Reactivation of Epstein-Barr Virus May Play a Role in the Pathogenesis of Rheumatoid Arthritis

Reactivation of Epstein-Barr Virus May Play a Role in the Pathogenesis of Rheumatoid Arthritis
Epstein-Barr virus EBV, a herpes virus which causes infectious mononucleosis and Burkitt’s lymphoma on colorful background. 3D illustration
Researchers determined the role of infection with Epstein-Barr virus on risk of developing rheumatoid arthritis.

Individuals with elevated Epstein-Barr virus (EBV) antibodies in the preclinical period have a likelihood of developing rheumatoid arthritis (RA), according to study results published in Arthritis & Rheumatology.

Research has shown that EBV persists in B cells with recurrent periods of activity. Although studies have shown a link between EBV and RA, the causal effect of EBV in the development of RA has not been established.

In a longitudinal cohort study, researchers investigated the role of EBV in the development of RA.  

Sera samples were collected from patients with RA before and after disease diagnosis and at similar time points from control participants. Sera were tested for 5 anti-EBV antibodies (anti-EBV nuclear antigen 1 immunoglobulin [Ig]G isotype, antiviral capsid antigen [anti-VCA] isotypes IgG and IgA, and antiearly antigen [EA] isotypes IgG and IgA), 7 RA-related autoantibodies (rheumatoid factor measured by nephelometry [RF-Neph] and isotype-specific IgA-RF, IgM-RF, and IgG-RF, and anticyclic citrullinated peptide [anti-CCP] antibodies, including anti-CCP2, anti-CCP3, and anti-CCP3.1), 22 cytokines/chemokines, 36 individual anticitrullinated protein antibodies, and IgG-cytomegalovirus (CMV) antibodies.

Differences in anti-EBV antibody levels between patients with RA and control participants were measured using random forest classification, mixed modeling, and joint mixed modeling.

A total of 83 participants with RA and 83 age-, sex-, and race-matched control participants without RA were included in the analysis. All participants were military members.

Among serum analytes, IgG-EA, IgG-VCA, and IgA-EA were among the top 20 most important variables for classifying RA cases. The IgG-EA antibody levels were significantly higher among patients with RA compared with control participants (0.82±0.72 international standardized ratio [ISR] vs 0.49±0.28 ISR, respectively; Holm-adjusted P =.001). In the preclinical period, IgG-EA levels were significantly correlated with serum IgM-RF (P =.007) among patients with RA, but not control participants (P =.15).

No difference was found in IgG-CMV antibodies between the groups, suggesting that the antibody response was specific to EBV and not due to general dysregulation of the immune system.

A limitation of the analysis was the study population, which only included individuals in the military and a higher percentage of men.

The researchers concluded, “[Individuals] whose serum IgG-EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.”


Fechtner S, Berens H, Bemis E, et al. Antibody responses to Epstein–Barr virus in the preclinical period of rheumatoid arthritis suggest the presence of increased viral reactivation cycles. Published online October 3, 2021. Arthritis Rheumatol. doi:10.1002/art.41994