Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions
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 relapsin...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/164429 |
| _version_ | 1826111224036720640 |
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| author | Zinger, Nicole Ponath, Gerald Sweeney, Elizabeth Nguyen, Thanh D. Lo, Chih Hung Diaz, Ivan Dimov, Alexey Teng, Leilei Zexter, Lily Comunale, Joseph Wang, Yi Pitt, David Gauthier, Susan A. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Zinger, Nicole Ponath, Gerald Sweeney, Elizabeth Nguyen, Thanh D. Lo, Chih Hung Diaz, Ivan Dimov, Alexey Teng, Leilei Zexter, Lily Comunale, Joseph Wang, Yi Pitt, David Gauthier, Susan A. |
| author_sort | Zinger, Nicole |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T02:47:10Z |
| format | Journal Article |
| id | ntu-10356/164429 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:47:10Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1644292023-03-05T16:54:10Z Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions Zinger, Nicole Ponath, Gerald Sweeney, Elizabeth Nguyen, Thanh D. Lo, Chih Hung Diaz, Ivan Dimov, Alexey Teng, Leilei Zexter, Lily Comunale, Joseph Wang, Yi Pitt, David Gauthier, Susan A. Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Dimethyl Fumarate Multiple Sclerosis 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. Published version Study Funding: This study was supported by NINDS/NIH RO1 NS102267, an investigator-initiated Clinical Trial/US-BGT-13-10516 (Biogen), BI-2007-36725 (NMSS), and by grant number UL1 TR 002384 from the National Center for Advancing Translational Sciences (NCATS) of the NIH. The Article Processing Charge was funded by the authors. 2023-01-25T01:21:55Z 2023-01-25T01:21:55Z 2022 Journal Article Zinger, N., Ponath, G., Sweeney, E., Nguyen, T. D., Lo, C. H., Diaz, I., Dimov, A., Teng, L., Zexter, L., Comunale, J., Wang, Y., Pitt, D. & Gauthier, S. A. (2022). Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions. Neurology® Neuroimmunology & Neuroinflammation, 9(2), e1138-. https://dx.doi.org/10.1212/NXI.0000000000001138 2332-7812 https://hdl.handle.net/10356/164429 10.1212/NXI.0000000000001138 35046083 2-s2.0-85123664843 2 9 e1138 en Neurology® neuroimmunology & neuroinflammation © 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. application/pdf |
| spellingShingle | Science::Medicine Dimethyl Fumarate Multiple Sclerosis Zinger, Nicole Ponath, Gerald Sweeney, Elizabeth Nguyen, Thanh D. Lo, Chih Hung Diaz, Ivan Dimov, Alexey Teng, Leilei Zexter, Lily Comunale, Joseph Wang, Yi Pitt, David Gauthier, Susan A. Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| title | Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| title_full | Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| title_fullStr | Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| title_full_unstemmed | Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| title_short | Dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| title_sort | dimethyl fumarate reduces inflammation in chronic active multiple sclerosis lesions |
| topic | Science::Medicine Dimethyl Fumarate Multiple Sclerosis |
| url | https://hdl.handle.net/10356/164429 |
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