Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Abstract

Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA-like IA (e.g., meeting established classification criteria) that warrants therapeutic intervention. However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (e.g., joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA. Indeed, the discovery of the "pre-RA" stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA. This review focuses on several issues pertinent to understanding the prevention of RA. These include discussion of the pathogenesis of pre-RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention. Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today.

Figure 1.. Model of Rheumatoid Arthritis (RA) Development

In this model, genetic and environmental factors lead to initiation and expansion of autoimmunity that may progress to clinically-apparent IA/RA and classified RA. There is some controversy whether the term Pre-RA should be applied once clinically-apparent IA is present if not classifiable as RA. Abbreviations: ACPA=antibodies to citrullinated protein antigens; IA=inflammatory arthritis; RA=rheumatoid arthritis; RF=rheumatoid factor

Figure 2.. Strategies for identification and intervention for rheumatoid arthritis (RA) prevention

Differing approaches are needed based on stage of RA development. There is some controversy whether the term Pre-RA should be applied once clinically-apparent IA is present if not classifiable as RA. Abbreviations: IA=inflammatory arthritis; PRAIRI=Prevention of clinically manifest rheumatoid arthritis by B-cell directed therapy in the earliest phase of the disease; APIPPRA=Arthritis Prevention in the Preclinical Phase with Abatacept; StopRA=Strategy for the Prevention of the Clinically-Apparent Onset of RA