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Annals of Clinical and Translational... Sep 2020Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple... (Comparative Study)
Comparative Study Observational Study
INTRODUCTION
Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist.
METHODS
Clinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator.
RESULTS
A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX.
INTERPRETATION
RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.
Topics: Adult; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Follow-Up Studies; Humans; Immunologic Factors; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Outcome Assessment, Health Care; Recurrence; Retrospective Studies; Rituximab
PubMed: 32767538
DOI: 10.1002/acn3.51111 -
Multiple Sclerosis (Houndmills,... Oct 2020Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited. (Observational Study)
Observational Study
BACKGROUND
Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited.
OBJECTIVE
To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden.
METHODS
We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF ( = 641) or interferons/glatiramer acetate (IFN/GA; = 555) as the initial therapy, or DMF ( = 703) or fingolimod (FGL; = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016.
RESULTS
The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy ( < 0.05 and = 0.20, respectively).
CONCLUSION
Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.
Topics: Dimethyl Fumarate; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies
PubMed: 31392923
DOI: 10.1177/1352458519866600 -
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 -
Anticancer Research May 2022Adult T-cell leukemia (ATL) is a peripheral T lymphocytic malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite treatment that includes...
BACKGROUND/AIM
Adult T-cell leukemia (ATL) is a peripheral T lymphocytic malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite treatment that includes novel agents that have been developed, most of ATL patients relapse and acquire multidrug resistance. As a result, the creation of newer agents is critical. Dimethyl fumarate (DMF) has several effects in cancer cells, including cell signaling, proliferation and cell death. However, its antitumor effects on ATL cells remain unknown. In this study, we looked at DMF's antitumor effects on ATL cells.
MATERIALS AND METHODS
We examined the effects of DMF on proliferation and apoptosis using the trypan blue exclusion assay and annexin V/propidium iodide staining in HTLV-1-infected and transformed T-cell lines, MT-1 and MT-2 cells. We also evaluated the effects of DMF on the nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) signaling pathways and anti-apoptotic proteins by immunoblotting.
RESULTS
DMF inhibited proliferation and induced apoptosis in MT-1 and MT-2 cells by activating poly ADP-ribose polymerase (PARP). Furthermore, DMF inhibited the constitutive activation of both canonical and non-canonical NF-κB pathways in MT-2 cells and the non-canonical NF-κB pathway in MT-1 cells. DMF also inhibited the constitutive tyrosine phosphorylation of STAT3 and the expression of anti-apoptotic proteins, c-IAP2 and survivin in both cells.
CONCLUSION
These results indicate that DMF inhibits proliferation and induces apoptosis in HTLV-1-infected and transformed T-cells by suppressing NF-κB and STAT3 signaling pathways. DMF should be investigated further as a novel agent for ATL.
Topics: Adult; Apoptosis; Dimethyl Fumarate; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma; NF-kappa B; STAT3 Transcription Factor; Signal Transduction
PubMed: 35489748
DOI: 10.21873/anticanres.15709 -
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 -
International Immunopharmacology Mar 2020Hepatic ischemia/reperfusion (I/R) injury occurs in different clinical settings as hepatic transplantation, and different types of shock. I/R injury is the main cause of...
BACKGROUND
Hepatic ischemia/reperfusion (I/R) injury occurs in different clinical settings as hepatic transplantation, and different types of shock. I/R injury is the main cause of hepatic damage and failure due to the production of reactive oxygen species (ROS) and inflammatory cytokines. Dimethyl fumarate (DMF), an immunomodulatory drug, activates cellularantioxidantsignaling pathways exerting cytoprotective properties. Curcumin (CUR), a natural phenolic compound, possesses antioxidant and anti-inflammatory properties.
METHOD
To study potential protective effects of DMF with CUR against hepatic I/R injury in rats, animals were randomly allocated into seven groups as follows: (1) Sham; (2) DMF (25 mg/Kg, p.o); (3) CUR (400 mg/Kg, p.o.); (4) I/R; (5) DMF + I/R; (6) CUR + I/R; and combination (COM) therapy + I/R. Drugs were given for 14 days before I/R.
RESULTS
Compared with I/R group, COM group showed the best amelioration in hepatic injury induced by I/R insult. This was confirmed by a significant reduction in serum ALT and AST activity with improved histopathological results when compared to every single treatment. Hepatic protection afforded by DMF was mediated by activating Nrf2/HO-1 signaling and increasing GSH and TAC contents. CUR treatment improved the inflammatory markers (TNF-α, IL-1β, Il-6 and iNOS) as well as neutrophilic infiltration assessed as MPO. Moreover, CUR potentiated Nrf2/HO-1 signaling induced by DMF with significant suppression in lipid peroxidation.
CONCLUSION
We concluded that combining DMF and CUR has more efficient hepatoprotective effects against hepatic-induced IRI via potentiating antioxidant and anti-inflammatory properties mediated by Nrf2/HO-1 pathway.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Curcumin; Dimethyl Fumarate; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Heme Oxygenase (Decyclizing); Humans; Immunosuppressive Agents; Liver Failure, Acute; Male; NF-E2-Related Factor 2; Rats; Reperfusion Injury; Signal Transduction
PubMed: 31981960
DOI: 10.1016/j.intimp.2019.106131 -
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 -
Therapeutic Advances in Neurological... 2020Dimethyl fumarate (DMF) is approved for the treatment of relapsing-remitting multiple sclerosis. It is unknown whether DMF or its primary metabolite monomethyl fumarate...
Dimethyl fumarate (DMF) is approved for the treatment of relapsing-remitting multiple sclerosis. It is unknown whether DMF or its primary metabolite monomethyl fumarate (MMF) are excreted into human milk. We present two cases of lactating patients who donated milk samples to study the transfer of MMF into human milk following a week of 2 × 240 mg daily oral dose. Samples were analyzed using liquid chromatography mass spectrometry. The calculated relative infant dose was 0.019% and 0.007%. This is the first study to demonstrate that MMF is transferred into human milk, with only limited exposure to an infant.
PubMed: 33193814
DOI: 10.1177/1756286420968414 -
Breast Cancer Research and Treatment Oct 2023The oncogenic factor ZNF217 promotes aggressive estrogen receptor (ER)+breast cancer disease suggesting that its inhibition may be useful in the clinic. Unfortunately,...
PURPOSE
The oncogenic factor ZNF217 promotes aggressive estrogen receptor (ER)+breast cancer disease suggesting that its inhibition may be useful in the clinic. Unfortunately, no direct pharmacological inhibitor is available. Dimethyl fumarate (DMF) exhibits anti-breast cancer activities, in vitro and in pre-clinical in vivo models. Its therapeutic benefits stem from covalent modification of cellular thiols such as protein cysteines, but the full profile of molecular targets mediating its anti-breast cancer effects remains to be determined.
METHODS
ER+breast cancer cells were treated with DMF followed by cysteine-directed proteomics. Cells with modulated ZNF217 levels were used to probe the efficacy of DMF.
RESULTS
Covalent modification of ZNF217 by DMF identified by proteomics was confirmed by using a DMF-chemical probe. Inhibition of ZNF217's transcriptional activity by DMF was evident on reported ZNF217-target genes. ZNF217 as an oncogene has been shown to enhance stem-like properties, survival, proliferation, and invasion. Consistent with ZNF217 inhibition, DMF was more effective at blocking these ZNF217-driven phenotypes in cells with elevated ZNF217 expression. Furthermore, partial knockdown of ZNF217 led to a reduction in DMF's efficacy. DMF's in vivo activity was evaluated in a xenograft model of MCF-7 HER2 cells that have elevated expression of ZNF217 and DMF treatment resulted in significant inhibition of tumor growth.
CONCLUSION
These data indicate that DMF's anti-breast cancer activities in the ER+HER2+models, at least in part, are due to inhibition of ZNF217. DMF is identified as a new covalent inhibitor of ZNF217.
Topics: Humans; Female; Breast Neoplasms; Dimethyl Fumarate; Receptors, Estrogen; Trans-Activators; MCF-7 Cells
PubMed: 37477798
DOI: 10.1007/s10549-023-07037-4 -
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