Environmental and gene-environment interactions and risk of rheumatoid arthritis

Abstract

Multiple environmental factors including hormones, dietary factors, infections, and exposure to tobacco smoke, as well as gene-environment interactions, have been associated with increased risk for rheumatoid arthritis (RA). The growing understanding of the prolonged period before the first onset of symptoms of RA suggests that these environmental and genetic factors are likely acting to drive the development of RA-related autoimmunity long before the appearance of the first joint symptoms and clinical findings that are characteristic of RA. This article reviews these factors and interactions, especially those that have been investigated in a prospective fashion before the symptomatic onset of RA.

Figure 1. Phases in the Development of Rheumatoid Arthritis

Phase 1) “asymptomatic” phase of genetic risk; Phase 2) asymptomatic “immune activation” phase with autoantibodies and elevated biomarkers such as cytokines and chemokines; Phase 3) “pre-clinical” phase with abnormal biomarkers of inflammation and perhaps arthralgias; and Phase 4) clinically-apparent inflammatory arthritis (defined as symptomatic joint disease including pain, stiffness and swelling, and identifiable synovitis on examination) that may be undifferentiated arthritis (UA), or fulfill classification for RA. Identifying the environmental factors associated with transitions between phases, key exposure windows leading to transition between phases, and the biologic mechanisms involved in these transitions is a challenge for the field.