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WHAT IS THIS SUMMARY ABOUT?: Patient registries contain anonymous data from people who share the same medical condition. The MSBase registry contains information from over 80,000 people living with multiple sclerosis (MS) across 41 countries. Using information from the MSBase registry, the GLIMPSE (Generating Learnings In MultiPle SclErosis) study looked at real-life outcomes in 3475 people living with MS who were treated with cladribine tablets (Mavenclad®) compared with other oral treatments. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets stayed on treatment for longer than other treatments given by mouth. They also had fewer relapses (also called flare ups of symptoms) than people who received a different oral treatment for their MS. WHAT DO THE RESULTS MEAN?: The results provide evidence that, compared with other oral treatments for MS, cladribine tablets are an effective medicine for people living with MS.

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BACKGROUND: Dimethyl fumarate (DMF) is a first-line oral therapy for relapsing-remitting multiple sclerosis (RRMS). This retrospective study aims to determine the utility of routine complete blood counts (CBC) in predicting lymphopenia, adverse effects and efficacy in a real-world clinical setting. METHODS: The Calgary Multiple Sclerosis (MS) Clinic manages over 1800 people with MS on disease-modifying therapies (DMT). Data of patients with relapsing-remitting MS (pwMS) who initiated DMF between July 1, 2013 and December 31, 2014 were included. Patients were followed for one year. DMT use is carefully monitored and pwMS need a screening CBC and have regular CBCs done at follow-up. Demographic, clinical, MRI and relapse information are collected prospectively in a clinic database. We analyzed CBCs at baseline and month 3. RESULTS: We identified 139 pwMS in the study period who started DMF. Median follow-up time on-drug was 12 (0.16-12) months. In our study, 15.8% of pwMS developed lymphopenia grade 2 or higher. Baseline lymphocyte counts and older age were significant predictors of lymphopenia. Higher baseline eosinophil counts predicted flushing/gastrointestinal adverse effects, and higher baseline monocyte counts were predictive of breakthrough disease activity. Neutrophil and platelet to lymphocyte ratios, markers that have been associated with overall mortality in the general population, were increased at month 3. CONCLUSIONS: Routinely obtained CBCs during the screening and monitoring of people with MS starting DMF offer clinically useful information and generate interesting hypotheses. Age and baseline lymphocyte counts are reinforced as clinically useful predictors of lymphopenia. Our novel findings that baseline eosinophil and monocyte counts could offer insights into usual adverse effects and efficacy, respectively, should be further investigated as a potentially new set of biomarkers.

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BACKGROUND: Dimethyl fumarate (DMF, Tecfidera®) is a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis. Lymphopenia is a frequent reason for discontinuation in fumarate-treated patients. Management strategies to minimize risk of lymphopenia are warranted. OBJECTIVE: The aims of this study were to investigate the correlation of body mass index (BMI), baseline absolute lymphocyte count (ALC), age and sex with risk of DMF-induced lymphopenia in MS patients. METHODS: The study was a retrospective cohort study of 452 MS patients who had been prescribed DMF at six clinics in two Danish regions between May 2014 and September 2017. Data on lymphocyte counts, BMI, age, sex, and reason for discontinuation of DMF were collected through the Danish Multiple Sclerosis Registry, with follow- up to two years after treatment start. RESULTS: 28.5% of patients had lymphopenia grade II or higher at some time in the first two years of DMF treatment. Increased risk of lymphopenia was observed in patients with baseline ALC of 1.00-1.49×109 cells/L (odds ratio, OR 5.48, p<0.0001) and 1.50-1.99×109 cells/L (OR 2.08, p = 0.0009). Reduced risk of lymphopenia was observed in patients with ALC of 2.00-2.49×109 cells/L (OR 0.51, p< 0.01) and ≥ 2.50×109 cells/L (0.12, p<0.0001). Patients aged ≥ 56 years had an increased risk of lymphopenia (OR 3.58, p<0.001), and patients with BMI ≥ 30 kg/m2 had a decreased risk of lymphopenia (OR 0.53, p value = 0.03). CONCLUSION: Low baseline ALC and older age were risk factors for DMF-induced lymphopenia, while BMI ≥ 30 kg/m2 and high baseline ALC were protective factors for developing lymphopenia in MS patients treated with DMF.

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Here we draw insights from the latest serendipitous findings made on the opposing roles of a proposed drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell-survival- vs. cell-death-promoting behaviors. In the process, we convey how understanding reactive chemical-signal regulation at the single-protein-specific level is an enabling necessity in deconstructing otherwise intricate reactive-small-molecule-responsive cellular pathways. We hope this opinion piece further spurs the broader interests of basic and pharmaceutical research communities toward better understanding of molecular mechanisms underpinning reactive small-molecule-regulated signaling subsystems.

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Dimethyl fumarate is a cytoprotective and immunomodulatory drug used in the treatment of multiple sclerosis. We performed a bibliometric study examining the characteristics and trends of the top 100 cited articles that include dimethyl fumarate in the title. On 21 September 2020 we carried out an electronic search in the Web of Science (WOS), seeking articles that include the following terms within the title: dimethyl fumarate, BG-12, or Tecfidera. To focus our investigation on original research, we refined the search to include only articles, early access, others, case report, and clinical trials. We obtained a total of 1115 items, which were cited 7169 times, had a citation density of 6.43 citations/item, and an h-index of 40. Around 2010, there was a jump in the number of published articles per year, rising from 5 articles/year up to 12 articles/year. We sorted all the items by the number of citations and selected the top 100 most cited (T100). The T100 had 4164 citations, with a density of 37 citations/year and contained 16 classic research articles. They were published between 1961 and 2018; the years 2010-2018 amassed nearly 80% of the T100. We noted 17 research areas with articles in the T100. Of these, the number one ranking went to neurosciences/neurology with 39 articles, and chemistry ranked second on the T100 list with 14 items. We noticed that the percentage of articles belonging to different journals changed depending on the time period. Chemistry held the highest number of papers during 1961-2000, while pharmacology andneurosciences/neurology led the 2001-2018 interval. A total of 478 authors from 145 institutions and 25 countries were included in the T100 ranking. The paper by Gold R et al. was the most successful with 14 articles, 1.823 citations and a density of 140.23 citations/year. The biotechnological company Biogen led the T100 list with 20 articles. With 59 published articles, the USA was the leading country in publications. We concluded that this study analyzed the use of and research on dimethyl fumarate from a different perspective, which will allow the readership (expert or not) to understand the relevance of classic and recent literature on this topic.

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One known adverse event associated with dimethyl fumarate (DMF) is grade III lymphopenia which usually resolves within 2-3 months upon DMF discontinuation. Here, we report a case of a 50-year-old woman with MS who developed grade III lymphopenia within 6 months of DMF initiation, and despite treatment cessation within the next 6 months, she has continued to have severe persistent lymphopenia for over 5 years. Our observation suggests prolonged and possibly irreversible lymphopenia as a possible adverse event of DMF, and it emphasizes the need for monitoring lymphocyte numbers, and to cease dosing promptly after onset of grade III lymphopenia.

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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.

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Diroximel fumarate (DRF) is a new emerging therapy for patients with multiple sclerosis. The levels of its active metabolite, monomethyl fumarate, are bioequivalent to the levels generated from dimethyl fumarate (DMF) treatment. The efficacy and safety profiles of DRF are expected to be similar to the well-established profiles of DMF. The metabolism of DRF leads to lower concentration of methanol in the small intestine than with DMF and thus reduced severity and frequency of gastrointestinal adverse events. DRF seems a promising alternative to DMF and other first-line therapies for multiple sclerosis. The current review is based on the two existing Phase III trials of DRF: the interim analysis of the EVOLVE-MS-1 trial and the completed EVOLVE-MS-2 trial.

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[This corrects the article DOI: 10.3389/fonc.2020.00022.].

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Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells.

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BACKGROUND: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown. OBJECTIVE: To assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT. METHODS: Patients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics. RESULTS: Discontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41-2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18-1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90-1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85-1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74-1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04). CONCLUSION: This combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF) is an effective treatment for multiple sclerosis (MS). Some patients experience gastrointestinal (GI) adverse events (AEs) that may lead to premature DMF discontinuation. This study characterized the impact of site-specific GI management strategies on the occurrence of GI events and discontinuation patterns. METHODS: Data on GI events and DMF persistence were retrospectively abstracted from medical records of patients treated with DMF in routine medical practice in the EFFECT study (NCT02776072). GI management strategies were assessed via a study site questionnaire. Discontinuation rates were analyzed according to counseling patterns. RESULTS: Of 826 DMF-treated patients at 66 sites, 809 from 65 sites were eligible for the GI analysis; of these, 27% experienced GI AEs. Within 1 year of treatment, 14% (118/826) of patients discontinued DMF, 5% (44/809) due to GI events. Most sites (92%) reported that patients were very likely (> 75% of the time) to be counseled about GI events at/before DMF treatment initiation and/or to be recommended that DMF be taken with food (86%); 48% of sites reported to be very likely to recommend using symptomatic therapies for GI AEs. Lower discontinuation rates were reported at sites very likely versus not very likely (≤ 75% of the time) to (1) provide counseling; (2) provide specific details regarding GI events; or (3) recommend taking DMF with food, and/or using symptomatic GI therapies. CONCLUSION: Counseling and other GI management strategies at initiation of DMF treatment appear to reduce the burden of GI events, and a variety of GI management strategies may improve DMF persistence. TRIAL REGISTRATION: NCT02776072. FUNDING: Biogen (Cambridge, MA, USA).

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BACKGROUND: Fingolimod (FTY) and dimethyl fumarate (DMF) are multiple sclerosis (MS) oral therapies that became available in 2010 and 2013, respectively. OBJECTIVE: The objective of this article is to compare discontinuation rates, efficacy, and adverse events (AEs) of FTY and DMF over two years. METHODS: Patients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data were retrospectively collected. Primary outcome was discontinuation of drug by the end of year two. Reasons for discontinuation were evaluated. RESULTS: A total of 271 FTY and 342 DMF patients were evaluated. Patients had a mean age of 42.5 (FTY) and 45.8 (DMF) years and were predominantly female (72.0% FTY; 69.6% DMF) and white (86.3% FTY; 82.2% DMF). At ≤24 months, 93 (34.3%) and 161 (47.1%) discontinued FTY and DMF, respectively, with an unadjusted odds ratio (OR) of 1.70 (1.23-2.37, p = 0.002), or 1.69 (1.16-2.46, p = 0.006) for the doubly robust propensity score weighted estimator. Primary reason for discontinuation was AEs, which were less likely for FTY 46 (17.0%) compared to DMF 82 (24.0%) (OR 1.54, 1.03-2.31, p = 0.035). Discontinuation due to disease activity (FTY (10%) DMF (11.1%); OR 1.13, 0.67-1.90, p = 0.647) and breakthrough disease activity, regardless of discontinuation (FTY (34.7%) DMF (33.6%); OR 0.95, 0.68-1.34, p = 0.783), were similar. CONCLUSIONS: The odds of discontinuation were less for FTY than DMF, and were driven by AEs for both drugs.

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BACKGROUND: Oxidative stress and inflammation exacerbate tissue damage in the brain after ischemic stroke. Dimethyl-fumarate (DMF) and its metabolite monomethyl-fumarate (MMF) are known to stimulate anti-oxidant pathways and modulate inflammatory responses. Considering these dual effects of fumarates, we examined the effect of MMF treatment after ischemic stroke in mice. METHODS: Permanent middle cerebral artery occlusion (pMCAO) was performed using adult, male C57BL/6 mice. Thirty minutes after pMCAO, 20mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48h after pMCAO. First, we examined whether a bolus of MMF was capable of changing expression of kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor (Nrf)2 in the infarcted brain. Next, we studied the effect of MMF on functional recovery. To explore mechanisms potentially influencing functional changes, we examined infarct volumes, edema formation, the expression of heat shock protein (Hsp)72, hydroxycarboxylic acid receptor 2 (Hcar2), and inducible nitric oxide synthase (iNOS) in the infarcted brain using real-time PCR and Western blotting. Concentrations of a panel of pro- and anti-inflammatory cytokines (IFNγ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, TNF) were examined in both the infarcted brain tissue and plasma samples 6, 24 and 48h after pMCAO using multiplex electrochemoluminiscence analysis. RESULTS: Administration of MMF increased the protein level of Nrf2 6h after pMCAO, and improved functional outcome at 24 and 48h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6h after pMCAO. Hcar2 mRNA levels increased significantly 24h after pMCAO, but were not different between saline- and MMF-treated mice. MMF treatment also increased the level of the anti-inflammatory cytokine IL-10 in the brain and plasma 6h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48h after pMCAO. CONCLUSIONS: A single intravenous bolus of MMF improved sensory-motor function after ischemic stroke, reduced edema formation, and increased the levels of the neuroprotective protein Hsp72 in the brain. The early increase in IL-10 and reduction in IL-12p70 in the brain combined with changes in systemic cytokine levels may also contribute to the functional recovery after pMCAO.

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