The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity

Plain Language Summary Patients with rheumatoid arthritis (RA) experience inflamed and damaged joints. RA is an autoimmune disease where proteins called autoantibodies in the blood of patients with RA target the patient's own joint tissue and organs by mistake. This causes inflammation. Patients with certain autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), may experience worse symptoms. There are certain genetic risk factors that may mean a person is more likely to develop RA. One example of a genetic risk factor is having the shared epitope (SE). Our study looked at almost 1000 patients with RA in the general population. It explored the impact of having SE and ACPAs on changes in RA disease activity. Patients with SE had RA for a longer time, had more severe disease, and were more likely to have other diseases compared with patients without SE. Patients with SE were also more likely to have ACPAs. Over the course of one year, patients with SE had larger increases in RA disease activity than those patients without SE, even though they were taking the same treatments. These results suggest that patients with the genetic risk factor, SE often have RA that is harder to treat. Doctors should take this into account when selecting treatment for RA. Introduction Shared epitope (SE) is present in high proportions of anti-citrullinated protein antibody (ACPA) + patients with rheumatoid arthritis (RA) and is associated with poor prognosis. We assessed the role of SE in RA prognosis, in relation to ACPA positivity. Methods Patients enrolled in the Brigham and Women's RA Sequential Study were included. Changes from baseline in disease activity (Disease Activity Score in 28 joints using C-reactive protein [DAS28 (CRP)], Clinical Disease Activity Index [CDAI], Simplified Disease Activity Index [SDAI]) to 1 year were assessed. Baseline characteristics were compared by SE and ACPA status (+/-; chi-squared, Kruskal-Wallis). Association between number of SE alleles and ACPA status (logistic regression models), relationships between baseline characteristics and changes in disease activity (adjusted linear regression model), and effect of ACPA on the association between SE and changes in disease activity (mediation analysis) were studied. Results Nine hundred twenty-six patients were included. SE + versus SE - patients had significantly longer disease duration and higher disease activity scores and were more likely to have erosive disease, have higher comorbidity burden, and be RF + (all p < 0.05). Among patients with one or two SE alleles (vs. 0), odds of being ACPA + were 1.97 (p = 0.0003) and 3.82 (p < 0.0001), respectively. SE + versus SE - patients had worse disease activity scores as indicated by mean increases in DAS28 (CRP) of 0.22, CDAI of 2.07, and SDAI of 2.43 over 1 year (all p < 0.05). Direct effect of SE + accounted for 76.4-80.1% of total effect in disease activity increases. Conclusions SE is strongly associated with ACPA positivity and higher disease activity in patients with RA. SE was associated with greater increases in disease activity over 1 year, which was partially mediated by the presence of ACPA.