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

Karl E. Carlström (), Ewoud Ewing, Mathias Granqvist, Alexandra Gyllenberg, Shahin Aeinehband, Sara Lind Enoksson, Antonio Checa, Tejaswi V. S. Badam, Jesse Huang, David Gomez-Cabrero, Mika Gustafsson, Faiez Al Nimer, Craig E. Wheelock, Ingrid Kockum, Tomas Olsson, Maja Jagodic and Fredrik Piehl
Additional contact information
Karl E. Carlström: Karolinska Institutet
Ewoud Ewing: Karolinska Institutet
Mathias Granqvist: Karolinska Institutet
Alexandra Gyllenberg: Karolinska Institutet
Shahin Aeinehband: Karolinska Institutet
Sara Lind Enoksson: Department of Clinical Immunology Karolinska University Hospital
Antonio Checa: Karolinska Institutet
Tejaswi V. S. Badam: University of Skövde
Jesse Huang: Karolinska Institutet
David Gomez-Cabrero: Universidad Publica de Nevarra (UPNA), IdiSNA
Mika Gustafsson: Linköping University
Faiez Al Nimer: Karolinska Institutet
Craig E. Wheelock: Karolinska Institutet
Ingrid Kockum: Karolinska Institutet
Tomas Olsson: Karolinska Institutet
Maja Jagodic: Karolinska Institutet
Fredrik Piehl: Karolinska Institutet

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11139-3

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