Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Hosseini, Abdolkarim; Masjedi, Ali; Baradaran, Behzad; Hojjat‐Farsangi, Mohammad; Ghalamfarsa, Ghasem; Anvari, Enayat; Jadidi‐Niaragh, Farhad

doi:10.1002/jcp.27930

Cited by 32 publications

(23 citation statements)

References 125 publications

(334 reference statements)

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“…Loss of function of FH in cancers increases fumarate levels leading to elevated accumulation of NRF2 [168,169]. Fumarate can attenuate autoimmune diseases, in part, through modulation of DC maturation and antigen-presenting capacity [170][171][172][173]. In general, fumarate is considered anti-inflammatory.…”

Section: Fumaratementioning

confidence: 99%

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Choi

Son

Baek

2021

Life

102

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The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression.

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Section: Fumaratementioning

confidence: 99%

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Choi

Son

Baek

2021

Life

102

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“…Despite the lack of effects on the frequency and the number of MCAM + lymphocytes, DMF could modulate the function of MCAM + lymphocytes through mechanisms such as the upregulation of the nuclear factor erythroid-derived 2-related antioxidant pathway and the inhibition of the nuclear factor-κB translocation. 40 There are certain limitations in this study. First, we used cryopreserved PBMC and CSF samples; cryopreservation may result in the modification of the expression of MCAM.…”

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Melanoma Cell Adhesion Molecule Expressing Helper T Cells in CNS Inflammatory Demyelinating Diseases

Ikeguchi

Shimizu

Kondo

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectiveTo elucidate the relationship between melanoma cell adhesion molecule (MCAM)-expressing lymphocytes and pathogenesis of CNS inflammatory demyelinating diseases (IDDs).MethodsPatients with multiple sclerosis (MS) (n = 72) and neuromyelitis optica spectrum disorder (NMOSD, n = 29) were included. We analyzed the frequency and absolute numbers of MCAM+ lymphocytes (memory helper T [mTh] cells, naive helper T cells, CD8+ T cells, and B cells) in the peripheral blood (PB) and the CSF of patients with MS and NMOSD, treated with/without disease-modifying drugs (DMDs) or steroids, using flow cytometry.ResultsThe frequency of MCAM+ cells was higher in the mTh cell subset than that in other lymphocyte subsets. A significant increase in the frequency and the absolute number of MCAM+ mTh cells was observed in the PB of patients with NMOSD, whereas no increase was observed in the PB of patients with MS. The frequency of CSF MCAM+ mTh cells was higher in relapsing patients with MS and NMOSD than that in the control group. Although there was no difference in the frequencies of MCAM+ lymphocytes among the DMD-treated groups, fingolimod decreased the absolute number of MCAM+ lymphocytes.DiscussionMCAM+ mTh cells were elevated in the CSF of relapsing patients with MS and in both the PB and CSF of patients with NMOSD. These results indicate that MCAM contributes to the pathogenesis of MS and NMOSD through different mechanisms. MCAM could be a therapeutic target of CNS IDDs, and further study is needed to elucidate the underlying mechanism of MCAM in CNS IDD pathogenesis.

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“…The small molecular weight (144.1 g/mol) of DMF and therefore small physical size allow it to access numerous receptors and proteins within the GI tract and GI wall [11, 24–26]. These interactions are beneficial when they are on target, thereby contributing to the efficacy of the drug.…”

Section: Discussionmentioning

confidence: 99%

Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study

et al. 2019

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IntroductionDiroximel fumarate (DRF) is a novel oral fumarate in development for patients with relapsing forms of multiple sclerosis (MS). Clinical findings from the DRF development program suggest that rates of gastrointestinal (GI) treatment-emergent adverse events (TEAEs) and discontinuation due to GI TEAEs are low, based on clinical and real-world observations of other fumaric acid esters, including dimethyl fumarate (DMF). The incidence of GI TEAEs varies from 40 to 88% in clinical and real-world studies of DMF. The objective of this study is to present GI tolerability findings from the EVOLVE-MS-1 study and present biologic hypotheses for the improved GI properties of DRF.MethodsGI TEAEs and treatment discontinuation because of GI TEAEs were assessed in DRF-treated patients with relapsing-remitting MS who were participating in the ongoing, 96-week, open-label, phase 3 EVOLVE-MS-1 study.ResultsAs of March 30, 2018, a total of 696 patients were enrolled in EVOLVE-MS-1. GI TEAEs were reported in 30.9% (215/696) of patients; the vast majority (96%; 207/215) experienced events that were mild or moderate in severity. When GI AEs did occur, they occurred early in treatment, resolved (88.8%; 191/215), and were of short duration [median 7.5 (range 1–87) days] in most patients. GI TEAEs led to < 1% of patients discontinuing treatment.ConclusionsWe suggest that the distinct chemical structure of DRF contributes to the observed low rates of GI TEAEs and GI-associated treatment discontinuations, possibly due to a combination of several factors. We hypothesize that these factors may include less reactivity with off-target proteins and/or lower production of a methanol leaving group that may contribute to GI irritation. A direct comparison of GI tolerability with DRF versus DMF is being evaluated in the EVOLVE-MS-2 study.Trial RegistrationClinicalTrials.gov number NCT02634307.FundingAlkermes Inc. (Waltham, MA, USA) and Biogen (Cambridge, MA, USA).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01085-3) contains supplementary material, which is available to authorized users.

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Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Cited by 32 publications

References 125 publications

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Melanoma Cell Adhesion Molecule Expressing Helper T Cells in CNS Inflammatory Demyelinating Diseases

Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study

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