Environmental factors associated with disease progression after the first demyelinating event: results from the multi-center SET study

PLoS One. 2013;8(1):e53996. doi: 10.1371/journal.pone.0053996. Epub 2013 Jan 8.


Objectives: To 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.

Methods: We 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.

Results: The 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.

Conclusions: Relapses 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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Viral / blood
  • Cohort Studies
  • Cytomegalovirus / immunology
  • Disease Progression
  • Environment
  • Epstein-Barr Virus Nuclear Antigens / immunology
  • Female
  • HLA-DRB1 Chains / genetics
  • Humans
  • Longitudinal Studies
  • Male
  • Multiple Sclerosis / etiology*
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / virology
  • Prospective Studies
  • Risk Factors
  • Smoking / adverse effects
  • Young Adult


  • Antibodies, Viral
  • Epstein-Barr Virus Nuclear Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*15:01 antigen
  • EBV-encoded nuclear antigen 1

Grants and funding

Supported by Czech Ministries of Education and Health (NT13237-4/2012, MSM 0021620849, PRVOUK-P26/LF1/4, RVO-VFN64165/2012). The SET study is an investigator-initiated study supported by Biogen Idec Inc. Support from the National Multiple Sclerosis Society (RG3743 and RG4836), the Department of Defense Multiple Sclerosis Program (MS090122) and a Pediatric MS Center of Excellence Center Grant) is gratefully acknowledged. The funders had no role in data analysis, decision to publish, or preparation of the manuscript.