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.

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.

Comparison of 2 Methods for Estimating Multiple Sclerosis-Related Mortality.

BACKGROUND AND OBJECTIVES: Determining whether multiple sclerosis (MS) causes death is challenging. Our objective was to contrast 2 frameworks to estimate probabilities of death attributed to MS (PMS) and other causes (Pother): the cause-specific framework (CSF), which requires the causes of death, and the excess mortality framework (EMF), which does not. METHODS: We used data from the Observatoire Français de la Sclérose en Plaques (OFSEP, n = 37,524) and from a comparative subset where causes of death were available (4,004 women with relapsing-onset MS [R-MS]). In CSF, the probabilities were estimated using the Aalen-Johansen method. In EMF, they were estimated from the excess mortality hazard, which is the additional mortality among patients with MS as compared with the expected mortality in the matched general population. PMS values were estimated at 30 years of follow-up, (1) with both frameworks in the comparative subset, by age group at onset, and (2) with EMF only in the OFSEP population, by initial phenotype, sex, and age at onset. RESULTS: In the comparative subset, the estimated 30-year PMS values were greater using EMF than CSF: 10.9% (95% CI 8.3-13.6) vs 8.7% (6.4-11.8) among the youngest and 20.4% (11.3-29.5) vs 16.2% (8.7-30.2) for the oldest groups, respectively. In the CSF, probabilities of death from unknown causes ranged from 1.5% (0.7-3.0) to 6.4% (2.5-16.4), and even after their reallocation, PMS values remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the 2 frameworks, and the estimated POther (EMF vs CSF) was 2.6% (2.5-2.6) vs 2.1% (1.2-3.9) and 18.1% (16.9-19.3) vs 26.4% (16.5-42.2), respectively, for the youngest and oldest groups. In the OFSEP population, the estimated 30-year PMS values ranged from 7.5% (6.4-8.7) to 24.0% (19.1-28.9) in patients with R-MS and from 25.4% (21.1-29.7) to 36.8% (28.3-45.3) in primary progressive patients, depending on sex and age. DISCUSSION: EMF has the great advantage of not requiring death certificates, their quality being less than optimal. Conceptually, it also seems more relevant because it avoids having to state, for each individual, whether death was directly or indirectly caused by MS or whether it would have occurred anyway, which is especially difficult in such chronic diseases.

Pregnancy and post-partum in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease.

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.

Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference.

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.

Effects of socioeconomic status on excess mortality in patients with multiple sclerosis in France: A retrospective observational cohort study.

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).

Overall and patient-level comparative effectiveness of dimethyl fumarate and fingolimod: A precision medicine application to the Observatoire Français de la Sclérose en Plaques registry.

Background: Comparing real-world effectiveness and tolerability of therapies for relapsing-remitting multiple sclerosis is increasingly important, though average treatment effects fail to capture possible treatment effect heterogeneity. With the clinical course of the disease being highly heterogeneous across patients, precision medicine methods enable treatment response heterogeneity investigations. Objective: To compare real-world effectiveness and discontinuation profiles between dimethyl fumarate and fingolimod while investigating treatment effect heterogeneity with precision medicine methods. Methods: Adults initiating dimethyl fumarate or fingolimod as a second-line therapy were selected from a French registry. The primary outcome was annualized relapse rate at 12 months. Seven secondary outcomes relative to discontinuation and disease progression were considered. A precision medicine framework was used to characterize treatment effect heterogeneity. Results: Annualized relapse rates at 12 months were similar for dimethyl fumarate and fingolimod. The odd of treatment persistence was 47% lower for patients treated with dimethyl fumarate relative to those treated with fingolimod (odds ratio: 0.53, 95% confidence interval: 0.39, 0.70). None of the five precision medicine scoring approaches identified treatment heterogeneity. Conclusion: These findings substantiated the similar effectiveness and different discontinuation profiles for dimethyl fumarate and fingolimod as a second-line therapy for relapsing-remitting multiple sclerosis, with no significant effect heterogeneity observed.

Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing-Remitting Multiple Sclerosis After Fingolimod Withdrawal.

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.

Estimation of sample size in randomized controlled trials in multiple sclerosis studying annualized relapse rates: A systematic review.

BACKGROUND: In multiple sclerosis (MS) studies, the most appropriate model for the distribution of the number of relapses was shown to be the negative binomial (NB) distribution. OBJECTIVE: To determine whether the sample-size estimation (SSE) and the analysis of annualized relapse rates (ARRs) in randomized controlled trials (RCTs) were aligned and compare the SSE between normal and NB distributions. METHODS: Systematic review of phase 3 and 4 RCTs for which the primary endpoint was ARR in relapsing remitting MS published since 2008 in pre-selected major medical journals. A PubMed search was performed on 30 November 2020. We checked whether the SSE and ARR analyses were congruent. We also performed standardized (fixed α/ß, number of arms and overdispersion) SSEs using data collected from the studies. RESULTS: Twenty articles (22 studies) were selected. NB distribution (or quasi-Poisson) was used for SSE in only 7/22 studies, whereas 21/22 used it for ARR analyses. SSE relying on NB regression necessitated a smaller sample size in 21/22 of our calculations. CONCLUSION: SSE was rarely performed using the most appropriate model. However, the use of an NB model is recommended to optimize the number of included patients and to be congruent with the final analysis.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

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.

Effects of Age and Disease Duration on Excess Mortality in Patients With Multiple Sclerosis From a French Nationwide Cohort.

OBJECTIVE: To determine the effects of current age and disease duration on excess mortality in multiple sclerosis (MS), we describe the dynamics of excess death rates over these 2 time scales and study the effect of age at MS clinical onset on these dynamics, separately in each initial phenotype. METHODS: We used data from 18 French MS expert centers participating in the Observatoire Français de la Sclérose en Plaques. Patients with MS living in metropolitan France and having a clinical onset between 1960 and 2014 were included. Vital status was updated on January 1, 2016. For each MS phenotype separately (relapsing onset [RMS] or primary progressive [PPMS]), we used an innovative statistical method to model the logarithm of excess death rates by a multidimensional penalized spline of age and disease duration. RESULTS: Among 37,524 patients (71% women, mean age at MS onset ± SD 33.0 ± 10.6 years), 2,883 (7.7%) deaths were observed and 7.8% of patients were lost to follow-up. For patients with RMS, there was no excess mortality during the first 10 years after disease onset; afterwards, whatever the age at onset, excess death rates increased with current age. From current age 70, the excess death rate values converged and became identical whatever the age at disease onset, which means that disease duration had no more effect. Excess death rates were higher in men, with an excess hazard ratio of 1.46 (95% confidence interval 1.25-1.70). In contrast, in patients with PPMS, excess death rates rapidly increased from disease onset, and were associated with age at onset, but not with sex. CONCLUSIONS: In RMS, current age has a stronger effect on MS mortality than disease duration, while their respective effects are not clear in PPMS.

Cumulative effects of therapies on disability in relapsing multiple sclerosis.

BACKGROUND: Long-term effectiveness of treatment remains a key question in multiple sclerosis (MS) and the cumulative effects of past treatment have not been investigated so far. OBJECTIVE: Explore the relationship between treatment exposure and disability risk in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A total of 2285 adult patients from the French nationwide cohort were included. Outcomes were irreversible EDSS4, and conversion to secondary progression of multiple sclerosis (SPMS). Associations between treatments and risk of disability were assessed using a novel weighted cumulative exposure model, assuming a 3-year lag to account for reverse causality. This flexible approach accounts for past exposure in a multivariate Cox proportional hazards model by computing a weight function. RESULTS: At baseline, mean ± standard deviation age of patients was 33.4 ± 8.9 years and 75.0% were women. A 15-year continuous treatment starting 20 years ago was associated with a decrease in risk of 26% for irreversible EDSS4, and 34% for SPMS compared to a 5-year treatment starting 10 years ago. The risk of disability decreased with increasing duration of exposure to disease-modifying treatment (DMT). CONCLUSION: Long-term use of treatments in RRMS has a stronger beneficial cumulative impact than only early uses and delays the occurrence of moderate disability and conversion to SPMS.

Aquaporin 4 distribution in the brain and its relevance for the radiological appearance of neuromyelitis optica spectrum disease.

BACKGROUND AND PURPOSE: To determine the precise incidence of lesions at sites of high Aquaporin-4 expression (hAQP4) and their possible association with known neuromyelitis optica spectrum disease (NMOSD) lesions patterns. MATERIALS AND METHODS: A retrospective analysis of brain and, when available, spinal cord MRI scans of 54 NMOSD patients recruited among the French NMOSD cohort was performed. Brain lesions were annotated as MS-like, non-specific, or evocative of NMOSD. The topography of hAQP4 was reassessed by human brain atlas. The incidence of lesions in hAQP4 and their association with lesions evocative of NMOSD was estimated. RESULTS: Among those included (41/54 female, mean age: 45 years) 47/54 (87%) presented brain lesions. Twenty-six/47 (55%) had lesions in hAQP4. Thirty-two/54 patients (60%) had lesions considered evocative of NMOSD. The majority of them also presented lesions in hAQP4 (65%, 21/32). Patients with lesions in hAQP4 and lesions evocative of NMOSD demonstrated more extensive myelitis compared to the other patients (7 [6-10] versus 4 [3-5] vertebral segments, P=0.009). CONCLUSION: The coexistence of lesions evocative of NMOSD and in hAQP4 is associated with significantly more extensive myelitis, and might have pathophysiological and clinical significance.

Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

OBJECTIVE: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD). METHODS: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives. RESULTS: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280). INTERPRETATION: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2021;89:30-41.

Predictive medicine in multiple sclerosis: A systematic review.

BACKGROUND: One of the main challenges in multiple sclerosis (MS) is to predict disease progression based on patient characteristics and therapeutic strategies. We therefore performed a systematic review to critically appraise the composite tools available for this purpose. METHODS: We performed electronic database searches in MEDLINE, EMBASE, Web of Science and the Cochrane Library. We included studies in English or French that developed and/or validated a predictive model for MS patients. Two reviewers independently screened articles by title and abstract. Three teams of two reviewers assessed the full text of each relevant study. RESULTS: Database searches yielded 6,035 studies after deduplication. Among the 42 screened full texts, 15 articles satisfied the eligibility criteria. Of these, six articles examined the development of predictive tools, six articles aimed to validate existing tools and three articles proposed both development and validation. We identified numerous methodological pitfalls, especially the lack of adequate validations in terms of discrimination and calibration. Only two scoring systems were externally validated several times: the Rio and the modified Rio scores. Nevertheless, their accuracies were highly variable, ranging from 65% to 91%. CONCLUSIONS: Overall, there is a lack of validated predictive tools in MS, and further external validation of the existing ones are required. Demonstration of the clinical usefulness is also needed prior to being transferred into clinical practice. Finally, our study illustrates that the MS literature needs to integrate good standards in developing and validating predictive models.

Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study.

OBJECTIVES: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis. MATERIAL AND METHODS: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0. RESULTS: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively), p = 0.007 and p = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group, p = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%), p < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0-4.0)) compared to SM patients (2.0, (1.0-3.0)), p = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01-1.95, p = 0.046). CONCLUSION: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.

Observatoire Français de la Sclérose en Plaques (OFSEP): A unique multimodal nationwide MS registry in France.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Frequency of myelin oligodendrocyte glycoprotein antibody in multiple sclerosis: A multicenter cross-sectional study.

OBJECTIVE: To address the frequency of myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) in an unselected large cohort of adults with MS. METHODS: This is a cross-sectional study in 2 MS expert centers (Lyon and Strasbourg University Hospitals, France) between December 1, 2017, and June 31, 2018. Patients aged ≥18 years with a definite diagnosis of MS according to 2010 McDonald criteria were tested for MOG-Ab by using a cell-based assay (CBA) in Lyon and subsequently included. Positive samples were tested by investigators blinded to the first result with a second assay in a different laboratory (Barcelona, Spain) by using the same plasmid and secondary Ab. RESULTS: Serum samples from 685 consecutive patients with MS were analyzed for MOG-Ab. Median disease duration at sampling was 11.5 (interquartile range, 5.8-17.7) years, and 72% were women. Two (0.3%) patients resulted to be MOG-Ab-positive. The 2 patients were women aged 42 and 38 at disease onset and were diagnosed with secondary and primary progressive forms of MS, respectively. This positive result was confirmed by the CBA in Barcelona. CONCLUSION: Our findings indicate that MOG-Ab are exceptional in MS phenotype, suggesting that the MOG-Ab testing should not be performed in typical MS presentation.