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RHEUMATOID ARTHRITIS.pdf 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 RHEUMATOID ARTHRITIS ISBN: 978-0-323-05475-1 Copyright © 2009 by Mosby, Inc., an affi liate of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (1) 215 239 3804 (US) or (44) 1865 843830 (UK); fax: (44) 1865 853333; e-mail: healthpermissions@elsevier.com. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions. Notice Knowledge and best practice in this fi eld are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. Th e Publisher Library of Congress Cataloging-in-Publication Data Rheumatoid arthritis / [edited by] Marc C. Hochberg ... [et al.]. — 1st ed. p. ; cm. Includes bibliographical references. ISBN 978-0-323-05475-1 1. Rheumatoid arthritis. I. Hochberg, Marc C. [DNLM: 1. Arthritis, Rheumatoid—diagnosis. 2. Arthritis, Rheumatoid—therapy. WE 346 R47357 2009] RC933.R423 2009 616.7’227—dc22 2008010947 Acquisitions Editor: Pamela Hetherington Developmental Editor: John Ingram Design Direction: Lou Forgione Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 FM_i-xx-A05475.indd iv 7/29/08 12:16:20 PM We would like to dedicate this book to our parents (living or of blessed memory), and our wives, children, and grandchildren. Susan Hochberg, Francine and Jeff rey Guiff rida, and Jennifer Hochberg Ruth Silman, Joanna, Timothy, and David Silman Alice Smolen, and Eva, Nina, and Daniel Smolen Barbara Weinblatt, Hillary and Jason Chapman, and Courtney Weinblatt Betsy Weisman, Greg, Nicole, Mia and Joey Weisman, Lisa, Andrew, David and Th omas Cope, and Annie and Bill Macomber FM_i-xx-A05475.indd v 7/29/08 12:16:20 PM vii According to the philosopher Søren Kierkegaard, “life can only be understood backward; but it must be lived forwards.”1 Much the same is true about individual diseases. Th e origins of rheumatoid arthritis are hazy and in dispute, but the disease that A. J. Landre-Beauvais called “goutte asthenique primitive” (primary asthenic gout) in his 1800 doctoral dissertation, based on studies of the exclusively female population of the Paris asy- lum and hospital for incurable conditions, is considered the fi rst description.2 His intention was to emancipate this entity from generalized gout, a generic term used for centuries to designate specifi c diseases of the joints and rheumatism (acute rheumatic fever). Features that Landre-Beauvais recognized as distinctive included the predominance in women, a chronic course, multi- ple joints involved simultaneously, and fi nally the absence of tophi, recognized as a fairly common accompaniment of ordi- nary gout. He emphasized that in primary asthenic gout the changes observed resulted from the swelling, softening, and coalescence of bones and suppuration within joints. J. M. Charcot’s dissertation in 1853,3 based on a statistical analy- sis of 41 women from the same Paris hospital (La Salpetriere), and his illustrations of the hand deformities in these patients, leaves little doubt that rheumatoid arthritis was the entity being de- scribed. Subsequently, he alluded frequently to this form of chronic arthritis and was the fi rst to draw attention to Sydenham’s earlier descriptions (1753) of typical hyperextension deformities of fi nger joints.4 In 18th century England, gout had become such a popular disorder that descriptions of alternative forms of joint disease were either overlooked or dismissed until the posthumous publication of William Heberden’s Commentaries (1802), which contained observations on forms of arthritis other than gout.5 Later, Alfred Baring Garrod, the infl uential clinician and scientist who used his famous thread test for the demonstra- tion of uric acid crystals in human blood, compared gouty patients with those suff ering from other arthropathies; in- cluded among these were acute (rheumatic fever) and chronic rheumatic gout. In an accompanying book he wrote, “If we agree to name a disease simply by its external characters then I admit that the term rheumatic gout is not appropriate.” Th en he proposed the term rheumatoid arthritis, “by which name I wish to imply an infl ammatory aff ectation of the joints, not unlike rheumatism in some of its characters, but diff ering ma- terially in its pathology.”6 As the years passed rheumatoid arthritis escaped from the grasp of gout and osteoarthritis, but luminaries such as Alfred Garrod, the son of the great man, still worried that “perhaps several maladies have been confused together under the term rheumatoid arthritis. For this name, which was introduced by my father, I have a pious respect, but I am fully alive to its short- comings.” And he asked “whether the condition so called is rather a syndrome which, like malignant endocarditis, might originate in infections by several kinds of bacteria.”7 In the early part of the 20th century, attempts to distinguish rheumatoid arthritis from other forms of chronic infl ammatory polyarthritis, for example, psoriatic arthritis, postinfectious ar- thritis, childhood forms of arthritis, and rheumatoid spondylitis (spondyloarthropathy), were pursued. Th e latter proved partic- ularly troublesome. Previously the names of Strumpell, von Bechterew, and Marie were associated with what each believed to be independent types of spinal arthritis. Th eir view that rheu- matoid spondylitis constituted a separate disease sui generis was supported by a number of distinctive clinical and radiological features: namely, a preponderance of males, earlier age of onset, increased frequency of uveitis, and the absence of subcutaneous nodules. Arguing against this position were clinical similarities between patients with spondylitis and rheumatoid arthritis— that is, the frequent peripheral joint involvement, including the small fi nger articulations and the indistinguishable pathological appearance of the synovium in joints and diarthrodial articula- tions of the spine. American authorities such as Walter Bauer argued that in the absence of specifi c etiologic or genetic diff er- ences spondylitis was best considered “rheumatoid arthritis of the spine.”8 Th is position was subsequently rendered moot by laboratory studies that failed to show typical rheumatoid arthri- tis autoantibodies (rheumatoid factors [see following discus- sion]) in the blood of patients with spondylitis and the frequent genetic association of the HLA-B27 locus with the disease.9 Th e observation that the serum of patients with rheumatoid arthritis contained material(s) that could potentiate the clumping of sheep red cells coated with subagglutinating doses of rabbit antibodies or similarly coated bacteria introduced the science of immunology to the study of rheumatoid arthritis.10,11 It was quickly recognized that the principals reactive with both rabbit and human gamma globulin antibodies resided in the high-molecular-weight fractions of serum gamma globulins (IgM) and that these soluble IgG-IgM antibody complexes were a Foreword FM_i-xx-A05475.indd vii 7/29/08 12:16:20 PM viii regular, but not exclusive, feature of some patients with rheuma- toid arthritis: hence, the term rheumatoid factors (RFs). When these subsequently were shown to be synthesized in response to antigenic determinants on the Fc fraction of “self” immunoglobu- lins whose confi rmation had been altered after reacting with an antigen (thus, autoantibodies), rheumatoid arthritis was incorpo- rated into the universe of autoimmune diseases. Th e serum of about 70% of patients with rheumatoid arthritis contains RF. Th e antibody is undoubtedly important in disease pathogenesis because patients who are sero-positive, especially those with high titers, have a more aggressive disease with greater joint de- struction, nodules, vasculitis, and extra-articular features.12 Conversely, because some normal individuals (10% to 20%) and patients with a variety of chronic viral infections and certain other autoimmune and hematologic diseases have detectable RF in the absence of arthritis, its pathogenicity has been challenged. What about an etiologic role? Th eoretical stimuli for RF synthesis in- clude (1) immunization with antigen-antibody complexes during anamnestic immune responses, (2) polyclonal B-cell activation, and (3) chronic viral infections. All have been extensively ana- lyzed, but they failed to provide insights until genetic studies suggested a possible explanation. Rheumatoid arthritis was known to appear in families, sug- gesting a role for genetic factors. Th e observation that the admixture of lymphocytes from diff erent individuals with rheumatoid arthritis elicited less of a proliferative response than when these same patient’s lymphocytes were cultured together with lymphocytes from normal individuals sug- gested they shared a similarity in certain histocompatability genes. Stastny subsequently pointed in the direction of the HLA system with the observation of an association of the B-cell alloantigen DR4 with rheumatoid arthritis.13 Rapid advances in the molecular understanding of the allelic poly- morphisms in the HLA-D region over the next two decades showed that rheumatoid arthritis was associated with a short sequence of amino acids (Q/RKRAA) at a site in the  helix that infl uences T-cell receptor–HLA interactions and the binding of peptide antigens.14 Th is disease-associated HLA-DRB1 polymorphism predicted onset, severity, and pat- terns of disease in a number of populations and was thereafter known as the “shared epitope” (SE). In the 1960s and 1970s occasional reports of highly specifi c antibodies for rheumatoid arthritis appeared. Initially they were referred to as antifi llagrin antibodies, but after several decades of research they were recognized as members of a diverse group of autoantibodies that targeted diff erent deiminated (citrulli- nated) proteins.15 Such anticitrullinated protein antibodies (ACPAs) are found in 60% to 70% of rheumatoid arthritis pa- tients, often before the appearance of clinical disease.16 Besides their diagnostic and prognostic import, ACPAs are at the center of contemporary thinking about the pathogenesis of rheuma- toid arthritis because of the fi nding that SE alleles are associated only with patients who are ACPA positive and not patients with rheumatoid arthritis who are ACPA negative.17 Gene–environment interactions are important as etiologic factors in a number of diseases. Smoking is a powerful environ- mental risk factor for the development of rheumatoid arthri- tis,18,19 but only in association with a number of recognized host factors. For instance, HLA-DR SE genes are risk factors in smokers, but this eff ect is limited to patients who are RF posi- tive.20 Th e occurrence and quantity of anticitrulline antibodies is associated in a dose-dependent fashion with a history of pre- vious smoking. Bronchoalveolar lavage cells from smokers immunostain for citrullinated proteins. Based on these fi ndings, Klareskog has proposed that the etiology of some cases of rheu- matoid arthritis can be explained by a hypothesis that incorpo- rates several factors: namely, a known environmental trigger (smoking), which in a host with an appropriate genetic constitu- tion (SE), will initiate an immune response (ACPAs) with the potential to contribute to disease.21 Th us, future studies of rheumatoid arthritis are likely to be based on subsets of patients with well-characterized biomarkers (such as ACPAs and RFs) and genetic factors. Th ese will provide insights into causation and predict disease outcomes and treat- ment responses. Th e current excellent text already hints at these developments, but undoubtedly they will become even more prominent in future editions. Nathan J. Zvaifl er, MD Professor of Medicine University of California, San Diego School of Medicine San Diego, California REFERENCES 1. Th e Journals of Søren Kierkegaard. Wikiquote. 10 July 2008, from: http://en.wikiquote.org/wiki/Soren_Kierkegaard 2. Landre-Beauvais AJ. Th e fi rst description of rheumatoid arthritis. Unabridged text of the doctoral dissertation pre- sented in 1800. Joint Bone Spine 2001;68:130–143. 3. Fraser KJ. Anglo-French contributions to the recognition of rheumatoid arthritis. Ann Rheum Dis 1982;41: 335–343. 4. Short C. Th e antiquity of rheumatoid arthritis. Arthritis Rheum 1974;17:193–205. 5. Heberden W. Commentaries on the history and cure of diseases. London: Payne, 1802. 6. Garrod AB. A treatise on gout and rheumatic gout. In Rheumatoid Arthritis, 3rd ed. London: Longmans, Green, 1875. 7. Garrod AE. Discussion on the ‘aetiology and treatment of osteoarthritis and rheumatoid arthritis’. Proc R Soc Med 1923;17:1–4. 8. Short C, Bauer W, Reynolds WE. Rheumatoid arthritis. A defi nition of the disease and a clinical description based on a numerical study of 293 patients and controls. Commonwealth Fund. Th e Harvard University Press, 1957, pages 24–26. 9. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973;1:904–907 Foreword FM_i-xx-A05475.indd viii 7/29/08 12:16:20 PM ...