Rheumatoid Arthritis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

RHEUMATOID ARTHRITIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES ...

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RHEUMATOID ARTHRITIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Rheumatoid Arthritis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83606-X 1. Rheumatoid Arthritis-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on rheumatoid arthritis. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON RHEUMATOID ARTHRITIS ......................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Rheumatoid Arthritis.................................................................... 9 E-Journals: PubMed Central ..................................................................................................... 134 The National Library of Medicine: PubMed .............................................................................. 142 CHAPTER 2. NUTRITION AND RHEUMATOID ARTHRITIS ............................................................. 277 Overview.................................................................................................................................... 277 Finding Nutrition Studies on Rheumatoid Arthritis ................................................................ 277 Federal Resources on Nutrition ................................................................................................. 283 Additional Web Resources ......................................................................................................... 284 CHAPTER 3. ALTERNATIVE MEDICINE AND RHEUMATOID ARTHRITIS ....................................... 291 Overview.................................................................................................................................... 291 National Center for Complementary and Alternative Medicine................................................ 291 Additional Web Resources ......................................................................................................... 312 General References ..................................................................................................................... 325 CHAPTER 4. DISSERTATIONS ON RHEUMATOID ARTHRITIS ......................................................... 327 Overview.................................................................................................................................... 327 Dissertations on Rheumatoid Arthritis ..................................................................................... 327 Keeping Current ........................................................................................................................ 331 CHAPTER 5. CLINICAL TRIALS AND RHEUMATOID ARTHRITIS ................................................... 333 Overview.................................................................................................................................... 333 Recent Trials on Rheumatoid Arthritis ..................................................................................... 333 Keeping Current on Clinical Trials ........................................................................................... 355 CHAPTER 6. PATENTS ON RHEUMATOID ARTHRITIS.................................................................... 357 Overview.................................................................................................................................... 357 Patents on Rheumatoid Arthritis............................................................................................... 357 Patent Applications on Rheumatoid Arthritis ........................................................................... 407 Keeping Current ........................................................................................................................ 421 CHAPTER 7. BOOKS ON RHEUMATOID ARTHRITIS ....................................................................... 423 Overview.................................................................................................................................... 423 Book Summaries: Federal Agencies............................................................................................ 423 Book Summaries: Online Booksellers......................................................................................... 424 The National Library of Medicine Book Index ........................................................................... 433 Chapters on Rheumatoid Arthritis............................................................................................. 434 CHAPTER 8. MULTIMEDIA ON RHEUMATOID ARTHRITIS ............................................................ 437 Overview.................................................................................................................................... 437 Video Recordings ....................................................................................................................... 437 Bibliography: Multimedia on Rheumatoid Arthritis ................................................................. 439 CHAPTER 9. PERIODICALS AND NEWS ON RHEUMATOID ARTHRITIS ......................................... 441 Overview.................................................................................................................................... 441 News Services and Press Releases.............................................................................................. 441 Newsletters on Rheumatoid Arthritis........................................................................................ 446 Newsletter Articles .................................................................................................................... 446 Academic Periodicals covering Rheumatoid Arthritis ............................................................... 448 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 451 Overview.................................................................................................................................... 451 U.S. Pharmacopeia..................................................................................................................... 451 Commercial Databases ............................................................................................................... 453 Researching Orphan Drugs ....................................................................................................... 454

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APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 459 Overview.................................................................................................................................... 459 NIH Guidelines.......................................................................................................................... 459 NIH Databases........................................................................................................................... 461 Other Commercial Databases..................................................................................................... 465 APPENDIX B. PATIENT RESOURCES ............................................................................................... 467 Overview.................................................................................................................................... 467 Patient Guideline Sources.......................................................................................................... 467 Associations and Rheumatoid Arthritis..................................................................................... 476 Finding Associations.................................................................................................................. 481 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 483 Overview.................................................................................................................................... 483 Preparation................................................................................................................................. 483 Finding a Local Medical Library................................................................................................ 483 Medical Libraries in the U.S. and Canada ................................................................................. 483 ONLINE GLOSSARIES................................................................................................................ 489 Online Dictionary Directories ................................................................................................... 493 RHEUMATOID ARTHRITIS DICTIONARY.......................................................................... 495 INDEX .............................................................................................................................................. 603

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with rheumatoid arthritis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about rheumatoid arthritis, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to rheumatoid arthritis, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on rheumatoid arthritis. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to rheumatoid arthritis, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on rheumatoid arthritis. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON RHEUMATOID ARTHRITIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on rheumatoid arthritis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and rheumatoid arthritis, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “rheumatoid arthritis” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Rheumatology Visit Frequency and Changes in Functional Disability and Pain in Patients With Rheumatoid Arthritis Source: Journal of Rheumatology. 24(1):35-42; 1997. Summary: This journal article for health professionals describes a study that examined the association between the number of visits to rheumatologists and changes in functional disability and pain over 6-month study periods among 127 patients who were treated by a rheumatologist at least once each year. The study also explored the association between the average annual frequency of visits to rheumatologists and both the progression of functional disability and average pain levels over periods of up to 10 years among these patients. Information on health care utilization and health status was obtained by biannual mailed Health Assessment Questionnaires (HAQ). Results indicate

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that the median visit frequency was 7.2 visits per year. The number of rheumatology visits was significantly associated with short-term changes in both functional disability and pain. Each additional visit in a 6-month study interval was associated with a decrease in the pain score in the current interval by an average of 0.02 points, and each additional visit was associated with a decrease in the HAQ Disability Index in the subsequent 6-month interval by an average of 0.0007 points. In analyses of long-term changes in health status, there was a U-shaped relationship between the frequency of rheumatology visits and the rate of progression of functional disability over time, with the lowest rates associated with average visit frequencies of between 7 and 11 visits per year. Average pain scores over time were positively correlated with the average annual frequency of rheumatology visits. Results demonstrate that short-term improvements in functional disability and pain were directly related to the number of visits patients made to rheumatologists. 21 references, 2 figures, and 3 tables. (AA-M). •

Importance of Enhancing Self-Efficacy in Rheumatoid Arthritis, The Source: Arthritis Care and Research. 10(1): 18-26. February 1997. Summary: This journal article presents health professionals with findings from a study that examined relationships among changes in self-efficacy and changes in other clinically relevant outcome measures among patients who had rheumatoid arthritis. The study population consisted of a subgroup of 44 participants from the stress management group of a prospective, randomized trial of a stress management intervention. Outcome measures included self-efficacy, depression, pain, health status, and disease activity. Correlational analyses reveal significant associations between changes in self-efficacy and changes in selected measures of depression, pain, health status, and disease activity. For example, as total self-efficacy increased, depressive symptoms decreased. At 15 months, higher self-efficacy was associated with lower pain on all four pain measures. At 3 months, improved functioning of the lower extremities was associated with enhanced self-efficacy. The speculation that health status changes may be related to changes in activity patterns is supported by data on walking speed. With higher selfefficacy, the time required for a 50-foot walk was reduced. However, improved walking speed may also have been associated with other observed changes, not just changes in disease activity per se. The observed associations were not due to changes in medication regimen or to nonadherence to the stress management program. The article concludes that the induced changes in self-efficacy following a stress management program were significantly related to other clinically important outcome measures. 5 tables and 34 references. (AA-M).

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Rheumatoid Arthritis: A Review and Suggested Dental Care Considerations Source: Journal of the American Dental Association. 130(5): 689-698. May 1999. Summary: This journal article provides dental health care workers with information from a study of the impact of rheumatoid arthritis (RA) and its treatment on the provision of oral health care. An extensive review of the medical literature in English on RA and dental care was undertaken. Although a MEDLINE search spanned the years from 1975 to the present, the most recent literature was prioritized. Appropriate medical and dental textbooks were also used. Nearly 200 articles and 7 textbooks were reviewed. Major features of RA, including its pathophysiology, diagnosis, clinical features, and treatment, were identified. The cause is unknown, but the etiology appears to be multifactorial and may involve infectious, genetic, endocrine, and immune participation. There is no specific laboratory test to diagnose RA. Although rheumatoid factors are found in more than two-thirds of adult patients with RA, they are not specific

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to it. The latest set of criteria for diagnosing RA was developed by studying patients who had already been diagnosed. The objective of RA therapies is to restore or maintain quality of life by relieving pain, reducing joint inflammation, and preventing joint destruction and deformity. Nonsteroidal anti-inflammatory drugs are the first-line treatment. Corticosteroids, another option, have both anti-inflammatory and immunosuppressive effects. Disease-modifying antirheumatic drugs, which have the potential to reduce disease activity or prevent joint damage, include gold, sulfasalazine, hydroxychloroquine, D-penicillamine, azathioprine, and leflunomide. Methotrexate has become a popular choice because of its immunosuppressive and anti-inflammatory effects. One of the latest and more novel approaches to treatment is cytokine therapy. However, long-term use of methotrexate and other antirheumatics can lead to various oral manifestations. The article discusses the clinical implications of RA in dental practice and provides guidelines on the dental management of people who have the disease. Considerations include the patient's ability to maintain adequate oral hygiene, xerostomia and its related complications, the patient's susceptibility to infections, impaired hemostasis, and untoward drug actions and interactions. 4 tables and 57 references. (AA-M). •

Rheumatoid Arthritis of the Cervical Spine Source: Journal of the American Academy of Orthopaedic Surgeons. 5(5): 240-248. September-October 1997. Summary: This journal article provides health professionals with an overview of rheumatoid arthritis of the cervical spine. Cervical involvement in patients who have rheumatoid arthritis occurs primarily in the upper cervical spine. The characteristic deformities are atlantoaxial subluxation, vertical settling, and subaxial subluxation. The typical patient complaints are neck pain and occipital pain. Subtle signs of myelopathy may also be present. Useful radiologic studies include plain radiography, tomography, and functional magnetic resonance imaging. The most helpful radiographic measurements are the anterior atlantodens interval, the posterior atlantodens interval, and assessment of vertical settling. Atlantoaxial subluxation greater than 9 millimeters (mm) with vertical settling and a posterior atlantodens interval less than 14 mm correlate with neurologic deficit. Nonoperative management does not change the natural history of cervical disease. Traditional surgical indications include intractable pain and neurologic deficit. The article discusses the more controversial indications for surgical intervention and proposes a rationale and protocol for treatment. The primary surgical objectives are to achieve stabilization of the affected segments and to relieve neural compression by reduction of subluxations or direct decompression. Arthrodesis provides reliable pain relief. Neurologic recovery occurs more consistently in patients with lower grades of preoperative myelopathy. 5 figures, 1 table, and 39 references. (AA-M).

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Arthritis 101: Juvenile Rheumatoid Arthritis Source: Arthritis Today. 14(1): 32-33. January-February 2000. Summary: This journal article uses a question and answer format to provide people who have children with juvenile rheumatoid arthritis (JRA) with information. There are three forms of childhood arthritis. Systemic onset JRA affects many bodily systems, including the joints, spleen, lymph nodes, liver, and heart. Polyarticular JRA affects more than four joints in a symmetrical manner. Joints most commonly affected are the knees, ankles, hips, feet, and small joints of the hands. This form of JRA has two subtypes. The first is characterized by the presence of rheumatoid factor and DR4 genetic type. The

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second is characterized only by joint involvement. Pauciarticular JRA usually affects four or fewer joints in an asymmetrical manner. The joints most commonly affected are the knees, elbows, wrist, and ankles. This form of JRA has three subtypes. In the first subtype, children have antinuclear antibodies and a high risk of iridocyclitis. In the second subtype, arthritis affects the spine and other joints, and children may test positive for the HLA-B27 gene. In the third subtype, joint involvement is the only feature. Although the cause of JRA is unknown, contributing factors likely include genetics and environmental factors. JRA can occur in boys or girls of any age, but it usually begins during the toddler or early adolescent years. Generally, it affects more girls than boys. Diagnosis of JRA is based on a medical history, physical examination, and possibly laboratory tests. Although in many ways JRA is treated the same as adult rheumatoid arthritis (RA), many drugs used to treat RA are not approved for children. Large doses of aspirin are usually used first, followed by disease modifying antirheumatic drugs if the disease progresses. 4 figures. •

Emerging Insights Into the Cause of Rheumatoid Arthritis Source: Journal of Musculoskeletal Medicine. 18(10): 459-461,464,469-472. October 2001. Summary: This journal article, the first in a special series of articles on the diagnosis and management of rheumatoid arthritis (RA), provides health professionals with information on the genetic and nongenetic factors that influence the onset, course, and severity of RA. This disease results from an abnormal immune response that occurs in a genetically susceptible host, leading to self sustaining, chronic inflammation that affects joints and, sometimes, organs. The strongest genetic components are polymorphisms of the major histocompatibility complex class (MHC) II genes. The MHC region contains several loci that encode for human leukocyte antigen (HLA). Allelic polymorphisms of HLA genes have been associated with several autoimmune diseases. Clinical studies suggest that HLA-DREB1 alleles modify the expression of established RA. Several environmental stimuli, possibly bacteria, viruses, or retroviruses, may contribute to RA in susceptible hosts. The immune system of persons with RA has features of premature aging, including reduced thymic function and T cell diversity. Oligoclonal T cell populations with natural killer features are common. A synovial cellular infiltrate is a consistent feature in RA. The inflamed synovium, or pannus, invades the joint and produces focal bone erosions. Cytokines, especially tumor necrosis factor alpha, are important mediators of inflammation in the rheumatoid joint. Although rheumatoid factors can exist in persons who do not have RA, the presence of rheumatoid factor foretells a more severe course of disease. 4 figures, 1 table, and 30 references. (AA-M).

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Part 1: The Role of Exercise: Rehabilitation Strategies for Patients With Rheumatoid Arthritis Source: Journal of Musculoskeletal Medicine. 17(4): 191-194,196-198, 203-204. April 2000. Summary: This journal article, the first of two parts and the ninth article in a special series on the diagnosis and management of rheumatoid arthritis (RA), provides health professionals with information on rehabilitation strategies. The article focuses on the general principles of rehabilitation as they apply to persons who have RA and the role of exercise in promoting optimal strength and function. For optimal preservation of joint function and range of motion (ROM), the patient who has RA should begin a rehabilitation program early. A history and physical examination focusing on musculoskeletal problems and functional evaluation are essential prerequisites. Progressive exercise is a key component of any rehabilitation program. The type, intensity, and duration of exercise depend on disease activity and stage. Patients begin

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with passive and active ROM movements, adding strengthening and aerobic exercise as tolerance and mobility permit. Primary strengthening exercises are isometric, isotonic, and isokinetic. Isometric exercise involves having the patient contract his or her muscle against a stationary object such as a belt, table, or machine that has a fixed arm. After muscles have been trained isometrically, the patient needs to incorporate isotonic exercises into the program. These involve moving the joint for several repetitions against resistance offered by free weights, elastic bands, or a machine. Isokinetic exercise is done with a machine and offers no strengthening advantage over isometric exercise. The best aerobic exercises for patients who have RA are stationary bicycling and swimming. Exercising at 70 percent maximum capacity for just 15 minutes 3 times a week usually produces improvement in 8 to 12 weeks. 3 figures, 9 tables, and 19 references. (AA-M). •

Rehabilitation Strategies for Patients With Rheumatoid Arthritis, Part 2: Modalities, Orthoses, and Assistive Devices Source: Journal of Musculoskeletal Medicine. 17(7): 385-387,391-393, 397-398. July 2000. Summary: This journal article, the second of two parts on rehabilitation strategies for patients with rheumatoid arthritis (RA), provides health professionals with information on the role of joint protective modalities, assistive devices, and orthoses that help patients exercise and function at their best. Modalities, orthoses, assistive devices, and education are important partners to exercise and medical therapy for patients with RA. Thermal modalities help decrease pain and muscle spasm in joints subacutely or chronically affected by RA; however, heat should be avoided during acute inflammation. Deep heat delivered via ultrasound or microwave is recommended for subacute and chronic capsular and tendon tightness that occurs in a large joint such as the shoulder or hip. Cold is recommended for decreasing pain, muscle spasm, and edema. Vehicles for delivering cold include ice packs, crushed ice, gel packs, and bags of frozen peas. Physical modalities that may increase comfort include massage, electrical stimulation, and, for patients with neck and back syndromes, traction. Orthoses help decrease inflammation, relieve pain, align and rest joints, and improve function, particularly in the hands, wrists, feet, and ankles. Orthoses can be static or dynamic. Assistive devices include large handled tools, sporting equipment, and kitchen utensils. Education improves compliance. Many patients resort to such alternatives as acupuncture or acupressure when conventional treatment brings no relief. Orthopedic referral is appropriate when joint realignment, stabilization, or reconstruction is necessary. 5 figures, 2 tables, and 10 references. (AA-M).

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Combination Therapy of Rheumatoid Arthritis Source: Journal of Musculoskeletal Medicine. 16(10): 583-589. October 1999. Summary: This journal article, the seventh in a special series on the diagnosis and management of rheumatoid arthritis, provides health professionals with information on the rationale for combination therapy with disease modifying antirheumatic drugs (DMARDs). These agents act slowly and suppress the chronic inflammation that leads to joint destruction in people who have rheumatoid arthritis. Combination therapy with multiple DMARDs theoretically offers the advantage of additive effects of drugs that act at different phases of the inflammatory process. At the same time, modification of one drug's metabolism by another's could reduce the potential for additive toxicities. Although early studies addressing the issue of simultaneous initiation of multiple DMARDs were discouraging or inconclusive, recent studies have more favorably demonstrated the enhanced efficacy of multiple DMARDs. Combinations that have shown promise in recent studies include methotrexate with sulfasalazine and

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hydroxychloroquine; methotrexate and cyclosporine; methotrexate, azathioprine, and hydroxychloroquine; and cyclosporine and intramuscular gold. Toxicities can be monitored according to American College of Rheumatology protocol. 1 figure, 4 tables, and 14 references. (AA-M). •

Emerging Therapies for Rheumatoid Arthritis Source: Rheumatic Disease Clinics of North America. 24(3): i-x, 465-662. August 1998. Summary: This journal provides health professionals with information on emerging therapies for rheumatoid arthritis (RA). The first article reviews the published data on the triple combination of methotrexate, sulfasalazine, and hydroxychloroquine to treat RA and compares the effectiveness of this triple combination with the combination of methotrexate and cyclosporin. An article on the use of cyclosporin in treating RA includes a discussion of its pharmacokinetics and efficacy, and guidelines for its use. Another article on the use of minocycline for the treatment of RA considers the scientific basis for the use of antibiotics in treating RA, the efficacy and toxicity of minocycline, and the place of tetracycline derivatives within the overall strategy of RA treatment. The next article reviews the expression, regulation, and activities of the cyclooxygenases; explains how nonsteroidal antiinflammatory drugs might interact with them, and comments on the new cyclooxygenase inhibitors that might be highly effective antiinflammatory agents without the gastrointestinal and renal side effects. Following are articles that present studies on oral tolerization as a treatment of rheumatoid arthritis; biologic agents and immunotherapy in RA; CD4 monoclonal antibody treatment of RA; soluble tumor necrosis factor receptor fusion protein as a therapy for rheumatoid arthritis; and antitumor necrosis factor-alpha monoclonal antibody therapy for RA. Other articles discuss interleukin (IL)-1 receptor antagonist and IL-10 as therapeutic agents in the treatment of RA, and T-cell receptor peptide vaccination in the treatment of RA. The final article focuses on the role of methotrexate in RA treatment and emerging therapies for RA. 17 figures, 19 tables, and numerous references.

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Arthroscopic Lavage Treatment in Rheumatoid Arthritis of the Knee Source: Journal of Rheumatology. 23(11):1872-1874. 1996. Summary: This study assessed the efficacy of outpatient arthroscopic lavage in rheumatoid arthritis (RA) of the knee. Researchers evaluated nine patients with RA and active synovitis of at least one knee. All patients were taking disease modifying antirheumatic drugs and nonsteroidal anti-inflammatory drugs and had failed intraarticular corticosteroid injection of the knee. Using the 1.9 mm office arthroscope and strict sterile technique, the affected knee was lavaged with at least 750 cc of normal saline. At the end of the procedure 40 mg triamcinolone acetonide was injected through the arthroscope. Assessment was done at baseline and 4, 8, and 12 weeks after the lavage using a visual analog scale for pain and 50 foot walk time. Results show that eight of the nine patients showed marked improvement in their pain and walk time. This effect was maintained at least 12 weeks after the procedure. The authors indicate that the procedure is simple and well tolerated, and may be an option when more conservative therapies have failed. 1 table, 1 figure, and 16 references.

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Validity of Self-Reported Diagnosis of Rheumatoid Arthritis: Results from a Population Survey Followed by Clinical Examinations Source: Journal of Rheumatology. 23(11):1866-1871. 1996.

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Summary: This study examined the validity of patient self-reported rheumatoid arthritis (RA); and assessed the predictive value of symptoms, health status measures, and demographic variables with respect to the actual diagnosis. Researchers used a postal survey in Oslo of 10,000 randomly selected individuals between 20 and 79 years old. Respondents reported musculoskeletal pain, stiffness, rheumatic diagnoses, disability, and mental distress. The patients reporting RA (either according to patient or doctor) were selected for further examination. Results show that of 5,886 respondents (3670 with musculoskeletal pain or stiffness) 158 patients (2.7 percent) reported having RA diagnosed by a doctor (n=107) and/or according to their own opinion (n=142). RA was confirmed by clinical examination in 35 of these 158 individuals (22 percent). Patients with perceived and actual RA differed regarding self-reported presence of swollen joints and disability score. Multivariate analyses failed to identify a set of useful predictors for the correct diagnosis. Researchers conclude that patient self-reported diagnosis of RA is unreliable for research or clinical purposes. 5 tables and 34 references. (AA-M).

Federally Funded Research on Rheumatoid Arthritis The U.S. Government supports a variety of research studies relating to rheumatoid arthritis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to rheumatoid arthritis. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore rheumatoid arthritis. The following is typical of the type of information found when searching the CRISP database for rheumatoid arthritis: •

Project Title: 5 FLUOROURACIL (5 FU) PLUS LEUCOVORIN IN TREATMENT OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Bunch, Thomas W.; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001 Summary: The main objective of this study is to provide patients that have refractory rheumatoid arthritis with a better treatment option. Rheumatoid arthritis affects 1-2 percent of the population, and current treatments are inadequately efficacious for many patients. Immunosuppressive agents have been shown to clearly suppress the immunopathogenic mechanisms response for much of the disease activity. This is a clinical trial to determine the maximally tolerated dose of 5-FU and leucovorin when given on a daily x 5 schedule in patients with rheumatoid arthritis, to define toxicity

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

10 Rheumatoid Arthritis

and to document any clinical benefit of this drug combination in patients with rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVATION OF COLLAGENASE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Windsor, L Jack. Oral Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2001; Project Start 01-SEP-1997; Project End 31-AUG-2003 Summary: (Adapted from the applicant's abstract) - Rheumatoid arthritis is characterized by chronic inflammation and joint degeneration. This erosion of the joint is likely due to an imbalance of extracellular matrix synthesis and metabolism induced, in part, by members of the matrix metalloproteinase (MMP) family. The MMPs are zincdependent endopeptidases that are capable of degrading most of the components of the extracellular matrix. Active collagenase has been identified in the synovial fluid and in tissue extracts from patients with rheumatoid arthritis as well as in conditioned media from cytokine-stimulated synovial fibroblasts. It has been suggested that this activation of collagenase was initiated via the plasminogen cascade and/or involves stromelysin-1. However, the activation pathway of collagenase is a pivotal step in collagen degradation that still remains poorly understood. The overall aim of this study is to identify and characterize the mode of activation of fibroblast-type collagenase (collagenase-1) by synovial fibroblasts and manipulate its activation to determine if control of this process could be beneficial in the treatment of rheumatoid arthritis. The following specific aims are proposed to accomplish these goals: Specific aim 1 - Human synovial fibroblast cell lines capable of mediating destruction of a reconstituted matrix consisting of type I collagen fibrils will be identified and characterized. Collagen degradation initiated by these cells will be blocked by addition of inhibitory antibodies to collagenase-1 to demonstrate that this collagen degradation is collagenase -1 dependent. Intermediates in the activation of collagenase-1 will be identified and characterized by alpha2macroglobulin and TIMP (tissue inhibitor of metalloproteinases) capture techniques as well as by their reactivity in a fluorescent maleimide. In order to determine processing sites, amino-terminal sequencing will be carried out using activation intermediates purified by antibody affinity chromatography or by immunoprecipitation. Specific aim 2 - The investigators propose to distinguish the roles stromelysin and other MMPs play in the activation of collagenase-1 by synovial fibroblasts through addition of inhibitory antibodies made to each enzyme. Inhibitory antibodies to TIMP-1 may be included to provide an imbalance of enzymes to inhibitors which might lead to the activation of collagenase-1. Activation intermediates will be identified and characterized. Specific aim 3 - Once a synovial fibroblast cell line is identified that activates collagenase-1 independent of stromelysin-1 and other MMPs, it will be used to identify the mechanism(s) or factor(s) that are responsible for CL-1 activation. The feasibility of this specific aim is limited and depends on identifying a synovial fibroblast cell line that meets these criteria. The long-term goal of this project is to identify drugs or other reagents (antibodies) that can block the mechanism by which cells activate collagenase-1 and the other MMPs in order to prevent the continuous or intermittent destruction of the joints as seen in rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 11

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Project Title: ACUTE STRESS REACTIVITY AND DISEASE EXACERBATION IN RA Principal Investigator & Institution: Boyce, Thomas; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: The objectives of this study are: (1) to conduct a laboratory investigation of 20 premenopausal women with RA in order to examine the effects of psychological stress on subjective, neuroendocrine, and immunologic responses that may be relevant to the pathogenesis of RA. For a subgroup of RA patients taking NSAIDs only, we will compare the magnitude of subjective and physiologic responses to a group of 20 healthy women who are diagnosed with carpal tunnel syndrome without RA, and matched for age, race, and NSAID use; (2) to determine if individual differences in the magnitude of physiologic stress responses can be demonstrated in patients with RA; (3) to conduct an exploratory and longitudinal investigation of whether such individual differences are associated with RA disease activity; (4) to carry out exploratory analyses examining potential associations between individual differences in physiologic reactivity and disease and psychosocial factors, including those that have been found to relate to distress and reported pain in RA samples. Examples include level of disease activity, social support, history of major negative events, and the personality traits of introversion and neuroticism, which have related to physiologic reactivity in healthy samples. The GCRC will be used as the site of the 3 hour laboratory investigation, which will be done during the follicular phase of each subject's menstrual cycle, and scheduled between 1-3 pm to control for circadian variations in hormone levels. The GCRC nurses will administer multiple questionnaires, perform frequent timed vital signs, coordinate two stress tasks and draw several timed blood samples during the stress producing tasks. The GCRC lab will perform the initial blood processing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADENO-ASSOCIATED VIRUS-MEDIATED SYNOVIAL GENE TRANSFER Principal Investigator & Institution: Hirsch, Raphael; Associate Professor of Pediatrics; Children's Hosp Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, PA 15213 Timing: Fiscal Year 2002; Project Start 10-SEP-1996; Project End 31-AUG-2007 Summary: (provided by applicant): Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are diseases for which current therapies are only partially effective and are associated with significant side effects. Gene therapy delivered locally to diseased synovium is a novel approach offering the potential to achieve steady-state levels of short-lived, specific biologic agents directly to diseased joints, thus minimizing possible toxicity associated with systemic delivery. Recombinant adeno-associated virus (rAAV) vectors have emerged as agents capable of delivering genes to tissues in vivo, including synovium, resulting in very long-term transgene expression. Importantly, a significant and growing number of reports show that rAAV vectors elicit minimal pathogenicity and immunogenicity. Preliminary data from our laboratory demonstrates that both proteasome inhibitors and certain adenovirus proteins dramatically improve rAAV mediated synovial gene transfer. We have also made the novel observation that proteasome inhibitors can regulate transgene expression in AAV-transduced synoviocytes. In this context, the current application will test the hypothesis that rAAVmediated, localized gene therapy can control human arthritis and will explore the


mechanism of proteasome- and adenovirus-enhancement of rAAV-mediated synovial gene transfer. We will determine the specific site or step of transduction at which enhancement by proteasome inhibition and adenovirus helper proteins occur. Using a human RA/JRA-SCID model in which human arthritic synovium is implanted into SCID mice, we will deliver soluble TNF receptor (sTNFR), IL-4 and IL-10 by rAAVmediated gene transfer. The effects on synovitis and cartilage destruction of local, versus systemic, expression will be compared. To test the effects on synovitis of the removal of sTNFR, IL-4, and IL-10 following a period of expression, we will utilize a system for rAAV-mediated gene transfer under the control of a promoter that is active only in the presence of rapamycin. The potential of proteasome inhibitors to regulate transgene expression will also be determined. rAAV is the first vector with properties sufficiently attractive to be of potential clinical utility in arthritis. The proposed studies will provide a small animal model for testing the potential of rAAV-mediated gene transfer for human arthritides and may serve as the basis for the clinical application of rAAV to the treatment of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AN L-SELECTIN LIGAND ANTIBODY FOR THERAPY OF ASTHMA Principal Investigator & Institution: Hemmerich, Stefan; Thios Biotechnology, Inc. 747 52Nd St Oakland, CA 94609 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 15-MAR-2003 Summary: (provided by applicant): Objective of this proposal is to develop a novel adhesion-blocking antibody for therapy of chronic inflammatory diseases like asthma and rheumatoid arthritis. Current treatments involve steroids or inhibition of inflammatory cytokines. An alternative approach is modulation of cell adhesion that is expected to limit inflammatory cell recruitment without immunosuppression inherent to anti-TNFalpha or steroid therapy. Leukocyte adhesion is mediated by the selectins. Lselectin binds to endothelial ligands defined by the monoclonal IgM MECA-79. MECA79 reactive vessels are found in peri-bronchial biopsies from asthmatics and in rheumatoid synovium. The MECA-79 epitope includes a functionally critical 6-Osulfation of N-acetylglucosamine contained within sialyl-Lewisx type capping groups of O-glycans on endothelial mucins. We have shown that MECA-79 treatment is therapeutic in asthmatic sheep. The MECA-79 epitope is therefore an attractive target for antibody-based anti-adhesive therapy. In specific aim 1 humanized single-chain antibodies specific to the MECA-79 epitope will be generated from phage display libraries. Aim 2 is to obtain a subset that blocks L-selectin binding. Aim 3 is to obtain a further set of antibodies that block lymphocyte adhesion and migration in-vitro and invivo. In phase II, resulting antibodies will be tested in disease-relevant animal models. Provided efficacy, a clinical lead will be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AN OUTCOME STUDY OF RHEUMATOID HAND ARTHROPLASTY Principal Investigator & Institution: Chung, Kevin C. Assistant Professor; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2003; Project Start 08-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Rheumatoid arthritis (RA) affects 2.1 million Americans and costs the United States an estimated $8.7 billion annually in medical costs and wages. RA is a progressive disease, and approximately 25% of RA patients

Studies 13

experience hand deformities associated with the destruction of the metacarpophalangeal (MCP) joints. For the past 30 years, Swanson Metacarpophalangeal Joint Arthroplasty (SMPA) has been performed to correct MCP joint deformity in the rheumatoid hand. The goals of SMPA are pain relief, restoration of function, and aesthetic improvement. Despite its wide application, SMPA remains a controversial procedure. Hand surgeons and rheumatologists frequently disagree about the indications for this procedure and its value to their patients. In addition, most published studies to-date have been hampered by inadequate consideration of research design, small sample size, and inconsistent outcome measures. To provide a better understanding of the effectiveness of SMPA, a multi-center international outcomes study will be carried out to evaluate a cohort of RA patients with severe MCP joint subluxation who will either be enrolled into a SMPA (surgery plus medical therapy) group or a non-SMPA (medical therapy alone) group. Our research question asks whether RA patients who undergo SMPA will have different outcomes than those who are treated only medically. Patients will be evaluated at six months, one year, two years, and three years after surgery (SMPA group) or study entry (non-SMPA group). Outcome evaluations will be based on the Michigan Hand Outcomes Questionnaire, the Arthritis Impact Measurement Scales questionnaire, and standard objective hand function tests. The purpose of this project is to measure shortand long-term outcomes following SMPA and to define its indications for members of specific patient groups and disease severity strata. Most importantly, this project will combine the experiences of both surgery and rheumatology services to jointly evaluate this surgical procedure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALOG PEPTIDES IN COLLAGEN-INDUCED ARTHRITIS Principal Investigator & Institution: Myers, Linda K. Professor; Pediatrics; University of Tennessee Health Sci Ctr Health Science Center Memphis, TN 38163 Timing: Fiscal Year 2001; Project Start 24-JUN-1995; Project End 28-FEB-2005 Summary: Collagen-induced arthritis (CIA) is an experimental model of autoimmune arthritis induced by immunization of susceptible strains of mice with type II collagen (CII). Our recent studies using HLA-DR transgenic (Tg) mice expressing HLA class II molecules associated with susceptibility to rheumatoid arthritis (RA) reveal that DR1 (DRB1*0101) and DR4 (DRB1*0401) can bind and present peptides derived from human (h) CII, and that mice bearing these transgenic DR molecules are susceptible to CIA. The immune response to hCII and arthritis can be down regulated by an analog peptide of CII, A12, CII 256-276 (F263->N, E266->D), when it is co-administered at the time of immunization with hCII. Human CII- sensitized spleen and lymph node cells from DR Tg mice produce increased amounts of IL-4 and IL-10 when cultured with Al2 in comparison to cells cultured with the wild-type CII peptide (CII 256-276). These observations suggest that the suppressive effect of A12 on immune response to CII and CIA in these DR Tg mice is mediated by a shift in the cytokine profile, from that of a Thl to a Th2. However, the mechanism(s) whereby the shift is brought about is not known. Al2 contains two amino acid substitutions as compared to the wild-type CII peptide. The substitutions are of two types, a) residue 263 that participates in peptide binding to the DR molecule, and b) residue 266 that interacts with the TCR. The hypothesis to be tested in this application is that the A12 effect on CIA is mediated through polarization of the specific immune response to a predominant Th2 profile, and that this polarization is caused by changes in the affinity between either DR and peptide or DR/peptide interaction with the TCR leading to altered T cell signaling and, consequently, the production of cytokines. We, therefore, plan to: 1) Identify the structural characteristics


of the analog peptide Al2 that mediate its modulation of the immune response to CIIl and CIA in DR Tg mice; 2) Determine whether encoding the Al2 substitutions within the triple helical CII molecule increases the efficacy in inhibiting the autoimmune response in CIA; 3) Determine whether the suppression of CIA produced by A12 administration is dependent on IL-l0 or IL-4 secretion; and 4) Determine the mechanism by which Al2 alters T cell function by analyzing signaling pathways involved in T cell activation. Information gained from these studies will provide important insight for the design of novel therapeutic approaches that may prove beneficial in the treatment of autoimmune arthritis in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF GENETIC AND NONGENETIC RISK FACTORS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Criswell, Lindsey A.; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001 Summary: Rheumatoid arthritis (RA) is a chronic, disabling illness of unknown cause. Although both genetic and non-genetic factors are clearly important in disease onset and progression, little is known about specific risk factors. Furthermore, interactions among genetic and non-genetic factors are likely to be important, yet this remains an underexplored area of investigation. Substantial evidence implicates the Major Histocompatibility Complex (MHC) region in RA susceptibility. However, existing studies fail to define precisely which of the numerous candidate genes in this region influence disease risk, and whether they have independent or interactive effects. Specifically, strong evidence supports a role for the HLA-DRB1 "shared epitope," however, there is strong evidence that other MHC region loci likely influence RA risk or severity. Non-MHC genes must also be important, yet little is known about other genetic risk factors. Preliminary data by our group and others suggest a role for T cell receptor B (TCRB) genes in RA susceptibility. Finally, although non-genetic factors are estimated to explain at least 50% of RA risk, little is known about specific non-genetic risk factors. In this study, we will focus on two gene regions and two categories of nongenetic factors that are implicated in RA etiology based on pathophysiologic considerations and previous genetic and epidemiologic studies. Specifically, we will examine four candidates within or near the MHC region (HLA-DRB1, -DMA, tumor necrosis factor exposure to cigarette smoke. Our analysis will explicitly assess the presence of independent and interactive effects upon certain patient and disease characteristics. Our choice of analytic method, the transmission disequilibrium test, will allow us to study an ethnically diverse sample while maintaining false positive associations arising from population admixture. The results of this study will: 1) more precisely define the MHC contribution to RA; 2) evaluate the role of the TCRB gene complex; 3) provide new and important information about discrete non-genetic risk factors in RA onset and disease expression; and 5) provide important information about potential sources of genetic heterogeneity that will inform the design and analysis of future genetic epidemiologic studies of RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ARTHRITIS

ANDROGEN

AS

ADJUNCT

THERAPY

IN

RHEUMATOID

Principal Investigator & Institution: Davis, John C. Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122

Studies 15

Timing: Fiscal Year 2001; Project Start 20-SEP-1999; Project End 30-JUN-2003 Summary: Rheumatoid arthritis (RA) is a chronic, debilitating multisystem disease affecting nearly two million persons in the United States alone. The incidence of RA in men under the age of forty-five is less than that reported in women, however the incidence approaches that of women in older age groups of men. This increased incidence in males coincides with decreasing levels of sex hormones. A hypogonadic condition characterized by low serum testosterone has been previously described in male RA patients compared with age-matched controls with osteoarthritis, ankylosing spondylitis and healthy controls. Patients with RA have significant disability with decreased function over time. Androgens have the potential to increase nitrogen retention, lean body mass, strength, and body weight which could slow the decline in function. Patients with RA also have both local and systemic forms of osteoporosis. There is evidence that androgens may stimulate the proliferation and differentiation of osteoblasts and osteoblast-like cells in vitro which may help reduce the rate of bone loss in RA. Previous studies in both animal models and humans seem to suggest that androgen administration may be beneficial in a number of autoimmune diseases including RA. In this study, we will examine the role of transdermal testosterone versus placebo in male patients with RA over a two-year period. Specifically, we will examine (1) the effect of testosterone on lean body mass and muscle strength with the use of whole body dual xray absorptiometry (DXA) scan and muscle strength testing, (2) the effect of testosterone on bone mineral density by DXA scan of the spine and hip, and (3) the effect of testosterone on disease specific measures of quality of life with validated instruments for quality of life. Additionally, measure of disease activity and side effects will also be assessed. The results of this study will (1) help to define the role of androgen administration and its effects on function through assessment of muscle mass and strength, (2) explore the potential benefits of testosterone therapy on bone mineral density in patients with both localized and systemic forms of osteoporosis, (3) define changes in quality of life in patients with RA treated with androgen, and (4) help to define the potential role of androgen therapy in other systemic illnesses where muscle wasting has a profound impact on quality of life (e.g. both inflammatory and noninflammatory muscle disease). In addition, this K-23 grant will provide opportunity for further career development through mentorship provided by an committee with multiple areas of expertise and formal education in the areas of clinical research design and conduct, outcome assessment development and analysis, and clinical trial analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANGIOGENESIS & ALPHA V INTEGRINS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Storgard, Chris M.; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001; Project Start 27-SEP-1999; Project End 30-JUN-2004 Summary: Angiogenesis is central to the pathophysiology of rheumatoid arthritis (RA), and anti-angiogenic therapy targeting vascular integrin alphavbeta3, a crucial effector of the angiogenic process, may provide a novel approach to the treatment of this disease. The Specific Aims of this Mentored Clinical Scientist Development Award are [1] To characterize the dominant integrin pathway promoting angiogenesis in human RA, [2] To evaluate the effects of rational combination therapy targeting angiogenesis, cytokineinduced inflammation, and T cell mediated immunity, to determine the relative contribution of angiogenesis to the pathophysiology of RA, and provide pre-clinical evaluation of potential synergistic therapeutic effects, and [3] To examine the molecular


mechanism of alpha V integrin-mediated endothelial cell survival during angiogenesis. The proposed research plan, in addition to providing valuable information, will equip the applicant with the necessary skills and techniques to investigate molecular mechanisms of cell function and signal transduction and perform anti-angiogenic gene delivery strategies as an independent investigator. Antagonists of alphavbeta3 are presently being evaluated in phase I/II cancer trials, and the results of this proposed study will provide the basis for alphavbeta3 antagonist therapy in future human arthritis trials. The strength of this career development award is based on the Mentor, Dr. David Cheresh, an international leader in angiogenesis research with a solid history of fostering the development of independent researchers. In addition, The Scripps Graduate Program in Macromolecular and Cellular Structure and Chemistry, in conjunction with The Scripps Research Institute and the Cheresh Laboratory, provide an outstanding training environment with exposure to state-of-the-art technology, permitting collaboration and intellectual exchange with many leading investigators. This comprehensive career development plan, in addition to the proposed research project will guarantee successful maturation of the applicant from physician to physician-scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI TNF CHIMERIC MONOCLONAL ANTIBODY IN PATIENTS WITH RHEUMATOID ARTHRITIS Principal Investigator & Institution: Schilling, Margo L.; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001 Summary: This study is evaluating the efficacy and safety of chronic treatment with cA2, an anti-TNF chimeric monoclonal antibody, in combination with methotrexate in subjects with active rheumatoid arthritis despite treatment with methotrexate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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ANTI-ANGIOGENIC

GENE

THERAPY

FOR

RHEUMATOID

Principal Investigator & Institution: Kasahara, Noriyuki; None; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, CA 90033 Timing: Fiscal Year 2001; Project Start 20-SEP-1999; Project End 31-JUL-2002 Summary: The purpose of these studies is to evaluate the therapeutic potential of the angiogenesis inhibitors thrombospondin-1, angiostatin, and endostatin, for gene therapy of rheumatoid arthritis. Using lentiviral and helper-dependent adenoviral vectors as gene delivery systems for these angiogenesis inhibitors, we propose to develop an intraarticular treatment for rheumatoid arthritis. A considerable body of experimental and clinical data has documented that the pathogenetic process in rheumatoid arthritis involves the induction of a neovascular response. The process of new blood vessel formation, or angiogenesis, involves the interaction of substances that either stimulate or inhibit endothelial cell proliferation and migration. During pathologic processes such as rheumatoid arthritis, increased expression of angiogenic stimulators or decreased production of inhibitors alters the balance of positive and negative inputs of endothelial cell proliferation in favor of active neovascularization. We hypothesize that by increasing the concentration of these angiogenesis inhibitors in the synovial tissues during chronic inflammation, we may prevent the induction of new blood vessels and retard disease progression. The proposed experiments will allow us to: 1) optimize

Studies 17

delivery and expression of transgenes encoding the angiogenesis inhibitors thrombospondin-1, endostatin and angiostatin, following intra- articular administration of lentiviral and helper-dependent adenoviral vectors, 2) to determine the extent of systemic absorption and investigate the systemic effects of intra- articularly delivered anti-angiogenic lentiviral and adenoviral vectors, 3) to determine the in vivo chemopreventive effects of increased local expression of angiogenesis inhibitors on the establishment of arthritic disease, and 4) to determine the ability of lentiviral-and adenoviral-mediated delivery and local overexpression of anti-angiogenic genes to inhibit disease progression and angiogenesis in established arthritis. The development of an effective anti-angiogenic therapy for rheumatoid arthritis utilizing a relatively non-invasive intra- articular gene delivery strategy could have significant impact on patient quality of life, and potentially improve long-term outcome. In addition, by taking advantage of the ease of access by the intra-articular route, we anticipate that it will be possible to establish high local concentrations of potent angiogenic inhibitors while minimizing potentially adverse effects associated with systemic administration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIBODY STRUCTURE AND DYNAMICS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Kirschner, Karl N. None; University of Georgia 617 Boyd, Gsrc Athens, GA 306027411 Timing: Fiscal Year 2001; Project Start 01-JUL-2001 Summary: Rheumatoid factor (RF) proteins are present in the tissue of individuals who suffer from the autoimmune disease rheumatoid arthritis, which can be extremely painful and disabling. RF binds to specific epitopes in the IgG class of antibodies, forming an immune complex, which initiates an inflammatory response and eventually results in tissue damage of diseased joints. The profile of the glycans obtained from immunoglobulins (IgGs) collected from inflammatory diseased tissue can be significantly different from "normal" IgGs. Notably, RF binds to Fc only when the terminating galactosyl residues are no longer present, as seen in the Fc/IgG-RF/IgM crystal structure complex. This change in glycan sequence correlates with disease symptoms. The specific aim of this proposal is to gain a better understanding of the structure-activity relationship between human immunoglobulin G isotype 4 (IgG4) antibody and human IgM rheumatoid factor through the use of theoretical tools. This will be accomplished by achieving the following four goals: 1) Development of a suitable computational model for the IgG4 cleavage fragment (Fc), 2) Quantifying the extent of the Fc glycan mobility, 3) Determining the effect of degalactosylation on the Fc fragment structure and dynamics, and 4) Exploring the influence of point mutations in the Fc domain in close proximity to the glycan. The AMBER program suite will be used to perform minimization and dynamics on the Fc fragment. Due to the similarities between all antibody types this research may have implications beyond the specific Fc/IgG4-RF/IgM immune complex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTIGEN AND NONANTIGEN DRIVEN TCR REPERTOIRES IN ARTHRITIS Principal Investigator & Institution: Winchester, Robert; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001


Summary: One overall goal of this project is to delineate changes in putative antigen and non antigen driven T-cell clonal repertoire in psoriatic arthritis synovia before and after receiving potential disease modifying therapy in pilot trials. Once progress has been made towards this end parallel studies will be initiated in rheumatoid arthritis as the second overall goal. The first objective is to validate this approach of repertoire analysis to gain insight into the mechanism and efficacy of therapeutic interventions and for advancing insight into the cognitive immune recognition events driving the disorder. This project is based on the preliminary observation that the vast majority of synovial Tcells in untreated psoriatic arthritis consists of apparently non antigen driven single sequence clones, with the balance containing oligoclonally expanded, and putatively autoantigen- driven, clones of both CD4 and CD8 lineage. After methotrexate, the uninflammed synovium, in striking contrast, exhibited a profound decrease in this polyclonal component and a marked expansion of clones identical in sequence to those found as a minor feature in the active synovitis sample from the same joint. Accordingly, we hypothesize that methotrexate is an example of an agents that acts to reduce the non antigen-specific polyclonal recruitment that underlies clinical synovitis, but does not significantly affect clonal expansions of autoreactive T-cells involved in the fundamental immune recognition events driving the psoriatic arthritis. The proposed experiments exploit the potential to determine whether novel therapeutic agents affect either the putative antigen specific oligoclonal or the non antigen specific polyclonal component of synovitis, or both. The methotrexate studies will be continued along with pilot studies exploring treatment of an additional group of patients with a novel CD3 Mab that appears to anergize activated TH1 cells, the sTNFR:Fc competitive inhibitor Embrel and, potentially CD40L Mab. With the hypothesis that SDF-1 plays a significant role in the localization of a autoimmune response to the joint and its subsequent development into autoimmune disease, an envisioned future trial of a CXCR4 blocking agent is preliminary sketched as an example of a concept developed out of a fundamental gene discovery effect on the distinctive phenotype of cultured rheumatoid arthritis synoviocytes. In a second objective additional proposed studies are proposed to increase information on the nature of the surprising CD4 clonal expansions that are made more evident upon methotrexate administration and initiate an understanding of their role in psoriatic arthritis. It is hypothesized that they illustrate an instance of the "three cell interaction" involved in the generation of effector cytotoxic T lymphocytes under the influence of a cognate regulatory helper cell interacting with a dendritic cell. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIOXIDANTS AND FEMALE HORMONES IN THE ETIOLOGY OF RA Principal Investigator & Institution: Karlson, Elizabeth W. Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 30-SEP-1998; Project End 31-AUG-2003 Summary: The candidate is an Instructor in Medicine in the Department of Medicine, Division of Rheumatology, Immunology and Allergy at the Brigham and Women's Hospital and Harvard Medical School. Her research area is the epidemiology of rheumatic diseases, and the social and biological determinants of outcome in rheumatic diseases. Dr. Matthew Liang, Director, Multipurpose Arthritis and Musculoskeletal Diseases Center (MAMDC), Professor of Medicine at Harvard Medical School and Professor of Health Policy and Management at Harvard School of Public Health, will be her sponsor and co-mentor along with Drs. Frank Speizer, Charles Hennekens, Walter Willett and Meir Stampfer from the Channing Laboratory and Division of Preventive

Studies 19

Medicine. The research training program consists of the two studies described below, Research Seminars in the MAMDC, Channing Laboratory and Division of Preventive Medicine, courses at the Harvard School of Public Health, and close review by an Advisory Committee. The goal of the proposed studies is to define the role of dietary and hormonal risk factors in the development of rheumatoid arthritis (RA) in women. Specifically, it will test the potential protective role of antioxidants and N-3 fatty acids on the risk of RA, whether postmenopausal estrogen reduces risk and whether menopause increases risk of RA. The study utilizes information from two separate, complementary cohorts, the Nurses' Health Study, a prospective cohort of 121,700 women aged 30-55 years at baseline, followed since 1976, and the Women's Health Study, a randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals, aged 45 years and older. RA will be confirmed by a screening questionnaire regarding rheumatic symptoms and review of medical records. The study will identify potentially modifiable risk factors for primary prevention of RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTI-PROPERDIN MOAB AS A NOVEL THERAPEUTIC FOR ARTHRITIS Principal Investigator & Institution: Bansal, Rekha; Director; Novelmed Therapeutics, Inc. Bioenterprise, 11000 Cedar Rd Cleveland, OH 44106 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 14-MAR-2004 Summary: (provided by applicant): The complement system is an important host defense system, however, inappropriate and/or excessive activation of the complement system has been implicated as contributing to the pathogenesis of many disease states, including rheumatoid arthritis (RA). Rheumatoid arthritis (RA) is characterized by the occurrence of painful, swollen joints and none of the drugs currently administered to RA patients has been shown to cause regression of the disease. Therefore, there is a clinical need for potent new therapeutic agents for RA. There is evidence that the complement alternative pathway (AP) contributes significantly to the generation of proinflammatory agents in RA. Complement activation products such as C3a, C5a, and sMAC have been found within inflamed rheumatic joints and a positive correlation has been reported between the degree of complement activation and the severity of RA. Gliatech Inc. has identified a potent inhibitor of the AP, which consists of a blocking monoclonal antibody (GT6067) to properdin. Based on its ability to prevent AP activation in models of immune complex-mediated inflammation, there is reason to believe that such a MoAb holds great promise as an effective therapeutic agent for the treatment of RA. The focus of this study is to evaluate GT6067 in an antigen-induced model of arthritis in rabbits. This rabbit model possesses several key similarities with human rheumatoid arthritis and has been widely used in studies to identify novel RA therapeutic agents. Both Rekha Bansal, Ph.D. (P.I.) and James B. Parent are co-authors of the issued patent" Gupta-BansalR., Brunden, K. R. and Parent, J. B., A process of inhibiting complement activation via the alternative pathway. U.S. Patent 6,333,034B1, December, 2002 Key Words Complement; Monoclonal Antibodies; Properdin; Inflammation; Reverse Passive Arthus; Arthritis Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: ARTHRITIS AND PHYSICAL TREATMENT Principal Investigator & Institution: Sun, Hui B. Anatomy and Cell Biology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, IN 462025167 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The long-term objectives of this proposal are to elucidate the effects of mechanical stimuli to tissue degradation of rheumatoid arthritis and to develop a physical treatment for relieving pain and stiffness of arthritic joints. Using two human synovial cell cultures isolated from rheumatoid arthritis patients, we have recently found that mechanical shearing at a few dyn/cm 2 transiently decreases the transcriptional levels of matrix metalloproteinase (MMP)-1, MMP-13 genes as well as ets-1 transcription factor, while the same shearing increases the mRNA levels of tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2 and c-fos. These preliminary gene expression results suggest a potential use of mechanical shear stress as a therapeutic tool and allow us to test the following hypothesis: An appropriate nonstationary temporal profile of gentle mechanical shear stress at a few dyn/cm2 can maintain simultaneously a reduced mRNA level of MMP-1, 3, and -13 as well as an increased mRNA level of TIMP-1 and 2 through the down-regulation of ets-1 transcription factor. Two specific aims of this project are (i) to evaluate the proposed five non-stationary shear stress profiles for decreasing MMP rRNAs and increasing TIMP mRNAs, and (ii) to identify the function of ets-1 on mechanical stress-induced response in the simultaneous regulation of MMPs and TIMPs. We will isolate RNA from the stress-treated synovial cell cultures and determine the cDNAs levels of the specific MMPs and TIMPs as well as AP-1 and ets gene family members using a reverse transcription-polymerase chain reaction procedure. We will also measure the level of MMP proteins by immunoblotting and determine MMP activities by using zymography and a fibril degradation assay. By transfecting ets-1, we will test the function of ets-1 under mechanical stimuli. The proposed project will contribute to answer whether a non-invasive physical treatment can be developed for preventing from tissue degradation in arthritis joints. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ARTHRITOGENIC IGS--WHAT ARE THEY? WHY ARE THEY MADE? Principal Investigator & Institution: Mathis, Diane J. Professor of Medicine; Joslin Diabetes Center Boston, MA 02215 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 28-FEB-2005 Summary: Rheumatoid arthritis is a common and debilitating autoimmune disease whose etiology and pathogenesis remain unknown. Small animal models of RA provide a means to dissect disease mechanisms. A mouse model that spontaneously develops a joint disorder with most of the characteristics of RA in humans was recently described. Disease in K/BxN mice is joint-specific, but is provoked by systemic T lymphocyte selfreactivity, resulting in pervasive T cell stimulation and broad B cell activation; both T and B cells are required. The critical role of B cells is to produce arthritogenic immunoglobulins: small amounts of serum from K/BxN mice can precipitate arthritis within days in healthy recipients, even those lacking lymphocytes; the serum activity resides in the IgG fraction and is neither rheumatoid factor nor anti-collagen antibodies. The two major goals of the experiments proposed here are to define the target(s) of the arthritogenic Igs generated in KBxN mice, and to determine what factors are responsible for their selective production, amongst the multitude of potentially autoreactive Igs.

Studies 21

More specifically, we propose to: (i) Identify the self-antigen(s) recognized by the arthritogenic Igs following three strategies - based on production of arthritis-promoting monoclonal antibodies, biochemical purification of tissue proteins, or screening of prokaryotic cDNA expression libraries. (ii) Elucidate the factors dictating selective secretion of the arthritogenic Igs, focussing on how the overwhelming T cell stimulation characteristic of this model, with its potential for universal non-cognate "help" for B cells, influences the fate and activity of B cells with various Ag specificities. Comparisons will be made between B cells that recognize self versus non-self Ags, and that see their Ags at different sites, in different forms or at different concentrations by crossing the KBxN strain with various already existing Ig or Ig/Ag transgenic or knockin lines. (iii) Determinate how tolerance of B cells expressing an arthritogenic specificity is maintained and broken by engineering the appropriate Ig gene knock-ins, and monitoring the behavior of their B cells in the normal context and in KBxN mice. We anticipate that these studies will provide important clues to the pathogenesis of arthritis in the K/BxN model and, hopefully, by extrapolation, in human patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ATHEROCLEROSIS IN RHEUMATOID ARTHRITIS COHORT Principal Investigator & Institution: Del Rincon, Inmaculada; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, TX 78229 Timing: Fiscal Year 2001; Project Start 18-JUL-2001; Project End 30-JUN-2006 Summary: This K 23 Career Development Award will accomplish the double objective of training the candidate in patient-oriented research, and advancing current knowledge of the relationship between inflammation and atherosclerosis. For the career development component, the candidate will participate in the Master of Science in Clinical Investigation program, established at her institution with funding from a K30 Award from the NHLBI. This outstanding program is tailored to the candidate's needs, and will provide an in depth exposure to study design, data management and analysis, research ethics and scientific writing. The candidate will benefit from a rich environment of national experts in epidemiology, vascular imaging, cardiology, neurology, rheumatology and biostatistics. The objective of the research component is to examine to what extent atherosclerosis and cardiovascular morbidity are explained by systemic inflammation in rheumatoid arthritis (RA), accounting for the competing influence of established cardiovascular risk factors. The candidate will pursue three Specific Aims: (1) To determine the extent of atherosclerosis that is explained by cumulative systemic inflammation in RA; (2) To determine the role of inflammation in the progression of atherosclerosis in patients with RA; and (3) To determine the role of ongoing inflammatory disease activity as a risk factor for cardiac and cerebrovascular atherothrombotic events in RA. For Specific Aim 1, 680 members of an established cohort of RA patients will undergo two non-invasive procedures to measure atherosclerosis: high resolution B-mode ultrasound of the carotid intima- media thickness (IMT) and ankle-arm systolic blood pressure index. These measures will be compared to the severity of joint damage, which reflects cumulative inflammation in RA. For Specific Aim 2, the candidate will examine the influence of inflammation on the progression of carotid IMT over three years. For Specific Aim 3, the candidate will assess the influence of ongoing inflammatory disease activity on the incidence of cardiac and cerebrovascular events in the RA cohort. This research is a novel approach to understanding the contribution of inflammation to atherosclerosis, and will point the way for future research into the mechanisms of atherogenesis. In addition, it will have implications for the management of patients with RA and other inflammatory diseases,


by extending the current indications for anti- inflammatory therapy to the prevention of atherosclerosis. This would ultimately lengthen life expectancy and improve the quality of life of people with inflammatory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ATHEROSCLEROSIS IN RA Principal Investigator & Institution: Stein, Charles M. Associate Professor of Medicine; Medicine; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Premature cardiovascular disease is a major cause of mortality in rheumatoid arthritis (RA). The mechanisms underlying accelerated atherosclerosis and its relationship to inflammation in RA are poorly understood. Recent studies indicate that inflammation through the effects of inflammatory cytokines, and oxidative stress, through lipid peroxidation, are important in the pathogenesis of atherosclerosis. We postulate that accelerated, inflammation-promoted atherosclerosis occurs in RA. Thus, we propose to test the hypotheses: 1) that structural and functional vascular damage is more frequent and more severe in patients with established RA than matched controls and is related to cumulative disease severity; 2) that this impairment of vascular integrity is associated with clinical and laboratory markers of inflammation, plasma homocysteine concentrations, and oxidative stress. To address these two hypotheses the relationship between longstanding inflammation and vascular integrity will be determined in a cross-sectional study of 75 patients with established RA in whom prospectively obtained clinical data are available for 15 years, and 75 matched non-RA controls. Endothelium-dependent, flow-mediated dilation of the brachial artery measured by ultrasound, and coronary calcium volume measured by electron beam computed tomography (EBCT) will provide functional and structural measures of vascular integrity, respectively. F2-isoprostane excretion, a reliable index of lipid peroxidation in vivo, homocysteine and lipid concentrations will be measured. Vascular integrity, oxidative stress, lipids and homocysteine will be compared in controls and RA patients. In the RA patients the relationship between RA activity and damage indices obtained over 15 years and vascular function and damage measures will be determined. Using the same techniques we will address hypothesis 3) that the rate of progression of vascular disease in patients with early RA can be altered by control of inflammation. In a prospective cohort of 100 patients with early RA receiving usual clinical care and 100 matched non-RA controls followed over 24 months the relationship between clinical and biochemical measures of inflammation and vascular integrity will be determined by comparing "responders" and "non-responders". These proposed studies will provide a basic understanding of the interrelationship between inflammation, lipids, oxidative stress and vascular damage, and will suggest strategies for reversing or preventing such damage in RA and, potentially, other diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ATIPRIMOD TO TREAT MULTIPLE MYELOMA AND BONE RESORPTION Principal Investigator & Institution: Jacob, Gary S.; Callisto Pharmaceuticals, Inc. 420 Lexington Ave, Ste 2500 New York, NY 10170 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2004 Summary: (provided by applicant): The goal of this proposal is to evaluate the potential of atiprimod, a drug previously explored for treating rheumatoid arthritis, to treat

Studies 23

human multiple myeloma (MM) and other metastatic osteolytic bone diseases. Atiprimod is an orally bioavailable drug that originally completed phase I/lla clinical trials in rheumatoid arthritis patients, with patient exposure of up to one year without serious side effects and no observable toxicity. Recent data on atiprimod's ability to induce apoptosis and inhibit proliferation of multiple myeloma cell lines and to inhibit osteoclast-mediated bone resorption, along with an increase in our understanding of the growth factors that drive multiple myeloma make atiprimod a unique therapeutic opportunity, as the drug simultaneously affects the multiple key growth factors of this disease along with the possibility of also inhibiting bone destruction, a major sequela of multiple myeloma. Atiprimod therefore also may be useful in treating primary and metastatic bone cancer as it provides a new mechanism to inhibit osteoclast-driven bone resorption, a major debilitating effect of these cancers. The specific aims of this Phase I proposal involve the use of cell culture experiments and appropriate animal models to evaluate atiprimod's ability to inhibit MM proliferation. We will evaluate the mechanism-of-action of this drug using techniques to determine how it inhibits cell growth, promotes apoptosis and inhibits secretion of VEGF. Using an in vitro model of adhesion of MM to BMSC cells that enables us to study juxtracrine and paracrine production and biological significance of IL-6, VEGF, stromal cell-derived growth factor 1, and IGF-1 in the BM milieu mediating growth, survival, drug resistance, and migration of MM cells, we will focus on how atiprimod exhibits its anti-MM activity. Atiprimod will also be evaluated in two animal models of human multiple myeloma at Dana-Farber Cancer Institute. Successful accomplishment of these studies will lead to a Phase II proposal to evaluate atiprimod in human multiple myeloma patients. Because atiprimod has already been in human safety clinical studies and there is a wealth of clinical and preclinical studies already available on the drug, we would expect to be able to expediously file an IND for atiprimod to treat MM patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOIMMUNE ARTHRITIS: NEW DIRECTIONS Principal Investigator & Institution: Stuart, John M. Chief; Medicine; University of Tennessee Health Sci Ctr Health Science Center Memphis, TN 38163 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant): We propose to hold a scientific meeting entitled: "Autoimmune Arthritis: New Directions," on October 23 and 24, 2002 in Memphis, TN. The meeting will take place in the facilities of the University of Tennessee and will be jointly supported by the University, the NIH and Industry. Participants in the meeting will include internationally recognized experts on the subject of autoimmunity in the development of arthritis, both MD and PhD investigators will be included to provide cross-fertilization of basic science approaches to the understanding of clinically relevant problems. The primary focus will be on the animal model of Collagen-Induced Arthritis and its potential relationship to inflammatory arthritis in humans particularly Rheumatoid Arthritis. The animal model was discovered at the University of Tennessee 25 years ago. It provided the first proof that tissue specific autoimmunity could cause inflammatory arthritis. Since the discovery of CIA, this model has become widely used as a system for the study of inflammatory arthritis in general and of Rheumatoid Arthritis (RA) in particular. Although substantial progress has been made in understanding the pathogenesis of disease, recent discoveries including association with RA susceptibility genes, mapping of susceptibility loci, the confusing role of interferon gamma in disease pathogenesis, and the emergence on new therapeutic modalities have cast new light on disease pathogenesis and make this a topical subject. The objective of


this meeting will be to disseminate information on the latest advances in understanding the development of autoimmune arthritis. The program will specifically address the following objectives: 1) Clarify the role of the major histocompatibility complex (MHC) in the pathogenesis of autoimmune arthritis 2) Establish how non-MHC genes contribute to both susceptibility and severity of disease 3) Determine the role of cytokines in regulating the expression of disease. 4) Investigate the ability of specific immunotherapy to prevent disease. Divergent views on these subjects have developed in different laboratories and in different parts of the world. This meeting will address those differences and provide a forum for developing new approaches and collaborations. Young Investigator travel awards are being provided to encourage involvement of trainees and other young investigators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION

AUTOIMMUNE

ARTHRITIS--GENETICS

AND

CELLULAR

Principal Investigator & Institution: Glant, Tibor T. Professor; Rush-Presbyterian-St Lukes Medical Ctr Chicago, IL 60612 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 29-FEB-2004 Summary: The overall theme of the Program project outlined in this application is the genetics, cytokine regulation and inflammatory cell migration into rheumatoid synovium of an autoimmune arthritis, induced by systemic immunization of mice with cartilage proteoglycan (aggrecan). This proteoglycan (aggrecan)-induced arthritis (PGIA) shows many similarities to human rheumatoid arthritis (RA) as indicated by clinical assessments such as radiographic analyses, scintigraphic bone scans and various functional tests, and by histopathologic studies of diarthrodial joints. The development, and then the progressivity, of this RA-like disease is based upon autoimmune reactions which develop against the mouse (self) cartilage proteoglycan. Arthritis develop only in genetically susceptible BALB/c mice or their F2 hybrids. It is accompanied with inflammatory cell migration into the joint, mediated by Th1 type cytokines. We combined three research projects in one program to utilize a very unique condition of accumulated information and experience of investigators. Project 1 will identify nonMHC-linked loci int he mouse genome which harbor genes responsible for proteoglycan arthritis, and then to identify these genes by positional cloning. Project 2 will evaluate the function and balance of Th1 and Th2 cytokines, manipulate the Th1 cytokine dominance in pre-arthritic stage of the disease and explore the mechanisms as how the anti-inflammatory cytokines suppress inflammation in synovium. In addition, this project will perform preventive studies in SCID mice using human synovium and antiinflammatory cytokines. Gene therapeutic approaches for delivery of Th2 cytokines in a site-specific fashion. Project 3 will study the function of CD44 in inflammatory cell migration and the different aspects of anti-CD44 treatment, and what the conditions of receptors of receptor shedding are in vitro and in vivo. This project will also utilize human synovium (normal or arthritic) in SCID mice to delineate how CD44 expression might be controlled by intracellular events (signal transduction). Each of the projects are highly integrated with each other and centered around a unique theme and supported by two Cores. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AVONEX IN JUVENILE RHEUMATOID ARTHRITIS Principal Investigator & Institution: Sundel, Robert; Children's Hospital (Boston) Boston, MA 021155737

Studies 25

Timing: Fiscal Year 2001 Summary: This pilot study will evaluate the safety and efficacy of interferon B in the treatment of polyarticular juvenile rheumatoid arthritis (JRA), and to establish a dosing range for this medication in the treatment of polyarticular JRA. JRA is an incurable idiopathic condition that affects at least 70,000 children in the United States (Cassidy JT, Nelson AM, The frequency of juvenile arthritis. J Rheumatol 1988; 15:535). Polyarticular disease, which makes up at least 1/3 of this number, is one of the most severe subtypes owing to its tendency to cause pain and damage of multiple joints. A recent summary of outcomes in polyarticular JRA reported that 45% of children with this form of arthritis have active disease 10 years after onset of symptoms, and 54% have radiographic evidence of joint damage (Levinson JE, Wallace CA, J Rheumatol 1992; 19:6). Although new medications-especially methotrexate-appear to have improved the prognosis of children with polyarticular JRA, a uniformly safe and effective therapy is elusive. Interferon B is an ideal agent to test as a novel therapy for polyarticular JRA. Large scale use in patients of all ages with autoimmune disease has documented its safety, and it inhibits many of the processes thought to be central to the pathogenesis of joint inflammation in JRA (Cirell R, Tyring SK. Major therapeutic use of interferons. Clin Immunother 1995; 3:27-87). Subjects will receive each of two dosages by intramuscular injection once weekly of interferon B for 12 weeks each in a cross-over fashion. The order in which each patient receives each dose will be randomized, and both patient and physician will be blinded to the dose being administered. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL TREATMENTS FOR RHEUMATOID ARTHRITIS Principal Investigator & Institution: Nicassio, Perry M. None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Behavioral interventions for rheumatoid arthritis (IRA) have had a salutary impact on patients' ability to manage difficult symptoms and other demands of this medical condition. Yet, the effects of behavioral treatments for RA on underlying disease activity and mood disturbance are largely undetermined. The proposed project compares cognitive-behavioral therapy (CBT), Tai Chi Chih (TCC), a form of movement-based meditation, and education control (EC) on measures of psychological adaptation (e.g., helplessness, coping), mood disturbance, sleep quality, pro-inflammatory cytokines, and RA disease severity. An important feature of the CBT intervention is that it incorporates strategies to enhance mood and diminish depressive symptoms. TCC has recently shown promise as an effective intervention in increasing physical activity and health functioning in older adults. Because of its emphasis on relaxation and exercise, TCC offers an interesting theoretical contrast to CBT. Two Ph.D. level psychologists will administer the CBT and EC interventions, while a highly experienced TCC instructor will administer the TCC protocol. A total of 210 IRA patients will be randomly assigned after a pre-treatment evaluation to one of the three interventions and will be assessed again at Week 8 of treatment, at post-treatment (Weeks 16-17), 8-month follow-up, and 1-year follow-up. A primary objective of the study will be to compare the clinical efficacy of CBT and TCC against EC. CBT and TCC are expected to contribute to significantly greater improvement in psychosocial functioning and IRA disease severity than EC. CBT, in turn, is hypothesized to lead to greater improvement than TCC on clinical endpoints because it teaches a variety of skills that patients can use to manage RA. This study will also explore the mechanisms through which CBT and TCC promote improvement in IRA disease severity. We


anticipate, for example, that improvement in RA disease severity resulting from CBT and TCC will be mediated by reductions in pro-inflammatory cytokines (IL-1, TNF, IL6). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOMECHANICAL FACTORS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Guilak, Farshid; Associate Professor; Surgery; Duke University Durham, NC 27706 Timing: Fiscal Year 2003; Project Start 10-JUN-2003; Project End 31-MAR-2006 Summary: (provided by applicant): Rheumatoid arthritis is a chronic arthropathy characterized by inflammation, proliferation and destruction of the articular cartilage. Although historically cartilage has been considered to be an "innocent bystander" of the disease, recent evidence suggests that the degradation of cartilage in arthritis involves an imbalance of the anabolic and catabolic activities of the articular chondrocytes, secondary to synovitis and joint inflammation. Chondrocyte metabolic activity is strongly influenced by soluble mediators (e.g., cytokines) and biophysical factors (e.g., mechanical stress). In particular, biomechanical factors may play an important role in the onset and progression of degenerative arthritis secondary to joint inflammation in rheumatoid arthritis. However, the sequence of biomechanical and biochemical processes regulating these events in vivo is still unclear. The primary hypothesis of this study is that, in rheumatoid arthritis, a loss of cartilage biomechanical function and the presence of inflammatory cytokines alters the metabolic response of chondrocytes to mechanical stress. Aim 1 of this project is to measure the mechanical properties of the cartilage extracellular and pericellular matrices in RA, and to incorporate this data in a theoretical model of the micromechanical environment of the cell. In Aim 2, we will determine the role of stress magnitude in the stimulation of nitric oxide and prostaglandin E2 production by chondrocytes, and determine the influence of these inflammatory mediators on matrix turnover. In Aim 3, we will determine whether mechanical stress has an additive or antagonistic effect on with certain inflammatory cytokines (interleukin 1, tumor necrosis factor alpha, and interleukin 17) in controlling the PGE2 synthesis and matrix metabolism. Currently, there is little information on the biomechanical changes in articular cartilage with RA. Understanding the biomechanical and molecular mechanisms of chondrocyte response to physiologic loading in an inflammatory environment may enable new therapies that are specific to the stage of the disease. As many pharmacologic therapies for RA are focusing on the NOS2 and COX2 pathways, investigation of the interaction of physical therapies with these pathways will hopefully lead to more safe and effective treatments for RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BMS 188667 & BMS 224818 INTRAVENOUS FOR RHEUMATOID ARTHRITIS Principal Investigator & Institution: Olsen, Nancy J. Professor; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001 Summary: Blockade of the second signal required for T cell activation in the immune response will alter the course of rheumatoid arthritis. The two agents to be tested bind to CD86 and CD80, which are signaling molecules on antigen presenting cells. SPECIFIC AIMS: This multi center trial will test the safety, preliminary clinical activity and immunogenicity of a new treatment for patients w/Rheumatoid Arthritis (RA). The

Studies 27

therapy that is being tested is multiple doses of BMS-188667 and BMS-224818. The major objectives of this study are to assess the preliminary efficacy of pharmacologic blockade of CD80 and CD86 w/these two drugs. The treatment is given via an intravenous infusion on study days 1, 15, 29 and 57. The patients will be followed for safety through study day 169. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


BMS

188667/BMS

224818

INTRAVENOUS--

RHEUMATOID

Principal Investigator & Institution: Simon, Lee S.; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN MECHANISMS OF RESILIENCE AND VULNERABILITY Principal Investigator & Institution: Davidson, Richard J. Vilas Professor; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2002 Summary: (adapted from investigator?s abstract): This project builds on studies in Davidson?s laboratory that have highlighted the important role of prefrontal cortex and amygdala in the production and regulation of affective reactivity and affective style. This corpus of work has also focused on relations between differences in the central circuitry of emotion and peripheral measures of endocrine, autonomic and immune function. The first study in this project will examine the central and peripheral biology of resilience using subjects from two ongoing longitudinal samples that are being studied in Project 1. Subjects will be selected based upon their life history profile in conjunction with measures of psychological well-being as being either vulnerable or resilient. These individuals will then participate in two laboratory sessions. The first session will consist of a functional MRI (fMRI) session during which w hole brain echo planar images using BOLD contrast will be obtained in an event-related paradigm while subjects view positive, negative and neutral pictures. Structural images will also be obtained at this session for both anatomical localization of the functional data and for morphometric measurement of the hippocampus. The second session will consist of a psychophysiological assessment during which measures of brain electrical activity, impedance cardiography, startle and salivary cortisol will be obtained while subjects anticipate receiving reward or punishment, as well as during a mental stressor task. Vulnerable subjects are predicted to show more right frontal and amygdala activation, greater startle reactivity to threat and slower recovery following punishment, greater cortisol reactivity and increased sympathetic activation. The second study will examine patients with rheumatoid arthritis (RA) and fibromyalgia (FMS) along with matched controls who will be evaluated in Project 2. The study in this part of the project will provide an intensive biological assessment of the changes produced by a mindfulness meditation intervention. The assessment procedure used in Study I will also be used in this study. Subjects will undergo this two-session assessment before, just after, and 6 months following an 8-week mindfulness meditation intervention. The investigators predict that the mindfulness intervention will increase left anterior activation, decrease amygdala reactivity to negative stimuli, improve the recovery following punishment, increase pre-ejection period (PEP, i.e., decrease sympathetic activation) in response to


mental stress and decrease cortisol compared with the initial assessment. Moreover, these biological changes are expected to predict improvements in clinical status among the patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CAPRINE ARTHRITIS ENCEPHALITIS VIRUS INFECT: IMMUNITY, GENOME: GOAT AIDS MODEL Principal Investigator & Institution: Mdurvwa, Emmanuel G.; Tuskegee University Tuskegee Institute, AL 36088 Timing: Fiscal Year 2001 Summary: Caprine arthritis encephalitis virus (CAEV) belongs to the lentivirus subfamily of retroviruses. It integrates into the host cell genome and induces a persistent infection of domestic goats. CAEV infection causes encephalomyelitis in young goats, and mastitis, chronic progressive arthritis and synovitis in adult goats. The arthritis which results is similar in pathology to rheumatoid arthritis (RA) in humans. There is recent evidence that a novel CAEV variant occurs in humans and generates immune cross-reactivity to human immunodeficiency virus- I (IUV- 1). It is evident that CAEV is important not only as a pathogen in goats but as a vehicle for studying human diseases. We will use CAEV-induced disease 'in goats as a model to study the pathogenetic mechanisms of lentiviruses and also to investigate further some of the mechanisms that lead to arthritis. The obiective of this proposed project is to study molecular mechanisms of CAEV pathogenesis. This is important in the light of the possible use of CAEV-1ike lentivuiuses as -prophylactic agents against human viruses like EDIV-1. Specifically we propose to: i) investigate virus-host cell interactions by identifying and characterizing cell surface receptor(s) and defining the role of viral gp 13 5 and i do tha are essential for interaction with the cellular receptors; and ii) investigate some mechanisms that may be involved in the initiation and progression of arthritis by determining the role of various cytokines and chemokines, oxygen radicals, intracellular calcium fluctuations, circulating immune complexes, rheumatoid factor and also by identifying genes that are differentially transcribed during the infection. These results will provide a better understanding of a disease condition that is very similar to RA and in which the etiology is known. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIOVASCULAR DISEASE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Morgan, Mary C. Assistant Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 27-JUL-2001; Project End 31-MAY-2006 Summary: (Taken from the applicants abstract): Rheumatoid Arthritis (RA) is a chronic, inflammatory autoimmune disorder that affects 1% of the U.S. population, with women of childbearing age preferentially stricken. There is a significant reduction in life expectancy in women with RA, which is due in part to premature cardiovascular disease. Acute myocardial infarction (MI) and congestive heart failure (CHF) are the leading causes of death in RA. The etiology of cardiovascular disease in RA likely involves an interaction between inflammation-induced and immune-mediated vascular injury, traditional risk factors, and hormonal factors. In RA, synovial inflammation is characterized by CD4+ T cell activation and pro-inflammatory cytokine excess, both within the joint and in the systemic circulation. The influence of such chronic immune system stimulation on atherogenesis and cardiovascular clinical events such as MI and

Studies 29

CHF is unknown. However, recent work has suggested that inflammation is responsible for atherosclerotic plaque disruption with vascular occlusion in non-RA patients. Increasing evidence implicates cellular and humoral components of the immune system in atherosclerotic plaque destabilization. Specifically, pro-inflammatory cytokines and CD4+ T cells have been identified in atherosclerotic lesions in association with plaque rupture and acute ischemic cardiac events, suggesting that they participate in plaque destabilization. This award will provide the opportunity for me, Mary Chester M. Wasko, MD, MSc, to obtain the specific skills necessary to develop into an independent clinical investigator. In this study I propose to: 1) determine the prevalence and predictors of vascular disease in women with RA; 2) compare the prevalence of vascular disease and associated risk factors in RA and systemic lupus erythematosus (SLE), an autoimmune disease also characterized by premature MI and CHF in young women; and 3) compare the prevalence of vascular disease in RA patients with and without a previous cardiovascular event. This study will provide valuable information for designing a future, prospective, multicenter study examining the value of B-mode ultrasound and EBCT in predicting incident cardiovascular events in patients with RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CD44 IN RHEUMATOID SYNOVITIS Principal Investigator & Institution: Mikecz, Katalin; Rush-Presbyterian-St Lukes Medical Ctr Chicago, IL 60612 Timing: Fiscal Year 2001 Summary: This research proposal concerns the role of the hyaluronan (HA) receptor CD44 in synovial pathology during rheumatoid synovitis. We have demonstrated in mice with proteoglycan- and collagen-induced arthritis that a monoclonal anti-CD44 antibody eliminates joint swelling and inflammatory leukocyte infiltration. Our results suggest that CD44 participates in a variety of cell-cell and cell-matrix interactions at the site of inflammation. CD44- and HA-mediated events in inflammatory synovitis are current not understood. CD44 is present on synovial cells, and HA is a major constituent of synovial fluid and extracellular matrix in the normal joint. However, the amounts of CD44 and HA increase dramatically during inflammatory processes. Rheumatoid synovial cells and activated leukocytes express CD44 variant isoforms that are not detected in normal synovium. In contrast to normal joints, rheumatoid synovial tissue produces HA molecules that are poorly associated with matrix and diffuse into the extracellular space thus effecting joint swelling. Leukocytes, via the CD44-HA interaction, can be recruited and activated by HA present in the interstitial compartment of synovial tissue. Our preliminary results suggest that the production of IL-1 and TNFalpha by synovial cells is augmented by HA. Furthermore, CD44 and HA appear to be associated with the invasion of articular cartilage by rheumatoid pannus. In this study, we will compare synovial tissues and cells from normal and inflamed joints, in both murine and human systems, with respect to the molecular and functional properties of HA and CD44. We will delineate some of the regulatory and signaling mechanisms which may contribute to persistent leukocyte and synovial fibroblast activation. We also intend to determine if abnormal cell-matrix and cell-cell interactions in the rheumatoid synovium can be corrected by modulating CD44 function. The results of in vitro experiments will be conveyed to in vivo studies on a chimeric model of destructive synovitis, utilizing human rheumatoid synovium and cartilage engrafted into SCID mice. We believe that the findings of the studies proposed here will provide a better understanding of CD44- and HA-mediated events in arthritic processes, and open new avenues for therapeutic intervention in rheumatoid arthritis.


Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR INFLAMMATION

MECHANISMS

OF

ENDOGENOUS

ANTI-

Principal Investigator & Institution: Devchand, Pallavi R. Instructor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 30-NOV-2003 Summary: (Taken from the applicant=s abstract): About 1% of the US population (2.1 million people) have rheumatoid arthritis(RA). The most common RA is a late-onset disease, beginning at middle age with increased frequency in adulthood. While the exact causes for the different types of RA vary, the symptoms in each (swelling, redness, heat and pain) are reminiscent of the cardinal signs of inflammation. The social and financial impact of RA on both individual and nation are substantial, and due primarily to the debilitating symptoms of the disease (daily joint injury and inflammation). One approach to relieving the discomfort of this disease, is to treat the symptoms, i.e. an antiinflammatory treatment. Our knowledge of the cellular mechanisms involved in the resolution of acute inflammatory reactions that are neutrophil-driven is limited. Lipoxin A4 is a potent lipid-signaling molecule that mediates protective actions. This eicosanoid provides a model system for the evaluation of key targets in anti-inflammatory pathways. This research proposal is intended to test the hypothesis that in vivo, ALXR is a ligand-activated cell-surface receptor that tranduces the anti-inflammatory LXA4 signal, in part via a nuclear receptor pathway, to regulate the dynamics of an acute inflammatory reaction. A combined approach using transgenics, eicosanoid chemistry and molecular and cell biology techniques will be used to evaluate three main aspects of LXA. signaling in mature myeloid cells: 1.) To establish, in vivo, that the Lipoxin A4 receptor (ALXR) is a primary site of action for LXA4 and aspirin-triggered lipoxins. 2.) Identify nuclear events associated with LXA4 signaling and understand how these events counter-regulate pro-inflammatory transcription factors; and 3.) Use a woundhealing animal model to understand how ALXR modulates the dynamics of an acute inflammatory reaction towards resolution. The control of leukocytes is important not only for therapeutic use in disorders associated with uncontrolled inflammation (e.g., R A), but also has potential as a preventative measure against second organ injury during routine surgical procedures. Knowledge of endogenous anti-inflammatory lipid mediators and their sites of action could provide a platform for new therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINE RECEPTOR ANTAGONISTS IN INFLAMMATORY DISEASE Principal Investigator & Institution: Shahrara, Shiva; Medicine; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): There are many similarities in inflammatory responses observed in atherosclerosis and rheumatoid arthritis (RA). Chemokines and their receptors are important in both diseases. The long-term objectives of this application are to study the clinical and biological effects of C-C chemokine receptor 2 (CCR2) and CCR1/CCR5 antagonists in rodent arthritis. Furthermore we plan to determine the effect of key proinflammatory (TNF-alpha and IL-1beta) and Th1 promoting (IL-12 and IL-18) cytokines on CCR5 and CCR2 post-receptor signaling

Studies 31

events in the 2D61L-12 T cell line and endothelial cells in the presence of CCR5/CCR2 antagonists. Using CCR2/CCR5 antagonists in a model of inflammatory disease (RA) in vivo in addition to the knowledge acquired from studying the mechanism of proinflammatory cytokines effects on CCR2/CCR5 signaling pathways in vitro will help us understand and design more efficient in vivo studies in both RA and atherosclerosis. Several studies have used antagonists, binding proteins and antisense sequences to target proinflammatory cytokines, including TNF-alpha (antagonist; Etanercept), IL-18 (binding protein) and chemokine receptors CCR2/CCR5 (antagonists, antibodies and gene knockouts) in hope of mitigating the inflammatory reaction in atherosclerosis and RA. In order to investigate the effect of IL-12 and IL-18 on CCR5 and the effect of TNFalpha, IL-1beta and IL-8 on CCR2 downstream signaling pathways, we will immunoprecipitate CC chemokine receptors in cytokine treated cells and detect associated pathways by Western blot analysis. The purpose of using CCR antagonists is to validate that the cytokines exert their effect through these receptors. Additionally we will use CCR2/CCR5 antagonists in an in vivo inflammatory model of RA (rat adjuvant induced arthritis (AIA)) to examine their ability to decrease the severity and delay the onset of the disease. For this purpose we will determine the progression of indicators of inflammation, such as arthritis index, joint circumference, paw volume, joint count, arthritis severity, cell type recruitment and markers of bone destruction. Achieving these goals may give us valuable information in regard to molecular inflammatory mechanisms involved in atherosclerosis and RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHONDROPROTECTION TRITERPENOID

BY

A

NOVEL

RETINOID

AND

Principal Investigator & Institution: Vincenti, Matthew P. Research Assistant Professor; Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, NH 03755 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: (Applicant's abstract): Rheumatoid arthritis (RA) and osteoarthritis (OA) are debilitating disorders that are characterized by progressive degradation of articular cartilage and bone. While the etiologies of these two diseases are quite different, the degradative components are similar in that the interstitial collagens of cartilage and bone are digested by a group of proteolytic enzymes that are collectively known as the matrix metalloproteinases (MMP). One MMP that has been recently implicated in the progression of RA and OA is collagenase-3, or MMP-13. Of the MMPs, MMP-13 is the most efficiently degrades type II collagen, the primary collagen present in articular cartilage. MMP- 13 is expressed in osteoarthritic cartilage and rheumatoid synovium, and is induced in chondrocytes that have been stimulated with the inflammatory cytokines interleukin-l (IL-I) and tumor necrosis factor-alpha (TNF). Thus, inhibition of MMP-13 in OA and RA is an important goal for therapies of chondroprotection. We have found that a novel retinoid, BMS-189453, inhibits MMP-13 synthesis in a mouse collagen-induced arthritis model. We have also demonstrated that a novel steroid, 2Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid (CDDO), also inhibits MMP-13 synthesis in chondrocytes and has potent anti-inflammatory properties. In this application, we propose studies that will define, on the cellular level, the mechanisms of MMP-13 gene repression in chondrocytes by BMS-189453 and CDDO. Specifically, these studies will define transcription factors and signal transduction intermediates that are targets of these compounds. Since steroids and retinoids inhibit collagen degradation more effectively together, we will test the combination of BMS- 189453 and CDDO, to see if lower doses of each can be used. We will extend this work to establish the


chondroprotective efficacy of BMS-189453 and CDDO, alone and in combination, in the STR/ORT spontaneous mouse model of OA, and in the mouse collagen-induced arthritis (CIA) model of RA. Our goals are to establish the potency of each compound in an inflammatory (CIA) and non-inflammatory (STR/ORT) model of arthritis, and assess the potential of combinatorial treatment, which may lead to therapies with fewer side effects. This work will examine cellular/molecular events and whole animal models to characterize the chondroprotective potential of a novel steroid and a novel retinoid for the treatment of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLAIMS DATA PROJECT Principal Investigator & Institution: Kahn, Katherine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001 Summary: The purpose of this study is to evaluate the utility of claims data as a data source to evaluate quality of care in new onset rheumatoid arthritis; to measure the quality of care for patients with new onset rheumatoid arthritis with regard to arthritis co-morbid conditions and health care maintenance, and to identify factors associated with better attainment of quality standards. This study will prospectively follow a cohort of 400 patients with new onset rheumatoid arthritis for two years through patient surveys and claims data. Subjects will be enrolled through one large managed care organization (MCO) located in Southern California which represents an average of 2.8 million covered lives per year. Using a claims based algorithm, the 1998 through 1999 claims data for this MCO will be screened for incident cases of rheumatoid arthritis. Patients between ages 18 and 62 will be eligible for enrollment. A screening survey which will ascertain 1) whether a patient has been diagnosed with rheumatoid arthritis and/or 2) if the patient meets the 1987 American Rheumatism Association (ARA) criteria for rheumatoid arthritis by self report will be sent by mail to all eligible patients to invite participation. The first 400 responding patients who have had a prior diagnosis or meet the ARA criteria will be enrolled. Patients will complete telephone surveys which assess health status every six during the study. By using data elements from claims data, patient self report. and medical records, the structure, process, outcomes and quality of care will be assessed. Items measured in the claims data will be validated through the patient self report and medical record review. This study will inform us regarding the predictive value of claims data for identifying patients with rheumatoid arthritis and describing utilization. It will also describe the utility of claims data for assessing the process and quality of care for rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•


CLINICALLY

IMPORTANT

CHANGES

IN

RHEUMATOID

Principal Investigator & Institution: Ward, Michael M. Associate Professor; Medicine; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 20-SEP-1999; Project End 31-AUG-2002 Summary: Proper interpretation of the results of controlled clinical trials requires an assessment of not only the statistical significance of treatment differences but also of the clinical importance of such differences. Efforts to define criteria for important improvement in rheumatoid arthritis (RA) have thus far not considered the patient's perspective, even though patients' values represent the normative standard on which

Studies 33

improvements should be judged. The specific aims of this project are to determine if group criteria for important improvement in arthritis activity measures can be defined by assessing the agreement among patients of judgments of important changes in arthritis activity, and to determine if preference measures are useful measures of the importance of clinical changes. Because the importance of changes can be meaningfully judged only for measures that are sensitive to change, the sensitivity to change of arthritis activity measures will also be assessed. This observational case series study will measure changes in 12 arthritis activity measures, changes in patient preference measures, and judgments of the importance of changes in arthritis activity over one to four months in 240 patients with active RA. Consensus among patients regarding the magnitude of change in each measure considered important would allow group criteria for important improvement to be defined that were based on patients' valuations. Lack of consensus among patients, and therefore inability to define meaningful group criteria for important improvement, may indicate that clinical trials should include endpoints that more directly reflect patients' valuations of health, such as preference measures. This study will therefore also examine the reliability, construct validity, and sensitivity to change of patient preference measures, and will determine if preference measures better reflect changes judged to be important than do changes in traditional arthritis activity measures. This study will allow investigators to plan studies with knowledge of clinically important differences in arthritis activity measures, and will help clinicians and patients to understand better the relative benefits of different treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COGNITIVE FIBROMYALGIA

FUNCTION

&

EXECUTIVE

CONTROL

IN

Principal Investigator & Institution: Glass, Jennifer M. Psychiatry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 30-JUN-2005 Summary: (provided by applicant): Fibromyalgia (FM) is a disorder characterized by widespread musculoskeletal pain and the presence of tender points. Other symptoms, including fatigue, sleep disturbance and neuropsychological complaints contribute significantly to the morbidity associated with FM. One of the most prominent complaints in patients with FM is impaired cognitive ability. However, there is limited data on actual cognitive function in FM. Nonetheless, these cognitive complaints interfere with work and disrupt the lives of FM patients. The data available from our current work on cognitive function in FM and from other research, point toward a deficit in executive control of cognitive processes, especially working memory. Two experiments are proposed that will investigate various aspects of executive control and task-switching ability. The design includes standard neuropsychological tests as well as techniques developed in cognitive psychology. The latter techniques involve manipulation of experimental factors such as delay between encoding and recall that affect particular cognitive processes, such as decay from memory. This type of design allows a detailed view of the specific cognitive processing mechanisms that are affected in FM. Because FM is associated with other symptoms that could impact cognitive function, two special control groups are included in the design in addition to healthy controls. A group of rheumatoid arthritis patients will provide a control for the attentional demands of managing chronic pain. A group of depressed patients will provide a control for depression in FM, since patients with FM frequently report more depressive symptoms than healthy controls. We hypothesize that FM is associated with cognitive dysfunction that cannot be explained solely on the basis of pain or depression.


This research will lead to a better understanding of the characterization of cognitive dysfunction in FM, as well as the potential causes of this dysfunction. The emphasis on executive control processes is important because these are critical in many demanding work and life situations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTERIZED RHEUMATOLOGY

PATIENT

SELF-ASSESSMENT

FOR

Principal Investigator & Institution: Soll, Andrew H.; Cpm Systems, Inc. 1665 Michael Ln Los Angeles, CA 90272 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-MAR-2004 Summary: (provided by applicant): Proposed work develops content and tests the feasibility of CarePrep, a Web-based patient self-assessment instrument, in patients with rheumatoid arthritis (RA). RA is a common disorder that usually causes rapid loss of function, but early, aggressive treatment improves outcomes. Instruments that measure health-related quality of life (HRQL) are useful to assess treatment in RA populations, and probably are useful in monitoring and adapting therapy in individual patients. Whereas paper HRQL instruments are difficult to use, Web-based instruments provide an attractive approach. The CarePrep interview has already been built for general medical and gastroenterological assessment. CarePrep uses a modular design wherein every element can be configured. Configuration profiles can be crafted for a variety of clinical or research tasks; profiles are selected at appointment time. Aims: 1) The wellestablished instruments for HRQL, the arthritis-specific Health Assessment Questionnaire (HAQ) and the generic RAND-36 (or Short Form 36) will installed into CarePrep. A streamlined HRQL tool (CPQL) with screening questions and configured branching will also be developed. The existing CarePrep review of systems (ROS) will be adapted to characterize symptoms, identifying extraarticular sites of disease activity and detecting potential drug toxicity. A graphic will gather patient-derived tender joint counts, a reliable index of disease activity. A modified Delphi process will be used to structure critique by experts. The CarePrep output is prioritized, problem-oriented report designed for efficient physician review; scores for joint counts and HRQL domains will be included. 2) The application will be pilot tested and focus groups held. 3) Testing 100 RA patients, accuracy of the ROS will be assessed by physician rating of CarePrep reports. The sensitivity of screening CPQL questions will be assessed by bypassing branching thresholds so that all HRQL questions will be asked. The patient's CarePrep joint count will be compared to a physician count. 4) Feasibility testing will be conducted that mimics anticipated use of CarePrep in practice settings. Patients will do the computer interview and then evaluate the experience. Practicing physicians will review the report, evaluate the patient, and then assess the utility of the report. We anticipate that CarePrep will be well accepted by patients and physicians and provide efficient monitoring of RA Status, thereby allowing more cost-effective care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTERIZED RHEUMATOID HANDS

RADIOGRAPHIC

OUTCOMES

FOR

Principal Investigator & Institution: Duryea, Jeffrey W.; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-MAY-2005

Studies 35

Summary: (provided by applicant): Rheumatoid arthritis (RA) is a very painful condition with tremendous societal impact. Nearly one percent of the population suffers from RA and the annual cost to the North American healthcare system from arthritis in general has been estimated at $64 billion. Symptoms range from mild discomfort and pain to loss of joint function as the disease progresses to its end-stage. This enormous healthcare problem is best met by the prescription and development of effective therapies. In order to evaluate these therapies, highly accurate and reproducible methods are required to quantify the state of the disease. Radiographic evaluation of hand films is currently used to assess disease progression though the use of semiquantitative subjective scoring systems. These methods, however, are subjective and suffer from significant reader variation. In addition, the need for specialized training makes the systems costly and difficult to implement on a widespread basis. There is currently no truly quantitative method to assess arthritis progression in the affected joints. To address this need we propose to apply sophisticated image processing, multivariate analysis, neural networks, and regression tree methods to hand radiography. We will perform a quantitative and systematic study of radiographically visible structural changes due to RA. This work will provide previously unavailable objective and disease sensitive radiographic outcome measures of RA progression. The result will be a computer-based system with improved disease sensitivity, which will lead to more accurate evaluation and appropriate prescription of therapies. This work will play a major role towards alleviating the effects of this debilitating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROLLED FIBROMYALGIA

FAMILY

STUDY

IN

PATIENTS

WITH

Principal Investigator & Institution: Arnold, Lesley M. Associate Professor; Psychiatry; University of Cincinnati 2624 Clifton Ave Cincinnati, OH 45221 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2003 Summary: Fibromyalgia, a chronic musculoskeletal pain disorder of unknown etiology, is a significant public health problem. Evidence from studies of phenomenology, comorbidity, family history, and pharmacologic treatment response suggest that fibromyalgia may be associated with major mood disorder, and possibly to a proposed group of conditions known as affective spectrum disorders. Prior psychiatric research has demonstrated that major mood disorder is highly familial. Family history studies provide a method by which to assess how medical disorders co-aggregate in families and, therefore may share a common risk factor or pathophysiologic mechanism. To date, few studies have explored the morbid risk of major mood disorder (and other proposed affective spectrum disorders) in probands with fibromyalgia and their first- degree relatives. All of these studies have used the family history method, which entails interviewing probands regarding their knowledge of psychiatric illness in relatives. Although most of these studies have provided important preliminary data suggesting an association between fibromyalgia and major mood disorder, this method has been demonstrated to be less sensitive in detecting illness in relatives than direct interview (the family interview method). In order to provide further evidence of a relationship between fibromyalgia and major mood disorder, we propose to study the prevalence of psychiatric and rheumatologic disorders in probands with fibromyalgia and their firstdegree relatives as compared to probands with rheumatoid arthritis and their relatives using the family interview method. In addition to assessing the degree of co-aggregation of these disorders within families, we will also study the occurrence of other conditions within the proposed group of affective spectrum disorders in relation to fibromyalgia,


and the association between the severity of fibromyalgia symptoms and the presence of major mood disorder within families. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COORDINATE REGULATION OF APOPTOSIS AND CELL CYCLE IN RA Principal Investigator & Institution: Perlman, Harris R. Medicine; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001; Project Start 15-SEP-2000; Project End 31-AUG-2002 Summary: The work proposed for this grant focuses on the coordinate regulation of proliferation and apoptosis in rheumatoid arthritis (RA). Analysis of human RA synovial tissues (ST) sections revealed increased rates of synovial fibroblast proliferation and low rates of apoptosis, though the functional significance of reduced apoptosis remains to be elucidated. However, analysis of the rates of in vivo proliferation and apoptosis are limited in human-STs as tissue sections were taken late in disease course. Thus, utilization of animal models is vital for an understanding of the molecular pathways of proliferation and apoptosis in RA. Recently, adenoviral mediated delivery of Fas ligand (Ad-FasL), a known apoptotic inducer ameliorated experimental arthritis, suggesting that enhancing the rate of apoptosis by gene therapy may be a potential effective therapy. A caveat to Ad-FasL therapy is that high levels of Fas ligand is cytotoxic to many tissues of the body, thus development of other genes to be delivered to the RA joint is essential. We demonstrated that the anti-apoptotic protein and cell cycle modulator, Bcl-2 was highly expressed in RA compared with osteoarthritis synovial tissues, particularly in the CD68- negative, fibroblast-like synoviocyte population. In order to determine the importance of endogenous Bcl-2, an adenoviral vector expressing a hammerhead ribozyme to Bcl-2 (Ad-Rbz-Bcl-2) mRNA was employed. Ad-Rbz-Bcl-2 infection resulted in reduced Bcl-2 expression and cell viability in synovial fibroblasts isolated from RA-synovial tissues. In addition, Ad-Rbz-Bcl-2induced mitochondrial permeability transition, cytochrome c release, activation of caspases 9 and 3, and DNA fragmentation. These data suggest that Bcl-2 is necessary for synovial fibroblast survival. In this proposal we describe studies to delineate the mechanism of the induction of mitochondrial permeabilty transition following Ad-RbzBcl-2 infection. In addition we will investigate whether adenoviral mediated delivery of the Bcl-2 ribozyme is efficient in ameliorating adjuvant- induced arthritis in rats. The expected outcome is the suppression of AIA through the inhibition of fibroblast proliferation and increased apoptosis. This approach could lead to the development of a new therapeutic strategy for gene therapy in patients with rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•


COPING

SKILLS

TRAINING

FOR

EARLY

RHEUMATOID

Principal Investigator & Institution: Keefe, Francis J. Professor and Associate Director; Psychiatry; Duke University Durham, NC 27706 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Rheumatoid arthritis (RA) is the most common inflammatory polyarthritis and a major health problem. Although medical interventions are being used much earlier in the course of RA, these interventions do not address the challenges of coping with the early stages of this disease. To date, only one, very recent study has evaluated the efficacy of coping skills training (CST) during the early course

Studies 37

of RA. Although its findings suggest CST may be helpful, the study had methodological limitations (e.g. lack of control for attention, relatively short-term follow-up). It also used a traditional CST intervention that did not specifically address the unique challenges posed by the early course of RA. The proposed study seeks to determine whether a comprehensive coping skills training intervention can improve pain, psychological disability, and physical disability in patients with early RA. 225 patients with early RA will be assigned to 1 of 3 conditions: 1) Comprehensive Coping Skills Training, 2) Arthritis Education, or 3) Standard Care. Patients in the comprehensive coping skills training condition will receive training in a variety of cognitive and behavioral coping strategies and training in specific techniques for improving communication, setting short- and long-term goals, and enhancing maintenance. Patients in the arthritis education condition will attend sessions providing them with detailed information on rheumatoid arthritis and its treatment. Patients in the standard care condition will continue to receive the standard medical care provided to RA patients. Measures of pain, physical disability, and psychological disability and traditional clinical outcome measures will be collected pre- and post- treatment and at 6, 12, and 18 months follow-up. A self-efficacy scale and daily measures of coping, life events, mood, and pain will be gathered at each evaluation in order to analyze how these variables relate to long-term outcome. If comprehensive CST is effective, it could lead to new research and a greater integration of CST methods into the medical management of early RA. Future studies could examine whether comprehensive CST alters the long-term disease course of persons with RA. Finally, future studies could examine whether comprehensive CST alters the immune responses of RA patients to daily stressors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CYTOKINE QUANTITATION Principal Investigator & Institution: Finkelman, Fred D. Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 15-MAR-2001; Project End 28-FEB-2006 Summary: The importance of cytokines in rheumatic diseases is illustrated by: 1) animal studies that demonstrate an important role for IL-1beta and TNF- alpha in collageninduced arthritis, down-regulation of collagen-induced arthritis by IL-10 and IL-4, and suppression of murine systemic lupus erythematosis by TNF-alpha; and 2) human studies that demonstrate the efficacy of TNF-alpha antagonists in the therapy of rheumatoid arthritis. The Cytokine Quantitation Core will facilitate studies of the roles of cytokines in rheumatic and related immune disorders by making available to members of the research base: a unique assay that allows measurement of in vivo cytokine production real-time PCR for measuring cytokine gene expression a new technique for identifying cytokine-secreting cells without killing these cells standard techniques for cytokine measurement, such as cytokine ELISAs and RNAse protection assays. Research base members have already collaborated on the use of some of these assays to study: 1) the roles of IL-2 and IFN-gamma in the regulation of collageninduced arthritis; 2) TGF-beta regulation of disease in murine models of SLE; 3) IL-4 and IL-10 regulation of human juvenile rheumatoid arthritis; 4) cytokine regulation of host protection against gastrointestinal nematode infections; and 5) regulation of type 2 cytokine responses. The Core will facilitate ongoing collaborations in studies of rheumatic diseases by; increasing the efficiency and economy of apply presently available techniques; promoting the use of these techniques by core group members;


and supporting further development and dissemination of novel and improved techniques for measuring cytokine secretion and cytokine gene expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--INCEPTION COHORT OF RHEUMATOID ARTHRITIS PATIENTS Principal Investigator & Institution: Fries, James F. Professor; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2002; Project Start 08-APR-2002; Project End 31-DEC-2006 Summary: This Core will establish, maintain, and provide access to inception cohorts totaling over 1500 rheumatoid arthritis (RA) patients enrolled within their first year of disease and will follow these patients using standard ARAMIS protocols within full Health Assessment Questionnaire (HAQ) administration each six months, for a period of longitudinal follow-up of nine years. These cohorts are (1) large, (2) broadly representative, (3) geographically diverse, (4) encompass alternative management strategies, (5) contain DNA typing data (DRBI *0401 and *0404), and (6) include standardized central laboratory determination of CRP and Rheumatoid Factor, (7) contain frozen cells and serum for future studies, (8) enable search for causative agents in RA through use of newly available protein micro-array technology on stored serum, (9) consist of consecutively seen patients without exclusions, and (10) be maintained for long-term follow-up, including standardized reading of hand radiographs at 4 and 8 years of disease. The Core tasks builds upon investigator and staff skills at physician and patient recruitment and in maintenance of large data sets over the long- term. These inception cohorts will provide a unique and powerful resource in support of Projects 1, 2, 3 and 4 and for national and international collaborations with other investigators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CORE--METHODOLOGY AND DATA MANAGEMENT Principal Investigator & Institution: Chang, Roland W.; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001 Summary: The Methodology and Data Management Core is critically important to the success of this MAMDC and its EEHSR Component in particular. The centralized availability of expertise in database and study form construction; data entry, monitoring, and retrieval, and the various analytic techniques used to test hypotheses and control for potential confounders are essential resources for all investigators. The Core has assisted educators, epidemiologists, and health services researchers from several divisions and departments in studying a wide variety of disease and demographic groups including systemic lupus erythematosus, osteoarthritis, juvenile dermatomyositis (JDMS), rheumatoid arthritis, and the elderly. Core resources have been used efficiently because of the economies of scale in addition to excellent coordination with the EEHSR component. Recognizing that newer analytic techniques have become available and more accepted and that this proposal represents an expansion of our work in clinical epidemiology and health services research, this proposed Core is both larger to support a greater volume of work and broader t utilize these new analytic techniques. As a result of the Executive Committee's decision to emphasize longitudinal and cost-effectiveness research, experts in advanced statistical techniques (generalized estimating equation (GEE), classification and regression trees (CART), econometric approaches to controlling selection bias, meta-analysis),

Studies 39

economics, and decision analysis (stochastic tree modeling, continuous- risk utility assessment) have been recruited as Core co-investigators. Clinical Epidemiology has also been formally included within the Core structure. The Core will support the four EEHSR proposals in this grant application and the funded activities of the JDMS registry and Children's Memorial Hospital. It will continue to contribute to the MAMDC research environment by providing data management and methodologic assistance to investigators who engage in arthritis related research. The institution of a EEHSR/Core research conference and enhanced viability and support for health services research on Northwestern University's Chicago Campus will further heighten the Core's influence on the environment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--RESEARCH RESOURCES Principal Investigator & Institution: Firestein, Gary S. Professor of Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001 Summary: The primary goal of this SCOR is to understand how human rheumatoid synovium is maintained in its chronic inflammatory state. This new information will help SCOR investigators propose and develop novel therapeutic interventions. To support these studies, a Research Resources Core will be created to help organize the collection of human clinical material as well as provide specialized support for the in vivo studies involving animal models of arthritis. The project requires human synovial tissue specimens, synovial mononuclear cells, or synovial fluid from patients with established and early rheumatoid arthritis (RA). One purpose of this core is to develop an implement an efficient, timely, and centralized mechanism for the acquisition and distribution of these research materials. Animal models of rheumatoid arthritis have also been used extensively to study the pathogenesis of chronic inflammatory arthritis. Proper conduct and evaluation of these animal models requires specialized expertise to ensure reliable and interpretable results. Therefore, the Core will help coordinate and centralize the efforts of the investigators and provide ready access to experienced investigators in animal models of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYR61-MEDIATED ANGIOGENESIS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Lau, Lester F. Professor; Molecular Genetics; University of Illinois at Chicago 1737 West Polk Street Chicago, IL 60612 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Rheumatoid arthritis (RA) is a chronic, painful, incurable, and potentially debilitating disease for which effective therapies are still lacking. One of the earliest histopathological features of RA is the increase of blood vessels in the synovium, which is thought to facilitate the infiltration of leukocytes. synovial hyperplasia, and persistent inflammation. Thus. although angiogenesis itself may not be the cause of RA, it can exacerbate the patholobiology of RA. By analogy to studies in tumor biology in which angiogenic inhibitors have been shown to severely restrict tumor growth, it follows that targeting angiogensis in the RA synovium. may be an efficacious therapeutic approach. We propose to study the role of Cyr61, a novel angiogenic inducer. in RA. Cyr61 can also induce expression of matrix metalloproteases (MMPs), enzymes that promote joint destruction. However. the potential role of Cyr6l has not been systematically examined in RA. Our hypothesis is that Cyr6l plays a critical


role in the angiogenic response in RA, and may serve as an attractive therapeutic target in this disease. We seek to evaluate the role of Cyr61 in RA in two specific aims. First, we will assess the correlation between Cyr61 expression and angiogenesis in human RA synovium by in situ hybridization and immunohistochemistry. The expression of Cyr61 in inflammatory arthritis will be investigated further in a murine model of collageninduced arthritis (CIA) using similar approaches. Then we will explore Cyr61 as a potential therapeutic target. We will test whether blockade of Cyr6l function, using monoclonal antibodies or inhibitory peptides, can prevent or ameliorate arthritis and joint destruction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE REGULATION IN EXPERIMENTAL ARTHRITIS Principal Investigator & Institution: Finnegan, Alison; Professor; Rush-Presbyterian-St Lukes Medical Ctr Chicago, IL 60612 Timing: Fiscal Year 2001 Summary: An imbalance in the expression of Th1 and Th2 type cytokine is implicated in the pathogenesis of rheumatoid arthritis. The correlation between the dominance of the Th1 type inflammatory cytokine, IFN-gamma, over the Th2-type anti-inflammatory cytokine, IL-4, and chronic arthritis suggests that the ration of Th1:Th2 cytokines is important in regulating inflammation. A critical question is whether the ration of Th1:Th2 cells can be changed and whether this alternation leads to long- term suppression of disease. It is important to understand how Th2 cytokines function to suppress arthritis and whether susceptibility and resistance to arthritis is regulated by the balance in Th1: Th2 type cells. In a murine model of inflammatory arthritis induced by immunization with cartilage proteoglycan (PG), susceptible BALB/c mice develop a higher IFN-gamma to IL-4 ratio, whereas resistant DBA/2 mice develop a higher IL-4 to IFN-gamma ration. This balance between Th1 and Th2 cytokines may regulate susceptibility and resistance to disease. Increasing the level of IL-4 by administering IL-4 protects BALB/c mice from the development of arthritis and suppresses the acute symptoms of established disease. Reducing the level of IFN-gamma by a deficient in the Stat4 gene results in a lower incidence and severity of arthritis. Based these observations we hypothesize that arthritis is a Th1 type disease and that shifting the balance to a Th2 type response will lead to long-term suppression of disease. To test this hypothesis we propose in aim one and two to confer either resistance or susceptibility to arthritis by manipulating cytokines. We will neutralize cytokines with mAbs, use mice with disruptions in cytokine genes IFN-gamma, IL-4 and IL-10 and transcription factors, Stat4 and Stat6, and reconstitute cytokine defects with exogenous cytokines. In aim three, the mechanism of suppression by Th2 cytokines will be defined in disease transfer and cell migration studies. As a model to study intervention in humans, Th2 activity will be studied by engraftment of SCID mice with human synovial tissue. In aim 4 as a model for prevention, we will examine study, site- specific delivery of cytokines to the joint by replication deficient adenoviral vectors encoding regulatory cytokines. The overall goal of this study is to advance the successful treatment of arthritis through understanding the role of Th1 and Th2 cytokines in the pathophysiology of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYTOKINE REGULATION OF COLLAGEN-INDUCED ARTHRITIS Principal Investigator & Institution: Ortmann, Robert A. Internal Medicine; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211

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Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): Collagen-induced arthritis is a well-studied animal model of human rheumatoid arthritis. An autoimmune process evolves after immunization with heterologous type II collagen in an adjuvant that induces an inflammatory response. The nature of the inflammatory response induced may be as critical as the antigen used, for mouse strains that have been previously believed to be resistant to disease can become susceptible when the immunization protocol is modified. The long-term objectives of this application are to develop an independent program of research that leads to an improved understanding of the etiopathogenesis of inflammatory arthritis based on a clearer characterization of the inflammatory responses necessary for an autoimmune disease to develop. Initially, characterization of immunomodulatory Th2 cytokines in disease progression will be performed. IL-4 and IL-10 deficient mice will be immunized with type II collagen, and the development of arthritis will be monitored. The immune response to collagen will be studied as determined by cytokine and chemokine expression in the absence of endogenous IL-4 or IL-10. The T cell response to antigen resulting from different immunization protocols will also be studied, as differences in the T cell repertoire may be responsible for the presence or absence of disease. T cell receptor V3 gene usage as well as epitope specificity of collagen-reactive T cells will be determined. Levels of collagen-reactive antibodies and binding specificities will be determined to assess the effect on B cell reactivity. Finally, innate immune responses to these immunization protocols will be ascertained. The expression and function of toll-like receptors will be studied by flow cytometry and immunoblotting, and the ability to produce cytokines such as IL-12 and IL-18 under different immunization conditions will be determined. By better understanding unique inflammatory pathways that are required for the development of disease, specific immunotherapy strategies for the treatment of autoimmune processes such as rheumatoid arthritis may be designed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE-INDUCED ACTIVATION OF SYNOVIAL FIBROBLASTS Principal Investigator & Institution: Fiore, Stefano; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, IL 60612 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-DEC-2005 Summary: Exaggerated activation of leukocyte immune functions in rheumatoid arthritis (RA) leads to accumulation of inflammatory mediators. The resulting imbalance, with prevalence of inflammatory Thl1 cytokines, contributes to chronic inflammation and tissue damage. A significant role in these processes has been attributed to the recruitment of tissue components, such as the synovial cell lining. For example, cytokine-induced activation of synovial fibroblasts amplifies the cytokine signaling cascade and the release of matrix-degrading enzymes. This contributes to the destructive processes occurring in RA joints. We hypothesize that lipoxins (LX), a novel class of naturally occurring lipid mediators with marked anti-inflammatory actions, activate feedback mechanisms that prevent the exaggerated amplification of these inflammatory processes. We have previously elucidated and cloned a specific LX receptor (LXA4R) that mediates LX anti-inflammatory actions in leukocytes. We recently found that LX functional receptors are expressed in human (hLX! R) and mouse (mLXA4R) synovial fibroblasts. We propose to determine if expression of LXA4R will subject synovial fibroblasts to LX regulatory activities. This goal will be pursue by: 1) characterizing, at the molecular and functional level, LXA4 signaling pathways in synovial fibroblasts; and 2) assessing LXA4 regulatory actions toward cytokine-induced


activation of synovial fibroblasts. Since, a decrease of the Th2/Th1 cytokines ratio is observed in RA, and Th2 cytokines positively regulate 15-LO gene transcription, a third Aim will evaluate synovial fibroblast 15-lipoxygenase (15-LO) pathway and LX biosynthetic potential. Decreased 15-LO activity can negatively impact the synthesis of 15-LO derived anti-inflammatory eicosanoids, such as LX and 15-hydroxy derivatives of arachidonic acid. Therefore, elucidation of cytokine-dependent regulation-of 15-LO pathways in synovium will elucidate 15-LO pathways and generated mediators in negative feedback loops relevant to the pathophysiology of RA and offer new targets for novel therapeutic strategies. Finally the biology and therapeutic potential of LX will be investigated in twomouse models of inflammatory arthritis: the antigen-induced and the proteoglycan-induced models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DBPA/B PROTEINS OF BORRELIA BURGDORFERI & LYME ARTHRITIS Principal Investigator & Institution: Parveen, Nikhat; Molecular Genetics & Microbiol; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, MA 01655 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2006 Summary: (provided by applicant): Lyme disease presents a unique clinical system to study cellular and molecular mecahnisms responsible for chronic inflammatory diseases. The disease, caused by the spirochete Borrelia burgdorfen, is the most prevalent arthropod borne disease in the United States. It is a multisystemic illness that affects skin, muscles, joints, heart and nervous system. If left untreated, chronic manifestations are frequenctly observed and Lyme arthritis is the most common symptom in North America. My Iong term qoal is to identify the virulence factors of B. burgdorferi involved in attachment to host cells and in colonization of various tissues, and characterize their role in the pathogenesis, diagnosis and prevention of chronic Lyme disease. Glycosaminoglycans (GAGs), ubiquitously expressed on the surface of all nucleated cells, are recognized by various Lyme spirochetes and several bacterial molecules are involved in this adherence. Decorin binding lipoproteins DbpA and DbpB of B. burgdorferi show affinity for heparin and dermatan sulfate GAGs in addition to the proteoglycan decorin. My hypothesis is that DbpA and DbpB contribute to the colonization of various tissues by B. burgdorferi binding to GAGs and decorin present on the host cells and trigger an inflammatory response in skin and joints causing erythema migrans and Lyme arthritis. The major question to be addressed in this study are: (1) Do DbpA and DbpB contribute to the GAGsmediated attachment of B. burgdorferi to host cells and to the inflammatory response in the joints of susceptible mice? (2) Does deletion of dbpA and dbpB genes affect attachment of B. burgdorferi to the host cells? (3) Are DbpA and DbpB lipoproteins essential virulence factors of B. burgdorferi that trigger Lyme arthritis? Si,qniflcance: Lyme arthritis exhibits several symptoms similar to those of rheumatoid arthritis. However, unlike rheumatoid arthritis, the causative agent is known in Lyme disease and hence, it is feasible to analyze the molecular mechanisms involved in this form of destructive arthritis. In addition, B. burgdorfer/ infected mouse exhibits symptoms similar to those of human Lyme disease, and hence, murine model provides an ideal system to analyze the mechanisms of Lyme borreliosis. This study will characterize the role of two spirochete lipoprotein adhesins in Lyme arthritis in the murine model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DENVER AUTOIMMUNITY CENTER OF EXCELLENCE Principal Investigator & Institution: Kotzin, Brian L. Professor; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, CO 800450508 Timing: Fiscal Year 2001; Project Start 28-SEP-1999; Project End 31-AUG-2003 Summary: The proposed Denver Autoimmunity Center of Excellence combines the efforts of investigators with faculty appointments at the University of Colorado Health Sciences Center. Affiliated institutions include the Barbara Davis Center for Childhood Diabetes, the National Jewish Medical and Research Center, the Children's Hospital of Denver, the University Hospital of Denver, the Rocky Mountain Multiple Sclerosis Center, as well as the Denver Arthritis Clinic. Faculty have been recruited from the Departments of Immunology, Pediatrics, Medicine, Neurology, Dermatology, Pathology, and Preventative Medicine/Epidemiology, and the Human Medical Genetics Program. Within the Departments of Pediatrics and Medicine, subspecialties include endocrinology, rheumatology, clinical immunology, nephrology, pulmonary and gastroenterology. There are unique resources for clinical investigation and strong basic faculty, and in many instances a track record for combining basic and clinical investigation. The proposed Autoimmunity Center includes a strong research and clinical base in type 1 diabetes, celiac disease, systemic lupus, rheumatoid arthritis, multiple sclerosis, autoimmune skin disease, autoimmune pulmonary diseases as well as other autoimmune disorders. One unique clinical resource involves ongoing studies of newborns from both the general population and relatives of patients with type 1 diabetes who are HLA typed using cord blood and then evaluated prospectively for the development of autoantibodies associated with type 1A diabetes and disease A major strength of the current proposal we believe sit he breadth of work in Denver studying T cell recognition and biology, genetics, and the biology of inflammatory and cytokine mediators. In the current proposal, two clinical trials are proposed. Clinical Project 1 will evaluate subcutaneous insulin vaccination to prevent the appearance of anti-islet autoantibodies in infants at high risk for the development of autoantibodies and disease. Clinical Project 2 will test humanized anti-C5 mAbs in patients with active lupus nephritis. The three proposed basic components are: 1) to define the T cell specificities and distribution of insulin- and islet antigen- reactive T cells in murine models and patients with type 1; diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine patients with type1 diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine production and disease in collageninduced arthritis and rheumatoid synovium; and 3) to define the non- MHC genetic contributions to different clinical subtypes of autoimmune polyendocrine syndrome II. The three basic projects will provide important information to design future clinical trials , to monitor the effectiveness of immunologic therapies, and/or provide surrogate markers to correlate with immunologic therapies in autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEPRESSION AND PRODUCTIVE WORK ACTIVITY Principal Investigator & Institution: Lerner, Debra J.; New England Medical Center Hospitals 750 Washington St Boston, MA 021111533 Timing: Fiscal Year 2001; Project Start 08-SEP-2000; Project End 31-AUG-2004 Summary: (Applicant's abstract): While depression is a leading cause of work disability in this nation, disability reduction efforts remain hampered by a lack of research. This study's long-term goal is to prevent work disability due to depression. A longitudinal study is proposed that addresses on-the-job work disability among employed primary


care patients with depression. The sample will include 350 patients who have Major Depressive Disorder (MDD) and/or dysthymia and are employed at baseline, and two comparison groups: 1)) 200 workers with rheumatoid arthritis (PA), a physically limiting condition with one of the highest work disability rates; and 2) 100 "healthy" controls. The study has 3 specific aims: 1) to prospectively assess and compare the rates at which four types of work disabilities (job loss, work time loss, reduced work hours and on-the-job limitations) occur among the groups; 2) to identify variables that contribute to successful and unsuccessful work outcomes among patients with depression; 3) to determine whether the variables that contribute to work disability are the same for depression and RA. The project's health-relatedness is its focus on a major public health problem (work disability due to depression) within an increasingly important segment of the mental health care delivery system (primary care). Subjects will be recruited from primary care practices, 18-62 years of age, employed at baseline and not planning to stop working for at least 2 years. Data will be collected from patient surveys (baseline and months 3, 6, 12 and 18), patient charts and clinic pharmacy records. We will also administer a new validated survey instrument; The Work Limitations Questionnaire, which assesses on-the-job performance and productivity and, thus, captures aspects of work disability not reflected in job loss and absenteeism data. The statistical analysis will: 1) establish the magnitude of the four types of work disability and work productivity costs within the depression sample); 2) identify variables that predict work disability or a sustained ability to work; and 3) determine the differential impact of a mental and a physical illness on work disability rates, the predictors of work disability and productivity costs. Study results will contribute to the design of disability prevention and productivity improvement programs and policies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF A BOTANICAL ANTI-ARTHRITIS DRUG, PMI001 Principal Investigator & Institution: Fridlender, Bertold; Phytomedics, Inc. 65 Stults Rd Dayton, NJ 08810 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2003 Summary: (provided by applicant): An extract of the roots of Tripterygium wilfordii, a plant with a long history of medicinal use in China, demonstrated great promise as a potential prescription botanical drug for rheumatoid arthritis. In-vitro, in-vivo and human clinical studies performed in the U.S.A. and in China indicate that the extract of Tripierygium roots (PMI-001) is effective against arthritis and other autoimmune disorders. PMI-001 contains triptolide and other related molecules that inhibit IL-2 release and COX-2 transcription, a dual mechanism that is unique among current arthritis treatments. The main difficulty to PMI-001 development as a successful botanical drug has been obtaining a supply of roots that are consistent in quantity, quality and efficacy. The proposed work will establish large-scale greenhouse based hydroponic cultivation of Tripterygium in order to optimize PMI-001 safety and efficacy and assure its continuous and cost-effective supply. This will be accomplished through determining optimum conditions for plant propagation, cultivation, harvesting and extraction. In addition, analytical methods and efficacy bioassays will be developed and validated, establishing the framework for the future QAIQC methods and GMP procedures necessary for the FDA approval of this novel, safe and efficacious product. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF THE NORTH CAROLINA RA COHORT Principal Investigator & Institution: Jonas, Beth L.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001 Summary: Rheumatoid arthritis (RA) is a chronic multi system disorder with predominant findings in the diarthroidal joints. Estimates of the prevalence of RA vary from 0.5% in some rural African communities to 5% among some Native American tribes. The clinical manifestations vary tremendously from mild synovial inflammation that is easy to control to a multi system inflammatory disease that progresses despite aggressive immunotherapy. The factors that predict disease severity and disease outcome are poorly understood. Genetic factors, such as the shared epitope, have been shown to play a significant role in disease susceptibility and severity among some Caucasians, but the data in African Americans and other racial groups are weak and variable. There are likely other genes that are important and there are data that suggests that disease expression in RA is multigenic. Little is understood about the role of socioeconomic status, environmental factors and health behaviors in the expression of RA in most populations. Since there are likely multiple genes and these genes may be predictive of the clinical characteristics of the disease, data on genotype is only useful if the disease phenotype is well characterized. One of the weaknesses of much of the research on the immunogenetics of RA is the failure to correlate the genetic data with solid clinical, patient-based information. Comprehensive and complete evaluation of patient-based factors and clinical status will allow us to better understand the meaning of the genotype and allow us to make more rational predictions about disease course and outcome based on the genetic data. In addition, we will have the opportunity to better study the interaction between genetic and environmental factors in the future. The purpose of this project is to develop a prospective, longitudinal, cohort study of RA among residents of North Carolina. The patients will come from the University of North Carolina Rheumatology and Orthopedic Clinics and the 10 Rheumatology practices throughout the state that comprise the participants of the North Carolina Arthritis Health Project. a cohort representative of both tertiary care and community based practices. The major focus of these studies is to determine the role of socioeconomic status, attitudes, health behaviors, and genetics in determining severity and damage in RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISABILITY IN VALUED LIFE ACTIVITIES IN PERSONS WITH RA Principal Investigator & Institution: Katz, Patricia P. Associate Professor; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): This project will describe disability in valued life activities (VLAs) among persons with rheumatoid arthritis (RA), as well as factors associated with maintenance of those activities and factors that may protect against negative psychological outcomes following VLA disability. The same physical manifestations of RA that may cause difficulty in mobility or in performing a self-care activity may also cause difficulty in more complex, discretionary activities such as hobbies or socializing with friends. The wide range of activities that individuals find meaningful or pleasurable, above and beyond activities necessary for survival or selfsufficiency, is what we term "valued life activities". Performance of VLAs appears to be linked to psychological well-being and satisfaction with function. Although loss of


VLAs has been found to be a risk factor for the onset of depressive symptoms, effects of difficulties in VLA performance are not known. Also, many individuals who lose the ability to perform VLAs do not develop depressive symptoms; factors that protect individuals from psychological distress after VLA disability have not been identified. This study will estimate VLA disability and identify factors associated with maintenance of VLAs, psychological outcomes of VLA disability, and factors associated with maintenance of psychological well-being after VLA disability, building on the Verbrugge and Jette disablement process model. Subjects will be queried about these topics in annual telephone interviews. Items to assess VLA disability and psychological outcomes will be included in the interview, as well as questions about potential risk and protective factors for VLA disability and psychological distress. These items will consist of existing scales and survey items when available, and items developed specifically for this study. Analyses based on the study model (Figure 1) will focus on 3 major areas: (1) description of VLA disability among individuals with RA over a 5-year period, (2) description of psychological outcomes of VLA disability, and (3) identification of factors associated with maintenance of VLAs and maintenance of psychological well-being after VLA disability. Mathematical models will be developed to describe these relationships in the context of the study model, using both cross-sectional and longitudinal analyses. The findings from this study will provide information that may help minimize VLA disability and the psychological distress that might result from VLA disability, thereby improving quality of life of persons with RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISABLEMENT PROCESS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Escalante, Agustin; Associate Professor; Medicine; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, TX 78229 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-MAY-2004 Summary: (adapted from investigator's abstract): The broad objective of this research is to understand disability in rheumatoid arthritis (RA) within the theoretical framework of The Disablement Process Model. This model postulates a main disease-disability pathway in which pathology causes impairments, which lead to functional limitations, which, in turn, cause disability. Risk factors that precede and interventions or exacerbation's that follow the onset of the process of disablement, modify the main pathway. The specific aims of this application are: (1) To define the temporal sequence of events in the development of disability due to RA attributable to altered articular structure; (2) To define the temporal sequence of events leading to disability in RA attributable to pain; (3) To define the temporal sequence of events leading to disability in RA attributable to symptoms of depression; (4) To evaluate the modifying effect of medical interventions and co-morbidity. The models and hypotheses of this application are based on cross-sectional analyses on a cohort of 455 persons with RA participating in Dr. Escalante's current ORALE Study (Outcome of Rheumatoid Arthritis Longitudinal Evaluation). The ORALE cohort will be augmented to 760 members by the end of the first year of this application. Four yearly follow-ups are planned after the initial baseline assessment, to be conducted during the first through fourth years of this 5-year application. Main pathway factors that will be assessed include the inflammatory response, serum rheumatoid factor, bone destruction and extra-articular signs and symptoms, corresponding to pathology; articular signs and symptoms, strength, ambulation and manual dexterity, corresponding to impairments; activities of daily living, under functional limitations; and physical disability. Risk factors are age, gender and ethnicity, the HLA-DRB1 genotype, education, occupation, income, functional

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health literacy and acculturation. Psychosocial modifiers include and social support, learned helplessness, self-efficacy, coping strategies, stress, symptoms of depression, and coexistent medical conditions. Interventions to be measured include anti-rheumatic drugs and joint surgery, the lag between disease onset and initiation of anti-rheumatic therapy, compliance, and rehabilitation interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIVERSITY OF T LYMPHOCYTES IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Goronzy, Jorg J. Professor; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001; Project Start 20-DEC-1993; Project End 31-MAR-2002 Summary: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a progressive destruction of the joint architecture. CD4+ T cells are likely to have a central role in promoting the synovial inflammation as well as the extraarticular spreading of the disease. Recent studies have led to the model that the global repertoire of CD4+ T cells is important in setting the stage for the inflammatory response. RA patients have several unique features of the CD4+ T cell repertoire. First, the repertoire of CD4+ T cells is influenced by the disease associated HLA-DRB1 polymorphism. Second, RA patients have a different BJ gene segment usage in the naive CD4 population compared to HLA matched controls, suggesting the existence of a genetic risk factor which is involved in BV-BJ gene recombination and/or thymic selection. Third, RA patients carry CD4+ T cells which undergo clonal expansion in vivo. Clonogenic CD4+ T cells recognize self antigens with a wide tissue distribution and are more resistant to apoptosis inducing stimuli. They lack the major costimulatory molecule, CD28, but are dependent on alternate costimulatory signals to proliferate and to escape anergy induction. It is the hypothesis of this proposal that these alternate costimulatory signals facilitate the proliferation and clonal expansion of autoreactive T cells in RA patients and that effector functions mediated by these clonogenic T cells contribute to synovial inflammation and to extra-articular disease. In the first specific aim, we will analyze how the different unique features of the T cell receptor repertoire of CD4+ T cells in RA patients are related and whether thymic selection mechanisms predispose patients to generate CD4+ CD28- autoreactive T cells. In the second specific aim, we propose to identify the costimulatory pathways in CD4+ CD28- T cells. These alternate costimulatory signals may be responsible for the defective downsizing of these T cells in vivo and for their resistance to apoptosis inducing signals in vitro. We propose to analyze pathways which are known to be important in controlling lymphoproliferation, to determine whether these pathways are intact in CD4+ CD28- T cells and to determine how they are regulated by the alternate costimulatory molecules. Finally, we have designed experiments to characterize effector functions of CD4+ CD28T cells and their dependence on costimulatory signals. In combination, these approaches will allow us to determine how autoreactive CD4+ CD28- T cells are clonally expanded in RA patients and how they function in the rheumatoid inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DNA VACCINE MEDIATED IMMUNOTHERAPY OF RHEUMATIC DISEASE Principal Investigator & Institution: Robinson, William H. Neurology & Neurological Scis; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005


Summary: My career goal is to develop treatments for patients with devastating clinical immune disorders. During the time of this award, with Dr. Lawrence Steinman as my mentor I propose to develop selective immune therapy for an animal model of rheumatoid arthritis (RA). RA is a chronic autoimmune inflammatory synovitis affecting 1 percent of the world population. Using collagen-induced arthritis (CIA) in mice as a model for RA and DNA vaccination as a tool for generating and modulating immune responses, I propose to answer several questions pertaining to therapeutic immunization against CIA. I will also develop and study peptide pulsed peripheral monocytes for therapy of CIA and autoimmunity. I will address the following specific aims: (1) Can we protect against CIA by injection of DNA encoding: (a) the Vbeta8.2 region of the T-cell receptor, (b) collagen or collagen peptide, and (c) tandem DNA constructs encoding collagen, collagen peptide, or Vbeta8 TCR plus Th2 promoting cytokines including IL-4, IL-10, and TGF-beta? (2) We will examine the mechanisms of DNA vaccine-mediated protection against CIA using (a) cytokine assays, (b) flow cytometry, (c) soluble tetrameric major histocompatibility complex class II-peptide complexes, (d) T cell proliferation assays, (e) bone marrow chimeric mice, and (f) DNA microarrays. (3) Can we protect against CIA by injection of collagen peptide pulsed peripheral monocytes? These experiments will be carried out at the Stanford University Beckman Center. During the course of the proposed award period the candidate will continue to practice clinical Rheumatology on a 10 percent basis and take formal coursework in immunology and the ethical conduct of research. The overall goal of the proposed training program is to prepare this candidate to establish an independent laboratory in an academic division of Rheumatology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY AGGRESSIVE TREATMENT OF POLYARTICULAR JRA Principal Investigator & Institution: Wallace, Carol A.; Children's Hospital and Reg Medical Ctr Box 5371, 4800 Sand Point Way Ne, Ms 6D-1 Seattle, WA 98105 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant): This is a 2-part application. PART 1: An abbreviated protocol for a randomized actively controlled trial of early aggressive therapy in polyJRA. PART II: A plan for development of essential components for the trial's conduct. PART 1: The overall goal of this trial is to improve the physical functional ability and health related quality of life outcomes of children with poly articular juvenile rheumatoid arthritis (poly-JRA). Specific Aim: To compare the efficacy and safety of an aggressive treatment regimen initiated within the first 6 months of disease in children with poly-JRA to that of the current standard-of-care in producing a state of complete clinical response and improve outcome via a randomized, open trial 6 months in duration. Primary hypotheses are: 1) That aggressive therapy initiated within 6-months of poly-JRA disease onset will result in a higher proportion of children entering a state of complete clinical response as compared to the proportion of children who achieve such a response by use of the current standard-of-care after 6 months of therapy. 2) That early aggressive therapy will result in better physical./functional ability as compared to the current standard-of-care after 6 months of therapy. 3) That early aggressive therapy will result in higher health related quality of life as compared to that produced by the current standard-of-care after 6 months of therapy. PART 2: The overall goal is to develop a written plan for the execution of the clinical trial described in PART 1, and to secure funding for the effort to allow commencement of the trial. SpecificAim 1: To determine by questionnaire survey the barriers to the effective participation in trials by the clinical sites involved in this trial as well as other potential sites, including ability to

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open for patient enrollment in an expeditious manner, recruitment of study participant, follow-up, case report form completion. Specific Aim 2: To convene a meeting of senior investigators, methodologists, and regulatory personnel to develop strategies for overcoming the barriers identified in Specific Aim 1. Specific Aim 3: To develop criteria for defining one of the primary outcome variables, complete clinical response, and the related term, clinical remission, to be used in the proposed trial. Specific Aim 4: To prepare and submit an application to fund the clinical trial described in PART 1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETANERCEPT THERAPY IN FOLLICULAR LYMPHOMA Principal Investigator & Institution: Freedman, Arnold S.; Dana-Farber Cancer Institute 44 Binney St Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Although several novel therapeutic approaches have been developed for treatment of follicular lymphomas (FL), the overall survival has not yet been significantly improved. In vitro studies have provided evidence that FL cell survival is influenced by signals from the neoplastic microenvironment. FL cells associate with stromal elements known as follicular dendritic cells (FDCs), which provide anti-apoptotic signals to FL cells and chemotactic factors that likely contribute to the localization of FL cells within lymphoid follicles. Since FDCs provide survival and homing signals to lymphoma cells, targeting these cells in the microenvironment may be a novel treatment approach for FL. TNF( is overexpressed by FL cells, and TNF( upregulates the expression of adhesion molecules, cytokines and chemokines which are critical to FL cell-FDC interactions. Etanercept is a soluble, dimeric, recombinant human p75 TNFR, fused to the Fc fragment of human IgG1, developed for neutralization of TNF( and is an approved therapy for rheumatoid arthritis with an favorable toxicity profile. We hypothesize that TNF( blockade will affect the tumor microenvironment and therefore alter FL celI-FDC interactions, and FL cell survival. To investigate this hypothesis we propose three specific aims. First, to undertake a clinical trial of etanercept for patients with relapsed FL. Second, to investigate effects of etanercept on the tumor microenvironment directly and indirectly through studies of surrogate markers. We will investigate effects on FDCs, surrogate peripheral blood and serum markers as well as utilize PET scanning to assess the potential biologic activity of etanercept. Third, to investigate the effects of etanercept on T cell activation. Since TNF( is important in T cell function, it will be important to understand the effects of etanercept on T cells in these patients. This study is a novel approach to treating FL, where targeting the microenvironment of the tumor may inhibit the growth and survival of the neoplastic cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FAS FIBROBLASTS

LIGAND

GENE

TRANSFER

APOPTOSIS

SYNOVIAL

Principal Investigator & Institution: Zhang, Haidi; Div/Pharmaceutics/Indust Pharm; Long Island University Brooklyn Campus Brooklyn Campus New York, NY 11201 Timing: Fiscal Year 2002; Project Start 24-SEP-2002; Project End 30-JUN-2005 Summary: (provided by the applicant): Rheumatoid arthritis (RA) is characterized by hyperplasia of synovial membrane and bone destruction. Fibroblast-like synoviocytes play an important role in the pathogenesis of rheumatoid arthritis because of their proliferation and secretion of an impressive array of cytokines/chemokines, adhesion


molecules, and proteases, which result in the progressive bone and joint destruction. Synovectomv is a surgical approach to remove the inflammatory synovium, ameliorate the inflammation and delay the progress of joint destruction. An efficient medicallyinduced programmed cell death (apoptosis) in the inflammatory synovium might play a role similar to synovectomy but without surgical tissue damage. The proposed research project focuses on developing the "FasL gene scalpel" for the replacement of the synovectorny for the treatment of rheumatoid arthritis and other arthropathies. This project simplifies the current problems of gene delivery, gene target and gene expression regulation in human gene therapy. The induction of apoptosis in the inflammatory synoviocytes is the main purpose of FasL gene transfer intra-articularly. A transient, localizable, immune tolerance and dose dependent gene transfer may be achieved by a direct intra-articular injection of the FasL gene carried by a suitable vector which infects synoviocytes but not chondrocytes in cartilage. To carry out this purpose, they have investigated the effects of FasL gene transfer on the human RA synovium. The results showed that the fibroblast-like synoviocytes can be infected by adenovirus-FasL as well as undergo apoptosis after infection in a dose-dependent fashion and that the inflammatory synovium from RA patients can be eliminated in situ in a RA-SCID mouse model by a repeated local administration of adenovirus vector mediated FasL gene transfer. In this application, they propose to produce an adenovirus carrying human Fas Ligand gene and GFP in the same vector to examine whether FasL gene transfer in human RA synovium in SCID mouse model in vivo through the mechanism of "bystander effects." If the bystander effects exist in FasL gene transfer into synovium, it would be possible to carry out a therapeutic level of gene transfer with non-viral vector and lower dosage of DNA. They are going to investigate the possible side effects involved in FasL gene transfer into synovial fibroblasts and synovium, such as induction of pro-inflammatory cytokines/chemokines production as well as their correlation with Fas/FasL interaction, in order to find an approach to control them. They will identify the effects of the long term, multiple FasL gene transfer on the viability and metabolism of chondrocytes in vivo. This is an important factor to evaluate the clinical potential of the FasL gene scalpel. The above studies could elucidate clinical potential and possible side effects of FasL gene transfer intra-articularly, and have a high likelihood of being translated into a novel approach for treating arthritis patients at the inflammatory site. The long-range goals are the development of a novel therapeutic approach--"Gene Scalpels" for arresting inflammatory synovium at an early stage of arthritis by intra-articular administration of an apoptosis inducer, such as FasL, using a suitable vector system, which may replace synovectomy for some arthritis patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAS LIGAND GENE TRANSFER IN ARTHRITIS Principal Investigator & Institution: Chen, Youhai H. Associate Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2002 Summary: (Adapted from the applicant's abstract) - Rheumatoid arthritis and related animal models are inflammatory diseases of the joints mediated by activated synovial cells and infiltrating bone marrow-derived cells. The long-term goal of research of the investigators is to eradicate the arthritic inflammation by somatic gene transfer. They hypothesize that intra-articular Fas-ligand gene transfer may convert an otherwise inflammatory joint into an immune privileged organ by inducing apoptosis of activated synovial cells and by deleting antigen-specific lymphocytes. To test this hypothesis they have developed four specific aims: 1). To study Fas-mediated apoptosis in the arthritic

Studies 51

synovium following adenoviral vector-mediated FasL gene transfer. The kinetics of apoptosis of both fibroblast-like synoviocytes and bone marrow-derived synovial cells will be studied; 2) to determine the frequencies and functions of collagen-specific lymphocytes in arthritic animals injected with FasL virus. Intra-articular expression of FasL may induce type II collagen-specific immune tolerance by selectively depleting collagen-specific lymphocytes. Thus, intra-articular injection of FasL virus may prevent the development of arthritis in other joints. This will be investigated by determining the frequencies and functions of collagen-specific TH1, TH2 and B cells in and outside of the arthritic synovium; 3) to determine the frequencies and functions of vector-specific lymphocytes in arthritic animals injected with FasL virus. Intra-articular FasL gene transfer may also induce apoptosis of vector-specific lymphocytes and help diminish the immune barrier impeding viral vector-mediated gene therapy. This will be investigated by examining the frequencies and functions of vector-specific lymphocytes in and outside of the arthritis joints and by monitoring the lengths and levels of transgene expression in vivo; 4) to study FasL gene transfer in spontaneous autoimmune arthritis. If FasL gene transfer eliminates activated synovial cells that mediate arthritic inflammation, it should be effective in diminishing arthritis regardless of its etiology or initiating antigens so long as the disease is mediated by activated synovial cells expressing the Fas molecule. To test this theory, they will study FasL gene therapy in a spontaneous arthritis model in which systemic autoimmunity leads to joint-specific inflammation. Information generated from these studies may help elucidate the mechanisms by which FasL gene transfer diminishes autoimmune arthritis and may lead to the development of a novel strategy for treatment of autoimmune arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION AND DIAGNOSIS OF AUTOIMMUNE DISEASE Principal Investigator & Institution: Aune, Thomas M. President; Arthrochip, Llc 117 Bromley Park Ln Franklin, TN 37069 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 14-FEB-2004 Summary: (provided by the applicant): Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, and multiple sclerosis, are thought to arise from abnormalities of innate or adaptive immune responses. Autoimmune diseases are often difficult to diagnose, as the symptoms can be typical of other conditions and quite vague, such as musculoskeletal complaints and pain, headaches or dizziness. No available blood test can accurately exclude the possibility of an autoimmune disease in a subject with these symptoms. At best, a battery of tests and a period of observation are usually required to establish that a patient does in fact have an autoimmune disorder. Thus, a single test that could readily exclude the possibility of an autoimmune disease would allow physicians to focus their efforts on patients who have the greatest likelihood of serious disease. Using microarray technology, we have compared differences in gene expression in peripheral blood mononuclear cells among individuals with four distinct autoimmune diseases, normal control individuals before and after immunization, and individuals with other chronic diseases. Surprisingly, we find that each individual with autoimmune disease has a common gene expression signature that is independent of the specific autoimmune disease but is totally distinct from the normal immune response and is not observed in individuals with other chronic diseases. Based upon these observations, we have developed a simple test for excluding the possibility that a subject has an autoimmune disorder. The main advantage of this test is that it is a quicker and more accurate test than those currently available. This test has thus far predicted autoimmune patients from normal patients with 100 percent


accuracy. The first goal of this proposal is to collect gene expression data from a sufficient number of individuals to design a test with optimal predictive power. The second goal is to validate the test by examining a cohort of individuals who do not yet carry a clear-cut diagnosis of an autoimmune disease. Long-term goals are to use results from microarray experiments to develop tests that have predictive value for the therapeutic management of individuals with autoimmune diseases. These include tests that classify diseases, predict severity, and predict the best therapeutic options. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE ACTIVATION

EXPRESSION

PROFILES--JRA

AND

MACROPHAGE

Principal Investigator & Institution: Grom, Alexei A.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2003; Project Start 22-AUG-2003; Project End 31-JUL-2008 Summary: This project will focus on gene expression profiles in the systemic form of Juvenile Rheumatoid Arthritis. Specific Aim 1 will focus on the gene expression profiles that will distinguish patients with systemic JRA from other clinical forms of the disease, and identify patients bound to develop progressive erosive arthritis at later stages of the disease. Specific Aims 2 and 3 will focus on Macrophage Activation Syndrome and its relationship to clinically similar familial hemophagocytic lymphohistiocytosis (FHLH). MAS is a well recognized life-threatening complication of soJRA. As in FHLH, its development is associated with uncontrolled expansion of T-cells and macrophages. The pathogenesis of FHLH has recently been associated with decreased natural killer (NK) and cytotoxic cell functions secondary to mutations in the gene encoding perforin. All MAS patients included on our preliminary studies had profoundly depressed NK function suggesting that this abnormality is likely to be central to the development of MAS as well. Moreover, patterns of perforin expression in some of the MAS patients were similar to those in FHLH carries. Therefore, in Specific Aim 2 we will assess the extent of NK dysfunction in soJRA and identify gene expression profiles associated with this particular immunologic abnormality. Specific Aim 3 will focus on the changes in the gene expression profiles specific to the acute phase of MAS and FHLH themselves rather than the underlying immunologic abnormalities. We expect that the comparison of the obtained expression profiles should clarify the relationship between MAS and HLH, a better understood disease with a known genetic defect. The long-term goal of this proposal to define the pattems of immune gene dysregulation which leads to the development of soJRA and MAS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR TREATMENT OF AUTOIMMUNE DISEASES Principal Investigator & Institution: Melo, Marco; American National Red Cross Rockville, MD 20855 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 28-JUN-2002 Summary: The goal of this proposal is to introduce a novel gene therapy approach for reversing progressive autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. Initial studies will emphasize animal models in which disease producing epitopes have been identified. The rationale is based on the finding that adult mice injected i.v. with bone marrow or peripheral cells expressing bacteriophage lambda cI epitope 12-26 in frame with an IgG carrier become profoundly tolerant to this determinant at both the B and T cell levels. This state of unresponsiveness can be

Studies 53

induced in previously immunized animals. Since the bone marrow-derived cells in the periphery continue to produce and present the tolerogenic epitopes to newly generated T cells, the experiments proposed herein will offer an opportunity to both induce and maintain tolerance to autoantigens by host antigen presentation. My hypothesis is that B cells are tolerogenic APC and that this protocol favors B cell presentation. Retroviral vectors, constructed to express myelin basic protein or collagen epitopes on an IgG scaffold, will be used to infect bone marrow and peripheral hematopoietic progenitor cells, which will then be injected into adult mice before and after induction of experimental allergic encephalomyelitis (EAE) or collagen induced arthritis. The aims of this project are: 1) To develop novel genetically-engineered constructs for the expression of myelin basic protein (MBP) and its immunodominant determinants as part of an IgG tolerogenic carrier. 2) To test the efficacy of these novel constructs to abrogate the immune response to MBP in susceptible strains in order to prevent and treat EAE. 3) To optimize this protocol for transfection into long-term bone marrow cultures containing B cell precursors for transfection with these constructs. 4) To test if our findings in the EAE model can be applied to another autoimmune models, e.g., collagen induced arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY TO PREVENT AUTOIMMUNE DISEASE Principal Investigator & Institution: Fathman, C Garrison. Professor; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 14-AUG-2006 Description (provided by applicant): We hypothesize that autoimmune diseases progress through several (at least two) "checkpoints", an early inflammatory and late phase destructive disease. We believe it might be possible to design common "prevention" strategies to arrest disease progression in one or both of these phases by the following. (1) Autoantigen reactive CD4+ T cells transduced with retroviral vectors to express "regulatory proteins" may provide tissue specific immunotherapy through the expression of the regulatory proteins at the site of autoimmune inflammation. (2) FcR non-binding anti-CD3 and anti-TNF antibodies might block disease progression. We plan to study the non-obese diabetic (NOD) mouse, that spontaneously develops insulin-dependent diabetes mellitus (IDDM) and shows many of the characteristics of human IDDM, and collagen induced arthritis (CIA) in the DBA/l mouse model, which shares certain characteristics of human rheumatoid arthritis (RA), to attempt these "disease prevention" strategies. We will use the antigen specific properties of autoantigen reactive T cells to develop an adoptive immunotherapy protocol to study the potential of one (or combinations) of various "regulatory" proteins to prevent both of these diseases. We will study the "anti-inflammatory" cytokines, IL-10 and IL-4, an antagonist of a "pro-inflammatory" cytokine receptor, IL-12 p40, and compare local delivery by retroviral transduction of auto antigen specific T cells with SC fV constructs of anti-CD3 and anti-TNF antibodies, to systemic use of the parent antibodies, in these two animal models, singly and in combinations. Additionally, we plan to analyze potential mechanistic effects of anti-CD3 on antigen reactive T cells compared to costimulatory blockade by looking at the expression of a novel anergy specific gene, GRAIL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: GENETIC ARCHITECTURE OF AUTOIMMUNE DISEASES Principal Investigator & Institution: Kantor, Aaron B.; Surromed, Inc. 2375 Garcia Ave Mountain View, CA 940431104 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Phenotypic and genetic markers are urgently needed in autoimmune diseases for early and accurate diagnosis and monitoring disease progression and therapeutic intervention. We are proposing comprehensive phenotypic analysis for the identification of biological markers and genetic mapping of these quantifiable inheritable traits. Rheumatoid Arthritis (RA), a chronic inflammatory disorder that preferentially affects women will serve as a model disease. This application describes SurroMed's comprehensive phenotyping platform and the power of genetic analysis conducted at Myriad Genetics using a rich resource of family material. Phase I focuses on recruitment of RA multi-case families, technology development, and an initial analysis of human serum from affected RA family members and unaffected first-degree relatives. The approach includes both broad discovery-based and hypothesis-driven strategies. We will test the hypothesis that there are multiple quantitative differences in cellular and serum phenotypic variables between RA subjects and unaffected first-degree relatives. If our efforts are successful, in Phase II, we will test the hypothesis that variation in the levels of multiple biomarkers are significantly inheritable. Potential results of the work include biomarker and genetic products for the clinical assessment of disease. The methods developed here will also be broadly applicable to other conditions, especially autoimmune and immunological diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC POLYMORPHISMS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Matteson, Eric L.; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2005 Summary: (provided by applicant): About one-third of patients who have rheumatoid arthritis (RA) develop symptoms of inflammation outside the synovium, so-called extra-articular manifestations (ExRA), such as pericarditis, pleuritis, interstitial lung disease, Felty's syndrome, scleritis, keratitis, and vasculitis including mononeuritis multiplex as well as vasculitis involvement of internal organs, and the central nervous system. ExRA manifestations have been reported to occur mainly in patients with severe articular disease and are associated with an excess morbidity for disease related and other conditions, and increased mortality. Suggested predictors of ExRA features include genetic, clinical and serologic factors. The highest frequencies of RA-associated HLA-DR molecules are seen in patients with extraarticular RA. This study seeks to identify genetic risk factors predisposing patients who develop ExRA. Special emphasis will be put on the effect of different HLA polymorphisms and allelic combinations on the targeting of RA to different organ systems. The specific aims are to: 1. Expand a DNA bank from patients and ethnically matched controls to create the facility for large scale association studies in RA. The genetic information from the DNA bank will be linked to a database of clinical parameters collected during long-term follow-up of RA patients seen at Mayo Clinic. 2. Evaluate the impact of a series of candidate genes on the clinical phenotype of RA, including HLA class I genes, HLA class II genes and polymorphisms of inflammatory cytokines. 3. Assess the use of phenotypic immunologic markers as predictors of the clinical course of RA including deficiency for CD28, and aberrant expression of CD158 and 161 on T lymphocytes. The long-term goal

Studies 55

is to establish profiles of genetic risk determinants associated with different patterns of RA to eventually be used as biomarkers in risk assessment and clinical management. This proposal is meant as the cornerstone for a long-term investigative initiative into the nature of RA, and will provide the resources and foundation for the development of a series of clinician-investigators at the beginning of their careers. The mentorship program proposed in this grant is critical to this long-term goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC TRAITS OF SIBLING PAIRS W/ RHEUMATOID ARTHRITIS Principal Investigator & Institution: Pisetsky, David S.; Duke University Durham, NC 27706 Timing: Fiscal Year 2001 Summary: Rheumatoid Arthritis (RA) is a complex polygenic disorder. On the basis of twin and family studies, it is likely that anywhere from three to ten different genes may be involved in this disease. Only one of these genetic regions, located in the HLA complex on chromosome 6, has been defined. A major challenge for researchers is to identify the remaining regions which are involved in predisposition to RA. The purpose of this contract is to identify 1000 families in which two or more siblings are affected with rheumatoid arthritis. Detailed clinical information on affected siblings will be obtained and entered into a database. In addition, hand x-rays, serum and peripheral blood DNA will be obtained from each affected sibling. DNA will also be obtained from the parents of these siblings, when available. This database, serum and DNA repository will form a resource for the entire scientific community to allow for a comprehensive analysis of genetic susceptibility to rheumatoid arthritis. Access to the database and DNA repository by qualified scientists will be governed by an oversight committee. PROGRESS TO DATE: Study enrollment began in November 1997 with a projected endpoint of July 31, 1999. Twenty eight families have been enrolled including 48 females and 16 males. Two families were withdrawn from the study because only one sibling was found to meet study criteria. Study visits have been completed for 16 families with 13 visits completed on the GCRC. Subjects have been recruited by physicians at DUMC and VA Medical Center in Durham, by notifying the Duke Affiliated Rheumatology Trials Consortium (DART) members, mailings to Rheumatologists in North Carolina, South Carolina and Florida requesting patient referrals, and participation in a national toll-free information line for prospective participants. The advertising campaign includes advertisements in Athritis Today, the National Arthritis Foundation Magazine and additional publicity provided by the National Institutes of Health. There are no preliminary results to date. SIGNIFICANCE: This study will help elucidate the genetic causes of rheumatoid arthritis. In addition, the following resources will be available at the conclusion of the study: a) family trees from at least 1000 families with two or more sibs with RA, without personal identifiers and b) DNA samples from affected sib pairs and their parents (when available). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS ANALYSIS OF RA SIB PAIRS Principal Investigator & Institution: Gregersen, Peter K. Professor; North Shore University Hospital 300 Community Dr Manhasset, NY 11030 Timing: Fiscal Year 2001; Project Start 05-JUL-1997; Project End 30-JUN-2005


Summary: (provided by applicant): This application is a competitive renewal of a project which has the overall goal of identifying susceptibility genes for rheumatoid arthritis which lie outside of the major histocompatibility complex (MH( We have completed a genome wide screen for allele sharing on an initial population of 300 affected sibling pairs with RA. We have identified five markers with evidence of linkage at the p80 alleles identified thus far) in disease predisposition is much less well understood. It is our hypothesis that specific combinations of alleles at multiple HLA loci determine the extent of susceptibility to a given disease. We will focus on three diseases: pauciarticular juvenile rheumatoid arthritis, type 1 diabetes, and cervical carcinoma. These diseases appear to have DPB1 associations as well as associations with specific alleles at the DRB1 and/or DQB1 locus. Our high resolution immobilized probe typing methods for the class II and class I loci will be applied to patient and control samples from a variety of populations. Family based material allows the analysis of haplotype sharing, transmission ratios, and linkage disequilibrium patterns as well as stratification analysis to see whether some of the associated alleles at DPB1, or any other individual HLA locus, confer increased risk or simply reflect linkage disequilibrium with high risk alleles at other HLA loci. Studying how HLA allelic diversity has evolved and how it is distributed in various human populations can provide insights into functional significance. The hypothesis that the patchwork patterns of polymorphism at the DPB1 and at other HLA loci reflects the operation of gene conversion (segmental exchange) will be tested by using a PCR-based method to measure the frequency of rare

Studies 59

variant DPB1 sequences in sperm and the evolution of DPB1 diversity will be analyzed via phylogenetic analysis of exon2 and adjacent intron sequences from human and nonhuman primates. The hypothesis that HLA disease associations reflect the differential tendency to promote Th1 and Th2 responses following specific antigen stimulation of CD4+T cells will be examined using quantitative kinetic PCR to monitor cytokine expression. This method will be applied to HPV-infected cervical samples and an in vitro system with GAD peptide stimulation to study the HLA associations with cervical cancer and type 1 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HLA-DRB1 ALLELE SPECIFIC SIGNALING ABERRATION IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Holoshitz, Joseph; Associate Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001 Summary: The association of rheumatoid arthritis (RA) with particular HLA DRB1 alleles containing a shared epitope in their third allelic hypervariable region is well documented. However, how those MHC genes confer RA susceptibility is presently unknown. The currently leading hypothesis postulates that RA-associated alleles encode DRbeta chains, which may allow presentation of putative self-antigens. The identity of such arthritogenic antigens, however, remains unknown. The proposed research is offering a novel paradigm based on exciting preliminary data in the applicant's laboratory. According to that hypothesis, shared epitope-contining beta chains interfere with certain G protein-coupled receptor (GPCR) signaling events in a way that renders cells expressing them refractory to activation. This hypothesis is based on the observation that HLA-negative cells transfected with cDNA encoding shared epitopecontaining DRB1 alleles acquire the same signaling defects, which are found in cells of patients with RA and healthy individuals naturally expressing those DR genes. Furthermore, analysis of point-mutated cDNA transfectants demonstrates that the very same residues on the DRbeta chain, previously found to correlate best with RA susceptibility are essential for the observed aberration. Preliminary results suggest that the mechanism may involve GPCR desensitization. The goal of proposed research is to allow general examination of the role of G protein receptor kinases (GRKs) -mediated desensitization of GPCRs in the aberration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HSV GENE VECTORS FOR TREATMENT OF ARTHRITIS Principal Investigator & Institution: Glorioso, Joseph C. Professor and Chairman; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 20-APR-1997; Project End 31-MAR-2002 Summary: (Adapted from the applicant's abstract) - Rheumatoid arthritis is a chronic inflammatory disease affecting an estimated 10 million individuals in the United States alone. Currently, no effective long-term treatment other than joint replacement surgery is available. The overall aim of this proposal is to develop an in vivo gene therapy protocol for the treatment of arthritis. The first-generation gene therapy protocol using retroviral-mediated gene transduction demonstrated that antagonists of two cytokines, interleukin-l (IL-l) and tumor necrosis factor alpha (TNFa), can provide a significant therapeutic outcome in animal models of arthritis. These results are encouraging and


provide the foundation of these proposed studies; however, it will never be practical to treat the millions of Americans who suffer from arthritis using an ex vivo strategy. Ex vivo treatments require sophisticated laboratories and protocols for transduction and selection of explanted cells. The goal of these studies is to develop an in vivo protocol in which gene transduction requires nothing more than an injection into the afflicted joint and thus, could become widely available in settings as simple as a physician's office. In vivo gene delivery will be accomplished with the injection of engineered Herpes simplex virus 1 (HSV1) vectors. HSV-l vectors have the advantages of high infectivity and the potential to express multiple transgenes. The major disadvantage of HSV vectors, their cytotoxicity, has largely been overcome by the deletion of the cytotoxic genes, ICP4, ICP22, ICP27, and UL41. These multiple deletion mutants are capable of replication only in complementing cell lines. They show greatly reduced cytotoxicity both in cell culture and in rabbit synovium with the acquired capacity for durable transgene expression in vivo. By using these replication-defective vectors, the principal investigator will be able to transduce synoviocytes in vivo to express antagonists of IL-l and TNFa, setting the stage for a simple and effective gene therapy treatment for arthritis. Four specific aims are proposed: 1) To construct HSV-l gene therapy vectors with further reduced cytotoxicity by deletion of the ICP0 gene; 2) to engineer HSV-1 vectors for coordinated expression of therapeutic genes; 3) to assess the effect of prior immunization with HSV on vector persistence and expression and to determine the effect of "antigenic stealthing" genes; 4) to assess the efficacy of HSV-l vectors for the direct in vivo gene therapy of the antigen-induced rabbit model of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN LYMPHOCYTE ACTIVATION--ROLE OF DENDRITIC CELLS Principal Investigator & Institution: Steinman, Ralph M.; Rockefeller University New York, NY 100216399 Timing: Fiscal Year 2001 Summary: Dendritic cells are a trace subpopulation of white blood cells. When antigens are presented on dendritic cells to the immune system, strong immune responses are induced. Methods have been developed to isolate dendritic cells from human blood, inflamed joints and skin. We use dendritic cells to study different aspects of the immune response in transplantation, arthritis, psoriasis, and resistance to tumors and infectious disease (influenza, AIDS). Our aims include: a) Develop monoclonal antibodies and DNA probes to cell surface and intracellular constituents of dendritic cells. b) Outline the range of inflammatory cytokines and cytokine receptors that are made by dendritic cells from blood and from diseased tissues. c) Clone T cells that may mediate autoreactivity in rheumatoid arthritis and psoriasis, and protective immunity in tumors, influenza, and AIDS. d) Study the transmission of a cytopathic infection with the AIDS virus from dendritic cells that have been exposed to the virus (HIV-1) to CD4+ T cells. Compare dendritic cells isolated from blood, skin, and inflammatory sites. Test the effect of different types of immune T cells and anti-HIV antibodies on this transmission. Generate HIV-specific immune T cells of both CD4 and CD8 subsets. Evaluate the effects of immune T cells on HIV-infected monocytes. e) Develop methods for generating large numbers of dendritic cells from immature progenitors, and use these to present antigens from tumors and infectious agents (influenza, HIV-1) to human T cells. f) Evaluate mechanisms whereby dendritic cells present superantigens to T cells, including attempts to identify superantigens that may be carried by dendritic cells in autoimmune disease. g) Evaluate in human allogeneic bone marrow chimeras

Studies 61

the ontogeny and kinetics of dendritic cell engraftment, the role of dendritic cells in immune reconstitution, and the identification of dendritic cell progenitors and conditions supporting their growth. h) Use dendritic cells to generate antigen-specific cytolytic T lymphocytes (CTLs) to viral, tumor, and auto antigens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN RETROVIRUS-5 AND ARTHRITIS Principal Investigator & Institution: Patel, Robin; Assistant Professor of Medicine; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: Osteoarthritis and rheumatoid arthritis are the most common joint diseases of mankind. To date, no infectious agent has been convincingly associated with rheumatoid arthritis or osteoarthritis, although preliminary data ,suggest an association with human retrovirus-5, a newly identified retrovirus. That human retrovirus-5 is associated with both rheumatoid arthritis and osteoarthritis is, on initial consideration, striking, because these diseases are felt to be epidemiologically, clinically and pathologically distinct. However, it is possible that rheumatoid arthritis and osteoarthritis are both associated with human retrovirus-5, but that the immunologic response to the infection differs in each instance. The response may depend on the genetic background of the patient. Alternatively, genetic polymorphisms amongst human retrovirus-5 isolates may account for its association with two, seemingly unrelated, disease processes. The purpose of this proposal is to establish the association of human retrovirus-5 with rheumatoid arthritis and osteoarthritis, and to further characterize human retrovirus-5 by sequencing the entire viral genome and culturing the putative retrovirus. To achieve these goals, three specific aims are proposed. Specific Aim 1: Study the association of human retrovirus-5 with rheumatoid arthritis and osteoarthritis. Specific Aim 2: Sequence the entire viral genome of human retrovirus-5. Specific Aim 3: Culture human retrovirus-5. Intraoperative synovial tissue and whole blood specimens from 50 patients with rheumatoid arthritis and 50 patients with osteoarthritis, and synovial tissue specimens from 15 patients with normal joints will be collected and tested by nested polymerase chain reaction for human retrovirus-5 proviral DNA. Positive samples will be sequenced. The frequency of detection of human retrovirus-5 proviral DNA in synovial tissues and blood from rheumatoid arthritis and osteoarthritis patients will be compared to that in patients with no known joint disease. These samples will be used as sources of human retrovirus-5 in experiments to extend the known sequence of the human retrovirus-5 genome and culture the novel virus. Identification of a specific infectious agent associated with these arthritides would potentially allo for the development of preventive strategies such as vaccination and novel therapeutic approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYALURONAN-MEDIATED NITRIC OXIDE PRODUCTION BY MACROPHAG Principal Investigator & Institution: Levesque, Marc C. Assistant Professor; Medicine; Duke University Durham, NC 27706 Timing: Fiscal Year 2001; Project Start 20-SEP-1999; Project End 30-JUN-2002 Summary: Rheumatoid arthritis (RA) is a common disease that causes important suffering, disability and increased mortality, and represents an example of a chronic inflammatory immune response. RA is characterized by the overproduction of


hyaluronan (HA) and production of low molecular weight HA oligosaccharides which have proinflammatory properties. Nitric oxide (NO) and TNFalpha are two important inflammatory mediators in RA. The mechanisms that induce NO production in human synovial macrophages and the downstream inflammatory effects of NO are poorly understood, especially in the context of diseases such as RA. Likewise, the mechanisms that perpetuate the continued production of TNFalpha in RA have not been completely characterized. This proposal will test the postulate that low molecular weight HA oligosaccharides perpetuate an inflammatory cycle of nitric oxide (NO) and TNFalpha production by synovial macrophages in RA, via the cell surface HA receptor CD44, that leads to further production of fragmented HA oligosaccharides. The specific aims are to: 1.) Compare the ability of HA oligosaccharides of different molecular weight to induce NO production by human monocytes and tissue macrophages. 2.) Determine whether HA oligosaccharides induce NO production by monocytes and synovial macrophages from patients with RA. 3.) Determine the ability of HA oligosaccharides to induce human macrophage cytokine production. 4.) Determine whether NO production by monocytes and synovial macrophages induces HA fragmentation. These studies will lead to future work that defines the molecular events involved in CD44 signaling and NO production by human macrophages and will also provide the rationale for therapeutic trials in RA patients that target inhibition of NO production and inhibition of CD44-HA interactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF A GENDER-SPECIFIC RAT ARTHRITIS LOCUS Principal Investigator & Institution: Gulko, Percio S.; North Shore-Long Island Jewish Res Inst Jewish Research Institute Manhasset, NY 11030 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): Collagen-induced arthritis (CIA) in rats is a wellestablished experimental animal model that has been used to gain insight into the pathogenesis of rheumatoid arthritis (RA), a chronic and commonly disabling disease with a prevalence of 1% in most populations. Both CIA and RA are complex trait diseases regulated by MHC and non-MHC genes, and both have an increased susceptibility among females, with a RA female to male ratio of 3:1. The factors that account for the increase female preponderance of RA are poorly understood. Gonadal hormones, particularly a reduction in their levels, have been implicated in disease pathogenesis, but that does not account for all the gender differences in disease expression. The underlying hypotheses of this proposal are that the non-MHC loci governing susceptibility and severity of CIA in rats will be highly relevant to the pathogenesis of RA, and also that at least part of the genetic susceptibility to CIA differs between females and males, with certain genes regulating disease in one gender but not in the other. The identification of these sex-specific genes, and the sex factors regulating their penetrance will be of great relevance to the understanding of the factors accounting for the increased female susceptibility, and could generate new targets for the development of more specific therapies, for prevention, diagnosis and prognosis. In a study of CIA in a F2 intercross between MHC identical inbred CIA-susceptible DA rats and CIA-resistant ACI rats, gender had a major effect in susceptibility and in arthritis severity. A genome-wide scan done separately for females and males led to the identification of a new non-MHC locus, Cia12, on chromosome 12, that regulates CIA in females, accounting for 24% of the genetic contribution to the variance in arthritis severity, but not in males. The rat Cia12 interval, and its syntenic regions in the mouse

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and human genomes contain loci regulating several forms of autoimmune diseases, including arthritis, suggesting that this gene may be relevant to different diseases, underscoring the broader relevance of this study. To identify this gene and to confirm and characterize its sex-specific effect a combined approach was planned. On Aim 1, speed-congenic lines will be generated, introducing the Cia12 interval from ACI rats into DA background, and vice-versa, and both genders will be studied separately for CIA. On Aim 2, gonadal hormones and neuro-endocrine manipulation are anticipated to determine the sex-specific mechanisms regulating Cia12. On Aim 3, sub- phenotypes involved in the autoimmune response, perhaps more directly regulated by Cia12 than the complex arthritic phenotype, will be identified and used in the narrowing of the interval of interest. This aim will also provide additional insight into the Cia12 gene function. On Aim 4 the specific gene will be identified based on candidate gene analysis or positional cloning, and disease-causing allelic variations characterized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDO: A NOVEL ENDOGENOUS SUPPRESSOR OF INFLAMMATION Principal Investigator & Institution: Varga, John M. Professor of Medicine; Medicine; University of Illinois at Chicago 1737 West Polk Street Chicago, IL 60612 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-JUL-2003 Summary: (Taken from the applicant's abstract): Rheumatoid arthritis (RA) is characterized by chronic progressive synovial inflammation and subsequent destruction of articular structures. The pathogenesis of rheumatoid synovitis involves complex interaction between T lymphocytes, autonomously activated fibroblast-like synovial cells (FLS) and networks of inflammatory cytokines. Activation of FLS with increased expression of matrix metalloproteinases (MMP) and cyclooxygenase-2 (Cox-2) enzymes are key steps in pannus formation and tissue invasion, and contribute to that catalyzes the initial and rate-limiting step in the metabolism of the essential amino acid tryptophan (TRP. IDO causes depletion of available TRP, culminating in local TRP starvation in tissue, and reduced TRP concentration in serum. IDO expression is induced by interferon-y (IFN-y) in multiple cells, including FLS. IDO activity is elevated in RA and other chronic inflammatory states, but the true physiologic role of this enzyme remains unknown. Recent observations from our laboratory and other investigators indicate that TRP depletion catalyzed by IDO exerts profound effects on immune and inflammatory pathways. We therefore now propose that IDO functions as a novel endogenous suppressor of inflammation, and modulates the course of inflammatory arthritis. Here we will examine the role of IDO in inflammatory arthritis in three interrelated Specific Aims. In Specific Aim 1, we will establish the fundamental importance of IDO and TRP catabolism in suppression of MMP and PGE production in normal FLS by IFN-y, and determine if constitutive IDO activation confers resistance of transfected cells to inflammatory stimuli in vitro. The cellular mechanisms underlying IDO-mediated suppression of inflammatory responses will be investigated in Specific Aim 2. In Specific Aim 3, we will examine if inhibition of IDO function in vivo murine collagen-induced arthritis using a competitive IDO inhibitor modulated the course of experimental arthritis. The potential of IDO and TRP starvation to modulate both early and late steps in the synovial inflammatory response makes an approach to synovitis treatment based on TRP depletion particularly appealing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: IG-REACTIVE T CELLS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Salter, Russell D. Professor; Pathology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Between 70-80% of rheumatoid arthritis (RA) patients produce antibodies against IgG, called rheumatoid factors (RF), suggesting that IgG is a common auto-antigen in the disease. Although anti-IgG antibodies are present in other diseases and during immune responses to pathogens, these are generally low affinity IgMs that are detectable only transiently. In RA however, RF are persistent, usually of moderate to high affinity, and may include multiple isotypes. In addition, IgM RF can show evidence of somatic hypermutation. We therefore hypothesize that activation of T cells reactive with IgG could mediate affinity maturation and/or isotype switching in RF-producing B cells in at least a subset of RA patients. To address this, we have developed class II MHC tetramers containing peptides of Ig kappa chain that are shown to bind increased numbers of CD4+ T cells in some RA patients. In specific aim 1, we propose to determine how tetramer reactivity relates to expression of particular class II HLA proteins, including subtypes of HLA-DR4 shown previously to be associated with RA. In specific aim 2, we will test whether increased tetramer reactivity found in some patients correlates with the presence of multiple isotype rheumatoid factors, and with several markers, which can be used to measure disease severity. These experiments should critically assess the hypothesis that T cell help is required for production of multiple isotype RF, and may distinguish subsets of patients based on tetramer reactivity that have different prognoses, and who might benefit from distinct treatment regimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IL18 AND COMPLEMENT IN COLLAGEN INDUCED ARTHRITIS Principal Investigator & Institution: Arend, William P. Professor; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, CO 800450508 Timing: Fiscal Year 2001 Summary: The long-term objectives of this project are to determine the roles of IL- 18 and the complement system in the induction of IL-1 and TNFalpha in collagen-induced arthritis (CIA) in mice and in rheumatoid synovial cells. IL-1 and TNFalpha are important mediators of tissue damage in rheumatoid arthritis (RA) and in CIA through stimulation of production of metalloproteinases in synovial fibroblasts and chondrocytes. The mechanisms of excess production of these cytokines in RA or CIA are probably multiple and largely unknown; IL-18 and the complement system are two potential inducers of IL1 and TNFalpha. The hypothesis to be examined in these studies is that inhibition of IL-18 with the specific IL-18 binding protein (IL-18BP), and of complement with the murine inhibitor, Crry, will attenuate the onset or ameliorate the course of CIA. This question will be addressed through three specific aims: 1) to examine the effects on CIA in mice of prevention of receptor binding of IL-18 with soluble IL-18BP; 2) to examine the effects of CIA in mice of blocking both the complement system and IL-18; and 3) to examine the relationship between production of IL-18, TNFalpha, and IL- 1beta in rheumatoid synovial tissue and cells. These experiments will utilize the administration of recombinant IL-18BP, the creation of mice transgenic for either, or both, proteins, and studies on isolated rheumatoid synovium tissue and cells. These studies are relevant to RA where IL-1 and TNFalpha are key mediators leading to inflammation and tissue destruction. The complement system and

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IL-18 may be important inducers of IL-1 and TNFalpha. These studies are further relevant to other autoimmune and inflammatory diseases where inhibition of injurious mechanisms at the proximal levels of complement and IL-18 may be efficacious. This research project will contribute towards the broad objective of the Autoimmunity Centers of Excellence program to study the mechanisms of new interventional approaches in both animal models of disease and in human disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IL-18 IN RHEUMATOID INFLAMMATION AND ANGIOGENESIS Principal Investigator & Institution: Koch, Alisa E. Gallagher Research Professor; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Rheumatoid arthritis (RA) is a prototype inflammatory disease characterized by leukocyte infiltration, which is in large part mediated by chemokines and cellular adhesion molecules. Angiogenesis, or new blood vessel growth, is integral to the development of the inflamed RA synovial tissue (ST) pannus. Without angiogenesis, leukocyte infiltration could not occur. A novel cytokine, interleukin (IL)-I8 has recently been identified. This cytokine stimulates T helper 1 (Thl) cytokine production by T cells. The functional role of this cytokine in RA is still unclear. In this proposal we hypothesize that IL-18 contributes to RA joint inflammation and angiogenesls. We plan to determine the mechanism by which IL-18 serves as an inducer of chemokine production in RA ST fibroblasts and whether this chemokine production occurs via G proteins, src family kinases, mitogen activated kinases, or PI3 kinases. Besides chemokines, cellular adhesion molecules are needed for leukocyte ingress into inflamed STs. We will examine whether IL-18 induces leukocyte-endothelial adhesion molecule expression and the mechanism of this expression. Finally, leukocyte ingress would not take place without angiogenesis. We will ascertain the mechanism by which IL-18 mediates angiogenesis in RA in terms of the endothelial signaling pathways, which are activated. Finally, we will study IL-18 gene-deficient mice to determine if they have impaired angiogenesis. We will employ these gene deficient animals bred on an arthritis-susceptible strain to examine whether arthritis associated angiogenesis in the joints is decreased. Several years ago cytokine modulation as a therapy for RA was simply a hope. Currently, cytokine modulation aimed at ablating tumor necrosis factoralpha is one of the best treatments available for RA and IL-1 targeting is beginning to be used therapeutically. IL-18, by virtue of its ability to induce chemokine release, adhesion molecule expression, and angiogenesis, appears to be a very critical cytokine to target. Our proposal should answer some key questions, which may determine the ability of IL18 to be a therapeutic target in RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNE DEVIATION INDUCED BY GENE VACCINATION-APPLICATIONS TO ARTHRITIS Principal Investigator & Institution: Corr, Mary P.; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001 Summary: Rheumatoid arthritis is a chronic inflammatory disease primary affecting peripheral synovial joints. The etiopathogenesis of rheumatoid arthritis appears to be multi-factorial, including hereditary susceptibility, postnatal events in immune


maturation, repeated exposure to environmental antigens and amplifying cytokine networks that perpetuate inflammation. The causative antigens may be directly expressed at the site of immune attack pr be cross reactive with antigenic epitopes naturally occurring in the joint. We postulate that stimulating a subset of T cells that respond to a joint specific antigen to secrete IL4 or IL10 by manipulating the antigen presenting environment may abrogate disease. In our preliminary experiments we have developed a system whereby limited epitopes are expressed by plasmid DNA injected into the dermis or muscle tissues of mice. The T cell response to these antigens is additionally biased not only by the epitope expressed, but also by different costimulatory molecules expressed in the vicinity. This method of providing different elements involved in priming of an immune response creates a local immunologic window. In our laboratory we have also developed a unique system to limit antigen presentation to an isoform of CD1. We aim to 1) assess the effects of different costimulatory molecules on deviating the immune response to collagen 2) determine if providing additional antigenic chaperones or covalently linking the antigen chaperones potentiates immune deviation 3) evaluate a regulatory role for the CD1D1 restricted responses in collagen induced arthritis and 4) determine if the findings form our three strategies in the collagen induced arthritis model apply to a different transgenic mouse model in which the mice spontaneously develop arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOGENETICS OF COLLAGEN INDUCED ARTHRITIS IN MICE Principal Investigator & Institution: David, Chella S. Professor of Immunology; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001; Project Start 01-JAN-1983; Project End 28-FEB-2006 Summary: (provided by applicant): Collagen induced arthritis is an animal model for rheumatoid arthritis that shares a number of clinical, hematological, serological, and radiographic features with human disease. Type II collagen is a major component of articular hyalin cartilage and is a potential autoantigen in RA. Predisposition to RA has been linked to the MHC class II genes with haplotypes HLA-DQ8/DR4 showing the highest relative risk, and DQ6/DR2 being resistant. We generated transgenic mice expressing the above class II genes in the absence of endogenous class II molecules to generate a new humanized mouse model for rheumatoid arthritis restricted by human HLA class II molecules. Several interesting findings have emerged from our studies so far. In the current proposal, we will generate HLA-DQ transgenic mice expressing HLADQ4 and -DQ9 linked to RA in Asian and South American populations, and HLADR*O4O2 and *0404 which differ only in the HVR3 region residues to determine the role of the "shared epitope" in human RA. Double, triple, and quadruple transgenic mice will be generated to simulate human haplotypes to understand the interaction, gene complementation, and additive effect of multiple DQ/DR genes in the human disease. We will replace the mouse CD4 with human CD4 in these lines. Using knockout mice for CD4, CD8, and CD28, we will explore the role of costimulators in the disease process. We will identify the T cell and B cell specific epitopes on type II collagen, and look at the T cell repertoire and the TCR VB CDR3 usage. We will produce HLA class II tetramers in the context of human type II collagen peptides to identify specificity of collagen reactive T cells in the joints. Finally, using synthetic peptides and cyanogen bromide fragment of human type II collagen, we will explore various avenues of immunotherapy in the disease process. These studies should reveal the mechanism by which human HLA class II molecules predispose to human RA, and their role in the

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onset and severity of the disease. Thus, this humanized disease model for RA will have HLA class II, human CD4, and human type II collagen peptides as critical elements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOLOGIC BASIS ENIVR MODULATION OF AUTOIM ARTHRITIS Principal Investigator & Institution: Moudgil, Kamal D. Associate Professor; Microbiology and Immunology; University of Maryland Balt Prof School Baltimore, MD 21201 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: (Taken from the Investigator's Abstract) Adjuvant arthritis (AA), inducible in susceptible rat strains by subcutaneous injection of heat-killed Mycobacterium tuberculosis H37Ra, serves as an excellent model for human rheumatoid arthritis (RA). Both arthritic rats and RA patients develop T cell responses to the 65-kilodalton (kDa) mycobacterial heat-shock protein (Bhsp65). Bhsp65 contains both arthritogenic and protective/regulatory T cell determinants. Heat-shock proteins (hsps) are highly conserved proteins both in prokaryotes and eukaryotes. The investigators have made an interesting observation that the susceptibility to AA of Fisher rats is very directly modulated by environmental agents: Fisher F344 rats bred and raised in a barrier facility (BB-Fisher) are susceptible to AA, whereas Fisher rats bred and maintained in a conventional (CV) facility (CVFisher) are resistant to AA. Furthermore, BB-Fisher rats, when transferred into a CV facility and kept there for several weeks, acquire resistance to AA. However, this acquisition of AA-resistance by BB-Fisher rats can be circumvented if rats are fed neomycin or acidified water (to prevent or diminish colonization of gut by environmental agents) beginning on the day of their transfer into the CV facility. Strikingly, naive CV-Fisher, and not BB- Fisher rats, spontaneously raised T cell responses to Bhsp65, including Bhsp65 C-terminal determinants (BCTD) [the investigators have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat]. Furthermore, AA-resistance of CV-Fisher rats can be adoptively transferred to naive BB- Fisher rats by unfractionated splenic cells of naive CV-Fisher rats restimulated in vitro with BCTD. These preliminary findings provide a novel perspective on the role of microbes in autoimmunity: protection from an autoimmune disease instead of disease induction (the latter effect has been observed in several other animal models of autoimmunity). The investigators will test the following propositions in this exploratory study: A) Environmental agents are directly involved in conferring resistance against AA to CV-Fisher rats. Experimental reconstitution of BB-Fisher rats with microbial flora derived from CV-Fisher rats (for simplicity, these reconstituted rats are referred to as BBCV-Fisher rats) should render these rats resistant to AA. B) Microbial flora (containing hsp6O homologs of Bhsp65 of M. tuberculosis) induce protection from AA in CV- and BBCV-Fisher rats through an immunological mechanism. This hypothesis will be tested by priming T cells that are cross-reactive with Bhsp65 of M. tuberculosis (molecular mimicry). A subset of these T cells serves to afford protection from AA by mechanism(s) to be defined in this study. Alternatively, microbial flora may induce immune deviation of potentially arthritogenic T cells. C) The "acquired" AA-resistance of CV- or BBCV-Fisher rats should be adoptively transferable to naive BB-Fisher rats by a defined T cell subset (CD4/CD81). The results of this study should have important implications both for understanding the influence of environmental factors on the pathogenesis of RA in human populations living under different geographical conditions, and in developing new preventive/therapeutic approaches for RA.


Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMMUNOPROBES FOR LUBRICIN FROM HUMAN SYNOVIAL FLUID Principal Investigator & Institution: Jay, Gregory D. Associate Professor; Rhode Island Hospital (Providence, Ri) Providence, RI 02903 Timing: Fiscal Year 2001; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: Specific or related causes in the pathogenesis of osetoarthritis remain unclear despite a great deal of investigation. This justifies a new venue of research into other factors involved in degenerative joint disease. The study of joint lubrication, biotribology, has been fraught with conflicting theories, failure to adequately use molecular techniques, standardize merchanical assays and assign clinical importance to lubrication by synovial fluid. This investigation addresses the molecular of synovial lubrication of animal joints. A considerable literature has demonstrated that these rubbing and pressurized surfaces (i.e., bearings) have low frictional properties (1-4). These properties arise in part from the slippery nature of articular cartilage. Most reports actually deal with the rheology of synovial fluid and may incorrectly assume that its viscosity is the basis for joint lubrication (5-10). Direct measurements documents that synovial fluid lowers the coefficient of friction between cartilage bearings and certain artificial surfaces. A lubricating glycoprotein termed "lubricin" from synovial fluid is responsible for this but no one has proposed a mechanism of how it does so or how to study it in vitro. An arthrotripsometer composed of latex oscillating against glass employed by the PI reproduced critical findings of previous studies using cartilage bearings. It isolated boundary mode lubrication measuring devices previously employed by others. Synovial fluid, saliva, and detergents are the only substances which display this activity (11). The observation that lubricin lubricated the latex: glass bearing is a recent discovery by the PI. This provides an experimental opportunity to implicate failed lubrication in the occurrence of degenerative joint disease in a large number of patients and to causally link this measure to lubricin. A low coefficient of friction (mu) is no necessarily a measure of wear protection but synovial fluid does in fact confer this property to cartilage (12). It is unknown if the absence or paucity of lubricin is significant to the initial or continued pathogenesis of either osteoarthritis or rheumatoid arthritis. This principal goal of this investigation is to develop new immunological probes and with these identify the concentration of lubricin in synovial fluid extracted from healthy and arthritic human joints. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INFLUENCE OF SEX AND HLA ON RHEUMATOID ARTHRITIS Principal Investigator & Institution: Moxley, George F. Associate Professor; Internal Medicine; Virginia Commonwealth University Richmond, VA 232980568 Timing: Fiscal Year 2001; Project Start 27-SEP-1999; Project End 30-JUN-2004 Summary: This application is to support a Midcareer Investigator Award allowing continued patient-oriented investigation into the genetic basis of rheumatoid arthritis (RA). The immediate goal is to examine how sex and HLA interact in RA heredity, while the long-term goal is to describe RA disease mechanisms in such detail that effective prevention or therapy will be possible. This award will provide career development support to protect time for this patient-oriented clinical research, develop new research skills, and do mentoring of junior investigators. The applicant will continue studies of sex influence on HLA penetrance in rheumatoid arthritis. The current studies have

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shown that RA is independently associated with several disease susceptibility loci in the HLA region, not just DRB1 variants but also independently with tumor necrosis factor (TNFalpha) variants. The future studies will define the functional correlates of TNF variants by identifying unrelated persons with common HLA genotypes and then examining inducible TNF production and MHC class II density in peripheral blood cells. Such results will be used to develop multivariate models to determine whether these explain sex differences in HLA penetrance. A second ongoing project, in cooperation with investigators at Case Western Reserve University, is to identify RA families suitable for genetic studies. A third project is proposed for this application. RA families will be studied to determine whether there is segregation distortion of RA-associated HLA haplotypes, that is, whether a child (either affected or not) is more likely than expected to inherit a RA-associated HLA haplotype from a mother with the HLA haplotype or a father with the HLA haplotype. Such parent-of-origin effects might represent genomic imprinting. Dr. Moxley has already demonstrated mentoring success, guiding junior investigators through design, performance, problem- solving, analysis, and publication. Virginia Commonwealth University has a rich patient population and strong programs to educate investigators in clinical research and biostatistics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHIBITION OF IL-6 AND STAT3 IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Ivashkiv, Lionel B. Associate Professor; Hospital for Special Surgery 535 E 70Th St New York, NY 10021 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 28-FEB-2005 Summary: Rheumatoid arthritis (RA) is a chronic inflammatory process that is characterized by the presence of activated monocytes/macrophages, T cells, B cells, plasma cells, and synovial fibroblasts in inflamed joints. Cytokines have been implicated in the activation of these cells and the pathogenesis of disease. Recent observations in a number of animal models of RA and in RA patients suggest that interleukin-6 (IL-6) plays a critical role in the pathogenesis have not been clarified, but potential mechanisms include activation of macrophages, stimulation of local antibody (rheumatoid factor) production, activation of T cells, and stimulation of myeloid and fibroblast differentiation into cells which directly degrade bone and cartilage. The activity of many cytokines, including IL-6, is mediated, in large part, by a major signal transduction pathway that utilizes Janus protein tyrosine kinases (Jaks) and STAT transcription factors. We have found that Stat3 is constitutively active in RA synovial fluid and tissues cells, that synovial fluids activate Stat3 in control cells, and that the major synovial fluid activator of Stat3 is IL-6. These observations have prompted an investigation of molecular mechanisms of inhibition of IL-6 signaling and Stat3 activation. One rapidly acting investigation of molecular mechanisms of inhibition of IL6 signaling and Stat3 activation. One rapidly acting inhibitory pathway that we have described involves the kinase cascade that activates the extracellular stimulus-regulated kinase (ERK) subfamily of mitogen activated protein kinases (hereafter termed the MEK-ERK pathway). This pathway inhibits signaling upstream of Stat3 activation and is relative specific for IL-6 and related cytokines that share the gp130 signaling subunit. We hypothesize that inhibition of IL-6 signaling is mediated by ERK kinase-dependent phosphorylation of the IL-6 receptor or an associated signaling molecule. We propose to delineate the molecular mechanism of inhibition and identify important regulatory molecules that can be targeted by novel therapies aimed at inhibiting cell activation during RA. Therefore, our specific aims are: (1) identify the IL-6 receptor sequences that mediate inhibition of signaling by the MEK-ERK pathway. (2) Determine the mechanism


by which ERK-mediated post-translational modification of the IL-6 receptor or associated signaling molecules regulates the function of this receptor. (3) Characterize the functional consequences of ERK-mediated inhibition of IL-6 signal transduction using the M1 myeloid cell differentiation system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERLEUKIN-18 IN INFLAMMATION AND ANGIOGENESIS Principal Investigator & Institution: Park, Christy C. Medicine; Northwestern University Office of Sponsored Programs Chicago, IL 60611 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (Adapted from Applicant's Abstract) The study of cytokines is important to understanding inflammation and the immune system. Cytokines function to mediate normal physiologic processes, such as infection control and wound healing, but they can also regulate disease states such as autoimmune disease, rheumatoid arthritis (RA), or asthma. Interleukin (IL)-18 is a proinflammatory Cytokine, initially described as interferon-gamma- inducing factor. It is produced by activated macrophages, Kupffer cells, articular chondrocytes, osteoblasts, kerotinocytes, and synovial fibroblasts. IL-18 is structurally similar to IL-l beta and shares some of its biological actions, such as upregulation of the TH1 Cytokine and cell activation. Previous work has demonstrated its increased presence in RA and in an animal arthritis model. Preliminary evidence from our lab also supports a role for IL-18 in mediating angiogenesis, or new blood vessel growth, which is integral to the vasculoproliferation seen in RA as well as in would healing and tumorigenesis. IL-18 clearly contributes to the Cytokine cascade and maintains inflammation. However, the mechanisms by which IL-18 functions and its contributions to inflammatory disease processes need further investigation. The goal of the proposed research plan is to test our hypothesis that IL-18 contributes to the development of inflammation and angiogenesis in RA. The specific aims of the research are to determine: (I.) the cellular effects of IL-18 on stimulation of inflammatory mediators in RA synovial fibroblasts, which will be accomplished by determining whether IL-18 upregulates chemokines (chemotactic cytokines), arachidonic acid metabolites, degradative enzymes, and cell surface markers of inflammation; (II.) the action of IL-18 on an / inflammatory joint disease model, by employing mice deficient in the IL-18 gene, and examining the development of inflammation clinically and immunohistologically compared to normal mice; (III.) the angiogenic role of IL-18 in vitro and in vivo, by testing IL-18 in various bioassays for angiogenesis, including endothelial cell chemotaxis, proliferation, and tube formation, as well as blood vessel growth in vivo; (IV.) the action of IL-18 in mediating angiogenesis, employing in vivo angiogenesis and granuloma assays; (V.) the mechanisms by which IL-18 functions are regulated in a component of angiogenesis, namely endothelial cell migration. These research aims, if answered by the experimental methods above, will broaden our understanding of IL-18 functions and may ultimately direct the development of novel therapeutic targets against inflammatory and angiogenesis driven diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTRARTICULAR SLPI THERAPY FOR RHEUMATOID ARTHRITIS Principal Investigator & Institution: Labhasetwar, Vinod D. Associate Professor; Pharmaceutical Sciences; University of Nebraska Medical Center Omaha, NE 681987835 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-JUL-2003

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Summary: (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by the loss of joint structure and function, resulting in significant pain and morbidity. In this proposal, we plan to investigate a new therapeutic strategy for the treatment of RA. In normal joints, the cartilage matrix turnover is maintained due to a balance between the activities of proteases and protease inhibitors. This balance is lost in arthritic joints, resulting in a greater protease activity, leading to cartilage and bone degeneration. Secretory leukocyte protease inhibitor (SLPI) has been identified as an endogenous potent protease inhibitor that maintains the critical balance against the proteases in the joint. Since SLPI is not produced by the joint tissue and the arthritic joints loose their ability to sequester SLP1 from the blood, it is hypothesized that intra articular administration of SLPI in a sustained release formulation would be effective in reinstating the balance between the proteases and protease inhibitors, and in inhibiting the progression of the disease. SLPI is also considered to be involved in protecting the cartilage growth factor (Link N) in the joint from protease-mediated degradation. The link N promotes the synthesis of proteoglycan and collagen, which are required for maintaining normal cartilage composition in the joint. Therefore, localized SLPI therapy could also lead to regeneration of the cartilage matrix and restoration of joint functions. Therefore, the objective of the proposed studies is to determine the efficacy of sustained intra articular delivery of SLPI using an injectable thermo reversible (TR) gel system in RA. The specific aims of the research program are: (1) To formulate a sustained release TR gel system for SLP1 using biodegradable and biocompatible Polyethylene oxide-Poly (L-Lactide)-Polyethylene oxide copolymer, and to evaluate the gel for sustained protein release properties, (2) To investigate the kinetics of intra articularly injected SLPI-gel system to provide localized and sustained delivery of the protein, and to determine the therapeutic efficacy of the gel to inhibit the progression of the disease in a rat streptococcal. cell wall-induced model of inflammatory erosive arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: JUVENILE RHEUMATOID ARTHRITIS: MRI ANALYSIS Principal Investigator & Institution: Dardzinski, Bernard; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-JUN-2006 Summary: Juvenile rheumatoid arthritis (JRA) is the most common chronic inflammatory arthritis of childhood. The end result of ongoing synovial inflammation is degradation of articular cartilage. Whether the control of synovitis halts further cartilage degradation is not known. Irreversible thinning and erosion of cartilage leads to significant morbidity and loss of function. Magnetic resonance imaging (MRI) is proven to be a useful modality for depicting articular cartilage and synovium in both children and adults with inflammatory arthritis. Quantitative T2 mapping of articular cartilage in adults has shown that increased T2 relaxation time is an early marker of cartilage injury. This application will test the hypothesis that increased T2 relaxation time in articular cartilage of the knee in children with JRA reflects early cartilage injury. This quantitative method might possibly detect potentially reversible articular cartilage changes prior to irreversible cartilage erosions detected by conventional MRI. The longitudinal relationship between serial short-term changes in articular cartilage T2 relaxation time, degree of synovial inflammation, and clinical evaluation of disease activity will be determined. Articular cartilage T2 relaxation time in children with limited disease duration undergoing therapy will be quantified and monitored for reversibility. Serum and synovial fluid biomarkers will be measured and compared with alterations in


articular cartilage T2 relaxation time. We will determine whether changes in T2 relaxation time profiles are predictive of articular cartilage erosions in children with JRA, and quantify and monitor reversibility of articular cartilage T2 relaxation time changes in children with longer disease duration. The long-term goal of this research is to provide a noninvasive, quantitative measure of early and potentially reversible degeneration in articular cartilage of children. These studies may extend the utility of MRI to quantitatively validate clinical outcomes in rheumatic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEUKOCYTE MICROARRAYS IN JUVENILE RHEUMATOID ARTHRITIS Principal Investigator & Institution: Jarvis, James N. Associate Professor; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, OK 73126 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Juvenile rheumatoid arthritis (JRA) is a family of illnesses characterized by chronic inflammation and hyperplasia of the synovial linings of joints. Its causes are unknown, and responses to treatment are often poor and associated with significant morbidity. Current theories of JRA pathogenesis have focused entirely on the role of T cells and adaptive immunity, failing to account for welldescribed abnormalities that implicate innate immunity in the disease process. We postulate that JRA pathogenesis involves complex interactions between innate and adaptive immunity. Traditional scientific approaches that focus narrowly and in depth on specific aspects of inflammation or immunity cannot grasp the complex pathogenesis at a single glance. DNA microarrays offer an ideal method for investigating these molecular interactions. Our preliminary experiments using DNA microarrays examined gene expression in peripheral blood buffy coat preparations from three children with polyarticular-onset JRA (poly-JRA). Our preliminary results indicate that the number of differentially expressed genes (compared to healthy age-matched controls) is 25-50 from an array of 2,400 genes. We now propose to continue to use buffy coat leukocyte preparations as the first step in identifying genes differentially expressed in additional children with active poly-JRA (Year 1). Once strong candidate genes have been identified, we will verify their expression and identify cellular localization in a single step using purified cell fractions (monocytes, granulocytes, and lymphocytes) and reverse transcriptase polymerase chain reaction (Year 2). We expect these pilot studies will provide the foundation for novel insights into the intersecting roles on innate and adaptive immunity in polyarticular JRA. Furthermore, these studies are likely to provide the basis for the elucidation of important prognostic markers and targets of novel therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LEUKOTRIENE B4 RECEPTORS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Bodduluri, Haribabu; Pathology and Lab Medicine; University of Louisville University of Louisville Louisville, KY 40292 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2007 Summary: (provided by applicant): Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Neutrophils are found in large numbers in rheumatoid synovium and have been suggested to be involved in clinical signs of inflammation and pain associated with RA. Neutrophil activation during host defense and inflammation is

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mediated by G-protein coupled receptors (GPCRs) for chemoattractants. Leukotriene B4 (LTB4), a potent chemoattractant for neutrophils activates its receptor (BLT-1) to mediate diverse physiological effects in neutrophils. A second LTB4 receptor (BLT-2) with distinct antagonist specificity and tissue distribution was recently described. GPCRs are regulated by receptor phosphorylation leading to desensitization as well as down regulation. We will test the hypothesis that LTB4 acting through the high affinity receptor BLT-1 mediates its effects on neutrophils in RA, while LTB4 acting through BLT-2 modulates T-lymphocyte activation and function in RA. The goal of the current studies is to develop comprehensive in vivo and in vitro models to determine the role of LTB4 and the relative contributions of BLT-1 and BLT-2 in the development of murine RA. In specific aim 1 we will define the role of BLT-1 in the development and progression of collagen induced arthritis in the BLT-1 deficient mice we have already generated by targeted gene disruption. In specific aim 2 we will use the well-established RBL-2H3 cell model to determine the differences in signaling, desensitization, internalization and antagonist specificity of BLT-1 and BLT-2. These studies take advantage of the novel video microscopy and live cell imaging methods we have recently developed. Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis, atherosclerosis, RA and asthma. Understanding the precise function of distinct LTB4 receptors in mice deficient in specific receptors and defining the role of these receptors in RA will identify novel targets for therapeutic intervention of RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


LMP

POLYMORPHISMS

IN

B27-ASSOCIATED

JUVENILE

Principal Investigator & Institution: Colbert, Robert A. Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 20-AUG-1997; Project End 31-JUL-2002 Summary: Juvenile rheumatoid arthritis (JRA) is a heterogeneous autoimmune disease likely to result from multiple genetic and environmental factors. One genetic factor encoded in the class I region of the major histocompatibility complex (MHC), and associated with late onset particular JRA, is HLA-B27. In preliminary studies we have identified homozygosity for the B allele of LMP2, one of two MHC-encoded proteasome subunit genes (LMP2 and LMP7), as an additional genetic risk factor for susceptibility to arthritis in HLA-B27-positive children. Since proteasomes ar involved in the generation of peptides presented by MHC class 1 molecules like B27, we hypothesize that polymorphisms in LMP7 may also affect susceptibility to JRA. Furthermore, LMP2, LMP7, and their allelic variants may influence the production of peptide epitopes presented by HLA-B27, thus influencing disease susceptibility in these individuals. This proposal outlines a career development program designed to complete the training of a physician-scientist interested in the molecular mechanisms of HLA-B27-associated autoimmune disease pathogenesis. It relies on the strengths and potential of a Howard Hughes Medical Institute research laboratory headed by Dr. John Monaco to provide further training in modern techniques of molecular immunology, particularly with regard to proteasome function, and strong Division of Rheumatology headed by Dr. David Glass, with long-term interests and expertise in genetic associations in JRA. In addition to the basic research component, the training program will provide the candidate an expanded knowledge base in immunology through participation in lab meetings, journal clubs, and research seminars. In Specific Aim 1 we propose to use molecular genotyping to confirm and extend our initial observations wit LMP2, and


determine whether LMP7 polymorphisms are associated with subgroups of JRA. In Specific Aim 2 we address the role of LMP subunits in influencing the cleavage site specificity of proteasomes by digesting oligopeptides containing known HLA class Irestricted peptide epitopes. Epitopes will be identified and their relative quantities assessed, using mass spectroscopy (MS) and cytotoxic T lymphocyte (CTL) assays. In Specific Aim 3 we will test hypothesis that LMP2 and LMP7 polymorphisms result in functional differences in proteasome activity. In vitro mutagenesis will be used to mimic naturally-occurring polymorphisms in LMP2 and LMP7, and cleavage site specificity of proteasomes containing these allelic variants will be assessed using MS and CTL recognition assays. These studies will define the association between LMP alleles and JRA, and contribute to our understanding of the function of MHC-encoded proteasome subunits and the significance of their allelic variation. Furthermore, they will essential to our determining how polymorphic gene products involved at different sites in the class I antigen processing pathway might interact to predispose certain individuals to JRA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LUBRICIN FUNCTION IN ARTICULATING JOINTS Principal Investigator & Institution: Warman, Matthew L. Assistant Professor; Genetics; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The integrity of the cartilage surface and its surrounding synovium affects the homeostasis and long-term function of an articulating joint. The loss of superficial zone chondrocytes and fibrillation of the cartilage surface are early signs of osteoarthritis. Intimal cell hyperplasia and sub-intimal fibrosis is striking in rheumatoid arthritis where joint destruction is, in part, mediated by aggressive and invasive synovial overgrowth. This application proposes to explore the role of the secreted protein lubricin (also known as megakaryocyte stimulating factor precursor, superficial zone protein, camptodactyly-arthropathy-coxa vara-pericarditis syndrome protein, and proteoglycan 4) in the maintenance of articulating joints. This protein has several important roles in joint homeostasis, including the protection and boundary lubrication of articulating surfaces, and the regulation of intimal cell growth. Genetic deficiency of this protein causes the autosomal recessive CACP syndrome, which is associated with precocious joint failure, and acquired deficiency of this protein likely contributes to joint failure in osteoarthritis and rheumatoid arthritis. Since lubricin is a protein that is synthesized by surface chondrocytes and synviocytes and is secreted into the synovial fluid, we speculate that it may be a useful agent, or target, in the treatment of common joint disease. This application has four major aims: Aim 1) Characterize the lubricin knockout mouse with respect to cell biological properties of synoviocytes, and the biophysical and structural properties of the articular surface (lamina splendens). Aim 2) Delineate which domains in lubricin are important for its post-translational modification and biologic properties, such as protein-protein interactions, lubrication, and cell growth regulation. Aim 3) Create a transgenic mouse in which lubricin expression can be exogenously regulated. This will allow us to explore the temporal role of lubricin in joint development and homeostasis. Aim 4) Identify hereditary and acquired alterations of lubricin function within synovial fluid from patients with CACP syndrome and common diseases of joints including osteoarthritis, rheumatoid arthritis, and traumatic joint injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISM OF INDUCED PROTECTIVE IMMUNITY IN MURINE CIA Principal Investigator & Institution: Haqqi, Tariq M. Associate Professor; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, OH 44106 Timing: Fiscal Year 2001; Project Start 15-SEP-1999; Project End 30-JUN-2003 Summary: Type-II collagen induced arthritis in mice (CIA) is a well studied animal model of inflammatory polyarthritis with many similarities to human rheumatoid arthritis (RA). In this model arthritis is induced in susceptible strains of mice and rats after immunization with hetrologous or autologous type-II collagen in complete Freund's adjuvant and the induction of arthritis is MHC restricted. In previous studies performed by our laboratory we identified a new CIA susceptible strain, BUB/BnJ (H2q, TCR Vba), and showed that induction of arthritis in BUB mice is associated with a restricted use T cell antigen receptor (TCR) variable region genes (Vbeta) in the arthritic joints and was limited to TCR Vbeta3 and Vbeta10 genes. Most recently we demonstrated that mice preimmunized either with a mixture of TCR Vbeta3 and Vbeta10 peptides or with TCR Vbeta10 peptide alone were highly protected against the induction of CIA upon subsequent challenge with chicken type-II collagen (C-II) in CFA. The experiments in this proposal focus on further characterizing and understanding the mechanism of this protective immune response. The fundamental hypothesis of this proposal is that protective immunization induces an anti-Vbeta10 peptide immune response characterized by IFN-gamma producing T cells and IgG2a subtype antibodies (Th1 immune response) and this immune response subsequently results in the elimination or downregulation of the arthritogenic immune response. In order to perform these studies we have developed a highly sensitive ELISA spot assay capable of detecting cytokine production by single T cells, and have used this assay to show that (1) we can preferentially induce either a Th1 type or Th2 type anti-Vbeta10 immunity in vivo by simply altering the immunization protocol; (2) arthritis protected mice had antiVbeta10 specific CD4+ T cells which produced IFN-gamma while arthritic mice had IL-4 producing T cells. We will now fully characterize the recall Th1 or Th2 immune responses after immunization with Vbeta10P using the ELISA spot assay, standard cytokine ELISA and RT-PCR for cytokine message and TCR Vbeta gene usage. We will then determine how the induced anti-Vbeta10 immune response affects the quantity and cytokine profile of pathogenic immunity directed towards type-II collagen and towards a newly identified immunodominant determinant in BUB mice derived from typecollagen. Finally we will study how passive transfer of Vbeta10 specific antibodies and T cells affects the clinical expression of CIA as well as how it affects the pathogenic immune response directed at type-II collagen. The results obtained are expected to provide novel insight into the mechanisms of induced protective immune responses that may be relevant to the treatment of human rehumatoid arthritis and other autoimmune disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS OF ANTIFOLATE EFFICACY Principal Investigator & Institution: Morgan, Sarah L.; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001 Summary: Low-dose methortrexate therapy suppresses autoimmune arthritis in human and animal models. It is our hypothesis that the effect of methotrexate in the treatment of rheumatoid arthritis is due to the inhibition of aminoimidazole-carboxamide ribotide


transformylase, a folate-dependent enzyme which catalyzes the last step in the de novo biosynthesis of inosine monophosphate. The resulting accumulation of aminoimidazole carboxamide riboside inhibits adenosine deaminase, therefore, interfering with normal adenosine metabolism. It is well known that children with adenosine deaminase deficiency have severe-combined-immunodeficiency syndrome. This suggests that adenosine deaminase activity is key to immune competence and is associated with the mechanism of efficacy in methotrexate therapy of rheumatoid arthritis. Several studies indicate that supplemental folinic acid (5- formytetrahydrofolate) used in large doses during low-dose methortrexate therapy for rheumatoid arthritis causes a flare in joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen the efficacy of the therapy. We further hypothesize that if methotrexate efficacy is driven by aminoimidazole carboxamide ribotide transformylase inhibition, folic acid supplementation should not alter urinary levels of aminoimidazole carboxamide, adenosine, and deoxyadenosine, while folinic acid supplementation should prevent the accumulation of these compounds. Our hypotheses will be tested both in patients with rheumatoid arthritis and in Lewis rat adjuvant arthritis. Objectives include A) to determine whether supplemental folic acid and folinic acid during methotrexate therapy normalize adenosine metabolism in patients with rheumatoid arthritis. The information obtained from the proposed research will enhance the understanding of the biochemical action of antifolates/ antimetabolites that are effective in the treatment of human and animal arthritis. To date, six patients have been enrolled in the trial. Because the trial is blinded, no data is yet available. It is planned inthe upcoming year to enroll patients, up to a total of 50 patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF MYCOPLASMA-INDUCED ARTHRITIS Principal Investigator & Institution: Dybvig, Kevin F. Genomics and Pathobiology; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-MAR-2003 Summary: ( applicant's abstract): Mycoplasma arthritidis causes a naturally-occurring, migratory polyarthritis in rodents that bears a close histological resemblance to rheumatoid arthritis of humans. M. arthritidis-induced arthritis has been extensively studied as a model for arthritides caused by infectious agents and also as a model for examining the role(s) of superantigens in the development of autoimmunity. All strains of M. arthritidis are thought to produce the superantigen MAM, but many an MAM must be required for the development of arthritis. One of these factors is the lysogenic bacteriophage MAV1. Avirulent strains of M. arthritidis become virulent when lysogenized with MAV1. MAV1 DNA integrates into the M. arthritidis chromosome at any of numerous sites, and the site of integration does not correlate with virulence. Therefore, the increase in virulence associated with MAV1 does not result from changes in regulation of chromosomal genes flanking MAV1 DNA inserts. We have proposed that MAV1 encodes a determinant that is involved with the development of arthritis. MAV1 is the first factor from any mycoplasma that has been shown to be associated with arthritis, and elucidation of this factor is important for fulfillment of the long-range goals of understanding the mechanisms of mycoplasma-induced arthritis and the role of phages as carriers of bacterial arthritogenic determinants. Factors analogous to the MAV1-encoded determinant may be prevalent in bacteria and mycoplasmas that cause arthritis in humans, and these factors may be important as vaccine candidates and as targets for drug design. The goals of the present application are to identify and characterize the MAV1-encoded determinant and initiate studies to elucidate its

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function. From the nucleotide sequence of the 16-kb MAV1 genome, we have identified a candidate virulence determinant that is predicted to encode a membrane lipoprotein. Specific Aim 1 is to conclusively identify the particular MAV1 gene(s) associated with virulence of M. arthritidis. Specific Aim 2 is to determine whether the MAV1 virulence factor is a cytoplasmic or membrane protein and is produced in vivo. Specific Aim 3 is to explore the role of MAV1 in disease pathogenesis. How lysogenization of M. arthritidis by MAV1 affects the progression of arthritic disease will be examined. Through the use of immunocompromised animals, we will address the question of whether MAV1 contributes to the virulence of M. arthritidis by affecting interactions with host factors such as B and T cells and complement. Thus, the process of dissecting the function of MAV1 in virulence will be begun. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF RHEUMATOID SYNOVIAL FIBROBLAST ACTIVATION Principal Investigator & Institution: Bucala, Richard J. Professor; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, CT 065208047 Timing: Fiscal Year 2002; Project Start 21-AUG-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Rheumatoid arthritis causes significant disability and mortality. The joint capsule or synovium undergoes profound phenotypic changes during this disease, resulting in the hyperplastic and invasive tissue known as rheumatoid pannus. Pannus leads to cartilage and bone destruction, and the synovial fibroblasts within pannus show a persistently activated state characterized by increased proliferation, decreased apoptosis, and sustained growth factor and matrix-degrading enzyme secretion. Precisely how these phenotypic changes are initiated and become perpetuated in synovial fibroblasts is not understood, and this lack of knowledge is an important problem because without this information, more selective approaches to the treatment of arthritis cannot be undertaken. Our long-range goal is to understand the pathogenesis of rheumatoid pannus. The objective of this application is to understand the mechanisms underlying the persistent activation of synovial fibroblasts. The central hypothesis is that the cytokine, macrophage migration inhibitory factor (MIF), induces sustained ERK-1/2 activation, invasive phenotype, and suppression of p53-dependent apoptosis in synovial fibroblasts. We have formulated this hypothesis on the basis of our discoveries showing that immunoneutralization of MIF prevents arthritis development in murine models, and that MIF induces a sustained pattern of activation of the ERK-l/2 MAP kinase cascade in the well-defined, NIH-3T3 cell line. MIF also has been shown to uniquely inhibit p53-dependent apoptosis. The rationale for this research is that once it is known how persistent pathways of cell activation become induced in synovial fibroblasts, new approaches for intervention in joint destruction may be devised. We will test our hypothesis and accomplish the objective of this application by pursuing the following two specific aims: 1) Define the Pathways by which MIF Activates Synovial Fibroblasts, and 2) Determine MIF's Role and Mechanism of Action in the Inhibition of p53-dependent Apoptosis. The proposed work is innovative because it capitalizes on two recently discovered and potentially unifying mechanisms, sustained ERK-1/2 activation and p53 functional inactivation, to explain the hyperplastic and invasive phenotype of rheumatoid pannus. It is our expectation that this work will define the molecular basis for the sustained pro-proliferative and invasive phenotype of rheumatoid synovial fibroblasts. These results will be significant because they will provide a precise understanding of the molecular pathways responsible for the erosive


properties of synovial pannus and ultimately facilitate the development of new and selective strategies for the treatment of rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MICROARRAY ANALYSIS--SYNOVIAL GENE EXPRESSION IN ARTHRIT Principal Investigator & Institution: Brahn, Ernest; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001 Summary: An analysis of the expression/regulation of specific genes in the synovium is critical to an understanding of the events that initiate and propagate chronic inflammatory synovitis in collagen-induced arthritis (CIA) and rheumatoid arthritis. Microarray technology represents a high-throughput approach to study and statistically compare numerous genes The LOU rat CIA system has several advantages over human autoimmune systems since it uses syngeneic rats, can be reproducibly studied at any time point in arthritis development, and allows the capacity to simultaneously harvest control tissue as well as the end organ of interest, the synovium. Because of limitations in microarray quantitation, RT-PCR will be needed for confirmation only of the selected genes that have altered expression. This analysis could define which gene products might be important at each stage of disease and could provide targets for fixture therapeutic interventions. Since not all LOU rats (even though they are syngeneic) develop CIA following immunization with collagen, early differences in gene expression, compared to their arthritic littermates, might explain this observation. Specifically targeted therapeutic interventions, such as sTNF-Rl, IL-lra, or p38 MAP kinase inhibitors, can be evaluated by microarray methods in the CIA system (and potentially in RA) to clarify their proximate (e.g. TNF, TNF-R2, IL-1) and subsequent (e.g. metalloproteinase) effects on synovial gene expression. This could result in a better understanding of the in vivo mechanisms of how these agents work (in rats with arthritis regression) or don't work (in rats with arthritis progression). An initial pilot study with normal LOU rat spleen/lymph node/liver (non-lymphoid control)/synovial tissue will define optimal procedures and conditions for rat microarray methodology. This utilizes tissue that is readily available and establishes a naive background level of gene expression for later comparison. Most of the previous studies on gene expression profiles in arthritis utilized a small panel of genes encoding potentially proinflammatory molecules. In contrast, the microarray includes, in addition, genes that encode molecules responsible for anti-inflammatory effects, metallo-proteinases, bmps, differentiation antigens and factors, transcription factors, and signaling molecules. All of these can help to reveal the on-going pathology and also become targets of therapy in the future. After induction of CIA on day 0, synovial and control tissue from rats will be harvested during the course of arthritis development (day 7-subclinical disease, day 10clinically evident arthritis onset, day 17-established arthritis, day 28-late arthritis). Microarray analysis will provide sequential data on gene expression as it relates to arthritis progression. Candidate genes will be confirmed by RT-PCR. By testing a number of individual rats, a common gene expression profile at each time point will be generated. Subsequent studies will analyze the effects of specific biologic interventions with sTNF-RI , IL-Ira, p38 MAP kinase inhibitors as single agent or combination interventions in rats with early (day 10) CIA. Patterns of gene expression will be compared with the typical expression defined in naive and CIA control rats at day l7 and day 28. If a therapeutic agent does not alter the gene expression profile, it would indicate that the agent is blocking certain final mediators of the disease. If a therapeutic

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agent alters the gene expression profile drastically, the changes in the downstream molecules are then responsible for the clinical improvement. This is especially useful when testing therapeutic agents that block signaling pathways. These investigations should identify direct and subsequent effects on gene expression using protocols that selectively target an inflammatory element that has already shown potential utility in rheumatoid arthritis therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR BASIS OF HUMAN VH GENE REPLACEMENT Principal Investigator & Institution: Zhang, Zhixin; Medicine; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: provided by applicant): The candidate is a molecular biologist who wishes to establish an independent research career in the molecular immunology field. Enhanced training under Dr. Max D. Cooper?s supervision in immunology is proposed for the initial two or three years in order to achieve research independence within the award period. The proposal will focus on the molecular basis and regulatory mechanism of human VH gene replacement and its contribution to normal B cell development, B cell responses, and rheumatoid arthritis in particular. The hypothesis builds on an analysis of a clonal human cell line, EU12, that undergoes continuous in vitro differentiation from proB (CD34+) to preB (CD34 mu SLC+) then to B cells (CD34 mu+LC) and generates intraclonal diversity through serial VH replacements. The ongoing VH replacement in the EU12 cells is verified by the detection of VH replacement excision circles and double stranded DNA breaks at the cryptic RSS sites. (Aim 1) The EU12 cells will be used as an experimental model to dissect the molecular basis for the VH replacement. Purified RAG 1, RAG 2, and HMG 1 proteins will be used in in vitro studies to define the function of the cryptic RSS site. (Aim 2) Using the methods and principles derived from the study of the EU 12 model, normal human bone marrow and tonsillar germinal center B lineage cells will be used to investigate the occurrence and stage(s) of VH replacement in humans. (Aim 3) The regulatory mechanism of VH replacement will be investigated using the EU12 model through evaluating the effects of. (i) modulating surrogate light chain (lamda 5/14. 1) or conventional light chain (kappa and lamdaX) expression, (iii) ligating cell surface receptors (pre BCR, BCR, and CD40), and (iii) stimulating with cytokines (IL 1 beta, TFNaphla, IL 6, and IL 7) on VH replacement. (Aim 4) Determine if VH replacement occurs in synovial B cells thereby contributing to the generation of autoantibodies and to search for potential VH replacement stimuli in rheumatoid arthritis synovial tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR MODELING OF MHC II-PEPTIDE ISOMERS Principal Investigator & Institution: Belmares, Michael P. Chemistry; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 30-NOV-2000 Summary: The molecular level modeling of MHC II-peptide systems to obtain a solid theory of the origins of autoimmune systems, particularly rheumatoid arthritis (RA) is proposed. The first modeling efforts will be directed toward a systematic search of the structure of a "kinetic" isomer of an MHC-peptide system where a long and a short lived isomer have been observed (MHC II I-E/kPiggeon Cyt c peptide). Then, a hypothesis has been laid out in the proposal where a specific kinetic isomer of a collagen peptide in


HLA-DR4 (DRB1 0401 allele) is not recognized as "self" by the immune system. The Tcells recognizing the "kinetic" isomer may not have been eliminated during the early maturation stage. Modeling of the proposed isomer will be done and may be eventually confirmed through experimental techniques at the McConnell lab. Specifically, it is proposed that water molecules solvating the two carboxylates in the P6 pocket of HLADR4 may interfere with the deep burial of the P6 Ala of the collagen peptide observed in the MHC-peptide crystal structure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR THERAPEUTICS OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Carson, Dennis A. Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001; Project Start 28-SEP-1998; Project End 31-AUG-2003 Summary: Current concepts of rheumatoid arthritis (RA) pathogenesis indicate that the disease is not caused by a single genetic defect, infection, or autoimmune reaction, but rather by improper control of host immune, inflammatory, and proliferative responses within the joints. This revised application for a Specialized Center for Research (SCOR) in RA focuses on this central theme. It contains four projects. Each concerns a molecular defect that may contribute to immune dysregulation and pannus formation in RA. Furthermore, each project aims to develop a therapeutic strategy to correct how bacterial and host-derived immunostimulatory DNA sequences can induce normal T1-type immune responses within the joints, and will demonstrate how ISS action might be interrupted therapeutically. Project 2: "The Synovium as an Immune Underprivileged Site" (Thomas J. Kipps, M.D. PhD. Project Leader) aims to delineate how the proteolytic environment within the joint prevents deletion of activated immune cells, and will devise gene therapeutic strategies to correct the defect. Project 3 "Immune Deviation Induced by Gene Vaccination: Applications to Arthritis" (Mary P. Corr, M.D. Project Leader) aims to deviate pro-inflammatory Th1 immune responses toward a less inflammatory Th2 phenotype by the creation of an "immunologic window" through genetic engineering of DNA vaccines. Project 4: "Properties of Shared Epitope-Specific T Cells in RA" (Salvatore Albani. M.D. Project Leader will discriminate the functional properties of isolated T cells from RA patients that recognize the shared epitope and will explore how pharmacological invention can change their frequency or function. The four projects will be supported by an Administrative Core (Dennis A. Carson, M.D. Director), that will coordinate the research and monitor its progress, and by a centralized Research Resources Core (Gary S. Firestein, M.D. Director), that will collect and distribute patient samples, and provide assistance with the evaluation of animal models. When completed, the experiments proposed in the SCOR will demonstrate how specific molecular abnormalities can promote the development of chronic arthritis, and will describe specific approaches for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MULTIDISCIPLINARY CLINICAL RESEARCH CENTER AT BOSTON U Principal Investigator & Institution: Felson, David T. Professor and Chair; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, MA 02118 Timing: Fiscal Year 2001; Project Start 24-SEP-2001; Project End 31-AUG-2006 Summary: OF THE OVERALL PROGRAM: (Taken from the application): This proposal represents a competitive renewal of the Boston University Multipurpose Arthritis and

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Musculoskeletal Diseases Center grant which was established in 1977 and built on a strong foundation of outstanding epidemiology and health services research along with basic biomedical research. We have parlayed this excellence in epidemiology and health services research into a Multidisciplinary Clinical Research Center (MCRC) application. The strong record of accomplishment in patient oriented medical research at Boston University has been not only maintained in the last four years but expanded. What we propose creates new directions and areas of research for this already productive group of investigators who work together closely, and it promises to produce further major insights into rheumatic disease causation and treatment. Led by Director, Dr. David Felson and Associate Director, Dr. Timothy McAlindon, this group of full time MCRC investigators who work together in shared office space will meet weekly in Methodology Core group meetings to discuss and review both projects proposed here and other funded and nonfunded clinical research. This Core will provide support for the four proposed projects: Project 1: A Randomized Trial of a Wedged Insole for Treatment of Osteoarthritis of the Knee, David T. Felson, PI; Project 2: Can Case-Control Studies Of Rare Diseases Be Performed Over The Internet, Timothy McAlindon, PI; Project 3: Work Disability: How are Persons with Rheumatoid Arthritis Currently Faring?, Saralynn Allaire, PI; and Project 4: Correlates of Articular Cartilage thickness in knees of subjects from the Framingham Study, David T. Felson, PI. An administrative unit will provide oversight to ensure that these projects are successfully accomplished and that core resources for support of these and other projects are allocated efficiently. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTIPURPOSE ARTHRITIS & MUSCULOSKELETAL DISEASES CENTER Principal Investigator & Institution: Hahn, Bevra H. Professor; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 15-JUL-1987; Project End 30-JUN-2003 Summary: The revised proposal from the UCLA MAMDC builds upon our prior work in the basic science of autoimmunity, and in defining and modifying some factors that impact on outcome in patients with rheumatoid arthritis (RA). Twenty- five investigators are participating directly in the proposed projects and core units; many more as expected to use the core to enrich their scientific endeavors. The proposal offers 4 development and feasibility (D&F) studies, all designed to develop the career of a beginning faculty- level investigator, and a biomedical core unit for peptide synthesis. The D&F studies will explore the role of CD1-restricted T cells in host defense against staphylococci, both in normal people and in patients with septic arthritis; 3) the influence of loading MHC Class I and II molecules with T-cell stimulatory peptides via administration of mini-genes on the T cell functions that influence autoantibody formation in murine lupus, and 4) the importance of a chromosome region near the beta2-glycoprotein I locus on ability to make antibodies to cardiolipin, and the influence of those antibodies on lipoprotein metabolism in autoimmune mice with accelerated coronary artery disease. In the education, epidemiology and health services research (EESHR) portion of the proposal, we aim to establish methods for assessing quality of care in patients with new onset RA, assuming that appropriate interventions in this cohort influence outcomes. A core unit and two projects will focus on developing valid methods to measure care as a function of structure (patient demographics and characteristics of the health unit administering care), process (the interventions that happen to patients such as physician visits), and outcome (physical, socioeconomic, administering care), process (the interventions that happen to patients such as physician


units), and outcome (physical, socioeconomic, psychological characteristics of patients from entry to two years later). The core will develop and validate measuring instruments, train data collectors, collect and clean data, and provide advise regarding data analysis. In one project (Claims Data), claims data on 400 patients with new onset RA from a large managed care organization will be analyzed and validity compared to information obtained from chart review and patient self-report. In the second project (Practice Patterns), information will be obtained from chart review and patient selfreport from 400 patients with new onset RA receiving care at VA Medical Centers, Kaiser Permanente, and Mullikin MedPartners. The purposes of this HSR component is to establish valid measures of quality of care in RA, based on structure process and outcomes. Each project will identify and enter patients, supervise the scientific aspects of data collection and management, and analyze the data. The MAMDC efforts will be supervised and coordinated by an administrative unit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTIPURPOSE ARTHRITIS & MUSCULOSKELETAL DISEASES CENTER Principal Investigator & Institution: Winfield, John B. Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 01-JUL-1982; Project End 30-JUN-2003 Summary: The Multipurpose Arthritis & Musculoskeletal Diseases Center at the University of North Carolina at Chapel H. chartered by the School of Medicine as the Thurston Arthritis Research Center, consists of a Biomedical Research Component, an Education, Epidemiology, & Health Services Research (E/E/HSR) Component, a Biomolecular Core, a Numerical Sciences Core, and an Administrative Unit. Ongoing and planned investigation in the Biomedical Research component encompasses many of the issues relevant to autoimmunity, arthritis, and musculoskeletal disease: genetics, regulation, and function of recognition elements in normal and abnormal immune responses; peptide/MHC structure function relationships; induction and regulation of cytokine and inflammatory responses genes; the repertoire of T cell receptor and B cell Ig genes and their role in autoimmunity; T cell activation and signal transduction; molecular genetics of autoantibody formation; contribution of autoantibodies to disease pathogenesis; immunosuppression; inciting agents in autoimmunity; inflammation in experimental arthritis and its therapy; biochemistry and cell biology of cartilage; pathophysiology of mechanical joint injury and its relationship to osteoarthritis; clinical investigation of arthritis, osteoporosis, and systemic connective tissue diseases; and mechanisms of pain. Three Development & Feasibility projects are proposed. "Mechanisms of anti-nRNP/Sm autoantibody spreading"; "The role of beta2GPI in apoptosis"; and "Prevention of Arthritis with Dietary Glycine". A Biomolecular Core provides: serological and clinical databases and a cell bank; flow cytometry; and inbred mouse colony; and a biomolecular imaging facility. Research themes in the E/E/HSR Component include: 1) studies aimed at increasing our understanding of how people adapt to and cope with arthritis; 2) development or validation of measurement procedures related to arthritis; 3) epidemiological studies aimed at describing the prevalence, correlates, and potential determinants of specific arthritic disorders (currently osteoarthritis and SLE) or their sequelae; 4) prevention strategies; 5) outcomes research; and 6) education programs for physicians and other health professionals who treat patients with arthritis. Four projects are proposed in the E/E/HSR Component: "Incidence and progression of knee and hip osteoarthritis in Johnston County, NC"; "Emotional contagion between people having arthritis and their spouses"; "Self-

Studies 83

management, education and outcomes in rheumatoid arthritis"; and "Osteoporosis prevention among women with rheumatoid arthritis receiving oral glucocorticoid therapy". A Numerical Sciences Core provides: methodological consultation and review; development and maintenance of patient databases; data entry and management; biostatistical consultation; education; and computer technology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUTATIONS IN PKA GENE TRANSCRIPTS OF LUPUS T CELLS Principal Investigator & Institution: Laxminarayana, Dama; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, NC 27157 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disorder of indeterminate etiology with multiple Immune effector dysfunctions, which afflicts females in the child bearing years. Protein kinase A (PKA) plays an important role in regulation of immune effector functions of T cells. Previous research has revealed a disorder of type I protein kinase A (PKA-I) enzyme activity in SLE T cells. Recently the applicant has identified mRNA transcript editing of PKA-I RIalpha-subunit and up-regulation of the transcript editing gene, adesosine deaminases that acts on RNA (ADAR) in SLE T lymphocytes. The RNA editing is the co- or posttranscriptional modification of RNA molecules, which results in the insertion, deletion or substitution of nucleotides, mRNA editing plays an important role in the regulation of gene expression and produces phenotypic variability by diversifying the information encoded within the corresponding genomic sequence. The objective of this proposal is to identify the molecular mechanism(s) leading to mRNA transcript editing in RIalphaand RIbeta-subunits of PKA-I and their role in deficient PKA-I isozyme phosphotransferase activity in SLE T lymphocytes. The specific aims of the project are;(1) to quantify mRNA transcript editing in RIa and RIbeta gene transcripts in T cells from patients with SLE and compare this with normal controls as well as patients with rheumatoid arthritis (RA) to characterize its association with SLE pathogenesis;(2) to characterize mutant RIa- and Ribeta-subunit proteins phosphotransferase activity in T cells from SLE patients;(3) to analyze regulation and expression of the ADAR gene in T cells from normal, RA and SLE patients and determine whether there is a selective association with SLE pathogenesis;(4) to quantify ADAR-mediated adenosine to inosine conversion in controls and SLE lymphocyte gene transcripts; and, (5) to quantify ADAR2 transcript editing in T cells of SLE patients and compare this with that in T cells of normals and RA patients to characterize its association with SLE pathogenesis. Therefore, the major goal of this project is to identify RNA editing events in the gene transcripts of SLE T cells and the subsequent dissection of editing mechanisms. The novel data derived from these experiments will prove crucial in addressing questions of functional, biological significance, and regulatory events responsible for deficient PKA-I isozyme phosphotransferase activity in SLE T lymphocytes. Identification of this new mechanism of transcript mutations will provide new insights into the mechanisms of aberrant T cell immune effector functions in SLE and open a new avenue of research to design molecular tools to control aberrant immune functions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MYCOPLASMA SUPERANTIGEN & RA MHC SUSCEPTIBILITY ALLELES Principal Investigator & Institution: Cole, Barry C. Professor; Internal Medicine; University of Utah 200 S University St Salt Lake City, UT 84112


Timing: Fiscal Year 2002; Project Start 01-MAR-1978; Project End 31-MAR-2007 Summary: (provided by applicant): Autoimmune diseases such as rheumatoid arthritis (RA) are currently considered to be due to a complex interplay of host genetics with environmental triggering agents, which include infectious agents bacteria, viruses or mycoplasms. The overall goals of this project are to determine how microbial products such as superantigens (SAgs) might interact with RA MHC-susceptibility alleles to drive a type 1 inflammatory cytokine profile that might trigger active disease in the human host. As a model we will use the newly developed murine class II knockout mice that display various human MHC molecules that predispose to development of collagen arthritis in mice. Mice expressing these molecules will be tested for their cytokine profiles in response to in vivo exposure to the mycoplasma SAg, MAM and other bacterial SAgs using RT PCR and ELISA methodologies. We shall also investigate the mechanisms of any differences seen including the potential role of MHC binding, cell type, role of co-stimulatory molecules, and region of the SAg molecule responsible. Also we will investigate the pathogenetic effects of M. arthritidis in these "humanized" mice and determine strategies to overcome the effect of the superantigen MAM in initiating disease pathogenesis by modification of the cytokine milieu. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NATURAL VITAMIN E IN CONTROLLING SYMPTOMS OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Roubenoff, Ronenn; New England Medical Center Hospitals 750 Washington St Boston, MA 021111533 Timing: Fiscal Year 2001 Summary: We will study the efficacy and safety of supplemental vitamin E therapy in patients with Rheumatoid Arthritis (RA). Since most patients in the United States are treated with at least one and as many as four medications, it is not realistic to study vitamin E therapy in the absence of other medications. Moreover, it is not likely that vitamin E would be used as the sole drug treatment in many Rheumatoid Arthritis patients even with its demonstrated benefit. Thus, the most important clinical trial should be designed to examine the potential use of vitamin E as an alternative/adjunct to NSAID in the typical multi-modality treatment of RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEW RAT MODEL OF AUTOIMMUNE DIABETES AND ARTHRITIS Principal Investigator & Institution: Guberski, Dennis L.; Biomedical Research Models, Inc. 10 New Bond St Worcester, MA 01606 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-MAY-2003 Summary: (provided by applicant): The objectives of this proposal are to develop and characterize a new congenic rat model with spontaneous autoimmune disease. In Phase 1 we will establish a foundation colony of LEW.1WR1 rats and begin genetic crosses to introgress traits from BBDR/Wor and LEW.1WR strains. This should increase the incidence of spontaneous diabetes and may induce spontaneous arthritis and thyroiditis. The incidence and age of onset of type 1 diabetes, and the occurrence of spontaneous arthritis will be monitored. In Phase 2, select Quantitative Trait Loci (QTL) markers will be used to construct speed a congenic strain with a high incidence of multiple spontaneous autoimmune disorders. Some 5 percent of the U.S. population is affected by one or more autoimmune diseases. Experimental animal models facilitate the study of the pathogenesis of autoimmune diseases and permit the evaluation of

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treatment protocols that are not immediately feasible or ethical in humans. Animal models also provide populations of genetically uniform subjects that can be maintained under environmentally controlled conditions. It is our expectation that this new model of autoimmunity will expedite the development of safe and effective pharmaceutical agents for the treatment of Rheumatoid Arthritis, Type 1 Diabetes, and Hashimoto's Thyroiditis. PROPOSED COMMERCIAL APPLICATION: This research effort will result in a new characterized model of autoimmune diseases. The animal model will generate income by direct sales and contract research within the 15,000 sq. ft. BRM facility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


NOVEL

IMAGING

TECHNOLOGIES

FOR

RHEUMATOID

Principal Investigator & Institution: Kimpel, Donald L. Medicine; Louisiana State Univ Hsc Shreveport P. O. Box 33932 Shreveport, LA 71103 Timing: Fiscal Year 2001; Project Start 27-SEP-1999; Project End 31-AUG-2004 Summary: The development of imaging technology for autoimmune diseases is crucial to mechanistically dissect these complex, chronic diseases. Without comprehending the process that leads to disease, it is difficult to develop therapies aimed at ameliorating or preventing autoimmunity. Our proposal is focused on development of imaging model for rheumatoid arthritis (RA), but the models are widely applicable. RA is a debilitating disease that afflicts a large number of people in the U.S. and the world, about 1-2 percent of the world's population. In addition, there are several rodent models that mimic RA. We are particularly interested in developing techniques and reagents to study the process of leukocyte migration from the blood through the synovium and into the joint. We reason that inhibiting leukocyte transmigration will prevent the disease. Indeed, preventing leukocytes from invading tissue will inhibit most autoimmune diseases as well as prevent graft rejection. Intravital microscopy provides a technique to image in vivo the microvasculature at high magnifications. Fluorescence labeled cells can be visualized traveling through the microvasculature and the rate of movement assessed by offline analyses. Various treatments can be administered to modulate in vivo cell movement through the tissues. To develop in vivo intravital microscopy for RA, we will develop a series of transgenic mice with selected cell-types expressing fluorescent proteins. These transgenic mice will allow imaging of selected cell-types in vivo by intravital microscopy. To image changes in cell adhesion molecule expression, which are essential for leukocyte transmigration, we will develop mice expressing fluorescent proteins with similar kinetics as the cell adhesion molecules. To bridge the gap between animal studies and human RA, we will develop a system to image in vivo human leukocyte and human synovium interactions by using the humanized SCID model system. Upon completion of these studies, we will have developed a comprehensive imaging system to study leukocyte migration during autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL IMMUNOTHERAPEUTIC APPROACH TO AUTOIMMUNE ARTHRITIS Principal Investigator & Institution: Geirger, Terrence L.; University of Tennessee Health Sci Ctr Health Science Center Memphis, TN 38163 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-AUG-2006


Summary: (provided by applicant): Autoreactive T lymphocytes (ATL) are critical regulatory and effector cells for rheumatoid arthritis and other autoimmune diseases. Eradication of these ATL may ameliorate or cure such diseases. Therapies capable of selectively targeting ATL are not available clinically. This proposal describes the develpment of a novel therapy that uses genetically modified T lymphocytes (GM-TL) to selectively eliminate ATL. The GM-TL will be transfected with a chimeric receptor capable of both recognizing ATL and activating the GM-TL. This receptor consists of- a. class II major histocompatability complex (MHC alpha and beta chains, b. covalently linked autoantigenic peptide, and c. activation domain derived from the T cell receptor complex. The ATL T cell receptor will specifically interact with the MHC-peptide complex of the chimeric receptor. This interaction will activate the GM-TL, which in turn will kill or downmodulate the ATL. By using GM-TL to selectively eliminate ATL it should be possible to modulate or abrogate ongoing autoimmune disease. This will be tested using a well characterized murine model for autoimmune arthritis, collagen induced arthritis (CIA). Chimeric construct design will be optimized using in vitro and in-vivo assays of GM-TL activity. These analyses will examine the capacity of GM-TL to kill or modulate the reactivities of type II collagen specific T lymphocytes. GM-TL will then be adoptively transferred into mice prior to, concurrent with, or following the induction of CIA. Pathologic and clinical measures of outcome will be assessed. These experiments will thus provide the initial studies assessing the usefulness of GM-TL in treating autoimmune arthritis. It will establish a precedent for the analagous use of GMTL as a therapy for human autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL OSTEOCLASTOGENIC T CELL FACTOR Principal Investigator & Institution: Rifas, Leonard; Barnes-Jewish Hospital Ms 90-94212 St. Louis, MO 63110 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2003 Summary: Rheumatoid arthritis (RA) is currently considered an autoimmune disease in which a pathologic immune response attacks synovial cells, cartilage and bone resulting in joint destruction and permanent disability. Loss of bone mass in RA is a common clinical problem occurring as both juxta-articular or localized bone loss and generalized osteoporosis leading to the risk of fracture. The juxta-articular bone loss is associated with an increase in blood- derived T cells infiltrating into the synovial cavity. Activated (Act) T cells are believed to mediate most of the tissue destruction, once the inflammation cascade has begun. The Act T cell is a source of cytokines known to regulate bone turnover, such as IL-6 , TNF-alpha and a new member of the TNF receptor family, TRANCE/RANKL/ODF/OPGL, but a causative T cell cytokine is presently unknown. This project is aimed at discovering whether a cytokine produced by activated T cells, that we have recently found regulates the expression of IL-6 in normal human osteoblasts and regulates osteoclast differentiation, is a novel protein. The identification of a novel T cell factor which may be inducing osteopenia in rheumatoid arthritis and perhaps other autoimmune diseases may lead to the development of inhibitory agents which may prove to be of therapeutic efficacy in preventing bone loss in these diseases. Thus our specific Aims are: To purify, characterize and clone the soluble factor(s) produced by activated T-cells that regulates IL-6 production in human osteoblasts and induces osteoclastogenesis; and 2) Prepare recombinant protein and produce antibodies to the T cell factor for future studies of its function. The factor(s) will be isolated using affinity chromatogphy, anion and cation exchange chromatography, gel filtration chromatography and SDS-PAGE. Identification of the proteins as novel will

Studies 87

be performed by N-terminal or internal sequencing. Internal sequence synthetic peptides will be synthesized and used for the production of polyclonal antibodies. Cloning will be performed using the rapid amplification of cDNA ends (RACE) technique to obtain a partial human cDNA from adaptor-ligated human T cell cDNA. Primers will be designed and the full length cDNA reading frame will be PCR amplified, primers prepared and ultimately a fusion protein cDNA prepared and ligated into a prokaryotic expression vector in order to produce recombinant protein. Antibodies will be prepared against the protein to characterize its function in vitro. We propose to determine whether the T cell factor induces TRANCE in hOB by probing isolated mRNA with labeled cDNA, generated by RT-PCR methods, and Northern blot analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL THERAPEUTIC INTERVENTIONS IN RA Principal Investigator & Institution: Maldonado, Michael A. Assistant Professor; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 27-SEP-1999; Project End 30-JUN-2004 Summary: Novel Therapeutic Interventions in Rheumatoid Arthritis: This proposal is organized as a training vehicle that reflects a new direction in my interests to combine mechanistic and translational investigation in rheumatoid arthritis. The core of this proposal is the desire to model the effectiveness and feasibility of two novel therapeutic interventions in RA, autologous bone marrow transplantation and gene therapy. Both of these modalities are already being investigated by other researchers and there is widespread, keen clinical interest. I believe that with this work we can, with a careful and judicious application of available information, obtain both useful insight into etiopathogenesis and practical therapeutic utility. We propose to perform this work as outlined in the following two Specific Aims: Specific Aim 1. The treatment of arthritis by immunoablation followed by stepwise immune reconstitution by drug resistancetransduced stem cells. The existent technologies for bone marrow reconstitution, peripheral blood stem cell harvesting, retroviral transduction, and in vivo drug selection will be combined to allow the gradual development of individual bone marrow chimeras. Several strategies for immunoablative conditioning prior to bone marrow reconstitution will be addressed. This approach will be applied to several mouse arthritis models. We believe that information gained from this work should have an immediate impact on the collaborative efforts that we have already begun with transplantation specialists at The University of Pennsylvania to develop strategies for bone marrow transplantation as a treatment for RA and other Autoimmune Diseases. Specific Aim 2. Gene Therapy in Arthritis as an Investigational Tool. We will expand FasL gene transfer work to other models of spontaneous and induced autoimmune arthritis and perform experiments designed to delineate the cells targeted by this intervention. This will confirm prior observations made in the collagen-induced arthritis model, validate the universality of this therapeutic approach in RA and serve to further understand mechanisms at play. We hypothesize that FasL gene transfer will be effective in preventing and ameliorating arthritis regardless of its etiology so long as the disease is mediated by activated synovial cells expressing Fas molecule. This work will allow me to develop new skills and a wider understanding of the usefulness of gene therapy approaches as both a therapeutic modality and an investigational tool. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: OLDER ADULTS & DRUG DECISIONS: COLLABORATION & OUTCOMES Principal Investigator & Institution: Chewning, Betty A. Associate Professor; None; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Midst growing time pressures on physicians, there is a need to maintain and even enhance the quality of physician-patient encounters, particularly for vulnerable, older adults with chronic conditions. Substantial research suggests that older adults are more passive than other age groups during their visits. Hence, physicians may miss key information about patient concerns and regimens that could affect health outcomes. This research addresses gaps identified by literature reviews calling for studies evaluating interventions that efficiently elicit patient pre-visit expectations for physicians and examine the longitudinal effect of expectation fulfillment on patient outcomes. The goal of this research is to study the impact of an intervention that identifies pre-visit concerns of older adult patients and then prompts both patients and physicians to address these concerns in the visit. Older adults' functional status concerns will be identified briefly in the waiting room using a handheld computer. A printout summarizing patient responses will be given both to the physician and patient. We hypothesize that this prompt will affect the nature of the patient-provider encounter in such a way that health outcomes will be improved. To test these hypotheses, a final sample of 580 patients age 60 or older, with a formal diagnosis of rheumatoid arthritis will be enrolled at their clinic visit. A one-year randomized, controlled experiment will be used in which an experimental group patients receive a computerized assessment and prompt about their visit concerns while a control group receives a parallel placebo computerized assessment of their exercise patterns. In both cases, patient assessment summaries are given to the patients and to their physicians in the medical record. Baseline, 6 month and 12 month data will be collected on each patient. We hypothesize improved health status at 12 months for the primary outcomes of pain and physical function. Selected encounter dynamics hypothesized to help explain these outcomes will also be examined. We will audiotape patient-physician encounters to study these interaction dynamics. The primary analyses will examine differences at 12 months between the control and experimental groups using ANCOVA for continuous variables with baseline values of outcomes as a covariate, Dichotomous outcomes will be analyzed primarily by the Mantel Haenszel test and logistic regression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OPTICAL TOMOGRAPHY FOR THE DIAGNOSIS OF JOINT DISEASES Principal Investigator & Institution: Hielscher, Andreas H. Associate Professor; Columbia Univ New York Morningside 1210 Amsterdam Ave, Mc 2205 New York, NY 10027 Timing: Fiscal Year 2001; Project Start 15-SEP-1999; Project End 31-AUG-2004 Summary: (Adapted from Applicant's Abstract): The long-term goal of this study is to develop an optical tomographic imaging method to assist in the diagnosis, characterization, and monitoring of joint diseases. In recent years, considerable progress has been made toward these novel imaging methods. The technology for making light transmission measurements on human subjects is now readily available and has been applied in a variety of pilot studies concerned with monitoring of blood oxygenation determination, hemorrhage detection, functional imaging of brain activity, diagnosis of

Studies 89

Alzheimer disease, and detection of breast cancer. The application of optical tomography (OT) to imaging and diagnosis of arthritis and musculoskeletal disorders has received little attention, even though imaging of joints with OT appears less challenging than breast or brain imaging. One can expect relatively good signal to noise ratios for the transmitted light intensities because of the comparatively small dimensions of, for example, finger joints. Furthermore, changes in the optical properties of various joint components can be expected for most diseases. For example, it is known that with the onset of rheumatoid arthritis, the synovial fluid in the articular cavity becomes increasingly turbid. Therefore, as a specific example, the applicants proposed to initially apply OT to the diagnosis and monitoring of rheumatoid arthritis in the joints of the hand. There remain two key problems to be solved for a successful implementation of an optical tomographic imaging system for joints. 1) Due to the presence of the almost non-scattering synovial fluid in all joints, commonly employed diffusion-theory-based image reconstruction schemes cannot be applied. 2) Due to the strong variation in optical properties within the joints, widely used perturbation-theory approaches to the image reconstruction problem are insufficient. To overcome these deficiencies of currently available reconstruction algorithms, and to develop an optical tomographic system suitable for imaging finger joints, the applicant plans to perform the following studies: (a) Develop non-perturbation 3D-reconstruction algorithm that uses the theory of radiative transfer for the prediction of detector readings. (b) Determine sensitivity of optical tomographic image system to changes in the optical properties of various joint components and evaluate accuracy of image reconstruction. (c) Correlate OT results with clinical findings of rheumatoid arthritis in finger joints. (d) Optimize the performance of the OT imaging system to achieve minimal computation time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ORAL LY333013 AND METHOTREXATE DRUG INTERACTIONS STUDY Principal Investigator & Institution: Branch, Robert A. Professor/Director; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001 Summary: This is a two-part study (A&B) designed to evaluate the safety and tolerability of commitant LY333013 and methotrexate administration in rheumatoid arthritis patients. Each part of this multicenter study will be conducted independently and will consist of a single blind, placebo controlled, randomized two period crossover. LY333013 is a prodrug of LY315920 which is a potent inhibitor of human non-pancreatic secretory phospholipase A2 (sPLA2). LY333013 is being developed for oral administration in patients with chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, asthma and chronic bronchitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ORAL TYPE II COLLAGEN & MISOPROSTOL TREATMENT OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Postlethwaite, Arnold E.; University of Tennessee Health Sci Ctr Health Science Center Memphis, TN 38163 Timing: Fiscal Year 2001


Summary: Tis study proposes to test the hypothesis that induction of oral tolerance to type II collagen is effective in rheumatoid arthritis patients when the PGE1 analog, misoprostol, is given to block NSAID effects on oral tolerance." Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OSTEOPENIA IN ADULTS WITH HISTORY OF JUVENILE RHEUMATIOID ARTHRITIS Principal Investigator & Institution: French, Anthony R.; Mayo Clinic Rochester 200 1St St Sw Rochester, MN 55905 Timing: Fiscal Year 2001 Summary: Utilizing a previously identified population-based cohort of adults who developed JRA while living in Rochester, Minnesota, between January 1, 1960, and December 31, 1993, we plan to investigate the prevalence and severity of osteopenia in adults with a history of JRA. This will allow testing of the hypothesis that JRAassociated osteopenia persists into adulthood in a significant number of patients placing them at an increased fracture risk. The first specific aim of this study is to utilize dualenergy x-ray absorptiometry (DEXA) scanning to measure bone mineral densities in a cohort of adults with a history of JRA previously identified using the Rochester Epidemiology Project by 1) delineating the prevalence and severity of osteopenia in this population-based cohort of adults with a history of JRA, and 2) comparing bone loss in the appendicular and axial skeleton in this population of patients. The second specific aim is to apply regression analysis techniques in identifying predictors of osteopenia in adults with a history of JRA including age at diagnosis, gender, JRA subtype, Steinbroker functional class, ANA and rheumatoid factor status, steroid use, calcium intake, and exercise level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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PATHOGENESIS

OF

BONE

EROSION

IN

RHEUMATOID

Principal Investigator & Institution: Gravallese, Ellen M.; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease that often produces severe destruction of articular cartilage and bone. Considerable evidence indicates that bone erosions in RA are produced by osteoclasts (OCs). An essential factor for the differentiation and activation of osteoclasts is receptor-activator of NF-KB ligand (RANKL), which mediates its effects via a specific cell surface receptor, receptor-activator of NF-kB (RANK). Recently, a novel secreted form of RANKL (secRANKL) has been identified which appears to be regulated by a unique promoter. The studies outlined in this proposal are designed to test the hypothesis that that there is enhanced local expression of RANKL at sites of bone erosion in RA and that regulation of RANKL expression in cells at sites of bone erosion is a critical determinant of focal bone loss. Specific Aim 1 will test the hypothesis that RANKL production by cells derived from RA synovium is critical in the pathogenesis of osteoclastic bone erosion. This Aim will address the following questions: What are the exact cellular sources of RANKL at sites of bone erosion in RA? Where is RANKL expressed in relation to OPG expression and to RANK positive OC precursors? Retrieved human tissues will be utilized initially to answer these questions. Cellular expression profiles will be confirmed and the temporal expression of these factors will

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be determined in two murine models of inflammatory arthritis: collagen-induced arthritis (CIA), and the KJBxN model. Dispersed cells from RA synovium will be used to determine the expression of RANKL isoforms in relevant cell types. Finally, the activity of the secRANKL isoform in osteoclastogenesis will be determined in an in vitro coculture model of osteoclastogenesis. Specific Aim 2 will test the hypothesis that T cellderived RANKL is required for bone erosion in RA. Arthritis will be generated in mice in which T cells provide the only source of RANKL, and in genetically engineered mouse strains lacking T cells, in order to definitively determine the role of T cell-derived RANKL in bone erosion. Specific Aim 3 will identify regulatory elements responsible for the constitutive and inducible expression of the membrane-bound RANKL isoform in cell types present in RA, and will test the hypothesis that the NFAT family of transcription factors is critical in the inducible regulation of the memRANKL gene. RTPCR analysis of RANKL expressing cell-types present in focal RA bone erosions demonstrates differential constitutive and inducible expression of the two known RANKL isoforms. Preliminary data also demonstrate a potential role of NFATs in RANKL regulation in T cells. This Aim will provide data on the regulation of RANKL gene expression in cell types present in bone erosion in RA and may lead to new therapeutic strategies for preventing bone destruction in this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PAUCI JRA SYNOVIAL CYTOKINES Principal Investigator & Institution: Glass, David N. Professor of Pediatrics and Director; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2001; Project Start 15-JUN-1989; Project End 31-AUG-2003 Summary: This proposal is based on the hypothesis that cytokines have a role in differentiating between the various clinical phenotypes that comprise juvenile rheumatoid arthritis (JRA), the commonest autoimmune rheumatic disease of childhood. Differences in synovial cytokine expression in JRA are likely to complement those already documented with respect to HLA and T cell receptor genes and will also distinguish some types of JRA from rheumatoid arthritis (RA) in adults. It is hypothesized that, based on preliminary data, IL-4 and IL-10 will protect against the more erosive destructive forms of joint disease in JRA and that this effect will be much more clearly demonstrated by the introduction of quantitative methodology. The proposal is based on three specific aims summarized as follows: 1.1 To determine cytokine profiles in joint tissues and fluids of patients with pauci juvenile rheumatoid arthritis and to make comparison with other arthropathies as follows: 1.2. To study the cytokine profile in the clinical evolution of pauci JRA. 1.3. To determine the cellular sources of cytokines which contribute to the pathogenesis of pauci JRA. These aims will be achieved through the use of quantitative methods RNase protection assays, ELISA and, for cellular sources, immunohistochemistry and FACS analysis. Very central to such studies is the availability of a very comprehensive synovial tissue bank now incorporated into the Cincinnati MAMDC. The tissue is added to on an ongoing basis. In the long term, these studies can lead to experimental protocols to explore the cellular mechanisms involved and help in the selection of therapeutic interventions with immune response modifiers in JRA. These interventions are likely to be different, in part, from those used in RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: PERIODONTAL DISEASE AND RHEUMATOID ARTHRITIS Principal Investigator & Institution: Mccracken, Michael S. Prosthodontics; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant) Candidate: Michael McCracken, DDS, PhD, is motivated and committed to an academic career involving clinical research. He has demonstrated his ability to complete projects and work independently in the past, and shows the qualtities necessary to become a productive researcher with the education and training provided by this grant. Mentors: Larry Moreland, MD, has as long track record of mentoring clinical researchers. He is the PI of the NIH-funded K30 program at UAB and is the Director of the Pittman General Clinical Research Center. Dr. Marjorie Jeffcoat has also mentored many young investigators, and is Chair of Periodontics at the UAB School of Dentistry and PI on the Oral Health Research Training Grant. Dr. Moreland and Dr. Jeffcoat have collaborated successfully on several previous projects, and are committed to the research outlined in this proposal. Dr. George Howard is the Chair of the Department of Biostatistics in the School of Public Health. He will work with the candidate with the didactic training portion of the training and with statistical support of the research. Dr. Graciela alarcon has a long history in outcomes research in musculoskeletal diseases. Environment: The UAB Medical Center provides depth and diversity of clinical research endeavors as well as the state-of-the-art physical resources that are necessary to support this K23 application. UAB is situated on more than 70 square blocks in the city of Birmingham. With over 16,000 faculty, staff and employees, an annual budget for l999-2000 of over $1.15 billion dollars, and extramural funding exceeding $286 million dollars in 1998-1999, UAB provides a solid environment for this training program. Research: The proposal for this training opportunity is to investigate the severity of periodontal disease in patients with rheumatoid arthritis. The hypothesis is that patients with inflammatory rheumatoid arthritis are more susceptible to inflammation of the periodontal tissues. Furthermore, it is hypothesized that among patients with rheumatoid arthritis, an association exists between the rate of progression of inflammatory arthritis and the progression of periodontal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHARMACOGENETICS OF METHOTREXATE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Bridges, S L.; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-DEC-2006 Summary: Methotrexate (MTX) is one of the most effective drugs for RA, but 20- 30% of patients have suboptimal clinical responses to MTX, and 15-25% have side effects limiting its use. Thus, it is important to elucidate influences on MTX efficacy and toxicity. We will test the hypothesis that single nucleotide polymorphisms (SNPs) in genes encoding key enzymes involved in folate or MTX metabolism or in the mechanism of actions of MTX (e.g. the adenosine pathway) influence clinical responses to MTX. We are uniquely positioned to utilize clinical outcomes (ACR response criteria, radiographic progression and toxicities) and genomic DNA from patients in two completed clinical trials: 153 MTX-treated RA patients from an Immunex trial comparing MTX and etanercept, and 79 MTX-treated RA patients from a UAB trial of folic acid supplementation. HLA DRB1 alleles and a total of 5 known SNPs in the following 4 key genes will be genotyped: 1) 5,10- methylenetetrahydrofolate reductase

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(MTHFR); 2) 5-methyl- tetrahydrofolate-homocysteine methyltransferase (methionine synthase) (MTR); 3) methionine synthase reductase (MTRR); and 4) adenosine receptor A2A [A(2A)R]. These SNPs were chosen on the basis of being common enough in the general population to allow meaningful analyses, their key roles in relevant pathways, and evidence of their biological activity. Through the MCRC Methodology Core, we will look for associations between SNP alleles and MTX efficacy or toxicity. Although these known SNPs are important, SNP haplotypes may be even more informative, aqs they allow characterization of the effect of multiple SNPs working in concert. Therefore, we will use both "in silico" in sequencing approaches to identify novel SNP haplotypes in these 4 and 3 other critical genes: dihydrofolate reductase (DHFR), 5- aminoimidazole-4carboxamide ribonucleotide transformylase (AICAR- T), and aldehyde oxidase (AO). In addition to data mining of public domain and proprietary (i.e. Celera) SNP databases, we will perform SNP discovery on 40 individuals from two racial/ethnic groups [20 African-American (A-A) and 20 Caucasian]. Differences in frequencies of novel haplotype related to disease status or race/ethnicity will be sought by analysis of 108AA Ra patients and 53-AA controls; 336 RA patients (mostly Caucasian); and 800 controls (mostly Caucasian) from established cohorts. Based on results from these studies, the role of selected novel SNP haplotypes on MTX efficacy and toxicity will be tested in patients from the folic acid and Immunex trials. We will compare the predictive power of two approaches to genetic profiling: the single SNP approach and the SNP haplotype approach. These studies may provide clinically useful markers of MTX efficacy or toxicity in RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHYSIOLOGICAL BENEFITS OF MENTAL WELLBEING IN CHRONIC DISEASE Principal Investigator & Institution: Coe, Christopher L. Professor; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2002 Summary: (adapted form the investigator's abstract): This project proposes to evaluate psychological well-being, symptom expression, and endocrine/immune functioning in women with two musculoskeletal conditions, fibromyalgia (FMS), and rheumatoid arthritis (RA). Specifically, the studies will assess whether a capacity to sustain a sense of psychological wellbeing results in severity and self-reported experience of symptoms. The first study will compare women with FMS, RA, and healthy controls across two phases of the menstrual cycle for symptom expression, pain sensitivity, and physiological function. In a second intervention study, an attempt will be made to enhance psychological wellbeing and positive affect with an eight-week training program in women newly diagnosed with RA and FMS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POSITIVE AND NEGATIVE REGULATION OF TNF ALPHA SIGNALING Principal Investigator & Institution: Lin, Xin; Microbiology; State University of New York at Buffalo 402 Crofts Hall Buffalo, NY 14260 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by the applicant): Arthritis is a class of disease that affects 43 million Americans. The causes of arthritis are, in general, unknown. However, dysregulated inflammatory and immune responses apparently play very important


roles in these diseases, since many types of arthritis involve chronic inflammation in different organs. Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine and plays an important role in the inflammatory processes of rheumatoid arthritis. Although TNFalpha is required for regulation of normal inflammatory and immune responses, acute elevated levels of TNFalpha may lead to septic shock during bacterial infection, while chronically elevated levels of TNFalpha are associated with the inflammatory processes of rheumatoid arthritis. Elevated levels of TNFalpha induce expression of many inflammatory genes. Expression of these genes is thought to elicit the swelling, pain and other effects of rheumatoid arthritis. Inhibition of TNFalpha function in vitro and in vivo has been shown to affect several animal models of inflammation. Modulation of TNFalpha levels has also been shown to reduce signs and symptoms of severely active rheumatoid arthritis patients. Thus, understanding the molecular mechanism of TNFalpha function will provide more therapeutic approaches for treatment of arthritic diseases. The present proposal seeks to apply molecular tools to elucidate the precise TNFalpha signaling pathway that leads to activation of NF-kB, a major transcription factor that controls the expression of various inflammatory genes. Specifically, we will investigate how RIP, a key signaling intermediate in the TNFalpha pathway, transmits TNFalpha signals to activate NF-kB. We will also examine how TNFalpha -induced signaling pathway is negatively regulated. Finally, we will use genetic complementation approaches to identify unknown signaling components that are required for TNFalpha -induced NF-kB activation. These studies will provide essential new information about the molecular mechanisms by which TNFalpha signals are transmitted to downstream components that activate the NF-kB family of transcription factors controlling expression of inflammatory genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRESERVING MOBILITY OF JRA CHILDREN USING NOCTURNAL TES Principal Investigator & Institution: Mcguire, John R. Phys Med and Rehabilitation; Medical College of Wisconsin Po Box26509 Milwaukee, WI 532264801 Timing: Fiscal Year 2001; Project Start 20-SEP-1997; Project End 31-AUG-2003 Summary: Therapeutic electrical stimulation (TES) is a modified form of traditional electrical stimulation which involves the use of low-intensity, subthreshold electrical stimulation applied during sleep. TES is well tolerated and has been used since 1988 in Canada for children with a variety of neuromuscular conditions. The efficacy of TES has not yet been examined in the child with juvenile rheumatoid arthritis (JRA). The purpose of this R29 proposal is to develop and test this innovative use of low-level muscle electrical stimulation as an adjunctive therapy to minimize or prevent movement limitations in the child with juvenile rheumatoid arthritis. Twenty JRA children with bilateral knee joint involvement will be studied during six months while using nocturnal TES as an adjunct to a physical therapy home program. This low-level subthreshold stimulation is done while the child is sleeping six nights a week. This study is very realistic for the child with juvenile rheumatoid arthritis as it done during sleep, the technology is noninvasive, easy to learn and does not add to "the burden of care." The electrical stimulation will be done unilaterally to allow the other leg to serve as a control. The child will be monitored in three major ways: clinical exam, quantitative muscle strength and muscle bulk, and functional assessments. The monthly clinical exam will document bilateral lower extremity A/PROM, MMT of key functional lower extremity muscle groups, leg length, thigh circumference and the Kraus-Weber flexibility test score. The quantitative muscle strength will be assessed by monthly

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isometric knee extensor torque measurements. The functional assessment will include monthly Childhood Health Assessment Questionnaire (CHAQ), and a modified Pediatric Evaluation of Disability Inventory (PEDI). At the beginning and end of the 6 month period, a gait analysis study including physiologic cost index as well as ultrasound measurement of quadriceps muscle thickness will be done. Our hypothesis is that nocturnal therapeutic electrical stimulation will minimize quadriceps weakness and/or atrophy thereby reducing the potential impairments of muscle weakness, knee flexion contracture and gait deviations which may contribute to long-term disability in the JRA population. If the efficacy of this intervention in preserving mobility is demonstrated, future research would explore the underlying neuromuscular and neuroendocrine mechanisms responsible for the clinical effect. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF TYPE 1 DIABETES WITH MMP INHIBITORS Principal Investigator & Institution: Bleich, David; City of Hope National Medical Center Duarte, CA 91010 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Lymphocyte infiltrates in the islets of Langerhans, "insulitis", is a characteristic hallmark of immune-mediated diabetes in rodent models and human beings. Strategies to prevent invading lymphocytes from reaching the pancreatic beta-cells have been effective in preventing diabetes in non-obese diabetic (NOD) mice. Recently, much attention has been focused on the regulation of matrix metalloproteinases (MMPs) in diseases ranging from metastatic breast cancer to rheumatoid arthritis because these key enzymes regulate tumor cell migration and lymphocyte migration to sites of inflammation. At present, several broad-spectrum MMP inhibitors are being tested in human phase II and Ill trials to determine whether these drugs can prevent tumor metastasis and rheumatoid arthritis. Similarly, we postulated that MMPs play a role in insulitis in NOD mice and possibly human type 1 diabetes. The studies presented here will determine whether a novel broad-spectrum MMP inhibitor can prevent insulitis and diabetes in NOD mice. Six week-old and eighteen week-old NOD mice will be treated with intraperitoneal injections of an MMP inhibitor and followed for development of diabetes. We will evaluate an early treatment protocol (6 weeks of age) to see if MMP inhibition can prevent insulitis and a late treatment protocol (18 weeks of age) to see if MMP inhibition can prevent diabetes once insulitis has progressed. Furthermore, splenic and pancreatic lymph node T cells will be obtained from NOD mice and challenged in vitro with glutamic acid decarboxylase 65. We will assess the Thl/Th2 profile of lymphocytes isolated from these two anatomic sites and whether MMP inhibition can alter the cytokine profile. In collaboration with the University of Arizona, we will evaluate the role of MMPs and their inhibitors in Tlymphocyte development and migration using an in vitro fetal thymic organ culture (FTOC) model. This system has been called "in vitro IDDM" because NOD thymic T lymphocytes can target and infiltrate NOD pancreatic islets when the two organs are cocultured. Since MMP inhibition not only regulates cell migration, but apoptosis, we will perform dose and time courses with MMP inhibitors to determine whether this strategy can alter thymic T-lymphocyte selection and maturation. Finally, TNF-alpha can regulate the production of diabetogenic T-cells and regulatory NKT cells bearing both natural killer and T-cell phenotypes (DX5+ cells) in the FTOC model. Cell membrane bound metalloproteinases called ADAMs (A Disintegrin And Metalloproteinase) process membrane-bound pro-TNF-a to the biologically active cytokine. Thus, we will determine whether MMP inhibition can downregulate intrathymic TNF-a production


and increase the levels of NKT cells. We will determine levels of CD4+,CD8+, and NKT cells using flow cytometry. We anticipate that these studies will give us supporting data to initiate a human trial to treat pre-type 1 diabetic patients with a broad-spectrum MMP inhibitor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROPERTIES OF SHARED EPITOPE SPECIFIC T CELLS IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Albani, Salvatore; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001 Summary: It is the hypothesis of this grant application that the pathogenesis of rheumatoid arthritis (RA) depends not upon the absolute numbers of T cells in the blood or the joints, but rather upon the relative percentages of auto-antigen specific T cells that produce and respond to pro-inflammatory and anti-inflammatory signals, including cytokines and chemokines. These T cell populations may be the target for therapeutic intervention. In preliminary experiments that prompted this grant application, we have shown that: i) peptides of bacterial origin (E. coli dnaJ heat shock protein) are strong immunogens in RA patients. dnaJ shares with HLA DRB1*0401 the susceptibility sequence to RA (shared epitope); ii) T cells in the blood RA patients that react with the shared epitope can be identified and isolated, using a novel technical approach; iii) T cell receptors usage and patterns of cytokine production by these shared epitope specific T cells can be analyzed. Based upon these initial results, we now need to test our hypothesis in a larger cohort of RA patients with different disease courses, and responses to treatment. Thus, the aims of this project are: 1. To characterize frequencies, function and phenotypes of T cells in RA patients reactive with the shared epitope. Parameters to be studied will include cytokine production, T cell receptor usage and membrane markers of activation and memory. Chemokine receptors will also be studied. 2. To determine the effects of disease activity and severity, and of slow acting anti rheumatic drugs, on function and phenotype of the shared epitope specific and bystander T cells. 3. To develop methods to modulate the Th1-type phenotype of shared epitope specific T cells, using in vitro immune manipulation with altered peptides. The long term objectives of this project are: i) to contribute to a better understanding of T cell-mediated events in the pathogenesis of rheumatoid arthritis; (ii) to develop paradigms for the prediction of disease outcome, and for evaluation rapidly new models of therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTECTIVE ROLE OF INNATE IMMUNITY IN AUTOIMMUNE DISEASE Principal Investigator & Institution: Carroll, Michael C. Professor; Cbr Institute for Biomedical Research 800 Huntington Ave Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-MAY-2007 Summary: The overall goal of this Program is to examine a protective role for innate immunity in autoimmune disease. Two murine models of autoimmunity will be characterized, i.e. systemic lupus erythematosus and rheumatoid arthritis. Four highly interrelated projects are proposed involving five senior investigators. The underlying theme connecting the four projects is the intimate role innate immunity plays in antigen clearance. Three of the projects will examine how self-reactive B- lymphocytes are

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negatively regulated by antigen in two well- characterized immunoglobulin transgenic models, i.e. hen lysozyme and dsDNA. Clonal deletion and receptor editing of selfreactive B- lymphocytes will be examined in mice deficient in innate proteins DNAse I, IgM, MBL, C1q, C4 and receptors CD21/CD35. Moreover, novel transgenic mice bearing an auto-reactive transgenic receptor or deficiency in Fas will be constructed using a conditional knock-in approach. The fourth project will examine if innate immunity is involved in T cell tolerance and/or elimination of self-antigen in the rheumatoid arthritis T-cell transgenic model. The significance of the program is that it not only addresses fundamental questions on regulation of adaptive immunity but could lead to novel therapies. Dissection of common pathways of innate immunity that protect against autoimmune disease could lead to therapeutic approaches with broad applications. A major strength of the Program is that it brings together senior investigators, each with specialized expertise, to interact in a synergistic manner. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PULSE THERAPY IN SYSTEMIC JUVENILE RHEUMATOID ARTHRITIS Principal Investigator & Institution: Lovell, Daniel J. Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, OH 45229 Timing: Fiscal Year 2000; Project Start 30-SEP-1998; Project End 31-OCT-2003 Summary: (adapted from applicant's abstract): Systemic juvenile rheumatoid arthritis (sJRA) is associated with significant long term morbidity and mortality. Current therapies including methotrexate are considered ameliorative rather than remission inducing or curative. There have been anecdotal reports suggesting that pulse therapy with intravenous corticosteroids, cyclophosphamide, and methotrexate may induce prolonged remissions in sJRA. Therefore, the objectives of this study are to determine and compare the ability of two pulse therapy regimens to induce remission in sJRA of less than 12 months duration during a 9-month, open-label, randomized, actively controlled clinical trial. The first pulse therapy regimen is composed of intravenous methylprednisalone 30 mg per kg per day (1 gram max) for three consecutive days, intravenous cyclophosphamide 0.4 grams per meter2 BSA on the third day, and up to 20 mg per meter2 per week of methotrexate. The second pulse therapy regimen is identical to the first, except no cyclophosphamide is given. Up to five cycles of these regimens may be given over a 9-month period. Patients in both groups may also receive background medications including a non-steroidal, anti-inflammatory drug and up to 0.5 mg/kg/d of oral prednizone. The primary outcome to measure the effect of this therapy will be the proportion of patients who achieve clinical remission according to the ACR criteria for remission in rheumatoid arthritis. Secondary outcome measures of effectiveness include proportion of patients who demonstrate clinical response according to the preliminary definition of improvement for JRA. In addition, time per remission and the duration of remission will be compared between the two groups among patients who do remit. Specific Aim 2 is to determine and compare the short and intermediate term (18 months) safety profiles of the pulse therapy regimens as defined in Specific Aim 1. Long term goals of the project are to determine and compare the longer-term safety profiles of this treatment regimen. This will involve analysis of patient/parent-derived data obtained by mail or phone follow-up to detect significant medical problems and reproductive or neoplastic complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: QUINAPRIL AND LOSARTAN IN FIBRIOLYTIC BALANCE Principal Investigator & Institution: Vaughan, Douglas E. Chief, Division of Cardiovascular Medici; Vanderbilt University 3319 West End Ave. Nashville, TN 372036917 Timing: Fiscal Year 2001 Summary: Test the effectiveness of a new treatment for patients with rheumatoid arthritis. Anti-TNF Chimeric Monoclonal Antibody is a biological product which acts to inhibit the action of tumor necrosis factor alpha, a major mediator of inflammation in rheumatoid arthritis. We are in the recruitment and enrollment phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RA ASSOCIATED AUTOIMMUNITY IN HIGH RISK POPULATIONS Principal Investigator & Institution: Holers, Michael; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, CO 800450508 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 14-AUG-2006 Summary: The long-term goal of these studies is to identify during the pre-clinical phase of disease those healthy individuals who are at sufficiently high risk for developing Rheumatoid Arthritis (RA) so that a rational primary prevention strategy can be employed. Such a strategy in RA or other autoimmune diseases has been previously thought to be unfeasible. However, extensive experience gained at the University of Colorado Health Sciences Center (UCHSC) in Type 1 or Insulin-Dependent Diabetes Mellitus (IDDM), an autoimmune disease in which disease- related autoimmunity can be detected in the pre-clinical state, has demonstrated that by using several informative strategies one can identify individuals at risk for the development of clinical disease in both the general population and within families. These studies are part of the Diabetes and Autoimmunity Study in the Young (DAISY). With this information, investigators in DAISY are currently employing prevention strategies designed to block the development of clinical signs and symptoms of disease in children with autoimmunity but no significant islet cell dysfunction yet detectable. Using collaborative investigators from the DAISY project, we propose in this funding period to use a very unique population resource of >21,000 HLA typed children and their parents identified during a general population screen in DAISY, as well as adult patients with RA identify by outreach efforts, in order to develop three unique cohorts of individuals at risk for RA. Using these cohorts, we will test the primary hypothesis that pre-clinical evidence of RA- related autoimmunity can be detected in a substantially increased percentage of healthy children and adults who are at increased risk for the development of RA as compared to controls. If this hypothesis is true, our secondary hypothesis will then be that genetic and environmental factors can be identified in these individuals that strongly correlate with pre- clinical RA-related autoimmunity. To test these hypotheses, we propose the following three Specific Aims. Specific Aim #1: Utilize DR4 HLA typing information in the DAISY newborn cohort to identify and characterize DR4-positive parents who are at increased risk for RA in order to determine the age-specific prevalence and incidence of RA- related autoimmunity. Specific Aim #2: Utilize HLA typing information in the DAISY newborn cohort to identify and characterize children for whom the presence of single of compound heterozygote DR0404/0401 alleles substantially increases the risk for RA in order to determine the age-specific prevalence and incidence of RA-related autoimmunity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RECEPTOR DIVERSITY IN RECOGNITION OF INFLUENZA HA Principal Investigator & Institution: Caton, Andrew J. Associate Professor; Wistar Institute Philadelphia, PA 191044268 Timing: Fiscal Year 2002; Project Start 01-APR-1987; Project End 28-FEB-2007 Summary: (provided by applicant): The objective is to analyze factors governing tolerance and autoreactivity among murine CD4+ T and B cells in transgenic mice that express the influenza virus PR8 hemagglutinin (HA) as a well-characterized neo-self antigen (HA Tg mice). In particular, how the distinct specificities of separate populations of CD4+ T and B cells affect their negative selection by the neo-self HA, and processes that can lead to the activation of autoreactive lymphocytes in HA Tg mice will be examined. Aim 1 will examine the selection and functional potential of autoreactive CD4+ T cells that have low avidities for a self-peptide in TCRxHA Tg mice. Whether activation increases the sensitivity of low avidity T cells to the extent that they become responsive to a self-peptide will be determined. In addition, how TCR specificity and/or virus infection contributes to the ability of CD4+ T cells to mediate autoimmune myocarditis in HA Tg mice expressing the HA in cardiac tissue will be assessed. Aim 2 will examine factors governing the phenotypic potentials of B cells that express characteristic variable region clonotypes, that are representative of primary versus memory responses to the HA in virus-immunized BALB/c mice, and that differ in their sensitivity to negative selection in HA Tg mice. Whether selection into different B cell subsets and/or affinity for the HA determines the distinct phenotypic potentials of B cells expressing these clonotypes will be evaluated. In addition, whether autoreactive CD4+ T cells rescue primary response B cells from deletion and/or promote memory B cell formation in response to the neo-self HA will be assessed. Aim 3 will examine the processes that lead to the development of organ-specific autoimmunity. An autoimmune syndrome resembling rheumatoid arthritis develops in TCRxHACII mice in which the HA is expressed on antigen presenting cells, and the cellular interactions that lead to its development will be assessed. Whether virus infection provokes autoimmunity in TCRxHACII mice expressing low affinity CD4+ T cells and/or CD4+ T cells directed to a cryptic self-peptide will also be examined. These studies will provide fundamental insights into the mechanisms of immune tolerance, and will have direct relevance to understanding the processes that lead to the development of autoimmune disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF COLLAGENASE 3 GENE EXPRESSION BY CYTOKINES Principal Investigator & Institution: Rahman, Mahboob U. Instructor of Medinice; Massachusetts General Hospital 55 Fruit St Boston, MA 02114 Timing: Fiscal Year 2001; Project Start 14-APR-1998; Project End 31-DEC-2002 Summary: The overall goal of this proposal is to study the cytokine-mediated regulation of collagenase-3 gene expression in order to better understand the mechanisms involved in the degradation of articular cartilage in rheumatic diseases such as rheumatoid arthritis (RA) and osteoarthritis ( OA). OA is the most common form of joint disease and is second only to cardiovascular disease as a cause of early retirement and disability. The destruction of hyaline articular cartilage is the hallmark of OA and disabling RA. Although various therapeutic regiment can cause symptom relief, no regiment has been proven to retard progression of articular cartilage degradation. In disease there is either a suppression of normal chondrocyte functions or in the constitutive inability of these


cells to match the rate of repair with the increased rate of degradation of the matrix. Various cytokines and inflammatory mediators have been shown to either derange the synthetic functions of the chondrocytes of increase cartilage matrix catabolism by regulating various matrix-degrading enzymes, including the collagenases. Collagenase3 is specifically expressed in skeletal cells including chondrocytes and has been shown to have an additional cleavage site when compared to other collagenases. It has aggrecanase and gelatinase activity as well. It's expression is response to IL-1 and other inflammatory cytokines. Thus it may play a significant role in physiological skeletal remodeling and destruction of cartilage in disease. The collagenase-3 gene has been recently cloned, but the role of various cytokines in the transcriptional regulation of this gene is yet to be elucidated. We have cloned the collagenase-3 promoter from a human genomic DNA library. We will prepare reporter gene constructs (CAT) containing collagenase-3 promoter and transfect immortalized human cell lines and analyze the effects of selected cytokines/ligands e.g. IL- 1beta, TNF-alpha and TGF1-beta. The ciselements and trans-acting factors will also be characterized employing transfection and DNA-binding assays. We will also develop transgenic mice containing the collagenase promoter- beta-galactosidase fusion gene to analyze the expression and role of collagenase in development of arthritis in vivo. Transgenic mice will be treated with IL1ra, TNFR1-IgG1 fusion protein, and dexamethasone after induction of arthritis and the role of cytokines/ligands in the control of expression of collagenase and its role in development of arthritis will be elucidated. This proposal will provide insight into the mechanisms involved in the expression of collagenase-3 by cytokines and thereby may provide targets for developing novel therapeutic measures to inhibit cartilage destruction in joint disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF COLLAGENASE GENE EXPRESSION Principal Investigator & Institution: Brinckerhoff, Constance E. Professor; Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, NH 03755 Timing: Fiscal Year 2001; Project Start 01-MAR-1980; Project End 31-MAY-2004 Summary: (adapted from applicant's abstract) The overall goal of these studies is to understand the role of matrix metalloproteinases (MMPs) in the severe and irreversible degradation of cartilage, bone and tendon that accompanies rheumatoid arthritis. The application proposes to continue examining molecular mechanisms controlling expression of the MMP-1 (collagenase-1) as well as MMP-13 (collagenase-3). Previous and preliminary studies have characterized the regulation of MMP-1 and MMP-13 by IL-1 and TNF-alpha in rabbit synovial fibroblasts and human chondrosarcoma cells. These studies and recent cloning of the rabbit MMP-13 gene in the applicant's laboratory indicate that the rabbit is an appropriate model for assessing the relative contributions of MMP-1 and MMP-13 in the invasion/degradation of collagen in RA. Preliminary studies also identified a single nucleotide polymorphism (SNP) within the human MMP-1 promoter, which creates a new PEA3 site that binds Ets transcription factors and enhances transcription of MMP-1 in human fibroblasts. These results suggest that RA patients with this allele may display heightened MMP-1 expression and particularly erosive synovitis. Thus, the specific aims are to (1) recapitulate the pathogenesis of RA in a rabbit model of polycation-induced arthritis and correlate the temporal expression of MMP-1 and MMP-13 gene with the erosive/invasive ability of synovial tissue through a matrix of type II collagen; (2) examine the mechanisms regulating expression of the endogenous MMP-13 gene in chondrocytes and fibroblasts treated with TNF and IL-1 and understand its regulation at the molecular level; and (3) determine the

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frequency and functional significance in patients with RA of a SNP in the human MMP1 promoter that augments transcription. These studies are expected to increase our molecular understanding of the relative roles of the two interstitial collagenases that are central mediators of the connective tissue destruction accompanying RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF INFLAMMATORY GENES IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Dong, Chen; Immunology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 26-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that affects a large human population. CD4+ helper T (Th) cells play a major role in RA, by mediating autoantibody production and inflammatory reactions in the joint tissue. In the autoimmune reaction, auto-reactive Th cells differentiate into Thl cells that make IFNgamma and TNFalpha and regulate cellular immunity. However, animals deficient in IFNgamma or its receptors exhibited greater susceptibility to CIA, suggesting that other Thl cytokine may be more important in autoimmune function. Th activation and function are regulated by co-stimulatory molecules. ICOS is a novel co-stimulatory receptor expressed by activated T cells. ICOS ligand, B7H is constitutively expressed on B-cells and induced in non-lymphoid tissues and cells as a result of inflammatory reactions. Although ICOS has been shown by us and others to be important for Th2 differentiation, we recently found ICOS-/- mice onDBA/1 background to be completely resistant to CIA. This resistance is associated with a selective deficiency of IL-17, a cytokine widely implicated in RA. We further found IL-17 is selectively expressed by Thl cells differentiated in vitro in an ICOSdependent manner. However, the molecular mechanisms by which IL-17 is regulated in Th differentiation and how it exerts its function in RA have been poorly defined. Therefore, we propose to utilize the gene-expression profiling tools to study these mechanisms. First, we will characterize the gene expression in IL-17+ mouse Thl cells. We will assess if IL-17 is expressed by a distinct subset of Thl cells that initiate the arthritis. Secondly, we will compare gene expression profiles of ICOS+/+ and ICOS-/Thl cells to identify factors regulating IL-17 expression. Thirdly, we will examine the role of IL-17 on inflammatory responses of the joint tissue. We will examine gene expression changes in the synovial fibroblasts and macrophages after exposure to IL-17 in vitro and in vivo. Furthermore, we will extend the results we yield in our animal studies to the human patient samples. This study will greatly advance our knowledge on the specific regulation and function of IL-17 in RA, and will likely generate novel diagnostic markers and therapeutic targets for this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF INFLAMMATORY RESPONSES Principal Investigator & Institution: Reimold, Andreas M. Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, TX 753909105 Timing: Fiscal Year 2001; Project Start 20-JUL-1998; Project End 30-JUN-2003 Summary: (Adapted from Investigator's abstract): Autoimmune and inflammatory conditions such as rheumatoid arthritis are characterized by cellular infiltrates and the cytokines they secrete. The stimuli controlling cellular activation are received at the surface of inflammatory cells by receptors, transmitted by a signal transduction cascade


to selected transcription factors, and result in modulation of gene transcription. The transcription factors that control the inflammatory response are therefore attractive candidates for therapeutic intervention in rheumatic diseases. The role of the transcription factor hXBP-1 (human X-box binding protein- 1) in inflammation has recently begun to emerge. hXBP-1 is strongly expressed in rheumatoid synovium, and in vitro studies suggest that hXBP-1 is involved in the control of MHC class II expression and in the B-lymphocyte differentiation pathway. However, the mechanism of action for hXBP-1 in these processes remains unknown. In order to gain a better understanding of the functions of hXBP-1, they have used gene targeting to generate mice deficient in hXBP-1 and have found an embryonic lethal phenotype. Therefore, they have additionally produced hXBP-1-deficient embryonic stem cells in order to generate hXBP1-deficient/RAG-2-deficient chimeric mice for study of B- and T-lymphocytes lacking hXBP-1. They will use hXBP-1-deficient cells and cell lines to establish if hXBP-1 is phosphorylated upon activation, and to define the proinflammatory stimuli and cellular stressors that act on hXBP-1. The preferred target genes for hXBP-1 will be identified by using a modified subtractive hybridization strategy. This knowledge will be applied to the HTLV-1-transgenic mouse model of rheumatoid arthritis to assess if a dominantnegative mutant of hXBP-1 reduces joint inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF INTEGRIN ALPHA 4 BETA 1 Principal Investigator & Institution: Ginsberg, Mark H. Professor; Scripps Research Institute 10550 N Torrey Pines Rd La Jolla, CA 920371000 Timing: Fiscal Year 2001; Project Start 01-AUG-1980; Project End 31-JAN-2006 Summary: (Applicant's Description Verbatim): lntegrin alpha4beta1 plays a central role in the trafficking of mononuclear leukocytes and is a potential therapeutic target in chronic inflammatory diseases such as rheumatoid arthritis. Continued support is requested for an analysis of the signaling properties of this integrin. Alpha4beta1 promotes increased cell migration and less cell spreading, stress fiber, and focal adhesion formation than other beta1 integrins. The applicant discovered that the alpha4 cytoplasmic domain binds tightly to the signaling adapter, paxillin. Furthermore, absence of paxillin or a mutation in the a4 tail that disrupts its binding reverses these biological effects. Consequently, the applicant proposes the hypothesis that the paxillinalpha4 interaction is responsible for the unusual biological responses to alpha4 integrins. To test this, he will map the paxillin-binding site in the alpha4 tail and define mutations that disrupt the interaction. He will introduce these mutations into intact integrins, and examine their effects on cell migration, cell shape, and organization of the cytoskeleton. Conversely, he will use the mapping information to engineer the paxillin binding sites in other integrin a cytoplasmic domains. He will determine whether gain of paxillin binding causes changes in cell shape and cell migration. Furthermore, he aims to assess the consequences of the alpha4-paxillin interaction for downstream signaling events such as activation of Jun Kinase and Focal Adhesion Kinase. To further assess the biologic significance of the alpha4-paxillin interaction, the applicant proposes to generate and characterize mice bearing mutations in the a4 tail that disrupts paxillin binding. He aims to analyze alpha4 integrin-dependent functions in mononuclear cells derived from such mice. As another test of the hypothesis, the applicant proposes to identify alpha4 cytoplasmic domain-binding sites in paxillin and assesses the effects of mutation of these sites on alpha4 specific responses. He proposes to analyze potential downstream "effectors" of paxillin by mutating their binding sites in paxillin and assessing the effects of the mutations on alpha4-specific signaling. Finally, the applicant

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has discovered that alpha4beta1 like other integrins, undergoes active affinity modulation. He hypothesizes that the affinity changes in alpha4beta2 are important in its biological functions. To test this hypothesis he will derive cell lines that manifest defective alpha4 integrin activation or discover subtle mutations in alpha4 that disrupt the activation process. The effect of these mutations on alpha4-dependent adhesive and migratory functions will be assessed. These studies will provide important fundamental insights into the functioning of integrin alpha4beta1 and may identify novel therapeutic targets for chronic inflammatory diseases such as rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF THE MAP KINASE PATHWAY IN THE CD4+ T CELLS Principal Investigator & Institution: Lu, Binfeng; Immunology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Previous studies have demonstrated that the p38 and JNK MAP kinase pathways are prominently activated by TCR stimulation in Th1 cells but not in Th2 cells. These data suggest that the p38/JNK MAP kinase pathways are regulated in helper T cells depending on the cell context. Preliminary data show that GADD45gamma and GADD45beta are highly expressed in Thl cells versus Th2 cells. Since GADD45 family proteins were shown to activate both JNK and p38 when overexpressed in COS-7 cells, they hypothesize that these molecules are responsible for the elevated p38 and JNK activities in Th1 cells and likely critical for the function of Th1 cells. Consistent with the hypothesis, in Th1 cells, deletion of GADD45gamma significantly elevated the threshold of TCR stimulated activation of p38 and JNKs. In addition, GADD45gamma also mediates Th1 functions such as IFN-gamma production and delayed type hypersensitivity. In addition to their roles in the function of Th1 cells, they discovered that GADD45beta is induced by TNF-alpha in synoviocytes. Therefore, they hypothesize that GADD45 family molecules may regulate the activation of the p38/JNK MAP kinase pathways in synoviocytes by inflammatory cytokines. Since the p38/JNK MAP kinase pathways are involved in the pathogenesis of rheumatoid arthritis, they hypothesize that GADD45 family proteins are involved in the development of such disease. To further study the role of GADD45 pathway in mediating the activation of p38/JNK MAP kinases and its relevance to rheumatoid arthritis, they propose to: Aim 1. Study the role of GADD45 pathway in mediating TCR stimulation using genetic and bioinformatic approaches. Aim 2. Study the role of GADD45 protein in mediating the activation of the p38/JNK MAP kinase pathway by cytokines. Aim 3. Study the effect of mutation of GADD45gamma, GADD45beta, or MEKK4 in murine collagen induced arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATORY MECHANISMS OF INFLAMMATORY OSTEOLYSIS Principal Investigator & Institution: Abu-Amer, Yousef; Associate Professor; Orthopaedic Surgery; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Inflammatory osteolysis, as in rheumatoid arthritis (RA), reflects increased osteoclast (OC) activity. OC recruitment is mediated via RANKL interaction with its receptor, RANK. We and others have established that TNF plays a


key role in the pathogenesis of inflammatory osteolysis and other forms of inflammation-induced bone loss Central to this proposal are our observations that RANKL and TNF both activate NF-kB and AP-1/cJun signaling pathways, and TNF dramatically stimulates RANKL-induced osteoclastogenesis via. TNFr1. Reduced osteoclastogenesis correlates with diminished NF-kB and c-Jun activation by TNF and RANKL in TNFr1-/- cells. These facts, together with our findings that RANKL and TNF stimulate recruitment of TRAF2 and TRAF6 to their receptors, points to a possible intracellular coupling between these two receptors which, in turn, leads to a super osteoclastic response. Supporting this hypothesis is the fact that RANK utilizes the traditional TNFr-recruiting machinery to activate NF-kB and c-Jun signaling pathways. Taken together, our data point that enhanced osteoclastogenesis (as in inflammatory osteolysis) requires the presence of TNFR1. Therefore, understanding the exact mechanisms by which TNF promotes RANKL-dependent osteoclastogenesis and thus, inflammatory osteopenia, may provide a foundation for developing osteoclast inhibitory strategies. Molecular inhibition of osteoclastogenesis by anti-inflammatory cytokines is under-investigated. IL-4, the major soluble factor secreted by T helper-2 (TH2) lymphocytes, is an anti-inflammatory cytokine and a potent inhibitor of osteoclast differentiation. However, its anti-osteoclastic mechanism is unknown. We provide evidence that IL-4 blocks RANKL-induced NF-kB activation in osteoclast precursors. More importantly, using STAT6-/- cells we find that inhibition of NF-kB activation and osteoclastogenesis by IL-4 is a STAT6-dependent event. Given the inflammatory and osteoclastogenic role of NF-kB and that STAT proteins can act as transcriptional inhibitors, our observations raise the possibility that IL-4 exerts its anti-osteoclastogenic effects via inhibition of RANKL activation of NF-kB and perhaps AP-1 signaling pathways. Understanding the molecular steps of IL-4/STAT6-inhibition of osteoclastogenesis may provide the foundation for controlling inflammatory osteolysis. Our Specific Aims are to determine: 1) the mechanism(s) by which the TNFr1 signaling pathway stimulates RANKL-mediated osteoclastogenesis, 2) the mechanism(s) by which IL-4 inhibits RANKL-mediated osteoclastogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RELAXATION RESPONSE,SOMATIC STYLE & RHEUMATOID ARTHRITIS Principal Investigator & Institution: Barsky, Arthur J. Professor; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 30-JUN-2006 Summary: This is a three-armed randomized, controlled intervention trial to determine the effect of relaxation response training (RR) and of relaxation training combined with cognitive/behavioral therapy (RRCBT) on the symptoms, functional ability, role impairment, and medical care utilization of patients with rheumatoid arthritis (RA). We will also examine the role of selected attitudes and beliefs expected to moderate the treatment response and predict outcome. These same attitudes and beliefs are also hypothesized to predict the incidence of medication side-effects and to be associated with the inter- individual variability in RA symptoms seen among patients with RA of comparable severity and extent. Three-hundred and seventy- five RA patients will undergo a baseline assessment of the independent variables (including hypochondriacal health anxiety, bodily amplification, normative beliefs about health, and alexithymia) and covariates (including RA severity, life stress, social support, and psychological distress). They will then be randomly assigned to RR, RRCBT, or an attention control group. The outcome variables (RA symptoms, functional ability, role impairment, and

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medical care utilization) will be measured immediately after treatment, and 6 and 12 (the primary outcome) months later. The effect of treatment will be determined by comparing each intervention group to the control group, and by within-subject comparisons before and after treatment. Additional group analyses will be conducted to determine the influence of cognitive and attitudinal variables on outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RHEUMATOID ARTHRITIS: PREDICTORS OF THERAPEUTIC RESPONSE Principal Investigator & Institution: O'dell, James R. Professor and Chief of Rheumatology; Internal Medicine; University of Nebraska Medical Center Omaha, NE 681987835 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: (investigator's abstract): Rheumatoid arthritis (RA) is a common, chronic disease that causes substantial morbidity and mortality while utilizing a large portion of health care resources. While recent therapeutic approaches have provided significant improvement in patients' functional status and well being, the selection of specific therapy remains empiric and highly variable. The ability to use surrogate markers to predict which patient is likely to respond to certain anti-rheumatic therapy would offer major advantages in the management of this chronic and progressive disease. Recent evidence has suggested a clear role for proinflammatory cytokines, membrane metalloproteinases, and genetic factors in influencing the severity and progressive nature of the disease. Thus, it is reasonable to suggest that the status of these factors may allow the characterization of patients into 'responder' versus 'non-responder' groups. The intent of this proposal is to utilize material from carefully controlled clinical trials where patient groups have been identified as either responding or not responding to specific therapies. This material will be evaluated for various cytokine, MMP, and genetic factors that may predict response to therapy. The hypothesis is that determining specific patient cytokine profiles, membrane metalloproteinase levels, and/or genetic phenotypes may predict the 'responder/non-responder' status of patients with specific therapy intervention. This hypothesis will be tested by three specific aims which are: Specific Aim #1 - correlate the response of patients with RA to specific therapies with changes in cytokine, matrix metalloproteinases and/or acute phase protein levels. Specific Aim #2 - correlate the response of patients with RA to specific therapies with HLA-DRB1 subtyping and non-MHC gene polymorphism. Specific Aim #3 - develop strategies for initiating prospective clinical trails using predictive cytokine, matrix metalloproteinase, and genetic factors. The unique strength of this proposal is the patient serum and DNA sample bank that is available from several controlled, randomized, blinded, clinical protocols that clearly define patients as responder or nonresponder. Retrospective analysis of this information can be utilized to plan prospective clinical trials using potentially predictive patterns of cytokine, matrix metalloproteinases, and genetic factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRATEGIES

RHEUMATOID

ARTHRITIS--ADHERENCE

INTERVENTION

Principal Investigator & Institution: Dunbar-Jacob, Jacqueline M. Professor; Health and Community Systems; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260


Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 28-FEB-2003 Summary: Nonadherence to prescribed medication is a major problem in the management of chronic disease. Estimates are that about 40 percent to 60 percent of patients adhere with the costs of nonadherence approaching 10 billion dollars per year. Yet very few randomized, controlled intervention trials have been conducted to guide efforts to improve adherence. The disease represented in the limited number of intervention studies include asthma, hypertension, epilepsy, schizophrenia and acute infection. No studies, other than our own, have been done with patients with rheumatoid arthritis (RA). The adherence rates for persons with RA are equivalent to those found for other chronic disorders. Adherence is particularly important for this population, as pharmacological treatment is directed toward the suppression of inflammation and resulting synovitis and the prevention of disability. In a recently completed study, we conducted a randomized, controlled intervention study of a behaviorally based, 12- session, telephone counseling intervention on adherence. We found differences in adherence between an intervention and usual care group of 12.3 percentage points (z=minus 1.91, p is less than or equal to.03) with changes in adherence associated with changes in pain (rs=minus.29, p is less than or equal to.01). Although promising, differences in adherence at six month follow-up were not statistically significant (p is less than or equal to.07). In this project we propose to replicate our intervention study using telephone counseling as well as to examine a less costly method of intervention delivery, mailed self-instruction, and further to examine the efficacy of an ongoing maintenance strategy on adherence, clinical outcomes, and costeffectiveness. Specifically our aims are to (1) compare the effect of telephone delivered intervention, mailed self-instruction, and usual care on adherence to pharmacological therapy, clinical outcomes, and cost-effectiveness as well as to (2) compare the effect of an adherence intervention plus maintenance intervention with adherence followed by observation only and usual care on adherence to pharmacological therapy, clinical outcome, and cost-effectiveness. We propose to recruit from two practice sites and randomize 198 persons with rheumatoid arthritis who report some difficultly with the medication regimen. Using a randomized, controlled design, patients would be randomized into telephone intervention, mailed self-instructional intervention, or usual care for a six month intervention period. Following the intervention phase, the two intervention groups would be randomized within groups to maintenance intervention or observation only for an additional six months. The usual care group would continue to be followed to generate natural history data for comparison purposes. Should one or more of the strategies prove successful, intervention manuals would be disseminated for use by nurses working in clinical settings with this population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RO45-2081 FOR PATIENTS WITH RHEUMATOID ARTHRITIS Principal Investigator & Institution: Polisson, Richard P.; Massachusetts General Hospital 55 Fruit St Boston, MA 02114 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF CD30: CD153-PATHOGENESIS OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Cerutti, Andrea; Pathology and Laboratory Medicine; Weill Medical College of Cornell Univ New York, NY 10021 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-JUL-2004 Summary: (provided by investigator): Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of synovial membranes and progressive joint destruction. In RA, B cells produce large amounts of IgM as well as class switched IgG and IgA that, by accumulating in the joints as highly reactive immunocomplexes, play a central role in the pathogenesis of synovitis. The mechanisms underlying the dysregulation of Ig class switching and antibody production in RA patients remain elusive. Human B cells initiate class switch DNA recombination (CSR) and antibody production upon engagement of CD4O by CD154 (CD4O ligand), a molecule expressed by T cells a few hours after activation by antigen. Later on, T cells express CD3O, a TNF receptor family member that negatively modulates both T and B cell immune responses. Engagement of T cell CD30 by B cell CD153 (CD30 ligand) inhibits CD40-mediated CSR and antibody production in two ways: by interfering with the CD40 signaling pathway and by hampering the CD3-mediated up-regulation of CD154. Dendritic cells reverse the CSR-inhibitory activity of CD3O+ suppressor T cells by inducing metalloprotease (MP)-dependent down-regulation of CD30. The long-term objective of this project is to assess the role of CD30:CD153 interaction in the pathogenesis of RA. We hypothesize that, in RA patients, the increased production of pathogenic antibodies stems from the profound dysregulation of the CD30:CD153-dependent inhibitory pathway. This may result from the ability of DC-like RA synoviocytes to impair the synovial pool of CD30 suppressor T cells by eliciting rapid MP-dependent cleavage of CD30. The relevance of this phenomenon in the pathogenesis of RA is supported by the observation that RA patients display increased levels of synovial soluble CD3O that positively correlate with the levels of circulating rheumatoid factor as well as with the disease activity. The following specific aims will address the role of CD30:CD153 interaction in the pathogenesis of RA. Aim 1. Analyze the expression, requirements and function of CD30 in RA T cells, and evaluate the mechanisms by which CD30 signaling down-regulates CD154. Aim 2. Analyze the ability of CD30:CD153 interaction to inhibit Ig class switching in CD154-activated B cells, and evaluate its possible dysregulation in RA. Aim 3. Analyze the ability of CD30:CD153 interaction to inhibit the CD154-mediated activation of RA synoviocytes, and evaluate the ability of synoviocytes to reverse the inhibitory activity of CD30+ T cells. In addition to elucidating the pathogenesis of RA, the experiments outlined in this application should allow to devise new strategies aimed at reducing the production of pathogenic antibodies, including rheumatoid factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF CYTOKINES IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Tsark, Eleanor C.; City of Hope National Medical Center Duarte, CA 91010 Timing: Fiscal Year 2001; Project Start 01-SEP-2001 Summary: Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of T cells and antigen presenting cells (APC) from the blood into the synovial joint. Activation of both cell types results in destruction of tissue within the joint. This tissue destruction leads to an abundance of self proteins available for uptake by phagocytic APC. Presentation of self peptide:MHC complexes by APC is believed to


lead to activation and expansion of autoreactive T cells. The most convincing evidence implicating a role for antigen presentation in RA is the observation that inheritance of certain subtypes of the HLA-DR4 allele predisposes people to developing RA. The nature of the self peptides being presented by these DR4 subtypes is currently not known, but studies performed in animal models have provided some candidate autoantigens. The following studies are proposed: Aim 1: Determine the array of epitopes derived from candidate autoantigens expressed by normal peripheral blood APC and determine how cytokines modulate presentation of these epitopes; Aim 2: Determine the array of epitopes derived from candidate autoantigens expressed by APC obtained from RA patients and determine how cytokines modulate presentation of these epitopes; Aim 3: Determine if mature dendritic cells obtained from rheumatoid synovia display enhanced ability to process and present soluble autoantigens due to the presence of inflammatory cytokines. T cell hybridomas which recognize peptides derived from human type II collagen HCgp39 and calreticulin in the context of DR4 have been generated by immunizing human DR4 transgenic mice with these candidate autoantigens. These T cell hybridomas can then be used to study presentation of these epitopes by APC from human DR4 donors with and without rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF DPP1 AND GRANZYMES IN INFLAMMATORY ARTHRITIS Principal Investigator & Institution: Pham, Christine Tn.; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects about 1 percent of the general population worldwide. The disease is characterized by inflammation of the synovial joints leading to destruction of cartilage and bone. The initiating events and the mechanisms that perpetuate the inflammation remain obscure. Although the role of CD4+ T cells has been established, the function of cytotoxic lymphocytes in this disease has not been entirely elucidated. Some studies suggest that cytotoxic lymphocytes may decrease the incidence or suppress inflammation in murine models of arthritis. Cytotoxic lymphocytes exert their effects mainly through target cell apoptosis. One of the major mechanisms utilized by these cells to kill their targets is the granule exocytosis pathway. Activated lymphocytes contain a family of highly related serine proteases termed granzymes. Recent evidence suggests that granzymes are required for cell-mediated cytotoxicity. We recently created a mouse with a null mutation in the cysteine protease dipeptidyl peptidase I (DPPI) and showed that this enzyme is required for the activation of granzymes A and B in vivo. Furthermore, we showed that DPPI-deficient cytotoxic lymphocytes have a severe defect in their ability to induce DNA fragmentation and apoptosis from different target cells. The objective of this proposal is to evaluate the role of DPPI/granzymes in models of murine arthritis. We hypothesize that cytotoxic lymphocytes, through the action of granzymes, may have a -protective role in murine inflammatory arthritis. To explore this hypothesis, we propose the following aims: 1. We will explore the role of DPPI and granzymes in models of murine arthritis. Since there is no single animal model that recapitulate all the features of RA, we will study 3 distinct murine arthritis models that differ in the degree and type of cartilage damage [zymosaninduced arthritis (ZIA), antigen-induced arthritis (AIA), and collagen-induced arthritis (CIA)]. 2. We will explore the role of CD8+ I cells and granzymes in CIA We hypothesize that CD8+ T cells may exert a protective role in CIA, through the actions of

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granzymes. In this aim, we propose to generate chimeric animals using severe combined immunodeficient (SCID) mice. Spleen cells from arthritic mice will be depleted of CD4+ or CD8+ T cells prior to transfer into SCID mice to elucidate the specific role of T lymphocyte subsets (and granzymes) in the induction and progression of arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF FATIGUE IN RHEUMATIC DISEASES Principal Investigator & Institution: Lange, Gudrun; Associate Professor; Psychiatry; Univ of Med/Dent Nj Newark Newark, NJ 07103 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 29-SEP-2004 Summary: (provided by applicant): Fatigue is a common complaint in rheumatic disorders and is one of the strongest predictors of physical dysfunction in patients with Fibromyalgia (FM) and other related disorders, rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). However, research addressing the causes and mechanisms of fatigue is rare in rheumatic illnesses. The lack of scientific evidence focusing on the role of fatigue in rheumatic illness directly impacts on the ability of health care professionals to assess the presence, severity and trajectory of fatigue and to evaluate the relationship of fatigue with other symptoms of these disorders in order to provide appropriate treatment recommendations. Fatigue is one of the most commonly reported, yet least understood and unrelieved symptoms accompanying chronic illnesses. The primary objective of the proposed workshop is to establish a knowledge base of current information on fatigue in rheumatic illness that will be compared with the state of knowledge gained from studies of fatigue in cancer, HIV/AIDS, stroke, and MS. This process will serve to identify knowledge gaps concerning the role of fatigue in rheumatic illness. Directions for future fatigue research in rheumatic illness will be suggested incorporating research methodologies that have proven successful in other somatic disorders. To achieve these objectives, a group of renowned fatigue and sleep researchers drawn from a variety of scientific areas including neuroscience, physiology, immunology, and psychiatry/psychology, clinical practice, as well as representatives of public interest groups will be invited to attend a workshop to be held on March 18 and 19, 2004 at the Dolce Hamilton Park Conference Center in Florham Park, NJ. Presentations addressing definition, conceptualization, and assessment of fatigue in general will proceed state-of-the-art overviews of fatigue research in FM, RA, OA, SLE, cancer, HIV/AIDS, stroke, and MS, and will be followed by concentrated discussions in break-out groups. A position statement summarizing the results from this workshop will be produced at the conclusion of the meeting and disseminated via publication in a peer-reviewed journal. The collaborative and interactive nature of the proposed workshop will ensure that the recommendations generated will have a broad impact on the scientific community, and will generate collaborative, interactive research amongst scientists and clinicians with an interest in rheumatic illnesses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ROLE OF SUPERANTIGENS IN TREATMENT OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Cannon, Grant W.; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2001


Summary: This project has now been completed. Twenty-three patients were enrolled at the University of Utah, with a total of 240 patients participating at twelve other sites across the nation. Although part of a multicenter trial, a specific hypothesis was tested by investigators at the University of Utah. Dr. Cannon doubted that immune complex absorption represented the mechanism by which protein A absorption exerted its therapeutic effect. An alternate hypothesis was proposed, stating that patients treated with protein A-perfused plasma developed immune responses to staphylococcal proteins leached from the column, which then altered immune responses to rheumatoid arthritis. The putative staphylococcal proteins were predicted to function as super antigens. Testing of the counter hypothesis was deemed an appropriate indication to make this a category A study by the GCRC Advisory Committee. The study has now been completed, and a preliminary analysis supports the hypothesis. A publication will be prepared describing the findings within the next year. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF UBIQUITIN REGULATED F-BX07 PROTEIN IN RA Principal Investigator & Institution: Zhang, Huang-Ge G. Medicine; University of Alabama at Birmingham Uab Station Birmingham, AL 35294 Timing: Fiscal Year 2002; Project Start 23-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): The overall goal of this proposal is to determine the biological effects of a novel F-box-containing protein (F-bx07) that we identified recently, with an emphasis on its role in the regulation of proliferation of rheumatoid synovial fibrobiasts (RASF). This goal will be achieved through three specific aims, centered on three objectives. The first objective is to determine if F-bx07 protein regulates the cell cycle of synovial fibroblasts. The second objective is to identify the protein(s) that F-bx07 targets leading to the attenuation of proliferation of RASF. The third objective is to determine if expression of F-bx07 protein is essential for prevention of the development of arthritis in vivo. The first objective is strongly supported by our initial observations that hyperproliferating RASFs lack of expression of F-bx07 mRNA, and transfection with AAVCMVF-bx07 attenuates RASFs proliferation. We will determine if inhibition of RASF proliferation of F-bx07 protein is controlled through regulation of the cell cycle. Cell cycle kinetics will be analyzed by flow cytometry analysis of cells stained with propidium iodide to determine the cell cycle stage controlled by F-bx07.1n the second aim, we will identify the molecules targeted by Fbx07 that directly and/or indirectly regulate cell cycle. Our preliminary data indicate that F-bx07 causes degradation of phosphorylated AKT and other investigators have shown that AKT participates in cell cycle regulation by controlling cell cycle kinase activity. To determine if additional cell cycle regulated proteins, especially those associated with the ubiquitin pathway are potential targets for F-bx07 degradation, the RASFs will be transfected with AAVCMVF-bx07 in the presence or absence of proteasome inhibitors and co-immunoprecipitated. Novel proteins will be identified by mass spectrometer analysis. Finally, we will validate our findings in vivo. Brdu labeling to track RASF proliferation in rheumatoid synovium organ culture, and immunohistostaining of F-bx07 and cell cycle regulated proteins including AKT will determine the biological roles of F-bx07 in vivo. Antiproliferative effects of F-bx07 protein on of RASF will be demonstrated by gene therapy in an RASF implanted SClD mouse model. The findings will have practical applications in the potential treatment of human arthritis. At a more basic level, these experiments will test the hypothesis that F-bx07 regulates synovial fibroblast proliferation and that loss of F-bx07 protein activity

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triggers synovial fibroblast hyperproliferation in RA. This will lead to a better understanding of the mechanisms underlying hyperproliferation of RASFs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SC-58635 COMPARED TO DICLOFENAC IN OSTEOARTHRITIS OR RHEUMATOID ARTHRITIS Principal Investigator & Institution: Friedman, Alan W.; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SCOR ON THE PATHOGENESIS OF RHEUMATOID ARTHRITIS Principal Investigator & Institution: Kang, Andrew H. Professor; Medicine; University of Tennessee Health Sci Ctr Health Science Center Memphis, TN 38163 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-JUL-2006 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SELECTIVE DISRUPTION OF TNFA SIGNALING IN MURINE CIA Principal Investigator & Institution: Scheinman, Robert I. Pharmaceutical Sciences; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, CO 800450508 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-JUL-2003 Summary: (provided by applicant): The inflammatory cytokine, TNF alpha, has been shown to play an important role in rheumatoid arthritis (RA) through the study of murine collagen induced arthritis (CIA). These results have propelled several TNF alpha blocking drugs into clinical use. These drugs are not universally effective and can have serious side effects. Importantly, the role of TNF alpha in RA is not fully understood. Blockade of TNF alpha signaling, both in CIA and in RA, does not stop the disease but rather slows disease progression. In the CIA model, signaling through the p55 TNF receptor (TNFRI) has been shown to mediate some TNF alpha effects however signal transduction through TNFRII has not yet been investigated. In addition, TNFRI signaling is complex. Through interactions with the adapter protein TRADD, TNFRI can activate both FADD and caspase mediated apoptosis as well as TRAF2 and RIP, leading to activation of JNK and proliferation as well as NF-KB mediated antiapoptotic and proinflammatory responses. Through interactions with the adapter protein FAN, TNFRI can activate neutral sphingomyelinase and the production of ceramide, which in turn activates a variety of signaling events. The relative importance of these signal transduction cascades for arthritis is currently unknown. TNFRI and TNFRII are present on multiple cell types. Thus it is likely that different cell types may favor different signaling pathways when activated by TNF alpha. We propose to identify specific subsets of tissues in which TNF alpha signaling contributes to the development of arthritis in the CIA system. Our strategy is to use bone marrow (BM) transplant technology to place TNFRI-'- BM into irradiated TNFR+/+ recipients or conversely, TNFRI+/+ BM into TNFRI -/- recipients. Similar experiments will be performed with TNFRII mice. By this means we can distinguish between the contribution of hematopoietic TNF alpha signaling versus non-hematopoietic TNF alpha signaling to


CIA as well as the relative importance of TNFRI and TNFRII signaling in this process. We will then begin to dissect the signal transduction cascades mediated by TNF alpha activation of TNFRI by introducing dominant negative adapter proteins using either retroviral mediated gene transfer into hematopoietic BM stem cells or by creating transgenic mice delivering the dominant negative proteins to the synovium. In summary, these experiments will increase our understanding of how TNF alpha signaling in different cell types contributes to CIA. By extension, these data will help us understand more fully the mechanisms of action of TNF alpha blocking drugs and potentially will identify new targets for future arthritis therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SELF MANAGEMENT, EDUCATION AND OUTCOMES IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Callahan, Leigh F. Associate Professor; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001 Summary: Low levels of formal education are associated with increased prevalence, morbidity and mortality of most common chronic diseases. Several studies suggest that formal education level may be a surrogate for behavioral/psychosocial variables, which are also independently correlated with health status and outcomes. While circumstances associated with lower levels of formal education and poor SES cannot be altered through medical intervention, certain behavioral variables may be amenable to improvement, at least in part. The set of behaviors an individual uses to cope with a chronic condition is known as self-management. Individuals with a chronic disease negotiate the specific practices in their self-management strategies based on their needs and resources. Formal education level may be a marker for the capacity of individuals with a chronic disease to develop optimal self-management strategies. The objective of this study to examine self-management strategies of individuals with rheumatoid arthritis (RA) in the context of measures of disease activity, perceived control, and formal education level vis a vis health outcomes. The objective will be approached through the following specific aims: 1) to characterize self-management in individuals with RA; 2) to examine associations between self-management and formal education level in individuals with RA; 2) to examine associations between self management and formal education level in individuals with RA; 3) to determine whether the domains and frequency of use of self-management strategies reported by individuals with RA vary over time with changes in measures of disease activity; and 4) to define the relative contribution of self-management strategies and formal education level to health care utilization and health-related quality of life over a three year period in individuals with RA. If associations between level of formal education and health status can be accounted for, at least in part, by psychological status and self- management strategies, health care providers might more effectively target patient education interventions to effect an improvement in health status. In addition, there is emerging evidence that helping patients manage not just their disease, but also common underlying needs, is cost effective. Therefore, clinicians, health care policy-makers, public health planners and voluntary health agencies could all benefit from a better understanding of possible mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SHARED EPITOPE AND RA SEVERITY: META-ANALYSIS Principal Investigator & Institution: Gorman, Jennifer D.; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 15-SEP-1977; Project End 31-DEC-2002 Summary: The shared epitope (SE) hypothesis was initially proposed to explain genetic susceptibility to rheumatoid arthritis (RA), but further study suggests that the primary role of the SE may be in the development of more severe manifestations of the disease. Despite numerous studies over the past decade, the true relationship of the SE and RA severity remains unclear. Difficulty in clarifying this relationship is likely due to differences in the populations studied: those of ethnicity, clinical factors and the particular SE allele inherited as well as the small number of patients in individual studies. In order to examine the association thoroughly, evaluation of a large, clinically and ethnically diverse population is required, and to date, no attempt has been made to initiate such a project. The goal of this proposal is to precisely define the role of the SE in severity of RA among patients with a broad range of ethnic and clinical characteristics. In order to accomplish this goal we have the following specific aim for this project: 1. To perform a meta-analysis of the association of the SE and severity of RA utilizing individual level data obtained from researchers worldwide. Because the relationship between genotype and RA severity appears to vary according to characteristics of the patients, such as ethnicity and gender, the importance of these covariates will be examined. The association will be analyzed in terms of three genetic models: presence or absence of the SE, SE dosage (0, 1, or 2 alleles), and by the specific SE genotype inherited. Severity of RA will be defined by the following outcome measures: seropositivity, presence of radiographic erosions, disease course, requirement for joint surgery, and presence of nodules or other extraarticular manifestations. This proposal of a meta-analysis with use of individual level data will allow us to more clearly define the precise relationship between the SE and RA severity and has the ability to provide genetic predictors of prognosis for RA patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SIGNALING RHEUMATIOID ARTHRITIS

PATHWAYS

CONTROLLING

NF-KB

IN

Principal Investigator & Institution: Makarov, Sergei S.; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Rheumatoid arthritis (RA) is a prototype of chronic inflammatory disease. Our preliminary studies in animal models of RA demonstrated crucial involvement of NF-kappaB in regulation of inflammation, apoptosis, and proliferation in the arthritic synovium. Thus, NF-kappaB emerges as very attractive target for therapeutic intervention in RA and other chronic inflammatory conditions. The most logical way to inhibit NF-kappaB activation is to modulate the signaling cascades which controls transcriptional activity of NF-kappaB. Two signaling cascades, the NIK/IKK and p38 MAP kinase pathways, are particularly important in regulation of NF-kappaB in RA. Our knowledge of the physiological function of these pathways is very limited, mainly due to inadequate experimental approaches. The major purpose of this proposal is to determine the physiological role of the NIK/IKK and p38 signaling pathways in activation of NF-kappaB in RA, and to assess the contribution of these pathways in major manifestations of RA, i.e. inflammation, tumor-like expansion of invasive synovium, and bone and cartilage resorption, and thus evaluate these pathways as


targets for therapeutic intervention. We will employ gene transfer technology for dissecting the role of the NIK/IKK and p38 MAPK for therapeutic intervention. We will employ gene transfer technology for dissecting the role of the NIK/IKK and p38 MAPK pathways in NF-kappaB activation in the RA pathology. Using intraarticular (i.a.) gene transfer of dominant negative (DN) inhibitors should allow for the clear-cut interpretation of the role of these pathways in RA and will validate these pathways as targets for drug discovery. In Aim 1, we will examine the role of the NIK/IKK and p38 pathways in NF-kappaB activation, inflammatory and mitogenic responses, and apoptosis on the cellular level in synovial fibroblasts and monocytic cells in vitro. Next, we will assess the role of the NIK/IKK and p38 pathways in vivo in NF-kappaB activation, inflammation, hyperplasia, and bone and cartilage resorption in SCW arthritis in rats (AIM 2). The relevance of these data to human disease will be examined by using a SCID mice/human models of RA (Aim 3). These experiments will determine the role of NF-kappaB, and the NIK/IKK and p38 pathways in regulation of inflammation, apoptosis, and cartilage destruction in human RA synovium. One unexpected result of our preliminary studies in animal arthritis was observation that local suppression of NF-kappaB in the synovium ameliorated disease not only in treated, but also in untreated, contralateral joints. This indicates the feasibility of alleviating systemic manifestations of the disease through local treatment. Aim 4 serves to explore two putative mechanisms underlying this effect. We will examine the influence of local suppression of NF-kappaB on the balance of pro- and antiinflammatory TH1 and Th2 subsets in circulating T cells, and in neurogenic mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP IN CHILDREN WITH JUVENILE RHEUMATOID ARTHRITIS Principal Investigator & Institution: Labyak, Susan E.; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Approximately 285,000 of America's children have been diagnosed with arthritis, and juvenile rheumatoid arthritis (JRA) is the most prevalent form. Children with JRA, regardless of disease severity, report poor sleep quality, excessive daytime sleepiness, anxiety, and altered mood. Adequate sleep is essential for health and normal growth and development in children. Insufficient sleep in healthy children has been associated with hyperactivity, decreased attention span, distractibility, impulsivity, excessive daytime sleepiness, poor neurobehavioral performance, decrements in school performance, and increased school absenteeism. Disturbed sleep in children with JRA is likely to have similar negative impact on the child's behavior, mood, school performance, ability to carry out daily physical and social activities, as well as disease symptom (pain, stiffness, fatigue) severity. Sleep quality may be an important predictor of symptom severity, school performance, and how well children with JRA adjust to living with this chronic illness. In our preliminary studies, we have begun to document the extent of disturbed sleep by self-report and behavioral and physiological indicators in a small sample of children with JRA. These data show for the first time that sleep is most disrupted during periods when inflammation and joint swelling are most acute, yet children complain of poor sleep quality and excessive daytime sleepiness even during periods of disease remission. The extent of disrupted sleep and its impact on daytime functioning has not been studied in children with JRA. The proposed study builds on our pilot studies findings and is unique in that it will use a within-subject, repeated-measures design to determine the extent of poor nighttime

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sleep and evaluate the impact of poor sleep on daytime sleepiness, neurobehavioral performance, academic performance, and emotional/affective indicators during both periods of arthritic flare and disease remission. The results of this study will provide key information about sleep quality and daytime functioning in children with JRA; thus setting directions for the development of clinical therapies to enhance sleep quality during periods of arthritic flare as well as disease remission as different treatment strategies likely will be required. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP REGULATION AND TUMOR NECROSIS FACTOR Principal Investigator & Institution: Krueger, James M. Professor of Neurobiology; Vet & Comp Anat/Pharm/Physiol; Washington State University 423 Neill Hall Pullman, WA 99164 Timing: Fiscal Year 2001; Project Start 01-AUG-1993; Project End 31-JUL-2005 Summary: (provided by applicant): Sleep is of central importance to neurobiology because to understand how the brain works, we will have to decipher the mechanisms and functions of sleep. The function(s) of sleep remain unknown and the humoral and neural mechanisms of sleep are incompletely understood. Most people intuitively recognize that sleep increases after sleep loss or during the course of an infection. There is much evidence that those sleep responses, as well as physiological sleep, are regulated, in part, by humoral mechanisms. We hypothesize that tumor necrosis factor alpha (TNF-alpha) is one of the key substances in sleep regulation. This hypothesis is based on studies showing: 1) TNF-alpha induces non-rapid eye movement sleep (NREMS); 2) inhibition of TNF-alpha inhibits spontaneous sleep and sleep responses induced by sleep loss or bacterial products; 3) TNF mRNA and TNF brain levels correlate with sleep propensity; 4) in humans, circulating TNF levels correlate with electroencephalogram slow-wave activity and increase after sleep loss or during several pathologies with associated fatigue, e.g., sleep apnea, rheumatoid arthritis, preeclampsia, multiple sclerosis. The proposed experiments seek to understand in mechanistic detail how TNF-alpha is involved in sleep regulation. We will determine whether blocking TNF-alpha or TNF-alpha production centrally attenuates systemic TNF-alpha-induced sleep responses; preliminary data show that vagotomy attenuates systemic TNF-alpha-induced NREMS (Specific Aim #1). We will investigate TNF-alpha regulation of NREMS within specific TNF-active sites in brain (Specific Aim #2). Preliminary data indicate that microinjection of TNF-alpha into the preoptic area enhances NREMS, whereas microinjection of an inhibitor of TNF-alpha reduces NREMS. Pharmacologic blockage of prostaglandins, adenosine, and interleukin-1, and sleep manipulation using sleep deprivation and acute mild increases in ambient temperature to enhance sleep, will be combined with microinjections of TNF-alpha or TNF-alpha inhibitors. We will also use gene arrays to determine the time course of sleep-sensitive changes in brain for TNF and TNF superfamily member mRNAs. Anticipated results will provide molecular-mechanistic advances to understand sleep regulation as well as aid our general understanding of cytokine regulation in the brain. We anticipate that results will be directly relevant to therapeutics, e.g., a TNF soluble receptor has already been shown to reduce fatigue associated with rheumatoid arthritis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRESS AND ADAPTATION TO RHEUMATOID ARTHRITIS Principal Investigator & Institution: Zautra, Alex J. Professor and Program Director; Psychology; Arizona State University P.O. Box 873503 Tempe, AZ 852873503


Timing: Fiscal Year 2001; Project Start 10-APR-1994; Project End 31-MAY-2005 Summary: Description (adapted from investigator's abstract): This research is designed to determine the extent to which variations in cognitive behavior therapy reduce disease activity and improve the mental health of older adults with rheumatoid arthritis (RA). The study combines field assessments, laboratory tests of stress reactivity and clinical evaluations of the mental and physical health of subjects in a longitudinal design. After pre-testing, 210 RA patients will be randomly selected in one of three treatments: Cognitive-Behavior Therapy for Pain (CBT-P), Cognitive-Behavior Therapy for Depression (CBT-D) or Education Group only (EG), which serves as a control. The distinction between pain and depression as foci of CBT in RA is supported by previously funded research by the investigator on interpersonal stress and disease activity in persons with arthritis. Illness severity, depressive symptoms and interpersonal difficulties are expected to predict psychological and physiologic stress responses in participants. Stress reactivity measures are expected to predict the course of illness over time. Those receiving CBT-D are expected to show the greatest improvement in physical functioning, mental health and disease activity. Successful treatment is expected to alter stress responses, leading to better physical and mental health over time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURAL BIOLOGY OF TYROSINE KINASE REGULATION Principal Investigator & Institution: Horita, David A. Biochemistry; Wake Forest University Health Sciences Winston-Salem, NC 27157 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The Src-family of nonreceptor kinases includes eight distinct proteins identified in humans. These proteins play wide-ranging roles in signal transduction in a variety of cell types, and are implicated in numerous diseases including cancer, HIV infection, rheumatoid arthritis, and Type I diabetes (DM1). Inhibition of Hck prevents onset of diabetes in animal models, suggesting this protein as a target for anti- DM1 drug development. The plethora of human tyrosine kinases makes design of high-specificity inhibitors difficult. The long term objective of this project is to develop a comprehensive, detailed understanding of the structural basis of Hck regulation which will be of use in the design of highly specific Hck inhibitors. Such drugs should have broad applicability in the treatment of rheumatoid arthritis and DM1. The specific aims of this pilot project are (1) to establish a bacterial expression system to produce Hck suitable for analysis by solution-state NMR spectroscopy and (2) to initiate NMR studies using these molecules. Specific aim 1 entails stable-isotope labeling of recombinant Hck and in vitro phosphorylation. Specific aim 2 entails assignment of 1H, 13C, and 15N resonance of Hck and collection and analysis of backbone 15N relaxation data. These studies will establish the feasibility of comprehensive analysis of tyrosine kinase structure and dynamics using NMR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURAL STUDIES OF IMMUNOPHILINS AND RELATED PROTEINS Principal Investigator & Institution: Clardy, Jon C. Professor; Chemistry and Chemical Biology; Cornell University Ithaca Office of Sponsored Programs Ithaca, NY 14853 Timing: Fiscal Year 2001; Project Start 10-JUL-1992; Project End 31-DEC-2003

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Summary: Immunophilins and related proteins participate in many fundamental biological processes, and this project's overall goal is analyzing these processes in structural terms. In addition to providing a basic structural understanding of these important proteins, the project has practical implications for prevent graft versus. host disease in transplant patients, alleviating autoimmune diseases such as rheumatoid arthritis and insulin- dependent diabetes, and developing small molecules for regulated gene therapy. Separate projects include: Structures of the large immunophilins FKBP51 and FKB952 along with their partners in the steroid receptor complex Hip and Hop. Structure of FRAP, a member of the ATM family of proteins involved in cell cycle checkpoints and DNA repair. Structure of dihydroorotate dehydrogenase, the protein target of the rheumatoid arthritis drug leflunomide (Arava) and the anti- cancer agent brequinar. Structure of the dimerizing agents based on FKBP12-rapamycin- FRB that are clinically useful in small molecule regulated gene therapy. Structures such as fyn SH2pYEEI/FK506-FKBP52 that illustrate the concept of using borrowed endogenous proteins to moderate the binding of hybrid small molecules. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STUDY ADMINISTERING MYCOPHENOLATE MOFETIL FOR ACTIVE RHEUMATOID ARTHRITIS Principal Investigator & Institution: Merkel, Peter A.; Boston University Medical Campus 715 Albany St, 560 Boston, MA 02118 Timing: Fiscal Year 2001 Summary: This study is an extension of the double-blind, randomized, parallel group, multicenter comparison of the efficacy and safety of Mycophenolate Mofetil and placebo in patients with active Rheumatoid Arthritis. The design is an open label trial of MMF therapy in RA patients for a minimum of 6 months and will have a duration of approximately 1 year, evaluating the long-term safety profile. Five patients are anticipated to participate in this extension study. Patients who are eligible to be included in this study are those who have completed the 6 month blinded treatment protocol and continuing abstinence of contradictions or exclusion factors relating to safety as defined in the protocol of the blinded study. Concurrent Glucocorticoids (Transcutaneous electrical nerve stimulation (TENS) for the treatment of rheumatoid arthritis in the hand. Author(s): Brosseau L, Yonge KA, Robinson V, Marchand S, Judd M, Wells G, Tugwell P. Source: Cochrane Database Syst Rev. 2003; (3): Cd004287. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12918009&dopt=Abstract

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Treatment of rheumatoid arthritis with a peptide diet: a randomized, controlled trial. Author(s): Holst-Jensen SE, Pfeiffer-Jensen M, Monsrud M, Tarp U, Buus A, Hessov I, Thorling E, Stengaard-Pedersen K. Source: Scandinavian Journal of Rheumatology. 1998; 27(5): 329-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9808394&dopt=Abstract

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Treatment of rheumatoid arthritis with electromagnetic millimeter waves applied to acupuncture points--a randomized double blind clinical study. Author(s): Usichenko TI, Ivashkivsky OI, Gizhko VV. Source: Acupuncture & Electro-Therapeutics Research. 2003; 28(1-2): 11-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12934956&dopt=Abstract

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Two configurations of static magnetic fields for treating rheumatoid arthritis of the knee: a double-blind clinical trial. Author(s): Segal NA, Toda Y, Huston J, Saeki Y, Shimizu M, Fuchs H, Shimaoka Y, Holcomb R, McLean MJ. Source: Archives of Physical Medicine and Rehabilitation. 2001 October; 82(10): 1453-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11588753&dopt=Abstract

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Uncooked, lactobacilli-rich, vegan food and rheumatoid arthritis. Author(s): Nenonen MT, Helve TA, Rauma AL, Hanninen OO. Source: British Journal of Rheumatology. 1998 March; 37(3): 274-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9566667&dopt=Abstract

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Use of alternative drug therapies by patients with rheumatoid arthritis in Korea. Author(s): Ji JD, Chun BC, Song GG. Source: The Journal of Rheumatology. 2000 June; 27(6): 1573-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10852304&dopt=Abstract

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Using nurse case management to promote self-efficacy in individuals with rheumatoid arthritis. Author(s): Barry J, McQuade C, Livingstone T. Source: Rehabilitation Nursing : the Official Journal of the Association of Rehabilitation Nurses. 1998 November-December; 23(6): 300-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10223032&dopt=Abstract

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Utilization characteristics of health care service for rheumatoid arthritis patients in Korea. Author(s): Cho KJ, Jang SH, Lee SK, Doh WS. Source: Yonsei Medical Journal. 1998 June; 39(3): 247-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9664830&dopt=Abstract

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Why do patients with rheumatoid arthritis use alternative treatments? Author(s): Jacobs JWG, Kraaimaat FW, Bijlsma JW. Source: Clinical Rheumatology. 2001; 20(3): 192-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11434472&dopt=Abstract


Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMD®Health: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to rheumatoid arthritis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Allergies and Sensitivities Source: Healthnotes, Inc. www.healthnotes.com Amyloidosis Source: Integrative Medicine Communications; www.drkoop.com Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Bursitis Source: Healthnotes, Inc. www.healthnotes.com Bursitis Source: Integrative Medicine Communications; www.drkoop.com Colds and Flus Source: Prima Communications, Inc.www.personalhealthzone.com


Indigestion, Heartburn, and Low Stomach Acidity Source: Healthnotes, Inc. www.healthnotes.com Osteoarthritis Source: Healthnotes, Inc. www.healthnotes.com Osteoarthritis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Prima Communications, Inc.www.personalhealthzone.com Raynaud's Phenomenon Source: Integrative Medicine Communications; www.drkoop.com Restless Legs Syndrome Source: Healthnotes, Inc. www.healthnotes.com Rheumatoid Arthritis Source: Healthnotes, Inc. www.healthnotes.com Rheumatoid Arthritis Source: Integrative Medicine Communications; www.drkoop.com Rheumatoid Arthritis Source: Prima Communications, Inc.www.personalhealthzone.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc. www.healthnotes.com Uveitis Source: Integrative Medicine Communications; www.drkoop.com •

Alternative Therapy Chiropractic Source: Healthnotes, Inc. www.healthnotes.com Chiropractic Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,681,00.html Feldenkrais Source: WholeHealthMD.com, LLC. www.wholehealthmd.com


Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,695,00.html Hellerwork Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,700,00.html Homeopathy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,703,00.html Massage Source: Integrative Medicine Communications; www.drkoop.com Naturopathy Source: Integrative Medicine Communications; www.drkoop.com Nutrition Source: Integrative Medicine Communications; www.drkoop.com Rolfing Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,732,00.html Trager approach Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,741,00.html Writing therapy Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,745,00.html •

Chinese Medicine Chuanwu Alternative names: Common Monkshood Mother Root; Radix Aconiti Source: Chinese Materia Medica Goupi Gao Alternative names: Goupi Plaster Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Goupi%20Gao&mh=10&sb=--&view_records=View+Records


Guogong Jiu Alternative names: Guogong Wine Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Guogong%20Jiu&mh=10&sb= ---&view_records=View+Records Haifengteng Alternative names: Kadsura Pepper Stem; Caulis Piperis Kadsurae Source: Chinese Materia Medica Jinqian Baihuashe Alternative names: Coin-like White-banded Snake; Jinqian Baihuashe (Jin Qian Bai Hua She); Bungarus Parvus Source: Chinese Materia Medica Liangtoujian Alternative names: Radde Anemone Rhizome; Rhizoma Ahemones Daddeanae Source: Chinese Materia Medica Mugua Wan Alternative names: Mugua Pills Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Mugua%20Wan&mh=10&sb=--&view_records=View+Records Qiannianjian Alternative names: Obscured Homalomena Rhizome; Rhizoma Homalomenae Source: Chinese Materia Medica Qishe Alternative names: Long-noded Pit Viper; Qishe (Qi She); Agkistrodon Source: Chinese Materia Medica Qufeng Shujin Wan Alternative names: Qufeng Shujin Pills Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Qufeng%20Shujin%20Wan&m h=10&sb=---&view_records=View+Records Shujin Huoluo Jiu Alternative names: Shujin Huoluo Wine; Shujin Huoluo Jiu
(Shu Jin Huo Luo Jiu) Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China


Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Shujin%20Huoluo%20Jiu&mh =10&sb=---&view_records=View+Records Shujin Wan Alternative names: Qufeng Shujin Pills; Qufeng Shujin Wan Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Hyperlink: http://www.newcenturynutrition.com/cgilocal/patent_herbs_db/db.cgi?db=default&Chinese=Shujin%20Wan&mh=10&sb=--&view_records=View+Records •

Homeopathy Arnica Source: Healthnotes, Inc. www.healthnotes.com Aurum metallicum Source: Healthnotes, Inc. www.healthnotes.com Bryonia Source: Healthnotes, Inc. www.healthnotes.com Calcarea carbonica Source: Healthnotes, Inc. www.healthnotes.com Calcarea fluorica Source: Healthnotes, Inc. www.healthnotes.com Causticum Source: Healthnotes, Inc. www.healthnotes.com Dulcamara Source: Healthnotes, Inc. www.healthnotes.com Kali bichromicum Source: Healthnotes, Inc. www.healthnotes.com Kali carbonicum Source: Healthnotes, Inc. www.healthnotes.com Kalmia latifolia Source: Healthnotes, Inc. www.healthnotes.com Ledum palustre Source: Healthnotes, Inc. www.healthnotes.com Pulsatilla Source: Healthnotes, Inc. www.healthnotes.com Rhododendron Source: Healthnotes, Inc. www.healthnotes.com


Ruta graveolens Source: Healthnotes, Inc. www.healthnotes.com •

Herbs and Supplements Adrenal Extract Source: Healthnotes, Inc. www.healthnotes.com ALA Source: Integrative Medicine Communications; www.drkoop.com Alpha-Linolenic Acid (ALA) Source: Integrative Medicine Communications; www.drkoop.com Amino Acids Overview Source: Healthnotes, Inc. www.healthnotes.com Ananas comosus Source: Integrative Medicine Communications; www.drkoop.com Antimalarial Drugs Source: Healthnotes, Inc. www.healthnotes.com Arginine Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10005,00.html Aspirin Source: Healthnotes, Inc. www.healthnotes.com Azathioprine Source: Healthnotes, Inc. www.healthnotes.com Beta-Carotene Source: Prima Communications, Inc.www.personalhealthzone.com BLACK COHOSH Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca BLADDERWRACK Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Boswellia Alternative names: Frankincense; Boswellia serrata Roxb. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org


Boswellia Alternative names: Boswellia serrata Source: Healthnotes, Inc. www.healthnotes.com Boswellia Source: Prima Communications, Inc.www.personalhealthzone.com Boswellia Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,759,00.html Bromelain Source: Healthnotes, Inc. www.healthnotes.com Bromelain Alternative names: Ananas comosus, Bromelainum Source: Integrative Medicine Communications; www.drkoop.com Bromelain Source: Prima Communications, Inc.www.personalhealthzone.com Bromelainum Source: Integrative Medicine Communications; www.drkoop.com Calciferol Source: Integrative Medicine Communications; www.drkoop.com Calcitrol Source: Integrative Medicine Communications; www.drkoop.com Cat’s Claw Alternative names: Uncaria tomentosa Source: Healthnotes, Inc. www.healthnotes.com Cat's Claw Source: Prima Communications, Inc.www.personalhealthzone.com Cayenne Alternative names: Capsicum annuum, Capsicum frutescens Source: Healthnotes, Inc. www.healthnotes.com Celecoxib Source: Healthnotes, Inc. www.healthnotes.com Celery Seed Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Cetyl Myristoleate Source: Healthnotes, Inc. www.healthnotes.com


Chaparral Alternative names: Larrea tridentata Source: Healthnotes, Inc. www.healthnotes.com Chemotherapy Source: Healthnotes, Inc. www.healthnotes.com Cholecalciferol Source: Integrative Medicine Communications; www.drkoop.com Chrysanthemum parthenium Source: Integrative Medicine Communications; www.drkoop.com Corticosteroids Source: Prima Communications, Inc.www.personalhealthzone.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc. www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Integrative Medicine Communications; www.drkoop.com Devil’s Claw Alternative names: Harpagophytum procumbens Source: Healthnotes, Inc. www.healthnotes.com Devil's Claw Source: Prima Communications, Inc.www.personalhealthzone.com DHEA Source: Integrative Medicine Communications; www.drkoop.com Diclofenac Source: Healthnotes, Inc. www.healthnotes.com Dioscorea villosa Source: Integrative Medicine Communications; www.drkoop.com DMSO Source: Healthnotes, Inc. www.healthnotes.com Docosahexaenoic Acid Source: Healthnotes, Inc. www.healthnotes.com Echinacea Source: Prima Communications, Inc.www.personalhealthzone.com Echinacea Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,775,00.html


Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com EPA Source: Integrative Medicine Communications; www.drkoop.com Erocalciferol Source: Integrative Medicine Communications; www.drkoop.com Etodolac Source: Healthnotes, Inc. www.healthnotes.com Eucalyptus Alternative names: Eucalyptus globulus Source: Healthnotes, Inc. www.healthnotes.com Evening Primrose Alternative names: Oenothera biennis, Sun Drop Source: Integrative Medicine Communications; www.drkoop.com Feverfew Alternative names: Tanacetum parthenium, Chrysanthemum parthenium Source: Integrative Medicine Communications; www.drkoop.com Feverfew Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,780,00.html Flavonoids Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,782,00.html Flurbiprofen Source: Healthnotes, Inc. www.healthnotes.com Gamma-Linolenic Acid (GLA) Source: Integrative Medicine Communications; www.drkoop.com Ginger Alternative names: Zingiber officinale Source: Healthnotes, Inc. www.healthnotes.com Ginger Source: Prima Communications, Inc.www.personalhealthzone.com Ginger Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,787,00.html


GLA Source: Integrative Medicine Communications; www.drkoop.com GLA (Gamma-Linolenic Acid) Source: Prima Communications, Inc.www.personalhealthzone.com Glucosamine Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,790,00.html Glutamine Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10030,00.html Green-Lipped Mussel Source: Healthnotes, Inc. www.healthnotes.com Histidine Source: Healthnotes, Inc. www.healthnotes.com Histidine Source: Prima Communications, Inc.www.personalhealthzone.com Horsetail Source: Prima Communications, Inc.www.personalhealthzone.com Hydroxychloroquine Source: Healthnotes, Inc. www.healthnotes.com Ibuprofen Source: Healthnotes, Inc. www.healthnotes.com Indomethacin Source: Healthnotes, Inc. www.healthnotes.com Inhalant, Systemic, and Topical Corticosteroids Source: Integrative Medicine Communications; www.drkoop.com Ketoprofen Source: Healthnotes, Inc. www.healthnotes.com Lipase Source: Integrative Medicine Communications; www.drkoop.com Meadowsweet Alternative names: Filipendula ulmaria Source: Healthnotes, Inc. www.healthnotes.com Melatonin Source: Integrative Medicine Communications; www.drkoop.com


Methotrexate Source: Healthnotes, Inc. www.healthnotes.com Methotrexate Alternative names: Rheumatrex Source: Prima Communications, Inc.www.personalhealthzone.com MSM Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,807,00.html Nabumetone Source: Healthnotes, Inc. www.healthnotes.com Nettle Alternative names: Urtica dioica Source: Healthnotes, Inc. www.healthnotes.com Nettle Source: Integrative Medicine Communications; www.drkoop.com Non-steroidal Anti-Inflammatory Drugs Source: Healthnotes, Inc. www.healthnotes.com Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Source: Integrative Medicine Communications; www.drkoop.com Oenothera biennis Source: Integrative Medicine Communications; www.drkoop.com Oral Corticosteroids Source: Healthnotes, Inc. www.healthnotes.com Oxaprozin Source: Healthnotes, Inc. www.healthnotes.com PABA Source: Healthnotes, Inc. www.healthnotes.com Penicillamine Source: Healthnotes, Inc. www.healthnotes.com Penicillamine Alternative names: Cuprimine, Depen Source: Prima Communications, Inc.www.personalhealthzone.com Phenylalanine Source: Healthnotes, Inc. www.healthnotes.com


Phenylalanine Source: Integrative Medicine Communications; www.drkoop.com Phenylalanine Source: Prima Communications, Inc.www.personalhealthzone.com Picrorhiza Alternative names: Picrorhiza kurroa Source: Healthnotes, Inc. www.healthnotes.com Piroxicam Source: Healthnotes, Inc. www.healthnotes.com Pollen Source: Healthnotes, Inc. www.healthnotes.com Pregnenolone Source: Healthnotes, Inc. www.healthnotes.com Pregnenolone Source: Prima Communications, Inc.www.personalhealthzone.com Proteolytic Enzymes Source: Prima Communications, Inc.www.personalhealthzone.com Rosemary Alternative names: Rosmarinus officinalis Source: Healthnotes, Inc. www.healthnotes.com Salsalate Source: Healthnotes, Inc. www.healthnotes.com Sarsaparilla Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Shark Cartilage Source: Integrative Medicine Communications; www.drkoop.com Sulfasalazine Source: Healthnotes, Inc. www.healthnotes.com Sulindac Source: Healthnotes, Inc. www.healthnotes.com Sun Drop Source: Integrative Medicine Communications; www.drkoop.com Tanacetum parthenium Source: Integrative Medicine Communications; www.drkoop.com


Turmeric Alternative names: Curcuma longa Source: Healthnotes, Inc. www.healthnotes.com Turmeric Source: Prima Communications, Inc.www.personalhealthzone.com Turmeric Source: WholeHealthMD.com, LLC. www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10062,00.html Urtica dioica Source: Integrative Medicine Communications; www.drkoop.com Urtica urens Source: Integrative Medicine Communications; www.drkoop.com White Willow Source: Prima Communications, Inc.www.personalhealthzone.com Wild Yam Alternative names: Dioscorea villosa Source: Integrative Medicine Communications; www.drkoop.com Wild Yam Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Willow Alternative names: Salix alba Source: Healthnotes, Inc. www.healthnotes.com Willow Bark Alternative names: There are several species of willow includingSalix alba, Salix nigra, Salix fragilis, Salix purpurea, Salix babylonica, White Willow, European Willow, Black Willow, Pussy Willow, Crack Willow, Purple Willow, Weeping Willow, Liu-zhi Source: Integrative Medicine Communications; www.drkoop.com Withania Ashwagandha Alternative names: Ashwagandha; Withania somnifera L. Source: Alternative Medicine Foundation, Inc. www.amfoundation.org Yucca Alternative names: Yucca schidigera , Yucca spp. Source: Healthnotes, Inc. www.healthnotes.com Yucca Source: Prima Communications, Inc.www.personalhealthzone.com


General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON RHEUMATOID ARTHRITIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to rheumatoid arthritis. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “rheumatoid arthritis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on rheumatoid arthritis, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Rheumatoid Arthritis ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to rheumatoid arthritis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Comparison of the Effects of Isometric and Isokinetic Training on Muscle Fibre Size and Strength in Women with Rheumatoid Arthritis by Wessel, Jean; Phd from University of Alberta (canada), 1983 http://wwwlib.umi.com/dissertations/fullcit/NK63989

•

A Cross-cultural Comparison of Pain Description in Children with Polyarticular Juvenile Rheumatoid Arthritis in the United States and in Egypt by Von Weiss, Renee Terese; Phd from University of Kansas, 2002, 140 pages http://wwwlib.umi.com/dissertations/fullcit/3083203

•

A Psychosocial Model for the Impact of Rheumatoid Arthritis on Well-being by Wilkins, Kendra E. Phd from Wayne State University, 1999, 162 pages http://wwwlib.umi.com/dissertations/fullcit/9954575


•

An Investigation of Oral History Narrative and Content Analysis Technique for Community Field Work in Rehabilitation Focusing upon Females with Rheumatoid Arthritis by Sirmons, Martha Ruddon, Edd from Auburn University, 1985, 166 pages http://wwwlib.umi.com/dissertations/fullcit/8518414

•

Correlates of Health Perceptions among Individuals with Rheumatoid Arthritis by Guccione, Andrew Anthony, Phd from Boston University, 1988, 174 pages http://wwwlib.umi.com/dissertations/fullcit/8813637

•

Determinants of Physical Activity in Older Women with Rheumatoid Arthritis by Semanik, Pamela A. Phd from University of Illinois at Chicago, Health Sciences Center, 2002, 204 pages http://wwwlib.umi.com/dissertations/fullcit/3058240

•

Development of a Measure of Investigativeness, and Its Role in Women's Adaptation to Rheumatoid Arthritis by Vagi, Anne Barbara; Phd from University of Waterloo (canada), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK66425

•

Economic Approaches to the Problem of Acceptable Clinical Risks: the Case of Prescription Drugs and Chronic Rheumatic Disease (clinical Risk, Rheumatoid Arthritis) by O'brien, Bernie J., Phd from Brunel University (united Kingdom), 1990, 385 pages http://wwwlib.umi.com/dissertations/fullcit/DX92575

•

Exploring the Lived Experience of Female Adolescents with Juvenile Rheumatoid Arthritis: a Model of Human Occupation Perspective by Tommasulo, Jeanmarie F. Ms from D'youville College, 2002, 109 pages http://wwwlib.umi.com/dissertations/fullcit/1409942

•

Exploring the Lived Experience of Women with Rheumatoid Arthritis: a Model of Human Occupation Perspective by Gee, Bryan Mark; Ms from D'youville College, 2002, 168 pages http://wwwlib.umi.com/dissertations/fullcit/1409937

•

Family Adaptability, Cohesion and Conflict in Families with Rheumatoid Arthritis, Chronic Pain and Depression by Caldwell, Karen Leigh, Phd from Virginia Polytechnic Institute and State University, 1988, 106 pages http://wwwlib.umi.com/dissertations/fullcit/8910943

•

From Social Theory to Social Policy: Social Class and the Epidemiology of Disability: a Case Study among Persons with Rheumatoid Arthritis. by Yelin, Edward Harris, Phd from University of California, Berkeley, 1979, 280 pages http://wwwlib.umi.com/dissertations/fullcit/8000583

•

Gender, Class and the Illness Experience of Rheumatoid Arthritis by Fifield, Judith Anne, Phd from The University of Connecticut, 1990, 158 pages http://wwwlib.umi.com/dissertations/fullcit/9110414

•

Gold in Rheumatoid Arthritis : Its Effect on Plasma Cortisol and Its Deposition in Skin by Jeffery, Dorothy A; Phd from University of Alberta (canada), 1974 http://wwwlib.umi.com/dissertations/fullcit/NK21856

•

Holistic Fatherhood: a Grounded Theory Approach to Understanding Fathers of Children with Juvenile Rheumatoid Arthritis (jra) by Mcneill, Harold Edwin (ted); Phd from University of Toronto (canada), 2001, 312 pages http://wwwlib.umi.com/dissertations/fullcit/NQ63799

Dissertations 329

•

Impact of Anti-inflammatory Medications, Methotrexate, and Steroidal Medications on Psychosocial Functioning and Medical Status in Juvenile Rheumatoid Arthritis Patients by Ryser, Christina Nicole; Phd from The University of Texas Southwestern Medical Center at Dallas, 2002 http://wwwlib.umi.com/dissertations/fullcit/f865233

•

Interpersonal Expectations and Psychosocial Adjustment to Chronic Illness: Reducing Discrepancies among Persons with Rheumatoid Arthritis by Thompson, Shawn Norvell; Phd from State University of New York at Stony Brook, 2002, 87 pages http://wwwlib.umi.com/dissertations/fullcit/3067559

•

Juvenile Rheumatoid Arthritis: a Psychosocial Assessment of Adolescent Females and Their Mothers (pediatric Chronic Illness, Coping Models, Family Systems) by Baird, Sally Felgenhauer, Phd from University of Washington, 1986, 141 pages http://wwwlib.umi.com/dissertations/fullcit/8613135

•

Juvenile Rheumatoid Arthritis: Implications for Nursing Education (childhood Illness) by Dressler, Mary Buckley, Edd from Temple University, 1992, 158 pages http://wwwlib.umi.com/dissertations/fullcit/9227454

•

Life Stress and Emotional Regulation Strategies during a Personal Disclosure Task: Health Implications for Patients with Rheumatoid Arthritis by Meyer, Tina Marie; Phd from Wayne State University, 2003, 139 pages http://wwwlib.umi.com/dissertations/fullcit/3086453

•

Lymphocytes and Rheumatoid Arthritis by Mandeville, Robert Parnell; Phd from Memorial University of Newfoundland (canada), 1979 http://wwwlib.umi.com/dissertations/fullcit/NK46760

•

Nutritional Status of Postmenopausal Women with and without Rheumatoid Arthritis by Woolf, Kathleen; Phd from Arizona State University, 2002, 158 pages http://wwwlib.umi.com/dissertations/fullcit/3057423

•

Pain Measurement in Rheumatoid Arthritis: Applications of a Behavioral Approach (arthritis) by Buescher, Keith Lee, Phd from University of Missouri - Columbia, 1989, 178 pages http://wwwlib.umi.com/dissertations/fullcit/9010541

•

Piroxicam in Healthy Adults and Rheumatoid Arthritis Patients Disposition Kinetics and Clinical Effects by Richardson, Corrie Jane; Phd from The University of Saskatchewan (canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL29256

•

Relationships between Coping Beliefs, Coping Practices, and Coping Resources and the Quality of Life in Rheumatoid Arthritis Patients (arthritis) by Strong, Thomas Irvin, Phd from University of Alberta (canada), 1990, 243 pages http://wwwlib.umi.com/dissertations/fullcit/NN64859

•

Social and Psychological Well-being, Pain, Functional Ability, and Choice of Coping Strategies in Patients with Rheumatoid Arthritis (counseling, Health) by Morgan, Cynthia Gray, Phd from University of California, Los Angeles, 1985, 362 pages http://wwwlib.umi.com/dissertations/fullcit/8603974

•

Socio-psychological Factors in Rheumatoid Arthritis by Steffenhagen, Ronald Albert, Phd from State University of New York at Buffalo, 1966, 142 pages http://wwwlib.umi.com/dissertations/fullcit/6607988


•

The Effect of an Individualized Instruction Program on the Education of Outpatients with Rheumatoid Arthritis by Neuberger, Geri Budesheim, Edd from University of Kansas, 1983, 108 pages http://wwwlib.umi.com/dissertations/fullcit/8403597

•

The Effects of Expressive Release Therapy upon the Physical and Psychological Wellbeing of Rheumatoid Arthritis Patients by Engle, David Eugene, Phd from The University of Arizona, 1985, 178 pages http://wwwlib.umi.com/dissertations/fullcit/8517495

•

The Effects of Music and Music Vibration Using the Mvt(tm) on the Relief of Rheumatoid Arthritis Pain by Chesky, Kris S., Phd from University of North Texas, 1992, 142 pages http://wwwlib.umi.com/dissertations/fullcit/9300593

•

The Experience of Rheumatoid Arthritis by Hovanec, Margret Anne, Phd from University of Toronto (canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/f468806

•

The Experience of Rheumatoid Arthritis by Hovanec, Margret; Phd from University of Toronto (canada), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK50276

•

The Functional Characterization of in Vivo Activated Interleukin-2 Responsive T Cells in Rheumatoid Arthritis by Cell Cloning Techniques by Ofosu-appiah, William A; Phd from The University of Manitoba (canada), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL47924

•

The Relationship between Pain Responsiveness and Disease Activity in Fibrositis and Rheumatoid Arthritis by Scudds, Roger A; Phd from The University of Western Ontario (canada), 1990 http://wwwlib.umi.com/dissertations/fullcit/NL55283

•

The Role of Inflammatory Cytokines in Rheumatoid Arthritis: Comparison to Allergic Diseases by Schuerwegh, Annemie Johanna; Phd from Universitaire Instelling Antwerpen (belgium), 2002, 214 pages http://wwwlib.umi.com/dissertations/fullcit/3066152

•

Variations in Compliance with Medical Regimens and Utilization of Medical Services among Patients with Rheumatoid Arthritis by Kasteler, Josephine Mix, Phd from The University of Utah, 1970, 140 pages http://wwwlib.umi.com/dissertations/fullcit/7023079

•

Why Does Formal Education Predict Mortality? an Evaluation of Mediational Processes (rheumatoid Arthritis, Education Level, Learned Helplessness) by Callahan, Leigh Fleming, Phd from Vanderbilt University, 1992, 150 pages http://wwwlib.umi.com/dissertations/fullcit/9315805

•

Women with Rheumatoid Arthritis: a Qualitative Investigation of Personality and Coping Methods (arthritis) by Thompson, Linda V., Phd from Arizona State University, 1993, 245 pages http://wwwlib.umi.com/dissertations/fullcit/9320665

Dissertations 331

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

333

CHAPTER 5. ARTHRITIS

CLINICAL

TRIALS

AND

RHEUMATOID

Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning rheumatoid arthritis.

Recent Trials on Rheumatoid Arthritis The following is a list of recent trials dedicated to rheumatoid arthritis.8 Further information on a trial is available at the Web site indicated. •

A Multicenter Study of the Safety of Human Anti-TNF Monoclonal Antibody D2E7 in Subjects with Active Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): Abbott Laboratories Purpose - Excerpt: Purpose of the study is to evaluate safety by collecting serious adverse events in subjects with moderately to severely active rheumatoid arthritis who are unable to obtain etanercept and who have failed one or more prior DMARDs. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00049751

•

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of the Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Rheumatoid Arthritis Condition(s): Arthritis, Juvenile Rheumatoid

8

These are listed at www.ClinicalTrials.gov.


Study Status: This study is currently recruiting patients. Sponsor(s): Abbott Laboratories Purpose - Excerpt: This is a multicenter, Phase III randomized, placebo-controlled study in which polyarticular JRA subjects who are either MTX treated or non-MTX treated will initially receive Adalimumab by subcutaneous injection every other week for a fourmonth open-label lead-in period. Subjects who respond to the open-label therapy will then be rolled over into the double-blind portion of the study and will be randomized to receive either adalimumab or placebo for an additional 32 weeks or until flare of disease, whichever is earlier. Subjects who experience disease flare during the double-blind portion of the study or subjects who complete 48 weeks of the study will be given the option to receive open-label treatment with adalimumab for an additional 44 weeks. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048542 •

A Phase 2 open-label clinical study using intravenous Paxceed(tm) to treat patients with rheumatoid arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): Angiotech Pharmaceuticals Purpose - Excerpt: Paxceed(tm) is being developed by Angiotech Pharmaceuticals, Inc. for the treatment of Rheumatoid Arthritis (RA). The main objective of this study is to determine the effectiveness of treatment with Paxceed(tm) in patients with RA. In RA, there is an increase in cell growth and changes in cell function. The active substance in Paxceed(tm), paclitaxel, has undergone clinical studies as a cancer chemotherapeutic agent and has demonstrated its usefulness as an agent that stops growth of cells and blocks certain types of cell function associated with RA. Because of these effects, it is thought that Paxceed(tm) might alter the destructive course of RA. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00055133

•

Clinically Important Changes in Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study will explore how patients with rheumatoid arthritis evaluate, or rate, symptom improvements. Physicians generally evaluate patients' health and treatment benefits based on laboratory measures, such as the number of tender or swollen joints, duration of morning stiffness, grip strength, pain severity and others. Less attention is given to whether these treatment results are meaningful to patients. This study will examine how much of an improvement in pain, stiffness, function, and

Clinical Trials 335

other symptoms is needed before patients consider the change an important improvement. Patients 18 years of age or older who were diagnosed with rheumatoid arthritis after age 16 and who have active arthritis (6 or more tender joints) may be eligible for this study. Of particular interest are patients beginning treatment with prednisone, methotrexate, leflunomide, infliximab, or etanercept, although patients receiving any type of treatment may be included. Participants will be evaluated twice at the NIH Clinical Center, once at the start of the study and again at either 1 month or 4 months later, depending on the individual's treatment regimen. Permission will also be requested to review patients' medical records for results of previous blood tests and xrays. At each NIH visit, patients will undergo the following tests and procedures: Medical history and physical examination, including evaluation of joint swelling and tenderness; - Questionnaires about rheumatoid arthritis symptoms; - Computer-based exercise to assess preferences for various state-of-health choices; - Grip strength test; Walking test on level ground, with or without the use of a cane or walker; - Blood test to measure inflammation. At the second visit, in addition to the above procedures, participants will complete a questionnaire to rate the importance of changes, if any, in pain, morning stiffness, fatigue, joint swelling, functioning, worry, depression, and overall impressions, since the first visit. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056602 •

Consistency of Traditional Chinese Medicine Diagnoses and Herbal Prescriptions for Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: Practitioners of Traditional Chinese Medicine (TCM) make diagnoses based solely on clinical symptoms. This study will evaluate whether TCM practitioners make diagnoses consistently. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00071149

•

Coping Skills Training for Early Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: Rheumatoid arthritis (RA) is the most common inflammatory arthritis and a major health problem. Medical treatments are now being used much earlier in the course of RA, but these treatments do not address the challenges of coping with the early stages of this disease. This study will determine whether a comprehensive coping skills training program can decrease pain, psychological disability, and physical disability in patients with early RA. Study Type: Interventional


Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056394 •

Effects of MEDI-522 On Disease Activity and Progression of Joint Damage in Patients with Active Rheumatoid Arthritis Suboptimally Responding to Methotrexate Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): MedImmune, Inc. Purpose - Excerpt: To compare, as a preliminary analysis, the effects of subcutaneously administered MEDI-522 versus placebo at 6 months on disease activity and progression of structural joint damage in patients with rheumatoid arthritis (RA), who have active disease despite ongoing treatment with methotrexate (MTX) with or without hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ). Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069017

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Efficacy & Safety of an Investigational Drug + Methotrexate Compared to Methotrexate Alone in Patients with Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: The purpose of this study is to help researchers confirm that an investigational drug given subcutaneously (injection given under the skin), once every 4 weeks, is an effective and safe treatment for rheumatoid arthritis in patients who are already taking methotrexate. Patients will be in this study for approximately 6 months and will need to attend the doctor's clinic on up to 12 occasions during that time. They will have a 50% chance of receiving the investigational drug and a 50% chance of receiving placebo in addition to their methotrexate. Prior to entry into this study patients will need to undergo chest x-ray and ECG (heart trace). Blood and urine tests, as well as arthritis assessments will be carried out regularly throughout the study, and patients will be required to complete health questionnaires at most clinic visits. Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048178

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Efficacy and Safety of Investigational Drug in Patients with Rheumatoid Arthritis Who Failed at Least One DMARD (Disease Modifying Anti-Rheumatic Drug) Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: A double-blind treatment with investigational drug compared to placebo in patients with rheumatoid arthritis Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00066105 •

ENBREL(R) (etanercept) as Treatment for Children with Systemic Onset Juvenile Rheumatoid Arthritis Condition(s): Juvenile Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): Immunex Corporation Purpose - Excerpt: Rationale: etanercept inhibits the effects of tumor necrosis factor, which plays an important role in the progression of rheumatoid arthritis. A study of children with polyarticular course juvenile rheumatoid arthritis showed that Enbrel had efficacy and was generally well tolerated in children ages 4-17 who had moderately to severely active disease and who failed treatment with one or more disease modifying antiarthritic drugs. The children in the study may have had arthritis onset of pauciarticular, polyarticular, or systemic nature. Systemic onset juvenile rheumatoid arthritis (SOJRA) may result in approximately one-third of patients having significant long-term disability. Purpose: the Phase 4 study is designed to further define the safety and efficacy of etanercept in those children with SOJRA. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00039949

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ENBREL(R) (Etanercept) Safety Study in Children with Juvenile Rheumatoid Arthritis Condition(s): Arthritis, Juvenile Rheumatoid Study Status: This study is currently recruiting patients. Sponsor(s): Immunex Corporation Purpose - Excerpt: This Phase 4 open-label, nonrandomized multicenter registry study is being conducted to evaluate the long-term safety of ENBREL(R) (etanercept) compared to methotrexate in patients aged 2 to 18 years with polyarticular-course or systemiconset juvenile rheumatoid arthritis (JRA). Patients will be evaluated for a total of 3 years. The registry will include patients who have recently started and are currently receiving ENBREL alone, ENBREL in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs), methotrexate alone, or methotrexate in combination with other DMARDs. Approximately 600 patients will be enrolled at sites in the United States and Canada, with 400 patients receiving ENBREL and 200 receiving methotrexate without ENBREL. One group of patients will receive ENBREL by subcutaneous (SC) injection twice a week for up to 3 years and may continue taking other medicines such as prednisone or methotrexate. Another group will continue to receive methotrexate, either alone or in combination with DMARDs other than ENBREL. Candidates will be screened with a medical history and physical examination, including height, weight, and Tanner scores. A behavioral assessment, quality of life assessment, and physician's global assessment of disease activity will be performed. A blood test and joint evaluation will also be done. Both treatment groups will have on-study evaluations at baseline and months 3, 6, 9, 12, 18, 24, 30, and 36. Each follow-up visit will include a repeat of the screening assessments and an evaluation of adverse events or toxicity, including psychiatric and behavioral effects and new symptoms of autoimmune


disorders. The two groups will be compared for safety, including effects on growth and development parameters. Patients will need to purchase or arrange the purchase of commercially available ENBREL. Patients entering the study during the period when ENBREL is in short supply will be able to obtain ENBREL after enrolling in the ENBREL Enrollment Program. Patients will receive ENBREL enrollment information at the time of registration into the study. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00016575 •

Genetic Registry for Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of Allergy and Infectious Diseases (NIAID); Arthritis Foundation Purpose - Excerpt: Many genes are thought to contribute to rheumatoid arthritis (RA). Currently only one such gene has been identified. This study will attempt to identify all of the genes that may contribute to RA and determine which specific genetic variations are responsible for the disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00069472

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Identification of Genes Associated with Lung Disease in Patients with Rheumatoid Arthritis Condition(s): Healthy; Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Data gathered from previous research studies suggest that genetics may play a role in the development of PF in patients with rheumatoid arthritis. However, the actual genetic factors involved in the disease process have not been identified. The goal of this study is to identify the genetic markers in patients with pulmonary fibrosis and rheumatoid arthritis. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001885

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Infliximab for the Treatment of Early Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis

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Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study will test whether the drug combination of methotrexate and infliximab (anti-TNF-alpha antibody) is more effective than methotrexate alone for treating rheumatoid arthritis early in the disease. (The Food and Drug Administration has approved both treatment regimens for patients with long-standing rheumatoid arthritis.) The study will also evaluate how effectively magnetic resonance imaging (MRI) can detect differences in the development of bone damage in the two treatment groups by as early as 6 months. Patients 18 years of age and older who have had rheumatoid arthritis for less than 2 years and who have four or more affected joints may be eligible for this 1-year study. Patients must have received methotrexate treatment in the past without complete success, and must not have been treated previously with Anti-Thymocyte therapy. All participants will receive 20 Mg./week of methotrexate. In addition, patients will be randomly assigned to receive a monthly infusion of infliximab or placebo (a fluid that contains no active drug). After 6 months, all patients will receive active infliximab for the remaining half year of the study. Patients will also receive folic acid (1mg/day), Vitamin D (400 IU/day), and calcium supplements. They may continue to take prednisone (no more than 10 Mg./day) and non-steroidal anti-inflammatory drugs (NSAIDS). Medication dosages will be adjusted as needed if pain and joint swelling worsen. Over the course of the study, patients will come to NIH for 15 visits and undergo the following tests and procedures: 1. Joint examination-at every visit. 2. Drug side effects evaluation-at every visit during the study and after the study at 24 and 36 months by questionnaires to be filled out and returned. 3. Hand and feet X-rays at the first visit, at 6 months and at 12 months. 4. MRIs of the wrist to examine damage in the bone and synovial tissue (tissue lining the joint)-before treatment begins and at weeks 15, 27 and 54. For this study, the patient lies still in a narrow cylinder (the scanner) with a strong magnetic field. A contrast material (gadolinium) is injected into the blood to enhance the images of the synovium. The MRI takes about 45 minutes. 5. DEXA scans (dual emission X-ray absorptiometry) of the lower spine, one hip and one wrist to measure bone density and assess bone loss-before treatment begins and at weeks 27 and 54. This X-ray test takes about 5 to 10 minutes. 6. CTs (computed tomography) of one hand to assess joint damage in the wrist-before treatment begins and at weeks 27 and 54. Only half the patients in the study will have this X-ray study, which produces 3dimensional images of the hand. It will be done to compare the location, size and change of damage in the wrist seen on CT with the information obtained on MRI. The procedure takes about 5 to 10 minutes to complete. 7. Blood tests-at every visit to evaluate treatment response and side effects. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006292 •

Infliximab to Treat Children with Juvenile Rheumatoid Arthritis Condition(s): Juvenile Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)


Purpose - Excerpt: This study will determine whether a stepwise increase of the drug infliximab (Remicade(r) (Registered Trademark)) controls juvenile rheumatoid arthritis more effectively than a fixed dose. It will look at the safety and effectiveness of increasing the dose to a maximum of 15mg/kg body weight per dose, examining the drug's effect on bone and cartilage, and whether it can improve abnormal growth, metabolism and hormones. Infliximab is approved for treating adults with rheumatoid arthritis and Crohn's disease. Children between 4 and 17 years of age with active juvenile rheumatoid arthritis who do not respond adequately to standard therapy may be eligible for this study. Participants will receive nine infusions of infliximab during this 62-week study. The drug is given intravenously (IV, into a vein) over 2 hours. The first three infusions will be at a dose of 5 mg/kg of body weight. Children who improve on this regimen will receive another 6 infusions at the same dose. Children who do not significantly improve on 5 mg/kg at the end of 6 weeks (the third infusion) may continue with phase 2 of the study, in which they will be randomly assigned to receive either: 1) 6 additional doses of the drug at 5 mg/kg per dose, or 2) a gradually increased dose to a maximum of 15 mg/kg. In addition, all children will continue to take methotrexate at the same dose as when they entered the study. Participants will visit the NIH Clinical Center 12 times (about every 8 weeks) during the study for the following tests and procedures: - History and physical examination, including a complete joint exam - Puberty assessment - breast development in girls, testicle size in boys, and pubic hair - Height and weight measurements Children will have imaging studies (x-rays, MRI and Dexa scan) at the beginning and end of the study and will collect a 24-hour urine sample before each infliximab infusion. Patients may elect to have an endocrine evaluation. This involves Clinical Center hospitalizations for 1-1/2 days on visits 1, 4 and 12. Small amounts of blood will be drawn every 20 minutes (through an indwelling catheter to avoid multiple needle sticks) for 8 hours while the child sleeps. The blood will be examined for the normal rhythm of growth hormone and other substances in the body and how they are affected by arthritis. Participants will complete a questionnaire once a year for 2 years to provide information on their health status and any problems that might be related to the study drug. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00029042 •

ISIS 104838, an Inhibitor of Tumor Necrosis Factor, for Active Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): Isis Pharmaceuticals Purpose - Excerpt: ISIS 104838 is an antisense oligonucleotide drug that reduces the production of a specific protein called tumor necrosis factor (TNF-alpha), a substance that contributes to joint pain and swelling in rheumatoid arthritis. ISIS 104838 works by blocking TNF-alpha messenger RNA, the "instruction" molecule that is required for the production of TNF-alpha protein. This trial will assess the safety and efficacy of ISIS 1048383 by subcutaneous injection, administered by 3 different dosing regimens for 3 months, versus placebo. Approximately 160 TNF-alpha inhibitor-naïve rheumatoid arthritis patients will be evaluated at 32 sites in the U.S. and Canada. Phase(s): Phase II

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Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048321 •

Long term safety and tolerability of an investigational drug in patients with rheumatoid arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): (Sponsor Name Pending) Purpose - Excerpt: Open-label treatment with investigational drug in patients with rheumatoid arthritis to evaluate long term safety and tolerability and long term efficacy. Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00055458

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Lung Disease Associated with Rheumatoid Arthritis Condition(s): Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Patients participating in this study will undergo a series of tests and examinations before and throughout the study. The tests include blood and urine tests, electrical measures of heart function (ECG), chest x-rays, CAT scans, nuclear medicine scans, breathing tests, exercise tests, and fiberoptic bronchoscopy. The goals of this study are to: 1. Estimate how common pulmonary fibrosis is in patients with rheumatoid arthritis, 2. Describe the natural course of pulmonary fibrosis in patients with rheumatoid arthritis, 3. Estimate the survival rate of patients with pulmonary fibrosis and rheumatoid arthritis, and 4. Learn more about the factors that contribute to the development or progression fibrotic lung disease. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001876

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Phase I Study of High-Dose Cyclophosphamide, Anti-Thymocyte Globulin, and Total Body Irradiation With T-Cell-Depleted Autologous Bone Marrow Rescue in Patients With High-Risk Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis; Juvenile Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): Northwestern Memorial Hospital Purpose - Excerpt: Objectives: I. Determine the toxicity of high-dose cyclophosphamide, anti-thymocyte globulin, and total body irradiation with T-cell-depleted autologous bone marrow rescue in patients with high-risk rheumatoid arthritis. II. Determine the safety and efficacy of this regimen in this patient population.


Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00017615 •

Phase III Study of BMS-188667 (CTLA4Ig) in patients with rheumatoid arthritis who are currently failing anti-TNF therapy or who have failed anti-TNF therapy in the past. Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): Bristol-Myers Squibb Purpose - Excerpt: The purpose of this clinical research study is to determine whether BMS-188667 will relieve the symptoms of rheumatoid arthritis in patients who are currently receiving anti-TNF therapy for at least 3 months and are not responding or have taken anti-TNF therapy in the last 3 months and did not respond. The safety of treatment with BMS-188667 will also be evaluated. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048581

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Relaxation Response Training for the Treatment of Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study will evaluate the relative effectiveness of Relaxation Response (RR) training for the treatment of rheumatoid arthritis (RA). The study will compare RR training to RR training with cognitive behavioral therapy and to a standard RA education program. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00056667

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Safety and efficacy of a monoclonal antibody for treatment of rheumatoid arthritis. Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): XOMA Purpose - Excerpt: The purpose of this study is to determine whether a humanized monoclonal antibody (efalizumab) is safe and effective in the treatment of rheumatoid arthritis.

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Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034203 •

Shared Epitope Peptides in Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study will test whether a small protein, or peptide (dnaJ peptide) can help people with rheumatoid arthritis (RA) by preventing their immune system cells from abnormally reacting against the body's own tissues. This study will look at whether taking small amounts of dnaJ peptide by mouth can "re-educate" immune cells in some people with RA so that the cells become tolerant to, or get used to, this substance and stop attacking joint tissues. The study involves a screening, treatment, and follow-up phase. If the person qualifies for the study, he or she will be assigned to one of two groups. One group will receive the placebo (an inactive substance) and the other group will receive the study drug (dnaJ peptide). We will examine study participants, collect their blood and urine for testing, and ask them to answer a questionnaire about their arthritis once every 4 weeks over a period of 24 weeks of treatment and at a follow-up visit one month after the end of the treatment period. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000435

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Specimen Collection for Individuals with Lung Disease Associated with Rheumatoid Arthritis Condition(s): Pulmonary Fibrosis; Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: Pulmonary fibrosis (PF) is a condition in which the lungs of a patient become scarred and fibrous. It has been known to occur in as many as 40% of patients diagnosed with rheumatoid arthritis (RA). The cause of the pulmonary fibrosis in patients with RA is unknown. Researchers hope to improve their understanding of the disease process involved in PF and RA by analyzing specimens collected by bronchoscopy, lung biopsy, lung transplantation, or autopsy from patients with these conditions. The purpose of this study is to collect specimens from rheumatoid arthritis patients with and without pulmonary fibrosis as well as patients with pulmonary fibrosis without associated diseases or cause (idiopathic pulmonary fibrosis). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001884


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Study of Families with Twins or Siblings Discordant for Rheumatic Disorders Condition(s): Rheumatic Diseases; Rheumatoid Arthritis; Erythematosus; Scleroderma; Dermatomyositis; Myositis

Systemic

Lupus

Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Environmental Health Sciences (NIEHS) Purpose - Excerpt: This study will examine families in which one sibling of a sibling pair, or twin pair, has developed a systemic rheumatic disease and one has not, to see if and how the two differ in the following: - Blood cell metabolism; - Types of cells in the blood; - Environmental exposures or genetic factors that might explain why one developed disease and the other did not. Families in which one sibling has developed a systemic rheumatic disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, dermatomyositis, or myositis, and the other has not, are eligible for this study. The siblings may or may not be twins, but must be of the same gender and be within a 3-year age difference. Biological parents, or, in some cases, children, will also be included in the study. Normal, healthy volunteers will serve as control subjects. Participants will undergo some or all of the following tests and procedures: - Medical history and physical examination. Participants will also be asked permission to obtain medical records for review. - Questionnaires about environmental exposures at work, at home, and elsewhere. Probands (participants with rheumatic disease) and their healthy siblings will also answer questions about infections, vaccinations, medications or dietary supplements, sun exposure, and stressful events during the year before disease diagnosis in the affected sibling. - Blood and urine collection for the following tests: Routine blood chemistries and other studies to rule out certain diseases or medical problems; - Evidence of past toxic exposures and certain infections; - Presence of cells from the mother in the child's blood and vice versa. (Recent studies suggest that during pregnancy or delivery, cells from the mother and baby may be exchanged and circulate in the body for many years, possibly causing problems); - In twin or sibling pairs, presence of certain genes that may be more common in patients with systematic rheumatic diseases as compared with their unaffected siblings and normal volunteers; In identical twins, comparison of their blood cell metabolism to see if and how the metabolism differs in people with rheumatic disease. Participants may be asked for permission to have some of their blood and urine samples stored and to obtain previously collected blood or tissue biopsy specimens that are no longer needed for clinical care, for research purposes. They may also be asked to give additional blood or urine samples. Participants will be followed every year for 5 years (either in person or by questionnaire) to evaluate any changes in their condition. The final 5-year evaluation will repeat some of the questionnaires and procedures described above. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00055055 •

The Role of Cytokines on Growth Hormone Suppression in Premenopausal Women with Rheumatoid Arthritis and the Effect of Treatment with Etanercept Condition(s): Rheumatoid Arthritis; Healthy Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

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Purpose - Excerpt: This study has two phases. Phase 1 will examine the role of inflammatory mediators called cytokines on growth hormone levels in women with rheumatoid arthritis (RA). Phase 2 will evaluate the effect of etanercept on these growth hormone levels. Etanercept is approved for the treatment of RA. It lowers the levels of a key inflammatory mediator called tumor necrosis factor-alpha and is very effective in reducing arthritis symptoms. Growth hormone promotes bone and muscle growth. With aging, people lose muscle mass and bone strength, possibly because of decreased levels of growth hormone. People with RA have bone and muscle changes similar to those in older people, perhaps also due to decreased levels of growth hormone. The first part of this study will see if the inflammatory mediators responsible for joint inflammation (warmth, redness, pain, and swelling) in RA are related to the lowered growth hormone levels in this disease. The second part will evaluate the effect of etanercept treatment on muscle mass and bone density, in addition to growth hormone levels. Premenopausal women between 18 and 55 years of age with a recent diagnosis of rheumatoid arthritis (less than 3 years) are eligible for this study. Healthy volunteers will also be enrolled in the first phase of the study as control subjects. This study is conducted at two sites, the NIH and the Johns Hopkins Medical Center in Baltimore. Healthy volunteers enrolled in this study will be interviewed about their health status and will fill out questionnaires on diet and general physical function, including fatigue, energy and well being. In addition, they will be hospitalized once at the NIH Clinical Center for 24-hour blood sampling and will visit to Johns Hopkins Medical Center in Baltimore for a brachial artery reactivity study, as follows: - 24-hour blood sampling for growth hormone levels. Blood samples (1/2 teaspoon each) will be collected every 20 minutes from 8 AM one day until 8 AM the following day through a plastic tube in an arm vein. - Dual energy X-ray absorptiometry (DEXA) scan on a small area of the spine, hip and wrist to assess bone density and a total body DEXA scan to assess the amount and distribution of muscle and body fat. - Blood vessel (brachial artery reactivity) study to measure the ability of the brachial artery to dilate and increase its blood flow. For this procedure, the subject lies on a table with electrocardiogram leads attached to the chest. A blood pressure cuff is inflated for several minutes and a drop of nasal spray of nitroglycerin is given that may cause a headache. Blood pressure and headache are monitored and treated as needed. Patients with rheumatoid arthritis will be seen at the NIH clinic on six separate visits (weeks 0, 1, 6, 12, 18, and 26) over 26 weeks. Week 0 is a screening visit. At weeks 1 and 26, patients will be admitted to the hospital for 24-hour blood sampling, DEXA scans, and brachial artery reactivity tests, as described above, plus X-rays of the hand and feet. After the first visit, they will start taking etanercept, given by self-injection under the skin (like insulin shots) twice a week. Follow-up visits at weeks 6, 12, and 18 will involve evaluations of disease activity and drug side effects through joint examination, blood tests, and questionnaires. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034060 •

Treating Rheumatoid Arthritis with Tripterygium Wilfordi Hook F or Sulfasalazine Condition(s): Rheumatoid Arthritis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)


Purpose - Excerpt: Various forms of the plant extract Tripterygium wilfordi Hook F (TwHF) have been used in China as a remedy for inflammatory diseases, including rheumatoid arthritis. The purpose of this study is to investigate how tolerable, safe, and effective TwHF is for patients with rheumatoid arthritis. Investigators will compare the therapeutic effects of TwHF with Sulfasalazine, an FDA-approved drug for arthritis. Participants in this 24-week study must have had active rheumatoid arthritis for at least six months. Approximately 120 patients will participate. Participants will be assigned to one of two drug-treatment groups, TwHF or Sulfasalazine. They will be given the study drug at each of six clinic visits and will be asked to take two capsules three times each day with meals and water. During the clinic visits, investigators will obtain multiple blood samples; give physical exams; assess swollen, tender, and painful joints; and administer x-rays. Study participants will be compensated up to $260 for their involvement in this study. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00062465 •

A Phase III Study of BMS-188667 in patients with active rheumatoid arthritis and inadequate response to methotrexate Condition(s): Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): Bristol-Myers Squibb Purpose - Excerpt: The purpose of this clinical research study is to learn if BMS-188667 in combination with methotrexate is better than methotrexate alone in subjects that have active rheumatoid arthritis and are not responding to methotrexate. The safety of this treatment will also be studied. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048568

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Autologous Peripheral Blood Stem Cell Transplantation in Patients With Life Threatening Autoimmune Diseases Condition(s): Purpura, Schoenlein-Henoch; Graft Versus Host Disease; Anemia, Hemolytic, Autoimmune; Rheumatoid Arthritis; Churg-Strauss Syndrome; Hypersensitivity Vasculitis; Wegener's Granulomatosis; Systemic Lupus Erythematosus; Giant Cell Arteritis; Pure Red Cell Aplasia; Juvenile Rheumatoid Arthritis; Polyarteritis Nodosa; Autoimmune Thrombocytopenic Purpura; Takayasu Arteritis Study Status: This study is no longer recruiting patients. Sponsor(s): Fairview University Medical Center Purpose - Excerpt: Objectives: I. Determine whether there is prompt engraftment after autologous peripheral blood stem cell transplantation using filgrastim (G-CSF) mobilization in patients with life threatening autoimmune diseases. II. Determine the kinetics of T- and B-cell immune reconstitution after a combination of timed

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plasmapheresis, high dose cyclophosphamide and total lymphoid irradiation, and posttransplant immunosuppression with cyclosporine in these patients. III. Determine whether this treatment regimen beneficially influences the clinical course of these patients. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006055 •

Calcium Supplements for Bone Health in Juvenile Rheumatoid Arthritis Condition(s): Juvenile Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study looks at the effects of taking calcium pills on bone health in young people with juvenile rheumatoid arthritis (JRA). In this 2-year study, children aged 6-18 who have JRA will take either a calcium supplement or a matching placebo (inactive or "dummy" pill) containing no calcium. During the study, researchers and patients will not know if a patient is taking calcium or placebo. We believe that patients who take calcium supplements will have at least a 10 percent greater increase in total body bone mineral density compared to patients who take the placebo. We will evaluate patients at Children's Hospital Medical Center every 6 months for 2 years. During this 2year period, participants in the study will take one multivitamin containing 400 IU (international units) of vitamin D and either 1,000 mg of calcium carbonate (Tums tablets) by mouth or a matching placebo once a day. We will check patients 6 and 18 months after the 2-year treatment period to find out if people in the Tums-treated group maintain any increases in bone formation that occurred during the 2-year treatment period. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000429

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Evaluation of the Efficacy of Combination Treatment with Anakinra and Pegsunercept in Improving Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): Amgen Purpose - Excerpt: The purpose of this study is to evaluate the effect of anakinra (IL-1 ra) and pegsunercept (PEG sTNF-RI) when they are used together in improving the signs and symptoms of rheumatoid arthritis. The study will also evaluate the safety of the combination treatment and its effect on slowing down bone and joint destruction due to rheumatoid arthritis. The results will be compared to the effect when only 1 single medication (anakinra or pegsunercept) is used. Phase(s): Phase II Study Type: Interventional


Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037700 •

Genetics of Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study attempts to identify the genes responsible for rheumatoid arthritis (RA), or inflammation of the joints. It is known that genes play an important role in RA, but their number and significance have not been determined. RA tends to run in families. This study will examine the DNA (hereditary material) of patients with RA and their family members to try to determine which chromosomes(s) contain the genes responsible for the disease. Patients with rheumatoid arthritis and their family members may be eligible for this study. Participants with RA who have a brother or sister with RA will undergo the following procedures: -Review of their medical records Medical history -Examination of the joints -Hand X-rays -Blood tests Participants who 1) do not have RA but who have a relative with the disease, or 2) have RA and a relative other than a brother or sister who has the disease will provide a blood sample or a buccal (cheek) cell sample. Cheek cells are obtained by swishing a small amount of mouthwash in the mouth or by lightly bushing the inside of the cheek with a swab or brush. The samples will be tested for rheumatoid factor, DNA studies, and HLA type (a blood type found on white blood cells). Certain HLA types have been associated with an increased risk or severity of RA. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001678

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Juvenile Rheumatoid Arthritis Condition(s): Juvenile Chronic Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): Amgen Purpose - Excerpt: The purpose of this study is to determine the safety and effectiveness of anakinra in patients with Polyarticular-Course Juvenile Rheumatoid Arthritis, a form of rheumatoid arthritis affecting children. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00037648

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Meloxicam suspension in Juvenile Rheumatoid Arthritis (JRA) Condition(s): Juvenile Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): Boehringer Ingelheim Pharmaceuticals

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Purpose - Excerpt: The purpose of this 6 month study is to determine how safe and effective meloxicam oral suspension (liquid taken by mouth) is in children with JRA. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00034853 •

Oral Collagen for Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This protocol allows us to determine whether doses of CII from 30130ug/day will induce oral tolerance to CII in RA patients. This will be a 2 year MultiCenter Clinical Trial (CT) with the University of Tennessee, Memphis as the Lead Center to determine whether oral administration of 6 different doses of bovine type II collagen (CII) to patients with rheumatoid arthritis (RA) will induce immune tolerance defined as a >30% reduction in IFN gamma/PBMC alpha 1(II)/PBS stimulation index. Patients will be enrolled with stable RA, without stopping DMARDs, NSAIDs or prednisone (equal to or less than 7 1/2 mg daily) and the study will not be restricted to patients with early disease. Patients taking NSAIDS will take misoprostol 100ug bid. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000401

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Safety Study for Remicade Condition(s): Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): Centocor Purpose - Excerpt: To assess the relative risk for serious infection in infliximab-treated patients within the first 22 weeks after initiation of therapy in a population of patients with rheumatoid arthritis (RA) reflective of the demographics (severity of RA, background disease-modifying anti-rheumatic drugs, concomitant diseases) seen in clinical practice. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036387

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Study to Assess Efficacy of Tacrolimus + Methotrexate Vs. Placebo + Methotrexate in Treatment of Rheumatoid Arthritis Condition(s): Rheumatoid Arthritis


Study Status: This study is no longer recruiting patients. Sponsor(s): Fujisawa Healthcare, Inc. Purpose - Excerpt: The purpose of this study is to evaluate the efficacy of the combination of tacrolimus + methotrexate compared to methotrexate alone in the treatment of the signs and symptoms of rheumatoid arthritis over 6 months in patients with partial response to methotrexate. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036153 •

Trial with HuMax-CD4 in Patients with Rheumatoid Arthritis failing treatment with Methotrexate and a TNF-alpha blocker. Condition(s): Rheumatoid Arthritis Study Status: This study is no longer recruiting patients. Sponsor(s): Genmab Purpose - Excerpt: The purpose of this study is to determine whether HuMax-CD4 is effective in the treatment of active rheumatoid arthritis in patients who have failed treatment with Methotrexate and at least one TNF-alpha blocking agent. Phase(s): Phase II; Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00042406

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A multi-center trial to compare the efficacy and safety of three doses of Meloxicam and placebo in patients with Rheumatoid Arthritis. Condition(s): Rheumatoid Arthritis Study Status: This study is completed. Sponsor(s): Boehringer Ingelheim Pharmaceuticals Purpose - Excerpt: A 12-week trial consisting of 5 visits (6 if follow up is needed) to find out how effective and safe three different doses of meloxicam are compared with placebo in Rheumatoid Arthritis. Patient will take one dose of study medication daily. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00042068

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A Phase III study of BMS-188667 in subjects with active rheumatoid arthritis Condition(s): Rheumatoid Arthritis Study Status: This study is completed. Sponsor(s): Bristol-Myers Squibb

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Purpose - Excerpt: The purpose of this clinical research study is to learn if BMS-188667 is safe when co-administered with other approved rheumatoid arthritis medications. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00048932 •

Antifolate Effectiveness in Arthritis Condition(s): Rheumatoid Arthritis; Adjuvant Arthritis Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Office of Dietary Supplements (ODS) Purpose - Excerpt: This study looks at how the arthritis drug methotrexate works in low doses to treat rheumatoid arthritis. (High doses of methotrexate are used to treat some types of cancer.) Methotrexate blocks the action of the B-vitamin known as folic acid. We are studying the biochemical reactions affected by this vitamin because we think that blocking many of these reactions may be necessary for methotrexate to work in treating rheumatoid arthritis. Through these studies, we hope to gain a better understanding of how this drug and related drugs work as treatments for arthritis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000395

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Genetic and Immune Studies of Rheumatoid Arthritis and Related Conditions Condition(s): Arthritis, Psoriatic; Autoimmune Diseases; Joint Diseases; Osteoarthritis; Rheumatoid Arthritis Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This protocol will examine blood, synovial fluid and synovial tissue from patients with rheumatoid arthritis and other chronic inflammatory joint diseases to study genetic and immunologic factors involved in the cause, development and progression of these conditions. Synovial fluid is the lubricating fluid in joints. The synovial membrane is a delicate tissue lining the inner surface of joints, which, in arthritic conditions, thickens and becomes infiltrated with various types of cells. Patients with rheumatoid arthritis and certain patients with other forms of arthritis may be eligible for this study. Those enrolled will be followed periodically for follow-up and disease evaluation. They may undergo the following procedures: 1. Synovial fluid aspiration, when medically indicated (for example, for joint swelling and inflammation). For this procedure, an area of skin around the joint is numbed with an anesthetic, and a needle is inserted into the joint to withdraw a small fluid sample. 2. Periodic blood sampling, not to exceed 450 milliliters (15 ounces) during any 6-week period, for genetic studies of rheumatoid arthritis. The samples are usually taken at the same times that synovial fluid is withdrawn. 3. Synovial tissues, collected by needle biopsy or during


surgical procedures for arthroscopy (examination of the interior of the joint and repair of the joint) or total joint replacement. For the needle biopsy, the skin over the biopsy site is washed and anesthetized. A needle is inserted and fluid is aspirated. The biopsy needle is then inserted through the outer needle and a tissue sample is suctioned. Patients who qualify for other research studies may be invited to participate. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001291 •

Methotrexate Alone Versus Combination of Methotrexate and Subcutaneous Fludarabine for Severe Rheumatoid Arthritis: Safety, Tolerance and Efficacy Condition(s): Arthritis, Rheumatoid; Synovitis Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: The safety profile and efficacy of combination therapy will be evaluated using methotrexate (MTX) and the nucleoside analog fludarabine in 40 patients with severe refractory rheumatoid arthritis. The patients enrolled will be those who have experienced inadequate disease control with MTX alone or in combination with other immunosuppressive drugs such as sulfasalazine (SSZ), cyclosporin A (CsA), or hydroxychloroquine (HCQ). In this randomized, double-blind, placebo controlled trial, patients will be maintained on oral MTX at 17.5 mg/week to which either placebo or subcutaneous fludarabine at 30 mg/m(2) daily for three consecutive days per month will be added for four months. The fludarabine (or placebo) treatment period will be followed by two months of follow-up, at which time patients will be evaluated for response. Patients will be monitored for adverse effects/tolerability, disease activity, and changes in synovial volume as measured by magnetic resonance imaging (MRI). Additionally synovial biopsies will be obtained before and after treatment for investigation of infiltrating cell numbers and phenotypes, cytokine profiles, Th1 versus Th2 responses, and angiogenesis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001677

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Patient Education in Rheumatoid Arthritis and Osteoarthritis Condition(s): Rheumatoid Arthritis; Osteoarthritis Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This project will evaluate the effectiveness and general usefulness of two arthritis patient education programs. The first, the Arthritis Self-Management Program, is a 6-week, community-based program taught in small groups by peer leaders. The second, the Self-Managed Arthritis Relief Therapy (SMART) Program, is a computer-driven program delivered through the mail. Participants in this project are people with rheumatoid arthritis or osteoarthritis who are taking part in the larger long-

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term studies being conducted by ARAMIS (the Arthritis, Rheumatism and Aging Medical Information System). Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000414 •

Positron Emission Tomography and Magnetic Resonance Imaging to Evaluate Synovial Blood Flow in Rheumatoid Arthritis Patients Condition(s): Rheumatoid Arthritis Study Status: This study is completed. Sponsor(s): National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Purpose - Excerpt: This study will test whether positron emission tomography (PET) imaging can be used to measure blood flow to joints in patients with rheumatoid arthritis (RA). It will also compare blood flow measurements using PET with measurements obtained with magnetic resonance imaging (MRI) to determine how useful MRI is in measuring blood flow to joints. Much of the joint damage in RA is caused by the synovium-the lining of the joint. In RA, the synovium increases in size and destroys bone and cartilage. The synovium maintains its growth by forming many new small blood vessels to nourish it. New drug treatments are being developed to stop the growth of these new blood vessels. The effect of these treatments on the synovium is usually measured by performing a biopsy-removing a small piece of synovium for examination under a microscope. The biopsy requires inserting a needle into the joint to withdraw the synovial tissue. This study will see if changes in blood flow can be assessed accurately using noninvasive imaging procedures, such as PET scanning, instead of a biopsy. Patients 18 years of age and older with rheumatoid arthritis who have at least one tender and swollen knee due to synovitis may be eligible for this study. Candidates will be screened with a medical history and physical examination. Participants will have a mold made of the knee to be studied and will have routine blood tests. Women who are able to become pregnant will have a pregnancy test. All participants will then undergo PET and MRI scanning as described below: PET - A needle is used to insert a catheter (small plastic tube) into an arm vein for injection of the radioactive substance H215O. The patient lies in a doughnut-shaped machine (the PET scanner) and a quick scan is done to measure body thickness. Then, a separate scan is taken following each of six or fewer injections of H215O. Each scan lasts about 13 minutes. MRI - The patient lies on a stretcher that is moved into a cylinder containing a magnetic field (the MRI scanner). A special coil is placed over the knee to improve the quality of the images. Earplugs are worn to muffle the loud thumping sound produced by electrical switching of the magnetic fields during the imaging. A contrast agent called gadolinium is injected through a catheter into a vein to improve the quality of the images. An intercom system permits the patient to communicate with the technician at all times during the procedure. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00014794


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Study of Gammalinolenic Acid for Juvenile Rheumatoid Arthritis Condition(s): Juvenile Rheumatoid Arthritis Study Status: This study is completed. Sponsor(s): FDA Office of Orphan Products Development; University of Massachusetts Medical Center Purpose - Excerpt: Objectives: I. Determine the efficacy and safety of gammalinolenic acid in the treatment of childhood arthritis. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004420

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Study of infliximab in combination with methotrexate for the treatment of patients with polyarticular juvenile rheumatoid arthritis Condition(s): Juvenile Rheumatoid Arthritis Study Status: This study is completed. Sponsor(s): Centocor Purpose - Excerpt: Research study to evaluate the safety and effectiveness of an investigational drug is currently being conducted in children diagnosed with polyarticular juvenile rheumatoid arthritis with active disease while receiving methotrexate therapy. Aim of the international study is to evaluate the efficacy and safety of the drug in patients with active JRA/JIA who are receiving methotrexate therapy. Study is being conducted in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, United Kingdom, and USA. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00036374

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The Safety and Efficacy of Chicken Type II Collagen on Uveitis Associated with Juvenile Rheumatoid Arthritis Condition(s): Arthritis, Juvenile Rheumatoid; Uveitis Study Status: This study is completed. Sponsor(s): National Eye Institute (NEI) Purpose - Excerpt: Current treatment modalities for uveitis associated with juvenile rheumatoid arthritis have not been beneficial in the juvenile population. A new approach for treating patients with presumed autoimmune disorders is oral tolerance therapy. Chicken type II collagen (Colloral) is being developed as an oral tolerance therapy for the treatment of rheumatoid arthritis. This open label pilot study will describe the safety of chicken type II collagen added to current anti-inflammatory medications as treatment for patients with uveitis associated with juvenile rheumatoid arthritis. The primary ophthalmic outcomes of this study will be a change from baseline in the number of anterior chamber cells and the number and dosage of antiinflammatory medications. Secondary outcomes for JRA will include change in physician's global assessment, parent/patient assessment of overall well-being,

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functional assessment, number of joints with active arthritis, number of joints with limited range of motion, and erythrocyte sedimentation rate (ESR). Secondary outcomes for uveitis will include change in visual acuity, vitreous haze, and anterior chamber flare. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001614 •

TNRF:Fc to Treat Eye Inflammation in Juvenile Rheumatoid Arthritis Condition(s): Juvenile Rheumatoid Arthritis; Uveitis Study Status: This study is completed. Sponsor(s): National Eye Institute (NEI) Purpose - Excerpt: This study will investigate the safety and effectiveness of the drug TNFR:Fc to treat uveitis (eye inflammation) in patients with juvenile rheumatoid arthritis. In other studies, TNFR:Fc significantly reduced joint pain and swelling in adult patients with rheumatoid arthritis, and the Food and Drug Administration has approved the drug for that use. Because medicines for arthritis often help patients with eye inflammation, this study will examine whether TNFR:Fc can help patients with uveitis. Patients with uveitis who are not responding well to standard treatment, such as steroids, and patients who have side effects from other medicines used to treat their uveitis or have refused treatment because of possible side effects may be eligible for this study. Candidates will be screened with a medical history, physical examination, and eye examination. The eye exam includes a check of vision and eye pressure, examination of the back of the eye (retina), and front of the eye, including measurements of protein and inflammation. Candidates will also undergo fluorescein angiography-a procedure in which photographs are taken of the retina to see if there is any leakage in the eye's blood vessels. A blood test and joint evaluation will also be done. Study participants will be given a shot of TNFR:Fc twice a week for up to 12 months and may continue other medicines they may be taking, such as prednisone or methotrexate. They will have follow-up examinations at week two and months one, two, three and four. Those who wish to continue treatment after the fourth month can receive the drug for another eight months and will have follow-up exams at months six, nine and 12, and one month after treatment ends. Each follow-up visit will include a repeat of the screening exams and an evaluation of side effects or discomfort from the medicine. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001862

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions.


The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “rheumatoid arthritis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON RHEUMATOID ARTHRITIS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “rheumatoid arthritis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on rheumatoid arthritis, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Rheumatoid Arthritis By performing a patent search focusing on rheumatoid arthritis, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.


The following is an example of the type of information that you can expect to obtain from a patent search on rheumatoid arthritis: •

1-[4-(4-Sulfanilyl)phenyl] urea and derivatives in compositions and methods of treating rheumatoid arthritis and immune complex diseases Inventor(s): Jones; Howard (Holmdel, NJ), Jacobus; David P. (Princeton, NJ), Jensen; Norman P. (New Providence, NJ) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 4,338,334 Date filed: February 29, 1980 Abstract: The invention relates to 1-[4-(4-sulfanilyl)phenyl] urea and derivatives thereof in pharmaceutical compositions and in methods of treating rheumatoid arthritis and immune complex diseases such as dermatitis herpetiformis. Excerpt(s): The present invention is concerned with pharmaceutical compositions containing as an active ingredient the known compound 1-[4-(4-sulfanilyl)phenyl]urea and known derivatives thereof, and the use of these compositions, or the compounds themselves, in treating rheumatoid arthritis, muscular dystrophy, immune complex diseases, including dermatitis herpetiformis, celiac disease, and certain forms of leukemia, and autoimmune endocrine diseases such as juvenile diabetes. Dapsone (4,4'diaminodiphenylsulfone) is an established antimalarial and antileprotic agent. It has been found to be effective in treating rheumatoid arthritis; see McConkey et al., Rheumatology and Rehabilitation, 1976, 15, 230-234. It has also been employed in clinical treatment of dermatitis herpetiformis; see Lorincz and Pearson, "Sulfapyridine and Sulfone Type Drugs in Dermatology", Arch. Derm. 85: 42-56 (1962). Derivatives of diaminodiphenyl sulfone have been described in the literature for many years; see E. H. Northey, "Sulfonamides", A.C.S. monograph No. 106 (1948). The compound 1-[4-(4sulfanilyl)phenyl]urea, as well as a variety of substituted diphenyl sulfones have been found useful in reducing mortality and decreasing lesion incidence of poultry exposed to Marek's disease. See U.S. Pat. Nos. 3,689,671; 3,702,362; 3,715,375; 3,775,403; 3,775,444; and 3,786,050. However, none of these patents suggests the use of the substituted diphenyl sulfones disclosed therein as agents for treating rheumatoid arthritis, muscular dystrophy, or immune complex diseases. The compound 1-[4-(4-sulfanilyl)phenyl]urea, and several substituted diphenyl sulfones have been found to inhibit the incorporation of chloline in chick peritoneal macrophages, an activity associated with the ability of such compounds to suppress growth or function of Marek's disease virus. See Shigeura et al., "Metabolic Studies on Diphenylsulfone Derivatives in Chick Macrophages", Biochemical Pharmacology, Vol. 24, pp. 687-691 (1975). Web site: http://www.delphion.com/details?pn=US04338334__

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Acyl cyanoguanidines for treating rheumatoid arthritis Inventor(s): Shen; Tsung-Ying (Westfield, NJ), Jones; Howard (Holmdel, NJ) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 4,202,903 Date filed: September 30, 1975

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Abstract: Certain novel acyl cyanoguanidines, their preparation, pharmaceutical compositions and novel methods of treating inflammation and autoimmune diseases such as rheumatoid arthritis are disclosed. Excerpt(s): In spite of the extensive antiinflammatory research in the past two decades there is still an obvious need for an effective and well-tolerated agent for the treatment of rheumatoid arthritis. Conventional antiinflammatory-analgesic-antipyretic agents, such as aspirin, and many experimental new drugs under clinical evaluation, are mostly effective in providing symptomatic relief of the acute syndrome only. As a consequence, the antirheumatic actions of two other remedies, gold and particularly D-penicillamine, have received renewed interest in the past few years. The clinical efficiancy of both drugs has been confirmed by well-controlled multi-center clinical studies. Impressed by these findings, a growing population of rheumatologists have expressed the opinion that compounds possessing properties similar to D-penicillamine should be a valuable contribution to medicine in this important field. Thus it is an important discovery that acyl cyanoguanidines possess immunological properties similar to that of Dpenicillamine, being of value in the treatment of rheumatoid arthritis and related inflammatory disorders, as well as antiinflammatory properties. 1-[3'-(4'methylthionicotinoyl)]-3-cyanoguanidine. Another aspect of this invention relates to the novel pharmaceutical compositions for treating inflammation and autoimmune diseases, such as rheumatoid arthritis, comprising a non-toxic pharmaceutically acceptable carrier and a compound of the formula I, supra, wherein R is as defined above. Web site: http://www.delphion.com/details?pn=US04202903__ •

Anti immune complex antibody for determining SLE, rheumatoid arthritis or tetanus Inventor(s): Kasahara; Yasushi (Tokyo, JP), Soma; Kazunori (Tokyo, JP) Assignee(s): Fujizoki Pharmaceutical Co., Ltd. (Tokyo, JP) Patent Number: 4,544,640 Date filed: April 7, 1983 Abstract: An antibody is obtained by using as an antigen a complex of an antigen and the F(ab').sub.2 fragment of the human antibody of this antigen or an aggregate of the F(ab').sub.2 fragment of human immunoglobulin. This antibody reacts with an immune complex in a blood serum of a patient of systemic lupus erythematosus and with an immune complex in a blood serum of a patient of rheumatoid arthritis, and it does not react with an aggregated IgG. The amount of immune complex in a blood serum is easily and exactly determined by using this antibody. Excerpt(s): This invention related to a novel antibody capable of detecting an immune complex and relates to its preparation method and use. Immune complex is the combined product of an antigen, an antibody and a complement. When this immune complex is formed in a human body, the immune complex is usually rendered harmless by a leucocyte or a macrophage. However, when a large quantity of antigen exists in a human body, or when an antigen the antibody of which forms with difficulty, exists in a human body, the amount of immune complex increases, and it causes various diseases such as acute glomerulonephritis, angitis, chronic urticaria, and thrombocytopenia. Various measuring methods of this immune complex are known such as the method utilizing a reaction of complement or rheumatoid factor with the immune complex, the method utilizing a reaction of the Fc receptor with the immune complex, and various


physicochemical methods such as the gel filtration method, the sucrose density gradient centrifuge and precipitation with polyethyleneglycol. However, the method using the complement or rheumatoid factor and the method using Fc receptor have a fatal defect in that these methods cannot distinguish between aggregated IgG and the immune complex. The physicochemical methods are complicated and they are insufficient in specificity. Web site: http://www.delphion.com/details?pn=US04544640__ •

Antibody against rheumatoid arthritis specific protein Inventor(s): Yamanaka; Naoki (Nagoya, JP), Yoshida; Makoto (Kawasaki, JP) Assignee(s): Asahi Medical Co., Ltd. (Tokyo, JP), Medecs Co., Ltd. (Nagoya, JP) Patent Number: 4,950,741 Date filed: February 16, 1988 Abstract: A substantially pure rheumatoid arthritis specific protein (RASP) and an antibody against the rheumatoid arthritis specific protein (anti-RASP antibody) are disclosed. The RASP is found specifically in the serum or plasma of a patient suffering from rheumatoid arthritis, and may be detected using an anti-RASP antibody easily and effectively. Therefore, the anti-RASP antibody of the present invention is useful for the diagnosis of rheumatoid arthritis by the criterion of the presence of RASP. Excerpt(s): (3) an electrophoretic mobility of about 0.30 to 0.45 in terms of a value as measured by a two-dimensional electrophoresis method as defined herein. and which antibody has a molecular weight of about 150,000 to 160,000 in terms of a value as measured by an SDS-polyacrylamide gel electrophoresis method as defined herein. Now, a substantially pure rheumatoid arthritis specific protein of the present invention will be explained below. Web site: http://www.delphion.com/details?pn=US04950741__

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Antigens recognized by antibodies to rheumatoid arthritis, their preparation and their applications Inventor(s): Serre; Guy (Toulouse, FR), Vincent; Christian (Lauzerville, FR), Somme; Gerard (Bures Sur Yvette, FR) Assignee(s): Biomerieux S.A. (Marcy L'Etoile, FR) Patent Number: 5,888,833 Date filed: June 3, 1994 Abstract: The present invention relates to antigens extracted from mammalian malpighian epithelia, in particular rat esophageal epithelium or human epidermis, which are specifically recognized by the autoantibodies present in patients suffering form rheumatoid arthritis in respect of antigenic determinants in common with filaggrin and human profilaggrin, as well as to the antigenic proteins of which said antigens are composed and to the peptide fragments derived therefrom. The invention relates to the use of these antigens, proteins and peptide fragments, and that of filaggrin and human profilaggrin, for the preparation of antigenic compositions, and to their applications, in particular for the diagnosis of rheumatoid arthritis. The invention also relates to the preparation of antibodies directed towards these antigens, and to their applications.

Patents 361

Excerpt(s): The present invention relates to the use of human filaggrin and antigens related thereto for the diagnosis or treatment of rheumatoid arthritis (RA). The presence of autoantibodies directed towards cellular components is the general feature of autoimmune diseases such as RA, systemic lupus erythematosus, scleroderma or polymyositis. Among the many types of autoantibodies identified in these diseases, those specifically present in patients suffering from RA and reacting with an esophageal epithelial antigen were described for the first time by B. J. J. Young et al. in Br. Med. J. 2:97-99, (1979). These autoantibodies were named at the time "antikeratin antibodies". Hitherto, it was commonly accepted that they were directed towards cytokeratins. These autoantibodies specific to RA are at the present time detected and titrated by indirect immuno-fluorescence (IIF) on transverse cryosections of rat esophagus. Web site: http://www.delphion.com/details?pn=US05888833__ •

Anti-human stromelysin monoclonal antibody and method for diagnosis of rheumatoid arthritis by enzyme immunoassay Inventor(s): Hayakawa; Taro (406, Mukaigaoka 3-chome, Tenpaku-ku, Nagoya-shi, Aichi-ken, 468, JP), Kodama; Shuji (603, Takaokasukaihaitsu, 1868, Nagae, Takaoka-shi, Toyama-ken, 933, JP), Shinmei; Masayoshi (4-4, Nakaaral 4-chome, Tokorozawa-shi, Saitama-ken, 359, JP), Okada; Yasunori (32, Wakamiya 2-chome, Matto-shi, Ishikawaken, 924, JP), Iwata; Kazushi (190 Ikarihigashimachi, Takaoka-shi, Toyama-ken, 933, JP), Korin; Yumi (Fu-134, Takamatsucho, Kahoku-gun, Ishikawa-ken, 929-12, JP), Yoshida; Shinichi (13-16, Nakajima 4-chome, Toyama-shi, Toyama-ken, 930, JP) Assignee(s): none reported Patent Number: 5,834,212 Date filed: April 6, 1995 Abstract: Anti-human stromelysin monoclonal antibodies reactive with latent and active forms of stromelysin without discrimination between the two, each being immunoreactive with only one of the antigenic determinants of human stromelysin, are provided. The use of a combination of two such monoclonal antibodies which specifically react with different antigenic determinants of human stromelysin renders it possible to accurately determine the amount of human stromelysin in human body fluids, and thus to carry out the diagnosis of rheumatoid arthritis.There are thus provided said monoclonal antibodies per se, a sandwich enzyme immunoassay for the determination of the amount of human stromelysin in human body fluid samples using a combination of two such monoclonal antibodies, and a method for the diagnosis of rheumatoid arthritis using said immunoassay. Excerpt(s): The present invention relates to anti-human stromelysin monoclonal antibodies, an enzyme immunoassay using such monoclonal antibodies, and a method for the diagnosis of rheumatoid arthritis by determination, on the basis of said immunoassay, of the amount of human stromelysin present in samples as the sum of the amount of latent stromelysin and that of active stromelysin. Stromelysin, also called proteoglycanase or MMP-3 (matrix metalloproteinase-3), is a substance produced in fibroblasts or tumor cells stimulated by different cytokines, growth factors, etc. In the live body, it is present in blood or synovial fluids, besides being produced locally in joints of patients with rheumatoid arthritis. Stromelysin has been considered to play an important role in the intraarticular cartilage destruction in patients with rheumatoid arthritis since it decomposes gelatin, laminin, type IV collagen, fibronectin etc. in


addition to proteoglycan and type IX collagen, both being important extracellular matrices for articular cartilage. Web site: http://www.delphion.com/details?pn=US05834212__ •

Benzoylecgonine or benzoylnorecgonine as active agents for the treatment of rheumatoid arthritis Inventor(s): Somers; Lowell (16630 Mountain View Rd., Desert Hot Springs, CA 92240) Assignee(s): none reported Patent Number: 4,512,996 Date filed: February 29, 1984 Abstract: Pharmaceutical formulation containing benzoylecgonine and/or benzoylnorecgonine and their use in the treatment of rheumatoid arthritis are disclosed. Excerpt(s): This invention relates to pharmaceutical compositions and dosage forms and their use in the treatment of chronic disease. More particularly, it concerns pharmaceutical compositions and dosage forms and their use in the treatment of the pain and locomotor dysfunction of rheumatoid arthritis. Rheumatoid arthritis is a serious, often crippling, disease characterized by pain and locomotor dysfunction. As pointed out by Nickander et al in their article "Nonsteroidal Antiinflammatory Agents" which appeared at Ann. Rev. Pharmacol. Toxical., 1979, 19:469-90, this sort of pain and locomotor dysfunction are among man's most common and frustrating afflictions. The gravity of this disease has led to the investigation and/or adoption of a wide range of drugs for its alleviation. Aspirin has been commonly used since the turn of this century. Other major drugs for arthritis have historically included indomethacin, other salicylates, phenylbutazone, steroids and gold. While more recently, fenoprofen, ibuprofen, naproxen, sulindac and tolmetin have been approved for use in the United States. While these compounds can offer antiinflammatory, antipyretic and analgesic effects and have proven helpful in the management of rheumatoid arthritis in many patients, when combined with other modalities such as proper rest, exercise, physical therapy and surgery, they are less than ideal. Many exhibit serious side-effects with many patients, particularly gastrointestinal damage and renal toxicity. Each of these materials have the failing of being far from universal--some patients will respond to one material while others respond favorably only to others. Web site: http://www.delphion.com/details?pn=US04512996__

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Benzoylecgonine, benzoylnorecgonine and ecgonine as active agents for the treatment of rheumatoid arthritis and osteoarthritis Inventor(s): Somers; Lowell M. (46861 Madison, Indio, CA 92201) Assignee(s): none reported Patent Number: 4,556,663 Date filed: August 31, 1984 Abstract: Pharmaceutical preparations containing benzoylecgonine, benzoylnorecgonine, and ecgonine are disclosed for treatment of rheumatoid arthritis, and in case of benzoylecgonine and benzoylnorecgonine for the treatment of osteoarthritis as well. The pharmaceutical preparations containing the active

Patents 363

compounds are administered to human patients in effective amounts orally, through inhalation, transdermally or through the mucosal membranes. Excerpt(s): This invention relates to pharmaceutical compositions, dosage forms and their use in the treatment of chronic disease. More particularly, it concerns pharmaceutical compositions and dosage forms and their use in the treatment of the pain and locomotor dysfunction of rheumatoid arthritis, and osteoarthritis. Rheumatoid arthritis is a serious, often crippling, disease characterized by pain and locomotor dysfunction. As pointed out by Nickander et al in their article "Nonsteroidal Antiinflammatory Agents" which appeared at Ann. Rev. Pharmacol. Toxicol., 1979, 19:469-90, this sort of pain and locomotor dysfunction are among man's most common and frustrating afflictions. The gravity of this disease has led to the investigation and/or adoption of a wide range of drugs for its alleviation. Aspirin has been commonly used since the turn of this century. Other major drugs for arthritis have historically included indomethacin, other salicylates, phenylbutazone, steroids and gold. While more recently, fenoprofen, ibuprofen, naproxen, sulindac and tolmetin have been approved for use in the United States. While these compounds can offer antiinflammatory, antipyretic and analgesic effects and have proven helpful in the management of rheumatoid arthritis in many patients, when combined with other modalities such as proper rest, exercise, physical therapy and surgery, they are less than ideal. Many exhibit serious side effects with many patients, particularly gastrointestinal damage and renal toxicity. Each of these materials have the failing of being far from universal--some patients will respond to one material while others respond favorably only to others. Web site: http://www.delphion.com/details?pn=US04556663__ •

Biological treatment for rheumatoid arthritis Inventor(s): Smith; J. Bruce (Philadelphia, PA), Fort; John G. (Philadelphia, PA) Assignee(s): Thomas Jefferson University (Philadelphia, PA) Patent Number: 5,723,503 Date filed: September 28, 1994 Abstract: A method of treating rheumatoid arthritis is provided which involves administering an effective amount of allogeneic mononuclear cells or a molecule derived from these cells to an individual having rheumatoid arthritis. Also provided are compositions for the treatment of rheumatoid arthritis. Excerpt(s): Tens of millions of people in the United States suffer from rheumatoid arthritis (RA) or a related disease. While arthritis results in significantly fewer deaths as compared to cancer and cardiovascular diseases, there is no other group of diseases that causes so much suffering in so many people for such a prolonged period of time. Because of the tendency to disable and even permanently cripple individuals suffering from arthritis, this group of diseases is extremely important both socially and economically. There is presently no satisfactory cure for rheumatoid arthritis because its cause is unknown. In addition, many of the therapeutic agents administered to alleviate pain and inflammation associated with the disease, such as disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory agents (NSAIDs), produce intolerable side effects. The understanding of the RA disease process has been considerably enhanced by the application of molecular immunology techniques. It is now generally accepted that rheumatoid arthritis represents a multifactorial disease with environmental factors (infectious agents or toxins), genetic susceptibility, and


immune or autoimmune responses playing inter-connected roles. After initiation of the disease process, it is believed that activated T cells and their products are responsible for the progressive destruction of articular cartilage and sub-chondral bone that is characteristic of rheumatoid arthritis. Advances in the understanding of the immunopathogenesis of rheumatoid arthritis have been coupled with immunologic strategies for treatment. Immunologic approaches to the treatment of rheumatoid arthritis are important and desirable given the potential toxicities associated with most remittive therapy in use today and the continued poor prognosis of rheumatoid arthritis despite aggressive drug treatment. Web site: http://www.delphion.com/details?pn=US05723503__ •

Collagen mimetic and method of treating rheumatoid arthritis using same Inventor(s): Braswell; A. Glenn (6100 Lake Forest Dr., NE., Suite 400, Atlanta, GA 30328), Ahmed; Aftab J. (Marina Del Ray, CA) Assignee(s): Braswell; A. Glenn (Atlanta, GA) Patent Number: 5,849,323 Date filed: June 12, 1997 Abstract: A collagen mimetic peptide having the nine amino acid sequence glycineproline-hydroxyproline-glycine -proline-glutamine-glycine-methionine-glycine, and analogs thereof is described. The collagen mimetic peptide may be included within a pharmaceutical composition also containing a pharmaceutically acceptable carrier and/or animal tissue. The collagen mimetic peptide is used in a treatment of rheumatoid arthritis by orally administering the collagen mimetic in an amount effective to reduce or alleviate one or more symptoms associated with rheumatoid arthritis. Excerpt(s): This invention relates to a specific collagen mimetic peptide, pharmaceutical compositions containing the peptide, and a method of treating rheumatoid arthritis through the oral administration of the peptide and/or pharmaceutical composition. Rheumatoid arthritis is an autoimmune disease wherein the immune system of the body mistakenly perceives the body's own collagen as foreign and mounts an abnormal immune response against it. Rheumatoid arthritis is characterized by persistent swollen and inflamed joints, and progresses into the destruction of cartilage and the erosion of bone, ultimately leading to destruction of joints. Collagen, in particular Type II collagen, is a major component of cartilage that is particularly affected. Known treatments for arthritis have involved the use of nonspecific immunosuppressive drugs which suppress the entire immune system and are incapable of selectively suppressing the abnormal autoimmune response. This restraint of the immune system also increases the risk of infection. In addition, prolonged use of such drugs can entail severe toxic side effects. Moreover, such immunosuppressive drugs are only partially effective in mitigating symptoms of rheumatoid arthritis, and this partial effectiveness greatly decreases even more over time. Web site: http://www.delphion.com/details?pn=US05849323__

Patents 365

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Combination therapy for rheumatoid arthritis Inventor(s): Ridolfo; Anthony S. (Zionsville, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 4,355,029 Date filed: June 1, 1981 Abstract: A therapeutic method for treating rheumatoid arthritis in which benoxaprofen plus aspirin are administered once a day and aspirin alone three times a day, all dosages being given at six hour intervals. Excerpt(s): This invention provides a novel treatment method for rheumatoid arthritis and other related inflammatory conditions, utilizing combination drug therapy in part, such as a combination of benoxaprofen, a lipoxygenase inhibitor, and a cyclo-oxygenase inhibitor such as aspirin. According to my invention, patients suffering from rheumatoid arthritis are administered from 200 to 800 milligrams of benoxaprofen and from 325 to 1170 of aspirin once a day and then at 6 hour intervals during the remainder of the 24 hour period from 325 to 1170 milligrams of aspirin alone. Preferably, the rheumatoid arthritis patient is given 600 mg. of benoxaprofen plus 975 milligrams (15 grains) of aspirin once a day and 975 milligrams of aspirin alone at 6 hour intervals. The regimen is then repeated on a daily basis. The basis for the enhanced therapeutic effect from my novel process is the use of drugs acting at different sites of the inflammatory process. Improvement occurs even though blood levels of benoxaprofen are decreased with the concomitant addition of aspirin. It is an advantage of this invention that in the combination of a lipoxygenase inhibitor such as benoxaprofen and a cyclo-oxygenase inhibitor, each drug can be employed at dose levels lower than the commonly accepted effective dose for the individual drug. Benoxaprofen, 2-(2-p-chlorophenyl-5benzoxazolyl)propionic acid, is disclosed in Example 2 of U.S. Pat. Re No. 29,608 reissued April 11, 1978. Web site: http://www.delphion.com/details?pn=US04355029__

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Compositions, methods and kits for treating rheumatoid arthritis Inventor(s): Albert; Daniel A. (Philadelphia, PA) Assignee(s): Super Gen, Inc. (Dublin, CA) Patent Number: 6,362,176 Date filed: July 20, 2000 Abstract: Disclosed are methods of treating rheumatoid arthritis by coadministering synergistic effective amounts of pentostatin and methotrexate to a host in need thereof, and kits and compositions that include pentostatin and methotrexate. Excerpt(s): This invention relates to treatment of rheumatoid arthritis through coadministration of pentostatin and methotrexate and analogs and derivatives thereof. Rheumatoid arthritis (RA) is a systematic inflammatory condition that results in swelling, pain, loss of motion, and tenderness of target joints throughout the body. RA is characterized by chronically inflamed synovium that is densely crowded with lymphocytes. The synovial membrane, which is typically one cell layer thick, becomes intensely cellular and assumes a form similar to lymphoid tissue, thus including vessels, dendritic cells, T, B, and NK cells, macrophages, and clusters of plasma cells. Additionally, there is often a plethora of immunopathological mechanisms at work,


including antigen-antibody complexes, polymorphonuclear neutrophils, inflammatory T cells, and activated macrophages. Eventually, these processes result in destruction of the integrity of the joint, resulting in deformity and permanent loss of function. A more detailed description of the etiology and physiology of RA can be found in Zvaifler, N., "Etiology and Pathogenesis of Rheumatoid Arthritis in Arthritis and Allied Conditions" 659-73 (ed. D. M. McCarty). This document, and all other documents or references, cited to herein are incorporated by reference as if reproduced completely herein. Rheumatoid arthritis is a common disease affecting 1 to 2% of the world's population with a female to male predominance of 3-4:1. The peak incidence is in the third to fourth decade. Once acquired the disorder is chronic; therefore the prevalence of the disease increases as one examines increasing age groups. The disease is of unknown cause, although genetics may impact the risk of developing rheumatoid arthritis. Although it is not certain, some common infection or infections might trigger the autoimmune process in susceptible individuals. Environmental influences are not thought to play a major role in the development of the disease. Interestingly, exogenous estrogens in the form of BCPS appear to reduce the risk. Web site: http://www.delphion.com/details?pn=US06362176__ •

Diagnosing autoimmune rheumatoid arthritis by measuring proteolytic activity of.alpha.sub.2 -macroglobulin Inventor(s): Spear; Gregory T. (Forest Park, IL), Skosey; John L. (Chicago, IL), Gaspar; Alexander M. (Chicago, IL), Ganea; Doina (Elmhurst, IL), Teodorescu; Marius C. (Westchester, IL) Assignee(s): University of Illinois, Board of Trustees (Urbana, IL) Patent Number: 4,499,186 Date filed: December 30, 1982 Abstract: A method for diagnosis of rheumatoid arthritis and related autoimmune diseases comprises blocking calcium ions contained in a blood sample, effecting hydrolysis of a selected substrate in the presence of.alpha.sub.2 -macroglobulin (.alpha.sub.2 M) from the blood sample, and determining the extent of hydrolysis of the substrate. Preferably,.alpha.sub.2 M in plasma is incubated with a hydrolyzable chromogenic substrate and the liberated chromogen is determined spectrophotometrically. A diagnostic kit is also provided. Excerpt(s): The invention described herein was made in the course of work supported in part by NCI Grant CA 21399 and in part by NIH Grant AM 28469. It is well-known that some diseases have an autoimmune pathogenetic mechanism. Among these are rheumatoid arthritis, systemic lupus erythematosus, and chronic active hepatitis. A general increase in the level of gammaglobulins (antibodies) often accompanies an increase in the level of a particular antibody or antibodies in patient serum. These observations have led to the suggestion that polyclonal (general) activation of Blymphocytes is involved in the disease process and might even precede the emergence of a particular antibody. For example, in rheumatoid arthritis the symptoms may appear before the characteristic antibody, i.e., the rheumatoid factor, develops. On the other hand, other arthritides are known to have no systemic autoimmune basis and are commonly described as "sero-negative". These include Reiter's syndrome, ankylosing spondylitis, psoriatic arthritis, osteo-arthritis, and gout. Web site: http://www.delphion.com/details?pn=US04499186__

Patents 367

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Diagnostic technique for rheumatoid arthritis Inventor(s): Chang; Jin-Lai (1648 Gilberto Dr., Glendale Heights, IL 60137), Skosey; John L. (4932 S. Kimbark, Chicago, IL 60615), Teodorescu; Marius C. (10547 Essex, Westchester, IL 60153) Assignee(s): none reported Patent Number: 4,402,934 Date filed: October 30, 1980 Abstract: A method for diagnosis of rheumatoid arthritis and related diseases comprises determination of polyclonal lymphocyte activation in B-cells cultured in the presence of patient serum. A diagnostic kit is also provided. Excerpt(s): Rheumatic diseases affect a significant proportion of the population, crippling many people and having only a palliative treatment at best. Diagnosis of rheumatic diseases is difficult and uncertain, and many patients escape classification until the disease has progressed to a stage where serious damage is evident. The classification of the different rheumatic diseases, including rheumatoid arthritis, is based on both clinical and laboratory data, and the same criteria are used to determine the efficiency of any selected treatment. In all of the rheumatic diseases, the common denominator is an abnormal function of the immune system. This abnormal function is suggested by the appearance of antibodies against a patient's own structures and also by the beneficial effect of immunosuppressive or cytotoxic drugs which destroy cells involved in the immune mechanisms. It has been shown that in some of these diseases the B-cells that produce antibodies are overactive, and produce antibodies against a variety of antigens, including some to which they may not have been previously exposed. Another relatively common feature is the increase in the serum immunoglobulin with polyclonal character. From such observations, it has been ascertained that B-cells programmed to produce antibodies against self antigens are present in normal individuals. It has likewise been suggested that polyclonal B-cell activation may be the cause of some autoimmune diseases. Despite such studies of rheumatic diseases, there remains a critical need for a diagnostic technique capable of providing, with suitable certainty, an early diagnosis of the incidence of such diseases. This is especially true of the crippling diseases, such as, particularly, rheumatoid arthritis. Web site: http://www.delphion.com/details?pn=US04402934__

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Drug for the treatment of rheumatoid arthritis Inventor(s): Okumura; Ko (Chiba, JP), Miyake; Sachiko (Tokyo, JP), Nishida; Tadashi (Osaka, JP), Yagita; Hideo (Tokyo, JP) Assignee(s): Kanebo, Ltd. (Tokyo, JP) Patent Number: 5,855,888 Date filed: October 17, 1996 Abstract: A drug for the treatment of rheumatoid arthritis, which comprises as an active ingredient a monoclonal antibody which recognizes specifically extracellular region of human VLA-2. Preferable drug for the treatment of rheumatoid arthritis comprises as an active ingredient a monoclonal antibody which recognizes specifically extracellular region of human VLA-2,.alpha. chain. The above drug for the treatment of rheumatoid


arthritis can suppress swelling due to arthritis in rheumatoid arthritis with low toxicity and hence is useful for the treatment of rheumatoid arthritis. Excerpt(s): This application is a 371 of PCT/JP95/00527 filed Mar. 22, 1995. This invention relates to a drug for the treatment of rheumatoid arthritis which comprises as an active ingredient a monoclonal antibody which can specifically recognize extracellular region of human VLA-2. Rheumatoid arthritis (hereinafter, abbrebiated as "RA") is a chronic inflammatory disease which shows an inflammatory symptom mainly in the articular synovial membrane, where various inflammatory cells permeate into synovial fluid through hemangioendotheliocytes of synovial membrane. It is assumed that the pathological symptoms may be participated by immunological mechanism, and the symptoms may become a trigger of immuno-response, but it is still difficult to specify the mechanism. It is also important to make clear the reason why the inflammatory symptoms are maintained at the synovial membrane even after the cause of the disease has been removed. A series of processes of these inflammation symptoms, particularly chronicity and duration thereof, will be deeply participated by lymphocytes which take charge of immunization. Web site: http://www.delphion.com/details?pn=US05855888__ •

Free fatty acids for treatment or propyhlaxis of rheumatoid arthritis arthritis Inventor(s): Rubin; David (San Diego, CA) Assignee(s): Century Laboratories, Inc. (Port Washington, NY) Patent Number: 4,843,095 Date filed: August 7, 1987 Abstract: Free fatty acids form fish oil, DHA and EPA, are useful in treating rheumatoid arthritis. The free fatty acids were an order of magnitude more effective in treating arthritis than unhydrolyzed fatty acids derived from fish oil. Excerpt(s): The present invention relates to the use of free fatty acids which can be used to treat or provide effective prophylaxis against rheumatoid arthritis. Rheumatoid arthritis is a serious, often crippling, disease characterized by pain and locomotor dysfunction. This sort of pain and dysfunction are among the most common and frustrating afflictions. The gravity of this disease has led to the investigation and/or adoption of a wide range of drugs for its alleviation. Aspirin has been commonly used since the turn of this century. Other major drugs used to treat arthritis include indomethacin, other salicylates, phenylbutazone, steroids, and gold. Other compounds which have been used to treat arthritis are fenoprofen, ibuprofen, naproxen, sulindac, and tolmetin. While the known compounds can offer anti-inflammatory, antipyretic, and analgesic effects, and have proven helpful in the management of rheumatoid arthritis in many patients, when combined with other modalities such as proper rest, exercise, physical therapy, and surgery, they are less than ideal. Many of these medications exhibit serious side effects with many patients, particularly gastrointestinal damage and renal toxicity. None of these materials is universally useful in treating rheumatoid arthritis, as some patients will respond to one material while others respond favorably only to others. Web site: http://www.delphion.com/details?pn=US04843095__

Patents 369

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Heteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid arthritis Inventor(s): Colwell; William T. (Menlo Park, CA), Piper; James R. (Birmingham, AL), DeGraw; Joseph I. (Sunnyvale, CA), Smith; R. Lane (Palo Alto, CA), Sirotnak; Francis M. (New York, NY) Assignee(s): SRI International (Menlo Park, CA) Patent Number: 5,354,751 Date filed: July 12, 1993 Abstract: There is disclosed certain heteroaroyl 10-deazaaminopterin and 5, 10 and 8, 10 di deazaminopterin compounds and their use for treatment of rheumatoid arthritis and related diseases and preparative process.Also disclosed are 10 alkenyl-(and alkynyl) 10deazaminopterins also disclosed for treatment of rheumatoid arthritis and for leukemia and ascites tumors and preparative process. Excerpt(s): The current invention concerns novel antiinflammatory and antineoplastic 10-deazaaminopterin compounds. In particular, the invention concerns heteroaroyl-10deazaaminopterins and 10-alkenyl or 10-alkynyl-10-deazaaminopterins having pronounced antiinflammatory activity, antileukemic and antitumorigenic activity, as well as a method for treatment of inflammatory diseases, leukemia and tumors. Pharmaceutical compositions containing these heteroaroyl-10-deazaaminopterin compounds are also disclosed. The invention further concerns a process for preparation of these compounds. Rheumatoid arthritis, malignant tumors and leukemia are severely debilitating diseases which are often fatal, as in cases of leukemia and malignant growths. Drugs which are currently available and used for treatment of these diseases typically have unpleasant secondary symptoms or are highly toxic. Rheumatoid arthritis is one of a number of forms of proliferative disease, and the development of drugs for amelioration or curing the disease has occupied the attention of research organizations for many years, until most recently without appreciable success. Web site: http://www.delphion.com/details?pn=US05354751__

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HLA-DRBI peptides with specific binding affinity for HLA-DQ molecules: prevention and treatment of rheumatoid arthritis Inventor(s): Luthra; Harvinder S. (Rochester, MN), David; Chella S. (Rochester, MN), Zanelli; Eric (Rochester, MN) Assignee(s): Mayo Foundation for Medical Education and Research (Rochester, MN) Patent Number: 5,965,787 Date filed: August 31, 1995 Abstract: Disclosed are transgenic mice carrying a human HLA-DQ sgene. The transgenic mice are deficient in mouse H-2 class II molecules. Such mice provide animal model systems to identify peptides useful for preventing or treating rheumatoid arthritis. Also disclosed are methods and materials for treating rheumatoid arthritis, including administration of peptides having specific binding affinity for HLA-DQ molecules expressed in a rheumatoid arthritis patient. Excerpt(s): Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis leading to destruction of joints and, sometimes, to severe systemic complications such as vasculitis, amyloidosis or Felty's syndrome. It is widely accepted that a strong genetic component contributes to the susceptibility or resistance to certain human autoimmune diseases


such as RA. Attempts to identify the particular genes involved in these disorders has been an area of major focus for many laboratories. Among the numerous genes studied, those encoding the class I and class II molecules of the human leukocyte antigen (HLA) complex have garnered particular attention. The primary function of HLA-class I and class II molecules is binding and presentation of processed antigenic peptides to T cells bearing receptors specific for particular HLA-peptide complexes. The presentation event plays a pivotal role in shaping the cellular immune repertoire and in shaping the nature and scope of the immune response against a given antigen. In Caucasians, genetic studies initially showed a high prevalence of certain HLA DR subtypes among RA patients. Specifically, predisposition to RA has been linked to the class 30 II HLA-DRB1 locus, and in particular to the DR4 specificity. Within the HLA-DR4 specificity, the Dw4 (DRB1*0401), Dw14 (DRB1*0404/0408), and Dw15 (DRB1*0405) subtypes confer genetic predisposition to RA, while the Dw10 (DRB1*0402) subtype does not confer such genetic predisposition. Nepom et al., Ann. Rev. Immunol. 9: 493-525 (1991); Wordsworth et al., Proc. Natl. Acad. Sci. USA 86: 10049-53 (1989); Ollier et al., Rheum. Dis. Clin. North. Am. 18: 741-59 (1992). Several studies have also shown that the incidence of RA is significantly decreased in patients expressing HLA-DR2 alleles compared with normal controls. Jaraquemada et al., Ann. Rheum. Dis. 45: 627-36 (1986); Deighton et al., Br. J. Rheumatol. 32: 893-98 (1993); Ollier et al., cited supra. Indeed, the DR2Dw12 subtype is associated with a low incidence of RA in the Japanese population. Ohta et al., Human Immunol. 5: 123-32 (1982). For a general review of HLA nomenclature, see Bodmer et al., Tissue Antigens 44: 1-18 (1994), incorporated herein by reference. A further caveat regarding studies aimed at identifying the precise HLA-D region gene responsible for susceptibility to RA is the presence of certain DQB alleles in linkage disequilibrium with particular HLA-DR genes. Such linkages further constrain any conclusions concerning the relative impact of particular HLA-D region genes on RA susceptibility. For example, two allelic forms of DQB, HLA-DQ7 and HLA-DQ8, are associated with the HLA-DR4 genotype in RA susceptibility. Gregersen et al., cited supra; Singal et al., Lancet 2: 111820 (1987); Lanchbury et al., Human Immunol. 26: 59-71 (1989). Moreover, an interesting, albeit small, study analyzing Indian patients with RA showed that 100% possessed the HLA-DQ8 allele, versus 33.3% for the normal subjects. Taneja, Rheumatol. Int. 11: 251-55 (1992). Thus, despite an association of the "Shared Epitope" with RA susceptibility, prior studies have also pointed to a possible role for HLA-DQ alleles in this disease. Web site: http://www.delphion.com/details?pn=US05965787__ •

Human phospholipase activating protein and methods for diagnosis of rheumatoid arthritis Inventor(s): Bomalaski; John S. (11 Chestnut La., Wayne, PA 19087), Clark; Mike A. (15 Westmore Dr., Denville, NJ 07835), Shorr; Robert (36 Overbrook Pky., Wynnewood, PA 19096) Assignee(s): none reported Patent Number: 5,367,063 Date filed: November 4, 1993 Abstract: The invention provides methods for detecting elevated levels of phospholipase A.sub.2 activating protein in persons suspected of having rheumatiod arthritis to thereby indicate the presence of rheumatoid arthritis in the person comprising the steps of providing a sample of body fluid or tissue from said person; contacting the sample with an antibody specific for phospholipase A.sub.2 activating protein such that the

Patents 371

antibody binds with phospholipase A.sub.2 activating protein in the sample; detecting the antibody thereby indicating the presence of phospholipase A.sub.2 activating protein, whereby elevated levels of phospholipase A.sub.2 activating protein in the sample as compared with levels found in persons not having rheumatoid arthritis indicates the presence of rheumatoid arthritis in the person. Kits and reagents for detecting rheumatoid arthritis are also provided. Excerpt(s): The present invention relates to the field of methods for diagnosing rheumatoid arthritis. More particularly the present invention relates to methods for diagnosing rheumatoid arthritis using immunoassays. Rheumatoid arthritis is the best known form of arthritic disease, affecting millions of patients worldwide. It is characterized by a progressive inflammation of joints and internal organs by immunocompetent cells and destructin of articular cartilage resulting in progressive morbidity and death. Prostaglandins and related eicosanoids are thought to be important mediators of these immune and inflammatory responses. Increased quantities of eicosanoids are produced by rheumatoid synovium in both organ and cell culture and are found in elevated levels in rheumatoid synovial fluid and from peripheral blood cells of affected patients. Clinical evidence suggests that early diagnosis and intervention with cytotoxic and immunomodulatory agents is essential to altering the course of the disease. Phospholipase A.sub.2 (PLA.sub.2) is a lipolytic enzyme which hydrolyzes the 2-acyl fatty acid ester of glycerophospholipids, thus releasing arachidonic acid. Arachidonic acid has been shown to be converted into a number of biologically active compounds known as eicosanoids. PLA.sub.2 activity has been shown to be ubiquitous and to reside in several different gene products. Both membrane bound and soluble forms of the enzyme have been described. Extracellular secretion of soluble PLA.sub.2 was first described in 1980. Circulating PLA.sub.2 was implicated in endotoxin shock and has since been implicated in acute and chronic inflammatory reactions. Web site: http://www.delphion.com/details?pn=US05367063__ •

Immunoassays for measuring the avidity of rheumatoid factor in rheumatoid arthritis Inventor(s): Newkirk; Marianna M. (Pierrefonds, CA) Assignee(s): McGill University (Montreal, CA) Patent Number: 5,679,537 Date filed: October 26, 1994 Abstract: The present invention relates to a novel immunoassay for measurement of rheumatoid factors (RFs) avidity for correlation with rheumatoid arthritis disease activity and for the presence of the different glycoforms of IgG. Excerpt(s): The invention relates to a novel ELISA immunoassay for measurement of rheumatoid factors (RFs) avidity for possible correlation with rheumatoid arthritis disease activity and for the presence of the different glycoforms of IgG. Rheumatoid factors (RF) have long been suspected to play a role in the pathogenesis of rheumatoid arthritis (RA), as they are detected in up to 70% of RA patients and are sustained at high titers for years. Their association with the pathogenic changes have been controversial, and indeed they are found in normal individuals generally in low titers and in patients with mixed cryoglobulinemia frequently in high titers, who lack the synovitis characteristic of RA. In the past decade, since the discovery of an imbalance of the different glycoforms of IgG in patients with RA, much research has focused on the


possible consequences of one of the glycoforms of IgG, namely the Gal(0) form. Since the oligosaccharide chain on IgG resides in between the two gamma-2 domains, it has been postulated that changes in the structure such as the absence of the terminal sialic acid and galactose ›gal(0)! could affect the binding of RFs since it is thought that they bind in the cleft between the gamma-2 and gamma-3 domains. It has been found that, whereas some purified monoclonal RFs bound maximally to IgG when the oligosaccharide chain was intact (Newkirk, M. M. et al., 1993, J. Rheumatol., 20:776), other RFs bound even when the oligosaccharide was altered or removed (Newkirk, M. M. et al., 1990, Arthritis Rheum., 33:800). These previous studies have all had the short coming that it was not known, which, if any, of the monoclonal antibodies studied, could be correlated with any pathogenic role. Web site: http://www.delphion.com/details?pn=US05679537__ •

Immunodiagnostic assay for rheumatoid arthritis Inventor(s): Stanworth; Dennis Raymond (Birmingham, GB2), Lewin; Ian Victor (Tamworth, GB2), Nayyar; Sarita (Penn, GB2) Assignee(s): Peptide Therapeutics Limited (Cambridgeshire, GB2) Patent Number: 5,827,668 Date filed: August 10, 1995 Abstract: The assay of rheumatoid arthritis by reference to IgA-.alpha.sub.1 antitrypsin complex present in analytes is facilitated by certain novel antibody reagents. These are ligands comprising an antibody domain specific for an antigenic determinant of a complex of human IgA and.alpha.sub.1 -antitrypsin, this antibody domain being substantially non reactive with free human IgA and free human.alpha.sub.1 -antitrypsin. Monoclonal antibodies to the naturally occurring IgA-.alpha.sub.1 AT complex and monoclonal or polyclonal antibodies to a synthetic peptide are preferred. The synthetic peptide in itself part of the invention and preferably has an amino acid sequence: ValSer-Val-Val-Met-Ala-Glu-Val-Asp-Gly-Thr-Cys-Tyr (SEQ ID NO:2) Excerpt(s): The present invention is directed to a method of assay of rheumatoid arthritis (RA). More particularly, the present invention is directed to the assay of human immunoglobulin A-.alpha.sub.1 -antitrypsin complex (IgA-.alpha.sub.1 AT) in patients who are suspected of having or are being treated for RA. Rheumatoid arthritis has been described as an unresolved systemic inflammation in which immune dysfunction and genetic susceptibility play roles. In earlier stages, it is often characterised by fluctuating remissions and exacerbations, and in later stages by a chronic granulatamous response (pannus formation) leading to tissue destruction notably of bone and cartilage. The synovial membrane in RA has many of the characteristics of a hyperactive immunologically stimulated lymphoid organ and the ratio of T suppressor to T helper lymphocytes has been shown to be significantly reduced. wherein diagnosis of 3 or 4 of these factors is considered representative of probable RA and diagnosis of 5 or more of the factors is considered representative of definite RA. Web site: http://www.delphion.com/details?pn=US05827668__

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Isolated nucleotide sequences associated with multiple sclerosis or rheumatoid arthritis and a process of detecting Inventor(s): Komurian-Pradel; Florence (Saint Cyr au Mont d'Or, FR), Jolivet-Reynaud; Colette (Bron, FR), Bedin; Frederic (Lyons, FR), Perron; Herve (Lyons, FR), Mandrand; Bernard (Villeurbanne, FR), Beseme; Frederic (Villefontaine, FR), Paranhos-Baccala; Glaucia (Lyons, FR) Assignee(s): Bio Merieux (Marcy l'Etoile, FR) Patent Number: 6,582,703 Date filed: November 26, 1997 Abstract: The invention provides viral material and nucleotide fragments associated with multiple sclerosis and/or rheumatoid arthritis for use in methods of diagnosis, prophylaxis, and therapy. Excerpt(s): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), the cause of which remains as yet unknown. Many studies have supported the hypothesis of a viral aetiology of the disease, but none of the known viruses tested has proved to be the causal agent sought: a review of the viruses sought for several years in MS has been compiled by E. Norrby (1) and R. T. Johnson (2). The discovery of pathogenic retroviruses in man (HTLVs and HIVs) was followed by great interest in their ability to impair the immune system and to provoke central nervous system inflammation and/or degeneration. In the case of HTLV-1, its association with a chronic inflammatory demyelinating disease in man (48) led to extensive investigations to search for an HTLV1-like retrovirus in MS patients. However, despite initial claims, the presence of HTLV-1 or HTLV-like retroviruses was not confirmed. Web site: http://www.delphion.com/details?pn=US06582703__

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Method for administration of azauridine and pyridoxine for the treatment of rheumatoid arthritis Inventor(s): Drell; William (San Diego, CA) Assignee(s): UR Labs, Inc. (San Diego, CA) Patent Number: 5,389,617 Date filed: November 12, 1993 Abstract: A method for treating patients with rheumatoid arthritis comprises administering azaribine to the patient at a dosage level of 10 to 50 mg/kg/day for an initial period of from about 1 to about 3 weeks and then administering azaribine to the patient at dosage levels of at least 50 mg/kg/day and preferably at least 100 mg/kg/day. Excerpt(s): This invention relates to the treatment of rheumatoid arthritis and more particularly to a method for administering, 6-azauridine, azaribine or other 6-azauridine compound for treating rheumatoid arthritis. Azaribine (2', 3', 5'-triacetyl-6-azauridine) has been found to be effective in oral dosage form for the treatment of psoriasis, psoriatic arthritis, mycosis fungoides, herpes simplex, and small pox. Typical dosage levels for the treatment of such conditions are 125 to 250 mg/kg/day. It has been found that such a dosage level may be given for many weeks without side effects, particularly when administered in combination with pyridoxine or other pyridoxine compound, such as pyridoxal phosphate. At high doses, azaribine demonstrates anti-inflammatory


properties. For this reason, azaribine has been tested for the treatment of rheumatoid arthritis. However, at dosage levels of azaribine of 100 mg/kg/day or higher given to patents with rheumatoid arthritis, severe side effects have been reported including fever, joint pain, joint swelling, edema, nausea, emesis, exanthema, painful and rigid muscles and depression. Elis and Raskova, "New Indications for 6-Azauridine Treatment in Man, A Review," Europ.J.Clin. Pharmacol. 4, 77-81 (1972); Elis, Slavik, Ruskova, "Side Effects of 6-Azauridine triacetate in Rheumatoid Arthritis," Clin. Pharmacol. & Therap., II., 404-407 (1970) It has further been reported that slight side effects were produced even at dosage levels of 50 mg/kg per day. Ruskova, Elis, Perlik, Polansky and Slavik, "Unexpected Side Effects of 6-Azauridine in Rheumatoid Arthritis and Feedback in Animal Experiments," Proc. Soc. Europ for the Study of Drug Toxicity," Upsala: June 1970, 12 191 (1971). It is believed that for this reason, no work has been done on this indication for the last 20 years. Web site: http://www.delphion.com/details?pn=US05389617__ •

Method for detecting bacteria in urine and for treating rheumatoid arthritis, essential hypertension and other diseases associated with bacteriuria Inventor(s): Hyman; Edward S. (3420 Jefferson Ave., New Orleans, LA 70125) Assignee(s): none reported Patent Number: 4,673,637 Date filed: April 23, 1984 Abstract: A novel method of urine specimen preparation comprising intense centrifugation and a lipid wash mitigates or prevents loss of bacteria-containing sediment prior to examination. Modifications of the method facilitate examination of urines with interfering constituents such as glucose, phosphates, and soluble and insoluble proteins. By this method, bacteria have been found in the urine of patients suffering from rheumatoid arthritis and essential hypertension. These bacteria were not detected in standard urine preparations. Administration of antibiotic agents effective against the bacteria detected, such as clindamycin, destroyed these bacteria and provided therapeutic relief. Excerpt(s): This invention relates to a new method of detecting abnormal levels of bacteria in urine, and to new methods for the treatment of patients suffering from rheumatoid arthritis, essential hypertension, and other diseases in which significant bacteriuria was detected by the novel specimen preparation of the present invention that would not have been easily demonstrated by known procedures. The direct microscopy and the culture methods each have pitfalls In the past 20-25 years the direct visualization of bacteria in urine has largely been abandoned in favor of the methods involving culturing and counting the colonies of bacteria. Indeed virtually all of the studies of the significance of bacteriuria are based upon culturing the urine, and the direct microscopic examination of urine has been relegated to the status of a quick but inadequate screening procedure which may be helpful because it can be correlated with the culture methods. Rheumatoid arthritis (RA) is a chronic inflammation of the joints, generally regarded as a systemic autoimmune disorder. Its etiology is unknown, but it has been postulated that it is associated with microbial infection. See, e.g., D. C. Demonde, ed., Infection and Immunity in the Rheumatic Diseases, 95-287 (Blackwell Scientific Publications, London: 1976). The evidence, however, until the present discovery, was inconclusive. See, e.g., D. J. McCarty, et al., ed., Arthritis and Allied Conditions: A Textbook of Rheumatology, ch 28 at 417 (9th ed. 1979); R. G. Petersdorf, et

Patents 375

al., ed., Harrison's Principles of Internal Medicine, Part Six, Chapter 346, at 1977 (McGraw Hill: 1983). Bacteriuria has not been associated with RA, and indeed one authority remarks "Urinary abnormalities are relatively uncommon in RA. Urinary tract infection was not found to be increased in RA patients." McCarty, supra, chapter 33, page 499, citing Ann. Rheum. Dis., 27: 345 (1968). Hypertension is a chronic elevation of blood pressure resulting from the obstruction of blood flow within the kidney (secondary hypertension) or without apparent cause (essential hypertension). One kidney disorder associated with secondary hypertension is pyelonephritis, the inflammation of the renal pelvis of the kidney as a result of bacterial infection, usually responsive to antibiotics. It has not been reported, however, that there is any correlation between essential hypertension and asymptomatic bacteriuria (bacteriuria observed in patients not reporting symptoms of urinary tract disorders). According to N. M. Kaplan, Clinical Hypertension, 14 (3d. ed. 1982), bacteriuria is found in 2-5% of hypertensives. Most of these positive cultures were of gram-negative rods. The method of the present invention has demonstrated a much higher incidence of bacteriuria in hypertensives, perhaps as high as 90%, and that cocci or "exploded cocci" are found in considerable numbers. Web site: http://www.delphion.com/details?pn=US04673637__ •

Method for determining susceptibility to rheumatoid arthritis Inventor(s): Shiozawa; Shunichi (11-6 Takenodai 2-chome, Nishi-ku, Kobe-shi, Hyogo, 651-2274, JP) Assignee(s): none reported Patent Number: 6,623,924 Date filed: January 31, 2000 Abstract: The application provides genes causative of rheumatoid arthritis, which are located within.+-.1 centimorgan from DNA sequences to which the microsatellite markers D1S214, D1S253, D8S556, DXS1001, DXS1047, DXS1205, DXS1227 and/or DXS1232 are hybridized: a method for diagnosing rheumatoid arthritis, including amplifying the genomic DNA of a subject by PCR using at least one of the microsatellite markers as primer and comparing the PCR products thereof with the PCR products prepared in the same manner using the genomic DNA of a normal control; and a method for identifying the causative factors of rheumatoid arthritis including the same as described above. Excerpt(s): The present invention relates to the genes causative of rheumatoid arthritis, a method for diagnosing rheumatoid arthritis using the mutations of these genes as the indicators, and a method for identifying the causative factors of rheumatoid arthritis. The aspects of arthritis and joint damage causing rheumatoid arthritis, particularly the pathological courses thereof, have been elucidated gradually through various research works. Because many of the autoimmune diseases including rheumatoid arthritis are induced by the concomitant participation of numerous causative factors and are then exacerbated progressively to the stage of apparent diseases, however, the interactive mechanism per se of such numerous factors should be elucidated for accurate characterization and appropriate therapeutic management of the disease. The prevalent rheumatoid arthritis is about 1% (N. Engl. J. Med., 322: 1277-1289, 1990), but the frequency of the disease is about 8 times increased in the siblings of the patients with the disease (Cell, 85: 311-318, 1996). Hence, it is predicted that a certain genetic factor may serve as one of the causative factors. Nevertheless, molecular genetic technology and


genetic engineering technology for general use for identifying of genetic factors of diseases never function effectively in case of autoimmune diseases, because the onset of autoimmune diseases is never induced via such a biologically simple mechanism as abnormal amplification of one mutated gene as in the case of cancer. Conventional strategies of traditional genetics for the elucidation of the fundamental genetic pathogenesis of diseases have demonstrated distinctively that autoimmune diseases are caused by genetic multi-factor inheritance, but the strategies were apparently insufficient. As has been described above, none of the genes involved in rheumatoid arthritis or none of the loci of the genes on chromosome have absolutely been evidenced so far. Web site: http://www.delphion.com/details?pn=US06623924__ •

Method for diagnosing rheumatoid arthritis Inventor(s): Prakash; Ramesh K. (Salt Lake City, UT) Assignee(s): Theratech, Inc. (Salt Lake City, UT) Patent Number: 5,395,753 Date filed: February 19, 1993 Abstract: A method is described for diagnosing rheumatoid arthritis by providing a recombinant IgM-specific rheumatoid arthritis-associated antigen and detecting antibodies against the antigen in patient sera. Preliminary steps of making a cDNA library from polyadenylated RNA purified from human cells, selecting recombinants that express the antigen, recloning cDNA containing the antigen gene in a high level expression vector, expressing the antigen in transformed cells, and purifying the antigen are also described. Excerpt(s): This invention relates to a method for diagnosing rheumatoid arthritis. More particularly, this invention relates to a method for objectively diagnosing rheumatoid arthritis by quantitative determination of the presence or absence of rheumatoid arthritis-associated antibodies in patient sera that react with a recombinant antigen. Rheumatoid arthritis is a chronic systemic rheumatic disease that affects a significant percentage of the population. Traditionally, it has been diagnosed subjectively through clinical observation and dominant complaints by a patient. P. Lipsky, Rheumatoid Arthritis, in Harrison's Principles of Internal Medicine 1423 (1987). Thus, clinical diagnosis of rheumatoid arthritis is subject to the skill of the diagnostician and the severity of disease symptoms in the patient. For an objective diagnosis of rheumatoid arthritis, the presence of rheumatoid factor (Rf) in the serum of rheumatoid arthritis patients is routinely determined. Rf has been detected in approximately 70% of patients exhibiting clinical symptoms of rheumatoid arthritis. These patients are thus termed "seropositive." The remaining 30% are classified as having "seronegative" rheumatoid arthritis. Numerous conditions besides rheumatoid arthritis are associated with the presence of rheumatoid factor. Therefore, the presence of Rf does not establish a conclusive diagnosis of rheumatoid arthritis. An objective method of diagnosing rheumatoid arthritis that is more closely correlated with clinical diagnoses than is the presence of Rf in sera is needed. Ideally, such an objective diagnostic test would be quick and easy to perform and would not involve radioisotopes or be invasive to the patient. Web site: http://www.delphion.com/details?pn=US05395753__

Patents 377

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Method for diagnosis of rheumatoid arthritis Inventor(s): Yoshida; Makoto (Kawasaki, JP), Yamanaka; Naoki (Nagoya, JP) Assignee(s): Medecs Co., Ltd. (Aichi, JP), Asahi Medical Co., Ltd (Tokyo, JP) Patent Number: 4,863,850 Date filed: February 16, 1988 Abstract: A substantially pure rheumatoid arthritis specific protein (RASP) and an antibody against the rheumatoid arthritis specific protein (anti-RASP antibody) are disclosed. The RASP is found specifically in the serum or plasma of a patient suffering from rheumatoid arthritis, and may be detected using an anti-RASP antibody easily and effectively. Therefore, the anti-RASP antibody of the present invention is useful for the diagnosis of rheumatoid arthritis by the criterion of the presence of RASP. Excerpt(s): This invention relates to a substantially pure rheumatoid arthritis specific protein. The present invention also relates to an antibody against the rheumatoid arthritis specific protein. More particularly, the present invention is concerned with a protein specifically found in the plasma of a patient suffering from rheumatoid arthritis and an antibody specific for the antigenic determinant of the rheumatoid arthritis specific protein. Conventionally, the diagnosis of rheumatoid arthritis has been effected according to the criteria proposed by the American Rheumatism Association. However, such criteria depend on doctor's observations and dominant complaints by a patient, and therefore, such criteria are insufficient with respect to objectivity and quantitative analysis of the degree of rheumatoid arthritis. For the quantitative analysis of the degree of rheumatoid arthritis, the presence and amount of rheumatoid factor (RF), immune complex (IC) or C-reactive protein (CRP) in the serum or plasma of a patient have been determined. However, such substances are not necessarily specific for the plasma or serum of a patient suffering from rheumatoid arthritis, and therefore, such substances are not useful as a conclusive factor. Web site: http://www.delphion.com/details?pn=US04863850__

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Method for the diagnosis of rheumatoid arthritis Inventor(s): Iwata; Kazushi (Takaoka, JP), Iwata; Hisashi (Nagoya, JP), Kodama; Shuji (Takaoka, JP), Hayakawa; Taro (Nagoya, JP), Kishi; Junichi (Nagoya, JP), Yamashita; Kyoko (Nagoya, JP) Assignee(s): Fuji Yakuhin Kogyo Kabushiki Kaisha (Toyama, JP) Patent Number: 5,190,861 Date filed: April 25, 1989 Abstract: A method for diagnosing rheumatoid arthritis, which is characterized by enzyme-immunologically measuring the amount of collagenase inhibitor present in sera, plasmas or synovial fluids by way of a sandwich assay wherein two different monoclonal antibodies which specifically bind to different antigenic determinants of the collagenase inhibitor are used, and comparing the measured amount with that for normal subjects. Excerpt(s): The present invention relates to a method of the diagnosis of rheumatoid arthritis by way of quantitation of collagenase inhibitor. More particularly the invention relates to a method for carrying out the diagnosis of rheumatoid arthritis, by means of a sandwich enzyme immunoassay for human collagenase inhibitor using monoclonal


antibodies to bovine collagenase inhibitor (tissue inhibitors of metallproteinases: TIMP), on the basis of the fact that the amount of collagenase inhibitor in sera, plasmas or synovial fluids from patients with rheumatoid arthritis is clearly higher than the amount of collagenase inhibitor in sera, plasmas or synovial fluids, respectively, from normal subjects. The enzyme immunoassay mentioned above is used to mean a method for determining collagenase inhibitor which is characterized in that there are used two different monoclonal antibodies which specifically bind to different antigenic determinants of collagenase inhibitor as an antibody to be bound to a solid phase support and an antibody to be labeled with an enzyme. Among heretofore used methods for the diagnosis of rheumatoid arthritis may be mentioned: Rose's method based on the detection of rheumatoid factor, modified Rose's method by Heller, RAHAtest and RA-test. These methods, however, have such disadvantages that they use complex experimental methods or that it takes many days to go through with the diagnosis. Collagenase inhibitor has been known to exist in human's and other animals' bones, skins, dental pulps, amniotic fluids, bloods and synovial fluids as well as in cultures of joint chondrocytes, synovial cells, fibroblasts derived from varied tissues and fibrosarcomatous cells. As means for determining the amount of collagenase inhibitor methods have heretofore been known which are based on measurement of its biological activity. As described by Eisen et al. in J. Lab. Clin. Med. 75, 258-263 (1973) and also by Cawston et al. in Arthritis and Rheumatism 27, 285-290 (1984), however, it is impossible, with the heretofore known methods of determination, to assay sera, plasmas or synovial fluids for collagenase inhibitor activity since there exist in such fluids proteins, such as.alpha.sub.2 -macroglobulin, which interfere disturbingly with the measurement. Hayakawa, Iwata et al. have already developed a sandwich enzyme immunoassay (EIA) using monoclonal antibodies to bovine collagenase inhibitor, a method which enables specific quantitation of collagenase inhibitor with very small volumes of samples in a precise, straightforward and rapid manner (Japanese Patent Application No. Sho 6242781). The present inventors have discovered that the level of collagenase inhibitor present in human sera, plasmas or synovial fluids apparently increases in association with affliction with rheumatoid arthritis, and found that it is possible to make a diagnosis of rheumatoid arthritis by determining, by the enzyme immunoassay mentioned above, the amount of collagenase inhibitor present in sera, plasmas or synovial fluids. Web site: http://www.delphion.com/details?pn=US05190861__ •

Method for treating rheumatoid arthritis Inventor(s): Farine; Jean-Claude (Eysins, CH), Schulthess; Adrian (Begnins, CH) Assignee(s): Laboratoires OM Societe Anonyme (Geneva, CH) Patent Number: 4,322,405 Date filed: April 6, 1981 Abstract: Lysates derived from strains of Escherichia coli, especially wherein said lysates are derived from at least one of the strainsNCTC 8603, 8621, 8622, 8623, 9026, 9111, 9119, 9707, 9708,I-081, I-082, I-083, I-084, I-085, I-086, I-087, I-088, I-089are useful for treating rheumatoid arthritis. Excerpt(s): is known as an immunobiotherapeutic agent, used against infectious diseases of the urinary and the gastro-intestinal tract (see German OS 30 19 448.0). This latter specification gives full details for the preparation of lysates of these strains. The abovementioned strains NCTC are listed by the National Collection of Type Cultures, London

Patents 379

(Great Britain), and are accessible to the public, whereas the above-mentioned strains I081 to I-089 have been deposited by the assignee of the present patent application on Mar. 7, 1979, at Collection Nationale de Cultures de Microorganismes, Institut Pasteur, Paris (France). We have now surprisingly found that bacterial lysates of Escherichia coli, and especially bacterial lysates of the above-mentioned strains NCTC and I, produce an anti-inflammatory action in animals. They have a non-specific immunostimulatory action in humans and are useful in patients with rheumatoid arthritis (RA). RA is known as an inflammatory disease with immunological etiology. In the following animal model, lysates of Escherichia coli showed an action in the chronic inflammatory phase. Web site: http://www.delphion.com/details?pn=US04322405__ •

Method for treatment of non-rheumatoid arthritis Inventor(s): Macias; William Louis (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 6,610,728 Date filed: February 24, 2000 Abstract: A method is disclosed for the treatment of non-rheumatoid arthritis by administering to a mammal in need thereof a therapeutically effective amount of an sPLA.sub.2 inhibitor. Excerpt(s): The present invention is directed to a method for treating non-rheumatoid arthritis. More specifically, the present invention is directed to a method for treating the causes and/or the symptoms of various forms of non-rheumatoid arthritis in mammals by administering a therapeutically effective amount of an sPLA.sub.2 inhibitor. The most common form of non-rheumatoid arthritis is osteoarthritis, a degenerative joint disease which primarily affects cartilage that covers and cushions the ends of the bones causing it to fray, wear, ulcerate, and in extreme cases, to disappear entirely leaving a bone on bone joint. The disease can result in severe disability particularly in the weight bearing joints such as the knees, hips, and spine. Osteoarthritis is distinguishable, for example, from rheumatoid arthritis in that osteoarthritis involves little or no inflammation and is confined to the joints and surrounding tissue where there is a breakdown or disintegration of cartilage and other tissue thereby making it difficult for the joints to operate properly. The occurrence of osteoarthritis frequently increases with advancing years. Non-rheumatoid arthritis is often treated with acetaminophen and ibuprofen. In addition, non-steroidal anti-inflammatory drugs (NSAIDSs) may be used to relieve pain by blocking the production of prostaglandins (e.g., choline magnesium salicylate, salicylsalicyclic acid). Corticosteroids such as methylprednisone, prednisone, and cortisone may be used to relieve pain and swelling. Each of these known drug therapies has possible long-term disadvanges such as kidney or liver damage, heartburn, stomach upset, ulcers, gastrointestinal bleeding, mood swings, weight fain, high blood pressure, muscle weakness and lowered resistance to infection. Web site: http://www.delphion.com/details?pn=US06610728__


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Method for treatment of rheumatoid arthritis Inventor(s): Jones; Frank R. (Edmonds, WA), Snyder, Jr. Harry W. (Seattle, WA), Balint, Jr. Joseph P. (Seattle, WA) Assignee(s): Cypress Bioscience, Inc. (San Diego, CA) Patent Number: 5,782,792 Date filed: December 12, 1994 Abstract: Rheumatoid arthritis is treated by the extra corporeal removal of IgG and IgGcontaining circulating immune complexes from the patient's blood. Removal is preferably accomplished by exposing the blood or blood plasma to a protein A immunoadsorbent which binds to IgG-containing immune complexes with high affinity. Excerpt(s): The present invention relates generally to the treatment of autoimmune disorders by extracorporeal plasma perfusion to remove immunoglobulin and immune complexes. More particularly, the present invention relates to the treatment of rheumatoid arthritis (RA) by continuous or discontinuous plasma perfusion through an immunoadsorbent capable of binding immunoglobulins and immune complexes. Autoimmune disorders are characterized by the destruction of a patient's body tissues by the patient's own immune system. Severe harm can arise from such a misdirected immune response, causing illness and even death to the patient. Rheumatoid arthritis is an autoimmune disorder of unknown etiology which is characterized by the presence of auto-antibodies. Rheumatoid arthritis (RA) is a chronic disease which can exhibit a variety of systemic manifestations. This disease has an unknown etiology and characteristically exhibits a persistent inflammatory synovitis which usually involves peripheral joints in a symmetric distribution. Despite the destructive potential of RA, its course can be quite variable. In about two-thirds of patients, a chronic polyarthritis begins insidiously with fatigue, anorexia, generalized weakness and vague musculoskeletal symptoms until the appearance of synovitis becomes apparent. In about 10% of patients, the onset can be more acute with rapid development of polyarthritis. In about one-third of patients, symptoms may initially be confined to one or a few joints. Overall, most patients will experience an intermediate course of the disease. As described above, the potential of the inflammation to cause cartilage destruction, bone erosions and, ultimately, joint deformities is the most important feature of this disease. Web site: http://www.delphion.com/details?pn=US05782792__

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Method of treating arthritis, including rheumatoid arthritis, with 166 Holmium radionuclide Inventor(s): Lieberman; Ephraim (Suffern, NY), Thornton; Alfred K. (New Hampton, NY), Bordoni; Maurice E. (Westtown, NY) Assignee(s): Cadema Medical Products, Inc. (Middletown, NY) Patent Number: 5,026,538 Date filed: June 16, 1989 Abstract:.sup.166 Holmium in a carrier metallic hydroxide aggregate is disclosed for the treatment of arthritis and, in particular, rheumatoid arthritis. The compound disclosed preferably has a particle size of 1 to 40 microns, Beta energy emissions in the range of 1.76-1.84 MeV, low levels of gamma ray emissions and a radioactive half-life of 26.8

Patents 381

hours. The preferred metallic hydroxide is selected from the group consisting of Ferric Hydroxide, Aluminum Hydroxide, Bismuth Hydroxide, Chromium Hydroxide, Cupric Hydroxide, Manganese Hydroxide and Stannous Hydroxide. Methods are also disclosed for the preparation of the compound, as well as for the methods of its administration to a patient in need thereof. Excerpt(s): The present invention relates to radioactive compounds, methods for the preparation thereof and a method for the treatment of arthritis, including rheumatoid arthritis. Arthritic disorders are the second leading cause of losses in time and earnings in the United States. Approximately six million of all arthritis sufferers are afflicted rheumatoid arthritis. Of these, over fifty percent (50%) ultimately will have involvement of the knee joint, over eighty percent (80%) will involve the hand joint and somewhat smaller percentages will have involvement of other joints such as the ankle, elbow and shoulder. Rheumatoid arthritis is believed to be an autoimmune disease wherein parts of the body are attacked by antibodies manufactured in the body. These antibodies may be produced in response to viruses present in the body. While the mechanism for rheumatoid arthritis is not defined, it is a systemic disease. When the disease is active, the erythrocyte sedimentation rate (ESR) is elevated and the blood tests positive for rheumatoid factor. Web site: http://www.delphion.com/details?pn=US05026538__ •

Method of treating rheumatoid arthritis Inventor(s): Wechter; William J. (Kalamazoo, MI), Brooks; Carter D. (Texas Township, Kalamazoo County, MI) Assignee(s): The Upjohn Company (Kalamazoo, MI) Patent Number: 4,118,484 Date filed: March 29, 1976 Abstract: A process of treatment for the management of the condition known as rheumatoid arthritis. The process manages rheumatoid arthritis by controlling the inflammatory process in a rheumatoid joint by the intra-articular administration to said joint of an effective amount for controlling the inflammatory process of certain N.sup.4 acyl-ara-cytidines, 5'-O-acyl-ara-cytidines and pharmaceutically acceptable acid addition salts thereof, and pharmaceutically acceptable acid addition salts of 5'-O-acyl2,2'-anhydro-ara-cytidines. Excerpt(s): The invention concerns a method of treating rheumatoid arthritis in mammals including humans. More specifically, the invention concerns a method of controlling the inflammatory process in a rheumatoid joint of a mammal. Belgium Pat. No. 773,027 of Mar. 24, 1972, and U.S. Pat. No. 3,920,630 issued Nov. 18, 1975, disclose 2,2'-anhydro-ara-cytidine compounds as useful in the treatment of autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. Belgium Pat. No. 773,027 and U.S. Pat. No. 3,920,630 do not disclose which, if any, of the compounds are effective as an intra-articularly administered agent in controlling the inflammatory process in a rheumatoid joint. Web site: http://www.delphion.com/details?pn=US04118484__


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Method of treating rheumatoid arthritis Inventor(s): Meier; Albert H. (Andover, MA), Cincotta; Anthony H. (Andover, MA) Assignee(s): Ergo Science Incorporated (Charlestown, MA) Patent Number: 5,905,083 Date filed: June 2, 1995 Abstract: Disclosed are methods for rectifying or ameliorating abnormal responses of mammalian immune systems, such as rheumatoid arthritis. Also disclosed are methods for modifying normal responses of the mammalian immune system. Further disclosed are methods for accomplishing the foregoing by administering to a mammal a prolactin reducer and/or enhancer at a pre-determined time or times during a 24-hour period that results in modification of the mammal's abnormal prolactin profile so that it approaches or conforms to the prolactin profile of a young, healthy mammal of the same species (or to a standard profile generated from such individuals). Additionally, methods of upregulating or augmenting an immune response in a mammal are disclosed. Excerpt(s): This invention relates to methods for rectifying or ameliorating abnormal responses of the mammalian immune system, and modifying normal responses of the mammalian immune system. More particularly, this invention relates to methods employing the alteration of prolactin rhythms as a method of adjusting mammalian immune response. The importance of neuroendocrine regulation of immunity has become increasingly evident during the past decade (Besedovsky, H. O. et al., J. Immunol. 135:750s-754s, 1985; Blalock, J. E., Physiol. Rev. 69: 1-54, 1989; Berozi, I., Dev. Comp. Immunol. 13:329-341, 1989). Much of this interest has focused on the anterior pituitary hormone prolactin, which has been reported to have potent, albeit inconsistent and often conflicting, effects on immune activity (Gala, R. R., Proc. Soc. Exp. Biol. Med. 198:5-13, 1991; Nicoletti, J. et al., Reprod. Immunol. 15:113-121, 1989; Vidaller, A., et al., Clin. Immunol. Immunopathol. 38:337-343, 1986; Gerli, R. et al., Clin. Immunol. 7:463470, 1987). The role of prolactin in immunity is exemplified by studies demonstrating exogenous prolactin-induced restoration of immune competence in hypophysectomized mammals (Gala, R. R., Proc. Soc. Exp. Biol. Med. 198:5-13, 1991; Bercal, I. et al., Acta Endocrinol. 98:506-513, 1981). In intact animals, prolactin administration has been associated with numerous immunological effects including stimulation of cellular or antibody responses, as well as stimulation of various immune system upregulating substances such as IL-2 (both IL-2 production and IL-2 receptor expression); enhancement of lymphocyte number, activity and mitogenic responses; and augmentation of macrophage cytotoxicity (Gala, R. R., Proc. Soc. Exp. Biol. Med. 198:513, 1991; Bernton, E. W. et al., Science 239:401-404, 1988; Rovensky, J. et al., Int. J. Immuno. Pharmac. 13:267, 1991). Web site: http://www.delphion.com/details?pn=US05905083__

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Method of treating rheumatoid arthritis and osteoarthrosis using tetrahydro WS9326A Inventor(s): Fujii; Takashi (Ikeda, JP), Tomoi; Masaaki (Higashiosaka, JP) Assignee(s): Fujisawa Pharmaceutical Co., Ltd. (Osaka, JP) Patent Number: 5,616,556 Date filed: November 18, 1993

Patents 383

Abstract: Rheumatoid arthritis and osteoarthrosis are treated by administering an effective amount of tetrahydro-WS9326A to a human being or animal suffering from rheumatoid arthritis or osteoarthrosis. Excerpt(s): This invention relates to an antiinflammatory or gastrointestinal motilitymodulating composition comprising a peptide derivative of the general formula (I) presented hereafter or a pharmaceutically acceptable salt thereof as an active ingredient, which composition finds application in the field of medicine. The peptide derivative of the invention, represented by the general formula (I) given below, is a per se known compound and is known to possess pharmacological activities such as substance P antagonism and neurokinin A antagonism (e.g. EP 0336230A2). However, there has not been the awareness that this peptide derivative has antiinflammatory or gastrointestinal motility-modulating activity. is a single bond or a double bond, or a pharmaceutically acceptable salt thereof as an active ingredient. Web site: http://www.delphion.com/details?pn=US05616556__ •

Method of treating rheumatoid arthritis using tetracycline Inventor(s): Cabezas; Orestes (10201 Fontainebleau Blvd., Unit 205, Miami, FL 33172) Assignee(s): none reported Patent Number: 5,250,442 Date filed: April 8, 1993 Abstract: A method of treating rheumatoid arthritis which includes first, taking a blood test to determine a rate of erythrocyte sedimentation and a rheumatoid factor, and then fasting for a 12-hour period prior to orally administering a 500 milligram dosage of tetracycline achromycin, and observing any change in the symptoms of the rheumatoid arthritis including reduction of swelling and pain in the affected sites. This process is repeated over 24-hour cycles until the rheumatoid factor has decreased by at least 50% from the first determined level prior to treatment and erythrocyte sedimentation decreased, at which point the 24-hour cycles are continued, reducing the dosage of tetracycline achromycin to 250 milligrams until the symptoms of the rheumatoid arthritis condition disappear. Excerpt(s): The present invention relates to a method for treating rheumatoid arthritis to alleviate the symptoms thereof. Presently, an estimated 7,000,000 Americans suffer from rheumatoid arthritis. The symptoms of rheumatoid arthritis including pain and swelling of the smaller joints in the hands and feet. The affected joints become swollen, painful and warm to the touch during the initial attack and ensuing flare-ups. Often, the joints in the hands and the feet will ache or become stiff after extended periods of motionless such as after sleeping. Rheumatoid arthritis is believed to be an autoimmune disease in which the body's immune system literally attacks itself. It is believed that rheumatoid arthritis initially develops from a virus which upsets the immune system. In response, the body's disease fighting cells attack the joints causing inflammation. Web site: http://www.delphion.com/details?pn=US05250442__


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Method of treatment of rheumatoid arthritis Inventor(s): Scheinberg; Israel H. (5447 Palisades Ave., Bronx, NY 10471) Assignee(s): none reported Patent Number: 4,487,780 Date filed: February 5, 1982 Abstract: Rheumatoid arthritis is treated with substituted cysteine compounds having a lower toxicity-to-effectiveness ratio than penicillamine. Such compounds are specific alpha-substituted cysteines, beta-monosubstituted cysteines, beta-di-substituted cysteines other than penicillamine, N-acetyl penicillamine and the N-acetyl derivatives of the alpha and beta-substituted compounds mentioned above.Any of the compounds may be used synergistically in combination with suitable copper compounds or with suitable gold compounds in the treatment of arthritis.The same compounds are effective in the treatment of cystinuria and heavy metal poisoning. The same compounds as well as penicillamine are effective in combination with copper in the treatment of heavy metal poisoning. Excerpt(s): Rheumatoid arthritis, commonly referred to as RA, is the second most crippling disease in man, ranking immediately behind cardiovascular defects. Until recently no effective treatment for RA has been known. A number of drugs which are moderately effective in the treatment of this disease have been found, examples being Dpenicillamine which is.beta.,.beta.-dimethylcysteine and certain compounds of gold, such as gold sodium thiomalate, aurothioglucose and sources of auric or aurous ion. Of these compounds, the most promising is the recently discovered penicillamine, a natural metabolite of penicillin. Unfortunately, not all patients respond to this medication; also, it carries with it considerable toxicity so that it can, in fact, be lethal. Another difficulty is that penicillamine is slow-acting so that generally it requires 8 to 12 weeks before it can be determined whether the patient is responding and whether the dosage needs adjusting. D-penicillamine usually produces a decrease in the titer of rheumatoid factor, an index of its specific therapeutic efficacy for this human disease. There are no genuine animal models of rheumatoid arthritis. At the present time, most rheumatologists treat moderately severe RA that has not responded to salicylates with either a gold compound or D-penicillamine. Penicillamine is also used initially in some patients with severe RA, and those in whom rheumatoid lung disease, vasculitis, amyloidosis, Felty's syndrome or rheumatoid nodulosis complicate the clinical picture. Web site: http://www.delphion.com/details?pn=US04487780__

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Methods and compositions for treating rheumatoid arthritis Inventor(s): Barlozzari; Teresa (Wellesley, MA), Haupt; Andreas (Northborough, MA), Banerjee; Subhashis (Shrewsbury, MA) Assignee(s): BASF Aktiengesellschaft (Ludwigshafen, DE) Patent Number: 6,015,790 Date filed: October 6, 1997 Abstract: The present invention provides compositions and methods for the treatment of rheumatoid arthritis in a subject wherein one or more compounds of Formula I as defined herein alone or in combination with one or more other antiarthritic drugs provide suppression of rheumatoid arthritis.

Patents 385

Excerpt(s): Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells (See, e.g., Harris, E. D., Jr., The New England Journal of Medicine, 322: 1277-1289 (1990)). Despite advances in treatment, rheumatoid arthritis remains a serious health problem. Although rarely fatal, arthritis is a major cause of morbidity, loss of time from work, lost productivity and decrease in quality of life. Rheumatoid arthritis causes severe pain and loss of joint mobility and can make accomplishing even simple tasks difficult. Current treatment methods and regimes for rheumatoid arthritis include administration of non-steroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin), ibuprofen, naproxen and other such agents, gold compounds, penicillamine, methotrexate, cytotoxic agents (e.g., azothrioprine), 4-aminoquinoline agents, and immunomodulators. However, improved treatments of rheumatoid arthritis, which can suppress or ameliorate symptoms such as inflammation, swelling, abnormal neovascularization, bone erosion, or cartilage erosion are needed. Preferably, such an improved method of treatment should be able to be combined with other treatment methods, should work rapidly to cause regression or stabilization of symptoms, and should be well tolerated. Preferably, such a treatment regime should also be useful in prophylaxis in susceptible individuals. --CH(CH.sub.3) CH(CH.sub.3).sub.2, also referred to as 1,2-dimethylpropyl. Web site: http://www.delphion.com/details?pn=US06015790__ •

Methods and materials for evaluating rheumatoid arthritis Inventor(s): Weyand; Cornelia M. (Rochester, MN), Goronzy; Jorg J. (Rochester, MN) Assignee(s): Mayo Foundation for Medical Education and Research (Rochester, MN) Patent Number: 6,555,320 Date filed: September 1, 1999 Abstract: The invention provides methods and materials for diagnosing a rheumatoid arthritis condition in a patient. Specifically, the invention provides methods and materials for classifying a rheumatoid arthritis condition as diffuse, follicular, or granulomatous. In addition, the invention provides methods and materials for determining if an individual suffering from a rheumatoid arthritis condition will develop severe disease. Excerpt(s): The invention relates to methods and materials for evaluating rheumatoid arthritis as well as for determining an individual's predisposition to have severe rheumatoid arthritis disease. Rheumatoid arthritis (RA) affects individuals in the prime of their life and is feared because of its potential to cause chronic pain and irreversible damage of tendons, ligaments, joints, and bones. The symmetrical involvement of small peripheral joints has an enormous impact on hand and foot functions and poses therapeutic challenges that cannot be easily overcome by joint replacement. Also, systemic manifestations of RA are not rare and can range from relatively minor problems, such as rheumatoid nodules, to life-threatening organ disease. In addition, RA is a systemic inflammatory disease that primarily manifests itself as synovial inflammation of diarthrodial joints. The typical histopathological changes include dense infiltration of the synovial membrane by mononuclear cells, neoangiogenesis, and hypertrophy and hyperplasia of the synovial lining (Harris E D (ed); Rheumatoid Arthritis, Philadelphia, WB Saunders Co., pp.3-212 (1997); and Hale L P, Haynes B F: Pathology of rheumatoid arthritis and associated disorders. Arthritis and Allied Conditions. A textbook of Rheumatology. Edited by Koopman W J. Baltimore, Williams & Wilkins, pp.993-1016 (1997)). The etiopathogenesis of the syndrome is not understood.


Several lines of evidence support a central role of T lymphocytes in the disease-specific pathogenic events (Todd, et al. Science, 240:1003-1009 (1988); Panayi, et al., Arthritis Rheum, 35:729-735 (1992); and Goronzy J J, Weyand C M: Rheum Dis Clin North Am, 21:655-674 (1995)). An alternative hypothesis, namely, that macrophages are the pivotal cell type in rheumatoid synovitis, has also been proposed (Firestein G S, Zvaifler N J: Arthritis Rheum 33:768-773 (1990); and Burmester, et al., Arthritis Rheum, 40:5-18 (1997)). Whether only T cells or only macrophages or both are the causative elements in RA remains a matter of controversy (Feldmann, et al., Cell, 85:307-310 (1996); and Fox, Arthritis Rheum 40:598-609 (1997)). Web site: http://www.delphion.com/details?pn=US06555320__ •

Methods and materials for treatment of rheumatoid arthritis Inventor(s): McMichael; John (P.O. Box 81, Cambridge Springs, PA 16403) Assignee(s): none reported Patent Number: 4,704,273 Date filed: February 27, 1986 Abstract: Disclosed are methods and compositions useful for alleviating the symptoms of rheumatoid arthritis. In preferred embodiments, the compositions are administered in essentially minute "neutralizing" doses. The compositions comprise mixtures of histamine, immunoglobulin G provocative of RF formation or an immunologically active fraction thereof, collagen and either attenuated measles virus or immunologically active fraction thereof. Illustratively significant relief of symptoms of arthritis disease symptoms is achieved through parenteral (e.g., subcutaneous or sublingual) administration of such compositions. Excerpt(s): This application is a continuation-in-part of my copending U.S. application Ser. No. 708,274 filed March 5, 1985 which is a division of my U.S. application Ser. No. 378,752 filed May 17, 1982, now U.S. Pat. No. 4,521,405. The present invention relates generally to the treatment of disease states involving immunological factors and more particularly to methods and materials for alleviation of symptoms of nonanaphylactic disorders wherein disease pathology results in whole or part from the victim's own humoral and/or cell-medicated immune response to one or more immunogenic substances. Disease states involving immunological factors may be seen to broadly comprise (1) immunodeficiency diseases, and (2) disorders wherein tissue injury occurs as a result of a humoral or cell-mediated response to immunogens (e.g., antigens) of endogenous or exogenous origin. This latter group of immunological disorders is frequently referred to as involving immune "hypersensitivity", with the numerous disease states comprehended by the term classified according to four hypersensitivity "reaction" types. Web site: http://www.delphion.com/details?pn=US04704273__

Patents 387

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Methods of treating rheumatoid arthritis using chimeric anti-TNF antibodies Inventor(s): Vilcek; Jan (New York, NY), Le; Junming (Jackson Heights, NY), Daddona; Peter (Menlo Park, CA), Siegel; Scott (Westborough, MA), Ghrayeb; John (Thorndale, PA), Knight; David (Berwyn, PA) Assignee(s): Centocor, Inc. (Malvern, PA), New York University Medical Center (New York, NY) Patent Number: 5,698,195 Date filed: October 18, 1994 Abstract: Anti-TNF antibodies, fragments and regions thereof which are specific for human tumor necrosis factor-.alpha. (TNF.alpha.) and are useful in vivo for diagnosis and therapy of a number of TNF.alpha.-mediated pathologies and conditions, including rheumatoid arthritis as well as polynucleotides coding for murine and chimeric antibodies, methods of producing the antibody, methods of use of the anti-TNF antibody, or fragment, region or derivative thereof, in immunoassays and immunotherapeutic approaches are provided. Excerpt(s): The present invention in the field of immunology and medicine relates to anti-tumor necrosis factor (TNF) antibodies, anti-TNF peptides and nucleic acids encoding therefor, and to pharmaceutical and diagnostic compositions and production, diagnostic and therapeutic methods thereof, and to methods for treating human TNFmediated pathologies. Cells other than monocytes or macrophages also make TNF.alpha. For example, human non-monocytic tumor cell lines produce TNF (Rubin, et al., J. Exp. Med. 164:1350 (1986); Spriggs, et al., Proc. Natl. Acad. Sci. USA 84:6563 (1987)). CD4.sup.+ and CD8.sup.+ peripheral blood T lymphocytes and some cultured T and B cell lines (Cuturi, et al., J. Exp. Med. 165:1581 (1987); Sung, et al., J. Exp. Med. 168:1539 (1988)) also produce TNF.alpha. Recent evidence associates TNF with infections (Cerami, et al., Immunol. Today 9:28 (1988)), immune disorders, neoplastic pathologies (Oliff, et al., Cell 50:555 (1987)), autoimmune pathologies and graft-versus host pathologies (Piguet, et al., J. Exp. Med. 166:1280 (1987)). The association of TNF with cancer and infectious pathologies is often related to the host's catabolic state. Cancer patients suffer from weight loss, usually associated with anorexia. Web site: http://www.delphion.com/details?pn=US05698195__

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Mouse model for rheumatoid arthritis Inventor(s): Hayashi; Takuma (Malden, MA), Faustman; Denise L. (Weston, MA) Assignee(s): The General Hospital Corporation (Boston, MA) Patent Number: 6,414,218 Date filed: January 18, 2000 Abstract: Nonobese Diabetic Mice (NOD mice) that do not develop diabetes may be bred to produce F.sub.1 offspring that develop a condition that closely mimics rheumatoid arthritis (RA) in humans. The RA-like disease in the F.sub.1 mice, designated NOD-RA mice, is similar to human RA in clinical, radiological, histological and serological characteristics. The parents (F.sub.0) and their progeny (F.sub.1) are not diabetic and never develop hyperglycemia, and the parental mice (F.sub.0) do not themselves exhibit any symptoms of the RA-like condition that afflicts some of their progeny. The incidence, penetrance, gender domination, progression, and lifelong


exacerbation of symptoms after pregnancy shown in the RA-like condition afflicting NOD-RA mice are all comparable to phenomena observed in the human disease. The NOD-RA mice provide a new spontaneous model of human RA that will be useful for studying rheumatoid arthritis and testing new drugs and reagents for treating or diagnosing the disease. Excerpt(s): The present invention pertains to the field of medical research, particularly to the development of mammalian models of human rheumatoid arthritis. Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint swelling, deformation and, ultimately, destruction, culminating in severe physical disability. De Graaf et al., in The Epidemiology of Chronic Rheumatism, Dellgren and Ball, eds. (Blackwell, Oxford, 1963), pp. 446-56; Meenam et al., Arthritis Rheum., 24:544-50 (1981); Gabriel et al., J. Rheumatol., 26:1269-74 (1999); James, Clin. Exp. Rheumatol., 17:392-93 (1999). RA is a progressive condition with well-recognized symptoms including symmetrical peripheral joint swelling and synovial inflammation while sparing the axial skeleton; the presence of rheumatoid factor (RF) autoantibodies; increased concentrations of interleukin-6 (IL-6) in serum and synovial fluid; and pregnancyinduced disease remission followed by severe postpartum flares, that is, while women with RA commonly undergo remission during pregnancy, the disease returns and may be even more severe and show a new onset or more accelerated course after delivery. See, Turgen, in Immunology and Serology in Laboratory Medicine, 2.sup.nd edition, Shanahan, ed. (Mosby Year Book, St. Louis, 1996), pp. 387-98; Hirano et al., Eur. J. Immunol., 18:1797-1801 (1988); Wilder et al., Ann. N.Y. Acad. Sci., 876:14-31 (1999); Iijima et al., J. Rheumatol., 26:755-56 (1999); Ostensen, Ann. N.Y. Acad. Sci., 876:131-43 (1999). In medical research directed to understanding, diagnosing and treating RA, several animal models of the disease have been described, but no spontaneous animal model that closely mimics all the features of the human disease has been discovered. Thus, it would greatly advance discovery research in the field of RA research if a mammalian model faithfully exhibiting the same characteristic physical symptoms of RA could be obtained. Web site: http://www.delphion.com/details?pn=US06414218__ •

Photodynamic therapy for the destruction of the synovium in the treatment of rheumatoid arthritis and the inflammatory arthritides Inventor(s): Trauner; Kenneth (Sacramento, CA), Hasan; Tayyaba (Arlington, MA) Assignee(s): The General Hospital Corporation (Boston, MA) Patent Number: 5,368,841 Date filed: February 11, 1993 Abstract: A method of treating proliferative diseases of the synovial joint using photodynamic therapy. In particular the method of the invention may be used to destroy synovial tissue in inflammatory joint conditions associated with diseases such as rheumatoid arthritis, lupus erythematosus and other rheumatoid variants. A number of methods of delivery are provided, some of which are non invasive. Excerpt(s): The invention relates to the use of photodynamic therapy for the destruction of diseased synovium. Photodynamic therapy generally refers to an experimental cancer treatment modality that selectively kills cancer cells by an interaction between absorbed light an a retained photoactivatable agent (Kessel, Photochem. Photobiol. 44:489-493; Bottiroli et al., Photochem. Photobiol. 47:209-214, 1988; Salet et al., Photochem.

Patents 389

Photobiol. 53:391-3, 1991; Gross, Photobiological Techniques (chapter 9), Valenzeno et al. eds., Plenum Press, New York, 1991; Star et al., Photochem and Photobiol, B: Biology 1:149-167, 1987; and Jori et al., Photodynamic Therapy of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989). Chemical sensitization of live tissues by light was first reported in 1900 by Raab. Uptake of hematoporphyrin derivative (HPD) in neoplastic tissue was first described by Auler and Banzer (Z. Krebforsch 53:65-68, 1942). Uptake was later confirmed by fluorescence by Figge et al (Proc. Soc. Exp. Biol. Med. 68:640-641, 1948). Lipson et al. demonstrated tumor localization of HPD in 1960 (JNCI 26:1-12, 1961). The HPD semipurified mixture of porphyrins was later further purified to a combination of esters and ethers of dihematoporphyrin (DHE). The formulation predominantly in use is marketed as Photofrin.RTM. and HPD/Photofrin.RTM. was the first FDA approved photosensitizing agent available for PDT trials. Photofrin.RTM. has subsequently been tested extensively for the destruction of multiple tumors in numerous medical disciplines (Dougherty et al., In Photodynamic Therapy of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989). Web site: http://www.delphion.com/details?pn=US05368841__ •

Polynucleotides encoding MIP-1.alpha., MCP-1, MIP-1.beta., Rantes and TNF-.alpha., and methods for treating rheumatoid arthritis Inventor(s): Karin; Nathan (Haifa, IL) Assignee(s): Rappaport Family Institute for Research in the Medical Sciences (Haifa, IL) Patent Number: 6,420,346 Date filed: February 7, 2000 Abstract: A method of treating rheumatoid arthritis of an individual is disclosed. The method comprises the step of expressing within the individual at least an immunologically recognizable portion of a cytokine from an exogenous polynucleotide encoding the at least a portion of the cytokine, wherein a level of expression of the at least a portion of the cytokine is sufficient to induce the formation of anti-cytokine immunoglobulins which serve for neutralizing or ameliorating the activity of a respective and/or cross reactive endogenous cytokine, to thereby treat rheumatoid arthritis. Excerpt(s): The present invention relates to pharmaceutical compositions and methods for treating rheumatoid arthritis in an individual. More particularly, the present invention relates to DNA vaccination approaches which induce the breakdown of selftolerance to cytokines and as such inhibit the progression of the disease. Rheumatoid arthritis (RA) is an inflammatory disorder characterized by infiltration of leukocytes into the synovial tissue (ST) and synovial fluid (SF) of joints (Harris, 1990). Depending on the type of immunization, a single administration of complete Freund's adjuvant (CFA) may result in the development of a local inflammatory process or chronic poly adjuvant induced arthritis (AIA, also termed AA) which histologically and clinically resembles human RA (Holoshitz et al., 1983). In the scientific and medical communities, AIA is considered a reliable animal model for testing drugs and treatments for RA. In both diseases proinflammatory cytokines and chemokines are believed to play a pivotal role in the attraction of leukocytes to the site of inflammation and in the initiation and progression of the inflammatory process. The role of proinflammatory cytokines, particularly TNF-.alpha. and IL-1, in disease manifestation has been intensively studied and explored in experimental models that have been expanded to clinical trials (Arend and Dayer, 1995; Arend et al., 1994; Elliott et al., 1994; Feldmann et al., 1997; Moreland et


al., 1997; Moreland et al., 1996; for a general review, see also, Feldmann et al., 1996). Other cytokines such as IL-4, TGF-.beta., IL-8, IL-17, IL-10, IL-11, IL-12 and IL-15 have also been implicated in the regulation of the disease. Such regulation can be attributed to either their direct effect on disease manifestation, their synergistic effect with other proinflammatory cytokines/chemokines, or their involvement in the regulation of chemokine transcription, and production (Badolato and Oppenheim, 1996; Badolato et al., 1997; Butler et al., 1999; Chabaud et al., 1998; Evans et al., 1998; Feldmann et al., 1996; Kasama et al., 1999; Ma et al., 1998; Parks et al., 1998; Sato et al., 1996; Schimmer et al., 1998; Schrier et al., 1998; Wahl et al., 1993). Web site: http://www.delphion.com/details?pn=US06420346__ •

Polyvalent equine immune serum composition and method for treating rheumatoid arthritis Inventor(s): Stephan; Peter M. (London, GB2) Assignee(s): Peter Stephan Center, Ltd. (Miami, FL) Patent Number: 4,732,752 Date filed: October 23, 1986 Abstract: A composition and method for treating rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering an effective amount of an equine immune serum, in dosage form, to a patient. The equine immune serum is obtained from horses which have been immunized with a solution containing tissue from prenatal or pregnant pigs. Excerpt(s): The present invention relates to a composition and method for treating rheumatoid arthritis, osteoarthritis, non-specific rheumatism and other related diseases in humans. Arthritis is a term generally used to describe a condition of inflammed joints which is characterized by pain and swelling. Both osteoarthritis and rheumatoid arthritis may result in stiffness, swelling and a considerable amount of pain. Treatment generally includes rest, the application of heat, and the administration of antiinflammatory drugs. Often, the treatment further includes the administration of diseasemodifying anti-rheumatic drugs such as gold, methotrexate and penicillamine. However, since these drugs are quite toxic and often result in serious side-effects, they must be used with caution. In view of the severity of rheumatoid arthritis, osteoarthritis, and other related diseases, there is a great need for a drug which is easily tolerated and free from serious side-effects. Thus, it is an object of the present invention to provide a novel composition for the treatment of rheumatoid arthritis, osteoarthritis, and related diseases. Web site: http://www.delphion.com/details?pn=US04732752__

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Prevention and treatment of rheumatoid arthritis Inventor(s): Stolle; Ralph J. (Lebanon, OH), Beck; Lee R. (Birmingham, AL) Assignee(s): Stolle Research and Development Corporation (Cincinnati, OH) Patent Number: 4,732,757 Date filed: December 9, 1983

Patents 391

Abstract: There is disclosed a novel method and product for the treatment and prevention of rheumatoid arthritis. The method involves passive immunization against a mixed spectrum of infectious bacteria which reside in the human gastrointestinal tract. The passive immunization is accomplished by oral injestion of IgG immunoglobulin obtained from the milk of cows that have been immunized against a specific spectrum of bacterial types. A unique combination of bacterial species is formulated into a vaccine which is used to immunize dairy cattle. The IgG antibody obtained from the milk of the immunized cows constitutes the product of the invention. Excerpt(s): This application is related to an application in the name of Lee Randolph Beck, Ser. No. 776,249 filed March 10, 1977. A number of years ago it was commonly believed that rheumatoid arthritis had an infectious etiology. This view is not popular today, although the inflammatory features and constitutional manifestations of rheumatoid arthritis--the synovitis and granulomatous lesions, the fever, tachycardia, leukocytosis, lymphadenopathy and occasional spelnomegaly, the accelerated erythrocyte sedimentation rate and other changes in "acute phases reactants"--are all compatible with an infectious process. Competent and repeated bacteriologic studies have failed to recover consistently a single infectious agent from the blood, synovial fluid, synovial tissues or subcutaneous nodules. Attempts to transmit the disease by injecting joint fluid from patients with rheumatoid arthritis into the joints of other human subjects have been unsuccessful. Subcutaneous nodules have failed to survive following homologous transplantation (Bauer, et al, 1951) the Practitioner 166:5. An infectious process may appear to precipitate the onset of rheumatoid arthritis in a significant number of patients, and may exert a deleterious influence on the course of the disease when it has already been established. There is statistical evidence to support this clinical impression (Lewis-Faning, 1950) Ann Rheum. Dis., Suppl. 9. Web site: http://www.delphion.com/details?pn=US04732757__ •

Process and product for treatment of rheumatoid arthritis Inventor(s): Moore; Eugene R. (5600 Woodview Pass, Midland, MI 48642) Assignee(s): none reported Patent Number: 5,529,786 Date filed: February 28, 1994 Abstract: This invention provides a therapeutic pill comprising animal tissue containing a therapeutic amount of Type II collagen and a method of preparing animal tissue containing Type II collagen for treatment of Rheumatoid Arthritis in humans. Excerpt(s): Rheumatoid Arthritis is a painful and often crippling disease that initially results in swollen and imflammed joints, but often progresses to deformed or completely destroyed joints. This is a result of the body mistakenly attacking collagen, which is the major portion of cartilage tissue. Cartilage tissue serves the function of a lubricant in the joints, keeping bone from rubbing on bone. As the disease progresses and more of the cartilage is destroyed, bone does begin to wear on bone. This results in even more severe pain and ultimately destruction of the joint itself. As the disease progresses, the body sometimes attacks other collagen in the soft tissues of the body which can cause a variety of arthritis-related diseases. In order to initiate the disease, it is apparent that an individual must have an inherent (perhaps genetic) susceptibility. Given this susceptibility, there is now strong evidence that the disease is initiated by exposure to the Epstein-Barr virus. The ability of the Epstein-Barr virus to initiate


Rheumatoid Arthritis has been linked to a key amino acid sequence which is identical to a sequence found in human collagen. Thus, in generating antibodies to destroy the Epstein-Barr virus, the body generates antibodies that are also capable of attacking its own collagen. In a similar manner, arthritis has been initiated in rats by the intradermal injection of highly purified Type II collagen extracted from chicken cartilage or by the well known complete Freund Adjuvant. It was also shown that rats could be prevented from getting arthritis or the effects greatly reduced from this injection of highly purified collagen. This was accomplished by feeding the same highly purified collagen to the rats for several days prior to the injection. It was also shown with rats that, once arthritis had been induced, the effects of the disease could be reduced by the oral administration of the same highly purified collagen. In a later study with humans having severe arthritis it has been shown that the oral administration of the highly purified collagen is similarly beneficial to humans in reducing the effects of the disease. Web site: http://www.delphion.com/details?pn=US05529786__ •

Protein which is characteristic of rheumatoid arthritis Inventor(s): Rosano; Carmen L. (23 Nancy Dr., Troy, NY 12180), Hurwitz; Charles (108 Mosher Rd., Delmar, NY 12054), Parhami; Nourollah (349 Torquay Blvd., Westmere, NY 12203), Hechemy; Karim (29 Pico Rd., Clifton Park, NY 12065) Assignee(s): none reported Patent Number: 4,645,748 Date filed: February 1, 1985 Abstract: Describes rheumatoid arthritis factor present in detectable amounts in rheumatoid arthritis patients, but not in patients with other arthritedes; preparation of antibodies to the factor; use of factor and antibodies to test for rheumatoid arthritis; and test kits for conducting the tests. Excerpt(s): Rheumatoid arthritis (RA) has been described as an unresolved systemic inflammation in which immune dysfunction and genetic susceptibility play roles. In earlier stages it is characterized by fluctuating remissions and exacerbations, and in later stages by a chronic granulatomous response (panus formation) leading to tissue destruction. The synovial membrane in RA has many of the characteristics of a hyperactive immunologically stimulated lymphoid organ and the ratio of T suppressor to T helper lymphocytes has been shown to be significantly reduced. Although a number of attempts have been made to implicate bacteria, viruses and mycoplasms as etiological agents, no specific causative agent has been clearly proven. It is possible that there is no specific etiological agent, and that the important agent or factor may be the result of an interplay of hereditary factors and physiological changes on non-specific inflammatory states. A great deal of work has been expended on the late, destructive phase of this disease in which anaphylactically induced leukotrienes and prostaglandins may play a chemotactic role in migration of neutrophils and macrophages into the rheumatoid synovium leading to destruction of bone and cartilage. Many attempts have been made to intervene between these events and the subsequent destructive phase occurring in the rheumatoid synovia. Web site: http://www.delphion.com/details?pn=US04645748__

Patents 393

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Recombinant antigen for diagnosing rheumatoid arthritis Inventor(s): Prakash; Ramesh K. (Salt Lake City, UT) Assignee(s): Research Corporation Technologies, Inc. (Tucson, AZ) Patent Number: 5,723,314 Date filed: April 10, 1996 Abstract: A method is described for diagnosing rheumatoid arthritis by providing a recombinant antigen (RAMA) and detecting rheumatoid arthritis-associated IgM antibodies against the RAMA antigen in patient sera. The RAMA antigen comprises SEQ ID NO:3 and peptides substantially homologous thereto. A purified and isolated DNA encoding the RAMA antigen and a transformed host containing the DNA are also disclosed. Excerpt(s): This invention relates to a method for diagnosing rheumatoid arthritis. More particularly, this invention relates to a method for objectively diagnosing rheumatoid arthritis by quantitative determination of the presence or absence of rheumatoid arthritis-associated antibodies in patient sera that react with a recombinant antigen. The invention also relates to the recombinant antigen and a molecular clone of the gene thereof. Rheumatoid arthritis is a chronic systemic rheumatic disease that affects a significant percentage of the population. Traditionally, it has been diagnosed subjectively through clinical observation and dominant complaints by a patient. P. Lipsky, Rheumatoid Arthritis, in Harrison's Principles of Internal Medicine 1423 (1987). Thus, clinical diagnosis of rheumatoid arthritis is subject to the skill of the diagnostician and the severity of disease symptoms in the patient. For an objective diagnosis of rheumatoid arthritis, the presence of rheumatoid factor (Rf) in the serum of rheumatoid arthritis patients is routinely determined. Rf is an autoantibody that binds to the constant region of IgG immunoglobulins. The standard test for determining the presence of Rf in blood is an aggregation test wherein Rf causes aggregation of IgG. Rf has been detected in approximately 70% of patients exhibiting clinical symptoms of rheumatoid arthritis. These patients are thus termed "seropositive." The remaining 30% are classified as having "seronegative" rheumatoid arthritis. Numerous conditions besides rheumatoid arthritis are associated with the presence of rheumatoid factor. Therefore, the presence of Rf does not establish a conclusive diagnosis of rheumatoid arthritis. An objective method of diagnosing rheumatoid arthritis that is more closely correlated with clinical diagnoses than is the presence of Rf in sera is needed. Ideally, such an objective diagnostic test would be quick and easy to perform and would not involve radioisotopes or be invasive to the patient. Web site: http://www.delphion.com/details?pn=US05723314__

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Substantially pure rheumatoid arthritis specific protein and an antibody against the same Inventor(s): Yamanaka; Naoki (Nagoya, JP), Yoshida; Makoto (Kawasaki, JP) Assignee(s): Medecs Co., Ltd. (Aichi, JP), Asahi Medical Co., Ltd. (Tokyo, JP) Patent Number: 4,742,157 Date filed: September 13, 1985 Abstract: A substantially pure rheumatoid arthritis specific protein (RASP) and an antibody against the rheumatoid arthritis specific protein (anti-RASP antibody) are


disclosed. The RASP is found specifically in the serum or plasma of a patient suffering from rheumatoid arthritis, and may be detected using an anti-RASP antibody easily and effectively. Therefore, the anti-RASP antibody of the present invention is useful for the diagnosis of rheumatoid arthritis by the criterion of the presence of RASP. Excerpt(s): This invention relates to a substantially pure rheumatoid arthritis specific protein. The present invention also relates to an antibody against the rheumatoid arthritis specific protein. More particularly, the present invention is concerned with a protein specifically found in the plasma of a patient suffering from rheumatoid arthritis and an antibody specific for the antigenic determinant of the rheumatoid arthritis specific protein. Conventionally, the diagnosis of rheumatoid arthritis has been effected according to the criteria proposed by the American Rheumatism Association. However, such criteria depend on doctor's observations and dominant complaints by a patient, and therefore, such criteria are insufficient with respect to objectivity and quantitative analysis of the degree of rheumatoid arthritis. For the quantitative analysis of the degree of rheumatoid arthritis, the presence and amount of rheumatoid factor (RF), immune complex (IC) or C-reactive protein (CRP) in the serum or plasma of a patient have been determined. However, such substances are not necessarily specific for the plasma or serum of a patient suffering from rheumatoid arthritis, and therefore, such substances are not useful as a conclusive factor. Web site: http://www.delphion.com/details?pn=US04742157__ •

Treatment of arthritis disorders, rheumatoid arthritis and manifestations associated with rheumatoid disorders Inventor(s): Murray; James (Dorfet, GB), Snorrason; Ernir (Stigahlid 80, 105 Reykjavik, IS) Assignee(s): Snorrason; Ernir (Reykjavik, IS) Patent Number: 6,358,941 Date filed: May 3, 1999 Abstract: The present invention relates to the use of pharmaceutically acceptable cholinesterase inhibitors for the preparation of a pharmaceutical composition for the treatment or prophylaxis of arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases such as Juvenile Arthritis, Systemic Lupus Erythematosis, Sjogren's Syndrome, Progressive Systemic Sclerosis, Polymyositis, Dermatomyositis, Ankylosing Spondilitis, Reiter's Syndrome, Psoriatic Arthritis, Relapsing Polychondritis, Relapsing Panniculitis, Crohn's Disease, Ulcerative Colitis, Heredity Complement Deficiencies, Collagen Vascular Diseases, Felty's Syndrome, rheumatological manifestations associated with bacterial and viral endocarditis or myocarditis and other rheumatological manifestations such as anaemia of chronic disorders. The invention also relates to a novel method of treatment or prophylaxis of such diseases and manifestations. Preferably, the cholinesterase inhibitors are selected from a group of nicotinic acetylcholinesterase inhibitors such as galantamine (the name of this drug was previously spelled galanthamine). Excerpt(s): The present invention relates to the use of pharmaceutically acceptable cholinesterase inhibitors of the preparation of a pharmaceutical composition for the treatment or prophylaxis of arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases such as Juvenile Arthritis, Systemic Lupus Erythematosis, Sjogren's Syndrome, Progressive Systemic Sclerosis, Polymyositis,

Patents 395

Dermatomyositis, Ankylosing Spondilitis, Reiter's Syndrome, Psoriatic Arthritis, Relapsing Polychondritis, Relapsing Panniculitis, Crohn's Disease, Ulcerative Colitis, Hereditary Complement Deficiencies, Collagen Vascular Diseases, Felty's Syndrome, rheumatological manifestations associated with bacterial and viral endocarditis or myocarditis and other rheumatological manifestations such as anaemia of chronic disorders. The invention also relates to a novel method of treatment or prophylaxis of such diseases and manifestations. Preferably, the cholinesterase inhibitors are selected from a group of nicotinic acetylcholinesterase inhibitors such as galantamine (The name of this drug was previously spelled galanthamine). In the present description and claims, the term "rheumatoid" covers any of a variety of disorders marked by degeneration or metabolic derangement of the connective tissue structures of the body, especially the joints and related structures, including muscles, bursae (snyovial membranes), tendons and fibrous tissue. They are attended by pain, stiffness, or limitation of motion of these parts. Rheumatoid Arthritis is a chronic, recurrent systemic inflammatory disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the snyovial membranes and articular structures and by atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop. Extra-articular manifestations include vasculitis, atrophy of the skin and muscle, subcutaneous nodules, lymphadenopathy, splenomegaly, leukopaenia and often chronic anaemia. Web site: http://www.delphion.com/details?pn=US06358941__ •

Treatment of arthritis, including rheumatoid arthritis with.sup.166 Holmium radionuclide Inventor(s): Thornton; Alfred (New Hampton, NY), Lieberman; Ephraim (Suffern, NY), Bordoni; Maurice (Westtown, NY) Assignee(s): Cadema Medical Products, Inc. (Middletown, NY) Patent Number: 4,849,209 Date filed: January 28, 1987 Abstract:.sup.1/3 Holmium in a carrier metallic hydroxide aggregate is disclosed for the treatment of arthritis and, in particular, rheumatoid arthritis. The compound disclosed preferably has a particle size of 1 to 40 microns, Beta energy emissions in the range of 1.76-1.84 MeV, low levels of gamma ray emissions and a radioactive half-life of 26.8 hours. The preferred metallic hydroxide is selected from the group consisting of Ferric Hydroxide, Aluminum Hydroxide, Bismuth Hydroxide, Chromium Hydroxide, Cupric Hydroxide, Manganese Hydroxide and Stannous Hydroxide. Methods are also disclosed for the preparation of the compound, as well as for the methods of its administration to a patient in need thereof. Excerpt(s): The present invention relates to radioactive compounds, methods for the preparation thereof and a method for the treatment of arthritis, including rheumatoid arthritis. Arthritic disorders are the second leading cause of losses in time and earnings in the United States. Approximately six million of all arthritis sufferers are afflicted rheumatoid arthritis. Of these, over fifty percent (50%) ultimately will have involvement of the knee joint, over eighty percent (80%) will involve the hand joint and somewhat smaller percentages will have involvement of other joints such as the ankle, elbow and shoulder. Rheumatoid arthritis is believed to be an autoimmune disease wherein parts of the body are attacked by antibodies manufactured in the body. These antibodies may be produced in response to viruses present in the body. While the mechanism for


rheumatoid arthritis is not defined, it is a systemic disease. When the disease is active, the erythrocyte sedimentation rate (ESR) is elevated and the blood tests positive for rheumatoid factor. Web site: http://www.delphion.com/details?pn=US04849209__ •

Treatment of arthritis, including rheumatoid arthritis, with radioactive isotopes Inventor(s): Bordoni; Maurice E. (Westtown, NY), Thornton; Alfred K. (New Hampton, NY), Lieberman; Ephraim (Suffern, NY) Assignee(s): Cadema Medical Products, Inc. (Middletown, NY) Patent Number: 4,752,464 Date filed: June 7, 1985 Abstract: Treatment of rheumatoid arthritis by administering a radioactive compound to the inflamed synovium of the articular joint. The compound comprises an aggregate suspension having a radionuclide entrapped therein. The aggregate suspension is a ferric or aluminum hydroxide aggregate, and the radionuclide is selected from the group consisting of.sup.166 Holmium,.sup.153 Samarium,.sup.175 Ytterbium,.sup.169 Erbium, and.sup.176m Lutetium. The radionculide may also consist of.sup.51 Chromium. Suitable leakage inhibitors or agents to reduce leakage of the radionuclide from the articular joint is included as part of the chemical composition of the final drug form. Excerpt(s): The present invention relates to a radioactive compound, the methods for the preparation thereof and a method for the treatment of arthritis and, more particularly, radioactive compounds and a method for the treatment of rheumatoid arthritis. Arthritic disorders are the second leading cause of losses in time and earnings in the United States. Approximately nine percent (9%) of all arthritis sufferers are afflicted with a type of arthritis known as rheumatoid arthritis. Of these, approximately fifty-six percent (56%) ultimately will have involvement of the knee joint, eighty-seven percent (87%) of the hand joint and somewhat smaller percentages will have involvement of other joints such as the ankle, elbow and shoulder. The source of disability for the sufferer of rheumatoid arthritis is an inflammatory response, of unknown origin, in the synovium, or lining, of the afflicted joint. This chronic inflammation, or synovitis, leads to pannus formation and, eventually, enzymatic destruction of the joint cartilage. Web site: http://www.delphion.com/details?pn=US04752464__

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Treatment of arthritis, including rheumatoid arthritis, with the radionuclide, tin SN121 Inventor(s): Bordoni; Maurice E. (R.D. 1, Box 680, Westtown, NY 10998), Thornton; Alfred K. (Box 500 Lower Rd., New Hampton, NY 10958), Lieberman; Ephraim (1 Victory Rd., Suffern, NY 10901) Assignee(s): none reported Patent Number: 4,906,450 Date filed: March 26, 1987 Abstract: The radionuclide Tin, Sn-121 in a carrier hydroxide aggregate is disclosed for the treatment of arthritis and, in particular, rheumatoid arthritis of the hands, the

Patents 397

interphalangeal joints of the fingers and the metacarpal joints of the hand.The radioactive compound disclosed preferably has a particle size of

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