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

Abstract

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.

Figure 1. Dependence of time to first relapse on demographic, MRI and environmental factors.

Figure 1A shows the cumulative hazard function for time to first relapse in all subjects. Figures 1B-D show the cumulative hazard functions for the age <35 years (red line) vs. age ≥35 years (green line), CEL present as baseline (red line) vs. CEL not present at baseline (green line) and CMV positive (red line) vs. CMV negative sub-groups, respectively. The corresponding covariate p-values from Cox regression are also shown.

Figure 2. Dependence of change in individual MRI lesion-related variables over 2-years on the specific genetic or environmental factors.

Figures 2A and 2B show the dependence of change in CEL number and change in CE-LV, respectively, on smoking status. Figures 2C shows the dependence of number of new and newly enlarging T2-lesions on anti-EBV VCA highest quartile status. Figure 2D shows the dependence of number of new T2-lesions on anti-EBV VCA highest quartile status. The bars represent mean values and the error bars are standard errors. The red colors denote the positive group and the green bars the negative group. The corresponding covariate p-values from regression are also shown.