Environmental Factors Associated with Disease Progression after the First Demyelinating Event: Results from the Multi-Center SET Study

Dana Horáková ,Haoying Yu,Ming Zhang,Darlene Badgett,Sara Hussein,Robert Zivadinov,Niels Bergsland,Jun Qu,Xiaotao Duan,Murali Ramanathan,Michael G Dwyer,Laura Willis,Eva Havrdová ,Zdeněk Seidl ,Miriam Tamaño‐Blanco ,Jan Krásenský ,Petra Lelková ,Tomáš Kalinčík ,Michaela Týblová ,Manuela Vaněčková ,Bianca Weinstock–Guttman

doi:10.1371/journal.pone.0053996

Abstract

ObjectivesTo investigate the associations of environmental MS risk factors with clinical and MRI measures of progression in high-risk clinically isolated syndromes (CIS) after the first demyelinating event.MethodsWe analyzed 211 CIS patients (age: 28.9±7.8 years) enrolled in the SET study, a multi-center study of high-risk CIS patients. Pre-treatment samples were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) early nuclear antigen-1 (EBNA-1), viral capsid antigen (VCA), early antigen-diffuse (EA-D), 25 hydroxy-vitamin D3 and cotinine levels and HLA DRB1*1501 status. The inclusion criteria required evaluation within 4 months of the initial demyelinating event, 2 or more brain MRI lesions and the presence of two or more oligoclonal bands in cerebrospinal fluid. All patients were treated with interferon-beta. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24 months.ResultsThe time to first relapse decreased and the number of relapses increased with anti-CMV IgG positivity. Smoking was associated with increased number and volume of contrast-enhancing lesions (CEL) during the 2-year period. The cumulative number of CEL and T2 lesions during the 2-year period was greater for individuals in the highest quartile of anti-EBV VCA IgG antibodies. The percent loss of brain volume was increased for those in the highest quartile of with anti-EBV VCA IgG antibodies.ConclusionsRelapses in CIS patients were associated with CMV positivity whereas anti-EBV VCA positivity was associated with progression on MRI measures, including accumulation of CEL and T2 lesions and development of brain atrophy.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain and spinal cord that causes physical and cognitive disability
Cross-sectional studies suggest that exposure to Epstein Barr virus (EBV), cigarette smoking and low vitamin D are associated with MS disease progression
Anti-CMV Positivity is Associated with Relapses Associations of Anti-CMV Positivity with Relapses

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain and spinal cord that causes physical and cognitive disability. Disease progression in MS is mediated by inflammatory and neurodegenerative processes that cause injury to the brain and spinal cord. Epstein-Barr virus (EBV) exposure, decreased vitamin D levels and smoking are the best-established environmental risk factors for MS [1,2,3]. Cross-sectional studies suggest that exposure to EBV, cigarette smoking and low vitamin D are associated with MS disease progression. Smoking increases lesion volume and the risk of developing secondary-progressive MS [7,8,9] whereas increased vitamin D levels have been associated with fewer relapses [10,11,12,13]

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