Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial.

ObjectiveNo evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis.MethodsThe proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients.ResultsThe majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes.InterpretationCompared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536

Clinical effects of natalizumab on multiple sclerosis appear early in treatment course

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects. To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri® Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p<0.0001) and in patients with highly active disease (0.30 vs. 0.94; p=0.0039). The low annualized relapse rate was maintained throughout the 2-year study period, and the risk of relapse in AFFIRM patients treated with natalizumab was reduced [hazard ratio against placebo 0.42 (95% CI 0.34-0.52); p<0.0001]. Rapid reductions in annualized relapse rate also occurred in TOP (baseline 1.99 vs. 0-3months 0.26; p<0.0001). Natalizumab resulted in rapid, sustained reductions in disease activity in both AFFIRM and in clinical practice. This decrease in disease activity occurred within the first 3months of treatment even in patients with more active diseas

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data

Alemtuzumab; Product surveillance; Risk assessmentAlemtuzumab; Vigilancia de productos; Evaluación de riesgosAlemtuzumab; Vigilància de productes; Avaluació de riscosDoes preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The CAMMS223 and CARE-MS studies, and their extensions, were supported by Sanofi and Bayer Healthcare Pharmaceuticals. Editorial and writing assistance was supported by Sanofi

Extensive myelitis associated with anti-NMDA receptor antibodies.

International audienceBACKGROUND: Encephalitis with anti-N-methyl-D-aspartate receptor antibodies (anti-NMDAR-Ab) is a rapid-onset encephalitis including psychosis, seizures, various movement disorders and autonomic system disturbances. CASE PRESENTATION: We report a very unusual case of extensive myelitis associated with anti-NMDAR-Ab. MRI also revealed a hyperintense T2 lesion, non-suggestive of MS, which progressively extended, associated with periventricular gadolinium enhancement visualized on brain MRI. Ophthalmological evaluation showed subclinical right optic neuritis. The absence of anti-AQP4 antibody argued against neuromyelitis optica spectrum disorder. A slight psychomotor slowing prompted us to search for various causes of autoimmune encephalitis. Anti-NMDAR-Ab was found in cerebrospinal fluid. CONCLUSION: In patients with extensive myelitis who are seronegative for anti-AQP4 antibodies, and after other classical causes have been excluded, the hypothesis of atypical anti-NMDAR-Ab encephalitis should also be considered

Changes Related to Age in Natural and Acquired Systemic Self-IgG Responses in Malaria

Background. Absence of acquired protective immunity in endemic areas children leads to higher susceptibility to severe malaria. To investigate the involvement of regulatory process related to self-reactivity, we evaluated potent changes in auto-antibody reactivity profiles in children and older subjects living in malaria-endemic zones comparatively to none-exposed healthy controls. Methods. Analysis of IgG self-reactive footprints was performed using Western blotting against healthy brain antigens. Plasmas of 102 malaria exposed individuals (MEIs) from endemic zone, with or without cerebral malaria (CM) were compared to plasmas from non-endemic controls (NECs). Using linear discriminant and principal component analysis, immune footprints were compared by counting the number, the presence or absence of reactive bands. We identified the most discriminant bands with respect to age and clinical status. Results. A higher number of bands were recognized by IgG auto-antibodies in MEI than in NEC. Characteristic changes in systemic self-IgG-reactive repertoire were found with antigenic bands that discriminate Plasmodium falciparum infections with or without CM according to age. 8 antigenic bands distributed in MEI compared with NEC were identified while 6 other antigenic bands were distributed within MEI according to the age and clinical status. Such distortion might be due to evolutionary processes leading to pathogenic/protective events

Serum Neurofilament Levels and PML Risk in Patients With Multiple Sclerosis Treated With Natalizumab

Natalizumab; Neurofilamento séricoNatalizumab; Neurofilament sèricNatalizumab; Serum NeurofilamentObjectives The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses. Methods NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations. Results Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses. Conclusions These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients. Classification of Evidence This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%

Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.This study was sponsored by EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany (in the United States), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (rest of the world)

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial

Background and Objectives. Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active. Methods. This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18–75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0–6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12–W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients. Results. A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of −0.097 (97% CI −0.192 to −0.002); p =0.0256. Safety was consistent with masitinib’s known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed. Discussion. Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data

Anti-SARS-CoV-2 vaccination in people with multiple sclerosis: Lessons learnt a year in.

It has been over a year since people with multiple sclerosis (pwMS) have been receiving vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With a negligible number of cases in which vaccination led to a relapse or new onset MS, experts around the world agree that the potential consequences of COVID-19 in pwMS by far outweigh the risks of vaccination. This article reviews the currently available types of anti-SARS-CoV-2 vaccines and the immune responses they elicit in pwMS treated with different DMTs. Findings to date highlight the importance of vaccine timing in relation to DMT dosing to maximize protection, and of encouraging pwMS to get booster doses when offered