The Pathogenesis of Rheumatoid Arthritis — NEJM

Mechanisms of Disease

The Pathogenesis of Rheumatoid Arthritis

Iain B. McInnes, F.R.C.P., Ph.D., and Georg Schett, M.D.

N Engl J Med 2011; 365:2205-2219December 8, 2011

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References

Rheumatoid arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications, early death, and socioeconomic costs.1 The cause of rheumatoid arthritis is unknown, and the prognosis is guarded. However, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes. The current treatment strategy, which reflects this progress, is to initiate aggressive therapy soon after diagnosis and to escalate the therapy, guided by an assessment of disease activity, in pursuit of clinical remission.

However, several unmet needs remain. Current conventional and biologic disease-modifying therapies sometimes fail or produce only partial responses. Reliable predictive biomarkers of prognosis, therapeutic response, and toxicity are lacking. Sustained remission is rarely achieved and requires ongoing pharmacologic therapy. The mortality rate is higher among patients with rheumatoid arthritis than among healthy persons, and cardiovascular and other systemic complications remain a major challenge. Molecular remission and the capacity to reestablish immunologic tolerance remain elusive. Elucidation of the pathogenic mechanisms that initiate and perpetuate rheumatoid arthritis offers the promise of progress in each of these domains. Rheumatoid arthritis is predominantly classified on the basis of the clinical phenotype.2 We believe it is important to make the transition to a new molecular taxonomy that defines discrete disease subgroups with distinct prognostic and therapeutic significance.3

Rheumatoid arthritis is characterized by synovial inflammation and hyperplasia (“swelling”), autoantibody production (rheumatoid factor and anti–citrullinated protein antibody [ACPA]), cartilage and bone destruction (“deformity”), and systemic features, including cardiovascular, pulmonary, psychological, and skeletal disorders. These clinical features pose critical mechanistic questions: What genetic–environmental interactions must occur to facilitate autoimmunity a priori, and why does this beget articular localization? Why does synovial inflammation perpetuate? What drives local destruction leading to joint dysfunction? Why does rheumatoid arthritis cause systemic illness? We herein summarize key pathogenetic advances informing these issues.

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The Pathogenesis of Rheumatoid Arthritis — NEJM