Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes

Nat Commun. 2019 Jul 12;10(1):3081. doi: 10.1038/s41467-019-11139-3.


Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • DNA Methylation / drug effects
  • Dimethyl Fumarate / pharmacology
  • Dimethyl Fumarate / therapeutic use*
  • Epigenesis, Genetic / drug effects
  • Female
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Leukocyte Count
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Multiple Sclerosis, Relapsing-Remitting / blood
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • NADPH Oxidases / genetics*
  • NADPH Oxidases / metabolism
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / metabolism
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Treatment Outcome


  • Immunosuppressive Agents
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Nox3 protein, human
  • Dimethyl Fumarate