Markers of Epstein–Barr Virus Infection in Association with the Onset and Poor Control of Rheumatoid Arthritis: A Prospective Cohort Study

Although the connection between Epstein–Barr virus (EBV) and rheumatoid arthritis (RA) has been studied for over 40 years, many questions still need clarification. The study aimed to analyze the possible association between anti-EBV antibody titers, EBV DNA viremia, EBV infection status and EBNA1 (Epstein–Barr nuclear antigen 1—EBNA1) variants and clinical parameters of RA patients. This prospective cohort study included 133 RA patients and 50 healthy controls. Active/recent EBV infection was more prevalent in RA patients than in controls (42% vs. 16%, p < 0.001). RA patients had higher titers of anti-EBV-CA-IgM (capsid antigen—CA) and anti-EBV-EA(D)-IgG (early antigen—EA) antibodies than controls (p = 0.003 and p = 0.023, respectively). Lower levels of anti-EBNA1-IgG and anti-EBV-CA-IgG were observed in RA patients who received methotrexate (anti-EBNA1 IgG p < 0.001; anti-EBV-CA IgG p < 0.001). Based on amino acid residue on position 487, two EBNA1 prototypes were detected: P-Thr and P-Ala. Patients with active/recent EBV infection had a five times more chance of having RA and a nearly six times more chance of getting RA. Also, EBV active/recent infection is twice more likely in newly diagnosed than in methotrexate-treated patients. Further studies are needed to clarify “who is the chicken and who is the egg” in this EBV–RA relationship.