In the double-blind, placebo-controlled, Phase 3 DEFINE study in patients with relapsing–remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) significantly reduced the proportion of patients ...relapsed (primary endpoint), the annualized relapse rate (ARR), and confirmed disability progression (secondary endpoints) at two years compared with placebo. We investigated the efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, expanded disability status scale score, T2 lesion volume, and gadolinium-enhancing lesions. The clinical efficacy of BG-12 was generally consistent across patient subgroups and reflected positive findings in the overall DEFINE study population. Treatment with BG-12 BID and TID reduced the proportion of patients relapsed and the ARR at two years compared with placebo in all patient subgroups. Reductions in the risk of relapse with BG-12 BID vs. placebo ranged from 68 % hazard ratio 0.32 (95 % confidence interval (CI) 0.16–0.62) to 26 % 0.74 (0.51–1.09) and from 66 % 0.34 (0.23–0.50) to 25 % 0.75 (0.42–1.36) with BG-12 TID vs. placebo. BG-12 also reduced the risk of disability progression at two years compared with placebo in most subgroups of patients treated with the BID dosing regimen and in all subgroups treated with the TID regimen. These analyses indicate that treatment with BG-12 is consistently effective across a wide spectrum of patients with relapsing–remitting multiple sclerosis with varied demographic and disease characteristics.
In this letter-to-the-editor the Task Force on Gender and Diversity issues in Neurology founded under the auspices of the European Academy of Neurology (EAN) addresses various gender issues that are ...arising during the COVID-19 pandemic. These issues concern different aspects, spanning from gender disparities in health care workforce to gender differences amongst patients suffering from COVID-19, risk factors, occurrence of neurological complications and (outcomes of) management. Due to the continuous flow of COVID-19 related papers this review cannot be comprehensive. We attempted to select the most relevant literature on this topic.
•Peripheral B cell responses have been targeted to inhibit active/relapsing multiple sclerosis.•Inhibition of advance (progressive) multiple sclerosis may be achieved by targeting B cell responses in ...the CNS.•Agents exist that could be used to target such B cell responses and could be used to show benefit.
There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.
The neurogenic bladder is well described in multiple sclerosis (MS). Bladder dysfunction increases risk of urinary tract infections (UTI) which can be recurrent and disabling. Moreover, infection may ...play a role in disease pathogenesis. We aimed to quantify this burden specifically; frequency of emergency department (ED) attendances and predictive factors for hospital admission.Data from electronic health records (EHR) of MSers was extracted to create ‘BartsMS Database’. Through this and using information from EHRs we analysed ED visits and hospital admissions over 6 years. Further data calculated cost of UTI admissions. Data was analysed using univariate analysis.991 MSers were encoded within the database. There were 690 ED attendances within this cohort with bladder dysfunction the commonest cause (240/690, 35%). 73% (175/240) of these required admission. 70% (168/240) had UTIs and 16% (38/240) had blocked urinary catheters. MSers with progressive disease and urinary catheters were most likely to be admitted for UTI (84%, 147/175 and 70%, 123/175 respectively) and had significantly longer admissions than patient with UTIs and other chronic diseases (mean 7.7 days MS vs 3.2 dementia vs 2.9 diabetes p<0.05). Annual cost of UTIs in MS was £700,000.This data demonstrates an unmet need within a local MS community. The individual and economic burden is significant. If concurrent infection plays a role in disease pathogenesis, the untreated UTI is a missed opportunity for disease modification. MSers with indwelling catheters are most vulnerable. Research into an innovation to prevent catheter associated UTIs is underway within our group.
In patients with relapsing-remitting MS (RRMS) and an inadequate response (≥1 relapse) to prior therapy, alemtuzumab improved Expanded Disability Status Scale (EDSS) functional systems scores (FSS) ...over 2 years versus subcutaneous interferon beta-1a (CARE-MS II; NCT00548405). Here we assess alemtuzumab's effect on FSS over 5 years. Patients received alemtuzumab at baseline and Month 12 in the core study. Patients entering an extension (NCT00930553) could receive as-needed alemtuzumab retreatment, or another disease-modifying therapy (DMT), for disease activity. EDSS was evaluated quarterly by blinded raters. 6-month confirmed FSS disability progression was defined as ≥1.0-point increase in an FSS. 393 (93%) alemtuzumab patients entered the extension; 357 (91%) remained on study through 5 years, 60% received no alemtuzumab after Month 12, and 92% received no other DMT. Over 5 years, mean cerebellar, pyramidal, sensory, and cerebral FSS did not exceed baseline; for each FSS, 71%–80% of patients were free from disability progression. Patients who received only 2 courses of alemtuzumab and no other DMT for 5 years generally had lower FSS than other patients. RRMS patients with inadequate response to prior therapy had persistent improvement/stability across multiple FSS over 5 years with alemtuzumab; most patients received no additional treatment since Month 12.Study supported by Sanofi Genzyme and Bayer Healthcare Pharmaceuticals.
BackgroundAs disease-activity-free status is now a viable treatment goal in relapsing multiple sclerosis (RMS), no evidence of disease activity (NEDA) is gaining increasing acceptance as an outcome ...measure.ObjectiveTo determine the percentage of RMS patients who achieved NEDA in the DECIDE study.MethodsDECIDE was a phase 3 study of 150 mg subcutaneous daclizumab high-yield process (DAC HYP) every 4 weeks versus weekly 30 mcg intramuscular (IM) interferon (IFN) beta-1a over 96–144 weeks. NEDA was defined as no relapses, no 12-week confirmed disability progression, no new/enlarging T2 (NET2) lesions, and no gadolinium-enhancing (Gd+) lesions.ResultsA greater percentage of patients receiving DAC HYP than IFN beta-1a achieved NEDA by week 96 (24.3% 198/816 vs 13.9% 116/834; odds ratio OR: 1.983 95% confidence interval (CI): 1.540–2.554; P<0.0001). Similarly, a greater percentage of patients receiving DAC HYP than IFN beta-1a achieved clinical NEDA (no relapses or disability progression) (68.0% 625/919 vs 56.3% 519/922; OR 95% CI: 1.651 1.365–1.996; P<0.0001) and MRI NEDA (no NET2/Gd+ lesions) (36.4% 281/772 vs 23.3% 181/778; OR 1.887 1.512–2.356; P<0.0001) by week 96.ConclusionsA significantly greater percentage of patients treated with DAC HYP than with IM IFN beta-1a achieved NEDA.Sponsors: Biogen, AbbVie Biotherapeutics.
The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis. Using an animal model of multiple ...sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity. We found that CB(1) receptor expression by neurons, but not T cells, was required for cannabinoid-mediated EAE suppression. In contrast, CB(2) receptor expression by encephalitogenic T cells was critical for controlling inflammation associated with EAE. CB(2)-deficient T cells in the CNS during EAE exhibited reduced levels of apoptosis, a higher rate of proliferation and increased production of inflammatory cytokines, resulting in severe clinical disease. Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.
La lymphopénie était l’effet indésirable le plus fréquent dans les études CLARITY/CLARITY Extension. La numération absolue des lymphocytes (NAL) revenait à la normale avec le temps.
Évaluer les ...effets de cladribine comprimés à la dose de 3,5mg/kg (CC 3,5) sur les cellules immunitaires innées dans les données de patients randomisés pour recevoir CC 3,5 (n=685) ou un placebo (PBO, n=435).
À l’inclusion (début de l’étude CLARITY ou CLARITY Extension), la numération médiane (Q1–Q3) des neutrophiles était : CC 3,5=4,19×10E9/L (3,30–5,31) et PBO=4,20×10E9/L (3,41–5,35). À la fin de la 1re année, la numération médiane des neutrophiles était : CC 3,5=3,80×10E9/L (2,91–4,94) et PBO=4,24×10E9/L (3,28–5,50). À la fin de la 2e année, la numération des neutrophiles était : CC 3,5=3,71×10E9/L (2,90–4,70) et PBO=4,30×10E9/L (3,32–5,46).
À la fin de la 3e et 4e année, la numération des neutrophiles avec CC 3,5 atteignait un plateau à 3,60×10E9/L, et avec PBO un plateau à 4,28×10E9/L (3,30–5,25) et 3,46×109/L (2,49–5,80), respectivement. Avec CC 3,5, la numération des neutrophiles restait dans la normale (>2,03×10E9/L) pendant les 2 années de traitement et au-delà, et ≤6 (<2 %) des patients traités par CC 3,5 ont signalé des événements de neutropénie de grade 3/4 à tout moment.
À la fin de la 3e et 4e année, la numération des neutrophiles avec CC 3,5 atteignait un plateau à 3,60×10E9/L, et avec PBO un plateau à 4,28×10E9/L (3,30–5,25) et 3,46×10E9/L (2,49–5,80). Avec CC 3,5, la numération des neutrophiles restait dans la normale (>2,03×10E9/L) pendant les 2 années de traitement et au-delà, et ≤6 (<2 %) des patients traités par CC 3,5 ont signalé des événements de neutropénie de grade 3/4 à tout moment.
Ces données de NAL confirment le concept que la sélectivité de CC réduit la numération des cellules immunitaires adaptatives avec un impact relativement mineur sur le système immunitaire inné.
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