Virus-specific effects of disease-modifying therapies on herpesvirus antibody titers in multiple sclerosis

Abstract Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have both been implicated in multiple sclerosis (MS), yet it remains unclear whether disease-modifying therapies (DMTs) shape antiviral humoral responses. We analyzed antiviral IgG titers in MS patients stratified by current DMT (N = 498 for HHV-6A/B, 410 for EBNA-1, 361 for cytomegalovirus (CMV)). Multivariable regression models were built separately for each virus, adjusting for age, sex, HLA-DRB1*15:01 carriage, EDSS, treatment duration, and prior treatment efficacy, using interferon-beta (IFN-beta) as the reference category. The HHV-6A/B model showed a significant global fit (p = 1.16 × 10^-6), with fingolimod independently associated with reduced titers relative to IFN-beta (p = 0.006), alongside negative effects of age (p = 0.001) and higher titers among HLA-DRB1*15:01 carriers (p = 0.028). Neither the EBNA-1 nor the CMV model reached global significance, although age remained a strong predictor of CMV IgG (p = 0.002). These findings indicate that DMTs do not exert a uniform effect on herpesvirus serology in MS: fingolimod is specifically associated with attenuated HHV-6A/B seroreactivity, whereas EBNA-1 and CMV titers appear to be governed mainly by host factors. Interpreting antiviral serology in MS from a treatment-stratified perspective may therefore be necessary to identify biologically significant signals specific to each drug.