Preclinical Rheumatoid Arthritis and Rheumatoid Arthritis Prevention.

PURPOSE OF REVIEW: This review is to provide an update on the current understanding of rheumatoid arthritis (RA) development related to disease development prior to the onset clinically apparent synovitis and opportunities for disease prevention. RECENT FINDINGS: A growing number of studies have demonstrated that serum elevations of autoantibodies rheumatoid factor and antibodies to citrullinated protein/peptide antigens (ACPA) are highly predictive of future development of IA/RA. This has underpinned the development of several prevention trials in RA. The full results from most of these prevention trials are pending, but ultimately, they should further inform several critical issues in RA prevention including identification and enrollment of individuals at high risk of imminent RA, the efficacy, safety and cost-effectiveness of prevention, and potentially the identification of new targets for prevention. Results from studies in RA prevention as well as other ongoing natural history studies of RA will help to change the paradigm of how RA is managed, potentially adding prevention to the possibilities for management.

Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis.

Background/Purpose: In rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing of future clinical RA. Materials and Methods: We evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR). Results: Twenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences. Conclusion: These findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution.