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Research Opportunities and Forecast: Rheumatoid Arthritis
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1.
Felson DT. Epidemiology of the rheumatic diseases. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:3-38.
2.
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis.  Arthritis Rheum.1987;30:1205-1213.
3.
Van Boxel JA, Paget SA. Predominantly T-cell infiltrates in rheumatoid synovial membranes.  N Engl J Med.1975;293:517-520.
4.
Janossy G, Panayi G, Duke O.  et al.  Rheumatoid arthritis: a disease of T lymphocyte/macrophage immunoregulation.  Lancet.1981;2:839-842.
5.
Fox DA. Etiology and pathogenesis of rheumatoid arthritis. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:1085-1102.
6.
Firestein GS, Zvaifler NJ. How important are T-cells in chronic rheumatoid synovitis?  Arthritis Rheum.1990;33:768-773 [published erratum appears in Arthritis Rheum. 1990;33:1437].
7.
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis.  Ann Rev Immunol.1996;14:397-440.
8.
Deleuran BW. Cytokines in rheumatoid arthritis: localization in arthritic joint tissue and regulation in vivo.  Scand J Rheumatol Suppl.1996;104:1-34.
9.
Müller-Ladner U, Kriegsmann J, Franklin BW.  et al.  Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice.  Am J Pathol.1996;149:1607-1615.
10.
Moreland LW, Koopman WJ. Biologic response modifiers for treating musculoskeletal disorders. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:877-930.
11.
O'Dell JR, Haise CE, Erikson N.  et al.  Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.  N Engl J Med.1996;334:1287-1291.
12.
Weinblatt ME, Kremer JM, Bankhurst AD.  et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor.  N Engl J Med.1999;340:253-259.
Research Opportunities for Specific Diseases and Disorders
February 7, 2001

Prospects for Autoimmune DiseaseResearch Advances in Rheumatoid Arthritis

Author Affiliations

Author Affiliation: Department of Medicine, University of Alabama at Birmingham.

JAMA. 2001;285(5):648-650. doi:10.1001/jama.285.5.648
Abstract

Rheumatoid arthritis (RA) is a common chronic inflammatory disease associated with progressive destruction of diarthrodial joints, substantial morbidity and economic burden, and a shortened lifespan. Significant progress has been made in understanding the pathogenesis of RA, and increasingly effective therapies have been introduced, including anti–tumor necrosis factor α agents. Advances made in the past quarter century will pale in comparison to those anticipated for the next 25 years, including delineation of the genetic basis of disease susceptibility and severity, genetic definition of disease subtypes that differ in severity and response to therapy, and prompt initiation of effective individualized treatment based on genetic and environmental assessment. Reconstructive surgery will become increasingly unnecessary and the morbidity, economic burden, and mortality due to RA will be reduced substantially.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease involving diarthrodial joints and other organs. Rheumatoid arthritis occurs worldwide and in all racial groups, and affects females 2 to 4 times more frequently than males, with prevalence estimates from 0.2% to 1.0% in most populations. There appears to have been a recent decline in RA incidence, an increase in the age at onset, and perhaps a diminution in the proportion of patients with severe disabling disease.

Nonetheless, RA causes substantial morbidity and attendant economic burden; approximately 50% of patients are unable to work within 10 years of onset and the lifetime costs of the disease rival those of coronary artery disease or stroke. Mortality rates among persons with RA are increased at least 2-fold and correlate with extent and severity of disease.1

Major Clinical and Research Advances in the Past 25 Years

Understanding and treatment of RA have been facilitated by development of widely accepted diagnostic criteria, instruments for functional assessment, and criteria for measuring disease activity. Genetic susceptibility to RA is strongly attributable to inheritance of specific HLA alleles (DRB 1) that encode a common 5–amino acid sequence ("shared epitope") in the antigen-binding groove of the DR molecule. Homozygosity for the epitope confers risk for more severe disease.2 The synovial membrane in RA (the target organ of the disease) is infiltrated predominantly by CD4 T cells3,4 that express activation markers5; however, cytokines elaborated by the synovium (eg, interleukin 1 [IL-1], IL-6, IL-8, tumor necrosis factor α (TNF-α), granulocyte-macrophage colony-stimulating factor) originate predominantly in macrophages and fibroblasts.6 The proinflammatory cytokines TNF-α and IL-1 play a central role in the pathogenesis of inflammation and tissue injury in RA.7,8 Fibroblastoid cells in RA synovium exhibit a transformed phenotype and are capable of adhering to and degrading cartilage in the apparent absence of T cells, presumably through expression of metalloproteinases.9

Clinical advances include more aggressive treatment of early RA, facilitated by the availability of increasingly effective therapeutic agents including methotrexate, leflunomide, and biologic agents directed against TNF-α.10 The latter agents are at least as effective as methotrexate and appear to be more active in retarding tissue destruction. Combination therapy, including concomitant use of methotrexate with anti–TNF-α agents, has enhanced efficacy (vs monotherapy) and caused less than anticipated toxicity.11,12 Advances in reconstructive surgery, including use of newer techniques and biomaterials, have improved the quality of life for patients with destructive disease.

Current Theories and Key Issues

While the etiology of RA is as yet unknown, it is presumed that the disease is likely triggered either directly or indirectly (eg, molecular mimicry) by an infectious agent(s) in a genetically predisposed individual. The ensuing pathogenetic events are believed to be driven by T-cell (and B-cell) responses to the inciting antigen(s), self-antigens, or both in the synovium with elaboration of proinflammatory cytokines that induce up-regulation of endothelial adhesion molecules, influx of chronic inflammatory cells, induction of protease expression, and subsequent tissue destruction. Non–T-cell dependent mechanisms may contribute to disease perpetuation, including aberrantly regulated cytokine cascades, impaired regulation of growth and programmed death among synovial cells, and cell-cell and cell-matrix interactions that autonomously drive inflammatory mechanisms, destructive pathways, or both.

In addition to addressing the obvious questions regarding the nature of the inciting event(s) in RA, delineation of the genes (and their functions) that contribute to disease susceptibility, phenotype, and response to therapy; elucidation of the specificity (and clonotype) of arthritogenic T cells (if these exist); determination of the molecular and cellular events linking chronic inflammation with tissue destruction; and identification of the cellular and molecular events underlying tissue destruction will be critical for unraveling the sequence of events responsible for the inflammatory and destructive paths of RA.

Forecast for Major Research Advances

Current leading research efforts likely to be most important in paving the way for the major advances in RA during the next quarter century are listed in Figure 1.

At least 10 genes, likely more, will be linked to disease susceptibility and severity and these genes will exhibit distinct patterns of distribution among ethnic groups. While some gene polymorphisms linked to RA susceptibility will influence cytokine/gene factor expression or responsiveness, immune functions, synovial cell growth and programmed cell death of synovial cells, others will act by unanticipated mechanisms to provide fresh insights into disease etiology and pathogenesis.

Individual genotype alone will confer a maximum increased risk of development of RA in the range of 10- to 20-fold greater than the general population frequency; however, with elucidation of gene-environmental interactions, this will increase to 20- to 40-fold. Based on genotype, RA will be classifiable into subgroups that exhibit characteristic differences in phenotype, severity, and response to individual therapies (or combinations thereof).

Diagnosis of RA will be possible earlier and with greater precision and accuracy. In individuals at high risk for developing RA (based on genotype and environmental assessment), blood and imaging diagnostic tests will be developed to detect disease onset prior to overt clinical symptoms.

No single etiologic agent will be identified for RA; rather several reasonably common infectious agents (likely both bacterial and viral) will be demonstrated to trigger the disease in predisposed individuals. While these agents (or their products) will be demonstrable in synovial tissue at disease onset, it is likely that they will be transient and that continued presence of the responsible agent(s) will not be required for disease perpetuation. Moreover, the specificity of T-cell (and B-cell) responses in RA synovial tissue will be defined; reactivities to local antigens liberated from damaged joint constituents and neo-antigens generated by posttranslational modification (eg, nitrosylation) will be implicated as important contributors to disease perpetuation.

Therapy for RA will consist of highly individualized combinations of oral cytokine and growth factor antagonists and T-cell–directed antigen-specific tolerance-inducing approaches based on the individual genotype and T-cell repertoire of the patient. Such therapeutic combinations will be instituted promptly after diagnosis, and clinical remissions will occur in a substantial fraction, perhaps half of patients so treated. In addition, reconstructive surgery will rarely be required for patients with RA after the year 2025. In patients diagnosed prior to this time and requiring reconstructive approaches for joint damage, techniques will be developed for resurfacing joints with autologously generated cartilage.

References
1.
Felson DT. Epidemiology of the rheumatic diseases. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:3-38.
2.
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis.  Arthritis Rheum.1987;30:1205-1213.
3.
Van Boxel JA, Paget SA. Predominantly T-cell infiltrates in rheumatoid synovial membranes.  N Engl J Med.1975;293:517-520.
4.
Janossy G, Panayi G, Duke O.  et al.  Rheumatoid arthritis: a disease of T lymphocyte/macrophage immunoregulation.  Lancet.1981;2:839-842.
5.
Fox DA. Etiology and pathogenesis of rheumatoid arthritis. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:1085-1102.
6.
Firestein GS, Zvaifler NJ. How important are T-cells in chronic rheumatoid synovitis?  Arthritis Rheum.1990;33:768-773 [published erratum appears in Arthritis Rheum. 1990;33:1437].
7.
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis.  Ann Rev Immunol.1996;14:397-440.
8.
Deleuran BW. Cytokines in rheumatoid arthritis: localization in arthritic joint tissue and regulation in vivo.  Scand J Rheumatol Suppl.1996;104:1-34.
9.
Müller-Ladner U, Kriegsmann J, Franklin BW.  et al.  Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice.  Am J Pathol.1996;149:1607-1615.
10.
Moreland LW, Koopman WJ. Biologic response modifiers for treating musculoskeletal disorders. In: Koopman WJ, ed. Arthritis and Allied Conditions. 14th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:877-930.
11.
O'Dell JR, Haise CE, Erikson N.  et al.  Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.  N Engl J Med.1996;334:1287-1291.
12.
Weinblatt ME, Kremer JM, Bankhurst AD.  et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor.  N Engl J Med.1999;340:253-259.
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