Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. ...Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.
We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.
Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 95% CI 0·86–20·85; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 95% CI 1·05–23·20; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.
We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab.
Biogen.
Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of ...developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.
To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.
The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.
COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.
The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 not hospitalized with no limitations on activities to 7 death) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.
A total of 347 patients (mean SD age, 44.6 12.8 years, 249 women; mean SD disease duration, 13.5 10.0 years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 95% CI, 1.4-2.5), EDSS (OR for EDSS ≥6, 6.3 95% CI. 2.8-14.4), and obesity (OR, 3.0 95% CI, 1.0-8.7) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).
In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
Background:
Long-term effectiveness of treatment remains a key question in multiple sclerosis (MS) and the cumulative effects of past treatment have not been investigated so far.
Objective:
Explore ...the relationship between treatment exposure and disability risk in patients with relapsing-remitting multiple sclerosis (RRMS).
Methods:
A total of 2285 adult patients from the French nationwide cohort were included. Outcomes were irreversible EDSS4, and conversion to secondary progression of multiple sclerosis (SPMS). Associations between treatments and risk of disability were assessed using a novel weighted cumulative exposure model, assuming a 3-year lag to account for reverse causality. This flexible approach accounts for past exposure in a multivariate Cox proportional hazards model by computing a weight function.
Results:
At baseline, mean ± standard deviation age of patients was 33.4 ± 8.9 years and 75.0% were women. A 15-year continuous treatment starting 20 years ago was associated with a decrease in risk of 26% for irreversible EDSS4, and 34% for SPMS compared to a 5-year treatment starting 10 years ago. The risk of disability decreased with increasing duration of exposure to disease-modifying treatment (DMT).
Conclusion:
Long-term use of treatments in RRMS has a stronger beneficial cumulative impact than only early uses and delays the occurrence of moderate disability and conversion to SPMS.
Background:
Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study.
Objective:
To confirm the efficacy and safety of ...MD1003 in progressive MS in a double-blind, placebo-controlled study.
Methods:
Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5–7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6–7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits.
Results:
A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo.
Conclusion:
MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.
Recent studies highlighted the importance of astrocytes in neuroinflammatory diseases, interacting closely with other CNS cells but also with the immune system. However, due to the difficulty in ...obtaining human astrocytes, their role in these pathologies is still poorly characterized. Here, we develop a serum-free protocol to differentiate human induced pluripotent stem cells (hiPSCs) into astrocytes. Gene expression and functional assays show that our protocol consistently yields a highly enriched population of resting mature astrocytes across the 13 hiPSC lines differentiated. Using this model, we first highlight the importance of serum-free media for astrocyte culture to generate resting astrocytes. Second, we assess the astrocytic response to IL-1β, TNF-α, and IL-6, all cytokines important in neuroinflammation, such as multiple sclerosis. Our study reveals very specific profiles of reactive astrocytes depending on the triggering stimulus. This model provides ideal conditions for in-depth and unbiased characterization of astrocyte reactivity in neuroinflammatory conditions.
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•Human iPSCs are differentiated from blood of control and multiple sclerosis subjects•Functional astrocytes are differentiated from hiPSC in serum-free conditions•In-depth characterization of the effect of serum on astrocyte phenotype•Multiple sclerosis cytokines trigger specific activation profiles in astrocytes
Perriot et al. describe a new protocol to differentiate both resting and reactive astrocytes from human induced pluripotent stem cells in serum-free conditions. They show that astrocytes exhibit highly contrasted responses to serum and to cytokines involved in multiple sclerosis, establishing that this model is suitable to study neuroinflammation.
Launched in the US in 2012, Choosing Wisely® is a campaign promoted by the American Board of Internal Medicine (ABIM) Foundation with the goal of improving healthcare effectiveness by avoiding ...wasteful or unnecessary medical tests, treatments and procedures. It uses concise recommendations produced by national medical societies to start discussions between physicians and patients on the relevance of these services as part of a shared decision-making process. The Multiple Sclerosis Focus Group (Groupe de Reflexion Autour de la Sclérose en Plaques; GRESEP) undertook a pilot study to assess the relevance and feasibility of this approach in the management of multiple sclerosis (MS) in France.
Recommendations were developed using the formal consensus method from the guidelines of the French National Health Authority (HAS). A steering committee selected the themes and drafted concise evidence reviews. An independent rating group then assessed these recommendations for clarity, relevance and feasibility.
Seven recommendations were accepted: (1) avoid systematic ordering of multimodal evoked potential studies for diagnosing MS; (2) do not treat MS relapses with low-dose oral corticosteroids; (3) when treating MS relapse with high-dose corticosteroids, the systematic use of the intravenous route is unnecessary if the oral route can be used; (4) systematic hospitalization is not necessary for treating MS relapse with high-dose corticosteroid therapy, particularly if the oral route is used, except for the first treated relapse and the presence of exclusion or non-eligibility criteria; (5) in the absence of clinical signs or symptoms of urinary infection, avoid systematic screening with urine microscopy and culture before the administration of corticosteroid therapy for MS relapse in patients using intermittent self-catheterization; (6) avoid antibiotic treatment of clinically asymptomatic MS patients using intermittent self-catheterization, even if urine microscopy and culture reveal the presence of microorganisms; and (7) avoid introducing symptomatic drug treatment for MS-related fatigue.
This pilot study, the first of its kind in France, has demonstrated the relevance and feasibility of adapting the Choosing Wisely® model to MS by practitioners specializing in the disorder. However, the acceptability of these recommendations by other practitioners in other specialist fields as well as their impact on everyday clinical practices now need to be studied.
Objective
We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5‐year risk for evolution from radiologically isolated ...syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10‐year, multinational, retrospectively identified RIS dataset.
Methods
RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models.
Results
Additional follow‐up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11–74 years), with a median clinical follow‐up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium‐enhanced lesions during follow‐up was also associated with the risk of a seminal event. The reason for MRI and gadolinium‐enhancing lesions at baseline did not influence the risk of a subsequent clinical event.
Interpretation
Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407–417.
Introduction
No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate‐to‐severe relapses of multiple sclerosis (MS).
Objective
To compare TPE ...to sham‐TPE in patients with a recent steroid‐resistant moderate‐to‐severe MS relapse.
Methods
Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate‐to‐severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month.
Results
Thirty‐eight patients were randomized. The intention‐to‐treat analysis included 14 patients in the TPE group and 17 in the Sham‐TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham‐TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed.
Conclusions
A significant difference between TPE and Sham‐TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham‐TPE group.
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