Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP)

International audienceSummaryBackground High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration. Methods We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18–55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov, number NCT00984984. Findings Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0·5%, 90% CI −9·5 to 10·4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 [77%]) than in the intravenous group (63 [64%]). Interpretation Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month after treatment and had a similar safety profile. This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians. Funding French Health Ministry, Ligue Française contre la SEP, Tev

Natalizumab alters the TCR repertoire after one year of treatment in four MS patients

International audiencen.

No lack of regulatory B cells in patients with Multiple Sclerosis

International audienc

JAMA Neurol

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus.Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity.Design, setting, and participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.Exposure: HET or MET at treatment initiation.Main outcomes and measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).Conclusions and relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.Observatoire Français de la Sclérose en Plaque

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR&nbsp;=&nbsp;2.05, 95%CI&nbsp;=&nbsp;1.39–3.02, p&nbsp;&lt;&nbsp;0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR&nbsp;=&nbsp;0.42, 95%CI&nbsp;=&nbsp;0.18–0.99, p&nbsp;=&nbsp;0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Prise en charge de la maladie de Creutzfeldt-Jakob sporadique (au CHR de Nantes)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Retentissement des stimulations ovariennes sur le taux de poussée au cours de la Sclérose en plaques

La Sclérose en Plaques est une maladie inflammatoire et démyélinisante du système nerveux central, probablement d'origine auto-immune, et atteignant préférentiellement la femme en âge de procréer. Il existe d'étroites relations entre les hormones sexuelles et le système immunitaire. La variation du taux de ces hormones peut avoir des conséquences sur l'activité clinique de la maladie, comme, par exemple, au cours de la grossesse. Nous avons donc étudié l'impact sur la maladie des traitements de stimulations ovariennes et des différents protocoles utilisés dans le cadre des fécondations in-vitro. Cinq patientes ont pu être retrouvées et, chez quatre d'entre elles, le taux de poussée de SEP semblait plus élevé au cours des trois mois suivants la FIV par rapport aux 3 mois la précédant et à deux périodes contrôle de 3 mois. Les patientes concernées avaient bénéficié d'un traitement par agoniste du GnRH, hormone ayant une activité potentiellement stimulante du système immunitaire. D'autres études, portant sur des nombres plus importants de malades seront nécessaires pour conclure plus aisément sur le retentissement des ces traitements sur l'activité de la sclérose en plaques.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells

International audienceBackground and Objectives: Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide. Methods: High-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles. Results: We found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFaand IFNg. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism. Discussion: Overall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS

Optic neuritis classification in 2021

International audienceOptic neuritis (ON) can be associated with inflammatory disease of the central nervous system or can be isolated, with or without relapse. It can also be associated with infectious or systemic disease. These multiple associations based on a variety of clinical, radiological, and biological criteria that have changed over time have led to overlapping phenotypes: a single ON case can be classified in several ways simultaneously or over time. As early, intensive treatment is often required, its diagnosis should be rapid and precise. In this review, we present the current state of knowledge about diagnostic criteria for ON aetiologies in adults and children, we discuss overlapping phenotypes, and we propose a homogeneous classification scheme. Even if distinctions between typical and atypical ON are relevant, their phenotypes are largely overlapping, and clinical criteria are neither sensitive enough, nor specific enough, to assure a diagnosis. For initial cases of ON, clinicians should perform contrast enhanced MRI of the brain and orbits, cerebral spinal fluid analysis, and biological analyses to exclude secondary infectious or inflammatory ON. Systematic screening for MOG-IgG and AQP4-IgG IgG is recommended in children but is still a matter of debate in adults. Early recognition of neuromyelitis optica spectrum disorder, MOG-IgG-associated disorder, and chronic relapsing idiopathic optic neuritis is required, as these diagnoses require therapies for relapse prevention that are different from those used to treat multiple sclerosis

Cumulative effects of therapies on disability in relapsing multiple sclerosis

International audienceBACKGROUND: Long-term effectiveness of treatment remains a key question in multiple sclerosis (MS) and the cumulative effects of past treatment have not been investigated so far. OBJECTIVE: Explore the relationship between treatment exposure and disability risk in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A total of 2285 adult patients from the French nationwide cohort were included. Outcomes were irreversible EDSS4, and conversion to secondary progression of multiple sclerosis (SPMS). Associations between treatments and risk of disability were assessed using a novel weighted cumulative exposure model, assuming a 3-year lag to account for reverse causality. This flexible approach accounts for past exposure in a multivariate Cox proportional hazards model by computing a weight function. RESULTS: At baseline, mean ± standard deviation age of patients was 33.4 ± 8.9 years and 75.0% were women. A 15-year continuous treatment starting 20 years ago was associated with a decrease in risk of 26% for irreversible EDSS4, and 34% for SPMS compared to a 5-year treatment starting 10 years ago. The risk of disability decreased with increasing duration of exposure to disease-modifying treatment (DMT). CONCLUSION: Long-term use of treatments in RRMS has a stronger beneficial cumulative impact than only early uses and delays the occurrence of moderate disability and conversion to SPMS