Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS

Talbot, Jacob; Chow, Helene Højsgaard; Hansen, Rasmus Hvass; Essen, Marina Rode von; Sellebjerg, Finn

doi:10.1016/j.jneuroim.2021.577756

Cited by 7 publications

(3 citation statements)

References 35 publications

(48 reference statements)

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“…The decrease in total T-cell counts in CSF observed in DMF-treated patients may be a consequence of the reduced circulating T-cell pool and thereby reduced CNS recruitment. 11 The unaffected populations of CD20 + T cells in the CSF, on the other hand, may indicate that CD20 + T cells are part of the CNS-compartmentalized immune response observed in progressive MS. Indeed, tissue resident memory CD20 + T cells have been detected in the perivascular space from controls and were found to accumulate in MS lesions.…”

Section: Discussionmentioning

confidence: 99%

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Intrathecal CD8 ⁺ CD20 ⁺ T Cells in Primary Progressive Multiple Sclerosis

Essen

Talbot

Hansen

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectiveDespite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20+T cells and the effect of dimethyl fumarate on CD20+T cells in PPMS.MethodsThe main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20+T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume.ResultsAssessing CD20+T cells in patients with PPMS and controls showed an increased percentage of CD20+T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8+CD20+T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8+CD20+T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20+T cells were unaffected.DiscussionThis study shows an association between intrathecal CD8+CD20+T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8+CD20+T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8+CD20+T cells in CSF.

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Section: Discussionmentioning

confidence: 99%

“…This showed substantial effects of DMF on circulating B cells and T cells and a reduced number of CD4 + T cells CSF in PPMS but no clear effects on other biomarkers of intrathecal inflammation. 10 , 11 Why the substantial effect of DMF on T cells did not translate into a positive clinical treatment effect is unknown.…”

mentioning

confidence: 99%

Intrathecal CD8 ⁺ CD20 ⁺ T Cells in Primary Progressive Multiple Sclerosis

Essen

Talbot

Hansen

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“…In people with primary progressive MS, there were reduced numbers of CD4+ T cells and increased concentrations of IL-7 in CSF. 65 IL-7 is a hematopoietic growth factor that stimulates the expansion of CD4+ T cells. Thus, the increase of IL-7 could be related to the peripheral lowering of CD4+ T cell counts by DMF and subsequently reduced transmigration to the CNS or the direct impact of MMF on CD4+ T cells within the CNS.…”

Section: Introductionmentioning

confidence: 99%

Diroximel Fumarate as a Novel Oral Immunomodulating Therapy for Relapsing Forms of Multiple Sclerosis: A Review on the Emerging Data

Hauer¹,

Sellner²

2022

DDDT

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Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Disease-modifying drugs (DMDs) and subsequent adherence are crucial for preventing reversible episodes of neurological dysfunction and delayed onset of progressive accumulation of irreversible deficits. Yet, side effects may limit their usage in clinical practice. Gastrointestinal (GI) side effects are a significant limitation of the use of dimethyl fumarate (DMF), the most frequently prescribed oral DMD in MS worldwide. Diroximel fumarate (DRF) is a second-generation oral fumaric acid ester (FAE) that was developed as a formulation with better GI tolerability. The improved tolerability is assumed to be related to a lower synthesis of gutirritating methanol. Other explanations for DRF's lower extent of GI irritation include a more modest off-target activity due to its chemical structure. The superior GI tolerability of DRF compared to DMF could be proven in clinical trials and lead to approval of DRF for the treatment of relapsing forms of MS/relapsing-remitting MS (United States Food and Drug Administration and European Medicines Agency, respectively). Here, we summarize the mode of action of oral FAE and compare the chemical and physiological characteristics of DMF and DRF. Moreover, we discuss the adverse effects of FAE and introduce the emerging preclinical and trial data leading to the approval of DRF in MS. This article additionally reviews our current understanding of coronavirus disease 2019 (COVID-19) and the efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in people treated with FAE.

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From bedside to bench: how existing therapies inform the relationship between Epstein–Barr virus and multiple sclerosis

et al. 2023

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Therapy for relapsing-remitting multiple sclerosis (MS) has advanced dramatically despite incomplete understanding of the cause of the condition. Current treatment involves inducing broad effects on immune cell populations with consequent off-target side effects, and no treatment can completely prevent disability progression. Further therapeutic advancement will require a better understanding of the pathobiology of MS. Interest in the role of Epstein-Barr virus (EBV) in multiple sclerosis has intensified based on strong epidemiological evidence of an association between EBV seroprevalence and MS. Hypotheses proposed to explain the biological relationship between EBV and MS include molecular mimicry, EBV immortalised autoreactive B cells and infection of glial cells by EBV. Examining the interaction between EBV and immunotherapies that have demonstrated efficacy in MS offers clues to the validity of these hypotheses. The efficacy of B cell depleting therapies could be consistent with a hypothesis that EBV-infected B cells drive MS; however, loss of T cell control of B cells does not exacerbate MS. A number of MS therapies invoke change in EBV-specific T cell populations, but pathogenic EBVspecific T cells with cross-reactivity to CNS antigen have not been identified. Immune reconstitution therapies induce EBV viraemia and expansion of EBV-specific T cell clones, but this does not correlate with relapse. Much remains unknown regarding the role of EBV in MS pathogenesis. We discuss future translational research that could fill important knowledge gaps.

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Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS

Cited by 7 publications

References 35 publications

Intrathecal CD8 ⁺ CD20 ⁺ T Cells in Primary Progressive Multiple Sclerosis

Intrathecal CD8 ⁺ CD20 ⁺ T Cells in Primary Progressive Multiple Sclerosis

Diroximel Fumarate as a Novel Oral Immunomodulating Therapy for Relapsing Forms of Multiple Sclerosis: A Review on the Emerging Data

From bedside to bench: how existing therapies inform the relationship between Epstein–Barr virus and multiple sclerosis

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Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS

Cited by 7 publications

References 35 publications

Intrathecal CD8 + CD20 + T Cells in Primary Progressive Multiple Sclerosis

Intrathecal CD8 + CD20 + T Cells in Primary Progressive Multiple Sclerosis

Diroximel Fumarate as a Novel Oral Immunomodulating Therapy for Relapsing Forms of Multiple Sclerosis: A Review on the Emerging Data

From bedside to bench: how existing therapies inform the relationship between Epstein–Barr virus and multiple sclerosis

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Product

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Intrathecal CD8 ⁺ CD20 ⁺ T Cells in Primary Progressive Multiple Sclerosis

Intrathecal CD8 ⁺ CD20 ⁺ T Cells in Primary Progressive Multiple Sclerosis