Evaluating the role of anti-EBV antibodies as biomarkers for the evolution of multiple sclerosis: A longitudinal study

Background: Epstein-Barr virus seropositivity has been strongly associated with the onset of multiple sclerosis (MS); however, the utility of measuring EBV-antibodies as biomarkers for MS progression remains uncertain. Objectives: To determine if baseline anti-EBV antibody titer levels are associated with mid-term evolution of MS. Methods: A total of 237 participants (187 MS patients and 50 healthy controls, HC) were tested for anti-EBNA1 and anti-VCA IgG levels, whose relative concentrations were categorized into lower and highest quartiles. Clinical disability progression, progression independent of relapse activity, and relapse-associated worsening were assessed at follow-up (5.5 years). MS patients also underwent brain MRI at baseline and follow-up, including measurement of contrast-enhancing, T2, T1, cortical, and paramagnetic rim lesions. In addition, changes in whole brain, white matter, gray matter, cortex, and lateral ventricle volumes were measured over time. Retinal nerve fiber layer thickness was obtained using optical coherence tomography (OCT) at baseline and follow-up. Serum neurofilament light (sNfL) chain levels were also measured at baseline and follow-up. The relationship between EBV antibody levels and clinical, MRI, OCT, and NfL measures was assessed using the chi-square test and a general linear model adjusted for age and sex. The effect of disease-modifying treatment was evaluated using a general linear model for continuous variables and logistic regression analysis for categorical variables. Results: MS patients showed significantly higher anti-EBV EBNA-1 and VCA titers compared to HC (p < 0.001) at baseline. Baseline anti-EBV antibody levels did not correlate with MRI, OCT or sNfL markers of disease activity, neurodegeneration, and clinical worsening over time. Conclusions: Although EBV remains likely as a key factor in the pathogenesis of MS, its role in the evolution of MS is uncertain.