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Abstract Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

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.

Introduction: Dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS). Some patients may develop lymphopenia on DMF; therefore, LymphoTEC evaluated absolute lymphocyte count (ALC) reconstitution after DMF discontinuation., Methods: LymphoTEC was a retrospective, multicenter study of patients with RRMS in the Observatoire Français de la Sclérose en Plaques registry. Times to ALC reconstitution and lymphopenia were estimated by the Kaplan-Meier method. Univariate and multivariate analyses evaluated factors associated with ALC reconstitution after DMF discontinuation or lymphopenia after DMF initiation. Patients treated with DMF for ≥ 3 months with ≥ 1 ALC in the 6 months before/close to DMF initiation and ≥ 1 ALC during treatment were included., Results: Overall, 1429 RRMS patients were included; 356 patients developed lymphopenia, of whom 183 discontinued DMF. Overall, ALC decreased by 33% over the first year and plateaued thereafter. The probability of developing lymphopenia was 18.2% after 1 year. In patients with lymphopenia, median times to ALC reconstitution after DMF discontinuation were 3.8 months overall, 4.0 months for Grade 1 lymphopenia, 3.0 months for Grade 2, and 9.7 months for Grade 3. At 12 months, 83.0% had reconstituted ALC. In DMF discontinuers, median time to discontinuation was 1.2 years. There was no increased risk of serious or opportunistic infections in patients with lymphopenia. No cases of progressive multifocal leukoencephalopathy were reported. First ALC reconstitution after DMF discontinuation was associated with diabetes, DMF duration, DMF duration before lymphopenia, and DMF duration after lymphopenia; first lymphopenia after DMF initiation was associated with age and ALC at DMF initiation., Conclusion: LymphoTEC confirms previous reports on DMF-induced lymphopenia; the benefit-risk profile of DMF remains favorable. Most cases of lymphopenia were not severe and ALC reconstitution typically occurred within 4 months of DMF discontinuation. Patients with shorter and milder lymphopenia had faster ALC reconstitution., Trial Registration: ClinicalTrials.gov NCT04756687., Competing Interests: Declarations. Conflict of Interest: Jérôme de Sèze: consultant, advisory boards, and scientific meetings for Alexion, Biogen, CSL Behring, Genzyme/Sanofi, Horizon Therapeutics, LFB, Janssen, Novartis, Roche, and Teva. Pierre Labauge: congresses and research grants from Biogen, BMS, Merck, Novartis, Sanofi Genzyme, and Teva. Roland Liblau: research grants from BMS, GSK, and Roche; speaker fees from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Mikel Martinez: no conflicts of interest to disclose. Thibault Moreau: research support and consultancy fees from Biogen, Merck, Novartis, Roche, and Sanofi. Laurent Suchet: consulting fees from Biogen, BMS-Celgene, Merck, Novartis, Roche, and Sanofi Genzyme; honoraria from Novartis and Sanofi. Patrick Vermersch: honoraria from AB Science, Ad Scientiam, Biogen, BMS-Celgene, Imcyse, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva; research support from Novartis, Roche, and Sanofi Genzyme. Sandra Vukusic: lecturing fees, travel grants, and research support from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sandoz, and Sanofi Genzyme. Guillaume Mathey: no conflicts of interest to disclose. Laure Michel: no conflicts of interest to disclose. Jonathan Ciron: consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Biogen, Horizon Therapeutics, Novartis, Merck, Roche, and Sanofi Genzyme. Aurelie Ruet: received honoraria for meeting speaking from Alexion, Horizon Therapeutics, Merck, and Sanofi Genzyme; received support for traveling from Biogen, Merck, and Novartis. Her institution received research grants from Biogen, BMS, Roche, and Sanofi Genzyme. Elisabeth Maillart: consulting and lecturing fees from Alexion, Biogen, Horizon, Janssen, Merck Serono, Novartis, Roche, Sandoz, Sanofi Genzyme, and Teva Pharmaceuticals; and research support from Biogen. Helene Zephir: consulting or lectures, and invitations for national and international congresses, from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and Teva; research support from Roche and Teva; and academic research grants from Académie de Médecine, ARSEP Foundation, FHU Imminent, and LFSEP. Caroline Papeix: no conflicts of interest to disclose. Gilles Defer: consulting and lecturing fees for Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva; and funding for travel from Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva. Institution granted for research supporting from Biogen, Genzyme, Merck Serono, and Novartis. Mikael Cohen: has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ad Scientiam, Alexion, Biogen, Celgene-BMS, Horizon Therapeutics, Janssen, Merck, Roche, and Sanofi. David Axel Laplaud: served on scientific advisory boards for Alexion, Biogen, BMS, Janssen, Merck, Novartis, Roche, and Sanofi; received conference travel support and/or speaker honoraria from Alexion, Biogen, BMS, Merck, Novartis, Roche, and Sanofi; and received research support from Agence Nationale de la Recherche, Fondation ARSEP, and Fondation EDMUS.​ Eric Berger: honoraria and consulting fees from Biogen, Genzyme, Novartis, Roche, Sanofi Aventis, and Teva Pharma. Pierre Clavelou: consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Janssen, Medday, Merck, Novartis, Roche, Sanofi Genzyme, and Teva Pharma. Eric Thouvenot: consulting and lecturing fees, travel grants, or unconditional research support from Actelion, Biogen, Janssen, Merck Serono, Novartis, Roche, and Sanofi. Olivier Heinzlef: consulting and lecturing fees from Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck, Novartis, and Teva; travel grants from Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva; and research support from Roche, Merck, and Novartis. Jean Pelletier: no conflicts of interest to disclose. Claire Giannesini: no conflicts of interest to disclose. Olivier Casez: Biogen (personal fees), Janssen (personal fees), Merck (personal fees, non-financial support [traveling/congress]), Novartis (personal fees, non-financial support [traveling/congress]), Roche (personal fees, non-financial support [traveling/congress]), and Sanofi (personal fees). Bertrand Bourre: served on scientific advisory board for Alexion, Biogen, BMS, Horizon, Janssen, Merck, Novartis, Roche, Sandoz, and Sanofi; and received funding for travel and honoraria from Alexion, Janssen, Merck, Novartis, Roche, and Sanofi. Abir Wahab: provided expert testimony for Roche and received travel grants from Biogen. Laurent Magy: no conflicts of interest to disclose. Jean-Philippe Camdessanché: consulting and lecturing fees from Akcea, Alexion, Alnylam, Argenx, Biogen, Bristol Myers Squibb, CSL Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Pharmalliance, SNF-Floerger, Teva, and UCB Pharma; travel grants from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, SNF-Floerger, and Teva. Inès Doghri: no conflicts of interest to disclose. Céline Labeyrie: no conflicts of interest to disclose. Karolina Hankiewicz: no conflicts of interest to disclose. Jean-Philippe Neau: no conflicts of interest to disclose. Corinne Pottier: support from Alexion, Biogen, Merck, Novartis, Roche, and Teva. Pamela Dobay, Seth Levin, Marilyn Gros, Marta Ruiz: employees of Biogen and may own stock in the company. Hanyue Li: employee of Biogen and may have owned stock in the company at the time this work was conducted. Fabien Rollot: no conflicts of interest to disclose. Ethical Approval: In accordance with French legislation, the OFSEP cohort was approved by the national data protection agency (Commission Nationale de l’Informatique et des Libertés; authorization request 914066v3) and the French ethical committee (Comité de Protection des Personnes: reference 2019-A03066-51). All patients in the OFSEP cohort provided informed consent to have their medical data shared anonymously for research purposes. Appropriate research information on the OFSEP registry research cohort is available on the OFSEP website [19, 20]. After 1 month without objections from the patient, patient data were extracted for analysis. As per French legislation (“Loi Informatique et Libertés” No. 78–17 on January 6, 1978, modified by Law No. 2016–41 on January 26, 2016), LymphoTEC was registered on ClinicalTrials.gov (NCT04756687) and was compliant with the “French Methodology of reference MR-004”. The study was conducted in accordance with the Declaration of Helsinki., (© 2025. The Author(s).)

Background: Currently, there are no available recommendations or guidelines on how to perform MRI monitoring in the management of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The issue is to determine a valuable MRI monitoring protocol to be applied in the management of NMOSD and MOGAD, as previously proposed for the monitoring of multiple sclerosis., Objectives: The objectives of this work are to establish proposals for a standardized and feasible MRI acquisition protocol, and to propose control time points for systematic MRI monitoring in the management of NMOSD and MOGAD., Methods: A steering committee composed of 7 neurologists and 5 neuroradiologists, experts in NMOSD and MOGAD from the French group NOMADMUS, defined 8 proposals based on their expertise and a review from the literature. These proposals were then submitted to a Rating Group composed of French NMOSD / MOGAD experts., Results: In the management of NMOSD and MOGAD, a consensus has been reached to perform systematic MRI of the brain, optic nerve and spinal cord, including cauda equina nerve roots, at the time of diagnosis, both without and after gadolinium administration. Moreover, it has been agreed to perform a systematic MRI scan 6 months after diagnosis, focusing on the area of interest, both without and after gadolinium administration. For long-term follow-up of NMOSD and MOGAD, and in the absence of clinical activity, it has been agreed to perform gadolinium-free MRI of the brain (+/- optic nerves) and spinal cord, every 36 months. Ideally, these MRI scans should be performed on the same MRI system, preferably a 3T MRI system for brain and optic nerve MRI, and at least a 1.5T MRI system for spinal cord MRI., Conclusions: This expert consensus approach provides physicians with proposals for the MRI management of NMOSD and MOGAD., Competing Interests: Declaration of competing interest Françoise DURAND-DUBIEF has nothing to disclose. Natalia SHOR has nothing to disclose. Bertrand AUDOIN has nothing to disclose. Bertrand BOURRE serves on scientific advisory board, has received funding for travel and honoraria from Alexion, Biogen, BMS, Horizon, Janssen, Merck, Novartis, Sanofi, Sandoz and Roche. Mikael Cohen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck, Sanofi, Roche, Celgene-BMS, Janssen, Alexion, Horizon Therapeutics and Ad Scientiam. Stéphane KREMER has nothing to disclose. Elisabeth MAILLART reports research support from Biogen and personal fees for lectures and advisory boards from Alexion, Biogen, Horizon, Janssen, Merck, Novartis, Roche, Sanofi, and Teva. Caroline PAPEIX has received personal compensation for consulting, serving on a scientific advisory board, speaking from Alexion, Horizon, Roche. Aurélie RUET has received funding for travel or speaker or consultant honoraria from Biogen, Alexion, Novartis, Sanofi, Merck, Horizon Therapeutic; and received research support from Biogen, BMS, Sanofi, Roche, Merck. Julien SAVATOVSKY has nothing to disclose. Thomas TOURDIAS has nothing to disclose. Xavier AYRIGNAC has received consulting fees and lecturing fess, travel grants and undoncitional research support from Alexion, Biogen, Genzyme, Janssen, Merck Serono, Novartis, Roche, Sanofi Aventis and Teva Pharma. Jonathan CIRON has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi, Roche, Alexion, Horizon Therapeutics, none related to this study. Nicolas COLLONGUES has received honoraria for consulting or presentation from Alexion, Biogen Idec, Bristol-Myers Squibb, Horizon Therapeutics, Merck Serono, Novartis, Roche and Sanofi-Genzyme and is a member of the Editorial Board of the Journal de la Ligue Française contre la Sclérose en plaques and the Neurology and Therapy Journal. David LAPLAUD served on scientific advisory boards for Alexion, BMS, Roche, Sanofi, Novartis, Merck, Janssen and Biogen, received conference travel support and/or speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi, BMS and Merck and received research support from Fondation ARSEP, Fondation EDMUS and Agence Nationale de la Recherche. Laure MICHEL has nothing to disclose. Romain DESCHAMPS has received personal compensation for serving on a scientific advisory board or travel grants from Biogen, Roche, Alexion, and Novartis. Eric THOUVENOT received consulting and lecturing fees, travel grants or unconditional research support from Actelion, Biogen, BMS, Merck, Novartis, Roche, Teva pharma. Hélène ZEPHIR received consulting fees and invitation for congresses from Alexion, Horizon Therapeutics, Roche, Sanofi, Janssen, Biogen Idex, Merck, BMS. HZ received research supports from Novartis, Roche. Romain MARIGNIER serves on scientific advisory boards for Horizon Therapeutics/Amgen; and has received funding for travel and fees from Alexion, Amgen Biogen, Roche, Sanofi. François COTTON reports grants, consulting fees, and non-financial support from Biogen, Bracco imaging, Merck-Serono, Novartis, Philips and Roche., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The clinical course of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is variable. However, robust markers of poor outcome and/or relapse risk are still missing., Objective: To evaluate the frequency of cerebrospinal fluid-restricted oligoclonal bands (CSF-OCB) in a national cohort of adult MOGAD patients and to assess their prognostic value for the risk of relapse and severity., Methods: We included MOGAD adult patients fulfilling the MOGAD 2023 criteria who underwent CSF analysis at maximum 3 months from onset., Results: Data from 190 patients were collected. We found the presence of CSF-OCB in 32 patients (16.8%). Positive and negative CSF-OCB patients were similar for median age at onset, sex, clinical presentation, severity at onset, and residual disability. Relapses were more frequent in the CSF-OCB+ group ( p = 0.049), particularly within the first year of follow-up ( p = 0.007). Although CSF-OCB+ was more frequently associated with imaging features suggestive of multiple sclerosis (MS) ( p = 0.014), 78% of these patients fulfilled the 2023 supportive features and 65% experienced lesion vanishing at follow-up magnetic resonance imaging (MRI)., Conclusion: We found a higher risk of relapse in MOGAD with CSF-OCB particularly during the first year. Close attention is recommended regarding the risk of misdiagnosis with MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.D. has received personal compensation for serving on a scientific advisory board or travel grants from Biogen, Alexion, and Novartis. J.C. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi, Roche, Alexion, and Horizon Therapeutics-Amgen, none related to this study. M.C. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck, Sanofi, Roche, Celgene-BMS, Janssen, Alexion, Horizon Therapeutics, and Ad Scientiam. Professor N.C. has received honoraria for consulting or presentation from Biogen Idec, Alexion, Novartis, Merck Serono, Bristol-Myers Squibb, Sanofi-Genzyme, and Roche and is a member of the Editorial Board of the Journal de la Ligue Française contre la Sclérose en plaques. A.R. has received grant research for the institution from Biogen, BMS, Merck, Roche, and Sanofi-Genzyme and non-financial support and honoraria from Biogen, Novartis, Alexion, and Horizon Th. B.B. serves on scientific advisory board and has received funding for travel and honoraria from Alexion, Biogen, BMS, Horizon, Janssen, Merck, Novartis, Sanofi, and Roche. C.P. reports personal fees for lectures and advisory boards or travel grants from Alexion, Horizon-Amgen, and Novartis outside the submitted work. All other authors have declared no conflict of interest.

Introduction: Myeloid cells trafficking from the periphery to the central nervous system are key players in multiple sclerosis (MS) through antigen presentation, cytokine secretion and repair processes., Methods: Combination of mass cytometry on blood cells from 60 MS patients at diagnosis and 29 healthy controls, along with single cell RNA sequencing on paired blood and cerebrospinal fluid (CSF) samples from 5 MS patients were used for myeloid cells detailing., Results: Myeloid compartment study demonstrated an enrichment of a peculiar classical monocyte population in 22% of MS patients at the time of diagnosis. Notably, this patients' subgroup exhibited a more aggressive disease phenotype two years post-diagnosis. This monocytic population, detected in both the CSF and blood, was characterized by CD206, CD209, CCR5 and CCR2 expression, and was found to be more frequent in MS patients carrying the HLA-DRB1*15:01 allele. Furthermore, pathways analysis predicted that these cells had antigen presentation capabilities coupled with pro-inflammatory phenotype., Discussion: Altogether, these results point toward the amplification of a specific and pathogenic myeloid cell subset in MS patients with genetic susceptibilities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Rodriguez, Couloume, Ferrant, Vince, Mandon, Jean, Monvoisin, Leonard, Le Gallou, Silva, Bourguiba-Hachemi, Laplaud, Garcia, Casey, Zephir, Kerbrat, Edan, Lepage, Thouvenot, Ruet, Mathey, Gourraud, Tarte, Delaloy, Amé, Roussel and Michel.)

Background: We hypothesized that differences in access to disease-modifying treatments (DMTs) could explain the association between socioeconomic status and disability progression in multiple sclerosis (MS)., Objective: This study aimed to analyze the association between education level and DMT use in France., Methods: All patients from OFSEP network with MS onset over 1996-2014 and aged ⩾ 25 years at onset were included. Three time-to-event outcomes were investigated using flexible parametric survival regression models: time from MS onset to first DMT (any) and to platform therapy, and time from platform therapy to switch to high-efficacy therapy., Results: Overall, 7563 patients were included (mean follow-up 12.6 ± 5.9 years). The percentages of patients aged less than 40 years at MS onset and who initiated treatment before the age of 40 years were significantly higher in the groups with a higher education level. The time-to-event outcomes showed no major difference in DMT practices according to education level, except for women who had a significantly shorter time to DMT initiation in medium to very high education level groups versus low, at 5 years from MS clinical onset., Conclusion: Our results suggest that the association between education level and MS disability progression does not solely reflect different therapeutic practices, particularly in men., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L., O.D., M.D., C.L.F., and J.P. have nothing to disclose. E.B. disclosed honoraria and consulting fees from Novartis, Sanofi Aventis, Biogen, Genzyme, Roche, and Teva Pharma. J.P.C. disclosed consulting and lecturing fees from Akcea, Alexion, Alnylam, Argenx, Biogen, Bristol Myers Squibb (BMS), CSL Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Pharmalliance, UCB Pharma, Teva, SNF Floerger; travel grants from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Teva, SNF Floerger. J.C. disclosed consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi Genzyme, Roche, Celgene BMS, Alexion. P.C. disclosed consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Janssen, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, and Teva Pharma. J.D.S. disclosed consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Roche, Sanofi Aventis, and Teva Pharma. O.H. disclosed consulting and lecturing fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, and Biogen Idec, travel grants from Novartis, Teva, Genzyme, Merck Serono, and Biogen Idec, and research support from Roche, Merck, and Novartis. P.L. disclosed consulting and lecturing fees, travel grants and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. D.A.L. served on scientific advisory boards for Alexion, BMS, Roche, Sanofi, Novartis, Merck, Janssen and Biogen, received conference travel support and speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi, BMS, Teva Pharma and Merck, and received research support from Fondation ARSEP, Fondation EDMUS and Agence Nationale de la Recherche. L.M. disclosed honoraria as speaker from Biogen, Merck Serono, BMS Celgene, Sanofi Genzyme, Roche, and Novartis. T.M. disclosed fees as scientific adviser from Biogen, MedDay, Novartis, Genzyme, Sanofi. A.R. disclosed consultancy fees, speaker fees, research grants (non-personal), and honoraria approved by the institutions from Novartis, Biogen Idec, Genzyme, Roche, and Merck. E.T. disclosed consulting and lecturing fees, travel grants, or unconditional research support from Actelion, Biogen, Celgene, Genzyme, Merck Serono, Novartis, Roche, Teva Pharma; has a patent pending for biomarkers of neurodegeneration and neuroregeneration and a patent pending for a diagnosis method of MS (EP18305630.8); and received academic research support from PHRC and ARSEP Foundation. S.V. disclosed lecturing fees, travel grants, and research support from Biogen, BMS Celgene, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, Teva. H.Z. disclosed consulting or lectures, and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi Genzyme, Novartis and Bayer, and research support from Teva and Roche, and academic research grants from Académie de Médecine, LFSEP, FHU Imminent, and ARSEP Foundation. G.D. disclosed Consulting and lecturing fees for Biogen, Novartis, Genzyme, Merck Serono, Roche, and Teva and funding for travel from Merck Serono, Biogen, Sanofi Genzyme, Novartis, and Teva. Institution granted for research support from Merck Serono, Biogen, Genzyme, and Novartis. E.L. disclosed consulting and lecture fees or travel grants from Biogen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Sanofi Aventis, and Roche.

Background: Studies have reported an association between socioeconomic status and disability progression in multiple sclerosis (MS), but findings using the pre-MS individual socioeconomic status are missing., Objective: The objective was to investigate the association between education level and disability progression., Methods: All Observatoire Français de la Sclérose en Plaques (OFSEP) patients with MS clinical onset over 1960-2014, and aged ⩾25 years at MS onset were included. Education level was classified into four categories from low (primary/secondary school) to very high (master/doctoral degree). Time from MS onset to EDSS 4.0 was studied using flexible parametric survival models adjusted for age, period, and center, and stratified by phenotype (relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS)) and sex., Results: A total of 11,586 patients were included (women/men ratio = 2.5; age = 36.7 ± 8.6 years; follow-up duration 16.7 ± 9.3 years; 86.4% RMS). For women with RMS, the risk of reaching the outcome at 5 years was inversely associated with the education level (Hazard Ratio medium: 0.74 (0.63-0.87), high: 0.51 (0.43-0.62), very high: 0.39 (0.30-0.50) vs low). Results were similar for men. In PPMS, the risk was significantly different between the extreme groups (very high vs low) for women (0.45 (0.28-0.75)) and men (0.54 (0.32-0.91)), but no gradient was evident., Conclusion: Our study showed a strong association between education level and disability progression, regardless of sex and phenotype., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L., O.D., M.D., C.L.-F., and J.P. had nothing to disclose. E.B. disclosed honoraria and consulting fees from Novartis, Sanofi Aventis, Biogen, Genzyme, Roche, and Teva Pharma. J.-P.C. disclosed consulting and lecturing fees from Akcea, Alexion, Alnylam, Argenx, Biogen, Bristol Myers Squibb, CSL-Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Pharmalliance, UCB Pharma, Teva, and SNF-Floerger; travel grants from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL-Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck Serono, Natus, Novartis, Pfizer, Teva, and SNF-Floerger. J.C. disclosed consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Celgene-BMS, and Alexion. P.C. disclosed consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Janssen, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva Pharma. J.D.S. disclosed consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Roche, Sanofi Aventis, and Teva Pharma. O.H. disclosed consulting and lecturing fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, and BiogenIdec; travel grants from Novartis, Teva, Genzyme, Merck Serono, and Biogen Idec; and research support from Roche, Merck and Novartis. P.L. disclosed consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. D.A.L. disclosed served on scientific advisory boards for Alexion, BMS, Roche, Sanofi, Novartis, Merck, Janssen, and Biogen; received conference travel support and/or speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi, BMS, Teva Pharma, and Merck; and received research support from Fondation ARSEP, Fondation EDMUS, and Agence Nationale de la Recherche. E.L.P. disclosed consulting or lectures, and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi-Genzyme, and Novartis Alexion; research support from Teva and Biogen academic research grants from PHRC and LFSEP; and travel grant from ARSEP Foundation. T.M. disclosed fees as scientific adviser from Biogen, MedDay, Novartis, Genzyme, and Sanofi. A.R. disclosed consultancy fees, speaker fees, research grants (non-personal), and/or honoraria approved by the institutions from Novartis, Biogen Idec, Genzyme, Roche, and Merck. E.T. disclosed consulting and lecturing fees, travel grants, or unconditional research support from the following pharmaceutical companies: Actelion, Biogen, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharma; has a patent pending for biomarkers of neurodegeneration and neuroregeneration and a patent pending for a diagnosis method of multiple sclerosis (EP18305630.8); and received academic research support from PHRC and ARSEP Foundation. S.V. disclosed lecturing fees, travel grants, and research support from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. H.Z. disclosed consulting or lectures and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi-Genzyme, Novartis, and Bayer, as well as research support from Teva and Roche, and academic research grants from Académie de Médecine, LFSEP, FHU Imminent, and ARSEP Foundation. G.D. disclosed Consulting and lecturing fees for Biogen, Novartis, Genzyme, Merck Serono, Roche, and Teva and funding for travel from Merck Serono, Biogen, Sanofi-Genzyme, Novartis, and Teva. Institution granted for research supporting from Merck Serono, Biogen, Genzyme, and Novartis. E.L. disclosed consulting and lecture fees or travel grants from Biogen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Sanofi Aventis, and Roche.

Background and Objectives: Because myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder, the natural history of MOGAD is still not well described. The objective of this study was to describe the long-term outcomes of adult patients with MOGAD. In addition, we aimed to identify factors affecting relapse risk and neurologic outcomes., Methods: Clinical and biological data were obtained from patients with a first event of MOGAD and included in the French nationwide incident cohort between February 2014 and March 2017. Only patients aged 18 years or older at disease onset and with observation period of at least 3 months were included. Data were collected prospectively until July 2023 and registered in the dedicated French nationwide database. This form includes every relapse with phenotype description during follow-up, date of last assessment, final clinical outcome with Expanded Disability Status Scale score and visual acuity, and maintenance therapy. The probability of recurrence-free survival was assessed using the Kaplan-Meier method., Results: We included 128 patients. The onset phenotype was isolated optic neuritis in 81 patients (63.3%) and isolated myelitis in 25 patients (19.5%). The median follow-up duration was 77.8 months (range 3.2-111.2), with 49 patients (38.3%) experienced at least one relapse. Median times from onset to second and third attacks were 3.2 (1.0-86.2) and 13.0 (2.6-64.4) months, respectively. At the last assessment, Expanded Disability Status Scale Score was ≥3 and ≥6 in 22 (17.2%) and 6 (4.7%) patients, respectively. Eighty patients received at least one maintenance treatment. This treatment was initiated after the first attack in 47 patients (36.7% of the whole cohort) and at the time of a second attack in 25 (19.5%). Multivariate analysis revealed that initiating maintenance treatment after the first attack was associated with a lower relapse risk (OR = 0.26 [95% CI 0.11-0.62], p = 0.002). In patients receiving maintenance therapy after first attack, the 2-year, 4-year, 6-year, and 8-year relapse risks were 11%, 15%, 20%, and 20%, respectively. In other patients, the risks were 41%, 46%, 51%, and 56%., Discussion: The highest risk of a relapse in MOGAD occurs early, and initiating maintenance therapy from the first attack substantially reduced the relapse risk., Classification of Evidence: This study provides Class III evidence that initiating maintenance therapy from the first attack in patients with MOGAD reduces the relapse risk.

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

Background and Objectives: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS., Methods: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk., Results: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS ( p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04)., Conclusion: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

Background: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown., Objective: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests., Methods: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race)., Results: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03)., Conclusions: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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

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

Objective: To assess the efficacy of dalfampridine in patients with neuromyelitis optica spectrum disorder., Methods: We included 15 consecutive patients, who were started on a treatment of dalfampridine 10 mg twice daily for 2 weeks. Efficacy assessment was based on walking ability improvement using Timed-25-Foot Walk and 12-item Multiple Sclerosis Walking Scale tests., Results: The mean Timed-25-Foot Walk score was reduced from 14.8 (±2.4) to 11.3 (±1.9) seconds ( p  = 0.01). The mean score on the 12-item Multiple Sclerosis Walking Scale was reduced from 41.2 (±3.5) to 31.4 (±3.2) ( p  = 0.004)., Conclusion: Dalfampridine seems to be useful for symptomatic treatment of walking impairment in neuromyelitis optica spectrum disorder., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2024.)

Hematopoietic stem cell transplantation (HSCT) for severe ADs was developed over the past 25years and is now validated by national and international medical societies for severe early systemic sclerosis (SSc) and relapsing-remitting multiple sclerosis (MS) and available as part of routine care in accredited center. HSCT is also recommended, with varying levels of evidence, as an alternative treatment for several ADs, when refractory to conventional therapy, including specific cases of connective tissue diseases or vasculitis, inflammatory neurological diseases, and more rarely severe refractory Crohn's disease. The aim of this document was to provide guidelines for the current indications, procedures and follow-up of HSCT in ADs. Patient safety considerations are central to guidance on patient selection and conditioning, always validated at the national MATHEC multidisciplinary team meeting (MDTM) based on recent (less than 3months) thorough patient evaluation. HSCT procedural aspects and follow-up are then carried out within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and SFGM-TC accredited centres in close collaboration with the ADs specialist. These French recommendations were performed according to HAS/FAI2R standard operating procedures and coordinated by the Île-de-France MATHEC Reference Centre for Rare Systemic Autoimmune Diseases (CRMR MATHEC) within the Filière FAI2R and in association with the Filière MaRIH. The task force consisted of 3 patients and 64 clinical experts from various specialties and French centres. These data-derived and consensus-derived recommendations will help clinicians to propose HSCT for their severe ADs patients in an evidence-based way. These recommendations also give directions for future clinical research in this area. These recommendations will be updated according to newly emerging data. Of note, other cell therapies that have not yet been approved for clinical practice or are the subject of ongoing clinical research will not be addressed in this document., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Objectives: Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD., Methods: Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies-MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead-based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis., Results: We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset ( p = 0.611) and female sex predominance ( p = 0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences ( p = 0.716). Median EDSS at sampling was 3.2 (interquartile range [IQR] 2-7.7) in the AQP4+NMOSD group and 4 (IQR [3-6]) in the DS-NMOSD group ( p = 0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL p = 0.001; median 1.2 vs 0.5 pg/mL, p = 0.001; and median 61.4 vs 35 pg/mL, p = 0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782, p = 0.001, AUC GFAP: 0.762, p = 0.001, AUC UCH-L1: 0.723, p = 0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD., Discussion: Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.

Introduction: Immunological checkpoint inhibitors (ICI) have led to a therapeutic revolution in the management of many cancers and indications are increasing. Neurological complications seem to have a profile quite distinct from that of toxicities related to chemotherapy, although it is possible that some manifestations remain under-reported or misdiagnosed., Objectives: (i) To evaluate the value of a self-questionnaire in screening for neurological ICI-related complications. (ii) To investigate whether, apart from the subacute complications described in the literature, neurological complications of more insidious onset might occur., Method: Patients followed in dermatology department for skin cancers treated with ICI, completed every infusion a neurological screening auto-questionnaire. Patients were selected for a neurological expertise based on the questionnaire's data., Results: In total, 149 patients completed≥1 questionnaire, with a median delay of 174 days from the start of treatment. A total of 229 questionnaires were completed between July 2019 and December 2019. 38 patients were identified for a neurological consultation. None of these patients had a neurological event attributable to ICI. During the follow-up, only one patient had a neurological event related to ICI, which was not revealed by the questionnaire., Discussion: Neurological signs in ICI-treated-skin-cancer context are more often due to tumoral progression. Neurological complications of ICI remain rare and unpredictable. The systematic neurological questionnaire has not been shown to be useful in this context. These results highlight the need to educate patients about possible subacute signs that should lead to contact the treating physicians and the need for a close cooperation between dermatologists/oncologists and neurologists., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised., Objectives: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS)., Methods: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients' history of COVID-19 infection., Results: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients., Conclusion: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Exit strategies such as de-escalations have not been evaluated for rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that they are associated with disease reactivations and aimed to estimate this risk., Methods: We describe a case series of real-world de-escalations from the French NMOSD registry (NOMADMUS). All patients met the 2015 International Panel for NMO Diagnosis (IPND) diagnostic criteria for NMOSD. A computerized screening of the registry extracted patients with rituximab de-escalations and at least 12 months of subsequent follow-up. We searched for 7 de-escalation regimens: scheduled discontinuations or switches to an oral treatment after single infusion cycles, scheduled discontinuations or switches to an oral treatment after periodic infusions, de-escalations before pregnancies, de-escalations after tolerance issues, and increased infusion intervals. Rituximab discontinuations motivated by inefficacy or for unknown purposes were excluded. The primary outcome was the absolute risk of NMOSD reactivation (one or more relapses) at 12 months. AQP4+ and AQP4- serotypes were analyzed separately., Results: We identified 137 rituximab de-escalations between 2006 and 2019 that corresponded to a predefined group: 13 discontinuations after a single infusion cycle, 6 switches to an oral treatment after a single infusion cycle, 9 discontinuations after periodic infusions, 5 switches to an oral treatment after periodic infusions, 4 de-escalations before pregnancies, 9 de-escalations after tolerance issues, and 91 increased infusion intervals. No group remained relapse-free over the whole de-escalation follow-up (mean: 3.2 years; range: 0.79-9.5), except pregnancies in AQP+ patients. In all groups combined and within 12 months, reactivations occurred after 11/119 de-escalations in patients with AQP4+ NMOSD (9.2%, 95% CI [4.7-15.9]), from 0.69 to 10.0 months, and in 5/18 de-escalations in patients with AQP4- NMOSD (27.8%, 95% CI [9.7-53.5]), from 1.1 to 9.9 months., Discussion: There is a risk of NMOSD reactivation whatever the rituximab de-escalation regimen., Trial Registration Information: Registered on ClinicalTrials.gov: NCT02850705., Classification of Evidence: This study provides Class IV evidence that de-escalation of rituximab increases the probability of disease reactivation., (© 2023 American Academy of Neurology.)

Importance: In patients with multiple sclerosis (MS), factors associated with severe COVID-19 include anti-CD20 therapies and neurologic disability, but it is still unclear whether these 2 variables are independently associated with severe COVID-19 or whether the association depends on MS clinical course., Objective: To assess the association between anti-CD20 therapies and COVID-19 severity in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS)., Design, Setting, and Participants: This multicenter, retrospective cohort study used data from the COVISEP study, which included patients with MS and COVID-19 from February 1, 2020, to June 30, 2022, at 46 French MS expert centers, general hospitals, and private neurology practices. Eligible patients with RRMS were those treated with high-efficacy MS therapy (ie, anti-CD20, fingolimod, or natalizumab), and eligible patients with PMS were those younger than 70 years with an Expanded Disability Status Scale (EDSS) score of 8 or lower. Patients were monitored from COVID-19 symptom onset until recovery or death., Exposures: Current anti-CD20 therapy (ocrelizumab or rituximab)., Main Outcomes and Measures: The main outcome was severe COVID-19 (ie, hospitalization with any mode of oxygenation or death). All analyses were conducted separately in patients with RRMS and PMS using propensity score-weighted logistic regression. Subgroup analyses were performed according to COVID-19 vaccine status, sex, EDSS score, and age., Results: A total of 1400 patients, 971 with RRMS (median age, 39.14 years [IQR, 31.38-46.80 years]; 737 [76.1%] female) and 429 with PMS (median age, 54.21 years [IQR, 48.42-60.14 years]; 250 [58.3%] female) were included in the study. A total of 418 patients with RRMS (43.0%) and 226 with PMS (52.7%) were treated with anti-CD20 therapies. In weighted analysis, 13.4% and 2.9% of patients with RRMS treated and not treated with anti-CD20 had severe COVID-19, respectively, and anti-CD20 treatment was associated with increased risk of severe COVID-19 (odds ratio [OR], 5.20; 95% CI, 2.78-9.71); this association persisted among vaccinated patients (7.0% vs 0.9%; OR, 8.85; 95% CI, 1.26-62.12). Among patients with PMS, 19.0% and 15.5% of patients treated and not treated with anti-CD20 had severe COVID-19, respectively, and there was no association between anti-CD20 treatment and severe COVID-19 (OR, 1.28; 95% CI, 0.76-2.16). In PMS subgroup analysis, anti-CD20 exposure interacted negatively with EDSS score (P = .009 for interaction) and age (P = .03 for interaction); anti-CD20 therapies were associated with risk of severe COVID-19 only in patients with less neurologic disability and younger patients with PMS., Conclusions and Relevance: In this cohort study, risk of severe COVID-19 was higher in patients with PMS than in those with RRMS. Use of anti-CD20 therapies was associated with an increased risk of severe COVID-19 among patients with RRMS. In patients with PMS, there was no association between anti-CD20 therapies and risk of severe COVID-19.

Background: To characterise the response to treatment of inaugural optic neuritis (ON) in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: We searched the French MOGAD database for adults with inaugural ON with a detailed report of acute treatment modalities and measures of high-contrast best-corrected visual acuity (BCVA) at nadir and after 3 months. Predictors of visual outcomes were assessed by multivariable analysis., Results: Among 245 patients with at least one episode of ON, 82 fulfilled all criteria, and data on the peripapillary retinal nerve fibre layer (pRNFL) were available for 44. All patients received methylprednisolone (MP), combined with plasma exchange in 18. After 3 months, 75 of 82 (91%) patients retained full BCVA recovery, and median (range) pRNFL of the affected eye was 72 µm (40-102). Failure to regain 0.0 logarithmic minimum angle of resolution vision (Snellen 20/20) at 3 months was associated with time to first MP treatment ≥10 days (OR 16, 95% CI 1.14 to 213, p=0.01). pRNFL thickness after 3 months was related to better BCVA at nadir and time to first MP treatment <10 days (r2=19%, p=0.004 and r2=11%, p=0.03, respectively)., Conclusions: Time to MP affects functional but also structural visual outcomes of ON in MOGAD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice., Competing Interests: JS has received fees for serving on scientific advisory boards andconsulting, and research support from Novartis and Roche. EM has received research support from Fondation ARSEP and Biogen Idec, travel funding and/or consulting fees from Alexion, Biogen Idec, BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. AG has received personal compensation for consulting, lecturing and congress participation from Novartis, Alexon, AEI/Roche andNovartis. DL has received fees for board membership and consultancy and grants from Alexion, Actelion, BMS, Biogen,Merck, Novartis, Roche, Sanofi and Teva. LM has received consulting fees from Biogen, Novartis Pharma, Teva, BMS, Roche,Sanofi-Genzyme and Janssen Cilag. ET has received honoraria, travel grants, or research grants from the following pharmaceutical companies: Actelion, Biogen, Bristol Myers Squibb/Celgene, Merck, Novartis, Roche, Teva. HZ has received personal fees from Novartisrelated to this work and consulting fees from Biogen, Roche,Alexion, Roche, BMS, Novartis and Merck, unrelated to this work. DB has received personal compensation for consulting,serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Celgene-BMS and Alexion. RL has received consultancy and speaker honoraria from Biogen, Sanofi-Genzyme, Merck-Serono,Novartis, Orion and GSK, and research grants from GSK, Population Bio and Roche. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de Sèze, Maillart, Gueguen, Laplaud, Michel, Thouvenot, Zephir, Zimmer, Biotti and Liblau.)

Background and Objectives: The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery)., Methods: We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up)., Results: We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate., Discussion: Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias., (© 2022 American Academy of Neurology.)

Background and Objective: Myelin-oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) frequently initiates during childbearing years. This study investigated the impact of pregnancy and post-partum on MOGAD activity., Methods: Retrospective analysis of clinical and demographic data from a multicenter French cohort of adult patients with MOGAD. All adult female patients who had a pregnancy after disease onset or in the year before disease onset were included. The annualized relapse rate was evaluated in patients who had a pregnancy after disease onset, to evaluate the impact of pregnancy and post-partum on MOGAD course., Results: Twenty-five informative pregnancies after disease onset were identified. No relapse was recorded during these pregnancies and only three relapses occurred during the first 3 months post-partum. The annualized relapse rate decreased from 0.67 (95% confidence interval: 0.40-1.10) during the pre-pregnancy period to 0 (95% confidence interval: 0-0.21) during pregnancy and to 0.22 (95% confidence interval: 0.09-0.53) during the first year post-partum. Among 144 female patients in their childbearing age recorded in the database, 18 (12.5%) reported their first symptoms during pregnancy or in the 12 months post-partum., Discussion: Our study suggests a marked reduction of MOGAD relapse rate during pregnancy and the post-partum period. Prospective studies on the role of pregnancy and delivery in MOGAD course are needed.

Introduction: Global lockdown in the context of the coronavirus disease 2019 (COVID-19) pandemic is an unprecedented experience. We report here the results of an anonymous questionnaire-based survey on the healthcare and control of chronic IMIDs (chronic immune-mediated inflammatory diseases) within the IMMINENT network during the French lockdown (March 17, 2020-May 11, 2020) and the 2-month period following the end of the lockdown (July 11, 2020). Methods: Two anonymous questionnaires were sent by email to 4500 patients who were followed in a university hospital for an IMID in the departments of gastroenterology, rheumatology, dermatology, pneumology, neurology, and internal medicine. Results: A total of 921/4500 (20.46%) responded to the first survey (impact of the lockdown), and 553/4500 (12.28%) to the second (impact at 2-months post-lockdown). Concerning the impact of the lockdown, 420/915 (45.9%) reported affected follow-up. Similarly, after the lockdown, 248/544 (45.6%) declared a negative impact on their follow-up. The repartition by departments of patients' perception of an altered follow-up during ( P  = .72) and at the end of the lockdown ( P  = .77) was not statistically different. Our study highlighted the effects of the COVID-19 pandemic and the restriction measures implemented on the self-reported impact felt by patients on the follow-up of their chronic IMIDs without significant differences among all departments. Conclusion: Our study is original by showing that patients, whatever the type of IMID, shared this same negative perception. This transdisciplinary study demonstrated the importance of a collaborative network among all departments., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: The effects of socio-economic status on mortality in patients with multiple sclerosis is not well known. The objective was to examine mortality due to multiple sclerosis according to socio-economic status., Methods: A retrospective observational cohort design was used with recruitment from 18 French multiple sclerosis expert centers participating in the Observatoire Français de la Sclérose en Plaques. All patients lived in metropolitan France and had a definite or probable diagnosis of multiple sclerosis according to either Poser or McDonald criteria with an onset of disease between 1960 and 2015. Initial phenotype was either relapsing-onset or primary progressive onset. Vital status was updated on January 1st 2016. Socio-economic status was measured by an ecological index, the European Deprivation Index and was attributed to each patient according to their home address. Excess death rates were studied according to socio-economic status using additive excess hazard models with multidimensional penalised splines. The initial hypothesis was a potential socio-economic gradient in excess mortality., Findings: A total of 34,169 multiple sclerosis patients were included (88% relapsing onset (n = 30,083), 12% progressive onset (n = 4086)), female/male sex ratio 2.7 for relapsing-onset and 1.3 for progressive-onset). Mean age at disease onset was 31.6 (SD = 9.8) for relapsing-onset and 42.7 (SD = 10.8) for progressive-onset. At the end of follow-up, 1849 patients had died (4.4% for relapsing-onset (n = 1311) and 13.2% for progressive-onset (n = 538)). A socio-economic gradient was found for relapsing-onset patients; more deprived patients had a greater excess death rate. At thirty years of disease duration and a year of onset of symptoms of 1980, survival probability difference (or deprivation gap) between less deprived relapsing-onset patients (EDI = -6) and more deprived relapsing-onset patients (EDI = 12) was 16.6% (95% confidence interval (CI) [10.3%-22.9%]) for men and 12.3% (95%CI [7.6%-17.0%]) for women. No clear socio-economic mortality gradient was found in progressive-onset patients., Interpretation: Socio-economic status was associated with mortality due to multiple sclerosis in relapsing-onset patients. Improvements in overall care of more socio-economically deprived patients with multiple sclerosis could help reduce these socio-economic inequalities in multiple sclerosis-related mortality., Funding: This study was funded by the ARSEP foundation "Fondation pour l'aide à la recherche sur la Sclérose en Plaques" (Grant Reference Number 1122). 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 "Investments for the Future" programme, under the reference ANR-10-COHO-002, Observatoire Français de la Sclérose en Plaques (OFSEP)., Competing Interests: Sarah Wilson, Fabien Rollot, Mathieu Fauvernier, Laurent Remontet, Laure Tron, Marc Debouverie, Jérôme de Sèze, Thibault Moreau, Christine Lebrun Frenay, Pierre Labauge, Jean Pelletier and Olivier Dejardin report no disclosures. Floriane Calocer: received funding for the present research from the ARSEP foundation for a Postdoctoral Fellowship (payment to the institution), from the “Réseau Bas-Normand pour la SEP” for a Postdoctoral Fellowship (payment to the institution), from the Regional Council of Normandy (payment to the institution), from the Ecole Doctorale of Caen University for a training in LSHTD to conduct this research (payment to the institution). She received support for attending meetings and/or travel from the ARSEP Foundation (paid directly to herself, unrelated to this work). Sandra Vukusic: received grants or contracts (paid to her university hospital) from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva; received consulting fees from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva (paid to her university hospital); received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva (paid to her university hospital); received support for attending meetings and/or travel from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, participated on a Data Safety Monitoring Board or Advisory Board for Biogen (contracts with her university hospital), all of the above unrelated to this work. Emmanuelle Le Page: received payment or honoraria for consulting or lectures from Biogen, Merck, Teva, Sanofi-Genzyme, Novartis Alexion; received research support from Teva and Biogen, and received academic research grants from PHRC and LFSEP, and a travel grant from the ARSEP Foundation; received payment for consulting from Biogen, Merck, Sanofi-Genzyme, and Novartis; received invitations for national and international congresses from Biogen, Merck, Sanofi-Genzyme, Novartis Alexion, all of the above unrelated to this work. Jonathan Ciron: participated on a Data Safety Monitory Board of Advisory Board with Biogen, Novartis, Merck, Sanofi, Roche, Alexion and BMS-Celgene (all unrelated to this work). Aurélie Ruet: Consultancy fees from Roche and Biogen, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, Roche, Biogen, research grants (paid to the institution) from Roche, Biogen and Sanofi-Genzyme, and support for attending meetings and/or travel from Biogen, Novartis and Alexion, all of the above unrelated to this work. Hélène Zephir: received research support for one PhD student from Roche, and research support for one MD student from FHU Imminent, consulting fees from Biogen IDEC (Symposium Biogen Idec in ISNI congress); received payment or honoraria for lectures from Merck, received payment or honoraria for lectures and boards from Novartis, all of the above unrelated to this work. David-Axel Laplaud: received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, Merck, Alexion, BMS, Roche and Novartis, all of the above unrelated to this work. Pierre Clavelou: received consulting fees from Biogen, Janssen, Medday, Merck, Novartis, Roche, Sanofi-Genzyme and Teva Pharma; and support for attending meetings and/or travel from Sanofi-Genzyme, and participated on a Data Safety Monitoring Board or Advisory Board for Medday, Merck and Novartis. All of the above unrelated to this work. Eric Berger: received consulting fees from Novartis, Sanofi Aventis, Biogen, Genzyme, Roche and Teva Pharma; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Sanofi Aventis, Biogen, Genyme, Roche and Teva Pharma (all of the above unrelated to this work). Olivier Heinzlef: consulting fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall and BiogenIdec, support for attending meetings and/or travel grants from Novartis, Teva, Genzyme, Merck Serono and Biogen Idec and other financial or non-financial interests from Novartis, Teva, Genzyme, Merck Serono and BiogenIdec (all of the above unrelated to this work). Eric Thouvenot: received grants or contracts from Novartis and Biogen (paid to the institution), consulting fees from Merck, Novartis, Biogen and Celgene (paid directly to himself); received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, Novartis, Biogen, Celgene (paid directly to himself). All of the above unrelated to this work. Jean Philippe Camdessanché: received grants or contracts from CSL-Behring, Grifols, Laboratoire Français des Biotechnologies, consulting fees from Akcea, Alexion, Alnylam, Argenx, Bristol Myers Squibb, Laboratoire Français des Biotechnologies, Pfizer, UCB Pharma, SNF-Floeger, received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL-Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck-Serono, Natus, Novartis, Pfizer, UCB Pharma and Teva. Received support for attending meetings and/or travel from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL-Behring, Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck-Serono, Natus, Novartis, Pfizer, Teva, SNF-Floeger, all of the above unrelated to this work. Emmanuelle Leray: received consulting fees from Alexion, Merck, Novartis, Roche and Biogen, received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi Genzyme, and received support for attending meetings and/or travel from Sanofi Genzyme, all of the above unrelated to this work. Gilles Defer Received research grants (paid to institution) from Biogen, Merck Serono, Novartis, Sanofi Genzyme; payment for speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Teva Pharmaceuticals, BMS; funding for travel from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Teva Pharmaceuticals; and personal compensation for scientific advisory boards from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Teva Pharmaceuticals, and BMS. All of the above unrelated to this work., (© 2022 The Author(s).)

Background and Objectives: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy., Methods: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation., Results: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80)., Discussion: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod)., Classification of Evidence: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy., (© 2022 American Academy of Neurology.)

Background and Objectives: Pure relapsing short myelitis with clinical and paraclinical features suggesting multiple sclerosis (MS) has been described recently. Here, we evaluated the existence of this potential new form of MS by retrospectively searching for similar cases in the databases of the French tertiary MS centers., Methods: Patients were included based on the present criteria: at least 2 short (<3 vertebral segments) myelitis episodes; minimum follow-up of 3 years; no MS-like brain lesion during all the follow-up; tested negative for both anti-myelin oligodendrocyte glycoprotein and anti-aquaporin 4 antibodies in serum; presence of oligoclonal bands in CSF; and comprehensive workup to exclude alternative diagnoses., Results: Eighteen patients fulfilled all criteria. The sex ratio (females/males) was 5/1; the median (range) age at first relapse was 35.5 (25-54) years, the disease duration was 80.5 (50-308) months, and the annualized relapse rate was 0.36 (0.1-0.5). The median (range) number of relapses per patient was 2 (2-5), and the median (range) Expanded Disability Status Scale score at last follow-up was 1 (0-7.5). In CSF, the median (range) protein level was 0.34 g/L (0.18-0.77), and the median (range) number of mononuclear cells was 3 (0-28). Spinal cord MRI demonstrated a median (range) number of 2 (1-5) lesions per examination and 3 [1-7] on the last examination. Fifty-five percent of lesions involved the cervical levels. Secondary progressive evolution occurred in 3 of 18 (17%) patients., Discussion: Pure spinal MS could be a rare entity in the MS disease spectrum. However, the existence of a distinct entity in the inflammatory CNS disorders cannot be excluded., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Neuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy., Methods: We performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as "good" if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome., Results: We included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was "good" in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response., Conclusions: We identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids., (© 2022. The Author(s).)

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing-remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Background and Objectives: Acute optic neuritis (ON) is a classical presenting symptom of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and anti-MOG-associated disorders. The resulting visual impairment is variable and can be severe. Clinicians are in need of predictive biomarkers to optimize the management of acute ON. In this longitudinal study (IRMANO, NCT03651662), we evaluated the ability of optic nerve lesion length measured on MRI at the acute phase of ON to predict retinal neuro-axonal loss and visual impairment at a chronic stage., Methods: We conducted a longitudinal study (IRMANO, NCT03651662) of patients who presented a clinical episode of ON (≤8 weeks). All patients underwent a retinal optical coherence tomography (OCT) and a brain/optic nerve MRI, including 3D double-inversion recovery (DIR) sequence at the acute phase of ON and 12 months later. Primary outcomes were optic nerve DIR hypersignal lesion length, macular ganglion cell-inner plexiform layer (GCIPL) volume measured on OCT, and low-contrast monocular visual acuity (LCMVA)., Results: The study group included 51 patients (33 women, mean age of 32.4 years ± 7.9). We recruited patients with a clinically isolated syndrome (n = 20), a relapsing-remitting MS (n = 23), an isolated ON (n = 6), and a first clinical episode of NMOSD (n = 2). Optic nerve DIR hypersignal was observed in all but 1 symptomatic optic nerves. At inclusion, the mean optic nerve lesion length (in mm) was 12.35 ± 5.98. The mean GCIPL volume (in mm 3 ) significantly decreased between inclusion (1.90 ± 0.18) and M 12 (1.67 ± 0.21; p < 0.0001). Optic nerve lesion length at inclusion was significantly associated with GCIPL thinning (estimate ± SD; -0.012 ± 0.004; p = 0.0016) and LCMVA at M 12 (0.016 ± 0.003; p < 0.001). Optic nerve lesion length significantly increased at M 12 (15.76 ± 8.70; p = 0.0007). The increase in optic nerve lesion length was significantly associated with the GCIPL thinning between inclusion and M 12 (-0.012 ± 0.003; p = 0.0011)., Discussion: At the acute phase of ON, optic nerve lesion length is an imaging biomarker predictive of retinal neuro-axonal loss and chronic visual impairment, which can help to stratify future therapeutic strategies in acute ON., Classification of Evidence: This study provides Class I evidence that optic nerve lesion length measured on MRI during the acute phase of a first episode of ON is associated with long-term retinal neuro-axonal loss and visual impairment., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD)., Methods: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab., Results: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD ( p = 0.04; for the brain) and in AQP4-IgG+ NMOSD ( p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy., Discussion: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined., Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest., Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score., Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51)., Conclusions: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used., Methods: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors., Results: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA., Interpretation: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown., Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria., Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021., Exposure: Diagnosis of RIS., Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors., Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%., Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups., Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation., Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants., Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5)., Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

Background: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS)., Objective: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS., Method: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity., Results: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group ( p  = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49, p  = 0.029)., Conclusion: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening., Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting., Results: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod., Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Today, there are no recommendations on switching disease-modifying treatments (DMTs) in multiple sclerosis (MS)., Objectives: To establish guidelines on switching DMTs MS., Methods: A Steering Committee composed of seven MS experts from the French Group for Recommendations in Multiple Sclerosis (France4MS) defined 15 proposals. These proposals were then submitted to a Rating Group, composed of 48 French MS experts, for evaluation. The proposals were classified as 'appropriate', 'inappropriate' or 'uncertain'., Results: Switching from a first-line therapy to another first-line therapy or a second-line therapy could be done without a washout period. Switching from a second-line therapy to a first-line therapy could be done without a washout period with fingolimod or natalizumab, after 3 months with ocrelizumab or mitoxantrone, and, if disease activity occurs with alemtuzumab or cladribine. The switch from a second-line therapy to another second-line therapy could be done after a washout period of 1 month with fingolimod or natalizumab, after 3 months with ocrelizumab, after 6 months with mitoxantrone, and, if disease activity occurs, with alemtuzumab or cladribine., Conclusion: This expert consensus approach provides physicians with some guidelines on optimizing the benefit/risk ratio when switching DMTs in patients with MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)