Antibody Responses to Epstein-Barr Virus in the Preclinical Period of Rheumatoid Arthritis Suggest the Presence of Increased Viral Reactivation Cycles.

OBJECTIVE Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein-Barr virus (EBV), but the presence and role(s) of EBV have not been fully explored in the preclinical period. We hypothesized that EBV infection, as evidenced by an altered anti-EBV antibody response, could either play an important role in driving the development or be a result of expanded RA-related autoimmunity. METHODS 83 subjects with RA based on 1987 ACR criteria and 83 matched controls were evaluated. Subject and matched control sera from the pre and post- RA diagnosis periods were tested for 5 anti-EBV antibodies (EBNA-1-IgG, VCA-IgG, EA-IgG, VCA-IgA, and EA-IgA), 7 RA-related autoantibodies (RF-neph, RF-IgA, RF-IgM, RF-IgG, CCP2, CCP3, CCP3.1), 22 cytokine/chemokine, 36 individual APCAs, and CMV-IgG antibodies. Random forest classification, mixed and joint mixed modelling were used to determine differences in anti-EBV antibodies between RA cases and controls. RESULTS Random Forest analysis identified preclinical EBV antibodies that differentiate RA subjects from controls. Specifically, EA-IgG antibody levels are higher in RA cases (0.82 ± 0.72) compared to controls (0.49 ± 0.28). Elevations in EA-IgG levels significantly correlated with increasing RF-IgM levels in future RA cases (p = 0.007) but not in controls (p = 0.150). CMV-IgG antibody levels did not differ between groups. CONCLUSION Subjects who eventually develop classified RA demonstrate elevated EA-IgG antibody levels in the preclinical period, which suggests the presence of increased EBV re-activation cycles. A combination of RF and EBV reactivation may play an important role in the development of RA.