Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and is associated with the risk of disease activity, but data on the benefits of supplementation are conflicting. To evaluate the efficacy of high-dose cholecalciferol as monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) typical for MS. The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial in 36 MS centers in France. Patients were enrolled from July 2013 to December 2020 (final follow-up on January 18, 2023). Untreated patients with CIS aged 18 to 55 years with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria for dissemination in space or 2 or more lesions and presence of oligoclonal bands were recruited. Patients were randomized 1:1 to receive oral cholecalciferol 100 000 IU (n = 163) or placebo (n = 153) every 2 weeks for 24 months. The primary outcome measure was disease activity, defined as occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up, also analyzed as separate secondary outcomes. Of the 316 participants enrolled and randomized (median [IQR] age, 34 [28-42] years; 70% women), the primary analysis included 303 patients (95.9%) who took at least 1 dose of the study drug and 288 (91.1%) ultimately completed the 24-month trial. Disease activity was observed in 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P = .004), and median time to disease activity was longer in the vitamin D group (432 vs 224 days; log-rank P = .003). All 3 secondary MRI outcomes reported significant differences favoring the vitamin D group vs the placebo group: MRI activity (89 patients [57.1%] vs 96 patients [65.3%]; HR, 0.71 [95% CI, 0.53-0.95]; P = .02), new lesions (72 patients [46.2%] vs 87 patients [59.2%]; HR, 0.61 [95% CI, 0.44-0.84]; P = .003), and contrast-enhancing lesions (29 patients [18.6%] vs 50 patients [34.0%]; HR, 0.47 [95% CI, 0.30-0.75]; P = .001). All 10 secondary clinical outcomes showed no significant difference, including relapse, which occurred in 28 patients (17.9%) in the vitamin D group vs 32 (21.8%) in the placebo group (HR, 0.69 [95% CI, 0.42-1.16]; P = .16). Results were similar in a subset of 247 patients meeting updated 2017 diagnostic criteria for relapsing-remitting MS at treatment initiation. Severe adverse events occurred in 17 patients in the vitamin D group and 13 in the placebo group, none of which were related to cholecalciferol. Oral cholecalciferol 100 000 IU every 2 weeks significantly reduced disease activity in CIS and early relapsing-remitting MS. These results warrant further investigation, including the potential role of pulse high-dose vitamin D as add-on therapy. ClinicalTrials.gov Identifier: NCT01817166

Importance:Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and is associated with the risk of disease activity, but data on the benefits of supplementation are conflicting. Objective:To evaluate the efficacy of high-dose cholecalciferol as monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) typical for MS. Design, Setting, and Participants:The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial in 36 MS centers in France. Patients were enrolled from July 2013 to December 2020 (final follow-up on January 18, 2023). Untreated patients with CIS aged 18 to 55 years with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria for dissemination in space or 2 or more lesions and presence of oligoclonal bands were recruited. Intervention:Patients were randomized 1:1 to receive oral cholecalciferol 100 000 IU (n = 163) or placebo (n = 153) every 2 weeks for 24 months. Main Outcomes and Measures:The primary outcome measure was disease activity, defined as occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up, also analyzed as separate secondary outcomes. Results:Of the 316 participants enrolled and randomized (median [IQR] age, 34 [28-42] years; 70% women), the primary analysis included 303 patients (95.9%) who took at least 1 dose of the study drug and 288 (91.1%) ultimately completed the 24-month trial. Disease activity was observed in 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P = .004), and median time to disease activity was longer in the vitamin D group (432 vs 224 days; log-rank P = .003). All 3 secondary MRI outcomes reported significant differences favoring the vitamin D group vs the placebo group: MRI activity (89 patients [57.1%] vs 96 patients [65.3%]; HR, 0.71 [95% CI, 0.53-0.95]; P = .02), new lesions (72 patients [46.2%] vs 87 patients [59.2%]; HR, 0.61 [95% CI, 0.44-0.84]; P = .003), and contrast-enhancing lesions (29 patients [18.6%] vs 50 patients [34.0%]; HR, 0.47 [95% CI, 0.30-0.75]; P = .001). All 10 secondary clinical outcomes showed no significant difference, including relapse, which occurred in 28 patients (17.9%) in the vitamin D group vs 32 (21.8%) in the placebo group (HR, 0.69 [95% CI, 0.42-1.16]; P = .16). Results were similar in a subset of 247 patients meeting updated 2017 diagnostic criteria for relapsing-remitting MS at treatment initiation. Severe adverse events occurred in 17 patients in the vitamin D group and 13 in the placebo group, none of which were related to cholecalciferol. Conclusions and Relevance:Oral cholecalciferol 100 000 IU every 2 weeks significantly reduced disease activity in CIS and early relapsing-remitting MS. These results warrant further investigation, including the potential role of pulse high-dose vitamin D as add-on therapy. Trial Registration:ClinicalTrials.gov Identifier: NCT01817166.

Background and objectives Neuromyelitis optica spectrum disorders (NMOSDs) are a group of diseases mainly characterised by recurrent optic neuritis and/or myelitis. Most cases are associated with a pathogenic antibody against aquaporin-4 (AQP4-Ab), while some patients display autoantibodies targeting the myelin oligodendrocyte glycoprotein (myelin oligodendrocyte glycoprotein antibodies (MOG-Abs)). Anti-Argonaute antibodies (Ago-Abs) were first described in patients with rheumatological conditions and were recently reported as a potential biomarker in patients with neurological disorders. The aims of the study were to investigate if Ago-Abs can be detected in NMOSD and to evaluate its clinical usefulness. Methods Sera from patients prospectively referred to our centre with suspected NMOSD were tested for AQP4-Abs, MOG-Abs and Ago-Abs with cell-based assays. Results The cohort included 104 prospective patients: 43 AQP4-Abs-positive cases, 34 MOG-Abs positive cases and 27 double-negative patients. Ago-Abs were detected in 7 of 104 patients (6.7%). Clinical data were available for six of seven patients. The median age at onset of patients with Ago-Abs was 37.5 [IQR 28.8–50.8]; five of six patients tested positive also for AQP4-Abs. Clinical presentation at onset was transverse myelitis in five patients, while one presented with diencephalic syndrome and experienced a transverse myelitis during follow-up. One case presented a concomitant polyradiculopathy. Median EDSS score at onset was 7.5 [IQR 4.8–8.4]; median follow-up was 40.3 months [IQR 8.3–64.7], and median EDSS score at last evaluation was 4.25 [IQR 1.9–5.5]. Conclusion Ago-Abs are present in a subset of patients with NMOSD and, in some cases, represent the only biomarker of an autoimmune process. Their presence is associated with a myelitis phenotype and a severe disease course.

Erdheim–Chester disease (ECD) is a rare condition with underestimated neurological involvement. Mild psychiatric symptoms such as mood swings have been rarely described in the clinical spectrum of neuro-ECD. We here describe the first patient with psychiatric manifestations of delirium revealing ECD with neurological involvement with favorable evolution under interferon followed by BRAF inhibitor monotherapy. An 81-year-old woman was referred to the hospital because of delirium and severe cognitive impairment associated with a cerebellar syndrome. Brain magnetic resonance imaging showed “FLAIR-changes” lesions in the pons and upper cerebellum peduncles. Blood and cerebrospinal fluid (CSF) analyses showed normal results except for an elevated neopterin level in the CSF. Whole-body CT scan ( 18 FDG-PET) showed peri-nephric fat infiltration and aorta adventitia sheathing with radiotracer uptake in the pons, vessels, peri-nephric fat, and bone lesions, which was characteristic of ECD. The diagnosis was confirmed on perirenal tissue biopsy, which also showed a BRAF V600E mutation. Treatment with interferon resulted in the resolution of delirium, and treatment with BRAF inhibitor subsequently resulted in a partial remission of all active sites. This case highlights that delirium can be the first manifestation of neurodegenerative ECD. ECD should be screened in unexplained psychiatric features as interferon and targeted therapy appear to be effective in this situation.

Les manifestions psychiatriques ne sont pas décrites dans le spectre des atteintes neurologiques de la maladie d'Erdheim-Chester [1] ; en particulier en tant que première manifestation de la maladie [2]. Une femme caucasienne de 81 ans souffrait d'un délire associé à des hallucinations. Elle avait pour antécédents une maladie de Basedow, une occlusion de la veine rétinienne bilatérale et une dégénérescence maculaire. Le tableau débute par des hallucinations auditives 7 mois auparavant suivi d'hallucinations visuelles et de logorrhée deux mois plus tard. La patiente présentait également un délire de persécution avec des épisodes de confusion. Le tableau semblait peu évocateur d'un trouble psychiatrique pur débutant. Lors de l'hospitalisation, l'examen objective un syndrome cérébelleux (Assessement and rating Ataxia score : 13/40). La patiente présentait également des signes de décompensation cardiaque mal tolérée. L'échographie cardiaque objectivait une péricardite avec des signes de pré-tamponnade motivant un drainage. Le liquide était inflammatoire sans cellules néoplasiques. Sur le plan neurologique, l'IRM montrait des hyper-signaux en séquence T-2 FLAIR du pont et des pédoncules cérébelleux supérieurs. La ponction lombaire était sans particularités en dehors d'une élévation de la néoptérine. Le scanner thoraco-abdomino-pelvien objectivait un épaississement de la graisse péri-rénale bilatérale donnant un aspect de « rein-chevelu », ainsi qu'un épaississement de l'adventice de l'aorte. Le PET-TDM révélait un ostéosclérose bilatérale et symétrique des os long évocatrices de maladie d'Erdheim-Chester, une fixation du traceur sur la graisse péri-rénale, l'aorte et sur l'oreillette droite. Une pseudotumeur de l'oreillette droite fut détectée par l'IRM cardiaque. Le diagnostic de maladie d'Erdheim-Chester a été confirmé par une biopsie de la graisse péri-rénale montrant une infiltration diffuse composée d'histiocytes CD68+, CD1a- avec mutation du gène BRAFV600E par technique de pyroséquençage. La patiente a reçu un traitement par interféron alpha(180 μg/semaine 2 fois) en attente du statut BRAF puis une thérapie ciblée par inhibiteur de BRAF (Vemurafenib). Une régression des manifestations psychiatriques a débuté sous interféron et s'est intensifié sous thérapie ciblée. À huit semaines de traitements, le délire et les hallucinations avaient complétement disparu. L'IRM cérébrale montre une régression partielle des lésions du pont et du cervelet. Le PET montre également une diminution de la fixation du traceur. Après 8 semaines, le patient avait récupéré cliniquement. L'IRM cérébrale montrait une régression partielle des lésions. Le 18FDG-PET montre une réduction de l'absorption du radio traceur sur tous les sites ECD compatible avec une réponse métabolique partielle. Nous rapportons le premier cas de maladie d'Erdheim-Chester révélé par une présentation psychiatrique avec une amélioration spectaculaire sous thérapie ciblée.

Background. - The professional identities, profiles and representations of Burundian health workers remain insufficiently explored. Our twofold objective is to identify the different socio-professional profiles of first-line caregivers and to explore their respective representations of health workers and work. Methods. - The first study describes the overall population of the 1047 staff members employed in 2014-2015 in 62 health centers. The second is a cross-sectional survey conducted in April 2014. Using IRAMUTEQ (c) software, we conducted textology analysis of the structure and contents of 911 respondents' representations via 3 free associations with regard to 6 questions on the "good worker'' and the "what renders one capable of doing good work''. Results. - At the normative level, among all categories of staff, a relational role is a foundation of professional identity, while technical or administrative functions remain marginal. At the positional level, responses differed according to initial qualification level but not as a function of their role with patients or their professional experience. Three socio-professional categories emerged. The most qualified category (one-quarter of the population) consists primarily of male caregivers, with a high turnover rate (4 years) associated with prospects for further training and career development. These persons present the most professionalized representations of the worker and work. The second quarter has an average level of qualification and turnover (10 years), and is mainly composed of female caregivers with limited professional perspectives. This group's representations are less technical and more patient-centered. Finally, the remaining half consists of relatively low-skilled staff members in charge of technical and logistical support, who are likely to spend their entire career in the same center (> 20 years). Largely disregarded by the health care system and its funders, they have few opportunities for training or advancement and despite their long experience, maintain profane representations of workers and work. Conclusion. - Our results shed light on the predicament of unskilled staff members whose expectations are rarely taken into consideration, even though they represent a significant proportion of the workforce, perform tasks essential to quality of care, and serve as bearers of the memory of their hospital center. These results also highlight the compartmentalization of practices and knowledge between categories of workers and underscore the failure of continuous training strategies targeting the unskilled. (C) 2021 Published by Elsevier Masson SAS.

Objective To assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments. Methods Sixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection. Results In 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin. Conclusion This study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

Le Fingolimod et le Diméthylfumarate sont des traitements de fond des formes récurrentes-rémittentes de la Sclérose en Plaques, responsables d'une lymphopénie et d'infections virales, en particulier du virus varicelle-zona. Nous présentons 4 patients d'âge moyen 34,3 ans suivis pour Sclérose en Plaques de forme rémittente-récurrente, compliquées de condylomes à HPV sous traitement immunosuppresseur, sans antécédent connu d'infection à HPV. 3 étaient des patientes traitées par Fingolimod et présentaient une lymphopénie prolongée comprise entre 200 et 400/mm3. L'une a développé ces lésions après 6 ans de traitement immunosuppresseur, d'évolution favorable sous laser, cryothérapie, exérèse chirurgicale et arrêt du Fingolimod. Une réactivation des condylomes a été constatée après l'introduction du Tériflunomide. La seconde patiente a présenté des condylomes quelques mois après l'introduction du Fingolimod, nécessitant des ablations chirurgicales mensuelles. Une modification thérapeutique pour un anti-CD20 a entraîné une régression partielle des infections, avec ablation seulement trimestrielle. La troisième patiente a été suivie pour une condylomatose vulvo-périnéale, 5 ans après le début du Fingolimod, d'évolution favorable sous traitement médicamenteux local et laser. Enfin, nous rapportons le cas d'un patient ayant présenté des condylomes génitaux après quatre ans de traitement par Dimethylfumarate, sans lymphopénie. Ces condylomes ont été traités efficacement par Imiquimod et n'ont pas récidivé au maintien du traitement immunosuppresseur. Seulement 5 cas dans la littérature rapportent des infections cutanéo-muqueuses à HPV chez des patients atteints de Sclérose en Plaques et traités par Fingolimod, suggérant un risque plus élevé de cancers muqueux dans cette population de patients. La lymphopénie prolongée semble en être le principal mécanisme, même si nous n'avions pas objectivé d'anomalie lymphocytaire chez le patient traité par Dimethylfumarate. La description de plusieurs cas d'infections à HPV parfois délabrantes fait soulever la question de la vaccination spécifique dans cette population, en prévention des cancers du col utérin et ORL.

La maladie de Rosai-Dorfman est une histiocytose non-langerhansienne rare caractérisée principalement par une lymphadénopathie cervicale massive. Parmi les atteintes extra-ganglionnaires, celles du système nerveux central sont rares. Nous rapportons deux cas de localisations intracrâniennes différentes et de bon pronostic. Un homme de 71 ans a présenté une baisse d’acuité visuelle sévère avec phosphènes associés à des céphalées progressives. L’IRM cérébrale révèle des lésions méningées multiples et volumineuses aux étages sus et sous-tentoriels, apparaissant en iso-hyposignal T1, isosignal T2 avec rehaussement homogène intense après injection de gadolinium. Le scanner thoraco-abdomino-pelvien retrouve des adénopathies médiastinales et cervicales. Le PET-scanner met en évidence un hypermétabolisme associé. La biopsie d’un ganglion cervical pose le diagnostic d’histiocytose de Rosai-Dorfman. Une corticothérapie au long cours a permis une amélioration clinique et une réduction nette du volume lésionnel. Un patient de 22 ans a présenté une tuméfaction temporo-occipitale droite associée à des céphalées, révélatrices à l’imagerie d’une lésion ostéolytique extensive de la voûte crânienne. L’IRM cérébrale avec injection de gadolinium retrouve un rehaussement punctiforme du nerf optique gauche. Le bilan d’extension est négatif. Le diagnostic est posé par la biopsie-exérèse de la lésion. Un traitement neurochirurgical a été réalisé avec une évolution clinico-radiologique favorable. Les manifestations neurologiques, de localisations crâniennes ou médullaires, sont rares (< 5 %). Comme sus-décrit, elles peuvent être inaugurales, parfois isolées. Les diagnostics différentiels sont nombreux (syndrome IgG4 en particulier). L’analyse immuno-histologique retrouve une prolifération hystiocytaire avec cytoplasme éosinophile ou spumeux et immunophénotypage CD68+, PS100+ et CD1a-. Chez nos deux patients, nous observons une évolution favorable sans récidive après traitement. L’atteinte neurologique de la maladie de Rosai-Dorfman est diverse. Le diagnostic de certitude est anatomopathologique. Il n’existe pas de consensus thérapeutique mais le pronostic est bon dans la majorité des cas.

Question Has the incidence of natalizumab-associated progressive multifocal leukoencephalopathy decreased since the introduction of the John Cunningham virus serologic test and risk-stratification recommendations? Findings In this multicenter study of 6318 patients with multiple sclerosis enrolled in the French multiple sclerosis registry, incidence rates were found to have decreased significantly by 23% each year since January 2013, when risk-minimization guidelines were implemented, compared with a 45% yearly increase observed before 2013. Meaning This study suggests that risk-minimization strategies should be continued and reinforced in the future to manage disease-modifying drug therapy in multiple sclerosis. 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 Francais de la Sclerose 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. This study uses a French multiple sclerosis cohort to examine the risk of developing progressive multifocal leukoencephalopathy before and after the release of nationwide risk-minimization recommendations among people with multiple sclerosis who used natalizumab.

On behalf of all authors, we would like to thank Mr. Tugemann for his interest in our article.1 It is correct that acute progressive multifocal leukoencephalopathy (PML) can, in some circumstances, lead to high(er) CD62L values. However, as the study was conducted prospectively and, more importantly, alongside treatment, we reported all results of samples shipped to us back to the treating physicians. At the time of measurement and reporting, we were not aware of the patients' disease state. Because this is the situation to be expected in postmarketing settings, we chose to report all measured values, even if the samples turned out to be less than 6 months before PML diagnosis. Although the exclusion of these samples would indeed have led to a perfect sensitivity with the threshold of 36.05, we believed that it would not accurately reflect the real-world situation. Similarly, we chose not to focus on other PML risk stratification factors such as previous immune suppression or anti-JC virus antibody serostatus because we could not rely on having this information for all samples shipped to us. We, therefore, decided to report on the feasibility of measuring one biomarker rather than presenting a holistic approach for risk stratification using all available markers, which was addressed before.2 As supported by this study, CD62L was proven to be a useful biomarker for PML risk stratification also in the real-world setting but could also help with monitoring immunologic changes because of natalizumab-extended interval dosing. Owing to its initial detection in a retrospective cohort, the validated methodology3 still requires a mandatory freeze/thaw cycle, thereby limiting its widespread use. However, we would be more than happy if methodological improvements could be achieved here.

OBJECTIVE:In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques.METHODS:A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.RESULTS:The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, p < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, p < 0.001).CONCLUSIONS:After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.