Anti-CD20 Therapies in Drug-Naive Patients With Primary Progressive Multiple Sclerosis: A Multicenter Real-Life Study.

BACKGROUND AND OBJECTIVES: Although rituximab failed to demonstrate a significant effect on disability progression in primary progressive multiple sclerosis (PPMS), ocrelizumab succeeded. Our main objective was to analyze confirmed disability progression (CDP) in a cohort of patients with PPMS treated with anti-CD20 therapies compared with a weighted untreated control cohort. METHODS: This was a retrospective study using data from the French MS registry (Observatoire Français de la Sclérose En Plaques). We included patients with PPMS treated or never treated with anti-CD20 therapies from 2016 to 2021, with an Expanded Disability Status Scale score of ≤6.5 at baseline. The primary outcome was time to first CDP. The secondary outcomes were time to first relapse, MRI activity at 2 years, identification of risk factors associated with CDP, and serious infection incidence rates (IIRs). Each outcome was studied using an inverse probability of treatment weighting method. The outcomes were modeled using a weighted proportional Cox model for the time-to-event outcomes and by a logistic regression regarding the MRI activity. RESULTS: A total of 1,184 patients (426 treated and 758 untreated) fulfilled the inclusion criteria. Median age (Q1-Q3) was 56 years (49.3-63.8), and 52.7% were female. Among treated patients, 295 received rituximab, whereas 131 received ocrelizumab. At baseline, anti-CD20-treated patients were younger (median 51.9 vs 58.6 years, Cohen d = 0.683) and had more active disease (54.5 vs 27.8%, Cohen d = 0.562). 91.6% were drug-naive at inclusion. In time to first CDP analysis, no statistical significance was observed (hazard ratio [HR], 1.13; 95% CI 0.93-1.36, p = 0.2113). In time to first relapse analysis, a nonsignificant trend toward fewer patients relapsing in the treated group was observed (HR 0.83; 95% CI 0.48-1.28, p = 0.0809). For MRI activity, no significant difference was found between the 2 groups. Risk factors associated with CDP in the treated group were male sex and MS duration. IIR was 6.67 (95% CI 3.12-14.25) per 100 person-years in the treated group vs 2.67 (95% CI 0.80-8.86) in the untreated group. DISCUSSION: Time to first CDP was not different between anti-CD20 treated and untreated patients with PPMS. Although our study is retrospective and mainly included patients treated by rituximab, our results indicate that there should be a constant evaluation of all available data to ascertain the best risk/benefit ratio for patients with PPMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-CD20 therapy of previously untreated patients with PPMS was not superior to no therapy in delaying time to first CDP.

Early Maintenance Treatment Initiation and Relapse Risk Mitigation After a First Event of MOGAD in Adults: The MOGADOR2 Study.

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.

Acute Clinical Events Identified as Relapses With Stable Magnetic Resonance Imaging in Multiple Sclerosis.

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.

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

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.

Holistic, Long-Term Management of People with Relapsing Multiple Sclerosis with Cladribine Tablets: Expert Opinion from France.

Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution therapy. In contrast to most high-efficacy DMTs, which act via continuous immunosuppression, two short courses of oral treatment with CladT at the beginning of years 1 and 2 of treatment provide long-term control of MS disease activity in responders to treatment, without the need for any further pharmacological treatment for several years. Although the labelling for CladT does not provide guidance beyond the initial treatment courses, real-world data on the therapeutic use of CladT from registries of previous clinical trial participants and patients treated in routine practice indicate that MS disease activity is controlled for a period of years beyond this time for a substantial proportion of patients. Moreover, this clinical experience has provided useful information on how to initiate and manage treatment with CladT. In this article we, a group of expert neurologists from France, provide recommendations on the initiation of CladT in DMT-naïve patients, how to switch from existing DMTs to CladT for patients with continuing MS disease activity, how to manage patients during the first 2 years of treatment and finally, how to manage patients with or without MS disease activity in years 3, 4 and beyond after initiating treatment with CladT. We believe that optimisation of the use of CladT beyond its initial courses of treatment will maximise the benefits of this treatment, especially early in the course of MS when suppression of focal inflammation in the CNS is a clinical priority to limit MS disease progression.

Efficacy of dalfampridine in neuromyelitis optica spectrum disorder: A pilot study.

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.

Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. OBJECTIVE: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). METHODS: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. RESULTS: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. CONCLUSION: These recommendations propose a strategic approach to managing cancer risk in PwMS.

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis.

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.

The Response Study: A French registry on pregnancy in women with MS and related disorders and their children up to 6 years-Protocol, recruitment status, and baseline characteristics.

BACKGROUND: Counseling on pregnancy is still challenging, particularly regarding the use of disease-modifying treatments (DMTs). We are lacking long-term outcomes in children exposed to DMTs. OBJECTIVES: This study aimed to set up a French pregnancy registry for women with multiple sclerosis (MS) and related disorders nested within the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. METHODS: Prospective, observational, multicentric, epidemiological study in France. Neurological visits are organized according to routine practice. Data are collected on the OFSEP minimal datasheet. Auto-questionnaires on pregnancy are completed by patients at Months 5-6 and 8 during pregnancy, and Months 3, 6, and 12 postpartum. A specific survey on analgesia is completed by anesthesiologists. Pediatric data are collected from the child's health book, where visits on Day 8, Month 9, and 24 are mandatory. Parents complete neurodevelopmental questionnaires at Year 1, Years 2 and 6. RESULTS: The RESPONSE study started in August 2019. On 7 April 2023, 515 women were included. Baseline demographics are presented. CONCLUSIONS: RESPONSE will provide rich information on the global management of pregnancy in France and prospective data on children until the age of 6 years, exposed or not to a DMT, including data on neurodevelopment that can be compared to the general population. STUDY FUNDING: EDMUS and ARSEP Foundation, Biogen, Roche.

COVID-19 outcomes in patients with multiple sclerosis: Understanding changes from 2020 to 2022.

BACKGROUND: Epidemiologic studies on coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (pwMS) have focused on the first waves of the pandemic until early 2021. OBJECTIVES: We aimed to extend these data from the onset of the pandemic to the global coverage by vaccination in summer 2022. METHODS: This retrospective, multicenter observational study analyzed COVISEP registry data on reported COVID-19 cases in pwMS between January 2020 and July 2022. Severe COVID-19 was defined as hospitalization or higher severity. RESULTS: Among 2584 pwMS with confirmed/highly suspected COVID-19, severe infection rates declined from 14.6% preomicron wave to 5.7% during omicron wave (p < 0.001). Multivariate analysis identified age (odds ratio (OR) = 1.43, 95% confidence interval (CI) = [1.25-1.64] per 10 years), male sex (OR = 2.01, 95% CI = [1.51-2.67]), obesity (OR = 2.36, 95% CI = [1.52-3.68]), cardiac comorbidities (OR = 2.36, 95% CI = [1.46-3.83]), higher Expanded Disability Status Scale (EDSS) scores (OR = 2.09, 95% CI = [1.43-3.06] for EDSS 3-5.5 and OR = 4.53, 95% CI = [3.04-6.75] for EDSS ⩾6), and anti-CD20 therapies (OR = 2.67, 95% CI = [1.85-3.87]) as risk factors for COVID-19 severity. Vaccinated individuals experienced less severe COVID-19, whether on (risk ratio (RR) = 0.64, 95% CI = [0.60-0.69]) or off (RR = 0.32, 95% CI = [0.30-0.33]) anti-CD20. DISCUSSION: In pwMS, consistent risk factors were anti-CD20 therapies and neurological disability, emerging as vital drivers of COVID-19 severity regardless of wave, period, or vaccination status.

Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum Disorder.

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.

Multiple sclerosis and bowel symptoms: Frequency and barriers to their management.

BACKGROUND: The frequency of bowel symptoms (BSs) is still a matter for debate in multiple sclerosis (MS) patients. However, BSs have been shown to cause significant distress. Our study aimed to (i) investigate the frequency of BSs, particularly those that are not managed, (ii) identify potential predictors for help-seeking care for patients with BSs, and (iii) evaluate the ability of the Neurogenic Bowel Dysfunction (NBD) score to screen for BSs. METHOD: Three hundred sixty-nine MS patients completed a cross-sectional demographic and clinical survey of MS and BSs and their management. RESULTS: BSs were reported by 47.7% of MS patients. Eighty-eight percent of MS patients had a very minor-minor Neurogenic Bowel Disorder (NBD) score and 12% had a moderate-severe NBD score. Forty-one percent of patients did not report their BS to a healthcare provider, mainly because they preferred not to talk about the problem. BS duration was the only significant predictor of help-seeking for BS management. Female sex, visual impairment, a digestive history, and longer MS duration were good predictors of BSs. Patients with BSs (86%) were correctly identified with an NBD score >2. CONCLUSION: BSs are under-detected in MS populations. This is partially related to non-declaration by patients. Targeting BSs using the NBD score is a good way to increase reporting.

Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial.

Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective: To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration: ClinicalTrials.gov Identifier: NCT03122652.

Impact of COVID-19 vaccination or infection on disease activity in a radiologically isolated syndrome cohort: The VaxiRIS study.

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.

Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients With Relapsing-Remitting and Progressive Multiple Sclerosis.

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.

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder.

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.

Time to steroids impacts visual outcome of optic neuritis in MOGAD.

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.

Pregnancy and neuromyelitis optica spectrum disorders: 2022 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: In 2020, the French Multiple Sclerosis (MS) Society (SFSEP) decided to develop a national evidence-based consensus on pregnancy in MS. As neuromyelitis optica spectrum disorders (NMOSD) shares a series of commonalities with MS, but also some significant differences, specific recommendations had to be developed. OBJECTIVES: To establish recommendations on pregnancy in women with NMOSD. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and universities databases (January 1975 through June 2021). The RAND/UCLA appropriateness method, which was developed to synthesise the scientific literature and expert opinions on health care topics, was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A sub-group of nine NMOSD experts was dedicated to analysing available data on NMOSD. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 66 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, loco-regional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses, and disease-modifying treatments. CONCLUSION: Physicians and patients should be aware of the new and specific evidence-based recommendations of the French MS Society for pregnancy in women with NMOSD. They should help harmonise counselling and treatment practise, allowing for better individualised choices.

Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society.

OBJECTIVE: The objective of this study was to develop evidence-based recommendations on pregnancy management for persons with multiple sclerosis (MS). BACKGROUND: MS typically affects young women in their childbearing years. Increasing evidence is available to inform questions raised by MS patients and health professionals about pregnancy issues. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and university databases (January 1975 through June 2021). The RAND/UCLA appropriateness method was developed to synthesise the scientific literature and expert opinions on healthcare topics; it was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 104 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, locoregional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses and disease-modifying treatments. CONCLUSION: The 2022 recommendations of the French MS society should be helpful to harmonise counselling and treatment practice for pregnancy in persons with MS, allowing for better and individualised choices.