No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT

Abstract

Objective: To evaluate whether Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels or tobacco use were associated with conversion to multiple sclerosis (MS) or MS progression/activity in patients presenting with clinically isolated syndrome (CIS).

Methods: In this prospective, longitudinal study, we measured EBV IgG antibody and cotinine (biomarker of tobacco use) levels at up to 4 time points (baseline, months 6, 12, and 24) among 468 participants with CIS enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) clinical trial. Outcomes included time to conversion to clinically definite or McDonald MS, number of relapses, Expanded Disability Status Scale (EDSS) changes, brain and T2 lesion volume changes, and number of new active lesions over 5 years. Analyses were adjusted for age, sex, treatment allocation, baseline serum 25-hydroxyvitamin D level, number of T2 lesions, body mass index, EDSS, steroid treatment, and CIS onset type.

Results: We found no associations between any EBV IgG antibody or cotinine levels with conversion from CIS to MS or MS progression as measured by EDSS or activity clinically or on MRI. The relative risk of conversion from CIS to clinically definite MS was 1.14 (95% confidence interval 0.76-1.72) for the highest vs the lowest quintile of EBNA-1 IgG levels, and 0.96 (95% confidence interval 0.71-1.31) for cotinine levels >25 ng/mL vs <10.

Conclusions: Neither increased levels of EBV IgG antibodies, including against EBNA-1, nor elevated cotinine levels indicative of tobacco use, were associated with an increased risk of CIS conversion to MS, or MS activity or progression over a 5-year follow-up.

Figure. Risk of conversion to CDMS by quintiles of EBV/CMV IgG antibody and tobacco use

Kaplan-Meier curves for risk of conversion to CDMS by (A) quintiles of EBNA-1 IgG antibody, (B) quintiles of VCA IgG antibody, (C) quintiles of CMV IgG antibody, and (D) tobacco use (cotinine levels >25 ng/mL indicates use vs <10 ng/mL indicates no use). Log-rank p values: baseline EBNA-1: p_log-rank = 0.10; 6-month VCA: p_log-rank = 0.39; 6-month CMV: p_log-rank = 0.33; cotinine: p_log-rank = 0.75. CDMS = clinically definite multiple sclerosis; CMV = cytomegalovirus; EBNA-1 = Epstein-Barr virus nuclear antigen-1; EBV = Epstein-Barr virus; IgG = immunoglobulin G; VCA = viral capsid antigen.