Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel.

BACKGROUND

Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized.

OBJECTIVES

The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS.

METHODS

We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks.

RESULTS

MS risk increased with increasing titers of anti-EBNA complex (p < 10(-9)) and anti-EBNA-1 (p = 5.8 × 10(-9)) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6-136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1.

CONCLUSIONS

Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.