Search

Background: SARS-CoV-2 seroconversion rate after COVID-19 may be influenced by disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMO-SD)., Objective: To investigate the seroprevalence and the quantity of SARS-CoV-2 antibodies in a cohort of patients with MS or NMO-SD., Methods: Blood samples were collected in patients diagnosed with COVID-19 between 19 February 2020 and 26 February 2021. SARS-CoV-2 antibody positivity rates and Ig levels (anti-S IgG titre, anti-S IgA index, anti-N IgG index) were compared between DMTs groups. Multivariate logistic and linear regression models were used to estimate the influence of DMTs and other confounding variables on SARS-CoV-2 serological outcomes., Results: 119 patients (115 MS, 4 NMO, mean age: 43.0 years) were analysed. Overall, seroconversion rate was 80.6% within 5.0 (SD 3.4) months after infection. 20/21 (95.2%) patients without DMT and 66/77 (85.7%) patients on DMTs other than anti-CD20 had at least one SARS-CoV-2 Ig positivity, while this rate decreased to only 10/21 (47.6%) for patients on anti-CD20 (p<0.001). Being on anti-CD20 was associated with a decreased odd of positive serology (OR, 0.07 (95% CI 0.01 to 0.69), p=0.02) independently from time to COVID-19, total IgG level, age, sex and COVID-19 severity. Time between last anti-CD20 infusion and COVID-19 was longer (mean (SD), 3.7 (2.0) months) in seropositive patients compared with seronegative patients (mean (SD), 1.9 (1.5) months, p=0.04)., Conclusions: SARS-CoV-2 antibody response was decreased in patients with MS or NMO-SD treated with anti-CD20 therapies. Monitoring long-term risk of reinfection and specific vaccination strategies in this population may be warranted., Trial Registration Number: NCT04568707., Competing Interests: Competing interests: Dr Louapre has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva and Merck Serono, and research grant from Biogen, none related to the present work. Dr Ibrahim has no disclosure. Dr Maillart has received consulting and lecturing fees, travel grants, from Ad Scientiam, Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi and Teva Pharma and research support from Biogen, Novartis and Roche, none related to the present work. Dr Abdi has no disclosure. Dr Papeix has received consulting or lecture fees from Alexion, Biogen, Medday, Merck, Roche, Novartis and Sanofi, none related to the present work. Professor Stankoff has received fees for advisory boards and lectures from Genzyme, Novartis, Teva and Biogen, and research support from Roche, Genzyme and Merck-Serono none related to the present work. Dr Dubessy has received consulting fees from Merck. Dr Bensa has received consulting or travel fees from Biogen, Genzyme, Novartis, Roche, Sanofi, Teva and Merck Serono, none related to the present work. Professor Creange has received grants and nonfinancial support from Medday, personal fees from Medday, personal fees from Merck, grants from Octapharma, grants and personal fees from Novartis, grants and personal fees from Roche, and grants and personal fees from Biogen, none related to the present work. Dr Chamekh has no disclosure. Professor Lubetzki has received grants and personal fees from Biogen, personal fees from Merck-Serono, personal fees from Roche, personal fees from Rewind, personal fees from Ipsen, none related to the present work. Professor Marcelin has received consulting fees and grants from VIIV Healthcare, Gilead and Merck, none related to the present work. Professor Corvol has served in advisory boards for Air Liquide, Biogen, Biophytis, Denali, Ever Pharma, Idorsia, Prevail Therapeutic, Theranexus, UCB, and received grants from Sanofi and the Michael J Fox Foundation, none related to the present work. Professor Pourcher has received consulting fees from Biogen, Novartis, Roche and Merck Serono none related to the present work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: To test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models., Methods: The effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting-sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures. In vivo, TF was administered orally, and remyelination was assessed both in myelin basic protein-GFP-nitroreductase ( Mbp:GFP-NTR ) transgenic Xenopus laevis demyelinated by metronidazole and in adult mice demyelinated by lysolecithin., Results: In cultures, low concentrations of TF down to 10 nM decreased OPC proliferation and increased their differentiation, an effect that was also detected on adult OPCs. Oligodendrocyte differentiation induced by TF was abrogated by the oxidosqualene cyclase inhibitor Ro 48-8071 and was mediated by the accumulation of zymosterol. In the demyelinated tadpole, TF enhanced the regeneration of mature oligodendrocytes up to 2.5-fold. In the mouse demyelinated spinal cord, TF promoted the differentiation of newly generated oligodendrocytes by a factor of 1.7-fold and significantly increased remyelination., Discussion: TF enhances zymosterol accumulation in oligodendrocytes and CNS myelin repair, a beneficial off-target effect that should be investigated in patients with multiple sclerosis., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing-remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator's normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39-0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9-47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials.

Background: Fatigue is one of the most disabling symptoms in Multiple Sclerosis (MS) patients and is associated with a low quality of life. Fingolimod (Fg), a sphingosine 1-phosphate receptor modulator, is the first oral MS disease modifying treatment. Little is known about its effect on fatigue. To assess the impact of Fg on fatigue within the first 6 months of treatment in MS patients, we conducted a prospective, open label study, in real life setting., Methods: Change of Modified Fatigue Impact Scale (MFIS) between Fg treatment start and at 6 months was used as a first outcome. Secondary outcomes were changes of MFIS subscales, Fatigue severity scale (FSS) and Visual Analogic Scale of Fatigue (VAS-F) scores, RESULTS: 54 completed the study at M6. No significant change was noted in global MFIS (and neither in sub analysis of MFIS), FSS or VAS-F at M6. Patients with high level of fatigue (MFIS or ≥38) had a higher EDSS score than patients with lower level of fatigue (MFIS <38), (mean 3.3, [SD 1.6] versus 1.6 [SD1.1], p=0.0002) but showed no significant difference in MFIS evolution at M6. There was no significant statistical difference in fatigue parameters evolution at M6 within patients Nz+ or Nz-., Conclusion: There is no significant impact of Fg on fatigue after 6 months of treatment., (Copyright © 2017. Published by Elsevier B.V.)

Background: Fingolimod is a widely used treatment for highly active relapsing-remitting multiple sclerosis., Objectives: To describe the case of a 27-year-old patient treated for more than 2 years by Fingolimod, who presented hemiplegia and speech disturbances associated with extensive white matter lesions on brain magnetic resonance imaging (MRI)., Methods: Case study., Results: Although initial presentation questioned the possibility of progressive multifocal leukoencephalopathy, final diagnosis was multiple sclerosis (MS) relapse. Appropriate treatment resulted in clinical and radiological improvement., Conclusion: Severe MS relapses under Fingolimod have been reported, but late onset after treatment initiation and extensive subcortical topography is unusual and represents a diagnostic challenge.

Background: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis., Methods: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed., Findings: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%)., Interpretation: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis., Funding: Novartis Pharma AG., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report two cases of multiple sclerosis (MS) patients with natalizumab-associated progressive multifocal leukoencephalopathy. Severe MS relapses occurred between four and five months after natalizumab discontinuation. After failure of immunomodulatory treatment, both patients were treated with fingolimod. The outcome was positive on clinical and MRI disease activity, without worsening of the progressive multifocal leukoencephalopathy. These observations suggest that using fingolimod for severe multiple sclerosis after natalizumab-associated progressive multifocal leukoencephalopathy may be an option, under close clinical and radiological monitoring.

Background: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI., Objective: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe., Methods: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years., Results: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44-0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (-28%, p=0.0209), fewer new T2 lesions/year (-42%, <0.0001) and lower T2 lesion volume (-22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate., Conclusions: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.

Multiple sclerosis is the main source of significant disability in young adults and is associated with inflammation, demyelinisation and neurodegeneration. Several trials in the past ten years have tested b interfons and other immunomodulators, with some success. Recently, Natalizumab (Tysabri), a monoclonal antibody which targets the a4-integrin expressed by immune effectors, thus preventing their migration from the circulation into the brain tissue, has demonstrated previously unseen efficacy in preventing relapses and disease progression in patients with remitting multiple sclerosis. However, this enthusiasm has been tempered by observed cases of opportunistic infection and especially progressive multifocal leucoencephalopathy, which led to its restricted use to a precise subgroup of patients. This example underlines the difficult evaluation of the benefit/risk ratio experienced by the pratician with these new and often very efficient innovative therapeutics.

Background: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis., Methods: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224., Findings: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%])., Interpretation: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI., Funding: Teva Pharmaceutical Industries, Israel.

Disease-modifying treatments in multiple sclerosis emerged during the last few years, concerning mainly relapsing-remitting forms of the disease. They are essentially represented by beta-interferons. beta-interferons reduce relapse rate, achieving about 30 p. cent, and have an effect on brain lesions detected on MRI. They are indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis characterized by at least 2 attacks of neurological dysfunction over the preceding 2 (or 3)-year period. Questions and controversies still remain concerning dose-response effect, early initiation and duration of treatment. Copolymer, which has a different mechanism of action, also decreases frequency of relapses, and the magnitude of the clinical effect is similar to beta-interferon. Copolymer is indicated for use in patients with relapsing-remitting multiple sclerosis, having either an intolerance or a contra-indication to beta-interferon.