Teriflunomide's effect on humoral response to Epstein-Barr virus and development of cortical gray matter pathology in multiple sclerosis

Mult Scler Relat Disord. 2019 Nov;36:101388. doi: 10.1016/j.msard.2019.101388. Epub 2019 Sep 9.


Background: Teriflunomide has been shown to slow cortical gray matter (GM) atrophy in patients with multiple sclerosis (MS). Previous work showed that higher levels of Epstein-Barr virus (EBV) are associated with greater development of cortical pathology in MS.

Objectives: To investigate whether the effect of teriflunomide on cortical volume loss in relapsing MS patients may be associated with the change in humoral response to EBV.

Methods: This was a prospective, observational, single-blinded, longitudinal study of 30 relapsing MS patients, who started treatment with teriflunomide, and 20 age- and sex-matched healthy controls (HCs). Subjects were assessed at baseline, 6 and 12 months with clinical, MRI and EBV examinations. MRI outcomes included percent changes in cortical, GM, deep GM and whole brain volumes. Serum samples were analyzed for IgG antibodies titers against EBV viral capsid antigen (VCA) and nuclear antigen-1 (EBNA-1).

Results: There were no significant differences in anti-VCA and anti-EBNA-1 IgG titers between MS patients and HC at baseline. However, over the 12-month follow-up, MS patients experienced a greater decrease in anti-EBNA-1 (-35.1, p = .003) and anti-VCA (-15.9, p = .05) IgG titers, whereas no significant changes were observed in HCs (-3.7 and -1.6, respectively). MS patients who showed the highest decrease in anti-EBV VCA and EBNA-1 IgG titers from baseline to follow-up, developed less cortical (p < .001 and p = .02) and GM volume loss (p = .004 for both), respectively.

Conclusions: Teriflunomide's effect on slowing cortical and GM volume loss may be mediated by its effect on altering humoral response to EBV.

Keywords: Anti-viral effect; Cortical atrophy; Epstein-Barr virus; Multiple sclerosis; Teriflunomide.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Antibodies, Viral / blood
  • Antibodies, Viral / drug effects*
  • Antigens, Viral / immunology*
  • Antiviral Agents / pharmacology*
  • Capsid Proteins / immunology*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / pathology
  • Crotonates / pharmacology*
  • Disease Progression
  • Epstein-Barr Virus Nuclear Antigens / immunology*
  • Female
  • Follow-Up Studies
  • Gray Matter / drug effects*
  • Gray Matter / pathology*
  • Humans
  • Hydroxybutyrates
  • Immunoglobulin G / blood
  • Immunologic Factors / pharmacology*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / blood
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / pathology
  • Nitriles
  • Single-Blind Method
  • Toluidines / pharmacology*


  • Antibodies, Viral
  • Antigens, Viral
  • Antiviral Agents
  • Capsid Proteins
  • Crotonates
  • Epstein-Barr Virus Nuclear Antigens
  • Epstein-Barr viral capsid antigen
  • Hydroxybutyrates
  • Immunoglobulin G
  • Immunologic Factors
  • Nitriles
  • Toluidines
  • teriflunomide
  • EBV-encoded nuclear antigen 1