Patients aged ≥ 35 years at multiple sclerosis (MS) symptom onset with an Expanded Disability Status Scale (EDSS) score ≥ 3 within the first year are at highest risk of developing aggressive MS (EDSS ≥ 6 within 10 years). Patients without these features are at lowest risk. This study aimed to evaluate whether high-efficacy disease-modifying therapy (HE-DMT) reduced the risk of relapse and disability accumulation in individuals at high risk of aggressive MS, and whether treatment benefit varied by MS severity. This observational cohort study used longitudinal data from two registries: MSBase (international) and OFSEP (France). Adults with relapse-onset MS and an EDSS score recorded within 12 months of symptom onset were included. Patients were classified into high-risk or low-risk groups for aggressive MS based on the above strata; those at intermediate risk were excluded. A pseudo-cohort framework compared periods of continuous HE-DMT (fingolimod, cladribine, monoclonal antibodies) with periods of non-HE-DMT states (on lower-efficacy DMTs or untreated) within each aggressive MS risk stratum. Marginal structural models with repeated adjustment for time-varying confounders of treatment and censoring were used to estimate counterfactual cumulative hazards of relapses and 6-month confirmed disability worsening and improvement. An interaction between MS risk stratum and treatment strategy was tested. A secondary analysis evaluated patients who received an HE-DMT during the study period. In total, 10,405 people (2021 high risk, 8384 low risk) were included. Continuous HE-DMT reduced the risk of relapse in both high-risk and low-risk groups. There was no evidence of a difference in disability outcomes between treatment approaches. There was no evidence of an interaction between aggressive MS risk and treatment effect. In stratified analyses, lowest relapse risk was observed in the low-risk group treated with HE-DMT (hazard ratio [HR] 0.75, 95

To report myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) epidemiology in two American regions using 2023 diagnostic criteria. We compared age- and sex-adjusted incidence and prevalence of MOGAD per 2023 diagnostic criteria in Olmsted County (Minnesota [USA]) and Martinique (Caribbean [FR]) (01/01/2003–12/31/2018, prevalence day) using Poisson regression. Archived sera in 68–85

BACKGROUND:Data on Escalation Therapy versus Early Intensive Therapy (EIT) Strategy in multiple sclerosis (MS) are lacking, particularly in Afro-Caribbean cases, known for their severity. OBJECTIVES:To assess efficacy and safety of these strategies in a predominantly Afro-Caribbean relapsing-remitting MS population. METHODS:A multicenter retrospective study of 195 MS patients, including 66 on EIT, with ≥2 years follow-up. PRIMARY OUTCOME:Kaplan-Meier curves and log-rank test were used to assess irreversible progression to EDSS scores of 3, 6, and 8. SECONDARY OUTCOMES:change in EDSS score, risk factors for EDSS progression, and severe adverse effects. RESULTS:EIT showed slower EDSS 3 progression than Escalation (median survival 13.5 vs. 9.8 years, p = 0.024). After a median follow-up of 8 years, 89.5% on EIT remained free from EDSS 3 versus 63.8% on Escalation. Univariate analysis linked Escalation (hazard ratio (HR; 95% CI): 2.42 [1.09-5.34]), age at first relapse (HR: 1.04 [1.01-1.06]), incomplete symptom regression (HR: 1.69 [1.02-2.77]), and EDSS 3 progression. EDSS stabilized or decreased with EIT but worsened with Escalation (p < 0.001). Safety profiles were similar. CONCLUSIONS:EIT extends median time to irreversible EDSS 3 in Afro-Caribbean individuals compared to Escalation, supporting its preference as initial treatment.

BACKGROUND:Real-world data suggest that the early use of highly active therapies (HAT) may reduce the risk of transition to secondary progressive MS (SPMS). However, current knowledge about predictive factors of outcomes needs to be improved. The primary objective of this study was to determine factors associated with the occurrence of SPMS in patients treated early after MS onset with an HAT. METHODS:Retrospective, multicentric study based on the French MS database. Patients who initiated a HAT within 5 years after MS onset, EDSS ⩽4, and had a follow-up >5 years were included. The association of each covariate at baseline with time to the occurrence of SPMS was quantified by hazard ratios (HRs) in unadjusted and adjusted Cox proportional hazards models. RESULTS:Two thousand two hundred and thirty-seven patients were included in the analysis: mean age 31.6 years, female/male sex ratio 2.3, and median EDSS 2.0. The estimated probability of reaching SPMS, progression independent of relapse activity (PIRA) and progression independent of activity (PIA) at 10 years was 8%, 22%, and 11%, respectively. After adjustment, we found that female patients (HR 0.64, p = 0.036) had a lower risk of developing SPMS. Older age, EDSS >0 (HR 7.44, p < 0.001), and oral versus intravenous HAT (HR 1.97, p = 0.003) were significantly associated with an increased SPMS risk. Early PIRA and PIA predicted conversion to SPMS. CONCLUSIONS:Early HAT use resulted in a low risk of developing SPMS over 10 years. Introducing the HAT before any residual disability was associated with a lower risk of progression.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, setting, and participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Fran & ccedil;ais de la Scl & eacute;rose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main outcomes and measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Introduction Dans les pathologies du spectre de la neuromyélite optique (NMOSD), la prévention de nouvelles poussées inflammatoires est fondamentale. Les nouvelles molécules efficaces dans la maladie sont souvent coûteuses, voire indisponibles dans certaines régions. Objectifs Évaluer l’efficacité et la sécurité d’alternatives thérapeutiques plus accessibles est une nécessité. Notre objectif était d’évaluer l’efficacité et la tolérance de la mitoxantrone (MiTX) dans la NMOSD. Méthodes Étude multicentrique comportant 86 NMOSD traités par MiTX au cours d’un suivi prospectif. Le critère de jugement principal était la survenue d’une rechute avant 96 semaines après introduction de MiTX. Les critères de jugement secondaires portaient sur le délai de rechute, l’évolution du taux de poussée (ARR) et de l’Expanded Disability Status Scale (EDSS) à 96 semaines, sur la recherche de facteurs de risque, et la survenue d’effets indésirables. Résultats À 96 semaines, 71 % des patients étaient indemnes de rechute. L’ARR moyen était passé de 0,85 à 0,32 (61 %), l’EDSS moyen de 4,9 à 4,2 (−0,71). Un délai d’introduction de la MiTX supérieur à 24 mois après la première poussée (HR 2,76), un statut anti-AQP4+(HR 12,3), et un ARR prétraitement 3 1 (HR 2,38) étaient des facteurs de risque de rechute. Trois effets indésirables graves (3,5 %) sont survenus (Fig. 1 et Fig. 2). Discussion Cette étude est la plus vaste cohorte multicentrique prospective de patients NMOSD traités par MiTX, incluant des patients NMOSD double-séronégatifs et des patient MOG+. L’efficacité et la tolérance de la MiTX semblent comparables à celles des autres molécules actuellement utilisées dans la NMOSD pour un coût 10 à 100 fois moindre et une accessibilité nettement meilleure à l’échelle mondiale. Conclusion La MiTX est un traitement efficace et sûr dans la NMOSD, peu coûteuse et très accessible, qui pourrait être une alternative thérapeutique dans des zones géographiques d’accès aux soins limité.

Background and Objectives Preventing relapses in neuromyelitis Optica spectrum disorder (NMOSD) is a primary goal. New effective molecules are often expensive and not readily available in regions with fragile health systems. Assessing the efficacy and safety of less costly therapeutic alternatives is necessary. We aim to evaluate the efficacy and safety of mitoxantrone (MiTX) in NMOSD. Methods This is an observational, multicenter, open study of 86 NMOSD-treated patients with prospective follow-up over 30 years. The first endpoint was the first relapse at the 96-week follow-up. The secondary endpoints were to evaluate the median delay to relapse, the annualized relapse rate (ARR), and the Expanded Disability Status Scale (EDSS) at 96 weeks of follow-up and to assess risk factors of relapse and the occurrence of severe adverse effects. Results At 96-week follow-up, 71% of our patients were relapse-free, and it was 87% when patients were treated with MiTX from the first attack. The ARR dropped from 0.85 (+/- 0.55) to 0.32 (+/- 0.63) (p < 0.001) and EDSS from 4.9 (+/- 2.4) to 4.2 (+/- 2.6) (p < 0.001). AQP4-IgG seropositivity (hazard ratio [HR] 12.3, 95% CI 1.64-91.6, p = 0.015), a delay between the first attack and MiTX >= 24 months (HR 2.76, 95% CI 1.23-6.17, p = 0.014), and a pretreatment ARR >= 1 (HR 2.38, 95% CI 1.05-5.39, p = 0.037) were predictors of relapse. During the entire follow-up, severe secondary adverse events occurred in 3 patients (3.5%). Discussion MiTX is an effective and safe treatment for most of our patients, drastically less expensive than new molecules, and could be allowed in NMOSD Afro-descendant patients in geographical areas where access to care is difficult.

Importance:Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development. Objective:To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI). Design, Setting, and Participants:This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection. Exposures:Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise. Main Outcomes and Measures:Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated. Results:Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs. Conclusions and Relevance:The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.

To evaluate and compare the performance of the 2023 and the 2009 adult criteria for the radiologically isolated syndrome (RIS) as predictors of a first clinical neurological event in children with RIS.

Introduction Deux stratégies thérapeutiques coexistent dans la sclérose en plaques (SEP) : l’escalade et l’induction. Cette dernière semble démontrer une efficacité supérieure, avec des données toutefois limitées à la population caucasienne. Objectifs L’objectif était de comparer l’efficacité et la tolérance entre les deux stratégies thérapeutiques, dans la population Afro-Caribéenne qui présente des formes plus sévères de SEP. Méthodes Étude rétrospective multicentrique sur 195 patients traités pour une SEP dont 66 en stratégie d’induction, suivis pendant au moins deux ans. Le critère de jugement principal était le franchissement irréversible de l’Expanded Disability Status Scale (EDSS) 3, 6 et 8 sous traitement. Les critères de jugement secondaires portaient sur l’évolution du score EDSS sous traitement, la détermination d’éventuels facteurs de risque du franchissement de l’EDSS, et la survenue d’Evènements Indésirables Graves (EIG). Résultats Le franchissement irréversible de l’EDSS 3 était retardé avec l’Induction vs Escalade (médiane de survie 13,5 ans vs 9,8, p=0,024). L’Escalade favorisait ce franchissement en analyse univariée (HR 2.42, 95 % CI [1.09–5.34], p=0,029). L’EDSS était stabilisé voire diminuait avec l’induction (0, IQR [−2–0], p<0,001). La survenue d’EIG était superposable entre les deux stratégies (Fig. 1 et Fig. 2). Discussion Ces résultats montrent une modification de l’histoire de la maladie dans la population Afro-Caribéenne avec l’induction par rapport à l’escalade (80 % de patients n’ayant pas franchi l’EDSS 3 à 13 ans d’évolution vs 40 % dans le groupe escalade), notamment avec son utilisation précoce, confortant les données retrouvées dans la population caucasienne. Conclusion Dans la population Afro-Caribéenne, la stratégie d’induction semble plus efficace que l’escalade, avec un profil de sécurité acceptable. Notre travail est en faveur de son utilisation précoce et en première intention dans cette population.

To compare the efficacy and safety of the two therapeutic strategies in this population.

Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher’s exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). We included 103 children with RIS (67

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 Francais de la Sclerose 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.

Abstract Early administration of plasma exchanges (PE) combined with intravenous methylprednisolone (IVMP) is considered the best treatment for neuromyelitis optica spectrum disorder (NMOSD) attack. However, up to 20% of patients fail to respond, suggesting the existence of idiosyncratic factors yet to be understood. We report cases of two women who suffered devastating Aquaporin-4 immunoglobulin G-positive (AQP4-IgG+) NMOSD attacks, worsening despite optimal treatment up to life-threatening, for which eculizumab was successfully administrated as a rescue therapy. The first case describes a fulminant onset of the disease with pan-medullary and bulbar lesions leading to tetraplegia and respiratory failure within a few days, directly refractory to PE/IVMP. The second case described the 4th attack within two years of an aggressive disease, currently treated with mycophenolate mofetil, with early post-mitoxantrone relapse. For both patients, acute administration of eculizumab immediately after usual treatment failure seemed to have rapidly aborted the inflammatory cascade, saving them from imminent death. In addition to its proven efficacy in preventing relapses in AQP4-IgG + NMOSD, eculizumab could also rapidly stop an attack before the installation of irreversible lesions or death. This raises therapeutic issues relative to the management of such complement inhibitor treatment as rescue therapy, and questions about pathophysiological mechanisms of resistance to PE.

•There was no significant difference between population from Europe and population from Caribbean Sea across almost all demographic criteria, no effect of migration was observed in those two region of France•There was no significant difference on MSSS between the two French MS populations, one living in the Caribbean Sea and the other in Europe.•This study is the first comparing two region of France that highlights a sufficiently strong care system across France, allowing to absorb environmental and medical/paramedical demographic disparities for low EDSS patients.