic mentoring of the blood counts. Although not studied as well as sulfasalazine, methotrexate has also been utilized, in doses not exceeding 20 to 25 mg per week. The potential for hepatotoxicity and bone marrow suppression mandates regular monitoring of the blood counts and serum chemistries, including serum transaminases.

Corticosteroids

Systemic Glucocorticoids Although corticosteroids are not well studied in patients with ReA, many clinicians add low-dose glucocorticoids to the management of active SpA in which NSAIDs or disease-modifying antirheumatic drugs fail to achieve a satisfactory response. On occasion, pulse steroids have also been used. Given the lack of controlled data on their effectiveness, the side effects of long-term glucocorticoid therapy, and the emergence of more effective treatments, their use is not recommended unless more effective treatments are not available.

Intra-articular or Intralesional Treatment Intra-articular and peritendinous injections of deposteroid preparations are frequently employed by clinicians for symptomatic relief of local flares, although they have not been extensively studied in controlled trials. Injecting around the Achilles’ tendon is generally not recommended because of the risk of tendon rupture.

Management

NSAID is used should be tailored to the preferences and profile of the patient; for example, patients with peptic ulcer disease or a history of gastrointestinal bleeding may prefer to start with a selective cyclooxygenase 2 antagonist (celecoxib is the only one available in the United States at this time). In any patient taking NSAIDs, extreme caution should be utilized where cardiovascular disease (or high risk thereof) is present or in the setting of renal insufficiency.

Tumor Necrosis Factor Blockers

Infliximab The use of a chimeric monoclonal antibody to TNF-α, infliximab, at a dose of 5 mg/kg every 6 weeks (after initial loading at 0, 2, and 6 weeks) has been shown to be beneficial in the axial and peripheral manifestations of spondyloarthritis in both open-label87,88 and placebocontrolled clinical trials.89 The onset of action is quite rapid, usually following the first infusion, with over 80% of patients achieving greater than 20% improvement in measures of disease activity. Improvement was seen not only clinically but also by ultrasonography90 and MRI, with clearing of lesions suggestive of disease activity on MRI (bone marrow edema on T2-weighted, fat-suppressed, or short-tau inversion recovery images).91 AntiTNF treatment is expensive and not without potential complications. Infusion reactions (flushing, fevers) are common, and anaphylaxis can occur. More feared are infections, especially with Mycobacterium tuberculosis, mandating that all patients for whom anti-TNF treatment is considered be screened with a purified protein derivative skin test before initiation of anti-TNF therapy. There is no evidence that malignancy is a complication of this treatment. Another concern is the development of antinuclear antibodies (and even anti–double-stranded DNA antibodies) after infliximab treatment,92 although reports of patients developing systemic lupus erythematosus or other connective tissue disease are extremely rare. Of particular interest is one report of the use of intra-articular infliximab, which might circumvent these issues in patients with limited refractory disease.93 Etanercept The soluble TNF-α receptor etanercept, given at 25 mg subcutaneously twice weekly or 50 mg once weekly, has been shown to be effective in the treatment of SpA in a longitudinal study of 10 SpA patients in the United Kingdom, with statistically significant improvement seen not only in all clinical and functional parameters but also in MRI-detectable entheseal lesions, of which 86% either regressed completely or improved.75 In another study, etanercept caused not only sustained clinical improvement but also a profound reduction in synovial cellular infiltration and T lymphocytes, with reduction in the different macrophage subsets (CD68, CD163, myeloid-related protein 8 [MRP8], and

145

SPECTRUM OF REACTIVE ARTHRITIS

MRP14) and decrease in both synovial expression and serum levels of matrix metalloproteinase 3 that are associated with inflammation.94 Similar positive results have been reported in psoriatic arthritis95 and AS,96 where substantial improvement was seen in the joint and entheseal involvement as well as in the extent and severity of the psoriatic skin lesions. The Food and Drug Administration (FDA) has approved the use of etanercept for the treatment of both AS and psoriatic arthritis, although not yet for ReA or spondyloarthritis in general. Adalimumab Reports have demonstrated the efficacy of the humanized monoclonal antibody adalimumab in patients with psoriatic arthritis,97 AS, and other SpAs.98 FDA approval has already been given for psoriatic arthritis and is pending for AS. As with other anti-TNF blockers, it is likely that this medication will also prove helpful and efficacious in patients with ReA.

Use of Tumor Necrosis Factor Blockers The use of TNF blockers in the treatment of nonmusculoskeletal manifestations of ReA, such as acute anterior uveitis, is less clear (see below).99 Given the efficacy of TNF blockers in psoriasis, the improvement of mucocutaneous problems associated with ReA after anti-TNF treatment is not surprising.

Other Biologic Agents Both rituximab and abatacept are being released for the treatment of rheumatoid arthritis and are likely to be tried in patients with spondyloarthritis. However, the rationale for their efficacy in ReA is less clear than that of anti-TNF blockers, and it will not be surprising if they fail to match the remarkable impact of these agents.

Treatment of Eye Disease Associated with Reactive Arthritis Acute anterior uveitis is usually treated with nonsteroidal anti-inflammatory agents and topical corticosteroid drops. However, ophthalmologic follow-up is necessary, as not all cases respond to conservative treatment, and occasionally systemic glucocorticoids are necessary. More refractory cases require immunosuppressive therapy (usually methotrexate or azathioprine). The most severely affected patients may need intraorbital or even intraocular steroid injections. The role of anti-TNF blockers is under investigation.99

DISEASE COURSE AND PROGNOSIS

146

Early studies of outcome in ReA suggested a relatively poor prognosis. After an interval of 20 years, Sairanan and colleagues examined 100 of the 350 cases of ReA diagnosed in 1944 during the epidemic of S. flexneri dysentery that affected nearly 150,000 cases in

Finland.100 Of these patients, 32% had spondylitis, 18% had chronic arthritis, and 20% had a brief and self-limited disease. Permanent disability developed in 42% (Table 17-3). Calin and Fries traced 5 of the original 10 patients from the USS Kitty Hawk epidemic and clinically assessed them 13 years after the initial episode.101 One of the five had minimal disease and was HLA-B27 negative. The remaining four had followed a chronic course, had persistent active disease, and were HLAB27 positive, leading the authors to conclude that the prognosis for postdysenteric Reiter’s syndrome was guarded, especially in HLA-B27–positive individuals. Fox and coauthors reported symptom persistence and disability in 131 consecutive patients with ReA from northern California in 1979. Eighty-three percent had some disease activity, 34% had sustained disease activity, 16% had had to change jobs, and 13 (11%) were unemployable. The authors concluded that most patients with Reiter’s syndrome have persisting symptoms that can lead to chronic disability.102 This rather dire forecast was not confirmed in other studies. In a report in 1979 from Canada, Butler and colleagues found that less than a third of patients with ReA had recurrent “major” symptoms.103 Subsequent reports from Scandinavia further suggested that the prognosis in ReA was not as severe as originally thought. Glennas and associates examined the 2-year prognosis in 25 Norwegian patients with Chlamydia-induced arthritis and 27 with arthritis induced by enterobacteria.104 After 1 year, 40% of patients with Chlamydia-induced arthritis and 20% of those with enteroarthritis still had clinical signs of arthritis. After 2 years, 100% and 95%, respectively, had recovered. Herrlinger and Asmussen reported the long-term prognosis of Yersinia ReA in 22 German patients followed up for a mean of 10.7 years after the acute infection. The clinical findings were unremarkable and no evidence of systemic inflammation was found.105 Leirisalo-Repo and Suoranta, in a 10-year follow-up study of patients with Yersinia arthritis, reported that even though peripheral joint symptoms occurred in more than half, these symptoms were mild in the overwhelming majority of patients.106,107 In fact, development of a new ReA or chronic arthritis was uncommon. One third of the patients experienced low back pain, and one third of the patients had radiologic evidence of sacroiliitis. Thomson and co-workers examined the long-term outcome of post–Salmonella infection ReA in a cohort of 423 Ontario Provincial Police officers with a clinical diagnosis of Salmonella food poisoning from 1984, of whom 27 individuals with dysentery were identified with acute ReA.108 In one third of them, the arthritis resolved within 4 months of onset. Two thirds continued to have subjective complaints, mostly of minor significance; however, symptoms were severe enough to force a change in work for four patients.

Author (Reference) Sairanen et al100

Site

Year 1969

Number of Patients 100

Follow-up (years) 20

Finland

Calin and 101 Fries

U.S. (Shipboard)

1976

5

13

One had minimal disease and was HLA-B27 negative. The remaining four had followed a chronic course, had persistent active disease, and were HLAB27 positive.

Fox et al102

U.S. (Stanford)

1979

122

5.6

34% had sustained disease activity, 16% had to change jobs, and 13 (11%) were unemployable.

Butler et al103

Canada (Edmonton)

1979

48

6.5

Less than one third had recurrent “major” symptoms. No major functional impairment.

LeirisaloRepo et al106,107

Finland

1982, 1988

160

10

B27-positive patients had a more severe acute disease and more frequent chronic back pain and sacroiliitis.

Herrlinger105 and Asmussen

Germany

1992

22

10.7

No evidence of systemic inflammation in any patient.

Glennas et al104

Norway

1994

52

2

After 2 years, nearly all had recovered completely.

Canada (Toronto)

1995

27

5

Arthritis resolved within 4 months of onset in one third; minor symptoms in two thirds continued. Objective changes to joints on examination in 37%.

108

Thomson et al

In general, the prognosis of ReA appears to be fairly good, at least in more recent series. Most cases appear to remit within 6 months of onset. Given the introduction of highly effective biologic agents such as antiTNF blockers, the long-term prognosis in ReA is likely to improve even further.

CONCLUSION Although it was long regarded as a classical example of the interplay of nature and nurture, changes in reclassi-

Notes

References

TABLE 17-3 OUTCOME OF REACTIVE ARTHRITIS

32% had spondylitis and 18% chronic arthritis, 20% had transient disease. Permanent disability was found in 42%.

fication and disease definition, changes in sexual mores brought on by the HIV epidemic, and the introduction of novel therapies have changed the face of what was called Reiter’s syndrome. It is now recognized as a spectrum of disease under the broad category of spondyloarthritis for which a triggering infection is often identified. Also now recognized is the overall good prognosis of this disorder, especially with the introduction of promising new treatments, such as the biologic modifiers (i.e., TNF blockers), whose impact on the natural history of ReA is only now being realized.

REFERENCES 1. Paronen I. Reiter’s disease. A study of 344 cases observed in Finland. Acta Med Scand 1948;131 (Suppl 212):1-232. 2. Reiter H. Ueber eine bister unerkannte Spirochateninfektion (Spirochaetosis arthritica). Dtsch Med Wochenschr 1916;42:1535. 3. Gottlieb NL, Altman RD. An ethical dilemma in rheumatology: Should the eponym Reiter’s syndrome be discarded? Semin Arthritis Rheum 2003;32:207. 4. Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 1969;15:232-253. 5. Arnett FC, McClusky OE, Schacter BZ, Lordon RE. Incomplete Reiter’s syndrome. Discriminating features and HL-A-W27 in diagnosis. Ann Intern Med 1976;84:8-12. 6. Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227.

7. Noer HR. An “experimental” epidemic of Reiter’s syndrome. JAMA 1966;198:693-698. 8. Inman RD, Johnston ME, Hodge M, et al. Postdysenteric reactive arthritis. A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31:1377-1383. 9. Ryan CA, Nickels MK, Hargrett-Bean NT, et al. Massive outbreak of antimicrobial-resistant salmonellosis traced to pasteurized milk. JAMA 1987;258:3269-3274. 10. Willkens RF, Arnett FC, Bitter T, et al. Reiter’s syndrome. Evaluation of preliminary criteria for definite disease. Arthritis Rheum 1981;24:844-849. 11. Braun J, Kingsley G, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000;27:2185-2192.

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12. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-799. 13. Morse HG, Rate RG, Bonnell MD, Kuberski T. High frequency of HLA-B27 and Reiter’s syndrome in Navajo Indians. J Rheumatol 1980;7:900-902. 14. Boyer GS, Templin DW, Cornoni-Huntley JC, et al. Prevalence of spondylo-arthropathies in Alaskan Eskimos. J Rheumatol 1994;21:2292-2297. 15. Iliopoulos A, Karras D, Ioakimidis D, et al. Change in the epidemiology of Reiter’s syndrome (reactive arthritis) in the postAIDS era? An analysis of cases appearing in the Greek Army. J Rheumatol 1995;22:252-254. 16. Michet CJ, Machado EB, Ballard DJ, McKenna CH. Epidemiology of Reiter’s syndrome in Rochester, Minnesota: 1950-1980. Arthritis Rheum 1988;31:428-431. 17. McColl GJ, Diviney MB, Holdsworth RF, et al. HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella typhimurium. Aust NZ J Med 2000;30:28-32. 18. Chopra A, Patil J, Billempelly V, et al. Prevalence of rheumatic diseases in a rural population in western India: A WHO-ILAR COPCORD study. J Assoc Physicians India 2001;49:240-246. 19. Wu ZB, Zhu P, Wang HK, et al. Prevalence of seronegative spondyloarthritis in the army force of China. Zhonghua Liu Xing Bing Xue Za Zhi 2004;25:753-755. 20. Winchester R, Bernstein DH, Fischer HD, et al. The co-occurrence of Reiter’s syndrome and acquired immunodeficiency. Ann Intern Med 1987;106:19-26. 21. Duvic M, Johnson TM, Rapini RP, et al. Acquired immune deficiency-associated psoriasis and Reiter’s syndrome. Arch Dermatol 1987;123:1622-1632. 22. Winchester R, Brancato L, Itescu S, et al. Implications from the occurrence of Reiter’s syndrome and related disorders in association with advanced HIV infection. Scand J Rheumatol Suppl 1988;74:89-93. 23. Hochberg MC, Fox R, Nelson KE, Saah A. HIV infection is not associated with Reiter’s syndrome: Data from the Johns Hopkins Multicenter AIDS Cohort Study. AIDS 1990;4: 1149-1151. 24. Mody GM, Parke FA, Reveille JD. Articular manifestations of human immunodeficiency virus infection. Best Pract Res Clin Rheumatol 2003;17:265-287. 25. Trier M. On Reiter’s syndrome, with special reference to cardiac complications and familial occurrence of the syndrome. Acta Med Scand 1950;239 (Suppl):123-128. 26. Fabregoule M. Familial Fiessinger-Leroy-Reiter syndrome. Alger Med 1951;55:1054-1055. 27. Hochberg MC, Bias WB, Arnett FC. Family studies in HLA-B27 associated arthritis. Medicine (Baltimore) 1978;57:463-475. 28. Yunus M, Calabro JJ, Miller KA, Masi AT. Family studies with HLA typing in Reiter’s syndrome. Am J Med 1981;70:1210-1214. 29. Zachariae H, Hjertshoj A, Kissmeyer-Nielsen F. Reiter’s disease and HL-A 27. Lancet 1973;2:565-566. 30. Woodrow JC. HL-A 27 and Reiter’s syndrome. Lancet 1973;2:671-672. 31. Prakash S, Mehra NK, Bhargava S, Malaviya AN. Reiter’s disease in northern India. A clinical and immunogenetic study. Rheumatol Int 1983;3:101-104. 32. Perez-Rojas GE, Paul-Moya H, Bianco NE, Abadi I. Seronegative spondyloarthropathies and HLA antigens in a Mestizo population. Tissue Antigens 1984;23:107-111. 33. Reveille JD, Ball EJ, Khan MA. HLA-B27 and genetic predisposing factors in spondyloarthropathies. Curr Opin Rheumatol 2001;13:265-272. 34. Good AE, Kawanishi H, Schultz JS. HLA 27 in blacks with ankylosing spondylitis or Reiter’s disease. N Engl J Med 1976;294:166-167. 35. Khan MA, Kushner I, Braun WE. Low incidence of HLA-B27 in American blacks with spondyloarthropathies. Lancet 1976;1:483. 36. Stein M, Davis P, Emmanuel J, West G. The spondyloarthropathies in Zimbabwe: A clinical and immunogenetic profile. J Rheumatol 1990;17:1337-1339. 37. Reveille JD, Conant MA, Duvic M. HIV-associated psoriasis, psoriatic arthritis and Reiter’s syndrome. A disease continuum? Arthritis Rheum 1990;33:1574-1578.

38. Ekman P, Kirveskari J, Granfors K. Modification of disease outcome in Salmonella-infected patients by HLA-B27. Arthritis Rheum 2000;43:1527-1534. 39. Arnett FC, Hochberg MC, Bias WB. Cross-reactive HLA antigens in B-27 negative Reiter’s syndrome and sacroiliitis. Johns Hopkins Med J 1977;141:193-197. 40. Arnett FC, Hochberg MC, Bias WB. HLA-C locus antigens in HLAB27 associated arthritis. Arthritis Rheum 1978;21:885-888. 41. Kemple K, Gatti RA, Leibold W, et al. HLA-D locus typing in ankylosing spondylitis and Reiter’s syndrome. Arthritis Rheum 1979;22:371-375. 42. Barron KS, Reveille JD, Carrington M, et al. Susceptibility to Reiter’s syndrome is associated with alleles of TAP genes. Arthritis Rheum 1995;38:684-689. 43. Kuipers JG, Raybourne RB, Williams KM, et al. Specificities of human TAP alleles for HLA-B27 binding peptides. Arthritis Rheum 1996;39:1892-1895. 44. Fraile A, Collado MD, Mataran L, et al. TAP1 and TAP2 polymorphism in Spanish patients with ankylosing spondylitis. Exp Clin Immunogenet 2000;17:199-204. 45. Colbert R. The immunobiology of HLA-B27: Variations on a theme. Curr Mol Med 2004;4:21-30. 46. Kuon W, Holzhutter HG, Appel H, et al. Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases. J Immunol 2001;167:4738-4746. 47. Fiorillo MT, Maragno M, Butler R, et al. CD8+ T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis. J Clin Invest 2000;106:47-53. 48. Dulphy N, Peyrat MA, Tieng V, et al. Common intra-articular T cell expansions in patients with reactive arthritis: Identical beta-chain junctional sequences and cytotoxicity toward HLAB27. J Immunol 1999;162:3830-3839. 49. Ugrinovic S, Mertz A, Wu P, et al. A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA-B27restricted CTL response in Yersinia-induced reactive arthritis. J Immunol 1997;159:5715-5723. 50. Montserrat V, Marti M, Lopez de Castro JA. Allospecific T cell epitope sharing reveals extensive conservation of the antigenic features of peptide ligands among HLA-B27 subtypes differentially associated with spondyloarthritis. J Immunol 2003;170:5778-5785. 51. Hillig RC, Hulsmeyer M, Saenger W, et al. Thermodynamic and structural analysis of peptide- and allele-dependent properties of two HLA-B27 subtypes exhibiting differential disease association. J Biol Chem 2004;279:652-653. 52. Hulsmeyer M, Fiorillo MT, Bettosini F, et al. Dual, HLA-B27 subtype-dependent conformation of a self-peptide. J Exp Med 2004;199:271-281. 53. Mear JP, Schreiber KL, Munz C, et al. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 1999;162:6665-6670. 54. Dangoria NS, DeLay ML, Kingsbury DJ, et al. HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem 2002;277:23459-23468. 55. Bird LA, Peh CA, Kollnberger S, et al. Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur J Immunol 2003;33:748-759. 56. Kollnberger S, Bird L, Sun MY, et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum 2002;46:2972-2982. 57. Ekman P, Saarinen M, He Q, et al. HLA-B27-transfected (Salmonella permissive) and HLA-A2-transfected (Salmonella nonpermissive) human monocytic U937 cells differ in their production of cytokines. Infect Immun 2002;70:1609-1614. 58. Kapasi K, Inman RD. HLA-B27 expression modulates gram-negative bacterial invasion into transfected L cells. J Immunol 1992;148:3554-3559. 59. Inman RD, Payne U. Determinants of synoviocyte clearance of arthritogenic bacteria. J Rheumatol 2003;30:1291-1297. 60. Boyle LH, Goodall JC, Opat SS, Gaston JS. The recognition of HLA-B27 by human CD4+ T lymphocytes. J Immunol 2001;167:2619-2624.

84. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42:2325-2329. 85. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2021-2027. 86. Dougados M, van der Linden S, Leirisalo-Repo M, et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995;38:618-627. 87. Van den Bosch F, Kruithof E, Baeten D, et al. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: An open pilot study. Ann Rheum Dis 2000;59:428-433. 88. Brandt J, Haibel H, Reddig J, et al. Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonal antibody infliximab. J Rheumatol 2002;29:118-122. 89. Van Den Bosch F, Kruithof E, Baeten D, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002;46:755-765. 90. D’Agostino MA, Breban M, Said-Nahal R, Dougados M. Refractory inflammatory heel pain in spondylarthropathy: A significant response to infliximab documented by ultrasound. Arthritis Rheum 2002;46:840-841. 91. Brandt J, Haibel H, Cornely D, et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum 2000;43:1346-1352. 92. De Rycke L, Kruithof E, Van Damme N, et al. Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy. Arthritis Rheum 2003;48:1015-1023. 93. Conti F, Priori R, Chimenti MS, et al. Successful treatment with intraarticular infliximab for resistant knee monarthritis in a patient with spondylarthropathy: A role for scintigraphy with 99mTc-infliximab. Arthritis Rheum 2005;52:1224-1226. 94. Kruithof E, De Rycke L, Roth J, et al. Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies. Arthritis Rheum 2005;52:3898-3909. 95. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: A randomised trial. Lancet 2000;356:385-390. 96. Davis J Jr, Webb A, Lund S, Sack K. Results from an open-label extension study of etanercept in ankylosing spondylitis. Arthritis Rheum 2004;51:302-304. 97. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab Effectiveness in Psoriatic Arthritis Trial Study Group. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:3279-3289. 98. Wick MC, Ernestam S, Lindblad S, et al. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): Results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol 2005;34:353-358. 99. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001;45:252-257. 100. Sairanen E, Paronen I, Mahonen H. Reiter’s syndrome: A follow-up study. Acta Med Scand 1969;185:57-63. 101. Calin A, Fries JF. An “experimental” epidemic of Reiter’s syndrome revisited. Follow-up evidence on genetic and environmental factors. Ann Intern Med 1976;84:564-566. 102. Fox R, Calin A, Gerber RC, Gibson D. The chronicity of symptoms and disability in Reiter’s syndrome. An analysis of 131 consecutive patients. Ann Intern Med 1979;91:190-193. 103. Butler MJ, Russell AS, Percy JS, Lentle BC. A follow-up study of 48 patients with Reiter’s syndrome. Am J Med 1979;67:808-810.

References

61. Lahesmaa R, Skurnik M, Vaara M, et al. Molecular mimickry between HLA-B27 and Yersinia, Salmonella, Shigella and Klebsiella within the same region of HLA alpha 1-helix. Clin Exp Immunol 1991;86:399-404. 62. Schwimmbeck PL, Yu DT, Oldstone MB. Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter’s syndrome. Molecular mimicry with Klebsiella pneumoniae as potential mechanism of autoimmune disease. J Exp Med 1987;166:173-181. 63. Braun J, Laitko S, Treharne J, et al. Chlamydia pneumoniae—A new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 1994;53:100-105. 64. Hannu T, Puolakkainen M, Leirisalo-Repo M. Chlamydia pneumoniae as a triggering infection in reactive arthritis. Rheumatology (Oxford) 1999;38:411-414. 65. Nikkari S, Rantakokko K, Ekman P, et al. Salmonella-triggered reactive arthritis: Use of polymerase chain reaction, immunocytochemical staining, and gas chromatography-mass spectrometry in the detection of bacterial components from synovial fluid. Arthritis Rheum 1999;42:84-89. 66. Gerard HC, Branigan PJ, Schumacher HR Jr, Hudson AP. Synovial Chlamydia trachomatis in patients with reactive arthritis/Reiter’s syndrome are viable but show aberrant gene expression. J Rheumatol 1998;25:734-742. 67. Schumacher HR Jr, Arayssi T, Crane M, et al. Chlamydia trachomatis nucleic acids can be found in the synovium of some asymptomatic subjects. Arthritis Rheum 1999;42:1281-1284. 68. Arnett FC. Seronegative spondyloarthropathies. In: Dale DC, Federman DD (eds). ACP Medicine, 2004-2005 ed. New York: Web MD, 2004, pp 1350-1361. 69. Popov I, Dela Cruz CS, Barber BH, et al. Breakdown of CTL tolerance to self HLA-B*2705 induced by exposure to Chlamydia trachomatis. J Immunol 2002;169:4033-4038. 70. Lassus A, Tiilikainen A, Stubb S, et al. Circinate erosive balanitis and HL-A 27. Acta Derm Venereol 1975;55:199-201. 71. Kiss S, Letko E, Qamruddin S, et al. Long-term progression, prognosis, and treatment of patients with recurrent ocular manifestations of Reiter’s syndrome. Ophthalmology 2003;110:1764-1769. 72. Thomsen NH, Horslev-Petersen K, Simonsen EE. Complete heart block in Reiter’s syndrome. Dan Med Bull 1985;32:272-273. 73. Deer T. Cardiac conduction manifestations of Reiter’s syndrome. South Med J 1991;84:799-800. 74. Braun J, Baraliakos X, Golder W, et al. Improvement of spinal inflammation in ankylosing spondylitis (AS) by infliximab therapy as assessed by magnetic resonance imaging (MRI) using a novel evaluated spinal scoring system. Arthritis Rheum 2003;48:1126-1136. 75. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: A clinical and magnetic resonance imaging study. Arthritis Rheum 2001;44:2112-2117. 76. Balint PV, Kane D, Wilson H, et al. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61:905-910. 77. Sieper J, Rudwaleit M, Braun J, van der Heijde D. Diagnosing reactive arthritis: Role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 2002;46:319-327. 78. Uhrin Z, Kuzis S, Ward MM. Exercise and changes in health status in patients with ankylosing spondylitis. Arch Intern Med 2000;160:2969-2975. 79. Dagfinrud H, Hagen K. Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev 2001;CD002822. 80. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 1991;34:6-14. 81. Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic treatment and long term prognosis of reactive arthritis. Ann Rheum Dis 2003;62:655-658. 82. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al. Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis. Ann Rheum Dis 2003;62:880-884. 83. Kvien TK, Gaston JS, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113-1119.

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104. Glennas A, Kvien TK, Melby K, et al. Reactive arthritis: A favorable 2 year course and outcome, independent of triggering agent and HLA-B27. J Rheumatol 1994;21:2274-2280. 105. Herrlinger JD, Asmussen JU. Long term prognosis in Yersinia arthritis: Clinical and serological findings. Ann Rheum Dis 1992;51:1332-1334. 106. Leirisalo-Repo M, Suoranta H. Ten-year follow-up study of patients with Yersinia arthritis. Arthritis Rheum 1988;31:533-557.

107. Leirisalo M, Skylv G, Kousa M, et al. Followup study on patients with Reiter’s disease and reactive arthritis, with special reference to HLA-B27. Arthritis Rheum 1982;25:249-259. 108. Thomson GT, DeRubeis DA, Hodge MA, et al. Post-Salmonella reactive arthritis: Late clinical sequelae in a point source cohort. Am J Med 1995;98:13-21.

REACTIVE ARTHRITIS

18

Enteric Infections and Arthritis Filip De Keyser and Herman Mielants

Inflammatory arthritis may follow infections of the gastrointestinal tract. Some enteric infection–related arthritides arise with typical features of spondyloarthropathy and are referred to as classical enterogenic reactive arthritis. They may follow infections with Salmonella typhimurium, Shigella flexneri, Yersinia enterocolitica, Yersinia pseudotuberculosis, and Campylobacter jejuni. Inflammatory arthritis has, however, also been described after other enteric infections with organisms such as Clostridium difficile, Brucella, or Giardia lamblia. These cases generally do not fulfill classification criteria for spondyloarthropathy and fail to show association with human leukocyte antigen HLA-B27. They are referred to as postinfectious or infection-related arthritis. In Whipple’s disease, the infectious nature was detected by molecular biologic techniques, identifying Tropheryma whippelii, an actinomycete, as the causative agent. Finally, bacterial overgrowth is a pathologic event in the induction of intestinal bypass arthritis. Here we review the causative enteropathogens associated with arthritis, the clinical presentation of the disease, and some pathogenetic considerations.

ENTEROGENIC REACTIVE ARTHRITIS Reactive arthritis arises as joint inflammation initiated by infectious agents, in which the causative microorganism cannot be cultured from the joint. Immunofluorescence and molecular biology techniques have demonstrated microbial antigens of arthritogenic gastrointestinal pathogens (Yersinia and Salmonella) in the synovial fluid and membrane of patients with reactive arthritis.1,2 Salmonella DNA3 and Yersinia4 DNA have been detected by polymerase chain reaction in joints with reactive arthritis. The reactive arthritides are considered to be spondyloarthropathies because of the typical pattern of peripheral joint involvement, the possible occurrence of enthesopathies and sacroiliitis, and the increased prevalence of HLA-B27. Enteropathogens related to reactive arthritis include S. typhimurium, S. flexneri, Y. enterocolitica (especially serotype 3), Y. pseudotuberculosis, and C. jejuni. With regard to Shigella, only S. flexneri, and not Shigella

sonnei, has been implicated as a causative agent of reactive arthritis, suggesting that the “arthritogenic” factor may not be a universal feature of a given family of pathogens. The high frequency of infectious enteritis, especially of Yersinia infections; the fact that the gastrointestinal symptoms preceding the arthritis are often minimal; and the fact that fecal cultures can be negative at the time the arthritis appears often render the definite diagnosis of enterogenic reactive arthritis difficult. The onset of arthritis is usually within 6 to 14 days after the onset of diarrhea but it can occur up to 3 months later. The duration of the articular episode is approximately 4 months.5 The arthritis is mainly monoarticular or pauciarticular and asymmetric and affects the lower limbs predominantly. In nearly 30% of patients, multiple episodes of arthritis occur, and in 5% to 20%, the arthritis becomes chronic. Chronic spondyloarthropathy was found in 13% of patients with reactive salmonella arthritis.6 In some cases, recurrence is caused by another enterogenic or urogenic infection. Enthesopathy usually involves the calcaneum, and dactylitis (“sausage” digits or toes) related to tenosynovitis of a digital tendon sheath may occur. In the course of the disease, some patients complain of buttock pain. Fever and diarrhea generally precede the arthritis by 1 to 2 weeks, although this interval can be longer and is sometimes more than 3 months. Diarrhea can be absent, and there is no relation between the severity of the gut symptoms and either the development of articular episodes or the severity of any joint symptoms. Conjunctivitis occurs in 30% of the patients. Urogenital symptoms, mainly urethritis or balanitis, complete the picture initially described as Reiter’s syndrome. Acute anterior uveitis occurs mainly in HLAB27–positive patients but appears to be independent and not related in time to the triggering infectious episode. Mouth ulcers and erythema nodosum have been reported after Yersinia infection. Keratoderma blennorrhagicum, described in the entity of urogenic reactive arthritis, does not occur in enterogenic forms. Synovial fluid analysis reveals mild to marked inflammation; the white blood cell count ranges from

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4000 to 120,000 cells/mm3, with predominantly polymorphonuclear cells. Radiographic lesions of the peripheral joints are rare. Radiographic evidence of sacroiliitis has been described in 6% to 9% of the patients, generally in those with chronic or recurrent peripheral arthritis. As in the other spondyloarthropathies, the prevalence of HLA-B27 is increased in reactive arthritis, including the forms induced by enterogenic agents. The reported prevalence of HLA-B27 ranges between 60% and 80%. Inflammatory low back pain and sacroiliitis are more frequent in HLA-B27–positive patients.6 Treatment of reactive arthritis is covered elsewhere in this book.

IMMUNOPATHOGENESIS OF ENTEROGENIC REACTIVE ARTHRITIS

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Early in the disease, the triggering organisms (Y. enterocolitica, S. typhimurium, S. flexneri, or Campylobacter) can be cultured from the stools, but culture from the joint has been repeatedly unsuccessful. Bacterial antigens from Yersinia and Salmonella were demonstrated in the synovial fluid and the synovial membrane of patients with enterogenic reactive arthritis.1,7-9 Only stable bacterial degradation products, not whole bacteria, are present at the site of inflammation in Yersinia-triggered reactive arthritis because no Yersinia chromosomal DNA could be detected.8 Concerning the humoral immunologic response, it was shown that Salmonella-specific antibodies in the joint are of the immunoglobulin A2 (IgA2) subclass, indicating a mucosal origin. The IgA2 levels in the synovial fluid are higher than the IgA2 serum levels; this finding can be due to a selective migration of IgA2-secreting lymphocytes from the gut mucosa to synovium, to specific trapping of IgA2secreting lymphocytes into the joint, or to the presence of antigen in the joint with local IgA2 production.10 The presence of serum IgA antibodies to plasmidencoded secreted proteins and the persistence of Yersinia in the gut or gut lymphoid tissue11,12 suggest impaired elimination of these antigens from the gut wall. Enteric infectious agents, bacterial overgrowth, or a local mucin defect13 might initiate increased epithelial permeability, abrogation of oral tolerance, and immunologic stimulation, followed by enhanced delayed hypersensitivity and a systemic IgG response. Molecular mimicry between bacterial antigens and HLA-B27 has been suggested as playing a role in the pathogenesis of reactive arthritides. Klebsiella pneumoniae nitrogenase shares a hexapeptide (QTDRED) with the HLA-B27.5 molecule.14 Yersinia adhesin A (YadA) shares a linear tetrapeptide (TRDE) with the

B27 molecule (between amino acids 70 and 78 in the variable region of the α1-helix),15 and OmpH of S. typhimurium shares five amino acids in a nonlinear fashion in the same site of the B27 molecule.16 Furthermore, it was shown that isolates of S. flexneri that cause enteric infection and reactive arthritis carry a 2-Md plasmid, pHS-2, that encodes a B27 mimetic peptide (a five-amino-acid peptide that is homologous with the polymorphic region of the HLA-B27 α1 domain).17 Molecular mimicry exists within these molecules, but its role in the pathogenesis of reactive arthritis is unclear.18 It is noteworthy that microorganisms that trigger reactive arthritis share three important features: they infect mucosal surfaces, they express lipopolysaccharides on their outer membrane, and they are intracellular organisms.19 It was shown that synovial mononuclear cells from patients with reactive arthritis proliferate specifically to the triggering bacterial agent in vitro.20 It was also demonstrated that the proliferation was inhibited by cyclosporine and by monoclonal antibodies to major histocompatibility complex (MHC) class II antigens, suggesting it was attributable to MHC class II–restricted T cells.21 Indeed, most of the T-cell clones from synovial fluid of patients with reactive arthritis are CD4+, MHC class II restricted, and of the T helper 1 type.22,23 However, the known association of reactive arthritis with the MHC class I gene B27 suggests that antigenic peptides should be presented for recognition by CD8+ T cells. Furthermore, the organisms associated with reactive arthritis are intracellular pathogens, whereas MHC class II molecules present exogenous antigen peptides that have been endocytosed by host antigen-presenting cells.22 These arguments prompted investigation of the local synovial CD8 T-cell population. It has been suggested that bacteria-specific cytotoxic T lymphocytes (CTLs) might provide the link between the initiating agent and the cellular immune response. Isolation of a large number of CD8+ T lymphocyte clones, derived from the synovial fluid of patients with spondyloarthropathy, allowed identification of three B27-restricted CTL clones with specificity for Yersinia and Salmonella.24 Further analysis of a large panel of T-cell clones will shed more light on the role of B27 in the presentation of arthritogenic peptides. The fact that, unlike other class I molecules, HLA-B27 molecules devoid of bound antigenic peptides (i.e., empty) can be found on the cell surface25 may be important in relation to molecular mimicry theory. In some cases, the triggering bacterium can be identified by means of an antigen-specific proliferative response of synovial fluid T cells, but usually several intracellular antigens are recognized by CD4+ T cells. More specific information about antigenic specificity

CLOSTRIDIUM DIFFICILE C. difficile infection frequently complicates antibiotic treatment that allows unrestrained growth of the organism; this commonly results in pseudomembranous colitis. In addition to pseudomembranous colitis, C. difficile is estimated to be responsible for 20% of cases of antibiotic-associated diarrhea without colitis. No studies have yet been undertaken on the frequency with which arthritis occurs among all patients with documented clostridial infection. However, C. difficile infection–related arthritis probably accounts for a significant proportion of undifferentiated oligoarthritis. In a review of the extracolonic manifestations of clostridium infection, 36 cases of arthritis were assessed.28 The arthritis was frequently polyarticular in nature, commencing a mean of 11 days from the onset of diarrhea. The knees and the wrist were the most commonly affected joints, and the condition resolved in an average of 2 months. The pathogenesis of C. difficile–associated arthritis is unclear, although the pathogenesis of the intestinal disease is well described and the importance of exotoxins produced by the bacteria well studied. C. difficile produces two potent exotoxins (A and B). In humans, exotoxin A increases intestinal permeability and perpetuates diarrhea and exotoxin B causes cytotoxic effects. It is possible that systemic absorption of these toxins directly mediates the arthritis, or it may be that increased intestinal permeability facilitates the entry of other bacterial antigens that themselves mediate the process.29 Sigmoidoscopic examination may be diagnostic, demonstrating yellow raised plaques, but is normal in about 20% of patients because of early involvement preferentially affecting the right side of the colon, in which case colonoscopy is the definitive test. In practice, identification of the pathogenic exotoxins (C. difficile toxins A and B) by the cytotoxin assay is the best diagnostic test. Immunoassays for the toxins are commercially available but show lower sensitivity than the cytotoxin assay, which remains the “gold standard.”30

GIARDIA LAMBLIA Although G. lamblia infection accounts for a significant proportion of enteric infections worldwide, reports of an association with postinfectious arthritis are relatively few. There have been no epidemiologic studies of the disease, but the anecdotal case reports suggest a propensity to affect lower limb joints. Interestingly, the case reports also suggest that the arthritis is resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) but responsive to antibiotics. Giardia-associated arthritis and arthralgia appear to affect the pediatric population more commonly than adults. In all ages, there is a predilection for the knees, although involvement of other small and large joints is reported. Gastrointestinal symptoms may or may not be present and can be mild. Cysts and trophozoites of the organism, which colonizes and multiplies within the small intestine, can be demonstrated in the stool, and this is the diagnostic test. A history of recent travel to endemic areas, family members with similar gastrointestinal symptoms, or an elevated eosinophil count should lead to clinical suspicion.

Whipple’s Disease

has been obtained by investigating T-cell clones. Immunodominant 60-kd heat shock protein of reactive arthritis–triggering bacteria has been found to be a target antigen for the cellular immune responses.26 From synovial fluid of a patient with Yersinia-triggered reactive arthritis, a clone has also been isolated that recognizes both enterobacterial and human heat shock protein, suggesting that autoimmune mechanisms also play a role.27 Other immunodominant proteins of Yersinia include the highly conserved ribosomal proteins L2 and L23 and the 19-kd subunit of the urease of Yersinia.

BRUCELLA Brucellosis is an uncommon cause of spondylitis and reactive arthritis.31,32 Depending on the geographic location, brucellosis is primarily caused by Brucella abortus (cow), Brucella melitensis (goat), or Brucella suis (pig). The arthritis associated with brucellosis may be caused by direct seeding of the synovium by the organism. However, some cases are clearly reactive in nature. Whereas Brucella septic arthritis is usually monoarticular and persistent and requires antibiotic therapy, the reactive form is associated with a sterile, nondestructive polyarthritis that tends to be intermittent and self-limited, does not require antibiotic therapy, and is associated with high titers of circulating immune complexes in 90% of patients.

WHIPPLE’S DISEASE Whipple’s disease is a multisystem disorder characterized in its fully expressed form by steatorrhea and severe weight loss (which are the main intestinal symptoms), fever, arthritis, serositis, lymphadenopathy, leukocytosis, and often thrombocytosis. Whipple’s disease occurs most often in men (90%), and the joint symptoms may antedate the intestinal complaints by more than 5 years. Arthritis flares are not related temporally to exacerbations of intestinal symptoms. Arthralgias are a common finding. The arthritis is polyarticular, symmetric, and usually transient but may become chronic. Synovial effusions

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contain between 4000 and 100,000 leukocytes/mm3, consisting mainly of polymorphonuclear cells. Radiographic lesions are rare. The incidence of sacroiliitis and spondylitis is controversial, as well as the relation with HLA-B27. A variety of ophthalmologic and neurologic syndromes may occur, including anterior and posterior uveitis, vitritis, ocular palsies, and progressive encephalopathy. Joint manifestations in Whipple’s disease are probably a form of enterogenic arthritis, caused by an infection of the intestine. Characteristic periodic acid–Schiff (PAS)–staining deposits are found in the macrophages of the small intestine and in the mesenteric nodes. These cells also contain rod-shaped free bacilli best seen by electron microscopy.33 These bacilliform bodies are considered to be the etiologic agent because they disappear when the patients are successfully treated with antibiotics. Synovial histologic studies suggest that the joint can also be directly invaded by the causative organism. A unique 1321-base-pair bacterial 16S ribosomal RNA sequence was amplified from duodenal tissue of five patients with Whipple’s disease but not from duodenal tissue of 10 patients without the disorder.34 Phylogenetic analysis showed the bacterium to be a gram-positive actinomycete, which was designated T. whippelii. The polymerase chain reaction for this sequence now provides a specific test for the disease. A correct diagnosis is important because the condition responds well to appropriate antibiotic therapy, which must be continued for more than 1 year. However, functional abnormalities of macrophages may persist after successful treatment, indicating a possible immunogenetic predisposition of the affected individual.

INTESTINAL BYPASS ARTHRITIS Intestinal bypass surgery (jejunocolostomy or jejunoileostomy), which has been a popular treatment for morbid obesity, may give rise to an arthritisdermatitis syndrome that is sometimes associated with

renal, hepatic, and hematologic disorders. Polyarthritis develops in 20% to 80% of the cases. Symptoms appear 2 to 30 months after surgery. The arthritis is polyarticular, symmetric, and migratory, affecting both upper and lower limb joints. Chronic arthritis develops in one fourth of the patients. The duration of the arthritis is unpredictable, and there is no relation between the joint symptoms and abnormal bowel movements. Radiographic deformities or erosions are not seen. Sacroiliac and spine involvement, although uncommon, has been described. In 66% to 80% of the patients, a variety of dermatologic abnormalities occur. Erythema nodosum, maculae progressing to papules and vesiculopustules, urticaria, and nodular dermatitis have been reported. Other associated features are Raynaud’s phenomenon, paresthesias, pericarditis, pleuritis, glomerulonephritis, retinal vasculitis, and superficial thrombophlebitis. The pathogenesis involves bacterial overgrowth and mucosal alterations in the blind loop. The disease seems to be immune mediated; cryoprecipitates and other circulating complexes containing immunoglobulins, complement, bacterial antibodies, and antigens are found in the serum.35 Bacterial overgrowth in the blind loop could be responsible for a substantial increase of antigenic stimulation. Acute symmetric polyarthritis involving the peripheral and axial skeleton has been described 1 week to 2 years after a restorative proctocolectomy with an ileal pouch and anastomosis for ulcerative colitis.36 In these cases, the dissemination of immune complexes resulting from the increased absorption of bacterial antigens related to the bacterial overgrowth was considered pathogenic. NSAIDs are usually sufficient to control the arthritis. Oral antibiotics, such as tetracycline, clindamycin, or metronidazole given intermittently or continuously, can reduce the symptoms through a reduction of bacterial overgrowth. Only surgical reanastomosis of the bypassed segment of the intestine gives complete resolution of all symptoms, and it may be necessary in refractory cases.

REFERENCES

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1. Granfors K, Jalkanen S, Von Essen R, et al. Yersinia antigens in synovial fluid cells from patients with reactive arthritis. N Engl J Med 1989;320:216-221. 2. Granfors K, Jalkanen S, Lindberg A, et al. Salmonella lipopolysaccharides in synovial cells from patients with reactive arthritis. Lancet 1990;335:6985-6988. 3. Nikkari S, Möttönen T, Saario R, et al. Demonstration of Salmonella DNA in the synovial fluid in reactive arthritis. Arthritis Rheum 1996;39:S185. 4. Wilkinson NZ, Ward ME, Kingsley GH. Detection of bacteria in rheumatoid and reactive arthritis synovial fluid using a

kingdom-specific polymerase chain reaction: Evidence in support of a role for bacteria in the pathogenesis of inflammatory arthritis. Arthritis Rheum 1997;40:S270. 5. Leirisalo-Repo M. Reactive arthritis. Scand J Rheumatol 2005;34:251-259. 6. Leirisalo-Repo M, Hannu T, Lehtinen A, et al. Long term prognosis of reactive salmonella arthritis. Ann Rheum Dis 1997;56:516-520. 7. Lahesmaa-Rantala R, Granfors K, Isomaki H, et al. Yersinia specific immune complexes in the synovial fluid of patients with Yersinia triggered reactive arthritis. Ann Rheum Dis 1987;46:510-514.

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reactive arthritis: Absence of a class I-restricted response. Clin Exp Immunol 1992;83:442-447. Lahesmaa R, Yssel H, Batsford S, et al. Yersinia enterocolitica activates a T helper type-1 like T cell subset in reactive arthritis. J Immunol 1992;148:3079-3085. Hermann E, Yu DTY, Meyer zum Büschenfelde KH, et al. HLAB27 restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 1993;342:646-650. Benjamin RJ, Madrigal JA, Parham P. Peptide binding to empty HLA-B27 molecules of viable human cells. Nature 1991;351: 74-77. Probst P, Hermann E, Meyer zum Büschenfelde K-M, et al. Multiclonal synovial T cell response to Yersinia enterocolitica in reactive arthritis. J Infect Dis 1993;167:385-391. Hermann E, Lohse AW, Van der Zee R, et al. Synovial fluidderived Yersinia-reactive T cells responding to human 65kDa heat-shock protein and heat stressed antigen-presenting cells. Eur J Immunol 1991;21:2139-2143. Jacobs A, Barnard K, Fishel R, et al. Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of literature. Medicine (Baltimore) 2001;80:88-101. Putterman C, Rubinow A. Reactive arthritis associated with Clostridium difficile pseudomembranous colitis. Semin Arthritis Rheum 1993;22:420-426. O’Connor D, Hynes P, Cormican M, et al. Evaluation of methods for detection of toxins in specimens of feces submitted for diagnosis of Clostridium difficile-associated diarrhea. J Clin Microbiol 2001;39:2846-2849. Zaks N, Sukenik S, Alkan M, et al. Musculoskeletal manifestations of brucellosis: A study of 90 cases in Israel. Semin Arthritis Rheum 1995;25:97-102. De Dios Colmenero J, Reguera JM, Fernandez-Nebro A, et al. Osteoarticular complications of brucellosis. Ann Rheum Dis 1991;50:23-26. Fleming J, Russel H, Wiesnek D, Shorter RG. Whipple’s disease: Clinical, biochemical and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988;63:539-551. Relman DA, Schmidt TM, MacDermott RP, et al. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992;327:293-301. Clegg DO, Zone JJ, Samuelson CD, et al. Circulating immune complexes containing secretory IgA in jejunoileal bypass disease. Ann Rheum Dis 1985;44:239-244. Axon JMC, Hawley PR, Huskisson EC. Ileal pouch arthritis. Br J Rheumatol 1993;32:586-588.

References

8. Hammer M, Zeidler H, Klisma S, et al. Yersinia enterocolitica in the synovial membrane of patients with Yersinia-induced arthritis. Arthritis Rheum 1990;33:1795-1800. 9. Nikkari S, Merilahti-Palo R, Saaro R, et al. Yersinia-triggered reactive arthritis: Use of polymerase chain reaction and immunocytochemical staining in the detection of bacterial components from synovial specimens. Arthritis Rheum 1992;35:682-687. 10. Mäki-Ikola O, Yli-Herttula U, Saario R, et al. Salmonella specific antibodies in serum and synovial fluid in patients with reactive arthritis. Br J Rheumatol 1992;31:25-29. 11. Mielants H, Veys EM, Cuvelier C, et al. Gut inflammation in children with late onset pauci-articular juvenile chronic arthritis and evolution to adult spondyloarthropathy: A prospective study. J Rheumatol 1993;20:1567-1572. 12. Hoogkamp-Korstanje JAA, de Koning J, Heeseman J. Persistence of Yersinia enterocolitica in man. Infection 1988;16:81-85. 13. Podolsky DK. Glycoproteins in inflammatory bowel disease. In: Jarnerot G (ed). Inflammatory Bowel Disease. New York: Raven Press, 1987, pp 53-65. 14. De Vries DD, Dekker-Saeys AJ, Gyodi E, et al. Absence of autoantibodies to peptides shared by HLA-B27.5 and Klebsiella pneumoniae nitrogenase in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter’s syndrome. Ann Rheum Dis 1992;51:783-789. 15. Lahesmaa R, Skurnik M, Vaara M, et al. Molecular mimicry between HLA-B27 and Yersinia, Salmonella, Shigella and Klebsiella within the same region of HLA α1-helix. Clin Exp Immunol 1991;86:399-404. 16. Hoski P, Rhen M, Kantele J, Vaara M. Isolation, cloning, and primary structure of a cationic 16-kDa outer membrane protein of Salmonella typhimurium. J Biol Chem 1989;264:18973-18975. 17. Stieglitz H, Lipsky P. Association between reactive arthritis and antecedent infection with Shigella flexneri carrying a 2-Md plasmid and encoding an HLA-B27 mimetic epitope. Arthritis Rheum 1993;36:1387-1391. 18. Schwimbeck P, Yu DTY, Oldstone MBA. Autoantibodies to HLAB27 in the sera of HLA-B27 patients with ankylosing spondylitis and Reiter’s syndrome. J Exp Med 1987;166:173-181. 19. Mäki-Ikola O, Granfors K. Salmonella triggered reactive arthritis. Lancet 1992;339:1096-1098. 20. Ford DK, Schuller M. Synovial lymphocyte responses to microbial agents differentiate the arthritis of enteric reactive arthritis from the arthritis of inflammatory bowel disease. J Rheumatol 1988;15:1239-1242. 21. Gaston JSH, Life PF, Granfors K, et al. Synovial T lymphocyte recognition of organisms that trigger reactive arthritis. Clin Exp Immunol 1989;76:348-353. 22. Hassell AB, Pilling D, Reynolds D, et al. MHC restriction of synovial fluid lymphocyte responses to the triggering organism in

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19

Chlamydia-Induced Arthritis Finbar D. O’Shea and Robert D. Inman

Chlamydia-induced arthritis (CIA) is a syndrome of asymmetric oligoarthritis, predominantly affecting the lower limbs and primarily occurring in young adults following mucosal infection with the genitourinary pathogen Chlamydia.1 Although preceded by a Chlamydia infection, the arthritis itself is a nonseptic process and is thought to reflect the host immune response to the organism. CIA is a form of reactive arthritis (ReA). ReA is a form of spondyloarthritis (SpA), which also includes ankylosing spondylitis (AS), arthritis associated with inflammatory bowel disease, psoriatic arthritis, undifferentiated spondyloarthritis, and some forms of juvenile idiopathic arthritis.2,3 These diseases share common features such as an association with human leukocyte antigen HLAB27, absence of rheumatoid factor, tendency toward family aggregation, and characteristic extra-articular features such as urethritis, iritis, conjunctivitis, enthesopathic manifestations (inflammation of tendinous and ligamentous insertions), or mucocutaneous lesions (balanitis, keratoderma blennorrhagica, stomatitis).4 CIA is commonly associated with enthesitis and sacroiliitis. Unlike most forms of arthritis, CIA has a known trigger, a defined genetic association (HLAB27), and a recognized cellular and immune response. Extra-articular symptoms associated with CIA may include urethritis, uveitis, and skin manifestations. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy. Trials of long-term antibiotic therapy have been conflicting. There are limited data regarding the use of conventional disease-modifying antirheumatic drugs (DMARDs) and newer anticytokine therapies.5

ETIOPATHOGENESIS

156

The extra-articular Chlamydia infection is usually of the genitourinary tract, with Chlamydia trachomatis the pathogen. However, other Chlamydia species, most notably Chlamydia pneumoniae, may also precipitate arthritis.6 Chlamydia are metabolically deficient in their ability to synthesize ATP and thus require an

exogenous source of this high-energy compound. They are therefore obligate intracellular organisms. There are four species—C. trachomatis and C. pneumoniae, which are primarily human pathogens, and Chlamydia psittaci and Chlamydia pecorum, which are primarily animal pathogens.7 Genital C. trachomatis infections are among the most frequently encountered sexually transmitted diseases in the world. It is currently estimated that about 4 million new Chlamydia infections occur each year in the United States at an estimated cost exceeding $2.4 billion.8 Worldwide, it is estimated that there are more than 50 million new cases of C. trachomatis infection annually. The prevalence in symptomatic women has been assessed to be as high as 18% in the United States and 13% in Scandinavia. The prevalence in asymptomatic women has been estimated to be around 5%. Similarly, the prevalence in asymptomatic men in different studies using urine-based testing is 5% to 7%.9,10 The main portal of entry for C. trachomatis is the urogenital tract, but the rhinopharyngeal and respiratory tracts as well as the conjunctivae may also be the sites of primary infections in adults. Chlamydial reproduction takes place in the single-layered columnar epithelium of the cervix, urethra, and paraurethral glands. Dissemination of whole bacteria from the genitourinary tract during acute infection is well recognized. It appears that the organism can be disseminated from the portal of entry to other tissues, including the joints, by inflammatory cells within the blood.11 C. trachomatis is the most common causative agent of nongonococcal urethritis in males and cervicitis in females, accounting for 50% to 60% of cases. Only a small proportion of all Chlamydia-infected persons develop CIA—it has been suggested that approximately 1% to 3% of patients with chlamydial urethritis go on to develop arthritis.12 C. pneumoniae is a common cause of acute respiratory tract infection. Population prevalence antibody studies have shown that in many countries more than 50% of adults have anti–C. pneumoniae antibodies, with the rate increasing rapidly from 5 to 20 years and

CLINICAL FEATURES CIA, like other SpAs, encompasses several clinical features: peripheral arthritis, enthesitis, axial inflammation, and extra-articular manifestations. The relative importance of these four findings varies from patient to patient and in a given patient during the course of the disease. It is unclear which factors determine the clinical course of CIA in an individual patient. CIA affects both males and females; however, the triggering Chlamydia infection in women is often asymptomatic, leading to a delay in diagnosis in many cases. The urethral syndrome in females is rarely diagnosed, and other urogenital inflammatory involvement (cervicitis and salpingitis) may be overlooked in the context of the rheumatic disease. Acute peripheral synovitis is usually the first musculoskeletal feature, although, as in other SpAs, the initial presentation may be with a painful enthesitis or low back pain. The pattern of joint involvement in CIA resembles that of other forms of ReA with oligoarticular, asymmetric arthritis and preferential involvement of the joints of the lower limbs.16 In approximately 10% of cases the course is a monoarthritis. Knees and ankles are the most commonly affected joints, but any joint may be involved. Although chronic arthritis can be seen, the persistent joint inflammation is rarely associated with articular erosions.17,18 The affected joints can be intensely inflamed, raising suspicion of septic arthritis, particularly in the context of a sexually transmitted disease. The severity of the arthritis varies from mild swelling with discomfort to a serious, incapacitating condition. Enthesitis is reported in 4% to 28% of patients with CIA. The sites of attachment of the Achilles tendon and the plantar fascia to the calcaneus are most com-

monly involved, but it may occur at other sites. With regard to the occurrence of enthesopathy, there appears to be no difference between HLA-B27–positive and –negative patients or between males and females.17 Inflammatory low back pain is reported in 28% to 35% of patients with CIA. Radiologic sacroiliitis is observed in 33% of patients, which indicates more local damage to this joint than is seen in peripheral joints. There is no difference in inflammatory low back pain in patients with silent versus symptomatic chlamydial infection. However, HLA-B27 is significantly associated with radiographic sacroiliitis. Nevertheless, the evolution into the full picture of AS appears to be rare.16,17 Ocular involvement, usually in the form of conjunctivitis or keratitis, is a feature reported in approximately one third of patients with CIA. Acute anterior uveitis (iritis) is reported in 5% to 13% of patients—it usually arises with more severe symptoms, whereas the conjunctivitis may often be asymptomatic. The ocular features may be the first, and even the only, manifestation of the disease. The patient usually complains of redness, photophobia, increased lacrimation, or decreased vision.18 It is necessary to carry out careful ophthalmologic examination in these cases because, if it is left untreated, serious impairment of vision may follow. Skin and mucous membrane involvement in the form of circinate balanitis, keratoderma blennorrhagicum, or gingivostomatitis has also been encountered in CIA.

Investigations

then increasing slowly into old age. The clinical features of this airborne infection transmitted from human to human vary from a mild upper respiratory disease to primary atypical pneumonia.6 The pathogenesis of the joint inflammation has not been completely resolved. Studies in experimental CIA have indicated that innate immune defenses are important. In particular, neutrophil migration has been implicated in both the acute and chronic phases of arthritis.13 A publication in experimental CIA contrasted resistant and susceptible strains of rats.14 Interestingly, resistance was associated with higher levels of expression of tumor necrosis factor α (TNF-α), interferon γ, and interleukin 4. This suggests a cautionary note that therapeutic manipulation of endogenous cytokines might have unintended consequences in infection-triggered arthritis. A study has demonstrated a distinctive profile of gene expression in CIA that mirrors that seen during infection with tuberculosis.15

INVESTIGATIONS The typical patient is a previously healthy young adult presenting with joint symptoms or eye inflammation. A thorough history and physical examination may point toward the diagnosis. Laboratory and radiographic investigations are an important part of the work-up. The erythrocyte sedimentation rate (ESR) and C-reactive protein values are usually elevated, and moderate anemia is often present. In the acute phase, a marked leukocytosis is also seen. Later, in more chronic cases, these values are generally normal. If septic arthritis cannot be ruled out, blood cultures should be performed. Rheumatoid factor is usually not detectable. Urinalysis should be carried out and the urine checked for Chlamydia by polymerase chain reaction (PCR) testing. Radiographs of affected joints reveal little in the acute phase of ReA. The findings include soft tissue swelling, juxta-articular osteoporosis, periosteal reaction, and proliferation at the tendon insertion sites—all nonspecific findings. Occasionally, plantar spurs may be seen, especially in more chronic

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158

cases. Radiographic investigations are indicated not so much for the diagnosis as to exclude other serious and erosive diseases such as rheumatoid arthritis.18 Radiographic evidence of sacroiliitis in the acute stage may indicate prior inflammation in the sacroiliac joints reflecting a preexisting SpA. Synovial fluid samples should always be obtained if possible. Synovial fluid leukocyte count can range from 2000 to 64,000/mm3. Gram stain and bacterial culture are necessary—by definition in CIA, bacteria cannot be cultured. Polarized light microscopy should be carried out to exclude gout or pseudogout. The measurement of HLA-B27 is generally not of great diagnostic significance because CIA can occur in its absence, but it may be of importance in assessment of prognosis. The use of serology for the diagnosis of infections with C. trachomatis is hampered by a relatively high prevalence of antichlamydial antibodies in the normal population and by possible cross-reactivities with C. pneumoniae. The microimmunofluorescence test is a reliable method for analysis of class-specific and species-specific antibodies19 but is time consuming. Various modifications of enzyme immunoassays exist. Among them are the use of recombinant lipopolysaccharide antigen detecting Chlamydia genus-specific antibodies and a species-specific method based on a peptide derived from the major outer membrane protein of Chlamydia.20 Determination of immunoglobulin G (IgG) antibodies alone is not informative, and these should be combined with tests for IgM and IgA antibodies. Current consensus indicates that positive serology alone without a history of a urogenital tract infection does not suffice for a definite diagnosis of CIA.21 Positive evidence of Chlamydia in the joint by PCR is an ideal approach, but it is rarely used in the clinical setting. If there is a clinical suspicion of CIA, an effort should be made to detect C. trachomatis in the urogenital tract. Although the urogenital swab can still be used, the test of choice is to probe for Chlamydia in the first portion of the morning urine using the ligase reaction because it is easier to use and the results are comparable to those obtained using the urogenital swab.21 A substantial number of patients with ReA are asymptomatic for the triggering infection. Therefore, laboratory tests are applied to identify the possible triggering infection. Sieper and colleagues have discussed the value of serologic and microbiologic assays for the diagnosis of ReA.21 If the clinical picture suggests ReA, positive serologic testing for Chlamydia, Yersinia, or Salmonella would have a sensitivity of 73% to 90% and a specificity of 78% to 90% and the detection of Chlamydia in the urogenital tract a sensitivity of 50% and a specificity of 96%. If the clinical picture is not

compatible with ReA, the post-test possibility of a diagnosis of ReA is much lower. The same holds true for the analysis of HLA-B27. Thus, in the presence of high clinical suspicion of ReA, laboratory tests aid in the diagnosis, but in a screening of the arthritis population as a whole, these tests show only low predictive value. In clinical settings, it should be kept in mind that the diagnosis of a preceding triggering infection is often hindered by the fact that in a substantial proportion of the patients the preceding infection is asymptomatic or only mildly symptomatic. It is also not uncommon that the symptoms of the antecedent infection have subsided when the patient presents to the physician.

PROGNOSIS In general, the literature is conflicted over the longterm prognosis in all types of ReA, including CIA. Some authors predict a good outcome with the majority of patients recovering within a year.18 However, others report more frequent recurrences. Across all forms of ReA it has been reported that 75% of patients have musculoskeletal symptoms persisting for more than 1 year and up to 30% of those patients have symptoms after 6 years. Recurrent attacks are more common in patients with CIA and patients who are HLA-B27 positive.22 Enthesitis and skin lesions may persist after joint symptoms resolve. Disease activity and arthritis are associated with increased type I collagen degradation,23 a possible biomarker to reflect disease activity. The presence of HLA-B27 has been linked to more severe disease, higher frequency of sacroiliitis and extra-articular manifestations, and an increased likelihood of persistent arthropathy.24,25 Male gender, positive family history for SpA, and the presence of coxitis are adverse prognostic factors; such patients have a higher frequency of radiologic sacroiliitis, syndesmophyte formation, and erosive coxitis. Seven features have been identified as prognostic markers during the first 2 years of disease: hip arthritis, ESR greater than 30 mm/hr, poor response to NSAIDs, limitation of movement of the lumbar spine, dactylitis, oligoarthritis, and onset before 16 years of age. If three of these seven features are present or if the hip is involved, a poorer outcome is predicted.22,26,27

TREATMENT There are no specific or curative treatments for CIA. As with any other articular inflammatory process, therapeutic management should be aimed at control or relief of pain, prevention of joint destruction or disability, and preservation of joint function. Extra-

between groups in terms of relapse time, joint inflammation, enthesitis, and symptoms of uveitis.31 A trial with azithromycin in ReA failed to produce any effect on duration and severity of symptoms.32 However, a smaller study comparing doxycycline with doxycycline and rifampin in a randomized controlled trial showed that combination therapy was more effective in decreasing morning stiffness and joint pain.33 Overall, the question of whether or not antibiotics work for CIA has not been fully answered. Studies of large groups of patients with the appropriate antibiotics (dose and duration of therapy) need to be conducted before this question can be definitively answered. For a more severe and prolonged disease course (symptoms lasting longer than 3 months), DMARD therapy needs to be instigated.34 Sulfasalazine has been shown to be effective in a large multicenter study in patients with a chronic mean ReA duration of 10 years and lack of response to conventional therapy. Although effective for the control of peripheral joint disease, this compound does not seem to alter the course of the axial disease and enthesitis.35 The effective use of methotrexate has also been reported.36 Various other DMARDs including azathioprine, cyclosporine, leflunomide, gold, and cyclophosphamide have also been used to treat various forms of chronic ReA, but controlled clinical trials are lacking.37 The effect of biologic therapies such as TNF blockers has been examined only in small studies—initial results suggest that they may be extremely effective in the chronic forms of the condition. The use of TNF inhibitors raises a number of issues that await further resolution. TNF is a key component in host defense against infectious microorganisms, and the use of these agents in an infection-related disorder may appear paradoxical. However, initial studies have suggested at least short-term effectiveness and safety of anti-TNF agents in reactive arthritis.38-40 Until controlled trials of these agents have been performed, it is recommended that anti-TNF agents should be used only in cases refractory to conventional therapy.

References

articular manifestations should be monitored under the direction of the relevant specialist. Even though conjunctivitis typically subsides without sequelae, a slit-lamp assessment is essential to diagnose uveitis, which, if untreated, may result in irreversible visual loss. Therapy for uveitis consists of topical corticosteroids, mydriatics, and cycloplegics.22 Initial treatment focuses on pain management— most patients have a good clinical response to NSAIDs. Pain at night and morning stiffness, particularly lower back pain and enthesopathic pain, are generally sensitive to NSAIDs. Corticosteroids have only limited value for axial symptoms but are effective for peripheral arthritis. In the case of monoarthritis, intra-articular corticosteroids may be very effective. If several joints are affected, oral corticosteroids may prove useful. They should be started in a high dose (prednisone 30 to 40 mg/day) and tapered down rapidly according to clinical response. Care must be taken to exclude true septic arthritis with appropriate cultures. The use of antibiotics in CIA remains controversial. Prompt treatment of new genitourinary Chlamydia infections reduces relapses of CIA. This was clearly shown in a study from Greenland in which the incidence of postvenereal ReA relapses was significantly reduced from 37% in untreated patients to 10% following short-term treatment with erythromycin or tetracycline.28 A 3-month placebo-controlled prospective study with lymecycline in 21 patients with acute CIA showed a beneficial effect on the duration of the arthritis in the treated group: 50% of treated patients recovered by 15 weeks compared with 50% of placebotreated patients recovering at 39.5 weeks.29 This cohort of patients was reevaluated 10 years after the initial report in order to assess the natural history of the condition. The results showed that in the long term, lymecycline treatment did not change the natural history of the disease.30 A small double-blind randomized placebo-controlled trial of ciprofloxacin in the treatment of ReA and anterior uveitis found no difference

REFERENCES 1. Inman RD, Whittum-Hudson JA, Schumacher HR, Hudson AP. Chlamydia and associated arthritis. Curr Opin Rheumatol 2000;12:254-262. 2. Amor B. Reiter’s syndrome. Diagnosis and clinical features. Rheum Dis Clin North Am 1998;24: 677-695. 3. Calin A. Terminology, introduction, diagnostic criteria, and overview. In: Calin A, Taurog JD (eds). The Spondylarthritides. Oxford: Oxford University Press, 1998, pp 1-15. 4. Khan MA. Update on spondyloarthropathies. Ann Intern Med 2002;136:896-907. 5. Petersel DL, Sigal LH. Reactive arthritis. Infect Dis Clin North Am 2005;19:863-883. 6. Zeidler HK, Schumacher HR. Chlamydia-induced arthritis. In: Calin A, Taurog JD (eds). The Spondylarthritides. Oxford: Oxford University Press, 1998, pp 69-96.

7. Weidner WJ, Waddell DS, Furlow JD. Chlamydial infections and prostatitis in men. BJU Int 2006;97:687-690. 8. Black CM. Current methods of laboratory diagnosis of Chlamydia trachomatis infections. Clin Microbiol Rev 1997;10:160-184. 9. Domeika M, Bassiri M, Butrimiene I, et al. Evaluation of vaginal introital sampling as an alternative approach for the detection of genital Chlamydia trachomatis infection in women. Acta Obstet Gynecol Scand 1999;78:131-136. 10 Schillinger JA, Xu F, Sternberg MR, et al. Prevalence of Chlamydia trachomatis infection among men screened in 4 U.S. cities. Sex Transm Dis 2005;32:74-77. 11. Kuipers JG, Zeidler H, Kohler L. How does Chlamydia cause arthritis? Rheum Dis Clin North Am 2003; 29:613-629.

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160

12. Keat AC, Thomas BJ, Taylor-Robinson D, et al. Evidence of Chlamydia trachomatis infection in sexually acquired reactive arthritis. Ann Rheum Dis 1980;39:431-437. 13. Zhang X, Glogauer M, Zhu F, et al. Innate immunity and arthritis: Neutrophil Rac and toll-like receptor 4 expression define outcomes in infection-triggered arthritis. Arthritis Rheum 2005;52:1297-1304. 14. Inman RD, Chiu B. Cytokine profiles in the joint define pathogen clearance and severity in Chlamydia-induced arthritis. Arthritis Rheum 2006;54:499-507. 15. Gerard HC, Whittum-Hudson JA, Schumacher HR, Hudson AP. Synovial Chlamydia trachomatis up regulates expression of a panel of genes similar to that transcribed by Mycobacterium tuberculosis during persistent infection. Ann Rheum Dis 2006;65:321-327. 16. Kvien TK, Glennas A, Melby K, et al. Reactive arthritis: Incidence, triggering agents and clinical presentation. J Rheumatol 1994;21:115-122. 17. Wollenhaupt J, Kolbus F, Weissbrodt H, et al. Manifestations of Chlamydia induced arthritis in patients with silent versus symptomatic urogenital chlamydial infection. Clin Exp Rheumatol 1995;13:453-458. 18. Toivanen A, Toivanen P. Reactive arthritis. Best Pract Res Clin Rheumatol 2004;18:689-703. 19. Wang SP, Grayston JT, Alexander ER, et al. Simplified microimmunofluorescence test with trachoma lymphogranuloma venereum (Chlamydia trachomatis) antigen for use as a screening test for antibody. J Clin Microbiol 1975;1:250-255. 20. Paukku M, Närvänen A, Puolakkainen M, et al. Detection of Chlamydia trachomatis antibodies by 2 novel tests: rELISA and peptide EIA. Int J STD AIDS 1998;10:604-607. 21. Sieper J, Rudwaleit M, Braun J, et al. Diagnosing reactive arthritis: Role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 2002;46:319-327. 22. Colmegna I, Cuchacovich R, Espinoza LR. HLA-B27-associated reactive arthritis: Pathogenetic and clinical considerations. Clin Microbiol Rev 2004;17:348-369. 23. Kotaniemi A, Risteli J, Aho K, Hakala M. Increased type I collagen degradation correlates with disease activity in reactive arthritis. Clin Exp Rheumatol 2003;21:95-98. 24. Rich E, Hook EW 3rd, Alarcon GS, Moreland LW. Reactive arthritis in patients attending an urban sexually transmitted diseases clinic. Arthritis Rheum 1996;39:1172-1177. 25. Amor B, Santos RS, Nahal R, et al. Predictive factors for the longterm outcome of spondyloarthropathies. J Rheumatol 1994;21:1883-1887. 26. Kingsley G, Sieper J. Third International Workshop on Reactive Arthritis. 23-26 September 1995, Berlin, Germany. Report and abstracts. Ann Rheum Dis 1996;55:564-584.

27. Leirisalo M, Skylv G, Kousa M, et al. Follow up study on patients with Reiter’s disease and reactive arthritis, with special reference to HLA-B27. Arthritis Rheum 1982;25:249-259. 28. Bardin T, Enel C, Cornelis F, et al. Antibiotic treatment of venereal disease and Reiter’s syndrome in a Greenland population. Arthritis Rheum 1992;35:190-194. 29. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 1991;34:6-14. 30. Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic treatment and long term prognosis of reactive arthritis. Ann Rheum Dis 2003;62:655-658. 31. Wakefield D, McCluskey P, Verma M, et al. Ciprofloxacin treatment does not influence course or relapse rate of reactive arthritis and anterior uveitis. Arthritis Rheum 1999;42:1894-1897. 32. Kvien TK, Gaston JS, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113-1119. 33. Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol 2004;31: 1973-1980. 34. Zeidler H, Kuipers J, Kohler L. Chlamydia-induced arthritis. Curr Opin Rheumatol 2004;16:380-392. 35. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42:2325-2329. 36. Ritchlin CT, Daikh BE. Recent advances in the treatment of the seronegative spondyloarthropathies. Curr Rheumatol Rep 2001;3:399-403. 37. Creemers MC, van Riel PL, Franssen MJ, et al. Second-line treatment in seronegative spondylarthropathies. Semin Arthritis Rheum1994;24:71-81. 38. Meador R, Hsia E, Kitumnuaypong T, Schumacher HR Jr. TNF involvement and anti-TNF therapy of reactive and unclassified arthritis. Clin Exp Rheumatol 2002;20 (6 Suppl 28):S130-S134. 39. Oili KS, Niinisalo H, Korpilahde T, Virolainen J. Treatment of reactive arthritis with infliximab. Scand J Rheumatol 2003;32:122-124. 40. Flagg SD, Meador R, Hsia E, et al. Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: An open-label trial. Arthritis Rheum 2005;53:613-617.

REACTIVE ARTHRITIS

20

Synovial Immunopathology in Spondyloarthropathy Elli Kruithof and Dominique Baeten

Reactive arthritis (ReA) and psoriatic arthritis (PsA) are two diseases belonging to the spondyloarthropathy (SpA) concept, a cluster of interrelated and overlapping chronic inflammatory rheumatic diseases that are etiologically and clinically clearly distinct from other autoimmune arthritides. Entities besides ReA and PsA belonging to the concept include ankylosing spondylitis (AS), arthritis associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthropathy (USpA), and juvenile spondyloarthropathies (JSpAs). Whereas each subtype of SpA has its own characteristic clinical presentation, they all share a number of common clinical, radiologic, and genetic features. These include involvement of the axial skeleton, familial aggregation and linkage with human leukocyte antigen HLA-B27, absence of rheumatoid nodules and autoantibodies such as rheumatoid factor and anti–citrullinated protein antibodies, and the presence of extra-articular manifestations such as skin psoriasis, uveitis, and gut inflammation. One of the major articular features of SpA is peripheral synovitis, associated or not with enthesitis. Clinically, peripheral joint involvement is generally oligoarticular, asymmetric, and affects predominantly the joints of the lower limbs. Less prevalent than axial inflammation in AS, it constitutes a key feature in SpA subtypes such as ReA and PsA. In the latter condition, a broad spectrum of peripheral articular manifestations can be seen: monoarthritis, distal interphalangeal joint involvement, asymmetric pauciarticular arthritis, more symmetric polyarthritis, and dactylitis. Although PsA arthritis can become chronic and erosive, the majority of other SpA subtypes exhibit a nonerosive and selfresolving arthritis. Considering that peripheral synovitis is one of the major characteristics of ReA and PsA and that the exact pathogenesis of SpA and its subtypes is still unknown, detailed histologic and immunopathologic analysis of diseased synovium may contribute to a better understanding of the cellular and molecular pathways involved in the chronic inflammatory process in SpA. In this chapter, we first briefly review the histology of normal synovial tissue and the characteristic features

of inflamed synovium as studied essentially in rheumatoid arthritis (RA). We then describe in detail the synovial immunopathology in SpA and SpA subtypes, relate this to disease activity and severity and to response to treatment, and finally discuss the pathogenic and clinical implications.

THE NORMAL SYNOVIAL MEMBRANE The synovial membrane is a connective tissue layer about 0.5 to 5 mm thick that covers the inner surface of joints, tendon sheaths, and bursae. Synovium supports normal joint functioning in different physiologic ways: (1) by providing an unobtrusive, smooth, lowfriction lining; (2) by transporting necessary nutrients into the joint and removing metabolic degradation products; (3) by playing a role in maintaining joint stability; and (4) by providing lubricants. Macroscopic evaluation of the synovial tissue surface in healthy individuals shows few blood vessels with a straight pattern and this in the absence of any synovial hypertrophic changes. At the microscopic level, normal synovium comprises a synovial or intimal lining layer and a synovial sublining layer compartment. The synovial lining layer delineates the joint cavity and is composed of one or two cell layers of synoviocytes, embedded in a specialized extracellular matrix. On the basis of their morphology, their expression of surface cell markers, protein synthesis pattern, and function, two distinct cell types can be distinguished. The type A synoviocytes or macrophage-like synoviocytes are derived from monocytic cells of the bone marrow and contain a prominent Golgi apparatus and numerous endocytic vacuoles. They express various cell surface macrophage markers (CD11b, CD14, CD33, CD68) and have the capacity to phagocyte and to present antigens in the context of major histocompatibility complex (MHC) class II. In addition, they express intercellular adhesion molecule 1 (ICAM-1) and CD97, the latter constituting a ligand for CD55. The type B synoviocytes or fibroblast-like synoviocytes are of mesenchymal origin and demonstrate a prominent rough endoplasmic endoreticulum as well as an

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SYNOVIAL IMMUNOPATHOLOGY IN SPONDYLOARTHROPATHY

active Golgi apparatus. The presence of a high uridine diphosphoglucose dehydrogenase (UDPGD) activity in these cells enables them to synthesize matrix molecules such as hyaluronic acid, collagen, and fibronectin. Their expression of the integrin α6β1 differentiates these synovial fibroblasts from other types of fibroblasts and facilitates their anchorage by interaction with the matrix ligand laminin. Synovial fibroblasts express decay-accelerating factor (DAF, CD55) and vascular cell adhesion molecule 1 (VCAM-1) at high levels. Both types of synoviocytes interact with each other by means of the CD97/CD55 receptor-ligand system as well as the α4β1 or very late antigen 4 (VLA-4)/VCAM1 system. The synovial sublining layer consists of loose connective tissue containing few cells—mostly fibroblasts, some macrophages, and adipocytes—as well as some scattered blood vessels. Because the lining and sublining layer are not separated by a basement membrane, both are in contact with the synovial fluid. In normal synovial tissue, sublining fibroblasts appear to be less specialized than those of the lining layer because they lack expression of UDPGD, VCAM-1, and DAF.

THE INFLAMED SYNOVIUM

162

Inflamed synovium is characterized by an increased number of blood vessels in the sublining, which express cell adhesion molecules. Blood vessel growth as such is likely to contribute to the proliferation of the inflammatory synovial pannus as well as to the ingress of inflammatory cells into synovium. Angiogenesis is carefully balanced both by inducers and inhibitors. In RA, a number of proangiogenic factors (vascular endothelial growth factor [VEGF], transforming growth factor β [TGF-β], basic fibroblast growth factor, hepatocyte growth factor, platelet-derived growth factor, tumor necrosis factor α [TNF-α], interleukin 8 [IL-8], fractalkine, IL-18, IL-1, soluble E-selectin, soluble VCAM-1, soluble CD146, the angiopoietin-Tie system) as well as angiogenic inhibitors (angiostatin, endostatin, thrombospondin, TGF-β, TNF-α, interferon γ [IFN-γ], tissue inhibitor of matrix metalloproteinase 1 [TIMP-1], TIMP-2, IL-4) have been identified to interact. In addition, endothelial activation with increased expression of E-selectin, ICAM-1, and platelet/endothelial cell adhesion molecule 1 (PECAM-1) and also increased expression of chemotactic factors (IL-8, monocyte chemoattractant protein 1 [MCP-1], regulated upon activation, normal T cell expressed and secreted [RANTES]) may contribute to an increased influx of inflammatory cells in the sublining layer. The synovial sublining of inflammatory arthritis is characterized by pronounced cellular infiltration with

T cells, B cells, plasma cells, macrophages, and to a lesser extent natural killer (NK) cells, dendritic cells, and mast cells. Polymorphonuclear cells are relatively scarce in synovium and seem to accumulate in synovial fluid. In rheumatoid synovium, the lymphocyte population mainly consists of CD4+ memory T cells. Differentiation in situ from CD27+ to CD27− memory T helper (Th) cells and the low expression of proliferation markers suggest that these cells infiltrate from the peripheral blood and mature in situ rather than proliferate locally. Two patterns of T-cell infiltration have been described: (1) perivascular lymphocyte aggregates (44%), sometimes forming lymphoid follicles with germinal centers, and (2) diffuse lymphocytic infiltrates (56%). CD8+ T cells, although less prominent, are considered to play a crucial role in structural integrity and functional activity of germinal centers in ectopic lymphoid follicles. B cells, the majority memory cells, are mainly located in lymphoid aggregates and are found in close association with CD4+ T cells. Follicular dendritic cells are considered to regulate Bcell accumulation by stimulatory effects on migration and proliferation and by inhibition of apoptosis. They also play a role in isotype switching and the final differentiation of B cells toward plasma cells. The latter are able to produce immunoglobulins, such as rheumatoid factor. Interdigitating dendritic cells constitute potent antigen-presenting cells, which are detected in the vicinity of CD4+ cells in perivascular aggregates and near the synovial lining layer. Activated NK cells have also been detected, by means of functional markers such as granzymes, which are present in specialized granules of NK cells as well as cytotoxic T cells. Macrophage infiltration represents another prominent feature of the inflamed synovial sublining layer. By their production of pro-inflammatory cytokines such as TNF-α, IL-1, IL-12, IL-15, and IL18, they add to the inflammatory cascade through their effect on blood vessel formation, inflammatory cell infiltration, proliferative impulse on type B synoviocytes, and enhancement of mediators of tissue destruction. Synovial lining layer hyperplasia (increased thickness of 3 to more than 10 cell layers) is another hallmark of inflamed synovium. Several factors are likely to contribute: (1) accumulation of type A synoviocytes (accounts for up to 80% in the thickened lining layer) through influx of bone marrow–derived monocytes that pass through endothelial cells and enter the sublining layer; (2) in situ proliferation of fibroblast-like synoviocytes induced by macrophage-derived inflammatory mediators such as TNF-α, resulting in an increase of type B synoviocytes (this mechanism is still under debate considering the restricted staining with the cell proliferation marker Ki67); and (3) impaired apoptosis

COMPARATIVE SYNOVIAL HISTOPATHOLOGY IN SPONDYLOARTHROPATHY Early reports comparing SpA and RA synovium have suggested that the alterations observed in inflamed RA synovium (synovial lining hyperplasia, hypervascularity, and inflammatory infiltration) are equally observed in other types of chronic arthritis and especially in SpA. However, most of these studies used surgical samples obtained in end-stage and destructive disease, in which active joint inflammation has often regressed. Moreover, these studies were largely restricted to a global morphologic evaluation without detailed quantification of the synovial features and without further characterization by immunohisto-

chemistry and other new molecular tools. In contrast, a number of studies have obtained clinically relevant synovial biopsy specimens from actively inflamed joints and analyzed these qualitatively and quantitatively by immunohistochemistry. These studies indicated clearly that a number of synovial features are differentially expressed between SpA and RA (Table 20-1 and Fig. 20-1).1 The synovial lining layer is hyperplastic in SpA, reaching three to five cell layers rather than the one or two in normal synovium. However, in comparison with RA, the synovial hyperplasia seems less pronounced in SpA, even in samples with a similar degree of global inflammation.2-5 This suggests that, although inflammation may contribute to this feature, different mechanisms may be active in both diseases. First, thickening of the synovial lining layer may result from an increased influx of CD68+ myeloid cells differentiating to type A synoviocytes. A detailed comparative analysis of infiltrating monocytes using myeloidrelated protein 8 (MRP8) and MRP14 as markers has indicated that this influx is slightly less pronounced in SpA than in RA, although these cells are found in both pathologies.6 Second, a relative decrease in apoptosis of lining synoviocytes may also contribute to lining layer hyperplasia. Although there are no marked differences in the number and type of apoptotic lining cells in RA, PsA, and ReA, some qualitative differences were noted with clustering of apoptotic cells in RA.7 Finally, lining hyperplasia may be related to local proliferation and, eventually, autonomous growth of type B synoviocytes. Indeed, a clear increase of Ki67-positive synovial fibroblasts was observed in inflammatory arthritis, with a trend toward higher expression in RA than in SpA subtypes.8 This increased proliferation in RA might be related to pseudotumoral growth related to mutations of oncogenes and tumor suppressor genes such as p53, which were not evident in SpA.9 Although the differences between SpA and RA for the described mechanisms (influx of myeloid cells, decreased apoptosis, and local proliferation of type B synoviocytes) are relatively small, it should be considered that the cross-sectionally observed difference in lining layer hyperplasia is the cumulative result of these three mechanisms over a period of several weeks or months. An important issue here is whether only lining thickness or also the function of synovial lining cells is different between both diseases, especially with regard to the potential role of these cells in invasion and destruction of cartilage. Functional differences are suggested by the differential expression of αVβ3, an integrin involved in proliferation and invasion, on the lining layer in SpA versus RA.10 Similarly, higher levels of synovial fluid sCD97 in RA compared with ReA may

Comparative Synovial Histopathology in Spondyloarthropathy

of type B synoviocytes as a result of mutations in the p53 tumor suppressor gene and the expression of antiapoptotic molecules such as sentrin. Together with angiogenesis and inflammatory infiltration, this leads to aggressive pannus formation, with so-called pannocytes. These pannocytes are considered to play a major role in mediating cartilage and bone destruction by adhering at the surface of articular cartilage and producing mediators of degradation and tissue destruction, including matrix metalloproteinases (MMPs). Moreover, at the pannus-bone interface in bone resorption lacunae, multinucleated osteoclasts exhibiting the calcitonin receptor and tartrate-resistant alkaline phosphatase can be detected. Synovial fibroblasts and activated CD4+ T cells contribute to the transformation of peripheral blood mononuclear cells into osteoclasts by expressing osteoclast differentiation factor. It needs to be emphasized that almost all data available and described in the preceding paragraphs were obtained in patients with RA. Some of these studies included a limited number of osteoarthritis samples, but it is unclear how far this mainly degenerative disease represents a good control for a chronic autoimmune disorder. Of particular interest to our topic, only few data are available in the second most frequent form of chronic autoimmune arthritis, SpA, and the available data are mostly restricted to limited numbers of samples and a single SpA subtype. A number of different strategies can be used to assess clinically and pathophysiologically relevant features of synovial immunopathology in SpA: (1) comparison with another type of chronic inflammatory arthritis, in this case RA; (2) analysis of specific clinical phenotypes such as the different SpA subtypes; (3) correlation with parameters of global disease activity and severity; and (4) comparison of paired synovial samples from the same patient obtained at two or more time points, for example, before and after a therapeutic intervention.

163

SYNOVIAL IMMUNOPATHOLOGY IN SPONDYLOARTHROPATHY

TABLE 20-1 IMMUNOPATHOLOGIC FEATURES OF THE INFLAMED SYNOVIAL MEMBRANE IN SPONDYLOARTHROPATHY (SPA) COMPARED WITH RHEUMATOID ARTHRITIS (RA) AND IN THE DIFFERENT SPA SUBTYPES* Feature2-5

RA

All SpA Subtypes

PsA

ReA

AS/USpA

5-10 cell layers

3-5 cell layers

3-5 cell layers

3-5 cell layers

3-5 cell layers

Infiltrating monocytes

++

+

+

Not investigated

+

Impaired apoptosis7

+/−

Not investigated

+/−

+/−

Not investigated

++

Not investigated

+

+

Not investigated

++

++

++

+

++

Lining layer thickness 6,17

In situ proliferation8 3-5,10

Inflammatory infiltration

++

+

+

+

+

T cytotoxic cells1,3-5,10

+

+/−

+/−

+/−

+/−

Activated T cells13

++

+/−

Not investigated

Not investigated

Not investigated

B cells1,3-5,10

+

+/−

+/−

+/−

+/−

Plasma cells1,3-5,10

+

+/−

+/−

+/−

+/−

++

++

++

++

++

+

+++

+++

Not investigated

+++

Infiltrating monocytes

+

+

+

Not investigated

+

Polymorphonuclear cells3-5

+/−

+

++

Not investigated

+

+

+/−

+/−

Not investigated

+

+/−

+/−

Not investigated

+/−

T helper cells

3-5,10

1-5,13,14

Macrophages

Resident macrophages

4,5,13,14

6,17

Dendritic cells

3-5,14

Perivascular aggregates Macroscopic vascularity

+

+++

+++

+++

+++

Macroscopic pattern3,10-12

Straight

Tortuous

Tortuous

Tortuous

Tortuous

++

+++

+++

+++

+++

+

Not investigated

++

Not investigated

Not investigated

ICAM-1

+

+

+

Not investigated

+

VCAM-15

+

+

+

Not investigated

+

+

+

+/−

Not investigated

+

High

Low

Not investigated

Low

Not investigated

++

+

+

+

+

+++

Not investigated

++

Not investigated

Not investigated

3,10,12

2-5,10

Microscopic vascularity Neoangiogenesis

11,14

5

2,5

E-selectin

Th1/Th2 ratio

12,15

IFN-γ+ cells12,15 TNF-α, IL-15

18

++

Not investigated

++

+++

Not investigated

MMP/TIMP20,21,23

++

++

++

Not investigated

++

RANKL expression38

++

++

++

++

++

+

++

++

++

++

Toll-like receptors 2 and 4

+

++

++

Not investigated

Bacterial and viral DNA19

+

+

Not investigated +

+

Intracellular citrul. proteins38

+++

−

−

Not investigated

−

39

+++

−

−

Not investigated

−

IL-10

18

OPG expression

39 37

MHC/HC gp-39 complexes

++

*

Psoriatic arthritis (PsA), reactive arthritis (ReA), and ankylosing spondylitis (AS)/undifferentiated SpA (USpA). The features include description of the changes in lining layer, sublining inflammatory infiltration, vascularity, cytokine patterns, mediators of tissue destruction, innate immunity, and autoantigens. The corresponding references are indicated in superscripts.

164

ICAM-1, intercellular adhesion molecule 1; IL-10, interleukin 10; MHC/HC, major histocompatibility complex/heavy chain; MMP, matrix metalloproteinase; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor κB ligand; Th1, T helper 1; TIMP, tissue inhibitor of MMP; VCAM-1, vascular cell adhesion molecule 1.

RA

Lining layer hyperplasia

Vascularity

Granulocytes

CD163

TLR2

Figure 20-1. Synovial immunopathology in spondyloarthropathy (SpA) compared with rheumatoid arthritis (RA). The most striking differences are the increased lining layer hyperplasia in RA, the higher degree of vascularity in SpA, the marked infiltration with granulocytes and CD163+ macrophages in SpA, and the higher expression of Toll-like receptors (TLRs) such as TLR2 in SpA. See also Color Plate.

point to an altered functional behavior of lining cells because the CD97/CD55 receptor-ligand system expressed on lining macrophages and lining fibroblasts, respectively, contributes to the specific architecture of the intimal lining layer. However, further phenotypic and functional characterization of lining synoviocytes in SpA is required to address this issue in more detail. Hypervascularity is a second feature that is observed in both SpA and RA synovial tissue samples. However, a consistent finding in almost all studies on SpA synovium is that this hypervascularity is more pronounced in SpA than in RA.2-5,10 This difference is not related to inflammation as such because this was observed in synovial tissue with similar levels of inflammatory infiltration and the marked hypervascularity can also be observed in SpA samples with few or no inflammatory changes. Moreover, this is associated at the macroscopic level with a specific morphology of the blood vessels with a predominance of a tortuous vessel pattern in SpA.3,10-12

Two questions are raised by this observation: which mechanisms lead to this hypervascularity in SpA, and how does it contribute to the pathogenesis of the disease? Several factors contributing to the process of increased angiogenesis in SpA have been identified. Synovial fluid levels of growth factors implicated in angiogenesis such as VEGF, MMP-9, and TGF-β were higher in early PsA than in early RA.11 Also, the expression in the synovial membrane of VEGF and MMP-9 was higher in PsA.11 In addition, high synovial coexpression of angiopoietin 2 (ANG-2)—a vascular growth factor implicated in vessel sprouting—and VEGF has been observed in perivascular regions in patients with early PsA, suggesting a primary shift toward angiogenesis in comparison with early RA. The fact that these observations were made at an early stage of inflammation further emphasizes the potential importance of these factors and the need for a more detailed mechanistic analysis of angiogenesis in SpA. As to the potential role of hypervascularity in SpA inflammation, it is interesting to note that this feature is associated with specific endothelial activation and increased expression of vascular adhesion molecules such as ICAM-1, VCAM-1, and Eselectin.5 The expression of these adhesion molecules on endothelium as well as of selected ligands on inflammatory cells may contribute to specific recruitment of inflammatory cells to the synovium, as indicated for P-selectin for gut-derived macrophages and for vascular adhesion protein 1 for intestinal lymphocytes and immunoblasts. However, the global hypervascularity and endothelial activation is also likely to play a role in nonspecific recruitment of inflammatory leukocytes to the inflamed synovium and may thereby perpetuate or enhance the local immunopathology. The global inflammatory cell infiltration in SpA synovium is roughly similar to what can be observed in RA synovium in terms of number of infiltrating cells.3-5,10 Morphologic analysis indicates that most of these cells are mononuclear cells of lymphocytic or myeloid origin in both diseases, but surprisingly the number of polymorphonuclear cells is increased in SpA and PsA synovium.3-5 This specific infiltration with polymorphonuclear cells may be related to increased levels of chemokines such as IL-8 in SpA synovium. More detailed immunohistochemical analysis of lymphocytic cells within the inflammatory infiltrate shows a tendency toward lower numbers of T and B cells, including plasma cells, in SpA compared with RA,1,3-5,10,12 although this was not confirmed in all studies.2,13 These cells are mostly organized as a diffuse infiltrate, but follicular aggregates can sometimes be observed. Preliminary studies tend to indicate that these follicular structures are less frequently observed in SpA than in RA.3-5 Accordingly, a relative scarcity of follicular CD1a+ dendritic cells has been

Comparative Synovial Histopathology in Spondyloarthropathy

SpA

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observed in most but not all studies on SpA synovium.3-5,14 These issues need to be confirmed by more detailed analyses, including the presence of follicular dendritic cells, chemokines such as CCL19 and CCL21, and T-cell clonality. Qualitative comparison between synovial lymphocytes in SpA and RA indicates a reduced level of Tcell activation as assessed by CD69 expression in SpA, which is related to higher local expression of CD163.13 At the cytokine level, IFN-γ+ cells are less frequently observed in SpA, leading to a fivefold difference in Th1/Th2 ratio in comparison with RA.12,15 These synovial data are in agreement with the cytokine profile of peripheral blood and gut lymphocytes in SpA. Collectively, these data indicate that the synovial lymphocyte infiltration is quantitatively similar or slightly reduced in SpA versus RA but that there are important qualitative differences with reduced activation and production of Th1 cytokines in SpA. As to the myeloid cells in SpA synovitis, a slightly reduced1,2 to comparable3-5,13,14 total number of macrophages as assessed by the panmacrophage marker CD68 is observed in SpA versus RA. Of interest, however, a specific subset of macrophages expressing the scavenger receptor CD163 is selectively increased in both the lining and sublining layer of SpA synovium,4,5,13,14 whereas a relative decrease of infiltrating macrophages expressing MRP8 and MRP14 is noted in the lining layer.6 Several pathways connect the CD163+ macrophage subset to inflammation in SpA: (1) CD163+ macrophages are also increased in noninflamed gut of patients with SpA, underscoring the link between gut and joint in this disease; (2) the synovial presence of CD163+ cells is more pronounced in HLAB27–positive than HLA-B27–negative SpA patients, indicating a possible link with the genetic background; (3) as indicated before, synovial CD163+ macrophages are able to produce locally soluble CD163, which can affect T-cell activation; and (4) CD163+ macrophages produce large amounts of pro-inflammatory cytokines such as TNF-α but not anti-inflammatory factors such as IL-10.13,14 In contrast to the synovial lymphocytes, there are thus clear alterations of macrophage-related pathways of inflammation in SpA synovitis. Beside the previously mentioned data on polymorphonuclear cells and dendritic cells, few or no data are available on synovial infiltration in SpA with other cell types such as NK cells, NK-T cells, mast cells, and regulatory T cells.

SYNOVIAL IMMUNOPATHOLOGY OF SPONDYLOARTHROPATHY SUBTYPES 166

Up to now, we have considered SpA as a single disease in comparison with RA. This approach is based on the concept that all different SpA subtypes share a

number of common clinical, radiologic, and genetic characteristics. On the other hand, each SpA subtype has its own phenotype and presentation, and it cannot be assumed a priori that the synovial immunopathology is identical in all these subtypes. Although this can be fully addressed only by a systematic and direct comparison of the subtypes in a single study, most available data on synovial immunopathology in specific SpA subtypes are from studies comparing one SpA subtype with RA. Despite this limitation, it appears that the findings obtained in these subgroups versus RA are globally very similar to what we described in SpA as a whole versus RA (see Table 20-1 and Fig. 20-1). Two subtypes have been studied in more detail: PsA and ReA. Although PsA is probably the best-studied SpA subtype and displays all the major features of SpA synovitis (as reviewed in Chapter 10), a number of studies have focused specifically on ReA. Although ReA is not the most common subtype of SpA, it is interesting from a pathogenetic viewpoint because of the clear relationship between an infectious trigger in the gut or urogenital tract and the development of a chronic autoimmune arthritis. Systematic comparison with RA and PsA shows that the synovial lining layer hyperplasia is less prominent than in RA, whereas the hypervascularity is increased both microscopically and macroscopically.7,8 In one study, the global inflammatory infiltration appeared to be less pronounced in ReA than in RA, which was reflected by lower numbers of lymphocytes and plasma cells.12 However, these data need to be confirmed in a separate cohort to exclude a bias related to differences in disease activity. Considering the possible role of bacterial persistence in the pathogenesis of ReA, it is interesting to note that, as in other SpA subtypes, the number of IFN-γ–producing cells is low in ReA,12 leading to an impaired Th1/Th2 balance. IL-15 and TNF-α appear to be reduced, in contrast to IL-10 and TGF-β, which are expressed at higher levels in ReA than in RA. Finally, a major issue with regard to ReA is the presence of bacteria or bacterial antigens, or both, in the affected joints. With the exception of Chlamydia, there is at present no evidence for viable microbes in the inflamed synovium in ReA. However, bacterial DNA is found in the synovial tissue of a majority of patients with SpA but also in a considerable proportion of patients with undifferentiated arthritis.16 Similar observations were made for viral DNA. Collectively, these data question the specificity of these findings for ReA and thus the role of persisting bacterial infection in the pathogenesis of this condition. This interpretation is further supported by the lack of efficacy of long-term treatment with antibiotic drugs.

Besides a systematic comparison with other types of chronic autoimmune arthritis in search of disease-specific rather than inflammation-related synovial features in SpA, the pathophysiologic relevance of cellular and molecular mediators in SpA synovitis can be assessed by correlating these features with parameters of local and systemic disease activity and severity. A first important observation here is that, as in RA, there is an important effect of local disease activity on synovial immunopathology. Comparison of synovial tissue obtained from SpA knee joints with and without clinical synovitis indicates higher scores for almost all synovial features in the former group.10 More important, the previously described differences in histopathology between SpA and RA were found in the samples obtained from clinically involved joints, but no difference was noted between both pathologies in the clinically uninvolved joints. These data parallel previous observations in RA and emphasize the importance of sampling actively involved joints. In this context, this observation is also a warning about potential biases when analyzing samples of end-stage disease obtained during joint replacement surgery. Whereas the correlation between synovial immunopathology and local disease activity is not unexpected, it is more surprising to see that in this oligoarticular disease there is also a link with systemic disease activity. The first observation was the correlation between the number of macrophages expressing CD163 in the synovial sublining layer and the parameters of systemic inflammation such as C-reactive protein serum levels and the erythrocyte sedimentation rate.14 In a followup study analyzing a large panel of synovial features, the link between CD163+ macrophages and global disease activity was confirmed, with similar findings for the polymorphonuclear cells.4 Of interest, there was no association between global disease activity and degree of vascularity or infiltration with other cell types such as lymphocytes. The specificity of the findings was further emphasized by the fact that CD163+ macrophages and polymorphonuclear cells did not correlate with disease activity parameters in a similar analysis of a panel of RA samples. Taken together with the selective increase of CD163+ macrophages and granulocytes in SpA synovium versus RA synovium, this link with global disease activity further supports the hypothesis that these innate immune cells may be important players in the pathogenesis of SpA synovitis. Along the same line, the in vivo relevance of specific immunopathologic features can be tested by relating them to disease severity rather than disease activity, with special attention to structural damage of soft tis-

sues, cartilage, and bone. Most studies addressing this issue have been restricted to the PsA subtype, probably because, in contrast to diffuse cartilage loss, focal bone erosions are not so common in other SpA subtypes. These studies can be further subdivided into analyses of proteases important in cartilage as well as bone degradation and studies on osteoclasts, which are primarily required for resorption of mineralized bone. An important family of proteases are the matrix metalloproteinases including MMP-1 and MMP-3. The expression of both MMPs is similar in PsA synovium and RA synovium, even when radiologic erosions are more pronounced in the RA group.17,18 There is also no difference in the expression of these MMPs between synovial tissue close to the cartilagepannus junction and samples obtained at a distance from this junction.18 Accordingly, the production of these mediators can be equally induced by in vitro stimulation of synovial fibroblasts from both PsA and RA samples. Of interest, MMP-1 as well as TNF-α levels correlate with collagen degradation in early PsA and RA.19 Extending these data to other SpA subtypes, a large comparative study showed that MMP-1, -2, -3, and -9 as well as TIMP-1 and -2 are equally expressed in different SpA subtypes and in RA.20 Of interest, the expression levels of these proteases correlate with synovial vascularization, cellular infiltration, and markers of cartilage degradation, suggesting active involvement of these molecules in SpA synovitis. Serum MMP-3 levels originate almost exclusively from the inflamed joint and are a good reflection of peripheral synovitis but not of axial inflammation. The active involvement of MMPs in peripheral synovitis in SpA raises the question of whether therapeutic modulation of synovial MMP expression could contribute to slow down or arrest structural damage and whether serum MMP-3 may be a valuable biomarker to assess the efficacy of such treatments. Finally, it should be noted that not only MMPs and their inhibitors but also other proteases such as cathepsins and granzymes are equally increased in SpA and in RA synovitis and may contribute to tissue destruction.17 Finally, an important and specific aspect of disease severity in SpA is that the structural changes are dominated not only by tissue destruction but also by new bone formation. Although of major interest, few data are available on this topic. It was demonstrated that bone morphogenetic proteins (BMPs) 2 and 6 are found in inflamed SpA synovium as well as RA synovium.21 These BMPs are involved in regulating synovial fibroblast apoptosis but experimental data also indicate their role in new bone formation, which can lead to partial healing as well as to ankylosis.22 Therefore, further characterization of these mediators

Relation with Disease Activity and Severity

RELATION WITH DISEASE ACTIVITY AND SEVERITY

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ments such as TNF-α blockade to analyze in depth the local immunomodulation by effective treatment (Table 20-2 and Fig. 20-2). A first major observation is that the global inflammatory infiltration is significantly reduced upon treatment with infliximab. Studies including patients with different SpA subtypes demonstrated that especially infiltrating polymorphonuclear cells and MRP8-positive monocytes were rapidly reduced 1 or 2 weeks after the first infusion.6,23,24 This trend was further confirmed at week 12 after three infusions, when not only infiltrating monocytes and granulocytes but also resident macrophages (CD163+) and T lymphocytes were significantly reduced.6,14,23,24 Surprisingly, the synovial infiltration with B cells and plasma cells was not reduced upon treatment and the presence of plasma cells was even augmented in single cases. Downregulation of the number of CD68+ macrophages and T cells with

in SpA synovium could be of major importance for both our understanding of the disease process and the design of new therapeutic approaches.

MODULATION OF SYNOVIAL IMMUNOPATHOLOGY BY TREATMENT Synovial biopsy sampling by needle arthroscopy facilitates the study of actively involved synovial tissue but also allows serial sampling in an individual patient and thus paired analysis of the effects of therapeutic interventions. In RA, this approach of sequential synovial tissue analysis has proved to be a powerful tool not only for confirming clinical effects on peripheral synovitis but also for providing insights into local immunomodulatory effects of the evaluated drugs. Translating this approach to SpA, several studies have taken advantage of the emergence of biologic treat-

TABLE 20-2 EFFECT OF TREATMENT ON SYNOVIAL IMMUNOPATHOLOGY IN SPONDYLOARTHROPATHY.

168

Feature

Infliximab29,30-32,34

Etanercept35

Methotrexate17,41

Alefacept36

rhIL-1037

Inflammatory infiltration

SpA

SpA

PsA

PsA

PsA

↓↓↓

↓↓↓

↓↓

↓

Not investigated

T cells

↓↓

↓↓

↓

↓↓

↓ (CD8 unchanged)

B cells

≅

≅

Not investigated

Not investigated

Not investigated

Plasma cells

≅ or ↑

≅

Not investigated

Not investigated

Not investigated

Macrophages

↓↓

↓↓

↓

↓

↓

Resident tissue macrophages

↓

↓↓

Not investigated

Not investigated

Not investigated

Infiltrating monocytes ↓↓↓

↓↓↓

↓

Not investigated

Not investigated

Polymorphonuclear cells

↓↓↓

↓↓↓

Not investigated

Not investigated

Not investigated

Cellular aggregates

↓

≅

Not investigated

Not investigated

Not investigated

Vascularity

↓

↓

≅

Not investigated

↓

Neovascularization

↓

↓

Not investigated

Not investigated

↓

Adhesion molecules

↓↓

↓↓

↓

Not investigated

Not investigated

Lining layer hyperplasia

↓

↓

↓

Not investigated

Not investigated

MMP/TIMP

↓↓↓

↓↓↓

↓↓

Not investigated

Not investigated

Toll-like receptors 2 and 4

↓↓

↓↓

Not investigated

Not investigated

Not investigated

Synovial cytokines

Not investigated

Not investigated ↓ (>IL-8)

Not investigated

Not investigated

* The studies were done either in different spondyloarthropathy (SpA) subtypes, as for infliximab and etanercept, or exclusively in the psoriatic arthritis (PsA) subtype, as for methotrexate, alefacept, and human recombinant interleukin 10 (rhIL-10). Corresponding references are indicated in superscripts.

MMP, matrix metalloproteinase; TIMP, tissue inhibitor of MMP.

Post-treatment

T cells

B cells

Macrophages

MMP3

Vascularity

Figure 20-2. Effect of treatment with tumor necrosis factor α blockers on synovial immunopathology in spondyloarthropathy. Treatment with etanercept resulted in a marked decrease of the inflammatory infiltration of most cell types, including T lymphocytes and macrophages, but not of B lymphocytes and plasma cells. This was paralleled by a downregulation of mediators of matrix degradation, such as matrix metalloproteinase 3 (MMP3), resulting in structural remodeling of the synovium including a decrease of the synovial vascularity. Similar results were obtained with infliximab. See also Color Plate.

unchanged numbers of B cells and plasma cells was furthermore confirmed in two studies investigating the effect of infliximab in PsA patients.25,26 Although the underlying mechanisms and the exact biologic meaning of this phenomenon are still unclear, it indicates that either B cells but not other cell types continue to infiltrate the synovium or that these cells proliferate and differentiate locally upon infliximab treatment. Interestingly, this phenomenon is completely uncoupled from clinical or histologic inflammation, indicating that these B cells and plasma cells are probably not primary players in the synovial immunopathology or may even have an anti-inflammatory role. This should also be interpreted in the context of other signs of de novo B-cell activation upon treatment with infliximab, such as the impressive induction of anti-nuclear anti-

bodies and immunoglobulin M (IgM) anti–double stranded DNA antibodies.27 Further investigation of the exact effects of TNF-α blockade on B-cell biology is warranted. The decrease of the cellular infiltration upon infliximab treatment could be due to either a reduced influx of inflammatory leukocytes or an increased local apoptosis of these cells. The fact that the number of infiltrating MRP8+ and MRP14+ monocytes is reduced more profoundly and more rapidly than the number of CD163+ resident tissue macrophages in synovium, together with the early and significant decrease of serum MRP8/MRP14 levels in contrast to the sCD163 levels, strongly suggests a primary effect on inflammatory cell recruitment into the inflamed tissue by TNFα blockade.6 This hypothesis is further confirmed by the effect of infliximab on endothelial activation and expression of vascular adhesion molecules,23,24,28 which coincided with a decrease of the soluble adhesion molecules ICAM-1 and E-selectin in serum. The reduction of endothelial activation is likely to restrain the migration and homing of inflammatory cells into the synovial membrane. As to the contribution of local cell death, it has been demonstrated that apoptosis of activated lymphocytes and macrophages is likely to play a major role in the immunomodulating effect of infliximab in Crohn’s disease, but the available data on RA synovial tissue are conflicting and do not allow any definite conclusion at this point. In SpA, no data are yet available with the exception of one study in PsA. Goedkoop and colleagues evaluated the effect of infliximab on skin biopsies of lesional epidermis and synovial biopsies of patients with PsA. In both skin and synovium, the decrease in T cells and macrophages, observed 48 hours after infliximab administration, could not be explained by induction of apoptosis at the site of inflammation.26 Studies on the induction of apoptosis in SpA synovium by TNF-α blockers are ongoing and should further clarify this issue. Besides the effect on inflammatory infiltration, a second major observation is that infliximab has a profound effect on structural features. First, the hypervascularity—considered one of the hallmarks of SpA synovitis with a distinct vessel morphology and growth factor expression—was also reduced after infliximab therapy. Besides a decrease in the number of vessels and the expression of the endothelial cell markers CD146 and von Willebrand factor, markers of neovascularization such as αVβ3 integrin, angiogenic factors such as synovial MMP-9, and adhesion molecules were downregulated.20,23,24,29 In PsA, a decrease of the synovial expression of VEGF and its receptor VEGFR2 (KDR/flk-1) was noted together with an increase of ANG-2.25 Although ANG-2 is an initiator of angiogenesis in the presence of VEGF, this

Modulation of Synovial Immunopathology by Treatment

Pre-treatment

169

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170

angiopoietin becomes essential for vascular regression when VEGF is downregulated. The increase of the ANG-2/VEGF ratio could in part explain the consistent reduction of synovial neovascularization.25 Second, lining layer hyperplasia in SpA is reduced upon infliximab treatment.23,24 As for sublining inflammatory infiltration, there is some evidence that this is at least in part mediated by a reduced influx of myeloid cells,6 but the contribution of local apoptosis or specific effects on lining layer fibroblasts deserve further attention. Also here it is important to investigate whether this is merely a structural feature or is associated with a modulation of the function of the lining layer synoviocytes, particularly in relation to aggressive behavior and contribution to cartilage and bone degradation. In this context, a report indicates that the increased expression of MMPs in the synovial lining as well as sublining layer of SpA synovium is rapidly and profoundly downregulated by infliximab treatment.20 Although large-scale, longitudinal studies are required to link this to a modulation of the progression of structural damage, these data at least suggest that TNF-α blockade could also inhibit tissue degradation in SpA. A similar suggestion is provided by the previously mentioned study on osteoclast precursor cells in PsA: anti–TNF-α antibodies inhibit the differentiation of these cells to osteoclasts in vitro, but anti–TNF-α treatment in vivo also reduces significantly the number of circulating osteoclast precursor cells in PsA patients.30 The influence of TNF-α blockade on the different cellular and molecular mechanisms involved in tissue destruction and remodeling in SpA is probably one of the most challenging questions to be addressed in the coming years. All the previously mentioned studies have been performed with the monoclonal anti–TNF-α antibody infliximab. Of interest, studies with the soluble TNFα receptor etanercept have shown similar clinical efficacy in different SpA subtypes. This is clearly different from the findings in Crohn’s disease, which indicate that the different TNF-α blockers can have distinct effects on specific disease manifestations. Considering the strong relationship between Crohn’s disease and SpA and between gut and joint inflammation in SpA, the effect of etanercept treatment on synovial immunopathology in SpA was investigated and compared with previously obtained results with infliximab. In contrast to gut inflammation in Crohn’s disease, the effects of etanercept and infliximab on synovium were quantitatively and qualitatively almost indistinguishable in SpA.29 The modulation of inflammatory infiltration, including the absence of decrease of synovial B lymphocytes and plasma cells; of synovial tissue microarchitecture; and of MMP expression was largely similar. The study evaluating

etanercept included a third biopsy at 52 weeks showing that the anti-inflammatory effect is maintained or even augmented in the long term and is associated with structural remodeling of the synovial tissue. Radiologic follow-up demonstrated that in cases with aggressive structural damage, no progression is observed over a 2-year period. Some minor synovial differences between the two drugs were noted. First, infliximab but not etanercept appeared to interfere with synovial follicular organization, which might be related to the fact that membranebound rather than soluble TNF/lymphotoxin is important for this process and that infliximab may be more potent than etanercept for the neutralization of membrane-bound TNF-α. Second, etanercept induced a strong reduction of infiltrating MRP8+ and MRP14+ monocytes in the synovial membrane but had no effect on serum MRP8/MRP14 levels, whereas both parameters were downregulated by infliximab. This phenomenon may suggest ongoing tissue inflammation at other disease localizations in the etanercept-treated patients because serum MRP8/MRP14 only partially originates from the inflamed joints.6,29 Studies exploring in more detail the previously mentioned differential effect on membrane-bound TNF-α and, subsequently, induction of apoptosis of activated T lymphocytes and monocytes of both drugs would be of great interest. In addition, given the gut-joint link in SpA, concomitant sequential evaluation of microscopic bowel inflammation of these SpA patients before and after therapy could contribute to elucidate these findings.

PATHOGENIC CONSIDERATIONS The specific features of synovial immunopathology in SpA in comparison with other types of chronic autoimmune arthritis and the response to experimental interventions in SpA provide a number of interesting insights into the pathogenesis of this condition. One of the major hallmarks of SpA synovitis is the marked hypervascularity, which is clearly more pronounced than in RA synovium with a similar degree of overall inflammation and which can even be observed in SpA tissues with only minimal inflammatory infiltration.2-5,8,10,11 These observations strongly suggest that the observed hypervascularity is not merely a reflection of the chronic inflammation but is a specific pathophysiologic process in SpA. This is confirmed by studies of other sites of tissue inflammation in SpA: increased vascularity has been reported in SpA-associated enthesitis and in psoriatic skin disease. Along the same lines, it should be noted that treatment with TNF-α blockers, which have a pronounced and rapid effect on inflammation, also reduces vascularity but only partially and in the longer term.23-25,28,29 It is

tissue does not reflect global disease activity in SpA.4 Although a number of reports indicated the presence of clonal expansions of T lymphocytes in synovial tissue of patients with PsA, JSpA, and ReA, similar expansions were also found in other types of chronic arthritis and can thus not be considered a specific disease-related event. Moreover, an extensive study in PsA indicated that most T-cell clones are polyclonal and unexpanded, are found only at sites of active inflammation, do not persist during treatment, exhibit no structural homology, and can be either CD4 or CD8 positive.31 Taken together with the immunopathologic data, these findings do not reveal specific features of antigen-driven T-cell activation but are merely compatible with a nonspecific bystander infiltration. Supporting this interpretation, functional analysis of T lymphocytes in SpA showed impaired production of Th1 cytokines by both the CD4+ and CD8+ subsets.15 Second, there is at present no hard evidence for recirculation of specific T-cell clones from sites where they could be primed by microbial triggers to the synovial membrane. Although this hypothesis is still under investigation for gut-derived lymphocytes,32 two studies failed to demonstrate the presence in synovial tissue of skin-derived, cutaneous lymphocyte antigen–positive lymphocytes in PsA.33,34 Of interest, in the HLA-B27 transgenic model, which is crucially dependent on gut flora, it has now been demonstrated that disease is not mediated by classical CD8+ T lymphocytes. Finally, although treatment with TNF-α blockers induces a rapid decrease of the synovial infiltration with T cells, probably by downregulating the endothelial activation allowing active recruitment of inflammatory leukcocytes,23,24,28,29 it leads to a restoration of a normal Th1/Th2 balance. Moreover, treatments such as MTX induce a significant clinical improvement despite residual T-cell infiltration,35 whereas therapies directed toward lymphocyte homing have beneficial effects in skin psoriasis and Crohn’s disease but only modest clinical efficacy in articular disease.36 Collectively, these observations suggest that the synovial T infiltration in SpA synovitis is probably an inflammatory bystander phenomenon rather than a primary event in the pathogenesis. In contrast to the T lymphocytes, the immuno-pathologic findings in SpA strongly support a central role of innate immune cells such as macrophages and granulocytes in SpA. First, both granulocytes and CD163+ macrophages are selectively increased in SpA synovium versus RA synovium.13,14 Second, the same cell types are found to be increased in psoriatic skin lesions and SpA gut mucosa,14 respectively. Third, synovial infiltration with these cell types correlated significantly with global disease activity in SpA.4,14 Fourth, the number of infiltrating CD163+ macrophages is associated with the

Pathogenic Considerations

therefore likely that some of the mediators of this process are not downstream of TNF-α. Although all these data tend to indicate that hypervascularity is at least partially uncoupled from synovial inflammation, it remains an open question how important this pathophysiologic feature is in the disease process because clinical improvement can be obtained without effect on hypervascularity, as illustrated by MTX treatment, and downregulation of the hypervascularity does not always lead to clinical efficacy, as in the case of IL-10. The specific mediators of hypervascularity in SpA should thus be further identified in order to study in detail their role in the immunopathology and to evaluate their value as novel therapeutic targets. The role of T lymphocytes in SpA pathogenesis has been a matter of extensive investigation and debate for several years. A major argument in favor of a pathogenic role of T lymphocytes is provided by the strong linkage with HLA-B27. Also, based on the importance of microbial triggers, at least for some subtypes such as ReA, it can be envisaged that CD8+ lymphocytes are primed by bacterial antigens in an HLA-B27–restricted way and contribute to synovial inflammation in the joint after reactivation by either the same bacterial pathogens or cross-reactive self-proteins. In favor of this hypothesis, athymic HLA-B27 transgenic rats fail to develop gut inflammation and arthritis or spondylitis resembling human SpA, whereas transfer of T cells from euthymic donors to nude rats induces disease, as does engraftment of the thymus. Surprisingly, the most efficient transfer occurs with purified CD4+ rather than CD8+ T cells. Similarly, studies in human ReA have identified HLA-B27–restricted CD8 epitopes from the Chlamydia trachomatis and the Yersinia enterocolitica proteome, but the T-cell response appears not to be restricted to CD8+ cells triggered in an MHC class I context because CD4+ T cells specific for Yersinia and Chlamydia antigens were also raised from the synovial fluid in ReA. Of interest, some of the CD4+ T-cell epitopes were nearly identical to the HLAB27–restricted cytotoxic T lymphocyte epitopes. In parallel with these findings in ReA, T-cell oligoclonality was demonstrated in both CD8+ and CD4+ T-cell subsets in AS. Several immunopathologic observations in SpA synovium argue against a prominent role of T lymphocytes in the pathogenesis. First, detailed analysis of the inflamed synovium in SpA indicates a clear presence of CD4+ and CD8+ T lymphocytes but without clear predominance of one subset.3,5,10 Moreover, the synovial lymphocytes do not appear to be strongly activated and are mostly found in diffuse infiltrates rather than in well-organized follicular structures as can be more frequently observed in RA.3,13 Also in contrast to RA, the number of T lymphocytes infiltrating the synovial

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SYNOVIAL IMMUNOPATHOLOGY IN SPONDYLOARTHROPATHY

HLA-B27 status of SpA patients.14 Finally, both innate immune cell types are rapidly and significantly reduced upon effective treatment.6,14,23,24,29 On the basis of these observations, we proposed that SpA inflammation might be triggered by an exaggerated and uncontrolled innate immune response rather than by specific activation of the adaptive immune system. This hypothesis is strongly supported by findings concerning expression and function of Toll-like receptors (TLRs) in SpA.37 Both TLR2 and TLR4 are significantly increased on CD163+ myeloid cells in SpA, resulting in strongly increased expression of both TLRs in SpA synovium in comparison with RA synovium with a similar degree of overall inflammation. Moreover, treatment with both infliximab and etanercept induces a sharp downregulation of the systemic and local expression of these TLRs as well as of TLRmediated pro-inflammatory cytokine production. TLRs are also involved in the activation of other important cell types in SpA such as neutrophils and synovial fibroblasts, and their expression is also increased at associated disease sites such as the gut in Crohn’s disease. Collectively, these data suggest that stimulation by bacterial products or by endogenous TLR ligands such as heat shock proteins or extracellular matrix molecules released at sites of biomechanical stress could lead to an abnormal activation of the innate immune response leading to chronic inflammation in SpA. In this context, further investigation of alterations of the innate immune system in SpA may be one of the most promising fields in the coming years. This would include analysis of other TLRs, expression on different cell types such as endothelial cells and CD8 T lymphocytes, investigation of extra-articular sites of SpA inflammation such as the skin and the gut, the relationship with genetic risk factors such as HLAB27 and CARD15 mutations, and functional analysis in experimental disease models.

CLINICAL APPLICATIONS

172

The studies on the synovial immunopathology of SpA have provided a number of important insights into the pathophysiology of this disease. Although it was not the primary aim of this approach, it has turned out that synovial biopsy sampling and analysis can also have some clinical applications for diagnosis and evaluation of new therapeutic strategies in SpA. Diagnosis in rheumatology generally poses no problem when considering patients’ medical history, clinical examination, routine laboratory tests, radiographic evaluation, and synovial fluid analysis. However, some patients may exhibit an atypical presentation or peculiar types of arthritis, which may require additional diagnostic investigations. In this context, synovial tissue analysis can be useful in cases of

suspected infection despite a negative synovial fluid culture or in the differential diagnosis of some less prevalent joint diseases such as hemochromatosis, amyloidosis, ochronosis, pigmented villonodular synovitis, chondromatosis, or chondrosarcoma. From the studies described previously, it also became clear that some synovial features are different in SpA and RA and may eventually be used in cases in which the diagnostic process in early stages of immune-mediated arthritis is hampered by an atypical presentation. This additional diagnostic approach in well-selected cases of undifferentiated arthritis may be particularly important because early and definitive diagnosis is of major value in improving the risk/benefit ratio for a given patient. First, not all patients with early arthritis develop persistent disease during followup; second, different forms of immune-mediated arthritis require distinct therapeutic approaches; and third, early therapeutic intervention is considered essential in order to prevent irreversible structural damage. In a first study addressing this issue, Kraan and associated demonstrated that immunohistochemical analysis can help to distinguish RA from other types of arthritis: logistic regression analysis showed that the diagnosis of RA can be predicted with an accuracy of 85% when massive infiltration by plasma cells and macrophages in the synovial sublining is present, and a diagnosis other than RA can be predicted in 96% of the cases when minimal infiltration by these cells is found.1 Two highly specific markers for the diagnosis of RA have been identified. Intracellular citrullinated proteins were detected in 50% of RA patients, whereas none of the control subjects stained positive for this antibody.4,5,38 The other independent feature with high specificity for RA is the presentation of the immunodominant epitope of the RA autoantigen human cartilage glycoprotein 39 in the context of the HLA-DR shared epitope as recognized by staining with the complexspecific monoclonal antibody 12A; here 61.5% of the inflamed RA synovial samples stained positively compared with only 3% of the control samples.39 The proof of concept that synovial histopathology can contribute to diagnostic decision making is provided by a prospective and longitudinal analysis evaluating both single-parameter and multiparameter algorithms.3 Using highly specific synovial markers such as the anti–L-citrulline antibody, the antibody recognizing the HLA-DR/HCgp-39 peptide complexes, and crystal deposition, a diagnosis with an accuracy of 90% could be predicted in nearly 40% of the patients with undifferentiated arthritis at the time of arthroscopy. By applying a multiparameter algorithm including six histopathologic characteristics,

Moreover, their ability to identify correctly effective treatment in small cohorts of patients makes them interesting biomarkers to facilitate conclusive earlyphase clinical trials in SpA. Further analyses are needed to validate these markers across different therapeutic regimens including both classical DMARDS and biologic targeted therapies different from TNF-α blockade.

CONCLUSIONS AND FUTURE DIRECTIONS The data presented and discussed here clearly indicate that analysis of the synovial immunopathology can contribute to yield new insights into the pathophysiology of SpA and can result in some promising clinical applications. More important, and despite some major advances such as the introduction of TNF-α blockers for treatment of SpA, these data also emphasize our lack of knowledge and understanding of the basic disease processes in this condition. Although the largely descriptive approach of immunopathology has obvious functional limitations, it may well turn out to be a critical tool in the translation of clinically relevant observations to experimental research questions, as illustrated by the effect of TNF-α blockade on B-cell biology in SpA, and in the assessment of the clinical relevance for SpA of basic cellular and molecular mechanisms such as TLR-mediated inflammation. Two issues partially addressed in the previous paragraphs seem to be most promising in this context. The first one relates to the role of the innate immune system in SpA inflammation as opposed to other T or B lymphocyte–mediated autoimmune diseases such as multiple sclerosis, RA, systemic lupus erythematosus, and Sjögren’s syndrome. Although much descriptive and functional work needs to be done to address the proposed hypothesis, it would be most interesting to explore how this relates to specific features of SpA such as the MHC class I linkage and male predominance in contrast to the MHC class II association and pronounced female predominance in most other forms of chronic autoimmune disease. It would also be challenging to explore the relative contribution of the innate immune system and adoptive immunity in the joint versus other target sites such as the skin and the gut and to try to relate this to the relative efficacy of well-defined targeted therapies such as alefacept or natalizumab. The second major issue is related to the relationship between inflammation on the one hand and tissue destruction and remodeling on the other hand. Although this question is of major importance for a wide panel of conditions from arthritis to cardiovascular diseases and from organ fibrosis to graft rejection, SpA may turn out to be a unique model because it

Conclusions and Future Directions

a positive predictive value of 80% was maintained but a much higher sensitivity of about 80% was obtained, allowing the diagnosis not only in an additional subset of RA patients but more impressively in more than 50% of the SpA patients. Interestingly, when reanalyzing the same cohort using a diagnostic multiparameter model based on classical diagnostic characteristics, only 57% of the patients could be classified with a positive predictive value of less than 75%, underscoring the added value of synovial histopathologic analysis. This is of special interest for SpA, which lacks autoantibodies that can be used for serologic diagnosis such as rheumatoid factor and anti–citrullinated protein/ peptide antibodies in RA. A second clinically oriented application of synovial tissue analysis relates to the use of synovial biomarkers of response to treatment in early-phase clinical trials in SpA. With the advent of the highly effective TNF-α blocking agents, it has become ethically difficult to perform large placebo-controlled long-term studies with new drugs in SpA. The necessity to explore new therapeutic strategies arises from different clinical observations: (1) a subset of patients experience an incomplete response or no response, (2) these agents can be contraindicated or induce serious side effects in some patients, (3) lasting remission is not maintained in most patients when treatment is interrupted, and (4) these drugs are extremely expensive. It therefore becomes increasingly important to develop sensitive and robust biomarkers that allow a proof of concept in early-phase clinical trials of limited size and treatment duration. As synovium represents the primary site of inflammation in immune-mediated rheumatic diseases such as SpA, sequential synovial tissue analysis could provide an interesting tool. In RA, synovial tissue macrophages have been identified as a highly sensitive biomarker for response to treatment. Because some synovial features are clearly distinct in RA and SpA, the observations in RA cannot be extrapolated to SpA. Cross-sectional evaluation of SpA synovium indicated that specific synovial features such as the infiltration with CD163+ resident tissue macrophages and polymorphonuclear cells reflect the global disease activity.4 As described previously, studies exploring the effect of TNF-α blocking agents demonstrated a profound synovial immunomodulation in SpA with downregulation of a variety of synovial features.6,20,23,24,29 Combining both observations, a follow-up study analyzed potential sensitive synovial biomarkers able to discriminate between effective and ineffective therapies in SpA. Changes in different macrophages subsets (CD163+ tissue resident macrophages and infiltrating MRP8+ or MRP14+ monocytes), polymorphonuclear cells, and MMP-3 expression reflected best response to treatment with TNF-α blockers versus placebo.

173

SYNOVIAL IMMUNOPATHOLOGY IN SPONDYLOARTHROPATHY

174

combines features of destruction and repair and because different SpA subtypes may behave differentially in this respect. Detailed analysis of the relation between inflammation and structural alterations and therapeutic targeting of specific cellular and molecular mediators such as osteoclasts and MMPs is therefore undoubtedly a major field of future interest in SpA.

Finally, both for more fundamental scientific research and for the development of clinically oriented biomarkers, the immunopathologic approach to SpA synovitis described here may greatly benefit in the future from combination with molecular techniques such as gene expression profiling40 and proteome analysis.41

REFERENCES 1. Kraan MC, Haringman JJ, Post WJ, et al. Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology 1999;38:1074-1080. 2. Veale D, Yanni G, Rogers S, et al. Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 1993;36:893-900. 3. Baeten D, Kruithof E, De Rycke L, et al. Diagnostic classification of spondylarthropathy and rheumatoid arthritis by synovial histopathology: A prospective study in 154 consecutive patients. Arthritis Rheum 2004;50:2931-2941. 4. Baeten D, Kruithof E, De Rycke L, et al. Infiltration of the synovial membrane with macrophage subsets and polymorphonuclear cells reflects global disease activity in spondyloarthropathy. Arthritis Res Ther 2005;7:R359-R369. 5. Kruithof E, Baeten D, De Rycke L, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005;7:R569-R580. 6. De Rycke L, Baeten D, Foell D, et al. Differential expression and response to anti-TNFalpha treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. J Pathol 2005;206:17-27. 7. Ceponis A, Hietanen J, Tamulaitiene M, et al. A comparative quantitative morphometric study of cell apoptosis in synovial membranes in psoriatic, reactive and rheumatoid arthritis. Rheumatology (Oxford) 1999;38:431-440. 8. Ceponis A, Konttinen YT, Imai S, et al. Synovial lining, endothelial and inflammatory mononuclear cell proliferation in synovial membranes in psoriatic and reactive arthritis: A comparative quantitative morphometric study. Br J Rheumatol 1998;37: 170-178. 9. Salvador G, Sanmarti R, Garcia-Peiro A, et al. p53 expression in rheumatoid and psoriatic arthritis synovial tissue and association with joint damage. Ann Rheum Dis 2005;64:183-187. 10. Baeten D, Demetter P, Cuvelier C, et al. Comparative study of the synovial histology in rheumatoid arthritis, spondyloarthropathy, and osteoarthritis: Influence of disease duration and activity. Ann Rheum Dis 2000;59:945-953. 11. Fraser A, Fearon U, Reece R, et al. Matrix metalloproteinase 9, apoptosis, and vascular morphology in early arthritis. Arthritis Rheum 2001;44:2024-2028. 12. Smeets TJ, Dolhain RJ, Breedveld FC, et al. Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis. J Pathol 1998;186:75-81. 13. Baeten D, Moller HJ, Delanghe J, et al. Association of CD163+ macrophages and local production of soluble CD163 with decreased lymphocyte activation in spondylarthropathy synovitis. Arthritis Rheum 2004;50:1611-1623. 14. Baeten D, Demetter P, Cuvelier CA, et al. Macrophages expressing the scavenger receptor CD163: A link between immune alterations of the gut and synovial inflammation in spondyloarthropathy. J Pathol 2002;196:343-350. 15. Canete JD, Martinez SE, Farres J, et al. Differential Th1/Th2 cytokine patterns in chronic arthritis: Interferon gamma is highly expressed in synovium of rheumatoid arthritis compared with seronegative spondyloarthropathies. Ann Rheum Dis 2000;59:263-268. 16. Wilbrink B, van der Heijden IM, Schouls LM, et al. Detection of bacterial DNA in joint samples from patients with undifferenti-

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improvement of clinical signs of arthritis. Arthritis Rheum 2002;46:2776-2784. De Rycke L, Vandooren B, Kruithof E, et al. Tumor necrosis factor alpha blockade treatment down-modulates the increased systemic and local expression of Toll-like receptor 2 and Tolllike receptor 4 in spondylarthropathy. Arthritis Rheum 2005;52:2146-2158. Baeten D, Peene I, Union A, et al. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: Relevance to antifilaggrin autoantibodies. Arthritis Rheum 2001;44:2255-2262. Baeten D, Steenbakkers PG, Rijnders AM, et al. Detection of major histocompatibility complex/human cartilage gp-39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker. Arthritis Rheum 2004;50:444-451. Rihl M, Baeten D, Seta N, et al. Technical validation of cDNA based microarray as screening technique to identify candidate genes in synovial tissue biopsy specimens from patients with spondyloarthropathy. Ann Rheum Dis 2004;63:498-507. Tilleman K, Van Beneden K, Dhondt A, et al. Chronically inflamed synovium from spondyloarthropathy and rheumatoid arthritis investigated by protein expression profiling followed by tandem mass spectrometry. Proteomics 2005;5:2247-2257.

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methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens. J Immunol 2004;172:1935-1944. May E, Marker-Hermann E, Wittig BM, et al. Identical T-cell expansions in the colon mucosa and the synovium of a patient with enterogenic spondyloarthropathy. Gastroenterology 2000;119:1745-1755. Jones SM, Dixey J, Hall ND, et al. Expression of the cutaneous lymphocyte antigen and its counter-receptor E-selectin in the skin and joints of patients with psoriatic arthritis. Br J Rheumatol 1997;36:748-757. Pitzalis C, Cauli A, Pipitone N, et al. Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 1996;39:137-145. Kane D, Gogarty M, O’leary J, et al. Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum 2004;50:3286-3295. Kraan MC, van Kuijk AW, Dinant HJ, et al. Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with

175

REACTIVE ARTHRITIS

21

Natural History, Prognosis, Socioeconomic Aspects, and Quality of Life Bert Vander Cruyssen and Filip De Keyser

176

The natural history and prognosis of reactive arthritis (ReA) depend on different factors, which can be better understood after a short reflection on the place of ReA within the spondyloarthropathy (SpA) concept.1 This concept was introduced in the late 1980s and was based on the fact that different common features such as human leukocyte antigen HLA-B27, sacroiliitis, enthesitis, and gut involvement could be found in patients with ankylosing spondylitis (AS), arthritis associated with inflammatory bowel disease, ReA, and psoriatic arthritis. In ReA, there is a clear association between the occurrence of arthritis, enthesitis, or spondylitis and a recent infection with Campylobacter jejuni, Chlamydia trachomatis (or Chlamydia pneumoniae), Salmonella, Yersinia enterocolitica, Shigella flexneri, Shigella sonnei, or Shigella dysenteriae (Box 21-1). For other SpAs, a role for infections can also be hypothesized. In undifferentiated SpA, up to 64% of patients may display antibodies to Salmonella, Shigella, or Yersinia.2 Other bacteria belonging to the normal gut flora, such as Escherichia coli or Klebsiella, have been linked with some types of SpA (but not ReA). This reflects the increasing evidence that there is a role of the gut in the maintenance of joint symptoms in patients with chronic SpA, even in absence of a history of preceding enteritis. Interestingly, the grading of the microscopic gut lesions that can be found in more than 80% of patients with gastrointestinal ReA seems to decrease during remission of the arthritis.3,4 This is consistent with the arthritis that may occur in patients with inflammatory bowel disease, in which it might be hypothesized that a genetically determined disturbed handling of the gram-negative flora by the inflamed gut may contribute to the development of peripheral and axial arthritis.4 Similarly to the gut, ongoing urogenital infections may support the joint inflammation in patients with AS.5 Besides the ReA that belongs to the SpA concept, other infection-related arthritides have been described

that do not belong to the ReA concept, such as arthritides following infections with Streptococcus, Borrelia burgdorferi, Mycoplasma, and Giardia. In the following, only ReA within the SpA concept is discussed.

NATURAL HISTORY Two types of ReA can be distinguished: a urogenital type following infection with Chlamydia and an enteric type following infection with Salmonella, Campylobacter, Shigella, or Yersinia. Interestingly, overlap between the urogenital and enteric types of ReA exists. Associated urethritis and balanitis may be present in 10% to 43% of patients with Salmonella ReA and in up to 70% of patients with Shigella-associated ReA.6,7,8 Inflammatory gut lesions can be found in 14% of patients with urogenital ReA.4,9 The natural history of ReA is heterogeneous and encompasses the evolution of the primary infection, the evolution of the arthritis, and the associated extraarticular manifestations.

Evolution of the Primary Infection The primary infection may evolve in a clinically silent or very pronounced manner. It is well known that sexually acquired infections with Chlamydia may evolve silently. Also, the enteritis may be clinically silent in 10% of patients with Yersinia ReA.8,10 In contrast, some gastrointestinal infections such as Shigella infections may be very pronounced and dysenteric. The evolution and the duration of the primary infection seem to be important prognostic factors for the occurrence of ReA.11

Evolution of the Rheumatic Symptoms Different patterns of arthritis have been described. It is well accepted to consider an acute phase (less than 6 months) and a chronic phase.12

Campylobacter jejuni Chlamydia trachomatis and Chlamydia pneumoniae Salmonella enterica Shigella flexneri, Shigella sonnei, and Shigella dysenteriae Yersinia enterocolitica and Yersinia pseudotuberculosis (Clostridium difficile)

The Acute Phase of Reactive Arthritis The rheumatic symptoms mostly occur within 30 days after the primary infection. The rheumatic manifestations encompass arthritis, inflammatory back pain, and enthesitis. The arthritis is usually an oligoarticular disease predominantly affecting knees, ankles, feet, and wrists. Enthesitis and tenosynovitis may occur in 5% to 13% of the patients with enteric ReA and in 22% of patients with genitourethral ReA.8 Inflammatory low back pain may be present in various patients and may be a clinical sign of underlying sacroiliitis or spondylitis, which is an important prognostic factor for a worse outcome. The duration of the acute period of ReA varies between reports. In Finnish studies, the average duration of the arthritis was 3 to 5 months.13

The Chronic Phase of Reactive Arthritis Although the acute episode resolves within 6 months in most patients, follow-up studies indicate that up to 80% of patients may suffer from some joint discomfort during the next few years. The diverse joint complaints consist of persistence of atypical joint symptoms, occurrence of relapses, and evolution to chronic SpA. In Finnish studies, about 15% of patients developed chronic sequelae or proceeded into chronic SpA. Atypical joint complaints may persist after the acute phase of ReA and encompass heel pain and painful metatarsophalangeal joints attributed to enthesopathy.14 Also, one third of ReA patients have occasional attacks of inflammatory low back pain.13 The evolution of ReA during the next 10 to 20 years depends upon the evolution to chronic SpA and the occurrence of relapses. These may start 3 to 4 years after the first episode and may consist of recurrence of the peripheral arthritis, enthesitis, or spondylitis. Iritis or other extra-articular symptoms may also occur.14,15 Relapses can be triggered by new infections or various stress factors.16 They are seldom seen after previous infections with Yersinia but are more frequent in patients with previous Salmonella or Shigella arthritis (Table 21-1).13 Reinfections with Chlamydia are also common.

TABLE 21-1 LONG-TERM (10 TO 20 YEARS) PROGNOSIS OF REACTIVE ARTHRITIS Status

Yersinia Salmonella Shigella

Chlamydia trachomatis

Recovered

45%

40%

20%

30%

Persistent arthralgia

20%

20%

NA

68%

Recurrent arthritis

6%

22%

18%

38%

Chronic arthritis

4%

19%

19%

17%

Ankylosing spondylitis

15%

12%

14%

26%

Radiologic sacroiliitis

20%

14%

32%

49%

Natural History

BOX 21-1 MOST IMPORTANT HLA-B27–ASSOCIATED ARTHRITOGENIC AGENTS IMPLICATED IN REACTIVE ARTHRITIS

Adapted from Leirisalo-Repo M. Prognosis, course of disease, and treatment of the spondyloarthropathies. Rheum Dis Clin North Am 1998;24:737-751.

Finally, evolution to chronic SpA may occur and encompasses chronic arthritis, sacroiliitis, and evolution to AS. The occurrence of those symptoms greatly depends upon the triggering infection and the followup time. Although the chronic arthritis generally affects the knees, joint space narrowing and erosions can be seen more easily in the small joints and in the sacroiliac joints.15 Especially sacroiliitis can be seen during long-term follow-up in up to half of patients and may be associated with other axial lesions in the context of AS in up to a quarter of the cases. It is not known exactly how the progression of acute ReA to chronic SpA occurs, but it has been hypothesized that there may be a persistent or recurrent urogenital or intestinal inflammatory focus. Chronic persistence of microbial antigens has been demonstrated in the gut, lymph nodes, and synovial tissue of ReA patients. Yersinia antigens may persist in the submucosa of the gut and in lymph nodes of patients with prolonged or chronic Yersinia-associated ReA. Yersinia and Salmonella antigens have also been demonstrated in the synovial fluid cells and synovial tissue of patients with ReA.13,16 Similarly, C. trachomatis may persist in the urogenital tracts and synovial tissue.13,16

Extra-articular Manifestations Besides the clinical symptoms of genital inflammation and enteritis caused by the primary infection, other extra-articular manifestations may occur. Conjunctivitis constitutes one of the key symptoms described by Reiter’s triad and is the most common ocular manifestation, occurring in about 10% to 25%

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NATURAL HISTORY, PROGNOSIS, SOCIOECONOMIC ASPECTS, AND QUALITY OF LIFE

of cases with enteric-associated ReA and in up to 35% of cases with Chlamydia-associated ReA. In the case of Chlamydia-associated conjunctivitis, the differential diagnosis should be made between a reactive form and a septic conjunctivitis, caused by microorganisms that have been transmitted from the genital tract to the eye.8 However, the discharge is normally sterile and subsides in 1 to 4 weeks.14 Acute anterior uveitis may be found in about 3% to 5% of all forms of ReA and seems to be related to more severe or recurrent arthritis and to the development of sacroiliitis. Anterior uveitis may also be dissociated from the arthritis.8,14 A complication of uveitis may be blindness caused by formation of a hypopyon or by intraocular hemorrhage. Other ocular lesions include corneal ulcerations, keratitis, optic neuritis, and posterior uveitis. Carditis is not a common or prominent part of the clinical picture of ReA. Occasionally, conduction disturbances or valvulitis is seen. Typical carditis, as described in rheumatic fever, is unusual in ReA. Renal pathology with aseptic pyuria and microhematuria is seen in about 50% of patients with ReA. Severe glomerulonephritis and permanent kidney damage are rare.16

PROGNOSIS Differences in infective organisms and in host factors influence both the acute and chronic phases of ReA. Also, the effect of some therapeutic strategies on the prognosis in ReA is discussed.

Infective Organism

178

During the acute phase, the infective organism may influence the severity and the occurrence of extraarticular manifestations. Although Reiter’s triad was initially described with urogenital infections, the syndrome may also occur in enteropathic ReA, especially in Shigella-associated ReA.8 Although the disease duration of the acute phase is similar for all infective organisms, there is greater variability in the number of patients who exhibit a prolonged duration (more than 1 year) of symptoms.8 Chronic arthritis and recurrent arthritis occur in about 4% to 6% of patients with Yersinia arthritis, in 19% to 22% of patients with Salmonella arthritis, in 18% to 19% of those with Shigella arthritis, and in about 17% to 38% of those with Chlamydia arthritis (see Table 21-1). Evolution to radiologic sacroiliitis and AS can be seen more frequently in patients with urogenital ReA than those with enteropathic ReA. This may indicate that the prognosis is better after enteric infections than after sexually acquired disease, which might be explained by the fact that reinfection is more common in the latter. It seems that a persistent or recurrent urogenital infection or a chronic inflammatory focus in the gut

may contribute to the progression of acute ReA to chronic SpA.9 Not only the kind of microorganism but also the amount of ingested microorganisms and a prolonged duration of diarrhea are risk factors for the occurrence of ReA.17

Host Factors The most important host factor in the occurrence and prognosis of ReA is certainly the presence of HLA-B27. Carriage of HLA-B27 is a risk factor for the development of ReA and is a major prognostic factor in the evolution of the acute and chronic phases. Also, the presence of HLA-B27 contributes to the severity and the occurrence of extra-articular manifestations (but not erythema nodosum) during the acute phase of ReA.13 HLA-B27 does not only affect the occurrence and clinical course of acute ReA; the allele is also linked with the prognosis of the disease. Carriage of HLA-B27 is associated with a higher frequency of persistent arthropathy and chronic inflammatory low back pain. Radiologic sacroiliitis and evolution to AS are more common in carriers of the HLA-B27 haplotype.13,18 Also, carriers of HLA-B27 more frequently experience joint damage and enthesitis after Salmonella infections.17 Other factors that influence the long-term prognosis are the patient’s gender (male patients have a greater risk for a worse prognosis), a positive family history for AS or SpA, and chronic gut lesions.4,14 Apart from HLA-B27, whether other genes that are postulated to be involved in bacterial handling (such as polymorphisms in the Toll-like receptor or NOD2/ CARD15)19 influence the occurrence and clinical evolution of ReA is under investigation. A prediction model for the outcome of SpA patients after 10 years was proposed by Amor in which hip arthritis, a high erythrocyte sedimentation rate (greater than 30 mm/hr), and unresponsiveness to nonsteroidal anti-inflammatory drugs (NSAIDs) were risk factors for a bad prognosis.14

Effect of Therapy on Prognosis of Reactive Arthritis In considering the therapeutic options, one should be aware that in many cases the primary infection is already cured at the time arthritic symptoms occur. In that case, therapeutic options can be undertaken in order to relieve the symptoms of the arthritis and to avoid an eventual bad outcome. NSAIDs are the cornerstone of the treatment and can be combined with local corticosteroids. NSAIDs together with physiotherapy maintain the range of motion and help the patient to regain muscle power, which is rapidly lost during acute inflammation.20 Two decades ago, sulfasalazine was proposed as a treatment for ReA.9 Later it was demonstrated that

SOCIOECONOMIC ASPECTS AND QUALITY OF LIFE Little is known about the socioeconomic aspects and quality of life of ReA patients. Much depends on the

clinical course of the disease, which is heterogeneous. The socioeconomic aspects encompass the effects of the primary infection, the acute phase, and the chronic phase of ReA. The socioeconomic effect of the primary infection can be considerable in case of an epidemic dysenteric disease. The subsequent acute phase of ReA may induce a prolonged absence from work. Because ReA can be seen in about 3% of patients with Shigella, Salmonella, or Campylobacter but is more frequent after Yersinia infections, the socioeconomic impact is more important in the latter case.8,22 Chronic withdrawal from work depends mostly upon the occurrence of chronic disease or AS. In a Dutch study with AS patients, 13% left work because of AS-related work disability during the first 5 years of disease, which increased to 31% after 20 years.23 Available studies with quality of life scales indicate that ReA patients have an impaired but a significant better quality of life than RA patients.17,24 It should be mentioned that many of the patients with ReA are young, otherwise healthy, and used to an active lifestyle. For these individuals, ReA, even when selflimiting, is a major life event that may take several months to resolve. Therefore, it is important to inform the patients that there is about 80% chance of complete resolution of the symptoms within the first year and that, even if AS develops, it is mostly a mild form.16 Nevertheless, it is advisable to organize a good followup, especially for patients who have a disease severe enough to require hospitalization and patients who are HLA-B27 positive. Although many ReA patients may have future episodes of gastroenteritis or urethritis without recurrence of arthritis, patients should be informed in order to minimize the risk of recurrent infection. Particularly younger patients may need advice on foreign travel and barrier contraception. With this knowledge, patients may tolerate the discomfort of ReA and learn to live with the disease rather well.

References

sulfasalazine is indeed effective but only on the shortterm outcome of acute ReA. Although they are effective in other SpAs, the value of biologicals such as tumor necrosis factor α blocking agents has not been formally established. The role of antibiotics in the treatment of ReA is controversial. There is no doubt about treating patients with adequate antibiotics in cases with an active primary infection in which the triggering bacteria can be isolated. Treatment in a very early stage of the primary infection seems to be effective in reducing the occurrence of urogenital ReA. In rat models, early treatment with effective antibiotics inhibited the development of enteric ReA.18 Different studies with different antibiotic strategies have been performed in patients with enteric ReA, but most of them, even in the case of sustained antibiotic therapy for 3 months, could not demonstrate a therapeutic effect on the acute phase of ReA or the extraarticular symptoms. However, one study indicated for the first time that combination therapy with doxycycline and rifampin might be effective in Chlamydia-associated ReA.21 Interestingly, in another study, in which the initial effect on the acute arthritis after 3 months of treatment with ciprofloxacin was negative, the 4-year prognosis was remarkably better in the treated group than the placebo group. This might be attributed to effective eradication of the microbes probably persisting in the (HLA-B27–positive) patients.16 These data should be confirmed. The current consensus is that a short conventional course of antibiotic therapy may eradicate the triggering infection in the majority of patients and may be effective in preventing the development of ReA, if given early enough.16

REFERENCES 1. Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227. 2. Aggarwal A, Misra R, Chandrasekhar S, et al. Is undifferentiated seronegative spondyloarthropathy a forme fruste of reactive arthritis? Br J Rheumatol 1997;36:1001-1004. 3. Mielants H, Veys EM, Goemaere S, et al. A prospective study of patients with spondyloarthropathy with special reference to HLA-B27 and to gut histology. J Rheumatol 1993;20: 1353-1358. 4. De Keyser F, Elewaut D, De Vos M, et al. Bowel inflammation and the spondyloarthropathies. Rheum Dis Clin North Am 1998;24:785-813. 5. Olhagen B. Urogenital syndromes and spondarthritis. Br J Rheumatol 1983;22 (Suppl 2):33-40.

6. Inman RD, Johnston ME, Hodge M, et al. Postdysenteric reactive arthritis. A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31:1377-1383. 7. Hannu TJ, Leirisalo-Repo M. Clinical picture of reactive salmonella arthritis. J Rheumatol 1988;15:1668-1671. 8. Keat A. Reiter’s syndrome and reactive arthritis in perspective. N Engl J Med 1983;309:1606-1615. 9. Mielants H, Veys EM, Cuvelier C, de Vos M. Ileocolonoscopic findings in seronegative spondylarthropathies. Br J Rheumatol 1988;27 (Suppl 2):95-105. 10. Weyand CM, Goronzy JJ. Clinically silent infections in patients with oligoarthritis: Results of a prospective study. Ann Rheum Dis 1992;51:253-258. 11. Thomson GT, Minenko A, Schroeder ML. Host risk factors for the development of reactive arthritis: A family study. J Rheumatol 1993;20:1350-1352.

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12. Braun J, Kingsley G, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 1999;27:2185-2192. 13. Leirisalo-Repo M. Prognosis, course of disease, and treatment of the spondyloarthropathies. Rheum Dis Clin North Am 1998;24:737-751. 14. Amor B. Reiter’s syndrome. Diagnosis and clinical features. Rheum Dis Clin North Am 1998;24:677-695. 15. Flores D, Marquez J, Garza M, Espinoza LR. Reactive arthritis: Newer developments. Rheum Dis Clin North Am 2003;29:37-59. 16. Toivanen A, Toivanen P. Reactive arthritis. Best Pract Res Clin Rheumatol 2004;18:689-703. 17. Thomson GT, DeRubeis DA, Hodge MA, et al. Post-Salmonella reactive arthritis: Late clinical sequelae in a point source cohort. Am J Med 1995;98:13-21. 18. Rich E, Hook EW 3rd, Alarcon GS, Moreland LW. Reactive arthritis in patients attending an urban sexually transmitted diseases clinic. Arthritis Rheum 1996;39:1172-1177.

19. Philpott DJ, Girardin SE. The role of Toll-like receptors and Nod proteins in bacterial infection. Mol Immunol 2004;41: 1099-1108. 20. Holden W, Orchard T, Wordsworth P. Enteropathic arthritis. Rheum Dis Clin North Am 2003;29:513-530. 21. Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol 2004;31: 1973-1980. 22. Nuorti JP, Niskanen T, Hallanvuo S, et al. A widespread outbreak of Yersinia pseudotuberculosis O:3 infection from iceberg lettuce. J Infect 2004;189:766-774. 23. Boonen A, Chorus A, Miedema H, et al. Withdrawal from labour force due to work disability in patients with ankylosing spondylitis. Ann Rheum Dis 2001;60:1033-1039. 24. Soderlin MK, Kautiainen H, Skogh T, Leirisalo-Repo M. Quality of life and economic burden of illness in very early arthritis. A population based study in southern Sweden. J Rheumatol 2004;31:1717-1722.

REACTIVE ARTHRITIS

22

Pathogenesis of Reactive Arthritis Joachim Sieper

Reactive arthritis (ReA) is an episode of a normally acute inflammatory articular involvement occurring in a genetically predisposed individual secondary to a primary infectious process elsewhere in the body.1 Although several forms of arthritis can be described as reactive, such as acute rheumatic fever, the term reactive arthritis is restricted to acute arthritis usually following acute genitourinary or gastrointestinal infection that is associated with human leukocyte antigen HLA-B27.2 Its other distinctive feature is typical of the whole group of spondyloarthritides, such as an association with other inflammatory symptoms including the spine, eye, mucocutaneous surfaces, and the entheses (tendon insertion sites onto bone).3 ReA occurs in 1% to 4% of patients with preceding bacterial infections of the gut with enterobacteria or the urogenital tract with Chlamydia trachomatis; however, this rate increases considerably to 20% to 30% in patients infected with one of these bacteria who are positive for HLA-B27.1 Furthermore, approximately 15% to 30% of patients develop chronic or recurrent arthritis or sacroiliitis-spondylitis in the long term, mostly if they are positive for HLA-B27.4,5 All these clinical and epidemiologic data point to a crucial role for both bacteria and HLA-B27 in the pathogenesis of ReA.

INFECTIONS TRIGGERING REACTIVE ARTHRITIS ReA can be triggered by a variety of arthritogenic organisms.1,6 The most common forms occur after genitourinary infection with C. trachomatis or an enteritis related to certain gram-negative enterobacteria, such as Shigella, Salmonella, Yersinia, or Campylobacter. Genitourinary tract infection with C. trachomatis is the more commonly recognized initiator of ReA in developed countries, and therefore this form of ReA (“uroarthritis”) mostly occurs in a young population that is sexually active. Gastrointestinal infections with enterobacteria, on the other hand, are a more frequent trigger of ReA (“enteroarthritis”) in

the developing parts of the world, affecting both young and old. Sterile urethritis and cervicitis can accompany arthritis after acute bacterial diarrhea, and the psoriasiform lesions over the external genitalia (circinate balanitis and circinate vulvitis) do not indicate the presence of genitourinary infection. Campylobacter has arisen as one of the most important infections to cause gastroenteritis in the Western world, such as in Finland,7 where the annual incidence of ReA related to Campylobacter is 4.3 per 100,000.8 This is a much higher figure than that for Shigella-induced ReA (1.3 per 100,000).9 About 50% of patients with ReA are positive for HLA-B27, with a higher frequency in more severe cases and a lower frequency in milder cases.1 However, other bacteria have also been implicated in the etiopathogenesis of ReA, suggesting that specific capacities of a single bacterium cannot explain the occurrence of an arthritis, which is rather due to features that are common to many bacteria. For example, respiratory tract infections by Chlamydia pneumoniae can also trigger ReA.10,11 Although infections with C. pneumoniae are more common than infections with C. trachomatis, this kind of ReA occurs less frequently,11 indicating that the site of infection (respiratory tract versus urogenital tract) is also of importance. Interestingly, there have also been cases of ReA following local intravesical injection of bacillus CalmetteGuérin (BCG) into bladder cancer that is surgically nonresectable.12,13 In contrast, such cases have not been observed if patients are vaccinated with BCG subcutaneously to decrease the risk of tuberculosis. Such cases have symptoms typical of the whole group of spondyloarthritides, such as inflammatory back pain and dactylitis, and 50% to 70% of these patients have HLA-B27. HLA-B27–associated ReA has not been described after viral infections or after bacterial infections with streptococci (of the throat) or with Borrelia burgfdorferi.1 All these examples demonstrate that ReA is unique for (multiple) bacteria but probably also the site of the primary infection, although the reason for this has not been clarified until now.

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PERSISTENCE OF BACTERIA IN REACTIVE ARTHRITIS Because no bacteria could be cultured from affected joints in ReA, it was assumed for many years that bacteria do not persist inside the joint. However, it has been shown over the past 15 to 20 years that bacteria or bacterial products from ReA-inducing bacteria such as C. trachomatis, Yersinia, Salmonella, and Shigella can be detected in synovial fluid (SF) and synovial membrane by various techniques and are therefore probably responsible for triggering the local immune response and the local inflammation. For C. trachomatis, chlamydial DNA and RNA have been detected in the joint,11,14,15 making it likely that live Chlamydia are present. Chlamydial DNA has even been detected in peripheral blood monocytes.16 This is different for enteric ReA. Yersinia or Salmonella DNA has not been detected in the ReA joint (with a few exceptions17), but by using bacteria-specific antibodies Yersinia18 and Salmonella antigens19 have been found in SF. Furthermore, animal models of Yersiniainduced arthritis indicate that enterobacteria probably persist outside the joint, at sites such as gut mucosa or lymph nodes.20 Bacterial antigens might then be transported, possibly by monocytes, to the joints.21 The detection of pieces from Yersinia or Salmonella in peripheral blood mononuclear cells (MNCs) and constantly elevated Yersinia- or Salmonella-specific immunoglobulin A (IgA) antibodies (indicating recent contact with the bacterium because of the short halflife of IgA antibodies)22,23 further support the concept that bacterial persistence in both acute and chronic forms of ReA is crucial for the pathogenesis of ReA.

ANTIBIOTICS IN REACTIVE ARTHRITIS

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Given the persistence of ReA-associated bacteria such as C. trachomatis and Yersinia in vivo, it has long been an obvious question whether antibiotics are effective in the treatment of ReA.1 However, most of the studies could not demonstrate a clear clinical benefit in patients treated with antibiotics in the long term.24-26 In the context of the role of bacterial persistence in the pathogenesis of ReA, one study is of special interest. In this study, 71 patients with acute ReA (disease duration of less than 6 months) were treated with ciprofloxacin or placebo for 3 months; 60 of these patients had an enteric ReA and 11 had a uroarthritis. No benefit of antibiotic treatment was observed when patients were observed for 12 months. However, these patients were contacted again 4 to 7 years after treatment with ciprofloxacin or placebo.27 Eleven of 27 (45%) patients from the previous placebo group had developed chronic rheumatic diseases, compared with

only 2 of 26 (7.7%) of the patients originally treated with ciprofloxacin. Furthermore, all the rheumatic manifestations in the former placebo group were compatible with spondyloarthropathy (SpA)-typical features, whereas the two cases in the former cipro floxacin group (psoriatic arthritis and seronegative polyarthritis) could have occurred independently of the former infection. Of most interest is the finding that 10 of 11 patients with rheumatic manifestations in the placebo group but none of the 2 in the ciprofloxacin group were positive for HLA-B27. These data suggest that persistent bacterial infection causes SpA-specific manifestations only if patients are positive for HLA-B27 and not if they are negative. Thus, the HLA-B27–positive subgroup might benefit in the long term from antibiotic treatment, although not in the short term. The importance of bacterial persistence for the pathogenesis and the potential benefit of antibiotic therapy for the prevention of long-term complications of ReA is supported by additional indirect evidence. In the 1940s and 1950s, arthritis associated with urogenital infections (not yet called reactive arthritis) was associated with the development of ankylosing spondylitis (AS) in Sweden in a higher percentage than 20 to 30 years later,28 when investigated by the same authors. As pointed out by these authors, consequent and long-term antibiotic treatment was the main difference in the management of these patients. Similarly, AS and related diseases were more severe in lower social classes with less hygiene (without a refrigerator) when investigated in North Africa29; AS starts at an earlier age and runs a more severe course in countries such as Mexico,30 China,31 and North Africa32 compared with Western Europe; and, finally, the first generation of immigrants from North Africa to France had more severe AS than the second generation (B Amor, unpublished observations). All these data indicate that persistent or repeated infection, probably of the gut, is a very important contributor for chronic courses and for a bad long-term outcome of ReA.

POTENTIAL ROLE OF CYTOKINE IMBALANCE FOR BACTERIAL PERSISTENCE IN REACTIVE ARTHRITIS Given the important role of bacterial persistence, the question was raised why these bacteria persist in some patients but not in others and why some patients (although the minority) develop chronic courses of their arthritis. The ReA-associated bacteria are obligate (such as Chlamydia) or facultative intracellular bacteria. It has been shown that T helper 1 (Th1) cytokines such as tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) are crucial for effective elimination of

Researchers from Germany and Finland then addressed the question of whether differences in the production of IL-10 in ReA patients might be genetically determined.43 In this study, 85 Finnish ReA patients and 62 HLA-B27–positive Finnish control subjects were investigated. From genomic DNA, IL-10 microsatellites G and R and IL-10 promoter polymorphisms at positions −1087 and −524 were typed by polymerase chain reaction, automated fragment length analysis, and restriction fragment digestion. There was a significant decrease in the promoter alleles G12 and G10 in the ReA group compared with the HLAB27–positive controls, indicating that these alleles might have a protective effect on the occurrence of ReA. Although it is not clear whether these alleles are associated with higher production of IL-10, these data raise the possibility that the relative increase of IL-10 found in ReA might be, at least partially, genetically determined. Thus, an imbalance of cytokines might be an important factor in the persistence of bacterial antigens in ReA. The immunopathology would then be caused by a hypersensitive immune response against bacterial antigens. Therapeutic options could be either elimination (e.g., by antibiotics; see preceding discussion) of the triggering foreign antigen or, if this does not work, suppression of the hypersensitive immune response.

Role of CD4+ T Cells in the Pathogenesis of Reactive Arthritis

these bacteria, whereas T helper 2 cytokines such as interleukin 4 (IL-4) or T helper 3 cytokines such as IL10 might inhibit effective elimination.33,34 These cytokines have been investigated in peripheral blood, SF, and synovial membranes of patients with ReA in comparison with other arthritides such as rheumatoid arthritis. It could be shown that there is a relative deficiency of Th1 cytokines in ReA, especially of TNF-α but also of IFN-γ, both locally in SF35 and synovial membrane35-40 and systemically in peripheral blood.41 Furthermore, a correlation between low TNF-α production in peripheral blood and a longer duration of arthritic symptoms could be demonstrated.41 Thus, a relative lack of Th1 cytokines may be relevant for the occurrence and persistence of ReA, probably mediated by persistence of bacteria. The cytokine IL-10 has received increasing interest as a potentially immunosuppressive cytokine. Although upregulation of such a cytokine would be wanted in assumed autoimmune diseases such as rheumatoid arthritis, it might also contribute to bacterial persistence in ReA, possibly by downregulation of the Th1 cytokines IFN-γ and TNF-α. To investigate this question, SF MNCs from ReA were stimulated in vitro with the responsible bacterium and cytokines were measured in the supernatant by enzyme-linked immunosorbent assay.35 SF MNCs produced high amounts of IFN-γ and IL-10, relatively less TNF-α, and no detectable IL-4. These amounts were significantly higher than cytokine production by SF MNCs stimulated with lipopolysaccharide and than cytokines secreted by peripheral blood MNCs derived from healthy control subjects. Interestingly, the amount of IL-10 was relatively highest compared with IFN-γ and TNF-α, resulting in a higher IL-10/IFN-γ ratio than in control subjects. It could also be shown that in the synovial membrane of patients with Chlamydia-induced38 and other ReA39 a relatively high amount of IL-10 messenger RNA or protein and a low amount of IFN-γ were present. It was further investigated whether IL-10 has a regulatory role in the production of IFN-γ and TNF-α by SF-derived MNCs. It could be demonstrated that IL-10 is most likely responsible for the inhibition of IFN-γ and TNF-α secretion within the ReA joint because neutralizing endogenous IL-10 in culture with anti–IL10 resulted in enhanced secretion of IFN-γ and TNF-α. The addition of exogenous IL-10 further reduced secretion of both cytokines.35 Interestingly, the enhanced effect of anti–IL-10 could be reduced by adding neutralizing antibody against IL-12, indicating that IL-10 suppressed IFN-γ and TNF-α secretion by inhibiting IL-12 synthesis. It had already been shown that the Th1 inhibitory effect of IL-10 might be mediated by suppression of IL-12.42

ROLE OF CD4+ T CELLS IN THE PATHOGENESIS OF REACTIVE ARTHRITIS CD4+ T cells have been investigated for many years in ReA, in both peripheral blood and SF. Many researchers showed that a CD4+ T-cell response specific for the triggering bacterium can normally be detected in ReA patients and that the response of T cells derived from SF is clearly higher compared with peripheral blood, suggesting that these T cells play a dominant role in the local immune response.44,45 Subsequently, CD4+ T-cell responses directed against dominant antigens derived from ReA-associated bacteria, especially from C. trachomatis and Yersinia, were investigated in more detail. These T cells produced both INF-γ and TNF-α and, to a lesser extent, IL-10 when stimulated with chlamydial major outer membrane protein (MOMP) or heat shock protein (HSP) 60 derived from Chlamydia or Yersinia.46-48 These results confirm that the potential to produce IL-10 could be an explanation for bacterial persistence. For the Yersinia HSP60 it was then possible to identify single immunodominant peptides in ReA patients by using various methods such as T-cell cloning47 and by raising highly antigen-specific T-cell lines by the cytometric cytokine secretion assay.49 However, these peptides were different for different patients depending

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on the patient’s HLA type, indicating that there is no single peptide immunodominant for all ReA patients. CD4+ T-cell responses have also been described directed against other ReA bacteria-derived proteins such as the 19-kd protein from Yersinia46 or against various Chlamydia-derived antigens50,51 such as outer membrane protein (OMP) 252 or HSP60.52 However, T-cell epitopes and antigen-specific cytokine secretion were not further investigated for these proteins.

ROLE OF HLA-B27 IN THE PATHOGENESIS OF REACTIVE ARTHRITIS The association of ReA with HLA-B27 discussed earlier suggests an important role for this molecule in the pathogenesis. There is also some evidence for this from animal models. HLA-B27 transgenic rats develop features of ReA, including gut inflammation, spondylitis, peripheral arthritis, and psoriasiform skin and nail changes. The importance of environmental factors is emphasized by the observation that many of these features, including gut inflammation and arthritis, do not develop in HLA-B27 transgenic rats born and bred in a germ-free environment, although they still develop skin and nail pathology.53,54 Germ-free animals rapidly develop inflammatory disease on removal from the sterile environment. This can be partially prevented by treatment with antibiotics. Several hypotheses have been put forward to explain the association between HLA-B27 and ReA and other spondyloarthritides such as AS. Because of a higher prevalence, a more severe course, and a higher association with HLA-B27, the clarification of the pathogenetic role of HLA-B27 would be of great interest especially for ankylosing spondylitis. However, because the triggering bacteria are normally known in ReA, most of these investigations have been performed using T cells from ReA patients stimulated with antigens derived from the triggering bacterium.

HLA-B27 AND THE ARTHRITOGENIC PEPTIDE HYPOTHESIS

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Because the main function of HLA class I molecules is to present peptide antigens to cytotoxic CD8+ T cells, it has been proposed that the antigen-presenting properties of HLA-B27 could be crucial in the pathogenesis of spondyloarthritides. Besides alternative mechanisms, which are discussed later, the favored theory for the association between HLA-B27 and spondyloarthritides is the arthritogenic peptide hypothesis.55,56 It suggests that some B27 subtypes, because of their unique amino acid residues, bind specific arthritogenic peptides that are recognized by CD8+ T cells. Furthermore, in response to these bacterial peptides, autoreactive

T cells recognizing antigens with sufficient structural similarity between bacteria and self may become activated by self-peptides, such as those in the joint or spine. The arthritogenic peptide hypothesis is supported by several direct and indirect observations. The strongest support for this hypothesis came from studies in humans showing the differential association of some of the HLA-B27 subtypes with AS.57-60 Whereas B*2705, B*2702, B*2704, and B*2707 are strongly associated with the disease, the HLA-B27 subtypes B*2709 in whites and B*2706 in Southeast Asians are not at all or only rarely present in the AS patients. Most interestingly, B*2709 differs from the disease-associated B*2705 by only one amino acid substitution involving the exchange of an Asp116 to His116. Similarly, B*2706 differs from the disease-associated B*2704 by only two amino acid substitutions involving exchange of His114 to Asp114 and of Asp116 to Tyr116. These differences are all located in the peptide binding groove. Therefore, it has been hypothesized that B*2706 and B*2709, the two subtypes that are not disease associated, do not present arthritogenic peptides, in contrast to the disease-associated subtypes. It was a dogma for a long time that bacteria-derived peptides cannot be presented to major histocompatibility complex (MHC) class I molecules because they cannot gain access to the class I pathway, with some exceptions such as Listeria. It has been shown that even peptides from proteins that originate through the extracellular environment of a cell, including the exogenous pathway by phagosomes, as well as through the classically endogenous pathway can induce a CD8+ T-cell response61 against intracellular bacteria. This has been demonstrated, for example, against C. trachomatis62 or against enterobacteria such as Yersinia63 or Salmonella.64 Major efforts were undertaken in the past to look for bacteria-derived peptides that are presented by HLAB27 to CD8+ T cells in ReA patients, hoping to identify one or several arthritogenic peptides. A synovial CD8+ T-cell response to a peptide from Yersinia HSP60 in patients with Yersinia-induced ReA63 and an HLAB27–restricted CD8+ T-cell response to peptides derived from several chlamydial proteins in patients with Chlamydia-induced ReA65 have been described. In the latter study, a novel approach to search the whole chlamydial proteome to identify peptides that stimulate patients’ derived CD8+ T cells in an HLAB27–restricted manner was applied. Synovial CD8+ T cells specific for C. trachomatis–derived peptides could also be identified by using HLA-B27/peptide tetramers.66 However, all the peptides described so far differed from each other. Thus, using this approach, the much wanted arthritogenic peptide has not yet been found.

OTHER HYPOTHESES ABOUT THE ROLE OF HLA-B27 IN SPONDYLOARTHROPATHIES Beside the “classical” arthritogenic peptide theory, other hypotheses have emerged. One interesting concept, the HLA-B27 misfolding hypothesis, states that HLA-B27 itself is directly involved in the pathologic process of SpA. It has been suggested that HLA-B27

can be misfolded, which might have consequences for the pathogenic process.70 The misfolding is suggested to be due to a particular feature of HLA-B27: newly synthesized HLA-B*2705 seems to fold by and associate with β2-microglobulin more slowly than other MHC class I molecules. Deglycosylated heavy chains were found in the cytosol and are supposed to be dislocated from the endoplasmic reticulum as a consequence of misfolding. However, a study performed in the animal model of HLA-B27 transgenic rats suggests that B27 misfolding is associated with intestinal inflammation but that B27 misfolding is not critical to B27-associated arthropathy in this model.71 Allen and co-workers reported that as a consequence of HLA-B27 misfolding, free HLA-B27 heavy chains can form abnormal heavy chain homodimers.72 This homodimer formation could be facilitated by unpaired free cysteine residues at position 67 (Cys67) of the HLA-B27 heavy chain α1 helix. Homodimerization was also suggested in HLA-B27 transgenic mice.73 However, in mice there was no evidence that HLA-B27 heavy chains could form a class II–like structure and present peptides to CD4+ T cells.73 In contrast, Boyle and colleagues reported that human CD4+ T cells could be stimulated by HLA-B27.74 A further hypothesis claims that HLA-B27 on the cell surface of immune cells modulates the uptake or intracellular replication, or both, of ReA-associated bacteria, which might play a role in induction and persistence of ReA.75,76 It has further been reported that Salmonella invasion can change the peptide repertoire presented by HLA-B27.77

References

Further evidence that there may be only a limited number of possibly relevant antigens comes from a different approach analyzing T-cell receptors from synovial T cells. In this study, an oligoclonal expansion of T cells has been demonstrated for CD8+ T cells in ReA.67 The SF derived from different HLA-B27–positive patients suffering from ReA and triggered by different bacteria revealed an astonishingly high homology of T-cell receptors. These results led to the suggestion that similar antigens are recognized by these oligoclonally expanded CD8+ T cells, which implies that under certain conditions specific arthritogenic peptides might indeed be produced and presented to the host’s immune system. In another study, the isolation of a new HLA-B27 selfderived dodecamer peptide from the intracytoplasmic tail of its own molecule has been reported.68 It was shown that the peptide was a natural ligand of three disease-associated subtypes, HLA-B*2702, HLA-B*2704, and HLA-B*2705, but not of the two nonassociated ones, B*2706 and B*2709. This peptide showed strikingly high homology to a peptide sequence derived from the DNA primase from the arthritogenic bacterium C. trachomatis. These results demonstrate that an HLA-B27 self-derived peptide can mimic a sequence from an arthritogenic bacterium. Whether this newly detected peptide that acts as a natural ligand of disease-associated B27 subtypes is crucial for the pathogenesis of ReA and other spondyloarthritides is a subject for future investigations. Finally, the breakdown of cytotoxic T lymphocyte tolerance to self HLA-B27 and the influence of the interrelationship with the pathogen C. trachomatis have been discussed.69 The investigators reported that because of exposure to Chlamydia, previously quiescent autoreactive T cells are activated, recognizing a B27 selfderived peptide even if there is no sequence homology with the bacterial peptide.

SUMMARY AND CONCLUSIONS The identification of bacteria triggering ReA and the association of ReA with HLA-B27 have allowed better insights into the pathogenesis of this disease. Furthermore, advances in immunologic and molecular biologic techniques have contributed to a better understanding of the pathogenesis of ReA, for which the persistence of bacteria and the interaction between bacteria and HLA-B27 seem to be crucial. Nonetheless, there are still many questions about the exact pathogenesis and about the optimal treatment for the prevention of chronic disease.

REFERENCES 1. Sieper J, Braun J, Kingsley GH. Report on the Fourth International Workshop on Reactive Arthritis. Arthritis Rheum 2000;43:720-734. 2. Braun J, Kingsley G, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International

Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000;27:2185-2192. 3. Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227. 4. Leirisalo-Repo M, Helenius P, Hannu T, et al. Long-term prognosis of reactive salmonella arthritis. Ann Rheum Dis 1997;56:516-520.

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5. Mannoja A, Pekkola J, Hamalainen M, et al. Lumbosacral radiographic signs in patients with previous enteroarthritis or uroarthritis. Ann Rheum Dis 2005;64:936-939. 6. Amor B. Reiter’s syndrome and reactive arthritis. Clin Rheumatol 1983;2:315-319. 7. Rautelin H, Hanninen ML. Campylobacters: The most common bacterial enteropathogens in the Nordic countries. Ann Med 2000;32:440-445. 8. Hannu T, Mattila L, Rautelin H, et al. Campylobacter-triggered reactive arthritis: A population-based study. Rheumatology (Oxford) 2002;41:312-318. 9. Hannu T, Mattila L, Siitonen A, Leirisalo-Repo M. Reactive arthritis attributable to Shigella infection: A clinical and epidemiological nationwide study. Ann Rheum Dis 2005;64:594-598. 10. Braun J, Laitko S, Treharne J, et al. Chlamydia pneumoniae—A new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 1994;53:100-105. 11. Schumacher HR Jr, Gerard HC, Arayssi TK, et al. Lower prevalence of Chlamydia pneumoniae DNA compared with Chlamydia trachomatis DNA in synovial tissue of arthritis patients. Arthritis Rheum 1999;42:1889-1893. 12. Buchs N, Chevrel G, Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: An experimental model of reactive arthritis. J Rheumatol 1998;25:1662-1665. 13. Tinazzi E, Ficarra V, Simeoni S, et al. Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: A systematic review. Rheumatol Int 2006;26:481-488. 14. Bas S, Griffais R, Kvien TK, et al. Amplification of plasmid and chromosome Chlamydia DNA in synovial fluid of patients with reactive arthritis and undifferentiated seronegative oligoarthropathies. Arthritis Rheum 1995;38:1005-1013. 15. Wilkinson NZ, Kingsley GH, Sieper J, et al. Lack of correlation between the detection of Chlamydia trachomatis DNA in synovial fluid from patients with a range of rheumatic diseases and the presence of an antichlamydial immune response. Arthritis Rheum 1998;41:845-854. 16. Kuipers JG, Jurgens-Saathoff B, Bialowons A, et al. Detection of Chlamydia trachomatis in peripheral blood leukocytes of reactive arthritis patients by polymerase chain reaction. Arthritis Rheum 1998;41:1894-1895. 17. Gaston JS, Cox C, Granfors K. Clinical and experimental evidence for persistent Yersinia infection in reactive arthritis. Arthritis Rheum 1999;42:2239-2242. 18. Granfors K, Jalkanen S, von Essen R, et al. Yersinia antigens in synovial-fluid cells from patients with reactive arthritis. N Engl J Med 1989;320:216-221. 19. Granfors K, Jalkanen S, Lindberg AA, et al. Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet 1990;335:685-688. 20. Zhang Y, Gripenberg-Lerche C, Soderstrom KO, et al. Antibiotic prophylaxis and treatment of reactive arthritis. Lessons from an animal model. Arthritis Rheum 1996;39:1238-1243. 21. Granfors K, Merilahti-Palo R, Luukkainen R, et al. Persistence of Yersinia antigens in peripheral blood cells from patients with Yersinia enterocolitica O:3 infection with or without reactive arthritis. Arthritis Rheum 1998;41:855-862. 22. Isomaki O, Vuento R, Granfors K. Serological diagnosis of salmonella infections by enzyme immunoassay. Lancet 1989;1: 1411-1414. 23. Maki-Ikola O, Lahesmaa R, Heesemann J, et al. Yersinia-specific antibodies in serum and synovial fluid in patients with Yersinia triggered reactive arthritis. Ann Rheum Dis 1994;53:535-539. 24. Sieper J, Fendler C, Laitko S, et al. No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: A three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum 1999;42:1386-1396. 25. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al. Effect of a three month course of ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis 2000;59:565-570. 26. Kvien TK, Gaston JS, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113-1119. 27. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al. Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis. Ann Rheum Dis 2003;62:880-884.

28. Olhagen B. Urogenital syndromes and spondarthritis. Br J Rheumatol 1983;22 (4 Suppl 2):33-40. 29. Claudepierre P, Gueguen A, Ladjouze A, et al. Predictive factors of severity of spondyloarthropathy in North Africa. Br J Rheumatol 1995;34:1139-1145. 30. Lau CS, Burgos-Vargas R, Louthrenoo W, et al. Features of spondyloarthritis around the world. Rheum Dis Clin North Am 1998;24:753-770. 31. Huang F, Zhang J, Zhu J, et al. Juvenile spondyloarthropathies: The Chinese experience. Rheum Dis Clin North Am 2003;29:531-547. 32. Hajjaj-Hassouni N, Maetzel A, Dougados M, Amor B. [Comparison of patients evaluated for spondylarthropathy in France and Morocco]. Rev Rhum Ed Fr 1993;60:420-425. 33. Autenrieth IB, Beer M, Bohn E, et al. Immune responses to Yersinia enterocolitica in susceptible BALB/c and resistant C57BL/6 mice: An essential role for gamma interferon. Infect Immun 1994;62:2590-2599. 34. Yang X, HayGlass KT, Brunham RC. Genetically determined differences in IL-10 and IFN-gamma responses correlate with clearance of Chlamydia trachomatis mouse pneumonitis infection. J Immunol 1996;156:4338-4344. 35. Yin Z, Braun J, Neure L, et al. Crucial role of interleukin-10/interleukin-12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis. Arthritis Rheum 1997;40:1788-1797. 36. Simon AK, Seipelt E, Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA 1994;91:8562-8566. 37. Smeets TJ, Dolhain RJ, Breedveld FC, Tak PP. Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis. J Pathol 1998;186:75-81. 38. Kotake S, Schumacher HR Jr, Arayssi TK, et al. Gamma interferon and interleukin-10 gene expression in synovial tissues from patients with early stages of Chlamydia-associated arthritis and undifferentiated oligoarthritis and from healthy volunteers. Infect Immun 1999;67:2682-2686. 39. Appel H, Neure L, Kuhne M, et al. An elevated level of IL-10- and TGFbeta-secreting T cells, B cells and macrophages in the synovial membrane of patients with reactive arthritis compared to rheumatoid arthritis. Clin Rheumatol 2004;23:435-440. 40. van Holten J, Smeets TJ, Blankert P, Tak PP. Expression of interferon beta in synovial tissue from patients with rheumatoid arthritis: Comparison with patients with osteoarthritis and reactive arthritis. Ann Rheum Dis 2005;64:1780-1782. 41. Braun J, Yin Z, Spiller I, et al. Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum 1999;42:2039-2044. 42. Uyemura K, Demer LL, Castle SC, et al. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest 1996;97:2130-2138. 43. Kaluza W, Leirisalo-Repo M, Marker-Hermann E, et al. IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients. Arthritis Rheum 2001;44:1209-1214. 44. Ford DK. Lymphocytes from the site of disease in reactive arthritis indicate antigen-specific immunopathology. J Infect Dis 1991;164:1032-1033. 45. Sieper J, Kingsley G, Palacios-Boix A, et al. Synovial T lymphocyte-specific immune response to Chlamydia trachomatis in Reiter’s disease. Arthritis Rheum 1991;34:588-598. 46. Mertz AK, Ugrinovic S, Lauster R, et al. Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis. Heatshock protein 60 drives a major immune response. Arthritis Rheum 1998;41:315-326. 47. Mertz AK, Wu P, Sturniolo T, et al. Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia-triggered reactive arthritis: Overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles. J Immunol 2000;164:1529-1537. 48. Thiel A, Wu P, Lauster R, et al. Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry. Arthritis Rheum 2000;43:2834-2842.

64. Diaz-Quinonez A, Martin-Orozco N, Isibasi A, Ortiz-Navarrete V. Two Salmonella OmpC K(b)-restricted epitopes for CD8+-T-cell recognition. Infect Immun 2004;72:3059-3062. 65. Kuon W, Holzhutter HG, Appel H, et al. Identification of HLAB27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases. J Immunol 2001;167:4738-4746. 66. Appel H, Kuon W, Kuhne M, et al. Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in Chlamydiatriggered reactive arthritis. Arthritis Res Ther 2004;6:R521-R534. 67. Dulphy N, Peyrat MA, Tieng V, et al. Common intra-articular T cell expansions in patients with reactive arthritis: Identical betachain junctional sequences and cytotoxicity toward HLA-B27. J Immunol 1999;162:3830-3839. 68. Ramos M, Alvarez I, Sesma L, et al. Molecular mimicry of an HLA-B27-derived ligand of arthritis-linked subtypes with chlamydial proteins. J Biol Chem 2002;277:37573-37581. 69. Popov I, Dela Cruz CS, Barber BH, et al. Breakdown of CTL tolerance to self HLA-B*2705 induced by exposure to Chlamydia trachomatis. J Immunol 2002;169:4033-4038. 70. Colbert RA. HLA-B27 misfolding: A solution to the spondyloarthropathy conundrum? Mol Med Today 2000;6:224-230. 71. Tran TM, Dorris ML, Satumtira MS, et al. Additional human ß2microglobulin curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27 transgenic rats. Arthritis Rheum 2006;54:1317-1327. 72. Allen RL, O’Callaghan CA, McMichael AJ, Bowness P. Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol 1999;162:50455048. 73. Khare SD, Bull MJ, Hanson J, et al. Spontaneous inflammatory disease in HLA-B27 transgenic mice is independent of MHC class II molecules: A direct role for B27 heavy chains and not B27-derived peptides. J Immunol 1998;160:101-106. 74. Boyle LH, Goodall JC, Opat SS, Gaston JS. The recognition of HLA-B27 by human CD4+ T lymphocytes. J Immunol 2001;167:2619-2624. 75. Penttinen MA, Heiskanen KM, Mohapatra R, et al. Enhanced intracellular replication of Salmonella enteritidis in HLA-B27expressing human monocytic cells: Dependency on glutamic acid at position 45 in the B pocket of HLA-B27. Arthritis Rheum 2004;50:2255-2263. 76. Vahamiko S, Penttinen MA, Granfors K. Aetiology and pathogenesis of reactive arthritis: Role of non-antigen-presenting effects of HLA-B27. Arthritis Res Ther 2005;7:136-141. 77. Ringrose JH, Meiring HD, Speijer D, et al. Major histocompatibility complex class I peptide presentation after Salmonella enterica serovar typhimurium infection assessed via stable isotope tagging of the B27-presented peptide repertoire. Infect Immun 2004;72:5097-5105.

References

49. Thiel A, Wu P, Lanowska M, et al. Identification of immunodominant CD4+ T cell epitopes in patients with Yersinia-induced reactive arthritis by cytometric cytokine secretion assay. Arthritis Rheum 2006;54:3583-3590. 50. Gaston JS, Deane KH, Jecock RM, Pearce JH. Identification of 2 Chlamydia trachomatis antigens recognized by synovial fluid T cells from patients with Chlamydia induced reactive arthritis. J Rheumatol 1996;23:130-136. 51. Goodall JC, Yeo G, Huang M, et al. Identification of Chlamydia trachomatis antigens recognized by human CD4+ T lymphocytes by screening an expression library. Eur J Immunol 2001;31:1513-1522. 52. Goodall JC, Beacock-Sharp H, Deane KH, Gaston JS. Recognition of the 60 kilodalton cysteine-rich outer membrane protein OMP2 by CD4+ T cells from humans infected with Chlamydia trachomatis. Clin Exp Immunol 2001;126:488-493. 53. Taurog JD, Richardson JA, Croft JT, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994;180:2359-2364. 54. Rath HC, Herfarth HH, Ikeda JS, et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest 1996;98:945-953. 55. Benjamin R, Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 1990;11:137-142. 56. Kingsley G, Sieper J. Current perspectives in reactive arthritis. Immunol Today 1993;14:387-391. 57. D’Amato M, Fiorillo MT, Carcassi C, et al. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol 1995;25:3199-3201. 58. Lopez-Larrea C, Sujirachato K, Mehra NK, et al. HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations. Tissue Antigens 1995;45:169-176. 59. Fiorillo MT, Greco G, Maragno M, et al. The naturally occurring polymorphism Asp116→His116, differentiating the ankylosing spondylitis-associated HLA-B*2705 from the non-associated HLA-B*2709 subtype, influences peptide-specific CD8 T cell recognition. Eur J Immunol 1998;28:2508-2516. 60. Khan MA. HLA-B27 polymorphism and association with disease. J Rheumatol 2000;27:1110-1114. 61. Pfeifer JD, Wick MJ, Roberts RL, et al. Phagocytic processing of bacterial antigens for class I MHC presentation to T cells. Nature 1993;361:359-362. 62. Kuon W, Lauster R, Bottcher U, et al. Recognition of chlamydial antigen by HLA-B27-restricted cytotoxic T cells in HLA-B*2705 transgenic CBA (H-2k) mice. Arthritis Rheum 1997;40:945-954. 63. Ugrinovic S, Mertz A, Wu P, et al. A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA-B27restricted CTL response in Yersinia-induced reactive arthritis. J Immunol 1997;159:5715-5723.

187

REACTIVE ARTHRITIS

23

Genetics of Reactive Arthritis Antoni Chan and Paul Wordsworth

The observation that arthritis can develop after gastrointestinal or genitourinary tract infection has been described over the past three centuries. The term reactive arthritis (ReA) was coined by Ahvonen and colleagues over three decades ago.1 ReA is defined as arthritis associated with infection elsewhere in the body in which microbes are not detected in the joint and which persists despite resolution of the primary infection. This definition has been reconsidered in the light of better detection techniques showing microbial DNA and RNA in the joints of patients with ReA.2,3 Thus, in ReA, viable and culturable bacteria are not present in the joint but immunogenetic bacterial antigens may reside in the joint and result in a persistent immune-mediated synovitis despite resolution of infection.4 ReA is usually triggered by the gram-negative bacteria Chlamydia, Campylobacter, Salmonella, Shigella, and Yersinia. ReA includes Reiter’s syndrome, a clinical triad of arthritis, urethritis, and conjunctivitis, but because of the often incomplete triad of clinical features in Reiter’s syndrome, ReA is the preferred term for this group of arthropathies. ReA has defined clinical (e.g., oligoarthritis) and genetic (e.g., human leukocyte antigen HLA-B27 association) features and should be distinguished from other postinfective arthritides such as acute rheumatic fever, acute meningococcemia, Lyme, and viral arthritis, which lack these features.

EPIDEMIOLOGY

188

ReA commonly affects young adults between the ages of 30 and 40 years and is relatively rare in children. Triggering gastrointestinal infection results in similar risk of ReA development in males and females. Preceding Chlamydia trachomatis infection is commoner in male ReA patients. The annual incidence of Campylobacter- and Shigella-induced ReA from the Finnish data is 4.3 per 100,000 in the former and 1.3 per 100,000 in the latter.5 ReA is associated with HLA-B27,6 and 68% to 85% of patients with ReA in hospital series are HLA-B27 positive. In epidemics, the frequency of HLA-B27 is considerably lower, typically less than 20%. Thus, one

report indicates that although joint symptoms may occur in about 20% of individuals after Salmonella typhimurium infection, only 17% of these were HLAB27 positive.7 Lower reported rates in community studies may be accounted for in part by the lack of strict diagnostic criteria for ReA in these studies, but it seems likely that HLA-B27 is also a marker for the more severe, persistent forms of the disease. The prevalence of ReA is associated with both the background prevalence of venereal disease and HLA-B27 as evidenced by an epidemiologic study in Greenland.8

CLASSIFICATION AND DIAGNOSTIC CRITERIA ReA is associated with a group of arthritides known as the spondyloarthropathies (SpAs) (Box 23-1), which also includes ankylosing spondylitis (AS), psoriatic arthritis (PsA), and enteropathic arthritis (associated with inflammatory bowel disease, IBD). The European Spondyloarthropathy Study Group (ESSG) criteria are most often used to classify SpA9 (Box 23-2). The ESSG criteria have a sensitivity and specificity of 87%, but the sensitivity drops significantly to 75% in the absence of radiographic sacroiliitis, although specificity is maintained at 87%. Although the ESSG criteria are widely used in SpA, no universally agreed upon classification criteria exist for ReA. All forms of SpA share several features in common, including a predilection for spinal arthritis and a strong association with HLA-B27.10 In the United Kingdom, the prevalence of HLA-B27 in the general population is 8%. In contrast, HLA-B27 is positive in 95% of white AS patients, 70% of patients with ReA, 50% to 60% of patients with PsA with axial skeletal disease, 50% of patients with anterior uveitis, and 80% to 90% of children with juvenile AS. There is also a tendency for familial aggregation, with a concordance rate of at least 63% in identical twins compared with 23% in nonidentical twins in AS.11 Shared clinical features of SpA include enthesitis and a characteristic joint distribution involving the axial skeleton and sacroiliac and asymmetric peripheral large joints. Extra-articular features include anterior uveitis, apical lung fibrosis, heart block, and lone aortic regurgitation.

Ankylosing spondylitis Reactive arthritis Psoriatic arthropathy Enteropathic arthropathy Juvenile enthesitis-related arthritis Undifferentiated spondyloarthritis

BOX 23-2 THE EUROPEAN SPONDYLOARTHROPATHY STUDY GROUP CRITERIA FOR SPONDYLOARTHRITIS Inflammatory spinal pain or Synovitis (either asymmetric or predominantly involving lower limbs) and One of the following: Positive family history Psoriasis Inflammatory bowel disease Urethritis, cervicitis, or acute diarrhea 1 month before arthritis Buttock pain alternating between right and left gluteal areas Enthesopathy Sacroiliitis

ETIOLOGY Susceptibility to SpA depends on a fine balance between environmental factors (e.g., exposure to pathogens) and host factors (e.g., genetic makeup and composition of host immune system). ReA is perhaps the clearest example of host-environment interactions in the pathogenesis of rheumatic disease. Some of the proposed immune mechanisms for the development of ReA are summarized in Figure 23-1.

ENVIRONMENTAL FACTORS Classically, gram-negative bacteria causing gastrointestinal or genitourinary tract infection are associated with ReA (Box 23-3). However, the condition has also been described following infection with a very broad range of bacteria, including gram-positive organisms. The range of individual pathogens associated with ReA has increased, and respiratory tract pathogens, Chlamydia pneumoniae, and β-hemolytic streptococci have also been implicated. Although in the original definition of ReA, bacteria are absent from the joint, it is now possible to detect the presence of bacterial proteins and nucleic acid in the joints from many patients. The presence of bacterial antigen in the joint can promote a persistent inflammatory response resulting in arthritis. The existence of at least two distinct forms of inflammatory arthritis associated with IBD is

particularly interesting in this respect. The type 1 arthropathy associated with IBD is very similar to ReA in its oligoarticular, lower limb distribution and its duration (typically less than 12 weeks). It is associated with flares of the IBD, raising suspicions that it may be triggered by alterations in gut flora. In contrast, the type 2 arthropathy is polyarticular, symmetrical, and runs a sustained course, typically independent of the activity of the bowel disease. These two forms of arthritis associated with IBD are not usually erosive,11a and, in keeping with their distinct clinical features, they are immunogenetically distinct; type 1 arthritis is positively associated with HLA-B*27, HLA-B*35, and HLA-DRB1*0503, whereas type 2 is associated with HLA-B*44. Of interest, HLA-DRB1*0103, HLA-B*27, and B*35 are also increased in postenteric forms of ReA, suggesting relevant immunogenetic similarities between the two arthropathies.11b New insights into the understanding of the recognition of bacterial antigens by innate immune cells come from the identification of pattern recognition receptors, which include the Toll-like receptors (TLRs). TLRs play a key role in the activation of cells of the innate immune system such as dendritic cells and monocytes. The TLRs have a common signaling pathway that includes the association with MyD88, activation of the interleukin 1 receptor activation kinase (IRAK), and subsequent nuclear translocation of nuclear factor κB (NF-κB).12 Activation of the TLR signaling pathway results in the production of proinflammatory cytokines (e.g., tumor necrosis factor α [TNF-α], interleukin 1 [IL-1], IL-8) and the maturation of dendritic cells, which then migrate to the lymph nodes to prime naïve T cells. Many of the ligands for TLRs arise from bacterial cell wall and point to a major influence of TLR in the bacteria-host interface. Of interest in ReA are TLRs 1, 2, 4, 5, 6, and 9. TLR2 binds to lipoproteins from Shigella and Chlamydia spp. and has a low activation threshold for Chlamydia lipoproteins and thus a higher efficacy for the development of mature inclusion bodies in dendritic cells.13 TLR1 and TLR6 function as accessory molecules to TLR2, with which they form heterodimers and modulate its responsiveness to pathogens. Lipopolysaccharide (LPS), the main component of the outer membrane of gram-negative bacteria, is bound by TLR4. LPS binding protein (LBP) enhances the interaction of LPS with CD14 and is crucial in LPS signaling. TLR4 is overexpressed in gut epithelia in IBD samples in comparison with healthy control samples14 and thus may enhance the bacteria-gut interface. TLR5 is the receptor for flagellin, a structural protein for bacterial flagella. Flagellin may play a dominant role in the invasiveness of enteropathic bacteria. Bacterial DNA contains a higher proportion of

Environmental Factors

BOX 23-1 THE SPONDYLOARTHROPATHIES

189

Joint Inflammation

GENETICS OF REACTIVE ARTHRITIS

Figure 23-1. Proposed mechanisms of the development of reactive arthritis. Bacterial components resulting from lysis of infected cells are taken up by antigen-presenting cells (APCs) and a pro-inflammatory response may result from direct recognition of bacterial products by Toll-like receptors, presentation of bacterial peptides by APCs resulting in cytotoxic T lymphocyte (CTL) activation, or recognition of HLA-B27 homodimer (B272) by natural killer (NK) receptors resulting in activation of natural killer and T cells. HLA, human leukocyte antigen; IL-1, interleukin 1; TNF, tumor necrosis factor.

unmethylated CpG DNA sequences, and these regions account for its direct potent immunostimulatory properties. Injection of CpG DNA into the joints of

BOX 23-3 MICROBIAL INFECTION ASSOCIATED WITH DEVELOPMENT OF REACTIVE ARTHRITIS

190

Enteric Pathogens Salmonella spp. (S. enteritidis and S. typhimurium) Shigella spp. (S. flexneri, S. sonnei, and S. dysenteriae) Yersinia spp. (Y. enterocolitica and Y. pseudotuberculosis) Campylobacter jejuni Clostridium difficile Bacteria causing urethritis Chlamydia trachomatis Mycoplasma genitalium Ureaplasma urealyticum Bacteria causing upper respiratory infection β-Hemolytic Streptococcus Chlamydia pneumoniae

mice caused persistent histologic synovitis and upregulation of proinflammatory cytokines.15 TLR9 is the receptor for CpG DNA, and its activation induces a T helper 1 (Th1) cell bias. Nucleotide oligomerization domains, such as NOD2 (also known as CARD15), have been implicated in the etiology of IBD.16 These receptors potentially play a key role in upregulation of the adaptive immune response and could be relevant to ReA.17 Functional polymorphisms of NOD2 are strongly associated with Crohn’s disease and may influence the severity of colitic SpA,18 but whether they play a role in ReA is not known.

HOST SUSCEPTIBILITY FACTORS Although the association between HLA-B27 and SpA was established three decades ago, the exact role of HLA-B27 in the pathogenesis of SpA remains unknown. In ReA, the presence of HLA-B27 and triggering of the condition by gram-negative bacteria are

against self-epitopes in ReA.22 CTLs recognizing peptides from C. trachomatis23 in patients with ReA have also been identified. A CTL line with cross-reactivity to both self and Yersinia 60-kd heat shock protein has also been demonstrated.24 In addition to CTLs, some of the peptides from C. trachomatis were recognized by CD4+ T cells, such as that from its outer membrane protein 2.25 However, a specific arthritogenic peptide recognized by either CTL or CD4+ T cells has yet to be demonstrated conclusively. The arthritogenic peptide hypothesis is further supported by the identification of endogenous HLA-B27 peptides with homology to bacterial epitopes, which results in molecular mimicry between the two. The introduction of HLA-B27 into Lewis rats by plasmid DNA immunization resulted in anti-Chlamydia CTL induction, suggesting possible cross-recognition between HLA-B27 and arthritogenic bacteria.26 HLAB27 or peptides derived from it could also act as autoantigens and be recognized by CD4+ T cells27 through presentation by HLA class II molecules. Clinical and experimental studies suggest the association of gut flora and AS.28 More than 50% of patients with AS and SpA have microscopic ileal inflammation on ileocolonoscopy.29 Patients with AS have increased intestinal permeability compared with healthy control subjects,30 and it is speculated that the initiating (and perpetuating) factor in SpA may be a breakdown in the gut-blood barrier to intestinal bacteria. Gram-negative microbes causing enteric infections are associated with a risk of ReA in approximately 1% to 15% of patients. Certain bacterial strains derived from normal gut flora possess strong arthritogenicity, and this is determined by the structure of peptidoglycan in the bacterial cell wall.31 HLA-B27 appears to enhance the invasion of Salmonella into intestinal epithelial cells.32 Cell susceptibility to arthritogenic bacteria may lead to its intracellular persistence, which can lead to prolonged nonspecific stimulation of the immune response. This adjuvant effect of intracellular bacteria may magnify the specific response that it elicits such as from CTLs. Monocytes from HLA-B27 patients have been shown in vitro to kill Salmonella less efficiently than controls33 and show upregulation of IL-10 and low TNF-α production.34 This has also been reproduced in Chlamydia-induced ReA, where there are elevated levels of IL-10 and transforming growth factor β in the synovium, pointing to ineffective elimination and persistence of microbes in the joint.35 The HLA-B27 homodimer hypothesis36 suggests that arthritis results from misfolded HLA-B27, which forms homodimers (B272) that recognize and cause inappropriate signaling to T and NK cells. T and NK cell activation may lead to a net pro-inflammatory effect by further activation of inflammatory cells such

Host Susceptibility Factors

associated with more severe prolonged forms of the condition, perhaps suggesting a role in sustaining local joint inflammation. Further, HLA-B27–positive patients with ReA are much more likely to progress over a period of years to full-blown AS (see later). It is reasonable to regard ReA and AS as two ends of a spectrum of SpA with very likely similar etiology and pathogenesis with HLA-B27 as the most obvious common link. HLA-B27 is a class I major histocompatibility complex (MHC) molecule and is expressed on the surface of all nucleated cells. It is composed of a polymorphic heavy (α) chain complexed with a light chain (β2microglobulin) and a peptide. Its peptide binding cleft commonly accommodates peptides 8 to 11 amino acids long and the classical function of HLA-B27 is to present peptides to a variety of ligands, in particular Tcell receptors on the surface of CD8+ cytotoxic T lymphocytes (CTLs). HLA-B27 has also been shown to bind to families of natural killer cell receptors (NKRs) present on both T and NK cells.19 These NKRs include killer immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LILRs). Twenty-six different alleles of HLA-B27 have been identified, and the most common alleles (HLA-B*2702, B*2704, B*2705, B*2707) are associated with disease risk, with an odds ratio of 171 (95% confidence interval 135 to 218) in AS.20 Two subtypes of HLA-B27, B*2709 (found in Sardinia) and B*2706 (found in Southeast Asia), are not associated with AS. The amino acid difference in the F pocket of the HLA-B27 antigen binding groove defines the molecular subtypes and appears to alter the composition of peptides presented. Many strands of research have now arisen that have helped to bridge the gap between HLA-B27 disease association and cause. The best evidence of HLA-B27 involvement in disease pathogenesis is from HLA-B27 transgenic rats, which on an appropriate genetic background develop a human SpA–like disease. The role of microbes in initiating SpA in HLA-B27 transgenic rats is supported by the fact that rats raised in a germ-free microenvironment do not develop the joint or gut inflammation seen in rats raised under conventional conditions.21 SpA may result from the ability of HLA-B27 to bind a unique repertoire of antigenic bacterial peptides and present these to CTL or NK cells. The response against a bacterial peptide showing antigenic mimicry with a self-peptide constitutively presented by HLA-B27 could result in a cross-reactive autoimmune inflammatory response in joints and other affected tissues. This is the basis of the arthritogenic peptide hypothesis. Evidence for this hypothesis comes from identification of HLA-B27 restricted CTLs in synovial fluid (SF) of ReA patients and HLA-B27 restricted CTLs directed

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GENETICS OF REACTIVE ARTHRITIS

as macrophages. Free heavy chains of HLA-B27 have been shown in vitro to be expressed on the cell surface and maintain their peptide binding groove in the absence of β2-microglobulin. The role of free heavy chains in SpA pathogenesis is supported by the finding that β2-microglobulin–deficient HLA-B27 transgenic mice develop spontaneous inflammatory arthritis.37 The incidence of this disease was significantly reduced by in vivo treatment with the HC10 monoclonal antibody, which reacts with β2-microglobulin–free HLA class I heavy chains.38 Two heavy chains of HLA-B27 can adhere to each other through disulfide bonds through their cysteine-67 residues in the extracellular α1 domain to form a B272 (Fig. 23-2). B272 is expressed on peripheral blood (PB) mononuclear cells from patients with SpA and also in HLA-B27 transgenic disease models.39 B272s are ligands for a number of NKRs including KIR3DL1, KIR3DL2, LILRB2, and LIR6. This pattern of recognition is distinct from that of HLA-B27 heterodimers, which are bound by KIR3DL1, LILRB1, LILRB2, and LIR6 but not by KIR3DL2.19 In SpA, an increased number of PB and SF NK and CD4+ T cells express the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells ~2.5 nm

α2 helix α1 helix

Disulphide bond between Cys67 residues

CLINICAL MANIFESTATIONS The triggering infection usually precedes the onset of arthritis by 1 to 4 weeks and can be asymptomatic. The arthritis that develops is classically an asymmetric oligoarthritis affecting the large joints in the lower limbs. A mild polyarticular pattern affecting the small joints of the hands or feet, giving a “sausage” digits appearance, may also be seen. The axial skeleton, particularly sacroiliitis, is affected in 50% of cases. Plantar fasciitis and Achilles tendonitis is often observed. HLA-B27+ ReA patients develop more extra-articular features. As with the other SpAs, enthesitis can occur as well as other extra-articular manifestations such as conjunctivitis, acute anterior uveitis, erythema nodosum, and nail dystrophy.

Peptide

PROGNOSIS

α1 helix α2 helix

192

had an activated phenotype and were protected from apoptosis by culture with a cell line expressing B272.40 It is postulated that protection of KIR3DL2+ NK and T cells from activation-induced cell death could lead to persistent inflammation. HLA-B27 misfolding occurs in the endoplasmic reticulum and is a unique and inherent property of this HLA molecule.41 The accumulation of misfolded HLAB27 may result in a pro-inflammatory unfolded protein response intracellularly in the endoplasmic reticulum leading to activation of NF-κB, which in turn might increase the production of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. In the context of ReA, the HLA-B27 misfolding could lower the threshold of activation by bacterial infection. This is consistent with stimulation of c-Fos synthesis in HLA-B27 cells following invasion by S. typhimurium.42 However, evidence showing arthritogenic bacteria interfering with HLA class I assembly and leading to the accumulation of misfolded class I heavy chains in the endoplasmic reticulum is lacking.

Figure 23-2. Model of human leukocyte antigen HLA-B27 homodimer (B272). Two heavy chains of HLA-B27, depicted as ribbons, can adhere to each other through a disulfide bond through their cysteine-67 residues in the extracellular α1 domain to form a B272. The (putative) bound peptides are depicted schematically as light gray tubes. (From Bowness P, Zaccai N, Bird L, Jones EY. HLA-B27 and disease pathogenesis: New structural and functional insights. Expert Rev Mol Med 1999;1999:1-10.)

ReA lasting more than 6 months is designated as chronic. Four percent to 20% of patients develop chronic ReA, and this is dependent on the type of triggering bacteria as well as HLA-B27 status. Fifteen percent of ReA patients proceeded to chronic SpA.43 Twenty percent to 40% of HLA-B27+ patients with Chlamydia-triggered ReA develop AS as a long-term complication.44

INVESTIGATIONS Stool cultures to detect the triggering enteric infection are usually negative at the time when arthritis develops.

TREATMENT

Nonsteroidal Anti-inflammatory Drugs and Corticosteroids Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment for symptom control in SpA. There are no strong data to suggest the superiority of any specific NSAID in ReA. In acute ReA, local corticosteroid injections may be useful for monoarthritis or oligoarthritis and enthesopathy. No controlled trials of systemic glucocorticoids in ReA have been conducted, and data to support their use are lacking.

Antibiotics The use of antibiotics in ReA can be divided into the treatment of the triggering infection and that of the ongoing arthritis. The benefit of antibiotic therapy is limited to the infectious phase before the development of arthritis. In the long term, introduction of antibiotics during ongoing arthritis does not modify the course of disease. This is evident from a double-blind, placebo-controlled study on early inflammatory

arthritis involving azithromycin versus placebo46 as well as from data on tetracycline treatment.47

Disease-Modifying Antirheumatic Drugs

References

Urethral swabs have a higher yield, allowing detection of genitourinary bacterial triggers. In C. trachomatis infection, urethral swabs are positive in 50% of cases.45 In the presence of urethritis, Chlamydia antigen can also be detected by urinary ligase reaction. In the absence of positive stool or urethral culture, the diagnosis is dependent on serologic tests, although there are no reliable serologic tests for Shigella. The advent of new methods of detection including nucleic acid amplification assays has contributed significantly to better detection of triggering bacteria and diagnosis.

There is limited information on the use of diseasemodifying antirheumatic drugs in ReA. Methotrexate and azathioprine have demonstrated beneficial effects and may be used in ReA with a recurrent course. Sulfasalazine48 resulted in quicker ReA clinical remission than placebo and may also be effective in chronic ReA.49

Biologic Treatment Anti–TNF-α treatment has been shown to be beneficial in the treatment of AS and PsA.50 In acute ReA, infliximab has been shown to be beneficial in case reports.51

CONCLUSION ReA represents one of the clearest examples of how host susceptibility factors interact with environmental influences in pathogenesis. There is growing evidence of the involvement of pathways beyond the adaptive immune response in the pathogenesis of ReA. These include the innate immune system, as evidenced by the involvement of Toll-like receptors on dendritic cells and monocytes as well natural killer cell family receptors. Genetic studies point to a polygenic susceptibility in SpA, and there may be candidate genes influencing innate immunity mechanisms in ReA. Unlocking the components of this finely balanced interaction may help our understanding of the pathogenesis of ReA and autoimmune disease.

REFERENCES 1. Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 1969;15:232-253. 2. Bas S, Griffais R, Kvien TK, et al. Amplification of plasmid and chromosome Chlamydia DNA in synovial fluid of patients with reactive arthritis and undifferentiated seronegative oligoarthropathies. Arthritis Rheum 1995;38:1005-1113. 3. Kuipers JG, Jurgens-Saathoff B, Bialowons A, et al. Detection of Chlamydia trachomatis in peripheral blood leukocytes of reactive arthritis patients by polymerase chain reaction. Arthritis Rheum 1998;41:1894-1895. 4. Toivanen A, Toivanen P. Reactive arthritis. Best Pract Res Clin Rheumatol 2004;18:689-703. 5. Hannu T, Mattila L, Siitonen A, Leirisalo-Repo M. Reactive arthritis attributable to Shigella infection: A clinical and epidemiological nationwide study. Ann Rheum Dis 2005;64:594-598. 6. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973;1:904-907. 7. Lee AT, Hall RG, Pile KD. Reactive joint symptoms following an outbreak of Salmonella typhimurium phage type 135a. J Rheumatol 2005;32:524-527. 8. Bardin T, Lathrop GM. Postvenereal Reiter’s syndrome in Greenland. Rheum Dis Clin North Am 1992;18:81-93. 9. Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the

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classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227. Wordsworth P. Genes in the spondyloarthropathies. Rheum Dis Clin North Am 1998;24:845-863. Brown MA, Laval SH, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000;59:883-886. Orchard T, Jewell DP. Review article: Pathophysiology of the intestinal mucosa in inflammatory bowel disease and arthritis: Similarities and dissimilarities in clinical findings. Ailment Pharmacol Ther 1997;11 (Suppl 3):10-15; discussion 15-16. Orchard TR, Thiyagaraja S, Welsh KI, et al. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology 2000;118:274-278. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 2001;413:78-83. Prebeck S, Kirschning C, Durr S, et al. Predominant role of Tolllike receptor 2 versus 4 in Chlamydia pneumoniae-induced activation of dendritic cells. J Immunol 2001;167:3316-3323. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of Toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 2000;68:7010-7017.

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15. Deng GM, Nilsson IM, Verdrengh M, et al. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 1999;5:702-705. 16. Hugot J-P, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599-603. 17. Sigal H. Basic science for clinicians: Toll-like receptors and nucleotide oligomerization domain. J Clin Rheumatol 2005;11:176-179. 18. Crane AM, Bradbury L, van Heel DA, et al. Role of NOD2 variants in spondyloarthritis. Arthritis Rheum 2002;46:1629-1633. 19. Kollnberger S, Bird L, Sun MY, et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum 2002;46:2972-2982. 20. Brown MA, Pile KD, Kennedy LG, et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis 1996;55:268-270. 21. Taurog JD, Richardson JA, Croft JT, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994;180:2359-2364. 22. Hermann E, Yu DT, Meyer zum Buschenfelde KH, Fleischer B. HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 1993;342:646-650. 23. Kuon W, Holzhutter HG, Appel H, et al. Identification of HLAB27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases. J Immunol 2001;167:4738-4746. 24. Mertz AK, Wu P, Sturniolo T, et al. Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersiniatriggered reactive arthritis: Overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles. J Immunol 2000;164:1529-1537. 25. Goodall JC, Yeo G, Huang M, et al. Identification of Chlamydia trachomatis antigens recognized by human CD4+ T lymphocytes by screening an expression library. Eur J Immunol 2001;31:1513-1522. 26. Popov I, Dela Cruz CS, Barber BH, et al. The effect of an antiHLA-B27 immune response on CTL recognition of Chlamydia. J Immunol 2001;167:3375-3382. 27. Boyle LH, Goodall JC, Opat SS, Gaston JS. The recognition of HLA-B27 by human CD4+ T lymphocytes. J Immunol 2001;167:2619-24. 28. Holden W, Orchard T, Wordsworth P. Enteropathic arthritis. Rheum Dis Clin North Am 2003;29:513-530, viii. 29. Mielants H, Veys EM, Goemaere S, et al. Gut inflammation in the spondyloarthropathies: Clinical, radiologic, biologic and genetic features in relation to the type of histology. A prospective study. J Rheumatol 1991;18:1542-1551. 30. Martinez-Gonzalez O, Cantero-Hinojosa J, Paule-Sastre P, et al. Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol 1994;33:644-647. 31. Zhang X, Rimpilainen M, Simelyte E, Toivanen P. Characterisation of Eubacterium cell wall: Peptidoglycan structure determines arthritogenicity. Ann Rheum Dis 2001;60:269-274. 32. Saarinen M, Ekman P, Ikeda M, et al. Invasion of Salmonella into human intestinal epithelial cells is modulated by HLA-B27. Rheumatology (Oxford) 2002;41:651-657. 33. Ekman P, Saarinen M, He Q, et al. HLA-B27-transfected (Salmonella permissive) and HLA-A2-transfected (Salmonella nonpermissive) human monocytic U937 cells differ in their production of cytokines. Infect Immun 2002;70:1609-1614.

34. Braun J, Yin Z, Spiller I, et al. Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum 1999;42:2039-2044. 35. Butrimiene I, Jarmalaite S, Ranceva J, et al. Different cytokine profiles in patients with chronic and acute reactive arthritis. Rheumatology (Oxford) 2004;43:1300-1304. 36. McMichael A, Bowness P. HLA-B27: Natural function and pathogenic role in spondyloarthritis. Arthritis Res 2002;4 (Suppl 3):S153-S158. 37. Khare SD, Luthra HS, David CS, et al. Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: A model of human spondyloarthropathies. J Exp Med 1995;182:1153-1158. 38. Khare SD, Hansen J, Luthra HS, David CS. HLA-B27 heavy chains contribute to spontaneous inflammatory disease in B27/human beta2-microglobulin (beta2m) double transgenic mice with disrupted mouse beta2m. J Clin Invest 1996;98:2746-2755. 39. Kollnberger S, Bird LA, Roddis M. HLA-B27 heavy chain homodimers are expressed in HLA-B27 transgenic rodent models of spondyloarthritis and are ligands for paired Ig-like receptors. J Immunol 2004;173:1699-1710. 40. Chan AT, Kollnberger SD, Wedderburn LR, Bowness P. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondyloarthritis. Arthritis Rheum 2005;52:3586-3595. 41. Mear JP, Schreiber KL, Munz C, et al. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 1999;163:6665-6670. 42. Ikawa T, Ikeda M, Yamaguchi A, et al. Expression of arthritiscausing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium. J Clin Invest 1998;101:263-272. 43. Leirisalo-Repo M, Skylv G, Kousa M. Follow-up study of Reiter’s disease and reactive arthritis. Factors influencing the natural course and the prognosis. Clin Rheumatol 1987;6 (Suppl 2): 73-82. 44. Leirisalo-Repo M. Prognosis, course of disease, and treatment of the spondyloarthropathies. Rheum Dis Clin North Am 1998;24:737-751, viii. 45. Galadari I, Galadari H. Nonspecific urethritis and reactive arthritis. Clin Dermatol 2004;22:469-475. 46. Kvien TK, Gaston JS, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113-1119. 47. Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic treatment and long term prognosis of reactive arthritis. Ann Rheum Dis 2003;62:655-658. 48. Egsmose C, Hansen TM, Andersen LS, et al. Limited effect of sulphasalazine treatment in reactive arthritis. A randomised double blind placebo controlled trial. Ann Rheum Dis 1997;56:32-36. 49. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2021-2027. 50. Braun J, Sieper J. Biological therapies in the spondyloarthritides—The current state. Rheumatology (Oxford) 2004;43: 1072-1084. 51. Flores D, Marquz J, Garza M, Espinoza LR. Reactive arthritis: Newer developments. Rheum Dis Clin North Am 2003;29:37-59.

REACTIVE ARTHRITIS

24

Imaging in Reactive Arthritis Juergen Braun

The term reactive arthritis (ReA) was first used in 1969 to describe the development of sterile inflammatory arthritis as a consequence of a remote infection in the gastrointestinal or urogenital tract.1,2 The demonstration of antigenic material such as Salmonella and Yersinia lipopolysaccharide, DNA, or RNA and occasionally even metabolically active microbes such as Chlamydia in the joints has complicated the differentiation between reactive and postinfectious forms of arthritis. In the absence of internationally accepted diagnostic criteria, the diagnosis of ReA is mostly clinical, based on acute oligoarticular arthritis of larger joints that develops within 2 to 4 weeks of the preceding infection. In 25% to 50% of the patients, the triggering infection can be asymptomatic. The demonstration of these triggering infections may be difficult because the isolation of the triggering microbes in the stool or the urethra by cultures (stool cultures for enteric microbes) or ligase chain reaction (Chlamydia trachomatis) is, after the onset of arthritis, often not possible, and a diagnosis relying solely on often not standardized serologic tests is not very specific.3 ReAs are usually grouped under the umbrella of spondyloarthritis (SpA), and classification criteria for SpA contain a preceding infection as diagnostic item.4 There is an argument whether some types of ReA should not be grouped accordingly because there are very transient forms of ReA such as those observed in population-based studies that do not have a clinical picture of SpA, are not human leukocyte antigen HLAB27 positive, and may even not be triggered by microbes established to cause SpA-related ReA. Therefore, it has been proposed to concentrate on ReSpA.5 The treatment of infections with antibiotics to cure Chlamydia infection is generally important, but either short or prolonged courses of antibiotics have largely failed to cure established arthritis. The long-term outcome of ReA is usually good; however, about 10% to 20% of the patients may proceed to a chronic form of SpA of varying activity at various locations.6

This chapter deals with the specific aspect of imaging of the musculoskeletal manifestations of ReA. Different sites may be involved in ReA (Table 24-1). Imaging modalities, such as computed tomography (CT), bone scintigraphy, magnetic resonance imaging (MRI), and ultrasonography (US) (Table 24-2), have improved the capabilities of detecting early disease and have become useful adjuncts to plain films. In addition, they have enabled more accurate detection of pathology at various anatomic sites of the musculoskeletal system predominantly involved in SpA.7 There is no huge role for imaging in ReA, and data are limited. Therefore, it was necessary to look at other SpAs with which there are many similarities and overlap. There are several different aspects of imaging in ReA: 1. Differentiation between arthralgia, arthritis, and enthesitis (US, scintigraphy, MRI) 2. Detection of involvement of the axial skeleton (xray, MRI) 3. Development to chronic osteodestructive disease (x-ray, CT)

JOINT INVOLVEMENT IN REACTIVE ARTHRITIS Using imaging techniques that potentially assess the magnitude of the musculoskeletal symptoms that may occur in ReA, in this case whole-body scintigraphy, a total of 262 lesions of enthesitis and arthritis were detected in 59 patients with Reiter’s disease, which equals more than 4 lesions per patient.8 The lesional distribution was asymmetric, and 68% were in the lower limb skeleton and 32% in the axial and upper limb skeleton. Enthesopathy, alone or in combination with arthritis, occurred in almost 80%, with a strong predilection for the foot bones, especially the calcaneus (26%). In an epidemiologic study,9 19 of 260 individuals infected with Salmonella typhimurium, all male with a mean age of 40 years, developed joint-associated symptoms (7.3%); the arthralgias were polyarticular in more

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TABLE 24-1 LOCALIZATION OF MUSCULOSKELETAL SYMPTOMS IN REACTIVE ARTHRITIS Peripheral arthritis of the lower limbs Enthesitis Dactylitis Sacroiliitis

than 80% of the cases. The joints most commonly affected were the elbow (47%), wrist (47%), knee (42%), low back (32%), and shoulder (32%). However, clear-cut arthritis in ReA may be less frequent and clinically less significant. In another Canadian study using MRI in AS patients,10 rotator cuff tendinitis was rather prevalent (15.1%). Bone marrow edema at any entheseal site was frequently noted in AS shoulders (70.6%). Intense acromial entheseal edema at the deltoid origin was observed only in AS shoulders (41.2%). It is unclear whether this is similar in ReA. The importance of enthesitis and bone marrow edema in SpA was originally stressed in a small MRI study with 20 SpA and RA patients with recent-onset knee effusion.11 All SpA patients but less than half of the RA patients had focal perientheseal high signal (compatible with fluid or edema) outside the joint. SpA patients had bone marrow edema that, unlike the situation in RA, was maximal at entheseal insertions and in some cases multifocal. In a patient positive for human immunodeficiency virus, a similar pattern and localization were reported.12 The insertion and the adjacent bone of 28 patients with plantar fasciitis (17 with SpA and 11 with enthesitis of mechanical origin) were analyzed in relation to HLA-B27 by the same authors.13 Edema within the soft tissue was evident in both groups; bone edema in the adjacent calcaneum was evident in 65% of HLAB27–positive patients with SpA but also in 45% of the HLA-B27–negative patients with mechanically induced disease. Extensive bone edema was seen only in HLA-B27–positive patients. This study supports the role of HLA-B27 as a severity rather than a susceptibility

TABLE 24-2 IMAGING TECHNIQUES IN REACTIVE ARTHRITIS Ultrasonography Radiography Magnetic resonance imaging

196

Scintigraphy

factor. The role of mechanical stress in the pathogenesis of the SpAs including ReA remains to be defined. In an Arabian study with many HLA-B27–negative patients14 in which scintigraphy was used in a proportion of the patients, enthesitis, on a clinical basis, was seen in only 20% of the patients. Lower limb large joints were affected at presentation in almost 70%, followed by combined presentation of peripheral joints and axial joints in 30% of patients; sacroiliitis was seen in only 15% of cases, and spondylitis was rare. Similar musculoskeletal findings in male and female, mostly HLA-B27–positive ReA patients were reported in a Finnish study.15 These included the frequency of monoarthritis or oligoarthritis (70%), polyarthritis (25%), and back complaints (75%). Inflammation of the knee and sternoclavicular joint and “sausage” toe occurred predominantly in males and finger involvements in females. No major differences between male and female, HLA-B27–positive and –negative ReA patients were found in an early study,16 but an increased prevalence of radiographic changes in the sacroiliac joints and chronic anterior uveitis in HLAB27–positive patients was described. There has been early evidence that active sacroiliitis occurs in Reiter’s disease as in other SpA subtypes.17,18 Severe damage of peripheral joints or the spine has been reported,19 but this is rare in ReA. Taken together, the pattern of joint involvement in ReA as in other SpAs is different from that in RA. A rather asymmetric involvement of the lower limbs and the entheses is characteristic. Imaging may be useful in individual patients to prove synovitis in patients with acute ReA.

DETECTION OF DISEASE-SPECIFIC GUT INFLAMMATION BY IMAGING TECHNIQUES Gut inflammation resembling that in Crohn’s disease as detected by ileocolonoscopy has been reported in SpA patients including those with ReA.20 Mainly nuclear medicine imaging techniques have been used to detect clinically silent gut inflammation in SpA patients. Gastrointestinal accumulation of indium 111–labeled granulocytes in some ReA patients was described in an early study.21 The concordance between abdominal scintigraphy using technetium99m hexamethylpropylene amine oxime (99mTcHMPAO)–labeled leukocytes and ileocolonoscopy was studied in 15 SpA patients without clinical evidence of inflammatory bowel disease.22 There was some correlation with endoscopy similar to that in another study using a different technique with 99mTcciprofloxacin, which also failed to show specific infection-related inflammation but rather showed nonspecific synovitis.23

INVOLVEMENT OF ENTHESES IN REACTIVE ARTHRITIS AND OTHER SPONDYLOARTHRITIDES Enthesitis is a major feature of the SpAs including ReA. The localization of the inflammation and the description of the imaging findings have been subjects of an increasing number of studies. In the earliest imaging study on this subject, 31 consecutive SpA patients (15 ReA, 12 AS, 4 psoriatic arthritis [PsA]) were studied for the presence of enthesitis in the lower extremities, independently by clinical examination and by highresolution sonography.24 Sonography detected inflammatory lesions at 44 entheses of 20 patients. Edema at the insertion of the tendon was the most common finding; signs of enthesitis and bursitis were more common in the lower legs. In addition, enthesitis was diagnosed in 56 sites in 20 patients by clinical examination, most frequently at the insertions of the Achilles tendon and the plantar fascia. Bursitis around the calcaneus and synovitis or pain in the hip and knee joints were most frequently misinterpreted to indicate enthesopathy at the clinical examination. Importantly, half of the insertions with only edema at sonography were clinically asymptomatic. Sonographic examination of ligamentous insertions may offer morphologic information that is unobtainable by the clinical judgment of tenderness at entheses in SpA patients. Using US and MRI, 19 Achilles tendons with severe enthesitis and 9 normal tendons of 14 Italian SpA patients were examined.25 Both methods showed a significant increase in the mean Achilles tendon thickness both at the superior calcaneal surface and 3 cm above in affected patients. MRI showed retrocalcaneal bursitis in 75% of the cases and superficial bursitis in 10%. US had 50% sensitivity and 100% specificity for the detection of retrocalcaneal bursitis; superficial bursitis was not detected. In another large study26 looking at several hundred heels of patients and control subjects, symptomatic plantar aponeurosis was associated with significant thickening in patients with clinically unilateral and bilateral plantar fasciitis including SpA patients. In patients with idiopathic plantar fasciitis, abnormal plantar aponeurosis echogenicity was seen in 78% and subcalcaneal bone spurs in 24%. Peritendinous edema was present in 5% of all symptomatic heels, subcalcaneal bone erosion in 4%, and intratendinous calcification in 3%. Retrocalcaneal bursitis was pres-

ent in 40% of the patients with SpA, 19% with RA, but only 7% of patients with idiopathic plantar fasciitis. Taken together, such changes at the entheses are not specific but are clearly more prevalent in SpA. Thickening of the tendon indicates a pathologic state of that organ. If retrocalcaneal bursitis is present, SpA is more likely. In a Scottish clinical and US study of 35 SpA (27 AS, 7 PsA, 1 ReA) patients, examination of both lower limbs was performed with focus on five entheseal sites—superior pole and inferior pole of patella, tibial tuberosity, Achilles tendon, and plantar aponeurosis.27 Whereas 75 of 348 (22%) entheseal sites were abnormal in the clinical examination, 195 of 348 (56%) sites were abnormal by US. Compared with US, clinical examination had low sensitivity (23%) and moderate specificity (80%) for the detection of enthesitis of the lower limbs. In a large French study, 164 consecutive patients with SpA and 64 control subjects underwent power Doppler US examination of major entheses of their limbs with particular attention to the detection of vascularization.28 The following sites were analyzed: cortical bone insertion of entheses, junction between tendon and entheses, body of tendon, and bursa. Abnormal US findings consistent with at least one feature of enthesitis were observed in almost all SpA patients (98%), affecting almost 40% of all entheses examined. In contrast, only 10% of entheses were found to be abnormal in control subjects. Enthesitis as detected by US was most commonly distributed in the distal portion of the lower limbs, irrespective of SpA subtype and of the skeletal distribution of clinical symptoms. None of the abnormal entheses in control patients showed vascularization, compared with 80% in SpA patients, in whom it was always detected at the cortical bone insertion and sometimes also in the bursa. Power Doppler may be even more sensitive to detect enthesitis in SpA. The question of clinically silent enthesopathy needs to be addressed. A detailed description of the US images of enthesitis29 showed loss of normal fibrillar echotexture of tendon (100%), no homogeneous pattern, blurring of tendon margins (56.2%), and irregular fusiform thickening (84.3%). The affected tendons showed intratendinous lesions with ill-defined focal tendon defects filled with a mixture of fluid, fat, and granulation tissue, with loss of their tightly packed echogenic dots. In comparison, MRI showed tendon enlargement (62.5%) with loss of the normal flattened hypointense appearance, focal thickening and rounded configuration at the insertion site (31.2%), intermediate T1 and high T2 signals, and diminished signals within the preAchilles fat pad because of inflammatory edema. Among all patients, 40.6% had evidence of osteitis.

Involvement of Entheses in Reactive Arthritis and Other Spondyloarthritides

It is possible to screen for gut inflammation by imaging techniques, especially scintigraphy, but endoscopy remains the “gold standard,” and there is no evidence that a positive result should have clinical consequences.

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In a comparative study30 of calcaneal entheses in different diseases including PsA, Achilles enthesitis was found in 8% of the patients with PsA and in 2% with RA, and retrocalcaneal bursitis was found in 18% of RA and in 6% of PsA patients. Posterior and inferior erosions were more frequent in RA (12% and 6%) than in PsA (5% and 1%). Plantar fasciitis was more frequently found in PsA (37%) than in RA (26%). This is expected to be rather similar in ReA, at least in clinical cases. Enthesitis is a characteristic finding in SpAs, including ReA. Imaging techniques such as US and MRI are more sensitive to detect enthesopathy. The clinical significance of this approach remains to be defined.

LONG-TERM PROGNOSIS AND IMAGING The role of imaging in the assessment of the long-term outcome of ReA is mainly concentrated on conventional radiographs of the axial skeleton to detect features of AS. In a retrospective study,31 17 patients with Reiter’s disease identified in an earlier prospective study were reviewed 21 years after their initial episode. Two patients had active synovitis, at least five had AS, and eight had multifocal marginal syndesmophytes. Plantar spur formation and hip and shoulder disease were associated with spondylitis, and destructive small joint changes were a feature of Reiter’s disease itself. Ten patients were HLA-B27 positive, and the clinical features at onset were unrelated to the B27 type. In clinical settings with patients with more severe ReA, up to 30% may develop AS over time.

The HLA-B27 background in the population has some influence. In an early study on native American Indians,32 the phenotype frequency of HLA-B27 was 36% and the frequency of sacroiliitis 11% in the Navajo; in another tribe, the Hopi, HLA-B27 was found in only 9% and sacroiliitis in 4%. Most Navajo men with sacroiliitis were HLA-B27 positive (83%). The increased frequency of radiologic sacroiliitis in the Navajo was related to the high frequency of HLA-B27 and Reiter’s syndrome in this population. In a 10-year follow-up of 85 Finnish patients with acute Yersinia arthritis,33 peripheral joint symptoms occurred frequently (52%), but these symptoms were mild (46%). Development of a new ReA (4.7%) or chronic arthritis (2.4%) was uncommon. One third of the patients experienced low back pain, and one third of the patients had radiologic evidence of sacroiliitis. The presence of sacroiliitis was greater in patients with low back pain (46.7%) than in those who did not have symptoms (21.2%). More patients with HLA-B27 had low back pain and sacroiliitis, but there was no such association with the residual symptoms in peripheral joints. In a more recent Finnish study34 with 90 ReA patients, 53 patients with triggering enteritis and 37 with urethritis or Reiter’s syndrome were included. In the lumbosacral radiographs taken 7 to 38 years after onset, 23% of patients had grade 2 to 4 sacroiliitis according to the New York criteria35 and 14% had syndesmophytes. Sacroiliac changes and syndesmophytes were more frequent in patients with triggering urethritis (32% and 24%, respectively) than enteritis (13% and 6%). This is the first study that suggests a different long-term outcome in relation to the initial triggering infection.

REFERENCES

198

1. Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheum Scand 1969;15:232-253. 2. Keat A. Reiter’s syndrome and reactive arthritis in perspective. N Engl J Med 1983;309:1606-1615. 3. Sieper J, Rudwaleit M, Braun J, et al. Diagnosing reactive arthritis: Role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 2002;46:319-327. 4. Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218-1227. 5. Zochling J, Brandt J, Braun J. The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis. Rheumatology (Oxford) 2005;44:1483-1491. 6. Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic therapy and long-term prognosis of reactive arthritis. Ann Rheum Dis 2003;62:655-658. 7. Grigoryan M, Roemer FW, Mohr A, Genant HK. Imaging in spondyloarthropathies. Curr Rheumatol Rep 2004;6:102-109. 8. Kim SH, Chung SK, Bahk YW, et al. Whole-body and pinhole bone scintigraphic manifestations of Reiter’s syndrome: Distribution patterns and early and characteristic signs. Eur J Nucl Med 1999;26:163-170. 9. Inman RD, Johnston ME, Hodge M, et al. Postdysenteric reactive arthritis. A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31:1377-1383.

10. Lambert RG, Dhillon SS, Jhangri GS, et al. High prevalence of symptomatic enthesopathy of the shoulder in ankylosing spondylitis: Deltoid origin involvement constitutes a hallmark of disease. Arthritis Rheum 2004;51:681-690. 11. McGonagle D, Gibbon W, O’Connor P, et al. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis Rheum 1998;41:694-700. 12. McGonagle D, Marzo-Ortega H, O’Connor P, et al. The role of biomechanical factors and HLA-B27 in magnetic resonance imaging-determined bone changes in plantar fascia enthesopathy. Arthritis Rheum 2002;46:489-493. 13. McGonagle D, Reade S, Marzo-Ortega H, et al. Human immunodeficiency virus associated spondyloarthropathy: Pathogenic insights based on imaging findings and response to highly active antiretroviral treatment. Ann Rheum Dis 2001;60: 696-698. 14. al-Arfaj A. Profile of Reiter’s disease in Saudi Arabia. Clin Exp Rheumatol 2001;19:184-186. 15. Yli-Kerttula UI. Clinical characteristics in male and female uroarthritis or Reiter’s syndrome. Clin Rheumatol 1984;3:351-360. 16. Fox R, Calin A, Gerber RC, Gibson D. The chronicity of symptoms and disability in Reiter’s syndrome. An analysis of 131 consecutive patients. Ann Intern Med 1979;91:190-193. 17. Russell AS, Lentle BC, Percy JS. Investigation of sacroiliac disease: Comparative evaluation of radiological and radionuclide techniques. J Rheumatol 1975;2:45-51.

27. Balint PV, Kane D, Wilson H, et al. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61:905-910. 28. D’Agostino MA, Said-Nahal R, Hacquard-Bouder C, et al. Assessment of peripheral enthesitis in the spondylarthropathies by ultrasonography combined with power Doppler: A cross-sectional study. Arthritis Rheum 2003;48:523533. 29. Kamel M, Eid H, Mansour R. Ultrasound detection of heel enthesitis: A comparison with magnetic resonance imaging. J Rheumatol 2003;30:774-778. 30. Falsetti P, Frediani B, Fioravanti A, et al. Sonographic study of calcaneal entheses in erosive osteoarthritis, nodal osteoarthritis, rheumatoid arthritis and psoriatic arthritis. Scand J Rheumatol 2003;32:229-234. 31. Kuberski TT, Morse HG, Rate RG, et al. A hospital-based survey of radiological sacroiliitis and HLA-B27 and Cw2 in Navajo and Hopi Indians. Hum Immunol 1981;3:77-83. 32. Marks JS, Holt PJ. The natural history of Reiter’s disease—21 years of observations. Q J Med 1986;60:685-697. 33. Leirisalo-Repo M, Suoranta H. Ten-year followup study of patients with Yersinia arthritis. Arthritis Rheum 1988;31:533-537. 34. Mannoja A, Pekkola J, Hamalainen M, et al. Lumbosacral radiographic signs in patients with previous enteroarthritis or uroarthritis. Ann Rheum Dis 2005;64:936-939. 35. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361-368.

References

18. Russell AS, Davis P, Percy JS, Lentle BC. The sacroiliitis of acute Reiter’s syndrome. J Rheumatol 1977;4:293-296. 19. Fox B, Sahuquillo J, Poca MA, et al. Reactive arthritis with a severe lesion of the cervical spine. Br J Rheumatol 1997;36:126129. 20. Mielants H, Veys EM, De Vos M, et al. The evolution of spondyloarthropathies in relation to gut histology. I. Clinical aspects. J Rheumatol 1995;22:2266-2272. 21. Beier JM, Andersen L, Hansen TM, Frederiksen PB. Gastrointestinal accumulation of indium-111 labelled granulocytes in reactive arthritis. Br J Rheumatol 1992;31:543-545. 22. El Maghraoui A, Dougados M, Freneaux E, et al. Concordance between abdominal scintigraphy using technetium-99m hexamethylpropylene amine oxime-labelled leucocytes and ileocolonoscopy in patients with spondyloarthropathies and without clinical evidence of inflammatory bowel disease. Rheumatology (Oxford) 1999;38:543-546. 23. Appelboom T, Emery P, Tant L, et al. Evaluation of technetium99m-ciprofloxacin (Infecton) for detecting sites of inflammation in arthritis. Rheumatology (Oxford) 2003;42:1179-1182. 24. Lehtinen A, Taavitsainen M, Leirisalo-Repo M. Sonographic analysis of enthesopathy in the lower extremities of patients with spondylarthropathy. Clin Exp Rheumatol 1994;12:143-148. 25. Olivieri I, Barozzi L, Padula A, et al. Retrocalcaneal bursitis in spondyloarthropathy: Assessment by ultrasonography and magnetic resonance imaging. J Rheumatol 1998;25:1352-1357. 26. Gibbon WW, Long G. Ultrasound of the plantar aponeurosis (fascia). Skeletal Radiol 1999;28:21-26.

199

REACTIVE ARTHRITIS

25

Outcomes in Reactive Arthritis Andrew Keat and Shahir Hamdulay

200

As curative treatment is not available, the selection of treatments for reactive arthritis is dependent on prediction of outcome. Such understanding of outcomes as is possible also provides a basis for future planning for patients and their doctors. Evidence relating to the natural history of this condition is limited but is available from early studies, such as those of Paronen1 and Sairainen and colleagues,2 in which very limited therapeutic options were available. Subsequent studies have used a range of antimicrobial and anti-inflammatory treatments so that the true natural history is obscured. Moreover, many potentially informative studies of large outbreaks of infection in which reactive arthritis occurred have not included long-term follow-up sufficient to determine the predictive value of background or acute features. Current data allow only a very incomplete view of the possible links between various treatment modalities and outcomes. In spite of the limited data, however, the wide range of possible treatments ranging from conservative management and local injections to biologic therapies renders the prediction of outcomes in both biologic and socioeconomic terms an essential element for the planning of appropriate management. Also, the prediction of outcome is increasingly important in legal proceedings as infections that provoke reactive arthritis may be acquired as a result of the negligence of others. Some studies have addressed outcome in reactive arthritis specifically; others have considered spondyloarthropathies as a group. The extent to which conclusions from spondyloarthropathies as a group can be applied to reactive arthritis is not clear, but it appears logical to recognize overlaps between reactive arthritis in particular and the “family” in general to which it has been assigned. Thus, such data are included in this chapter. For practical purposes, reactive arthritis is regarded as a homogeneous disease, although it is recognized that there may be significant differences between arthritides provoked by different causal infections. What outcomes of reactive arthritis are important? The ultimate “hard” outcome of death or reduced life expectancy is, fortunately, rare and there are few data on which to base clear predictions other than a normal

life expectancy. Perhaps the key elements are the likelihood of developing reactive arthritis, duration of disease, extent of joint damage, likelihood of recurrence, likelihood of sequelae such as ankylosing spondylitis or inflammatory eye disease, effect on work capacity, and likely responses to treatment. Background factors specific to the individual and his or her family at the particular age and time are clearly relevant. Chief among these are the putative infectious trigger and the genetic status of the proband. Features of the disease episode may also allow some prediction of episode outcome. Treatment itself may also affect the course and duration of the episode and possibly the likelihood of complications, recurrence, and incapacity.

LIKELIHOOD OF DEVELOPING ACUTE REACTIVE ARTHRITIS

Causal Infections Reactive arthritis is one outcome of an episode of infection capable of triggering the condition. Many different infections have been anecdotally linked with reactive arthritis (Table 25-1); for the majority of infective agents listed, the likelihood of developing reactive arthritis appears extremely small and for many the association may be entirely spurious. These reports tell us that arthritis consistent with the clinical picture of reactive arthritis occurs in many settings and might be related to a wide range of infective triggers. However, they do not establish causality, and it is clear from the tiny number of reports that the risk of developing reactive arthritis following most of these infections is extremely small. Even the modest number of individual reports of arthritis associated with Clostridium difficile infection3-6 appears inconsistent with the experience of this common infection in many hospitals. Although the idea that some specific infecting agents possess the capacity to incite reactive arthritis whereas others do not remains unproved, data from specific outbreaks of infection are informative. Available epidemic-outbreak and population data relate to infection by a small number of species only as summarized in Table 25-2. Studies in which symptom reporting

Genitourinary Tract

Gastrointestinal Tract

Respiratory Tract

Probable

Probable

Probable

Chlamydia trachomatis

Shigella flexneri Salmonella enteritidis Salmonella typhimurium Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter jejuni

Possible

Possible

Possible

Neisseria gonorrhoeae

Enterotoxigenic Escherichia coli

Streptococcus pyogenes

Mycoplasma fermentans

Cryptosporidium

Chlamydia pneumoniae

Mycoplasma genitalium

Entamoeba histolytica

Chlamydia psittaci

Ureaplasma urealyticum

Giardia lamblia

Mycoplasma pneumoniae

Likelihood of Developing Acute Reactive Arthritis

TABLE 25-1 MICROORGANISMS CAUSING INFECTIONS POSSIBLY ASSOCIATED WITH REACTIVE ARTHRITIS

Legionella pneumophila Bacillus Calmette-Guérin

Clostridium difficile

Coxiella burnetii

Shigella sonnei Strongyloides stercoralis Brucella abortus Taenia saginata Giardia lamblia Leptospira icterohaemorrhagica

only has been used as the basis for the diagnosis of reactive arthritis have been excluded. As can be seen, the likelihood of developing arthritis varies considerably between outbreaks. This is true within one species and between species. Thus, the prevalence of arthritis in Shigella flexneri outbreaks varies from 0.2% to 7% with no cases of arthritis being reported after Shigella sonnei infection. Salmonella infections are also very variably associated with reactive arthritis, with apparently no cases when the outbreak affected children.18 The few available outbreak studies of yersiniosis confirm the impression given by hospital-based reports30 that reactive arthritis may be more likely to occur (12%) than after the other infections considered. The explanation for such variability in the incidence of arthritis between ostensibly comparable outbreaks is unclear. The population prevalence of the human leukocyte antigen HLA-B27 may be one factor, although within the same population great variability exists. Variation in diagnostic sensitivity is also important; in some studies rheumatic symptoms developed but did not conform to reactive arthritis and so were not included, whereas in others virtually all symptomatic individuals were deemed to have reactive arthritis.

Thus, the risk of developing reactive arthritis after infection by S. flexneri ranges from 0.2% to 7%, being apparently negligible with S. sonnei, and after Salmonella enteritidis and Salmonella typhimurium the risk appears higher, up to 29%. Campylobacter infection appears to confer a risk similar to that of Shigella with the incidence of arthritis ranging from fewer than 1% to 7%. The assessment of Yersinia infection in this regard is hampered by the small number of outbreaks, although good population studies are available. The high prevalence of reactive arthritis after both Yersinia enterocolitica and Yersinia pseudotuberculosis infection is consistent with previous reports,30 although it cannot be determined whether this is related primarily to the arthritogenic potential of the bacteria themselves or the populations in which infection occurs. Sexually transmitted infection is also well recognized as a provoking cause of reactive arthritis. The term sexually acquired reactive arthritis (SARA) has been applied to this form of arthritis.31 Data related to the development of reactive arthritis among unselected cases of sporadic sexually transmitted infection are surprisingly few; almost all studies have introduced

201

OUTCOMES IN REACTIVE ARTHRITIS

TABLE 25-2 OUTBREAKS OF ENTERIC INFECTION ASSOCIATED WITH DEVELOPMENT OF REACTIVE ARTHRITIS Bacterium

Author/Reference

No. Affected

No. Arthritis (%)

% HLA-B27 Positive

~150,000

344 (0.2)

—

602

9 (1.5)

—

Shigella S. flexneri Shigella

Paronen, 19481 7

Noer, 1966

Shigella

Calin and Fries, 1976

—

5

80 (4/5)

S. flexneri 1b

Simon et al, 19819

204

3 (1.4)

—

S. flexneri 2a

9

206

3 (1.4)

—

Simon et al, 1981

8

S.sonnei

Simon et al, 1981

85

0

—

S.sonnei

Kaslow et al, 197910

1970

0

—

S.flexneri 2a

Finch et al, 198611

205

5 (2.4)

80

211

14 (7)

36

330

13 (3.9)

9/13

S.sonnei, flexneri and dysenteriae

9

Hannu et al, 2005

12*

Salmonella S. typhimurium

Hakansson et al, 197513

S. typhimurium

Inman et al, 1988

260

19 (7.3)

36 (4/11)

S. typhimurium

Locht et al, 199315

108

17 (15)

—

224

16 (6.9)

84

S. enterica spp.

14

Mattila et al, 1994

16

S. typhimurium

Thomson et al, 1995

423

27 (6.4)

17

S. enteritidis

Rudwaleit et al, 200118

286†

0

—

217

(29)

—

S. enteritidis

17

Dworkin et al, 2001

19

S. enteritidis

Locht et al, 2002

91

13 (14)

—

S. typhimurium

Hannu et al, 200221

63

5 (8)

40

S. typhimurium

Lee et al, 200522

261

(14.6)

33

C. jejuni

Eastmond et al, 198323

130

1 (0.8)

—

C. jejuni

Bremell et al, 199124

35

1 (2.9)

1

330

2 (0.6)

—

20

Campylobacter

C. jejuni

25

Melby et al, 2000

C. jejuni

Hannu et al, 2002

870

45 (7)

14

C. jejuni and C. coli

Hannu et al, 200427

350

9 (2.6)

33

Y. pseudotuberculosis

Press et al, 200128

59

7 (12)†

—

Y. enterocolitica

Hannu et al, 200329

33

4 (12)

75

26*

Yersinia

* Population study. †Children. ‡ Joint symptoms only.

202

bias. Csonka recorded reactive arthritis in 1% of unselected men attending a genitourinary medicine (GUM) clinic with nongonococcal urethritis (NGU).32 Similarly, Keat and colleagues noted SARA in 16 of 531 (3%) men presenting to a GUM clinic with NGU.33 The risk of developing reactive arthritis for women with nongonococcal genitourinary (GU) infection is assumed to be lower, although figures comparable to

those for men do not exist. Similarly, reactive arthritis may develop after genital gonococcal infection, although no prevalence figures are available from which to assess the risk of arthritis. Szanto and Hagenfeldt detected salpingitis in some women with sacroiliitis34; again, no clear data exist to establish or quantify any risk of progression to arthritis among women with salpingitis or upper GU infection.

HLA-B27 and Age Although familial occurrence of reactive arthritis is rare, the operation of the HLA-B27 gene as a risk factor is well known.2,31,46 Among sporadic cases drawn from hospital clinics, up to 80%30,31,46,47 are HLA-B27 positive. However, it is clear from Table 25-2 that more recent reports of outbreaks have found a lower prevalence of HLA-B27, especially in Salmonella and Campylobacter infections, as low as 17%17 and 14%.26 This may be explained by the inclusion of all affected arthritis cases including those with mild disease, suggesting that HLA-B27 acts both as a susceptibility factor and as a determinant of arthritis severity. Because reactive arthritis occurs principally between the ages of 18 and 40 years but enteric infections occur throughout life, it can be concluded that the outcome of provoking infections is significantly influenced by the age of the affected individual. Some studies have found that children are less likely than adults to develop reactive arthritis after a potential trigger infection,18,22 although others have not and the development of reactive arthritis in children is well recognized.

ACUTE EPISODE

Duration and Severity Most episodes of reactive arthritis resolve within 3 to 5 months, with a mean episode duration of 19 weeks.30,48 Glennas and colleagues49 reported that, among patients with SARA and enteric reactive arthritis, 60% and 80% were in remission at 12 months and 100% and 95% at 2 years. Colmegna and colleagues36 also found that 75% of their patients were in remission at 2 years. Most information has been derived from hospital attenders and follow-up of individuals affected by outbreaks has inevitably been more limited, although data from outbreaks do not differ substantially from hospital data in this respect. In some outbreaks arthritis is relatively short lived, and in these circumstances there is no evidence that the triggering agent, acute phase response, or HLA-B27 status influences episode duation.49,50 However, the presence of sacroiliitis and subsequent ankylosing spondylitis is strongly associated with HLA-B27.50,51 In hospital-based studies B27-positive individuals are likely to have longer episode duration, more extra-articular features, especially iritis, and erosive joint damage.52 Amor and colleagues53 found that within spondyloarthopathies, male gender, a positive family history, the presence of chronic gut lesions detected endoscopically, and hip involvement predicted long episode duration. Recurrent episodes and chronic disease are also linked to HLA-B27 positivity.52 Thus, it appears that in outbreaks many individuals, whether HLA-B27 positive or negative, have self-limiting relatively mild disease but that a minority with B27 develop sacroiliitis, destructive peripheral arthritis, and iritis. These individuals are more likely to suffer chronic symptoms, recurrence, and disability and subsequently to develop ankylosing spondylitis. Indeed, in some studies, sacroiliitis, extra-articular features, recurrence, and chronic disease occurred only in HLAB27–positive individuals. Persistence of arthralgia, fatigue, and pain resulting from joint damage is not uncommon for 2 or 3 years despite quiescence of the arthritis.

Acute Episode

Chlamydia trachomatis has been particularly implicated, although its specific role remains unclear. Evidence for its involvement in the pathogenesis of SARA is based on its identification in the genital tract, marked specific humoral and cellular specific immune responses, and the detection of chlamydial antigens, DNA, and RNA in joint samples from patients with SARA.35,36 So strong has this evidence been considered by some authorities that arthritis associated with C. trachomatis infection has also been labeled chlamydiainduced arthritis (CIA).37 However, epidemiologic data are again insufficient to allow clear risk assessment. C. trachomatis genital infection has been identified by conventional microbiologic techniques in 36% to 69% of patients with SARA.38-40 This is comparable to figures for detection of C. trachomatis in men with uncomplicated NGU.41 Thus, reactive arthritis appears as likely to develop in chlamydia-negative NGU as in chlamydia-positive infection. Whereas NGU is a clear risk factor for SARA, it is by no means clear, therefore, that the refinement of the cause of the infection further informs the risk of developing arthritis. Reactive arthritis has, exceptionally, been associated with other GU pathogens. Ureaplasma urealyticum has rarely been isolated from patients with reactive arthritis or Reiter’s syndrome,42,43 and mycoplasmal DNA has been detected in joint samples from patients with a range of inflammatory arthritides, including reactive arthritis.44,45 However, existing data provide insufficient evidence to give any prognostic weighting to such microbiologic findings.

Persistence of Disease and Recurrence Although the majority of episodes settle within 6 months, up to 19% of individuals have symptoms lasting for longer than a year.30,52 Active persistent disease may be progressive arthritis, enthesitis, or sacroiliitis. Chronic arthritis is more frequent in cases related to Shigella, Salmonella, and Chlamydia infection and is uncommon in Yersinia arthritis. Back pain persisting beyond the acute episode occurs in up to 25% of patients.52 The cause of the pain is not clear in all patients. Sacroiliitis, on plain

203

OUTCOMES IN REACTIVE ARTHRITIS

radiography, develops in 14% to 49% of patients. Some studies have reported a high incidence of ankylosing spondylitis on follow-up.2,52,54 However, such data are selective and give a misleading impression. Follow-up of outbreaks suggests a much lower prevalence of ankylosing spondylitis, although probably significantly higher than the background prevalence among unselected HLA-B27–positive individuals.55 Development of sacroiliitis and progression to AS occur almost exclusively in HLA-B27 positives. The presence of chronic gut lesions on endoscopy predicts the development of chronic spondyloarthropathy including ankylosing spondylitis; conversely, absence of such gut lesions or possession of HLA-Bw62 correlates positively with remission of arthritis without sequelae.56 Between 30% and 50% of patients with SARA have a relapse of the illness that may be related to reinfection.30 In contrast, relapse is less common in the enteric forms. Colmegna and colleagues36 noted that recurrence of disease is dependent on the triggering organism. In that study, 6% of patients with Yersinia, 22% of patients with Salmonella, 18% with Shigella, and 38% of patients with chlamydial infection had recurrent disease. In addition to predisposing to recurrence or chronicity of arthritis and the development of iritis and of sacroiliitis, HLA-B27 positivity is associated with a higher acute phase response.51

WORK DISABILITY AND POOR FUNCTIONAL OUTCOME

204

Meaningful estimates of work disability are difficult to derive from existing data because hospital data are selective, follow-up is often incomplete, and social and unemployment support systems differ between countries. However, some patients are unable to continue working, usually because of persistent disease, painful foot joint damage, or spondylitis. Thomson and colleagues17 found that 4 of 27 patients had to change their work as a consequence of reactive arthritis, and Fox and coauthors57 reported that 16% of their patients with acute reactive arthritis had to change their jobs as a consequence of the arthritis. Eleven percent of patients were unemployable. The presence of heel disease was a predictor of poor outcome. These findings contrast with those of many studies in which substantially all patients recovered and resumed normal life. A weighted risk analysis for severe prognosis in spondylarthropathy has been proposed (Table 25-3).53 Each feature is scored and a total score is calculated. A poor outcome is predicted if hip arthritis is present or if more than three factors are present. A score greater than 7 predicts a poor outcome.

TABLE 25-3 FACTORS PREDICTING POOR LONG-TERM OUTCOME IN SPONDYLOARTHROPATHY Predictors of severe disease at presentation Arthritis of the hip

4

ESR > 30

3

Poor response to NSAIDs

3

Lumbar spine stiffness

3

Dactylitis

2

Oligoarthritis

1

Onset < 16 years of age

1

Hip arthritis or > 3 factors at presentation associated with severe disease. ESR, erythrocyte sedimentation rate; NSAID, nonsteroidal antiinflammatory drug. Amor B, Santos RS, Nahal R, et al. Predictive factors for the long-term outcome of spondyloarthopathies. J Rheumatol 1994;21:1883–1887.

HLA-B27 AS A PREDICTOR OF OUTCOME Around the world, the prevalence of reactive arthritis is generally linked to the background prevalence of HLAB27. It is clear from the preceding discussion that it is a weaker risk factor for the development of reactive arthritis than has been supposed but that HLAB27–positive individuals are more likely to experience joint damage, long episode or chronic disease, extraarticular features especially iritis, recurrent episodes, sacroiliitis, and ankylosing spondylitis. Although HLA-B27–positive individuals may handle arthritisprovoking bacteria in a different way from nonsusceptible individuals,58,59 there is no evidence that B27 positivity or the presence of arthritis influences the persistence in the body of arthritogenic bacteria. The issue of non–HLA-B27 genes within populations affected by outbreaks of bacterial diarrhea has not been explored.

EFFECTS OF PROPHYLAXIS AND TREATMENT

Antimicrobial Treatment The identification of microbes, or microbial elements, in the joint and their possible persistence at other sites raised the possibility that effective antimicrobial therapy might prevent reactive arthritis or influence the outcome of established episodes. Unfortunately, in spite of many studies, the value of prophylactic, shortterm, and long-term antibiotic treatment remains unclear. Salient studies of antibiotic therapy for reactive arthritis are summarized in Table 25-4. Undoubtedly, many patients develop arthritis in spite of short courses of antibiotics, usually for the treatment of sexually transmitted infection. Studies

Study Design

Diagnosis (No.)

Intervention

Duration Outcome of Therapy

Author

Prospective, randomized study

Enteric ReA (40)

No treatment vs penicillin, erythromycin, co-trimoxazole cinaxin

10–14 days

No significant difference in outcome

Fryden et al, 199061

Retrospective

SARA (60)

Penicillin, tetracycline, or erythromycin treatment

10 days

37% untreated or treated with penicillin developed ReA vs 10% treated with tetracycline or erythromycin

Bardin et al, 199262

Open

SARA (10) C. trachomatis ReA

Minocycline therapy

3 mo

Improvement in clinical parameters

Panayi and Clark, 198963

Double blind randomized

Enteric ReA (17) & SARA (21) (total 40)

Lymecycline vs placebo

3 mo

Reduction in duration of illness in chlamydia ReA but not other groups

Lauhio et al, 199164

Double blind randomized

Enteric ReA (32) Chlamydia (4) (total 36)

Ciprofloxacin vs placebo

3 mo

No significant difference in outcome

Toivanen et al, 199365

Double blind randomized

ReA (116)

Ciprofloxacin vs placebo

3 mo

No significant difference Sieper et al, in outcome 199966

Double blind randomized

Yersinia arthritis

Ciprofloxacin vs placebo

3 mo

? shorter episode duration. Greater elimination of Yersinia

HoogkampKorstanje et al, 200067

Double blind randomized

ReA (71) Ciprofloxacin vs (Enteric 60, SARA 11) placebo

3 mo

No significant difference in outcome

Yli-Kerttula et al, 200068

Triple blind randomized

Chronic ReA and seronegative arthritis (60)

Doxycycline vs placebo

3 mo

No difference between treatment arms in terms of symptoms and function

Smieja et al, 200169

Double blind randomized

ReA (186)

Azithromycin vs placebo

3 wk

No significant difference

Kvien et al, 200470

ReA (72)

Ciprofloxacin vs placebo

12 mo

No significant difference

Wakefield et al, 199971

3 mo

3 months lymecycline treatment did not change the late outcome

Laasila et al, 200372

3 months ciprofloxacin treatment may reduce late development of spondylitis, uveitis, and sacroiliitis

Yli-Kerttula et al, 200373

Short-Term Treatment

Effects of Prophylaxis and Treatment

TABLE 25-4 OUTCOME OF ANTIBIOTIC TREATMENT OF REACTIVE ARTHRITIS

Medium-Term Treatment

Long-Term Treatment Double blind randomized

Late Outcome of Treatment Double blind controlled

ReA (17)

Lymecycline vs placebo

Follow-up study 4-7

ReA (53) (mainly enteric

Ciprofloxacin vs placebo 3 mo

ReA, reactive arthritis; SARA, sexually acquired reactive arthritis.

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such as that of Popert and colleagues60 established a widespread view that antibiotic therapy is ineffective for prevention or treatment of reactive arthritis for this reason. This view is essentially supported by studies of treatment given for between 10 days and 12 months (see Table 25-4). There are, however, several reasons for regarding the uselessness of antibiotic therapy for reactive arthritis as likely but unproven. In one open study, Bardin and associates62 showed that appropriate treatment of acute urethritis appeared to reduce, but not abolish, the likelihood of the development of acute reactive arthritis in individuals who are known to be susceptible to the disease by virtue of having had a previous episode. Conversely, individuals who had no treatment, or an inappropriate choice of antimicrobial, were more likely to experience a further episode after acute sexually transmitted infection. This aspect of antimicrobial treatment has not been clearly addressed in other studies, so that the true value of early antibiotic treatment of sexually transmitted infection in the prophylaxis of reactive arthritis is unknown. Similarly, prophylaxis against gastrointestinal infection has not been explored; indeed, in outbreaks or threatened outbreaks of gastrointestinal infection, antibiotics are not usually recommended. Among medium-term treatment studies, only that of Lauhio and colleagues64 suggested some improvement of outcome of established reactive arthritis and then only in sexually acquired disease. Treatment for a year with ciprofloxacin71 did not influence outcome. Two studies assessing the possible late benefits of a 3month course of antibiotic treatment72,73 failed to reach a consensus, although the evidence of benefit73 is tenuous. More important, these studies do not clarify two key issues: Are these the right antibiotics? Does antibiotic treatment eradicate the potentially arthritis-causing bacteria? More studies are needed.

In clinical practice, it is clear that eradication of GU infection is important but that there is no place for long-term antibiotic treatment in routine management of reactive arthritis.

Anti-inflammatory Treatment Clear evidence for impact of conventional treatment of reactive arthritis on outcome, rather than symptom control, is sparse but is summarized in a guideline for the treatment of sexually acquired reactive arthritis.74 Nonsteroidal anti-inflammatory drugs (NSAIDs), with or without simple or opioid analgesics, are usually prescribed as first-line treatment. In more severe, NSAIDresistant, systemic or prolonged disease, systemic corticosteroid may be used. However, there is no evidence that these agents make any difference to outcome. In recurrent, chronic, or erosive disease, second-line agents may be used as in rheumatoid arthritis. Of these, sulfasalazine is probably effective for peripheral joint disease.75,76 Other agents including methotrexate and leflunomide may be of benefit in the management of the spondyloarthropathies, although formal evidence for this in reactive arthritis is lacking.77 Anti–tumor necrosis factor therapy has been used successfully on an anecdotal basis in a few patients with severe, chronic disease.78 The place of such biologic therapy in this condition is, however, far from established.

MORTALITY Death is an extremely uncommon outcome of reactive arthritis. Anecdotally, occasional deaths have been attributed to carditis, cardiac valvular disease, and amyloidosis. Although appropriate treatment may benefit outcome, there are insufficient data to provide useful predictive information.

REFERENCES

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1. Paronen I. Reiter’s disease: A study of 344 cases observed in Finland. Acta Med Scand (Suppl) 1948;212:1-112. 2. Sairainen E, Paronen I, Mahohen H. Reiter’s syndrome: A followup study. Acta Med Scand 1969;115:57-63. 3. Vermeulen C, Lemaire V, Liote F. Joint manifestations related to Clostridium difficile. Presse Med 2000;29:476-481. 4. Loffler HA, Pron B, Mouy R, et al. Clostridium difficile-associated reactive arthritis in two children. Joint Bone Spine 2004;71:60-62. 5. Ducroix-Roubertou S, Genet C, Rogez JP, et al. Reactive arthritis due to Clostridium difficile. Med Mal Infect 2005;35:419-421. 6. Guillemain P, Gerster JC. Reactive arthritis induced by Clostridium difficile enteritis. Schweitz Rundsch Med Prax 2005;94:471-474. 7. Noer HR. An “experimental” epidemic of Reiter’s syndrome. JAMA 1966;198:693-698. 8. Calin A, Fries JS. An “experimental” epidemic of rheumatoid arthritis revisited: Follow-up evidence on genetic and environmental factors. Ann Intern Med 1976;84:564-566.

9. Simon DG, Kaslow RA, Rosenbaum J, et al. Reiter’s syndrome following epidemic shigellosis. J Rheumatol 1981;8:969-973. 10. Kaslow RA, Ryder RW, Calin A. Search for Reiter’s syndrome after an outbreak of Shigella sonnei dysentery. J Rheumatol 1979;6:562-566. 11. Finch M, Rodey G, Lawrence D, Blake P. Epidemic Reiter’s syndrome following an outbreak of shigellosis. Eur J Epidemiol 1986;1:26-30. 12. Hannu T, Mattila L, Siitonen A, Leirisalo-Repo M. Reactive arthritis attributable to shigella infection: A clinical and epidemiological nationwide study. Ann Rheum Dis 2005;64:594-598. 13. Hakansson U, Low B, Eitrem R, Winblad S. HL-A 27 and reactive arthritis in an outbreak of salmonellosis. Tissue Antigens 1975;6:366-367. 14. Inman RD, Johnston OAE, Hodge M, et al. Post-dysenteric reactive arthritis. A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31:1377-1383.

41. Martin DH, Bowie WR. Urethritis in males. In: Holmes KK, Sparling PF, Mardh P-A, et al (eds). Sexually Transmitted Diseases, 3rd ed. New York: McGraw-Hill, 1999, pp 833-845. 42. Middleton PJ, Highton TC. Failure to show mycoplasmas and cytopathic virus in rheumatoid arthritis. Ann Rheum Dis 1975;34:369-372. 43. Horowitz S, Horowitz J, Taylor-Robinson D, et al. Ureaplasma urealyticum in Reiter’s syndrome. J Rheumatol 1994;21:877-882. 44. Scheverbaeke T, Gilroy CB, Bébéar C, et al. Mycoplasma fermentans but not M. penetrans detected by PCR assays in synovium from patients with rheumatoid arthritis and other rheumatic disorders. J Clin Pathol 1996;49:824-828. 45. Gilroy CB, Keat A, Taylor-Robinson D. The prevalence of Mycoplasma fermentans in patients with inflammatory arthritides. Rheumatology (Oxford) 2001;40:1355-1358. 46. Brewerton DA, Caffrey M, Nicholls A, et al. Reiter’s disease and HLA-27. Lancet 1973;2:996-998. 47. Reveille JD, Arnett FC. Spondyloarthritis: Update on pathogenesis and management. Am J Med 2005;118:592-603. 48. Leirisalo-Repo M. Prognosis, course of disease, and treatment of the spondyloarthopathies. Rheum Dis Clin North Am 1998;24:737-751. 49. Glennas A, Kvien TK, Melby K, et al. Reactive arthritis: A favourable 2-year course and outcome independent of triggering agent and HLA-B27. J Rheumatol 1994;21:2274-2278. 50. Mattila L, Leirisalo-Repo M, Pelkenen P, et al. Reactive arthritis following an outbreak of Salmonella bovismorbisicans infection. J Infect 1998;36:289-295. 51. Leirisalo-Repo M, Helenius P, Hannu T, et al. Long-term prognosis of reactive salmonella arthritis. Ann Rheum Dis 1997;56: 516-520. 52. Leirisalo-Repo M. Prognosis, course of disease and treatment of the spondyloarthopathies. Rheum Dis Clin North Am 1998;24:737-751. 53. Amor B, Santos RS, Nahal R, et al. Predictive factors for the longterm outcome of spondyloarthopathies. J Rheumatol 1994;21:1883-1887. 54. Good AE. Reiter’s syndrome: Long-term follow-up in the relation to development of ankylosing spondylitis. Ann Rheum Dis 1979;38 (Suppl):39. 55. Van der Linden SM, Valkenburg HA, de Jong BM, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984;27:241-249. 56. Mielants H, Veys EM, Cuvelier C, et al. The evolution of spondyloarthopathies in relation to gut histology. III. Relation between gut and joint. J Rheumatol 1995;22:2279-2284. 57. Fox A, Calin A, Gerber RC, Gibson D. The chronicity of symptoms and disability in Reiter’s syndrome. An analysis of 131 consecutive patients. Intern Med 1979;91:190-193. 58. Penttinen MA, Ekman P, Granfors K. Non-antigen presenting effects of HLA-B27. Curr Mol Med 2004;4:41-49. 59. Inman RD, Payne U. Determinants of synoviocyte clearance of arthritogenic bacteria. J Rheumatol 2003;30:1291-1297. 60. Popert AJ, Gill SM , Laird AJ. A prospective study of Reiter’s syndrome. An interim report on the first 82 cases. Br J Vener Dis 1964;40:160-165. 61. Fryden A, Bengtsson A, Foberg U, et al. Early antibiotic treatment of reactive arthritis associated with enteric infections: Clinical and serological study. BMJ 1990;301:1299-1302. 62. Bardin T, Enel C, Cornelis F, et al. Antibiotic treatment of venereal disease and Reiter’s syndrome in a Greenland population. Arthritis Rheum 1992;35:190-194. 63. Panayi GS, Clark B. Minocycline in the treatment of patients with Reiter’s syndrome. Clin Exp Rheumatol 1989;7:100-101. 64. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 1991;34:6-14. 65. Toivanen A, Yli-Kerrtula T, Luukainen, R, et al. Effect of antimicrobial treatment on chronic reactive arthritis. Clin Exp Rheumatol 1993;11:301-307. 66. Sieper J, Fendler C, Laitko S, et al. No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis. Arthritis Rheum 1999;42: 1386-1396.

References

15. Locht H, Kihlstrom E, Lindstrom FD. Reactive arthritis after salmonella among medical doctors—Study of an outbreak. J Rheumatol 1993;20:845-848. 16. Mattila L, Leirisalo-Repo M, Koskimies S, et al. Reactive arthritis following an outbreak of Salmonella infection in Finland. Br J Rheumatol 1994;33:1136-1141. 17. Thomson GT, De Rubeis DA, Hodge MA, et al. Post-salmonella reactive arthritis: Late clinical sequelae in a point source cohort. Am J Med 1995;98:13-21. 18. Rudwaleit M, Richter S, Braun J, Zieper J. Low incidence of reactive arthritis in children following a salmonella outbreak. Ann Rheum Dis 2001;60:1055-1057. 19. Dworkin MS, Shoemaker PC, Goldoft MJ, Kobayashi JM. Reactive arthritis and Reiter’s syndrome following an outbreak of gastroenteritis caused by Salmonella enteritidis. Clin Infect Dis 2001;33:1010-1014. 20. Locht H, Molback F, Krogfelt KA. High frequency of reactive joint symptoms after an outbreak of Salmonella enteritidis. J Rheumatol 2002;29:767-771. 21. Hannu T, Mattila L, Siitonen A, Leirisalo-Repo M. Reactive arthritis following an outbreak of Salmonella typhimurium phage type 193 infection. Ann Rheum Dis 2002;61:264-266. 22. Lee AT, Hall RG, Pile KD. Reactive joint symptoms following an outbreak of Salmonella typhimurium phage type 135a. J Rheumatol 2005;32:524-527. 23. Eastmond CJ, Rennie JA, Reid TM. An outbreak of Campylobacter enteritis—A rheumatological follow-up survey. J Rheumatol 1983;10:107-108. 24. Bremell T, Bjelle A, Svedhen A. Rheumatic symptoms following an outbreak of campylobacter enteritis: A 5-year follow-up. Ann Rheum Dis 1991;50:934-938. 25. Melby KK, Svendby JG, Eggebo T, et al. Outbreak of campylobacter infection in a sub-arctic community. Eur J Clin Microbiol Infect Dis 2000;19:542-544. 26. Hannu T, Mattila L, Rautelin H, et al. Campylobacter-triggered reactive arthritis: A population-based study. Rheumatology (Oxford) 2002;41:312-318. 27. Hannu T, Kauppi M, Tuomala M, et al. Reactive arthritis following an outbreak of Campylobacter jejuni infection. J Rheumatol 2004;31:528-530. 28. Press N, Fyfe M, Bowie W, Kelly M. Clinical and microbiological follow-up of an outbreak of Yersinia pseudotuberculosis serotype 1B. Scand J Infect Dis 2001;33:523-526. 29. Hannu T, Mattila L, Nuorti JP, et al. Reactive arthritis after an outbreak of Yersinia pseudotuberculosis serotype O:3infection. Ann Rheum Dis 2003;62:866-869. 30. Keat A. Reiter’s syndrome and reactive arthritis in perspective. N Engl J Med 1983;309:1606-1615. 31. Keat AC, Maini RN, Pegrum GD, Scott JT. The clinical features and HLA associations of reactive arthritis associated with nongonococcal urethritis. Q J Med 1979;48:323-342. 32. Csonka GW. The course of Reiter’s syndrome. Br Med J 1958;1:1088-1090. 33. Keat AC, Maini RN, Nkwazi GC, et al. Role of Chlamydia trachomatis and HLA-B27 in sexually acquired reactive arthritis. Br Med J 1978;1:605-607. 34. Szanto E, Hagenfeldt K. Sacro-iliitis and salpingitis: Quantitative 99m Tc pertechnetate scanning in the study of sacro-iliitis in women. Scand J Rheumatol 1979;8:129-135. 35. Hughes RA, Keat AC. Reiter’s syndrome and reactive arthritis: A current view. Semin Arthritis Rheum 1994;24:190-210. 36. Colmegna I, Cuchacovich R, Espinosa LR. HLA-B27-associated reactive arthritis: Pathogenetic and clinical considerations. Clin Microbiol Rev 2004;17:348-369. 37. Wollenhaupt J, Schneider C, Zeidler H, et al. Clinical and serological characterization of Chlamydia-induced arthritis. Dtsch Med Wochenschr 1989;114:1949-1954. 38. Kousa M, Saikku P, Witmand S, Lassus A. Frequent association of chlamydial infection with Reiter’s syndrome. Sex Transm Dis 1978;5:57-61. 39. Keat AC, Thomas BJ, Taylor-Robinson D, et al. Evidence of Chlamydia trachomatis infection in sexually acquired reactive arthritis. Ann Rheum Dis 1980;39:431-437. 40. Silveira LH, Gutierrez F, Scopelitis E, et al. Chlamydia-induced reactive arthritis. Rheum Dis Clin North Am 1993;19: 351-362.

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208

67. Hoogkamp-Korstanje JA, Moesker H, Bruyn GA. Ciprofloxacin v placebo for treatment of Yersinia enterocolitica triggered reactive arthritis. Ann Rheum Dis 2000;59:914-917. 68. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al. Effect of a three month course of ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis 2000;59:565-570. 69. Smieja M, MacPherson DW, Kean W, et al. Randomised, blinded, placebo controlled trial of doxycycline for chronic seronegative arthritis. Ann Rheum Dis 2001;60:1088-1094. 70. Kvien TK, Gaston JSH, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113-1119. 71. Wakefield D, McCluskey P, Verma M, et al. Ciprofloxacin treatment does not influence course or relapse rate of reactive arthritis and anterior uveitis. Arthritis Rheum 1999;42: 1894-1897. 72. Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic treatment and long term prognosis of reactive arthritis. Ann Rheum Dis 2003;62:655-658.

73. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al. Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis. Ann Rheum Dis 2003;62:880-884. 74. Carlin EM, Keat AC. European guideline for the management of sexually acquired reactive arthritis. Int J STD AIDS 2001;12 (Suppl 3):94-102. 75. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). A Department of Veterans Affairs cooperative study. Arthritis Rheum 1996;39:2021-2027. 76. Charlotte E, Hansen TM, Andersen LS, et al. Limited effect of sulphasalazine treatment in reactive arthritis. A randomised double blind placebo controlled trial. Ann Rheum Dis 1997;56:32-36. 77. Anandarajah A, Ritchlin CT. Treatment update on spondyloarthropathy. Curr Opin Rheumatol 2005;17:247-256. 78. Oili KS, Niinisalo H, Korpilahde T, Virolainen J. Treatment of reactive arthritis with infliximab. Scand J Rheumatol 2003;32:122-124.

REACTIVE ARTHRITIS

26

Management of Reactive Arthritis Tracy M. Frech and Daniel O. Clegg

DEFINITION AND NATURAL HISTORY

Reactive Arthritis and Human Immunodeficiency Virus Disease

Hans Reiter first reported the association of arthritis, nongonococcal urethritis, and conjunctivitis in 1916.1 In the early 1970s the association between Reiter’s syndrome and human leukocyte antigen HLA-B27 positivity was made, and from that association arose the concept of “incomplete” Reiter’s syndrome,2 which described a group of patients with asymmetric oligoarthritis and HLA-B27 positivity. Because of the frequent association between sexually transmitted and enteric infections and the subsequent development of Reiter’s syndrome, the term reactive arthritis3 was proposed in 1969. It now seems clear that fully manifest Reiter’s syndrome is seen in a subset of patients with reactive arthritis. Thus, the term reactive arthritis seems more appropriate to describe the condition in this unique group of patients whose main clinical manifestations include asymmetric oligoarthritis, an increased prevalence of HLA-B27 positivity, nongonococcal urethritis, conjunctivitis, distinct rashes (including circinate balanitis and keratoderma blennorrhagicum), oral ulcers, uveitis, subclinical enterocolitis, carditis, and nephritis.4 The natural history of reactive arthritis is extremely variable; most patients experience exacerbations and remissions, which can last from several weeks to several months.5 Typically reactive arthritis occurs from 1 day to 4 weeks after a gastrointestinal infection (commonly Salmonella, Shigella, Yersinia, or Campylobacter) or a genitourinary infection (usually Chlamydia or Ureaplasma). Although a few patients have but a single episode of the disease, the rule would be to have multiple flares of disease activity. Fox and colleagues6 reported that 83% of 122 patients with reactive arthritis had persistent disease at 5.6 years. Approximately one fourth of those patients were unable to work or had changed their vocation because of their disease. Inman’s series of postenteric infection reactive arthritis patients at 1 year follow-up found that 7 of 15 patients continued to have persistent joint symptoms.7

There have been several reports of reactive arthritis in association with human immunodeficiency virus (HIV) infection. Although reactive arthritis can occur after the patient becomes seropositive for HIV, clinical features of reactive arthritis frequently precede the recognition of clinical HIV-associated diseases. Therefore, a high index of suspicion is warranted.8 HIV infection does not appear to alter the course of the reactive arthritis per se; however, there have been reports in which the use of immunosuppressive medications in this population of patients resulted in abrupt clinical deterioration and the onset of other manifestations of the acquired immunodeficiency syndrome.9

PATHOGENESIS Among the several hypotheses proposed for the pathogenesis of reactive arthritis, experimental evidence has supported that it may result from the aberrant profiling of T helper cells secondary to an imbalance of cytokines provided by antigen-presenting cells. A proper T-cell response with appropriate cytokine release is necessary for eradication of a microbe. An imbalance of T helper 1 (Th1) cytokines, such as interferon γ and tumor necrosis factor α (TNF-α), and T helper 2 (Th2) cytokines, such as interleukin 4 (IL-4) and IL-10, may be responsible for incomplete eradication of an infectious organism and persistence of inflammation.10 Treatment options focus on reducing inflammation and modulating cytokine profiles as well as ensuring that the primary infection has been properly treated.

TREATMENT Patients with reactive arthritis are frequently relatively young and geographically mobile. As already mentioned, reactive arthritis has a highly variable course that is punctuated by remissions and exacerbations.

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MANAGEMENT OF REACTIVE ARTHRITIS

These factors, combined with the relatively low incidence of the disease, make it extremely difficult to conduct controlled trials with a follow-up period that is adequate to assess response and with sufficient numbers of patients to obtain clinical and statistical meaning. Therefore, rather than report on uncontrolled and controlled experience, this section is subdivided by drug class.

Nonsteroidal Anti-inflammatory Drugs The nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in treating the musculoskeletal manifestations of reactive arthritis. Indomethacin has, perhaps, been most extensively used,11 but there are no published data to suggest that any nonsteroidal agent is either more effective or less toxic in patients with reactive arthritis. At this time there is no published experience specific to use of the selective cyclooxygenase 2 agents in reactive arthritis. To our knowledge, there are no studies to suggest that patients with reactive arthritis have any unique susceptibility or resistance to the adverse drug reactions that are commonly associated with NSAIDs. As with other inflammatory arthropathies, NSAIDs seem to improve the articular complaints associated with reactive arthritis. Choice of any given agent often requires balancing clinical response against the potential for medication toxicity.

Steroids Oral corticosteroids can be a very useful treatment modality in the acute setting for control of pain related to articular swelling. An initial dose of prednisone of 30 to 40 mg/day followed by a consecutive taper based on clinical response has been suggested as an effective adjuvant to NSAIDs.12 Intra-articular steroids may be preferable to systemic steroids if disease is localized to one or two joints. Injectable steroids can also be useful in the acute management of enthesitis or bursitis.13

Sulfasalazine

210

Sulfasalazine was shown to be well tolerated and effective in the treatment of reactive arthritis in a 9-month double-blind, placebo-controlled trial involving 134 patients with reactive arthritis from the United States and Canada.14,15 The toxicity of sulfasalazine in reactive arthritis appears comparable to the toxicity seen in other patients with spondyloarthropathy.15 As has been seen with ankylosing spondylitis, some patients with reactive arthritis appear to have histologic enterocolitis that also improves with sulfasalazine therapy. The causal association of these findings with a clinical response to sulfasalazine remains unclear16 but again demonstrates the complex interplay between the spondyloarthropathies and the gut.

Immunosuppressive Drugs Methotrexate, azathioprine, and cyclosporine have been used empirically to treat patients with recalcitrant reactive arthritis. Some improvement has been reported, although the results are not striking and published anecdotal reports are obviously biased in favor of positive results. Use of either methotrexate or azathioprine in patients with reactive arthritis and HIV seropositivity may hasten the manifestations of acquired immunodeficiency syndrome.9 Thus, the use of these medicines should be carefully considered in patients at risk for HIV positivity.

Anti–Tumor Necrosis Factor Therapy TNF-α is an important mediator of inflammation and is detectable in synovium in early reactive arthritis.17 Although several studies have shown reduction of inflammation and symptomatic improvement with anti–TNF therapy in undifferentiated spondyloarthopathy, its role in reactive arthritis is less clear.10 TNF-α is important and necessary for microbial eradication, and a deficit of this cytokine may contribute to bacterial persistence. Low TNF-α and HLA-B27 status contribute to longer disease duration.18 In fact, a TNF microsatellite allele has been found to have an independent effect on B27-negative patients with reactive arthritis.19 Thus, the role of TNF-α inhibition is yet to be determined.

Antibiotics The demonstration of bacterial cell wall products and nucleic acids in the synovia of patients with reactive arthritis20-23 raises concern for the presence of chronic subclinical infection and makes the concept of longterm antibiotic therapy intriguing. Conflicting data have been developed addressing this issue. In an early report,24 10 patients with peripheral arthritis after Chlamydia trachomatis infection were treated for 3 months with minocycline and showed improvement in morning stiffness and number of active joints. Subsequently, a controlled trial involving 40 patients who received either 2 weeks of antibiotics appropriate for their culture-demonstrated infections (Salmonella, Yersinia, or Campylobacter) or placebo did not reveal a difference between the two groups.25 In a doubleblind, placebo-controlled trial of 3 months of treatment with a tetracycline derivative, a group of patients with primarily postchlamydia arthritis showed some improvement compared with the placebo group.26 A 9month trial comparing doxycycline with the combination of doxycycline and rifampin in patients with undifferentiated spondyloarthropathy suggested some efficacy for the combination.27 More recently, a 24week double-blind, placebo-controlled trial evaluated the efficacy of azithromycin in reactive arthritis and

Approach to Management Recommendations for treatment of reactive arthritis are difficult to define on evidence-based clinical data alone. Education of patients and physical therapy goals are probably important in patients with persistent chronic inflammatory disease, although there have not been trials involving such patients. Conventional medical therapy would be to use an NSAID or corticosteroid injection in an attempt to control the articular manifestations. Sulfasalazine improves chronic peripheral arthritis. It should probably be tried before either methotrexate or azathioprine is considered. Therapy with antibiotics for articular complaints remains controversial. If antibiotic therapy is useful, it appears that prolonged (3 months or longer) oral tetracycline would be the medication of choice. Immunosuppressive drugs such as methotrexate or azathioprine may produce some benefit in chronic, unrelenting articular disease. The data on treatment of established chronic Reiter’s syndrome with either methotrexate or azathioprine are empirical. A ration-

ale for recommending one over the other cannot be substantiated. Although anti–TNF-α therapy does not clearly have a role, the experience and comfort level of the treating physician with the use of these agents and with the necessary monitoring for potential toxicity play an important role in choice of agent. Drug side effects and recommended monitoring have been covered in previous sections of this chapter. Except for the caveat that HIV-positive patients may have untoward reactions to immunosuppressive medications, no unique drug interactions are seen in patients with arthritis.

References

found no benefit.28 These data, along with others, suggest that antibiotics do not seem to affect the course of enteropathic reactive arthritis. If it is treated early, the course of urogenital reactive arthritis may be affected by antibiotic therapy,29 as may the course of the primary insult, and thus antibiotic treatment should be considered in this subset of patients with reactive arthritis. Longer term antibiotic treatment may have some role, although additional trials with patients with disease defined by urogenital cultures and other appropriate additional studies are necessary to better define such a role.30 The mechanism of response to antibiotics remains undefined.

FUTURE DIRECTIONS The reactive arthritides constitute a spectrum of fascinating rheumatologic disorders with a genetic basis (HLA-B27) and an environmental component (postenteric or postvenereal infections). Basic research aimed at further elucidating the complex interactions between these factors is ongoing and is likely to provide answers to the pathophysiology of not only the reactive arthritides but also the other spondyloarthropathies and, perhaps, other rheumatologic disorders. Clinical research in reactive arthritis is problematic because new cases seem to be diminishing both in the United States and abroad. This may be the result of changes in sexual practices related to HIV as well as improved safety of the world’s food supply. Controlled clinical trials in the reactive arthritides, therefore, are difficult because of the low incidence and diminishing prevalence of the disease, its variable natural history, and the young, mobile population that it most frequently affects. Thus, current therapy is empirical and anecdotal and must be highly individualized.

REFERENCES 1. Reiter H. Uber eine bisher unerkannte Spirochanteninfektion (spirochaetosis arthritica). Dtsch Med Wochenschr 1916;42:1535. 2. Arnett FC, McClusky OE, Schacter BZ, Lordon RE. Incomplete Reiter’s syndrome: Discriminating features and HL-A W27 in diagnosis. Ann Intern Med 1976;84:8-12. 3. Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 1969;15:232253. 4. Lahesmanaa-Rantala R. Clinical spectrum of reactive arthritis. In: Toivanen TP (ed). Reactive Arthritis. Boca Raton, Fla: CRC Press, 1988, p 1. 5. Keat A. Reiter’s syndrome and reactive arthritis in perspective. N Engl J Med 1983;309:1606-1615. 6. Fox R, Calin A, Gerber RC, Gibson D. The chronicity of symptoms and disability in Reiter’s syndrome. An analysis of 131 consecutive patients. Ann Intern Med 1979;91:190-193. 7. Inman RD, Johnston ME, Hodge M, et al. Postdysenteric reactive arthritis. A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31:1377-1383. 8. Keat A, Rowe I. Reiter’s syndrome and associated arthritides. Rheum Dis Clin North Am 1991;17:25-42.

9. Winchester R, Bernstein DH, Fischer HD, et al. The co-occurrence of Reiter’s syndrome and acquired immunodeficiency. Ann Intern Med 1987;106:19-26. 10. Meador R, Hsia E, Kitumnuaypong T, Schumacher HR. TNF involvement and anti-TNF therapy of reactive and unclassified arthritis. Clin Exp Rheumatol 2002;20 (6 Suppl 28):S130-S134. 11. Thim Fan P. Reiter’s syndrome. In: Kelley WN, Ruddy S, Sledge CB (eds). Textbook of Rheumatology. Philadelphia: WB Saunders, 1993, p 961. 12. Palazzi C, Olivieri I, D’Amico E, et al. Management of reactive arthritis. Expert Opin Pharmacother 2004;5:61-70. 13. Toivanen A. Managing reactive arthritis. Rheumatology (Oxford) 2000;39:117-119. 14. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2021-2027. 15. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheum 1999;42:2325-2329.

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16. Mielants H, Veys EM. The gut in the spondyloarthropathies. J Rheumatol 1990;17:7-10. 17. Kotake S, Schumacher HR Jr, Arayssi TK, et al. Gamma interferon and interleukin-10 gene expression in synovial tissues from patients with early stages of Chlamydia-associated arthritis and undifferentiated oligoarthritis and from healthy volunteers. Infect Immun 1999;67:2682-2686. 18. Braun J, Yin Z, Spiller I, et al. Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum 1999;42:2039-2044. 19. Tuokko J, Koskinen S, Westman P, et al. Tumour necrosis factor microsatellites in reactive arthritis. Br J Rheumatol 1998;37:1203-1206. 20. Granfors K, Jalkanen S, von Essen R, et al. Yersinia antigens in synovial-fluid cells from patients with reactive arthritis. N Engl J Med 1989;320:216-221. 21. Granfors K, Jalkanen S, Lindberg AA, et al. Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet 1990;335:685-688. 22. Schnarr S, Putschky N, Jendro MC, et al. Chlamydia and Borrelia DNA in synovial fluid of patients with early undifferentiated oligoarthritis: Results of a prospective study. Arthritis Rheum 2001;44:2679-2685.

23. Gerard HC, Branigan PJ, Schumacher HR Jr, Hudson AP. Synovial Chlamydia trachomatis in patients with reactive arthritis/Reiter’s syndrome are viable but show aberrant gene expression. J Rheumatol 1998;25:734-742. 24. Panayi GS, Clark B. Minocycline in the treatment of patients with Reiter’s syndrome. Clin Exp Rheumatol 1989;7:100-101. 25. Fryden A, Bengtsson A, Foberg U, et al. Early antibiotic treatment of reactive arthritis associated with enteric infections: Clinical and serological study. BMJ 1990;301:1299-1302. 26. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 1991;34:6-14. 27. Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol 2004;31:1973-1980. 28. Kvien TK, Gaston JS, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 2004;63:1113-1119. 29. Leirisalo-Repo M. Are antibiotics of any use in reactive arthritis? APMIS 1993;101:575-581. 30. Sieper J, Braun J. Treatment of reactive arthritis with antibiotics. Br J Rheumatol 1998;37:717-720.

INDEX

Note: Page numbers followed by the letter b refer to boxes, those followed by f refer to figures, and those followed by t refer to tables. A Abatacept, 108, 146 Abortion, therapeutic, psoriatic arthritis related to, 49 Achilles tendon enthesopathy of, in psoriatic arthritis, 15, 84 reactive arthritis in, 134 imaging of, 197, 198 Acitretin, for psoriasis, 118 ACR (American College of Rheumatology) anti-angiogenesis response criterion of, 63 psoriatic arthritis joint count tool, 91, 91t ACR20 response, in drug trials, on psoriatic arthritis, 103-106, 108 Activator protein 1 (AP-1), in psoriatic arthritis, 57 Activities of daily life, psoriatic arthritis and, 95 Adalimumab for psoriasis, 115t, 120 for psoriatic arthritis, 8, 105-106 for reactive arthritis, 146 ADEPT study, 105 Adhesion molecules, cell in inflamed synovium, 162, 164t in psoriatic arthritis, 7 biologic agents targeting, 108 intercellular in psoriatic arthritis, biologic agents targeting, 108 in spondyloarthropathy, 164t, 165 treatment effect on, 168-170, 168t synoviocytes expression of, 161 vascular in spondyloarthropathy, 164t, 165 synoviocytes expression of, 162

Adipocytes, in synovial membrane, 162 Age at onset of psoriatic arthritis, 37, 76 of reactive arthritis, 158, 179 clinical outcome and, 203 Agglutination assays, in reactive arthritis diagnosis, 136, 136t Ahvonen’s description, of reactive arthritis, 130 AIMS (Arthritis Impact Measurement Scales), 34, 95 Alanine transaminase (ALT), leflunomide impact on, 99 Alefacept for psoriasis, 115t, 118-119 for psoriatic arthritis, 8, 98, 107-108 for spondyloarthropathy, 168t, 173 Alibert, Jean Louis, 6 Alleles in psoriasis-susceptibility genes, linkage disequilibrium of, 71-72, 71t, 75, 77 in psoriatic arthritis complexity of identifying, 66-67 HLA, 37, 39 autoimmune mechanisms of, 40-41, 42, 43, 43f candidate genes and, 72-77 pathogenic role, 48 psoriasis-susceptibility maps to, 70-72, 70f, 71t Lys80, 39 ALT (alanine transaminase), leflunomide impact on, 99 American College of Rheumatology (ACR) anti-angiogenesis response criterion of, 63 psoriatic arthritis joint count tool, 91, 91t American Rheumatism Association, 1, 6, 19

Amyloidosis, secondary, psoriatic arthritis and, 33 Anakinra, for psoriatic arthritis, 108 Angelman syndrome, 77 Angiogenesis in psoriatic arthritis, 7, 61-64 as therapeutic target, 62-63 description of, 61-62, 62f summary, 63-64 pathophysiologic role, 51, 62 in spondyloarthropathy, 162, 163, 165 treatment effect on, 168t, 169-170 inhibition of immunohistochemical analysis of, 63 novel therapeutic strategies for, 63 Angiopoietins (ANGs), in psoriatic arthritis, 51, 61, 62 therapy targeted at, 62, 63 Angiostatin, for angiogenesis inhibition, 63 Animal models of psoriatic arthritis, 56-57, 56t of reactive arthritis, 184, 185, 191 of spondyloarthropathy, 171 Ankylosing spondylitis (AS) classification criteria for, 188, 189b historical aspects of, 130 idiopathic skeletal hyperostosis vs., 128 in psoriatic arthritis, 6, 14, 16, 104 diagnostic applications of, 21t, 22 hip disease and, 32 natural history of, 30 in reactive arthritis, 130, 136 acute outcomes related to, 203, 204 prognosis of, 177t, 178

213

INDEX

214

Ankylosing spondylitis (AS) (Continued) synovial histopathology, 164t synovial immunopathology in, 161, 171 Anthralin, for psoriasis, 115t, 116 Anti-citrullinated protein antibodies, 144 in psoriatic arthritis, 7, 54 as diagnostic criteria, 20 in spondyloarthropathy, 161, 172-173 Anti-interleukin 15 (IL-15), for psoriatic arthritis, 108 Anti-tumor necrosis factor α. See Tumor necrosis factor α inhibitors. Antiapoptotic molecules, in inflamed synovium, 163 Antibiotics for reactive arthritis bacterial persistence and, 182 clinical outcomes related to, 195, 204, 205t, 206 effect on prognosis, 179, 210-211 efficacy of, 145, 156, 159, 210, 211 goals of, 193 long-term, for Chlamydia-induced arthritis, 156, 159 Antibody(ies) antifillagrin, 20 in psoriatic arthritis, acquired response of, 54 in reactive arthritis, microorganismspecific, 152, 158 monoclonal for psoriatic arthritis, 8, 108 for reactive arthritis, 192 in spondyloarthropathy, 172 to cyclic citrullinated peptides, 7, 20, 54, 144 in psoriatic arthritis, 7, 54 as diagnostic criteria, 20 in spondyloarthropathy, 161, 172-173 Antidepressant therapy, 109 Antifillagrin antibodies, 20 Antigen(s) in psoriasis, 114 in psoriatic arthritis, 7, 8, 39 autoimmune mechanisms of, 41, 42, 43f cross-presentation of, 39, 42, 43f in reactive arthritis, 152-153, 158, 195 animal models of, 184, 191 arthritogenic peptide hypothesis of, 184-185

Antigen(s) (Continued) bacterial, 189-190, 190f CD4+ T cells and, 183-184 chronic persistence of, 177, 182 cross-reactive group, 140 intestinal surgery stimulation of, 154 in spondyloarthropathy, 162, 164t, 171 leukocyte function in psoriasis, 114 in psoriatic arthritis, biologic agents targeting, 8, 108 Antigen-presenting cells (APCs) in inflamed synovium, 162, 164t in psoriasis, 114 in psoriatic arthritis, 41, 42, 43f in reactive arthritis, 209 Antimalarial agents, for psoriatic arthritis, 100 AP-1 (activator protein 1), in psoriatic arthritis, 57 Aponeurosis, plantar, in reactive arthritis, 197 Apoptosis, in spondyloarthropathy, 163 treatment effect on, 169-170, 169t Arthralgia, reactive arthritis causing, 133, 135t imaging of, 195-196 prognosis of, 177t, 178 Whipple’s disease and, 153-154 Arthritis axial skeleton BASDAI outcomes, 94-95 Chlamydia-induced, 157, 159 historical aspects of, 5-6 infectious, 157, 159 natural history of, 177 reactive, 143, 188, 192 spondyloarthropathy and, 161 crystal-induced, 16 infective. See Reactive arthritis (ReA). Chlamydia-related. See Chlamydia-induced arthritis (CIA). enteric organisms in. See Enterogenic reactive arthritis. inflammatory. See Inflammatory arthritis. psoriasis link to, 130 psoriatic. See Psoriatic arthritis (PsA). reactive. See Reactive arthritis (ReA). seronegative current views on, 130-131, 131t historical aspects of, 5, 128, 130 pathogenesis of, 131 prognosis studies on, 31

Arthritis Impact Measurement Scales (AIMS), 34, 95 Arthritis mutilans in psoriatic arthritis pencil-in-cup change with, 16, 17f prognosis studies on, 31 synovitis findings, 12t, 13-14, 13f with sacroiliitis, 2 radiography of, 82, 82f Arthritogenic peptide hypothesis, of HLA-B27, in reactive arthritis, 184-185, 190f, 191 Arthropathy(ies), psoriatic arthritis associated with, 1, 2, 6, 8 Articular cartilage, in inflamed synovium, 163 AS. See Ankylosing spondylitis (AS). Auranofin, for psoriatic arthritis, 99 Auspitz, Heinrich, 5 Auspitz phenomenon, 5 Autoimmune disease in psoriatic arthritis, 7 complexity of identifying, 66-67 etiopathogenesis role, 40-44, 43f-44f genetic knowledge supporting, 65-66, 66f pedigrees illustrating, 67f, 68, 69f, 70 spondyloarthropathy research and, 173 Axial skeleton, arthritis of BASDAI outcomes, 94-95 Chlamydia-induced, 157, 159 historical aspects of, 5-6 infectious, 157, 159 natural history of, 177 reactive, 143, 188, 192 spondyloarthropathy and, 161 Azathioprine for psoriatic arthritis, 99-100 for reactive arthritis, 146, 211 Azithromycin for Chlamydia-induced arthritis, 159, 210-211 for reactive arthritis, 193, 205t, 206 B B-cell antigen specific clonal receptors, in psoriatic arthritis, 68, 70 B lymphocytes in psoriatic arthritis, 7, 39 acquired response of, 54 in spondyloarthropathy, 162, 164t, 173 treatment effect on, 168-170, 168t, 169f

Biologic markers, of psoriatic arthritis, 94 Biopsy liver, indications for, 98 synovial for psoriatic arthritis diagnosis, 23, 24t for spondyloarthropathy, 168, 169, 170, 172 Blood urea nitrogen, in reactive arthritis, 135, 135t Blood vessels. See also Vascularization. growth of. See Angiogenesis. in spondyloarthropathy, 163, 165, 165f in synovial membrane, 162 Blumberg, Baruch S., 6 BMD (bone mineral density), biologic agents impact on, 109 BMPs (bone morphogenetic proteins) in psoriatic arthritis, 53 in spondyloarthropathy, 167-168 Bone disease in psoriatic arthritis, clinical features of, 16-17, 17f in spondyloarthropathy, 163, 167 Bone formation, in psoriatic arthritis extra, 16-17, 17f juxta-articular, 22, 23f, 23t, 26, 26t new, 53 radiography of, 82 Bone marrow edema, in reactive arthritis with enthesis, 196 Bone mineral density (BMD), biologic agents impact on, 109 Bone morphogenetic proteins (BMPs) in psoriatic arthritis, 53 in spondyloarthropathy, 167-168 Bone remodeling in psoriatic arthritis, 52-53, 53f in spondyloarthropathy, 173-174 Bone resorption in psoriatic arthritis, 52-53, 53f in spondyloarthropathy, 163, 167 Borrelia burgdorferi, reactive arthritis triggered by, 181 Bourdillon, Charles, 6 Bowel, psoriatic arthritis involvement of, 15 Brewerton’s description, of reactive arthritis, 131 Brodie’s description, of reactive arthritis, 128, 129t, 130 Bromocriptine, for psoriatic arthritis, 100

Brucella spp., reactive arthritis caused by, 153 Bursitis, in reactive arthritis, imaging of, 197, 198 C C-reactive protein in psoriatic arthritis, 93 measurement of, 94 therapy impact on, 99, 100 with synovitis, 63 in reactive arthritis, 134, 135t, 144, 157 E-Cadherin, in psoriatic arthritis, 42 Calcaneal lesions, plantar, in psoriatic arthritis, 15 Calcipotriene, for psoriasis, 115t, 116 Campylobacter spp., reactive arthritis caused by, 123, 124t, 142 diagnostic isolation of, 151, 152 genetics of, 188 likelihood of, 201, 201t, 202t natural history of, 176, 177b outbreak cohorts, 124, 125t pathogenesis of, 181 socioeconomic impact of, 179 survey programs on, 125-126 Candidate genes, in psoriatic arthritis, 72-77 genome scans for linkage, 76-77 identification challenges of, 65-67, 66f models of, 67-68, 67f psoriasis-susceptibility maps to, 70-72, 70f, 71t Capillaroscopy, 61 CARD (caspase recruitment domain), N-terminal, 77 CARD15 gene in psoriatic arthritis, 37 genome scan for linkage, 76-77 in spondyloarthropathy, 172 Cardiovascular system psoriatic arthritis involvement of, 15, 32, 33 biologic agents impact on, 109 reactive arthritis involvement of, 134, 143, 178 CART (classification and regression tree), 24 Cartilage articular, in spondyloarthropathy, 163, 167, 172 destruction of, in psoriatic arthritis, 49, 52 CASPAR (Classification of Psoriatic Arthritis), 3, 17 diagnostic applications of, 20, 22, 24, 26-27, 26t

Index

Bacillus Calmette-Guérin (BCG), in reactive arthritis, 181 Back pain chronic, 133-134 in Chlamydia-induced arthritis, 157 Bacterial infections reactive arthritis caused by, 123, 124t antigen identifications, 189-190, 190f cultures for, 135-136, 136t, 144, 152, 154, 158 enteric pathogens in, 125-126 genetics of, 188-193 pathogenesis of, 181 persistence of, 182 cytokine imbalance role, 182-183 prevalence of, 123-124 single-source outbreaks, 124-125, 125t, 126t study techniques in, 124-126, 124t reactive arthritis vs., 136 Bath Ankylosing Spondylitis Metrology Index (BASDAI), of psoriatic arthritis outcomes axial joint damage, 95 fatigue, 95 spinal involvement, 93 Bauer, Walter, 6 Bazin, Ernest, 6 BCG (bacillus Calmette-Guérin), in reactive arthritis, 181 Behçet’s syndrome, 130 Bennett criteria, for psoriatic arthritis, 21t, 23-24, 24t comparative accuracy of, 24, 26, 26f β-Hemolytic streptococci, reactive arthritis associated with, 189 Biologic agents for psoriasis management, 115, 115t, 118-120 for psoriatic arthritis, 102-109. See also specific agent, e.g., Alefacept. cytokine targets of, 90, 102, 108 inflammation and, 108-109 leukocyte function antigen targets of, 8 miscellaneous other, 107-108 outcome measures of, 90, 95, 95t potential, 108 summary of, 102-103, 109 tumor necrosis factor α inhibitors, 103-107. See also Tumor necrosis factor α inhibitors. for reactive arthritis, 146, 193 for spondyloarthropathy, 168-170, 168t, 169f

215

INDEX

216

Caspase recruitment domain (CARD), N-terminal, 77 CCP. See Cyclic citrullinated peptide (CCP). CD4+ cells in psoriatic arthritis, 7, 38 acquired response of, 54 Alefacept impact on, 108 autoimmune mechanisms of, 42, 43f genetic knowledge supporting, 65, 66f cytokine network and, 40, 41f regulatory T-cells and, 39 in reactive arthritis genetics of, 190f, 191, 192 pathogenesis role, 140-142, 141f, 183-184 in spondyloarthropathy, 171 CD8+ cells in psoriatic arthritis, 7, 38 acquired response of, 54 autoimmune mechanisms of, 41, 42, 43f genetic knowledge supporting, 65-66, 66f enthesis and, 51 immunopathology of, 49, 53 regulatory T-cells and, 39 in reactive arthritis, 152 genetics of, 190f, 191 pathogenesis role, 140-142, 141f arthritogenic peptide hypothesis of, 184-185 in spondyloarthropathy, 171, 172 CD14+ cells, in psoriatic arthritis, 52 CD163 macrophages, in spondyloarthropathy, 166, 167 clinical applications of, 173 pathogenic considerations of, 171-172 treatment effect on, 168, 169 CEG (cross-reactive group) antigens, in reactive arthritis, 140 Cellini, Benvenuto, 128 Cellular immunopathology, in psoriatic arthritis, 49-51, 50f Celsus, Aurelius Cornelius, 4 Cervical spine, spondyloarthritis of, in psoriatic arthritis, as diagnostic criteria, 22 Cervicitis, Chlamydia-induced arthritis associated with, 157 Chemokines, in psoriatic arthritis, 56 CHF (congestive heart failure), tumor necrosis factor α inhibitors associated with, 107

Chlamydia-induced arthritis (CIA), 156-159 clinical features of, 157 description of, 156 etiopathogenesis of, 142, 156-157 genetics of, 188, 189, 192, 193 immunopathology of, 166 investigations of, 157-158, 193 natural history of, 146, 176, 177, 177b pathogenesis of, 171, 181-185 prognosis of, 158, 177t, 178 recurrence of, 203, 204 treatment of, 145, 156, 158-159 Chlamydia pneumoniae, reactive arthritis caused by, 123, 124t, 142, 156 natural history of, 176, 177b Chlamydia trachomatis, reactive arthritis caused by, 123, 124, 124t, 156 clinical features of, 157 etiopathogenesis of, 142, 156-157 genetics of, 191 historical aspects of, 129, 131 investigations of, 157-158 likelihood of, 202t, 203 natural history of, 176, 177, 177b pathogenesis of, 181-185 prognosis of, 158, 177t, 178 treatment of, 145, 158-159 2-Chlorodeoxyadenosine, for psoriatic arthritis, 101 Chromosome 6p21 in psoriasis, 70-72, 70f sex of the affected parent and, 78 in psoriatic arthritis, genome scan for linkage, 77 CIA. See Chlamydia-induced arthritis (CIA). Cimetidine, for psoriatic arthritis, 101 Ciprofloxacin 99m Tc-labeled, for reactive arthritis detection, 196 for Chlamydia-induced arthritis, 159 for reactive arthritis, 145, 205t, 206 bacterial persistence and, 182 Citrullinated proteins cyclic. See Cyclic citrullinated peptide (CCP). intracellular, in spondyloarthropathy, 172, 173 CLA (cutaneous lymphocyte antigen), 49, 114 CLA+ cells, in psoriatic arthritis, 42 Classification and regression tree (CART), 24

Classification of Psoriatic Arthritis (CASPAR), 3, 17 diagnostic applications of, 20, 22, 24, 26-27, 26t Classification schemes for psoriatic arthritis, 1, 3, 6 diagnostic applications of, 20, 22-23 future prospects for, 27 imaging based, 81, 87 Moll and Wright, 20, 22, 24, 68, 81 for reactive arthritis, 138-139 Clinic-based surveys, of psoriatic arthritis, 6-7, 11, 24 Clinical depression, psoriatic arthritis and, biologic agents impact on, 109 Clinical history, in reactive arthritis diagnosis, 133, 157 Clinical outcomes in psoriatic arthritis, 90-95 core domains for, 95, 95t disease activity assessment, 90-94, 92t function assessment, 92t, 94-95 need for, 90, 95 quality of life assessment, 92t, 95 in reactive arthritis, 200-206 acute episodes, 203-204 likelihood of developing, 200-203, 201t-202t HLA-B27 as predictor of, 201, 204 acute episodes and, 203-204 age and, 203 life expectancy and, 200, 206 mortality, 200, 206 poor functional, 204, 204t prophylaxis effects on, 204, 205t, 206 treatment effects on, 204, 205t, 206 work disability, 204 Clostridium difficile, reactive arthritis caused by, 123, 124t epidemiology of, 153 likelihood of, 200, 201t natural history of, 176, 177b pathogenesis of, 153 Co-trimoxazole cinaxin, for reactive arthritis, 205t Coccidioidomycosis, tumor necrosis factor α inhibitors and, 106 Colchicine, for psoriatic arthritis, 100 Collagen, synoviocyte synthesis of, 162

Crohn’s disease (Continued) reactive arthritis vs., 134, 196 spondyloarthropathy and, 170, 171, 172 Cross-presentation, of antigens in psoriasis, 42, 44f in psoriatic arthritis, 39, 42, 43f Cross-reactive group (CEG) antigens, in reactive arthritis, 140 Cross-sectional studies, on psoriatic arthritis prognosis, 31 Crystal-induced arthritis, 16 CT. See Computed tomography (CT). CTLA4 gene, in psoriatic arthritis, genome scan for linkage, 77 CTLs (cytotoxic T lymphocytes), in reactive arthritis, 185, 190f, 191 Cultures, bacterial, in reactive arthritis, 144, 154, 158 difficulties with, 182 genetics and, 192-193 stool, 135-136, 136t, 152 urethral swabs vs., 192-193 Cutaneous lymphocyte antigen (CLA), 49, 114 Cyclic citrullinated peptide (CCP), antibodies to, 7, 20, 54, 144 in psoriatic arthritis, 7, 54 as diagnostic criteria, 20 in spondyloarthropathy, 161, 172-173 Cyclooxygenase 1 (COX-1), for psoriatic arthritis, 8 Cyclooxygenase 2 (COX-2) antagonist for psoriatic arthritis, 8 for reactive arthritis, 145, 210 Cyclosporine for angiogenesis inhibition, 62, 63 for psoriasis, 115t, 117 Cyclosporine A (CyA), for psoriatic arthritis, 8, 100 Cytokine inhibitors, for psoriatic arthritis, 90, 102-103, 108 Cytokines in Chlamydia-induced arthritis, 157 in psoriasis, 114 in psoriatic arthritis, 40, 41f, 42 angiogenic, 61, 62 as candidate genes, 65, 76 biologic agents targeting, 90, 102-103, 108 innate response of, 56 genetic knowledge supporting, 65-66, 66f pathogenic role, 51-52 in reactive arthritis, 157, 209 genetics of, 189, 190f, 192

Cytokines (Continued) imbalance of, bacterial persistence and, 182-183 in spondyloarthropathy, 162, 164t, 165-166 Cytolysis, in psoriatic arthritis, 42 Cytotoxic T lymphocytes (CTLs), in reactive arthritis, 185, 190f, 191 Cytotoxin assays, C. difficile, in reactive arthritis, 153 D Dactylitis in psoriatic arthritis, 14-15, 14f, 29 as diagnostic criteria, 21t, 22, 26t disease activity measures of, 93 MRI of, 87 prognosis studies on, 31-32 ultrasonography of, 84 in reactive arthritis, 143, 151, 158 DAS (Disease Activity Score), in psoriatic arthritis, 92-93 for joint vascularity, 63 DC. See Dendritic cells (DC). Decay-accelerating factor (DAF), synoviocytes expression of, 162 Deformity(ies), in psoriatic arthritis, progressive, 30 Dendritic cells (DC) in psoriasis, 42, 44f in psoriatic arthritis, 39 autoimmune mechanisms of, 41, 42, 43f innate response of, 55 in reactive arthritis, 189, 190f in spondyloarthropathy, 162, 164t, 165-166 Depression, clinical, psoriatic arthritis and, biologic agents impact on, 109 Dermal dendritic cells, in psoriatic arthritis, 39 Dermatitis, contact, with psoriasis treatment, 115 Dermatologic management, of psoriasis, 114-120 biologic therapies for, 115, 118-120 phototherapy for, 115, 116-117 summary overview of, 114-115, 115t systemic therapies for, 115, 117-118 topical therapies for, 114, 115-116 treatment models for, 115 Dermatology Life Quality Index (DLQI), 8, 95, 99 Devergie, 5, 6

Index

Combination therapy for Chlamydia-induced arthritis, 159 for psoriasis management, 115 for psoriatic arthritis, 99, 100, 101, 103-105, 108 Community-based studies, of psoriatic arthritis mortality, 33-34 Composite responder indices, of peripheral arthritis, 91-93 Computed tomography (CT) in psoriatic arthritis, 87 in reactive arthritis, findings with, 195 Congestive heart failure (CHF), tumor necrosis factor α inhibitors associated with, 107 Conjunctivitis, reactive arthritis associated with Chlamydia-induced, 157 clinical presentations of, 129, 129t, 134, 143, 151 natural history of, 177-178 Conjunctivo-urethro-synovial syndrome, 129-130 Contact dermatitis, with psoriasis treatment, 115 Cooper’s description, of reactive arthritis, 129t Corneodesmosin, 72 Corticosteroids for Chlamydia-induced arthritis, 159 for psoriasis, 115, 115t for psoriatic arthritis, 97 for reactive arthritis, 145, 159, 210 effect on prognosis, 178, 211 Corticotropin-related hormone (CRH) receptor I26, in psoriatic arthritis, 50 Costs of care, for psoriatic arthritis, 34 Counseling, for reactive arthritis management, 144 COX-1 (cyclooxygenase 1), for psoriatic arthritis, 8 COX-2 antagonists. See Cyclooxygenase 2 (COX-2) antagonist. CpG DNA sequences, in reactive arthritis, 190, 190f Creatinine, serum, in reactive arthritis, 135, 135t CRH (corticotropin-related hormone) receptor I26, in psoriatic arthritis, 50 Crohn’s disease psoriatic arthritis and, 104 genetic linkage of, 76-77

217

INDEX

218

Diagnostic criteria for psoriatic arthritis, 19-27 accuracy studies of, 20, 24, 26, 26f challenges with, 19-20 future prospects for, 27 historical aspects of, 3, 6, 8 miscellaneous other, 22-24, 25t Moll and Wright, 20, 22, 24, 81 primary role, 20 research focused on, 8 summary of proposed, 20, 21t for reactive arthritis, 133-136, 135t clinical history, 133 differential, 136 evolution of, 138-139 gastrointestinal manifestations, 134 general symptoms, 133 ileocolonoscopy findings, 136 joint symptoms, 133-134 laboratory findings, 134-135, 135t microbiologic, 135-136, 136t mucous membrane symptoms, 134 ocular lesions, 134, 136 problems regarding, 136, 195 serologic, 135-136, 136t skin symptoms, 134 visceral manifestations, 134 Diarrhea, in reactive arthritis, 151, 204 Dietary supplements, for psoriatic arthritis, 101 Digit(s), arthritis in. See Dactylitis. DIP. See Distal interphalangeal (DIP) joints. Disability psoriatic arthritis and, 32, 33 axial joint damage in, 94 fatigue in, 95 global assessments of, 94-95 measurement of, 90, 92t, 94-95 natural history of, 29-30 peripheral joint damage in, 94 prognosis studies on, 31-32 quality of life with, 92t, 95 socioeconomics of, 34 reactive arthritis and, 146, 147t, 179 measurement of work, 204 Disease activity assessment in psoriatic arthritis, 63, 90-94, 92t in reactive arthritis duration and severity, 203 persistence and recurrence, 203-204 in spondyloarthropathies, 163 immunopathology relation with, 167-168

Disease Activity Score (DAS), in psoriatic arthritis, 92-93 for joint vascularity, 63 Disease-modifying antirheumatic drugs (DMARDs) for Chlamydia-induced arthritis, 156, 159 for psoriatic arthritis angiogenesis as target of, 62-63 conventional agents, 97-100 in combination trials, 99, 104-106 miscellaneous agents, 100-101 placebo response rates in, 97, 98, 98f, 99 PsARC response criteria for, 97, 98t summary of, 8, 30, 31, 33, 97, 101 for reactive arthritis, 145, 156, 159, 193, 210 Distal interphalangeal (DIP) joints, psoriatic arthritis of, 2, 61 as diagnostic criteria of, 23t clinical outcomes in, 90 historical aspects of, 5, 6 inflammation vs., 16 MRI of, 86-87, 87f synovitis findings, 12, 13f ultrasonography of, 84, 84f Distal tufts, lysis of, in psoriatic arthritis, 16, 17f as diagnostic criteria, 23f, 23t DLQI (Dermatology Life Quality Index), 8, 95, 99 DMARDs. See Disease-modifying antirheumatic drugs (DMARDs). DNA, in reactive arthritis, 151, 182, 188, 190 animal models of, 191 DNA recombination, in psoriatic arthritis, 37-38 Doppler studies. See Power Doppler MSUS. Doxycycline for Chlamydia-induced arthritis, 159, 179, 210 for reactive arthritis, 205t, 206 Drinking water contamination, reactive arthritis associated with, 124, 125-126 Dropout rates, in psoriatic arthritis therapy trials, 97, 98f, 99 Drug-induced lupus, 107 Drug-induced psoriasis, 107 Drug reactions, tumor necrosis factor α inhibitors causing, 106

Dysentery, reactive arthritis associated with, 124, 125-126 historical aspects of, 129-130 pathogenesis role, 142 prognosis of, 146 worldwide prevalence of, 138, 139t E E-Cadherin, in psoriatic arthritis, 42 E-Selectin expression in psoriatic arthritis, 49 in spondyloarthropathy, 162, 164t, 165 EBV (Epstein-Barr virus), in psoriatic arthritis, 54 Edema bone marrow, in reactive arthritis, with enthesis, 196 distal limb, psoriatic arthritis manifesting as, 16, 16f soft tissue, in reactive arthritis, 196, 197 Efalizumab for psoriasis, 115t, 119 for psoriatic arthritis, 8, 108 Endoscopy, of reactive arthritis, 134, 136, 196, 197 Endostatin, for angiogenesis inhibition, 63 Endothelial cells human umbilical vein, VEGFR2 inhibitor of, 62 in psoriatic arthritis, 40 angiogenesis role, 61, 62, 63 proteins expressed in, 50 in spondyloarthropathy, 169-170 Enteric pathogens, arthritis caused by. See Enterogenic reactive arthritis. Enterogenic reactive arthritis, 123, 124t, 151-154 brucellosis in, 153 C. difficile in, 153 classification of, 188, 189b clinical presentations of, 151-152 environmental factors, 189-190, 190b G. lamblia in, 153 historical aspects of, 129-130 immunopathogenesis of, 152-153 immunopathology of, 166 intestinal bypass in, 154 natural history of, 176 pathogenesis of, 181-185 survey programs of, 125-126 Whipple’s disease in, 153-154 Enthesis, normal, 51

Erythromycin, for reactive arthritis, 205t Escherichia coli, reactive arthritis caused by, 123, 124t survey programs on, 125 ESR. See Erythrocyte sedimentation rate (ESR). ESSG. See European Spondyloarthropathy Study Group (ESSG). Etanercept for psoriasis, 115t, 119 for psoriatic arthritis, 8, 103-104 for reactive arthritis, 145-146 for spondyloarthropathy, 168t, 169f, 170 Ethnicity psoriatic arthritis and, susceptibility genes related to, 66-67, 73, 77 reactive arthritis and genetics of, 188 pathogenesis in, 181-185 prevalence studies, 139-140 Etretinate for psoriasis, 118 for psoriatic arthritis, 100 European League Against Rheumatism (EULAR), response criteria of, for psoriatic arthritis, 92-93 European Spondyloarthropathy Study Group (ESSG), 2 diagnostic criteria of for psoriatic arthritis, 21t, 23, 25t comparative accuracy of, 24, 26, 26f for reactive arthritis, 138, 139, 188 for spondyloarthritis, 138, 188, 189b EuroQoL, 32 Evidence-based medicine, for reactive arthritis, 211 Exotoxins, C. difficile, in reactive arthritis, 153 Extra-articular manifestations of psoriatic arthritis, 15-16, 16f of reactive arthritis, 134, 143-144, 192 Chlamydia-induced, 156, 157 treatment of, 158-159 classification of, 188, 189b natural history of, 146, 177-178 Extracellular matrix in psoriatic arthritis, etiopathogenesis role, 40 in synovial membrane, 161-162

Eye infections, reactive arthritis associated with as diagnostic criteria, 134, 135t, 136 Chlamydia-induced, 157 clinical presentations of, 129, 129t, 143, 151 natural history of, 177-178 treatment of, 146 F FACIT (Functional Assessment of Chronic Illness Therapy) scale, 95 Factor XIIIa, in psoriatic arthritis, 39 Facultative bacteria, in reactive arthritis, 182-183 False-negative rate, in psoriatic arthritis diagnosis, 19 False-positive rate, in psoriatic arthritis diagnosis, 19 Familial aggregation of psoriatic arthritis, 37, 65, 68 pedigrees illustrating, 68, 69f penetrance in, 68, 70 sex of the affected parent effect on, 77-78 sporadic pattern vs., 70 of reactive arthritis, 188 of spondyloarthropathies, 161 Family history, of psoriatic arthritis, 2-3, 7 as diagnostic criteria, 21t, 23, 25t, 26t etiopathogenesis role, 37-38 Fever, in reactive arthritis, 151 Fibroblasts in psoriatic arthritis, 40 in spondyloarthropathy, 163, 164t, 167 pathogenic considerations of, 172 treatment effect on, 170 in synovial membrane, 161-162 Fibromyalgia, tender points of, 16 Fibronectin in psoriatic arthritis, etiopathogenesis role, 40 synoviocyte synthesis of, 162 Fiessinger’s description, of reactive arthritis, 129-130 Flagellin, in reactive arthritis, 190, 190f Flexural psoriasis, 11 Flt-1-positive neutrophils, in psoriatic arthritis, 50 Foodborne Diseases Active Surveillance Network (FoodNet), 125 Foot (feet), psoriatic arthritis in, radiography of, 81 c-Fos synthesis, in reactive arthritis, 192

Index

Enthesitis/enthesopathy in psoriatic arthritis, 15, 15f as diagnostic criteria, 21t, 23, 25t, 26 disease activity measures of, 93 imaging of. See specific modality, e.g., Ultrasonography. susceptibility gene identification challenges, 66-67 in reactive arthritis Chlamydia-induced, 156, 157, 158 clinical presentations of, 134, 135t, 143, 151 imaging of, 195, 196t, 197-198 bone marrow edema with, 196 natural history of, 177 Environmental factors in psoriatic arthritis, 48-49 genetic factors vs., 65, 68 in reactive arthritis, 128, 129, 156, 157, 211 genetics vs., 189-190, 190b host susceptibility factors vs., 190-192, 192f Epidemiology of psoriatic arthritis, 1-3 genetics in, 2-3, 7, 65 present studies of, 6-7 of reactive arthritis, 123-126 enteric pathogen survey programs in, 125-126 genetics in, 188 hospital series in, 124 population-based studies, 124, 124t prevalence of infections, 123-124 worldwide, 138, 139t single-source outbreaks, 124-125, 125t, 126t spectrum of, 139-140 Epidermis hyperplasia of, in psoriasis, 53 regenerative maturation of, in psoriatic arthritis, 42-43, 43f Epstein-Barr virus (EBV), in psoriatic arthritis, 54 Erosive lesions in spondyloarthropathy, 167 psoriatic arthritis associated with, 7 historical aspects of, 5 in bone, 16-17, 17f Erysipelas, reactive arthritis vs., 136 Erythrocyte sedimentation rate (ESR) psoriatic arthritis and, 8, 31 measurement of, 92, 94 reactive arthritis and, 134, 135t, 144 Chlamydia-induced, 157, 158 Erythroderma, in psoriasis, 11

219

INDEX

220

Fournié criteria, for psoriatic arthritis, 21t, 23-24, 25t comparative accuracy of, 24, 26, 26f Fumarate, for psoriatic arthritis, 98f, 100 Fumaric acid, for psoriatic arthritis, 101 Functional Assessment of Chronic Illness Therapy (FACIT) scale, 95 Functional assessments of psoriatic arthritis patients, 34, 90 global, 94-95 outcome measures, 92t, 94-95 of reactive arthritis patients, 146, 147t, 179 poor results with, 204, 204t G Galen, 4 Gastroenteritis, reactive arthritis associated with. See Enterogenic reactive arthritis. Gastrointestinal system/tract psoriatic arthritis involvement of, 15-16 reactive arthritis involvement of, 134, 135t, 144 imaging of, 134, 136, 196-197 Gender, psoriatic arthritis and, 19, 31 in morbidity and mortality, 33 influences on inheritance of, 77-78 Gene expression analysis in spondyloarthropathy, 174 of psoriatic arthritis, 43 Gene linkage, disequilibrium of, in psoriasis-susceptibility genes, 71-72, 71t, 75, 77 Genetics of psoriatic arthritis, 65-78 candidate genes in, 72-77 psoriasis-susceptibility maps to, 70-72, 70f, 71t conclusions about, 78 epidemiology in, 2-3, 7, 65 etiopathogenesis role, 37-38 formal, 68-70, 69f HLA studies, 32 pathogenic role, 48 sex influences on inheritance, 77-78 structures related to psoriasis, 67-68, 67f susceptibility gene identification challenges, 65-67, 66f of reactive arthritis, 188-193 clinical manifestations in, 192 diagnostic classification criteria and, 188, 189b

Genetics (Continued) DNA/RNA in, 151, 182, 188, 190 environmental factors and, 189-190, 190b epidemiology in, 188 etiology and, 189, 190f host susceptibility factors and, 190-192, 192f investigations for, 192-193 pathogenic predispositions, 140 prognosis in, 192 summary overview, 123, 188, 193 treatment strategies and, 193, 211 Genitourinary (GU) infections. See Urogenital infections. Genome-wide linkage studies, of psoriatic arthritis, 2-3, 38, 43 for candidate genes, 76-77 Germline, penetrance of, in psoriatic arthritis, 68, 70 Giardia lamblia, reactive arthritis caused by, 153 Gladman criteria, for psoriatic arthritis, 21t, 31 comparative accuracy of, 24, 26, 26f Glucocorticoids, systemic, for reactive arthritis, 145, 146 Glycosaminoglycans, in psoriatic arthritis, etiopathogenesis role, 40 Gold compounds, for psoriatic arthritis, 99 Golgi apparatus, in synoviocytes, 161, 162 Gonococcal infections, reactive arthritis caused by, 123, 124t historical aspects of, 128-129 likelihood of, 201t, 202 Gout, reactive arthritis vs., 136, 158 Gram stain, in reactive arthritis diagnosis, 135, 136t, 144, 158 genetic applications of, 189, 190 Granulocytes in spondyloarthropathy, 167 pathogenic considerations of, 171-172 indium 111-labeled, for reactive arthritis detection, 196 Group A streptococcus, streptococcal pyogenic exotoxin serotype C-producing, 49 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), 8, 93, 95 Growth factors, angiogenic in psoriatic arthritis, 7, 61 etiopathogenesis role, 40, 41f, 43f, 51

Growth factors, angiogenic (Continued) therapy targeted at, 62-63 in spondyloarthropathy, 162, 164t, 165 treatment effect on, 168t, 169-170 GU (genitourinary) infections. See Urogenital infections. Gut inflammation, in reactive arthritis genetics of, 189-190, 190f, 191 imaging of, 134, 136, 196-197 Guttate psoriasis, 11 autoimmune mechanisms of, 40, 41, 42 T cells generation of, 42, 44f, 49 H Hand(s). See also Dactylitis. psoriatic arthritis in MRI of, 86-87, 87f radiography of, 81, 82f reactive arthritis in, 133, 143, 151, 158 Hansen’s disease, 4 Haplotypes, in psoriasis-susceptibility genes candidate stratification of, 72-77 linkage disequilibrium of, 71-72, 71t, 75, 77 Health Assessment Questionnaire (HAQ), on psoriatic arthritis applications of, 8, 31, 33, 34 disease activity assessment with, 91-92, 92t global function and, 94-95 in drug trials, 99, 104, 105 Health care costs, for psoriatic arthritis, 34 Heart psoriatic arthritis involvement of, 15, 32 reactive arthritis involvement of, 134, 143, 178 Heart failure, congestive, tumor necrosis factor α inhibitors associated with, 107 Heat shock protein (HSP), in reactive arthritis, 183 Hebra, 4, 5 Heliotherapy, for psoriatic arthritis, 100 Helliwell, Phillip, 8 Hematologic system, tumor necrosis factor α inhibitors impact on, 107 β-Hemolytic streptococci, reactive arthritis associated with, 189

HLA-B27 in psoriatic arthritis candidate genes and, 72, 73, 74 stratification of, 76 in reactive arthritis, 123, 124, 125 acute episodes correlated to, 203-204 age and, 203 as diagnostic criteria, 133, 136, 144 as outcome predictor, 201, 204 as prognosis factor, 178 Chlamydia-induced, 156, 157, 158 genetics of, 140, 188, 192, 211 environmental factors and, 189-190, 190f host factors in, 190-192, 192f historical aspects of, 128, 130 imaging results correlated with, 196, 198 immunopathogenesis of, 152 natural history of, 146, 176, 176b, 209 pathogenic role, 140-142, 141f, 182, 184 arthritogenic peptide hypothesis of, 184-185, 190f, 191 other hypothesis about, 185 prevalence of, 139-140, 152, 154 survey programs on, 125, 126 in spondyloarthropathies, 161, 166 pathogenic considerations of, 171, 172 HLA-B27 homodimer hypothesis, of reactive arthritis, 185, 191-192 HLA-B27 misfolding hypothesis, of reactive arthritis, 185, 191-192 HLA-B37, in psoriasis, telomeric susceptibility maps of, 70f, 71 HLA-B38, in psoriatic arthritis, candidate genes and, 72-73, 74 HLA-B39, in psoriatic arthritis, candidate genes and, 72, 73, 74 HLA-B57, in psoriasis, telomeric susceptibility maps of, 70f, 71-72 HLA-C alleles. See also specific allele. in psoriasis, telomeric susceptibility maps of, 70-72, 70f in psoriatic arthritis, 39, 48 autoimmune mechanisms of, 41, 43 candidate genes and, 73-74 in reactive arthritis, 140

HLA-C*0602 allele, in psoriatic arthritis candidate genes and, 73 heterogeneity of, 74 in centromeric region, 74-75 HLA-Cw6 allele, in psoriatic arthritis, 37, 39 autoimmune mechanisms of, 40-41, 42, 43, 43f candidate genes and, 73, 74, 76 pathogenic role, 48 stratification of, 76 HLA-Cw*0602 allele, in psoriasis genome scan for linkage, 77 stratification of, 72 telomeric susceptibility maps of, 70f, 71-72 HLA-DR in reactive arthritis, 140, 142 in spondyloarthropathy, 172 HLA-DR7, in psoriatic arthritis, pathogenic role, 48 HLAs. See Human leukocyte antigens (HLAs). Homodimer hypothesis, HLA-B27, of reactive arthritis, 185, 191-192 Hospital series, of reactive arthritis, 124 Host susceptibility factors. See also Genetics. of reactive arthritis, 190-192, 192f environmental factors vs., 189-190, 190b HRUS (high-resolution ultrasonography), of synovitis, 63 HSP (heat shock protein), in reactive arthritis, 183 Human Genome Project, 72, 76 Human immunodeficiency virus (HIV) infection psoriatic arthritis response to, 1, 7, 39 reactive arthritis and, 138, 140, 209, 210, 211 Human leukocyte antigens (HLAs). See also specific antigen, e.g., HLA-B27. psoriasis association with, 11 autoimmune mechanisms of, 40-41 candidate genes of, 70-71, 70f haplotypes of, 71-72, 71t psoriatic arthritis association with, 3, 30 animal models of, 56t, 57 ankylosing spondylitis vs., 16 as diagnostic criteria, 21t, 22, 23, 24

Index

Hench, Philip S., 6 Heparin sulfate, in psoriatic arthritis, etiopathogenesis role, 40 Hepatic system methotrexate impact on, 98 reactive arthritis and, 135, 135t tumor necrosis factor α inhibitors impact on, 107 Heterodimer hypothesis, of reactive arthritis, 192, 192f High-resolution ultrasonography (HRUS), of synovitis, 63 Hip, psoriatic arthritis in prognosis studies on, 32 radiography of, 82 Histopathology, of synovial membrane in psoriatic arthritis, 7 in spondyloarthropathy, 163, 164t, 165-166, 165f Histoplasmosis, tumor necrosis factor α inhibitors and, 106 Historical aspects of psoriatic arthritis the future, 8 the past, 1, 4-6 the present, 6-8 of reactive arthritis, 128-131 background perspectives on, 128, 131 early descriptions of, 128 evolving concepts of, 130-131, 131t in early twentieth century, 129-130 in nineteenth century, 128-129, 129t pathogenesis in, 131 HIV. See Human immunodeficiency virus (HIV) infection. HLA alleles, in psoriatic arthritis. See also specific allele. autoimmune mechanisms of, 43 candidate genes and, 73-74 HLA-B alleles, in psoriatic arthritis. See also specific allele. candidate genes and, 73-74 genome scan for linkage, 77 in centromeric region, 74-75 HLA-B13 in psoriasis, telomeric susceptibility maps of, 70f, 71 in psoriatic arthritis, pathogenic role, 48 HLA-B17 in psoriasis, telomeric susceptibility maps of, 70f, 71 in psoriatic arthritis, pathogenic role, 48

221

INDEX

222

Human leukocyte antigens (HLAs) (Continued) candidate genes and, 72-77 etiopathogenesis role, 39 genetic studies on, 7, 38, 66, 69f innate response of, 55, 65-66, 66f prognosis studies on, 32 T cell response and, 54, 55 reactive arthritis association with, 123, 124, 125 as diagnostic criteria, 133, 136 Chlamydia-induced, 156, 157, 158 historical aspects of, 128, 130 immunopathogenesis of, 152, 154 survey programs on, 125, 126 reactive arthritis susceptibility and genetics of, 140, 211 natural history of, 146, 176, 176b pathogenic role, 140-142, 141f prognosis of, 178 Human umbilical vein endothelial cell (HUVEC), VEGFR2 inhibitor of, 62 Hyaluronan, in psoriatic arthritis, etiopathogenesis role, 40 Hyaluronic acid, synoviocyte synthesis of, 162 Hydroxychloroquine, for psoriatic arthritis, 100 Hydroxyurea, for psoriasis, 118 Hyperkeratotic scales, in psoriasis, 53 Hyperostosis, skeletal, 128 Hyperplasia epidermal, in psoriasis, 53 of synovial lining, in spondyloarthropathy, 162-163, 165f treatment effect on, 168t, 170 Hypervascularity, in spondyloarthropathy, 162, 163, 165, 165f pathogenic considerations of, 170-171 treatment effect on, 168t, 169-170 Hypothalamic-pituitary-adrenal (HPA) axis, suppression of, with psoriasis treatment, 115 I IBD. See Inflammatory bowel disease (IBD). ICAM-1. See Intercellular adhesion molecule 1 (ICAM-1). ICF (International Classification of Functioning, Disability and Health), psoriatic arthritis and, 32

IFN-α (interferon α), in psoriatic arthritis, 39-40 IFN-γ. See Interferon γ (IFN-γ). Ig (immunoglobulins). See specific immunoglobulin, e.g., Immunoglobulin A (IgA). IGF-II (insulin-like growth factor II), angiogenesis role, therapy targeted at, 62 Ileocolonoscopy, reactive arthritis findings with, 134, 136, 196 Iliac crest, enthesopathy of, in psoriatic arthritis, 15 ILs. See Interleukins (ILs). Imaging. See also specific modality. in psoriatic arthritis, 81-87 computed tomography, 87 magnetic resonance imaging, 84-87, 85f-86f high-resolution, 86, 87f plain radiography, 81-83, 82f-83f scintigraphy, 85, 87 ultrasonography, 83-84, 83f-84f in reactive arthritis, 195-198, 196t aspects of, 195 long-term prognosis and, 198 of entheses, 197-198 of gut inflammation, 196-197 of joint involvement, 195-196, 196t of spondyloarthritides, 197-198 Immature dendritic cells (iDC), in psoriatic arthritis, 39 Immune response in psoriasis, 114 acquired vs. innate, 53-56, 65 in psoriatic arthritis genetic knowledge supporting, 65-66, 66f pathogenic role, 53-56 in spondyloarthropathy, innate, 171-172, 173 pathologic. See Immunopathology. Immunoassays, in reactive arthritis diagnosis, 136, 136t, 151, 158 Immunogenicity, of tumor necrosis factor α inhibitors, 107 Immunoglobulin A (IgA), in reactive arthritis, 158 Immunoglobulin A2 (IgA2), in reactive arthritis, 152 Immunoglobulin G (IgG), in reactive arthritis, 158 Immunoglobulin M (IgM), in reactive arthritis, 158 Immunohistochemical analysis of angiogenesis inhibition, 63

Immunohistochemical analysis (Continued) of synovium, in spondyloarthropathy, 163, 164t, 165-166, 165f clinical applications of, 172-173 Immunomodulatory agents, for psoriatic arthritis, tumor necrosis factor α inhibitors as, 8, 49, 103-107 Immunopathology of psoriatic arthritis cellular, 49-51, 50f etiopathogenesis role, 38-40, 41f pathogenic role, 57, 58t synovial, 7 of reactive arthritis, 152-153 cell surface modulation hypothesis, 185 cytokine imbalance role, 182-183 synovial, in spondyloarthropathy, 161-174 clinical applications of, 172-173 disease activity/severity relation with, 163, 167-168 future directions for, 173-174 histopathology comparisons of, 163, 164t, 165-166, 165f inflamed synovium features, 162-163 normal synovium vs., 161-162 of subtypes, 164t, 166 pathogenic considerations, 170-172 treatment modulation of, 168-170, 168t, 169f Immunosuppressive agents. See also specific drug, e.g., Methotrexate (MTX). for psoriasis, 118 for reactive arthritis, 145, 146, 159, 210, 211 IMPACT studies, 104-105 Incidence, of psoriatic arthritis, 2 Indium 111-labeled granulocytes, for reactive arthritis detection, 196 Indomethacin, for reactive arthritis, 209 Infectious microorganisms. See also specific organism, e.g., Clostridium difficile. enteric, arthritis caused by. See Enterogenic reactive arthritis. psoriatic arthritis triggered by, 7, 49 genetics and, 37

Infliximab for angiogenesis inhibition, 63 for psoriasis, 115t, 119-120 for psoriatic arthritis, 8, 86, 104-105 for reactive arthritis, 145, 193 for spondyloarthropathy, 168-170, 168t Inheritance mode, of psoriatic arthritis, 37, 65, 68 pedigrees illustrating, 68, 69f penetrance in, 68, 70 sex-of-the-affected-parent effect on, 77-78 sporadic pattern vs., 70 Insulin-like growth factor II (IGF-II), angiogenesis role, therapy targeted at, 62 Integrin in psoriatic arthritis, etiopathogenesis role, 40 in spondyloarthropathy, 163, 164t treatment effect on, 169-170 synoviocyte synthesis of, 162 Intercellular adhesion molecule 1 (ICAM-1) in psoriatic arthritis, biologic agents targeting, 108 in spondyloarthropathy, 162, 164t, 165 treatment effect on, 168-170, 168t synoviocytes expression of, 161 Interferon α (IFN-α), in psoriatic arthritis, 39-40 Interferon γ (IFN-γ) in psoriasis, 114 in psoriatic arthritis, 40, 42, 51, 100 T cell response and, 54 in reactive arthritis, 157, 209 bacterial persistence and, 182-183 in spondyloarthropathy, 166 Interleukin 1 receptor activation kinase (IRAK), in reactive arthritis, 189, 190f Interleukin 2 (IL-2), in psoriatic arthritis, 51, 108 Interleukin 6 (IL-6), in psoriatic arthritis, 40, 41f Interleukin 10 (IL-10), in reactive arthritis, 183 Interleukin 11 (IL-11), in psoriatic arthritis, 108 Interleukin 12 (IL-12) in psoriatic arthritis, 108 in reactive arthritis, 183 Interleukin 18 (IL-18), in psoriatic arthritis, 62, 108

Interleukins (ILs). See also specific interleukin. in psoriasis, 114 in psoriatic arthritis as candidate genes, 76 biologic agents targeting, 108 in reactive arthritis, 157, 192, 209 in spondyloarthropathy, 162, 164t, 165, 166 International Classification of Functioning, Disability and Health (ICF), psoriatic arthritis and, 32 Intestinal bypass surgery, reactive arthritis association with, 154 Intra-articular treatment of psoriatic arthritis, 97 of reactive arthritis, 145, 210, 211 Intralesional treatment, of reactive arthritis, 145 IRAK (interleukin 1 receptor activation kinase), in reactive arthritis, 189, 190f Iritis, psoriatic arthritis manifesting as, 15 Irradiation, lymph node, for psoriatic arthritis, 101 Isotretinoin, for psoriasis, 117-118 J Jasaliq, 4 Jejunocolostomy, reactive arthritis association with, 154 Jejunoileostomy, reactive arthritis association with, 154 Joint(s) psoriatic arthritis involvement of, 7 angiogenesis inhibition for, 63 DMARD therapy for, 97-101, 98t functional assessment for, 92t, 94 historical aspects of, 5 natural history of, 29-30 osteolysis with, 16, 17, 17f as diagnostic criteria of, 23t prognosis studies on, 31, 32 research on, 8 symmetry considerations, 2, 22 synovitis findings, 11-12, 13f-14f, 13t reactive arthritis involvement of clinical presentations of, 133-134, 143, 154, 157 imaging of, 195-196, 196t natural history of, 146, 176-177 spondyloarthropathy involvement of, 161 end-stage, 167

Index

Infectious microorganisms (Continued) streptococcal, 7, 37, 40, 41 T cell response and, 54 reactive arthritis triggered by, 123-126, 124t, 125t, 126t, 142 as environmental factor, 189, 190, 190b as prognosis factor, 146, 147t, 158, 178 enterogenic, 151-154 laboratory isolation of, 135-136, 136t likelihood of acute disease, 200-203, 202t-203t mechanisms of, 131 natural history of, 146, 176, 177b pathogenesis in, 181 persistence of, 182 cytokine imbalance role, 182-183 recurrence of, 203-204 symptoms of, 133, 134 tumor necrosis factor α inhibitors associated with, 106 Inflammation in psoriasis, 114 in psoriatic arthritis, 7, 11-12 biologic agents and, 108-109 extra-articular, 33 molecular pathways of, 65, 66f, 68 natural history of, 29-30 prognosis studies on, 31 synovial, 49 vascular endothelium, 50 in reactive arthritis, 123, 133, 146, 157 imaging of gut, 134, 136, 196-197 joint, 195-196, 197-198 in synovial membrane, 162-163 immunopathology of, 162-168 tissue destruction vs., 173-174 treatment effect on, 168-170, 168t Inflammatory arthritis. See also Reactive arthritis (ReA). enteric infections and, 151-154 psoriasis with pattern of, 2 prevalence of, 2 psoriatic arthritis vs., 16, 19 Inflammatory bowel disease (IBD) arthritis associated with, 161 psoriatic arthritis manifesting as, 15-16 reactive arthritis manifesting as, 134 genetics of, 188, 189, 190

223

INDEX

Joint(s) (Continued) symmetry of, 2 as psoriatic arthritis diagnosis criteria, 22 JSpA (juvenile spondyloarthropathy), 161 c-Jun, in psoriatic arthritis, animal models of, 56-57, 56t JunB, in psoriatic arthritis, animal models of, 56-57, 56t Juvenile spondyloarthropathy (JSpA), 161 Juxta-articular bone formation, in psoriatic arthritis, as diagnostic criteria, 22, 23f, 23t, 26, 26t K Keratinocytes in psoriasis, proliferation of, 42, 44f, 114 in psoriatic arthritis, 40, 43f innate response of, 54-55 Keratins psoriatic arthritis and, 43, 43f streptococci virulence and, 41-42 Ki67 marker, in spondyloarthropathy, 162, 163 Kidney(s), reactive arthritis involvement of, 134, 135, 135t, 143-144, 178 Killer immunoglobulin-like receptors (KIRs), in reactive arthritis, 190f, 191, 192 KIR genes in psoriatic arthritis, 39 as candidates, 75-76 in reactive arthritis, 140 Klebsiella spp., reactive arthritis caused by, 123, 124t immunopathogenesis of, 152 Knee, psoriatic arthritis in MRI of, 86, 86f radiography of, 82 ultrasonography of, 83 Koebner phenomenon, 5, 43f, 48

224

L λR values, in familial aggregation, of psoriatic arthritis, 68, 69f, 70 Langerhans cells, in psoriatic arthritis, 39, 43f Larsen score, of psoriatic arthritis, radiographic validation of, 82 Latent class analysis, in psoriatic arthritis criteria research, 19

Leflunomide, for psoriatic arthritis, 99 Left ventricular dysfunction, psoriatic arthritis and, 32 Leprosy, historical aspects of, 4, 5, 6 Leroy’s description, of reactive arthritis, 129-130 Leukocyte function antigens (LFAs) in psoriasis, 114 in psoriatic arthritis, biologic agents targeting, 8, 108 Leukocyte immunoglobulin-like receptors (LILRs), in reactive arthritis, 190f, 191, 192 Leukocytes in psoriatic arthritis, 39 in reactive arthritis, 135, 135t radiolabeled, for diagnosis, 136, 196 LFAs. See Leukocyte function antigens (LFAs). Life expectancy, reactive arthritis and, 200, 206 LILRs (leukocyte immunoglobulinlike receptors), in reactive arthritis, 190f, 191, 192 Limb edema, distal, psoriatic arthritis manifesting as, 16, 16f Linkage disequilibrium, of alleles, in psoriasis-susceptibility genes, 71-72, 71t, 75, 77 Linkage studies, of psoriatic arthritis, genome-wide, 2-3, 38, 43 for candidate genes, 76-77 Lipopolysaccharide (LPS) binding protein, in reactive arthritis, 189-190, 190f Liver function tests in reactive arthritis, 135, 135t methotrexate impact on, 98 tumor necrosis factor α inhibitors impact on, 107 Locomotor system, reactive arthritis symptoms in, 133-134, 135t Logarithm of the odds (LOD) score, in genome scans, 76-77 Logistic regression analysis, in psoriatic arthritis criteria research, 22, 24 Lomholt, Gunnar, 37 Longitudinal studies, on psoriatic arthritis prognosis, 31 LPS (lipopolysaccharide) binding protein, in reactive arthritis, 189-190, 190f Lumbar spine, spondyloarthritis of, in psoriatic arthritis, as diagnostic criteria, 22 Lupus, tumor necrosis factor α inhibitors causing, 107

Lymecycline for Chlamydia-induced arthritis, 159 for reactive arthritis, 205t Lymph nodes, irradiation of, for psoriatic arthritis, 101 Lymphocytosis, in reactive arthritis, 135 Lymphoid cells. See also specific cell, e.g., B lymphocytes. in psoriatic arthritis, 7, 38-39 Lys80 allele, in psoriatic arthritis, 39 M M proteins, streptococci virulence and, 41-42 Macrophages in psoriatic arthritis, 50, 52 innate response of, 55 in reactive arthritis, 154, 191-192 in spondyloarthropathy, 162, 166, 167 clinical applications of, 173 pathogenic considerations of, 171-172 treatment effect on, 168-170, 168t, 169f in synovial membrane, 161, 162 Magnetic resonance imaging (MRI) in psoriatic arthritis as diagnostic criteria, 23 findings with, 30, 84-85 of large synovial joints, 85-86, 86f of peripheral joints, 86-87, 87f of sacroiliac joints, 85, 85f of spine, 85 of sternoclavicular joint, 85, 86f in reactive arthritis, 144 findings with, 195, 196, 196t, 197 Main en lorgnette deformity, in psoriatic arthritis, 30 Major histocompatibility complex (MHC). See also Human leukocyte antigens (HLAs). in psoriasis, 114 candidate genes of, 70-71, 70f haplotypes of, 71-72, 71t in psoriatic arthritis, 1, 39 animal models of, 56t, 57 autoimmune mechanisms of, 40-41, 66 candidate genes and, 74-77 genetic studies on, 7, 37, 38, 48, 70 pathogenic role, 48 in reactive arthritis, 140, 152 genetics of, 191-192, 192f pathogenesis of, 184-185 synoviocytes expression of, 161, 171, 173

Micanol, for psoriasis, 116 Microbiology, in reactive arthritis diagnosis, 135-136, 136t, 158 β-Microglobulin in psoriatic arthritis, knockout model of, 56t, 57, 75 in reactive arthritis, 140, 141, 141f genetics of, 191, 192 Microimmunofluorescence test, in reactive arthritis diagnosis, 158 Microorganisms. See Infectious microorganisms. Microsatellite maps, of psoriasissusceptibility genes, 70f, 72, 77 Minocycline, for reactive arthritis, 205t Misfolding hypothesis, HLA-B27, of reactive arthritis, 185, 191-192 MMPs. See Matrix metalloproteinases (MMPs). MNCs. See Mononuclear cells (MNCs). Molecular basis, of psoriatic arthritis susceptibility, 72-77 genome scans for linkage, 76-77 identification challenges of, 65-67, 66f models of, 67-68, 67f psoriasis-susceptibility maps to, 70-72, 70f, 71t Molecular biology studies in reactive arthritis, 151 in spondyloarthropathies, 173, 174 Moll and Wright classification, of psoriatic arthritis, 81 Moll and Wright criteria, for psoriatic arthritis, 20, 21t, 22, 68 comparative accuracy of, 24, 26, 26f Moll and Wright description, of seronegative arthritis, 130 MOMP (major outer membrane protein), in reactive arthritis, 183 Monoarthritis, in reactive arthritis, 143, 156, 159 imaging of, 196 Monoclonal antibodies for psoriatic arthritis, 8, 108 for reactive arthritis, 192 in spondyloarthropathy, 172 Monocytes in psoriatic arthritis, innate response of, 55 in synovial membrane, 161, 163

Mononuclear cells (MNCs) in inflamed synovium, 163, 164t in reactive arthritis, 183 8-MOP (8-methoxypsoralen), for psoriasis, 117 Morbidity, psoriatic arthritis risk for extra-articular disease, 15-16, 16f, 22 other extra-articular complications, 32-33 Mortality psoriatic arthritis risk for, 8, 33-34 reactive arthritis risk for, 206 MRI. See Magnetic resonance imaging (MRI). MRPs. See Myeloid-related proteins (MRPs). MS (multiple sclerosis), tumor necrosis factor α inhibitors exacerbation of, 106-107 MSUS, in psoriatic arthritis, findings with, 83-84, 83f-84f MTX. See Methotrexate (MTX). Mucous membranes, reactive arthritis involvement of, 143, 157 as diagnostic criteria, 133, 134, 135t treatment of, 146 Multifactorial model, genetic, of psoriatic arthritis, 37 Multiple sclerosis (MS), tumor necrosis factor α inhibitors exacerbation of, 106-107 Multiplex inheritance, of psoriatic arthritis, 70. See also Familial aggregation. Multivariate analysis, in psoriatic arthritis criteria research, 20, 22 Munro, William John, 5 Munro microabscess, 5 Musculoskeletal system, reactive arthritis involvement of, 123, 143, 196t imaging modalities for, 195-198, 196t Mycobacterium vaccae, for psoriatic arthritis, 98f, 100 Mycophenolate mofetil for psoriasis, 118 for psoriatic arthritis, 100 Mycoplasma genitalium, reactive arthritis caused by, 123, 124t likelihood of, 201t Myeloid cells in psoriatic arthritis, 39-40 in spondyloarthropathy, 164t, 166

Index

Major outer membrane protein (MOMP), in reactive arthritis, 183 Malignancy(ies), tumor necrosis factor α inhibitors and, 107 Mander and Maastricht Ankylosing Spondylitis Enthesis Score (MASES), 93 Matrix metalloproteinases (MMPs) in psoriatic arthritis, 52 in spondyloarthropathy, 163, 164t, 165 future directions for, 174 treatment effect on, 168-170, 168t, 169f Matrix molecules, synoviocyte synthesis of, 162 Mature dendritic cells (mDCs) in psoriasis, 44f in psoriatic arthritis, 39 McGonagle criteria, for psoriatic arthritis, 21t, 23, 25t comparative accuracy of, 24, 26, 26f Medical Outcomes Study, on 36-Item Short Form Survey (SF-36), 8 6-Mercaptopurine, for psoriatic arthritis, 99-100 Metalloproteinases. See Matrix metalloproteinases (MMPs). Methotrexate (MTX) for angiogenesis inhibition, 62, 63 for Chlamydia-induced arthritis, 159 for psoriasis, 115t, 117 for psoriatic arthritis, 8, 56, 98-99 in combination trials, 103, 105, 107-108 for reactive arthritis, 145, 146, 159, 210, 211 for spondyloarthropathy, 168t, 171 8-Methoxypsoralen (8-MOP), for psoriasis, 117 Methylprednisolone, intravenous pulse, for psoriatic arthritis, 97 MHC. See Major histocompatibility complex (MHC). MHC class I polypeptide-related sequence A, in psoriatic arthritis, 78 candidate genes and, 74-75 MHC-KIR epistasis, in psoriatic arthritis, 75-76 MICA gene, in psoriatic arthritis, as candidate, 74-75

225

INDEX

226

Myeloid-related proteins (MRPs) in psoriatic arthritis, 49-50, 50f in spondyloarthropathy, 163, 164t, 165-166 clinical applications of, 173 treatment effect on, 168t, 169-170 Myocardial infarction, psoriatic arthritis related to, 49 N N-terminal caspase recruitment domain, 77 Nail lesions in psoriasis, 11, 12f disease activity measures of, 94 in psoriatic arthritis, 61 angiogenesis factors, 61, 62 as diagnostic criteria, 26, 26t prognosis studies on, 32 Nail Psoriasis Severity Index (NAPSI), 94 Narrowband ultraviolet B, for psoriasis, 115t, 116 Natalizumab, for spondyloarthropathy, 173 Natural history of psoriatic arthritis, 29-30 of reactive arthritis, 146, 176-178 extra-articular manifestations, 177-178 primary infection evolution, 176 rheumatic symptoms evolution, 176-177 treatment implications of, 209 Natural killer cell receptors (NKRs), in reactive arthritis, 190f, 191 Natural killer (NK) cells in inflamed synovium, 162, 164t in psoriatic arthritis etiopathogenesis role, 39, 57 genetic perspectives of, 65-66, 66f, 70 centromeric candidate genes and, 74-75 innate response of, 55, 65 in reactive arthritis genetics of, 190f, 191-192 pathogenesis role, 140, 141f Natural killer-T (NK-T) cells, in psoriatic arthritis candidate genes and, 75 etiopathogenesis role, 39, 55 Negative predictive value, in psoriatic arthritis diagnosis, 19 Neisseria gonorrhoeae, reactive arthritis caused by, 123, 124t historical aspects of, 128-129 likelihood of, 201t, 202

Neutrophils in psoriatic arthritis, 39, 49 Flt-1-positive, 50 innate response of, 55 in reactive arthritis, 157 NF-κβ (nuclear factor-κβ), in reactive arthritis, 189, 190f, 192 NGU (nongonococcal urethritis), reactive arthritis caused by, 202-203 Nitrogen mustard, parenteral, for psoriatic arthritis, 101 NK. See Natural killer (NK) cells. NKRs (natural killer cell receptors), in reactive arthritis, 190f, 191 NK-T. See Natural killer-T (NK-T) cells. NOD (nucleotide-binding oligomerization domain), 77 Nongonococcal urethritis (NGU), reactive arthritis caused by, 202-203 Nonsteroidal anti-inflammatory drugs (NSAIDs) for Chlamydia-induced arthritis, 156, 159 for psoriatic arthritis, 8 in combination trials, 103, 105 for reactive arthritis, 153, 154, 158, 211 effect on prognosis, 178, 206 efficacy of, 144-145, 193, 210 Nuclear factor-κβ (NF-κβ), in reactive arthritis, 189, 190f, 192 Nucleic acid amplification assays, in reactive arthritis, 193 Nucleotide-binding oligomerization domain (NOD), 77 O Obligate bacteria, in reactive arthritis, 182-183 OCPs (osteoclast precursors), in psoriatic arthritis, 52-53, 57, 58t Ocular lesions, reactive arthritis associated with as diagnostic criteria, 134, 135t, 136 Chlamydia-induced, 157 clinical presentations of, 129, 129t, 143, 151 natural history of, 177-178 treatment of, 146 Oligoarthritis Chlamydia-induced, 156, 158 in psoriatic arthritis, 61 asymmetric, 2, 22 natural history of, 29-30

Oligoarthritis (Continued) prognosis studies on, 31 synovitis findings, 12-13, 12t, 13f in reactive arthritis, 143, 156, 158, 177 as diagnostic, 195 imaging of, 196 spondyloarthropathy and, 161, 167 OMERACT 7 (Outcome Measures in Rheumatology Clinical Trials 7), 84, 93, 95 OMP (outer membrane protein), in reactive arthritis, 184 major, 183 OPG (osteoprotegerin), in psoriatic arthritis, 52 Ophthalmologic examination, in reactive arthritis, 134, 136 follow-up, 146 Opportunistic infections, tumor necrosis factor α inhibitors causing, 106 Oral lesions, reactive arthritis causing, 134, 143 Osteoclast precursors (OCPs), in psoriatic arthritis, 52-53, 57, 58t Osteoclasts in psoriatic arthritis, 49, 52 in spondyloarthropathy, 163, 167 future directions for, 174 Osteoporosis, in psoriatic arthritis, 17 biologic agents impact on, 109 Osteoprotegerin (OPG), in psoriatic arthritis, 52 Outcome Measures in Rheumatology Clinical Trials 7 (OMERACT 7), 84, 93, 95 Outer membrane protein (OMP), in reactive arthritis, 184 major, 183 P Pain back chronic, 133-134 in Chlamydia-induced arthritis, 157 joint in psoriatic arthritis, 7, 11-12 as diagnostic criteria, 23, 24t, 25t prognosis studies on, 32 in reactive arthritis, 133, 143, 177, 195, 197 Pain management, for Chlamydiainduced arthritis, 159 Pannocytes, in inflamed synovium, 163

Pedigrees, of psoriatic arthritis inheritance mode defined by, 68, 69f two-generation example, 67, 67f Pencil-in-cup deformities, in psoriatic arthritis, 52 Penetrance, of germline, in psoriatic arthritis, 68, 70 D-Penicillamine for psoriatic arthritis, 100 for reactive arthritis, 205t Penicillins, for reactive arthritis, 205t Peptide T, for psoriatic arthritis, 101 Peptides arthritogenic, in reactive arthritis, 190f, 191 keratin psoriatic arthritis and, 43, 43f streptococci virulence and, 41-42 Periodic acid-Schiff (PAS) stain, in reactive arthritis, with Whipple’s disease, 154 Periostitis, in reactive arthritis, 144 Peripheral joints psoriatic arthritis in disease activity assessment, 90-93, 92t composite responder indices, 91-93 tender/swollen joint counts, 90-91, 91t DMARD therapy for, 97-101, 98t functional assessment of, 92t, 94 MRI of, 86-87, 87f radiography of, 81, 82f ultrasonography of, 83-84, 84f reactive arthritis in clinical presentations of, 133, 143, 157 historical aspects of, 128 imaging of, 144, 152, 196 spondyloarthropathy and, 161 end-stage, 167 Peroxisome proliferator–activated receptor γ (PPAR-γ) agonists for angiogenesis inhibition, 63 for psoriatic arthritis, 108 PET (positron emission tomography), in psoriatic arthritis, 87 Phalanx lysis of, in psoriatic arthritis, 16, 17, 17f psoriatic arthritis in radiography of, 81-82, 82f ultrasonography of, 84f

Pharmacotherapy for Chlamydia-induced arthritis, 156, 158-159 for psoriasis biologic agents, 115, 118-120 models for, 115 summary overview of, 114-115, 115t systemic agents, 115, 117-118 topical therapies, 114, 115-116 for psoriatic arthritis angiogenesis target of, 62-63 combination, 99, 100, 101, 103-105, 108 cytokine targets of, 90 leukocyte function antigen targets of, 8 molecular targets of, 65 Pharyngitis, streptococcal, psoriatic arthritis associated with, 40, 41, 43f, 49 Phenotypes of psoriasis, 11 of psoriatic arthritis clinical definition of, 65 models of, 67-68, 67f of spondyloarthropathies, 163 Phosphoric ester poisoning, psoriatic arthritis related to, 49 Photochemotherapy for psoriasis, 115t, 117 for psoriatic arthritis, 100 Phototherapy, for psoriasis management, 115, 115t, 116-117 retinoids in combination with, 118 Physical therapy, for reactive arthritis management, 144 Pioglitazone for angiogenesis inhibition, 63 for psoriatic arthritis, 108 PIP. See Proximal interphalangeal (PIP) joints. Placebo response rates, in psoriatic arthritis therapy trials, 97, 98, 98f, 99 Plantar fascia enthesopathy of, in psoriatic arthritis, 84 reactive arthritis in, 134, 157 imaging of, 196, 197, 198 Plaque psoriasis, 11 autoimmune mechanisms of, 40, 42 immunopathology of, 49 T cells generation of, 42, 44f, 114

Index

Pannus-bone interface, in spondyloarthropathy, 163, 167 Parent-of-origin effect, in psoriatic arthritis, 3 PAS (periodic acid-Schiff) stain, in reactive arthritis, with Whipple’s disease, 154 PASI (Psoriasis Area and Severity Index), 63, 94 in drug trials, 98, 99, 103-105, 108 Patellar tendon, enthesopathy of, in psoriatic arthritis, 15 Pathogenesis of psoriatic arthritis, 37-44, 48-58 autoimmune, 40-44, 43f-44f bone remodeling in, 52-53, 53f cartilage destruction in, 52 cellular immunopathology in, 49-51, 50f cytokines in, 51-52 environmental factors in, 48-49 genetics in, 37-38, 48, 65-66, 66f immune response in, acquired vs. innate, 53-56 genetic knowledge supporting, 65-66, 66f immunology in, 38-40, 41f model of, 57, 58t metalloproteinases in, 52 models of, 56-57, 56t summary of, 37, 44, 57, 58t of reactive arthritis, 181-185, 209 antibiotics and, 182 bacterial persistence in, 182 cytokine imbalance role, 182-183 CD4+ T cells role, 183-184 genetic predispositions, 140 historical understandings in, 131 HLA-B27 role, 140-142, 141f, 182, 184. See also HLA-B27. arthritogenic peptide hypothesis, 184-185, 190f, 191 other hypothesis about, 185 immunology in, 152-153 infectious triggers, 123-126, 124t, 125t, 126t, 142, 181. See also specific organism, e.g., Salmonella spp. Patient education, for reactive arthritis management, 144 PCR. See Polymerase chain reaction (PCR). PDGF (platelet-derived growth factor), in psoriatic arthritis, 51

227

INDEX

228

Plasma cells in psoriatic arthritis, acquired response of, 54 in spondyloarthropathy, 162, 164t, 172 treatment effect on, 168-170, 168t Plasma viscosity, in psoriatic arthritis, measurement of, 94 Plasmacytoid dendritic cells (pDC), in psoriatic arthritis, 39 Platelet-derived growth factor (PDGF), in psoriatic arthritis, 51 Poisoning, phosphoric ester, psoriatic arthritis related to, 49 Polyarthritis in psoriatic arthritis, 61 as prognostic indicator, 14 chronic, 6 prognosis studies on, 31 symmetric, 2 synovitis findings, 12t, 13, 13f in reactive arthritis, 151, 154, 189, 192 Polymerase chain reaction (PCR), in reactive arthritis diagnosis, 136, 136t, 151 Chlamydia-induced, 157 with Whipple’s disease, 154 Population-based studies of psoriatic arthritis, 1-2, 6-7, 24 genetic, 7 on diagnostic classifications, 27 synovitis findings with, 11, 12t of reactive arthritis, 124, 124t, 139-140 genetics in, 188 pathogenesis in, 181-185 Positive predictive value, in psoriatic arthritis diagnosis, 19 Positron emission tomography (PET), in psoriatic arthritis, 87 Power Doppler MSUS in psoriatic arthritis, 83-84, 84f in reactive arthritis, 197 PPAR-γ. See Peroxisome proliferator– activated receptor γ (PPAR-γ) agonists. Prader-Willi syndrome, 77 Prevalence of psoriatic arthritis among psoriasis patients, 2 population-based, 1-2 of reactive arthritis population-based, 124, 124t spectrum of, 139-140 with infections, 123-124 worldwide, 138, 139t

Probabilistic statements, in psoriatic arthritis diagnosis, 19-20 Proband, in genetic structures, 67, 68 pedigree examples of, 67f, 68, 69f Prognosis in psoriatic arthritis, factors contributing to, 8, 30-32 in reactive arthritis, 147t, 178-179 host factors of, 178, 192 imaging correlations to long-term, 198 infective organism and, 146, 158, 177t, 178 poor, 204, 204t, 206 therapy effect on, 178-179, 206, 210-211 Protein kinase C pathway, angiogenesis role, therapy targeted at, 62 Proteoglycans, in psoriatic arthritis, 40, 49 Proteome analysis, in spondyloarthropathy, 174 Proximal interphalangeal (PIP) joints, psoriatic arthritis in MRI of, 86 ultrasonography of, 84f Ps. See Psoriasis (Ps). PsA. See Psoriatic arthritis (PsA). PsAQoL, 95 PsARC. See Psoriatic Arthritis Response Criteria (PsARC). Pseudogout, reactive arthritis vs., 136, 158 Psora, 4 Psoralen plus ultraviolet A (PUVA) for psoriasis, 115t, 117 for psoriatic arthritis, 100 Psoriasis (Ps) angiogenesis in, 61-64 as therapeutic target, 62-63 description of, 61-62, 62f summary, 63-64 novel therapeutic strategies for, 63 pathophysiologic role, 62 arthritis link to, 130 autoimmune mechanisms of, 42, 44f clinical characteristics of, 61 description of, 114 drug-induced, 107 early- vs. late-onset, 11 etiology of, 114 historical aspects of, 4-5 immune response in, 53 acquired, 53-54 innate, 54-56 in psoriatic arthritis as diagnostic criteria, 21t, 22, 26t clinical features of, 11, 61

Psoriasis (Ps) (Continued) genetic models of, 67-68, 67f vascular features of, 62 inflammatory arthritis with pattern of, 2 prevalence of, 2 management of, 114-120 biologic therapies for, 115, 118-120 phototherapy for, 115, 116-117 summary overview for, 114-115, 115t systemic therapies for, 115, 117-118 topical therapies for, 114, 115-116 treatment models for, 115 phenotypes of, 11 skin, disease activity measures of, 93-94 T cell mediation of, 39, 41-42, 114 tumor necrosis factor α inhibitors causing, 107 Psoriasis Area and Severity Index (PASI), 63, 94 in drug trials, 98, 99, 103-105, 108 Psoriasis Foundation, 34 Psoriasis vulgaris, 2 clinical features of, 11, 12f genetics of, 72 Psoriatic arthritis (PsA) angiogenesis in, 7, 61-64 as therapeutic target, 62-63 description of, 61-62, 62f summary, 63-64 novel therapeutic strategies for, 63 pathophysiologic role, 51, 62 animal models of, 56-57, 56t biologic agents in, 102-109. See also specific agent, e.g., Alefacept. inflammation and, 108-109 miscellaneous other, 107-108 potential, 108 summary of, 102-103, 109 tumor necrosis factor α inhibitors, 103-107. See also Tumor necrosis factor α inhibitors. classification criteria for, 188, 189b classification schemes for, 1, 3, 6 diagnostic applications of, 20, 22-23 future prospects for, 27 imaging based, 81, 87 Moll and Wright, 20, 81 clinical features of, 11-17, 61 bone disease in, 16-17, 17f enthesopathy, 15

Psoriatic arthritis (PsA) (Continued) extra-articular disease with, 15-16, 16f, 32-33 genetics of, 65-78 candidate genes in, 72-77 psoriasis-susceptibility maps to, 70-72, 70f, 71t conclusions about, 78 epidemiology in, 2-3 formal, 68-70, 69f sex influences on inheritance, 77-78 structures related to psoriasis, 67-68, 67f susceptibility gene identification challenges, 65-67, 66f historical aspects of the future, 8 the past, 1, 4, 5-6 the present, 6-8 imaging in, 81-87 computed tomography, 87 magnetic resonance imaging, 84-87, 85f-86f high-resolution, 86, 87f plain radiography, 81-83, 82f-83f scintigraphy, 85, 87 ultrasonography, 83-84, 83f-84f immunopathology of cellular, 49-51, 50f etiopathogenesis role, 38-40, 41f pathogenic role, 57, 58t synovial, 7 incidence of, 2, 90 inflammatory pattern of, 2 morbidity with, 32-33 mortality with, 8, 33-34 natural history of, 29-30 pathogenesis of, 48-58 bone remodeling in, 52-53, 53f cartilage destruction in, 52 cellular immunopathology in, 49-51, 50f cytokines in, 51-52 environmental factors in, 48-49 genetic factors in, 48, 65-66, 66f immune response in, acquired vs. innate, 53-56 genetic knowledge supporting, 65-66, 66f immunopathic model of, 57, 58t metalloproteinases in, 52 models of, 56-57, 56t summary of, 57, 58t prevalence of among psoriasis patients, 2 population-based, 1-2 prognostic factors for, 8, 30-32 psoriasis in

Psoriatic arthritis (PsA) (Continued) as diagnostic criteria, 21t, 22, 26t clinical features of, 11, 61 genetic models of, 67-68, 67f vascular features of, 62 quality of life and, 8, 32, 33 measurement of, 90, 92t, 95 socioeconomics of, 34 synovial membrane in histopathology of, 7, 164t immunopathology of, 7, 166 therapy for advances in, 8 angiogenesis as target of, 62-63 vascular features of, 62 Psoriatic Arthritis Response Criteria (PsARC) for anti-angiogenesis agents, 63 in drug trials, 97, 98t, 103 measures of, 91 Psoriatic spondylitis, 7, 16 PSORS1 genes, in psoriatic arthritis, 37 as candidates, 73 genome scan for linkage, 77 psoriasis-susceptibility map to, 70f, 71 stratification of, 72 PSORS2 gene, in psoriatic arthritis, 37 PSORS3 gene, in psoriatic arthritis, 37 PSORS4 gene, in psoriatic arthritis, 38, 43 PSORS8 gene, in psoriatic arthritis, 38 PSORS9 gene, in psoriatic arthritis, 37 Psychological stress, psoriatic arthritis related to, 49 Psychoneuroimmunology, 109 Psychosocial assessment, of psoriatic arthritis patients, 34 Purplish discoloration, in psoriatic arthritis, inflammation vs., 16 Pustular psoriasis, 11 PUVA (psoralen plus ultraviolet A), for psoriasis, 115t, 117 Pyrazine-pyridine biheteroaryl, 62 Pyrimidine synthesis inhibitors, for psoriatic arthritis, 99 Q Quality of life (QOL) psoriasis-specific instruments for, 11, 95 psoriatic arthritis and, 8, 32, 33 measurement of, 90, 92t, 95, 99 socioeconomics of, 34 reactive arthritis and, 179 Quinacrine, for psoriatic arthritis, 100

Index

Psoriatic arthritis (PsA) (Continued) extra-articular manifestations, 15-16, 16f historical aspects of, 7-8 inflammatory arthritis vs., 16 prognosis based on, 7-8 psoriasis as, 11, 61 synovitis as, 11-15, 12t, 13f-14f, 13t clinical outcomes in, 90-95 core domains for, 95, 95t disease activity assessment, 90-94, 92t function assessment, 92t, 94-95 need for, 90, 95 quality of life assessment, 92t, 95 diagnostic criteria for, 19-27 accuracy studies of, 20, 24, 26, 26f challenges with, 19-20 future prospects for, 27 historical aspects of, 3, 6, 8 miscellaneous other, 22-24, 25t Moll and Wright, 20, 22, 24, 68 primary role, 20 summary of proposed, 20, 21t disability with, 32, 33 axial joint damage in, 94 fatigue in, 95 global assessments of, 94-95 measurement of, 90, 92t, 94-95 natural history of, 29-30 peripheral joint damage in, 94 prognosis studies on, 31-32 quality of life with, 92t, 95 socioeconomics of, 34 disease activity assessment in, 90-94, 92t disease-modifying antirheumatic therapies for angiogenesis as target of, 62-63 conventional agents, 97-100 in combination trials, 99, 104-106 miscellaneous agents, 100-101 placebo response rates in, 97, 98, 98f, 99 PsARC response criteria for, 97, 98t, 99 summary of, 8, 30, 31, 33, 97, 101 enthesis in, 51 epidemiology of, 1-3 genetics in, 2-3, 7, 65 present studies of, 6-7 etiopathogenesis of, 37-44 autoimmune, 40-44, 43f-44f genetics in, 37-38 immunology in, 38-40, 41f summary overview, 7, 37, 44

229

INDEX

230

R RA. See Rheumatoid arthritis (RA). Radiation synovectomy, for psoriatic arthritis, 101 Radiation therapy, for lymph nodes, in psoriatic arthritis, 101 Radiography in psoriatic arthritis as diagnostic criteria, 21t, 22, 24t comparative accuracy of, 24, 26, 26f discriminant value of, 22, 23t findings with, 81-83, 82f-83f prognosis based on, 8 synovitis findings, 14, 14f, 15 in reactive arthritis, 144, 152, 154, 157-158 findings with, 195, 196-198, 196t Radionuclide scans, in psoriatic arthritis, 87 RANKL (receptor activator of nuclear factor-κβ ligand), in psoriatic arthritis, 7, 52, 53f, 57 RAP (transporters associated with antigen processing) alleles, in reactive arthritis, 140 RAPTOR gene, in psoriatic arthritis, 37 Reactive arthritis (ReA) antibiotics for, 145, 146, 159 bacterial persistence and, 182 clinical outcomes related to, 195, 204, 205t, 206 effect on prognosis, 179, 210-211 efficacy of, 145, 156, 159, 210, 211 goals of, 193 bacterial infections in, 123, 124t enteric pathogens, 125-126 outbreak cohorts, 124-125, 125t, 126t prevalence of, 123-124 study approaches to, 124-126, 124t classification criteria for, 138-139, 188, 189b clinical outcomes in, 200-206 acute episodes, 203-204 likelihood of developing, 200-203, 201t-202t HLA-B27 as predictor of, 201, 204 acute episodes and, 203-204 age and, 203 mortality, 200, 206 poor functional, 204, 204t prophylaxis effects on, 204, 206 treatment effects on, 204, 205t, 206 work disability, 204

Reactive arthritis (ReA) (Continued) clinical presentations of, 142-144 gastrointestinal, 134, 144 general symptoms, 133, 143 ileocolonoscopy findings, 134, 136 joint symptoms, 133-134, 143 mucous membrane symptoms, 134, 143 musculoskeletal, 123, 143, 196t ocular lesions, 134, 136, 143 skin symptoms, 134 study recommendations based on, 134-136, 135t, 136t visceral, 134, 143-144 definitional description of, 123, 138, 209 diagnostic criteria for, 133-136, 135t clinical history, 133 evolution of, 138-139 laboratory tests in, 134-135, 135t, 144, 158 microbiologic, 135-136, 136t, 158 of ESSG, 188, 189b problems regarding, 136, 195 serologic, 135-136, 136t, 158 system-specific, 133-134 differential diagnosis of, 136, 158 disease activity assessment of duration and severity, 203 persistence and recurrence, 203-204 enteric infections and, 151-154 brucellosis in, 153 C. difficile in, 153 clinical presentations of, 151-152 G. lamblia in, 153 immunopathogenesis of, 152-153 intestinal bypass in, 154 Whipple’s disease in, 153-154 epidemiology of, 123-126 hospital series in, 124 population-based studies, 124, 124t prevalence of infections, 123-124, 139-140 single-source outbreaks, 124-125, 125t, 126t survey programs in, 125-126 genetics of, 188-193 animal models of, 184, 185, 191 clinical manifestations in, 192 diagnostic classification criteria and, 188, 189b DNA/RNA in, 151, 182, 188, 190 environmental factors and, 189-190, 190b epidemiology in, 188 etiology and, 189, 190f

Reactive arthritis (ReA) (Continued) host susceptibility factors and, 190-192, 192f investigations for, 192-193 pathogenic predispositions, 140 prognosis in, 192 summary overview, 123, 188, 193 treatment strategies and, 193, 211 historical aspects of, 128-131 background perspectives on, 128, 131, 138 early descriptions of, 128 evolving concepts of, 130-131, 131t in early twentieth century, 129-130 in nineteenth century, 128-129, 129t pathogenesis in, 131 HIV infection and, 138, 140, 209, 210, 211 imaging in, 195-198, 196t aspects of, 195 long-term prognosis and, 198 of entheses, 197-198 of gut inflammation, 196-197 of joint involvement, 195-196, 196t of spondyloarthritides, 197-198 immunopathology of, 152-153 cytokine imbalance role, 182-183 inflammatory spondylopathies with, 125 laboratory findings with, 134-135, 135t, 144, 158 management of, 144-146, 209-211 anti-inflammatory agents for, 206 antibiotics for, 145, 156, 159, 179, 210-211 clinical outcomes related to, 195, 204, 205t, 206 approach to, 211 biologic agents for, 146 corticosteroids for, 145, 159, 178, 210 DMARDs for, 145, 156, 159, 193, 210 future directions for, 211 general measures for, 144 immunosuppressive drugs for, 145, 146, 159, 210 NSAIDs for, 144-145, 153, 154, 158, 178, 206, 210 tumor necrosis factor α inhibitors for, 145-146, 159, 179, 206, 210 musculoskeletal symptoms of, 123, 143, 196t

Recombinant interleukin-10 agent, for psoriatic arthritis, 108 Recombinant interleukin-11 agent, for psoriatic arthritis, 108 Recurrence risk analysis, for psoriatic arthritis, 37 Recursive partitioning technique, in psoriatic arthritis criteria research, 24 Regenerative maturation (RM), of epidermis, in psoriatic arthritis, 42-43, 43f Regulatory authorities, access criteria of, for psoriatic arthritis, 27 Regulatory T cells in inflamed synovium, 162, 164t in psoriatic arthritis, 39 Reiter’s disease, reactive arthritis associated with, 124, 125, 211 clinical presentations of, 142, 151 genetics of, 188 historical aspects of, 129-130, 138 imaging of, 195, 196 long-term prognosis and, 198 natural history of, 146, 177 pathogenesis of, 131 Renal function tests, in reactive arthritis, 135, 135t, 143-144, 178 Research on psoriatic arthritis for diagnosis criteria, 20 formal group for, 8, 93, 95 issues to focus on, 8, 19 prognostic factor studies, 30-33 selection bias in, 24 statistical analysis in, 19, 20, 22, 24 on prognostic factors, 30-32 on spondyloarthropathy, 173 Respiratory infection, reactive arthritis caused by, 123, 124t, 156-157 pathogenesis of, 181, 189 Resting memory T cells, in psoriatic arthritis, 42, 43f Retinoids for psoriasis, 115t, 116, 117-118 phototherapy in combination with, 118 for psoriatic arthritis, 100 Rheumatoid arthritis (RA) angiogenesis in, 62 evolving concepts of, 130-131, 131t historical aspects of, 130 in psoriatic arthritis, 6 biologic agents impact on, 109 prognosis studies on, 31 in reactive arthritis, 144, 176-177

Rheumatoid arthritis (RA) (Continued) acute phase of, 177 chronic phase of, 177 psoriatic arthritis vs., 1, 6, 16 synovial histopathology in, 163, 164t, 165-166, 165f synovial immunopathology in, 161-174. See also Synovial immunopathology. Rheumatoid factor historical discovery of, 6 in psoriatic arthritis, 6-7, 19 as diagnostic criteria, 20, 21t, 24, 24t, 26, 26t in reactive arthritis, 135, 135t, 157 in seronegative arthritis, 130 in spondyloarthropathy, 161 rhIL-1037, for spondyloarthropathy, 168t Rifampin, for Chlamydia-induced arthritis, 159, 210 Ritchie Articular Index, of peripheral arthritis, 91, 92 Rituximab, for reactive arthritis, 146 RM (regenerative maturation), of epidermis, in psoriatic arthritis, 42-43, 43f RNA, in reactive arthritis, 182, 188 Rochester Epidemiological Project, 2 Rotational therapy, for psoriasis management, 115 Rotator cuff, enthesopathy of, in psoriatic arthritis, 15 RUNX1 gene, in psoriatic arthritis, 37 S S100 proteins, in psoriatic arthritis, 49 Sacroiliac joints psoriatic arthritis in MRI of, 85, 85f radiograph of, 83, 83f ultrasonography of, 84 reactive arthritis in, 151, 154, 158 historical aspects of, 128 Sacroiliitis in psoriatic arthritis, 12t, 14, 16 arthritis mutilans with, 2 as diagnostic criteria, 20, 21t, 22, 24t, 25t imaging of, 82-83, 85, 85f natural history of, 30 in reactive arthritis, 143, 152 acute outcomes related to, 202, 203, 204 Chlamydia-induced, 156, 157 natural history of, 177, 178 prognosis of, 146, 177t, 178 imaging correlation to, 198

Index

Reactive arthritis (ReA) (Continued) imaging modalities for, 195-198, 196t natural history of, 146, 176-178 extra-articular manifestations, 177-178 primary infection evolution, 176 rheumatic symptoms evolution, 176-177 treatment implications of, 209 pathogenesis of, 140-142, 181-185, 209 antibiotics and, 182 bacterial persistence in, 182 cytokine imbalance role, 182-183 CD4+ T cells role, 183-184 genetic predispositions, 140 historical understandings in, 131 HLA-B27 role, 140-142, 141f, 182, 184. See also HLA-B27. arthritogenic peptide hypothesis, 184-185, 190f, 191 other hypothesis about, 185 immunology in, 152-153 infectious triggers, 123-126, 124t, 125t, 126t, 142, 181. See also specific organism, e.g., Salmonella spp. prevalence of population-based, 124, 124t spectrum of, 139-140 with infections, 123-124 worldwide, 138, 139t prognosis of, 147t, 178-179 host factors of, 178 imaging correlations to long-term, 198 infective organism and, 146, 158, 177t, 178 poor, 204, 204t, 206 therapy effect on, 178-179, 206, 210-211 prophylaxis effects on anti-inflammatory agents in, 206 antibiotics in, 204, 205t, 206 quality of life with, 179 radiography of, 144, 152, 154, 157-158 rheumatic symptoms with, 176-177 acute phase of, 177 chronic phase of, 177 socioeconomic aspects of, 179 synovial membrane in histopathology of, 164t immunopathology of, 166 Receptor activator of nuclear factor-κβ ligand (RANKL), in psoriatic arthritis, 7, 52, 53f, 57

231

INDEX

232

St. Thomas’s Hospital description, of reactive arthritis, 129, 129t Salmonella enterica, reactive arthritis caused by, 124, 126t Salmonella spp., reactive arthritis caused by, 123, 124, 124t, 142 diagnostic isolation of, 151, 152 genetics of, 188, 191, 192 imaging of, 195 immunopathogenesis of, 142, 152 likelihood of, 201, 201t, 202t natural history of, 146, 176, 177, 177b outbreak cohorts, 124, 126t pathogenesis of, 181, 182, 184, 185 prognosis of, 146, 177t, 178 recurrence of, 203, 204 socioeconomic impact of, 179 survey programs on, 125 worldwide prevalence of, 138, 139t Salpingitis, reactive arthritis associated with, 157, 202 SAPHO syndrome, 85, 85f SARA (sexually acquired reactive arthritis), 201-203 Schober test, for axial joint damage, in psoriatic arthritis, 95 Schumacher, Ralph, 7 Scintigraphy in psoriatic arthritis, 85, 87 in reactive arthritis, 136 findings with, 195-198, 196t disease-specific gut inflammation, 196-197 SEEK1 gene, in psoriatic arthritis, as candidate, 73 E-Selectin expression in psoriatic arthritis, 49 in spondyloarthropathy, 162, 164t, 165 Selection bias, in psoriatic arthritis research, 24 Sentrin, in inflamed synovium, 163, 164t Sequential synovial fluid analysis, in spondyloarthropathy, 173 Sequential therapy, for psoriasis management, 115 Serial partitioning analysis (SPAN), 24 Serology, in reactive arthritis diagnosis, 135-136, 136t, 158, 193 Seronegative arthritis. See also Reactive arthritis (ReA). current views on, 130-131, 131t historical aspects of, 5, 128, 130 pathogenesis of, 131 prognosis studies on, 31

Seronegative spondyloarthropathies evolving concepts of, 130-131, 131t pathogenesis of, 131 Sex-of-parent, psoriatic arthritis inheritance and, 77-78 Sexually acquired reactive arthritis (SARA), 201-203 Sexually transmitted disease, reactive arthritis associated with, 128, 129, 156, 157, 211 antimicrobial treatment for, 204, 205t, 206 pathogenesis of, 181-185 SF-36 (36-Item Short Form Survey), psoriatic arthritis applications of, 8, 11, 33 Sharp score, of psoriatic arthritis, radiographic validation of, 82 Shigella spp., reactive arthritis caused by, 123, 124, 124t, 142 diagnostic isolation of, 151 genetics of, 188, 189, 193 historical aspects of, 130 likelihood of, 201, 201t, 202t natural history of, 176, 177, 177b outbreak cohorts, 124, 125t pathogenesis of, 181, 182 prognosis of, 177t, 178 recurrence of, 203, 204 socioeconomic impact of, 179 survey programs on, 125, 126 worldwide prevalence of, 138, 139t Shoulder, psoriatic arthritis in, radiography of, 82 Signal transduction pathways in psoriasis, 114 in psoriatic arthritis, 77 therapy targeted at, 62-63 Simplex inheritance, of psoriatic arthritis, 70 Single-nucleotide polymorphism (SNP), in psoriatic arthritis genes, 72, 74, 77 Single-source outbreaks, of reactive arthritis, 124-125, 125t, 126t 6p21 chromosome in psoriasis, 70-72, 70f sex of the affected parent and, 78 in psoriatic arthritis, genome scan for linkage, 77 Skeletal hyperostosis, idiopathic, 128 Skin psoriatic arthritis involvement of as diagnostic criteria, 21t, 22 blood vessel growth and, 61. See also Angiogenesis. disease activity measures, 93-94 morbidity risk for, 32

Skin (Continued) research on, 8 synovitis findings, 11, 14 reactive arthritis involvement of as diagnostic criteria, 134, 135t Chlamydia-induced, 156, 157, 158 SLC12A8 gene, in psoriatic arthritis, 37 SM. See Synovial membrane (SM). SMR (standardized mortality rate), for psoriatic arthritis, 33 SNP (single-nucleotide polymorphism), in psoriatic arthritis genes, 72, 74, 77 Socioeconomic aspects of psoriatic arthritis, 34 of reactive arthritis, 179 Sodium thiomalate, for psoriatic arthritis, 99 Soft tissue edema of, with reactive arthritis, 196, 197 inflammation of with psoriatic arthritis treatment, 84 with reactive arthritis, 157 Somatostatin, for psoriatic arthritis, 100 Sore throat, streptococcal, psoriatic arthritis associated with, 40, 41, 43f SpA. See Spondyloarthropathy (SpA). SPAN (serial partitioning analysis), 24 SPEC (streptococcal pyogenic exotoxin serotype C-producing) group A streptococcus, 49 Spine, spondyloarthritis of diagnostic criteria for, 12t, 14, 14f, 182, 183b in psoriatic arthritis, 12t, 14, 14f as diagnostic criteria, 21t, 22 disease activity measures of, 93 MRI of, 85 natural history of, 30 in reactive arthritis, 125, 133-134, 158, 195 Spirochaetosis arthritica, 129 Spondylitis ankylosing. See Ankylosing spondylitis (AS). in psoriatic arthritis disease activity measures of, 93 radiography of, 82-83 in reactive arthritis, 143, 154 psoriatic, 7, 16 Spondyloarthritis in psoriatic arthritis spinal. See Spine. synovitis findings, 12t, 14, 14f, 52 in reactive arthritis, 125, 195 prevalence of, worldwide, 138, 139t

Streptococcal pyogenic exotoxin serotype C-producing (SPEC) group A streptococcus, 49 Streptococcus spp. psoriatic arthritis triggered by, 7, 49 autoimmune mechanisms of, 40, 41, 43f genetics and, 37 reactive arthritis triggered by, 181, 189 Stress, psychological, psoriatic arthritis related to, 49 SU5416, for angiogenesis inhibition, 63 Sulfasalazine/sulphasalazine for Chlamydia-induced arthritis, 159 for psoriatic arthritis, 8, 97-98, 98f for reactive arthritis, 145, 159, 210, 211 effect on prognosis, 178-179 Surgery, psoriatic arthritis related to, 48-49 Survey programs for psoriatic arthritis clinic-based, 6-7, 11, 24 36-Item Short Form for, 8, 11, 33 for reactive arthritis, on enteric pathogens, 125-126 Susceptibility genes, in psoriatic arthritis, 72-77 genome scans for linkage, 76-77 identification challenges of, 65-67, 66f models of, 67-68, 67f psoriasis-susceptibility maps to, 70-72, 70f, 71t Swelling, joint in psoriatic arthritis, count for assessment of, 90-91, 91t in reactive arthritis, 133-134 Synovectomy, radiation, for psoriatic arthritis, 101 Synovial biopsy for psoriatic arthritis diagnosis, 23, 24t for spondyloarthropathy, 168, 169, 170, 172 Synovial fluid analysis in psoriatic arthritis, 23, 24t, 52 in reactive arthritis, as diagnostic, 135, 135t, 144, 151-152 bacterial persistence and, 182, 183, 184 Chlamydia-induced, 158 in chronic phase, 177 Whipple’s disease and, 153-154 in spondyloarthropathy, 161, 172 sequential, 173

Synovial immunopathology, in spondyloarthropathy, 161-174 clinical applications of, 172-173 disease activity/severity relation with, 163, 167-168 future directions for, 173-174 histopathology comparisons of, 163, 164t, 165-166, 165f inflamed synovium features, 162-163 normal synovium vs., 161-162 of subtypes, 164t, 166 pathogenic considerations, 170-172 treatment modulation of, 168-170, 168t, 169f Synovial joints, large psoriatic arthritis in MRI of, 85-86, 86f radiography of, 82 ultrasonography of, 83, 83f, 84 reactive arthritis in, 133 Synovial lining, in spondyloarthropathy histopathology of, 163, 164t, 165-166, 165f hyperplasia of, 162-163, 165f treatment effect on, 168t, 170 thickness vs. cell function differentiation, 163, 165 Synovial membrane (SM) functional anatomy of, 161-162 immunopathology in spondyloarthropathy, 161-174. See also Synovial immunopathology. in psoriatic arthritis abnormal vascularity of, 61, 62f diagnosis of, 23, 24t histopathology of, 7 immunopathology of, 7, 49 cellular, 49-51, 50f inflamed characteristics of, 162-163 normal features of, 161-162 vascularization of in psoriatic arthritis, 61, 62f in spondyloarthropathy, 162, 163, 165, 165f pathogenic considerations of, 170-171 treatment effect on, 168t, 169-170 Synoviocytes, type A vs. type B, 161-162 accumulation with inflammation, 162-163 histopathology of, 163

Index

Spondyloarthritis (Continued) psoriatic arthritis vs., 16 spinal. See Spine. Spondyloarthropathy (SpA) classification of, 188, 189b ESSG criteria for, 188, 189b in psoriatic arthritis, 2 biologic agents impact on, 109 synovitis and, 50 in reactive arthritis, 125, 152 genetic predispositions, 140 HLA-B27 role, 140-142, 141f imaging of, 197-198 natural history of, 146, 176, 177 prognosis of, 147t, 177t, 178, 179 psoriatic arthritis vs., 16, 161 reactive arthritis vs., 161 seronegative evolving concepts of, 130-131, 131t pathogenesis of, 131 subtypes of, common features in, 161 synovial immunopathology in, 161-174 clinical applications of, 172-173 disease activity/severity relation with, 163, 167-168 future directions for, 173-174 histopathology comparisons of, 163, 164t, 165-166, 165f inflamed synovium features, 162-163 normal synovium vs., 161-162 of subtypes, 164t, 166 pathogenic considerations, 170-172 treatment modulation of, 168-170, 168t, 169f Sporadic inheritance, of psoriatic arthritis, 70 Standardized mortality rate (SMR), for psoriatic arthritis, 33 Statistical analysis, in psoriatic arthritis criteria research, 19, 20, 22, 24 on prognostic factors, 30-32 Steinbrocker score, of psoriatic arthritis, radiographic validation of, 82 Sternoclavicular joint, psoriatic arthritis in, MRI of, 85, 86f Steroids, for psoriatic arthritis, 31 Stiffness, joint, in reactive arthritis, 133-134, 159 Stool cultures, in reactive arthritis, 135-136, 136t, 152 urethral swabs vs., 192-193

233

INDEX

234

Synovitis high-resolution ultrasonography of, 63 in psoriatic arthritis, clinical features of, 11-15, 12t, 13f-14f, 13t in spondyloarthropathy, 169 Synovium. See Synovial membrane (SM). Systemic therapy(ies), for psoriasis management, 115, 115t, 117-118 T T-cell receptor (TCR), usage, in psoriasis, 53-54, 114 T cells in guttate psoriasis, 42, 44f in inflamed synovium, 162-163, 164t in plaque psoriasis, 42, 44f, 49 in psoriasis acquired response of, 53-54 mediation role, 39, 41-42, 114 in psoriatic arthritis, 7 acquired response of, 54 autoimmune mechanisms of, 40-41, 42 biologic agents targeting, 8, 108 etiopathogenesis role, 38-39, 57 innate response of, 55 genetic knowledge supporting, 65-66, 66f, 68 natural killer-, 39, 55 regulatory, 39 resting memory, 42, 43f synovium immunopathology and, 49, 50f type 1 interferons effect on, 39-40 in reactive arthritis, 152-153 cytotoxic, 185, 190f, 191 pathogenesis role, 140-142, 141f, 209 in spondyloarthropathy, 164t, 166 pathogenic considerations of, 171 treatment effect on, 168-170, 168t, 169f T helper 1 (Th1) cytokines in psoriasis, 114 in psoriatic arthritis, 51 in reactive arthritis, 190, 190f, 209 bacterial persistence and, 182-183 in spondyloarthropathy, 164t, 166 pathogenic considerations of, 171 Tachyphylaxis, from corticosteroids, for psoriasis, 115 Tacrolimus, for psoriasis, 118

Tar regimens, for psoriasis, 115-116, 115t Tazarotene, for psoriasis, 115t, 116 TB (tuberculosis), tumor necrosis factor α inhibitors and, 106 TCR (T-cell receptor), usage, in psoriasis, 53-54, 114 Technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO)-labeled leukocytes, for reactive arthritis detection, 196 Telomeres, in psoriasis-susceptibility gene maps, 70-72, 71t stratification of, 72, 73 Tenderness, joint, in psoriatic arthritis, 7, 11-12 count for assessment of, 90-91, 91t inflammation vs., 16 Tendon(s) enthesopathy of, in psoriatic arthritis, 15 extra bone formation at, psoriatic arthritis and, 16, 17, 17f Tenosynovitis, in reactive arthritis, 177 Teratogens, in psoriasis therapies, 118 Tetracycline, for reactive arthritis, 193, 205t TGF (transforming growth factor), in psoriatic arthritis, 7 etiopathogenesis role, 40, 41f, 51 TGF-β. See Transforming growth factor-β (TGF-β). Th1. See T helper 1 (Th1) cytokines. 6-Thioguanine, for psoriasis, 118 36-Item Short Form Survey (SF-36), psoriatic arthritis applications of, 8, 11, 33 Thomson’s description, of reactive arthritis, 128, 129t Thrombophlebitis, psoriatic arthritis related to, 49 Tie2, in psoriatic arthritis, angiogenesis role, 61 therapy targeted at, 62-63 TNFs. See Tumor necrosis factors (TNFs). TNP-470, for angiogenesis inhibition, 63 Toll-like receptors (TLRs) in psoriatic arthritis, 55-56 in reactive arthritis, 178, 189-190, 190f in spondyloarthropathy, 164t, 165f, 168t future directions for, 173 pathogenic considerations of, 172 Tonsillitis, streptococcal, psoriatic arthritis related to, 41, 49

Topical therapy(ies), for psoriasis management, 114, 115-116, 115t Transcription factors, in psoriatic arthritis, animal models of, 56-57, 56t Transforming growth factor (TGF), in psoriatic arthritis, 7 etiopathogenesis role, 40, 41f, 51 Transforming growth factor-β (TGF-β) in psoriatic arthritis, 53 in reactive arthritis, 191 in spondyloarthropathy, 162, 164t, 165, 166 Transgenic mice models of psoriatic arthritis, 56t, 57 of reactive arthritis, 184, 185, 191 of spondyloarthropathy, 171 Transporters associated with antigen processing (TAP) alleles, in reactive arthritis, 140 Trauma, psoriatic arthritis related to, 48 Tuberculosis (TB), tumor necrosis factor α inhibitors and, 106 Tuft osteolysis, distal, in psoriatic arthritis, 16, 17f as diagnostic criteria, 23f, 23t Tumor necrosis factor α (TNF-α) in psoriasis, 114 in psoriatic arthritis, 51-52 candidate genes and, 74-75 in reactive arthritis, 142, 157, 209 bacterial persistence and, 182-183 in spondyloarthropathy, 162, 164t, 166 treatment effect on, 168t, 169-170 Tumor necrosis factor α inhibitors for Chlamydia-induced arthritis, 159 for psoriatic arthritis, 8, 49, 103-107 administration reactions to, 106 angiogenesis as target of, 62, 63 cardiovascular disease linked to, 109 congestive heart failure related to, 107 hematologic side effects of, 107 hepatic side effects of, 107 immunogenicity and, 107 infection related to, 106 lupus induced by, 107 malignancy rate with, 107 MRI findings following, 85, 86 multiple sclerosis exacerbations with, 106-107 psoriasis induced by, 107 safety of, 106-107 specific agents as, 97, 103-106 for reactive arthritis, 145-146, 159, 210, 211

U UDPGD (uridine diphosphoglucose dehydrogenase), in synoviocytes, 162 Ulcerative colitis, reactive arthritis vs., 131, 134, 154 Ultrasonography (US) high-resolution of psoriatic arthritis, 83 of synovitis, 63 in psoriatic arthritis, findings with, 83-84, 83f-84f in reactive arthritis, 144 findings with, 195, 196t, 197-198 Ultraviolet (UV) light, for psoriasis, 37, 115t, 116-117 Ultraviolet A (UVA), psoralen plus, for psoriasis, 115t, 117 Ultraviolet B (UVB), for psoriasis, 115t, 116 narrowband, 115t, 116 Undifferentiated spondyloarthropathy (USpA), 161 synovial pathology in, 164t, 166, 172 Ureaplasma urealyticum, reactive arthritis caused by, 123, 124t likelihood of, 201t, 203 Urethral swabs, in reactive arthritis, 193 Urethral syndrome, in Chlamydiainduced arthritis, 157 Urethritis nongonococcal, reactive arthritis caused by, 202-203 psoriatic arthritis manifesting as, 15

Urethritis (Continued) reactive arthritis associated with, 123, 124t, 129, 151 detection of, 193 pathogenesis of, 131, 156 Uridine diphosphoglucose dehydrogenase (UDPGD), in synoviocytes, 162 Urinalysis, for reactive arthritis diagnosis, 135, 135t, 144, 157 Urinary ligase reaction, in reactive arthritis, 193 Urogenital infections, reactive arthritis associated with, 123, 124t, 151 as diagnostic criteria, 134, 135t Chlamydia-induced, 156, 159 clinical manifestations of, 143 mucocutaneous, 143 natural history of, 176, 178 pathogenesis of, 181-185 treatment of, 210-211 US. See Ultrasonography (US). USpA (undifferentiated spondyloarthropathy), 161 synovial pathology in, 164t, 166, 172 UV. See Ultraviolet (UV) light. Uveitis psoriatic arthritis manifesting as, 15 reactive arthritis manifesting as, 157, 178 V Vascular cell adhesion molecule 1 (VCAM-1) in spondyloarthropathy, 162, 164t, 165 synoviocytes expression of, 162 Vascular endothelial growth factor (VEGF) in psoriatic arthritis, 7, 49 angiogenesis role, 61-62, 64 therapy targeted at, 62-63 bone formation and, 53 etiopathogenesis role, 40, 41f, 50f, 51, 52 in spondyloarthropathy, 169-170 Vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor for angiogenesis, 62 for spondyloarthropathy, 169 Vascular growth factors, in psoriatic arthritis, 7, 61 Vascularization in psoriatic arthritis. See Angiogenesis. synovial in psoriatic arthritis, 61, 62f

Vascularization (Continued) in spondyloarthropathy, 162, 163, 165, 165f pathogenic considerations of, 170-171 treatment effect on, 168t, 169-170 Vasey and Espinoza criteria, for psoriatic arthritis, 21t, 23, 25t comparative accuracy of, 24, 26, 26f VCAM-1. See Vascular cell adhesion molecule 1 (VCAM-1). VEGF. See Vascular endothelial growth factor (VEGF). VEGFR2 See Vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. Venereal disease, reactive arthritis associated with, 128, 129, 156, 157, 211 antimicrobial treatment for, 204, 205t, 206 Viscera, reactive arthritis involvement of, 134, 135t

Index

Tumor necrosis factor α inhibitors (Continued) effect on prognosis, 179, 193, 206 for spondyloarthropathy, 168t, 169-170 clinical applications of, 173 future directions for, 173 pathogenic considerations of, 170-171 Tumor necrosis factors (TNFs), in psoriatic arthritis, 32, 40, 41f angiogenesis and, 61 candidate genes and, 74-75 genome scan for linkage, 77 pathogenic role, 50f, 51-52, 57, 58t Twin studies of psoriatic arthritis, 37-38, 68 of reactive arthritis, 188 Tyrosine kinase pathway, angiogenesis role, therapy targeted at, 62, 63

W Waaler, F., 6 Whipple’s disease, 130 reactive arthritis associated with, 153-154 Willan, Robert, 4 Willan-Plumbe syndrome, 5 Willan’s syndrome, 5 Work disability psoriatic arthritis and, 34 reactive arthritis and, 204 Wright classification, of psoriatic arthritis, 81 Wright criteria, for psoriatic arthritis, 20, 21t, 22, 68 comparative accuracy of, 24, 26, 26f Wright description, of seronegative arthritis, 130 Y Yersinia spp., reactive arthritis caused by, 123, 124, 124t, 142 diagnostic isolation of, 136, 136t, 151, 152 genetics of, 191 historical aspects of, 131 immunopathogenesis of, 152, 153 likelihood of, 201, 201t, 202t natural history of, 146, 176, 177, 177b

235

INDEX

236

Yersinia spp., reactive arthritis caused by (Continued) outbreak cohorts, 124, 125t

pathogenesis of, 171, 181-184 prognosis of, 177t, 178 recurrence of, 203-204

socioeconomic impact of, 179 survey programs on, 125