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.
Glossary
- 2D=
- 2 dimensional;
- 3D=
- 3 dimensional;
- CIS=
- clinically isolated syndrome;
- DMF=
- dimethyl fumarate;
- EDSS=
- Expanded Disability Status Scale;
- ETL=
- echo train length;
- FA=
- flip angle;
- FLAIR=
- fluid-attenuated inversion recovery;
- GA=
- glatiramer acetate;
- HBSS=
- Hanks Balanced Salt Solution;
- IL=
- interleukin;
- iPSC=
- induced pluripotent stem cell;
- MMF=
- monomethyl fumarate;
- MS=
- multiple sclerosis;
- QSM=
- quantitative susceptibility mapping;
- RRMS=
- relapsing-remitting MS;
- SCF=
- stem cell factor;
- T1w=
- T1 weighted;
- T2w=
- T2 weighted;
- TE=
- echo time;
- TI=
- inversion time;
- TNF=
- tumor necrosis factor;
- TR=
- repetition time
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally as co–senior authors.
The Article Processing Charge was funded by the authors.
Class of Evidence: NPub.org/coe
- Received September 18, 2021.
- Accepted in final form December 10, 2021.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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