Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.

TitleDimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.
Publication TypeJournal Article
Year of Publication2022
AuthorsZinger N, Ponath G, Sweeney E, Nguyen TD, Lo CHung, Diaz I, Dimov A, Teng L, Zexter L, Comunale J, Wang Y, Pitt D, Gauthier SA
JournalNeurol Neuroimmunol Neuroinflamm
Volume9
Issue2
Date Published2022 Mar
ISSN2332-7812
KeywordsAdult, Cells, Cultured, Dimethyl Fumarate, Female, Glatiramer Acetate, Humans, Immunosuppressive Agents, Induced Pluripotent Stem Cells, Male, Microglia, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Neuroinflammatory Diseases, Retrospective Studies
Abstract

BACKGROUND AND OBJECTIVES: To determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro.

METHODS: This was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell-derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared.

RESULTS: Rim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI -5.87 to -0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro.

DISCUSSION: Together, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity.

CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping.

DOI10.1212/NXI.0000000000001138
Alternate JournalNeurol Neuroimmunol Neuroinflamm
PubMed ID35046083
PubMed Central IDPMC8771666
Grant ListR01 NS102267 / NS / NINDS NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States

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