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FASEB Journal : Official Publication of... Aug 2023In sporadic amyotrophic lateral sclerosis (sALS), IL-17A- and granzyme-positive cytotoxic T lymphocytes (CTL), IL-17A-positive mast cells, and inflammatory macrophages...
In sporadic amyotrophic lateral sclerosis (sALS), IL-17A- and granzyme-positive cytotoxic T lymphocytes (CTL), IL-17A-positive mast cells, and inflammatory macrophages invade the brain and spinal cord. In some patients, the disease starts following a trauma or a severe infection. We examined cytokines and cytokine regulators over the disease course and found that, since the early stages, peripheral blood mononuclear cells (PBMC) exhibit increased expression of inflammatory cytokines IL-12A, IFN-γ, and TNF-α, as well as granzymes and the transcription factors STAT3 and STAT4. In later stages, PBMCs upregulated the autoimmunity-associated cytokines IL-23A and IL-17B, and the chemokines CXCL9 and CXCL10, which attract CTL and monocytes into the central nervous system. The inflammation is fueled by the downregulation of IL-10, TGFβ, and the inhibitory T-cell co-receptors CTLA4, LAG3, and PD-1, and, in vitro, by stimulation with the ligand PD-L1. We investigated in two sALS patients the regulation of the macrophage transcriptome by dimethyl fumarate (DMF), a drug approved against multiple sclerosis and psoriasis, and the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway inhibitor H-151. Both DMF and H-151 downregulated the expression of granzymes and the pro-inflammatory cytokines IL-1β, IL-6, IL-15, IL-23A, and IFN-γ, and induced a pro-resolution macrophage phenotype. The eicosanoid epoxyeicosatrienoic acids (EET) from arachidonic acid was anti-inflammatory in synergy with DMF. H-151 and DMF are thus candidate drugs targeting the inflammation and autoimmunity in sALS via modulation of the NFκB and cGAS/STING pathways.
Topics: Humans; Cytokines; Interleukin-17; Dimethyl Fumarate; Leukocytes, Mononuclear; Amyotrophic Lateral Sclerosis; Granzymes; Inflammation; Nucleotidyltransferases
PubMed: 37436778
DOI: 10.1096/fj.202300573R -
Cells Dec 2022Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory,... (Review)
Review
Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF's mechanism of action, an extensive analysis of the and evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene-disease (-AMD) database search, followed by a protein-protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts.
Topics: Dimethyl Fumarate; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Antioxidants
PubMed: 36552824
DOI: 10.3390/cells11244061 -
Multiple Sclerosis and Related Disorders Dec 2023Adherence is a prerequisite for the efficacy of any drug, and previous studies have shown that non-adherence is associated with disease activity and increased health...
BACKGROUND
Adherence is a prerequisite for the efficacy of any drug, and previous studies have shown that non-adherence is associated with disease activity and increased health care cost in multiple sclerosis (MS). The aim of this study was to investigate rates and reasons for discontinuation of dimethyl fumarate (DMF) among people with MS on a national level and differences between clinics in Denmark.
METHODS
This was a nationwide, registry and population study of patients treated with DMF. We calculated standard residuals (SR) demonstrate differences between clinics. For survival analysis regarding discontinuation rates and discontinuation due to specific AEs we used log-rank test Cox-proportional hazards and plotted Kaplan-Meier graphics.
RESULTS
We included 2,448 people with MS, treated with DMF from 2013 to 2020. Average treatment duration was 26 months (5,382 treatment years). 49.2 % of patients who initiated treatment with DMF (n = 1205) were continuously treated. Reasons for discontinuation were adverse events (54.5 %, n = 656), active disease (26.1 %, n = 315), pregnancy (9.4 %, n = 113) or other reasons (13.2 %, n = 159). We compared SR to the mean regarding reasons for discontinuation and found significant differences between sites regarding gastrointestinal adverse events, flushing and lymphopenia. Discontinuation due to all adverse events, flushing and lymphopenia were more frequent in female than male patients.
CONCLUSION
In this population-based study, we found major differences between the MS clinics in rates and reason for discontinuation of DMF. Our results suggest that management strategies during DMF treatment can reduce discontinuation rates.
Topics: Humans; Male; Female; Dimethyl Fumarate; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Lymphopenia
PubMed: 37956521
DOI: 10.1016/j.msard.2023.105127 -
Multiple Sclerosis (Houndmills,... Jul 2021Severe prolonged lymphopenia as rare side-effect of dimethyl fumarate is mostly reversible. Caldito et al. report a case of persistent severe lymphopenia over 5 years...
Severe prolonged lymphopenia as rare side-effect of dimethyl fumarate is mostly reversible. Caldito et al. report a case of persistent severe lymphopenia over 5 years after discontinuation of dimethyl fumarate. We discuss several clinical implications. Safe withdrawal of disease modifying therapies in terms of reoccurrence of disease activity and drug related adverse events need further attention as our treatment armamentarium continues to grow.
Topics: Dimethyl Fumarate; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Lymphopenia
PubMed: 33620267
DOI: 10.1177/1352458521996698 -
Multiple Sclerosis (Houndmills,... Feb 2022Teriflunomide and dimethyl fumarate (DMF) are first-line disease-modifying treatments for multiple sclerosis with similar labels that are used in comparable populations.
BACKGROUND
Teriflunomide and dimethyl fumarate (DMF) are first-line disease-modifying treatments for multiple sclerosis with similar labels that are used in comparable populations.
OBJECTIVES
The objective of this study was to compare the effectiveness and persistence of teriflunomide and DMF in a Swedish real-world setting.
METHODS
All relapsing-remitting multiple sclerosis (RRMS) patients in the Swedish MS registry initiating teriflunomide or DMF were included in the analysis. The primary endpoint was treatment persistence. Propensity score matching was used to adjust comparisons for baseline confounders.
RESULTS
A total of 353 teriflunomide patients were successfully matched to 353 DMF. There was no difference in the rate of overall treatment discontinuation by treatment group across the entire observation period (hazard ratio (HR) = 1.12; 95% confidence interval (CI) = 0.91-1.39; = 0.277; reference = teriflunomide). Annualised relapse rate (ARR) was comparable ( = 0.237) between DMF (0.07; 95% CI = 0.05-0.10) and teriflunomide (0.09; 95% CI = 0.07-0.12). There was no difference in time to first on-treatment relapse (HR = 0.78; 95% CI = 0.50-1.21), disability progression (HR = 0.55; 95% CI = 0.27-1.12) or confirmed improvement (HR = 1.17; 95% CI = 0.57-2.36).
CONCLUSION
This population-based real-world study reports similarities in treatment persistence, clinical effectiveness and quality of life outcomes between teriflunomide and dimethyl fumarate.
Topics: Crotonates; Dimethyl Fumarate; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Quality of Life; Registries; Sweden; Toluidines
PubMed: 34080926
DOI: 10.1177/13524585211019649 -
Pharmacology 2023Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the central nervous system. Dimethyl fumarate (DMF) and monomethyl fumarate...
INTRODUCTION
Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the central nervous system. Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) belong to the disease-modifying drugs in treatment of MS. There is evidence that astrocytes and microglia are involved in MS pathology, but few studies are available about MMF and DMF effects on astrocytes and microglia. The aim of this study was to investigate the effects of MMF and DMF on microglial activation and morphology as well as potential effects on glial viability, Cx43, and AQP4 expressions in different set-ups of an in vitro astrocyte-microglia co-culture model of inflammation.
METHODS
Primary rat glial co-cultures of astrocytes containing 5% (M5, mimicking "physiological" conditions) or 30% (M30, mimicking "pathological, inflammatory" conditions) of microglia were treated with different concentrations of MMF (0.1, 0.5, and 2 μg/mL) or DMF (1.5, 5, and 15 μM) for 24 h. Viability, proliferation, and cytotoxicity of glial cells were examined using MTT assay. Immunocytochemistry was performed to analyze the microglial phenotypes. Connexin 43 (Cx43) and aquaporin 4 (AQP4) expressions were quantified by immunoblot analysis.
RESULTS
Treatment with different concentrations of MMF or DMF for 24 h did not change the glial cell viability in M5 and M30 co-cultures. Microglial phenotypes were not altered by DMF under physiological M5 conditions, but treatment with higher concentration of DMF (15 μM) induced microglial activation under inflammatory M30 conditions. Incubation with different concentrations of MMF had no effects on microglial phenotypes. The Cx43 expression in M5 and M30 co-cultures was not changed significantly by immunoblot analysis after incubation with different concentrations of DMF or MMF for 24 h. The AQP4 expression was significantly increased in M5 co-cultures after incubation with 5 μm DMF. Under the other conditions, AQP4 expression was not affected by DMF or MMF.
DISCUSSION
In different set-ups of the astrocyte-microglia co-culture model of inflammation, MMF has not shown significant effects. DMF had only limited effects on microglia phenotypes and AQP4 expression. In summary, mechanisms of action of fumarates probably do not involve direct effects on microglia phenotypes as well as Cx43 and AQP4 expression.
Topics: Rats; Animals; Dimethyl Fumarate; Microglia; Astrocytes; Connexin 43; Coculture Techniques; Inflammation
PubMed: 36724743
DOI: 10.1159/000528938 -
European Journal of Pharmacology Jul 2022Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF... (Review)
Review
Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified.
Topics: Animals; Dimethyl Fumarate; Fumarates; Humans; Mice; Multiple Sclerosis; NF-E2-Related Factor 2; Neurodegenerative Diseases; Neuroprotective Agents; Signal Transduction
PubMed: 35569547
DOI: 10.1016/j.ejphar.2022.175025 -
Multiple Sclerosis Journal -... 2021For patients with MS, medication switches increase the risk of disease reactivation.
BACKGROUND
For patients with MS, medication switches increase the risk of disease reactivation.
OBJECTIVE
Compare discontinuation rates due to treatment failure or side effects between teriflunomide and dimethyl fumarate, and investigate clinical variables affecting discontinuation rates.
METHODS
All patients who received teriflunomide or dimethyl fumarate at Haukeland University Hospital from 2013 until 2018 were identified. Clinical and demographic variables were extracted from the Norwegian MS Registry. Cause-specific Cox regression models estimated the rate of discontinuation due to treatment failure or side effects.
RESULTS
We included 354 patients treated with either dimethyl fumarate ( = 185) or teriflunomide ( = 169). We found 38% lower risk of discontinuation because of treatment failure for patients using dimethyl fumarate compared to teriflunomide ( < 0.05). In a treatment-naive subgroup ( = 183), we found a 38% reduced risk of discontinuation for any reason among patients using dimethyl fumarate ( < 0.05). There was no significant difference between treatment groups in discontinuation rate due to side effects, although more patients reported side effects when treated with dimethyl fumarate.
CONCLUSION
Our findings suggests that dimethyl fumarate has a lower risk of discontinuation because of treatment failure among both treatment-experienced and treatment-naive patients.
PubMed: 34188949
DOI: 10.1177/20552173211022027 -
JCI Insight Nov 2023New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory...
New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.
Topics: Animals; Mice; Mice, Inbred mdx; Dimethyl Fumarate; Muscular Dystrophy, Duchenne; Prednisone; Muscles
PubMed: 37751291
DOI: 10.1172/jci.insight.165974 -
Inflammation Apr 2023Rheumatoid arthritis (RA) as a chronic inflammatory disorder affects around 1% of the world population. Fibroblast-like synoviocyte (FLS), one of the main cells in RA...
Rheumatoid arthritis (RA) as a chronic inflammatory disorder affects around 1% of the world population. Fibroblast-like synoviocyte (FLS), one of the main cells in RA pathogenesis is characterized by hyperproliferation and resistance to apoptosis resulting to synovial hyperplasia. Dimethyl fumarate (DMF) has been licensed for the treatment of multiple sclerosis (MS) and psoriasis; however, its role in RA is unknown. DMF has immunomodulatory properties and may be considered as therapeutic approach in RA treatment. In this study, we aimed to investigate the effect of DMF on controlling FLS-mediated synovial inflammation and joint destruction in RA. FLSs were isolated from synovial tissues of 8 patients with RA and treated with DMF. Apoptosis rate was analyzed by Annexin V-FITC. Cell proliferation was measured by carboxyfluorescein succinimidyl ester (CFSE) dye. The matrix metalloproteinase 3 (MMP3) and NF-кB pathway protein (p65) mRNA expression were evaluated by RT-PCR. Also, the IL-6 production and lactate release were measured in FLS supernatant. DMF treatment decreased the cell proliferation and increased apoptosis in a dose dependent manner. DMF-treated FLS showed a reduction in IL-6 and lactate release. Moreover, it was revealed that DMF inhibited the expression of p65 and MMP3. Our data demonstrate that DMF treatment suppresses the aggressive and inflammatory features of RA FLSs. Our Results suggest that DMF might be expected to be evaluated as a therapy for RA.
Topics: Humans; Synoviocytes; Dimethyl Fumarate; Matrix Metalloproteinase 3; Interleukin-6; Arthritis, Rheumatoid; Synovial Membrane; Inflammation; Fibroblasts; Cell Proliferation; Cells, Cultured
PubMed: 36253500
DOI: 10.1007/s10753-022-01759-1