Exploring the etiologic role of omega-3 fatty acids in the pathogenesis of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint destruction and systemic inflammation, and follows a disease paradigm characterized by three stages of the disease, where first there is an initial genetic risk, measured by positivity for the HLA shared epitope (SE) as well as other genetic factors, followed by a preclinical phase of RA-related autoimmunity, measured by the presence of anti-cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF), and, finally, followed by progression to clinically-apparent disease. Environmental factors are thought to influence transitions through each stage of this disease paradigm. This thesis investigates omega-3 fatty acids (n-3 FAs), which are hypothesized to be protective against the development of RA, and their association with the preclinical autoimmunity phase of RA. We utilized the multicenter Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort, which follows RA-free individuals who are at increased risk for future RA. We conducted a nested case-control study, a cross-sectional study of the baseline visit, and a prospective cohort study within SERA to determine whether n-3 FAs are associated with presence and development of RA-related autoimmunity. Within the nested case-control study, we observed a novel association where increasing levels of n-3 FAs in erythrocyte membranes (n-3 FAs in RBCs) were inversely associated with anti-CCP2 positivity and RF positivity; furthermore the association with RF positivity was modified by SE status, where n-3 FAs in RBCs were inversely associated with RF positivity only in participants positive for SE. Similar associations were observed in the SERA cohort at the baseline visit, where n-3 FA supplement use was inversely associated with presence of RF and/or anti-CCP2 positivity, but only in SE positive participants. In our prospective cohort analysis of incident autoimmunity, we found that n-3 FA supplement use was associated with a decreased incidence of RF, although this was only marginally significant, likely due to the fact that we had 16 incident RF cases. In summary, our novel results suggest that n-3 FAs could be protective against the development of RA-related autoimmunity, implicating a possible mechanism of action by which n-3 FAs could be used to prevent RA.