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TEXTBOOK OF PEDIATRIC RHEUMATOLOGY Copyright © 2005, Elsevier Inc.
ISBN 1-4160-0246-4
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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 the practitioner, 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 or related to any use of the material contained in this book.
Library of Congress Cataloging-in-Publication Data Textbook of pediatric rheumatology / [edited by] James T. Cassidy, Ross E. Petty–5th ed / associate editors, Ronald M. Laxer, Carol B. Lindsley p.; cm. Includes bibliographical references and index ISBN 1-4160-0246-4 1. Pediatric rheumatology 2. Rheumatism in children. I. Cassidy, James T. II Petty, Ross E. [DNLM: 1. Rheumatic Disease–Child 2. Arthritis–Child 3. Connective Tissue Diseases–Child 4. Vasculitis–Child. WE 544 T355 2006] RJ482.R48.C37 2006 618.922723-dc22
Publishing Director: Kim Murphy Developmental Editor: Janine Kusza Project Manager: David Saltzberg Marketing Manager: Megan Carr
Printed in the United States Last digit is the print number: 9
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CONTRIBUTING AUTHORS
'\,
KhaIed Alsaeld, MD Chief of Pediatric Rheumatology, Department of Pediatrics, Kuwait University, Faculty Medicine, Safat, Kuwait
Frank Dressler, MD Lecturer, Department of Pediatrics, Hannover Medical School, Assistentzarzt, Kinderklinik der Medizinischen, Hochschule Hannover, Hannover, Germany
Balu H. Athreya, MD Division of Rheumatology, Alfred 1. duPont Hospital for Children, Wilmington, Department of Pediatrics, Wilmington, Delaware, USA
Oaran M. Duffy, MB, BCH, M5c Associate Professor of Paediatrics and Director, Division of Paediatric Rheumatology, Montreal Children's Hospital, and McGill University, Montreal, Quebec, Canada
Ella M. Ayoub, MD (deceased) Distinguished Service Professor, Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA
Fernanda Faldnl, MD Department of Pediatrics, University of Florence and Oespedale Meyer, Florence, Italy
Susannah Brydges, PHD Fellow, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
Ruben Burgos-Vargas, MD Professor of Medicine, Universidad Nacional, Auton6ma de Mexico, Mexico DF James T. Cassidy, MD Professor Emeritus of Child Health and Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, and Professor Emeritus of Pediatrics and Communicable Diseases and Internal Medicine, University of Michigan, Medical School, Ann Arbor, Michigan, USA Rolando Omaz, MD Dirigente Medico, Department of Pediatrics, Fondazione Policlinico Mangiagalli, University of Milan, Milan, Italy Robert A. Colbert, MD, PHD Associate Professor of Pediatrics, Associate Director, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Marco Gattorno, MD Department of Pediatrics, University of Genoa, Genoa, Italy Edward H. Giannini, MSc DR PH Professor of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA David N. Glass, MD Professor of Pediatrics, Director, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Judith G. Hall, OC, MD Professor Emeritus, Medical Genetics and Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada Robert M. Hamilton, MD Professor, Department of Paediatrics, University of Toronto; and Section Head, Electrophysiology, Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada Hans-Iko Huppertz, MD Professor of Pediatrics, Head, and Director, Children's Hospital CProfessor-Hess-Kinderklinik), Bremen, Germany
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CONTRIBUTING AUTHORS
Daniel L. Kastner, MD, PHD Chief, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA Wletse Kuls, MD, PhD Professor of Pediatrics, University of Utrecht and Department of Pediatrics, University Medical Center, Utrecht, The Netherlands Ronald M. Laxer, MD, FRCPC Professor of Paediatrics and Medicine, University of Toronto; and Vice President, Clinical and Academic Affairs and Staff Rheumatologist, The Hospital for Sick Children, Toronto, Ontario, Canada Carol B. Lindsley, MD Professor, Department of Pediatrics, Chief, Pediatric Rheumatology, University of Kansas Medical Center, Kansas City, Kansas, USA Daniel J. Lovell, MD, MPH Professor of Pediatrics, University of Cincinnati College of Medicine; Associate Director, William G. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio, USA Peter N. Malleson, MBBS Professor of Pediatrics, Division of Pediatric Rheumatology, University of British Columbia, British Columbia Children's Hospital, Vancouver, British Columbia, Canada Alberto Martini, MD Professor and Head, Department of Pediatrics, Gaslini Children's Hospital, University of Genoa, Genoa, Italy Audrey M. Nelson, MD Emeritus Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Anne-Marie Prieur, MD Hopital Necker Enfants Malades, Paris, France L1eke A.M. Sanders, MD, PhD Associate Professor of Pediatric Immunology, University of Utrecht and Department of Pediatrics, University Medical Center, Utrecht, The Netherlands David D. Sherry, MD Professor of Pediatrics, University of Pennsylvania, Director, Clinical Rheumatology, Attending, Pain Management, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Earl D. Silverman, MD, FRCPC Professor of Pediatrics and Immunology, University of Toronto, Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada Taunton R. Southwood, MD, BM, BS Professor of Paediatric Rheumatology, Department of Rheumatology, University of Birmingham Medical School, Birmingham Children's Hospital, Birmingham, United Kingdom Dawn Spence, RN, MSN, PNP Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada Robert P. Sundel, MD Assistant Professor of Pediatrics, Harvard Medical School, Director of Rheumatology, Children's Hospital Boston, Boston, Massachusetts, USA Janltzla V6zquez-Mellado, MD, PhD Professor of Medicine, Universidad Nacional Aut6noma de Mexico; Senior Investigator, Rheumatology Service, Hospital General de Mexico, Mexico City, Mexico
Benedlcte Neven Unite d'Immunologie-Hematologie et Rhumatologie, Hopital Necker Enfants Malades, Paris, France
Nlco M. Wulffraat, MD, PhD Associate Professor in Pediatric Immunology, University of Utrecht and Department of Pediatrics, University Medical Center, Utrecht, The Netherlands
Seza Ozen, MD Professor, Department of Pediatrics, Hacettepe University 02, Faculty of Medicine, Ankara, Turkey
Francesco Zullan, MD Professor, Chief, Division of Pediatric Rheumatology, Universita di Padova, Padua, Italy
Ross E. Petty, MD, PHD Professor of Pediatrics, University of British Columbia, Division of Rheumatology, Department of Pediatrics, Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
FOREWORD
In the beginning, we were a handful of naive but eager and explorative young physicians of disparate training, background, and temperament. We joined together with a vision of doing whatever was necessary to find better ways to study the rheumatic diseases of childhood and adolescence, and to treat our patients more effectively in a comprehensive continuum of care. Our successes resulted from consistent and collegial cooperation in pursuit of these common goals. With the first pediatric rheumatology centers in the u.s. in Ann Arbor, Boston, Dallas, Houston, Los Angeles, New York City, and Seattle, expansion had occurred to 27 by 1976 at the time of the First Park City Meeting, to 77 today, with a similar development of centers of excellence in clinical care and research in pediatric rheumatology around the globe on every continent. Over the years, the acquisition of spe-
cific knowledge in this field has developed at an astounding, accelerated pace. To a major extent the scientific and clinical progress of these decades and its publication has been organized and codified in this Textbook ofPediatric Rheumatology, beginning with the first edition in 1982. It is therefore our distinct privilege to join together to dedicate this fifth edition not only to that early small group of clinics and to their expansion in numbers and effectiveness, but even more to the children with rheumatic diseases, to their families, and to the now thousands of healthcare professionals endeavoring to ameliorate or cure these diseases and to improve the lifestyles and career opportunities of their patients. EARL
J.
BREWER,
JOSEPH
E.
MD, FAAP, MACR MD, MACR
LEVINSON,
xIII
PREFACE
The first edition of the Textbook of Pediatric Rheumatology was published in 1982. The intervening years have encompassed an enormous increase in our understanding of the pathophysiologic mechanisms operative in the genesis of pediatric rheumatic diseases, much of which is specific for the discipline. It was not so many years ago that the rheumatologic literature reflected data primarily from studies of adults. These recent and gratifying developments in scientific studies specific to the younger age groups have afforded us opportunities for better diagnosis and treatment of children with rheumatic disorders. Yet much remains to be accomplished. The present edition continues the tradition of incremental reassessment of authorship established by its predecessors, and represents a complete revision of the original text. We trust it will be a testament to the clinical scope and science of pediatric rheumatology, its codification as a distinct specialty, and the gratifying maturity that it has achieved. It is our belief that the advances in the practice and science of pediatric rheumatology described herein are increasingly recognized as an integral and essential element of the clinical, investigative, and educational programs of academic institutions of medical training and research. This edition was reorganized in order to provide a comprehensive source of information regarding the rheumatic diseases of childhood during the last five years for specialists concerned with the care of these children, and for those in primary fields of medicine in order to facilitate early diagnosis and treatment through timely referral. Significant advances in practice and knowledge have been incorporated including exhaustive reviews of the major clinical syndromes resulting in the rheumatic and inflammatory diseases of childhood and investigative efforts directed toward validation of their classification. The chapters on health care assessment, the conduct of clinical trials, and the design and statistical analysis of therapeutic investigations have been carefully revised. Most importantly, the text continues to reflect the ongoing therapeutic revolution in rheumatology involving biologic modification of the cytokine network which reqUired a reworking and considerable enlargement of the chapter on pharmacology. Chapters on the periodic
fever syndromes and the genetic profiles of related neonatal inflammatory disorders have been added. In the process of documenting these innumerable additions to our knowledge, the cited references have been extensively updated, retaining only those regarded as "classics" or having historic importance, and incorporating recent publications that specifically contribute to understanding the pathophysiology and clinical presentation of the over 100 rheumatic "diseases" that afflict children. The majority of these publications are now specific to children, in contrast to the first edition where much had to be assumed from adult studies. In fact, publications in this field are now so extensive that one can only suggest the depth of the investigations. To give due credit to all would require substantial additional text. It should be noted that much of the material summarized in previous editions has been deleted by acknowledging duplicative studies and tenets now universally accepted. Reviews where appropriate have been emphasized. Thirty-four of our colleagues have been enlisted in these efforts in what is now an international, multiauthored text. The contributions of these authors represent expert appraisals of specific fields of clinical concentration. We are incredibly grateful for their enthusiastic cooperation in this endeavor. Their efforts have clarified areas of immunogenetics that emphasize the extensive advancement in knowledge that will ultimately result from sequencing the human genome, immunologic mechanisms of inflammatory disease, neuroendocrine dysregulation, and developmental defects contributing to the inflammatory arthropathies. Much revision has also resulted from careful and exhaustive reviews of previous editions by John Bohnsack, Hermine Brunner, Edward Giannini, Carol Lindsley, David Sherry, and Carol Wallace. In addition to our colleagues, we are deeply indebted to our families and spousal support throughout this process of revision spanning more than three years, without whose patience and understanding this new edition would not have been possible. A transition in editorial direction, with the appointment of two associate editors who have been contributors to this and previous editions, has been of enormous aid in the preparation of this
xv
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PREFACE
text, and in assuring the continuation of the contributions that it has brought to the specialty. We have also given our last farewells to two former contributors and dear friends who have now left us: Carol G. Ragsdale and Elia M. Ayoub. We trust that the fifth edition of the Textbook ofPediatric Rheumatology will aid physicians caring for children with rheumatic diseases to interpret the complex web of symptoms, signs, and laboratory abnormalities that are characteristic of these disorders, and their often inherent ambiguity; will inspire students of medicine to recognize
the challenges and excitement of this pediatric discipline; and ultimately will ensure the provision of prompt and optimal care to the hundreds of thousands of children and their families around the world who endure the pain and limitations imposed by these disorders. T. CASSIDY, MD PEITY, MD, PHD
JAMES
Ross E.
RONALD CAROL
B.
M. LAxER, MD LINDSLEY, MD
C HAP T E R
1
INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN Ja.s T. Cassidy and Ross E. Petty
~
The rheumatic diseases are chronic multisystem disorders that represent clinical manifestations of acute and chronic inflammation of the connective tissues of the musculoskeletal system, blood vessels, and skin. They range from arthritis limited to one joint, to widespread inflammation of joints, muscles, skin, blood vessels, and organs as diverse as the eye, lung, brain, and bone marrow. Homo sapiens has been afflicted with a variety of these disorders for thousands of years. Chronic arthritis-like changes have been identified in the spines of prehistoric Egyptian mummies circa 8000 BC,I and ankylosing spondylitis may be the most ancient of the defined rheumatic diseases, having been documented in skeletal remains from medieval Europe. 2 However, rheumatoid arthritis may be a more recent development, at least in Europe, where it was first described clinically in the 19th century, although it may have originated much earlier among aboriginals of North America. 3 Rheumatic diseases are worldwide in distribution, although there are notable differences in the frequency of some diseases in different racial groups. Considering the early age at onset of many rheumatic diseases of childhood, as well as their chronicity, they constitute an important burden for society.
EVOLUTION OF TERMINOLOGY In 1883, Barlow introduced a discussion on "Rheumatism and its allies in childhood" as follows: "The fundamental difficulty in discussing rheumatism consists in defining what we mean by it.,,4 The term rheumatism is derived from the Greek rheumatismos: a flux. The first use of this term has been ascribed to Galen, 5 to describe inflammatory or degenerative diseases of the joints, bones, muscles, or bursae. Baillou 0558-1616) first employed the word rheumatism to distinguish acute arthritis from gout. 6 The noun "rheumatism" currently has no precise meaning and has generally fallen into disuse. The adjective rheumatic originally referred to acute rheumatic fever and today has the connotation of "inflammatory."
2
Rheumatic fever per se was distinguished from acute gouty arthritis only in the 17th century by Sydenham in England7 ; he later described chorea. The word arthritis is derived from the Greek arthron, meaning joint. It entered the English language about 1544, when it was used to refer only to gout with the suffix -itis, meaning inflammation (-ites, originally an adjectival inflection, gradually evolved to -itis as a suffix to imply an inflammatory disorder). The term arthralgia indicates joint pain without objective evidence of inflammation. Garrod first proposed the designation rheumatoid arthritis to differentiate this disorder from gout and rheumatism. 8 However, it is likely that Hippocrates recognized these diseases in his innumerable observations on the origin of disease from natural phenomena, separate from sacred or philosophical causation or superstition. 9 In the absence of specific knowledge of etiology or pathogenesis, it is not surprising that the terminology used to describe and classify rheumatic diseases, including those of childhood, continues to evolve. Discrepancies between the American College of Rheumatology criteria for classification of juvenile rheumatoid arthritis (JRA)1O and those of the European League Against Rheumatism for juvenile chronic arthritis (JCA)ll exemplify this point. The problem of definition and classification has been a persistent one and is addressed again in the proposed criteria for juvenile idiopathic arthritis (JIA) of the International League of Associations for Rheumatology (see Chapter 9).12 Terminology for the other rheumatic diseases affecting children has been less controversial; however, validated classification criteria are often lacking. In large part, terms used to describe similar diseases in adults have been adopted without consideration for age-related differences in disorders such as systemic lupus erythematosus (SLE), scleroderma, dermatomyositis, and some of the vasculitides. Proposed criteria for the first three of these are now being validated by international studies. Diagnostic or classification criteria have been developed for "new" diseases such as Kawasaki disease, Lyme disease, and parvovirus Bl9-associated arthritis. Recent
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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN
genetic discoveries, as in the periodic febrile syndromes, have led to a reclassification of these disorders. In recent decades, chronic noninflammatory pain syndromes have become major clinical components of the field of rheumatology in its broadest sense in both children and adults; criteria for these disorders in children and adolescents have been adopted or modified from those used in adults.
THE RHEUMATIC DISEASES OF CHILDHOOD Pediatric rheumatology is a clinical discipline that embraces the study of inflammatory and noninflammatory disorders of the connective tissues and joints in children. Its boundaries continue to expand, and although inflammatory disorders of joints, muscles, and connective tissues constitute the core of the discipline, the differential diagnosis of these diseases necessitates a broad knowledge of potentially confusing disorders, the majority of which are included in chapters of this textbook. A summary of the history of arthritis in children has been published by Hayem. 13 The first book on pediatrics written by an Englishman, which contains the first English-language reference to rheumatism in children, is the 1545 text by Phaire, 1be Regiment ofLife Whereunto Is Added a Treatise of the Pestilence, with 1be Boke of Chytdren. In this work, the author refers to the "stifnes or starckenes of the limmes" resulting from exposure of a child to cold,14.15 a complaint that may not represent any specific rheumatic disease, and also says, "Here to doo them good that haue most nede, that is to saye children." In 1864, Cornil described a woman in whom polyarthritis had developed when she was 12 years 01d. 16 The disease pursued a chronic relapsing course and terminated in her death from uremic coma at the age of 28 years. Necropsy documented myocardial degeneration, nephrotic syndrome, and ankylosis of some joints, with synovial proliferation and marked destruction of cartilage in others. This girl may have had amyloidosis complicating chronic polyarticular arthritis. In 1873, Bouchut described chronic rheumatism in six children,17 and in 1870 .Moncorvo l8 diagnosed childhood arthritis in one of his own patients in Brazil and in eight patients from the literature. West's 1881 Lectures on the Diseases ofInfancy and Childhood!9 noted that "chronic rheumatic arthritis in children is a rare occurrence." In 1883, Barlow, a mentor to Still at the Hospital for Sick Children, Great Ormond Street, London, chaired a discussion on rheumatism in childhood. 4 In the report of this meeting, the term rheumatism was used to describe poststreptococcal disease, including acute rheumatic fever. Barlow recognized clearly the extent and complexity of these disorders: "For there are in children many affections of joints, and of structures around joints, which do not suppurate, and yet are not rheumatic; and there is much rheumatism in children which does not affect joints." What we would today call toxic synovitis of the hip, acute pyogenic arthritis, syphilitic arthritis, hemophiliac arthropathy, Henoch-Schonlein purpura, poststreptococcal arthritis, and acute rheumatic fever,
3
including carditis, arthritis, nodules, erythema marginatum, and chorea, are all identifiable in this paper. This physician was careful to exclude rickets and scurvy because he considered that the joint itself was not primarily involved in these conditions. In 1891, Diamant-Berger published a detailed account of chronic arthritis in 38 children whom he had seen or whose cases had been documented in the literature. 2o He noted the heterogeneity of onset, its predominance in girls, and involvement of the cervical spine and temporomandibular joints as well as ocular inflammation. He also stated that the prognosis in children was generally better than for chronic arthritis in adults. Five years later, Still described 22 cases of acute and chronic arthritis in children, almost all of whom were observed at the Hospital for Sick Children. 21 This treatise, written under the mentorship of Barlow,22 documented the clinical characteristics and the differing modes of onset in these children. Still was the first English physician to confine his practice to diseases of children and the first Professor of Paediatrics at King's College Hospital Medical School, London. Unfortunately, after his classic study, he rarely returned to the field of pediatric rheumatology, although his scholarly work comprised 108 papers and five books, including the History of Paediatrics (931) and Common Diseases in Children. Also in 1896, Koplick 23 described the first American child with chronic arthritis. Although these descriptions of arthritis in childhood rank as the most important milestones in the early development of pediatric rheumatology, other rheumatic diseases began to be identified in children in the 19th century. The clinical characteristics of leukocytoclastic vasculitis were described by Schonlein24 and Henoch25 in the mid-1800s. Juvenile dermatomyositis was identified by Unvericht in 1877,26 although it was not until the 1960s that significant experience with this disease was reported. SLE has been recognized in children at least since 1904. 27 The original description of scleroderma was in a 17-year-old girl,28 but the disease was rarely diagnosed thereafter in a child until the early 1960s. Ankylosing spondylitis was also perhaps first identified in a child 29 ; it was certainly known to occur in childhood in the 19505,30 but specific studies of the disorder in children did not emerge until the late 1960s. 31.32 More recent additions to the family of pediatric rheumatic diseases include Kawasaki disease, which was reported in some detail in 1967,33 although its clinical characteristics (in infants dying of "polyarteritis nodosa") were described by Munro-Faure in 1959. 34 Other rheumatic diseases, such as neonatal-onset multisystem inflammatory disease or NOMID (also called chronic infantile neurologic, cutaneous, and articular [CINCA] syndrome), neonatal lupus, and Lyme disease, have recently been identified. Noninflammatory musculoskeletal pain syndromes are more recent additions to the expanding list of disorders that cause musculoskeletal pain and dysfunction in children and adolescents. Very little further information about these rheumatic diseases was published until the last half of the 20th century. This development coincided with the availability of penicillin and the retreat of acute rheumatic fever in
4
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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN
Europe and North America. Until the mid-1940s this disease was the major rheumatic disease, and it still is in many areas of the developing world. With its control, however, attention was shifted to the chronic nonstreptococcal rheumatic diseases, principally chronic arthritis. Today, the specialty of pediatric rheumatology is concerned with a diverse group of disorders (Table 1-1), most of which are manifestations of systemic disorders and require the greatest expertise for prompt diagnosis and optimal management. Of all of the specialties, rheumatology, one of the most stimulating and challenging areas in all of medicine, may deal with the broadest spectrum of disease, both organ-specific and systemic. It is sometimes considered a "gray area" of medicine because there are few useful diagnostic tests, pathognomonic clinical signs are sparse, and therapy often lacks specificity. This specialty requires a diagnostic and therapeutic approach that embraces the "whole" child and family unit, patience, careful observation over long periods, and a heightened ability to tolerate ambiguity and uncertainty. Sometimes only the passage of time makes a diagnosis evident.
EMERGENCE OF THE SPECIALTY OF PEDIATRIC RHEUMATOLOGY The roots of contemporary pediatric rheumatology are found in pediatrics, internal medicine, immunology, and orthopedics; however, as experience with rheumatic diseases in children accumulates, it is apparent that many aspects of these disorders demand a uniquely pediatric approach. Furthermore, many of the diseases, or their complications, are confined to the childhood and adolescent population but have lasting effects on health and socioeconomic well-being or cause disability well into adulthood. These considerations first emerged in the United Kingdom in particular, where the study of rheumatic disease in children was established in earnest after World War II by the founding in 1947 of the Rheumatism Research Unit at the Canadian Red Cross Memorial Hospital in Taplow, Berkshire, England. 3S .36 Initially the Taplow unit dealt almost exclusively with rheumatic fever. As the frequency of this disease declined in England during the mid-20th century, its focus shifted to
I!:.
TABlE I-I
the other chronic rheumatic diseases and laid the foundation for the specialty of pediatric rheumatology. Pediatric rheumatology began to develop in the United States in the early 1940s. Hospitals for the treatment and rehabilitation of children with rheumatic fever were established after World War II in Chicago (La Rabida) and New York City (Irvington House) that were later expanded in scope to care for children with other rheumatic diseases and chronic illnesses. Establishment of clinical and academic centers of pediatric rheumatology in the United States and subsequently in many other countries marked the "coming of age" of the specialty. The American College of Rheumatology established the Pediatric Council in 1975; its first Conference on the Rheumatic Diseases of Children was held in Park City, Utah, in 1976. The first edition of this textbook was published in 1982. Reminiscences of six of the pioneers of pediatric rheumatology (Stillman, Hanson, Levinson, Ansell, Brewer, and Stoeber) are recommended to the interested reader. 37--42
FACTORS THAT MAY MODIFY RHEUMATIC DISEASES IN CHILDREN One of the fundamental questions that has pervaded research in pediatric rheumatology is the extent to which the rheumatic diseases of childhood are the same as, or different from, rheumatic diseases in adults. It is important to differentiate semantic from biologic similarities: The fact that two diseases bear the same name or share some physical findings, abnormalities in laboratory markers, or even treatments (e.g., JRA and adult rheumatoid arthritis) does not necessarily imply that they are the same disorder biologically. Historically, the pediatric diseases were usually named in ignorance of epidemiology, genetics, or biology. Any distinction based on age at onset alone is arbitrary and unlikely to represent biologic truth. There is no age at which these rheumatic diseases abruptly change from one to the other, yet age-related associations are often evident. For example, there are characteristic age-atonset distributions for the individual chronic arthritides. 43 The spectrum of int1ammatory myositis is very different in the child or adolescent than in the adult. Morphea is a common form of scleroderma in the child, whereas in the
Frequt'll(y ollhe Major Pedialri( (onnedive Tisslle Ubeases in 11,300 Children
Disease Juvenile rheumatoid arthritis Connective tissue diseases Spondyloarthropathy and reactive arthritis Psoriatic arthropathy Infectious arthritis and osteomyelitis Malignancy/hematologic Chronic pain syndromes Hypermobility and overuse syndromes Other diseases
Number of eases 7,368 3,861 2,973 173 1.620 290 4,483 2,745 34,216
%
12.8 6.7
5.1 0.3 2.8 0.5 7.8 4.8 59.3
57,729 diagnoses from 48.934 consecutive patients with definite diagnoses entered into the Pediatric Rheumatic. Disease Registry of the Pediatric Rheumatology Database Research Group. 1992-2002. Courtesy of Suzanne Bowyer. M.D., Pediatric Rheumatology Database Research Group.
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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN
adult, systemic scleroderma predominates. There is little doubt that some rheumatic diseases occur only in young children (e.g., oligoarthritis with uveitis, Kawasaki disease), and others affect almost exclusively adults (e.g., gout, osteoarthritis). Neonatal lupus, and rarely other rheumatic diseases, represent the effect of maternal autoimmunity on the fetus. In diseases such as SLE and the vasculitides, clinical and laboratory characteristics in children and adults are very similar, if not identical in many cases. However, the reasons that one individual has childhood onset of disease, whereas another has onset in adulthood, are not known. More commonly, however, diseases with similar names and similar biologic characteristics occur in both pediatric and adult populations (e.g., scleroderma, ankylosing spondylitis, SLE). Age-related manifestations of these diseases are well recognized. Some of the prominent differences between children and adults that may modify the clinical expression of a rheumatic disease are presented in Table 1-2. Most, if not all, rheumatic diseases are characterized by disordered immunity, and often there is a genetic predisposition that is expressed clinically early in life. This is particularly true for the inherited dysplasias of bone and cartilage and for biochemical disorders such as mucopolysaccharidoses, hemophilia, and the periodic febrHe syndromes. The influence of age on expression of diseases associated with specific histocompatibility antigens is becoming better understood44 ; however, the strongest major histocompatibility-complex disease association remains that of human leukocyte antigen B27 with ankylosing spondylitis, a disease that begins in childhood in only about 10% of cases. The fact that this genetic predisposition does not more frequently result in childhood onset may reflect yet other factors that differentiate the child from the adult, such as the extent of environmental antigenic experience and the ability of the immune system to respond to its accumulating impact year after year. One argument in support of the significance of antigenic memory and immune reactivity might be exemplified by oligoarthritis. This disease has a narrow age-at-onset distribution: In the majority of children, onset occurs between the ages of 1 and 4 years. 38 Another striking age restriction is apparent in Kawasaki disease, which in North America affects most frequently the 1- to 3-year-old age group.45 One might speculate that these diseases reflect the effect of age at initial exposure to an environmental pathogen such as a virus or bacterium, together with the absence of specific protective immunity, in a genetically predisposed individual.
,1 • TABLE 1-2 Factors rlMt Potentially Modify Expression of Rheumati< Diseases in Childhood
Early expression of genetically determined abnormalities Immaturity and relative inexperience of the immune system Limited antigenic exposure Immaturity of the skeleton and the potential for growth and development Imn:laturity of the gonads and variable hormonal intluences
5
The degree and manner in which skeletal maturity influences the expression of rheumatic diseases is poorly understood. It seems probable, however, that physical and biochemical differences between younger and older cartilage and bone influence the effect of an inflammatory process involving these structures. Because physes are not fused in the growing child with arthritis, local growth abnormalities (e.g., leg-length inequality) may occur. Short stature is a frequent result of widespread arthritis in the child, but it is not an expected development in the skeletally mature adult with arthritis. The anatomy of the blood supply to the physis and epiphysis in the infant is reflected in this age group's predisposition to septic arthritis as a complication of osteomyelitis. The impact of gonadal immaturity on the expression of rheumatic diseases is unclear. SLE occurs predominantly in the pubertal and postpubertal age range. In some studies of SLE,46 girls and boys were affected with equal frequency in early childhood, but in adulthood, women developed this disorder 8 to 9 times more frequently than men. That these observations may reflect the role of reproductive hormones in pathogenesis is supported by studies of adult men with Klinefelter's syndrome cLe., males with two X chromosomes and one Y chromosome), in whom the frequency of SLE is high,47,48 and by studies of lupus-like disease in mice. 49 In contrast, men are much more likely than women to develop ankylosing spondylitis, a characteristic that does not appear to be significantly affected by age.
CHILDHOOD RHEUMATIC DISEASES: EXTENT OF THE PROBLEM It has been difficult to establish the extent of childhood
rheumatic diseases in defined populations with any accuracy. 50 In many of the most densely populated areas of the world, incidence and prevalence data for these disorders do not exist. In the developed world, inconsistencies of definition and classification, the rarity of occurrence for many of these diseases, and brevity of follow-up, have prevented accumulation of any substantial body of epidemiologic data. Two fundamental questions require answers: (1) How many children and adolescents have each of the identifiable rheumatic diseases; and (2) What is the functional outcome for these children? Estimates of the relative frequencies of adult-onset and childhood-onset rheumatic diseases are in Table 1-3. Three national registries from 1996 provided some comparative insights concerning the relative prevalence of the rheumatic diseases of childhood in the United States? Canada,52 and the United Kingdom53 (Table 1-4). Conspicuously under-represented are children with acute rheumatic fever, which is the major rheumatic disease of childhood in much of the world. A study by Manners and Diepeveen54 in Western Australia documented that many cases of chronic arthritis in children went undiagnosed and untreated. If this is the reality of identification in a developed area of the world with readily available expert medical care, the proportion of such children in geographic areas where medical care is less accessible may be even higher. In Finland, Kunnamo and colleagues55
6
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TABLE. I 3
I
INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN
FIl'clueiKY ollhe Rheullldtic [)isedses in Adults dnd Iheir Onset in Childhood
No, Affected
Sex RaUo
Rheumatic Disease In Adults
(xl()5)
(F:M)
Ethnic RaUo (Whlte:Black)
Peak Age at Onset (yr)
Qlldhood Onset (0/0)
Ankylosing spondylitis Rheumatoid arthritis Systemic lupus erythematosus Dermatomyositis/polymyositis Scleroderma Polyarteritis
SOD-WOO 800 50
1:5 3:1 10:6 11:8 4:1 1:1
White> Black Equal 1:4 1:3 Black> White Equal
Young adult Increases with age (20-30) 15-40 45-60 Increases with age 00-50) 40-60
5 18 20 3 Rare'
1.~3.s
24-29 6,3
10
'Except for Kawasaki disease, Modified from data in ref. SO and Chaplers 9-24.
surveyed all children younger than 16 years of age who had swelling or limitation of motion of a joint, walked with a limp, or had hip pain as determined by a primary care physician, pediatrician, or orthopedic surgeon. All of these patients were subsequently examined by a single group of pediatric rheumatologists. Overall, the incidence of arthritis was estimated to be 109 per 100,000 children per year. Transient synovitis of the hip accounted for 48%; other acute transient arthritis CHenoch-Schbnlein purpura, serum sickness) 24%; chronic arthritis, 17%; septic arthritis, 6%; and reactive arthritis, 5%. Connective tissue diseases such as SLE were not identified in this survey. Determination of outcome and the lifelong burden of a pediatric rheumatic disease requires much more precise and comprehensive data than those currently available. The impact of childhood rheumatic diseases on life expectancy, their contribution to morbidity and costs of medical care, and their effect on quality of life are all prognostic parameters of importance about which there is little information even in North Amer:ica and Europe, and no information whatsoever on the global scene. Nevertheless, there can be little doubt that a child who, for example, has arthritis beginning at the age of 2 or 3 years will carry a lifelong burden in one or more of these areas. The expense and inconvenience for other members of the family are also significant.
ADVANCES IN PEDIATRIC RHEUMATOLOGY In the last half century, there have been dramatic advances in understanding the nature of inflammation, the cells and molecules that mediate it, and the therapeutic pOSSibility of specifically regulating the aberrant
I.
TABLE 1-4
immunoinflammatory response. The genetics of rheumatic diseases and, more recently, of the polymorphisms of inflammatory mediators, are pointing the way to therapeutic manipulations at an even more fundamental level, that of the gene. Although this approach is still only a hope for the future, it has been successful experimentally in animal models of arthritis. Currently, specific therapeutic modulation of certain mediators of inflammation is possible, and in particular blockade of tumor necrosis factor-a CTNF-a) has demonstrated great benefit in children with chronic arthritis. It may be premature to consider further advances in understanding of the childhood rheumatic diseases, because so much more must be illuminated. Nevertheless, it is evident that mortality from diseases such as chronic arthritis complicated by amyloidosis, dermatomyositis, and SLE has been dramatically reduced since the 1970s. Disability associated with many rheumatic diseases has been minimized: Wheelchair dependence is now rare, the need for aids to ambulation uncommon, and significant leg-length inequalities increasingly infrequent. Visual outcome in children with uveitis is improved. But much more progress is necessary and should be demanded and expected. Morbidity and mortality, although diminished, still remain serious threats to the child with SLE, vasculitis, or scleroderma, among other disorders. Although there have been major improvements in short- and medium-term outcomes of these and other rheumatic diseases, long-term outcomes are still often disappointing. For example, half of the children with chronic arthritis have active disease 10 years after onset, and children with SLE accumulate visceral damage with the passage of time, with an enduring impact on quality of life, despite much better control of acute lifethreatening events.
Reldtive Frequencies 01 Rheullldtic Disedses in I)edidtrl< Rhellllidtoloyy Clinic s in North Alllericd dnd the United KlIlydolll
U.S.A.S1 Juvenile rheumatoid arthritis/juvenile chronic arthritis Mechanical!orthopedic Vasculitis Systemic lupus erythematosus Juvenile dermatomyositis Systemic scleroderma Rheumatic fever/poststreptococcal arthritis Total
33.1 34.9 10.2 7,1 5,2 0,9 8.6 100.0
CANADASZ 50.0 40,6 3.0 3,9 1.6 0,2 0,7 100,0
U.K." 61.7 32.6 1.9 1.3
2,3 0,2
o 100.0
C HAP T E R
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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN
The reasons for these improvements in outcomes are multiple; chief among them are the establishment of a body of knowledge and expertise and involvement of a multidisciplinary team of health professionals in diagnosis and care. Improved application of old techniques and the development of new approaches have been important contributors to improved prognosis. Therapeutic landmarks of importance to the child with a rheumatic disease must include the introduction of cortisone for treatment of rheumatoid arthritis: Its influence on pediatric rheumatology has been profound. Intra-articular steroid use has improved management of oligoarthritis in children, just as methotrexate has radically improved the course and outcome of childhood polyarthritis. More judicious use of glucocorticoids and cytotoxic drugs has minimized toxicity and maximized effectiveness in diseases such as SLE and dermatomyositis. Biologic agents acting against TNF-lX and interleukin1 count among the major advances of the last decade. Although not curative, these agents and their successors promise to revolutionize management of the severe rheumatic diseases of childhood. Identification of the cause of Lyme disease and the pathogenesis of neonatal lupus, and the aggressive treatment of Kawasaki disease with intravenous immunoglobulin, represent landmarks of progress. Collaborative clinical trials led by the Pediatric Rheumatology Collaborative Study Group (PRCSG) and, more recently, the Pediatric Rheumatology International Trials Organisation (PRINTO) and the Childhood Arthritis and Rheumatology Research Alliance (CAARA), have facili~ted the study of therapeutic interventions in chronic arthritis as well as in the rarer connective tissue diseases. Recognition of the appropriateness of patient and family involvement at all stages of decision-making and care has enabled individualized treatment options and improved compliance. Family support organizations such as the American Juvenile Arthritis Organization in the United States and similar groups abroad have helped to promote education and research and to provide psychosocial support for patients and families.
REFERENCES 1. Ruffer MA. Rietti A: On osseous lesions in ancient Egyptians. J Pathol Bacterial 16: 439. 1912. 2. Kramer C: A case of ankylosing spondylitc, in mediaeval Geneva. Ossa 8: 115, 1982. 3, Rothschild BM. Woods RJ: Symmetrical erosive disease in Archaic Indians: the origin of rheumatoid arthritis in the New World? Semin Arthritis Rheum 19: 27~284, 1990. 4. Barlow T: 51st Annual Meeting of the British Medical Association; Section of Diseases of Children. BM] 2: 509-519, 1883. 5. Dieppe P: Did Galen describe rheumatoid arthritis? Ann Rheum Dis 47: 84-85, 1988. 6. Baillou G: De Liber de Arthritede. Paris, 1591. Quoted by Delpeuch G: La Goulle et Ie Rhumatisme, Paris. 1900. 7. Sydenham T: A Treatise of the Gout and Dropsy. London, 1683. 8. Garrod AB: The Nature and Treatment of Gout and Rheumatic Gout. London. Walton and Maberly, 1859. (Cited by Baethge BA.] Rheumatol19: 185, 1992.) 9. Adams F: The Genuine Works of Hippocrates. Translated from the Greek. London, The Sydenham Society, 1849. (Published as the Loeb Classical Libraty translation of the works of Hippocrates, Harvard University Press. Cambridge. MA. reprinred in 1967-68; also reprinted by The Classics of Medicine Library. Gryphon Editions, Ltd. Birmingham, AL. 1985.) 10. Brewer E] ]r, Bass ]C, Cassidy]T, et al: Criteria for the classification of juvenile rheumatoid arthritis. Bull Rheum Dis 23: 712-719, 1972. II. European League Against Rheumatism: EULAR Bulletin No.4: Nomenclature and Classification of Arthritis in Children. Basel, National Zeitung AG, 1977.
7
12. Petty RE, Southwood TR, Manners p. et al: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31: 390-392, 2004. 13. Hayem F: The history of chronic joint diseases in children. Rev Rhum Engl Ed 66: 499-504, 1999. 14. Phaire T: The Regiment of Life, Whereunto is Added a Treatise of the Pestilence, with The Boke of Chyldren. Newly Corrected and Enlarged. London, Edw. Whitechurch, 1545. (Reprinted 1955 by E. & S. Livingston Ltd., London, p. 31.) 15. Bywaters EG: The history of pediatric rheumatology. Arthritis Rheum 20: 145-152. 1977. 16. Cornil MV: Memoire sur des coincidences pathologiques du rhumatisme articulaire chronique. C R Soc Bioi (Paris) Series 4, 3: 3, 1864, 17. Bouchut E: Traite pratique des Malades des Enfanrs. Ed. 6. Paris. 1875. 18. Moncorvo: Du Rhumatisme Chronique Noueux Des EnI'ants, Paris, 1880. 19. West C: Lectures on the Diseases of Infancy and Childhood. Ed. 7, Philadelphia, 1881. 20. Diamant-Berger M-S: Du Rhumatisme Noueux (Polyarthrite Deformante) Chez les Enfants. Paris, Lecrosnier et Babe. Libraires -Editeurs, 1891. (Reprinted by Editions Louis Pariente, Paris, 1988,) 21. Still GF: On a form of chronic joint disease in children. Med-Chirurg Trans 80: 47-59, 1897, (Reprinted in Arch Dis Child 132: 195, 1978.) 22. Keen ]H: George Frederic Still-Registrar. Great Ormond Street Children's Hospital. Br] Rheumatol 37: 1247, 1998. 23. Koplick H: Arthritis deformans in a child seven years old. Arch Pediatr 13: 161, 1896. 24, Schonlein ]L: Allgemeine und specielle Pathologie und Therapie. Nach dessen Vorlesungen niedergeschrieben und hrsg. von einigen seiner Zuhi'lrer. ed. 3. Ellinger, Herisau Lit Compt. Wurzburg, 1837. 25, Henoch EHH: Ober eine eigenthumliche Form von Purpura. Berl Klin Worchschr 11: 641, lR74. (Translated and reprinted in Am] Dis Child 128: 78. 1974,) 26. Unvericht H: Uber cine eigenrumliche Form von acuter Muskelentzundung mit einem der Trichinose ahnelnden Krankheitsbilde. Munch Med Wochenschr 34: 488, 1887. 27, Osler W: On the visceral manifestations of the erythema group of skin diseases, Am] Med Sci 127: I, 1904. 28. Watson R: An account of an extraordinary disease of the skin. and its cure. Extracted from the Italian of Carlo Crusio: accompanied by a letter of the Abbe Nollet, F.R.S. to Mr. William Watson, F.R.S, Philos Trans R Soc Lond 48: 579, 1754. (Cited by Rodnan GP, Benedeck GT: An historical account of the study of progressive systemic sclerosis [diffuse scleroderma). Ann Intern Med 57: 305, 1968.1 29, Travers B: Curious case of anchylosis of a great part of the vertebral column, probably produced by an ossification of the intervertebral substance. Lancet 5: 254, 1814, (Cited by Bywaters EGL. In Moll ]MH: Ankylosing Spondylitis. Edinburgh. Churchill Livingstone, 1980. p. 14.1 30, Hart FD, Maclagan NF: Ankylosing spondylitis: a review of 184 cases. Ann Rheum Dis 14: 77-83, 1955. 31. Schaller ], Bitnum S, Wedgwood R]: Ankylosing spondylitis with childhood onset.] Pediatr 74: 505-516, 1969. 32. Ladd ]R. Cassidy JT. Martel W: Juvenile ankylosing spondylitis. Arthritis Rheum 14: 579-590, 1971. 33, Kawasaki T: [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children!. Arerugi 16: 178-222, 1967, 34, Munro-Faure H: Necrotising arteritis of the coronary vessels in infancy; case report and review of the literature. Pediatrics 23: 914-926, 1959. 35, Ansell BM, Bywaters EGL, Spencer PE, et al: Ansell BM: Looking back 1947-1985. The Canadian Red Cross Memorial Hospital. Taplow, United Kingdom, 1997, 36, Smythe HA: Historical vignette. Professor Eric Bywaters, 1910-2003. Memories of Taplow.] Rheumatol 31: 601-604, 2004, 37. Stillman ]S: The history of pediatric rheumatology in the United States, Rheum Dis Clin North Am 13: 143-147, 1987. 38, Hanson V: Pediatric rheumatology: A personal perspective. Rheum Dis Clin North Am 13: 155-159. 1987. 39. Levinson JE: Rellections of a pediatric rheumatologist. Rheum Dis Clin North Am 13: 149-154, 1987, 40. Ansell BM: Taplow reminiscences.] Rheumatol 19 (Suppl 33): 105-107, 1992, 41. Brewer E] .Ir: The last thirty and the next ten years.] Rheumatol19 (SuppI33): 108, 1992. 42. Stoeber E: Zur Geschichte Der Kinderklinik und Rheumakinderklinik in Garmisch-Partenkirchen: 1952-1986: Garmisch-Partenkirchen, Umschloggestalrung Christa J. Burges, 1986. 43, Sullivan DB, Cassidy]T, Petty RE: Pathogenic implications of age of onset in juvenile rheumatoid arthritis. Arthritis Rheum 18: 251-255, 1975. 44. Murray K], Moroldo MB, Donnelly P, et al: Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles, Arthritis Rheum 42: 1843-1853. 1999. 45, Wortmann OW, Nelson AM: Kawasaki syndrome. Rheum Dis Clin North Am 16: 363-375, 1990. 46. Cassidy JT, Sullivan DB, Perty RE, et al: Lupus nephritis and encephalopathy: prognosis in 58 children. Arthritis Rheum 20: 315-322, 1977, 47, Ortiz-Neu C, LeRoy EC: The coincidence of Klinefelter's syndrome and systemic lupus erythematosus. Arthritis Rheum 12: 241-246. 1969.
8
CHAPTER
I
INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN
48. Jimenez-Balderas r], Tapia-Serrano R, Fonseca ME, et al: High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction. Arthritis Res 3: 362-367, 2001. 49. Roubinian J. Talal N, SHteri PK, et al: Sex hormone modulation of autoimmunity in NZBINZW mice. Arthritis Rheum 22: 1162-1169, 1979. 50. Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41: 778-799, 1998. 51. Bowyer S, Roettcher P: Pediatric rheumatology clinic populations in the United States: results of a 3 year survey. Pediatric Rheumatology Database Research Group. J Rheumatol 23: 1968-1974, 1996.
52. Malleson PN, Fung MY, Rosenberg AM: The incidence of pediatric rheumatic dbeases: results from the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol 23: 1981-1987, 1996. 53. Symmons DPM, Jones M, Osborne J, et al: Pediatric rheumatology in the United Kingdom: data from the Britbh Pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 23: 1975-1980, 1996. 54. Manners PJ, Diepeveen DA: Prevalence of juvenile chronic arthritis in a population of 12-year-old children in urban Australia. Pediatrics 98: 84--90, 1996. 55. Kunnamo 1, Kallio P, Pelkonen P: Incidence of arthritis in urban Finnish children: A prospective study. Arthritis Rheum 29: 1232-1238, 1986.
2
C HAP T E R
STRUCTURE AND FUNCTION Ross E. Petty and James T. Cassidy
~
Rheumatic diseases frequently affect many different organ systems, but inflammation of the structures of the musculoskeletal system-particularly joints, connective tissues, and muscles-is common to almost all. 1 An appreciation of some of the fundamental aspects of the development, structure, and biochemistry of the connective tissues and the components of the musculoskeletal system is important to the study of pediatric rheumatology. This chapter is intended as an overview of selected aspects of the anatomy and biochemistry of tissues that are particularly important to the study of rheumatic diseases of childhood and as a stimulus for further study.
JOINTS Oassltlcatlon of Joints Joints may be classified as ji'brous, cartilaginous, or synovial (Table 2-1).2 Fibrous joints (synarthroses) are those in which little or no motion occurs and in which the bones are separated by fibrous connective tissue. Cartilaginous joints (amphiarthroses) are those in which little or no motion occurs but the bones are separated by cartilage. Synovial joints (diarthroses) are those in which considerable motion occurs and a joint space lined with a synovial membrane is present between the bones. It is the synovial joint that is the site of inflammation in most of the chronic arthritides of childhood.
the "cavity" regresses and becomes filled with fibrous tissue. 7 The synOVial lining forms subsequent to cavitation, and the development of other structures, such as bursae, intra-articular fat, tendons, muscle, and capsule, quickly ensues. The whole process takes place between the fourth and seventh weeks of gestation, except for the temporomandibular joint, which develops much later. 8
Anatomy of Synovial Joints The anatomy of a typical synovial joint is illustrated in Figure 2-1. The bones of such joints are almost always covered by hyaline cartilage. 9 The synovial membrane attaches at the cartilage-bone junction so that the entire joint "space" is covered by either hyaline cartilage or synovium. The temporomandibular joint is unusual in that the articular surface of the condyle is covered by fibrocartilage rather than by hyaline cartilage. In some synovial joints, intra-articular fibrocartilaginous structures are present. For example, a disk (or meniscus) separates the temporomandibular joint into two spaces; the knee joint contains two menisci that separate the articular surfaces of the tibia and femur; and the triangular fibrocartilage of the wrist joins the distal radioulnar surfaces. Other intra-articular structures include the anterior and posterior cruciate ligaments of the knee, the interosseous ligaments of the talocalcaneal joint, and the triangular ligament of the femoral head. These structures are actually extrasynovial, although they cross through the joint space.
Development of Dlarthrocllal Joints In the fetus, diarthrodial joints develop by the differentiation of a noncartilaginous interzone within the cartilage core of the limb bud. Subsequently, cavitation occurs in this location, resulting in the formation of a joint "space. "3 The most important signals for joint morphogenesis are provided by the cartilage-derived morphogenetic protein 1 (CDMPl) and the bone mOl'phogenetic proteins (BMPs).4,5 The joint "cavity" is occupied at first by hyaluronic acid-rich joint fluid secreted by fibroblast-like cells lining the synovial membrane. Continued development of the diarthrodial joint depends on fetal movement, 6 which induces formation of cartilage and synovial membrane, and without which
ARTICULAR CARTILAGE The hyaline cartilage, which covers subchondral bone, facilitates relatively frictionless motion and absorbs the compressive forces generated by weight-bearing.9--15 The cartilage is firmly fixed to subchondral bone, and its margins blend with the synovial membrane and the periosteum of the metaphysis of the bone. In children, hyaline cartilage is white or slightly blue and is somewhat compressible. It is composed of chondrocytes within an extracellular matrix (ECM) and becomes progressively less cellular throughout the period of growth; the cell volume in adult articular cartilage is less than 2%.16 The
9
10
1'111
C HAP T E R
lABlE
2-)
2
STRUCTURE AND FUNCTION
(Iassifi
CD
~
~
CD CD CD CD ~ ial peptides, The highly specific TCR has a low probability of meeting its corresponding antigen and may never be eng'lged in the immune response; the highly degenerated TCR has a higher probability of being engaged but may also theoretically cross-react with self-peptide and induce an autoimmune response. 65 TCR engagement by different peptide ligands may lead to different functional outcomes that depend on whether the peptide acts as an agonist, partial agonist, or antagonist. Indeed, the functional consequences of T cell antigen recognition may vary depending on the nature of the peptide that contacts the TCR. It has been shown that peptides in which one or two TCR contact residues have been changed (known as altered peptide ligands, or APL15 mg, intolerance, or nonadherence Administer with folic or folinic acid (see text) Clinical Monitoring Improvement should be seen by 6–12 wk Monitor every 3–6 mo, depending on course Reduce dose or discontinue and monitor for clinical or laboratory adverse events Laboratory Monitoring CBC with WBCC, differential, and platelet count; MCV; AST, ALT, albumin every 4–6 wk (see also Table 5–9) ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; MCV, mean cell volume; WBCC, white blood cell count.
seen by about 6 to 8 weeks on effective doses, but may take up to 6 months. Children seem to tolerate much higher doses than adults, and some series have described using up to 20 to 25 mg/m2/week or up to 1.1 mg/kg/week in children with resistant disease with relative safety in the short term.169,170 The efficacy of the use of higher doses was not supported by a randomized controlled trial.151 Furthermore, the longer-term safety of MTX therapy at these doses is not known. Parenteral MTX administration should be considered in those children who (1) have a poor clinical response to orally administered MTX (this may be due to poor compliance or to reduced oral bioavailability for a variety of reasons); (2) need a dose in excess of about 10 to 15 mg/m2/week in order to achieve maximum clinical response (oral MTX absorption is a saturable process, whereas subcutaneous administration is not) (Fig. 5–8)189,190; or (3) develop significant GI toxicity with 24 20
AUC (M.h)
C H A P T E R
ou
16
ut bc u S
12
s
e an
8
Oral
4 0 0
10
20
30
40
50
60
Dose (mg/m2)
■ Figure 5–8 Bioavailability of oral and subcutaneously administered methotrexate. AUC, area under the curve. (Adapted from Wallace CA: New uses of methotrexate. Contemp Pediatr 11: 43–53, 1994.)
92
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orally administered MTX (because there is some anecdotal experience that patients complain of less GI irritation when the drug is given parenterally).152,191 Studies in adult rheumatoid arthritis suggest that oral absorption of MTX is considerably reduced at doses of 15 mg or more and therefore should be administered parenterally.192,193 Furthermore, bypassing the enterohepatic circulation may also reduce hepatotoxicity. Some pediatric rheumatologists even advocate using parenteral MTX at initiation of treatment to ensure complete absorption and achievement of early disease remission.152,194 The issue of when, how, and by what criteria to attempt withdrawal of MTX therapy in JRA is currently undecided. There have been a number of studies in children treated with variable doses of MTX for variable periods in whom discontinuation of MTX was attempted after clinical “remission” of variable length was achieved.195–197 The criteria for “remission” or “relapse” have usually not been well defined or standardized among various studies, and the assessment of outcomes has been nonblinded. Given these limitations, no firm conclusions can be drawn about the optimal time and mode of MTX discontinuation in children with JRA. MTX withdrawal may result in disease flare in more than 50% of patients; this rate may be even higher in younger children.195,197 A longer period on MTX treatment after remission may not prolong the duration of improvement after stopping treatment, but the duration of clinical remission may be predicted by the degree of subclinical synovial inflammation at the time of stopping MTX.198 There are conflicting data about the ease with which remission can be reestablished when MTX is restarted after disease relapse, which may be related to the different doses of MTX used and the differing lengths of follow-up in the studies reported to date. Prospective studies with more standardized assessments of outcome and durations of follow-up are needed to address these issues.
Safety MTX is currently considered the second-line agent with the best toxicity/efficacy profile for the treatment of various rheumatic diseases in children and adults.172 Although MTX is associated with a number of potential toxicities, the documented overall frequency and severity of adverse effects in children with arthritis have been low (Table 5–8).150,152,199 Most side effects are mild and reversible and can be treated conservatively. The two areas of greatest concern and debate, especially in children, have been the potentially increased risk of hepatic cirrhosis in patients exposed to large cumulative doses of MTX and a possible increased risk of malignancies. Although the precise mechanism of all MTX-related toxicities is not yet clearly understood, at least some of its adverse effects are directly related to its folate antagonism and its cytostatic effects.200 This is especially evident in tissues with a high cell turnover rate, such as the GI tract and bone marrow, which have a high requirement for purines, thymidine, and methionine. Supplementation with folic or folinic acid may diminish these but not other types of toxicities which, along with MTX efficacy, may be mediated by different mechanisms (see later discussion).200
Gastrointestinal Toxicity Abdominal discomfort and nausea, the most frequently reported symptoms, occur in about 12% of children with JRA who receive MTX. Stomatitis or oral ulcers are reported in about 3% of children.152 Higher rates are reported in adults, with up to 60% of patients taking low-dose MTX developing GI adverse events in the form of stomatitis, anorexia, abdominal pain, indigestion, dyspepsia, nausea, vomiting, weight loss, or diarrhea.201,202 MTX-related abdominal discomfort, anorexia, nausea, or oral ulcers usually occur within 24 to 36 hours after administration of the weekly dose and can be diminished by the addition of folic acid supplementation (see later discussion), by dose reduction, or, in some troublesome cases, by conversion to subcutaneous MTX administration, although the evidence for the effectiveness of the latter strategy is only anecdotal.152 Liver Toxicity The effect of MTX on liver function and the development of hepatic fibrosis remains a major concern and has been extensively reviewed.203 MTX is associated with the potential for both acute and chronic hepatotoxicity. Mild acute toxicity, with elevations of transaminases, is common, occurring in about 9% of MTX-treated children with JRA.152 These elevations are usually transient and resolve with either MTX discontinuation or lowered dose after a brief interval off treatment.148,150 In some of these cases, concurrent administration of NSAIDs may be contributing to the elevation in transaminases, and discontinuation of NSAID treatment may allow normalization of liver function.204 The issue of greatest concern with the long-term use of low-dose MTX in children has been the potential for significant liver fibrosis or cirrhosis. However, the risk of this complication in children with JRA may differ from that in adults with rheumatoid arthritis or psoriasis treated with low-dose MTX. Long-term studies of MTX use in adult patients with rheumatoid arthritis have found a much lower incidence of liver fibrosis and cirrhosis than that initially reported in psoriatic patients; one retrospective study of 16,000 patients with rheumatoid arthritis reported a 5-year cumulative incidence of liver cirrhosis or failure of 1 in 1000 MTX-treated patients.205 Another study suggested that the incidence may be higher, with a 5-year cumulative incidence of cirrhosis of 9.4 in 1000 MTX-treated patients with rheumatoid arthritis.206 A meta-analysis of patients with rheumatoid arthritis and psoriasis found that higher cumulative dose of MTX, heavy alcohol consumption, and the presence of psoriasis were associated with higher risk of progressive liver histologic abnormalities.207 Other risk factors include preexisting liver disease, obesity, insulin-dependent diabetes mellitus, and renal insufficiency.203,208 The American College of Rheumatology has suggested guidelines for monitoring liver toxicity in patients with rheumatoid arthritis based on regular measurement of liver enzymes and performance of liver biopsy in selected cases with persistent abnormalities of liver enzymes (Table 5–9).209 These guidelines were developed by expert consensus and subsequently evaluated for their usefulness; they were found to be cost-effective
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TABLE 5–8 Reported Adverse Effects in Children Treated with Methotrexate* Study 1
Study 2
Study 3
Study 4
Study 5
Study 6
Study 7
Study 8
Totals
19
23
12
19
30
62
86
27
277
10.5 4–10
19.2 6–52
6 6
18.5 8–39
— 6–30
27 19–65
6 —
— 6–72
— 4–72
4–17 —
— 0.1–0.6
8–25 —
5–15 —
— 0.4–0.8
5–20 —
5 or 10 —
10–15 —
— —
2
0
1
2
6
14
8
0
33
0 1 1 0 ND 0 0 1 0 3
0 0 0 0 0 0 0 0 ND 10
ND ND 1 ND ND ND ND 0 1 1
0 1 0 0 0 0 ND 0 ND 1
0 0 2 ND ND ND ND 1 ND 3
4 0 0 0 2 ND 4 1 ND 9
0 2 1 1 0 0 0 0 0 1
1 1 0 0 0 1 ND ND ND 4
5 5 4 1 2 1 4 3 1 25
0 0 0 3
0 0 0 0
0 0 0 0
0 0 0 0
0 1 0 0
0 0 1 0
0 0 0 0
0 0 0 0
0 1 1 3
Patients (n) Treatment Duration (mo) Mean Range Methotrexate Dose mg/m2/wk mg/kg/wk
Adverse Effects (no. patients) Gastrointestinal symptoms Peptic ulcer Stomatitis Mouth ulcers Rashes Alopecia Jaundice Bacterial infections Herpes zoster Mood changes Liver function test elevations Hematuria Leukopenia Anemia Proteinuria
*Studies cited: Study 1: Truckenbrodt H, Hafner R: Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. Arthritis Rheum 29: 801–807, 1986. Study 2: Wallace CA, Bleyer WA, Sherry DD, et al: Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum 32: 677–681, 1989. Study 3: Speckmaier M, Findeisen J, Woo P, et al: Low-dose methotrexate in systemic onset juvenile chronic arthritis. Clin Exp Rheumatol 7: 647–650, 1989. Study 4: Rose CD, Singsen BH, Eichenfield AH, et al: Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 117: 653–659, 1990. Study 5: Halle F, Prieur AM: Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype. Clin Exp Rheumatol 9: 297–302, 1991. Study 6: Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM: Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 120: 468–473, 1992. Study 7: Giannini EH, Brewer EJ, Kuzmina N, et al: Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N Engl J Med 326: 1043–1049, 1992. Study 8: Huang JL: Methotrexate in the treatment of children with chronic arthritis—long-term observations of efficacy and safety. Br J Clin Pract 50: 311–314, 1996. ND, not determined. Modified from Singsen BH, Goldbach-Mansky R: Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatic and nonrheumatic disorders. Rheum Dis Clin North Am 23: 811–841, 1997.
and clinically useful, with a sensitivity of 80% and a specificity of 82% but a low positive predictive value of 27%.208 Although a similar level of consensus does not exist for monitoring MTX-treated JRA in children, most pediatric rheumatologists tend to follow these guidelines or a variation of them.152 A study examining the relationship between hepatotoxic risk factors and liver histopathology in MTX-treated JRA found that serial biochemical abnormalities were significantly associated with Roenigk grade and the presence of liver fibrosis, suggesting that the guidelines for monitoring MTX hepatotoxicity in rheumatoid arthritis may also be applicable to patients with JRA.210 It must be remembered, however, that even close monitoring of liver function tests does not eliminate the possibility of progressive hepatic fibrosis. Erickson and colleagues208 reported one patient in a series who developed cirrhosis despite normal results on liver function tests. Furthermore, these guidelines may
not apply to patients receiving more than 25 mg/week or a cumulative dose of greater than 10 g; surveillance liver biopsies may be indicated for these patients.203 In a number of small studies in children, liver biopsies were performed after cumulative doses of up to 3000 mg had been reached; none showed any cirrhosis.150,211,212 A cross-sectional study213 reported on results of liver histology in children exposed to even higher cumulative doses of MTX (more than 3000 mg or more than 4000 mg/1.73 m2), with the mean duration of treatment being about 6 years (and some children treated for up to 10 years); no significant fibrosis or cirrhosis was found. However, 13 (93%) of 14 biopsies showed some histologic abnormality, with only 1 graded as Roenigk grade II. In addition, higher weekly doses of MTX (20 mg/m2/week or more) were not associated with significant hepatic fibrosis in 10 patients who underwent liver biopsy.214
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TABLE 5–9 Recommendations for Monitoring for Hepatic Safety in Patients with Rheumatoid Arthritis Receiving Methotrexate (MTX) A. Baseline 1. Tests for all patients a. Liver blood tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies b. Other standard tests, including complete blood cell count and serum creatinine 2. Pretreatment liver biopsy (Menghini suction-type needle) only for patients with a. Prior excessive alcohol consumption b. Persistently abnormal baseline AST values c. Chronic hepatitis B or C infection B. Monitor AST, ALT, albumin at 4- to 8-wk intervals C. Perform liver biopsy if 1. Five of nine determinations of AST within a given 12-mo interval (6 of 12 if tests are performed monthly) are abnormal (defined as an elevation above the upper limit of normal) 2. There is a decrease in serum albumin below the normal range (in the setting of well-controlled rheumatoid arthritis) D. If results of liver biopsy are 1. Roenigk grade I, II, or IIIA: resume MTX and monitor as in B, C1, and C2 above 2. Roenigk grade IIIB or IV: discontinue MTX E. Discontinue MTX in patient with persistent liver test abnormalities, as defined in C1 and C2 above, who refuses liver biopsy From Kremer JM, et al: Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum 37: 316–328, Copyright © 1994 Wiley-Liss, Inc. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
Although these data are encouraging, their interpretation requires some caution: First, the number of children studied is small, so the statistical power for detection of infrequent events, such as cirrhosis, is low (type II error); second, only 58% of eligible MTX-treated patients underwent biopsy, so selection bias may have occurred; and third, the clinical significance, if any, of the minor histologic abnormalities detected in most of the biopsies is not known, and there were no control biopsies to help distinguish the effects of disease (e.g., systemiconset JRA) or concomitant medications (e.g., NSAIDs) on liver histology. A follow-up study from the same group reported the results of 33 liver biopsies in 25 patients; 27 biopsies (82%) were classified as Roenigk grade I; 4 (12%) as grade II; and 2 (6%) as grade IIIA; none demonstrated significant fibrosis. The frequency of biochemical abnormalities and body mass index were the only risk factors found to significantly relate to the Roenigk grade.210 However, the same limitations as with the earlier study apply, particularly with respect to the small number of patients studied (possibility of type II error) and the unknown significance of the minor histologic abnormalities observed in most patients. Further longterm, prospective studies in larger numbers of MTXtreated children are needed to define more accurately the risk of MTX-related liver fibrosis or cirrhosis and to develop appropriate guidelines for monitoring therapy in JRA.
Infection Although MTX may potentially increase the risk for common bacterial infections, herpes zoster, and opportunistic infections, these complications are infrequently reported in treated patients. One study of 62 children with JRA treated for a mean of 161 weeks reported only 2 cases of recurrent cellulitis, 1 of osteomyelitis, and 1 of an infected Hickman catheter site; there were 8 viral infections, including 1 case of herpes zoster, 1 case of mononucleosis, and 6 cases of primary varicella. Many of the patients with varicella infection were also concurrently receiving glucocorticoids.150 The randomized controlled clinical trial of MTX treatment in JRA did not document an increased frequency of infection in children treated with MTX compared with placebo.148 Although the overall risk of infection appears to be low, it has not been precisely quantitated in adults or in children. Infections in MTX-treated patients are usually common bacterial infections (e.g., lungs, skin) or herpes zoster. The development of hypogammaglobulinemia in MTX-treated patients may predispose to infection.215 Opportunistic infections associated with MTX treatment are rare unless there is concurrent treatment with highdose glucocorticoids.216 Immunization with inactivated vaccines is not contraindicated in MTX-treated children, but immunization with live attenuated vaccines should be avoided.217 There are currently no generally accepted guidelines regarding varicella immunization in these children. However, active varicella immunization of susceptible children and family members may need to be considered before initiation of MTX therapy.205 Family members of MTX-treated patients who require polio immunization should receive inactivated vaccine. Hematologic Toxicity Hematologic toxicity includes macrocytic anemia, leukopenia, thrombocytopenia, and pancytopenia. In adult patients with rheumatoid arthritis, pancytopenia has been reported in about 1% to 2% of MTX-treated patients.218 Identified risk factors in this population include impaired renal function, advanced age, concurrent viral infection, alcohol ingestion, folate deficiency, hypoalbuminemia, and drug interactions (e.g., trimethoprim-sulfamethoxazole). MTX-associated pancytopenia has not been reported in children, and hematologic toxicity is uncommon overall; a 1997 review of published studies, including a total of 277 MTX-treated children, found only 1 case of leukopenia and 1 case of macrocytic anemia.152 Although supplemental folate treatment results in lowering of the mean corpuscular volume in MTX-treated patients, whether this will prevent pancytopenia is not yet known. Spontaneous recovery is usual within 2 weeks after withdrawal of MTX in patients with mild bone marrow suppression. Patients with moderate to severe bone marrow suppression may require folinic acid rescue and supportive therapy (e.g., colony-stimulating factors).202 MTX may have triggered the macrophage activation syndrome in one patient with systemic-onset JIA.219 Reversible asymptomatic eosinophilia has also been described.220 Malignancy The issue of whether MTX treatment is an independent risk factor for various malignancies is controversial and remains unresolved. Although in vitro
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studies have shown that MTX has mutagenic and carcinogenic potential, in vivo studies in animal models (mice, rats, hamsters) have failed to demonstrate any carcinogenicity. In humans, low-dose weekly MTX therapy has not been convincingly linked to malignancy.221 However, there have been a number of case reports of an association between MTX treatment and lymphoproliferative diseases in adult patients with rheumatoid arthritis.222,223 It has not been possible to determine whether these observations were merely coincidental or were causally linked to MTX or to the underlying disease process.221 Rheumatoid arthritis is known to be associated with an increased risk of hematologic malignancy.224 There have been several cases of Epstein-Barr virus (EBV)–associated lymphoma manifesting during the course of MTX treatment for rheumatoid arthritis or dermatomyositis that regressed with discontinuation of MTX.225 Some of the reported cases demonstrated features typical of immunosuppression-induced lymphoproliferation, including extranodal location, large cell or polymorphous histology, geographic areas of necrosis, and the presence of EBV.226 The association of MTX with reversible lymphoproliferation suggests a causative role. However, MTX has not been shown to increase the risk of lymphoproliferative disorders when used in the treatment of other diseases such as psoriasis227,228 or in bone marrow transplantation.221 Several cases of both Hodgkin’s lymphoma229–231 and non-Hodgkin’s lymphoma232,233 have been reported in children with JRA treated with MTX. In two of these, EBV was implicated.231,233 Long-term prospective cohort studies, with appropriate controls, are needed to define the risk of hematologic or other malignancies in MTX-treated patients.
Pulmonary Toxicity Significant pulmonary toxicity occurring during the course of treatment with low-dose weekly MTX has been described in adult patients with rheumatoid arthritis; reported prevalence rates in published studies range from 0.3% to 18%, with a mean prevalence of 3.3%.234 However, the actual frequency of this complication is difficult to estimate, because the literature has not been clear in defining toxicity related to the drug itself rather than to secondary problems associated with MTX therapy (e.g., opportunistic lung infections). The issue is clouded further by the fact that rheumatoid arthritis itself is associated with interstitial lung disease. The mechanism of this toxicity and the risk factors for its development are poorly defined, although a number of studies implicate preexisting lung disease as an important predisposing factor in the development of MTX pneumonitis.202,234,235 Interestingly, MTX-associated pneumonitis is rarely reported in psoriatic patients. In 1998, the first pediatric case of possible MTX-induced pneumonitis was reported in an 11-year-old girl with rheumatoid factor (RF)–positive, antinuclear antibody–negative polyarticular JRA.236 However, the clinical course of lung disease in this case was not typical of that described in adults with MTX pneumonitis, clinical and laboratory information was insufficient to satisfactorily exclude alternative causes, and no biopsy was performed. Prospective studies of lung function in children with
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various types of JRA have not demonstrated any significant abnormalities in pulmonary function test results in those treated with MTX.149,150,237–239
Accelerated Nodulosis MTX has been associated with a syndrome of “accelerated nodulosis,” with an estimated prevalence of 8% in adult patients with rheumatoid arthritis.201 This association was described in two teenagers with RF-positive JRA240 and in one 3-year-old girl with systemic-onset JRA.241 The nodules were similar in distribution and size to those reported in adults and developed within 6 months after the initiation of MTX treatment in these children. Although discontinuation of MTX is associated with regression of nodulosis, some patients have been successfully treated with hydroxychloroquine240 or colchicine,242 allowing stabilization of nodulosis with continued MTX treatment of the underlying disease. Although the exact mechanism of MTX-associated nodulosis is not known, it is thought to be mediated by MTX-enhanced adenosine production; therapies that inhibit adenosine production or interfere with adenosine A1 receptor function may be effective in treating MTX-associated nodulosis.201
Other Adverse Effects Central Nervous System Various CNS symptoms, including headaches, mood alterations, change in sleep patterns, irritability, fatigue, and impaired academic performance, have been reported by some pediatric rheumatologists to occur transiently in the 12 to 48 hours after the weekly dose of MTX.152 These problems may be subtle and need to be differentiated from effects of underlying disease and from various psychosocial issues that may coexist. Osteopathy Animal studies have shown that prolonged administration of low-dose MTX is associated with suppression of osteoblast activity and stimulation of osteoclast recruitment, resulting in increased bone resorption and osteopenia.243 Similar effects have been described in a small number of case reports in adults with rheumatoid arthritis or psoriasis treated with lowdose weekly MTX.244,245 Although leg pain and spontaneous fractures attributed to MTX therapy in pediatric oncology have been recognized for some time, this phenomenon has been described in only one patient with polyarticular JRA and a disease duration of 25 years recently treated with low-dose MTX.246 Teratogenicity MTX therapy is associated with spontaneous abortions.247 In 1997, a case of multiple congenital abnormalities in a baby whose mother was treated with low-dose MTX for JRA was reported.248 Although it is difficult to quantitate the risk of teratogenicity with lowdose weekly MTX treatment, women of child-bearing age should be counseled to practice effective contraception during the course of treatment. Patients should be informed that past MTX use does not predispose to congenital abnormalities and that, ideally, MTX should be discontinued before attempts at conception. There have not been any reports of azoospermia due to low-dose MTX treatment of JRA.152 MTX is excreted in breast milk
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in low concentrations, but it is not known whether this affects the newborn. Women taking MTX should be advised not to breast-feed.249
N CI CHOHCH3
Folate Supplementation A number of studies have examined the issue of minimizing MTX toxicities with the use of concurrent folic or folinic acid (leucovorin) supplementation in adults with rheumatoid arthritis.250–253 These studies have evaluated the effect of folate supplementation on both the efficacy and the toxicity of low-dose weekly MTX therapy. Although the doses and regimens of folic and folinic acid used in the various trials, the doses of concurrent MTX therapy, and the assessment of “toxicity” have not been standardized, there is evidence for overall effectiveness of folate supplementation. A 1998 systematic review of all published clinical trials found that folic acid supplementation was associated with a significant reduction in mucosal and GI toxicity in MTX-treated adults with rheumatoid arthritis.254 There was no adverse effect on efficacy except with high-dose folinic acid supplementation. Currently, data are insufficient to assess the effect of long-term folate supplementation on hepatic or hematologic toxicities. It also is not clear whether folate supplementation should be commenced as prophylaxis with initiation of MTX therapy in all patients or as treatment if specific toxicities develop. There has not been any formal cost-benefit study to address this issue. Folic acid is cheaper and has a greater margin of safety in dosing compared with folinic acid. However, the two agents have not been directly compared for their clinical effectiveness and cost. Studies in children are limited. A short-term, randomized, double-blind, placebo-controlled, crossover trial of folic acid (1 mg/day) added to a stable dose of MTX (mean, 9–9.7 mg/week) in 19 children with JRA showed no effect on clinical efficacy.255 There were no observable abnormalities of liver function, but no information about other toxicities is available from this small study. Folinic acid administered 24 hours after the weekly dose of MTX at doses of approximately one-third of the MTX dose has been used effectively to treat manifestations of MTX toxicity in children with JIA,256 but at high doses this treatment was associated with disease flares.257 At present, it is not possible to make firm recommendations about routine folate supplementation in MTX-treated children. However, based on the information from adult studies and the small trial in children with JRA, it appears that low-dose (1 mg/day) folic acid supplementation does not have any detrimental effect on disease control and confers a beneficial effect in terms of GI and mucosal toxicities associated with low-dose weekly MTX treatment. Folic acid supplementation should be considered at least in symptomatic patients. High-dose folinic acid rescue should be reserved for those with severe, life-threatening toxicity (e.g., aplastic anemia).
Antimalarials Hydroxychloroquine sulfate (Fig. 5–9) is the least toxic of the 4-aminoquinolone drugs and has generally supplanted chloroquine in rheumatologic practice,258–260 although other antimalarial agents are occasionally used for recalcitrant skin disease in SLE. Hydroxychloroquine is rapidly absorbed from the intestine. Equilibrium concentrations
NH
CH(CH2)3 CH3
■ Figure 5–9
N CH2CH3
Structure of hydroxychloroquine.
are reached after 2 to 6 months of a constant daily dose, and the half-life exceeds 40 days.261 Tissue levels are much greater than plasma concentrations, and there is increased affinity of the drug for melanin as well as for the liver, pituitary, spleen, kidney, lung, and adrenals. Excretion is primarily via the kidney, although hepatic oxidative deamination accounts for part of the excretion. The antimalarial drugs inhibit the synthesis of DNA, RNA, and protein by interacting with nucleic acid.258 These drugs alter lysosomal pH, thereby interfering with ligand-receptor dissociation and antigen processing; stabilize lysosomal membranes262; inhibit antigen–antibody reactions263; suppress lymphocyte responses to mitogens; act as antioxidants262; inhibit phospholipase activity264; and inhibit neutrophil chemotaxis and phagocytosis.258 They may also antagonize the action of some of the prostaglandins.265 Antimalarials interfere with IL-1 release by monocytes263; interfere with production of TNF-α, IL6, and IFN-γ266; inhibit natural killer activity267; and induce apoptosis.268 They also have antiplatelet and antihyperlipidemic effects that are extremely important in patients with SLE.269 Antimalarials are important in many rheumatic diseases. In JRA, the therapeutic efficacy has never been established, and the only placebo-controlled study did not prove these agents to be better than placebo.270 However, recent work in adult rheumatoid arthritis has demonstrated them to be effective, especially in early disease.271 Antimalarials are also effective in combination with other DMARDs in adult rheumatoid arthritis.272 Hydroxychloroquine reduces some MTX-related toxicity, such as elevated liver enzymes and nodulosis.273,274 Studies in adult SLE have also provided proof of efficacy for hydroxychloroquine, especially in preventing flares of disease.275 Its role in SLE is primarily for treatment of dermatitis, arthritis, and serositis. It may have particular benefit as a result of its lipid-lowering effect in steroid-treated SLE patients.276–278 It has also been used in dermatomyositis, especially for skin disease, but the results are not clear.279,280
When used at recommended doses, the antimalarials are considered extremely safe. However, at least four young children have died from respiratory failure after accidental ingestion of large doses (1 to 3 g) of chloroquine,281 and it is recommended that antimalarials be used with great caution in the very young child because there is no antidote. GI intolerance occurs in 10% of adults but is probably less common in children. Antimalarials occasionally cause bleaching of the skin and hair. Rarely, neuropathy or myopathy occurs. CNS side effects are common, may be reversible with dose reduction, and may remit spontaneously. These include headache, lightheadedness, tinnitus, insomnia, and increased nervousness. Myasthenia and muscle weakness have been described.282
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The major side effect of concern is retinal toxicity.283–285 Antimalarials accumulate in the pigmented cells of the retina and persist for long periods after they have been discontinued; however, the binding to melanin may not be predictive of ocular damage. Retinal toxicity, although rare, can cause blindness, even after the medication has been stopped. Retinitis is sometimes, but not always, reversible.284 Evidence in adults suggests that retinal toxicity will not occur if the dose of hydroxychloroquine is maintained at less than 6.5 mg/kg/day, even for as long as 7 years.286 Early detection of pre-maculopathy prevents visual loss if the medication is discontinued and forms the basis for routine ophthalmologic monitoring (every 6 months) with visual field testing, color vision testing, corneal examination, and visual acuity testing. A progressive loss of color vision may signify early retinopathy and is an indication for stopping the drug. Corneal deposits are not visually limiting but are also probably an indication to lower the dose. Debate continues as to the necessity of an initial ocular examination, or of biannual examinations. The author’s current policy is to continue to perform these examinations every 6 months but not to perform a baseline examination. Recommendations differ somewhat in adults.287 Each examination should include visual acuity, color vision testing, visual field corneal examination,286,288 and retinoscopy. Retinal abnormalities or interference with vision, especially with foveal recognition of red,289 is an absolute indication for discontinuing the medication. Use of hydroxychloroquine in children younger than 7 years of age may be limited by difficulty in obtaining satisfactory evaluation of color vision in this age group.
The dose of antimalarials is limited by retinal toxicity. For hydroxychloroquine, the recommended dose is less than or equal to 6.5 mg/kg/day to a maximum of 400 mg/day.290 The overall retinal toxicity seems to be related to daily dose rather than to cumulative dose. One study of children with JRA did correlate outcome with serum levels of hydroxychloroquine,291 but levels are not measured in clinical practice. Hydroxychloroquine crosses the placenta but is considered safe to use during pregnancy.292 Hydroxychloroquine does appear in breast milk, but the amount ingested per day by the breast-feeding infant would be very low.293 It seems reasonable for the mother taking hydroxychloroquine to breast feed if she had taken hydroxychloroquine during pregnancy.
Sulfasalazine Sulfasalazine is an analogue of 5-aminosalicylic acids linked by an azo bond to sulfapyridine, a sulfonamide (Fig. 5–10). Its development was based on the concept that rheumatoid arthritis might be an infectious disease and would respond to combination therapy with an anti-
COOH N HO
N
N
SO2NH
■ Figure 5–10 Structure of sulfasalazine.
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bacterial agent and an anti-inflammatory drug.294,295 Sulfasalazine has become a primary therapeutic choice in the treatment of mild to moderate inflammatory bowel disease, and it has been reported to be beneficial in the management of childhood arthritis,296–303 psoriatic arthritis,304 and reactive arthritis.305 Its role in ankylosing spondylitis is controversial,306–308 although it does seem to be effective for the peripheral arthritis.309 Sulfasalazine is poorly absorbed from the GI tract.310–312 Peak serum concentrations are reached after 5 days of therapy. The half-life of the drug is 10 hours. Approximately one third of the dose is absorbed in the small intestine and excreted unchanged in the bile. The remaining 70% enters the colon intact, where the azo linkage is split by bacterial enzymes to sulfapyridine, which is absorbed and excreted in the urine, and 5-aminosalicylate, which reaches high concentrations in the feces. Approximately 90% of the sulfapyridine is absorbed from the colon. Sulfapyridine is tightly protein bound and acetylated, hydroxylated, and conjugated with glucuronic acid in the liver. Both sulfasalazine and sulfapyridine reach synovial fluid in concentrations comparable to those in serum. About one third of the 5-aminosalicylic acid is absorbed, acetylated, and excreted in the urine. The rest is eliminated unchanged in the stool. The small amount of salicylate absorbed is not sufficient to reach anti-inflammatory levels in the plasma. Several mechanisms of action may explain the antiinflammatory effect of sulfasalazine. Bacterial growth is reduced by sulfasalazine and sulfapyridine, and thus the bacterial antigenic load delivered to the gut-associated lymphoid tissue may be reduced. This may be important for patients with spondyloarthropathies, in whom bacteria may gain access through inflamed gut mucosa and stimulate the immune system. Sulfasalazine interferes with a number of enzymes that are important in inflammation, in the formation of leukotrienes and prostaglandins.313 Sulfasalazine is a potent inhibitor of AICAR transformylase; as a result, there is an accumulation of extracellular adenosine with a consequent reduction in inflammation via occupancy of A2 receptors on inflammatory cells.314 Levels of matrix metalloproteinase 3 (MMP3) are decreased in patients with early rheumatoid arthritis responsive to sulfasalazine.315 Sulfasalazine reduces the release of IL-1, IL-2, TNF-α, IL-6, and IFN-γ.316–318 This effect is most likely mediated by inhibition of the degradation of I-κB (inhibitor of nuclear factor-κB [NF-κB]), which results in an inhibition of NF-κB upregulation of gene transcription,319 and by the induction of apoptosis through the activation of caspase 8.320 Sulfasalazine decreases natural killer cell activity and induces neutrophil apoptosis in vitro.321 In vitro effects on macrophages include suppression of production of IL-12, production of nitric oxide, and expression of major histocompatibility complex (MHC) class II molecules.322 Sulfasalazine may also have anti-angiogenic properties.322,323 Intolerance and toxic reactions occur in approximately 20% of sulfasalazine-treated adults with rheumatoid arthritis (range, 5% to 55%).324–348 In a placebo-controlled study of children with JRA, 29% of 35 patients developed adverse effects that led to discontinuation of the drug.299
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Toxicity may be more common in patients with a slow acetylator phenotype, but there is no clinical indication to document a patient’s acetylator status before starting sulfasalazine.349 Enteric-coated preparations probably cause fewer GI side effects (anorexia, nausea, vomiting, dyspepsia, diarrhea). Rashes occur in 1% to 5% of patients. A maculopapular rash occurring within 2 days after institution of therapy, especially on sun-exposed skin, is the most common dermatologic complication.324 In patients who develop hypersensitivity reactions (usually early), desensitization protocols can be carried out. Oral ulcers325 and the Stevens-Johnson syndrome326 are uncommon but important complications. Neutropenia occurs in up to 4.4% of patients treated with sulfasalazine.327 Sulfasalazine-induced thrombocytopenia has also been reported,328 and pancytopenia329 and macrocytic anemia330 may occur. It is important to note that serious hematologic toxicity can develop many months after starting treatment. Drug-induced SLE,331 Raynaud’s phenomenon,332 interstitial pneumonitis, fibrosis, alveolitis,333,334 and hepatitis (granulomatous hepatitis, elevated transaminases)335 are rare complications of sulfasalazine therapy. Hypogammaglobulinemia and IgA deficiency have been reported,350 and immunoglobulin levels should be monitored. However, serious infections have not been reported. A reversible decrease in sperm count has been observed,336 but there are no reports of increased fetal wastage or abnormalities. The drug should not be used in infants or in those with known hypersensitivity to sulfa drugs or salicylates, impaired renal or hepatic function, or specific disease contraindications (e.g., porphyria, glucose-6-phosphate dehydrogenase deficiency). Most authors also believe that sulfasalazine is contraindicated in patients with systemic-onset JRA because of an apparent increased risk of diffuse intravascular coagulation (DIC)–like reactions,298,351 as well as in patients with adult-onset Still’s disease.352 The suggested dosage in children is 30 to 50 mg/kg/day in two to three divided doses, usually taken with food or milk.296,353 Treatment is initiated at a lower dose (10 to 15 mg/kg/day) and increased weekly over 4 weeks to achieve maintenance levels. A satisfactory clinical response may occur within 4 to 8 weeks. Sulfasalazine should probably be continued for at least 1 year after disappearance of clinical disease before tapering is begun (Table 5–10). It has been reported that sulfasalazine can be used safely during pregnancy354 and that women can breast feed while taking sulfasalazine.355
Leflunomide Leflunomide (Fig. 5–11) is an immunomodulatory agent that, through its active plasma metabolite, A77-1726, inhibits de novo pyrimidine synthesis by inhibiting the enzyme dihydro-orotate dehydrogenase.356 Activated lymphocytes require de novo pyrimidine synthesis for proliferation. As a result of the inhibition, p53 in the cytoplasm translocates to the nucleus and initiates cellular arrest in the G1 phase of the cell cycle. It also inhibits tyrosine kinase,357 inhibits leukocyte-endothelial
TABLE 5–10
Guidelines for Use of Sulfasalazine
Dose Initially, 12.5 mg/kg/day (maximum, 500 mg), given in one dose; increase to maintenance dose over 4 wk Maintenance dose: 50 mg/kg/day to a maximum of 2 g/day for 1 yr or longer Clinical Monitoring After first month, then every 2–3 mo to follow disease course; discontinue if rash appears Laboratory Monitoring CBC with WBCC differential, and platelet count; hepatic enzymes; and urinalysis every week until maintenance dose is achieved, then monthly for 2 mo, then every 3 mo. Immunoglobulin levels every 6 mo. Discontinue if persistent neutropenia, thrombocytopenia, elevated hepatic enzymes, or decreased immunoglobulins CBC, complete blood count; WBCC, white blood cell count.
CF3 O N H N O
CH3
■ Figure 5–11 Structure of leflunomide.
adhesion,358 and affects cytokine production leading to immunosuppression.359 Because its actions are similar to those of MTX, it might be better classified as a DMARD. In vitro, leflunomide inhibits the production of prostaglandin E2, MMP1, and IL-6 and modulates various tyrosine kinases and growth factor receptors.360 Leflunomide is rapidly converted to A77-1726, which is highly protein bound and has a prolonged half-life of up to 18 days.361 As a result, loading doses have been recommended for the first 3 days of administration to rapidly achieve steady state. Another result of this prolonged half-life is that the metabolite remains in the circulation for prolonged periods (Table 5–11). Initial studies in adults with rheumatoid arthritis showed that, after a 3-day loading dose of 100 mg/day, daily doses of 10 and 25 mg of leflunomide were more effective than placebo361,362 as effective as sulfasalazine over 24 weeks363 and as effective as MTX at 1 year364 and at 2 years.365 After a 3-day loading dose of 100 mg/day, daily doses of 10, 20, and 25 mg have shown benefit as early as 4 weeks and continuing improvement for up to 20 weeks, after which the clinical improvements are maintained. The major side effects from leflunomide have been related to the liver, with elevation on liver function tests occurring in approximately 5% of patients with rheumatoid arthritis. However, the risk of serious hepatic disease appears to be minimal and, as with MTX, associated with preexisting liver disease, viral hepatitis, or heavy alcohol consumption. More significant hepatotoxicity was observed when MTX was combined with leflunomide.366 Side
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TABLE 5–11
Guidelines for the Use of Leflunomide in the Treatment of Juvenile Idiopathic Arthritis Dose 10–20 mg/day, based on weight (usual adult dose = 20 mg/day) Clinical Monitoring Improvement should be seen by 6–12 wk Monitor every 3–6 mo, depending on course Reduce dose or discontinue and monitor for clinical or laboratory adverse events Laboratory Monitoring CBC with WBCC, differential and platelet count; AST, ALT, albumin every 4–6 wk ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; WBCC, white blood cell count.
effects from leflunomide have been mild and doserelated. These include GI side effects (abdominal pain, dyspepsia, anorexia, diarrhea, gastritis), allergic rash, reversible alopecia, mild weight loss, and elevation of liver function test results.363,367 No increase in infection has been reported. Silverman et al reported on 27 patients with polyarticular course JRA who had failed treatment with or were intolerant of methotrexate and were treated with leflunomide.368 After an initial loading dose of ~100 mg/1.73 m2, patients received 10 mg/1.73 m2; the dose could be increased to 20 mg/1.73 m2 after week 8 for a poor response. After 26 weeks, 14 patients (52%) had improved according to the ACR Pedi 30 criteria; 44% and 19% met criteria for an ACR Pedi 50 and 70 respectively. Forty-four percent of patients responded as early as 4 weeks, and all who responded did so by 12 weeks. Seventeen of 27 patients entered an extension phase during which 65% of patients achieved an ACR Pedi 30, 47% an ACR Pedi 50 and 35% an ACR Pedi 70. Adverse events led to discontinuation in two. Other adverse events reported in at least 30% of patients were transient elevation of liver function tests, headache, alopecia, abdominal pain, nausea, diarrhea and dizziness. In a subsequent study, Silverman et al also compared the safety and efficacy of leflunomide with methotrexate in the treatment of patients with polyarticular course JRA in a multinational, randomized controlled trial.368a The dose of leflunomide was dependent on the weight of the child. A loading dose of 100 mg for 1, 2 or 3 days for a weight 40 kg, respectively, was followed by a dose of 10 mg every other day, 10 mg daily, or 20 mg daily for a weight 40 kg, respectively. Methotrexate was given at a dose of 0.5 mg/kg/week (maximum 25 mg per week). In addition, pharmacokinetic studies were performed at week 16. At week 16, 68% of patients receiving leflunomide showed an ACR Pedi 30, versus 89% of patients treated with methotrexate; the improvements achieved were maintained at a similar rate in a 32 week extension study. The median time to an ACR 30 did not differ between the two groups (52 days in leflunomide, 56 days in methotrexate). Body weight was a significant determinant of response, and patients weighing less than 20 kg showed the greatest discrepancy between the two groups. The incidence of treatment related adverse events was similar in both groups. The clinically active metabolite of leflunomide, M1, was lower in patients weighing less than 40 kg than those associated with clinical responses in adult rheumatoid arthritis, which may have
5 PHARMACOLOGY
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explained the discrepancy between responses in the patients weighing less than 40 kg.
Leflunomide is teratogenic.369 Because of the very long half-life of this drug, it has been recommended that cholestyramine be administered and then that drug levels lower than 0.02 mg/L be verified on two separate tests at least 2 weeks apart, in both men and women.369 In addition, women of child-bearing potential must have a negative pregnancy test before starting leflunomide and must practice contraception. The place of leflunomide in the treatment of patients with JRA is not yet established. At the moment, it should be considered for patients who do not tolerate MTX. A loading dose is recommended in adults with rheumatoid arthritis to rapidly achieve steady state but is not necessary and may lead to significant GI upset. The usual daily dose for adults is 20 mg, which may be reduced to 10 mg in the face of adverse effects.
Gold Compounds The use of gold and penicillamine has waned dramatically since the introduction of MTX and the newer biologic agents, and the descriptions included here are primarily for historical interest and importance. Sulfhydryl-containing organic gold compounds have been prescribed for treatment of rheumatoid arthritis since the observations of Forestier370,371 in the 1920s. In the management of JRA, they have essentially been replaced by MTX and sulfasalazine, except perhaps for patients with RF-positive disease.
Pharmacology The mechanisms of action of gold compounds are not entirely clear372 but appear to depend on the sulfhydryl bond, which is also thought to be responsible in part for the beneficial effects of D-penicillamine. Gold compounds may diminish vascular permeability, reduce the number of inflammatory cells in rheumatoid foci, and impair phagocytosis. They stabilize lysosomal membranes and suppress enzymatic activity in general. They may prevent denaturation of proteins induced by free oxygen radicals. In vitro lymphocyte responses to mitogens and specific antigens are inhibited, and monocyte interaction in cell-mediated immune function is impaired.373–375 The intramuscular preparations are 50% gold by weight (Fig. 5–12).376 The oral gold compound auranofin is 30% gold by weight and is lipid soluble. With aurothiomalate, the gold is predominantly bound to serum albumin; however, with auranofin, approximately 50% of the gold is bound to leukocytes and erythrocytes. Gold compounds are excreted in both urine and stool. They cross the placenta in substantial concentrations, apparently without harm to the fetus, and the level in breast milk is low. The gold concentration in synovial fluid is approximately half of that in blood. Gold is concentrated in organs rich in mononuclear phagocytes and in synovial type A cells. The initial half-life of intramuscularly administered gold is approximately 7 days but increases with chronic administration. After discontinuation of gold injections, plasma concentration falls to undetectable levels by 40 to 80 days, but gold is still excreted in the urine for up to 1 year.377 Auranofin is more hydrophobic than the intramuscular gold compounds and is readily absorbed orally.378,379 The tissue halflife of gold is approximately 80 days. Plasma gold concentrations in patients treated with auranofin take longer to reach
100
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AU
TABLE 5–12
Guidelines for Use of Aurothiomalate or Aurothioglucose
HC HC
Initial Course
OH
HCOH
0.75–1.0 mg/kg/wk Test doses of 5 mg, then 10 mg, then 25 mg weekly; maximum of 50 mg/wk for at least 20 wk
HCO
Maintenance
HOCH
1 mg/kg (maximum, 50 mg) every 2 wk for 3 mo; then every 3 wk for 3 mo, then every 4 wk thereafter
CH2OH AUROTHIOGLUCOSE
Clinical Monitoring Clinical evaluation before every injection: dermatitis, pruritus, stomatitis, vasomotor (nitritoid) reaction
CH2COONa Au
S
Laboratory Monitoring
CHCOONa
Weekly before each dose: CBC, WBCC, differential, and platelet count; urinalysis. Monthly: hepatic enzymes, BUN, creatinine Discontinue drug if WBCC d Child Behaviour Profile. Burlington, VT, Queen City, 1983, 98. MaUl)\iIksela Fl, Olkkala KT, Korpela R: Measurement of pain in children with self-reporting and behavioural assessment. Clin Pharmacal Ther 42: 137, 1987, 99. Duffy CM, Arsenault L, Watanabe Duffy KN, et al: Validity and sensitivity to chanlle of the Juvenile Arthritis Quality of Life Questionnaire (JAQQ) [ab,tractJ. Arthritis Rheum 36 (Supp!): S144, 1993. 100. Duffy CM, Arsenault L, Watanabe Duffy KN, et al: Relative sensitivity to change of the Juvenile Arthritis Quality of Life Questionnaire following a new lteaunent [abstract). Arthritis Rheum 37 (Supp!): 5196, 1994. 101. Duffy CM, Arsenault L, Watanabe Duffy KN, et al: Relative sensitivity to chanJle of the Juvenile Arthritis Quality of Life Questionnaire on sequential follow up [abstractJ. Arthritis Rheum 38 (Supp!): S178, 1995. 102. Duffy CM, Watanabe Duffy KN, Gibbon M, et al: Accuracy of functional outcome measures in defining improvement in juvenile idiopathic arthritis [abstract). Ann Rheum Dis 59: 724. 2000. 103. Takken T, van del' Net], Kuis W, Heidel'S PJ: Aquatic fitness training for children with juvenile idiopathic arthritis. Rheumatology 42: 1408, 2003.
183
104. Selvaag AE, Flato B, Lien G, et al: Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the Child Health Questionnaire. J Rheumatol 30: 1602, 2003. 105. Varni lW, Seid M, Smith Knight T, et al: The Peds QL in Pediatric Rheumatology: reliability, validity and responsiveness of the Pediatric Quality of Life Inventory Generic Core Scales and Rheumatology Module. Arthritis Rheum 46: 714, 2002, 106. Isenberg DA, Allen E, Farewell V, et al: International consensus on outcome measures for patients with idiopathic inflammatory myopathies: development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology 42: 1, 2003. 107. Miller FW, Rider LG, Chung YL, et al: Proposed core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology 40: 1262, 2001. 108. Ruperto N, Ravelli A, Murray K], et al: Preliminary core set of measures for disease activity and damage assessment in juvenile systemic lupus erythematosu, and juvenile dermatomyositis. Rheumatology 42: 1, 2003. 109. Rider L, Giannini EH, Harris-Love M, et al: Defining clinical improvement in adult and juvenile myositis, J Rheumatol 30: 603, 200} 110, Lovell 0], Lindsley CB, Rennenbohm RM, et aI: Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies: 11. The Childhood Myositi, Assessment Scale (CMAS): a quantitiative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Arthritis Rheum 42: 2213, 1999. 111. Feldman BM, Ayling-Campos A, Luy L, et al: Measuring disability in juvenile dermatomyositis: validity of the Childhood Health Assessment Questionnaire, J Rheumatol 22: 326, 1995. 112. Huber AM, Lang B, LeBlanc C, et al: Medium and long-term functional outcomes in a multi-center cohort of children with juvenile dermatomyositis. Arthritis Rheum 43: 541, 2000, 113. Huber AM, Hicks ]E, Lachenbruch PA, et al: Validation of the Childhood Health Assessment Questionnaire in the juvenile idiopathic myopathies. J Rheumatol 28: 1106, 2001. 114. Takken T, Elst E, Spermon N, et al: The physiological and physical determinants of functional ability measures in children with dermatomyositis, Rheumatology 49: 591, 2003. 115. Brunner HI, Feldman BM, Bombardier C, Silverman ED: The SLEDAI, SLAM and BILAG are sensitive to clinical change in childhood-onset sy'temic lupus erythematosus. Arthritis Rheum 42: 1354. 1999. 116, Brunner HI, Silverman ED, Bombardier C, Feldman BM: European Consensus Lupus Activity Measurement is sensitive to change in childhoodonset sy'temic onset lupus erythematosus. Arthriti, Rheum 49: 335, 2003. 117. Brunner HI, Silverman ED, To T, et al: Risk factors for damage in childhoodonset systemic lupus erythematosus: cumulative disease activity and medication u,e predict disease damage. Arthritis Rheum 46: 436, 2002. 118, Ravelli A, Duarte-Salazar C, Buratti S, et al: Assessment of damage in juvenile-onset systemic lupus erythematosus: a multi-centre cohort ,tudy. ArthritiS Rheum 49: 501, 2003.
( HAP T E R
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A GENERAL ApPROACH TO MANAGEMENT OF RHEUMATIC DISEASES IN CHILDREN Balu H. Athreya and Carol B. Lindsley
IJif
Rheumatic diseases are chronic, multisystem diseases characterized by an unpredictable course with periods of exacerbation and remission. Care of affected children requires consultations with medical and surgical specialists. Many of these disorders cause muscle weakness and joint contractures with functional disabilities. Therefore, children with rheumatic diseases often require physical and occupational therapy, counseling, and social services (Table 8-1). Treatment of these diseases with anti-inflammatory agents, immunosuppressives, and the new biologic immune modulators is discussed in various chapters dealing with individual disease categories. This chapter discusses general principles of management of issues, other than medical, that are common to all chronic diseases. This includes discussions on compliance issues, strategies to improve self-image and coping skills, schoolrelated issues, transition to adult care, physical and occupational therapy, and one specific aspect of well-child care-immunization. There are multiple dimensions to the effects of chronic illness on children and on members of their families.! Several early studies suggested a negative impact of chronic illness on psychosocial deveiopment,I-3 family,4 school life,s.6 and family finances. 7 •H Studies focusing on children with rheumatic diseases growing up before the availability of modern drugs showed that 30% to 50% entered adult life with active disease. 9.10 Severe disability was common in this young adult population with decreased physical functions, poor health perception, and pain. ll ,12 All of the psychosocial and physical problems assume greater importance when such children reach adolescence!3 or when they grow up to be adults with continuing disease activity. For all of these reasons, a program of care for children with rheumatic diseases should plan for the whole child and the future and should be comprehensive (e.g., family-centered, community-based, coordinated, and cost-effective) (Table 8-2).14 More recent studies have not substantiated earlier pessimistic outcomes for children with rheumatic diseases. Even earlier studies that emphasized the continuing disease activity and functional problems of young
184
adults growing up with juvenile rheumatoid arthritis QRA) showed that many of these patients completed college, worked full time, and raised chiidren. ll ,I5--17 Recent well-designed studies seem to indicate that JRA is not necessarily a psychosocial stressor, and families of children with JRA are, in general, resilient.!8,19 Although these studies suggest that psychosocial intervention is not needed for every child with arthritis, they also show that some of these children do suffer disabilities, have reduced function and employment status and decreased social acceptance,21) and have overall adjustment problems and internalization of symptoms. 21 Current research efforts suggest that planning for care for these children should be based on new concepts of disablement, should be evidence-based, and should be individualized. New concepts of the "disablement" process include four distinct constructs: active pathology, impairment, functional limitation, and disability.22 Each of these stages offers potential for intervention. In addition, there may be other factors, such as coping skills, access to care, economics, and the family's psychosocial climate, that contribute to this disablement process and therefore are appropriate targets for intervention. In planning for the management of functional and psychosocial disabilities in chronic illness, one must address the issue of why some patients and families are vulnera-
I-, • 1ABLE 8 -I ,-
(olllponenb of M,lIIdgemenl of RlwllIIldli( Oisedses in (hildren
Medical and surgical management Family-centered, community-based, coordinated care (school, outreach) Psychosocial management (social services, mental health services, financial) Musculoskeletal rehabilitation (physical therapy, occupational therapy, orthopedics) Well-child care issues (growth and development, nutrition, immunization, anticipatory guidance) Continuity of care Cost-effective care
C HAP T E R 8
I'll • -
ApPROACH TO MANAGEMENT OF RHEUMATIC DISEASES IN CHILDREN
185
TEAM CARE
IABLE l'l-2 Steps in Implementing [,unity-Centered, \ (llIlmunity-Based (an'
Tertiary Center Recognizing the pivotal role of the child and the family in the planning of care Developing resources in the community where the child lives Recognizing parents and professionals as equals in a partnership of care Emptlwering the family with information through education and support Encouraging pediatricians to assume a greater role in casecOOirdination, become knowledgeable about available local resources, and work with community agencies Increasing communication among disciplines and from patients to hea'lth professionals Breaking barriers to development of such a system
Pediatric Rheumatologist; Rheumatology Nurse; Allied Services; Other Pediatric Specialists; Special Laboratory; Imaging; etc.
I I
Child and Parent
School .....- - Primary Physician
ble and others are not. 18,19 Based on their well-designed study, Noll and colleagues suggested that "randomly occurring, challenging life events do not alter the child's potential for inclusive fitness by denigrating their social status or emotional well-being."23 One concept to explain this qifference in vulnerability suggests that there are some risk factors that tend to push children with chronic illness and their families to dysfunction and disability, and there are resilience factors that tend to give more stability,24,25 An imbalance between these two groups of factors influences outcomes (Table 8-3). Therefore, in planning for the care of these children, emphasis should be on the child and the family, and efforts should be aimed at not only controlling the disease and managing the current problems, but also at planning for the future. Steps should be taken to improve the resilience of patients and families through better education to cope with the vicissitudes of these diseases, improved social and peer support for the children and their parents, and stress management education to help them cope better with their disease and disability. Accurate diagnosis is the first step. Rheumatic diseases may be acute and explosive in onset, or they may evolve over a period of months and years. Only one organ system may be affected, or several systems may be involved, mimicking several other inflammatory and noninflammatory diseases. It may not be possible to place an accurate diagnostic label at first, and yet life-threatening complications and functional disabilities may have to be managed. Great skill and patience are required to support the families in managing their problems in the face of uncertainties in diagnosis and prognosis. Therein reside the 0 but 1.5
POLYARTHRITIS
271
articular involvement. Widespread symmetrical involvement of the PIP and MCP joints of the hands or feet is characteristically associated in polyarthritis with a more guarded outlook than for disease that is confined to the large joints. This is the so-called adult pattern of JIA, and it is related to development of RF seropositivity. Hip disease occurs in approximately one half of the children and almost always is accompanied by persistent inflammatory diseasey,115 It often leads inexorably to destruction or abnormal development of the femoral heads and acetabula. This type of severe hip disease is a major cause of disability in JIA, and hip involvement is justifiably interpreted as a poor prognostic sign. Limitation of range of articular motion often develops early and is related to synovial proliferation, effusion, or muscle spasm. Later on, it may result from contractures of soft tissues, joint destruction, or ankylosis. Remission is unlikely if arthritis has persisted longer than 7 years. Onset of puberty has no relation to activity of the disease or likelihood of a remission. In the Cincinnati series, 45% of the patients still had active arthritis 10 years after onset. 1l6 Fantini and colleagues ll7 noted that 15.7% of their patients with polyarticular JCA were in remission at last visit, 8.3% had a temporary remission, but 75.9% had never had a remission. Oen and colleagues lB described the outcome of children with JRA in a multicenter cohort that included 80 children with RF-negative polyarticular JRA and 40 with RF-positive polyarticular JRA (Table 10-10). All had been diagnosed between 1977 and 1994 and had been monitored for a minimum of 5 years. Although the ACR criteria were used for classification, children with psoriatic arthritis, ERA, seronegative enthesitis arthritis syndrome, juvenile ankylosing spondylitis, or arthritis with inflammatory bowel disease were excluded. Oen's group concluded that for children with RF the disease was unremitting; only 25% of children with negative tests for RF had gone into remission by age 16 years. Furthermore, children who had not gone into remission by this age were likely to have ongoing active arthritis into their late 20s or early 30s. These quite recent data suggest that polyarthritis continues to be associated with significant morbidity and functional disability.
REFERENCES
Prognosis 01 Polyarthritis
RF-Negatlve Polyarticular IRA (n= SO)
10
RF-PosIUve Polyarticular IRA (n= 40)
19 (24%) 4 (5%) 1509%)
0 0 0
36% 31% 25% 8%
8% 34% 40% 18%
'Remission - absence of active arthritis while off medication for at least 2 yr (no. and "", of patients), CHAQ, Childhood Health Assessment Questionnaire; JRA, juvenile rheumatoid arthritis; RF, rheumatoid factor. Data modified from Oen K, Malleson PN, Cabral DA. et al: Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specifiC correlations. J Rheumatol 30: 585-593. 2003.
1. Brewer EJ. Bass J. Baum J, et al: Current proposed revision of JRA criteria. Arthritis Rheum 20 (Supp\); 195-199, 1977. 2. European League Against Rheumatism: EULAR Bulletin No.4: Nomenclature and Classification of Arthritis in Children, Basel. National Zeitung AG, 1977, 3. Petty RE, Southwood TR, Manners P, et al: International League of Associations for Rheumatology classification of juvenile idiopathic anhritis: Second Revision, Edmonton 2001. J Rheumatol 31: 390-392, 2004. 4. Bowyer S, Roettcher P: Pediatric rheumatology clinic popuiations in the United States: results of a 3 year survey. Pediatric Rheumatology Database Research Group, J Rheumatol 234: 1968--1974, 1996. 5, Oen K, Schroeder M, Jacobson K. et al: Juvenile rheumatoid arthritis in a Canadian First Nations (aborigina\) population: onset subtypes and HLA associations. J Rheumatol 25: 783-790, 1998. 6. Moe N, Rygg M: Epidemiology of juvenile chronic anhritis in nonhern Norway: a ten year retrospective srudy. Clin Exp Rheumatol 16: 99-101, 1998. 7, Malleson PN, Fung MY, Rosenberg AM: The incidence of pediatric rheumatic diseases: results from the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol 23: 1981-1987, 1996. 8. Sullivan DB, Cassidy JT. Petty RE: Pathogenic implications of age of onset in juvenile rheumatoid arthritis, Arthritis Rheum 18: 251-255, 1975. 9. Moroldo MB, Chaudhari M. Shear E, et al: Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype concordance. Arthritis Rheum 50: 1928--1934.2004.
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10. Boyer GS, Lanier AP, Templin OW, et al: Spondyloarrhropathy and rheumatoid althritis in Alaskan Yupik Eskimos. .I Rheumatol 17: 48~96, 1990. 11. Oen KG, Cheang M: Epidemiology of chronic arrhritis in childhood. Semin Arrhritis Rheum 26: 575-591, 1996. 12. Mangge H, Kenzian H, Gallistl S, et al: Serum cytokines in juvenile rheumatoid arrhritis: correlation with conventional inflammation parameters and clinical subtypes. Arrhritis Rheum 38: 211-220, 1995. 13. De Benedetti F, Massa M, Pignatti P, et al: Serum soluble imerleukin 6 OL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Coo Invest 93: 2114-2119, 1994. 14. De Benedetti F, Alonzi 1', Moretla A, et al: Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I: a model for stunted growth in children with chronic inflammation. .I Clin Invest 99: 643--650, 1997. 15. Lipnick RN, Sfikakis PP, Klipple GL, et al: Elevated soluble CD8 antigen and soluble interleukin-2 receptors in the Sera of patients with juvenile rheumatoid arthritis. Clin Immunol Immunopathol 68: 64--67, 1993. 16. Madson KL, Moore n, Lawrence .1M 1Il, et al: Cytokine levels in sentm and synovial fluid of patients with juvenile rheumatoid arthritis. J Rheumatol 21: 2359-2363, 1994. 17. Kutukculer N, Caglayan S, Aydogdu F: Study of pro-inflammatory (TNFalpha, IL-1 alpha, IL-6) and l' cell-derived ClL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: correlations with clinical and laboratory parameters. Clin Rheumatol 17: 288-292, 1998. 18. Gattorno M, Picco P, Buoncompagni A, et al: Sentm p55 and p75 tumour necI'Dsis factor receptors as markers of disease activity in juvenile chronic arrhritis. Ann Rheum Dis 55: 243-247, 1996. 19. Rooney M, Varsani H, Marrin K, et al: Tumour necrosis factor alpha and its soluble receptors in juvenile chronic arthritis. Rheumatology (Oxf) 39: 432-438, 2000. 20. Yuilmaz M, Kendirli SG, Altintas 0, et al: Cytokine levels in sentm of patient swith juvenile rheumatoid arrhritis. Clin Rheumatol 20: 30--35, 2001. 21. DeBenedetti F, Vivarelli M, Pignatti P, et al: Circulating levels of soluble Eselectin, P-selecting and intercellular adhesion molecule-l in patients with juvenile idiopathic arrhritis. .I Rheumatol 27: 2246-2250, 2000. 22. Jarvis IN: Pathogenesis and mechanisms of inflammation in childhood rheumatic disease. Curr Opin Rheumatol 10: 45~67, 1998. 23. Agarwal V, Misra R, Aggarwal A: Immune complexes contain immunoglobulin A rheumatoid factor in serum and synovial t1uid of patients with polyarticular juvenile rheumatoid arrhritis. Rheumatology (Oxf) 41: 466-467, 2002. 24. Grom AA, von Knorre C, Murray KJ, et al: T-cell receptor BV6s1 null alleles and HLA-DR1 haplotypes in polyarricular outcome juvenile rheumatoid arthritis. Hum Immunol 45: 152-156, 1996. 25. Clemens LE, Albert E, Ansell BM: HLA studies in IgM rheumatoid-factor-positive arrhritis of childhood. Ann Rheum Dis 42: 431-434, 1983. 26. Forre 0, Dobloug JH, Hoyeraal HM, et al: HLA antigens in juvenile arthritis: genetic basis for the different subtypes. Arthritis Rheum 26: 35-.~8, 198327. Nepom BS, Nepom GT, Mickelson E, et al: Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arrhritis. J Clin Invest 74: 287-291, 1984. 28. Murray KJ, Moroido MB, Donnelly P, et al: Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles. Arrhritis Rheum 42: 1843-1853, 1999. 29. Vehe RK, Begovich AB, Nepom BS: HLA susceptibility genes in rheumatoid factor positive juvenile rheumatoid arrhritis. .I Rheumatol Suppl 26: 11-15, 1990. 30. Oen K, EI Gabalawy HS, Canvin .1M, et al: HLA associations of seropositive rheumatoid arrhritis in a Cree and Ojibway population. J Rheumatol 25: 2319-2323, 1998. 31. Morling N, Hellesen C, Jakobsen BK, et al: HLA-A, B, C, 0, DR antigens and primed lymphocyte typing (PLT) defined DP-antigens in juvenile chronic arrhritis. Tissue Antigens 17: 433-441, 1981. 32. Morling N, Friis J, Heilmann C, et al: HLA antigen frequencies in juvenile chronic arrhritis. ScandJ Rheumatol 14: 209-216, 1985. 33. Fernandez-Vina MA, Fink CW, Stastny P: HLA antigens in juvenile arthritis: pauciarticuiar and polyarricular juvenile arthritis are immunogenetically distinct. Arthritis Rheum 33: 1787-1794, 1990. 34. Arnaiz-Villena A, Gomez-Reino JJ, Gamir ML, et al: DR, C4, and Bf allotypes in juvenile rheumatoid arthritis. Al'lhritis Rheum 27: 1281-1285, 1984. 35. Gao X, Fernandez-Vina M, Olsen NJ, et al: HLA-DPBl'0301 is a major risk factor for rheumatoid factor-negative adult rheumatoid arrhritis. Al'lhritis Rheum 34: 1310--1312, 1991. 36. F0rre 0, Smerdel A: Genetic epidemiology of juvenile idiopathic arthritis. ScandJ Rheumatol 31:123-128, 2002. 37. Naidu SH, Ostrov BE, Pellegrini VD Jr: Isolated digital swelling as the initial presentation of juvenile rheumatoid arthritis. J Hand Surg Am 22: 653--657, 1997. 38. Chaplin 0, Pulkki 1', Saarimaa A, et al: Wrist and finger deformities in juvenile rheumatoid arthritis. Acta Rheumato! Scand 15: 206-223, 1969. 39. Ansell BM: Joint manifestations in children with juvenile chronic polyarthritis. Arthritis Rheum 20: 204-206, 1977. 40. LiemJJ, Rosenberg AM: Growth patterns in juvenile rheumatoid arthritis. Clin Exp Rheumatoi 21: 663--668, 2003. 41. Bywaters EGL, Glynn LE, Zeldis A: Subcutaneous nodules of Still's disease. Ann Rheum Dis 17: 278, 1958.
42. Bywaters EG, Cardoe N: Multiple nodules in juvenile chronic polyarrhritis. Ann Rheum Dis 31: 421, 1972. 43. Kaye BR, Kaye RL, Bobrove A: Rheumatoid nodules: review of the spectntm of associated conditions and proposal of a new classification, with a reporr of four seronegative cases. Am J Med 76: 279-292, 1984. 44. Altman RS, Caffrey PR: Isolated subcutaneous rheumatic nodules. Pediatrics 34: 869, 1964. 45. Burrington JD: "Pseudorheumatoid" nodules in children: report of 10 cases. Pediatrics 45: 473-478, 1970. 46. Simons FE, Schaller JG: Benign rheumatoid nodules. Pediatrics 56: 29--.l~, 1975. 47. Schaller JG: Benign rheumatoid nodules. Arthritis Rheum Suppl 20: 277, 1977. 48. Mesara BW, Brody GL, Oberman HA: "Pseudorheumatoid" subcutaneous nodules. Am J Clin Pathol45: 684--691, 1966. 49. Kabukcuoglu S, Tel N, Pasaoglu 0, Ilhan H: Benign rheumatoid nodules in chIldhood.Turk J Pediatr 41: 365-368, 1999. 50. Mersara BW, Brody GL, Oberman HA: "Pseudorheumatoid" subcutaneous nodules. Am J Clin Pathol 45: 684--691, 1966. 51. Havill S, Duffill M, Rademaker M: Multicentric reticulohistiocytosis in a child. Australas J Dermatol 40: 44-46, 1999. 52. Forsyth CC: Calcification of the digital arteries in a child with rheumatoid arthritis. Arch Dis Child 35: 296, 1960. 53. Reid MM, Fannin TF: Extensive vascular calcification in association with juvenile rheumatoid arrhritis and amyloidosis. Arch Dis Child 43: 607-610. 1968. 54. Gedalia A, Gewanter H, Baum J: Dark skin discoloration of finger joints in juvenile arthritis. J Rheumatol 16: 797-799, 1989. 55. Bloom BJ, Smith P, Alario AJ: Felty syndrome complicating juvenile rheumatoid arrhritis. J Pediatr Hematol Oncol 20: 511-513. 1998. 56. Leak AM, Millar-Craig MW, Ansell BM: Aortic regurgitation in seropositive juvenile arthritis. Ann Rheum Dis 40: 229-234, 1981. 57. Ozer S, Alehan 0, Ozme S, et al: Mitral and aortic insufficiency in polyarticular juvenile rheumatoid arthritis. Pediatr Cardiol15: 151-153, 1994. 58. Delgado EA, Petty RE, Malleson PN, et al: Aortic valve insuf!1ciency and coronary arrery narrowing in a child with polyarticular juvenile rheumatoid arthritis. J Rheumatol 15: 144-147, 1988. 59. Uziel Y, Hen B, Cordoba M, Wolach B: Lymphocytic interstitial pneumonitis preceding polyarticular juvenile rheumatoid arthritis. Clin Exp Rheumatol 16: 617-619, 1998. 60. DiKensoy 0, Bayram N, Bingol A, Filiz A: Bronchiolitis obliterans in a case of juvenile rheumatoid arthritis presented with pneumomediastinum. Respiration 69: 100--102, 2002. 61. Rohayem J, Leupold W, Paul K-D, Gahr M: Pulmonary fibrosis and other clinical manifestations of small vessel vasculitis in a family with seropositive juvenile rheumatoid arthritis. Pediatr Pulmonol 33: 65-70, 2002. 62. Ragsdale CG, Petty RE, Cassidy .IT, Sullivan DB: The clinical progression of apparent juvenile rheumatoid arrhritis to systemic lupus erythematosus. J Rheumatol 7: 50--55, 1980. 63. De Cuelaer K, Forbes M, Roper 0, Serjeant GR: Non-gouty arthritis in sickle cell disease: reporr of 37 consecutive cases. Ann Rheum Dis 43: 599-603, 1984. 64. Nistala K, Murray KJ: Co-existent sickle cell disease and juvenile rheumatoid arthritis: two cases with delayed diagnosis and severe destntctive arrhropathy. J Rheumatol 28: 2125-2128, 2001. 65. Davies K, Stiehm ER, Woo P, Murray K.f: Juvenile idiopathic polyarricular arrhritis and 19A deficiency in the 22qll deletion syndrome. J Rheumatol 28: 2326-2334, 2001. 66. Jacobs JC, Downey JA: Juvenile rheumatoid arthritis. In Downey, .lA, Low NL (eds); The Child with Disabling mness. Philadelphia, WB Saunders, 1974, p 5. 67. Athreya BH, Schumacher HR: Pathologic features of a familial arrhropathy associated with congenital flexion contractures of fingers. Arrhritis Rheum 21: 429-437, 1978. 68. Malleson P, Schaller JG, Dega F, et al: Familial arthritis and camptodactyly. Arthritis Rheum 24: 1199-1204, 1981. 69. Bulutlar G, Yazici H, Ozdogan H, et al: A familial syndrome of pericarditis. arrhritis, camptodactyly, and coxa vara. Arthritis Rheum 29: 436-438, 1986. 70. Laxer RM, Cameron BJ, Chaisson 0, et al: The camptodactyly-arrhropathypericarditis syndrome: case reporr and literature review. Arrhritis Rheum 29: 43~44, 1986. 71. Robinson RP, Franck WA, Carey EJ, et al: Familial polyarticular osteochondritis dissecans masquerading as juvenile rheumatoid arthritis. J Rheumatol 5: 190--194, 1978. 72. Zulian F, Schumacher HR, Calore A, et al: Juvenile arthritis in Turner's syndrome: a multicenter study. Clin Exp Rheumatol 16: 489-494, 1998. 73. Pugh MT, Southwood TR: Tuberculous rheumatism, Poncet disease: a sterile controversy? Rev Rhum Ed Fr 60: 855-860, 1993. 74. Eisenstein OM, Poznanski AK, Pachman LM: Torg osteolysis syndrome. Am J Med Genet 80: 207-212, 1998. 75. Singh JA, Williams CB, McAlister WH: Talo-patello-scaphoid osteolysis, synovitis, and shorr fourth metacarpals in sisters: a new syndrome' Am J Med Genet 121A: 118-125, 2003. 76. Harris ED Jr: Rheumatoid Al'lhritis. Philadelphia, WE Saunders 1987. 77. Cooke TDV: The interaction and local disease manifestations of immune complexes in arricular collagenous tissue. In Maroudas A. Holborow EJ (eds): Studies in Joint Disease. London, Pittman, 1980, p 158.
CHAPTER 78. Bernstein B, Forrester 0, Singsen B, et 011: Hip joint restoration in juvenile meumatoid arthritis. Anhritis Rheum 20: 1099--1104, 1977. 79. Berg E, Wainwright R, Barton B, et 011: On the nature of rheumatoid rice bodies: an immunologic, histochemical, and electron microscope study. Arthritis Rheum 20: 1343-1349, 1977. 80. Wynne-Roberts CR, Cassidy JT: Juvenile rheumatoid arthritis with rice bodies: light and electron microscopic studies. Ann Rheum Dis 38: 8-13, 1979. 81. Chung C, Coley BD, Martin LC: Rice bodies in juvenile rheumatoid arthritis. AJR Am J Roentgenol 170: 698-700, 1998. 82. Bennett GA, Zeller .TW, Bauer W: Subcutaneous nodules of rheumatoid arthritis and rheumatic fever: a pathologic study. Arch Pathol 30: 70, 1970. 83. Bowyer S, Roetlcher P: Pediatric rheumatology clinic populations in the United States: results of a 3 year survey. Pediatric Rheumatology Database Research Group. J Rheumatol 23: 1968-1974, 1996. 84. Oen K, Schroeder M, Jacobson K, et 011: Juvenile rheumatoid arthritis in a Camldian First Nations (aboriginal) population: onset subtypes and HLA associations. J Rheumatol 25: 783-790, 1998. 85. Eichentield AH, Athreya BH, Doughty RA, Cebui RD: Utility of rheumatoid factor in the diagnosis of juvenile rheumatoid arthritis. Pediatrics 78: 48Q....484, 1986. 86. Cassidy./T, Valkenburg HA: A five year prospective study of rheumatoid factor tests in juvenile rheumatoid arthritis. Arthritis Rheum 10: 83-90, 1967. 87. Schlump lJ, Howard A, Ansell BM: IgG-anti-igG antibodies in juvenile chronic arthritis. Scand J Rheumatol 14: 65--{58, 1985. 88. Miller JJ 111, Olds-Arroyo L, Akasaka T: Antiglobulins in juvenile rheumatoid arthritis. Arthritis Rheum 20: 729-735, 1977. 89. Lawrence JM 3rd, Moore TL, Osborn TG, et 011: Autoantibody studies in juvenile rheumatoid arthritis. Semin Ar ..
I ABLE ]] -4
Characteristics of Children with Chronic Uveitis
Charac:terlstlc
Female/Male ratio Mean age at onset of arthritis (yr) Arthritis category (%) Oligoarthritis Polyarthritis Systemic Serology (%) Rheumatoid factor positive Antinuclear antibody positive
Overall Avenge Reported Range 4.4:1 4
82 18 15
Age (y)
12 11 10
9
~Ql
8
0.
7 6
~
0
...
il
5
E ;:]
4
Z
3
Pathology
2 1 0 1
C
to 80% of children. 14 ,139,158 Patients with unilateral disease are unlikely to develop bilateral involvement after the first year of disease; however, there are exceptions, and unilateral uveitis may persist for many years in a few children before the other eye is involved. The early detection of chronic uveitis requires slitlamp biomicroscopy, which should be performed at the time of diagnosis in every child with ]IA and repeated at prescribed intervals during the first few years of the disease. The frequency of ophthalmic examinations is influenced by the level of risk of uveitis (Table 11-6). The authors recommend that slit-lamp examinations be performed every 3 months for the first 2 years in children in the high-risk group (early age at onset, oligoarthritis, female sex, ANA seropositivity) and every 4 to 6 months thereafter for a period of 7 years at a minimum. In children with polyarticular disease, slit-lamp examinations should be done initially at 4- to 6-month intervals. In children with a systemic onset, examinations once a year after the first year are probably sufficient. Any child who has had uveitis should be considered to be at high risk, even if it has remitted, and continued surveillance is mandatory. The earliest signs of uveitis on slit-lamp examination are the presence of inflammatory cells and increased protein concentration ("flare") in the aqueous humor of the anterior chamber of the eye (Fig. 11-5). Deposition of inflammatory cells on the inner surface of the cornea (keratopunctate deposits or keratic precipitates) may develop later. Posterior synechiae between the iris and the anterior surface of the lens result in an irregular or poorly reactive pupil (Table 11-7; Fig. 11-6). This abnormality may be the first obvious clue to the presence of uveitis on ophthalmoscopic examination, but it is often a sign of disease of considerable duration or severity. Band keratopathy occurs late (Fig. 11-7). Secondary cataracts and glaucoma are also quite common, but phthisis bulbi is a rare late manifestation of uveitis. Band keratopathy and cataracts occurred in 42% to 58% of patients in reported series, and glaucoma occurred in 19% to 22%.144.159,160 These complications are still occasionally encountered in some children with chronic uveitis in spite of vigorous and carefully monitored ophthalmic treatment, although their frequency may be diminishing
2
3
4
5
6
7
8
9 10 11 12 13 14 15 >15
Time of onset (y)
• Figure 11-4 Graphs showing the temporal relationships between arthritis and uveitis in children with juvenile rheumatoid arthritis. A, The distribution of age at onset of arthritis in aseries of 38 children who developed uveitis, B, The distribution of age at onset of uveitis in the same children. Note that in four patients, uveitis began after their 15th birthday: at 15{1I2}, 18,31, and 39 years of age. C, Interval between onset of arthritis and diagnosis of uveitis in these patients. Note that for 1 patient the interval was 29 years, and for another, 34 years.
Reports of the histopathology of uveitis are few. Descriptions of extremely severe, long-standing disease that led to blindness do not necessarily illuminate the pathogenic process. 161 Reported changes include increased iris vascularity162 with scanty lymphocyte and plasma-cell infiltrates. 162.163 Plasma cells containing immunoglobulin M (IgM) were described in one patient. 164 Patients in whom granulomatous changes were present may have had sarcoidosis rather than ]RA.165.166 Immunoglobulin levels were increased in the aqueous humor of children with ]RA and uveitis.167.168 Studies of the vitreous showed an increased IgG concentration,
C HAP T E R
,--
II ..
TABLE I 1-6
RIsk*
Examination
Type of
Antinuclear
Frequency (mo)
Disease
AntIbodies
6
Moderate
3-4
High
OLIGOARTHR1TIS
281
Frequenty of Uveitis Monitoring
12
Low
II
Systemic arthritis Polyarthritis
Age at Onset (yr)
+ or-
Disease DuratIon (yr)
>7
Polyarthritis Oligoarthritis Oligoarthritis
+ or-
~6
~6 ~6
9
+
Oligoarthritis
+
~6
9
>7
'Risk decreases by one level for age at onset >6 yr.
• FI. . . 11-5 A slit-lamp examination shows "flare" in the fluid of the anterior chamber (caused by increased protein content) and keratic predpitates on the posterior surface of the cornea, representing small collections of inflammatory cells. (Courtesy of Dr. H. J. Kaplan.) (See color insert.)
.~ III
I ABLE 11-7 Frequency of Complications of Chronic Uveitis ... Reported Cases
Complication
Mean Frequency (%)
Synechiae Band keratopathy Cataract Glaucoma Phthisis bulbi
62 37 40 19
9
Range (%)
37-75 11-56 6-75 8-25 0-14
From Petty RE: Current knowledge of the etiology and pathogenesis of chronic uveitis accompanying juvenile rheumatoid arthritis. Rheum Dis Clin North Am 13: 19-36, 1987.
activated complement C3c, and increased C1q binding, suggesting the presence of immune complexes. t69 Kaplan and associates 170 found that 90% of vitreous lymphocytes in one adult with uveitis and "juvenile" RA were B lymphocytes,
Differential Diagnosis Uveitis and arthritis occur together in a number of diseases with high frequency.144,171 Uveitis also occurs in
• Figure 11-6 Left eye of a 7-year-old boy shows an irregular pupil that resulted from adhesions of the iris to the anterior surface of the lens. (See color insert.)
children without evidence of joint involvement as an isolated disorder. 172 Inflammation of the anterior uveal tract is found in Kawasaki disease,173 complicates ERA QAS),174 and is observed in psoriatic arthritis,138,17'; arthropathy of inflammatory bowel disease,176-178 and reactive arthritis with urethritis and conjunctivitis,179,1HO Uveitis also occurs in chronic infantile neurologic cutaneous and articular syndrome (CINCA), 181-184 sarcoidosis, 165,166,185,186 Blau's syndrome,187,188 Vogt-Koyanagi-Harada syndrome, and Beh~et's disease. 144 Posterior uveitis rarely complicates rheumatic diseases in children, and its presence suggests the diagnosis of sarcoidosis rather than JIA.
Laboratory Examination The most characteristic laboratory abnormality found in children with arthritis and uveitis is the presence of ANAs, usually in low titer (less than 1:640). The specificities of these antibodies are unknown,126,189-191 and the pattern of immunofluorescence on HEp-2 cells is speckled or homogeneous. Occasionally ANAs react with nucleoli, but antibodies to double-stranded DNA (dsDNA) and the extractable nuclear antigens (ENAs) are absent. Antibodies that are specific for granulocyte nuclei
282
C HAP T E R
II
OLIGOARTHRITIS
• Rgure 11-7 A, Early band keratopathy is noted as a semilunar band just inside the limbus medially and laterally. It does not extend across the pupil. 8,The semiopaque band extends across the midplane of the comea in this example of more advanced band keratopathy. It is fenestrated and does not extend to the limbus. (8, See color insert.)
have been reported to occur in children with uveitis. 192 These antibodies were complement fixing and correlated with disease activity. 193 When tissue sections were used as substrate, ANAs were found with significantly higher frequency (65% to 88%) in children with oligoarticular JRA and uveitis than in those with oligoarticular JRA alone. 189,190 Neuteboom and coworkers l94 found ANAs in 55% of children with uveitis and chronic arthritis with HEp-2 cells substrate, but in only 32% when rat liver was used. They detected antibody to dsDNA in 3 of 22 children and antiSS-A in 1 of 22 children with uveitis. Using HeLa cells as a source of nuclear material, they also demonstrated reactivity of sera from children with arthritis and uveitis to a 15-kD antigen by Western blotting. Reactivity to histones has been associated with oligoarticular disease and uveitis. 195 ,196 Massa and colleagues l97 reported that ANA-seropositive patients had significantly elevated IgG antibodies to nucleosomes H3 and H4, to DNA-free subparticles, and to H3H4-DNA, hut that these antibodies were generally not associated with uveitis.
Management The treatment of chronic uveitis should be supervised by an ophthalmologist who is experienced in management of this complication. 198 The initial approach consists of glucocorticoid eye drops (dexamethasone or methylprednisolone), with or without a mydriatic agent to dilate the pupil and help prevent posterior synechiae. A shortacting mydriatic drug is preferred, given if possible once a day in the evening, so that pupillary dilatation does not interfere with school work and reading. Some data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may be of some benefit. 199-201 Although this effect is not a major one, it should be considered when NSAID treatment of arthritis is altered. In unresponsive disease, glucocorticoid drops may be given hourly during waking hours, with glucocorticoid ointment placed in the conjunctival sac at bedtime. Chylack lS reported that 36% of children had no response to topical glucocorticoids after 6 months of intensive therapy and therefore required systemic administration of the drug. In a few instances, subtenon injections of glucocorticoid may be required. It may be advisable in severe or resistant disease to employ supplemental oral prednisone in low dosage (e.g., 2 to 4 mg/day). Some
children require larger amounts of oral glucocorticoid; single daily or alternate-day therapy may be useful in these patients. 126 Occasionally, high-dose intravenous methylprednisolone (30 mg/kg) is of benefit. Although the results of slit-lamp examination may return to normal soon after treatment is initiated, it is not advisable to discontinue steroids at that time, because signs of inflammation frequently reappear. Long-term ophthalmic glucocorticoid administration may lead to the development of Cushing's syndrome. Methotrexate may be an effective mode of therapy in children with severe uveitis in whom all other forms of treatment have failed. 202 ,203 Chlorambucil,204,20s cyclosporine,206 and plasmapheresis 207 may be useful in some cases of idiopathic uveitis, but their role in the uveitis of JIA is not clarified. Cyclosporine was given to 14 children with chronic uveitis refractory to glucocorticoids for a mean duration of 21 months. 20B Visual acuity was improved or did not deteriorate further in 92% of eyes, and results of the ophthalmic examination were improved in 76%. In a follow-up study, the same investigators studied the effect of mycophenolate mofetil in nine eyes that had not responded to cyclosporine. 209 Eight eyes improved in visual acuity; by ophthalmoscopy score, 5 were unchanged and 2 eyes worsened. Refractory uveitis has also been treated with intravenous immunoglobulin (IVIG).209 Smiley 131 noted that neither adrenocorticotrophic hormone nor azathioprine had proved efficacious in controlling ocular inflammation, although some ophthalmologists believe that azathioprine may be useful. The efficacy of anti-TNF biologic agents in the treatment of uveitis is uncertain. Reifplo reported effectiveness of etanercept in an uncontrolled study of seven children with active uveitis and JRA that had not responded satisfactorily to corticosteroids and methotrexate or cyclosporine. Follow-up of these patients indicated that at least four had a sustained response. 21l Smith and coworkers 212 conducted a randomized, blinded, placebo-controlled trial in 12 children with JRA and uveitis in whom the methotrexate response was insufficient and found no difference between etanercept and placebo at 6 months. Infliximab has been anecdotally reported to be of benefit, but there are also reports of new onset or worsening of uveitis during treatment with anti-TNF agents. 2B
C HAP T E R
Band j<eratopathy has been treated with topical chelation and by lasers. Cataracts seldom interfere significantly with vision in childhood, but they may require surgical removal. The managem~nt of complicated uveitis and glaucoma remains unsatisfactory, but results of lensectomy or vitrectomy for complicated catara~t are improved. 158 The subject of cataract surgery in children with JRA and uveitis was thoroughly reviewed by Hooper and cbworkers. 214 It was their recommendation that cataract surget'y should be performed only in the absence of vitreous opacit~es, hypotony, or cyditic membrane formation; that the anteri?r chamber should be free of inflammatory cells; and that combining anterior segment surgery with a pars plana vitrectomy IS the safest approach. Perioperative glucocorticoids are recor~mended. The timing of cataract extraction challenges the judgment of the ophthalmologist in weighing the danger of opera~ion on an inflamed eye against the risk of amblyopia. Oper~tive complications are minimized with microsurgery and cryoe*traction.
Cou~ and Prognosis of Uveitis Srniley 134 emphasized that the course of chronic uveitis is rarel~ less than 2 years and often as long as 17 or 18 years: The authors' experience and that of others,132 however, indicates that some children have much shorter courses. The activity of the uveitis does not parallel that of the arthritis,14,133,1 34,160,215 and it may occur for the first time after the arthritis is in remission. Visual loss may occult because of complications of the uveitis or as a result of amblyopia related to suppression of visual images from a cataract. Although prognosis for sight in chronic uveitis has been improving, visual outcomes still remain far less than satisfactory, with estimates of blindness (less than 20/400 AU) in both eyes as high as 15% to 30%.14,134,139 It has been suggested that the frequency and severity of uveitis may actually be decreasing. 13~,140.J41,216,217 Whether this represents intrinsically less severe disease (a "benign" form of uveitis), earlier treatment, or more aggressive therapy is not certain. The prognosis for uveitis is worse in children in whom the onset of uveitis occurs before diagnosis of arthritis or shortly thereafter. 158,137,140 It is also worse in those with an initial severe inflammatory response,137 chronicity of inflarnmation,34 or ANA seronegativity.l40 Kanski's review l58 of the Taplow experience confirmed that visual prognosis was good in 25% and fair in 50% of studied patients. The remaining 25% developed visual impairment from cataract or ghiucoma, In the early Ann Arbor series, 3 children (8%) completely recovered from their uveitis, and 55% retained normal vision, 14 However, 16% of the children were blind in one or both eyes. During the course of the disease, even minimal symptoms were associated with moderate-to-advanced ocular disease, Twentyfive children had protracted or recurrent ocular inflammation. A series of patients from the same center 10 years later137 described an improved prognosis. Visual outcome was worse if uveiti$ was present at the time of diagnosis of arthritis and in children with persistently active disease. In the Taplow series, however, Kanski noted that 8 of 26 eyes with continuously active uveitis for more than 10 years remained unaffected by seconpary complications and retained normal visual acuity. 126 Cabral and colleagues,138 in a study of 49 patients (82 affected eyes), reported that only 15 affected eyes had corrected visual acuity of 20/40 or worse, at an average of 9.4 years after onset
II OLIGOARTHRITIS
283
of uveitis, and 8 had corrected visual acuity of 20/200 or worse. This study confirmed the correlations between a poor visual prognosis and the presence of uveitis at diagnosis of arthritis, the presence of complications (e.g" synechiae), and persistent disease activity. Complications of uveitis were frequent in the recent series reported by Paroli and associates. 156 Of 42 children with ]RA-associated uveitis who were observed for at least 1 year, cataract was present in 64%, band keratopathy occurred in 59%, and glaucoma occurred in 25%. Nonetheless, visual acuity was normal or good in almost two thirds of these children.
LABORATORY EVALUATION Laboratory indicators of inflammation may be normal in children with oligoarthritis, although mild to moderate elevation of the erythrocyte sedimentation rate (ESR) and elevation of C-reactive protein levels may occur. Hemoglobin levels and white blood cell and platelet counts are usually normal, and the presence of marked abnormalities in these parameters should suggest a diagnosis other than oligoarthritis. Tests for RF are almost always negative, although, occasionally, children with a single affected joint (often the wrist) have RF. In contrast, tests for ANAs are positive in low titer (1:640) in 65% to 85% of children with oligoarthritis, particularly in girls and in those with uveitis. 36 ,189.190,218 Antibodies that react with citrullinated peptides have rarely been demonstrated in children with oligoarthritis, their frequency depending to some extent on the antigen used. 21 9-221 Anticardiolipin antibodies were reported in 18% of children with oligoarthritis (compared with 4% in a healthy population).222 They do not appear to be associated with intravascular thrombosis, however. Elevated concentrations of activated C3 (C3c, C3d) were demonstrated in about one third of children with active oligoarthritis (a lower frequency than in children with systemic arthritis or polyarthritis).223 Circulating immune complexes are not characteristic of oligoarthritis. Routine synovial fluid analysis does not distinguish one type of JIA from another. The fluid is usually moderately inflammatory, with a cell count of 5 to 20,000 cells/mm3, mostly polymorphs.
RADIOGRAPHIC EVALUATION The radiographic changes in oligoarthritis are similar to those seen on other kinds of arthritis, although often less severe. In a recent follow-up study224 of 97 children with pauciarticular ]RA, joint space narrowing was present in only 5% of children early in the disease course, increasing to approximately 15% at a median of 6.2 years after disease onset. Erosions were seen in 10% of children with early disease, and in approximately 25% of children 6 years later. Bone overgrowth was more common; it occurred in more than 20% of children early in the disease and slightly more frequently later in the disease course. Not surprisingly, overgrowth was most common at the knee (Figs. 11-8 and 11-9).
284
C HAP T E R
II
OLIGOARTHRITIS
• Figure 11-8 A-e, Anteroposterior and lateral radiographic films of the knees of a 3-year-old girl who developed monarthritis of the left knee at the age of 2 years with an initial flexion contracture of 32 degrees.There is marked joint space narrowing with regional osteoporosis of the left knee and epiphyseal enlargement. D, Post-gadolinium magnetic resonance imaging sagittal studies of the left knee.There is a large joint effusion with marked inflammatory synovial hypertrophy, demonstrated by enhancement of the pannus throughout all compartments of the joint.There is also thinning and irregularity of the articular cartilage involving the femur, tibia, and patella.There is almost bone-on-bone apposition of the femorotibial articulation. Asymmetrical enlargements of the epiphyses of the left knee are visible, with relative hypoplasia of the menisci.
Magnetic resonance imaging with gadolinium confirms the presence of synovitis, and increased intra-articular fluid, and, occasionally, bone marrow edema. Its main utility, however, is in differentiating other causes of joint swelling, particularly in the child with monoarthritis. 225
MANAGEMENT Prompt and accurate diagnosis is essential to the optimal outcome of oligoarthritis. Because of the subtlety of the signs and symptoms, medical attention may not be
sought early in the disease course. The aim of therapy should be to achieve total remission of signs and symptoms of joint inflammation. Initial management of oligoarthritis should include careful clinical general and musculoskeletal assessment. In the child with monarthritis, other possible causes of inflammation in a single joint should be excluded. Evaluation by a physical therapist and occupational therapist to assess joint range, muscle strength, and function should be obtained. A slit-lamp examination by an experienced ophthalmologist is essential to exclude the pOSSibility of uveitis, as soon as possible after the diagnosis of
C HAP T E R
II
OUGOARTHRITIS
285
• FIgure 11-9 These radiographs illustrate the 5-year progression of osteoporosis, joint space narrowing, and degenerative changes in the !taniemi K, Kaipiainen-Seppanen 0, Savolainen A, et al: A populationbased study on uveitis in juvenile rheumatoid arthritis. Clin Exp Rheumatol 11: 119-122, 1999. 133. Chylack LT ]r, Bienfang DC, Bellows AR, et aI: Ocular manifestations of juvenile rheumatoid arthritis. Am] Ophthalmol 79: 1026-1033, 1975. 134. Smiley WK: The eye in juvenile chronic polyarthritis. Clin Rheum Dis 2: 413, 1976. 135. S50
27 13
>50 >25
13
>50
9
>10
9 Common
>50
6
Occasional
Occasional
hrilis
May be the initial immune complex lesion Usually no clinical features of renal disease, or there may be minimal proteinuria or hematuria Remission or progression of the nephritis may occur with transition to diffuse or membranous disease
• FlllUre 16-18 Focal proliferative lupus nephritis. A lobular area of hypercellularity and necrosis is seen in an otherwise normal glomerulus. The majority of the glomeruli appeared normal on light microscopy.
C HAP T E R
• r:...- II-I'
Focal proliferative glomerulonephritis demonstrated on direct immunofluorescence microscopy staining for Clq. Some areas of the glomerulus show intense staining, whereas others are entirely normal. (Courtesy of Dr. David Lirenman.)
coccal glomerulonephritis. Segmental proliferation of the glomerular tufts, which is usually accompanied by mesangial proliferation, is also present. Granular or "lumpybumpy" deposits of immunoglobulins and complement components are seen by immunofluorescence microscopy along the basement membranes. By ultrastructural studies, these are subendothelial electron-dense deposits of immune complexes along the capillary basement membrane with accompanying proliferative changes. Less often, a few subepithelial and intramembranous deposits may be found. Focal segmental proliferative nephritis may progress to diffuse disease in from 70/0346 to 35% of patients. 347 This transition is most likely to occur with prolonged, severe, active disease (Table 16-21). Diffuseproliferative glomerulonephritis (WHO class IV) is characterized by the uniform hypercellularity of more than 50% of the glomeruli in the biopsy specimen (Figs. 16-20, 16-21, and 16-22). The severity of the individual glomerular changes is usually more pronounced than in focal, disease. Fluorescence microscopy demonstrates the characteristic "lumpy-bumpy" deposition of immunoglobulin and complement along the peripheral capillary walls, as well as in the mesangium. Interstitial infiltrates and extraglomerular immune complex deposition may also be noted along the tubular basement membranes, within the walls of the peritubular capillaries, or in the interstitium. By electron microscopy, extensive immune deposits can be seen in the mesangium and subendothelial spaces, and, to a lesser extent, in the subepithelial areas and intramembranously. Ultrastructurally, these electrondense deposits may exhibit a fingerprint or microtubular . : . I ARL E 16 21
16
SYSTEMIC
Lupus
ERYTHEMATOSUS
363
• Figure l1-Z0 Diffuse proliferative lupus glomerulonephritis. All glomeruli in the biopsy core were uniformly involved. Marked hypercellularity, hyaline thrombi, hematoxylin bodies, and areas of necrosis were present. Ared blood cell cast (atrow) is seen in an adjacent tubule.
appearance, a result of crystallization within the immune complexes (Table 16-22). Membranous glomerulonephritis (WHO class V) has been considered to be quite uncommon as an isolated abnormality. The frequency of this lesion may be increasing; it was found in 28% of initial biopsy samples of children with SLE in one center. 344 The frequency of this histologic pattern at the same center increased from 17% before 1995 to 64% after 1995. The characteristic lesion is deposition of immune complexes along the subepithelial surface of the glomerular basement membrane with obliteration of the foot processes but little cellular proliferation (Figs. 16-23 and 16-24). The basement membranes assume a rigid, enlarged, glassy appearance. There may be slight increases in the number of mesangial cells and in the density of the mesangial matrix. Silver or periodic acid-Schiff stains define a
Focal Proliferalive I upus Glomerulonephritis
Minimal proteinuria Microscopic hematuria Nephrotic syndrome or renal insufficiency in 20% Responsive to glucocorticoid therapy Does not usually progress to renal failure
• Figure 11-21 Fluorescence microscopy image of a renal biopsy section from ayoung girl who died with central nervous system lupus and nephrotic syndrome. Deposits of immunoglobulin Gare shown in a"lumpy-bumpy' pattern (subendothelial) and afiner granular pattern (epimembranous).
364
C HAP T E R
16
SYSTEMIC
Lupus
ERYTHEMATOSUS
• Figure 16-22 Electron microscopy study of a biopsy specimen from a patient with diffuse proliferative glomerulonephritis showing subendothelial and paramesangial immune deposits (atrow).
I!. Ii
TABLE 16-22
Diffuse Proliferative Lupus Glomerulonephritis
Proteinuria and hematuria Nephrotic syndrome and renal insufficiency in 60% Limited remission in 50% Renal failure in some patients, 5-10 yr after onset
• Figure 16-24 Electron microscopic section of membranous nephritis showing an epimembranous complex (atrow).
spike pattern along the basement membrane related to immune complex deposition on the capillary loops. Fluorescence microscopy shows a granular deposition of IgG and complement along the basement membrane that is usually finer and smaller than the deposits found in diffuse glomerulonephritis. In addition, there may be intra-basement membrane deposits, suggesting that in certain situations immune complexes can traverse the basement membrane from the subendothelial to the subepithelial surfaces (Table 16-23). Glomerular sclerosis (class VI) is actually not a category of the WHO classification but is customarily appended to it to accommodate the classification of patients in whom the predominant histologic change is focal segmental glomerular sclerosis. Although extensive sclerosis indicates a poor prognosis, minimal to mild sclerosis may be present in patients who have a stable disease course..~46 Correlations between glomerular histopathologic changes and clinical features of renal disease are summarized in Table 16-10. Children with mesangial lupus nephritis seldom have clinical evidence of renal disease, although there may be minimal proteinuria and microscopic hematuria. In focal segmental proliferative glomerulitis, there may be proteinuria and mild hematuria, but renal insufficiency is either absent or minimal, and the nephrotic syndrome is distinctly uncommon. Children with diffuse proliferative glomerulonephritis have proteinuria and hematuria in most cases, and, in 60%, nephrotic syndrome or renal insufficiency. Children with membranous lupus glomerulonephritis have persistent nephrotic
1_-
IlIi .. TABLE 16-23
• Figure 16-23 Membranous lupus nephritis.This patient was a 17-yearold white girl with nephrotic syndrome and congestive heart failure. She died of arrhythmia. libman-Sacks endocarditis was found at necropsy (see Rg. 18-27). There was uniform thickening of endothelial walls with a"glassy" refractivity on hematoxylin-eosin staining. Minimal hypercellularity was observed, and deposits of inflammatory cells were present in the tubular interstitial tissues.
Membr'\I1ous Lupus Glomerulonephntis
Persistent nephrotic syndrome Hypertension in 30% Remissions in 30% Eventual renal insufficiency in majority
C HAP T E R
syndrome, and one third have hypertension. Severe glomerular sclerosis represents an end-stage lesion in which the nephrotic syndrome, renal failure, and hypertension are common. In addition to histologic type, an estimate of the level of in:t1ammatory activity can be made on the basis of the renal biopsy by comparing the number of active lesions with those of chronic disease. 348 Active disease is characterized histologically by the presence of intracapillllry cellular proliferation; polymorphonuclear infiltrates; karyorrhexis; epithelial crescents; subendothelial fibrinoid change (wire loops); hyaline, fibrin, or platelet thrombi; interstitial inflammation; and necrotizing vasculitis. Chronicity is marked by segmental, global, mesangial, or vascular sclerosis, glomerular obsolescence, thickening of capillary basement membrane, fibrous adhesions or crescents, and tubulointerstitial scarring (Table 16-24).349
Inter$tltlal Nephritis Approximately half of the children with significant involvement of the glomerulus also have evidence of interstitial nephritis,350 and the severity of interstitial disease usually correlates with the severity of the glomerular changes. Rarely, severe interstitial nephritis is observed in the absence of glomerular abnormalities. Focal and diffuse infiltration with inflammatory cells, tubular necrosis, and interstitial fibrosis may be observed. Immunoglobulins and complement are deposited along the peritubular capillaries or the tubular basement membrane in a granular pattern. In some patients, tubular acidosis is present.351 Other patients have interstitial nephritis and isosthenuria as part of Sjogren's syndrome. Analgesic nephropathy as a cause of interstitial inflammation and tubular damage should always be considered in patients with these changes. The importance of renal tubular disease in determining outcome was evaluated by Daniel and colleagues. 352 The more severe the tubular lesion, the greater the likelihood of end-stage renal failure. Tubule cell expression of ICAM-I and CD40 also predicted progression of disease, even in the absence of limited tubular atrophy.
Necrotizing Angiitis Some children with lupus nephritiS may also demonstrate an lmmune complex arteriolitis in renal tissues that may be 'indistinguishable from other forms of necrotizing arteritis. Fibrinoid necrosis, thrombosis, and arteriolar
I,:
I( IABU 16-24 lupus
Assessment of Activity and Chronicity in Renal
~cators of ActIYe Disease
Indicators of Chronicity
C,Uular proliferation N~crosis, karyorrhexis Cellular crescents Wire loops, hyaline thrombi Leukocytic glomerular infiltration Interstitial infiltration
Glomerular sclerosis Interstitial fibrosis Fibrous crescents Tubular atrophy
16
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365
inflammation are usually present. This type of vasculitis may be associated clinically with fulminant renal failure and malignant hypertension or renal venous thromboses. The role of the renal biopsy in the evaluation of lupus nephritis is controversia1,353 It is seldom needed to make the diagnosis of SLE, but it is indicated in at least three circumstances: (1) in the child with nephrotiC syndrome in whom differentiation of diffuse proliferative from membranous glomerulonephritis is important; (2) in one in whom, despite high-dose glucocorticoids, renal function is deteriorating, or there is persistent hematuria or proteinuria or both, to determine whether the renal disease is likely to be responsive to cytotoxic agents (Le., if there is evidence of activity or chronicity); and (3) as a prerequisite to entry into clinical therapeutic trials. 353 Extensive glomerular abnormalities have been identified on biopsy of patients who have no clinical evidence of renal disease. 354-356 Diffuse nephritis without clinically apparent disease may not always portend as poor a prognosis as that for clinically obvious disease. 357- 359 Histologic abnormalities change over time in many patients,344 and sequential biopsy findings have provided some insight into the progression of the renal lesions. However, these studies must be interpreted with caution, because indications for biopsy and the influence of therapy undoubtedly affect the results.348.360 In general, however, sequential biopsies in children have demonstrated progression of mesangial or focal proliferative glomerulonephritis to diffuse proliferative glomerulonephritis in months to years.347.361.362 Occasionally, progression from diffuse proliferative to membranous disease or, less commonly, from focal proliferative to membranous disease has been documented. 363 .364 In some studies, improvement was noted in 15% to 20% of patients in whom the initial biopsy had shown diffuse proliferative or focal proliferative glomerulonephritis, but membranous disease tended to be worse on subsequent examination.
Skin The typical cutaneous lesion of acute SLE is liquefaction of the epidermal basilar layer with disruption of the dermal-epidermal junction, edema of the dermis, infiltration of T lymphocytes throughout the epidermis and around blood vessels, and fibrinoid degeneration of the connective tissues (Fig. 16-25). In more chronic lesions, there is epidermal atrophy, hyperkeratosis, follicular plugging, and proliferation of elastic tissues. IgG and C3 can be identified by fluorescence microscopy along the epidermal basement membranes in uninvolved and non-sunexposed skin as well as in lesional biopsy specimens (Fig. 16-26).365-367 This finding of the "lupus band" on dermal punch biopsy specimens is not pathognomonic for SLE but may be a useful diagnostic test in difficult cases.
Lungs The pulmonary histology in acute pulmonary involvement in SLE is nonspecific. A basilar interstitial pneumonitis may lead to atelectasis and basophilic mucinous
366
C HAP T E R
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fibrosis, especially in steroid-treated patients,247 The basic lesion of the endocardium consists of nodule formation along the atrial or ventricular surfaces of the valve leaflets, or on the endocardium of the chambers (Fig. 16-27). The Libman-Sacks lesion has been described as having three zones: an outer exudative zone of fibrin containing nuclear debris, including hematoxylin bodies; a middle zone of proliferating fibroblasts; and the inner zone characterized by neovascularization. 369 The mitral valve is most commonly involved.
CenkalNe"ousSydem
All layers of the heart may be involved by the pathologic processes of SLE. Pericarditis consists of focal or diffuse fibrinous depOSits or fibrosis. Pericardial fluid contains high numbers of leukocytes, almost all of which are neutrophils. 368 Myocarditis is typified by plasma cell and lymphocyte infiltration of the myocardium, sometimes with
There are no pathognomonic pathologic findings in CNS lupus, and anatomically identifiable lesions do not always account for the neurologic manifestations of the disease. 37o True vasculitis is rare; perivasculitis is more common and may lead to infarction, encephalomalacia, or other focal lesions (Figs. 16-28 and 16-29). Microinfarcts and nonspecific destructive and proliferative arteriolar and capillary lesions occur. 371 Thrombosis as part of the APLS may affect small arterioles or venules, although the direct evidence that this is responsible for many of the CNS lesions is unclear. In a study of the brains of patients with chorea (many of whom were children), infarcts, but not arteritis, were found in the basal ganglia. 212 Most patients with chorea and SLE have aPL. 372 Retinal cotton-wool spots (cytoid bodies) represent areas of inflammatory edema and degeneration of the ganglion cells arising from a periarteriolitis within the nerve fiber layer, presumably related to immune complex deposition. In an immunofluorescence microscopy study, immunoglobulin was demonstrated in the vascular layer of the capillaries of the choroid and around the basement membranes of the ciliary processes and bulbar conjunctivae. 373
• Rgare 16-26 Direct immunofluorescence photomicrograph showing granular deposits of immunoglobulin Galong the basement membrane zone ("lupus band") in a biopsy sample of nonaffected skin in a patient with systemic lupus erythematosus. (Courtesy of Dr. Richard Crawford.)
• figure 16-27 libman-Sacks endocarditis.This patient was a 17-year-old girl with an acute exacerbation of systemic lupus erythematosus who had cardiac and pulmonary failure.The heart was minimally enlarged. A loud systolic murmur and afaint diastolic murmur were present at the apex. Necropsy examination of the mitral valve leaflets showed many nonbacterial verrucae at the margins.
• Rgare 16-25 Skin biopsy of systemic lupus erythematosus rash (hematoxylin and eosin stain, magnification x 33) demonstrating follicular plugging, squamatization, and vacuolation of the basal keratinocytes; thickening of the basement membrane zone; and telangiectasia. There is a small dermal perivascular lymphocytic infiltrate. (Courtesy of Dr. Richard Crawford.)
edema of the alveoli with hyaline membrane formation. There is interstitial infiltration of lymphocytes and other inflammatory cells, alveolar hemorrhage, formation of hyaline membranes, and focal necrosis. Fibrinoid necrosis of arterioles and capillary thrombi may occur, and hematoxylin bodies may be seen.
Heart
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SYSTEMIC
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ERYTHEMATOSUS
367
The walls of the gastrointestinal tract are also sites of focal or diffuse vasculitis. Acute hemorrhage or infarction results from thrombosis of the mesenteric vessels. Mesenteric vasculitis is a rare but serious occurrence in the child with SLE. Hepatic biopsies in 33 adults with SLE and elevated liver enzymes demonstrated steatosis (12 patients), cirrhosis (4), chronic active hepatitis (3), chronic granulomatous hepatitis (3), centrilobular necrosis (3), chronic persistent hepatitis (2), and microabscess (2).374 More recent studies have reported the presence of multiple fibrin microthrombi, liver infarction, hepatic veno-occlusive disease, and Budd-Chiari syndrome (hepatic vein occlusion with cirrhosis and ascites) related to the presence of aPL,375 Hyperplasia of plasma cells, vasculitis, and the occurrence of hematoxylin bodies characterize lesions of the lymph nodes.
LABORATORY EXAMINATION
• fItI-e 16-28 Magnetic resonance image of the brain of a 12-year-old girl wlttl systemic lupus erythematosus who suffered widespread seizures due to central nervous system vasculitis. Pale areas of the deep cortex were observed on the initial study.
Laboratory investigations include indicators of inflammation, tests for the presence of autoantibodies (particularly those directed to nuclear antigens), tests that evaluate end-organ involvement, and tests that monitor the effects of therapy, including drug-related toxicity. A useful overall approach to use of the laboratory in diagnosis of SLE has recently been described. 376
Indicators of Inflammation
• ,.... 16-29 The abnormalities seen in Rgure 18-28 were no longer demonstrated on a second study 1 month later.
Most acute phase indices of inflammation are increased in children in proportion to the activity of the systemic disease. These include an increased erythrocyte sedimentation rate (ESR), polyclonal hypergammaglobulinemia, and increased serum levels of a2-globulins. 376 C-reactive protein (CRP), an important acute phase protein that is elevated in most inflammatory conditions, is often normal.376-379 However, it is increased in patients with SLE and systemic infection380 and in those with serositis377 or arthritis. 38 1.382 Serum ferritin levels are high in adult patients with active SLE and correlate with elevated anti-dsDNA and low complement. 383 In one study, factor VIII-related antigen (von Willebrand's factor) was elevated in approximately half of the children. 384 The discrepancies among the acute phase responses may reflect the intricate eytokine abnormalities in SLE and their influence on the synthesis of specific acute phase proteins. Patients with SLE have low levels of IL-l, the cytokine responsible for the induction of CRPj high ferritin levels may reflect the high IL-6 or TNF-a. levels seen in this disease. In some studies, however, correlations between eytokine levels and acute phase protein levels were inconsistent.385
Other Organs The synovitis in children with SLE is nonspecific and is usually mild in degree. Changes include proliferation of syrtovial lining cells and microvascular abnormalities, including vasculitis and inflammatory cell infiltration. The myopathy is not specific and includes necrotizing arteritis, mild interstitial myositis, and vacuolization of muscle fibers.
Hematologic Abnormalities Anemia Mild or moderate anemia occurs in approximately one half of children with SLE and is usually typical of chronic disease (normocytic, hypochromic), with decreased
368
I!'.
c
HAP T E R
16
SYSTEMIC
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ERYTHEMATOSUS
TABLE 16-25 Hematologic Abnormalities in Systemi( lupus Erythematosus
Abnormality Anemia (hematocrit 25% binding by Farr assay or above normal range for testing laboratory. >38'C. Exclude infectious cause. 6 mo Premature gonadal failure Diabetes (regardless of treatment) Malignancy (excluding dysplasia)
1 1
1
1 (score 2 if >1 site)
P2, pulmonic second sound; RV, right ventricular. Damage: (non-reversible change, not related to active inflammation) occuring since onset of SLE, ascertained by clinical assessment and present for 6 months unless othetwise stated. Repeat episodes must occur at least 6 months apart to score 2. From Gladman DO, Ginzler E, Goldsmith C, et al: The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus. ArthritLq Rheum 39: 363-369, 1996.
3
Pul"""''' Puhnonary hypertension (RV prfdominance or loud P2) Pulmonary fibrosis (physical and
16
1 1 1
able, not to mention often impossible. Except during periods of severe active disease, regular school attendance should be expected, and communication with and education of concerned teachers and physical education instructors helps ensure the child's optimal participation in school activities. The child should be encouraged to participate in compatible extracurricular activities as the disease permits.
~Iar
Angina or coronary artery bypass MY(lCardial infarction (M!) ever Cardiomyopathy (ventricular dysfunction) Valvular disease (murmur >3/6) Pericarditis for 6 mo or pericardiectomy
1 1 (score 2 if >1 MI) 1 1 1
PerIpheral VlllCUIar disease Cla~dication for 6 mo Minor tissue loss (pulp space) SigjJ:ificant tissue loss ever (loss of digit or limb) Venous thrombosis with swel1ing, ulcer, or stasis
1 1 1 (score 2 if >1 site) 1
Continued next column.
General Counseling, education, team approach Adequate rest, appropriate nutrition Use of sunscreen Immunizations, especial1y antipneumococcal vaccine Prompt management of infection
Nonsteroidal Anti-Inflammatory Drugs
Anticoagulation 1 (score 2 if >1 site) 1 1 1
M~I
Ml.1scle atrophy or weakness Deforming or erosive arthritis induding reducible deformities Osteoporosis with fracture or vertebral col1apse Avascular necrosis Osteomyelitis
TABLE 16-40 Approach to Malldgl'nll'nt 01 Systl'lllic lupus Erythematosus
For musculoskeletal signs and symptoms
~nal
Infarction or resection of bowel below duodenum, spleen, liver, or g"Ubladder ever for any cause Mesenteric insufficiency Chtonic peritonitis Stricture or upper gastrointestinal trllct surgery ever
I!.
1
If anticardiolipin antibodies are present in significant titers: Low-dose aspirin unless thrombosis has occurred Heparin, followed by warfarin if thrombosis has occurred
Hydroxychloroqulne For cutaneous disease and as an adjunct to glucocorticoids for systemic disease
Glucocortlcolds
1
Oral prednisone 1-2 mg/kg/day IV methylprednisolone initially, and at monthly intervals for maintenance therapy in severe disease
1 1 (score 2 if >1 site) 1
Immunosuppresslves Azathioprine 1-2 mg/kg/day (PO) Cyclophosphamide 1-2 mg/kg/day (PO), or 500-1000 mg/m'/mo (IV) in severe disease
376
C HAP T E R
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ERYTHEMATOSUS
Although there are no foods that have been demonstrated to be either helpful or detrimental to the patient with SLE, a well-balanced diet with appropriate caloric intake is important. Because of the probability of unwanted weight gain in the child with SLE who is being treated with glucocorticoids, early nutritional counseling should be provided. Avoidance of "junk food" and foods high in sodium helps minimize excessive weight gain. Education of patient, family, and teachers about the effects of treatment on body image assists the child and adolescent adapt to such changes. Hypertension must be carefully controlled. Certain general aspects of treatment are of primary importance. The dangers of exposure to excessive sunlight should be stressed. Sunscreens with sun protection factors (SPF) greater than 15 that protect against UVB light169 should be applied to all exposed skin whenever the child is outside, whether or not it is sunny. (Many experts recommend an SPF of at least 30.) Even exposure to fluorescent lights that emit DYB may be associated with symptoms. 434 A variety of suitable sunscreens is available; some have a water base and are most appropriate for use on the face, and others contain alcohol and may be used on other exposed skin. Some are water resistant, but reapplication after bathing or swimming is adVisable. The risk of infection is increased in SLE, and the sequelae of infection may be catastrophic. Functional asplenia328.329 makes the child with SLE extremely susceptible to severe, sometimes fatal pneumococcal sepsis. Prevention of infection by immunization is particularly important in these children, and the recommendations in this regard outlined in Chapter 8 should be followed. Other factors that predispose to infection include neutropenia and lymphopenia, immunosuppressive treatment, hypocomplementemia, and the nephrotiC syndrome. A high index of suspicion for infections facilitates prompt diagnosis and appropriate treatment. Antibiotics should not be used prophylactically and should not be given before appropriate cultures have been obtained. Fever, which may accompany active SLE, should always be considered first to be caused by infection, and cultures of blood, pharynx, and urine should be taken. Basilar pneumonitis should always be initially regarded as bacterial, and blood cultures as well as cultures and a Gram stain of sputum should be obtained. Acute CNS disease should also be regarded initially as an effect of infection, and cerebrospinal fluid examinations should be performed. Exposure to varicella in the immunosuppressed child requires administration of zoster immune globulin within the first 96 hours after exposure. Varicella should be treated with acyclovir in the immunosuppressed child or adolescent. Laboratory markers of infection may be somewhat blunted by the primary disease. In a child with SLE, elevation of a previously low white blood cell count into the normal range may represent the maximal response to infection. Marked elevations of serum levels of CRP are strongly suggestive of infection in a patient with SLE. The many complications of tuberculosis should be considered in the differential diagnosis.
CNS infection with organisms such as Cryptococcus may occur.
General Aspects of Pharmacologic Therapy SpeCific treatment should be individualized and based on the extent and severity of the disease (see Table 16-40). Pharmacologic management of SLE in children was recently reviewed by Carreno and associates. 435
Nonsteroidal Anti-inflammatory Drugs The primary role of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of pediatric SLE is to treat musculoskeletal complaints.436 Myalgia, arthralgia, or arthritis may respond well to anti-inflammatory doses. Low-dose aspirin is indicated in the child with significant titers of aPL. Occasional reports have linked the use of ibuprofen436-438 or naproxen438 to the occurrence of aseptic meningitis or other hypersensitivity reactions in patients with SLE. There are no studies of the use of selective cyclooxygenase-2 inhibitors in SLE.
Hydroxychloroquine Hydroxychloroquine is most often given as an adjunct to therapy with glucocorticoids, rather than as the mainstay of treatment. 439 The role of this medication has been changing since the studies of the Canadian Hydroxychloroquine Study Group 440.441 reported that this drug made an important contribution to control of the disease. In a randomized, double-blind, placebocontrolled study of the effect of withdrawing hydroxychloroquine therapy in adults with clinically stable SLE, the frequency and severity of flares of SLE activity were much higher in patients who received the placebo than in those maintained on hydroxychloroquine. In addition, hydroxychloroquine may also have a role in reversing glucocorticoid-induced changes in plasma lipids. 442--444 For these reasons, it is the authors' practice to treat children and adolescents with hydroxychloroquine (up to 6 mg/kg/day) at the initiation of steroid therapy and for up to 2 years or longer. 445 Because of the possibility that the risk of retinal toxicity from antimalarials may be increased in the presence of impaired renal function, children with SLE should be carefully monitored for retinal toxicity related to the drug (see Chapter 5). Children with SLE may be more prone than those with ]IA to develop retinal damage.
Glucocorticoids Without doubt, glucocorticoids constitute the mainstay of pharmacologic therapy, and almost all children with SLE require oral prednisone or prednisolone or intravenous methylprednisolone at some stage of the disease. These agents have wide application in the treatment of many of the manifestations of SLE. 446 The choice between prednisone and prednisolone is one of personal experience and preference; prednisone is most frequently used in North America, and prednisolone is
C HAP T E R
often favored in Europe. High-dose intravenous methylprednisolone (30 mg/kg/day to a maximum of 1 g/day on 1 to 3 consecutive days) is often indicated in children with severe acute disease such as acute hemolytic anemia, CNS disease, or overwhelming systemic disease ("lupus crisis"), or as part of the long-term management of l\lPUS nephritis.
16
I! II
SYSTEMIC
Lupus
TABL E 16-42
Approa(h to Therapy for Lupus Nephritis'
II
'--
IABLE 16-41 GllI(ocorti(oid Therapy for Children with Systeuu( Lupus Erythematosus
In'1tallon of Thet'lllpy (lint 4-6 wk)
Orj1I prednisone
IV methylprednisolone
1'Hi0 mg/day (0.5-2 mg/kg/day) in at least two divided doses (depending on severity and type of organ involvement) Indicated for severe disease (active lupus nephritis, hematologic crisis, CNS disease)30 mg/kg/day on 1 to 5 consecutive days
hperlng the Prednisone Dose If the dose is 20-60 mg/day If the dose is 10-20 mg/day If nhe dose is ,244
ANIMAL MODELS OF NEONATAL LUPUS ERYTHEMATOSUS The major targets of NLE are the heart, skin, and liver. To better determine the pathogenesis of NLE, in vivo and in vitro models have been established. The in vivo models have used the infusion of human autoantibody containing sera or have generated autoantibodies by immunization of mice to generate autoantibodies. The in vitro models have used isolated cardiac myocytes or whole organ culture.
In Vitro Experiments Culture of isolated neonatal, but not adult, rabbit cardiac myocytes with sera from anti-Ro or anti-La antibodypositive women led to changes in the repolarization of these cells. 245 ,246 Binding of the maternal sera to rabbit tissue was likely the result of the presence of RoRNP antigen on the surface of fetal hearts. 247 ,248 However, unlike that which occurs with keratinocytes, the cellular localization of 48-kD La, 52-kD Ro, or 60-kD Ro in fetal cardiac myocytes is not altered by culture in the presence of 17~-estradiol or progesterone (discussed later). 249
Calcium channels are important in maintaining cardiac rhythm, and antibodies against these ions therefore are important in CAVB. Experiments using cultured human fetal cardiomyocytes have demonstrated that anti-Ro antibodies (particularly anti-52-kD Ro antibodies) alter calcium L-type and T-type channels. 250 ,251 Affinity-purified antibodies, which recognize both 52-kD Ro forms, also recognize the human 5-HT4 receptor and antagonized the serotonin-induced L-type calcium channel activation on isolated human atrial cells. 252 However, a study using sera from the Research Registry for Neonatal Lupus failed to show an association of anti-5HT4 receptor antibodies and the development of CAVB.253 Autoantibodies from mothers of children CAVB have been shown to bind to and modify the response of muscarinic acetylcholine receptor activation of neonatal but not adult rat atria. 254-256 Taken together, it appears that antibodies directed against calcium channels and receptors important in generation of cardiac rhythm, which are present on cardiomyocytes, may playa role in the pathogenesis of CAVB.
Skin Irradiation of keratinocytes enhances the expression of Ro, U1RNP, and Sm antigens.257-259 Estradiol treatment of keratinocytes can induce a marked increase in mRNA and expression of Ro, U1RNP, and Sm autoantigens. 248,257,258,260 Other factors, including TNF-a and exposure to viruses, upregulate the surface expression of 52-kD Ro and La on keratinocytes. 261 The direct binding of antiRoRNP antibodies to skin has been demonstrated. 248 ,262 The difference in disease expression in offspring born to the same mother may be at least partially explained by the demonstration that sera from children with C-NLE can be cytotoxic to keratinocytes from patients with NLE but not to cells obtained from normal individuals. This cytotoxicity was enhanced by ultraviolet B irradiation. These data suggest that keratinocytes from children with C-NLE may have abnormal surface expression of the Ro and La antigens and that ultraviolet irradiation can further increase that expression. 263 These results are consistent with the demonstration that the rash of C-NLE may be present at birth or later and that it does not occur in all infants born to mothers with autoantibodies directed against RoRNP.
Langendorff Experiments Initial ex vivo experiments examined the effect of antiRo- and anti-La-containing sera on conduction in isolated rabbit hearts. The perfusion of isolated Langendorff preparations of adult rabbit hearts with purified IgG from sera containing anti-Ro and anti-La antibodies induced heart block and altered the peak slow inward current.264 However, sera from women with SLE or Sjogren's syndrome without a history of delivering a child with NLE also resulted in heart block in the isolated, whole rabbit heart, although the heart block occurred only with perfusion with affinity-purified anti-52-kD antibodies. 265 These observations are not unique to anti-Ro antibody-containing sera, because similar alterations of cardiac conduction have been observed with sera from
C HAP T E R
patients with conduction defects associated with Chagas' disease. 266 Perfusion of Langendorff preparations of human fetal hearts with affinity-purified anti-52-kD Ro derived from mothers of children with CAVB also resulted in the development of complete AV block. At a wholecell and single-channel level, perfusion experiments with the human heart demonstrated an inhibition of L-type calcium currents. 267 Similarly, when isolated rat hearts were used, a 2: 1 AV block followed by complete inhibition of AV nodal action potential was demonstrated, and calcium channels were inhibited in isoll.lted cellular preparations. 268 These results suggested that rodents may be an appropriate species for monitoring the fetal effects of maternal anti-Ro and anti-La antibodies.
In VIvo Experiments Immunization of female BALB/c mice with recombinant RoRNP proteins generates high-titer antibodies that cross the placenta during pregnancy and are associated with various degrees of AV conduction abnormalities in the pUpS.267 However, conduction abnormalities were seen in only a low percentage of the offspring born to these mice, and advanced conduction abnormalities rarely developed. 269 Apoptosis has been proposed as a mechanism for the tissue damage. 270- m In human fetal cardiac myocytes, apoptosis results in surface translocation of RoRNP.273 In vivo murine experiments have supported this hypothesis because the passive transfer of human IgG containing anti-52-kD Ro, anti-60-kD Ro, and anti-La autoantibodies led to the formation of human IgG-apoptotic cell complexes in organs targeted in NLE (Le., heart, skin, liver, and bone) but not in thymus, lung, brain, or gut. Experiments with affinity-purified antibodies demonstrated that anti-La, but not anti-Ro, antibodies formed these complexes.274 It is possible that apoptosis, a normal event during cardiac development, may result in the binding of maternal anti-RoRNP to the apoptotic cells that cause an inflammatory reaction. The neighboring cells may be damaged as bystanders. Initial binding may be by maternalanti-52-kD Ro antibodies or antibodies to isoforms of the La protein, which are maximally expressed early in gestation, with levels decreasing with gestational age until 25 weeks, when adult levels are achieved. 33,40 This hYIJothesis allows for the selective damage to fetal but not to maternal conducting tissue.
REFERENCES 1. Smeenk RJ: Immunological aspects of congenital atrioventricular block. Pacing Clin Electrophysiol 20: 2093-2097, 1977. 2. Zhu J: Cytomegalovirus infection induces expression of 60 kD/Ro antigen on human keratinocytes. Lupus 4: 396-406. 1995. 3. Wolin S, Stietz]: The Ro small cytoplasmic ribonucleoproteins: identification of the antigenic protein and its binding site on the Ro RNAs. Proc Nat! Acad Sci USA 81: 1996--2000, 1984. 4. Lerner MB, Boyle ]A, Hardin JA, Steitz JA: Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus. Science 21 L 400-402. 1981.
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401
5. Ben-Chetrit E, Chan EKL, Sullivan KF, Tan EM: A 52-kD protein is a novel component of the SS-AlRo antigenic particle. J Exp Med 167: 1560-1571, 1988. 6. Harmon CE, Deng J-5. Peebles CL, Tan EM: The importance of tissue substrate in the SS-AlRo antigen-antibody system. Arthritis Rheum 27: 166-173, 1984. 7. Hendrick JP, Wolin SL, Rinke J, et al: Ro small cytoplasmic ribonucleoproteins are a subclass of La ribonucleoproteins: further characterization of the Ro and La small ribonucleoproteins from uninfected mammalian cells. Mol Cell Bioi I: 1138-1149, 1981. 8. Rosa MD, Gottlieb E, Lerner MR, Steitz ]A: Striking similarities are exhibited by two small Epstein-Barr virus-encoded ribonucleic acids and the adenovirus-associated ribonucleic acids VAl and VAIl. Mol Cell Bioi 1: 785-796, 1981. 9. Rinke J, Steitz JA: Precursor molecules of both human 5S ribosomal RNA and transfer RNAs are bound by a cellular protein reactive with anti-La lupus antibodies. Cell 29: 149-159, 1982. 10. 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Gordon PA, Rosenthal E, Khamashta MA, Hughes GR: Absence of conduction defects in the electrocardiograms [correction of echocardiogramsJ of mothers with children with congenital compiete heart block. J Rheumatol 28: 366--369, 2001. 157. Carpenter RJ Jr, Strasburger JF, Garson A Jr, et al: Fetal ventricular pacing for hydrops secondary to complete atrioventricular block. J Am Call Cardiol 8: 1434-1436, 1986. 158. Walkinshaw SA, Welch CR, McCormack J, Walsh K: In utero pacing for fetal congenital heart block. Fetal Diagn Ther 9: 183-185, 1994. 159. Groves AM, Allan LD, Rosenthal E: Therapeutic trial of sympathomimetics in three cases of complete heart block in the fetus. Circulation 92: 3394-3396, 1995. 160. Yoshida H, Iwamoto M, Sakakibara H, et al: Treatment of fetal congenital complete heart block with maternal administration of beta-sympathomimetics (terbutaline): a case report. Gynecol Obstet Invest 52: 142-144, 2001. 161. Minassian VA, Jazayeri A: Favorable outcome in a pregnancy with complete fetal heart block and severe bradycardia. Obstet Gynecol 100: 1087-1089, 2002. 162. Matsushita H, Higashino M, Sekizuka N, et al: Successful prenatal treatment of congenital heart block with ritodrine administered transplacentally. Arch Gynecol Obstet 267:51-53, 2002. 163. Kiuttu J, Hartikainen AL, Makitalo R, Ruuska P: Congenital heart block with hydrops fetalis treated with high-dose dexamethasone: a case report. Eur J Ohstet Gynecol Reprod Bioi 42: 155-158, 1991. 164. Deloof E, Devlieger H, Van Hoestenberghe R, et al: Management with a staged approach of the premature hydropic fetus due to complete congenital heart block. Eur J Pediatr 156: 521-523, 1997. 165. Copel JA, Buyon JP, Kleinman CS: Successful in utero therapy of fetal heart block. Am J Obstet Gynecol 173: 1384-1390, 1995. 166. Bierman FZ, Baxi L, Jaffe I, Driscoll J: Fetal hydrops and congenital complete heart block: response to maternal steroid. J Pediatr 1988: 646-648, 1988. 167. Buyon JP, Swersky SH, Fox HE, et al: Intrauterine therapy for presumptive fetal myocarditis with acquired heart block due to systemic lupus erythematosus: experience in a mother with a predominance of SS-BiLa) antibodies. Arthritis Rheum 30: 44-49, 1987. 168. Buyon J, Roubey R, Swersky S, et al: Complete congenital heart block: risk of occurrence and therapeutic approach to prevention. J Rheumatol 15: 1104-1108, 1988. 169. Kaaja R, Julkunen H, Ammala P, et al: Congenital heart block: successful prophylactic treatment with intravenous gamma globulin and corticosteroid therapy. Am J Obstet Gynecol 165: 1333-1334, 1991. 170. Wong JP, Kwek KY, Tan JY, Yeo GS: Fetal congenital complete heart block: prophylaXis with intravenous gammaglobuJin and treatment with dexamethasone. Aust N Z J Obstet Gynaecol 41: 339-341, 2001. 171. Eronen M, Siren MK, Ekblad H. et al: Short- and long-term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 106: 86--89, 2000. 172. Balmer C, Fasnacht M, Rahn M, et al: Long-term follow up of children with congenital complete atrioventricular block and the impact of pacemaker therapy. Europace 4:345-349, 2002. 173. Jaeggi ET, Hamilton RM, Silverman ED, et al: Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block. A single institution's experience of 30 years. J Am Coil Cardiol 39: 130-137, 2002. 174. Ercmen M, Heikkila P, Teramo K: Congenital complete heart block in the fetus: hemodynamic features, antenatal treatment, and outcome in six cases. Pediatr Cardiol 22: 385-392, 2001. 175. Moak JP, Barron KS, Hougen TJ, et al: Congenital heart block: deveiopment of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coil Cardiol 37: 238-242, 2001.
176. Michaelsson M, Riesenfeld T, Jonzon A: Natural history of congenital complete atrioventricular block. Pacing Clin Electrophysiol 20: 2098-2101. 1997. 177. Michaelsson M, Jonzon A, Riesenfeld T: Isolated congenital complete atrioventricular block in adult life: a prospective study. Circulation 92: 442-449, 1995. 178. Friedman RA: Congenital AV block. Pace me now or pace me later? Circulation 92: 283-285, 1995. 179. McCuistion CH, Schoch EP: Possible discoid lupus erythematosus in a newborn infant. Arch Dermatol 70: 782-785, 1954. 180. Franco HL, Weston WL, Peebles C, et al: Autoantibodies directed against sicca syndrome antigens in the neonatal lupus syndrome. J Am Acad Dermatol 4: 67-72, 1981. 181. Cimaz R, Spence DL, Hornberger L, Silverman ED: Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr 142: 678-683, 2003. 182. Weston WL, Morelli JG, Lee LA: The clinical spectnun of anti-Ro-positive cutaneous neonatal lupus erythematosus. J Am Acad Dermatol 40: 675-681. 1999. 183. Ng PP, Tay YK, Giam YC: Neonatal lupus erythematosus: our local expelience. Ann Acad Med Singapore 29: 114-118, 2000. 184. Deng J-S, Sontheimer RD, Gilliam ]N: Relationships berween antinuclear antibodies and anti-Ro/SSA antibodies in subacute cutaneous lupus erythematosus. JAm Acad Dermatol 11: 494-499, 1984. 185. Vazquez-Botet M, Rodriguez R, Sanchez JL: Neonatal lupus erythematosus. P R Health Sci J 16: 162-166, 1997. 186. Neiman AR, Lee LA, Weston WL, Buyon JP: Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry. J Pediatr 137: 674-68, 2000. 187. Scheker LE, Kasteler JS, Callen JP: Neonatal lupus erythematosus mimicking Langerhans cell histiocytosis. Pediatr Dermatol 20: 164-166, 2003. 187. Miyagawa S, Kitamura W, YoshiokaJ, Sakamoto K: Placental transfer of anticytoplasmic antibodies in annular erythema of newborns. Arch Dermatol 117: 569-572, 1981. 188. Thornton CM, Eichenfield LF, Shinall EA, et al: Cutaneous telangiectases in neonatal lupus erythematosus. J Am Acad Dermatol 33: 19-25, 1995. 189. High WA, Costner MI: Persistent scarring, atrophy, and dyspigmentation in a preteen girl with neonatal lupus erythematosus. J Am Acad Dermatol 2003; 48: 626-628, 2003. 190. Lee LA: Neonatal lupus erythematosus. J Invest Dermatol 100: 95-13S, 1993. 191. Bielsa I, Herrero C, Collado A, et aJ: Histopathologic findings in cutaneous lupus erythematosus. Arch Dermatol 130: 54-58, 1994. 192, Solomon BA, Laude TA, ShaJita AR: Neonatal lupus erythematosus: discordant disease expression of UlRNP-positive antibodies in fraternal twins-is this a subset of neonatal lupus erythematosus or a new distinct syndrome' JAm Acad Dermatol 32: 858-862, 1995. 193. Dugan EM, Tunnessen WW, Honig PJ, Watson RM: U1RNP antibody-positive neonatal lupus. A report of rwo cases with immunogenetic studies. Arch Dermatol 128: 1490-1494, 1992. 194. Provost TT, Watson R, Gammon WR, et al: The neonatal lupus syndrome associated with UlRNP (nRNP) antibodies. N Engl J Med 316: 1135-1138, 1987. 195. Sheth AP, Esterly NB, Ratoosh SL, et al; U1RNP positive neonatal lupus erythematosus: association with anti-La antibodies? Br J Dermatol 132: 520-526. 1995. 196. Bouderlique C, Debillon T, Mesnard B, et al: Neonatal lupus presenting as telangiectatic and atrophic lesions. Pediatrie 45: 251-254, 1990. 197. Carrascosa JM, Ribera M, Bielsa I, et al: Cutis marmorata telangiectatica congenita or neonatal lupus? Pediatr Dermatol 13: 230-232, 1996. 198. Giam YC: Cutaneous neonatal lupus erythematosus in Chinese neonates. J Singapore Paediatr Soc 34: 39-43, 1992. 199. Kettler AH, Stone MS, Bruce S, TschenJA: Annular eruptions of infancy and neonatal lupus erythematosus. Arch Dermatol 123: 298-299, 1987. 200. Lee LA, Weston WL: Cutaneous lupus erythematosus during the neonatal and childhood periods. Lupus 6: 132-138, 1997. 201. Puig L, Moreno A, Alomar A, de Moragas JM: Erythema gyratum atrophicans transiens neonatale: a variant of cutaneous neonatal lupus erythematosus. Pediatr Dermatol 5: 112-116, 1988. 202. Vaughn RY, GuiJI MA, Cook J: Atrophic plaques in a neonate. Neonatal lupus erythematosus iNLE). Arch Dermatol 128: 683, 686, 1992. 203. Laxer RM, Roberts EA, Gross KR, et al: Liver disease in neonatal lupus erythematosus. J Pediatr 116: 238-242, 1990. 204. Lee LA, Reichlin M, Ruyle SZ, Weston WL: Neonatal lupus liver disease. Lupus 2: 333-338, 1993. 205. Lee LA, Sokol RJ, Buyon JP: Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry. Pediatrics 109: Ell, 2002. 206. Schoenlebe J, Buyon JP, Zitelli BJ, et al: Neonatal hemochromatosis associated with maternal autoantibodies against Ro/SS-A and La/SS-B ribonucleoproteins. Am J Dis Child 147: 1072-1075, 1993. 207. RoshJR, Silverman ED, Groisman G, et al: Intrahepatic cholestasis in neonatal lupus erythematosus. J Pediatr Gastroenterol Nutr 17: 310-312, 1993. 208. Fonseca E. Contreras F, Garcia-Frias E, Carrascosa MC: Neonatal lupus erythematosus with multisystem organ involvement preceding cutaneous lesions. Lupus 1: 49-50, 1991.
C HAP T E R 209, Watson R, Kang IE, May M, et al: Thrombocytopenia in the neonatal lupus ~yndrome, Arch Dermatol 124: 560-563, 1988. 210, Kleinman D, Katz VL, Kuller JA: Perinatal outcomes in women with systemic lupus erythemalOsus, I Perinatol 18: 178-182, 1998. 211, Lockshin MD, Bonfa E, Elkon K, Druzin ML: Neonatal lupus risk to newborns of mothers with systemic lupus erythemalOsus, Arthritis Rheum 31: (,97-701, 1988, 212, Kurata Y, Miyagawa S, Kosugi S, et al: High-liter antinuclear antibodies, antiSSAIRo antibodies and anti-nuclear RNP antibodies in patients with idiopathic thrombocytopenic purpura, Thromb Haemost 71: 184-187, 1994, 213, Alexander EL, Arnett FC, Provost TT, Stevens MB: Sjogren's syndrome: assodation of anti-Ro(SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyperreactivity, Ann Intern Med 98: 155-159, 1983, 214, Watson RM, Braunstein BL, Watson AI, et al: Fetal wastage in women with 3nti-Ro (SSA) antibody, I Rheumatol 13: 90-94, 1986. 215. K)lnagasegar S, Cimaz R, Kurien BT, et al: Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions. I Rheumatol 29: 187-191, 2002. 216. Wolach B. Choc L, Pomeranz A, et al: Aplastic anemia in neonatal lupus erythematosus, Am I Dis Child 147: 941-944, 1993, 217. Selander B, Cedergren S, Domanski H: A case of severe neonatal lupus erythematosus without cardiac or cutaneous involvement. Acta Paediatr 87: 10S-107, 1998, 218, Fonseca E. Contreras F, Garcia-Frias E, Carrascosa MC: Neonatal lupus erythematosus with multisystem organ involvement preceding cutaneous lesions. Lupus 1: 49--50, 1991. 219. Kaye EM. Butler IJ, Conley S: Myelopathy in neonatal and infantile lupus erythematosus, I Neurol Neurosurg Psychiatry 50: 923-926, 1987. 220. Wang HS, Kuo MF, Chang TC: Sonographic lenticulostriate vasculopathy in infants: some associations and a hypothesis, AINR Am I Neuroradiol 16: 97-102, 1995. 221. Cabanas F, Pellicer A, Valverde E, et al: Central nervous system vasculopathy in neonatal lupus erythematosus, Pediatr Neurol 15: 124-126, 1996, 222, Nakayama FF, Takigawa M, Iwatsuki K, et al: Hydrocephalus in two female siblings with neonatal lupus erythemalOsus, Arch Dermatol 130: 1210-1212, 1994. 223. IUder LG, Sherry DD, Glass ST: Neonatal lupus erythematosus simulating transient myasthenia gravis at presentation. I Pediatr 118: 417-419, 1991. 224. Inoue K, Fukushige I, Ohno T, et al: Central nervous system vasculopathy associated with neonatal lupus. Pediatr Neurol 26: 68-70, 2002, 225. l'rendiville IS, Cabral DA, Poskitt KI, et al: Central nervous system involvement in neonatal lupus erythematosus, Pediatr Dermatol 20: 60-67, 2003. 226. "lcioglu N, Hall CM: Maternal systemic lupus erythematosus and chondrodysplasia punctata in two sibs: phenocopy or coincidence? I Med Genet .~5: 690-694, 1998. 227. Austin-Ward E, Castillo S, Cuchacovich M, et al: Neonatal lupus syndrome: a case with chondrodysplasia punctata and other unusual manifestations. I Med Genet 35: 695-697, 1998. 228, Westenend PJ: Congenital nephrotic syndrome in neonatal lupus syndrome. I Pediatr 126: 851, 1995. 229. Ruas E, Moreno A, Tellechea 0, et al: Neonatal lupus erythematosus in an infant with Turner syndrome. Pediatr Dermatol 13: 298-302, 1996. 230. Jackson R, Gulliver M: Neonatal lupus erythematosus progressing into systemic lupus erythematosus. Br I Dermatol 101: 81-86, 1979. 231. Fox RI, McCuistion CH, Schoch EP: Systemic lupus erythematosus association with previous neonatal lupus erythemalOsus. Arch Dermatol 115: 340, )979. 232. Martin V, Lee LA, !\skanase AD, et al: Long-term followup of children with neonatal lupus and their unaffected siblings, Arthritis Rheum 46: 2377-2383, 2002. 233. Reichlin M, Friday K, Harley IB: Complete congenital heart block followed by anti-Ro/SSA in adult life. Am I Med 84: 339--344, 1988. 234. McCue CM, Manatakas ME, Tingelstad IB, Ruddy S: Congenital heart block in newborns of mothers with connective tissue disease. Circulation 56: !l2-90, 1977. 235. Waterworth RF: Systemic lupus erythematosus occurring with congenital romplete heart blork. N Z Med I 92: 311-312, 1980. 236. Esscher E, Scott IS: Congenital heart block and maternal systemic lupus erythematosus. Br Med I 1: 1235-1238, 1979. 237. lanham IG, Walport MI, Hughes GR: Congenital heart block and familial connective tissue disease. I Rheumatol 10: 823-825, 1983. 238, Hrucato A, Franceschini F, Gasparini M, et al: Isolated congenital complete ileart block: long-term outcome of mothers, maternal antibody specificity tlhd immunogenetic background, I Rheumatol 22: 533-540, 1995. 239. Julkunen H, Eronen M: Long-term outcome of mothers of children with isolated heart block in Finiand. Arthritis Rheum 44: 647- 90%) • Cervical lymphadenopathy with at least one node > 1.5 cm (50%) 'Numbers in parentheses indicate the approximate percentage of children with Kawasaki disease who demonstrate the criterion, 'Moditled from Centers for Disease Control: Revised diagnostic criteria for Kawasaki disease, MMWR Morb Mortal WkJy Rep 39: 27-28. 1990.
disease in 1967. 16 Among japanese children younger than 5 years, the attack rate is 90 cases per 100,000 children per year. 17 Children of japanese descent who reside outside japan also face a higher risk of KD than do white children. 18 African Americans are at intermediate risk,ll In one large area of Great Britain, the annual incidence rate was 5.5 cases per 100,000 for children younger than 5 years old; the incidence for children of Asian ancestry was more than double that for white and African American children. 19 In japan, KD is more common in boys than in girls (male/female ratio of 1.36: 1). Among boys, the highest incidence occurs between the ages of 9 and 11 months (227.3 cases per 100,000 children), and among girls, the highest incidence occurs between the ages of 3 and 8 months 033.9 cases per 100,000 children).2o In North America, the peak age at onset of KD is somewhat older, and children in the 2- to 3-year-old age group are most commonly affected. In an Australian study, only 20% of children were younger than 1 year at diagnosis, and 25% were older than 5 years. The reasons for the geographic differences in age at onset are unclear. 21 Several reports document a seasonal incidence of KD,21 and in North America, cases have tended to occur between November and May.22 Clustering of cases in time and geographic area further suggests an unrecognized vector. Although distinct epidemics of KD were documented in japan up to 1987, none has occurred since that time. 23 In japan, siblings of affected children have a risk of contracting KD that is approximately 10 times higher than the risk in the general population,24 but cases among children sharing the same home in other countries are uncommon. 2S The 3% recurrence rate l6 and increased incidence of KD occurring simultaneously in twins also support the theory that an infectious agent causes KD.
ETIOLOGY AND PATHOGENESIS The cause of KD remains unknown. 26 Many of its epidemiologic and clinical manifestations suggest an infectious origin. The fever, exanthem, lymphadenopathy,
conjunctivitis, and lesions of the oral mucosa are reminiscent of a bacterial or viral illness, and bear a partiClIlarly close resemblance to scarlet fever. If an infectious agent causes KD, it is of very low communicability, or almost all cases of infection are subclinical. Repeated attempts to identify a particular infectious trigger have been unsuccessfu1. 27 Consequently, researchers have also evaluated the possibility that vasculitis in KD is caused by antigens that trigger an immune response to endothelial cells, rather than by direct infection of the vessels. Whether such a trigger may be a conventional antigen or a so-called superantigen is debated. 28 Superantigens are produced by several bacteria, notably certain strains of Staphylococcus and Streptococcus, and they are capable of stimulating large numbers of T cells in an antigennonspecific manner by interaction with the Bchain of the T cell receptor. An indicator of the effect of superantigens is skewing of the T cell receptor V~ repertoire. Overrepresentation of T cells bearing V~2 among lymphocytes in coronary artery aneurysms and intestinal mucosa from patients with KD supports the hypothesized role of superantigens in the pathogenesis. 29.3o Brogan and colleagues31 have demonstrated that major histocompatibility complex (MHC) class II-positive endothelial cells are capable of activating CD4+ and CD8+ T cells in the presence of superantigens. A protective effect of maternal antibodies to superantigens has been suggested,32 In a murine model of KD, Duong and associates 33 demonstrated the superantigenic activity of Lactobacillus casei cell wall extracts. Mycobacterial antigens also may function as superantigens, and children with KD have unique reactions to these organisms. Inflammatory changes occur at the site of a previous bacillus Calmette-Guerin (BCG) immunization,34 as do temporarily positive responses to mycobacterial antigens in vivo and in vitro during the acute phase of the disease. 3s Lymphocytes from convalescent patients react with the 65-kD heat-shock protein from mycobacteria. 36 Whether these responses represent a specific response to mycobacterial antigens or cross-reactivity with other antigens is not clear. A predominance of immunoglobulin A (IgA)-secreting plasma cells in the blood vessel walls of children with fatal KD suggests that an organism that gained entry through mucosal surfaces underlies the disease. v No single pathogen is regularly demonstrable, although associations with Epstein-Barr virus,38 rotavirus,39 and other viruses 40-42 and with bacteria43,44 have been reported. This suggests the possibility that the vascular injury in KD may be the result of direct cell-mediated attack of endothelial cells that are infected with an unidentified infectious agent,4S Additional clues to the cause of KD come from the humoral factors, including anti-endothelial cell antibodies, circulating immune complexes,18 and antineutrophil c:ytoplasm antibodies (ANCAs) that are demonstrated in a large proportion of patients. 46 Whed1er these are involved in pathogenesis or are epiphenomena is not known. High levels of serum IgE in children with infantile polyarteritis nodosa and KD have been interpreted as evidence of immune dysregulation in this disorder. 47 Levels of a wide variety of cytokines, including serum tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6),48 and growth
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factors, such as vascular endothelial growth factor,49 are elevated, generally in proportion to the severity of the illness. As with many other vasculitides, a reasonable working hypothesis is that KD is a stereotyped, pathologic immune response to one or a variety of environmental or infectious triggers, to which certain individuals are predisposed by virtue of their genetic constitution. The predilection for childhood onset may reflect the presence of developmental antigens that are targets for the inflammatory response only early in life, subtle maturational defects in immune responsiveness,5o or the timing of exposure to environmental triggers.
GENmC BACKGROUND Studies from Japan indicate that approximately 1% of patients with KD have a family history of an affected sibling,5l and concordance for KD was 13.3% in dizygotic twins and 14.1 % in monozygotic twins. 52 There is a significantly increased frequency of the history of KD in the parents of children with the disease. 53 These observations indicate that there is a genetic predisposition to this disease, although the fact that affected twin pairs became ill within 2 weeks of each other also suggests an important role for an environmental agent. 52 The exact genetic factors that may underlie the disorder are not known. Candidate genes include those at the histocompatibility locus and those for TNF and other proteins involved in immunoregulation (e.g., polymorphism of an immune response gene, SLC11Al). Human leukocyte antigen (HLA) genes for B5, B44, Bw51, DR3, and DRB3*0301 have been associated with KD in whites; B54, Bw15, and Bw35 in Japanese; and Bw51 in Israelis. S4 There has been no reported association of any HLA antigen with the risk of coronary artery disease. 5s Similarly ambiguous are studies of the TNF-a gene (7NF). In white children with KD, there was increased frequency of the lymphotoxin-a + 250 AIA allele and the TNF-a-308 A/G high secretor allele. This TNF-a polymorphism was particularly increased in children with coronary artery abnormalities. 56 These differences were not observed in Japanese or Korean children,57 however, and their pathogenic significance remains uncertain. Yet to be confirmed are reports of a polymorphism of the promoter of the CD14 gene (CD14)'8 and genotype II of the angiotensin I converting enzyme59 that have been associated with the development of coronary artery lesions in KD.
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a useful framework for considering the natural history of the disease. With current therapy, the three-phase pattern of disease is considerably altered, and the first two phases are markedly abbreviated. After IVIG administration, the acute phase usually persists no more than 1 or 2 days, followed by another 3 to 4 weeks of the subacute phase.
Acute Febrile Phase KD characteristically begins abruptly, often preceded by symptoms of an upper respiratory or gastrointestinal illness. The child becomes febrile and is usually very irritable. Over the next 3 to 4 days, cervical adenitis, conjunctivitis, changes in the lips and oral mucosa, a pleomorphic rash, and erythema and edema in the hands and feet develop (in no particular order). Untreated, these manifestations persist for an average of 12 days and then subside. If carditis occurs, it often does so early and may be manifested by tachycardia, an S3 gallop, and subtle or occasionally marked signs of congestive heart failure. Abdominal pain and hydrops of the gallbladder may occur at this time.
Subacute Phase After the acute phase, the child may be entirely asymptomatic if given IVIG. Untreated, the fever gradually resolves by the third or fourth week. Sites of earlier involvement, such as the tongue, begin to heal during this period, and the child develops a so-called glossy tongue. Desquamation of the skin of the digits and perineum (which may begin earlier) may be the only clinically apparent residual feature of the illness. Some children develop arthritis of one or several joints during the late acute and subacute phases. Coronary artery aneurysms most commonly first develop during the subacute phase, occasionally earlier, but rarely later in children treated with IVIG.
Convalescent Phase Most children are asymptomatic during the convalescent phase. The acute phase response has usually returned to normal, unless there are complications. Horizontal ridging of the nails, known as Beau's lines and characteristic of many acute inflammatory conditions, may appear during this period.
CLINICAL MANIFESTAnONS
Disease Course The disease course can be divided into three phases (Fig. 25-1): 1. Acute febrile period of approximately 10 to 14 days 2. Subacute phase of approximately 2 to 4 weeks, ending with a return to normal of the platelet count and erythrocyte sedimentation rate 3. Convalescent or recovery period lasting months or years, during which time vessels affected by the disease undergo healing, remodeling, and scarring
There are no precise markers of the transition from one phase to another, but this concept of progression provides
Clinical Charaderlstics of the Classification CrIteria The diagnosis of KD is complicated by the fact that the signs and symptoms of the condition are common, and each of them is nonspecific. Although there is often uncertainty in diagnosing KD, the characteristic clinical manifestations of the disease help distinguish KD from its mimics, and the occurrence of several of these criteria in the same patient at the same time helps secure the diagnosis.
Fever Fever, often up to 40"C or higher, is the most consistent manifestation of KD. The fever is typically persistent and
524
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25 K AWAS A KID I 5 E A 5 E • Figure Z5-1 Kawasaki disease can be viewed as an illness with acute, subacute, and recovery phases. the temporal characteristics outlined here are typical of the course of the disease. (Adapted from ref. 1)
Fever
Platelet Count Arthritis
CardioVascular Skin
Lips & Mucous Membrane Conjunctiva
Cervical Adenitis
Duration (weeks) minimally responsive to antipyretic agents, tending to remain above 38,5" C during most of the illness. It reflects elevated levels of pro-inflammatory cytokines, such as TNF-a and interleukin-l, which are also thought to mediate the underlying vascular inflammation. 60 The diagnosis of KD should be considered in all children with prolonged, unexplained fever, irritability, and laboratory signs of inflammation, especially in the presence of mucositis and rash. Conversely, the diagnosis must be suspect in the absence of fever, although the physician must be sure that elevated temperatures were not missed by anxious or inexperienced parents.
mimics of KD. Exceptionally, there may be a conjunctival exudate,62 conjunctival scarring,63 or changes in the retina and vitreous. 64
Changes in the Lips and Oral Mucosa Oral mucosal changes often become evident as the mucositis of KD evolves. Vertically cracked, red lips and a strawberry tongue are characteristic; the latter is caused by sloughing of filiform papillae and denuding of the inflamed glossal tissue (Fig. 25-2). Discrete oral lesions, such as vesicles or ulcers, and tonsillar exudate suggest a viral or bacterial infection rather than KD. 6
Conjunctivitis Bilateral, nonexudative bulbar conjunctivitis occurs in more than 85% of patients with KD. Conjunctival injection spares the limbus, the zone immediately around the iris. Inflammation of the palpebral conjunctiva is not prominent. Purulent discharge is especially unusual and suggests an alternative diagnosis. During the first week of illness, about three fourths of children are photophobic, an effect of anterior uveitis. 61 Slit-lamp examination may be helpful diagnostically in ambiguous situations; the presence of uveitis provides further evidence for the diagnosis because it is uncommon in
Exanthem The cutaneous manifestations of KD are protean. Although the rash usually begins on the trunk, there is often a perineal confluence during the first days of the illness, followed by desquamation in the diaper area by day 6 in most cases. Macular, morbilliform or targetoid lesions of the trunk and extremities are most characteristic. The rash is seldom pruritic, and vesicular or bullous lesions are rare. Psoriasis has been reported in several children with KD (Fig. 25-3).65 Pastia's lines, faint petechial lines in the skin folds of the antecubital fossae
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2S KAWAS A KID I SEA S E
525
• Rgure ZS-Z A, The intense reddening, swelling, and vertical cracking of the lips are characteristic of Kawasaki disease (KD). Anonspecific facial rash is also seen in this 2-year-old boy with acute KD. B, Notice the strawbeny tongue of acute KD with hypertrophied papillae on an erythematous base and the peeling of the facial skin.
and inguinal and axillary regions, suggest the alternate diagnosis of scarlet fever rather than KD.
Lymphadenopathy Anterior cervical lymphadenopathy occurs during the acute phase of the disease, is usually unilateral, and may appear to involve only a single node. However, ultrasound or computed tomographic imaging of the neck typically reveals grapelike clusters of enlarged nodes similar to those seen in Epstein-Barr virus infections rather than the isolated adenopathy typical of bacterial adenitis. 66 Occasionally, a node enlarges rapidly and may be mistaken for bacterial infection. After 3 or 4 days, it usually shrinks with or without specific therapy. Diffuse lymphadenopathy and splenomegaly are not typical of KD and should raise suspicions of a viral illness.
Extremity Changes Indurated edema of the dorsum of the hands and feet and a diffuse red-purple erythema of the palms and soles
• FIgure ZS-3 The polymorphous exanthem of Kawasaki disease is shown in this photograph taken during the acute phase of the disease. Its appearance is not diagnostic, and its character may evolve as the disease progresses, although it is rarely purpuric, vesicular or bullous.
occur early and last for 1 to 3 days. Sheetlike desquamation typically occurs 10 days or more after the start of the fever and begins at the tips of the fingers and, less commonly, the toes just below the distal edge of the nails (Fig. 25-4). Flaky desquamation may occur in the perineum or elsewhere. Because skin peeling occurs late, it is useful more for retrospective confirmation of the diagnosis than for making therapeutic decisions.
Atypical Kawasaki DIsease Children suspected of haVing KD who do not fulfill diagnostic criteria may have incomplete or atypical disease. Early reports have suggested a grim prognosis for children with atypical KD; one review cited a 41% mortality rate, although only children with coronary artery aneurysms were included in this series. 67 However, when clinical judgment of reliable observers is used to define atypical KD, signs, symptoms, and outcome parallel those of children who fulfill the diagnostic criteria. In a study of 242 patients hospitalized for KD in Japan during a 9-year period, 25 00%) ultimately failed to meet diagnostic criteria. 68 Three criteria were met in 17 (680/0) of the 25 patients, and 7 (28%) met two criteria. Only one patient ultimately developed transient dilatation of a coronary artery. A particularly high level of suspicion is needed in infants younger than 1 year old. In a retrospective review of 45 cases of KD, 5 (45%) of 11 infants had atypical disease, compared with 4 02%) of 33 older children.69 Unfortunately, infants are the group at the highest risk for developing coronary artery aneurysms, and in this study, coronary artery complications occurred in seven infants (64%), compared with three older children (9%), including all five infants with atypical disease. 69 Overall, among the 2221 children younger than 5 years who were analyzed in the 1995 to 1996 Japanese nationwide survey of KD, the odds ratio for development of cardiac sequelae in infants younger than 1 year was 1.54. 70 A retrospective survey reported that 8.5% of patients younger than 12 months developed coronary artery abnormalities, compared with 1.8% of those 12 months old or older. 71
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• Figure 25-4 A, Edema of the hand and early peeling of the skin begins around the nail margins during the subacute phase of Kawasaki disease. B, Desquamation of the skin of the hand occurs later in the subacute and early recovery phase of the disease. In many children. the degree of desquamation is much less than is depicted here.
Other Clinical Manifestations of Kawasaki Disease In addition to the manifestations encompassed in the classification criteria, a number of other abnormalities occur with various frequencies (Table 25-2).
Cardiovascular Disease The most significant and characteristic complications of KD involve the cardiovascular system. Up to 25% of untreated patients develop coronary artery aneurysms, making KD the leading cause of acquired heart disease among children in the developed world (Figs. 25-5 and 25-6). Giant coronary artery aneurysms, with an internal diameter larger than 8 mm, are associated with the highest risk of morbidity and mortality. Up to one third of such aneurysms become obstructed, leading to myocardial infarction, arrhythmias, or sudden death. 72 Treatment with IVIG decreases the incidence of giant aneurysms by
If. II
TABLE 25 Z
more than 95%, and the overall incidence of aneurysms by 85%. Coronary aneurysms may cause morbidity early in the course due to rupture or thrombosis, resulting in sudden death or myocardial infarction,73 Development of de novo coronary artery abnormalities more than 2 weeks after the acute illness is extremely unusual, although ongoing vascular scarring of existing lesions may result in progressive coronary insufficiency. Approximately one half of coronary artery aneurysms demonstrated by echocardiogram ultimately resolve, usually those under 6 mm in diameter,74 but persistent vasodilatory abnormalities have been observed in arteries where aneurysms have resolved. 75 At onset, there is usually a tachycardia commensurate with the degree of fever. Early myocarditis occurs in at least one half of patients76 and is characterized by arrhythmias and signs of congestive heart failure. Pericarditis may also occur. Depressed myocardial contractility, occasionally progressing to congestive heart failure, can occur during the acute illness. 77 Clinically,
M,lI1ifesl"liolls of K"wasilki Disease
FInding Organ System
Common
Uncommon
Suggests Alternate Diagnosis
Skin
Targetoid, urticarial, morbilliform rashes, livedo reticularis Pleural effusion Urethritis, pyuria Irritability, lethargy, anterior uveitis, sensorineural hearing loss Diarrhea, vomiting, hydrops of gallbladder, hepatomegaly Anemia, thrombocytosis, leukocytosis
Psoriasiform rash
Pustular, vesicular rashes
Lungs Urinary tract Nervous system Gastrointestinal system Hematologic system Reticuloendothelial system Mucosa
Anterior cervical lymphadenopathy
Musculoskeletal system Cardiac system
Extremity edema, arthritis Tachycardia, gallop rhythm, myocarditis, pericarditis
Nodules, interstitial infiltrates Hematuria, proteinuria, orchitis Seizure, stroke, cranial nerve palsy Intestinal hemorrhage, mptured viscus Thrombocytopenia, consumptive coagulopathy, hemophagocytic syndrome Posterior cervical, axillary lymphadenopathy
Mucositis, glossitis, conjunctivitis
'Except during the convalescent phase.
Raynaud's phenomenon Coronary artery aneurysm, aortic root dilatation, valvulitis
Lymphocytosis' Diffuse lymphadenopathy, splenomegaly Discrete oral lesions, exudative conjunctivitis
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• fItue Z5-5 Echocardiographic demonstration of aneurysms of three coronary arteries in a child with Kawasaki disease. A, aneurysms; CIRC, drcumflex; LAD, left anterior descending coronary artery; RVOT, right ventricular outflow tract. (Courtesy of Dr. Dennis Crowley.)
this is often manifested by an 53 gallop that may become more prominent with hydration but that typically resolves after treatment with IVIG. Long-term abnormalities of cardiac contractility are very uncommon in children treated during the acute phase of KD. 78 Although involvement of the coronary arteries is the most characteristic manifestation of the vasculitis of KD, other medium-sized muscular arteries may be involved. Aneurysms of brachial and femoral arteries may be palpable clinically or demonstrable angiographically (Fig. 25-7). In severe cases, peripheral arterial obstmction may lead to ischemia and gangrene. This vasculitis usually spares visceral arteries, although there are reports of gastrointestinal obstmction79 and acute abdominal
catastrophe80 occurring as a result of vasculitis. This complication generally accompanies other manifestations of critical disease, such as giant coronary artery aneurysms and aneurysms in peripheral arteries.
Central Nervous System Complications One of the most consistent clinical observations of children with KD, particularly infants and very young children, is their extreme irritability. This probably represents the effect of aseptic meningitis and associated headache. 8! Numerous other central nervous system complications have been reported, including cerebrovascular accident82 and facial nerve paralysis. 83
A, Angiography of the coronary vessels in a 7-month-old boy with Kawasaki disease shows a huge aneurysmal dilatation of the right coronary artery (annw). 8, Aneurysm of the left coronary artery in a 3-year-old girl with Kawasaki disease (annw). (A and 8, Courtesy of Dr. Zuidi Lababidi.) • figure Z5-6
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• Figure Z5-7 Angiographic study of a 2-year-old boy with severe Kawasaki disease resulting in multiple aneurysms of the coronary, axillary, iliac, and femoral arteries.The study revealed large aneurysms of the aorta and iliac (A) and femoral (B) arteries (arrows). Aneurysms that were palpable in the axilla and groin in this patient later resolved. (A and B, Courtesy of Dr. G. Culham.)
Ocular Disease Although conjunctivitis is the most characteristic ocular abnormality in KD, additional abnormalities are common,H.j Asymptomatic uveitis occurs in approximately three fourths of children. It is more common in those older than 2 years. It is bilateral and begins a little later than the conjunctivitis, peaking between days 5 and 8 of illness. 6t Posterior synechiae are rare,HS and the signs listed in Table 25-3 usually disappear without visually significant sequelae and require no specific therapy.
Musculoskeletal Disease
TABLE 25::1 frequency of (l7 days
3-7 days
Erysipeloid erythema
Cold-induced urticaria-like rash Nausea
Urticaria-like rash
Urticaria-like rash
Sometimes abdominal pain Rare Polyarthralgia, oligoarthritis
Uncommon
Migratory rash, underlying myalgia Peritonitis, diarrhea, or constipation
Nonmigratory maculopapular rash on trunk, limbs; urticaria Severe pain, vomiting, diarrhea >constlpation, rarely peritonitis Rare Symmetric polyarthritis, arthralgia
Ocular
Conjunctivitis
Neurologic
Headache
Headache
Lymph/ spleen Vasculitis
Splenomegaly> lymphadenopathy HSP, polyarteritis nodosa Variable risk depending on MEFV, SAA genotypes, family history, gender, compliance with treatment
Not seen
Rare
Not seen
Not seen
Rare
Occurs in =25%
Amyloidosis
Fevers
FCAS
Peritonitis, constipation> diarrhea Frequent Monarthritis, occasionally protracted in knee or hip Rare
Pleural AJ1hropathic
~Iereditary Periodic
Not seen Polyarthralgia
Conjunctivitis, episderitis Sensorineural deafness
Rare Epiphyseal overgrowth, contracnlres, intermittent or chronic arthritis Conjunctivitis, uveitis, vision loss Headache, deafness, aseptic meningitis, mental retardation Adenopathy, hepatosplenomegaly Occasional May develop in a portion of patients reaching adulthood
Frequent Arthralgia, arthritis in large joints
Conjunctivitis, periorbital edema Rare
Rare
Splenomegaly > lymphadenopathy HSP, lymphocytic vasculitis Occurs in =10%
Cervical adenopathy
Headache
Cutaneous vasculitis, rarely HSP Rare
CINCA/NOMID, chronic infantile neurologic cutaneous and articular syndrome, also called neonatal onset multisystem inflammatory disease; FCAS, familial cold autoinflammatory syndrome; FMF. familial Mediterranean fever; HIDS, hyperimmunoglobulinemia D with periodic fever syndrome; HSP, Henoch-Schonlein purpura; MWS. Muckle-Wells syndrome; TRAPS, tumor necrosis factor receptor-associated periodic syndrome.
with rigidity.68 Constipation is more common than diarrhea, and in extreme cases, peristalsis may cease and result in paralytic ileus. Pain can be generalized or focused in a quadrant, sometimes mimicking acute appendicitis. Pleural pain is generally unilateral, occurring with decreased breath sounds. Less commonly, a small effusion, friction rub, or atelectasis may be present. 73 Joint manifestations are common and sometimes the first sign of the disease in children. 74 Arthralgia occurs more frequently than arthritis. Arthritis in adults usually is monarticular, although children may have involvement of several joints, symmetrically or asymmetrically, with pain and large effusions. 75.76 Synovial aspirates from joints are sterile, but they may demonstrate elevated leukocyte counts that are usually associated only with septic arthritis. Rarely, arthritis in the knee and hip may have a protracted course.77 In these cases, radiographic changes may include severe juxta-articular osteoporosis, erosions, and osteonecrosis. Cutaneous findings are less common than serosal or synovial involvement. Most commonly, there is an erysipeloid erythematous rash (Fig. 34-1) on the dorsum of the foot, ankle, or lower leg. 78.79 The rash may occur alone or in conjunction with other manifestations. Biopsies of the rash are characterized by a prominent mixed cellular infiltrate. 79 Findings less commonly associated with FMF include episodes of unilateral acute scrotal pain in prepubescent boys,8CH32 febrile myalgia,83.84 and diverse cutaneous
manifestations including Henoch-Sch6nlein purpura.68.72.85 Rarely, pericarditis is observed. 86 Beh~et's disease,87-9t polyarteritis nodosa,92-98 microscopic polyarteritis,98 and glomerulonephritis99-102 may occur more frequently in FMF patients than in the general population. Although headache and febrile seizures may occur
• Figure 34-1 Erysipeloid erythema on the right ankle of a patient with familial Mediterranean fever. This painful rash usually lasts for several days and may occur alone with fever or in conjunction with arthritis of the adjacent joint. (See color insert.)
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PERIODIC FEVER SYNDROMES IN CHILDREN
in p¢diatric patients, other neurologic symptoms are rare. 'There may also be a higher than expected frequency of inflammatory bowel disorders among FMF patients. lo3.J04
Laboratory Investigations During attacks, concentrations of acute phase reactants such as C-reactive protein (CRP), serum amyloid A (SAA), and complement increase. Leukocytosis and an increased erythrocyte sedimentation rate (ESR) are commonly obse~ed.
The continuous elevation of these acute phase serum proteins during and even between attacks lO5-107 sometimes eventuates in the development of AA systemic amyloidosis, the most serious sequela of FMF. SAA deposition occurs in several organs,68 and renal failure occurred by age 40 in many patients before effective treatment was available. The risk of amyloidosis increases with a positive family history of this complication, male sex, the ala. genotype at the serum amyloid Al (SAAl) locus, and poor compliance with colchicine therapyyl8-112 In most studies, homozygosity for the M694V mutation also predisposes patients to amyloidosis, as well as to arthritis and erysipeloid erythema,74,110.112-114 although the association with amyloidosis has not been observed in Turkey.1I5 For reasons that are not clear, the risk of amyloidosis appears greater in the Middle East than in the United States. An early indicator of impaired renal function is microalbuminuria, and periodic urinalyses are an important part of continuing care for FMF patients. After proteinuria occurs, amyloidosis can be confirmed by biopsy of the kidney or rectum. Although kidney biopsy is more sensitive, rectal biopsy is preferred because it is safer, less invasive, and still has a sensitivity of 75%.11 6
Diagnosis The diagnosis of FMF is based on the presence of short (12 to 72 hours), recurrent (three or more) febrile episodes, with abdominal, chest, joint, or skin manifestation$ and no discernible infectious cause. 1I7 A favorable resBonse to colchicine, appropriate ethnicity, positive famUy history, and onset before the age of 20 also support the diagnosis. Because physicians in the Western Hemisphere are not' as familiar with FMF as clinicians in regions with a higliler prevalence, genetic testing has become a valuable adjlJnct to clinical diagnosis, especially in North America and, Europe. Based on its autosomal recessive inheritanqe, patients with FMF were expected to be homozygous for a single mutation or heterozygous for two diffhent mutations. However, the reality is not always tha~ simple. Certain mutations, most notably the substitution of alanine for valine at residue 726 (V726A) and the sUbftitution of glutamine for glutamic acid at position 148 (E148Q), are sometimes found in cis in so-called comple~ alleles,37.44 and it is possible for some patients to have three or even four demonstrable mutations. Depending on the laboratory, DNA samples are often screened only for the most common mutations, and patients with rare mutations therefore may appear to
661
have no mutations or only one. Even complete sequencing of MEFV exon 10 (where most mutations lie) will fail to diagnose patients with mutations in other regions of the gene. Sequencing of the entire MEFV coding sequence fails to identify any abnormalities in a small number of patients who respond well to colchicine and exhibit FMF symptoms, suggesting that there may be more than one gene causing FMFYS-120 To further complicate the issue, some rare mutations appear inherited in a dominant fashion,121 and approximately 30% of patients with clinical signs of FMF have only one demonstrable mutation. 37.113,120,122-124 A diagnosis of FMF should never be excluded based solely on the results of genetic testing, However, the clinical and ethnic spectra of FMF have definitely expanded with the availability of genetic testing,36 suggesting that a combination of clinical evaluation with genetic testing for selected patients is the most sensible diagnostic approach.
Treatment Colchicine therapy is highly effective for most patients in preventing febrile episodes and systemic amyloidosiS. 12 5-129 Approximately 95% of patients demonstrate a marked improvement in symptoms, whereas almost 75% have a near-complete remission. Continuous therapy is generally more effective in controlling the attacks of FMF than intermittent treatment at the time of attacks, and daily therapy has the important added benefit of reducing the subclinical inflammation between episodes that potentially leads to amyloidosis.I05-107 Colchicine is generally safe in children, although colchicine pharmacokinetics may differ in younger patients, and doses adjusted for body weight may be greater in children than those used in adults. The recommended adult colchicine dose is 1.2 to 1.8 mg/day. Dosage should be started as low as possible (one half of a O.6-mg tablet once daily) and slowly increased, titrating to maximize efficacy and minimize side effects, but usually not exceeding 1.8 mg/day.130,131 A gradual increase in dose often prevents or lessens diarrhea, the most common adverse effect. Some patients develop lactose intolerance due to colchicine, and a lactose-free diet may help to control gastrointestinal symptoms. 132 Simultaneous treatment with colchicine and other drugs that are metabolized by-or that inhibit-the CYP3A4 liver enzyme system, such as erythromycin and cimetidine, can increase colchicine blood levels to toxic concentrations. 132- 135 There are no established alternatives in patients who are unresponsive to or cannot tolerate therapeutic doses of colchicine, although the role of pyrin, the FMF protein, in cytokine regulation suggests a possible future role for biologics.
Outcome and Prognosis Among FMF patients with end-stage renal amyloidosis, the survival rate on hemodialysis is lower than among agematched controls, perhaps because of poor vascular access and hemodynamic instability.I36-140 Studies have confirmed little difference in patient and graft survival between FMF and control kidney transplant recipients 14I ,142;
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PERIODIC FEVER SYN DROMES IN CHILDREN
transplantation (with oral colchicine administration to prevent amyloidosis in the transplanted kidney) is the preferred treatment for renal failure. 143
The Cryopyrlnopathles A second group of inherited recurrent fevers are the cryopyrinopathies (see Chapter 35): familial cold autoinflammatory syndrome (FCAS), MWS, and CINCA!NOMID). All three disorders arise from autosomal dominant mutations in the eIASl IOCUS,I44-148 which encodes a protein that contains an N-terminal PYRIN domain. Although these three syndromes had been recognized as separate entities, there is a continuous range in severity, with a number of cases falling between the clinical boundaries defined in the literature. All three disorders share an urticaria-like rash (Fig. 34-2) and involve episodic or fluctuating but continuous inflammation, which varies from fairly mild to debilitating, depending on the particular genetic lesion and other factors (see Table 34--4).144-151
Tumor Neaosls Fador Receptor-Assodated Periodic Syndrome One of the first clinical descriptions of TRAPS was that of a large family of Irish/Scottish ancestry, with an illness denoted as familial Hibernian fever. 30,ls2 With the discovery of mutations in the TNFRSF1A gene,23 which encodes the 55-kD TNF receptor in this family and in several other families of non-Irish ancestry, the current TRAPS nomenclature was proposed.
Genetics and Pathogenesis TRAPS is inherited as an autosomal dominant trait, although in some cases, a clear pattern of inheritance cannot be discerned because of reduced penetrance in mutation-positive relatives or, rarely, because of de novo mutation. TRAPS has occurred in patients of many ethnicities. It is the second most common periodic fever disorder, with more than 40 known mutations in 1NFRSF1A. 23,IS3-i64 The 55-kD TNF receptor is widely expressed on cell surfaces and mediates a number of proinflammatory effects on ligand binding. Signaling through the receptor
• Figure 34-2 Generalized, urticaria-like rash in a patient with MuckleWells syndrome. Unlike true urticaria, in which mast cells are present, the inflammatory infiltrate is composed primarily of neutrophils. (See color insert.)
during an immune response usually leads to the shedding of the extracellular domains of both the p55 and p75 TNF receptors. 16S ,166 This process contributes to a pool of soluble receptors that compete with the membrane-bound receptor for its ligand (Le., TNF) and cause an attenuation of the inflammatory response. 167 Several TRAPS-associated TNFRSF1A mutations impair normal receptor shedding, which has been hypothesized to result in repeated signaling and prolongation of the inflammatory response. Impaired receptor shedding has been observed by flow cytometry in patients with some but not all mutations. 23 ,ISS,161,162 Moreover, impaired cleavage does not seem to correlate with disease severity, suggesting that there must be additional mechanisms by which TNFRSF1A mutations cause autoinflammatory disease.
Clinical Manifestations The clinical manifestations of TRAPS are more similar to FMF than to the cryopyrinopathies (see Table 34--4). TRAPS causes episodic fever and inflammation with serosal, synovial, and cutaneous manifestations. Distinguishing characteristics of TRAPS include longer attacks (1 to 4 weeks or more) and conspicuous eye and skin symptoms. 168,169 TRAPS attacks may be precipitated by minor trauma or infection or by stress and physical exertion. During attacks, patients exhibit vigorous acute phase responses that sometimes persist into the intercritical period, albeit at lower intensity,169 Cutaneous symptoms associated with TRAPS are often distinctive, consisting of migratory, macular areas of erythema that occur on the torso (Fig, 34-3) or on an extremity.I68,169 These cutaneous lesions are warm and tender and consist of superficial and deep perivascular infiltrates of mononuclear cells. When lesions occur on the limbs, there may be an associated myalgia due to inflammation of the underlying fascia. 170 Other types of rash may also occur, including annular patches and generalized serpiginous plaques. 168,169
• Figure 34-3 Migratory, erythematous macular rash on the abdomen and chest of a patient with the tumor necrosis factor receptor-assodated periodic syndrome (TRAPS).The rash extends from the midline to the right lateral chest wall. Notice the surgical scars from previous exploratory laparotomies. (See color insert.)
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PERIODIC FEVER SYNDROMES IN CHILDREN
Clihical attacks may include peritoneal inflammation or pleurisy, or both. Ocular inflammation with periorbital edeIlla or conjunctivitis is common. 169 Arthralgia is more prominent than arthritis, and it generally involves single joints, especially the hips, knees, and ankles. Scrotal inflammation may occur. IS2 Amyloidosis, although less common than in untreated FMF, affects about 10% of patients and can lead to renal or hepatic failure. IS 5-IS7,169.171 The risk of amyloidosis appears to be greater among patients with cysteine mutations. ISS A positive family history of amyloidosis may increase the risk for other relatives.
Laboratory Investigations Levels of SAA, CRP, and serum complement components are increased, and most patients exhibit leukocytosis and thrombocytosis, with an accelerated ESR.
Diagnosis More than 40 point mutations in TNFRSFl have been described. 23,IS3-164,172 The specific diagnosis is defined by mutations in this locus. Patients without mutations are considered to have a TRAPS-like phenotype,lss,162 possibly caused by mutations in related genes.
Treatment Treatment depends on the severity of the underlying disease. For some patients with relatively infrequent episodes, tapering doses of prednisone at the time of attacks may be effective and relatively safe. For patients with more severe disease, the recombinant TNF receptor antagonist, etanercept (0.4 mg/kg, with a maximum of 25 mg, twice each week), is effective in preventing attacks. 24,169,173 Some patients require dosing three times each week or 0.6 mg/kg twice weekly to achieve an adequate response. Colchicine usually has no effect on symptoms or the development of amyloidosis.1 69 .171 The prognosis depends on the development of amyloidosis. More aggressive anti-TNF therapy may be indicated in patients with a positive family history of amyloidosis or mutation at cysteine residues to suppress subClinical inflammation.
Hyperlmmunoglobullnemla Dwith Periodic Fever Syndrome HIDS is an autosomal recessive disease l74 that was initially described in several patients of Dutch heritage. 31 HIDS is caused by mutations in the MVK gene, which encodes mevalonate kinase.l75-177 HIDS occurs mainly in patients of northern European ancestry, and approximately 50% of patients are of Dutch ancestry. 178-183
Genetics and Pathogenesis Mevalonate kinase is a peroxisomal enzyme that catalyzes the conversion of mevalonic acid to 5-phosphomevalonic acid in the synthesis of sterols (Le., cholesterol, steroid hormones, vitamin D, and bile salts) and' nonsterol isoprene compounds (Fig. 34-4).177.184.185
663
Isoprenes are involved in a variety of cellular functions, including electron transport, protein glycosylation and synthesis, and prenylation of adenine transduction proteins. Mutations associated with HIDS lead to markedly reduced mevalonate kinase enzymic activity,17S,176 whereas the mutations in the clinically more severe mevalonic aciduria result in the absence of enzymic activity.186 Excessive production of proinflammatory cytokines by HIDS mononuclear cells may result from excessive accumulation of mevalonic acid substrate or be related to deficiencies in isoprenoids synthesized through the mevalonate pathway.187 If the latter possibility is correct, small GTP-binding proteins, which undergo prenylation, may be the link between the mevalonate pathway and the febrile attacks of HIDS.I88
Clinical Manifestations HIDS manifests in early childhood, often by 6 months of age (see Table 34-4). Attacks last about 3 to 7 days, usually separated by 1- to 2-month, symptom-free intervals. Episodes are often heralded by chills and headache, a rising fever, abdominal pain, nausea, and vomiting, sometimes precipitated by immunizations, surgery, trauma, and mild infections.180 The mevalonate kinase enzyme in patients with HIDS-associated mutations loses activity at supraphysiologic temperatures, perhaps explaining the association of immunizations, upper respiratory infections, and other inflammatory provocations with attacks. 189 Some patients develop a nondestructive arthritis, usually in the large joints, that is associated with attacks. 180 ,190-192 This arthritis is often polyarticular, unlike that associated with FMF. Protracted joint manifestations are rare. During attacks, widespread, erythematous macules develop that are sometimes painful,lso.193 The rash is usually not migratory, differentiating it from the rash associated with TRAPS, and it has no predilection for the lower legs, unlike that of FMF. The HIDS rash may be a diffuse maculopapular eruption (Fig. 34-5) extending to the palms and soles, or it can be nodular, urticarial, or morbilliform. Skin biopsies show perivascular inflammatory cells and deposits of antibody or complement component C3, or both. Oral and vaginal aphthous ulcers are common. Henoch-Schonlein purpura l90 and erythema elevatum diutinum (a benign type of necrotiZing vasculitis)179 have been reported. Cervical lymphadenopathy is a common manifestation of HIDS, as are severe headache and splenomegaly.ISO Pleurisy is uncommon. Clinical findings are summarized in Table 34-4.
Laboratory Investigations Most patients have elevated serum immunoglobulin D levels, but how this observation contributes to the clinical disease is poorly understood. Some patients with periodic fever and MVK mutations have normal IgD levels, suggesting that an elevated IgD concentration may be an epiphenomenon.l76,188,I94.19s Patients also exhibit an accelerated ESR, leukocytosis, and elevated levels of CRP I80 ,182,194 during and, less commonly, between attacks. Elevated levels of mevalonic acid are usually detected in urine during attacks. 17S ,176,1%,197
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PERIODIC FEVER SYNDROMES IN CHILDREN
A_O_s/_C_OA_U~oA
A"'YI CoA [
3-hydroxy3-methylglutaryl CoA
[
.JLU
OH
CoA
}
_ _ YI CoA
J
' - - - -
Mevalonate
['----OH~_O OH
OH
]
.. Mevalonate kinase
Mevalonate-P
[
O_H~_H
P_____'O,]
Mevalonate-PP
Isopentenyl-PP
[....._
Geranyl-PP
~_C_H_2
P02 P03
...-J_ -. 1,0p""yl,dwno-.RNA
(~~-p--------~pO'
]
Famesyl-PP
[
....
Dolichol PO PO ..... Heme A 2 3 Ubiquinone ----' Famesylated proteins
J
Squalene
Cholesterol
Steroid honnones ..... Vitamin D Bile acids Lipoproteins
OH • Figure 34-4 The mevalonate pathway. Patients with the hyperimmunoglobulinemia 0 with periodic fever syndrome have mutations in mevalonate kinase that result in enzyme activity that is markedly diminished but not absent. Patients with clinically more severe mevalonic aciduria have mutations leading to an almost total loss of enzyme activity.
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PERIODIC FEVER SYNDROMES IN CHILDREN
665
Periodic Fever due to (ydle Hematopoiesis Cyclic hematopoiesis (CH), or cyclic neutropenia, is a rare disorder consisting of febrile episodes due to periodic granulocytopenia, interspersed between intervals of relatively normal granulocyte counts. CH may occur as a sporadic congenital disorder, an autosomal dominant inherited disease, or an acquired condition. 204-207 Cyclic neutropenia is a more common term for this condition, although cyclic hematopoiesis is more descriptive, because other formed elements of blood in addition to neutrophils also demonstrate cyclic variations in numbers. 206 Although the fevers associated with CH are sometimes caused by infectious agents, patients with CH may develop fevers in the absence of apparent infection,5 perhaps due to the large-scale apoptotic death of bone marrow precursors that underlies the variation in circulating mature forms. 207
• FIture 34-5
Adiffuse maculopapular rash also extended over the palms and soles of a patient with the hyperimmunoglobulinemia 0 with periodic fever syndrome. (See color insert.)
Diagnosis A diagnosis may require several lines of inquiry, including clinical observation, genetic testing, serum IgD measurement, and assay of mevalonate in urine. Modest elevations in IgD should be interpreted with caution, because this phenomenon is common in several other conditions, including chronic infections, acquired immunodeficiency syndrome (AIDS), Hodgkin's disease, and other periodic fever syndromes. 180 ,198-200 Most laboratories that perform genetic testing for HIDS screen for the V377I mutation (Le., substitution of isoleucine for valine at residue 377), because most HIDS patients are heterozygous for this mutation.]83,196 However, even with complete sequencing of the coding region of MVK, genetic testing may be inconclusive. About 25% of patients do not have MVK mutations, suggesting the existence of other genetic phenotypes. 20 ] Based on a combination of diagnostic indicators, three types of HIDS with very similar symptoms have been proposed. Classic RIDS is defined by elevated IgD levels, a mutation in MVK, and mevalonic acid in the urine during attacks. Variant RIDS patients also have recurrent fevers and elevated IgD levels, but they lack mutations in Ml/K and do not excrete high levels of mevalonate. 201 Dutch-type periodic fever patients have normal levels of IgD but are positive for mutations in MVK and excrete increased levels of mevalonate in urine. 194
Treatment Various treatment" have been proposed. A few patients may respond to colchicine. Glucocorticoids, immunoglobulin, and cyclosporine have all been tried with various success rates. Two small studies demonstrated improvement with etanercept l88 and simvastatin. 202 HIDS is not generally associated with a shortened lifespan,l80 although HIDS-associated amyloidosis has been reported. 203
Genetics and Pathogenesis The clinical features of autosomal dominant, familial CH are indistinguishable from those of the sporadic form, suggesting that the sporadic variety may represent unrecognized familial cases or de novo mutations in CH genes. Inherited CH is caused by mutations in the neutrophil elastase-2 gene (EIA2J,208-21O which encodes neutrophil elastase (NE). Mutations in the growth factor independent-1 gene (GFIl),211 which encodes a transcription factor that controls expression of NE, causes severe congenital neutropenia, a noncyclical disorder. CH has also been related to mutations in dogs in an adaptor protein (AP3Bl) bound to NE,21O,212 although a causal connection has yet to be established between CH and AP3B1 in humans. The current hypothesis is that CH is a mistrafficking disorder of NE. Computational modeling suggests that NE is a membrane protein, and that EIA2 mutations affect primarily the transmembrane domains, leading to excessive deposition of NE in intracellular granules. 212 In contrast, AP3Bl mutations modify the adaptor protein in such a way that there is excessive transport to the plasma membrane. 212 Adult-onset CH may be a benign neoplasm with clonal proliferation of large granular lymphocytes. m -215
Clinical Manifestations Clinical manifestations of CH start in early childhood, with the earliest reported case occurring in the first few weeks of life (Table 34-5).206 The cycle length is typically 21 days (range, 14 to 36 days), and each febrile cycle lasts 3 to 10 days.206,216 In older persons, the cycles may not be evident. During attacks, the absolute neutrophil count (ANC) is less than 200/dL (0.2 x 109 L) and may be O. While patients are neutropenic, they are highly
I!: II
TABLE 3/.-5
Clinical Features of Cyclic
Ilenldtop()le~is
1. Typical cycles recur approXimately every 21 days. 2, Absolute neutrophil count is less than 0.2 x 109fL. 3. Absolute neutrophil count is low normal to mildly neutropenic between cycles,
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PERIODIC FEVER SYNDROMES IN CHILDREN
susceptible to infections from normal flora, resulting in recurrent oral ulcers, gingivitis, fever, and lymphadenopathy. Although these infections are usually mild to moderate in severity, severe infections due to Clostridium or Escherichia coli, with abdominal pain and vomiting rapidly progressing to necrotizing enterocolitis, may occur. Clostridium septicum infection has caused enterocolitis, myonecrosis, and death.217-220 Other uncommon and less serious symptoms include bone pain, fatigue, malaise, diarrhea, and headache. Symptoms improve rapidly as neutrophil counts recover. Children are well between attacks, with ANCs in the low normal to mildly neutropenic range. Blood monocyte counts cycle in opposite fashion, so that the peak monocyte count coincides with the nadir of the ANC. 21S Reticulocytes, platelets, and eosinophils also may oscillate with neutrophils. 221 An acute phase response may be observed during the neutropenic episodes. Results of bone marrow examination are characterized by intramedullary destruction of promyelocytes and defects in granulopoiesis 222 due to accelerated apoptosis. 223
Diagnosis Based on extensive family studies,206 the diagnosis of autosomal dominant CH can be established with reasonable accuracy based on the following criteria: regular, cyclic fluctuations in peripheral blood neutrophil counts, with a periodicity ranging from 19 to 21 days, and documentation of neutrophil counts less than 0.2 x 109/L during periods of neutropenia. Complete blood counts should be determined two or three times each week for at least 6 weeks. 206 Genetic testing may play an adjunctive role, especially in families in which formes fruste are suspected or when there is no family history but is a suspicion of de novo mutation.
rare. Early loss of permanent teeth associated with chronic gingivitis is common to all forms of neutrope. t'Ion WIt. h mal'Ignancy h as been nl'a . 221>-230 N0 assocla observed.
Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Adenitis Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome (Le., Marshall's syndrome) was described in 1987. 231 It is a relatively benign and common condition that has been reported in several areas of the world.232.233 The underlying cause is unknown. No infectious cause has been discovered, although the clinical features suggest it. PFAPA does not appear to be inherited, because most cases occur sporadically. PFAPA can be considered idiopathic.
Clinical Manifestations The onset of PFAPA is usually before the age of 5 years. In an American series23 4, febrile episodes occurred approximately every 28 days (range, 26 to 30) and lasted for a mean of 5 days, although a French group reported a longer interval between flares. 235 Children are healthy between episodes and grow normally. Malaise, fatigue, and oral lesions may herald the onset of a cycle. In the largest series reported,234 70% of patients had aphthous stomatitis, characterized by shallow ulcers in the buccal mucosa and pharynx that lasted for 3 to 5 days and healed without scarring. Seventy-two percent had pharyngitis, consisting of an intensely red, ulcerated pharynx, without exudate. Although cervical adenitis is a major feature of the disease in 88% of patients, lymph nodes in other locations usually are not enlarged. Hepatosplenomegaly is rare. Arthralgia is reported in 10% to 15%. The maximum temperature of 40 C to 41' C is usually reached within the first day and may end abruptly or settle down over 1 or 2 days. 0
Treatment Treatment with granulocyte colony-stimulating factor (G_CSF)224-226 or granulocyte-macrophage colony-stimulating factor (GM-CSF)227 may be effective. The recommendation is to administer G-CSF subcutaneously at doses of 1 to 5 Ilglkglday. Symptoms are controlled by this treatment, and the cycles are shortened, with an increase in the nadir ANc. 225 Infections must be treated promptly and aggressively. E. coli and Clostridium species precipitate serious and often fatal illness. Appropriate cultures should be obtained, particularly if a child develops abdominal pain with diarrhea and vomiting. Typhlitis (i.e., inflammation of the cecum) and perforating enterocolitis should always be considered.
Outcome and Prognosis Prognosis appears to be good, except for the increased mortality rate associated with infection. 206 With age, the cycles are less prominent, and symptoms improve. Sinusitis and bone pain become more common, whereas fever, lymphadenopathy, and skin infections become
Laboratory Investigations During episodes, there is an increase in the total white blood cell count and elevation of acute phase reactants. Neutropenia usually is not present, but mild elevations in serum IgG, IgM, and IgA may occur. Elevated levels of IgD were reported in one study236 but not in another. 234 Increased serum levels of interferon-y, TNF, and IL-6 have been observed with fevers,234 suggesting that perturbations in the cytokine network may be responsible for this disease.
Diagnosis Based on a 10-year registry, which includes 94 PFAPA patients,234 the following diagnostic criteria were suggested (Table 34-6): recurrent febrile cycles with an onset before age 5 and at least one of the following features: aphthous stomatitis, cervical adenitis, or pharyngitis. Patients are asymptomatic and grow normally between cycles.
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IABLE 34-6 Clinical Featu~~s of the Sy.n~rome of P~riodic Fever with Aphthous Stomahtls. Pharyngitis, and Cervical Adenopathy
1. 'Regularly recurring fevers at an early age at onset «5 years of
age) 2. Constitutional symptoms in the absence of upper respiratory infection with at least one of the following: a. Aphthous stomatitis b. Cervical adenitis Co Pharyngitis 3. Exclusion of cyclic neutropenia and known hereditary periodic fever syndromes 4. Asymptomatic intervals between episodes 5. Normal growth and development
Treatment Several treatments have been proposed, including nonsteroidal anti-inflammatory drugs CNSAIDs), colchicine, glucocorticoids, and cimetidine. In many patients, glucocorticoids started early during a cycle seem to be effectiv¢ in aborting attacks. 234 ,235 Although a single dose is often effective, some children may require treatment for 3 to 4 days, Steroid therapy often aborts attacks, but it results in a shorted interval between episodes. 234 Acetaminophen or NSAIDs with or without antibiotics may be of modest benefit,237 although the cycles will return. Cimetidine may be effective at preventing recurrences. 238,239 Some investigators have noticed that tonsillectomy and adenoidectomy may eliminate attacks. 240
Outcome and Prognosis Prognosis seems to be excellent. In a lO-year registry,234 cyclic episodes ceased after a mean of 4.5 years from the on~etj approximately one third of patients stopped having episodes. In other patients, the symptoms became less intense and less frequent with the passage of time. Two patients continued to have episodes even after 17 years of follow-up. Neither developed malignancies or autoimmune disorders.
REFERENCES 1. Petersdorf RG, Beeson PB: Fever of unexplained origin: repon on 100 cases. Medicine (Baltimore) 40: 1, 1961. 2. Durack DT, Street AC: Fever of unknown origin-reexamined and redefined. Curr Clin Top Infect Dis 11: 35, 1991. 3. Miller LC, Sisson BA, Tucker LB, et al: Prolonged fevers of unknown origin in children: pallerns of presentation and outcome.] Pediatr 129: 419, 1996. 4. Lorin M, Feigin R: Fever of undetermined origin. In Oski F, McMillan]A (ed): Oski's Pediatrics: Principles and Practice, 3rd ed. Philadelphia, Uppincoll Williams & Wilkins, 1999, pp 1116--1119. 5. John CC, Gilsdorf ]R: Recurrent fever in children. Pediatr Infect Dis] 21: 1071, 2002. 6. Al Dahouk S, Tomaso H. Nockler K, et al: Laboratory-based diagnosis of brucellosis-a review of the literature. Part n. Serological tests for brucellosis. Clin Lab 49: 577, 2003. 7. Glass WI: Brucellosis as an Occupational Disease in New Zealand. N Z Med ] 63: 301, 1964. 8. Foley BV, Clay MM, O'Sullivan D]: A study of a brucellosis epidemic. lr] Med Sci 3: 457, 1970. 9. Williams E: Brucellosis and the British public. Lancet 1: 1220, 1970. 10. Mantur BG, Akki AS, Mangalgi SS, et al: Childhood brucellosis-a microbiological, epidemiological and clinical study. ] Trop Pediatr 50: 153, 2004. 11. Ojukwu IC. Christy C: Rat-bite fever in children: case report and review. Scand] Infect Dis 34: 474. 2002.
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12. Rat-bite fever-New Mexico. 1996. MMWR Morb Mortal Wkly Rep 47: 89, 1998. 13. Parker F]. Hudson NP: The etiology of Haverhill fever (erythema arthriticum epidemicum). Am] Pathol 2: 357. 1926. 14. Raffin B]. Freemark M: Streptobacillary !"dt-bite fever: a pediatric problem. Pediatrics 64: 214. 1979. 15. Place EH. SUllon LE: Erythema arthriticum epidemicum (Haverhill fever). Arch Intern Med 54: 659. 1934. 16. Obermeir 0: Vorkommen feinster eine eigenbewegung zeigender faden im blute von rekurrenskranken. Zentralbl Med Wiss 11: 145. 1873. 17. Barbour AG, Hayes SF: Biology of Borrelia species. Microbiol Rev 50: 381, 1986. 18. Paster B]. Dewhirst FE. Weisburg WG. et aI: Phylogenetic analysis of the spirochetes.] Bacteriol173: 6101. 1991. 19. Barbour AG, Fish D: The biological and social phenomenon of Lyme disease. Science 260: 1610. 1993. 20. Fukunaga M. Takahashi Y, Tsuruta Y, et al: Genetic and phenotypic analysis of Borrelia miyamotoi sp. nov., isolated from the ixodid tick Ixodes persulcatus, the vector for Lyme disease in Japan. Int] Syst Bacteriol 45: 804. 1995. 21. Barbour AG. Maupin GO, Teltow G]. et al: Identification of an uncultivable Borrelia species in the hard tick Amblyomma americanum: possible agent of a Lyme disease-like illness. ] Infect Dis 173: 403. 1996. 22. Cadavid D. Barbour AG: Neuroborreliosis during relapsing fever: review of the clinical manifestations. pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis 26: 151, 1998. 23. McDermott MF, Aksentijevich I, Galon ], et al: Germline mutations in the extracellular domains of the 55 kDa TNF receptor. TNFRI. define a family of dominantly inherited autoinflammatory syndromes. Cell 97: 133, 1999. 24. Galon]. Aksentijevich I. McDermoll MF, et al: TNFRSFIA mutations and autoinflammatory syndromes. Curr Opin Immunol 12: 479, 2000. 25. Hull KM. Shoham N. Chae J]. et al: The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol 15: 61. 2003. 26. Kile RM. Rusk HA: A case of cold unicaria with an unusual family history. ]AMA 114: 1067. 1940. 27. Siegal S: Benign paroxysmal peritonitis. Ann Intern Med 23: 1, 1945. 28. Heller H. Sohar E. Sherf L: Familial Mediterranean fever. Arch Intern Med 102: 50. 1958. 29. Muckle 1], Wellsm: Urticaria, deafness, and amyloidosis: a new heredofamilial syndrome. Q] Med 31: 235. 1962. 30. Williamson LM. Hull D. Mehta R, et al: Familial Hibernian fever. Q] Med 51: 469, 1982. 31. van der Meer ]W, Vossen ]M. Radl,J, et al: Hyperimmunogiobulinaemia D and periodic fever: a new syndrome. Lancet 1: 1087, 1984. 32. Hassink SG, Gold.mith DP: Neonatal onset multisystem inflammatory disease. Arthritis Rheum 26: 668, 1983. 33. Prieur AM, Griscelli C: Arthropathy with rash. chronic meningitis. eye lesions, and mental retardation. ] Pediatr 99: 79, 1981. 34. The International FMF Consortium: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90: 797, 1997. 35. The French FMF Consortium: A candidate gene for familial Mediterranean fever. Nat Genet 17: 25, 1997. 36. Samuels]. Aksentijevich I. Torosyan Y. et al: Familial Mediterranean fever at the millennium. Clinical spectrum. ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine 10° hyperextension of elbow (one point each for right and left) >10° hyperextension of knee (one point each for right and left) Touch palms to floor with knees straight (one point)
Other nonalterla features of many children with hypermoblllty: Put heel behind head Excessive internal rotation to hip Excessive ankle dorsiflexion Excessive eversion of the foot Passively touch elbows behind the back 'Carter C. Wilkinson]: Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br 46: 40-45. 1964. lBeighton P, Solomon L, Soskolne C: Articular mobility in an African population. Ann Rheum Dis 32: 413-418. 1973.
sphincter dysfunction" may be more common in children with hypermobility.22 Although hypermobility may enable a child to be a good gymnast or ballet dancer, injuries may be more frequent in hypermobile athletes. 23- 25 Therefore, having the benign hypermobility syndrome may actually mitigate against a successful professional career in ballet dancing26 or against strenuous training, such as in military recruits. 27 Temporomandibular joint dysfunction may be a consequence of hypermobility.28-30 Proprioception of the knee, reported to be diminished in hypermobile females, may lead to poor biomechanicalloading and microtrauma. l1 In addition to altered proprioception, there is some recent evidence suggesting a disturbance in the autonomic nervous system, though the significance of this finding is unclear. 31 Patients with anterior knee pain (often called chondromalacia patellae, although the evidence for any pathology of the patella in children is usually lacking) are more likely to be hypermobile than are control patients. 32 Back pain is also more common in hypermobile patients, especially those who spend more time sitting or standing; individuals whose activities require frequent changes of position experience less back pain. 32 .33 Premature osteoarthritis has been suggested as a consequence of hypermobility, but the evidence is not convincing. 34 One study showed no difference in bone density between those with and those without hypermobility.3s Attempts to determine whether benign hypermobility is a risk factor for later joint disease may be confounded in crosssectional studies by the fact that hypermobility in late
adult life appears to be a marker of fitness, with flexible older adults having less osteoarthritis and osteopenia. 36 Children who "crack their knuckles" are frequently hypermobile. Parents are often concerned that this activity might lead to joint damage, but it is probably not a cause of later osteoarthritis. 37 Children with benign hypermobility syndrome do not seem to be at an increased risk for aortic dilatation or mitral valve prolapse..ls..l8 ,39
Pes Planus The flexible flat foot is normal in very young children. Most infants have no longitudinal arch, and the development of this arch is part of normal growth. 40 In children, particularly those with hypermobility, the arch may exist when they are toe standing or lying (and they may actually appear to have a high arch) but disappears on weight-bearing. Usually, flexible flat feet are not a cause of significant discomfort. A study in adults with flexible feet found no relationship between pain scores and arch configuration. 41 A patient with flat feet and hindfoot valgus is shown in Figure 36-1. The occasional adolescent with a short Achilles tendon and hypermobile flat foot may have pain from excessive weight-bearing on the talar head. 42 This is rare, however, being present in only 25 of 3619 male soldiers. 43 Treatment is controversial. Wenger and associates 44 reported a prospective randomized trial of 98 children with flat feet who received either no treatment or corrective orthopedic shoes, a Helfet heel-cup, or a custom-molded plastic insert. There was significant improvement in most children, irrespective of treatment group. Orthotic devices that involve only the hindfoot do not reduce the mediolateral ground forces in adults with pes planus. 45 Mosca recommended aggressive heel cord stretching and adjusting of the shoes; if that failed, then a soft foot orthosis could be triedY Surgery to lengthen the heel cord is indicated only in the most extreme cases in skeletally mature adolescents. 42 ,46 Pes planus (and pes cavus) in the athlete may be associated with overuse injury more commonly than is a nor-
• Rgure 36-1 Kuchta.)
Pes planus with left hindfoot valgus. (Courtesy of Dr. G.
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mal-appearing arch. 47 However, neither pes planus nor pes cavus (which can also be a cause of foot discomfort) has been shown to be a significant predictor of injury in army recruits,48 and one study reported fewer stress fractures in those with low arches. 49 No therapeutic studies in these populations are available. In contrast to the mobile flat foot, a rigid flat foot is always pathologic. It may result from tarsal coalition, in which a bone or cartilaginous bridge is present between tarsal bones, usually the talus and the calcaneus or the navicular and the calcaneus (Fig. 36-2). As the bridge ossifies, motion is restricted and pain may result; 25% of children with tarsal coalition have symptoms. 50 Computed tomography or magnetic resonance imaging (MRI) usually shows the coalition, and surgical intervention is required if conservative management fails.
679
condition may be associated with a congenital abnormality of the patella (unifaceted or bipartite patella), of the femoral condyles (shallow intercondylar groove), or of the patellar ligament (lateral attachment). Femoral anteversion, patella alta, and an increased Q-angle are also commonly found. Repeated episodes of dislocation lead to premature degeneration of the articular cartilage of the patellofemoral joint. The patellar apprehension sign-contraction of the quadriceps muscle when the examiner attempts to displace the patella laterally-suggests the diagnosis. Treatment consists of short-arc active and resistive exercises to strengthen the musculature around the knee joint, especially the vastus medialis, and center the patella. If these interventions fail, surgical realignment of the extensor system may be indicated.52
Hypomobllity Genu Recurvatum Genu recurvatum, like pes planus, may be part of a generalized hypermobility syndrome or may occur as an isolated phenomenon. Symptomatic genu recurvatum occurs most commonly in adolescent girls and is associated with popliteal pain and an increased incidence of anterior cruciate ligament injury.27.51 Symptoms are worse with standing or walking and are relieved by rest. Athletes may have particular difficulty.27 Treatment includes correction of bicpmechanical faults by use of orthotics; improving knee proprioception and muscle control (especially quadriceps strength) as well as gait; and maintaining good knee alignment during functional activities. 51
Recurrent Patellar Dislocation As part of the hypermobility syndrome or as an isolated
phenomenon, the patella may dislocate laterally. This is accompanied by a sensation of giving way with sudden pain and the inability to straighten the leg. The knee is held in a position of about 25 degrees of flexion. The
.: FIgure J6-Z Computed tomographic scan illustrates the bony bridge between the calcaneus and talus on the right side.The left hindfoot is normal.This feature may not be detectable on plain radiographs. (Courtesy of Dr. R. Caims.)
Although it has not been studied in a formal fashion, it is the authors' impression that a few children with slightly limited joint mobility (either as part of an underlying syndrome or as one end of the normal spectrum of joint mobility) may also present with arthralgias. It is not uncommon for children with back and lower-extremity arthralgias to have tight hamstring, quadriceps, and calf muscles. 53 Bowyer reported that four of five children with hip contractures due to an underlying spondyloarthropathy experienced hip pain. 54 The authors and others have seen children with a variety of individually relatively uncommon disorders, including hyalinosis and familial fibrosing serositis,55.56 who seemed to be in pain because of very stiff joints (Table 36-3). Most children with
I!:.
TABLE 36-3 Seleded Conditions Associated with HYPolllobility or Joint Contraclures'
Diabetes mellitus (diabetic cheiroarthropathy) Tightening of skin and soft tissues of fingers Short stature Scleroderma and scleroderma-like conditions Mucopolysaccharidoses and mucolipidoses with dysostosis multiplex Autosomal recessive inheritance (except in Hunter's syndrome, which is X-linked) Hyalinosis Familial fibrosing serositis Progressive contractures of fingers and toes Fibrosing pleuritis and constrictive pericarditis Probably autosomal recessive inheritance Camptodactyly syndromes (several familial conditions including B1au's syndrome) Flexion contractures of fingers Beals' contractural arachnodactyly syndrome Marfanoid features Crumpled ears Cardiac abnormalities unusual Linked to fibrillin-like gene on chromosome 5 (autosomal dominant inheritance) Winchester's syndrome Multicentric osteolysis particularly of fingers, starting in infancy Autosomal recessive inheritance 'For further details about the inherited conditions listed here, 1he reader is referred to Jones KL: Smith's Recognizable Patterns of Human Malformation, 5th ed. Philadelphia, WB Saunders, 1997, Chapter 37, and Beighton P: McKusick's Heritable Disorders of Connective Tissue, 5th ed., St. LOUis, Mosby, 1993.
680
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marked stiffness due to conditions such as arthrogIYposis, Williams' syndrome, and cerebral palsy do not seem to complain unusually of arthralgias, so careful evaluation for other explanations for pain needs to be undertaken in children with joint contractures.
PAIN SYNDROMES RELATED TO OVERUSE Patellofemoral Pain Pain in the anterior aspect of the knee, originating in the patellofemoral joint, is quite common (Table 36-4).57,58 It is characterized by pain and tenderness in the region of the medial patellar facet and crepitation on movement of the joint. There are several possible causes of this disorder. 59-63 If the syndrome is accompanied by fissuring and fibrillation of the posterior surface of the patella, the term chondromalacia patellae is used. It is most common in teenage girls. There is insidious development of retropatellar knee pain. Pain occurs at first with activity that stresses the quadriceps (particularly eccentric contraction), such as deep knee bends or climbing or descending stairs, and is lessened by rest. Pain recurs with prolonged sitting with the knee flexed and can be relieved by extension of the leg. On physical examination, knee flexion may be accompanied.by patellar crepitus. Pain may be reproduced by compreSSIon of the patella and by palpation along its inferomedial edge. Pain may also be elicited if the upward movement. of the patella is restrained while the quadriceps. m~scle IS contracted. A small effusion may be present. Fmdmgs on standard radiographs and laboratory investigations are normal, but MRI can be diagnostic, showing decreased signal intensity, irregularity with focal thinning of the articular cartilage, or even cartilage denudation and subchondral cyst formation. Arthroscopy (if performed) may reveal ridging and strands of degenerating cartilage on the retropatellar sur. face, blistering, or frank denudation of cartilage. Patellofemoral pain syndromes can be chronic and difficult to treat, and no controlled studies have been done. Activities that provoke pain should be curtailed initially, and then reintroduced with a carefully graded increase of the activity in association with specific exercises aimed at strengthening the muscles around the knee, especially the vastus medialis muscle. A variety of different braces or strapping techniques are available, whose main .fu~ction is to maintain the movement of the patella wlthm the patellar groove. They are of limited value but may provide
J~.
TABl E 3b 4
Age at onset Sex ratio Symptoms
Signs
Pdlellofemordl Pdin
Syndroll1e~
Adolescence to young adulthood Girls> boys Insidious onset of exertional knee pain, difficulty descending stairs and walking downhill, need to sit with legs straigbt ("theater sign") Patellar tenderness on compression; quadriceps weakness; inhibition sign; small joint effusion
some help. Correction of pronated feet by custom-fitted orthoses and weight reduction in the overweight teenager may help. Surgical procedures, including shaVing off the patellar irregularities, are of questionable benefit.
Plica Syndromes The medial and lateral plicae arise from incomplete involution of the synovial membranes that separate the compartments of the knee during embIYologic development. These folds do not usually cause symptoms; however, if they become thickened, they can cause pain in the knee (Table 36-5).64 Occasionally the membranes do not involute at all, leaving a complete septum. A nonperforated septum can result in unusual swelling that may mimic a soft tissue tumor. 65 The mediopatellar plica syndrome is the more common condition associated with pathologic plicae and causes pain with flexion of the knee; erosion of the cartilage apposing the plica may eventually occur. There is often an area of tenderness over the superomedial border of the femoral condyle and locking or snapping during movement of the joint. The thickened plica can often be palpated as a thickened band on the medial aspect of the knee. MRI may show a thickened synovial plica occasionally accompanied by synovitis or cartilage erosion. The diagnosis is confirmed by arthroscopy; resection of the band can be performed at the same time and is often curative.
Stress Fractures and Physeal and Apophyseal Injuries Stress injuries occur when bones, physes, or apophyses (sites of growth cartilage where tendons insert) are damaged by their exposure to repetitive, nonviolent loads. They are particularly common in the adolescent athlete. 66 The intensity and duration of the sport is significantly related to the fracture rate. 67 The onset of pain and localized weakness due to reflex inhibition is usually insidious, occurring in an athletic adolescent who is performing a repetitive activity, such as long-distance running. Physical examination reveals localized bone tenderness with reproduction of pain on resisted movement. Early radiographs may be normal, or they may show only soft tissue swelling. Later radiographs demonstrate callus formation (Fig. 36-3), physeal widening, or apophyseal fragmentation. If there is diagnostic concern
I: II
TABlE 36 '}
Age at onset Symptoms Signs Arthroscopy
MediolJdlellar Pli(,l Syndrollle
Adolescence Medial knee pain, intermittent aching increased with activity or motion, giving way on weight-bearing, locking Medial palpable band, snapping on motion Fibrous band with hemorrhage and inflammation identified
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681
• fIture 36-3
Serial radiographs document the evolution of astress fracture in a lO-year-old giri who was the hopscotch champion of her block.Two weeks after the onset of leg pain, the fracture line is evident. After 4 weeks, the fracture callus is seen. (Courtesy of Dr. Robert N. Hensinger.)
because of persistent bone pain or pain with activity, bone scintigraphy is the imaging technique of choice. There is significant overlap between these conditions and the osteochondroses (see later text and Table 36-7). The classic stress fracture is the march fracture of the metatarsals seen in members of the military. The most common site of a stress fracture in children, however, is the proximal third of the tibia (see Fig. 36-3), with metatarsal fractures being uncommon. Femoral fractures also occur with some frequency in young children. Some of these may be associated with nonaccidental trauma, and this possibility should be seriously considered if the child is not yet walking. 68
Lower-Limb Conditions Pelvic Apophysitis Pain may occur where abdominal and hip muscles insert into the pelvis. Particular conditions involve the insertion of the sartorius into the anterior superior iliac spine, the insertion of the rectus femoris into the anterior inferior iliac spine, the insertion of the iliopsoas into the lesser trochanter, and the insertion of the abdominal musculature into the iliac crest apophysis. 69 These conditions are associated with adolescent athletes, especially runners, but are usually not associated with a single traumatic event; they cause a dull pain in the general area of the hip on activity and may therefore be confused with intra-articular hip disease. The occurrence of pain on resisted contractions of involved muscles, in which the hip joint itself is not allowed to move, indicates that the pain is not caused by intrinsic hip disease. Additionally, a relatively common benign cause of pelvic pain in adolescents is apophysitis of the iliac crest. In this condition, pelvic brim or lumbar pain may occur spontaneously and is reproduced by direct palpation of the affected area of the iliac crest.70 The condition settles spontaneously after a few weeks or rest, much like Osgood-Schlatter disease. Once healed, the adolescent should gradually return to strenuous activity. Recognition of this entity prevents unnecessary investigations and interventions.
Osgood-Schlatter Disease Osgood-Schlatter disease 71 ,72 is an osteochondrosis caused by repeated trauma to the tibial tuberosity. Essentially, it is a microavulsion fracture that results when the infrapatellar tendon pulls out from the tibial tuberosity.73 It commonly occurs in athletic adolescents (Table 36-6).74 There is a complaint of pain over the tibial tubercle that is exacerbated by exercise or kneeling. On examination, tenderness and, often, swelling of the tibial tubercle and patellar tendon insertion are present. Radiographs-which should be obtained to exclude other conditions including infection, neoplasia, avulsion fracture, and stress fracture-may show soft tissue swelling and an enlarged and fragmented tubercle (Fig. 36-4). However, it is normal for the tibial tubercle to appear irregular in adolescence, and it may be difficult to differentiate normal development from disease. Ultrasonography can help in identifying the lesion. 75 Laboratory studies reveal no evidence of chronic inflammation. There is no association with the human leukocyte antigen HLA-B27, so it is not a forme fruste of enthesitis-related juvenile idiopathic arthritis. 76 Rest or use of a basketball knee protector is usually sufficient treatment. The outcome is usually very good.?7
Sinding-Larsen-Johansson Disease Sinding-Larsen-Johansson disease is an osteochondrosis caused by repeated trauma to the inferior pole (secondary ossification center) of the patella (Fig. 36-5); essentially
11:'.
TABLE 36-6
Age at onset Sex ratio Symptoms Signs Investigations
Osgood-Schlaller Disease
Athletic adolescents Boys> girls Pain over the tibial tubercle exacerbated by exercise, unable to kneel because of pain Tenderness and swelling over the attachment of the infrapatellar tendon Radiograph shows soft tissue swelling, enlarged and sometimes fragmented tubercle
682
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Sever's Disease Sever's disease is a common cause of heel pain that usually occurs in physically active individuals in early adolescence. The cause is uncertain. Liberson and colleagues80 suggested that radiographic findings of a dense calcaneal apophysis are normal, occurring as commonly in control subjects as in subjects with heel pain, but that radiographic lucencies or fragmentation changes are more commonly associated with pain. Based on radiographic changes, computed tomographic scans, and histologic examinations, they hypothesized that the cause of Sever's disease is a process of remodeling of the calcaneal apophysis secondary to repetitive stresses of traction from the Achilles tendon and plantar fascia and impact from weight-bearing. This remodeling process is usually a normal, subclinical event but it becomes symptomatic when it is excessive.
Upper Limb Conditions
• Figure 36-4 Radiograph of the knee of a boy with Osgood-Schlatter
disease. In addition to fragmentation of the apophysis, the soft tissues overlying the tibial tuberde are thickened. (Courtesy of Dr. R. Cairns.)
it is an avulsion fracture that results when the infrapatellar tendon pulls out from the patella. 78 ,79 It may be confused with Osgood-Schlatter disease or infrapatellar tendinitis, in which pain at the inferior pole of the patella may also occur. Treatment consists of rest and temporary reduction in physical activities that involve the legs. Most cases resolve within 3 to 12 months.
Upper limb stress injuries occur less commonly than lower limb conditions. Shoulder pain on active and resisted movement is associated with widening of the proXimal humeral physis. Known as little league shoulder, it occurs in children participating in sports activities, such as baseball pitching, that involve repetitive overarm movements,Rl These overarm movements can also be associated with pain at the elbow, caused by an apophyseal injury to the medial epicondyle (golfer's elbow). A similar injury is tennis elbow, in which the pain is caused by apophysitis of the lateral epicondyle at the insertion of the common wrist extensors. These elbow syndromes can be helped by the use of a "tennis elbow strap," which is applied fairly tightly around the forearm just distal to the tender site. It is believed to help diminish the pain by inhibiting full muscle expansion, thereby diminishing intrinsic muscle force on the lateral epicondyle. Glucocorticoid injections into the site of maximal tenderness may be required if the symptoms do not respond to conservative measures. Little league elbow is another stress injury in which there is a painful fragmentation of the capitellum of the distal humerus. It is probably the same condition as Panner's osteochondrosis, which usually affects preadolescent boys. The whole ossific nucleus becomes flattened and fragmented, but the condition resolves with no long-term sequelae. 82 A variety of bony injuries around the elbow occur in young gymnasts; those involving the articular surface of the joint necessitate permanent discontinuation of competitive gymnastics, whereas those involving the olecranon have a good outcome. R3 ,84
Soft nssue Stress Injuries
3~ Radiograph of the knee of a boy with Sindling-LarsenJohansson disease.The lower pole of the patella has been separated from the patella.
• Figure
Repetitive trauma can cause soft tissue injuries in addition to bony lesions. Tenosynovitis is relatively common, particularly in the athletic adolescent and in relatively inactive children who, without proper preparation, overengage in an activity (the "weekend warrior").
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Shin Splints The term shin splints is applied to a pain syndrome in the posteromedial aspect of the lower half of the shin, usually in o~der adolescents. It is associated with running, jogging, or walking; is worse with the activity; and is relieved by rest. s; It is caused by periostitis at the insertion of the sole~s muscle. 86 The diagnosis is confirmed by the demonstration of tenderness at the posteromedial border of the distal tibia. Stress fractures can mimic shin splints. Rarely, an anterior compartment syndrome resulting from hemorrhage or edema, accompanied by ischemic changes in the foot, is confused with shin splints. Shin splints are best prevented by adequate stretching and strengthening and avoidance of jogging or walking on hard surfaces. Treatment is symptomatic, with rest, stretching, ice, nonsteroidal anti-inflammatory drugs, proper footwear, and a graduated rehabilitation program. S;,86 Orthotics may help patients with pronated feet or excessive subtalar motion.
Tenosynovitis Although tenosynovitis commonly accompanies rheumatic disease, it can also occur as a result of unaccustomed repetitive movement, especially around the ankle (Achilles tenosynovitis, anterior tibial tenosynovitis) or at the wrists, or as stenosing tenosynovitis of the abductor pollicis longus or extensor pollicis brevis (de Queroain's disease). Treatment requires rest, with splinting if needed, and possibly injection of glucocorticoid into the tendon sheath. For a complete discussion of these and other overuse syndromes, the reader is referred to the work of Sheon and associates. 87
OStEOCHONDROSES As indicated earlier, there is a great deal of commonality among many of the stress-related injuries and the osteochondroses, and dividing the discussion into individual conditions is somewhat arbitrary, Some members of this heterogeneous group of disorders (apophyseal injuries) were described earlier; others, of particular significance to pediatric rheumatologists, are discussed briefly in the following sections. Some of the conditions commonly considered to be osteochondroses are probably variants of normal ossification, some are probably the result of stress injury, and others may be caused by avascular necrosis without any obvious precipitating trauma, perhaps occurring because of some inherent predisposition to vascular insufficiency. This uncertainty of the etiology has led to confusion and contradictory nomenclature and classification. Brower defined osteochondrosis as "a condition in which the primary or secondary ossification center in the growing child undergoes aseptic necrosis with gradual resorption of dead bone and replacement by reparative osseous tissue."88 Resnick uses a somewhat broader definition, stating that an osteochondrosis is any of "a group of disorders that share certain features: predilection for the immature skeleton; involvement of an epiphysis,
683
apophysis, or epiphysioid bone; and a radiographic picture that is dominated by fragmentation, collapse, sclerosis, and frequently, reossification with reconstitution of the osseous contour."S9 From a clinical point of view, osteochondroses might be defined as idiopathic, acquired, localized disorders of cartilage and bone, often characterized by localized pain. The osteochondroses usually affect a single site but may be bilateral; they are characteristically observed in children between the ages of 3 and 12 years and are much more common in boys than in girls. In large part, these disorders have been defined by their radiologic appearance, although, as already discussed, it is now clear that some of these findings are normal variants. In Table 36-7, the osteochondroses are listed according to the sites affected, and the putative causes are indicated.
li'~
TABtE 36-7
The Osteochondroses
Eponym
Mechanism
Basal phalanges Second metacarpal head Lunate Carpal navicular Distal ulna Capitellum of humerus
Thiemann Mauclaire Kienoock Prieser Burns Panner
Head of humerus
Hass
Trauma Trauma Osteonecrosis Trauma Trauma Trauma? Avascular necrosis Trauma
Area Affected Upper Extremity
Lower Extremity Second metatarsal head Fifth metatarsal base Tarsal navicular Talus Calcaneal apophysis Distal tibia Tibial tubercle Proximal tibia Intercondylar spines Primary patellar center Secondary patellar center Greater trochanter Femoral epiphysis Femoral epiphysis
Freiberg Iselin Kohler Diaz Sever Liffert-Arkin OsgoodSchlatter Blount Caffey Kohler Sinding-LarsenJohansson Mandl Legg-CalvePerthes Meyer's dysplasia
Osteonecrosis Trauma Normal variation Trauma Normal variation Trauma Trauma Trauma ? ?
Repeated trauma ? Osteonecrosis Normal variation
AxIal Skeleton Vertebral body Disk Vertebral epiphysis Iliac crest Symphysis pubis Ischiopubic synchondrosis Ischial apophysis
Calve Schmorl Scheuermann Buchman Pierson Van Neck Milch
? ? Repeated trauma ? ? Normal variant ?
Adapted from Brower AC; The osteochondroses. Orthop elin North Am 14: 99, 1983: Resnick D: The osteochondroses. In Resnick D, Niwayama G (eds): Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1981, p 2874: and other sources.
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36 NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS
Legg-Calve-Perthes Disease Legg-Calve-Perthes disease was independently and simultaneously described by Legg,90 Calve,91 and Perthes. 92 It is an idiopathic avascular necrosis of the femoral head that occurs in children between about 5 and 10 years of age. It is approximately four times more common in boys than in girls, and it affects both hips in 10% to 15% of cases. There is an increased incidence among family members of an index case; Asians and whites are more frequently affected than are Native Australians, Native Americans, and blacks; and the disease occurs more frequently in urban than in rural areas.9.~ It has been observed that children with Legg-Calve-Perthes disease have delayed skeletal maturation and reduced height. 94 The cause of Legg-Calve-Perthes disease is unknown, but it is generally accepted that the condition occurs in individuals whose vascular supply to the femoral head is particularly vulnerable to interruption. There is evidence that children in the Legg-Calve-Perthes age range have a less extensive anastomotic vascular network to the femoral epiphysis than at other ages, and that boys have a less complete network than do girls. There is also increasing evidence of a thrombotic predisposition in some children. Data from two studies suggest that the factor V Leiden gene, responsible for resistance to protein C activation and therefore associated with an increased risk of thrombosis, is found more commonly in individuals with Legg-Calve-Perthes disease. 95.% However, another study failed to find any evidence of a thrombotic diathesis. 97 A recent study found both an increased frequency of the ~-fibrinogen gene G-455-A polymorphism and an increased exposure to passive smoke in children with Legg-Calve-Perthes disease, compared with controls. 98 Children who were perinatally infected with human immunodeficiency virus (HIV) appeared to be at increased risk of developing Legg-Calve-Perthes disease. 99 Affected children present with a limp and varying degrees of hip pain. Radiographs taken shortly after the onset of symptoms are often normal, but later radiographs show a progression through four stages: (1) an initial stage, at which there may be a small ossific nucleus, widening of the joint space, irregularity of the physis, and a subchondral radiolucent area; (2) a fragmentation stage, at which the bony epiphysis begins to fragment and there are patchy areas of increased radiolucency and radiodensity; (3) a reossification stage, at which normal bone density returns, radiodensities develop in previously radiolucent areas, and abnormalities of the shape of the femoral head and neck appear; and (4) the healed stage, at which the bone density is normal but the head is left with residual deformities. These changes may take several years to complete. Bone scans and MRI studies have a greater sensitivity for the detection of early disease than do plain radiographs (Fig. 36-6). The prognosis of Legg-Calve-Perthes disease depends on how extensive is the involvement of the epiphyseal head. Based on a study of 48 patients (51 involved hips) who were monitored for a mean of 50.2 years, the best prognostic indicator for long-term outcome appears to be the shape of the femoral head at skeletal maturity: normal or flattened spherical heads cause little problem, but
irregular heads are associated with a poor outcome. 100 The greater the extent of the necrosis, the more likely the femoral head is to become widened and flattened and uncontainable within the acetabulum. These changes predispose the individual to decreased range of movement at the hip and later changes of osteoarthritis. The aim of all forms of treatment for this condition is to maintain the femoral head well covered within the acetabulum, so as to minimize the deformity of the head. There is considerable uncertainty about the benefits of various surgical procedures compared with nonsurgical interventions such as splints.JOJ.102 A study by Lahdes-Vasarna and associates lOJ demonstrated that femoral heads with less than 50% involvement had a significantly better radiographic outcome than did those with greater than 500/0 involvement, and that hips treated by femoral varus osteotomies did only a little better than those treated with containment splints. The more severely affected hips may benefit from operative intervention. A recent study of 610 children with Legg-Calve-Perthes disease found that only 24% of untreated patients had a spherical femoral head at follow-up. 103
Scheuermann's Disease Scheuermann's disease (juvenile kyphosis) may be considered to be an osteochondrosis of the ring apophysis of the vertebral body, perhaps caused by repeated trauma, although the cause is far from clear and there is no consistency to its definition. It is most common in girls between 13 and 17 years of age, who present with pain in the midthoracic or lumbar spine; it may, however, be painless but causes a round-shouldered appearance and dorsal kyphosis. Radiographically, it is associated with anterior wedging of one to three adjacent vertebral bodies by at least 5 degrees each. 104 The kyphosis is thoracic in 75% of patients and thoracolumbar in most of the rest, except for the rare child with disease limited to the lumbar spine. 105 A prominent fixed dorsal kyphosis with a compensatory increase in the lumbar lordosis is characteristic. Tightness of the pectoral and hamstring muscles has been noted. 106 A standing lateral radiograph of the spine reveals anterior vertebral wedging, irregularity of vertebral end plates (Schmorl's nodes), increased anteroposterior diameter of the affected vertebral bodies, and increased dorsal kyphosis (Fig. 36-7). Treatment usually consists of simple analgesia and, occasionally, the use of a back brace to prevent flexion. The outcome is usually very good. Surgical interventions are restricted to patients with severe kyphoses (greater than 60 or 70 degrees). A significant correction of the degree of kyphosis can usually be obtained immediately postoperatively, but the curve tends to worsen again over time. 107 There is no correlation between functional outcome and radiographic outcome. J07 A cohort study of all 63 patients treated in a single institution by exercise and observation only, by Milwaukee bracing, or by surgical fusion using Harrington rods failed to find any statistical difference in quality of life, pain, function, or degree of curve between the different treatment modalities at a mean of 14 years after treatment. 108 Patients with curves exceeding 70
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36 NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS
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• Figure 36-6 Progression of Legg-Calve-Perthes disease. A, On the right side, the capital femoral epiphysis is flattened and sderotic; on the left, it is fragmented.The femoral metaphyses are widened, especially on the left side. B, Technetium 99m bone scan of another patient shows absence of uptake of the isotope in the right capital femoral epiphysis (arrow) but normal uptake on the left side. C, Magnetic resonance image of aseptic necrosis of the right femoral head, thought to be related to prolonged glucocorticoid intake, in a boy with dermatomyositis. The entire femoral head and the marrow in the metaphysis are abnormal. (A and C, courtesy of Dr. R. Cairns; B, courtesy of Dr. H. Nadel.)
degrees at follow-up did have inferior function. These data suggest that operative intervention should be reserved only for very large curves.
Ki5hler's Disease Kohler's disease is an osteochondrosis of the tarsal navicular bone. It tends to affect children between 4 and 9 years of age, who present with onset of insidious foot pain and a limp. The affected child characteristically bears weight on the lateral aspect of the foot. 109 Some authorities consider the radiographic findings of navicular narrowing, increased density, and sometimes fragmentation to be a variant of normal ossification (Fig. 36-8). There is no evidence that treatment affects outcome, which is almost always complete recovery; any
persistent or late-onset foot complaints are usually caused by other, unrelated pathology yo
Freiberg's Disease Freiberg's disease is an osteochondrosis of the second metatarsal head occurring most frequently in adolescent girls. Other metatarsal heads are occasionally affected. It causes localized pain on weight-bearing, sometimes with swelling in the region of the second metatarsal head. This condition has usually been ascribed to trauma. ll1 A retrospective study of 31 patients, however, elicited a history of trauma in only 15%, and pedobarographic studies failed to show abnormally high pressure at the affected metatarsal head. 112 The researchers observed that, in 85% of cases, the affected metatarsal was the
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• Figure :16-. Freiberg's disease affecting the left second metatarsal head. (Courtesy of Dr. R. Cairns.)
heads and rest; casting may be necessary for pain control. 46 The outcome is usually good.
• Fllure :16-7 Lateral radiograph of the spine illustrating the abnonnalities of the anterior margins of the vertebral bodies that are characteristic of Scheuennann's disease and result in anterior wedging. (Courtesy of Dr. R. Calms.)
longest in the foot, and that this might, in some poorly explained way, predispose the metatarsal head to vascular insufficiency and infarction. Radiographs reveal increased density or flattening of the affected metatarsal head (Fig. 36-9). Treatment is usually supportive, with shoe inserts to reduce weight-bearing on the metatarsal
thiemann's Disease Thiemann's disease is an osteochondrosis caused by osteonecrosis of the phalangeal epiphyses, possibly secondary to trauma. Thiemann's disease is characterized by progressive, painless enlargement-during adolescence-of the epiphyses of the proximal interphalangeal joints of the hands and the interphalangeal joints of the first toes. 113 ,114 Flexion contractures of the large joints also occur. Radiographically, there is irregularity of the epiphyses of the digits. Results of tests for acute phase reactants are normal. Disability is minimal. The condition may be familial. ll5- 117
TRAUMA-INDUCED CONDITIONS In some patients with the apophyseal stress injuries described earlier, the injury may be more severe and may be associated with avulsion. In these situations, surgical intervention may be required. This next section does not attempt to cover all types of musculoskeletal conditions caused by trauma; rather, it focuses on conditions that are more likely to come to the attention of the pediatric rheumatologist. For more detailed information, the reader is referred to a standard orthopedic textbook.
Osteochondritis Dissecans
Flgure:l6-8 Kohler's disease.The tarsal navicular on the left (arrow) is flattened and sderotic. (Courtesy of Dr. R. Cairns).
Osteochondritis dissecans is a condition that has been described as a primary avascular necrosis of bone with a secondary involvement of the overlying cartilage,118 but it has also been characterized as a disturbance of endochondral ossification. 119 Osteochondritis dissecans manifests clinically with activity-related pain, and sometimes with recurrent bland effusions, although there may only be localized tenderness on examination. If there has been complete separation of a fragment, there may also
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be joint-locking. It is related to trauma, but it is more frequently caused by repeated microtrauma and overuse than by a single traumatic episode.u s In a study of 51 knees in 38 patients with osteochondritis of the lateral condyle using MRI, there were some associated meniscal tears or discoid menisci, suggesting that altered mechanics is an important etiologic factor. 12o Bilateral lesions are common (approximately 20%). Occasional familial cases suggest that a genetic predisposition to vascular insufficiency of the subchondral bone may be of etiologic importance .116 Although the condition is usually recognized by plain radiography, because of the appearance of a subchondral fracture, the use of MRI has led to an increased recognition that pure cartilaginous separation can occur, even if radiographs appear normal (Fig. 3~1O). The inner aspect of the distal femoral medial condyle is the most commonly affected area (Fig. 3~11); however, osteochondritis dissecans of the dome of the talus (Fig. 3~12), the capitellum, or the patdla also occurs fairly commonly. MRI is almost as accurate as arthroscopy at staging the condition l21 and predicting outcome. 122 It has become the method of choice for staging the lesion. Intact cartilage, contrast enhancement of the lesion, and absence of osseous "cystic" defects are designated stage 1. Treatment can be conservative (avoidance of weight-bearing for a few weeks), precluding the need for arthroscopy. A cartilage defect with or without complete separation of the fragment, fluid around an undetached fragment, an osseous "cystic" lesion, and a dislodged fragment are stage 2 findings, which probably require arthroscopy and surgical intervention. 11S Persistence of symptoms despite non-weight-bearing in individuals with stage 1 findings also usually requires arthroscopic investigation. Surgical interventions include trying to relocate the fragments, by various fixation methods, and removing the loose bodies. Patients with open physes and small lesions tend to have
• 'figure 36-10 In this magnetic: resonance image, the area from which the osteochondral fragment has arisen is seen as a black area in the posterior part of the articular surface of the femur (curved arrow).The loose fragment of cartilage is indicated by the straight arrow. (Courtesy of Dr. R. Caims.)
687
• RlIUre 36-11 Osteochondritis dissecans is evident in the posterior aspect of the medial femoral condyle (arrow). The loose fragment of cartilage and bone is not evident. (Courtesy of Dr. R. Caims.)
a better prognosis than do those with closed physes or larger lesions. I22
Traumatic Arthritis Joint swelling associated with trauma occurs in older school-aged children and adolescents. An effusion arising immediately after an injury is more likely to be associated
• RlIUre 36-1Z dome of the talus.
Osteochondritis dissecans is seen on the medial side of the
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36 NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS
with intra-articular hemorrhage, fracture, or joint derangement than is swelling that develops over several hours. A history of injury is often elicited in children with juvenile rheumatoid arthritis, because a minor injury brings a swollen joint to parental attention. Trauma, especially minor trauma, is not an explanation for joint swelling in a young child, and internal joint derangements (meniscal tears) are very rare. Juvenile rheumatoid arthritis is far more common than traumatic arthritis in the very young. Transient joint swelling can result, however, from patellar subluxation or from repetitive trauma associated with overuse syndromes or structurally abnormal joints in older children.
Slipped Capital Femoral Epiphysis Although slipped capital femoral epiphysis (SCFE) and acute chondrolysis of the hip are discussed here, their actual relationship to trauma is unclear, and often no significant history of trauma is elicited, although it seems probable that abnormal mechanical loading contributes to their occurrence. The condition most commonly affects overweight boys in early to middle adolescence. Children with SCFE have a higher average body mass index than other children. 123 There are ethnic differences in the frequency of the condition, which occurs more commonly among blacks and Polynesians. 124 The explanation for the racial differences is unclear. It has been postulated that individuals with an increased acetabular depth are at increased risk; but a study of healthy adults showed that the racial differences in acetabular depth did not match the known racial prevalence of SCFE.125 The mean age at onset of SCFE is about 11 years in girls and 12.5 years in boys, but the range is large, and children as young as 8 years of age can be affected. 124 The condition usually manifests with limp and pain in the affected hip. In the case of a subacute or a chronicon-subacute slip, the onset of symptoms is insidious. Occasionally an acute slip develops after a moderate injury, resulting in more severe pain and inability to walk. Radiographs are usually diagnostic, assuming a good lateral (axial) view of the hip is obtained; they show a posterior and downward slip of the femoral head on the neck caused by a separation through the growth plate between the zones of hypertrophic and calcified cartilage. Occasionally, symptoms can precede radiographic changes. If the condition is suspected, MRI can be helpful in diagnosing a "pre-slip."126 Once the diagnosis is suspected, the child should be given crutches and told to avoid weight-bearing until he or she can be seen urgently by the orthopedic surgeon. In general, the slip is classified as mild if it is less than one third the diameter of the femoral head and severe if it is greater than this amount. More recently, new classification schemes have been described that are probably of more prognostic utility than the traditional ones. 127 It has also been suggested that decreased radionuclide uptake on bone scans by the physis of the greater trochanter on the affected side, and later its premature closure on radiographs, is a predictive sign for the development of acute chondrolysis. 128 Although SCFE usually manifests with the
involvement of one hip only, the other hip frequently becomes involved with time. Eventually, between 300/0 and 45% of affected individuals will have evidence of bilateral involvement.124.129 Very mild slips may be treated conservatively, but there is always a risk of slip progression, so careful observation is mandatory. If the slip progresses surgical intervention is required. I3O Treatment is by fixation, usually with a single central screw. Acute chondrolysis is a complication of both treated and untreated SCFE and occurs in about 6% of cases; avascular necrosis occurs in about 5% of cases. 129,131
Acute Chondrolysls of the Hlp Acute chondrolysis of the hip is an unusual condition in which there is an insidious onset of hip pain and limitation of movement in association with radiographic evidence of progressive loss of articular cartilage. It can occur as an apparently idiopathic event or secondary to other hip pathology, particularly SCFE or Legg-Calve-Perthes disease. Idiopathic chondrolysis usually occurs in adolescents and may be more frequent in black girls. 13I Some children reportedly have minimal symptoms on long-term followup, with radiographs showing apparent restoration of joint cartilage, often with lateral overgrowth of the femoral head and lateral acetabular osteophyte formation. 132 However, a much worse outcome has also been described; in one study, all 11 patients, a mean of 13 years after presentation, had constant pain and stiffness with severe radiologic damage. 133 It has been suggested that idiopathic chondrolysis may be caused by synovitis of the hip, perhaps from a spondyloarthropathyl31,134; however, other studies have failed to show histologic evidence of significant synovial inflammation. 132 MRI shows cartilage loss (especially centrally), small hip joint effusions, and regional muscle wasting without synovial enhancement. Chondrolysis associated with a SCFE appears to have a better long-term prognosis than does idiopathic chondrolysis. 127
Nonacddental Injury An abused infant or child is sometimes thought to have a rheumatic disease because of a refusal to walk or bear weight, the presence of a joint effusion, or the presence of skin lesions that are believed to be vasculitic in origin. These children may be misdiagnosed as having juvenile idiopathic arthritis if a proper history is not obtained. Beating a child over the hands and knuckles results in brawny induration of the dorsal surfaces of the hands as well as thickened, dense round bones and bone chips on radiographs. Physical abuse should be considered in the child who has a history of repeated visits to the emergency department because of poorly explained trauma, the occurrence of allegedly spontaneous bruises, or hemarthrosis without an underlying bleeding disorder. Radiographic demonstration of multiple fractures and periosteal new bone formation is characteristic. The syndrome termed Munchausen's syndrome by proxy is a bizarre form of child abuse induced by the parent to bring the child to medical attention, usually to meet the pathologic psychological needs of the mother.
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Rarely, a child with ecchymoses and deep bruising due to Henoch-Schonlein purpura or autoerythrocyte sensitization syndrome is thought to have been abused. 135 Awareness of this condition can save such children and their families much suffering.
Frostbite Arthropathy Frostbite is a cold-induced necrosis of the superficial tissues caused by freezing. The acral or exposed areas, including the fingers, toes, nose, and ears, are predominantly affected. Immediately after exposure, the diagnosis of frostbite can be made by the characteristic appearance of swollen, red fingers or toes. The history of cold exposure should be obvious, although the parents may not have been aware of the increased susceptibility of the very young child to cold injury. Vasomotor changes suggesting Raynaud's phenomenon may persist for months. In the growing child, frostbite produces a characteristic stunting of growth of the small bones and aero-osteolysis (Fig. 36-13).136-138 Secondary symptoms of osteoarthritis may develop in early adulthood.
689
Congenital Indifference to Pain In the rare syndromes of congenital indifference to pain, affected children develop swollen but painless joints associated with induration or necrosis of the toes and fingers (Fig. 36-14). Children with this condition, which may be an autosomal recessive trait, also frequently have anhydrosis, self-mutilating behaviors, and mental retardation. This neurogenic arthropathy (Charcot'sjoint) results in severely damaged, unstable joints that may eventually require arthrodesis to maintain some degree of function. One study suggested that substance P containing nerve fibers may be absent in this condition, confirming the importance of substance P in nociception within normal diarthrodial joints. 139 In three unrelated children with this condition, different mutations of the tyrosine kinase receptor gene for nerve growth factor were found, indicating that abnormalities of this gene may be responsible for this condition. 140 This finding was confirmed in other studies. Neurogenic arthropathy in children can also be caused by other lesions, for example as a consequence of spinal dysraphism. 141
PAIN SYNDROMES AFFECI1NG THE BACK, CHEST, OR NECK
• fItpn 3&-U The effects of frostbite. A and B, Necrosis of the distal epiphyses of all digits except the thumbs and left second and third fingers has resulted in growth failure.
Noninflammatory disorders of the back, chest, or neck are important causes of chronic or recurrent pain in children. Pain can arise from a wide variety of causes, including congenital, developmental, or acquired defects and nonmusculoskeletal diseases. Back pain in the general pediatric population is very frequent in developed countries. A study from Denmark reported that at least 50% of teenagers had one episode of back pain 142 j a frequency of 74% was reported from Switzerland143 and 44% from Iceland 144 (where 21% had weekly back pain). The prevalence is even higher in athletes144.145 but, perhaps surprisingly, is lower (only 32%) in those with idiopathic scoliosis. 146 Volinn 147 reviewed the literature and concluded that low back pain was twofold to fourfold higher in Swedish, German, and Belgium populations than in southern Chinese, Indonesian, Nigerian, and Filipino farmers. In contrast, back pain is a relatively infrequent reason for referral to a pediatric orthopedic surgeon,148 accounting for 2% of referrals. Among those children seen by an orthopedic surgeon because of low back pain, no specific cause could be found in almost half; Scheuermann's disease was present in 15%, spondylolysis in 13%, infection in 8%, disk prolapse in 6%, and tumor in 6%.148 A fairly common cause of back pain in very young children is diskitis (see Chapter 28). A number of studies have explored what factors might contribute to back pain in children for which no specific cause could be found. The weight of backpacks carried by schoolchildren is a plausible contributing factor, but recent data do not support the hypothesis that this causes back pain. 149 There is some evidence that long hours sitting at a computer or in front of the television may be an adverse factor. However, back pain (like most pain conditions) is multifactorial in origin, and psychosocial factors such as
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• Figure 36-14 Radiographs of the effects of congenital indifference to pain. A, This chila has lost the tips of several fingers (atrow). B Hypertrophic and destructive changes are visible in the calcaneus, talus, and mldfoot (atrow). Cand D There is marked loss of the medial compartment space and calcifications typical of Charcot's arthropathy (arrow in D). Oinically, the knees were warm and contained large effusions. J
J
mood, parental support, and health perception seem to be at least as important as mechanical factors such as body mass index or backpack load. 149 Relatively little is known about the most effective way to treat back pain in children. In a chiropractic study, 40% of adult patients rated themselves as "much improved" after 7 days of treatment, and 82% after 30 days; those with chronic back pain were less likely to improve quickly.150 Whether children would improve at the same rate without treatment is unknown. In a longitudinal study, more than 50% of children who reported back pain initially denied ever having had back pain
when reinterviewed 2 years later, indicating that for many children back pain resolves spontaneously. J5J A controlled study suggested that a back education program may be an effective way of reducing pain prevalence for at least 1 year. J52 Chest pain is also a fairly frequent complaint in the pediatric population. Rowe and coworkers l53 reported that 6 of 1000 emergency department visits in a children's hospital were for chest pain. Chest pain occurred with equal frequency in boys and girls. Of 366 patients, 28% were diagnosed with chest wall pain; only 1% (5 of 336) had cardiac causes (Table 36-8). Precordial catch syn-
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IABl E 36-8
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Causes of Chest Pain in Children Presenting
to all Emergellcy Oepartmen
t
Cat8aorY
%
Conditions Induded
Chest wall
28
Lung/pleura
19
Tmuma Psychogenic
15 5
Otl1er
21
Unknown
12
Costochondritis, Tietze's syndrome, musculoskeletal pain, breast tenderness Asthma, infection, embolism, pleurisy, pneumothorax Contusion, abrasion Depression, anxiety, conversion disorder, hyperventilation Esophagitis, gastritis, upper respiratory tract infection, constipation, cardiac causes Chest pain of undetermined cause
Adapted and reprinted from Rowe BH, Dulberg CS, Peterson RG, et aI: Chamcteristics of children presenting with chest pain to a pediatric emergency department. Can Med Assoc J 143: 388, 1990, by permission of the publisher.
drome, previously known as Texidor twinge, is a very under-recognized condition in which there is a history of recurrent, well-localized, sharp chest wall pain of sudden on$et lasting a few seconds to minutes only, with negative findings on examination or laboratory testing. 154
SponcIyIolysls and Spondylolisthesis Spondylolysis is a defect in the pars interarticularis, most commonly of the fifth lumbar vertebra (L5). In one study of 185 children with spondylolysis, 193 defects were detected: 1 at L2, 6 at L3, 16 at L4, 168 at L5, and 2 at L6. 155 If there is bilateral spondylolysis, the affected vertebra may slip anteriorly, giving rise to spondylolisthesis; slips do not seem to happen with unilateral lesions. 156 Pars lesions are rare before the age of 5 years and usually occur in adolescents. The condition occurs in 6% of the population and frequently is asymptomatic. 156-158 Thirty children with pars lesions who were diagnosed during a prospective study of 500 first-grade children were monitored for 45 years. 156 There was no association between slippage and low back pain. The rate of progression of spondylolisthesis slowed with each passing decade, and none of the subjects developed a slip of 40%. The overall well-being of the group, as measured by the Medical Outcome Study Short-Form Health Survey (SF-36), did not differ from normative data. Spondylolysis is usually caused by a stress or fatigue fracture of the pars interarticularis, but there may be a genetic component, because it is more common in first-order reiatives. 158 Certain high-risk sports, including gymnastics, American football (especially in interior linemen), fast bowling in cricket, dance, and weight-lifting, have been associated with spondylolysis. Either condition can give rise to low back pain that may occur with activity and radiate down the posterior thigh. Occasionally, pain can be elicited by palpation of the involved vertebra, and a defect may be noted if a slip has occurred. Results of the neurologic examination are usually normal, but there may be tightness and spasm of the hamstring muscles. Having the child hyperextend the back and lift a leg often exacerbates the pain. 159 The diagnosis is usually clear from
691
oblique and lateral radiographs (Fig. 36-15), although bone scintigraphy may be needed in selected cases. 159 Treatment is usually conservative, with rest, analgesics, and a back corset or bracing to limit extension.155.157,158 Continuation in sports usually is allowable once the pain has subsided and range of motion has been regained. '60 If surgery is performed, the outcome appears to be excellent, with the great majority of athletes being able to return to their chosen sport. 161
Intervertebral Disk Herniation Disk herniation is rare in childhood, with estimates of the incidence in the Japanese population ranging from 1.69 per 100,000 in the 10- to 12-year-old age group, to 3.15 per 100,000 in the 13- to 15-year-old age group, and 9.63 per 100,000 in high school students aged 16 to 18 years. 162 These estimates are similar to those for the adult population in the United States. 163 Disk herniation accounted for 6% of 61 children younger than 16 years of age who were seen in one orthopedics clinic because of low back pain. l48 In another study of 1920 patients who underwent surgery for herniated disks, only 10 (0.5%) were children, and none was younger than 12 years of age. l64 Only 5 children aged 9 years or younger have been reported with disk herniation. 165 Boys may be slightly more frequently affected than girIS. 166-168 The vast majority of herniated disks are at L4-L5 and LS-S1. They are subligamental and usually posterolateral in position.l64 Although they often seem to be sports or injury related, the exact cause of the herniations is not clear. One study showed marked degenerative changes in 11 of 15 disks examined,'69 but another study of
• R.un 36-15 Spondylolysis affecting the pars interarticularis of L5 (alTOw) is visible in this oblique view radiograph of the lumbar spine of a child with low back pain.The posterior elements on the oblique view form the ·Scotty dog," and the pars interarticularis appears as the dog's neck.There is also spondylolisthesis with an anterior slip of L5 on S1.
692
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36 NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS
10 adolescent disks failed to show such changes. 1M The onset of pain is usually insidious, with stiffness of the lower lumbar spine with or without radicular pain down the leg (which is the presenting complaint in some patients). Coughing, sneezing, and bending may aggravate the pain. Examination reveals limitation of forward bending and straight-leg raising and, in 25%, weakness of the plantar flexors. Plain radiographs are seldom helpful, although the disk space is narrowed in 200!o of patients and there may be a slight posterior calcification if there is a slipped apophysis; diagnosis is evident on MRI or computed tomographic scans. Conservative treatment with rest, analgesics, and physical therapy is successful in up to 80% of cases. 1S7 The long-term success of surgery in adolescents is quite goOd.167.168 However, in one study of 129 children younger than 18 years of age,170 at a mean follow-up of 12.4 years the outcome was excellent in only 40%, good in 47%, and poor in 13%, with reintervention required in 10%. (See also the discussion of diskitis in Chapter 28.)
Slipping Rib Syndrome The slipping rib syndrome is produced by trauma to the costal cartilages of the 8th to 10th ribs. 171 These cartilages attach to each other by fibrous tissue rather than to the sternum. Interruption of this fibrous tissue by trauma permits a rib to impinge on the adjacent rib, causing a click and sharp pain under the ribs. The symptoms may be precipitated in a number of ways, including forward flexion, deep breathing, and raising of the ipsilateral arm. The physician can reproduce the symptoms by hooking fingers under the inferior margins of the affected ribs and pulling anteriorly. Treatment consists of injection of local anesthetic or, if it does not heal, surgical excision of the subluxating cartilaginous rib tip.172
Costochondrltls Costochondritis, characterized by anterior chest wall pain that is reproduced by palpation of one or more of the costal cartilages, has been reported to be quite common in adolescents, constituting the reason for 4% of outpatient visits to one adolescent clinic. 173 It may result from trauma or idiopathic inflammation. 174 One, or occasionally, two or more costochondral junctions (usually the second or third) are painful and tender. The associated pain is usually acute and stabbing, often related to position or deep breathing. The syndrome can be self-limited or chronic and intermittent, lasting from a few months to a few years. Local anesthetic injections and anti-inflammatory medication may provide symptomatic relief. The term Tietze's syndrome is usually applied to a costochondritis in which, in addition to pain and tenderness of one or more costal cartilages, there is swelling overlying the affected costal cartilage.
Torticollis Torticollis, or wryneck, can accompany juvenile rheumatoid arthritis as a manifestation of cervical spine disease, develop due to a neurologic abnormality, or be caused by
an idiopathic shortening of a sternocleidomastoid muscle. Squints, if uncorrected surgically, may lead to a head tilt that can become permanent, with consequent asymmetry of the facial structures. Acute torticollis is transient if associated with trauma or cervical adenitis. The phenothiazine group of drugs and psychogenic disorders may also cause an acute torticollis. 17s Although acute torticollis has usually been considered to be caused by an atlantoaxial rotatory subluxation or atlantoaxial rotatory fixation, a careful imaging study of 33 children failed to demonstrate any such abnormalities. 176 Intensive physiotherapy177 and botulinum toxin178 should be administered before consideration of surgical release.
MISCELLANEOUS CONDITIONS
Growing Pains The term growing pains has significant positive and negative connotations. The positive aspect is that most parents accept it as a benign condition. Frequently, an immediate family member or family friend was diagnosed with growing pains that resolved without sequelae. The negative aspect is that this diagnosis has been too frequently applied to children who actually have a serious rheumatic or malignant disease. The term is a misnomer, because growth itself is not associated with the cause of the pain. The authors prefer the term benign nocturnal pains of childhood; however, no generally accepted alternative term exists. 179-181 The term should be restricted to identification of a fairly narrow spectrum of complaints (Table 36-9). Children who have unusual symptoms or abnormal findings on examination should not be diagnosed as having growing pains. Surveys of school-aged children have indicated that as many as 10% to 20% have had growing pains.179.181.182 Most growing pains occur in preschool- to school-aged children. The pain is sometimes crampy, usually localized to the lower extremities, and often located deep in the thigh, shin, or calf or behind the knee. Benign pain in the groin, back, or upper extremity is far less frequent. Growing pains may be precipitated by exercise and are usually relieved by massage. They occur in the evening or at night and often interrupt sleep. A few children have pain almost every night. Growing pains are never associ-
Ill'.
IABI E 3(, 'I
1_
of Childhood)
Age at onset Sex ratio Symptoms
Signs Investigations
GrowinlJ Pains (BenilJn NOt Illmal Pams
4 to 12 years Probably equal, slightly more girls in some series Deep aching, cramping pain in thigh or calf, usually in the evening or during the night; never present in the morning; bilateral; responds to massage and analgesia Physical examination results are normal Laboratory and radiographic studies (if done) have normal results
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NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS
ated with a limp, and symptoms disappear by morning. Children with such pain have completely normal patterns of activity and normal physical examinations during and after the episode. Results of laboratory studies and radiography are normal. The pathophysiology of the pain is unknown. Long experience with such pains in many children, however, has proved that they do not portend serious illness. Successful management of growing pains includes education of the child and family about the benign nature of the problem. Gentle massage with or without analgesics is usually effective. In children with frequent attacks, administration of an evening dose of either acetaminophen or a nonsteroidal anti-inflammatory drug may prove preventive. Passive stretching can also be of benefit. 183
Pernlosls (Chilblains) Perniosis is a cold-induced condition in which there are painful or pruritic, erythematous or violaceous, papular or nodular lesions, usually on the fingers or toes. 184,185 A history of wet cold exposure and typical skin changes establish the diagnosis. It can recur within a few minutes after re-exposure to cold. Perniosis may occur as an idiopathic condition, or it may be associated with an underlying systemic disease such as systemic lupus erythematosus. The histology of idiopathic perniosis consists of a predominantly T-cell papillary and deep infiltrate with a perieccrine accumulation, associated with dermal edema and necrotic keratinocytes. l86 Histology can help differentiate idiopathic pernio from lupus, but immunohistochemistry appears not to be helpful. 186 If the condition is severe, treatment with nifedipine may be beneficial. Ca~alTunnel Synd~rne
Carpal tunnel syndrome is a rare condition in children. A revtew of 64 cases found that about 50% were secondary to various lysosomal storage diseases and 25% were idiopathic. 187 The children often had long-standing, rather nonspecific symptoms, such as complaints of poor manual dexterity, before diagnosis. By the time of diagnosis, clinical findings of weakness and thenar wasting are often marked. Therefore, although the disease is uncommon, it is important to have a low threshold of suspicion, particularly in children with skeletal abnormalities. A controlled study of the clinical diagnostic tests in adults with electrophysiologically proven carpal tunnel syndrome found that the wrist-flexion test (Phalen maneuver) was the most sensitive, whereas the nerve-percussion or compression test (Tinel's sign) was least sensitive but most specific. l88 The tourniquet test was not very accurate, and these researchers suggested that it not be used in clinical practice. Because the results of all of these clinical tests are often normal, electrophysiologic testing is essential in any child in whom the diagnosis is suspected. 187 Importantly electrophysiologic tests often show bilateral abnormalities in children even if only one hand is affected clinically. Open operative release is the only treatment documented to be effective in children.
693
Neuralgic Arnyot~phy Neuralgic amyotrophy (brachial plexus neuropathy) is a rare condition with an annual incidence rate of 1 to 2 per 100,000 individuals. 189 It is more common in adults, but it does occasionally affect older children. It almost always manifests as an acute onset of pain in a shoulder, followed by localized muscle wasting, without restricted passive range of motion. 190-194 In a study of 40 affected individuals, there was bilateral involvement in 17.5% of cases. 195 In about half of the cases, it was preceded by a fever and symptoms of an upper respiratory tract infection. Seven of the cases were recurrent; in a number of individuals, there was evidence of a mononeuritis multiplex, with involvement of cranial or other nerves outside the brachial plexus. Some cases are familial. l90 ,191 It can occur after vaccination. The overall prognosis is good, but recovery may take many months, and physiotherapy is needed to minimize the risk of permanent joint contracture. Brachial neuritis follows a similar pattern but is accompanied by paralysis of the affected part. In a similar fashion, lumbosacral plexus neuropathy can occur, leading to leg pain and paralysis. l96 Characteristic electromyographic findings of damage to both the nerve roots and the peripheral nerves usually confirm the diagnosis.
Eryth~rnelalgla
Erythromelalgia (erythro = red, mel = limb, algia = pain) is a rare condition that manifests as episodic burning pain with accompanying erythematous, warm, swollen hands or feet (or both) that is eased by cold and elevation. 197 Affected patients refuse to stop using ice or cold water for their painful extremities. Exercise or heat (even wearing socks) can precipitate an attack. This condition occurs in three forms: erythromelalgia associated with thrombocythemia, primary erythromelalgia, and secondary erythromelalgia. l98 The most common form is that associated with thrombocythemia, which can occur in isolation or in association with polycythemia vera or myelofibrosis and is sensitive to treatment with aspirin. Primary erythromelalgia begins in childhood or adolescence and can be familial (autosomal dominant). 199 It affects girls more often than boys. It is almost always symmetrical and is resistant to treatment. Secondary erythromelalgia is more common in adults; it is associated with an underlying condition other than one associated with a platelet dysfunction and therefore is not aspirin responsive, It usually responds to treatment of the underlying disorder. Additionally, an epidemic form was reported in southern China that was caused by a poxvirus. zOO Treatment includes avoidance of exposure to heat, elevation of the extremity, and application of cold during acute attacks. If aspirin is unsuccessful, a host of treatments have been tried, each with a few case reports of benefit, including nifedipine, verapamil, nicardipine, pergolide, bromocriptine, busulfan, propranolol, posterior pituitary extract, epinephrine, biofeedback, hypnosis, sympathectomy, clonazepam, nitroprusside, prostaglandin El' amputation, and stereotactic destruction of the ventroposteromedial and centromedian regions of the thalamus.
694
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Restless Legs Syndrome Restless legs syndrome is a feeling of discomfort in, and an inability to keep from moving, the legs at night after resting or going to bed. It was reported in 17% of children attending two community-based general pediatric clinics. 20J It is relieved by activity and, therefore, frequently leads to insomnia. Periodic movements of the limb during sleep are common. These last less than 1 minute and rarely cause the child to awaken. Restless legs syndrome is more common in older adults but has been reported in children.202.203 The cause of this condition is unknown. It has been postulated that some children with "growing pains" really have the restless legs syndrome, but this would not seem to be true for the majority of such children. 204 Hyperactivity/attention deficit disorder may be more common in children with restless legs syndrome. 20J Recently, a study of a large French Canadian family mapped a locus conferring susceptibility to restless legs syndrome to chromosome 12q.205 Reducing caffeine intake is the first therapeutic step. A wide variety of medications, including pramipexole, clonidine, carbidopa/levodopa, and levodopa, have been reported to be helpful. 202.206
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99. Gaughan DM, Mofenson LM, Hughes MD, et al: Osteonecrosis of the hip (Legg-Calve-Perthes disease) in human immunodeficiency virus-infected children. PediatriCs 109: E74, 2002. 100. Lecuire F: The long-term outcome of primary osteochondritis of the hip (Legg-Calve-Perthes' disease). ] Bone Joint Surg Br 84: 636--640, 2002. 101. Lahdes-Vasama TT, Marttinen E], Merikanto ]E: Outcome of Perthes' disease in unselected patients after femoral varus osteotomy and splintage. J Pediatri Orthop 6B: 229-234, 1997. 102. Wang L, Bowen ]R, Puniak MA, et al: An evaluation of various methods of treatment for Legg-Calve-Perthes disease. Clin Orthop (314): 225-233, 1995. 103. Joseph B, Varghese G, Mulpuri K, et al: Natural evolution of Perthes disease: a study of 610 children under 12 years of age at disease onset. ] Pediatr Orthop 23: 590--600, 2003. 104. Sorenson KH: Scheuermann's Juvenile Kyphosis. Copenhagen, Munksgaard, 1964. 105. Tachdjian MO. Pediatric Orthopedics. Philadelphia, WB Saunders, 1972. 106. Moe ]H, Winter RB, Bradford DS, et al. Juvenile Kyphosis, Scoliosis and Other Spinal Deformities. Philadelphia, WB Saunders, 1978. 107. Poolman RW, Been HD, Ubags LH. Clinical outcome and radiographic results after operative treatment of Scheuermann's disease. Eur Spine] 11: 561-569, 2002. 108. Soo CL, Noble PC, Esses SI: Scheuermann kyphosis: long-term follow-up. Spine] 2: 49-56, 2002. 109. Giannestras NJ: Other problems of the forepart of the foot. In Giannestras N] (ed): Foot Disorders. Philadelphia, Lea & Febiger, 1973, p 410. 110. Borges ]L, Guille ]T, Bowen ]R: Kohler's bone disease of the tarsal navicular. J Pediatr Orthop 15: 596--598, 1995. 111. Braddock GTF: Experimental epiphyseal injury and Freiberg'S disease. ] Bone Joint Surg Br 41: 154, 1959. 112. Stanley D, Betts RP, Rowley 01, Smith TW: Assessment of etiologic factors in the development of Freiberg's disease.] Foot Surg 29: 444-447, 1990. 113. Molloy MG, Hamilton EB: Thiemann's disease. Rheumatol Rehabil 17: 179-180, 1978. 114. Gewanter H, BaumJ: Thiemann's disease.] Rheumatol 12:150-153, 1985. 115. Allison AC, Blumberg BS: Familial osteoarthropathy of the fingers. ] Bone Joint Surg Br 40: 538, 1958. 116. Stougaard J: Familial occurrence of osteochondritis dissecans. ] Bone Joint Surg Br 46: 542, 1964. 117. Robinson RP, Franck WA, Carey E], Goldberg EB: Familial polyarticular osteochondritis dissecans masquerading as juvenile rheumatoid arthritis. ] Rheumatol 5: 190-194, 1978. 118. Bohndorf K: Osteochondritis (osteochondrosis) dissecans: a review and new MRl classification [reviewl. Eur Radiol 8: 103--112, 1998. 119. Koch S, Kampen WU, Laprell H: Cartilage and bone morphology in osteochondritis dissecans. Knee Surg, Sports Traumatol, Arthrosc 5: 42-45, 1997. 120. Yoshida S, Ikata T, Takai H, et al: Osteochondritis dissecans of the femoral condyle in the growth stage. Clin Orthop (346): 162-170, 1998. 121. Nelson DW, DiPaola], Colville M, Schmidgall ]:. Osteochondritis dissecans of the talus and knee: prospective comparison of MR and arthroscopic classifications. ] Comput Assist Tomogr 14: 804-808, 1990. 122. De Smet AA, Ilahi OA, Graf BK:. Untreated osteochondritis dissecans of the femoral condyles: prediction of patient outcome using radiographic and MR findings. Skeletal Radiol 26: 463-467, 1997. 123. Poussa M, Schlenzka D, Yrjonen T:. Body mass index and slipped capital femoral epiphysis.] Pediatr Orthop B 12: 369-371, 2003. 124. Stott S, Bidwell T:. Epidemiology of slipped capital femoral epiphysis in a population with a high proportion of New Zealand Maori and Pacific children. N Z MedJ 116: U647, 2003. 125. Loder RT, Mehbod AA, Meyer C, Meisterling M:. Acetabular depth and race in young adults: a potential explanation of the differences in the prevalence of slipped capital femoral epiphysis between different racial groups? ] Pediatr Orthop 2003; 23: 699-702, 2003. 126. Lalaji A, Umans H, Schneider R, et al: MRl features of confirmed "pre-slip" capital femoral epiphysis: a report of two cases. Skeletal Radiol31: 362-365, 2002. 127. Loder RT:. Slipped capital femoral epiphysis in children. Curr Opin Pediatr 7: 95-97, 1995. 128. Mandell GA, Keret D, Harcke HT, Bowen ]R:. Chondrolysis: detection by bone scintigraphy. ] Pediatr Orthop 1992; 12: 8Q--85, 1992. 129. Spero CR, Masciale JP, Tornetta P3d, et al: Slipped capital femoral epiphysis in black children: incidence of chondrolysis. J Pediatr Orthop 12: 444-448, 1992. 130. Carney BT, Weinstein SL: Natural history of untreated chronic slipped capital femoral epiphysis. Clin Orthop (322): 43-47, 1996. 131. Duncan JW, Nasca R, Schrantz J: Idiopathic chondrolysis of the hip. J Bone Joint Surg Am 61: 1024-1028, 1979. 132. Bleck EE: Idiopathic chondrolysis of the hip. ] Bone Joint Surg Am 65: 1266--1275, 1983. 133. del Couz GA, Fernandez PL, Gonzalez MP, et al: Idiopathic chondrolysis of the hip: long-term evolution. J Pediatr Orthop 19: 449-454, 1999. 134. Koot MF, Berendsen HA, vad der Hoeven H, et al: Three adolescenl~ with hip pain caused by idiopathic chondrolysis. Ned Tijdschr Geneeskd 137: 86--90, 1993. 135. Brown], Melinkovich P: Schonlein-Henoch purpura misdiagnosed as suspected child abuse: a case report and literature review.]AMA 256: 617--618. 1986. 136. Carrera GF, Kozin F, McCarty DJ: Arthritis after frostbite injury in children. Arthritis Rl1eum 22: 1082-1087, 1979.
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NONINFLAMMATORY MUSCULOSKELETAL PAIN CONDITIONS
137. Dreyfuss ]R, Glimcher MJ Epiphyseal injury following frostbite. N Engl ] Med 253: 1065, 1955. 138. Brown FE, Spiegel PK, Boyle WE]: Digital deformity: an effect of frostbite in children. Pediatrics 71: 955-959, 1983. 139. Derwin KA, Glover RA, Wojtys EM: Nociceptive role of substance-P in the knee joint of a patient with congenital insensitivity to pain. ,T Pediatr Orthop 14: 258-262, 1994. 140. Indo Y, Tsuruta M, Hayashida Y, et al: Mutations in the TRKAINGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13: 485-488, 1996. 141. Nellhaus G: Neurogenic arthropathies (Charcot's joints) in children: description of a case traced to occult spinal dysraphism. Clin Pediatr 14: 647-653, 1975. 142. Leboeuf-Yde C, Kyvik KO: At what age does low back pain become a common problem? A study of 29,424 individuals aged 12-41 years. Spine 23: 228-234, 1998. 143. Balague F, Skovron ML, Nordin M, et al: Low back pain in school children: a study of familial and psychological factors. Spine 20: 1265-1270, 1995. 144. Kristjansdottir G: Prevalence of self-reported back pain in school children: a study of sociodemographic differences. Eur] Pediatr 155: 984--986, 1996. 145. Kujala UM, Taimela S, Erkintalo M, et al: Low-back pain in adolescent athletes. Med Sci Sports Exerc 28: 165-170, 1996. 146. Ramirez N, Johnston CE, Browne RH: The prevalence of back pain in children who have idiopathic scoliosis.] Bone Joint Surg Am 79: 364-368, 1997. 147. Volinn E: The epidemiology of low back pain in the rest of the world: areview of surveys in low- and middle-income countries. Spine 22: 1747-1754, 1997. 148. Turner PG, Green ]H, Galasko CS: Back pain in childhood. Spine 14: 812-814, 1989. 149. Malleson P, Clinch]: Pain syndromes in children. Curr Opin Rheumatol 15: 572-580, 2003. 150. Hayden lA, Mior SA, Verhoef M]: Evaluation of chiropractic management of pediatric patients with low back pain: a prospective cohort study. ] Manipulative Physiol Ther 26: 1-8, 2003. 151. Szpalski M, Gunzburg R, Balague F, et al: A 2-year prospective longitudinal study on low back pain in primary school children. Eur Spine] 11: 45~64, 2002. 152. Cardon GM, De Clercq DL, De Bourdeaudhuij 1M: Back education efficacy in elementary schoolchildren: a I-year follow-up study. Spine 27: 299-305, 2002. 153. Rowe BH, Dulberg CS, Peterson RG, et al: Characteristics of children presenting with chest pain to a pediatric emergency department. Can Med Assoc] 143: 388-394, 1990. 154. Gumbiner CH: Precordial catch syndrome. South Med] 96: 38-41, 2003. 155. Morita T, 1kata T, Katoh S, Miyake R: Lumbar spondylolysis in children and adolescents.] Bone Joint Surg Br 77: 620-625, 1995. 156. Beutler WI, Fredrickson BE, Murtland A, et al: The natural history of spondylolysis and spondylolisthesis: 45-year follow-up evaluation. Spine 28: 1027-1035, 2003. 157. Sponseller PD: Evaluating the child with back pain. Am Fam Physician 54: 1933-1941, 1996. 158. Payne WK3, OgilVie JW: Back pain in children and adolescents. Pediatr Clin North Am 3: 899-917, 1996. 159. Ralston S, Weir M: Suspecting lumbar spondylolysis in adolescent low back pain. Clin Pediatr 37: 287-293, 1998. 160. Muschik M, Hahnel H, Robinson PN, et al: Competitive sports and the progression of spondylolisthesis. ] Pediatr Orthop 16: 364-369, 1996. 161. Debnath UK, Freeman B], Gregory P, et al: Clinical outcome and return to sport after the surgical treatment of spondylolysis in young atWetes. ] Bone Joint Surg Br 85: 244-249, 2003. 162. Matsui H, Terahata N, Tsuji H, et al: Familial predisposition and clustering for juvenile lumbar disc herniation. Spine 17: 1323-1328, 1992. 163. Bruske-Hohlfeld I, Merritt ]L, Onofrio BM, et al. Incidence of lumbar disc surgery: a population-based study in Olmsted County, Minnesota. Spine 1990; 15: 31-35, 1990. 164. Villarejo-ortega F], Torres Campa-Santamarina 1M, Bencosme-Abinader ]A, et al: [Lumbar disc disease in adolescents,] Rev Neurol 36: 514-517, 2003. 165. Martinez-Lage ]F, Fernandez CV, Lopez F, Poza M: Lumbar disc herniation in early childhood: case report and literature review. Childs Nerv Syst 19: 258-260, 2003. 166. Nelson CL, ]anecki C], Gildenberg PL, Saya G: Disk protrusions in the young. Clin Orthop 88: 142-150, 1972. 167. Ishihara H, Matsui H, Hirano N, Tsuji H: Lumbar intervertebral disc herniation in children less than 16 years of age: long-term follow-up study of surgically managed cases. Spine 22: 2044-2049, 1997. 168. Papagelopoulos P], Shaughnessy WJ, Ebersold M], et al: Long-term outcome of lumbar discectomy in children and adolescents sixteen years of age or younger. Spine 22: 2044-2049, 2004. 169. Lee ,TV, Ernestus RI, Schroder R, K1ug N: Histological study of lumbar intervertebral disc herniation in adolescents. Acta Neurochir (Wien) 142: 1107-1110,2000.
170. ParL.ini P, Di Silvestre M, Greggi T, et al: Lumbar disc excision in children and adolescents. Spine 26: 1997-2000, 2001. 171. Taubman B, Vetter VL: Slipping rib syndrome as a cause of chest pain in children. Clin Pediatr 35: 403-405, 1996. 172. Porter GE: Slipping rib syndrome: an infrequently recognized entity in children. A report of three cases and review of the literature. Pediatrics 76: 810-813, 1985. 173. Brown RT: Costochondritis in adolescents.] Adolesc Health Care 1: 198-201. 1981. 174. Calabro ]], Marshesano ]M: Tietze's syndrome: report of a case with juvenile onset. ] Pediatr 68: 985, 1966. 175. Bolthauser E: Differential diagnosis of torticollis in childhood. Schweiz Med Wochenschr 106: 1261, 1976. 176. Hicazi A, Acaroglu E, Alanay A, et al: Atlantoaxial rotatory fixation-subluxation revisited: a computed tomographic analysis of acute torticollis in pediatric patients. Spine 27: 2771-2775, 2002. 177. Smith DL, DeMario MC: Spasmodic torticollis: a case report and review of therapies.] Am Board Fam Pract 9: 435-441, 1996. 178. Lew MF, Adornato BT, Duane DO, et al: Botulinum toxin type B: a doubleblind, placebo-controlled, safety and efficacy study in cervical dystonia. neurology 49: 701-707, 1997. 179. Peterson H: Growing pains. Pediatr Clin North Am 33: 1365-1372, 1986. 180. Brady M, Grey M: Growing pains: a myth or reality. I Pediatr Health Care .~: 219-220, 1989. 181. Oster], Nielsen A: Growing pains: a clinical investigation of a school population. Acta Pediatr Scand 61: 329-334, 1972. 182. Apley]: One child. In Apley], Ounsted C (edsl: One Child. Philadelphia, ]B Lippincott, 1982, pp 23-47. 183. Baxter MP, Dulberg C: "Growing pains" in childhood: a proposal for treatment.] Pediatr Olthop 8: 402-406, 1988. 184. Goette DK: Chilblains (perniosis). J Am Acad Dermatol 23: 257-262, 1990. 185. Crowson AN, Magro CM: Idiopathic perniosis and its mimics: a clinical and hIstological study of 38 cases. Hum Patho! 28: 478-484, 1997. 186. Cribier S, Djeridi N, Peltre B, Grosshans E: A histologic and immunohistochemical study of chilblains. I Am Acad Dermatol 45: 924-929, 2001. 187. Lamberti PM, Light TR: Carpal tunnel syndrome in children. Hand Clinics 18: 331-337, 2002. 188. Gellman H, Gelberman RH, Tan AM, Botte M]: Carpal tunnel syndrome: an evaluation of the provocative diagnostic tests. ] Bone ,Toint Surg Am 68: 735-737, 1986. 189. Rubin 01: Neuralgic amyotrophy: clinical features and diagnostic evaluation. Neurology 7: 350-356, 2001. 190. Lane R], Dewar ]A: Bilateral aneuralgic amyotrophy. Br Med] 6117: 895, 1978. 191. Dunn HG, Daube ]R, Gomez MR: Heredofamilial brachial plexus neuropathy (hereditary neuralgic amyotrophy with brachial predilection) in childhood. Dev Med Child Neurol 20: 28-46, 1978. 192. Shaywitz BA: Brachial plexus neuropathy in childhood. ] Pediatr 86: 913-915, 1975. 193. Bale IF ]r, Thompson lA, Petajan IH, Ziter FA: Childhood brachial plexus neuropathy.] Pediatr 95: 741-742, 1979. 194. Zeharia A, Mukamel M, Frishberg Y, et al: Benign plexus neuropathy in children. I Pediatr 116: 276-278, 1990. 195. Cruz-Martinez A, Barrio M, Arpa]: Neuralgic amyotrophy: variable expression in 40 patients. ] Peripher Nerv Syst 7: 198-204, 2002. 196. van A1fen N, van Engelen BG: Lumbosacral plexus neuropathy: a case report and review of the literature. Clin Neurol Neurosurg 99: 138-141, 1997. 197. Kurzrock R, Cohen PR: Erythromelalgia: review of clinical characteristics and pathophysioiogy. Am] Med 91: 416-422, 1991. 198. Drenth ]P, Michials]]: Three types of erythromelalgia. Br Med] 301: 454-455, 1990. 199. Finley WH, Lindsey]R], Fine ]0, et al: Autosomal dominant erythromelalgia. Am] Med Genet 42: 310-315, 1992. 200. Zheng ZM, Zhang,TH, Hu ]M, et al: Poxviruses isolated from epidemic erythromelalgia in China. Lancet 8580: 296, 1988. 201. Chervin RD, Archbold KH, Dillon ]E, et al: Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep 25: 213-218, 2002. 202. Walters AS, Picchietti DL, Ehrenberg BL, Wagner ML: Restless legs syndrome in childhood and adolescence. Pediatr Neurol 11: 241-245, 1994. 203. Walters AS, Hickey K, Maltzrnan ], et al: A questionnaire study of 138 patients with restless legs syndrome: the "Night-Walkers" survey. Neurology 46: 92-95, 1996. 204. Walters AS: Is there a subpopulation of children with growing pains who really have restless legs syndrome? A review of the literature. Sleep Med 3: 93-98, 2002. 205. Desautels A, Turecki G, Montplaisir ], et al: Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am I Hum Genet 69: 1266-1270, 2001. 206. Lin S-C, Kaplan], Burger CD: Effect of paramipexole in treatment of resistant restless legs syndrome. Mayo Clin Proc 73: 497-500, 1994.
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PAIN AND THE PAIN AMPLIFICATION SYNDROMES David D. Sherry and Peter N. Malleson
~ ANATOMY, PHYSIOLOGY, AND MEASUREMENT OF PAIN This chapter discusses a wide variety of musculoskeletal conditions that are not primarily caused by inflammation. Because pain is often the main symptom in these conditions, as it is for the so-called amplified pain syndromes, it is important to have some understanding of the nociceptor system and how pain is generated and perceived by the child. Pain has been defined by the Committee for Taxonomy of the International Association for the Snldy of Pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."] Pain therefore is a subjective interpretation of a noxious or apparently noxious stimulus. For most acute pain, the noxious stimulus is ohvious; however, for many children with chronic pain syndromes, the origin of the pain is much less clear. What is certain is that pain, whether acute or chronic, is influenced by multiple modulating factors and occurs at all levels of the nervous system. To understand a child's pain, one must be aware of the meH although many patients are only mildly affected and the diagnosis can be difficult. Children with the Marfan syndrome are tall; their arm span exceeds their height, and the pubis-to-heel measurement is greater than the crown-to-pubis distance. The palate is high and arched, and there may be other skeletal abnormalities such as moderate to severe kyphoscoliosis, pectus carinatum, slipped capital femoral epiphysis, and talipes equinovarus. Muscular hypotonia is common. Skin lesions include striae distensae and elastosis perforans serpiginosa. Ectopia lentis, with upward dislocation of the lens and iridodonesis, and cardiovascular abnormalities occur in about one third of patients.
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Cardiovascular involvement includes aortic root dilation and aneurysm formation, mitral valve prolapse, and conduction defects. Affected patients often die unexpectedly from cardiac complications, and the value of pharmacologic approaches to the prevention of such developments is uncertain. 148 Criteria for the diagnosis of Marfan syndrome have been proposed. 149 A definite diagnosis requires the presence of an abnormality in at least three of the categories listed in Table 40-11. Collagen turnover is increased, and a cross-linking defect has been proposed. The defective type 1 fibrillin gene has been localized to chromosome 15, and the disease is inherited in an autosomal dominant manner. A number of variants of the Marfan syndrome have been associated with different mutations in the fibrillin gene (FBN1J,l50 An excellent overview of the Marfan syndrome is provided by Pyeritz.I'i1 Objective measurements that are of some use in the diagnosis of the Marfan syndrome include the ratio of the upper segment (US, vertex to pubis) to the lower segment (LS, top of the pubis to floor) and the II
II
I ABLE 4()- 11
Diagnosis of Marfan Syndrome
757
metacarpal index. The US-to-LS ratio is usually increased to greater than 0.85 in children with the Marfan syndrome, but normal age-related changes and complications such as kyphoscoliosis make it difficult to apply, and the overall excessive height is a more important indicator. 152 The metacarpal index, a radiographic measurement of arachnodactyly, is the ratio of the length to the width of the midshaft of metacarpals (2-5). The normal value ranges from 5.4 to 7.9. In children with the Marfan syndrome, the ratio ranges from 8.4 to 10.4. 153
Congenital Contradural Arachnodactyly Congenital contractural arachnodactyly (McKusick 121020) may be confused with the Marfan syndrome. 154 There are congenital contractures of the knees, elbows, and proximal interphalangeal joints, but the hands and the feet are long as in the Marfan syndrome, and the head is elongated. Linear growth is accelerated. Early and progressive kyphoscoliosis may develop. The helix of the ear is abnormal. The defect is associated with a defect in the type 2 fibrillin gene (FBN2) localized to 5q23-q31, and the disorder in inherited as an autosomal dominant trait. ISS The contractures tend to improve as the child grows older.
Abnormalities of Skeletal and Connective nssue
Homocystinuria
Tall stature Long limbs (dolichostenomelia) Long fingers (arachnodactyly) High arched palate Joint laxity Congenital contractures (digits and elbows) Pectus deformity (carinatum or excavatum) Scoliosis Pes planus
Patients with type I homocystinuria resemble those with the Marfan syndrome. They are tall, have long limbs, and may have a high arched palate, arachnodactyly, myopia, peripheral retinal degeneration, and inferior (rather than superior) displacement of the lensY Affected children are light skinned and fair haired. Cutaneous ulcerations and livedo reticularis are common. Hypotonia is present, but the joints are usually stiff rather than hyperextensible. Progressive severe osteoporosis and mental retardation are characteristic. The basic biochemical defect, a deficiency of cystathionine synthetase, is inherited as an autosomal recessive trait. There is an accumulation in tissues of the sulfur-containing amino acids homocystine, homocysteine, serine, and methionine. There may also be a defect in collagen cross-linking. Demonstration of homocystine in the urine clearly differentiates children with homocystinuria from those with the Marfan syndrome. Treatment includes methionine restriction and pyridoxine supplementation. 156 Without therapy, arterial or venous thromboses lead to premature death. Types II and III homocystinuria differ from type I homocystinuria in the nature of the biochemical defect and in the absence of skeletal abnormalities and occlusive arterial disease. 157
OCular AbnormallUes Myopia Upward subluxation of the lens Flat cornea Retinal detachment
cardiovascular Abnonnalltles Aortic root dilatation Mitral valve prolapse Mitral valve regurgitation Aortic valve regurgitation Aortic dissection
Abnormalities of Skin and Integument Striae distensae Inguinal hernia Pneumothorax
Centnl Nervous System Abnonnalltles Dural ectasia Sacral meningocele Dilated cisterna magna
Family History Marfan syndrome in a first-degree relative Data from Pyeritz RE. McKusick VA: The Marfan syndrome: diagnosis and management. N Eng! J Med 300: 772, 1979.
DYSOSTOSIS MULTIPLEX The dysostosis multiplex group of disorders includes the mucopolysaccharidoses, the mucolipidoses, mannosidosis, fucosidosis, gangliosidosis, sialidosis, sialic storage disease, galactosialidosis, and mucosulfatidosis. Deficiency of a lysosomal degradative enzyme leads to an accumulation of its substrate within the lysosomes of
758
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~. TABLE flO 12 MU((lPoIYSd((h,uidoses Type
Name
Inheritance
MPS
Enzyme Defect
Clinical Features
IH
Hurler
AR
OS, HS
a-L-iduronidase
IS
Scheie"
AR
OS, HS
a-L-iduronidase
II IlIA
Hunter Sanfilippo
XR AR
OS, HS HS
IIID IVA
Morquio
AR
KS
Iduronate sulfatase Heparan-N-sulfatase N-acetyl-a-n-glucosaminidase Acetyl-CoA-glucosaminidase acetyltransferase N-acetyl-glucosamine-6-sulfatase N-acetylgalactosoamine-6-sulfatase
Corneal clouding, dysostosis multiplex, heart disease, severe mental retardation, death in childhood Milder skeletal disease, normal intelligence, normal life span (?) Milder than type I; no corneal clouding Mild skeletal, severe CNS abnormalities
IVB VI
Maroteaux-Lamy
AR
OS
N-acetylgalactosoamine-4-sulfatase
VII
Sly
AR
OS, HS
~-Glucuronidase
IIIB IIIC
Severe skeletal changes; corneal clouding; normal intelligence
~-Galactosidase
Severe skeletal changes, corneal clouding, heart disease, normal intelligence Dysostosis multiplex, variable intelligence, hepatosplenomegaly, white blood cell inclusions
'Formerly classified as Type V. DS, dermatan sulfate; GS, heparan sulfate; KS, keratan sulfate; MPS, mucopolysaccharide found in urine. Modified from Beighton P: McKusick's Heritable Disorders of Connective Tissue, 5th ed. St. Louis, Mosby-Year Book, 1993.
the cell. 45 The phenotype of the specific disease depends on the tissue distribution of the enzyme deficiency. The resulting multisystem degenerative disorders are progressive and unremitting, Skeletal changes include dwarfism, joint contractures, and dysostosis multiplex. Although these disorders are classified as osteochondrodysplasias, they differ from all other members of that group in that they are storage disorders.
In Scheie's syndrome (MPS type I S) CMcKusick 252800), intelligence is normal, and stature is preserved. However, there is progressive stiffening of the joints of the hands, elbows, and knees without swelling or pain. Corneal clouding occurs. All acute phase reactants are normal, but urinary excretion of dermatan sulfate is increased.
Mucollpldoses Mucopolysaccharldoses The mucopolysaccharidoses are genetically determined deficiencies of enzymes involved in the metabolism of glycosaminoglycans (Table 40-12).45 Progressive skeletal dysplasia particularly affects the vertebrae, hips, and hands. 45 ,J58 In the more severe types, such as Hurler's syndrome (i.e., mucopolysaccharidosis [MPS] type I H), dwarfism and marked coarsening of the facial features are present. Deposition of mucopolysaccharide leads to mental retardation and corneal clouding, A claw-hand deformity is often the first clue to the diagnosis. Two of these storage diseases particularly mimic inflammatory arthritis. The comparatively mild dysostosis but severe dwarfing of Morquio's syndrome (MPS type IV) CMcKusick 253000, 252300, 230500) may suggest ]IA. Children with this syndrome, who have normal intelligence, may present with an effusion of a large joint (particularly the knee) or with progressive musculoskeletal stiffness, usually by 3 or 4 years of age. The small joint,> of the hands become enlarged and stiff, a valgus deformity of the knees develops, and the gait becomes stiff and waddling. The joints are not always stiff, however, and some joints (such as the wrists), although enlarged, may be hypermobile. A pectus deformity and barrel chest are usual features. Characteristic radiographic flndings include platyspondyly and odontoid hypoplasia and should help differentiate this disorder from the various forms of spondyloepiphyseal dysplasia. J59 Urinary excretion of keratan sulfate is increased.
The term mucolipidosis (ML) is applied to a group of four disorders that are characterized by the intracellular accumulation of glycosaminoglycans and sphingolipids but without excess urinary glycosaminoglycan excretion. Progressive neurologic and ocular abnormalities occur in all of these autosomal recessive disorders (Table 40-13).44 ML type I (McKusick 256550), an isolated neuraminidase (sialidase) deficiency, causes a Hurler-like syndrome with joint contractures, short trunk and stature, and dysostosis multiplex (i.e., vertebral anomalies, hypoplastic odontoid and ilia, coxa valga, and deformed capital femoral epiphyses). Urinary excretion of sialated
II Type
TABL E 40 13
Mucolipidoses
Name
Enzyme Defect
Sialidase deficiency
Sialidase deficiency
II
I-cell disease
Phosphotransferase deficiency
III
Pseudo-Hurler's polydystrophy
Phosphotransferase deficiency
IV
Sialolipidosis
Uncertain
Musculoskeletal Features Contractures, short stature, dysostosis multiplex Progressive limitation of range of motion Progressive limitation of range of motion; dysostosis multiplex No characteristic skeletal changes
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urinary oligosaccharides (bound sialic acid) is markedly elevated. I-cell disease (i.e., ML type II) also causes a Hurler-like syndrome with progressive limitation of joint range of motion; the name is derived from the presence of prominent intracytoplasmic CD inclusions in cultured fibroblasts. The biochemical defect is not clearly understood but appears to involve an abnormality in the cellular localization of acid hydrolases. Pseudo-Hurter's polydystrophy is a term applied to ML type III (McKusick 252500). Restriction of joint mobility becomes apparent by 2 years of age, but there is no inflammatory arthritis. Radiologic findings are those of dysostosis multiplex. By 6 years of age, features of Hurler's syndrome dominate the clinical picture. Prognosis for life is good. Inclusions are also found in cultured fibroblasts from some patients with this disease; they probably represent a milder form of ML type II. In ML type IV (McKusick 252600), there are no characteristic skeletal abnormalities.
759
Chondrodysplasia punctata is a peroxisomal disorder. A milder form (McKusick 302960) is associated with deletion of the distal short arm of the X chromosome and manifests as an X-linked recessive disorder. In the X-linked dominant ConradiHunermann disease (McKusick 302960), the limbs are characteristically affected asymmetrically, and contraetures or deformities of the feet may be present. Radiologic abnormalities include stippling of the vertebrae and epiphyses representing disturbed epiphyseal maturation that leads to asymmetric growth. The skin often has patches of ichthyotic change. Only females are affected; it appears to be lethal in males. Genetically determined abnormalities in sterol metabolism may be pathogenically related. 165
Chondrodysplasia punctata has been observed in one infant with neonatal lupus. 166.167 The disorder is also associated with the maternal use of warfarin 168 and maternal vitamin K deficiency.169
Osteopetrosis
A great many disorders of cartilage and bone defy classification. Some appear to have a genetic basis; others have an inflammatory component as well. Those likely to be of interest to the pediatric rheumatologist are briefly summarized in this section.
Osteopetrosis (McKusick 166600, 259700) is a rare disorder that may manifest at birth with frontal bossing, hypertelorism, exophthalmos, nasal obstruction, and cranial nerve palsies. It progresses in severity during infancy and early childhood with repeated fractures, abnormal bleeding, seizures, and early death. The density of all bones is increased, and the metaphyses are flared. Bone marrow transplantation offers hope of effective treatment. 170 Albers-Schonberg disease is a form of osteopetrosis with late onset that is milder in degree than the early-onset form. It is inherited as an autosomal dominant trait. 171
Pseudopseudohypoparathyroidism
Melorheostosis
Pseudopseudohypoparathyroidism, also known as Albright's hereditary osteodysplasia, is characterized by short fourth metacarpals, short stature, and sometimes by mental retardation, a round face, and subcutaneous calcifications. Hypocalcemia and hyperphosphatemia may occur. The condition results from defects in the ~ subunit of the G protein. 160 There is an unusual pattern of inheritance in that children who inherited the gene from the mother are more severely affected than those who inherited the gene from the father (i.e., genomic imprinting).161
Patchy disorders such as melorheostosis (McKusick 155950) and McCune-Albright syndrome (McKusick 174800) appear to result from somatic mutations. Melorheostosis develops after the neonatal period and commonly affects only one limb. Clinically, there may be intermittent swelling and pain around joints, with loss of range of motion and development of contractures at the wrists, elbows, hips, and knees. 172 Skin changes may precede contractures and include tense, red, shiny skin with edema of the subcutaneous tissues. Melorheostosis may occur together with other radiographic abnormalities such as osteopoikilosis (Fig. 40-9).173,174 Melorheostosis of the iliac bone has been described in a boy with linear scleroderma. m Radiographs show cortical hyperostosis in a pattern resembling dripping candle wax, sometimes with endosteal hyperostosis and prominent soft tissue calcification.
OTHER DISORDERS
Pseudoachondroplasia Pseudoachondroplasia, a relatively common form of disproportionate short stature (McKusick 177170), is not present at birth but becomes obvious between the ages of 1 and 2 years. There is mild shortening of the trunk, shortening of limbs with hyperextensible joints, but normal face and skull. The spectrum of short stature is very broad, and it has been suggested that mosaicism plays a role in determining severity.162 Radiographs show platyspondyly and delay in maturation of epiphyses. Because of ligamentous laxity, degenerative arthritis develops, and joint replacement may become necessary. Pseudoachondroplasia is caused by mutations in the cartilage oligomeric matrix protein. 163
Engelmann's Syndrome Engelmann's syndrome, or progressive diaphyseal dysplasia (McKusick 131300), manifests early in childhood with leg pain, abnormalities of gait, muscle weakness, and pain. Radiographs reveal thickening and sclerosis of the cortex of long bones (Fig. 40-10). It is an autosomal dominant disorder, although the gene is not known. Glucocorticoid therapy was reported to be successful in one patient. 176 The abnormalities may resolve spontaneously in adolescence. 177
Chondrodysplasia Punctata The term chondrodysplasia punctata describes a radiologic appearance rather than a specific disease and occurs in a number of conditions. In the autosomal recessive rhizomelic type of chondrodysplasia punctata (McKusick 215100), there are joint contractures, large head, cataracts, and ichthyosis-like skin changes. Most infants with this syndrome die within the first year of life. l64
Osteolyses There are several disorders in which bone dissolves or disappears (McKusick 166300, 259600). The idiopathic osteolyses are grouped according to the area predominantly affected: phalangeal, carpal/tarsal, or multicentric. Familial aero-osteolysis is
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• Figure 40-10 Radiograph illustrates the thickening and sderosis of the diaphyseal cortex of the femurs of a child with diaphyseal dysplasia (i.e., Camurati-Engelmann syndrome). (Courtesy of Dr. R. Cairns.) • Figure 40-9 Radiograph of the hand of a 15-year-old girl with a history of fractures in her toes and diffuse musculoskeletal pain. All bones except the skull were affected by osteopoikilosis, melorheostosis, and fibrous dysplasia.These abnormalities may occur in isolation, with cate-au-Iait spots and sexual precocity (fibrous dysplasia in McCune-Albright syndrome), or as multiple sclerosing bone dysplasia, as in this patient. (Courtesy of Dr. R. Cairns.)
inherited as an autosomal dominant trait and becomes apparent at about 3 years of age (Fig. 40-11).178,179 The carpus or tarsus alone may be affected, or the bones of the hands, feet, elhows, and knees may be involved. The onset can mimic JIA in that affected areas are swollen and warm. Eventually, radiographs show progressive bone lysis and destruction of the involved joints. Spontaneous remissions during the young adult years are characteristic. 1Ho ,lHI The osteolysis is often associated with pain or neuropathic changes and may lead to skin ulcerations that overlie the bony abnormalities. Hereditary distal osteolysis, inherited as an autosomal dominant trait, involves the phalanges and metacarpal or metatarsal bones, and it produces recurrent ulcerations at the affected sites, It usually manifests during late childhood. Spontaneous remission is usual, but unfortunately does not occur before there is loss of digits. IH2
Disorders such as Winchester's syndrome (McKusick 277950), a form of multicentric osteolysis, begin at about 6 weeks of age with restricted joint mobility, swelling, and pain of the proximal interphalangeal joints and enlargement of the wrists. 56 ,1 83,1H4 Later, corneal clouding, coarsening of the face, and joint contractures occur. Osteoporosis, bone erosion, and atlantoaxial subluxation are characteristic radiographic findings. Phantom bone disease (Le., Gorham's disease) occurs between the ages of 5 and 10 years and is not hereditary.18S A carpal/tarsal osteolysis is usual. Carpal/tarsal osteolysis associated with nephropathy has also been described.IHO,IHI
• Figure 40-11 Radiograph of the hand of a 3-year-old child with familial aero-osteolysis shows swelling of the wrist, dissolution of the carpal ossification centers, and generalized osteoporosis of the hand. The radius has overgrown the ulna.This child died later, probably from associated nephropathy.
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Arthrogryposls Arthrogryposis is the term used to refer to a number of disorders characterized by the presence of multiple congenital contractures. They all appear to result from decreased movement in utero and often produce apparent enlargement of joints, which is actually caused by loss of connective tissue and muscle. 22•23 These disorders tend to be nonprogressive and are not usually associated with pain.
Larsen's Syndrome Larsen's syndrome (McKusick 150250, 145600) is characterized by multiple dislocations of large joints, dysplasias of the spine, and midface hypoplasia. Dislocations cause pain and, if recurrent, may lead to degenerative joint disease. It is inherited as an autosomal dominant condition. 67 Analysis of one family suggests that the responsible gene is located on 3p21.1-pI4.1, which is close to, but distinct from, the collagen type VII (Xl chain gene. l l!6
Menkes' Syndrome The skeletal abnormalities of Menkes' syndrome include osteoporosis, repeated fractures, metaphyseal spurring, and wormian bones in the sutures of the skulL These features reflect an abnormality of copper metabolism, with low serum levels of ceruloplasmin and copper but high tissue levels of copper. 187 The OCCipital horn syndrome, formerly classified as EDS type IX, is also thought to be an abnormality of copper metaboIism. l88 It is characterized by bony occipiral horns, cutaneous hyperextensibility, joint hypermobility, and (in many patients) chronic diarrhea.
761
Cortical Hyperostosis Pachydermoperlostosls Pachydermoperiostosis is a rare autosomal dominant disorder characterized by onset (usually in adolescent boys) of a spadelike enlargement of the hands and feet, sometimes accompanied by pain along the distal long bones. 191- 193 In addition to the cylindrical enlargement of the digits, forearms, and lower legs, there may be minimal joint effusions, coarsening of the facial features, excessive oiliness of the skin, and occasionally gynecomastia, female hair distribution, striae, and acne.
Familial Infantile Cortical Hyperostosis (Caffey's Disease) Caffey's disease is a rare disorder that manifests before 4 months of age with fever, irritability, abnormal acute phase indices, and swelling, tenderness, erythema, or altered contour of the mandible, shoulder girdles, and long bones (Fig. 40-12).194-196 Bony involvement tends to be asymmetric. The calvaria is never affected. The ribs and clavicles are often involved by marked cortical thickening with altered bone shape. The cause is unknown, although the condition appears to be inflammatory and may be triggered by an infection. It usually has a self-limited course of weeks to months, after which it subsides without sequelae. Short-term treatment with glucocorticoids may be considered for the infant with severe disease and marked systemic symptoms. There appears to be a familial but nongenetic basis for this disorder (see also Chapter 28).
Camptodactyly The term camptodactyly refers to the presence of congenital or acquired flexion contractures of the proximal interphalangeal joints, resulting from soft tissue tightening without limitation of flexion. 189 It is most common in the fifth finger but can occur in all digits of the hand except the thumb. The cause is not certain but appears to be related to fibrotic changes in the subcutaneous tissue of the palmar aspect of the joint. Radiographs reveal neither bony nor articular abnormalities. Camptodactyly may occur with diseases such as the Marfan syndrome and has been reported in association with familial arthritis by Malleson and associates. 19O Three children in one family had iridocyclitis, and one boy died suddenly at the age of 4 years. Postmortem examination revealed chronic synovitis and granulomatous arteritis affecting the aorta, coronary arteries, myocardium, and pericardium. There have been other reports of familial camptodactyly, and a syndrome of camptodactyly, arthritis, coxa vara, and pericarditis has been described. The camptodactyly, arthritis, coxa vara, and pericarditis syndrome is inherited as an autosomal recessive disorder caused by a defective gene on chromosome lq25-q31Y It is characterized by congenital camptodactyly and childhood onset of noninflammatory synovial hyperplasia. Some patients have pericarditis; others have coxa vara. r'
• Figure 40-12 Marked hyperostosis of the radius in a 5-month-old boy with Caffey's disease.
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Disordered Development of Cartilage Trevor's Disease Patients with Trevor's disease have overgrowth of one of the tarsal or carpal bones or of an epiphysis, often at the knee or ankle. The abnormality is more common in boys than in girls, and it is self-limited. 197
Diaphyseal Aclasis Diaphyseal aclasis is characterized by cartilaginous and bony outgrowths from the metaphyses of long bones, ribs, pelvis, and scapulae. These may interfere with joint function. The gene causing this autosomal dominant condition has been localized to the long arm of chromosome 8 (8q23-q24.l).5
Oilier's Disease Multiple enchondromatosis, or Ollier's disease, becomes evident during childhood, with multiple juxta-articular outgrowths or fractures. Radiographs demonstrate the radiolucent cartilaginous areas in the metaphyseal regions of the tubular and flat bones. Multiple enchondromatosis with hemangiomas is called Maffucci's syndrome (see also Chapter 39).
Fetal Alcohol Syndrome Children with fetal alcohol syndrome have a characteristic facial appearance (i.e., flattening of the midface, short palpebral fissures, and smooth, elongated upper lip) but may also have flexion contractures of the elbows, restricted motion of the metacarpophalangeal joints, camptodactyly, and clinodactyly. Developmental delay, impaired linear growth, and cardiac septal defects are associated problems. 198
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159. Mikles M, Stanton RP: A review of Morquio syndrome. Am ./ Orthop 26: 533-540, 1997. 160. Ringel MD, Schwindinger WF, Levine MA: Clinical implications of genetic defects in G proteins: the molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy. Medicine (Baltimore) 75: 171, 1996. 161. Davies S./, Hughes HE: Imprinting in Albright's hereditary osteodystrophy. ./ Med Genet 30: 101-103, 1993. 162. Ferguson HL, Deere M, Evans R, et al: Mosaicism in pseudoachondroplasia. Am./ Med Gent 70: 287-291,1997. 163. Deere M, Sanford T, Ferguson HL: Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia. Am./ Med Genet 80: 510--513, 1998. 164. Spranger./, Opitz ./M, Bidder U: Heterogeneity of chondrodysplasia punctata. Humangenetik 11: 190--212, 1971. 165. 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765
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I
A A77-1726, 98 Aarskog's syndrome, 747t Absolute risk, 146t Abuse, 688-689 Academic research organizations, 155 Acanthosis nigricans, 741 Accelerated nodulosis, 95, 234 Acetylsalicylic acid administration of, 87 contraindications, 88 description of, 77-78 dosing of, 811 drug interactions, 88 glucocorticoids' effect on, 88 hypersensitivity to, 86 mechanism of action, 80, 87 pharmacology of, 87 stnJcture of, 77f toxicities associated with, 83t Achondroplasia, 746 Acne, 579 Acrocyanosis, 449 Acrodermatitis chronic atrophicans, 591, 593--594 Acromelic dysplasias, 755 Acromelic shortening, 744 Acro-osteolysis, 457 Actin, 16f Actin filaments, 15 Activation-induced cell death, 44, 45f, 46 Activities of daily living, 196 Actomyosin, 15 Actuarial method, 169 Acute adrenal insufficiency, 110-111 Acute chondrolysis of hip, 688 Acute interstitial nephritis with nephrotic syndrome, 85 Acute lupus pneumonitis, 355 Acute pain, 703 Acute rheumatic fever age at onset, 614 alleles with, 618t antistreptolysin 0 test, 616, 622 aortic insufficiency in, 619 arthritis in, 618, 623 carditis in, 618--619, 621-622 classification of, 614, 621-622 clinical manifestations of, 618--620, 619f course of, 624 definition of, 614 description of, 51 diagnosis of, 621-622 differential diagnosis, 622 endocarditis and, 619, 621 epidemiology of, 614-615 erythema marginatum associated with, 620, 620f etiology of, 615-616 gender ratio for, 614 genetic background of, 617-618 geographic distribution of, 614-615
group A streptococcus, 615-616 HLA antigens, 618 incidence of, 614 mitral regurgitation in, 619 morbidity in, 624 myocarditis in, 619 pathogenesis of, 615f pathologic findings in, 620-621 prevalence of, 614 prognosis for, 624 racial distribution of, 614-615 rheumatic heart disease prophylaxis, 623-624 skin manifestations of, 620, 620f streptococcal antibody tests for, 616-617 differential diagnosis, 622 pyrogenic exotoxins, 616 treatment of, 622, 623t subcutaneous nodules in, 620-621 Sydenham's chorea associated with, 620-623 tissue injury mechanisms, 617 treatment of, 622-623 Adalimumab, 123 Adaptive immune response, 28 Adaptive immunity characteristics of, 26, 28 definition of, 19 disorders of description of, 643t rheumatic disease associated with, 646-653 interleukin-6's role in, 57 Adaptive randomization, 153 Adenosine deaminase deficiency, 647t Adherence, 186, 186t Adolescent transition to adult care, 187-188 Adult-onset Still's disease, 297-298 Adverse drug effect, 150 Adverse event, 150 Affinity maturation, 30 Aggrecan, 11 Aldolase, 426, 477-478 A1endronate, 724f Alkaline phosphatase, 717, 717t Alkylating agents chlorambucil, 117, 117f cyclophosphamide. See Cyclophosphamide fertility effects of, 116 Allergic granulomatosis, 494t, 547f A1lodynia, 698, 706, 707t Allogeneic bone marrow transplantation with high-dose immunotherapy, 126 A1lotypes, 30 Alopecia, 352 Alphaviruses, 582-583 Altered peptide ligands, 37 Alternative hypothesis, 144 American College of Rheumatology description of, 2 founding of, 4
Page numbers followed by f refer to figures; page numbers followed by I refer to tables.
N D E
x
juvenile rheumatoid arthritis criteria, 206, 207t liver toxicity monitoring gUidelines of, 92 systemic lupus erythematosus criteria, 342, 343t American Juvenile Arthritis Organization, 7 t-Aminobutyric acid, 700 5-Aminoimidazole-4-carboxamide ribonucleotide, 88-89, 97 Amphiarthroses, 9 Amyloidosis juvenile psoriatic arthritis and, 331 juvenile rheumatoid arthritis and, 244 systemic arthritis and, 296-297 Amyopathic dermatomyositis, 413 Anakinra, 124, 238 Analysis of covariance definition of, 168 multivariate, 170 Analysis of variance multivariate, 170 multi-way, 167 nonparametric, 167 one-way, 167 Anaphylactoid purpura, 496 Anchor residues, 33 ANCOVA. See Analysis of covariance Androgenic hormone deficiency, 348 Anemia sickle cell, 635 in systemic lupus erythematosus, 367-368, 368f Anergy, 31, 119 Aneurysmal bone cyst, 735 Angiogenesis definition of, 57 juvenile psoriatic arthritis pathogenesis and, 326 Angiokeratoma corporis diffusum universale, 639 Ankle, 229 Ankle exercises, 194f Ankylosing spondylitis frequency of, 6t genetics of, 308-309, 309t New York diagnostic criteria for, 305t, 306 ANOVA. See Analysis of variance Anterior knee pain, 678 Anti-annexin XI, 425 Antibiotics description of, 118 Lyme disease treated with, 598t, 598-599 septic arthritis treated with, 573, 573t Antibodies diversity of, 30-31 to extractable nuclear antigens, 370-371 heavy chains, 28 light chains, 28 myositis-associated, 424-425 mYOSitis-specific, 424-425 structure of, 28 Antibody-dependent cellular cytotoxicity, 23,42 Anticardiolipin antibodies, 357-358, 368t
767
768
INDEX
Anti-CD40 ligand, 120--121 Anti-dsDNA antibodies, 369t, 369-370 Anti-a-fodrin antibodies, 394 Antigen(s) definition of, 28 human leukocyte. See Human leukocyte antigens oral administration of, 47-48 TO,39 TI,39 "Antigen" arrays, 73 Antigenic determinant, 30 Antigenic mimicry, 617 Antigen-presenting cells activation of, 48 B cells. See B cells dendritic cells, 36 description of, 28, 32 receptors, 36 T-cell interactions with, 34 T-cell recognition of, 41 types of, 36 Antiglobulins, 371 Antihistone antibodies, 371, 371t Anti-IL6 receptor antibody, 124-125 Anti-laminin autoantibodies, 394 Anti-La/SS-B antibodies in neonatal lupus erythematosus, 392-393 in systemic lupus erythematosus, 370, 370t Antimalarials description of, 96-97 juvenile rheumatoid arthritis treated with, 239 Antineutrophil cytoplasmic antibodies description of, 337 in Kawasaki disease, 522, 530 in polyarteritis nodosa, 515 small-vessel vasculitis, 504 in Wegener's granulomatosis, 541, 542f, 542t Antinuclear antibodies in diffuse cutaneous systemic scleroderma, 456 juvenile rheumatoid arthritis findings, 224-225 in morphea, 477 in polyarthritis, 268 in systemic lupus erythematosus, 369-371, 383 tests for, 224-225 in uveitis, 281-282, 328 Antiphospholipid antibodies, 368-369 Antiphospholipid syndrome catastrophic, 357-358 characteristics of, 357 description of, 346, 506 diagnostic criteria for, 357t management of, 380 systemic lupus erythematosus and, 357-358 Anti-Ro/SS-A antibodies in neonatal lupus erythematosus, 392 in systemic lupus erythematosus, 370, 370t Anti-Sm antibodies, 370--371, 371t Antistreptolysin 0 test, 616, 622 Anti-synthetase antibodies, 425 Anti-synthetase syndrome, 425 Anti-Ul RNP antibodies, 371, 371t Anti-UlRNP antibodies, 425 Antley-Bixler syndrome, 747t Aortic insufficienc.y, 619 Apert's syndrome, 747t Aphthous stomatitis description of, 352, 564 periodic fever with, 666-667 Apophyseal joints description of, 217 juvenile ankylosing spondylitis findings, 311
Apophysitis, pelvic, 681 Apoptosis activation-induced, 44 B cell, 42 definition of, 125 description of, 642 frequency of, 44 passive cell death, 44 pathways of, 44, 45f, 642 in systemic lupus erythematosus, 347 T-cell, 46 Arachidonic acid, 105 Area under the time-concentration curve, 150 Arteritis Takayasu's, 337, 548-550, 551f temporal, 493t-494t, 550--551 Arthralgia, 2 Arthritis. See also speeific arthritis acne and, 579 aseptic, 652 chronic,5 fungal, 584 gonococcal, 574 in immunocompromised patients, 575-576 infectious agents that cause, 214 ]acoub type of, 352 in juvenile ankylosing spondylitis, 310 Lyme, 597, 597t pancreatitis with, 638 postinfectious, 568, 585 sacroiliac in inflammatory bowel disease, 335 in juvenile ankylosing spondylitis, 315-316 in juvenile rheumatoid arthritis, 230--231 with scoliosis, 746t in systemic lupus erythematosus, 352 traumatic, 687-688 tuberculous, 574, 574f-575f word origin of, 2 Arthritis-dermatitis syndrome, 585 Arthrogryposis, 747t, 761 Arthropathy frostbite, 689, 689f gouty, 633 hemophilic, 636f psoriatic, 4t rubella virus-associated, 581-582 Articular cartilage anatomy of, 11£ chondrocytes of, 10--11 description of, 9-10 zones of, 10 Aschoff body, 621 Aseptic arthritis, 652 Aseptic meningitis, 673 Aseptic necrosis, 352, 353f Aspartic proteinases, 13, 14t Aspirin dosing of, 233-234 juvenile rheumatoid arthritis treated with, 233-234 Kawasaki disease treated with, 531 Assay sensitivity, 154 Ataxia telangiectasia, 647t Atheromata, 355 Atlantoaxial subluxation, 230, 231f Atrioventricular block, congenital animal models of, 400 description of, 393-394 endomyocardial fibroelastosis in, 395 epidemiology of, 395 history of, 394-395 long-term outcome for, 396 pathologic findings, 395 treatment of, 395-396 Atrophoderma of Pasini and Pierini, 472
Anributable risk, 146t Auranofin description of, 99-100 juvenile rheumatoid arthritis treated with, 239-240 Aurothioglucose, 100, lOOt Aurothiomalate description of, 99-100, lOOt juvenile rheumatoid arthritis treated with, 239 Autoantibodies in juvenile dermatomyositis, 424-426 in juvenile rheumatoid arthritis, 212 in neonatal lupus erythematosus, 393-394 in oligoarthritis, 277 in systemic arthritis, 292 Autoantigens, 48 Autoimmune diseases common variable immunodeficiency and, 652 development of, 48 environmental factors associated with, 49-50 gene mutations associated with, 49 genetic predisposition to, 48-49 juvenile rheumatoid arthritis and, 71, 216 major histocompatibility complexes and, 49 multifactorial origin of, 48 pathogenic effects in, 48, 49f tissue injury in leukocytes involved in, 52, 54-55 mechanisms of, 50--59 type I hypersensitivity, 50 Autoimmune lymphoproliferative syndrome, 45,642 Autoimmune polyendocrinopathy candidiasisectodermal dystrophy, 46 Autoimmune regulator, 46 Autoimmunity diffuse cutaneous systemic scleroderma and, 443-444 infection and, 49-50 Autologous bone marrow transplantation, 380 Autologous stem cell transplantation description of, 126 diffuse cutaneous systemic scleroderma treated with, 459-460 juvenile dermatomyositis treated with, 431-432 juvenile rheumatoid arthritis treated with, 240 severe combined immunodeficiency treated with,647 systemic arthritis treated with, 300 Autorecognition, 48 Avascular necrosis glucocorticoid-related, 107 Legg-Calve-Perthes disease, 684, 685f of femoral head, 684 Axial loading test, 707t Axial skeleton, 313-314 Azathioprine description of, 113f, 113-114, 114t systemic lupus erythematosus treated with, 378,378t Azurophilic granules, 19-20
B B7-1, 35, 43 B7-2, 35, 43 B cell(s) abnormalities of primary, 646-648 in systemic lupus erythematosus, 346
INDEX
activation of cytokines involved in, 41-42 signals for, 39 T helper-dependent mechanism of, 41-42 thymus-dependent, 40, 40f thymus-independent, 39-40, 40f apoptosis of, 42 development of, 31 immature, 31 immunodeficiencies of, 647t memory, 43 selection of, 31 T-cell interactions with, 40-42 B cell receptor complex, 40, 41£ B cell-activating factor of TNF, 42 Bl cells, 31 Back exercises, 193f Back pain diskitis, 689-690 epidemiology of, 689 nonorganic, 707t treatment of, 690 Baker's cyst, 217, 218f Band keratopathy, 280, 282f, 283 Bartonella henselae, 575 Basilar interstitial pneumonitis, 365-366 Bayesian approach, 161 Beaded filament-forming collagens, 12t Beals' contractural arachnodactyly syndrome, 6791, 747t Beh~et's syndrome central nervous system disease in, 563 classification of, 561 clinical manifestations of, 562-564 course of, 565 definition of, 561 description of, 102, 505 diagnosis of, 5611, 562t, 564 epidemiology of, 561 etiology of, 562 fever associated with, 658 gastrointestinal disease in, 564 genetic background for, 561-562 genital ulcers in, 565 history of, 561 HLA-B51 and, 562 imaging studies for, 564 laboratory examination for, 564 methylprednisolone for, 565 mucocutaneous disease associated with, 562-563 musculoskeletal disease and, 563 ocular disease in, 563, 565 oral ulcerations in, 562, 563f, 565 pathogenesis of, 562 pathologic findings of, 564 prednisone for, 565 prognosis for, 565 renal disease in, 564 skin manifestations of, 562-563 treatment of, 565 ulcerations in, 562, 563f, 565 uveitis in, 563 vascular disease in, 563-564 Benign angiitis of the central nervous system, 547 Benign hypermobility syndrome, 676 Benign rheumatoid nodules, 264, 264f Benign tumors chondroma, 730-731, 732f-733f eosinophilic granuloma, 735-736 fibrous cortical defect, 731-732, 734f fibrous dysplasia, 732-733 giant cell tumor, 735
juvenile fibromatosis, 732 of bone, 728-730 of cartilage, 730-731 of fibrous tissue, 731-734 of soft tissue, 734-735 osteochondroma, 730, 731£-732f pigmented villonodular synovitis, 734 synovial chondromatosis, 734-735 synovial hemangioma, 734, 734f Bias confounding, 159 description of, 158-159 interview, 159 measurement, 159 recall, 159 selection, 159 Bibasilar pulmonary fibrosis, 457, 459f Bimodal distribution, 160 Binomial test of proportions, 164 Bioavailability, 76 Bioinformatics, 66-67 Biologic therapies adalimumab, 123 anakinra, 124 etanercept, 121-122, 237 infliximab, 122-123 intravenous immunoglobulin, 118-119, 119t juvenile dermatomyositis treated with, 431-432 juvenile rheumatoid arthritis treated with, 237-238 tolerance induction, 119-120 Biotechnology, 66-67 Bisphosphonates adverse effects of, 724t chemical structure of, 724f osteogenesis imperfecta treated with, 749 osteoporosis treated with, 110, 724 Bleomycin, 454-455 Blind assessor, 152-153 Blinded withdrawal design, 154 Blinding, 152-153 Blocked randomization, 153 Bloom's syndrome, 349 Bone anatomy of, 716 biochemical markers associated with, 717-718 calcium-regulating hormones in, 718 composition of, 716-717 cortical, 716 diaphysis of, 716 endochondral ossification of, 716 epiphysis of, 716 glucocorticoid-related loss of, 107, 722 membranous ossification of, 716 metaphysis of, 716 remodeling of, 717t resorption of, 717-718 testosterone effects on, 716 trabecular, 716 turnover of, 717 Bone cysts, 735, 735f Bone disorders age at onset, 744 diagnosis of, 744-745 distribution of involvement, 744 molecular mechanisms of, 745 radiographic abnormalities associated with, 744-745 Bone marrow transplantation, 126, 380 Bone mass childhood arthritis effects on, 721 determinants ot~ 719 heredity factors, 719
769
low description of, 721 pediatric disorders associated with, 723t peak, 718-719 sex differences in, 718 Bone mineral(s) calcium-regulating hormones, 718 1,25-dihydroxyvitamin 03, 718 metabolism of, 716-717 osteoprotegerin, 718 receptor activator of nuclear factor-KB, 718 receptor activator of nuclear factor-leB ligand, 718 types of, 716-717 Bone mineral content, 718 Bone mineral density areal,720 description of, 718 drug treatment effects on, 722 measurement of dual x-ray absorptiometry,719-720 dual-energy x-ray absorptiometry, 719-720, 720f methods for, 720t quantitative computed tomography, 720, 720t quantitative high-frequency sonography, 720t, 720-721 volumetric, 720 Bone morphogenetic proteins, 9 Bone tumors benign, 728-730 characteristics of, 729t classification of, 728, 728t clinical presentation of, 728 malignant, 736-738 metastatic, 739 osteoblastoma, 729-730 osteoid osteoma, 729, 730f-731f, 730t osteosarcoma, 736-738, 737f Bonferroni correction, 162 Borrelia burgdorferi description of, 475, 592 laboratory detection of, 595-597 Brachial neuritis, 693 Brachial synovial cyst, 217, 217f Brachydactyly, 219, 219f, 227, 2291' Brain pain modulation by, 700 periaqueductal gray area of, 700 Brain-derived neurotrophic factor, 699 British Isles Lupus Assessment Group Activity Index, 372, 374t Broadband ultrasound attenuation, 720-721 Brodie's abscess, 576-577, 577t, 5781' Brucellosis arthritis associated with, 575 fever caused by, 657 Budd-Chiari ~)'ndrome, 367 Bullous morphea, 472 Bursae function of, 14 subscapular, 14 Bystander activation hypothesis, 50 Bystander immunosuppression, 48
c Cl deficiency of, 645-646 immune complex binding of, 645 inhibitors of, 25 C2 deficiency, 645, 646
770
INOEX
C3 deficiency of, 644, 646 description of, 24 juvenile rheumatoid arthritis levels, 225 C4 deficiency, 646 C5 deficiency, 646 C fibers, 697 Cadherins, 54t Caffey's disease, 578, 761 Calcineurin, 34, 117 Calcinosis in diffuse cutaneous systemic scleroderma, 447, 449f in juvenile dermatomyositis course of, 433 description of, 413, 416f management of, 432 Calcinosis circumscripta, 416f Calcinosis universalis, 417f Calcitriol, 110, 718 Calcium hormones that regulate, 718 osteoporosis prevention and, 722-723 Calcium pyrophosphate deposition disease, 635 Calreticulin, 393 Camptodactyly, 266, 761 Camptodactyly-arthropathy-coxa varapericarditis syndrome, 11, 746t, 761 Candidate genes, 68, 71 Canonical correlation, 170-171 Capacity-limited kinetics, 77 Carboxylterrninal propeptide of type I procollagen, 717, 717t Cardiac disease in diffuse cutaneous systemic scleroderma, 451 in juvenile rheumatoid arthritis, 221 in polyarthritis, 264-265 Cardiac tamponade juvenile rheumatoid arthritis and, 221 systemic arthritis and, 294 Cardiovascular system glucocorticoids effect on, 109 Kawasaki disease and, 526-527 Carpal tunnel syndrome, 693 Cartilage benign tumors of, 730-731 disordered development of, 762 malignant tumors of, 738 Cartilage oligometric matrix protein gene, 754 Cartilage-derived morphogenetic protein 1, 9 Cartilage-hair hypoplasia, 647t, 648 Cartilaginous joints, 9, lOt Cartilaginous tumors, 730-731 Case exposure rate, 146t Case-control classroom peers, 146 Case-controlled retrospective study, 145-146 Caspase-1, 56-57 Caspases, 44 Cataracts, 109 Catastrophic antiphospholipid syndrome, 357-358 Categorical variables, 157 Cathepsin B, 14t Cathepsin 0, 14t Cathepsin G, 14t Cathepsin L, 14t CCR7, 41, 43 CD!,29t C02,29t C03 deficiency of, 647t description of, 29t, 32 C04, 29t, 32
C05,29t C08 deficiency of, 647t description of, 32 COlla,29t C018,29t C019,29t C021,29t C027,29t C028, 29t, 35 C034,29t C040, 29t, 41 C040 ligand, 35, 38, 41 C044, 29t, 43, 444 C045, 29t, 43 C080,29t C086,29t C095, 29t, 44 C0152, 29t C0154, 29t, 120 cONA molecules, 65 Ceiling effect, 175t Celecoxib gastrointestinal effects of, 84 structure of, 78f Cell adhesion molecules description of, 54t in juvenile psoriatic arthritiS, 329 Cell cycle, 113 Cell-mediated immune reactions, 108 Central nervous system Beh~et's syndrome and, 563 benign angiitis of, 547 diffuse cutaneous systemic scleroderma effects, 451 glucocorticoids effect on, 108-109 juvenile ankylosing spondylitis findings, 311 juvenile rheumatoid arthritis findings, 222 Kawasaki disease effects, 527 methotrexate effects on, 95 nociceptive pathways, 697-698 nonsteroidal anti-inflammatory drug-related toxicities, 85 primary angiitis of, 547-548 systemic lupus erythematosus manifestations, 353-354, 354t, 366-367, 380 Central sensitization, 698f Central tolerance, 45-46 Cervical spine arthritis of, 311 radiographs of, 318f Charcot's joint, 689 Chediak-Higashi syndrome, 644 ChemokineCs) definition of, 54 description of, 52 inflammatory, 54 lymphoid, 54 subfamilies of, 54 types of, SSt Chemokine receptors, 26t Chest pain, 690-691, 69lt Chilblains, 449, 693, 708t Child Health Questionnaire, 177t, 180 Childhood Arthritis Health Profile, 177t, 179 Childhood Arthritis Impact Measurement Scales, 177 Childhood Health Assessment Questionnaire, 177t, 177-178,242-243 Childhood Myositis Assessment Scale, 180 Children's Hospital of Eastern Ontario Pain Scale, 702 Chi-square test errors with, 166
goodness-of-fit, 164 Mantel-Haenszel, 159, 166 McNemar, 166, 166t with more than one degree of freedom, 167 with one degree of freedom, 165, 165t Chlorambucil description of, 117, 117f juvenile rheumatoid arthritis treated with, 238 Choline magnesium trisalicylate, 77f, 234 Chondroblastoma, 731, 733f Chondrocalcinosis, 635 Chondrocytes, 10-11 Chondrodysplasia punctata, 399, 759 Chondroitin sulfate, 11 Chondroma, 730-731, 732f-733f Chondromalacia patellae, 680 Chondromyxoid fibroma, 731 Chondrosarcoma, 738 Chorea, 354 Chromosome maps, 65 Chronic arthritis. See also Juvenile chronic arthritis; Juvenile idiopathic arthritis; Juvenile rheumatoid arthritis American College of Rheumatology criteria for, 206, 207t classification of, 206 clinical manifestations of, 216-220 definition of, 206 European League Against Rheumatism classification criteria for, 206-207, 207t family history of, 213 historical review of, 208-209 International League of Associations for Rheumatology classification criteria for, 207-208 juvenile psoriatic arthritis as cause of, 324 osteoporosis risk factors in, 721t pain associated with, 216-217 selective IgA deficiency and, 649, 650f signs and symptoms of, 216 Chronic graft-versus-host disease, 453-454, 454t Chronic granulomatous disease, 643-644 Chronic infantile neurologic cutaneous and articular syndrome characteristics of, 67If clinical manifestations of, 660t, 673f--674f, 673-674 genetics of, 672 ocular findings in, 674f skin manifestations of, 673, 673f Stickler's syndrome vs., 750 treatment of, 674 Chronic pain, 192, 194, 703 Chronic recurrent multifocal osteomyelitis, 577-578, 580f, 708t Churg-Strauss syndrome, 493t, 545-546 Circinate balanitis, 607, 608f Circulus articularis vasculosus, 14 Clearance, 76-77 Clinical epidemiology, 144 Clinical equipoise, ISS Clinical research definition of, 143 obstacles to, 142 translational blocks in, 142 view of, 142 Clinical research organizations, 155 Clinical response claims, 156 Clinical studies bias in, 158-159 case-controlled retrospective, 145-146 concepts associated with, 143 confidence intervals, 161
INDEX experimental, 143 hypothesis-generating, 143 hypothesis-testing, 143 measures of central tendency, 159-160 meta-analysis, 143 non-normal distributions, 161 objectives of, 143 observational, 143 prospective, 143 prospective cohort study, 146 report of, 171 retrospective, 143 standard deviation, 160 standard error of the mean, 161 terminology associated with, 143 variables categorical, 157 concepts related to measurement of, 158-159 continuous, 157-158 ordinal, 157, 157f variance, 160 Z scores, 160-161 Clonal anergy, 46 Cluster of differentiation, 28, 29t Coagulation, 86 Cochrane Collaboration, 142 Cockayne's syndrome, 349, 747t Coefficient of concordance, 169 Cogan's syndrome, 518 Cohen's kappa, 169 Colchicine characteristics of, 101-102 diffuse cutaneous systemic scleroderma treated with, 460 dosing of, 102 familial Mediterranean fever treated with, 661 structure of, 102f Cold therapy, 197-198 Collagen beaded filament-forming, 12t biosynthesis of, 12, 13f characteristics of, 11-12 diffuse cutaneous systemic scleroderma and,445 fibril-associated collagens with interrupted triple-helices, 12t fibril-forming, 12t nerwork-forming, 12t of anchoring fibrils, 12t proteinases for, 13 with transmembrane domain, 12t type II, 749-750 types of, 11-12, 12t Collagen disorders classification of, 748t description of, 747 Ehlers-Danlos syndromes, 747-748, 749t Kniest's syndrome, 745, 751, 751£ osteogenesis imperfecta, 748-749, 749t-750t, 750f spondyloepiphyseal dysplasias, 751-752, 752f,752t Stickler's syndrome, 677t, 745, 746t, 750-751 type I, 748-749 type II, 749-752 type III, 752-753 type IV, 753 type IX, 754 type V, 753 type VI, 754 type X, 754
Collagenase, 14t Collectin, 26 Combined immunodeficiency, 648 Common variable immunodeficiency, 649, 651-653 Comparative clinical trials, 152, 154-155 Complement cascade, 25, 50 Complement deficiencies description of, 25 rheumatic diseases associated with, 644-646 in systemic lupus erythematosus, 344-345, 371 Complement receptors, 24-25, 25t Complement system activation of, 24 alternative pathway of, 24, 25f biologic activities of, 24-25 classic pathway of, 24, 25f description of, 24 fragments, 24-25 lectin pathway of, 24, 25f Complex genetic traits description of, 67-68 pediatric rheumatic illnesses as, 69-71 Complex regional pain syndrome, 704, 705t Compliance, 186, 186t Confidence intervals for clinical studies, 161 for statistical tests, 164 Confounding bias, 159 Congenital atrioventricular block animal models of, 400 description of, 393-394 endomyocardial fibroelastosis in, 395 epidemiology of, 395 history of, 394-395 long-term outcome for, 396 pathologic findings, 395 treatment of, 395-396 Congenital contractural arachnodactyly, 757 Conjunctivitis, 524, 607 Connective tissue collagens of, 11-12, 12t composition of, 12-13 entheses, 15 fasciae, 15 ligaments, 15 tendons, 15 Connective tissue diseases and disorders arthritis associated with, 745, 746t diagnosis of, 744-745 frequency of, 4t ligamentous laxity, 745-746 mixed anti-UI-70Kd antibodies in, 485 characteristics of, 483t classification of, 482 clinical manifestations of, 482-483 course of, 485-486 definition of, 482 diagnostic criteria for, 483-484, 484t differential diagnosis, 483-484 epidemiology of, 482 immunogenetic background of, 482 laboratory examination for, 484-485 pathologic findings in, 483 prognosis for, 485-486 treatment of, 485 molecular mechanisms of, 745 mosaicism associated with, 745 osteopenia and, 721-722 osteoporosis and, 721-722 types of, 746t Connective tissue growth factor, 444 Conradi-Hiinermann syndrome, 747t, 759
771
Conserved sequence elements, 64 Consolidated Standards of Reporting Trials, 171 Content validity, 175t Continuity correction of Yates, 165-166 Continuous variables, 157-158 Control exposure rate, 146t Convergent validity, 175t Coombs' test-positive hemolytic anemia, 358 Coordinating center, 155 Cornelia de Lange syndrome, 747t Coronary artery aneurysms, 526, 527f Coronary artery disease description of, 109 systemic lupus erythem:llosus and, 354-355 Correlation canonical, 170-171 intraclass, 169 Pearson product-moment, 167-168 Spearman rank, 168 Cortical bone, 716 Cortical hyperostosis, 761 Costimulatory molecules, 35 Costochondritis, 692 Cotton-wool spots, 358, 359f, 366 Counseling description of, 186 family, of juvenile rheumatoid arthritis patients, 242 Covariates, 168 CRl,25t CR2,25t CR3,25t CR4,25t CRZ-CD19-CD81 complex, 39-40 C-reactive protein acute rheumatic fever and, 622 description of, 26 juvenile rheumatoid arthritis and, 223 septic arthritis and, 571 Creatine kinase description of, 15 in juvenile dermatomyositis, 426 Creatine/creatinine ratio, 424 CREST syndrome, 442 Criterion validity, 175t CRMO syndrome, 329 Crohn's disease. See also Inflammatory bowel disease antineutrophil cytoplasmic antibody in, 337 gastrointestinal manifestations, 335 laboratory examination of, 337 methotrexate for, 338 Cronkhite-Canada syndrome, 506 Crossover design, 153 Cryoglobulins, 371 Cryopyrin-associated periodic syndromes mutations in, 672f overview of, 671-672 Cryopyrinopathies, 662 Cryptic epitopes, 47 Cryptic self, 47 C-terminal telopeptides, 717t CTLA-4, 43, 46, 120 Cumulative percentage of drug recovered, 150 Cushing'S syndrome clinical features of, 106-107 glucocorticoids and, 106t, 106--107, 236, 430 iatrogenic, 107 Cutaneous leukocytoclastic angiitis, 493t Cutaneous neonatal lupus erythematosus dermatitis of, 397 description of, 393 differential diagnosis of, 398
772
INDEX
Cutaneous neonatal lupus erythematosus (Continued) epidemiology of, 396 history of, 396 lesions of, 397 pathologic findings in, 397-398 rash associated with, 396 subacute, 396, 397f-398f telangiectasias in, 397 treatment of, 398 Cutaneous polyarteritis, 517-518, 518f Cutis laxa, 754 CYRR,643 Cyclic citrullinated peptides, 268 Cyclic hematopoiesis, 66~66 Cyclooxygenase-l, 58,78 Cyclooxygenase-2 description of, 58, 78-79 inflammation-induced, 699 physiologic function of, 79 Cyclooxygenase-2 inhibitors effectiveness of, 79 juvenile psoriatic arthritis treated with, 330 juvenile rheumatoid arthritis treated with, 233 mechanism of action, 78-79 structure of, 78f Cyclophosphamide administration of, 116, 116t adverse effects of, 116 Cogan's syndrome treated with, 518 diffuse cutaneous systemic scleroderma treated with, 459 dosing of, 115t fertility effects of, 116 guidelines for, 115t intravenous pulse, 379 malignancies associated with, 116-117 pharmacokinetics of, 115 polyarteritis nodosa treated with, 515 structure of, 115f syndrome of inappropriate antidiuretic hormone secretion and, 116 systemic lupus erythematosus treated with, 378t, 379 lOxicities associated with, 116 Wegener's granulomatosis treated with, 542, 544t Cyclosporine description of, 117f, 117-118, 118t diffuse cutaneous systemic scleroderma treated with, 459 juvenile dermatomyositis treated with, 431 juvenile rheumatoid arthritis treated with, 238 systemic arthritis treated with, 299 systemic lupus erythematosus treated with, 379 uveitis treated with, 292 Cysteine, 13, 14t Cystic fibrosis, 637-{)38 Cystinosis, 633f Cytokine(s) antibody response functions of, 41-42 cell activation mechanisms, 56f classification of, 26, 27t definition of, 26 description of, 55-57 in juvenile psoriatic arthritiS pathogenesis, 326 in juvenile rheumatoid arthritis pathogenesis, 211-212 methotrexate effects on, 89 monocyte-derived, 121 of adaptive immunity, 27t of innate immunity, 26, 27t
in polyarthritis pathogenesis, 261-262 proinflammatory, 23-24 in systemic arthritis, 291-292 in systemic lupus erythematosus, 345 Thl cell production of, 38 Th2 cell production of, 38 Cytokine receptors, 26, 26t Cytotoxic agents azathioprine, 113f, 113-114, 114t description of, 113 juvenile rheumatoid arthritis treated with, 238 mycophenolate mofetil, 114f, 114-115, 115t Cytotoxic lymphocyte-associated antigen 4, 35,36f Cytotoxic T-cells apoptosis induced by, 39 description of, 31-32 effector functions of, 39 function of, 28
D Dactylitis, 266, 327f, 574 Data analysis plan analysis sets, 157 description of, 155 primary response variables, 156 response variables, 156-157 secondary response variables, 156 Data collation, 155 de Quervain's disease, 683 Death domain, 44, 45f Decision analysis, 148-149 Deep morphea, 473-474, 476 Deflazacort, 109-110 Degree of freedom, chi-square test with, 165, 165t, 167 Dehydroepiandrosterone, 212-213 Delayed-type hypersensitivity, 52 Dendritic cells description of, 19, 23, 36 follicular, 42 in systemic lupus erythematosus, 347 Dependent variable, 161 Dermatan sulfate, 11 Dermatitis, 397 Dermatomyositis sine myositis, 413 Dermatomyositis-like syndrome, 652-653, 653t Descriptive epidemiology, 144 Descriptive statistics, 159 Dexamethasone dosing of, 103t structure of, 103f Diabetes cheiroarthropathy, 636, 637f Diabetes mellitus hemochromatosis and, 637 juvenile rheumatoid arthritis and, 216 musculoskeletal complications of, 636-{)37 Diabetes osteopathy, 637 Diabetic cheiroarthropathy, 456 Diagnosis accuracy in, 185 description of, 146-147 Diagnostic test validity, 147, 147t Diapedesis, 52 Diaphyseal aclasis, 762 Diarthrodial joints, 9 Diarthroses, 9 Diastrophic dwarfism, 747t Diastrophic dysplasia, 754
Diclofenac dosing of, 82t mechanism of action, 79 structure of, 77f Differential misclassification bias, 159 Diffuse cutaneous systemic scleroderma age at onset, 442-443 antinuclear antibodies in, 456 autoimmunity associated with, 443-444 bibasilar pulmonary fibrosis in, 457, 459f calcinosis in, 447, 449f cardiac disease in, 451 cardiac function and, 456 CD44 and, 444 central nervous system disease in, 451 chemokines involved in, 444 chronic graft-versus-host disease vs., 453-454, 454t clinical manifestations of, 445-452 collagen abnormalities in, 445 connective tissue growth factor and, 444 course of, 462-463 cytokines involved in, 444 deaths caused by, 462-463 definition of, 442 diabetic cheiroarthropathy vs., 456 differential diagnosis, 453-456 disease activity and severity assessments, 457,459t endothelial cell factors associated with, 445 epidemiology of, 442-443 etiology of, 443-445 familial patterns of, 445 fibroses differentiated from, 455 gastrointestinal disease in, 450-451, 461 genetic background of, 445 histopathologic findings in, 452-453 immunologic factors in, 444 incidence of, 442 laboratory examination in, 456-457 mortality rates for, 462-463 musculoskeletal disease in, 449-450 myocardial fibrosis in, 452, 453f nail fold abnormalities in, 448, 448f nephrogenic fibrosing dermopathy vs., 454 pathogenesis of, 443-445 pathologic findings in, 452-453 phenylketonUria vs., 455 porphyria cutanea tarda vs., 456 progeria vs., 455 prognosis for, 462-463 pseudosclerodermas vs., 455 pulmonary disease in, 451, 461 pulmonary function and, 456-457 pulmonary hypertension in, 461 radiologic examination in, 457 Raynaud's phenomenon in description of, 447-449, 453 treatment of, 460, 461t renal disease in, 451,460-461 renal function and, 457 scleredema vs., 455-456 sclerosis associated with, 446 Sicca syndrome and, 451-452 signs and symptoms of, 445, 446t skin manifestations of, 445-447 telangiectases in, 446, 447f-448f treatment of colchicine, 460 cyclophosphamide, 459 cyclosporine, 459 description of, 457-458 glucocorticoids, 459 hematopoietic stem cell transplantation, 459-460
INDEX immunomodulatory therapy, 459-460 interferons, 460 methotrexate, 459 mycophenolate mofetil, 459 D-penicillamine, 460 recombinant human relaxin, 460 skin care, 458 supportive measures, 458 tumor necrosis factor inhibitors, 459 vascular factors associated with, 444-445 Werner's syndrome vs., 455 Diffuse proliferative glomerulonephritis, 363, 363f-364f, 380 Diffusing capacity in the lung, 356 DiGeorge syndrome, 647t, 648 Dihydrofolate reductase, 88 1,25-Dihydroxyvitamin D3, 718 Dimers,30 Disability claim, 156 Disabling pansclerotic morphea of children, 474 Discoid lupus erythematosus, 643 Discriminant function analysis, 170 Discriminant instrument, 175t Disease diagnosis of, 146-147 etiology of, 145 prognosis of, 147-148 Disease-modifying antirheumatic drugs antimalarials and, 96 combination therapies using, 125 definition of, 88 juvenile rheumatoid arthritis treated with, 238-239 Disease-specific susceptibility, 68 Disk herniation, 691 Diskitis, 579-580, 581f, 689-690 Distal interphalangeal joint polyarthritis, 263 Distracted straight leg raising, 707t Domains, 175t Double-blind clinical trials, 152 Double-dummy design, 153 Down syndrome, 216, 677t Dressing, 196, 197f Drug absorption, 76 Drug biotransformation, 77 Drug safety, 150 Drug tolerability, 150 Drug-induced systemic lupus erythematosus, 348, 348t, 382-383 Dual x-ray absorptiomerry, 718 Dual-energy x-ray absorptiometry, 719-720, 720f Dual-photon absorptiometry, 719 Dupuytren's contracture, 455, 637 Dutch-type periodic fever, 665 Dyggve-Melchior-Clausen dysplasia, 754 Dynamic randomization, 153 Dynamic splints, 198, 198f Dyslipidemia, 109 Dyslipoproteinemia, 225, 381 Dysostosis multiplex description of, 757-758 mucolipidoses, 758t, 758-759 mucopolysaccharidoses, 758, 758t
E Ectrodactyly-ectodermal dysplasia syndrome, 747t Ehlers-Danlos syndromes clinical manifestations of, 677t, 747-748, 749t description of, 747-748 type I, 749t, 753, 753f
type II, 749t, 753 type III, 749t, 752 type IV, 749t, 752 type V, 749t, 754 type VI, 749t, 753 type VII, 749, 749t type VIII, 749t, 753 type X, 749t, 754 Eicosanoids, 58, 58f Eigenvalue, 170 Elastase, 14t Elastin, 12 Elbow exercises, 190f Ellis-van Creveld syndrome, 745 Embryopathy, 102 En coup de sabre scleroderma, 472, 474f, 476 Enchondromatosis, 731, 762 Endemic osteoarthritis, 631-633 Endocarditis acute rheumatic fever and, 619, 621 juvenile rheumatoid arthritis and, 221 Libman-Sacks, 355, 366, 366f, 622 prophylaxis for, 624 systemic arthritis and, 294 Endochondral ossification, 716 Endomyocardial fibroelastosis, 395 Endomysium, 15, 16f Endotenon, 15 Endothelial cells antigen antibodies in juvenile dermatomyositis, 425-426 in Kawasaki disease, 530 diffuse cutaneous systemic scleroderma and, 445 Endothelin-l, 107 Engelmann's syndrome, 759, 760f Entheses description of, 15, 309 examination of, 312, 312f radiographic evaluation of, 317, 318f Enthesitis arthritis caused by, 265 differential diagnosis, 311 in juvenile ankylosing spondylitis, 309-311, 319 in juvenile psoriatic arthritis, 328 management of, 319 in reactive arthritis, 606 Enzyme-linked immunosorbent assay, 224 Eosinophil(s), 38 Eosinophilia-myalgia syndrome, 475 Eosinophilic fasciitis, 474 Eosinophilic granuloma, 735-736 Epidemiology clinical, 144 descriptive, 144 frequency of disease occurrence, 144-145 Koch's postulates, 145 Epimysium, 15, 16f Epiphyseal dysplasias, 756 Epiphyseal plate, 14 Epiphysis, 14-15 Epitenon, 15 Epitope, 30 Epitope spreading, 49 Epstein-Barr virus-associated lymphoma, 95 EqUivalence margins, 154 Errors Chi-square test, 166 nonrandom, 158 random, 158 statistical, 162-163 type I, 162 type II, 162
773
Erysipeloid erythema, 660, 660f Erythema elevatum diutinum, 507 Erythema marginatum, 620, 620f Erythema migrans, 594, 594f, 598-599 Erythema nodosum, 336, 336f Erythrocyte sedimentation rate, 223 Erythromelalgia, 693, 708t E-selectin, 52, 54t, 329, 445 Essential cryoglobulinemic vasculitis, 493t Etanercept description of, 121-122 juvenile ankylosing spondylitis treated with, 319 juvenile dermatomyositis treated with, 429t juvenile rheumatoid arthritis treated with, 237 polyarthritis treated With, 269 tumor necrosis factor receptor-associated periodic syndrome treated with, 663 Etiology of disease, 145. See also specific disease European League Against Rheumatism, 2, 206-207, 207t European Spondyloarthropathy Study Group, 305 Evans' syndrome, 368 Evidence-based medicine, 142 Ewing's sarcoma, 738-739, 739f Exercises play-related, 196t range of motion, 189, 189f-194f stretching, 195, 195f therapeutic, 195-196 water, 198-199 Experimental myositis, 410 Experimental studies, 143 Exploratory studies, 143 Expressed sequence tags, 64-65 External validity, 158 Extracellular matrix composition of, 11 description of, 9-11 proteoglycans, 11
F F ratio, 167 Fabry's disease, 639, 639t, 708t, 747t Face validity, 175t Faces Rating Scale, 702, 702f Factor analYSiS, 170 Factor loading, 170 Factor loading matrix, 170 Factorial design, 153 Fairbank's multiple epiphyseal dysplasia, 754 False pOSitive, 147 Familial aero-osteolysis, 759-760 Familial chondrocalcinosis, 635 Familial cold autoinflammatory syndrome characteristics of, 671f clinical manifestations of, 660t, 672-673 description of, 662 genetics of, 672 Familial fibrosing serositis, 679t Familial Hihernian fever, 659 Familial hypertrophic synovitis, 266 Familial infantile cortical hyperostosis, 761 Familial lipochrome histiocytosis, 644 Familial Mediterranean fever amyloidosis associated with, 661 clinical manifestations of, 659-661, 660t colchicine for, 661 cutaneous manifestations of, 660 description of, 101, 505 diagnosis of, 661 genetics of, 659
774
INDEX
Familial Mediterranean fever (Continued) joints affected by, 660 laboratory studies of, 661 outcome of, 661--662 pathogenesis of, 659 prognosis for, 661--662 skin manifestations of, 660 treatment of, 661 vasculitis and, 518 Farber's disease, 638--639, 6391, 747t Fas gene mutations, 642-643 Fas-associated death domain, 45f, 642 Fasciae, 15 Fast muscle fibers, 16, 16t Fatigue, 191 Fc receptors description of, 38, 42, 43t polymorphisms of, in systemic lupus erythematosus, 345 Felty syndrome, 264 Femoral head osteonecrosis, 230 Fenoprofen dosing of, 81t structure of, 77f toxicities associated with, 83t Fetal alcohol syndrome, 762 Fever description of, 657 Kawasaki disease and, 523-524 periodic syndromes. See Periodic fever syndromes rat-bite, 657--658 relapsing, 658 repeated episodes of, 657 rheumatic. See Acute rheumatic fever in systemic arthritis, 293, 297 Fever of unknown origin, 657 Fibril-associated collagens with interrupted triple-helices, 12t Fibril-forming collagens, 12t Fibroblasts, 23-24 Fibrodysplasia ossificans progressiva, 424 Fibroma nonossifying, 731-732, 734f ossifying, 734 Fibromatosis collJ, 455 Fibromatosis hyallnica multiplex, 455 Fibromyalgia, 705t, 709 Fibronectin, 12 Fibrosarcoma, 738 Fibrous cortical defect, 731-732, 734f Fibrous dysplasia, 732-733 Fibrous joints, 9, lOt Fibrous tissue benign tumors of, 731-734 malignant tumors of, 738 Finger exercises, 192f First-order kinetics, 77 First-pass effect, 77 Fisher's exact test, 166 FK506,34 Flat foot, 679, 679f Floor effects, 175t Fluorosis, 631 Focal segmental proliferative glomerulitis, 362f-363~ 362-363 Folate supplementation, with methotrexate, 96, 234 Follicular dendritic cells, 42 Foot juvenile rheumatoid arthritis of, 229 pes cavus, 678--679 pes planus, 678--679 FoxP3,47
Freiberg's disease, 685--686, 686f Frequency distribution, 159
Frostbite arthropathy, 689, 689f Full-analysis set, 157 Functional asplenia, 360 Functional genomics description of, 71-72 in pediatric rheumatic diseases, 73-74 Functional map, 66 Functional splints, 198 Functional status definition of, 174 measurement of description of, 175 Instruments for, 177-180 Fungal arthritis, 584
G G-actin, 15 Gangliosidosis, 747t Gardner-Diamond syndrome, 358f Gardner's syndrome, 455 Gastrointestinal system azathioprine effects on, 114 Beh~et's syndrome manifestations, 564 celecoxib effects on, 84 diffuse cutaneous systemic scleroderma manifestations of, 450-451 Henoch-Schonlein purpura manifestations, 497 inflammatory bowel disease symptoms, 335-336 juvenile rheumatoid arthritis findings, 221 methotrexate effects on, 92 nonsteroidal anti-inflammatory drugs effect on, 80, 82-84 rofecoxib effects on, 84 Gastropathy, nonsteroidal anti-inflammatory drug-associated, 83 GATA-3,37 Gaucher's disease, 639, 639t Gaussian distribution, 159, 160f Gelatinase, 13, 14t GEMSS syndrome, 747t Gene therapy, 125-126 Generalizability, 158, 175t Generalized morphea, 472, 476 Genetic map, 65--66 Genome definition of, 64 polymorphic elements of, 65 polymorphisms, 65 structure of, 64--65 Genome maps, 65 Genome screen, 68--69 Genomics definition of, 64 functional, 71-72 Genu recurvatum, 679 Giant cell arteritis clinicopathologic characteristics of, 494t definition of, 493t, 548 Takayasu's arteritis, 337, 493t-494t, 548-550, 551f temporal arteritiS, 493t-494t, 550-551 Giant cell tumor, 735 Glaucoma, 109 Glomerular sclerosis, 364-365 Glomerulonephritis. See also Lupus nephritis diffuse proliferative, 363, 363f-364f, 380 Henoch-Schonlein purpura and, 497-498 membranous, 363-364, 364f, 377t systemic lupus erythematosus and, 361-365 Glucocorticoid(s) acetylsalicylic acid excretion affected by, 88
acute adrenal insufficiency caused by, 110-111 adverse effects of avascular necrosis, 107 bone loss, 107, 722 cardiovascular system, 109 cataracts, 109 cell-mediated immune reactions, 108 central nervous system, 108-109 coronary artery disease, 109 Cushing's syndrome, 106t, 106-107, 236, 430 dyslipidemia, 109 glaucoma, 109 growth suppression, 107, 218, 236, 240 hematologic system, 108 immunity, 108 infection, 108 muscle wasting, 109 myopathy, 109, 430 osteoporosis, 107, 108f, 723 overview of, 106t psychoses, 108-109 anti-inflammatory actions of, 105 behavioral effects of, 111-112 carbohydrate metabolism and, 104 carditis treated with, 623 Cogan's syndrome treated With, 518 description of, 102-103 diffuse cutaneous systemic scleroderma treated with, 459 dose-effect relationships of, 104t dosing of description of, 103t reductions In, 110 tapering of, 110, 377-378 high-dose intravenous, 111-112 hypothalamic-pituitary-adrenal axis suppression caused by, III immunizations and, 200 immunosuppressive actions of, 105 indications for, 105-106 intra-articular adverse effects of, 112-113 description of, 112 dosage of, 112 frequency of, 112 juvenile rheumatoid arthritis treated with, 236-237 oligoarthritis treated With, 285 triamcinolone hexacetonide, 112 types of, 112 intravenous, 236 juvenile ankylosing spondylitis treated with, 319 juvenile dermatomyositis treated with, 429-430 juvenile psoriatic arthritis treated with, 330 juvenile rheumatoid arthritis treated with, 235-237 Kawasaki disease treated with, 533-534 lipid metabolism and, 104 maintenance of, 378 pharmacologic effects of, 103-104 pharmacology of, 103, 103f physiologic effects of, 103-104, lOSt polyarteritis nodosa treated With, 515 polyarthritis treated with, 270 presurgical supplementation of, III production of, 59--60 protein metabolism and, 104 reactive arthritis treated with, 611 sarcoidosis treated with, 555 short-acting, 110
INDEX structure of, 103f systemic, 110t, 235-236 systemic lupus erythematosus treated with, 376-378 T-cells affected by, 105 Takayasu's arteritis treated with, 550 toxicity caused by, 109-110 uveitis treated with, 292 Wegener's granulomatosis treated with, 542-543 Glucocorticoid-responsive elements, 104 Glucose-6-phosphatase deficiency, 635 Glycolipids, 24 Glycosaminoglycans description of, 11 synovial fluid levels of, 225-226 Gold compounds adverse effects of, 100 description of, 99 intramuscular administration of, 100 juvenile rheumatoid arthritis treated with, 239-240 oral administration of, 101 pharmacology of, 99-100 structure of, 100f toxicity of, 101 Goldbloom syndrome, 638 Golfer's elbow, 682 Gonadal immaturity,S Gonococcal arthritis, 574 Goodness-of-fit chi-square test, 164 Goodpasture's syndrome, 51, 504-505 Gorham's disease, 760 Gottron's papules, 412, 423 Gout, 633, 634t Gouty arthropathy, 633 Gowers' sign, 411 gp130, 57, 292 Graft-versus-host disease autoimmune hematologic phenomena secondary to, 648 chronic, 453-454 diffuse cutaneous systemic scleroderma vs., 453-454, 454t Granzymes, 39 Graves' disease, 51 Griseofulvin, 460 Group A streptococcus, 615-616 Group sequential designs, 153--154 Growing pains, 692--693 Growth chronic arthritis effects on, 218--219 glucocorticoid-related suppression of, 107, 218,240 juvenile rheumatoid arthritis effects on, 218--219, 227~ 227-228 Growth factors, 57 Growth hormone, for juvenile rheumatoid arthritis, 240 Growth-regulated oncogene-a, 444 Guanethidine, 461t Guttate morphea, 472
H Haemophilus influenzae, 569 Half-life, 76, 150 Haplotypes, 66 Haptens,40 Hashimoto's thyroiditis, 360, 637 Haversian canals, 716 Health-related quality of life, 174 Heat and cold therapy, 197-198 Heat-shock proteins
description of, 22, 33 in juvenile rheumatoid arthritis, 213 in oligoarthritis, 277 Heliotrope discoloration, 41Of, 412, 423 Helper T-cells description of, 31 differentiation of, 37-38 effector functions of, 37 function of, 28 Th1 cytokines produced by, 38 description of, 31, 37, 119 development of, 38f effector functions of, 38--39 interleukin-4 effects on, 37 interleukin-10 effects on, 37 macrophage recruitment by, 38 Th2 anti-inflammatory cytokines released by, 39 cytokines produced by, 38 description of, 31, 37 development of, 38f effector functions of, 38--39 reactive, 119 Hemarthrosis, 636 Hematologic system methotrexate-related tOXicities, 94 neonatal lupus erythematosus manifestations in, 398--399 Hematophagocytic lymphohistiocytosis, 295 Hematoxylin bodies, 360 Hematuria, 222 Hemifacial atrophy, 472--473 Hemochromatosis, 637 Hemoglobinopathies, 635 Hemophilia, 635-636 Henoch-Schonlein purpura in adults, 500 anaphylactoid purpura, 496 arthritis associated with, 217, 498--499 classification of, 496 clinical manifestations of, 497--499 clinicopathologic characteristics of, 494t course of, 501 defmition of, 493t, 496 diagnostic criteria for, 500, SOOt differential diagnosis, 500, SOOt epidemiology of, 495, 495t, 496 in familial Mediterranean fever, 505 features of, 498t gastrointestinal disease in, 497 genetic background of, 496--497 glomerulonephritis in, 497-498 histopathologic fmdings, 499f, 499-500 19A-containing immune complexes in, 500 laboratory examination in, 500 leukocytoclastic vasculitis in, 499f pathologic findings, 499f, 499-500 prognosis for, 501 radiologic examination in, SOD-SOl renal disease in, 497--498, 501 skin manifestations of, 497, 498f--499f treatment of, 501 Hepatitis, 84 Hepatitis B arthritis-dermatitis syndrome, 582 Hepatomegaly juvenile rheumatoid arthritis and, 221-222 progressive, 296 systemic arthritis and, 296 systemic lupus erythematosus and, 360 Hereditary angioneurotic edema, 25 Hereditary osteolysis, 746t Herpesviruses, 583
775
Heterotopic inhibition, 700 High endothelium venules, 40-41, 41£ High mobility group box chromosomal protein 1, 57 High-dose immunotherapy with transplantation, 126 High-dose intravenous glucocorticoids, 111-112 Hip exercises, 193f Hip joint acute chondrolysis of, 688 juvenile rheumatoid arthritis effects, 230 septic arthritis of, 572f, 573--574 transient synOVitis of, 583, 583t Histocompatibility antigens, 344 HLA-B27 description of, 64, 68, 215 juvenile ankylosing spondylitis and, 308, 314-315 juvenile psoriatic arthritis and, 326 oligoarthritis and, 275 post-streptococcal reactive arthritis and, 625 reactive arthritis and, 604--606 HLA-B51, 562 Homocystinuria, 677t, 747t, 757 Hotelling's T' test, 170 Howell-Jolly bodies, 360 Human Genome Project, 64, 66 Human immunodeficiency virus, 583 Human leukocyte antigens description of, 32 juvenile dermatomyositis and, 410-411 juvenile psoriatic arthritis and, 326 neonatal lupus erythematosus and, 394 oligoarthritis and, 275-276, 276t polyarthritis and, 262 Human pharmacology study, 151t Hunter's syndrome, 747t Hurler's syndrome, 747t, 758t Hyaline cartilage anatomy of, 9-10 composition of, 9-10 Hyaluronan, 11 Hyaluronic acid, 14 Hydrocortisone dosing of, 103t during stress, 111 structure of, 103f Hydroxyapatite, 716 Hydroxychloroquine sulfate description of, 96, 96f juvenile dermatomyositis treated with, 429t, 430-431 juvenile rheumatoid arthritis treated with, 239 systemic lupus erythematosus treated with, 376 7-Hydroxymethotrexate, 90 Hydroxyproline, 717t Hyperalgesia, 698 Hypergammaglobulinemia, 223 Hyperimmunoglobulinemia D with periodic fever syndrome clinical manifestations of, 660t, 663 description of, 659, 663 diagnosis of, 665 erythematous macules associated with, 663 genetics of, 663 laboratory studies, 663 maculopapular rash associated With, 663, 665f pathogenesis of, 663 treatment of, 665
776
INDEX
Hyperlipoproteinemia, 635 Hypermobility in athletes, 678 benign hypermobility syndrome, 676 conditions associated with, 677t, 748t diagnostic criteria for, 678t genu recurvatum, 679 ligamentous laxity and, 745-746 osteoarthritis associated with, 678 pain associated with, 676--680 pes cavus, 678-679 pes planus, 678-679 recurrent patellar dislocation secondary to, 679 Hyperostosis cortical, 761 description of, 638 Hyperparathyroidism, 637 Hyperpyrexia, 293 Hypersensitivity delayed-type, 52 immediate, 50 nonsteroidal anti-inflammatory drug-related, 86-87 type I, 50, 51t type II, 50-51, 51£, 51t type III, 51, 51t type IV, 51t, 52 Hypersensitivity angiitis, 494t, 501-503 Hyperthyroidism, 637 Hypertrophic osteoarthropathy description of, 335, 638 secondary, 741 Hyperuricemia, 633-635, 634t Hypervitaminosis A, 631 Hypochondroplasia, 747, 747t Hypocomplementemic urticarial vasculitis, 503-504 Hypogammaglobulinemia characteristics of, 651 t dermatomyositis-like syndrome associated with, 652-653, 653t description of, 94, 650 X-linked agammaglobulinemia, 650-651 Hypomobility, 679t, 679-680 Hypophosphatasia, 631 Hypophosphatemic vitamin D-resistant rickets, 630 Hypothalamic-pituitary-adrenal axis description of, 59 glucocorticoids effect on, 111 Hypotheses, 143-144 Hypothesis-generating studies, 143 Hypothesis-testing studies, 143 Hypothyroidism, 637 Hypoxanthine-guanine phosphoribosyltransferase, 634
I Ibuprofen dosing of, 81t indications for, 81 juvenile psoriatic arthritis treated with, 330 juvenile rheumatoid arthritis treated with, 233 structure of, 77f toxicities associated with, 83t I-cell disease, 747t, 758t, 759 Idiotopes, 30 Idiotype, 30 ling, 37 Immediate hypersensitivity, 50
Immune complex vasculitis illustration of, 361f juvenile dermatomyositis and, 409 Immune complexes C1 binding to, 645 in Henoch-Sch6nlein purpura, 500 19A-containing, 500 juvenile rheumatoid arthritis and, 211, 225 in systemic lupus erythematosus, 346, 371 Immune response adaptive, 28 effectors of, 20, 20f Immune system genetic disorders of, 642 innate, 211 juvenile rheumatoid arthritis pathogenesis and, 211 Immunity adaptive. See Adaptive immunity antibody-mediated, 42 glucocorticoids effect on, 108 innate. See Innate immunity Immunizations, 199-200 Immunodeficiency disorders classification of, 643t common variable immunodeficiency, 649, 651-653 hypogammaglobulinemia characteristics of, 651t description of, 650 X-linked agammaglobulinemia, 650-651 primary humoral, 648-653 severe combined immunodeficiency, 647-648 T-cells, 648 Wiskott-Aldrich syndrome, 647t, 648 Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, 47 Immunogens, 45 Immunoglobulin(s) antigen binding to, 31 Fc portion of, 42 functions of, 28 heavy chains, 28 hypervariable regions of, 30 in juvenile rheumatoid arthritis, 223-224 light chains, 28 membrane, 30 structure of, 28, 29f surface, 39--40 types of, 28, 30t Immunoglobulin G subclass deficiencies, 653 Immunoglobulin M, 211 Immunologic memory, 42-43 Immunologic tolerance, 45 Immunomodulators diffuse cutaneous systemic scleroderma treated with, 459--460 juvenile rheumatoid arthritis treated with, 238 sarcoidosis treated with, 555-556 Immunoreceptor tyrosine activation motifs, 30 Immunosuppression bystander, 48 immunization considerations in children undergoing, 200 Immunosuppressive drugs juvenile dermatomyositis treated with, 429t, 431 juvenile rheumatoid arthritis treated with, 238 systemic lupus erythematosus treated With, 378-379 Immunotherapy high-dose, 126 transplantation and, 126
Incidence, 145, 146t Independent variable, 161 Individualized education plans, 187 Indomethacin bronchospasm induced by, 86 central nervous system toxicities, 85 dosing of, 82t indications for, 81 juvenile psoriatic arthritis treated with, 330 juvenile rheumatoid arthritis treated with, 233 mechanism of action, 79 structure of, 77f toxicities associated With, 83t Inducible costimulator, 34 Inducible nitric oxide synthase, 22, 22f, 59 Infantile acute hemorrhagic edema, 500 Infantile myofibromatosis, 455 Infantile polyarteritis nodosa, 521 Infantile systemic hyalinosis, 732 Infections autoimmunity and, 49-50 glucocorticoid-related, 108 juvenile psoriatic arthritis and, 325 juvenile rheumatoid arthritis pathogenesis and, 213 methotrexate and, 94 musculoskeletal manifestations of, 585 myositis after, 421 periodic fever syndromes caused by, 657-658 systemic lupus erythematosus and, 348, 376, 381 Infectious arthritis Bartonella henselae, 575 brucellosis, 575 frequency of, 4t gonococcal arthritis, 574 Mycoplasma pneumoniae, 575 septic arthritis. See Septic arthritis tuberculous arthritis, 574, 574f-575f Infective endocarditis, 585 Inflammation cyclooxygenase-2 released secondary to, 699 cyrokines involved in, 23-24 endocrine mediators in, 59-60 growth factors secreted in, 57 hyperalgesia in, 699 hypothalamic-pituitary-adrenal axis activation in, 59 inducible nitric oxide synthase in, 59 markers of, 267, 367 in polyarthritis, 267 sacroiliac joint, 316 in systemic lupus erythematosus, 367 tumor necrosis factor-u's role in, 56 Inflammatory bowel disease. See also Crohn's disease; Ulcerative colitis age at onset, 334 classification of, 334 clinical manifestations of arthritis, 335, 335t erythema nodosum, 336, 336f gastrointestinal disease, 335-336 hypertrophic osteoarthropathy, 335 mucocutaneous lesions, 336 osteoporosis, 335 pyoderma gangrenosum, 336, 337f sacroiliac arthritiS, 335 skin, 336-337 uveitis, 337 vasculitis, 337 course of, 338 definition of, 334
INDEX di~gnosis of, 337 epidemiology of, 334 etiology of, 334 geJllder ratio of, 334 geJlletic background of, 334-335 histopathologic findings, 337 HLA.-B27-associated spondylitis of, 338 inddence of, 334 joint involvement in, 334 la~ratory examination of, 337 pathogenesis of, 334 pathologic findings, 337 prevalence of, 334 pro~nosis for, 338 radiplogic examination of, 337, 338f treatment of, 337-338 Inflammatory chemokines, 54 Inflixirtlab desqription of, 122-123 juvenile dermatomyositis treated with, 431-432 juvellile rheumatoid arthritis treated with, 237-238 Inhibit~ry regulatory T-eells, 46 Innate Immunity cells involved in dendritic, 23 fibroblasts, 23-24 natural killer, 23, 24f phagocytes. See Innate immunity, J!>hagocytes in circulating proteins involved in, 26 complement system, 24-26 eytok,nes of, 26, 27t definition of, 19 disorders of, 643t phagOCytes in acti~ation of, 20-22 alternative activation of, 22-23 description of, 19 effector functions, 20-22 maqrophages, 19, 20f microbe binding to, 22 m0'locytes, 19, 20f neutrophils, 19-20 sUrf~ce receptors, 20 Toll1like receptors, 21-22, 22t Insulin-li\<e growth factors, 722 Integrins, 54t, 445 Interferom-a, 74 Interferon-j3, 74 Interferon-y description of, 23, 38, 74 recomqinant, for juvenile rheumatoid arthritis, 238 Interferons, 27t Interleukih-l biologiC agents against, 7 functiot:ls of, 56 glucocqrticoids effect on, 105 isoform$ of, 56 in phagPcytosis, 23 sulfasalazine effects on, 97 Interleukil)-1 receptor antagonist, 124 Interleukil)-l receptor-associated kinase, 57 Interleukirl-1a description of, 27t, 56 in polya/thritis, 261 Interleukine1~ description of, 27t, 56-57 oligoarthil'itis and, 276 Interleukin.lA2, 215 Interleukin.1Ra, 23
InterJeukin-2 characteristics of, 27t description of, 44 T-cell activation effects on, 35 InterJeukin-4, 27t Interleukin-5, 27t, 38 Interleukin-6 in adaptive immunity, 57 anti-IL6 receptor antibody, 124-125, 299-300 description of, 27t, 42 in polyarthritis, 261-262 pro-inflammatory functions of, 57 soluble receptor for, 291-292 in systemic arthritiS, 291 Interleukin-IO description of, 23, 27t, 37, 47 in oligoarthritis, 276 Interleukin-12, 27t, 37 InterJeukin-13, 27t Interleukin-15, 27t Interleukin-18, 27t Interleukin-23, 27t, 37 Internal validity, 158 International League of Associations for Rheumatology juvenile idiopathic arthritis classification criteria, 207-208, 274 oligoarthritis classification, 275t polyarthritis defined by, 261 Internet resources, 186 Interquartile range, 161 Inter-rater agreement, 169 Interstitial nephritis, 365 Intervertebral disk herniation, 691 Interview bias, 159 Intra-articular glucocorticoids adverse effects of, 112-113 description of, 112 dosage of, 112 frequency of, 112 triamcinolone hexacetonide, 112 types of, 112 Intraclass correlation, 169 Intra-rater agreement, 169 Intravenous immunoglobulin description of, 118-119, 119t juvenile dermatomyositis treated with, 429t, 431 juvenile rheumatoid arthritis treated with, 238 Kawasaki disease treated with, 531-533, 533t polyarteritis nodosa treated with, 515-516 systemic arthritis treated With, 299 systemic lupus erythematosus treated With, 379-380 Investigational new drug, 149 Iritis, 310 Isotype switch, 31 Ixodes scapularis, 592, 593f
J Jaccoud's arthritiS, 624 Jansen's dysostosis, 747t Jarisch-Herxheimer reaction, 599 JAS. See Juvenile ankylosing spondylitis Job's syndrome, 644 JointCs) apophyseal, 217 cartilaginous, 9, lOt classification of, 9, lOt diarthrodial, 9
777
fibrous, 9, lOt inflammation of, 217 polyarthritis manifestations, 262-263, 263f stiff, 754-755 synovial, 9, lOt vascular supply to, 14-15 Joint contractures, 745 JPsA. See Juvenile psoriatic arthritis JRA. See Juvenile rheumatoid arthritis Juvenile ankylosing spondylitis age at onset, 308 antiphospholipid antibodies in, 314 characteristics of, 306t classification of, 304 clinical manifestations of apophyseal joints, 311 arthritis, 310 cardiopulmonary disease, 310-311 central nervous system, 311 description of, 309 enthesitis, 309-311, 319 iritiS, 310 pleuropulmonary disease, 310-311 renal disease, 311 course of, 319-320 definition of, 304 diagnostic criteria for, 304-306, 305t differential diagnosis, 311-312 entheses in, 317, 318f epidemiology of, 307-308 etiology of, 308 gender ratio for, 308 genetics of, 308-309 geographic distribution of, 308 histopathologic findings in, 311 HLA-B27 and, 308, 309t, 314-315 incidence of, 307t, 307-308 juvenile rheumatoid arthritis vs., 313t laboratory examination in, 314-315 musculoskeletal examination in axial skeleton, 313-314 entheses, 312, 312f peripheral joints, 312-313, 317, 318f musculoskeletal signs and symptoms in, 3lOt occupational therapy for, 319 outcome measures for, 320 pathogenesis of, 308 pathologic findings in, 311 peripheral arthropathy in, 312 physical therapy for, 319 prevalence of, 307-308 prognosis for, 320 racial distribution of, 308 radiologic characteristics of, 315f-317f, 315-317 range of motion limitations secondary to, 319-320 selective IgA deficiency and, 314 seronegative enthesitis and arthritis syndrome and, 304-306, 307t surgery for, 319 treatment of etanercept, 319 general approach to, 317-318 glucocorticoids, 319 individualized approach to, 318 methotrexate, 319 naproxen, 319 nonsteroidal anti-inflammatory drugs, 318-319 sulfasalazine, 319 Juvenile Arthritis Functional Assessment Scale and Report, 177t, 178
788
INDEX
Juvenile Arthritis Quality of Life Questionnaire, 177t, 179, 181 .Juvenile Arthritis Self-Report Index, 177t, 178-179 Juvenile chronic arthritis. See also Chronic arthritis diagnostic criteria for, 206-207, 207t European League Against Rheumatism classification criteria for, 206-207, 207t pauciarticular, 286 polyarticular, 263, 271 Juvenile dermatomyositis age at onset, 407-408, 409f arteries in, 419 arthritis in, 412 blood vessels in, 418-419 calcinosis in course of, 433 description of, 413, 416f treatment of, 413, 416f capillaries in, 419 cardiac findings, 420 cardiopulmonary disease in, 413-414 classification of, 407 clinical manifestations of, 411-414 course of, 432-434 deaths from, 434 definition of, 407 diagnostic criteria for, 407, 407t differential diagnosis, 420-424 dual-energy x-ray absorptiometry evaluations, 428 dystrophic calcification in, 41St electromyography of, 427, 427t endocrinopathies vs., 422 environmental factors associated with, 410 epidemiology of, 407-408 erythema associated With, 349 etiology of, 408-410, 409t familial patterns of, 410 features of, 432t frequency of, 6t functional disability in, 433 gastrointestinal tract findings, 420 gender ratio for, 407-408 genetic background of, 410-411 geographic distribution of, 408 Gottron's papules and, 412, 423 heliotrope discoloration associated with, 410f, 412, 423 historical review of, 407 human leukocyte antigens and, 410-411 immune complex-mediated vasculitis associated with, 409 immunoglobulins in, 416, 418 incidence of, 407, 408t interleukin-1 expression in, 409 juvenile polymyositis vs., 420-421 laboratory examination for aldolase, 426 anti-UlRNP, 425 autoantibodies, 424-426 creatine kinase, 426 creatine/creatinine ratio, 424 endothelial cell antigen antibodies, 425-426 general findings, 424 lactate dehydrogenase, 426-427 muscle enzymes, 426-427 myositis-associated antibodies, 424-425 myositis-specific antibodies, 424-425 transaminases, 426 lipodystrophy in description of, 414, 418f management of, 432
magnetic resonance imaging of, 427-428 maternal cell chimerism in, 409 mortality from, 434 mucocutaneous disease associated With, 412-413 muscle biopsy findings, 427 muscle histopathology findings in, 418t muscular dystrophy vs., 421 musculoskeletal disease associated with, 411-412 myoadenylate deaminase deficiency vs., 421-422 neuromuscular diseases and, 421-422 osteoporosis in, 427, 428f pathogenesis of, 408-410, 409t pathologic findings in, 414-420 patient counseling for, 429 periungual erythema in, 412, 412f-413f, 423 phases of, 432t polyarthritis and, 265 postinfectious myositis vs., 421 prognosis for, 432-433, 433t psychosocial outcome of, 433-434 racial distribution of, 408 radiologic examination in, 427-428 Raynaud's phenomenon in, 414 renal findings, 420 signs and symptoms of, 411 skeletal muscle findings in, 415-416, 418, 418f skin manifestations of, 412-413, 419 Toxoplasmagondii and, 410 treatment of biologic agents, 429t, 431-432 cyclosporine, 431 etanercept, 429t general supportive care, 429 glucocorticoids, 429-430 hydrochloroquine, 429t, 430-431 immunosuppressive drugs, 429t, 431 infliximab, 431-432 intravenous immunoglobulin, 429t, 431 methotrexate, 431 overview of, 428 physiotherapy, 432 plasmapheresis, 431 prednisone, 429 stem cell transplantation, 431-432 tumor necrosis factor-a inhibitors, 431 ultrasound findings in, 428f vasculitis in, 413 veins in, 419 Juvenile fibromatosis, 732 Juvenile gastrointestinal polyposis, 506 Juvenile hyaline fibromatosis, 732 Juvenile idiopathic arthritis combination therapies for, 125t diagnostic criteria for, 207t, 207-208 illustration of, 106f infliximab for, 123t International League of Associations for Rheumatology classification criteria for, 207-208, 274 juvenile psoriatic arthritis vs., 327 oligoarticular, 278 systemic. See Systemic arthritis Juvenile polymyositis, 420-421 Juvenile psoriatic arthritis age at onset, 324 amyloidosis and, 331 angiogenesis in, 326 CD8+ T-cells and, 325-326 chronic arthritis caused by, 324 classification of, 324
clinical manifestations of arthritis, 327 enthesitis, 328 extra-articular, 328-329 nail changes, 328, 328f rash, 328, 328f skin disease, 328, 328f uveitis, 328-329 course of, 331 cyclooxygenase-2 inhibitors for, 330 cytokines' role in, 326 dactylitis in, 327f definition of, 324 diagnostic criteria for, 324, 325t epidemiology of, 324--325, 325t etiology of, 325-326 gender ratio for, 324--325 genetics of, 326-327 glucocorticoids for, 330 histopathologic findings in, 329 HLA-B27 and, 326 incidence of, 324 joints affected in, 327t juvenile idiopathic arthritis vs., 327 juvenile rheumatoid arthritis vs., 327 laboratory examination for, 329 methotrexate for, 330-331 naproxen, 330 nonsteroidal anti-inflammatory drugs for, 329-330 pathogenesis of, 325-326 pathologic findings in, 329 prevalence of, 324 prognosis for, 331 radiologic features of, 329, 330f studies of, 326t treatment of, 329-331 viral infections associated with, 325 Juvenile rheumatoid arthritis age at onset, 210 American College of Rheumatology criteria for, 206, 207t amyloidosis and, 244 animal models of, 214 ankle abnormalities, 229 arthrography evaluations, 226 atlantoaxial subluxation associated With, 230, 231£ autoimmune diseases associated with, 71, 216 cardiac disease associated with, 221 cartilage destruction associated With, 228, 228f chromosomal abnormalities associated with, 216 classification of, 206 clinical manifestations of, 216-220 complex genetic traits, 67-68 counseling, 242 course of, 242-244 criteria for, 206, 207t deaths caused by, 244 description of, 206 diabetes mellitus and, 216 diagnostic criteria for, 206, 207t Down's syndrome and, 216 in elbow, 228 endocarditis and, 221 epidemiology of, 209-211 etiology of, 211 extra-articular manifestations of, 218-220 facial morphology abnormalities associated with, 219, 219f family counseling, 242
INDEX
fanilly history of, 64, 213 foot abnormalities, 229 footwear for, 241 frequency of, 4t functional disability secondary to, 242-244 functional status measurement instruments, 177-180 ga$trointestinal tract manifestations of, 221 gehder rates for, 210 genetics of family background, 213 human leukocyte antigen relationships, 214-215 geographic distribution of, 210-211 gr(Jwth and development abnormalities associated with, 218-219, 227f, 227-228 m hands, 228, 228f hepatic disease associated with, 221-222 hip abnormalities, 230 histopathologic findings, 222f, 222-223 historical review of, 208-209 hypergammaglobulinemia and, 223-224 incidence of, 2091, 209-210, 307t influenza virus A2H2N2 and, 213 insulin-dependent diabetes mellitus and, 216 joints affected, 217 apophyseal, 217 inflammation of, 217 pain m, 216, 241 subluxation of, 227 ju,venile ankylosmg spondylitis vs., 313t jl.lvenile psoriatic arthritis vs., 327 knee abnormalities, 229 laboratory studies for antinuclear antibodies, 224-225 blood mdices, 223 C3,225 complement, 225 C-reactive protein, 223 description of, 223 erythrocyte sedimentation rate, 223 immune complexes, 225 immunoglobulins, 223-224 lipids, 225 plasma lipids, 225 rheumatoid factors, 224 synovial flUid analysis, 225-226 leg-length mequality secondary to, 219 leukocytosis associated with, 223 lymphadenopathy associated with, 221 lymphedema associated with, 220 macrophage inhibitory factor in, 211 magnetic resonance imagmg of, 226 micrognathia associated with, 219, 219f mortality caused by, 244 muscle disease associated with, 220-221 myocarditis and, 221 neurologic disease associated with, 222 riutrition for, 240 occupational therapy for, 240-241 oligoarticular characteristics of, 207t description of, 206 hip jomt arthritis associated with, 278 human leukocyte antigens associated with,276 onset of, 206 osteopenia and, 219-220 osteoporosis associated with, 226 0utcomes of, 242-244, 243t pain associated with, 216-217 pathogenesis of
autoantibodies, 212 cytokines, 211-212 description of, 211 hormones, 212-213 immune complexes, 211 irnmunopathogenic mechanisms, 211 infections, 213 peripheral blood mononuclear cells, 212 psychologic factors, 213 studies regarding, 213 T-cells, 211, 222 T-cell receptor polymorphism, 212 trauma, 213 pathologic findings, 222f, 222-223 pauciarticular description of, 69, 74, 274 joint erosion associated with, 286 pericarditis and, 221 physical therapy for, 240-241 pleuropulmonary disease and, 221 polyarticular cervical spine arthritis vs., 311 characteristics of, 207t description of, 206 outcome for, 243t radiographic fmdings, 234f soft tissue swelling associated with, 228 postvaccination, 213 prevalence of, 209t, 210 prognosis for, 242-244 psychosocial outcome of, 242-244 racial distribution of, 210-211 radiologic examination in imaging techniques for, 226 overview of, 226-228 subluxation findings, 227 radionuclide imaging in, 226 reconstructive surgery for, 242 renal disease associated with, 222 m shoulder, 228-229 signs and symptoms of, 216 skin manifestations of, 220, 220f slipped capital femoral epiphysis vs., 278 soft tissue surgery for, 242 spmal abnormalities, 230f, 230-231 splenomegaly associated with, 221 subcutaneous tissue manifestations of, 220, 220f subtalar jomt abnormalities, 229 synovial cysts associated with, 217, 217f-218f systemic characteristics of, 207t clinical features of, 208f description of, 206 technetium 99m imaging of, 226 temporomandibular jomt in, 219, 229, 229f tenosynovitis associated with, 218 transaminases in, 84 treatment of anakinra, 238 analgesics, 234 antimalarials, 239 approaches to, 231-232 aspirin, 233-234 autologous stem cell transplantation, 240 azathioprine, 114 basic program for, 232-233 biologic response modifiers, 237-238 chlorambucil, 238 COX-2 mhibitors, 233 cyclosporine, 118, 238 cytotoxic drugs, 238
779
disease-modifying antirheumatic drugs, 88, 238-239 etanercept, 237 glucocorticoids, 235-237 goals of, 231-232 gold compounds, 239-240 growth hormone, 240 hydroxychloroqume, 239 ibuprofen, 233 immune modulators, 238 immunosuppressive drugs, 238 indomethacin, 233 infliximab, 237-238 intravenous immunoglobulin, 238 leflunomide, 991 methotrexate, 89-92, 911, 232, 234-235 methylprednisolone, 236 naproxen, 233 nonsteroidal anti-inflammatory drugs, 83, 232-234 objectives of, 231t, 231-232 orthopedic surgery, 241-242 D-penicillamine, 240 prednisone, 235-236 recombinant interferon-'t, 238 slow-acting antirheumatic drugs, 238-239 sulfasalazine, 239 synovectomy, 241 tolmetin sodium, 233 triamcinolone hexacetonide, 236 tumor necrosis factor-a, 237 urinary tract abnormalities associated with, 222 uveitis associated with antinuclear antibodies in, 281-282 band keratopathy, 280, 282f, 283 clinical manifestations of, 279-280 course of, 283 description of, 278 differential diagnosis, 281 epidemiology of, 279, 279t etiology of, 279 genetics of, 279 glucocorticoids for, 282 histopathology of, 280-281 laboratory examination of, 281-282 management of, 282-283 monitoring of, 2811 pathogenesis of, 279 pathology of, 280-281 prognosis of, 283 slit-lamp biomicroscopy of, 280, 281£ vasculitis associated with, 220, 220f in wrist, 228 Juvenile temporal arteritis, 551
K Kaplan-Meier survival analysis, 169 Kappa test ratio, 169 Kashin-Beck disease, 632, 633t Kawasaki disease antineutrophil cytoplasmic antibodies in, 522,530 atypical, 525 cardiac status monitoring in, 534-536 cardiovascular disease and, 526-527 central nervous system complications, 527 cerebrospmal fluid analysis in, 530 clinicopathologic characteristics of, 494t conjunctivitis and, 524 coronary artery aneurysms and, 526, 527f course of, 523, 524f, 536
780
INDEX
Kawasaki disease (Continued) cutaneous manifestations of, 524-525, 525f definition of, 493t, 521 diagnostic criteria for, 521, 522t differential diagnosis, 529, 529t discovery of, 3 epidemiology of, 495, 495t, 521-522 etiology of, 522-523 extremiry changes, 525, 526f fever and, 523-524 follow-up for, 535t gastrointestinal tract disease in, 528 genetic background of, 523 genitourinary tract involvement in, 528-529 giant aneurysms and, 535 histopathologic findings, 529 historical background of, 521 incidence of, 521-522 intravenous immunoglobulin for, 119 laboratory examination for, 529-530 lymphadenopathy and, 525 mucosal changes associated with, 524 musculoskeletal disease and, 528 ocular disease associated with, 528, 528t pathogenesis of, 522-523 pathologic findings, 529 phases of, 523, 524f prevalence of, 521-522 prognosis for, 536 relapses of, 534 respiratory tract disease in, 528 salicylates for, 87 treatment of algorithm for, 532f aspirin, 531 general approach to, 530, 530t glucocorticoids, 533-534 goals for, 530--531 intravenous immunoglobulin, 531-533, 533t methylprednisolone, 534 pentoxifylline, 534 prednisone, 533 uveitis and, 528 Kendall's W, 169 Keratoconjunctivitis sicca, 451 Keratocytes, 400 Keratoderma blennorrhagicum, 607, 608f, 611 Ketoprofen dosing of, 81t structure of, 77f Kidneys aCllte interstitial nephritis with nephrotic syndrome, 85 juvenile ankylosing spondylitis findings, 311 nonsteroidal anti-inflammatory drug-related toxicities, 84-85 papillary necrosis of, 85 Kikuchi's disease, 296, 360 Klinefelter's syndrome,S Knee exercises for, 193f sagittal section of, lOf Knee pain, 678 Kniest's syndrome, 745, 751, 751f Koch's postulates, 145 Koebner phenomenon, 294 Kohler's disease, 685, 686f Kohlmeier-Degos syndrome, 506 Kozlowski's syndrome, 747t K-sample tests, 167
Kupffer cells, 19 Kurtosis, 160 Kveim-Siltzbach skin test, 555
L La protein, 392 Laboratory research, 143 Lactate dehydrogenase, 426--427 Laminin, 12 Langer-Gledion syndrome, 755 Langerhans cell histiocytosis, 735-736 Larsen's syndrome, 761 Last-observation-carried-forward approach, 157 Lectin pathway, 24, 25f Leflunomide description of, 98-99 polyarthritis treated with, 269 Leg exercises, 194f Legg-Calve-Perthes disease, 684, 685f Leg-length inequality in juvenile rheumatoid arthritis, 219 management of, 285 in oligoarthritis, 285 Leptin,432 Leri pleonosteosis, 747t Leri-Weill dyschondrosteosis, 747t Leri-Weill dysostosis, 755, 755f Lesch-Nyhan syndrome, 633-634, 634t Leukemia, 739-741 Leukocyte(s) in autoimmune diseases, 52, 54-55 inflammatory site recruitment of, 53f migration of, 52 Leukocyte adhesion deficiency type 1, 52 type 2, 52 Leukocyte function-associated antigen-1 description of, 52 in Lyme disease, 593 Leukocytoclastic vasculitis conditions associated with, 497t definition of, 496 in Henoch-Schonlein purpura. See HenochSchonlein purpura histopathologic findings in, 496, 497f historical descriptions of, 3 Leukotriene(s) A4,58 B4, 58 definition of, 58 synthesis of, 78f Libman-Sacks endocarditis, 355, 366, 366f, 622 Ligamentous laxity, 745-746 Ligaments, 15 Limited cutaneous systemic scleroderma, 463-464, 464f-465f Linear morphea, 475-476 Linear scleroderma, 472-473, 473f Lipocortins, 105 Lipodystrophy description of, 414, 418f management of, 432 Lipogranulomatosis subcutanea of RothmannMakai,455 Lipoid dermatoarthritis, 639 Lipopolysaccharide-binding protein, 26 Lipoxins, 58 5-Lipoxygenases, 58 Little league elbow, 682 Little league shoulder, 682 Livedo reticularis, 350--351, 517
Liver cirrhosis of, 92 methotrexate-related toxicity, 92-94 neonatal lupus erythematosus-related dysfunction of, 398 LJP-394, 120 Localized scleroderma bullous morphea, 472 characteristics Of, 472 clinical manifestations of, 475-476 course of, 478-479 deep morphea, 473-474 differential diagnosis, 477 epidemiology of, 474-475 etiology of, 475 generalized morphea, 472 immunologic abnormalities in, 478t incidence of, 474-475 laboratory examination of, 477-478 linear scleroderma, 472-473, 473f pathogenesis of, 475 pathologic findings in, 476--477 plaque morphea, 472, 473f prognosis for, 478-479 treatment of, 478 Locus ceruleus, 698 Long-term depression, 699 Long-term potentiation, 699 Lower leg exercises, 194f L-selectin, 43, 52, 54t Lubricin, 11 Lupoid hepatitis, 360 Lupus Activity Index, 372, 373t Lupus anticoagulants, 368 Lupus crisis, 358 Lupus erythematosus discoid, 643 neonatal. See Neonatal lupus erythematosus systemic. See Systemic lupus erythematosus Lupus erythematosus cell, 369, 369f Lupus nephritis. See also Glomerulonephritis characteristics of, 352-353, 353t, 361t, 372 end-stage, 38lt treatment of, 377t, 380--381 Luteinizing hormone-releasing hormone, 116 Lyme disease in acrodermatitis chronic atrophicans, 593-594 age at onset, 591 antibiotics for, 598t, 598-599 arthritis associated with, 597, 597t
Borrelia bur,gdorferi avoidance of, 599--600 description of, 475, 592 immunizations against, 600 laboratory detection of, 595-597 classification of, 591 clinical manifestations of, 593-595, 594t course of, 600 cutaneous manifestations of, 594 definition of, 591 description of, 584 diagnosis of, 597-598 epidemiology of, 591 erythema mlgrans associated with, 594, 594f, 598-599 etiology of, 592 gender ratio for, 591 genetic background of, 592 geographic distribution of, 591 history of, 591 immunizations against, 600 immunoglobulin G responses in, 596
INDEX ~munoglobulin M responses in, 596
in¢idence of, 591 lxlJdes scapulaTis and, 592, 593f laboratory examination for, 595-597 lel1k ocyte function-associated antigen-1 in, 593 microbiologic findings in, 592 musculoskeletal disease associated with, 594-595 n¢uroborreliosis in, 600 ocular involvement in, 595 p~thogenesis of, 592-593 pathologic findings of, 595 Prevalence of, 591 ptevention of, 599--600 ptognosis for, 600 s~rologic tests for, 597 skin manifestations of, 594 synovial fluid analysis in, 598 treatment of, 598-599 Lymphadenopathy juvenile rheumatoid arthritis and, 221 Kpwasaki disease and, 525 sarcoidosis and, 552 systemic arthritis and, 295 Lymphadenosis cutis benigna, 594 Lymphedema, 220 Lymphocytes attivation of, 43-44 See B cell(s) defective control of, 642-643 morphologic features of, 28 naive, 28 self-antigens and, 45 T. See T-cell(s) Lymphoid chemokines, 54 Lymphoma, Epstein-Barr virus-associated, 95 LYlJ1phomatoid granulomatosis, 546-547 Lymphotoxin, 27t
a.
M M proteins, 615 MaCrophage(s)
