Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.

Nicole Zinger, Gerald Ponath, Elizabeth Sweeney, Thanh D Nguyen, Chih Hung Lo, Ivan Diaz, Alexey Dimov, Leilei Teng, Lily Zexter, Joseph Comunale, Yi Wang, David Pitt, Susan A Gauthier

Journal: Neurology(R) neuroimmunology & neuroinflammation 2022;9(2):e1138

PMID: 35046083

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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.

Address: From the Department of Neurology (N.Z., L.Z., S.A.G.), Weill Cornell Medicine, New York; Department of Neurology (G.P., C.H.L., D.P.), Yale School of Medicine, New Haven, CT; Department of Population Health Sciences (E.S., I.D.), and Department of Radiology (T.D.N., A.D., J.C., Y.W., S.A.G.), Weil Cornell Medicine, New York; Department of Medicine (L.T.), Yale New Haven Hospital, New Haven, CT; Feil Family Brain and Mind Institute (S.A.G.), Weill Cornell Medicine, New York; and Lee Kong Chian School of Medicine (C.H.L.), Nanyang Technological University, Singapore.; From the Department of Neurology (N.Z., L.Z., S.A.G.), Weill Cornell Medicine, New York; Department of Neurology (G.P., C.H.L., D.P.), Yale School of Medicine, New Haven, CT; Department of Population Health Sciences (E.S., I.D.), and Department of Radiology (T.D.N., A.D., J.C., Y.W., S.A.G.), Weil Cornell Medicine, New York; Department of Medicine (L.T.), Yale New Haven Hospital, New Haven, CT; Feil Family Brain and Mind Institute (S.A.G.), Weill Cornell Medicine, New York; and Lee Kong Chian School of Medicine (C.H.L.), Nanyang Technological University, Singapore. [email protected].

DOI: 10.1212/NXI.0000000000001138

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MeSH Terms: Adult, 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