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.

BACKGROUND/OBJECTIVES:Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. METHODS:The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. RESULTS:Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines (p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. CONCLUSIONS:The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher.Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast.

Peripheral neuropathies may present with vascular skin lesions, such as livedo racemosa, ulcers, palpable purpura, or necrosis. These rare neurocutaneous associations can be severe and life-threatening. To determine (1) whether phenotypic correlations exist between neuropathy profiles and vascular skin lesion subtypes, and (2) whether these syndromes share a specific mechanism. We conducted a monocentric retrospective study at Montpellier University Hospital (1993–2022) including patients with peripheral neuropathy and vascular skin lesion(s) occurring as a syndrome. Clinical, electrophysiological, and histopathological data were analyzed. Forty-one patients (median age 54 years) were included: 27 had mononeuritis multiplex (MM) and 14 polyneuropathy (PNP). Purpura (p = 0.001) and livedo (p < 0.05) were associated with MM, while ulcers were linked to PNP (p < 0.001). Ulcers were plantar in PNP and supraplantar in MM. Median delay between neuropathy and skin lesion was 1 month in MM versus 58 months in PNP (p < 0.001). In PNP subgroup, the neuropathy systematically preceded skin lesion. MM etiologies involved ischemic mechanisms related to vasculitis and/or vaso-occlusion [systemic angiitis (n = 19), type I cryoglobulinemia (n = 6), and primary antiphospholipid syndrome (n = 2)], whereas PNP was due to diabetes (n = 9), chronic renal failure (n = 1), alcohol (n = 1), leprosy (n = 1), or transthyretin-amyloidosis (n = 2). MM correlates with livedo, purpura, and supraplantar ulcers, reflecting ischemia from vasculitis or vaso-occlusion. Conversely, plantar ulcers result from chronic PNP affecting large and small fibers. Skin lesion type may guide neuropathy phenotype and underlying etiology.

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.

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 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.

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.

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.

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.

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.

Background and ObjectivesColony-stimulating factor receptor 1-related disorder (CSF1R-RD) is an underrecognized, adult-onset genetic leukodystrophy with a devastating clinical course. Disease monitoring is critical as patients with CSF1R-RD can benefit from hematopoietic stem cell transplantation. Here, we aimed to compare blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels between patients with CSF1R-RD and those with alternative diagnoses and to correlate blood biomarkers values with clinical severity.MethodsWe analyzed 22 patients with CSF1R-RD and patients with fronto-temporal lobar degeneration due to GRN pathogenic variants (GRN-FTLD, n = 22), CADASIL (N = 9), cerebral adrenoleukodystrophy (13), and primary progressive multiple sclerosis (n = 14).ResultsNfL and GFAP were elevated in CSF1R-RD and GRN-FTLD as compared with the other groups. After adjusting for age, GFAP was higher in patients with CSF1R-RD compared with those with GRN-FTLD (p = 0.035). Among CSF1R-RD patients, both NfL (p = 0.0054) and GFAP (p = 0.0065) correlated with Expanded Disability Status Scale scores. For a subset of patients with cognitive testing, GFAP correlated with the processing speed index of the Wechsler adult intelligence scale (p = 0.025) and state anxiety (p = 0.0088).DiscussionOur results show that blood NfL and GFAP are promising biomarkers of disease progression in patients with CSF1R-RD.

BACKGROUND:Effectiveness of disease-modifying treatment (DMT) in people affected by primary progressive multiple sclerosis (PPMS) is limited. Whether specific subgroups may benefit more from DMT in a real-world setting remains unclear. Our aim was to investigate the potential effect of DMT on disability worsening among patients with PPMS stratified by different disability trajectories. METHODS:Within the framework of the Big MS Data network, we merged data from the Observatoire Français de la Sclérose en Plaques, the Swedish and Italian MS registries, and MSBase. We identified patients with PPMS that started DMT or were never treated during the observed period. Subpopulations with comparable baseline characteristics were selected by propensity score matching. Disability outcomes were analysed in time-to-recurrent event analyses, which were repeated in subclasses with different disability trajectories determined by latent class mixed models. RESULTS:Of the 3243 included patients, we matched 739 treated and 1330 untreated patients with a median follow-up of 3 years after pairwise censoring. No difference in the risk of confirmed disability worsening (CDW) was observed between the groups in the fully matched dataset (HR 1.11, 95% CI 0.97 to 1.23, p=0.127). However, we found a lower risk for CDW among the class of treated patients with an aggressive disability trajectory (n=360, HR 0.68, 95% CI 0.50 to 0.92, p=0.014). CONCLUSIONS:In line with previous studies, our data suggest that DMT does not ameliorate disability worsening in PPMS, in general. However, we observed a beneficial effect of DMT on disability worsening in patients with aggressive predicted disability trajectories.

OBJECTIVES:Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular B-cell profiles in patients prior to OCR treatment, on OCR treatment, and after 15 months of therapy discontinuation. This study aims to provide new clues about the mechanisms of action of OCR and about disease pathophysiology. METHODS:Patients with early, treatment-naive, RR-MS were included from 11 centers participating in an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic B-cell immune profile was comprehensively assessed in 18 patients by spectral flow cytometry at baseline, after 1 year of OCR treatment, and compared with 10 healthy volunteers (HVs) (matched for age and sex) on cryopreserved peripheral blood mononuclear cells (PBMC). We also analyzed B-cell reconstitution after a median time of 15 months after trial withdrawal in three patients by flow cytometry and single-cell RNA sequencing. RESULTS:Using spectral flow cytometry we defined the proportions and absolute numbers of naive, transitional, Ig-G, Ig-A, Ig-M memory B cells, Ig-G, Ig-A, Ig-M plasmablasts, and plasma cells. At baseline we found an increased frequency of IgG-secreting B cells in MS patients compared to HV. During OCR treatment, the proportion of the different subsets of B cells was strongly modified. In the mature clusters, we observed that the treatment partially spared memory IgA B cells. In parallel, we observed that differentiated IgA plasmablasts and plasma cells were more increased than the other differentiated clusters. Interestingly, in the three patients who stopped the treatment single-cell RNA sequencing showed that the B cells that reappeared were mainly naive with an inflammatory and migratory phenotype concomitantly to a rise of regulatory B cells. DISCUSSION:Our findings support an increased regulatory phenotype of remaining B cells under treatment with OCR and replenishment of undifferentiated B cells accumulating features of inflammatory and migratory patterns after OCR discontinuation, counterbalanced by an increased proportion of regulatory B cells.

Importance:In women with multiple sclerosis (MS), disease-modifying therapy (DMT) management during pregnancy might impact relapse risk. Objective:To estimate the effect of DMT management during pregnancy on MS relapse rate and compare different therapeutic strategies. Design, Setting, and Participants:This was a multicenter retrospective cohort study using data from January 1990 to December 2023. Data were extracted in December 2023 from the French MS registry. Among 52 955 women in the registry, we included pregnancies identified through childbirths in patients with relapsing-onset MS who were monitored for at least 18 months before delivery and 9 months after. Pregnancies occurring less than 18 months apart or with missing month of birth were excluded. Exposures:Mediation analysis was used to estimate the total, direct, and indirect (mediated by DMT management) effects of pregnancy. Different therapeutic strategies were compared: DMT interruption, switching to or maintaining interferon β or glatiramer acetate, switching to or maintaining natalizumab until the third trimester, and switching to or maintaining intravenous anti-CD20 and interrupting it 3 months before conception. Main Outcomes and Measures:The primary outcome was the annualized relapse rate (ARR) during the preconception, gestation, and postpartum periods. Within a causal inference framework, counterfactual ARRs were estimated using longitudinal g-computation, combining a random forest algorithm for predicting DMTs, and a mixed-effects Poisson model for relapses. Results:We included 6341 pregnancies occurring in 4998 women (mean [SD] age at conception, 31.5 [4.5] years). DMT management during pregnancy significantly increased ARR during gestation (causal rate ratio [cRR], 1.13; 95% CI, 1.06-1.22) and postpartum (cRR, 1.08; 95% CI, 1.01-1.16) periods. This led to a deleterious total effect of pregnancy on ARR, particularly in women receiving natalizumab before pregnancy with prolonged interruption (ie, interruption before the second trimester or resumption more than 3 months after delivery; cRR, 2.18; 95% CI, 1.76-2.69), and in women receiving fingolimod (cRR, 2.15; 95% CI, 1.60-2.93). Compared to DMT interruption, anti-CD20 strategy was the most effective (cRR, 0.38; 95% CI, 0.25-0.52), followed by the natalizumab strategy with short interruption (cRR, 0.80; 95% CI, 0.71-0.90), whereas interferon β (cRR, 0.93; 95% CI, 0.86-0.99) and glatiramer acetate strategies (cRR, 0.91; 95% CI, 0.84-0.99) were less effective. Conclusion:In this study, DMT management during pregnancy significantly increased relapse risk, particularly in patients receiving natalizumab with prolonged interruption or fingolimod. The strategy based on the use of anti-CD20 before pregnancy was the most effective to mitigate this risk.

Clinically defined relapses are the traditional primary endpoint of randomized control trials (RCTs) in multiple sclerosis (MS), yet a substantial proportion lack new inflammatory lesions. Confirming relapses with brain and spinal cord MRI to distinguish relapses with active MRI (RAM) from acute clinical events with stable MRI (ACES) may provide a more sensitive primary outcome for future trials. To estimate RAM and ACES rates in MS trials and evaluate the impact on statistical power of using RAM. We used two approaches: an aggregated data (AD) approach, combining population-level data from RCTs with observational data from the French MS registry, and an individual patient data (IPD) approach from the PRIMUS platform. Trials were selected if they evaluated DMTs sufficiently represented in the OFSEP ancillary study or were available in PRIMUS. Eleven pivotal RCTs were included, evaluating natalizumab, cladribine, dimethyl fumarate, teriflunomide, fingolimod, or ocrelizumab; 7 were analyzed with AD only, 1 with IPD only, and 3 with both. For the AD approach, population-level characteristics were extracted from published reports; expected RAM probabilities were then derived from a RAM model fitted on OFSEP observational data, applied to each RCT arm population. For the IPD approach, clinically defined relapses were directly classified as RAM/ACES according to radiological activity on subsequent brain MRI. Main outcomes were the treatment effect on RAM and ACES rates, compared with the effect on clinically defined relapses. Across 11 RCTs, treatment effects were consistently equal or greater for RAM than for clinically defined relapses, with both AD and IPD approaches. No DMT significantly reduced ACES rates, which remained stable at approximately 0.08 events/year across arms. The IPD approach yielded systematically lower RAM probabilities than the AD approach. Using RAM as the endpoint improved statistical power in most scenarios: e.g. a trial with annualized relapse rates of 0.15/year (active arm) vs 0.30 (control arm) requires one-third fewer participants. Adopting RAM as the primary outcome could substantially enhance the power of future MS trials and better target the effect of treatment on inflammatory activity.

Background and ObjectivesAbnormal brain MRI is associated with poor outcomes in anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). We aimed to characterize the lesions on brain MRI in NMDARE and to assess the clinical and prognostic associations. MethodsThis retrospective cohort study included patients with NMDARE identified at the French Reference Center for Autoimmune Encephalitis, with at least a one-year follow-up, and with available brain MRI results. In case of brain extralimbic lesion, the image files were reviewed when available. Clinical data were collected from medical records. Multivariable logistic regression analysis was used to study the outcomes at 2-year follow-up; recovery was defined as modified Rankin Scale score <= 1. ResultsAmong the 255 patients included, 37 (14.5%) had limbic hyperintensities and 41 (16.1%) had extralimbic lesions that included multiple sclerosis (MS)-like lesions (14/41, 34.1%); extensive lesions (5/41, 12.2%); and poorly demarcated fluffy lesions, either multifocal (10/41, 24.4%) or involving the cerebral cortex or cerebellum (6/41 each, 14.6%). Extralimbic lesions coexisting with limbic lesions (19/41 patients, 46.3%) were mostly fluffy lesions (11/19, 57.9%). Ten patients had overlapping demyelinating syndromes: 4 with MS, 4 with myelin oligodendrocyte glycoprotein-associated disorder, and 2 with neuromyelitis optica spectrum disorder; all had MS-like (7/10 patients) or extensive (3/10 patients) lesions, and none had fluffy lesions. Extralimbic lesions were associated with symptoms nontypical for NMDARE (23/41, 56.1%, p < 0.001), especially cerebellar ataxia (17/41, 41.5%) and motor impairment (12/41, 29.3%). At 2 years, patients with MS-like or extensive lesions had a lower recovery rate (5/12, 41.7%, and 1/4, 25%, respectively) compared with the patients without extralimbic lesions (124/162, 76.5%; p = 0.014 and p = 0.047, respectively). In multivariable analysis, MS-like lesions, but not hippocampal nor fluffy lesions, were associated with absence of recovery at 2 years (adjusted OR 0.1, 95% CI 0.03-0.42, p = 0.002; extensive lesions [n = 4] not included in the analysis). DiscussionBrain MRI lesions in NMDARE include limbic hyperintensities and 3 patterns of extralimbic lesions, which are associated with nontypical NMDARE symptoms. Moreover, MS-like and extensive lesions, but not fluffy nor hippocampal lesions, are associated with overlapping demyelinating syndromes and poor clinical outcomes at 2 years. These findings can have practical implications on the monitoring of patients with NMDARE.

BACKGROUND:Retrospective studies did not show strong evidence of higher risk of adverse neonatal or pregnancy outcomes in women with multiple sclerosis (MS) compared to general population, but there are contradictory data on prematurity, cesarean section, and small birthweight for gestational age (SGA). METHODS:We compared pregnancy and birth outcomes in MS women included in RESPONSE, a French prospective cohort, with a recent survey (Enquête Nationale Périnatale (ENP)) describing leading indicators in perinatal epidemiology in France. RESULTS:On 7 April 2023, 476 pregnancies (461 MS women, 482 expected newborns) from RESPONSE were available. The ENP study reported 12,723 women and 12,939 expected newborns in March 2021. MS patients were older (mean age 32.6 ± 4.4 vs. 30.9 ± 5.3 years, p < 0.001), with similar rate of cesarean (23.8% vs. 21.4%, p = 0.115) and use of locoregional analgesia (86.6% vs. 85.1%, p = 0.51). Preterm birth was less frequent (4.0% vs. 7.0%, p = 0.001). Birthweight of children from MS mothers was similar to general population (3240 ± 477.2 vs. 3264.5 ± 552.9 g, p = 0.22), with slightly more children with SGA (13.4% vs. 9.8%, p = 0.04). CONCLUSION:This prospective and contemporary comparison of pregnancy in MS women and the French population provides reassuring results. In the future, we need to assess the impact of disease-modifying treatment exposure during conception.