Rheumatoid Arthritis—Heresies and Speculations

RHEUMATOID ARTHRITIS—HERESIES AND SPECUIATIONS DAVID A. FOX" Introduction Since rheumatoid arthritis (RA) gradually became defined as a distinct clinical entity early in the 20th century, intensive and prolonged efforts to understand its cause have met largely with frustration. Concurrently, improvement in the treatment of RA has occurred slowly and has made only a modest impact on the natural history of this condition. In the course of RA, polyarticular inflammation is generally followed by destruction of cartilage, bone, and other structures of the joint, with consequent deformity and disability. The dogma that joint damage is the consequence of inflammation, rather than a parallel process, has been called into question by discrepancies between the anti-inflammatory potencies ofvarious therapeutic maneuvers and their generally unimpressive effects on erosion of cartilage and bone. Ultimately, RA is certainly capable of being a fatal condition , and on average, the mortality of individuals with this condition is approximately doubled, once adjustments for age and other comorbid conditions have been made. In this essay, I will present a series of "heresies" and speculations designed to challenge current concepts of the pathogenesis of RA. I will attempt to focus on issues for which current dogma leads to predictions that are difficult to verify, or seems to be hampering our understanding of RA rather than yielding clear insights. Heresy #1: RA Does Not Have a Cause It seems reasonable that clues to proper treatment of RA will come from delineation ofits cause. Figure 1 shows four hypotheses or paradigms within This work was supported in part by NIH grant AR-38477. The author wishes to thank Gigi Rowe for preparation of the manuscript. *Rackhara Arthritis Research Unit, Division of Rheumatology, Specialized Center of Research in Rheumatoid Arthritis, and The University of Michigan Multipurpose Arthritis and Musculoskeletal Diseases Center, Ann Arbor, MI 48109.© 1997 by The University of Chicago. AU rights reserved. 0031-5982/97/4002-1001$01.00 Perspectives in Biology and Medicine, 40, 4 ¦ Summer 1997 | 479 Synoviocyte transformation, synoviocyte interaction with macrophages, cartilage, and bone Cellular immune mechanisms (T cells, cytokines, monocytes) Humoral immune mechanisms (RF, immune complexes,---------complement ) Infection_______________________^. 19201940196019802000 Fig. 1.—Hypotheses for the cause of RA. which the cause of RA has been sought for most of this century. Once RA was defined as a distinct entity, early concepts of its etiology centered on infectious agents. However, with the discovery of rheumatoid factor and subsequent understanding of antibodies at a protein and genetic level, humoral immune mechanisms took center stage in studies of the pathogenesis and even the etiology of RA. It was believed at that time that an autoimmune response mediated by antibodies could cause RA, as well as a variety of other autoimmune diseases. In the 1980s, the development of monoclonal antibodies led to rapid growth in understanding of T cell development , T cell activation, and T lymphocyte surface structures, and immunogenetic studies established the association of various rheumatic diseases, including RA, with specific major histocompatibility complex (MHC) polymorphisms . In this setting cellular immune responses driven by T lymphocytes became the focus ofattention in the pathogenesis ofRA, as the disease was redefined as a T cell-driven autoimmune condition [I]. Within the past few years, however, the role of the T cell has come into question, in view of the presence of only modest amounts of T cell cytokines in the synovial compartment and disappointing results in therapeutic trials of anti-T cell monoclonal antibodies [2]. The apparently autonomous destructive potential of synoviocytes in chronic RA has intensified focus on the transformation of such cells and unusual cell-cell interactions within the joint as central to the etiology and pathogenesis of this disease. Each new paradigm for looking at RA has been too simple at its inception and has been accompanied by excessive enthusiasm. Therefore, when limitations of the paradigm have been encountered, scientific opinion has shifted abruptly to a new model, unfortunately forgetting valuable clues gained by exploration of the previous model. In trying to identify the cause of RA, a reasonable question would be whether the correct technology exists to address this question. One might argue that until recently this may not have been the case. But given the imposing...