Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions

Abstract

Background and ObjectivesTo 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.MethodsThis 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.ResultsRim 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.DiscussionTogether, 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 EvidenceThis 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.

Quantitative susceptibility mapping versus phase imaging to identify multiple sclerosis iron rim lesions with demyelination

“…Fourth, we used a cross‐sectional design in this study. It would be clinically important to study the relationship between rim lesion evolution, 7,37 including change in rim susceptibility, and tissue damage over time and in response to MS drug treatments 38 . Finally, our study cohort consisted of RRMS patients, and further investigation in MS patients with progressive disease is warranted.…”

Peripheral Hemolysis in Relation to Iron Rim Presence and Brain Volume in Multiple Sclerosis

“…This knowledge may reveal new therapeutic targets to stop the vicious cycle of iron-induced CNS tissue damage. A first hint in this direction may be the observation of decreasing iron content of rim lesions per year in patients treated with dimethyl fumarate compared to patients treated with glatiramer acetate ( 48 ). In addition, dimethyl fumarate but not glatiramer acetate reduced inflammatory activity and associated iron levels in human microglia ( 49 ).…”

From pathology to MRI and back: Clinically relevant biomarkers of multiple sclerosis lesions

“…Notably, although the effect of treatment on rim lesions has not been extensively evaluated, preliminary data suggest that currently approved therapies for MS have poor efficacy in controlling this type of inflammation ( Absinta et al, 2019 ), urging development of new drugs that can modulate the inflammatory and glial response within these lesions. A recent retrospective study of 34 cases showed a significant decrease of susceptibility signal in PRL, measured by 3T QSM, in patients on dimethyl fumarate ( n = 50 PRL analyzed) compared to those treated with glatiramer acetate ( n = 41 PRL analyzed) ( Zinger et al, 2022 ). To date, two clinical trials are implementing this biomarker as primary (phase I/II studies, clinicaltrials.gov identifiers: NCT04025554; NCT04742400) outcome measures, but other trials have incorporated it for secondary or exploratory analysis ( Reich et al, 2021 ).…”