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Background: Currently available predictive models for chemotherapy-related toxicity are not sufficiently discriminative in older patients with cancer and do not consider moderate toxicities. The purpose of this study was to identify factors associated with moderate and severe chemotherapy toxicities in older patients with cancer., Materials and Methods: Patients aged 70+ recruited in the prospective ELCAPA cohort were analyzed. A total of 837 patients with data on toxicities had received chemotherapy without other systemic treatment and were included between 2015 and 2022. To adjust for any imbalances in the distribution of covariates between patients receiving single-agent chemotherapy vs combination chemotherapy, we applied overlap weighting (a propensity-score-based technique). We used multinomial logistic regression., Results: Median (interquartile range) age was 81 (77-84). Forty-one percent experienced moderate toxicity, and 33% experienced severe toxicity. Hematologic toxicities accounted for 53% of severe toxicities and 66% of moderate toxicities. Age <80 years, cancer type, metastatic status, Eastern Cooperative Oncology Group performance status (ECOG-PS) >1, no cognitive impairment were associated with combination chemotherapy decision. In a univariate analysis with overlap weighting, no factors were associated with moderate toxicity. Hemoglobin < 10 g/dL and a CIRS-G score >12 were associated with severe toxicity. In a multivariate analysis, only hemoglobin < 10 g/dL was independently associated with severe toxicity, adjusted OR 2.96 (95% CI, 1.20-7.29)., Conclusion: By addressing indication bias for combination chemotherapy decision, only anemia and not cancer type, combination chemotherapy was predicting for severe chemotherapy-related toxicity in older patients with cancer. We did not find any predictors of moderate chemotherapy-related toxicity., (© The Author(s) 2024. Published by Oxford University Press.)

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.

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.

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.

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., 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: S.V. has received consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Janssen, Merck, Novartis, Roche, Sandoz, and Sanofi. B.B. has received consulting and lecturing fees, travel grants, and unconditional research support from Alexion, Biogen, Horizon, Janssen, Merck, Novartis, Roche, Sandoz, and Sanofi. R.C. has no financial disclosure to declare. K.D. has received consulting and lecturing fees, travel grants, and consulting fees for advisory boards from Alexion, Biogen, Horizon, Novartis, Roche, and Sanofi. A.M.G. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi, and Roche. F.R. and C.L.F. have no financial disclosure to declare. E.L. has received consulting and lecturing fees, and travel grants from Alexion, Merck, Novartis, Roche, and Sanofi. L.B. and C.G. have no financial disclosure to declare. R.M. has received personal fees from Horizon Therapeutics, Alexion, Roche, and UCB and non-financial support from Horizon Therapeutics, Merck, Biogen, and Roche, outside the submitted work. E.M. reports research support from Biogen and ARSEP foundation and personal fees for lectures and advisory boards from Biogen, Janssen, Merck, Novartis, Roche, Sanofi, and Teva.

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 (P MS ) and other causes (P other ): 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. P MS 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 P MS 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, P MS values remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the 2 frameworks, and the estimated P Other (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 P MS 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.

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.)

Purpose: The intended clinical value of frailty screening is to identify unfit patients needing geriatric assessment (GA) and to prevent unnecessary GA in fit patients. These hypotheses rely on the sensitivity and specificity of screening tests, but they have not been verified., Methods: We performed a cross-sectional analysis of outpatients age ≥ 70 years with prostate, breast, colorectal, or lung cancer included in the ELCAPA cohort study (ClinicalTrials.gov identifier: NCT02884375) between February 2007 and December 2019. The diagnostic accuracy of the G8 Geriatric Screening Tool (G8) and modified G8 scores for identifying unfit patients was determined on the basis of GA results. We used decision curve analysis to calculate the benefit of frailty screening for detecting unfit patients and avoiding unnecessary GA in fit patients across different threshold probabilities., Results: We included 1,648 patients (median age, 81 years), and 1,428 (87%) were unfit. The sensitivity and specificity were, respectively, 85% (95% CI, 84 to 87) and 59% (95% CI, 57 to 61) for G8, and 86% (95% CI, 84 to 87) and 60% (95% CI, 58 to 63) for the modified G8 score. For decision curve analysis, the net benefit (NB) for identifying unfit patients were 0.72 for G8, 0.72 for the modified G8, and 0.82 for GA at a threshold probability of 0.25. At a threshold probability of 0.33, the NBs were 0.71, 0.72, and 0.80, respectively. At a threshold probability of 0.5, the NBs were 0.68, 0.69, and 0.73, respectively. No screening tool reduced unnecessary GA in fit patients at predefined threshold probabilities., Conclusion: Although frailty screening tests showed good diagnostic accuracy, screening showed no clinical benefits over the GA-for-all strategy. NB approaches, in addition to diagnostic accuracy, are necessary to assess the clinical value of tests.

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.

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: 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., Competing Interests: Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FP, MR, CM, GS, XJ, and CdM are employees of Biogen and hold stocks of the company. LT and MC received consulting fees from Biogen. The funder participated in the study conception and design, interpretation of findings, and drafting of the manuscript. FP had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. SV and FR have nothing to disclose., (© The Author(s), 2022.)

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/β, 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.

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.)

Faced with an ageing population, carers are real allies and partners who are essential to the smooth running of the care of elderly patients. The objective of this study was to analyse their needs in oncogeriatrics, in order to verify the relevance of developing a serious game to support them. Although the need for better support for carers in oncogeriatrics was recognized, they especially value the need for human exchanges., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

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.