Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis.

BACKGROUND: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. OBJECTIVES: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. METHODS: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. RESULTS: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. CONCLUSIONS: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.

Early intensive versus escalation treatment in patients with relapsing-remitting multiple sclerosis in Austria.

OBJECTIVES: To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing-remitting multiple sclerosis (RRMS). MATERIALS AND METHODS: The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study. RESULTS: Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16-0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13-0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40-0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort. CONCLUSIONS: ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course.

Prediction of disease activity and treatment failure in relapsing-remitting MS patients initiating daily oral DMTs.

BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). OBJECTIVES: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. METHODS: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. CONCLUSION: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully.

Inhalation of dimethyl fumarate-encapsulated solid lipid nanoparticles attenuate clinical signs of experimental autoimmune encephalomyelitis and pulmonary inflammatory dysfunction in mice.

RATIONALE: The FDA-approved Dimethyl Fumarate (DMF) as an oral drug for Multiple Sclerosis (MS) treatment based on its immunomodulatory activities. However, it also caused severe adverse effects mainly related to the gastrointestinal system. OBJECTIVE: Investigated the potential effects of solid lipid nanoparticles (SLNs) containing DMF, administered by inhalation on the clinical signs, central nervous system (CNS) inflammatory response, and lung function changes in mice with experimental autoimmune encephalomyelitis (EAE). MATERIALS AND METHODS: EAE was induced using MOG35-55 peptide in female C57BL/6J mice and the mice were treated via inhalation with DMF-encapsulated SLN (CTRL/SLN/DMF and EAE/SLN/DMF), empty SLN (CTRL/SLN and EAE/SLN), or saline solution (CTRL/saline and EAE/saline), every 72 h during 21 days. RESULTS: After 21 days post-induction, EAE mice treated with DMF-loaded SLN, when compared with EAE/saline and EAE/SLN, showed decreased clinical score and weight loss, reduction in brain and spinal cord injury and inflammation, also related to the increased influx of Foxp3+ cells into the spinal cord and lung tissues. Moreover, our data revealed that EAE mice showed signs of respiratory disease, marked by increased vascular permeability, leukocyte influx, production of TNF-α and IL-17, perivascular and peribronchial inflammation, with pulmonary mechanical dysfunction associated with loss of respiratory volumes and elasticity, which DMF-encapsulated reverted in SLN nebulization. CONCLUSION: Our study suggests that inhalation of DMF-encapsulated SLN is an effective therapeutic protocol that reduces not only the CNS inflammatory process and disability progression, characteristic of EAE disease, but also protects mice from lung inflammation and pulmonary dysfunction.

Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS.

Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4+ T cells presumably resulting in higher concentrations of intrathecal IL-7.

Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology.

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients' immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.

Safety and efficacy of dimethyl fumarate in ALS: randomised controlled study.

OBJECTIVE: Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. METHODS: Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life. RESULTS: A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (-1.12 [-3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [-0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. INTERPRETATION: Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.

Diroximel Fumarate in Relapsing Forms of Multiple Sclerosis: A Profile of Its Use.

Diroximel fumarate (Vumerity®), an orally administered disease-modifying drug (DMD), expands the available treatment options for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS (RRMS), and active secondary progressive MS. It demonstrates bioequivalence to dimethyl fumarate and was developed to provide similar clinical benefits, but with an improved gastrointestinal (GI) tolerability profile. In RRMS patients who are treatment-naïve or were previously treated with interferon-ß or glatiramer acetate, diroximel fumarate reduces annualized relapse rates, with most patients experiencing no relapses during treatment, and reduces the formation of new MS-associated brain lesions. Diroximel fumarate has an acceptable tolerability profile that is consistent with that of dimethyl fumarate, albeit with a significantly lower rate of GI adverse events.

Dimethyl fumarate preserves left ventricular infarct integrity following myocardial infarction via modulation of cardiac macrophage and fibroblast oxidative metabolism.

Myocardial infarction (MI) is one of the leading causes of mortality and cardiovascular disease worldwide. MI is characterized by a substantial inflammatory response in the infarcted left ventricle (LV), followed by transition of quiescent fibroblasts to active myofibroblasts, which deposit collagen to form the reparative scar. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is an important mechanism by which these cell types transition towards reparative phenotypes. Thus, we hypothesized that dimethyl fumarate (DMF), a clinically approved anti-inflammatory agent with metabolic actions, would improve post-MI remodeling via modulation of macrophage and fibroblast metabolism. Adult male C57BL/6J mice were treated with DMF (10 mg/kg) for 3-7 days after MI. DMF attenuated LV infarct and non-infarct wall thinning at 3 and 7 days post-MI, and decreased LV dilation and pulmonary congestion at day 7. DMF improved LV infarct collagen deposition, myofibroblast activation, and angiogenesis at day 7. DMF also decreased pro-inflammatory cytokine expression (Tnf) 3 days after MI, and decreased inflammatory markers in macrophages isolated from the infarcted heart (Hif1a, Il1b). In fibroblasts extracted from the infarcted heart at day 3, RNA-Seq analysis demonstrated that DMF promoted an anti-inflammatory/pro-reparative phenotype. By Seahorse analysis, DMF did not affect glycolysis in either macrophages or fibroblasts at day 3, but enhanced macrophage OXPHOS while impairing fibroblast OXPHOS. Our results indicate that DMF differentially affects macrophage and fibroblast metabolism, and promotes anti-inflammatory/pro-reparative actions. In conclusion, targeting cellular metabolism in the infarcted heart may be a promising therapeutic strategy.

Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate).

BACKGROUND: Tecfidera® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy. OBJECTIVE: The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera® capsule containing 240 mg of DMF, a prodrug of MMF. METHODS: This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC0-t which is the area under the plasma concentration-time curve (AUC) from time zero (dosing time) to the last time point, t, with measurable analyte concentration, and AUC0-inf, which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18-101.64), 96.35% (91.81-101.12), and 104.84% (95.54-115.05) for AUC0-t, AUC0-inf, and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera®, respectively. CONCLUSIONS: Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera® DR 240 mg capsule. CLINICAL TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.

Possible progressive multifocal leukoencephalopathy and active multiple sclerosis under dimethyl fumarate: the central role of MRI in informing therapeutic decisions.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) can rarely occur in Multiple Sclerosis (MS) patients undergoing dimethyl fumarate (DMF) treatment. Our case stresses the limits of current diagnostic and stratification risk criteria, highlighting the potential role of Magnetic Resonance Imaging (MRI) in advising clinical choices. CASE PRESENTATION: A 54 years old MS male patient treated with DMF, after 3 years of clinical stability developed a subacute clinical worsening. He had no severe lymphopenia but MRI signs suggestive of a coexistence of PML and MS activity. Although his viral title was negative, DMF was discontinued, with clinical and radiological improvement. CONCLUSIONS: This case highlights the challenges behind PML diagnosis, especially in patients not fulfilling the risk stratification criteria and that might present with concurrent disease activity, stressing the potential role of MRI in informing therapeutic decisions.

Dimethyl fumarate attenuates 2-VO-induced vascular dementia via activating the Nrf2 signaling pathway in rats.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia. METHODS: Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague-Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus. RESULTS: The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1ß, NF-κß, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment. CONCLUSION: Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia.

Short-term laboratory and related safety outcomes for the multiple sclerosis oral disease-modifying therapies: an observational study.

BACKGROUND: Real-world safety data for the oral multiple sclerosis (MS) disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide are important. We examined laboratory test abnormalities and adverse health conditions in new users. METHODS: Linked laboratory and administrative health data were accessed for all persons with MS (PwMS) filling their first oral DMT prescription in two Canadian provinces. PwMS were followed from first prescription fill until discontinuation, death, emigration or study end. Proportions of PwMS, and incidence rates (IR)/100 person-years, were calculated for ≥1 event of elevated alanine aminotransferase (ALT) (>the upper limit of normal [ULN]; all DMTs), liver toxicity (ALT>3xULN; fingolimod); lymphopenia and proteinuria (DMF), and cardiac arrhythmia, hypertension and pneumonia (all DMTs). RESULTS: Overall, 1,140 PwMS were followed for up to 2 years. De novo elevated alanine aminotransferase affected 13.2% (DMF), 12.4% (teriflunomide), and 30.0% (fingolimod) of users. Liver toxicity affected 2.8% of fingolimod, lymphopenia 3.1% of DMF, and proteinuria 2.9% of DMF users. The incidences of cardiac arrhythmia, pneumonia and hypertension ranged from <1 to 1.86/100 person-years depending on the DMT. CONCLUSIONS: The short-term, real-world incidences of abnormal laboratory results or adverse events were consistent with the pivotal clinical trial findings. Longer-term safety data are still needed.

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study.

BACKGROUND: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. OBJECTIVE: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. METHODS: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. RESULTS: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. CONCLUSIONS: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.

Rituximab versus natalizumab, fingolimod, and dimethyl fumarate in multiple sclerosis treatment.

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.

Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-ß, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab.

BACKGROUND: Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets. METHODS: We performed a cross sectional study on PB B cells in MS patients treated with interferon-ß (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++). RESULTS: Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-ß treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages. CONCLUSION: Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-ß and fingolimod treated patients which might contribute to the drugs' mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.

Facioscapulohumeral muscular dystrophy (FSHD) and multiple sclerosis: a case report.

Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant neuromuscular disorder, associated with reduction of tandemly arrayed repetitive DNA elements D4Z4 (DRA), at 4q35. Few cases, especially carriers of 1-3 DRA show a syndromic form. Anecdotally the association of FSHD with multiple sclerosis (MS) is reported. Herein we report a 33 years old Caucasian with a molecular diagnosis of FSHD1 with classical phenotype (clinical category A2) and concomitant white matter lesions suggestive of MS. White matter lesions in patients with FSHD have often been described but rarely investigated in order to evaluate a possible diagnosis of MS. We think that MS and FSHD remain clearly distinct diseases, but growing evidences show a widespread and variable activation of the immune system in patients suffering from FSHD probably an hypotheses on a potential common pathogenetic mechanism between these two disorders could should be better investigated.

An evaluation of dimethyl fumarate for the treatment of relapsing remitting multiple sclerosis.

INTRODUCTION: In recent years there has been a dramatic rise in available disease-modifying therapies for the treatment of relapsing multiple sclerosis (MS). Dimethyl fumarate (DMF) is an oral drug approved by the FDA for relapsing MS with unique immunomodulatory and cytoprotective effects. AREAS COVERED: Herein, the authors provide the reader with a review of the literature obtained via a PubMed database search and provide their expert opinion on the use of DMF in clinical practice. The article details DMF's mechanism of action, long-term data on efficacy, tolerability and safety. EXPERT OPINION: Since approval, growing experience with DMF in clinical practice demonstrates a combination of efficacy, ease of administration along with an acceptable safety profile. The authors believe that DMF is a valuable long-term treatment option in patients with relapsing MS. However, long-term follow up studies are needed to provide further data on progressive multifocal leukoencephalopathy (PML) risk stratification for MS patients on treatment with DMF. Indeed, despite the strong association with lymphopenia, not all patients with DMF associated PML experienced prolonged overall lymphopenia, suggesting that additional predictive metrics are still needed.

Protective effect of dimethyl fumarate for the development of pressure ulcers after cutaneous ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) is associated with various pathogenic conditions, and there has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. Several studies demonstrated that oxidative stress is a key player in I/R injury, and the inhibition of oxidative stress may be capable of protecting tissue damage after I/R injury in various organs including skin. Dimethyl fumarate (DMF) approved by the Food and Drug Administration is Nrf2 activator, and recent studies revealed the antioxidative and anti-inflammatory effects of DMF on I/R injury in animal models. Our objective was to assess the effects of oral administration of DMF on the development of PUs after cutaneous I/R injury in mice. We found that DMF administration significantly decreased the size of PUs after cutaneous I/R. Cutaneous I/R-induced oxidative stress was also significantly inhibited by DMF in OKD48 mice, in which oxidative stress can be visually assessed. In addition, DMF treatment decreased hypoxic area, the numbers of apoptotic cells, and vascular loss in I/R area. DMF treatment suppressed the infiltration of MPO+ neutrophils and the production of proinflammatory cytokines in I/R site after cutaneous I/R injury. in vitro experiments, DMF treatment suppressed the production of reactive oxygen species in pericyte-like cells. These results suggest that DMF treatment might prevent the formation of PUs induced by cutaneous I/R injury via suppressing oxidative stress and subsequent inflammation. DMF treatment during the early phase of decubitus ulcers might protect against further progression.

Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate.

The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1-CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.