Lessons from a Genomewide Association Study of Rheumatoid Arthritis

Rheumatoid arthritis is a chronic inflammatory disorder in which the articular joints are gradually destroyed. Occasionally there is systemic involvement, which can include vasculitis in various organs and pulmonary fibrosis. The disease has multifactorial causes to which genetic and environmental factors are thought to contribute. The presence of autoantibodies to cyclic citrullinated peptide (CCP) is specific to rheumatoid arthritis; although the mechanistic significance of these autoantibodies is obscure, their detection contributes both to the differential diagnosis and to a prediction of the severity of joint destruction. Rheumatoid arthritis causes substantial morbidity and mortality and is sometimes accompanied by severe infection or accelerated atherosclerosis.

During the past couple of decades, therapy for rheumatoid arthritis has been improved through the introduction of new antirheumatic drugs, such as the antimetabolite and antifolate drug methotrexate, and biologic therapeutics, such as antagonists to tumor necrosis factor (TNF). However, these treatments can have adverse effects,¹ and responsiveness to these treatments varies considerably. Perhaps "personalized medicine" may one day address such variation. An improved understanding of the genetic causes of the disease represents a step toward this goal and the development of other therapeutic approaches.

The article by Plenge et al.² in this issue of the Journal is therefore welcome. The authors report the results of a genomewide association study of an anti–CCP-positive subclass of rheumatoid arthritis. It is reassuring that the authors observed associations between rheumatoid arthritis and loci in and around HLA-DRB1 and PTPN22; these loci have been repeatedly implicated as genetic risk factors in persons of European descent.

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