Can rheumatoid arthritis be prevented?

Abstract

The discovery of elevations of rheumatoid arthritis (RA)-related biomarkers prior to the onset of clinically apparent RA raises hopes that individuals who are at risk of future RA can be identified in a preclinical phase of disease that is defined as abnormalities of RA-related immune activity prior to the clinically apparent onset of joint disease. Additionally, there is a growing understanding of the immunologic processes that are occurring in preclinical RA, as well as a growing understanding of risk factors that may be mechanistically related to RA development. Furthermore, there are data supporting that treatment of early RA can lead to drug-free remission. Taken as a whole, these findings suggest that it may be possible to use biomarkers and other factors to accurately identify the likelihood and timing of onset of future RA, and then intervene with immunomodulatory therapies and/or risk factor modification to prevent the future onset of RA in at-risk individuals. Importantly, several clinical prevention trials for RA have already been tried, and one is underway. However, while our growing understanding of the mechanisms and natural history of RA development may be leading us to the implementation of prevention strategies for RA, there are still several challenges to be met. These include developing sufficiently accurate methods of predicting those at high risk of future RA so that clinical trials can be developed based on accurate rates of development of arthritis and subjects can be adequately informed of their risk of disease, identifying the appropriate interventions and biologic targets for optimal prevention, and addressing the psychosocial and economic aspects that are crucial to developing broadly applicable prevention measures for RA. These issues notwithstanding, prevention of RA may be within reach in the near future.

Keywords: Pathophysiology; Preclinical disease; Prediction; Prevention; Rheumatoid arthritis.

Figure 1. Phases of development of rheumatoid arthritis (RA)

In this model of RA development, disease begins with genetic and environmental risks (Phase 1), followed by asymptomatic inflammation and autoimmunity (e.g. autoantibodies, cytokines and chemokines; Phase 2), with progression to symptoms that may be present in absence of inflammatory arthritis (IA) on physical examination (Phase 3), and eventual development of undifferentiated IA (Phase 4) that may progress to classifiable RA (Phase 5). Phase 6 is defined as evolution of disease (e.g. exacerbations, remissions, and response to therapy) after clinically apparent articular disease has developed. ‘Preclinical’ RA is defined as Phases 2 and 3 as they are identifiable by biomarker testing and prior to IA that is identifiable by joint examination. This developmental process is characterized by expanding autoimmunity and inflammation, detectable through assessment of circulating biomarkers, although Phase 1 could also be included. The double-headed arrows indicate that progression of RA may be halted, or reversed, perhaps through immunomodulatory pharmacologic intervention(s), especially if initiated prior to the onset of clinically apparent IA (Phase 4).