Search

Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Background and purpose: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS).Methods: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow -up >= 1 year, and Expanded Disability Status Scale (EDSS) score >= 3, with >= 1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12 -month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.Results: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45- 0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41- 0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09- 1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.Conclusions: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age. This study was financially supported by the National Health and Medical Research Council of Australia (1129189, 1140766, 1080518) We thank the patients and their carers who have agreed to participate in the global MSBase cohort study. The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme, and Teva. The study was conducted separately and apart from the guidance of the sponsors. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been implicated in numerous chronic inflammatory diseases, including multiple sclerosis (MS). GM-CSF impacts multiple properties and functions of myeloid cells via species-specific mechanisms. Therefore, we assessed the effect of GM-CSF on different human myeloid cell populations found in MS lesions: monocyte-derived macrophages (MDMs) and microglia. We previously reported a greater number of interleukin (IL)-15

Purpose Describing patterns of use, including changes in dose and interruptions is challenging. Group-based trajectory modelling (GBTM) can be used to identify individuals with similar dose patterns. We provide an intuitive graphical representation of dose patterns in groups identified using GBTM. We illustrate our approach using two drugs with different combinations of available dosages. Methods We drew data on patients with MS followed from 1977 to 2014 in Montreal using two sub-cohorts of subjects. A sub-cohort of patients taking interferon-beta-1a and another of patients taking amitriptyline were identified from the initial cohort. We use GBTM to identify groups of patients with homogeneous dose patterns for each of the two drugs. We compared the graphical representation obtained from the fitted values of GBTM with our proposed approach, which consisted of using step functions whose values corresponded to the mode. Differences in characteristics across groups were identified using chi-squares and analysis of variance, both weighted by the posterior probability of group membership. Results Seven patterns of dose were identified for interferon-beta-1a and five for amitriptyline. The graphical representations of the patterns of dose from GBTM included values outside of the prescribed doses and did not capture changes in dose as clearly as the proposed representation using step functions. Conclusion Our proposed approach which is based on the mode at each visit in each pattern provides an intuitive and realistic representation of dose patterns in groups identified with GBTM.

Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual. NHMRC [1129189, 1157717, 1140766]; Merck; Biogen; Novartis; Roche; Bayer; Schering; Sanofi Genzyme; Teva Pharmaceutical Industries

It is now well recognized that brain damage and/or atrophy apparent on MRI is only moderately correlated to cognitive functioning. The cognitive reserve (CR) hypothesis has been proposed to explain this functional heterogeneity, but it has only been addressed recently in the MS literature and has not yet been thoroughly investigated. The objective of this study is to examine the protective role of CR in cognition using a standardized CR tool in a population with a wide age range.A neuropsychological evaluation was performed on 84 pwMS aged between 27 and 78 years old and the CR Index questionnaire (CRIq) was used to estimate CR. The EDSS scale was used to assess the degree of neurologic impairment and estimate the disease burden.A moderating effect of CR was observed in the relationship between EDSS score and specific cognitive domains: processing efficiency, visuospatial learning and memory, as well as a tendency for verbal memory. In pwMS with a high level of CR, there was no negative relationship between these cognitive domains and EDSS.The results support the protective role of CR in a sample of pwMS with a wide age range. This role seems to be limited to specific cognitive tasks that pose a greater challenge and therefore require greater adaptability.

Objective: The aim of this study was to evaluate the effect of continuous positive airway pressure (CPAP) treatment on the Fatigue Severity Scale (FSS, preplanned primary outcome), another fatigue measure, sleep quality, somnolence, pain, disability, and quality of life in multiple sclerosis (MS) patients with obstructive sleep apnea-hypopnea (OSAH). Methods: In a randomized, double-blind trial (NCT01746342), MS patients with fatigue, poor subjective sleep quality, and OSAH (apnea-hypopnea index of ⩾ 15 events per hour/sleep), but without severe OSAH (apnea-hypopnea index > 30, and 4% oxygen desaturation index > 15 events/hour or severe somnolence), were randomized to fixed CPAP or sham CPAP for 6 months. Outcome assessments were performed at 3 and 6 months. Results: Of 49 randomized patients, 34 completed the protocol. Among completers, FSS did not improve with CPAP compared to sham at 6 months. FSS tended to improve ( p = 0.09), and sleepiness (Epworth Sleepiness Scale) improved significantly ( p = 0.03) at 3 months with CPAP compared to sham, but there were no other improvements with CPAP at either study evaluation. Conclusion: In non-severe OSAH patients, CPAP did not significantly improve the primary outcome of FSS change at 6 months. In secondary analyses, we found a trend to improved FSS, and a significant reduction in somnolence with CPAP at 3 months.

Background: Recent progress in multiple sclerosis (MS) management has contributed to a greater life expectancy in persons with MS. Ageing with MS comes with unique challenges and bears the potential to greatly affect quality of life and socioeconomic burden. Objectives: To compare frailty in ageing persons with multiple sclerosis (pwMS) and controls; to correlate frailty with MS clinical characteristics. Methods: PwMS and controls over 50 years old were recruited in a cross-sectional study. Two validated frailty measures were assessed: the frailty index and the Fried’s phenotype. Several multiple linear regressions accounting for demographic and clinical characteristics were performed. Results: Eighty pwMS (57 females, mean age 58.5 ± 6 years old) and 37 controls (24 females, mean age 61 ± 6.5 years old) were recruited. Multivariable analysis identified significantly higher frailty index in pwMS (0.21 ± 0.12 vs 0.11 ± 0.08, p Conclusion: Our results suggest that frailty can be routinely assessed in pwMS. Increased frailty in MS patients suggests that, along with MS therapeutics, a tailored multidisciplinary approach of ageing pwMS is needed.

Objective: To estimate, among people with multiple sclerosis, the extent to which a personally tailored exercise programme (MSTEP©) resulted in greater improvements in exercise capacity and related outcomes over 12 months in comparison with general exercise guidelines. Design: Two-group randomized trial. Subjects: Ambulatory and sedentary. Interventions: MSTEP©, a personally adapted exercise regimen done on most days including two days of high intensity exercise; guidelines recommending 30 minutes of moderate intensity aerobic and strength training two times per week. Main measures: Primary outcome was peak oxygen consumption (VO2peak) at 12 months; secondary outcomes were composite measures of physical function, fatigue, and health-related quality of life. Results: In total, 137 people were randomized, 66 were lost over 12 months leaving 71 with outcome data, 34 in MSTEP© group, and 37 in the Guideline group. Exercise enjoyment and confidence and exercise-induced fatigue predicted retention. There were no differences between groups on the proportion making a 10% increase in VO2peak (27.1% MSTEP© vs 29.6% Guidelines; OR: 0.83; 95% CI: 0.23–3.08) by the 12 month assessment. The effect on fatigue was larger in the MSTEP© group than the Guideline groups (OR: 1.59; 95% CI: 0.93–2.74), the effect on physical function was more modest (OR: 1.35; 95% CI: 0.80–2.25), and null for health-related quality of life outcomes. Conclusions: The disappointing exercise retention suggests that people with multiple sclerosis may not consider exercise important to their brain health. Either type of exercise resulted in stable exercise capacity over 1 year in those sticking with the programme.

Background and ObjectivesIn multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor–like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS.MethodsExpression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP.ResultsUsing bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS.DiscussionCollectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.

The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (T

DICAM contributes to the pathogenesis of autoimmune neuroinflammation by promoting the migration of T H 17 lymphocytes across the blood-brain barrier.

The bacillus Calmette-Guerin (BCG) vaccine could reduce the incidence of multiple sclerosis (MS) through immunomodulation. Previous studies, presenting some limitations, reported no association. We re-examined this association in a large cohort focusing on relapsing-remitting MS (RRMS).The cohort included 400,563 individuals, and was linked with the Quebec provincial BCG vaccination registry and administrative health data. Individuals were followed up from 1983 to 2014 and then within Period 1 (1983-1996) and Period 2 (1997-2014), for the occurrence of MS. Incident MS cases were defined as those with ≥3 hospital or physician claims for MS. Subjects with ≥1 drug reimbursement for MS disease-modifying therapies were classified as RRMS. Cox proportional hazards regression was used to estimate hazard ratios (HRs) over the follow-ups, adjusting for potential confounders. Possible effect modification due to sex was assessed.A total of 178,335 (46%) individuals were BCG vaccinated. There were 274 (0.06%) incident MS cases identified in 1983-1996, and 1433 (0.4%) in 1997-2014. No association was found with RRMS, either in Period 1 (adjusted HR [HRFindings suggest that BCG vaccination does not decrease the risk of RRMS, and that future studies should consider phenotypes of MS.

Objective To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Methods Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included (modern cohort). Annualised relapse rates (ARR) were calculated before, during and after pregnancy. Predictors of intrapartum and early postpartum (1st3 months) relapse were determined by clustered logistic and Cox regression analyses, respectively. Results We included 1640 pregnancies from 1452 women. Disease-modifying therapy (DMT) used in the one-year preconception included natalizumab (n=219), fingolimod (n=147), dimethyl fumarate (DMF; n=57) and low-efficacy therapies (n=845). Preconception ARR by DMT class used before conception were: natalizumab, 0.29 (95% CI 0.22-0.37); fingolimod, 0.37 (0.28-0.49); DMF, 0.24 (0.13-0.41); low-efficacy, 0.29 (0.25-0.33); and none, 0.24 (0.19-0.31). Among women who used fingolimod or natalizumab, ARR increased during pregnancy. Intrapartum ARR decreased in preconception DMF, low-efficacy or no DMT groups. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p Conclusion Women with MS prescribed natalizumab or fingolimod preconception had higher rates of intrapartum and postpartum relapse. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 32-34 weeks gestation, with early re-initiation after delivery is an effective option to minimise relapse risks. Strategies of DMT use have to be balanced against potential foetal/neonatal complications.

Studies suggest that emotion recognition and empathy are impaired in patients with MS (pwMS). Nonetheless, most studies are restricted to young samples, to facial emotion recognition and to self-report assessments of empathy. The aims of this study are to determine the impact of MS and age on multimodal emotion recognition (facial emotions and vocal emotional bursts) and on socioemotional sensitivity (as reported by the participants and their informants). We also aim to investigate the associations between emotion recognition, socioemotional sensitivity, and cognitive measures.We recruited 13 young healthy controls (HC), 14 young pwMS, 14 elderly HC and 15 elderly pwMS. They underwent a short neuropsychological battery, an experimental emotion recognition task including facial emotions and vocal emotional bursts. Both participants and their study informants completed the Revised-Self Monitoring Scale (RSMS) to assess the participant's socioemotional sensitivity.There was a significant effect of age and group on recognition of both facial emotions and emotional vocal bursts, HC performing significantly better than pwMS, and young participants performing better than elderly participants (no interaction effect). The same effects were observed on self-reported socioemotional sensitivity. However, lower socioemotional sensitivity in pwMS was not reported by the informants. Finally, multimodal emotion recognition did not correlate with socioemotional sensitivity, but it correlated with global cognitive severity.PwMS present with multimodal emotion perception deficits. Our results extend previous findings of decreased emotion perception and empathy to a group of elderly pwMS, in which advancing age does not accentuate these deficits. However, the decreased socioemotional sensitivity reported by pwMS does not appear to be observed by their relatives, nor to correlate with their emotion perception impairments. Future studies should investigate the real-life impacts of emotion perception deficits in pwMS.

CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4+ T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4+ T lymphocytes is induced by TGF-β1 and TGF-β3, which promote a pathogenic phenotype. In addition, CD70 is associated with a TH1 and TH17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70-/-CD4+ T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4+ T lymphocytes. CD70+CD4+ T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory TH1/TH17 lymphocytes infiltrating the CNS.

Background The few observational studies that investigated the long-term effects of interferon-beta and glatiramer acetate were usually focused on progression to irreversible disability and other outcomes such as number of relapses and transition to secondary-progressive multiple sclerosis (SPMS) have been rarely studied. The objective of this paper is to estimate the effect of interferon-beta/glatiramer acetate on progression to irreversible disability, transition from relapsing-remitting multiple sclerosis (RRMS) to SPMS and the rate of relapses over 10 years. Methods Analyses included 2498 patients with confirmed diagnosis of RRMS followed in Montreal from 1977 to 2016. Marginal structural models with propensity score for treatment and censoring were used to account for potential confounding and attrition. Specifically, we used pooled logistic regression for progression to irreversible disability and transition to SPMS, and Poisson models for the rate of relapses. Results 77% of subjects were female and the median age at RRMS diagnosis was 35 years. The hazard of progression to irreversible disability was lower among treated patients than untreated patients (HR=0.73, 95% CI [0.57–0.94]). We did not find evidence of an association between interferon-beta/glatiramer acetate and the rate of transition to SPMS either over the 3-month intervals or for the duration of treatment. Patients treated for >5 years had a lower rate of relapses compared to those untreated (HR=0.70, 95% CI [0.57–0.86]). Conclusion Treatment with interferon-beta/glatiramer acetate suggests a beneficial effect on progression to irreversible disability and rate of relapses, but not on transition to SPMS.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform meth-odologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed. BiogenBiogen; NovartisNovartis; MerckMerck & Company; RocheRoche Holding; Teva; Sanofi GenzymeSanofi-AventisGenzyme Corporation; NHMRCNational Health and Medical Research Council of Australia [1140766,1129789, 1157717]; French State; Agence Nationale de la Recherche-French National Research Agency (ANR)European Commission [ANR-10-COHO-002]; Eugene Devic EDMUS Foundation; ARSEP Foundation

International audience; Objective: To explore the associations of patient and disease characteristics with the duration of therapeutic lag for relapses and disability progression.Background: Therapeutic lag represents the delay from initiation of therapy to attainment of full treatment effect. Understanding the determinants of therapeutic lag provides valuable information for personalised choice of therapy in multiple sclerosis (MS).Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment follow up and yearly review were included in the analysis. By studying incidence of relapses and 6-month confirmed disability progression, the duration of therapeutic lag was calculated by identifying the first local minimum of the first derivative after treatment start in subgroups stratified by patient and disease characteristics. Pairwise analyses of univariate predictors were performed. Combinations of determinants that consistently drove differences in therapeutic lag in pair by pair analyses were included in the final model.Results: Baseline EDSS, ARR and sex were associated with duration of therapeutic lag on disability progression in univariate and pairwise bivariable analyses. In the final model, therapeutic lag was 27.8 weeks shorter in females with ARR6 compared to those with EDSS>=6 (26.6, 18.2–34.9 vs 54.3, 47.2–61.5). Baseline EDSS, ARR, sex and MS phenotype were associated with duration of therapeutic lag on relapses in univariate analyses. Pairwise bivariable analyses of the pairs of determinants suggested ependently associated with therapeutic lag. In the final model, therapeutic lag was shortest in those with RRMS and EDSS

Objectives Pro‐ and anti‐inflammatory properties have been attributed to interleukin‐27 (IL‐27). Nevertheless, the impact of this cytokine on chronic inflammatory diseases such as multiple sclerosis (MS) remains ill‐defined. We investigated the biology of IL‐27 and its specific receptor IL‐27Rα in MS patients. Methods Levels of IL‐27 and its natural antagonist (IL‐27‐Rα) were measured by ELISA in biological fluids. CD4+ and CD8+ T lymphocytes were isolated from untreated relapsing–remitting MS patients and healthy donors. Transcriptome‐wide analysis compared T‐cell subsets stimulated or not with IL‐27. Expression of the IL‐27Rα, key immune factors, STAT phosphorylation and cytokine production was assessed by flow cytometry. Results We observed elevated levels of IL‐27 in the serum and cerebrospinal fluid of MS patients compared with controls. Moreover, we show that specific IL‐27‐mediated effects on T lymphocytes are reduced in MS patients including the induction of PD‐L1. IL‐27‐triggered STAT3 signalling pathway is enhanced in CD4+ and CD8+ T lymphocytes from MS patients. Elevated IL‐27Rα levels in serum from MS patients are sufficient to impair the capacity of IL‐27 to act on immune cells. We demonstrate that shedding of IL‐27Rα by activated CD4+ T lymphocytes from MS patients contributes to the increased IL‐27Rα peripheral levels and consequently can dampen the IL‐27 responsiveness. Conclusion Our work identifies several mechanisms that are altered in the IL‐27/IL‐27R axis in MS patients, especially in T lymphocytes. Our results underline the importance of characterising the biology of cytokines in human patients prior to design new therapeutics., T lymphocytes play a central role in the pathobiology of chronic inflammatory diseases including multiple sclerosis (MS). We identified perturbations in the IL‐27/IL‐27R pathway in MS patients; IL‐27 triggers higher STAT3p response in T lymphocytes from MS vs. controls and induces PD‐L1 less efficiently on T cells from MS patients. Moreover, elevated IL‐27Rα levels in serum from MS patients, shed from activated CD4 T lymphocytes, are sufficient to impair the capacity of IL‐27 to act on immune cells.

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients’ sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed withweighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15–41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65–0.88); in those aged ≤38 years (0.64; 0.54–0.76); in those withdisease duration ≤7 years (0.63; 0.53–0.76); in those with EDSS score 38 years (1.34; 1.04–1.73); those with disease duration >7 years (1.33; 1.01–1.74); those with EDSS score

ObjectiveTo investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.MethodsUsing data from the MSBase Registry, we included pregnancies conceived after December 31, 2010, in women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses.ResultsWe included 1,998 pregnancies from 1,619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% confidence interval 0.27–0.32), fell to 0.19 (0.14–0.24) in the third trimester, and increased to 0.59 (0.51–0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28–0.49) and 0.29 (0.22–0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (odds ratio 0.76 per month [0.60–0.95], p = 0.017). DMT reinitiation with natalizumab protected against postpartum relapse (hazard ratio [HR] 0.11 [0.04–0.32], p < 0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41–0.91], p = 0.016). We found that 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum.ConclusionIntrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation with early reinitiation after delivery is an effective option to minimize relapse risks. Strategies of disease-modifying therapy use have to be balanced against potential fetal/neonatal complications.

The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.

Background:Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.Objective:The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.Methods:This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.Results:The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37, p Conclusion:Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.

Background:Although cognitive deficits are frequent in multiple sclerosis (MS), screening for them with tools such as the Montreal Cognitive Assessment (MoCA) test is usually not performed unless there is a subjective complaint. The Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) is among the instruments most commonly used to assess self-reported subjective complaints in MS. Nonetheless, it does not always accurately reflect cognitive status; many patients with cognitive deficits thus fail to receive appropriate referral for detailed neuropsychological evaluation. The objective of this study was to examine the validity of the MoCA test to detect the presence of objective cognitive deficits among patients with MS without subjective complaints using the Minimal Assessment of Cognitive Function in MS (MACFIMS) as the gold standard.Methods:The sample included 98 patients who were recruited from a university hospital MS clinic. The MSNQ was used to select patients without subjective cognitive complaints who also completed the MACFIMS, MoCA test and MSQOL-54.Results:23.5% of patients without subjective cognitive complaints had evidence of objective cognitive impairment on the MACFIMS (z score < -1.5 on two or more tests). The MoCA had a sensitivity of 87% and a specificity of 68% for detecting objective cognitive impairment in this patient population using a cut-off score of 27.Conclusion:A significant proportion of patients without self-reported cognitive impairment do have evidence of cognitive deficits on more exhaustive cognitive assessment. The MoCA is a rapid screening test that could be used to target patients for whom a more detailed neuropsychological assessment would be recommended.

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset. Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model. Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p

none 24 si Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: The rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P =.009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS. open Lizak N.; Malpas C.B.; Sharmin S.; Havrdova E.K.; Horakova D.; Izquierdo G.; Eichau S.; Lugaresi A.; Duquette P.; Girard M.; Prat A.; Larochelle C.; Trojano M.; Grand'maison F.; Grammond P.; Sola P.; Ferraro D.; Hupperts R.; Bergamaschi R.; Boz C.; Van Pesch V.; Spitaleri D.; Terzi M.; Kalincik T. Lizak N.; Malpas C.B.; Sharmin S.; Havrdova E.K.; Horakova D.; Izquierdo G.; Eichau S.; Lugaresi A.; Duquette P.; Girard M.; Prat A.; Larochelle C.; Trojano M.; Grand'maison F.; Grammond P.; Sola P.; Ferraro D.; Hupperts R.; Bergamaschi R.; Boz C.; Van Pesch V.; Spitaleri D.; Terzi M.; Kalincik T.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis., National Health and Medical Research Council of Australia; Roche; Merck; Biogen; Novartis; Bayer Schering; Sanofi Genzyme; Teva

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; McCombe, Pamela/0000-0003-2704-8517; Altintas, Ayse/0000-0002-8524-5087; Jokubaitis, Vilija G./0000-0002-3942-4340; Slee, Mark/0000-0003-4323-2453; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Vucic, Steve/0000-0002-8323-873X WOS: 000481049900001 PubMed: 31397221 Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766]; BiogenBiogen; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva; MerckMerck & Company; NovartisNovartis The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1083539 and 1129189 and fellowship 1140766). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Roche, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.