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 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.

Importance:Therapeutic deescalation strategies are increasingly considered in demyelinating diseases to mitigate the risks associated with prolonged immunosuppression. The impact of treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not established. Objective:To assess the relapse risk following treatment discontinuation in adult patients with MOGAD and to evaluate factors associated with disease reactivation. Design, Setting, and Participants:This retrospective cohort study including 41 centers was conducted using the French NOMADMUS database. Adult patients with MOGAD diagnosed between January 2013 and April 2024 were included. Data were extracted on July 1, 2024. A total of 1047 patients with MOGAD were screened, and 705 patients fulfilled the inclusion criteria. Among them, 319 (45.2%) received at least 1 maintenance therapy. Exposure:All instances of treatment discontinuation were collected and categorized according to their underlying reasons. Only discontinuations that were scheduled or related to adverse events were analyzed. Main Outcomes and Measures:Time to first relapse was estimated using Kaplan-Meier survival curves, and differences between groups were assessed using the log-rank test. Results:A total of 83 patients (median [IQR] age, 42.7 [28.9-53.3] years; 52 [63.7%] female) discontinued either oral immunosuppressants (azathioprine or mycophenolate mofetil) or rituximab in 60 (72.1%) and 23 (27.7%) individuals, respectively. Discontinuations were scheduled (n = 54 [65.1%]) or related to adverse events (n = 29 [34.9%]). After discontinuation, 7 patients relapsed, with a median (IQR) time to relapse of 0.5 (0.1-1.4) years. The Kaplan-Meier estimated cumulative incidence of relapse at 1 year after discontinuation was 8.7% (95% CI, 1.0-15.9). Severity of relapses was mild, with a median (IQR) change in the Expanded Disability Status Scale score of 0 (0-1) points. Factors associated with an increased relapse risk were a treatment duration of less than 1 year (7 relapses [19.4%] vs 0 relapses; log-rank P = .002) and a time since last relapse of less than 2 years (7 relapses [15.9%] vs 0 relapses; log-rank P = .01). Conclusions and Relevance:The low risk of disease reactivation found in this study suggests that discontinuing treatment may be considered in selected adult patients with MOGAD. Future clinical trials are necessary to confirm these results and establish guidelines in this situation.

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 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.

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.

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.

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.

The assessment of new Multiple Sclerosis (MS) lesions is a time-consuming and difficult task that may lead to an underestimation of patient disease activity. Efficient methods to detect new T2/FLAIR lesions are therefore critical to assist clinicians in this process. In this context, we proposed and organized in 2021 the MSSeg2 challenge aiming at comparing methods segmenting new MS lesions. For this purpose, we built a high-quality dataset of 100 pairs of FLAIR MRI with precise delineation of new MS lesions with a size superior to 3 mm[Formula: see text]. From these 100 pairs of MS patient images from various scanners and French clinical centers, 40 were shared to the challengers before they submitted their methods. 30 methods from 24 international teams were submitted and evaluated on the FLI-IAM dedicated platform on the 60 remaining images. Overall, we observed that even at lesion scale, expert annotations were variable (40% of lesions were annotated by two or fewer experts out of the four). The best expert exhibited a mean F1 score of 0.679 (SD = 0.345) while the best method exhibited a mean F1 score of 0.698 (SD = 0.295) on the 35 patients with new lesions. Moreover, we did not observe evidence of differences between the top-ranked methods and the best expert performances as evaluated by the F1 score (9 methods exhibited no clear evidence against no difference of mean F1). Similarly, we did not observe evidence of difference in performances between the top-ranked methods and the best expert in classifying patients into a 3 categories clinically relevant scale (0 lesion, 1 or 2 lesions and >2 lesions; 21 methods exhibited no clear evidence against no difference of performances with a best classification accuracy of 85 % for both the best expert and the best method). While results from current automated methods still remain perfectible, our results highlight their potential usefulness in detecting new FLAIR MS lesions.

OBJECTIVES:Aquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare conditions with evolving diagnostic and therapeutic approaches. Our study aims to describe these evolutions in France, using data from the NOMADMUS cohort. METHODS:We retrospectively analyzed clinical, imaging, and therapeutic data collected across 98 French centers as of June 8, 2024. Patients were classified based on serologic status into AQP4+NMOSD or MOGAD. RESULTS:The cohort included 769 AQP4+NMOSD and 957 patients with MOGAD, 68.6% female with a mean age at onset of 37.4 years (18.3). The mean annualized relapse rates decreased from 2010-2014 to 2022-2023 in both groups (for example, from 0.45 (0.41-0.48) to 0.04 (0.03-0.05) in AQP4+NMOSD, Welch's t tests, p < 0.0001). Rituximab use increased in AQP4+NMOSD patients over time and was associated with a lower risk to reach Expanded Disability Status Scale (EDSS) 6 (HR 0.38; p < 0.001, 0.21-0.68). Risk to reach EDSS 3 or 6 was lower in patients with MOGAD compared with AQP4+NMOSD patients. DISCUSSION:This nationwide registry revealed a reduction of the time to diagnosis, a decreased disease activity over time, and an evolution in the therapeutic strategies these past 15 years. This collaborative effort provides valuable insights into current knowledge about clinical practice and treatment patterns in real-world settings.

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.

BACKGROUND AND OBJECTIVES:The therapeutic strategy in patients with late-onset MS (LOMS) remains poorly defined. In this study, we aimed to evaluate both clinical and MRI outcomes between 2 cohorts of patients with relapsing-remitting LOMS treated or not yet treated. METHODS:Patients with relapsing-remitting MS were included for the analysis if disease onset occurred after 55 years and if they had at least one follow-up visit. The primary outcome was time to first relapse between 2 matched groups of patients with LOMS (treated and not yet treated). Secondary outcomes were as follows: (1) time to first confirmed disability progression (CDP), (2) time to first progression independent of relapse activity (PIRA) event, (3) time to secondary progression (SPMS), (4) time to first MRI activity, and (5) serious infection incidence rates (IIRs). For the comparative analyses, we adopted a time-dependent propensity score matching approach. RESULTS:A total of 881 patients fulfilled the inclusion criteria. The mean (SD) age at onset was 59.9 (4.43) years. After applying propensity score matching, 436 patients were matched. The mean (SD) follow-up duration was 5.2 (4.27) years in the treated group and 5.0 (3.86) years in the not-yet-treated group. Mean (SD) time to first relapse was significantly longer in the treated group compared with the not-yet-treated group (7.0 years [0.33] vs 5.4 years [0.33]; p = 0.001). Mean (SD) time to first MRI activity was significantly longer in the treated group (5.9 years [0.33] vs 5.0 years [0.33]; p = 0.049). However, the mean time to CDP, PIRA, or SPMS was not different between the 2 groups (difference = 0.32 years; p = 0.585 for CDP; difference = 0.40 years; p = 0.442 for PIRA; difference = -0.02 years; p = 0.952 for SPMS). No increase in serious IIRs was observed with an incidence rate ratio of 0.38 (95% CI 0.07-2.10, p = 0.265) in the never-treated group compared with the treated one. DISCUSSION:This study demonstrates a beneficial effect of disease-modifying therapy (DMT) on disease activity in patients with LOMS but without significant impact on disability progression. Main limitations are linked to the challenge of data collection and to the baseline imbalances between the 2 groups. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that in patients with LOMS, treatment with DMTs is associated with a longer time to first relapse compared with those not treated with DMTs.

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 OBJECTIVES:Older studies reported an increased risk of relapse after in vitro fertilization (IVF) in women with multiple sclerosis (MS), which has not been confirmed by more recent works. All these studies had several limitations, such as small sample sizes, absence of a control population, or lack of neurologic validation of the relapses. The aim of this study was to determine the risk of relapse after IVF in women with MS. METHODS:This retrospective cohort study included all women with MS who underwent IVF between 2009 and 2019 and a control group of women with MS who did not undergo IVF matched on age, MS duration, number of relapses, and MS-specific treatments in the previous year. Data on MS (disease duration, treatments, and relapses) were from the French MS Registry (OFSEP), whereas data on IVF (number of procedures, stimulation protocol type, and outcomes) were from the French national health insurance database. For this, the 2 databases were linked by indirect matching. RESULTS:In total, 115 women with MS underwent 199 IVF procedures (mean age at first IVF: 33.9 ± 4.0 years; 45.2% had ≥2 IVF procedures), and 175 IVFs (88.0%) could be matched to specific patients. The risk of relapse in the 3 months after index date was the same in both IVF group and control group (0.06 relapse per patient-year), as confirmed also by the before-after analysis in the IVF group (0.06 vs 0.08). DISCUSSION:This study, using a 10-year clinical and administrative dataset, did not find any increased risk of relapse after IVF. The maintenance of disease-modifying therapies until IVF was a determining factor in reducing the risk of relapse.

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.

Multiple Sclerosis (MS) is a central nervous system (CNS) autoimmune inflammatory disease targeting the myelin sheath and affecting 2.8 million patients worldwide, mostly in economically advanced countries. The OFSEP-HD (French Multiple Sclerosis Registry - High Definition) multi-centric cohort comprises 2,667 genetic samples of patients with MS including 5 years of clinical, biological and imaging follow up. Here we described the genetic background of the cohort using data generated from the Affymetrix Precision Medicine Research Array (PMRA) genotyping chips to collect 888,799 genomic variants, and up to 8.5 million variants after imputation. Our analysis focused on genetic ancestry, admixture analysis and Human Leukocyte Antigen (HLA) including haplotypes inference. Principal Components Analysis (PCA) clustering identified seven ancestral clusters with 2177 patients (85.6 %) from clearly defined European ancestry. We observed 232 MS patients from North-African genetic ancestry while 120 of those patients (51.7%) did not self-report North-African origins, highlighting once again the limitations of self-assessed population descriptors. To promote data sharing we implemented the generation of a realistic and anonymous synthetic dataset using an adaptation of a known synthetic data generation methodology. This work unveils the genetic landscape and heterogeneous profiles of the OFSEP-HD cohort and proposes an open synthetic genetic dataset for further analyses. ### Competing Interest Statement J.P, N.S.B, M.M, I.F, S.D, M.B, S.L, L.B, A.S-E, S.B-H, F.C, R.C, L.B, N.V, declare that they have no competing interest. Prof. PA. Gourraud is the founder of Methodomics (2008) and the co-founder of Big data Sante (2018). He consults for major pharmaceutical companies, all of which are handled through academic pipelines (AstraZeneca, Biogen, Boston Scientific, Cook, Edimark, Ellipses, Elsevier, Methodomics, Merck, Merieux, Sanofi-Genzyme, Octopize). PA Gourraud is a volunteer board member at AXA non-for-profit mutual insurance company (2021). He has no prescription activity with either drugs or devices. Dr. D. Laplaud has participated in advisory boards for Alexion, Merck, Novartis, and Roche in the last 3 years. Pr. S Vukusic has received lecturing fees, travel grants, and research support from Biogen, Janssen, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, and Teva. ### Funding Statement We thank OFSEP for providing source data. Indeed, data collection has been supported by a grant provided by the French State and handled by the Agence Nationale de la Recherche, within the framework of the France 2030 program, under the reference ANR-10-COHO-002, Observatoire Francais de la Sclerose en Plaques (OFSEP) - Eugene Devic EDMUS Foundation against multiple sclerosis. I also wish to thank the Marie-Curie institute (Paris, France) for genotyping the samples. In addition, we thank the historical contributors of REFGENSEP, Lena Guillot-Noel and Isabelle Rebeix. This work has been supported by the PRIMUS project (Projection in Multiple Sclerosis), part of a government grant managed by the French National Research Agency (Agence Nationale de la Recherche, ANR) as its 3rd PIA, integrated into the France 2030 plan under reference [ANR-21-RHUS-0014]. This work was supported by Nantes Metropole, Region des Pays de la Loire and European Union (FEDER) via the Programme d investissements d Avenir (NExT, SHLARC Project, Nantes Universite). Moreover, insights and encouragement from following collaborators were instrumental in the completion of this work. I am grateful to CR2TI for providing the necessary facilities and technical support, and Dr. Vincent Mauduit for his assistance with data analysis. We thank the Curie genomic platforms for technical support and GWAS genotyping. We are also grateful to the Bioinformatics Core Facility BiRD, member of Biogenouest and Institut Francais de Bioinformatique (IFB) (ANR-11-INBS-0013) for the use of their resources and their technical support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the non-interventional research ethics committee of Nantes University (IRB00013074) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at (https://github.com/jp3142