J. S. Smolen J.R. Kalden R.N. Maini (Eds.)

Rheumatoid Arthritis Recent Research Advances

With 53 Figures and 58 Tables

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest

Professor Dr. Josef S. Smolen 2. Medizinische Abteilung Zentrum fUr Diagnostik und Therapie rheumatischer Erkrankungen Krankenhaus der Stadt Wien-Lainz und Ludwig Boltzmann Institut fUr Rheumatologie und Balneologie WolkersbergenstraBe 1, A-ll30 Wien, Austria

Professor Dr. Joachim R. Kalden Medizinische Klinik III mit Poliklinik und Institut fUr Klinische Immunologie und Rheumatologie Friedrich-Alexander-U niversitat Erlangen-N urnberg KrankenhausstraBe 12, W-8520 Erlangen Federal Republic of Germany

Professor Dr. Ravinder N. Maini Mathilda and Terence Kennedy Institute of Rheumatology 6 Bute Gardens, Hammersmith London W6 7DW, United Kingdom

Library of Congress Cataloging-in-Publication Data Rheumatoid arthritis: recent research advances / J. S. Smolen, J. R. Kalden, R. N. Maini (eds.). p. cm. Includes bibliographical references and index.

ISBN-13: 978-3-642-76191-1 e-ISBN-13: 978-3-642-76189-8 DOl: 10.1007/978-3-642-76189-8

I. Rheumatoid arthritis. I. Smolen, Josef S., 1950- . II. Kalden, J. R. (Joachim Robert) III. Maini, R. N. [DNLM: 1. Arthritis, Rheumatoid. WE 346 R47307] RC933.R4288 1992 616.7'227--dc20 DLC for Library of Congress 91-5068 CIP

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To our families

Preface

Clinical medicine first recognized rheumatoid arthritis (RA) as a disease entity in the nineteenth century. In the early days the major development in understanding this disease came at the bedside, in distinguishing it from rheumatic fever and gout. Later, with the advances in medicine and the powerful ideas emanating from the fast­growing fields of pathology and microbiology, interest turned to the description of its morbid anatomy and the quest for an infectious etiology. The development of immunology and biochemistry made an impact too, and hypotheses tracing RA to infection, fibrinoid degeneration of collagen, and eventually autoimmunity had their proponents by the middle of this century.

RA was meanwhile being split up into further nosological entities as a result of developments emerging on at least two fronts: first, with the discovery of IgM rheumatoid factor, seropositive and seronegative disease were differentiated; second, on clinicopathological grounds, adherents of rheumatoid spondylitis were conceded the existence of ankylosing spondylitis, a movement which eventually led to the concept of spondyloarthropathies. The heterogeneity of RA was further emphasized more recently with the description of "marker" autoantibodies and associated with the chronic polyarthritis of conditions such as systemic lupus erythematosus (SLE), primary Sjogren's syndrome, overlap, and mixed connective tissue disease, usefully distinguished from RA.

These introductory comments provide a background to our interest in promoting this book. Having recognized the influence of scientific thought and technology on clinical research in arthritis and the central importance of clinical observation in posing questions and guiding enquiry, it seemed appropriate to ask whether the time was ripe to attempt to take stock of progress in the field. Recent information presented by leading researchers at meetings and in journals convinced us that this was indeed the case and that there were exciting new prospects for progress. The generosity of the individuals we ap-

VIII Preface

proached, in agreeing to write for this book, will, we hope, bear testimony to there being grounds for our optimism.

The book begins with a challenging chapter by an epidemiologist on the incidence and prevalence of RA. Considerable interest sur­rounds the question whether RA is a new disease and whether, as has been claimed, it is already beginning to disappear. To a large extent such issues depend on definitions and ascertainment. However, there is little doubt now that there are geographic variations in disease expression. The part that genes play in this process can now be addressed to a degree, and the two succeeding chapters examine this by reviewing molecular research and taking a fresh look at RA in the southeastern region of Europe.

The next section deals with aspects of progress in cellular and immunological fields which have contributed to our understanding of the pathogenesis ofRA. The role that cytokines and surface molecules play in regulating cellular function and interactions has been in the forefront of progress recently and is covered here. This inevitably leads to contributions on T and B cells, endothelial cells and dendritic cells, polymorphs, and finally regulation and expression of MHC class II antigens and the V genes involved in rheumatoid factors.

In the next section, we have selected contributions that highlight the possible role of environmental factors - principally infectious agents - and of autoimmunity in initiating and perpetuating RA. This includes most current candidates, namely, heat shock proteins, mycobacterial antigens, collagen, streptococcal antigens, retroviruses, and Epstein-Barr virus. Autoantibodies observed in RA, including antiperinuclear factor and antikeratin antibodies, are reevaluated, and new findings on anti-RA 33 are presented. Discussion of the acute phase response, amyloid, and markers of cartilage destruction pro­vides necessary vignettes to mark progress in the field.

In the final section, therapeutic initiatives are dealt with in two chapters. Although modern drugs, monoclonal antibodies, and T cell vaccination are covered, the information is most likely to prove to be outdated in the near future as a result of intense activity in this area.

Progress in research is not an orderly affair, and our initial approach in getting the contents of this book together was to make a list of areas that we felt were witnessing advances. It is a sign of the times that even though we did this relatively recently, it is likely that other fields will have opened up which are not covered. HowevlH, by inviting some of the key figures in research we expected to gain from their perceptions and knowledge and thereby secure maximum coverage of the cutting edge in research. We trust that the result will justify oUf hopes and that the contents, individually or as a whole, will coalesce into a worthwhile statement of the state of the art. Ifit inspires new ideas or a debate, so much the better. It is quite likely that we have

Preface IX

failed to be comprehensive, but for this we do not apologize, since our wish was not to publish a reference volume but to put together an enjoyable and readable book.

Wien, Erlangen, and London, May 1992 1. S. Smolen 1.R. Kalden R.N. Maini

Contents

Introduction

Is Rheumatoid Arthritis a Disappearing Disease? A. J. Silman ............................................ 3

Genetics

Genetic Factors in Rheumatoid Arthritis J. S. S. Lanchbury, L. 1. Sakkas, and G. S. Panayi 17

Rheumatoid Arthritis in Southeastern Europe H. M. Moutsopoulos and P. G. Vlachoyiannopoulos ............ 29

Pathogenesis

Pathogenesis of Rheumatoid Arthritis: Cellular and Cytokine Interactions M. Feldmann, F. M. Brennan, M. Field, and R. N. Maini ......... 41

Role of Cellular Adhesion in Rheumatoid Synovitis M.Ziff ................................................ 55

Endothelial Cells and Dendritic Cells in Rheumatoid Inflammation fJ. Fnrre, K. Waalen, and J. B. Natvig ....................... 71

Cellular and Humoral Immune Response Against Articular Chondrocytes and Proteoglycans in Rheumatoid Arthritis G. R. Burmester, S. Alsalameh, and J. Mollenhauer ............ 91

XII Contents

Role and Regulation of Synovial MHC Class II Antigens in Rheumatoid Arthritis and Related Diseases L. Klareskog ........................................... 112

CD5+ B Cells and Double-Negative T Cells in Rheumatoid Arthritis C. Plater-Zyberk, R. N. Maini, F. M. Brennan, and M. Feldmann . 122

The Genetics of Rheumatoid Factors (RF): The V-gene Repertoire of RFs in Rheumatoid Arthritis as Analyzed by Hybridoma Clones J. B. Natvig, 1. Randen, K. Thompson, and fl. Ferre ............ 137

Neutrophil Polymorphonuclear Cell Function in Rheumatoid Arthritis P. Youinou, A. Lamour, A. Dumay, and P. Le Goff ... .......... 150

Etiologic Factors -Bacterial Antigens, Autoantigens, Viruses

Heat-Shock Proteins and Mycobacterial Antigens W. van Eden, C. J. P. Boog, E. J. M. Hogervorst, M. H. M. Wauben, R. van der Zee, and J. D. A. van Embden 167

Type-II Collagen in the Pathogenesis of Rheumatoid Arthritis R. Holmdahl ............................................ 180

Streptococcal Cell Wall Antigens and Rheumatoid Arthritis L. J. Crofford and R. L. Wilder ............................. 202

Caprine Arthritis-Encephalitis E. Peterhans, B. Pohl, R. Zanoni, and S. Lazary

Oncogenes and Retroviruses in Rheumatoid Arthritis G. Stransky, R. E. Gay, A. Trabandt, W. K. Aicher,

216

S. R. Barnum, and S. Gay ................................. 231

Are Retroviruses Involved in the Pathogenesis of Autoimmune Diseases? E. F. Krapf ............................................. ,244

Epstein-Barr Virus and Rheumatoid Arthritis M. Lotz and J. Roudier ................................... 257

Antibodies to EBV-Encoded Proteins in Rheumatoid Arthritis P. J. W. Venables ........................................ 281

Contents XIII

Autoantibodies and Markers of Disease Activity

The Antiperinuclear Factor (APF) and Antikeratin Antibodies (AKA) in Rheumatoid Arthritis R. M. Hoet and W. J. van Venrooij .......................... 299

Anti-RA33: A New Antinuclear Antibody in Rheumatoid Arthritis W. Hassfeld, G. Steiner, W. Graninger, and 1. S. Smolen

Acute-Phase Response and Amyloid

319

G. Husby . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 328

Markers of Cartilage Destruction F. A. Wollheim and T. Saxne ............................... 348

Therapy

Progress in the Therapy of Rheumatoid Arthritis J. R. Kalden ............................................ 365

T-Cell Vaccination - A Prosp~ct F. C. Breedveld and R. R. P. de Vries . . . . . . . . . . . . . . . . . . . . . . . .. 385

Subject Index .......................................... 395

List of Contributors

Aicher, W. K. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Alsalameh, S. Institute of Clinical Immunology and Rheumatology, Department of Medicine III, University of Erlangen-Niirnberg, Krankenhausstrasse 12, W-8520 Erlangen, FRG

Barnum, S. R. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Boog, C. J. P. Department of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, P.O. Box 80.165, 3508 TD Utrecht, The Netherlands

Breedveld, F. C. Department of Rheumatology, University Hospital Leiden, P.O. Box, 9600 RC Leiden, The Netherlands

Brennan, F. M. Charing Cross Sunley Research Centre, Lurgan Avenue, Hammersmith, London W6 8LW, UK

Burmester, G. R. Institute of Clinical Immunology and Rheumatology, Department of Medicine III, University of Erlangen-Niirnberg, Krankenhausstrasse 12, W-8520 Erlangen, FRG

XVI List of Contributors

Crofford, L. J. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 9N240, Bethesda, MD 20892, USA

Dumay, A. Laboratory of Immunology and Clinic of Rheumatology, Brest University Medical School Hospital, BP 824, 29285 Brest C6dex, France

van Eden, W. Department of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, P.O. Box 80.165, 3508 TD Utrecht, The Netherlands

van Embden, J. D. A. Department of Bacteriology, National Institute of Public Health and Environmental Hygiene, P.o. Box 1, 3720 BA Bilthoven, The Netherlands

Feldmann, M. Charing Cross Sunley Research Centre, Lurgan Avenue, Hammersmith, London W6 8LW, UK

Field, M. Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith, London W6 7DM, UK

Fnrre,l2I. Oslo Sanitetsforenings Rheumatism Hospital, Akersbakken 27, 0172 Oslo 1, Norway

Gay, R.E. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Gay, s. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Graninger, W. Second Department of Medicine, University of Vienna, Garnisongasse 13, 1090 Vienna, Austria

List of Contributors XVII

Hassjeld, W. Second Department of Medicine, Center for Rheumatic Diseases, Lainz Hospital, Wolkersbergenstrasse 1, 1130 Vienna, Austria

Hoet, R.M. Department of Biochemistry, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

Hogervorst, E. J. M. Department of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, P.o. Box 80.165, 3508 TD Utrecht, The Netherlands

Holmdahl, R. Department of Medical and Physiological Chemistry, Box 575, Uppsala University, 75123 Uppsala, Sweden

Husby, G. Department of Rheumatology, The University Hospital of Troms0, 9000 Troms0, Norway

Kalden, J. R. Institute of Clinical Immunology and Rheumatology, Department of Internal Medicine III, Friedrich Alexander University Erlangen-Niirnberg, Krankenhausstrasse 12, W-8530 Erlangen, FRG

Klareskog, L. Department of Clinical Immunology, Uppsala University Hospital, 75185 Uppsala, Sweden

Krapf, E. F. Institute of Clinical Immunology and Rheumatology, Department of Internal Medicine III, Friedrich Alexander University Erlangen-Niirnberg, Krankenhausstrasse 12, W-8530 Erlangen, FRG

Lamour, A. Laboratory of Immunology and Clinic of Rheumatology, Brest University Medical School Hospital, BP 824, 29285 Brest Cedex, France

Lanchbury, J. S. S. Molecular Immunogenetics and Rheumatology Units, Division of Medicine, United Medical and Dental Schools, Guy's Hospital, London SEI 9RT, UK

XVIII List of Contributors

Lazary, s. Institute of Animal Husbandry, University of Berne, Uinggass-Strasse 122,3012 Berne, Switzerland

Le Goff, P. Laboratory of Immunology and Clinic of Rheumatology, Brest University Medical School Hospital, BP 824, 29285 Brest Cedex, France

Lotz, M. Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA

Maini, R. N. Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith, London W6 7DW, UK

Mollenhauer, 1. Institute of Pharmacology and Toxicology, University of Erlangen-Nurnberg, Krankenhausstrasse 12, W-8520 Erlangen, FRG

Moutsoupoulos, H. M. Department of Internal Medicine, School of Medicine, University of Ioannina, Greece

Natvig, 1. B. Institute of Immunology and Rheumatology, The National Hospital, Oslo, Norway

Panayi, G. Molecular Immunogenetics and Rheumatology Units, UMDS, Guy's Hospital, London SEl 9RT, UK

Peterhans, E. Institute of Veterinary Virology, University of Berne, Uinggass-Strasse 122,3012 Berne, Switzerland

Plater-Zyberk, C. Kennedy Institute of Rheumatology, 6 Bute Gardens, Hammersmith, London W6 7DW, UK

Pohl, B. Institute of Veterinary Virology, University of Berne, Uinggass-Strasse 122, 3012 Berne, Switzerland

List of Contributors XIX

Randen, 1. MRC Centre, Molecular Immunopathology Unit, Cambridge, UK

Roudier, I. Universite d'Aix Marseille, 13385 Marseille Cedex 5, France

Sakkas, L. 1. Molecular Immunogenetics and Rheumatology Units, UMDS, Guy's Hospital, London SEI 9RT, UK

Saxne, T. Department of Rheumatology and Department of Physiological Chemistry, University of Lund, Lund, Sweden

Silman, A. I. Arthritis and Rheumatism Council Epidemiology Research Unit, Manchester University Medical School, Manchester, UK

Smolen, 1. S. 2nd Department of Medicine and Ludwig Boltzmann Institute for Rheumatology, Krankenhaus der Stadt Wien-Lainz, Wolkersbergenstrasse 1, 1130 Wien, Austria

Steiner, G. Ludwig Boltzmann Institute for Rheumatology and Balneology, c/o 2nd Dept. of Medicine, Lainz Hospital, Wolkersbergenstrasse 1, 1130 Vienna, Austria

Stransky, G. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Thompson, K. Department of Immunology, Institute of Animal Physiology and Genetics Research, Cambridge, UK

Trabandt, A. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Venables, P. I. W. Division of Clinical Immunology, Kennedy Institute, London W6 7DW, UK

xx List of Contributors

van Venrooij, W. J. Department of Biochemistry, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

Vlachoyiannopoulos, P. G. Department of Internal Medicine, School of Medicine, University of Ioannina, Greece

de Vries, R. R. P. Department of Immunohematology, University Hospital, 2300 RC Leiden, The Netherlands

Waalen, K. Department of Animal Genetics, Norwegian College of Veterinary Medicine, Oslo, Norway

Wauben, M. H. M. Department of Infectious Diseases and Immunology, Veterinary Faculty, University of Utrecht, P.O. Box 80.165, 3508 TD Utrecht, The Netherlands

Wilder, T. L. Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Nationallnstitutes of Health, Building 10, Room 9N240, Bethesda, MD 20892, USA

Wollheim, F. A. Department of Rheumatology, Lund University Hospital, Lund, Sweden

Youinou, P. Laboratory of Immunology and Clinic of Rheumatology, Brest University Medical School Hospital, BP 824, 29285 Brest Cedex, France

Zanoni, R. Institute of Veterinary Virology, University of Berne, Uinggass-Strasse 122,3012 Berne, Switzerland

van der Zee, R. Department of Bacteriology, National Institute of Public Health· and Environmental Hygiene, P.O. Box 1,3720 BA Bilthoven, The Netherlands

Ziff, M. The University of Texas Southwestern Medical Center, Dallas, Texas, USA