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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 -
Redox Biology Aug 2015Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in...
Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in diseases such as multiple sclerosis. Dimethyl fumarate, a small molecule therapeutic for multiple sclerosis, activates cellular antioxidant signaling pathways and may promote myelin preservation. However, it is still unclear what mechanisms may underlie this neuroprotection and whether dimethyl fumarate affects oligodendrocyte responses to oxidative stress. Here, we examine metabolic alterations in oligodendrocytes treated with dimethyl fumarate by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography-mass spectrometry and shotgun lipidomics. Prolonged treatment of oligodendrocytes with dimethyl fumarate induces changes in citric acid cycle intermediates, glutathione, and lipids, indicating that this compound can directly impact oligodendrocyte metabolism. These metabolic alterations are also associated with protection from oxidant challenge. This study provides insight into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis.
Topics: Cell Line; Chromatography, High Pressure Liquid; Citric Acid Cycle; Dimethyl Fumarate; Humans; Hydrogen Peroxide; Hydrophobic and Hydrophilic Interactions; Immunosuppressive Agents; Lipid Metabolism; Metabolome; Oligodendroglia; Principal Component Analysis; Tandem Mass Spectrometry
PubMed: 25967672
DOI: 10.1016/j.redox.2015.04.011 -
Dermatology Reports Mar 2022Psoriasis is a chronic condition for which multiple therapies are currently available. In particular, in cases of moderate- severe psoriasis, traditional systemic drugs...
Psoriasis is a chronic condition for which multiple therapies are currently available. In particular, in cases of moderate- severe psoriasis, traditional systemic drugs or the new biological drugs can be administered. However, the treatment of patients who require systemic therapy and have multiple comorbidities can be particularly complex. Some treatment options may be in fact contraindicated or may lose effectiveness over time, reducing the options available to the dermatologists. In such circumstances, dimethyl fumarate may represent a safe and effective choice, also in patients who have already attempted biological therapies. In this regard, we report the case of a patient with moderate-severe psoriasis treated over time with various therapies (including topicals, phototherapy, traditional and biological drugs) that were discontinued due to ineffectiveness or incompatibility caused by the occurrence of concomitant diseases, who finally achieved clinical remission with dimethyl fumarate.
PubMed: 35371425
DOI: 10.4081/dr.2022.9091 -
Brain Research Oct 2021Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One...
INTRODUCTION
Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One possibility to expand the treatment repertoire is repurposing of existing drugs such as dimethyl fumarate (DMF). DMF is approved for treatment of multiple sclerosis and previous animal studies have suggested that DMF may also have a beneficial effect for the treatment of AD.
METHODS
We used an APPPS1 transgenic model of senile β-amyloidosis and treated female mice orally with DMF in two treatment paradigms (pre and post onset). We quantified learning and memory parameters, β-amyloidosis, and neuroinflammation to determine the potential of DMF as AD therapeutics.
RESULTS
Treatment with DMF had no influence on water maze performance, β-amyloid accumulation, plaque formation, microglia activation, and recruitment of immune cells to the brain. Compared to vehicle-treated animals, oral DMF treatment could not halt or retard disease progression in the mice.
DISCUSSION
Our results do not favour the use of DMF as treatment for AD. While our results stand in contrast to previous findings in other models, they emphasize the importance of animal model selection and suggest further studies to elucidate the mechanisms leading to conflicting results.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Brain; Cognitive Dysfunction; Dimethyl Fumarate; Disease Models, Animal; Female; Hippocampus; Humans; Inflammation; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Peptide Fragments
PubMed: 34233173
DOI: 10.1016/j.brainres.2021.147579 -
British Journal of Clinical Pharmacology Oct 2021Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA ) and induce flushing. It is not known whether HCA mediates other adverse drug...
AIM
Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA ) and induce flushing. It is not known whether HCA mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA -mediated.
METHODS
We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA expression.
RESULTS
Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" (OR 1.3 [0.7-2.6]) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]).
CONCLUSION
The gastrointestinal ADRs common to both substances may be mediated by HCA . Other ADRs not common to both substances are compound or indication-specific reactions and likely do not involve HCA .
Topics: Adverse Drug Reaction Reporting Systems; Animals; Databases, Factual; Dimethyl Fumarate; Drug-Related Side Effects and Adverse Reactions; Humans; Mice; Niacin
PubMed: 33605454
DOI: 10.1111/bcp.14787 -
JAMA Network Open Nov 2021As disease-modifying treatment options for multiple sclerosis increase, comparisons of the options based on real-world evidence may guide clinical decision-making. (Comparative Study)
Comparative Study
IMPORTANCE
As disease-modifying treatment options for multiple sclerosis increase, comparisons of the options based on real-world evidence may guide clinical decision-making.
OBJECTIVE
To compare the relapse outcomes between 2 pairs of disease-modifying treatments: dimethyl fumarate vs fingolimod and natalizumab vs rituximab.
DESIGN, SETTING, AND PARTICIPANTS
This comparative effectiveness study integrated data from a clinic-based multiple sclerosis research registry and its linked electronic health records (EHR) system between January 1, 2006, and December 31, 2016, and built treatment groups for each pairwise disease-modifying treatment comparison according to both registry records and electronic prescriptions. Parallel analyses were conducted from October 11, 2019, to July 7, 2021.
MAIN OUTCOMES AND MEASURES
The main outcomes were the 1-year and 2-year relapse rates as well as the time to relapse. To compare relapse outcomes, the study adjusted for covariates from 2 sources (registry and EHR) and corrected for confounding biases among the covariates by the doubly robust estimation.
RESULTS
The study included 4 treatment groups: dimethyl fumarate (n = 260; 198 women [76.2%]; 227 non-Hispanic White individuals [87.3%]; mean [SD] age at diagnosis, 41.7 [10.4] years), fingolimod (n = 267; 190 women [71.2%]; 222 non-Hispanic White individuals [83.1%]; mean [SD] age at diagnosis, 37.9 [9.9] years), natalizumab (n = 204; 160 women [78.4%]; 172 non-Hispanic White individuals [84.3%]; mean [SD] age at diagnosis, 37.2 [10.6] years), and rituximab (n = 115; 83 women [72.2%]; 99 non-Hispanic White individuals [86.1%]; mean [SD] age at diagnosis, 44.1 [11.1] years). No significant differences were found in the relapse outcomes between dimethyl fumarate and fingolimod after correcting for confounding biases and multiple testing (difference in 1-year relapse rate, 0.028 [95% CI, -0.031 to 0.084]; difference in 2-year relapse rate, 0.071 [95% CI, 0.008-0.128]; relative risk of 2-year non-relapse, 0.957 [95% CI, 0.884-1.035] with dimethyl fumarate as reference). When compared with rituximab, natalizumab was associated with a higher relapse rate for all 3 outcomes after bias correction and multiple testing (difference in 1-year relapse rate, 0.080 [95% CI, 0.013-0.137]; difference in 2-year relapse rate, 0.132 [95% CI, 0.043-0.189]; relative risk of 2-year non-relapse, 0.903 [95% CI, 0.822-0.944]). Confounders were identified from EHR data not recorded in the registry data through data-driven feature selection.
CONCLUSIONS AND RELEVANCE
This study reports real-world evidence of equivalent relapse outcomes between dimethyl fumarate and fingolimod and relapse reduction in favor of rituximab relative to natalizumab. This approach illustrates the value of incorporating EHR data as high-dimensional covariates in real-world treatment comparison.
Topics: Adult; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Rituximab
PubMed: 34783826
DOI: 10.1001/jamanetworkopen.2021.34627 -
Gut Microbes 2023Neutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the...
Neutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the underlying mechanisms whereby neutrophils regulate IELs to inhibit intestinal inflammation are still not completely understood. Here, we found that depletion of neutrophils (especially CD177 subset) caused expansion of colitogenic TCRγδCD8αα IELs, increased intestinal inflammation, and dysbiosis after dextran sulfate sodium exposure or infection in mice. scRNA-seq analysis revealed a pyroptosis-related gene signature and hyperresponsiveness to microbiota in TCRγδCD8αα IELs from colitic mice. Microbiota-derived fumarate and its derivative dimethyl fumarate (DMF), as well as fumarate-producing microbiotas, decreased in the feces of colitic mice. Elimination of dysbiosis by antibiotics treatment or co-housing procedure and DMF supplementation restrained TCRγδCD8αα IEL activation. Consistently, DMF significantly alleviated intestinal mucosal inflammation in mice through restricting gasdermin D (GSDMD)-induced pyroptosis of TCRγδCD8αα IELs. Therefore, our data reveal that neutrophils inhibit intestinal inflammation by promoting microbiota-derived DMF to regulate TCRγδCD8αα IEL activation in a GSDMD-mediated pyroptosis-dependent manner, and that DMF may serve as a therapeutic target for the management of intestinal inflammation.
Topics: Mice; Animals; Dimethyl Fumarate; Intraepithelial Lymphocytes; Mice, Knockout; Dysbiosis; Neutrophils; Gastrointestinal Microbiome; Intestinal Mucosa; Inflammation; Mice, Inbred C57BL
PubMed: 36729914
DOI: 10.1080/19490976.2023.2172668 -
Cells Aug 2021Cystic Fibrosis (CF) is caused by mutations on the gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced...
Cystic Fibrosis (CF) is caused by mutations on the gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced CFTR dysfunction in airway epithelial cells is due to an early oxidative stress. Dimethyl fumarate (DMF) is an approved anti-inflammatory and anti-oxidant drug for auto-immune and inflammatory diseases, but its role in the CF has never been investigated. In this study, we examined the effect of DMF on CF-related cytokines expression, ROS measurements and CFTR channel function. We found that DMF reduced the inflammatory response to LPS stimulation in both CF and non-CF bronchial epithelial cells, both as co-treatment and therapy, and restored LPS-mediated decrease of Trikafta™-mediated CFTR function in CF cells bearing the most common mutation, c.1521_1523delCTT (F508del). DMF also inhibited the inflammatory response induced by IL-1β/HO and IL-1β/TNFα, mimicking the inflammatory status of CF patients. Finally, we also demonstrated that DMF exhibited an anti-oxidant effect on CF cells after different inflammatory stimulations. Since DMF is an approved drug, it could be further investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF and improve the CFTR modulators efficacy.
Topics: Anti-Inflammatory Agents; Cystic Fibrosis; Dimethyl Fumarate; Epithelial Cells; Humans; Interleukin-1beta; Oxidative Stress; Reactive Oxygen Species; Tumor Necrosis Factor-alpha
PubMed: 34440900
DOI: 10.3390/cells10082132 -
Journal of Immunology (Baltimore, Md. :... Nov 2021PGs are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of nonsteroidal anti-inflammatory drugs...
PGs are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of nonsteroidal anti-inflammatory drugs in the treatment of inflammation. 4-Octyl itaconate (4-OI), a derivative of the Krebs cycle-derived metabolite itaconate, has recently garnered much interest as an anti-inflammatory agent. In this article, we show that 4-OI limits PG production in murine macrophages stimulated with the TLR1/2 ligand Pam3CSK4. This decrease in PG secretion is due to a robust suppression of cyclooxygenase 2 (COX2) expression by 4-OI, with both mRNA and protein levels decreased. Dimethyl fumarate, a fumarate derivative used in the treatment of multiple sclerosis, with properties similar to itaconate, replicated the phenotype observed with 4-OI. We also demonstrate that the decrease in COX2 expression and inhibition of downstream PG production occurs in an NRF2-independent manner. Our findings provide a new insight into the potential of 4-OI as an anti-inflammatory agent and also identifies a novel anti-inflammatory function of dimethyl fumarate.
Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Dimethyl Fumarate; Humans; Macrophages; Mice; Prostaglandins; Succinates
PubMed: 34635585
DOI: 10.4049/jimmunol.2100488 -
Neurology Apr 2019To compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple... (Comparative Study)
Comparative Study Observational Study
OBJECTIVE
To compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple sclerosis (RRMS) in a real-world setting.
METHODS
We identified all patients starting TFL or DMF from the Danish Multiple Sclerosis Registry and compared on-treatment efficacy outcomes between DMF using TFL, adjusted for clinical baseline variables and propensity score-based methods.
RESULTS
We included 2,236 patients in the study: 1,469 patients on TFL and 767 on DMF. Annualized relapse rates (ARRs) in TFL and DMF were 0.16 (95% confidence interval [CI] 0.13-0.20) and 0.09 (95% CI 0.07-0.12), respectively. Relapse rate ratio for DMF/TFL was 0.58 (95% CI 0.46-0.73, < 0.001). DMF had a higher relapse-free survival proportion at 48 months of follow-up ( < 0.05). We observed no difference in Expanded Disability Status Scale score worsening. Discontinuations due to disease breakthrough were 10.2% (95% CI 7.6%-12.8%) and 22.1% (95% CI 19.2%-25.0%) for DMF and TFL, respectively. A subgroup analysis of ARRs in 708 patients with available baseline MRI T2 lesion amount reported similar results after adjustment.
CONCLUSION
We found lower ARR, higher relapse-free survival, and lower incidence of discontinuation due to disease breakthrough on treatment with DMF compared with TFL.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that for patients with RRMS, DMF is more effective in preventing relapses and has lower discontinuation due to disease breakthrough compared with TFL.
Topics: Adult; Cohort Studies; Crotonates; Denmark; Dimethyl Fumarate; Disability Evaluation; Female; Humans; Hydroxybutyrates; Immunosuppressive Agents; Male; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Survival; Toluidines; Treatment Outcome
PubMed: 30877188
DOI: 10.1212/WNL.0000000000007314