Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice

Neurology. 2019 Apr 9;92(15):e1724-e1738. doi: 10.1212/WNL.0000000000007262. Epub 2019 Mar 27.


Objective: To assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis.

Methods: Using peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed.

Results: In DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses.

Conclusions: DMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients.

Trial registration numbers: EUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B-Lymphocytes / drug effects
  • CD4-CD8 Ratio
  • Cross-Sectional Studies
  • Delayed-Action Preparations
  • Dimethyl Fumarate / adverse effects
  • Dimethyl Fumarate / pharmacology
  • Dimethyl Fumarate / therapeutic use*
  • Female
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Longitudinal Studies
  • Lymphocyte Count
  • Lymphocytes / drug effects*
  • Lymphopenia / blood
  • Lymphopenia / chemically induced
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / blood*
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Risk Assessment
  • T-Lymphocytes / drug effects


  • Delayed-Action Preparations
  • Immunosuppressive Agents
  • Dimethyl Fumarate

Associated data

  • ClinicalTrials.gov/NCT00168701
  • ClinicalTrials.gov/NCT00420212
  • ClinicalTrials.gov/NCT00451451
  • ClinicalTrials.gov/NCT00835770