OBJECTIVE:To determine whether discontinuing anti-CD20 therapy in people with relapsing-onset MS aged over 50 is associated with an increased risk of relapse, inflammatory activity, confirmed disability accrual, and serious infection compared with continuing therapy. METHODS:This observational, multicenter, retrospective cohort study included 2283 patients from the French MS registry aged > 50, who had received at least two cycles of anti-CD20 and had experienced no relapses or MRI activity for at least one year prior to inclusion. Patients were classified as discontinuing or continuing therapy and 1:1 matched using a time-dependent propensity score. Outcomes were time to first relapse, inflammatory activity (relapse and/or MRI activity), confirmed disability accrual, and serious infection. RESULTS:Among 1900 patients continuing therapy and 383 discontinuing, 224 in each group were matched (mean age = 57.7 ± 5.9 years; mean EDSS = 5.4 ± 1.7; median follow-up after matching = 34.8 [21.6-50.4] months). There were no significant differences between groups in time to first relapse (HR = 0.6, 95% CI 0.3-1.3, p = 0.2), inflammatory activity (HR = 0.9, 95% CI 0.5-1.4, p = 0.6), confirmed disability accrual (HR = 1.2, 95% CI 0.9-1.7, p = 0.2), and serious infections (HR = 1.0, 95% CI 0.6-1.8, p = 0.9). INTERPRETATION:This retrospective study found no evidence of differences between stopping and continuing anti-CD20 therapy regarding relapse, inflammatory activity, disability accrual, or serious infections in older patients with long-standing non-active MS over a median 2.9-year follow-up.

Myasthenia gravis, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are antibody-mediated neuroimmune disorders that frequently affect women in their reproductive years and require careful treatment planning around pregnancy. Disease exacerbations (for myasthenia gravis) and attacks (for NMOSD and MOGAD) can occur during pregnancy, are common postpartum, and can cause preventable, long-term maternal disability. Many drug labels are conservative or recommend unnecessary prolonged washouts or avoidance of breastfeeding, creating uncertainty for physicians and patients. This Personal View integrates available evidence on conventional immunosuppressants and biological therapies, including complement inhibition, B-cell depletion, and neonatal Fc receptor blockade. Although data on pregnancy safety for newer treatments are few, preliminary data suggest that selected therapies could be continued during pregnancy to maintain disease stability and are compatible with breastfeeding. We offer expert recommendations for therapy choice, infant vaccinations, and fetal and infant monitoring in myasthenia gravis, NMOSD, and MOGAD.

BACKGROUND AND OBJECTIVES:The therapeutic strategy for late-onset multiple sclerosis (LOMS) with a relapsing-remitting onset remains unclear, potentially leading to underexposure to disease-modifying therapies (DMTs) compared with adult-onset multiple sclerosis (AOMS). We investigated the differences in DMT use between LOMS and AOMS within the French MS registry at comparable levels of disease severity. METHODS:This retrospective cohort study used data extracted in December 2024 from the French MS registry on patients with relapsing-remitting onset MS between 1997 and 2023. The primary outcome was the annual probability of receiving a DMT according to age at MS onset, adjusted for disease severity. Secondary outcomes included the annual probability of receiving a highly effective DMT (HEDMT), each DMT separately, having ≥1 EDSS measurement, having ≥1 brain MRI, and DMT initiations and discontinuations. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. RESULTS:A total of 36,148 were included patients; 26,540 (73.4%) were female, mean age was 33.5 years (SD, 9.7), and 2,308 (6.4%) were aged ≥50 at disease onset. Median follow-up was 10.8 years (interquartile range, 5.6-17.0). Patients with LOMS had a lower annual probability of receiving a DMT compared with patients with AOMS (73.7% vs 83.1%; odds ratio [OR], 0.57 [95% CI 0.52-0.62]). The difference was greater for HEDMT (24.6% vs 44.4%; OR, 0.41 [95% CI 0.36-0.46]). Patients with LOMS were more likely to receive teriflunomide and less likely to receive fumarates, S1PR modulators, natalizumab, or anti-CD20. Clinical and radiologic follow-up did not differ significantly between patients with LOMS and AOMS. The rate of DMT initiation was lower in patients with LOMS (0.13 vs 0.17 initiation per patient-year). Although the proportions of DMT discontinuation were similar (59.7% vs 60.4%, excluding pregnancy-related discontinuations), these discontinuations were more often attributed to a complete discontinuation strategy (27.9% vs 22.3%) and less often to an escalation strategy (9.2% vs 13.8%) in patients with LOMS. DISCUSSION:At comparable levels of disease severity, patients with LOMS were less likely to be treated with DMTs, particularly HEDMT, than patients with AOMS. This gap was driven both by fewer DMT initiations and more frequent complete discontinuations.

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

BACKGROUND:Early initiation of high-efficacy therapies (HETs) has been associated with improved disease control in pediatric-onset multiple sclerosis (POMS). However, some children remain clinically stable on low-/moderate-efficacy therapies (METs), highlighting the need for decision-support tools. OBJECTIVE:To develop a Therapeutic Escalation Score (TES) to identify children at low risk of early escalation after initiating MET. METHODS:We analyzed treatment-naïve children with POMS who initiated MET between 2010 and 2024 in the French MS registry (Observatoire Français de la Sclérose en Plaques (OFSEP)). TES was derived using Cox regression modeling based on baseline clinical and magnetic resonance imaging (MRI) variables, with internal validation in OFSEP and external validation in the Italian MS registry Registro Italiano Sclerosi Multipla (RISM). RESULTS:We included 455 children from OFSEP (training n = 303; validation n = 152) and 573 from RISM. TES incorporated age, year of treatment initiation, Expanded Disability Status Scale score, prior-year relapses, brain lesion location, and T2 spinal cord lesions. A TES threshold of 1.34 stratified patients by 1-year escalation risk. In OFSEP, low-risk patients had a 1-year escalation probability of 3.6% (negative predictive value: 97.0%). In RISM, discrimination was similar (area under the curve (AUC): 72.8%-73.8%). CONCLUSION:TES is a baseline-only prognostic tool using routine clinical and MRI data to identify children with POMS unlikely to require early escalation after MET initiation.

BACKGROUND:Ocrelizumab, a monoclonal antibody targeting CD20+ B cells, is a high-efficacy therapy for multiple sclerosis (MS). METHODS:Patients with relapse-onset MS treated with ocrelizumab, fingolimod, natalizumab or alemtuzumab for ≥6 months were identified from three registries: MSBase, OFSEP and Danish MS Registry. Pairwise comparisons were performed in the overall cohort and 14 predefined clinicodemographic subgroups based on sex, disease activity, MS duration, Expanded Disability Status Scale, prior therapy and reason for prior treatment cessation. Relapses, progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) were compared in pairwise-censored groups. RESULTS:Fingolimod was associated with a higher annualised relapse rate (ARR) (0.14 vs 0.06, p<0.001), relapse risk (HR 2.26, 95% CI 1.98 to 2.58), RAW (1.62, 1.08 to 2.43) and lower risk of disability improvement (0.78, 0.63 to 0.96) than ocrelizumab. Superiority of ocrelizumab over fingolimod on relapses was maintained in all subgroups. Natalizumab was associated with marginally higher ARR (0.10 vs 0.07, p<0.001), relapse risk (1.35, 1.16 to 1.57) and RAW (1.77, 1.07 to 2.94) than ocrelizumab. Alemtuzumab was associated with higher ARR (0.18 vs 0.12, p<0.001) and relapse risk (1.48, 1.25 to 1.76) than ocrelizumab, but there was no evidence for a difference in risk of RAW. There was no evidence for a difference on PIRA in any comparisons. Ocrelizumab was superior to natalizumab and alemtuzumab on relapses in patients who were not treatment-naïve, experienced disease activity on the prior therapy or stopped prior therapy due to lack of efficacy. CONCLUSIONS:Ocrelizumab provides superior control of relapses and RAW, especially among patients with prior on-treatment disease activity. Treatment of PIRA remains an unmet need.

Introduction Ofatumumab est un traitement de haute efficacité dans les SEP-RR actives. Son utilisation depuis sa commercialisation en France en septembre 2021 est peu documentée. Objectifs Les objectifs de cette étude observationnelle, longitudinale et multicentrique étaient de décrire les caractéristiques des patients ayant initié ofatumumab, la persistance à 2 ans et les motifs d’arrêt du traitement. Méthodes Cette analyse intermédiaire est basée sur l’utilisation des données des patients ayant initié ofatumumab en 2021 et 2022 et suivis dans les centres du réseau OFSEP. Une analyse descriptive des caractéristiques des patients à l’initiation d’OFA, de la persistance au traitement (méthode de Kaplan-Meier) et des raisons d’arrêts a été réalisée. Les sous-populations suivantes ont aussi été analysées : naïfs de traitement de fond (TdF), 1 TdF antérieur et au moins 2 TdF. Résultats Au total, 673 patients ont été inclus (âge moyen 39,3 ans). Parmi eux, 31,1 % étaient naïfs (N=209, âge moyen 36 ans), 27,5 % avaient initié après 1 TdF (N=185, 38 ans) et 41,5 % après ≥ 2 TdF (N=279, 42,8 ans). La persistance était de 93,9 % à 1 an et 87,3 % à 2 ans. Elle atteignait 90 % chez les naïfs à 2 ans, 87,9 % si initiation après 1 TdF et 84,3 % après ≥ 2 TdF. Discussion Les résultats sur la persistance à l’ofatumumab à 2 ans reflètent la forte adhésion des patients au traitement. Les arrêts étaient rares, concernant 71 patients (25 pour intolérance (3,7 %), 15 pour grossesse, 8 pour convenance personnelle, seulement 6 (0,9 %) pour inefficacité), confirmant la bonne tolérance d’ofatumumab en vraie vie, ce qui a déjà été rapporté dans d’autres pays. Conclusion Ces données montrent que le traitement présente une forte persistance, notamment en 1ère intention, ce qui avec son efficacité en fait une option privilégiée. Cela devrait être confirmé par l’analyse de données plus récentes à venir.

BACKGROUND:The revised McDonald criteria shifted toward the recognition of the radiologically isolated syndrome (RIS) as the first phase of the multiple sclerosis (MS) spectrum. OBJECTIVES:To characterize differences between RIS individuals, early MS patients, and healthy controls (HCs) using a high-precision clinical assessment tool based on digital technology. METHODS:We performed a multicentric, cross-sectional study involving RIS, early MS patients, and HC. Subjects were assessed using Neuraccure, an iPad application capable of detecting subtle abnormalities in four neurological functions: hand coordination, low-contrast vision, reaction time, and eye movements. RESULTS:In total, 565 individuals were included (MS: 255, RIS: 146, HC: 164). HC performed better than RIS and MS across all digital measures (p < 0.0001 to 0.03). There was no statistical difference between RIS and MS patients, except for the coordination test, which was slightly worse in MS patients (p = 0.03). The receiver operating characteristic (ROC) analysis indicated that the presence of at least two impaired functions could detect RIS and MS from HC with 83.2% sensitivity and 84.3% specificity. A higher number of impaired functions were associated with lower brain magnetic resonance imaging (MRI) volumes. CONCLUSION:High-precision neurological evaluation can distinguish HC from RIS and MS at an individual scale with a good performance.

Background Multiple sclerosis (MS) is a frequent neurological condition affecting young adults with acute disabling neurological episodes (relapses). MS relapses are not recorded in claims databases despite their importance for (pharmaco)epidemiological studies. This study aimed to validate and improve an algorithm identifying relapses in relapsing-remitting MS initiating disease-modifying therapy (DMT) within the French nationwide claims database (SNDS). Methods Clinical data from the French MS registry (OFSEP) linked to the SNDS were used. The cohort included MS patients with a first DMT claim between July 2015 and December 2017, naive to any MS treatment, followed until December 2018 (n=1,640). The initial relapse algorithm combined high-dose corticosteroid prescriptions and hospitalization duration. Incidence of the first relapse identified in the SNDS was compared with OFSEP confirmed relapses that have been treated by corticosteroid or hospitalized (gold standard). Performances were estimated using Sensitivity, Specificity, PPV, NPV. Algorithm were reevaluated after revision of its criteria based on experts’ review of false positive and negative cases’ claims, and finally after adding non-naive MS patients (n=9,966). Results The performances of the initial algorithm were Specificity 85.2%, Sensitivity 74.0%, NPV 89.8%, PPV 65.3%. After revision of corticosteroid dosages and hospitalization durations thresholds, performance slightly improved: 85.0%, 75.4%, 90.2%, 65.3%, respectively. When considering naive and non-naive MS patients, Sensitivity and NPV stayed similar (75.1% and 91.6%) while Specificity and PPV decreased (81.8% and 55.4%). Conclusion The final algorithm of treated/hospitalized relapses can be applied accurately in naïve MS patients initiating a DMT, in the SNDS and likely in other claims databases after adapting to each country’s reimbursement and care practices.

Introduction L’évolution récente de la prise en charge des patients SEP avec l’avènement des traitements de haute efficacité justifie l’analyse des données de vie réelle pour décrire l’ajustement de la stratégie thérapeutique et du suivi des patients en France. Objectifs Cette étude vise à décrire l’évolution de la stratégie thérapeutique chez des patients avec un diagnostic de SEP identifié pour la première fois dans le SNDS entre 2016 et 2023 et leur suivi IRM dans les deux ans suivant l’initiation du premier traitement. Méthodes Les patients SEP âgés de 18 à 45 ans ont été identifiés sur la 1re date parmi : hospitalisation pour SEP, début d’affection de longue durée ou délivrance d’un traitement de fond (TdF) spécifique. Un clustering des patients sous TdF (n=23105) a été réalisé à partir du mode d’exercice des prescripteurs et 3 sous-groupes d’analyse ont été définis : suivi principalement en centre hospitalier général (CHG), en centre expert ou en libéral. Résultats Au total, 30 444 patients ont été identifiés. L’utilisation des traitements plateforme en 1re intention est passée de 65,6 % en 2016–2018 à 42,0 % en 2022–2023, et celle des anti-CD20 de 1,3 % à 24,4 %. Du fait du risque infectieux sous anti-CD20, les dispensations d’antibiotiques systémiques ont été analysées dans ce sous-groupe (n= 7 296) rapportant que cela concernait, dans les 2 ans suivant l’initiation du traitement, 38,8 % et 53,7 % des patients sous ofatumumab et ocrélizumab respectivement. Parmi les 14 707 patients toujours traités à 2 ans, 83,4 % ont bénéficié d’au moins 1 IRM la 1re année (CHG : 85,1 %, centres experts : 86,3 %, libéral : 76,4 %) et 95,6 % sur 2 ans (96,6 %, 96,8 % et 93,1 % respectivement). Discussion L’étude suggère une évolution de la prise en charge initiale de la SEP en France de 2016 à 2023, avec une diminution d’utilisation des traitements plateforme au profit des anti-CD20 en 1re intention. L’analyse rapporte aussi que l’utilisation de traitements concomitants est différente au sein de la classe des anti-CD20. Enfin, la grande majorité des patients bénéficie d’un suivi IRM dans les 2 ans suivant l’instauration d’un traitement. Conclusion L’étude illustre l’essor des anti-CD20 en 1re intention dans la SEP en France, en accord avec les données scientifiques encourageant l’instauration précoce de traitements hautement efficaces.

BACKGROUND:Ofatumumab and ocrelizumab are widely used high-efficacy anti-CD20 therapies for relapsing-remitting multiple sclerosis (RRMS), but direct comparative evidence remains limited. We aimed to compare their effectiveness in routine clinical practice. METHODS:We conducted an observational cohort study emulating a target trial using data from the MSBase and Observatoire Français de la Sclérose en Plaques registries (January 2021 to December 2024). Adults with RRMS initiating ofatumumab or ocrelizumab were included. Patients were matched 1:1 using propensity scores. Primary outcomes were annualised relapse rate (ARR) and time to first relapse. Secondary outcomes included time to confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), MRI activity and treatment discontinuation. Negative binomial and Cox regression models were applied. RESULTS:A total of 5288 patients were matched with a median follow-up of 1.2 years for ofatumumab and 1.4 years for ocrelizumab. ARR was 0.07 (95% CI 0.05 to 0.08) with ofatumumab and 0.04 (0.03 to 0.05) with ocrelizumab, corresponding to an ARR ratio of 1.75 (1.43 to 2.13). Ofatumumab was associated with a lower risk of CDP (HR 0.66; 0.49 to 0.87) and PIRA (0.53; 0.39 to 0.73), but a lower probability of CDI (0.76; 0.60 to 0.96). No significant differences were observed in MRI activity or treatment discontinuation. CONCLUSIONS:Both therapies were highly effective in a large cohort of patients with RRMS, with very low relapse or CDP rates. Ofatumumab was associated with slightly greater disability control, while ocrelizumab more effectively suppressed relapses. These differences were modest, and their clinical relevance requires further evidence and should be interpreted with caution.

BACKGROUND AND OBJECTIVES:Children with multiple sclerosis (MS) are increasingly treated with high-efficacy monoclonal antibody therapies; however, treatment approaches vary widely, largely because of regulatory restrictions that often delay access until adulthood. We hypothesized that initiating these therapies during childhood confers greater benefits than their initiation in adulthood. This study, therefore, evaluated long-term disability in patients with pediatric-onset MS treated with monoclonal antibodies before age 18 compared with those who initiated these therapies in adulthood. METHODS:In this retrospective cohort study, patients younger than 18 years at the onset of MS symptoms were identified across 3 MS registries: MSBase, Observatoire Français de la Sclérose en Plaques, and the Italian MS Register. We categorized patients who commenced natalizumab, ocrelizumab, or rituximab between ages 12 and 17 into the pediatric high-efficacy therapy (HET) initiation group and those who began treatment between ages 20 and 22 into the adult HET initiation group. A landmark study design was used, with age 18 designated as the baseline and the outcome period spanning ages 23-27 years. The primary outcome was the change in Expanded Disability Status Scale (EDSS) scores, evaluated using a Bayesian weighted generalized linear mixed model. RESULTS:We included 277 patients (72% female), with a mean (SD) age at onset of MS symptoms of 14.97 (2.23) years. Of these, 108 initiated HET during childhood and 169 during adulthood. The postbaseline increase in EDSS scores was 0.53 steps lower in the pediatric HET initiation group compared with the adult group (β -0.53 [95% credible interval -0.87 to -0.19]). This benefit of pediatric HET initiation was most pronounced within the EDSS range of 4.5-6.0, with up to a 97% reduction in the odds of further disability worsening (odds ratio of EDSS score 5.0 over 4.5: 0.03 [95% credible interval 0.003-0.22]). DISCUSSION:Commencing high-efficacy monoclonal antibody therapy in childhood is associated with more favorable long-term disability outcomes than delayed initiation in adulthood. Early use of highly effective therapy is crucial for preserving neurologic function in children with MS. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that, in children aged 12-17 years with MS, initiating therapy with monoclonal antibodies before age 18 (vs 20-22) is associated with less disability accrual between the ages of 23 and 27.

The impact of high-efficacy therapies (HET) on progression independent of relapse and MRI activity (PIRMA) remains poorly defined. In this context, using the French MS registry, we aimed to assess the real-life effectiveness of HET compared with moderate-efficacy therapies (MET) on PIRMA in patients with relapsing-onset multiple sclerosis. Data were collected from patients with relapsing-onset multiple sclerosis of the French MS registry, between January 2010 and June 2023, with a mean follow-up of 3.7 years. Patients with relapsing-onset multiple sclerosis were included in the analysis if they were treated first with HET (2666 included) or MET (7833 included) and had expanded disability status scale and MRI follow-up every 2 years. Each outcome was studied using a propensity score framework. The primary outcome was time to first PIRMA. Secondary outcomes were PIRMA incidence, time to first confirmed disability progression, relapse-associated worsening (RAW), MRI-associated worsening (MAW) and identification of risk factors associated with PIRMA. A total of 10 499 patients fulfilled the inclusion criteria. The mean and standard deviation (SD) age at treatment initiation was 36.4 (10.3) years, with a mean (SD) disease duration of 3.1 (5.1) years. The restricted mean (SD) survival time to first PIRMA was slightly, but significantly shorter in the HET group compared with the MET group [8.7 (0.08) versus 8.9 (0.05) years, P = 0.017]. However, when looking at time to first confirmed disability progression, it tend to be longer in the HET group compared with the MET group [7.6 (0.10) versus 7.3 (0.06) years, P = 0.071], and it was probably linked to the shorter time to first RAW and MAW in the MET group [9.2 (0.06) versus 8.7 (0.05) years, P < 0.001 for RAW; and 9.0 (0.05) versus 8.5 (0.07) years, P < 0.001 for MAW]. Baseline risk factors associated with increased PIRMA incidence in the whole population were high expanded disability status scale, higher age at baseline and the presence of spinal cord lesions. Even if HET gives better control on disability accumulation related to disease activity than MET, our real-life study suggests that PIRMA-related mechanisms are not differentially affected by HET versus MET.

Ocrelizumab is an anti-CD20 monoclonal antibody that is highly effective in multiple sclerosis (MS) but is associated with an increased risk of opportunistic infections that may be difficult to diagnose. We report three MS patients treated with ocrelizumab who developed severe meningoradiculitis. Routine investigations failed to identify any pathogen, whereas metatranscriptomic analysis of cerebrospinal fluid (CSF) detected Borrelia miyamotoi RNA. All patients improved after appropriate antibiotic therapy. B. miyamotoi should be considered in anti-CD20-treated MS patients presenting with meningoradiculitis, and CSF metatranscriptomics should be used to investigate undiagnosed central or peripheral nervous system infections, particularly in immunocompromised individuals. Ocrelizumab is a highly effective treatment widely used in MS but has been associated with an increased risk of infection. We report three cases of B. miyamotoi infections in patients receiving ocrelizumab in which routine laboratory tests failed to detect the pathogen.

Objectives The "Projections In Multiple Sclerosis" (PRIMUS) project aims to develop a precision medicine platform enabling neurologists to support therapeutic decisions in multiple sclerosis by visualizing similar patient data in a reference database. We present a data integration method to combine randomized clinical trials (RCTs) and observational studies data and optimize the informativeness of the resulting database. Material and Methods We developed an extract-transform-load data integration pipeline to combine 13 source databases: the "mother" and "high-definition" cohorts from the French MS registry and 11 industrial RCTs (31 786 patients). We aimed to inform each treatment class initiation with at least 500 patients with a 2-year clinical and MRI follow-up. Our data integration strategy used every patient visit as a potential baseline time point to inform a specific neurologist' query to the platform, thus tailoring the actual analysis cohort to each visiting patient. Results The PRIMUS database had 12 953 patients with at least one informative visit, using the per-visit integration. It could inform treatment initiation scenarios with at least 485 patients for glatiramer acetate and at most 1754 for natalizumab. For instance, our per-visit integration method identified 1306 patients in the high-definition cohort against 610 with the classical epidemiological per-patient integration. Although the mother cohort's longitudinal data were deemed sparse, we identified 6128 informative patients. Discussion Neurologists would query the PRIMUS database through a web application to support discussions with their patients and the selection of disease-modifying treatments.Conclusion Our data integration pipeline enabled the creation of a highly informative reference database.

BackgroundTarget trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data. METHODS:This multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment. RESULTS:14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions. CONCLUSION:The combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS.

Introduction Les troubles urinaires sont fréquents dans la sclérose en plaques (SEP), altèrent la qualité de vie et augmentent le risque de complications en cas de prise en charge insuffisante. Objectifs Décrire, à l’échelle nationale, la prise en charge des troubles urinaires chez les personnes atteintes de SEP à partir des données du Système National des Données de Santé. Méthodes Étude rétrospective incluant les patients SEP identifiés dans le SNDS entre 2005 et 2020 selon le statut ALD, les hospitalisations (G35) ou les traitements de fond. La prise en charge urinaire incluait examens urinaires, traitements pharmacologiques, dispositifs médicaux, interventions invasives et chirurgie urologique. Deux périodes ont été analysées : période historique 2013–2020 et période de suivi 2021–2022. Les patients étaient classés en cinq niveaux de prise en charge. Résultats Au total, 127 987 patients SEP ont été inclus. Une évaluation urinaire a concerné 26,6 % des patients, incluant 24,2 % d’échographies et 7,9 % de bilans urodynamiques. 8,9 % des patients ont été hospitalisés pour motif urinaires. Un traitement a été délivré chez 29,8 % : non invasif 26,7 %, invasif 10,2 % et chirurgical 1,4 %. Parmi les patients avec une ancienneté d’ALD de 0 à 5 ans, 20,3 % ont été traités. Discussion La faible proportion de patients explorés et traités suggère un sous-dépistage persistant des troubles urinaires, un accès limité aux consultations spécialisées de neuro-urologie, une possible fatigue thérapeutique, ainsi qu’une coordination interdisciplinaire insuffisante entre neurologues, spécialistes en MPR et urologues dans le suivi longitudinal des patients atteints de SEP. Conclusion Les troubles urinaires dans la SEP restent sous-diagnostiqués et sous-traités en France, avec une prise en charge majoritairement non invasive, en décalage avec les recommandations de prise en charge graduée.

Memory CD8+ T cells are central to multiple sclerosis (MS) and undergo clonal expansion, but disease-associated states remain incompletely defined. By single-cell profiling of circulating memory CD8+ T cells from patients with relapsing-remitting MS, healthy volunteers, and neuroinflammatory controls, we identified an MS-associated cytotoxic subset with NK-like features. These cells increase around relapse activity and belong to an oligoclonal reservoir. In an independent cohort sampled at the first clinical event, an elevated frequency of NK-like CD8+ T cells predicted an aggressive MS course two years later and was associated with a migratory/inflammatory program. Bulk and single-cell RNA-seq confirmed the NK-like transcriptional signature, and functional assays demonstrated TCR-independent cytotoxicity. Immunostaining and spatial transcriptomics revealed enrichment of these cells in MS lesions and a spatial association with macrophages/microglia. Together, our results identify a cytotoxic NK-like CD8+ T-cell subset that links peripheral inflammation to CNS lesions and may serve as an early biomarker of MS severity.