Publications by authors named "Marc Debouverie"

66 Publications

Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts.

CNS Drugs 2021 11 18;35(11):1217-1232. Epub 2021 Sep 18.

Neurology Unit, Garibaldi Hospital, Catania, Italy.

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 with weighted 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 with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51).

Conclusions: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity.
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http://dx.doi.org/10.1007/s40263-021-00860-7DOI Listing
November 2021

Comparative effectiveness of dimethyl fumarate in multiple sclerosis.

Br J Clin Pharmacol 2021 Sep 9. Epub 2021 Sep 9.

Univ. Bordeaux, INSERM CIC-P1401, Bordeaux PharmacoEpi, Bordeaux, France.

Aims: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse subject to treatment (ARRt) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real-life setting.

Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between 1 July 2015 and 12 December 2017, with 4.5 years of database history and 1-3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional propensity score. Negative binomial regression and a logistic regression model were used to estimate the relative risk (RR ± [95% CI]) of ARRt and the odds ratio (OR ± [95% CI]) of disability progression, respectively.

Results: Overall, 9304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF-IMM patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARRt compared to IMM (RR 0.72 [0.61-0.86]) and TERI (0.81 [0.68-0.96]) and did not show any significant difference when compared with FTY. The risk of the progression of MS-specific disability was not significantly different for any matched cohorts.

Conclusion: DMF is associated with lower risk of treated relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).
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http://dx.doi.org/10.1111/bcp.15071DOI Listing
September 2021

Effects of High- and Low-Efficacy Therapy in Secondary Progressive Multiple Sclerosis.

Neurology 2021 08 30;97(9):e869-e880. Epub 2021 Jun 30.

From the CORe (I.R., C.M., T.K.), Department of Medicine, University of Melbourne; Melbourne MS Centre (I.R., K.B., C.M., T.K.), Department of Neurology, Royal Melbourne Hospital, Australia; Rennes University (E.L.), EHESP, REPERES EA 7449; Univ Rennes (E.L.), CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes); Université de Lyon (R.C.), Université Claude Bernard Lyon 1; Hospices Civils de Lyon (R.C.), Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Bron; Observatoire Français de la Sclérose en Plaques (R.C.), Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292; EUGENE DEVIC EDMUS Foundation Against Multiple Sclerosis (R.C.), state-approved foundation, Bron, France; Department of Neurology and Center of Clinical Neuroscience (D.H., E.H.), First Faculty of Medicine, Charles University; General University Hospital (D.H., E.H.), Prague, Czech Republic; Hospital Universitario Virgen Macarena (G.I., S.E.M.), Sevilla, Spain; Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia; Multiple Sclerosis Center (F.P.), University of Catania, Italy; Centre hospitalier universitaire de Rennes (G.E.), Hôpital Pontchaillou, Service de neurologie, CIC1414 INSERM; Nancy University Hospital (M.D.), Department of Neurology; Université de Lorraine (M.D.), APEMAC, Nancy, France; Aix Marseille Univ (J.P.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, France; Dokuz Eylul University (S.O.), Konak/Izmir, Turkey; Department of Neurosciences, Psychology, Drugs and Child Health Area (NEUROFARBA) (M.P.A.), Section Neurosciences, University of Florence, Italy; CHU Clermont-Ferrand (P.C.), Department of Neurology; Université Clermont Auvergne (P.C.), Inserm, Neuro-Dol, Clermont-Ferrand, France; CISSS Chaudière-Appalache (P.G.), Lévis, Canada; KTU Medical Faculty Farabi Hospital (C.B.), Trabzon, Turkey; Department of Neurology (K.B., O.S., H.B.), Box Hill Hospital, Monash University; The Alfred Hospital (O.S.), Melbourne, Australia; CHU de Toulouse (J.C.), Hôpital Pierre-Paul Riquet, Department of Neurology, CRC-SEP, Toulouse Cedex 9, France; Department of Neurology (O.G.), Zuyderland Medical Center, Sittard-Geleen, the Netherlands; Neuro Rive-Sud (F.G.), Quebec, Canada; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Hunter New England Health, Newcastle; Central Clinical School (H.B.), Monash University; Department of Neurology (H.B.), The Alfred Hospital, Melbourne, Australia; Service de neurologie (S.V.), sclérose en plaques, pathologies de la myéline et neuro-inflammation; Hôpital Neurologique Pierre Wertheimer (S.V.), Hospices Civils de Lyon, Lyon/Bron; France Centre des Neurosciences de Lyon (S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292; and Université Claude Bernard Lyon 1 (S.V.), Faculté de médecine Lyon Est, France.

Objective: To compare the clinical effectiveness of high- and low-efficacy treatments in patients with recently active and inactive secondary progressive multiple sclerosis (SPMS) after accounting for therapeutic lag.

Methods: Patients treated with high-efficacy (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferon beta, glatiramer acetate, teriflunomide) therapies after SPMS onset were selected from MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP), 2 large observational cohorts. Therapeutic lag was estimated for each patient from their demographic and clinical characteristics. Propensity score was used to match patients treated with high- and low-efficacy therapies. Outcomes after the period of therapeutic lag was disregarded were compared in paired, pairwise-censored analyses.

Results: One thousand patients were included in the primary analysis. Patients with active SPMS treated with high-efficacy therapy experienced less frequent relapses than those on low-efficacy therapy (hazard ratio [HR] 0.7, = 0.006). In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR 0.8, = 0.39). No evidence for a difference in the risk of disability progression was observed.

Conclusion: In treated patients with SPMS, high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active but not those with inactive SPMS. However, more potent therapies do not offer an advantage in reducing disability progression in this patient group.

Classification Of Evidence: This study provides Class III evidence that high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active SPMS, although we did not find a difference in disability progression between patients treated with high- and low-efficacy therapy.
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http://dx.doi.org/10.1212/WNL.0000000000012354DOI Listing
August 2021

The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies.

Mult Scler Relat Disord 2021 Aug 8;53:103012. Epub 2021 May 8.

KTU Medical Faculty Farabi Hospital, Trabzon, Turkey.

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 methodologies, 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.
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http://dx.doi.org/10.1016/j.msard.2021.103012DOI Listing
August 2021

Mass Cytometry Identifies Expansion of T-bet B Cells and CD206 Monocytes in Early Multiple Sclerosis.

Front Immunol 2021 4;12:653577. Epub 2021 May 4.

INSERM, Unité Mixte de Recherche U1236, Université Rennes, Etablissement Français du Sang Bretagne, LabEx IGO, Rennes, France.

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206 classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation.
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http://dx.doi.org/10.3389/fimmu.2021.653577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129576PMC
September 2021

Intra-database validation of case-identifying algorithms using reconstituted electronic health records from healthcare claims data.

BMC Med Res Methodol 2021 05 1;21(1):95. Epub 2021 May 1.

INSERM CIC-P1401, Bordeaux PharmacoEpi, Univ. Bordeaux, Bordeaux, France.

Background: Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative.

Objectives: To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs).

Methods: Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm.

Results: Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV.

Conclusion: The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.
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http://dx.doi.org/10.1186/s12874-021-01285-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088022PMC
May 2021

Clinical and radiological activity of secondary progressive multiple sclerosis in a population-based cohort.

Eur J Neurol 2021 07 18;28(7):2238-2248. Epub 2021 May 18.

Université de Lorraine, Vandoeuvre-Lès-Nancy, France.

Background And Purpose: Patients with secondary progressive multiple sclerosis (SP MS) and clinical and/or radiological activity could be the more likely to benefit from disease-modifying treatments. To evaluate the proportions each year after progression onset, patients with SP MS onset between 2002 and 2012 from a population-based multiple sclerosis registry in northeastern France were studied.

Methods: Progression onset was first identified by the neurologist's diagnosis (N cohort), and then by using an automated data-driven definition (D cohort). In a given year after onset of progression, clinical activity was defined as at least one relapse, and radiological activity as at least one new T2 and/or gadolinium-enhancing lesion. A multivariate mixed logistic regression was used to assess factors associated with activity during the year.

Results: In the N cohort, amongst 833 patients with SP MS with a median follow-up of 8 years, 10.0%-14.8% had at least one relapse in a year during the first 5 years of progression. Including both clinical and radiological activity increased these proportions to 11.9%-23.7%, with the proportion having a magnetic resonance imaging scan in the year ranging from 29.8% to 40.5%. The first year of progression, a young age and a high relapse rate during the 5 years before progression were associated with activity in a given year. The D cohort results confirmed these findings.

Conclusions: A substantial proportion of patients with SP MS present disease activity. Further studies should evaluate the impact of disease-modifying treatments on the disease course of these patients.
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http://dx.doi.org/10.1111/ene.14861DOI Listing
July 2021

Comparison of Simoa and Ella to assess serum neurofilament-light chain in multiple sclerosis.

Ann Clin Transl Neurol 2021 05 8;8(5):1141-1150. Epub 2021 Apr 8.

Department of Neurology, CHU Nîmes, Univ Montpellier, Nîmes, France.

We compared Simoa and Ella immunoassays to assess serum neurofilament-light chain levels in 203 multiple sclerosis patients from the OFSEP HD study. There was a strong correlation (ρ = 0.86, p < 0.0001) between both platforms. The Ella instrument overestimated values by 17%, but as the data were linear (p = 0.57), it was possible to apply a correction factor to Ella results. As for Simoa , serum neurofilament-light chain levels measured by Ella were correlated with age and EDSS and were significantly higher in active multiple sclerosis, suggesting that these assays are equivalent and can be used in routine clinical practice.
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http://dx.doi.org/10.1002/acn3.51355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108418PMC
May 2021

Long-term analysis of patients with benign multiple sclerosis: new insights about the disability course.

J Neurol 2021 Oct 31;268(10):3817-3825. Epub 2021 Mar 31.

Université de Lorraine, EA 4360 APEMAC, 54500, Nancy, France.

Objective: To describe the course of disability in patients with benign multiple sclerosis-i.e., with an expanded disability status scale score < 3 10 years after disease onset-for up to 30 years after disease onset. We evaluated the proportion of patients remaining in the benign state on the long term and the factor associated with this favorable outcome and determined the pattern of disability course after the loss of the benign status.

Methods: Patients were selected from the ReLSEP, a French population-based registry. We studied the probability (Kaplan-Meier method) and predictors (multivariate Cox model) of remaining < 3 after year 10, and the course of disability after score 3 according to the duration of the benign phase in patients with ≥ 30 years of follow-up (graphs of the course of the mean expanded disability status scale scores in subgroups of patients).

Results: 2295/3440 patients had benign multiple sclerosis (66.7%). The probability of remaining benign at year 30 was 0.26 (95% CI 0.26-0.32). A young age at disease onset and a good recovery after the first relapse were associated with remaining benign. Graphs illustrate that those who lost their benign status between years 10 and 30 follow a two-stage course. Beyond score 3, disability accumulation is similar in all but lower disability scores at advanced age are associated with longer benign periods.

Conclusion: The longer a patient remains in the benign state, the lower the final EDSS at advanced age.
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http://dx.doi.org/10.1007/s00415-021-10501-0DOI Listing
October 2021

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 10 11;27(12):1838-1851. Epub 2021 Jan 11.

CHU de Caen, MS Expert Centre, Department of Neurology, avenue de la Côte-de-Nacre, Normandy University, Caen, France.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups.

Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation.

Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants.

Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5).

Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
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http://dx.doi.org/10.1177/1352458520981300DOI Listing
October 2021

Cumulative effects of therapies on disability in relapsing multiple sclerosis.

Mult Scler 2021 10 6;27(11):1760-1770. Epub 2021 Jan 6.

Département de Neurologie, CHU Nantes, Nantes, France; CIC Inserm 1415, CHU Nantes, Nantes, France; Centre de Recherche en Transplantation et Immunologie, Inserm U1064, Nantes, France.

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.
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http://dx.doi.org/10.1177/1352458520980366DOI Listing
October 2021

Assessing the experience of the quality of care of patients living with multiple sclerosis and their caregivers: The MusiCare questionnaire.

Eur J Neurol 2021 03 5;28(3):910-920. Epub 2021 Jan 5.

Public Health: Quality of Life and Chronic Diseases EA3279, Aix-Marseille University, Marseille, France.

Background And Purpose: Patients with a chronic illness, such as multiple sclerosis (MS), and their natural caregivers have a specific experience of healthcare and health services. These experiences need to be assessed to evaluate the quality of care. Our objective was to develop a French-language questionnaire to evaluate the quality of care as experienced by MS patients and their natural caregivers.

Methods: Eligible patients had been diagnosed with MS according to the McDonald criteria. Eligible caregivers were individuals designated by the patients. The MusiCare questionnaire was developed in two standard phases: (i) item generation, based on interviews with patients and caregivers; and (ii) validation, consisting of validity, reliability, external validity, reproducibility, and responsiveness measures.

Results: In total, 1088 patients (n = 660) and caregivers (n = 488) were recruited. The initial 64-item version of MusiCare was administered to a random subsample (n = 748). The validation process generated a 35-item questionnaire. Internal consistency and scalability were satisfactory. Testing of the external validity revealed expected associations between MusiCare scores and sociodemographic and clinical data. The questionnaire showed good reproducibility and responsiveness.

Conclusions: The availability of a reliable and validated French-language self-report questionnaire probing the experience of the quality of care for MS will allow the feedback of patients and caregivers to be incorporated into a continuous healthcare quality-improvement strategy.
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http://dx.doi.org/10.1111/ene.14685DOI Listing
March 2021

Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

Mult Scler 2021 08 3;27(9):1458-1463. Epub 2020 Dec 3.

INSERM U 1195, Le Kremlin-Bicêtre, France.

Background: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy.

Objective: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo.

Methods: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo.

Results: Recruitment was stopped prematurely due to slow inclusions ( = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) ( = 0.79)).

Conclusion: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.
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http://dx.doi.org/10.1177/1352458520978218DOI Listing
August 2021

BEST-MS: A prospective head-to-head comparative study of natalizumab and fingolimod in active relapsing MS.

Mult Scler 2021 09 30;27(10):1556-1563. Epub 2020 Oct 30.

Service de Neurologie, CRCSEP, Unité de Recherche Clinique Cote d'Azur (UR2CA), Centre Hospitalier Universitaire Pasteur 2, Nice, France.

Background: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS).

Objective: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS.

Method: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity.

Results: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group ( = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49,  = 0.029).

Conclusion: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.
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http://dx.doi.org/10.1177/1352458520969145DOI Listing
September 2021

Discontinuation of disease-modifying treatments for multiple sclerosis in patients aged over 50 with disease Inactivity.

J Neurol 2020 Dec 2;267(12):3518-3527. Epub 2020 Jul 2.

Department of Neurology, University Hospital of Nancy, 29 avenue Maréchal de Lattre de Tassigny, 60034-54035, Nancy, CO, France.

Background: Treatments may become redundant in older patients with multiple sclerosis (MS). Our aim was to explore whether stopping treatments might be possible in patients aged over 50 with disease inactivity.

Methods: Patients over 50 were included from the population-based MS Lorraine registry if they had a relapsing-remitting course at onset and had experienced no relapse for ≥ 3 years. Patients who stopped treatments were defined as "stoppers", and the others as "stayers". The outcomes were the time to first relapse, to first disability progression, and to the occurrence of EDSS score of 6, assessed by multivariate analysis using a propensity score.

Results: 132 stoppers and 366 stayers had a median follow-up of 7 years. There was no difference in Log-rank tests for the times to first relapse (p = 0.61) and to first disability progression (p = 0.22). In Cox models, stopping treatments was not associated with an increased risk of relapse (adjusted Hazard ratio (aHR) = 0.92 [0.72-1.16; p = 0.47]) or of an increase in EDSS score (aHR = 0.89 [0.71-1.13; p = 0.34]). However, stopping was associated with a higher risk of occurrence of EDSS score of 6 (aHR = 3.29 [2.22-4.86; p < 0.0001]), with a significant difference for the time to occurrence of EDSS score of 6 (p = 0.003).

Conclusion: Our study suggests that stopping injectable disease-modifying treatments, in patients over 50 with disease inactivity, is not associated with an increased risk of relapse or EDSS progression, but there might be a higher risk of reaching EDSS 6. These results have to be confirmed by interventional studies.
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http://dx.doi.org/10.1007/s00415-020-10029-9DOI Listing
December 2020

The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial.

Trials 2020 Jun 29;21(1):591. Epub 2020 Jun 29.

Centre d᾿Investigation Clinique INSERM 1434, Strasbourg, France.

Background: Central nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair. It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS.

Methods/design: This report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes.

Discussion: The action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality. Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases.

Trial Registration: ClinicalTrials.gov NCT03910738. Registered on 10 April 2019.
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http://dx.doi.org/10.1186/s13063-020-04517-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322908PMC
June 2020

Memory improvement in multiple sclerosis after an extensive cognitive rehabilitation program in groups with a multicenter double-blind randomized trial.

Clin Rehabil 2020 Jun;34(6):754-763

Department of Neurology, Nancy University Hospital, Nancy, France.

Objective: The aim of this study is to determine the effectiveness of an extended cognitive rehabilitation program in group's sessions in multiple sclerosis.

Design: Double-blind multicenter randomized trial.

Participants: People with multiple sclerosis of 18 to 60 years, Expanded Disability Status Scale ⩽6.0, mild to moderate cognitive impairment.

Interventions: They were randomized into cognitive rehabilitation program (ProCog-SEP) or in a placebo program. ProCog-SEP comprises 13 group's sessions over 6 months and includes psychoeducational advices and cognitive exercises. Placebo program included non-cognitive exercises. No strategy and no cognitive advice were provided.

Main Measures: The primary endpoint was the percentage of verbal memory learning measured by the Selective Reminding Test. A comprehensive neuropsychological assessment is carried out before and after interventions by a neuropsychologist blinded to intervention. Effectiveness of the ProCog-SEP versus Placebo has been verified using linear regression models.

Results: In total, 128 participants were randomized and 110 were included in the study after planning session in groups; 101 completed this trial (77.2% females); mean age: 46.1 years (±9.6); disease duration: 11.8 years (±7.5). ProCog-SEP was more effective in increasing in learning index (9.21 (95% confidence interval (CI): 1.43, 16.99);  = 0.02) and in working memory on manipulation (0.63 (95% CI: 0.17, 1.09);  = 0.01), and updating capacities (-1.1 (95% CI: -2.13, -0.06);  = 0.04). No difference was observed for other neuropsychological outcomes. Regarding quality of life outcomes, no change was observed between the two groups.

Conclusion: These findings suggest that ProCog-SEP could improve verbal learning abilities and working memory in people with multiple sclerosis. These improvements were observed with 13 group sessions over 6 months.
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http://dx.doi.org/10.1177/0269215520920333DOI Listing
June 2020

Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis.

J Clin Apher 2020 Aug 5;35(4):281-289. Epub 2020 May 5.

CHU de Bordeaux, Service de Neurologie, Bordeaux, France.

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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http://dx.doi.org/10.1002/jca.21788DOI Listing
August 2020

Economic burden of multiple sclerosis in France estimated from a regional medical registry and national sick fund claims.

Mult Scler Relat Disord 2019 Nov 10;36:101396. Epub 2019 Sep 10.

CHRU de Nancy, Inserm, Université de Lorraine, CIC 1433 Epidémiologie clinique -Hôpitaux de Brabois, 9 allée du Morvan, 54505 Vandoeuvre-les-Nancy, France.

Background: Estimating direct healthcare costs of patients with multiple sclerosis (MS) and identifying risk factors of high costs including relapse are important drivers of public health decision making in France.

Methods: This is a longitudinal retrospective study based on patient charts (qualified registry of MS in Lorraine (ReLSEP)) and claims data (from the main compulsory health insurance and national hospital database estimated monthly. All patients with MS not deceased or lost to follow-up reported in the registry in 2013-2014 were included. Outpatient costs were those paid to the healthcare provider and inpatient costs were those related to national cost estimates. Mean total costs per patient by disease severity were estimated monthly, accounting for MS evolution over the study period. Costs of MS relapse were estimated using a general linear model.

Results: A total of 4373 patients were identified in the ReLSEP registry, and 2166 of these patients were included in the study. Among those, outpatient claims were available for 1366 and 627 were hospitalized at least once. The average annual direct costs for patients with MS were estimated to be €12,296 in 2014. Furthermore, ambulatory costs represented 87.8% out of those costs and were mainly driven by medications (60.6%) and paramedic visits (11.2%). Monthly direct costs were higher in patients with severe disease (€1249 for EDSS 7-9) compared to those with mild or moderate disease (€992 for EDSS 0-3; €953 for EDSS 4-6) (p < 0,006). Interestingly, drug costs were higher in patients with mild disease, whereas costs related to paramedical care, medical devices, and transportation were higher in those with severe MS. The unit cost of relapse was estimated between €1681 and €2193.

Conclusions: Costs were mainly driven by medications and highly related to disease severity. Relapse cost was the main contributor to total cost.
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http://dx.doi.org/10.1016/j.msard.2019.101396DOI Listing
November 2019

Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis.

Neurology 2019 08 12;93(7):e635-e646. Epub 2019 Jul 12.

From INSERM (D.-A.L., L.B.), CIC 0004, Nantes; CRTI-INSERM UMR U1064 (D.-A.L.), Université de Nantes; Service de Neurologie (D.-A.L., S.W., L. Michel), CHU Nantes; Centre des Neurosciences de Lyon (R.C., F.R., S.V.), Observatoire Français de la Sclérose en Plaques, INSERM 1028 and CNRS UMR5292, Lyon; Université Claude Bernard Lyon 1 (R.C., F.R., S.V.), Université de Lyon; Department of Neurology (M.D.), Nancy University Hospital; Université de Lorraine (M.D.), EA 4360 APEMAC, Vandoeuvre-Lès-Nancy; Department of Neurology and Clinical Investigation Center (J.D.S.), CHU de Strasbourg, INSERM 1434; Department of Neurology (D.B.), CHU de Toulouse; Service de Neurologie (B. Brochet), CHU de Bordeaux; Service de Neurologie (J.P.), Hôpital de la Timone, CRMBM, CNRS, APHM, Aix Marseille Univ, Marseille; Univ Lille (P.V.), CHU Lille, LIRIC (Lille Inflammation Research International Center), INSERM UMR995; Service de Neurologie (G.E., L. Michel), CHU de Rennes; CRCSEP Nice (C.L.-F.), Neurologie Pasteur 2, Université Nice Cote d'Azur, Nice; Service de Neurologie (P. Clavelou), CHU de Clermont-Ferrand; Service de Neurologie (E.T.), CHU de Nîmes; Department of Neurology (J.-P.C.), Hôpital Nord, CHU Saint-Étienne; Service de Neurologie et Faculté de Médecine de Reims (A.T.), CHU de Reims, URCA; Service de Neurologie (B.S.), CHU Saint-Antoine; Service de Neurologie (A.A.K.), CHU d'Amiens; Service de Neurologie (P. Cabre), CHU de Fort de France; Service de Neurologie (C. Lubetzki, C.P.), CHU Pitié-Salpêtrière; Service de Neurologie (E.B.), CHU de Besançon; Service de Neurologie (O.H.), CH de Poissy; Service de Neurologie (T.D.), CH de Saint-Denis; Service de Neurologie (T.M.), CHU de Dijon; Service de Neurologie (O.G.), Fondation Rothschild; Service de Neurologie (B. Bourre), CHU de Rouen; Department of Neurology (A.W.), Hôpital Henri Mondor, Créteil; Service de Neurologie (P.L.), CHU de Montpellier; Service de Neurologie (L. Magy), CHU de Limoges; Service de Neurologie (G.D.), CHU de Caen; CRC SEP and Department of Neurology (A.-M.G.), CHU Bretonneau, Tours; Department of Neurology (N.M.), CHU La Milétrie, Poitiers; Department of Neurology (C. Labeyrie), CHU Bicêtre, Le Kremlin Bicêtre; Department of Neurology (I.P.), Hôpital Sud Francilien, Corbeil Essonnes; Department of Neurology (C.N.), CHU Versailles; Department of Neurology (O.C.), CHU de Grenoble; Ecole des Hautes Etudes en Santé Publique (E.L.), Rennes; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (S.V.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron; and INSERM (Y.F.), UMR 1246-SPHERE, Nantes University, Tours University, Nantes, France.

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, < 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, < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, < 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.
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http://dx.doi.org/10.1212/WNL.0000000000007938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715507PMC
August 2019

Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS.

Mult Scler 2019 04 20;25(4):591-600. Epub 2018 Mar 20.

Service de Neurologie A, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France/Observatoire Français de la Sclérose en Plaques (OFSEP), Lyon, France/Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR5292, Equipe Neuro-Oncologie et Neuro-Inflammation, Lyon, France/Université de Lyon 1, Lyon, France.

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses.

Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy.

Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992-1995 and 2005-2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis.

Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78).

Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.
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http://dx.doi.org/10.1177/1352458518763080DOI Listing
April 2019

High performance of cerebrospinal fluid immunoglobulin G analysis for diagnosis of multiple sclerosis.

J Neurol 2019 Apr 1;266(4):902-909. Epub 2019 Feb 1.

Inserm CIC-EC 1433, Nancy University Hospital, Université de Lorraine, 54 000, Nancy, France.

Background: The 2017 revision of the McDonald criteria highlights the usefulness of cerebrospinal fluid (CSF) immunoglobulin G (IgG) analysis to diagnose multiple sclerosis (MS). The objective of this study was to assess the diagnostic performances of CSF IgG analysis in the absence of a gold standard.

Methods: All patients who underwent CSF IgG analysis for events suggestive of MS in Nancy University Hospital (France) from 2008 to 2011 were retrospectively included. A latent class analysis with Bayesian approach was used to infer MS prevalence (latent variable) as well as the diagnostic properties of the 2005 and 2010 McDonald criteria and CSF IgG analysis (observed variables).

Results: Data from 673 patients were analysed. For CSF IgG analysis, the Bayesian latent class analysis estimated sensitivity of 0.93 (95% CrI 0.89-0.96) and specificity of 0.81 (95% CrI 0.77-0.85). The true prevalence estimate was 36% (95% CrI 0.33-0.40). Sensitivity and specificity estimates for patients with events suggestive of remitting-onset MS were similar to those for the whole sample-0.92 (95% CrI 0.85-0.96) and 0.80 (95% CrI 0.76-0.84), respectively-but higher for patients with signs of progressive-onset MS-0.95 (95% CrI 0.84-0.99) and 0.88 (95% CrI 0.78-0.94), respectively.

Conclusions: In the absence of a gold standard, latent class analysis indicates good diagnostic properties of CSF IgG analysis for MS. This test could thus be useful, especially for patients who tested negative for the 2005 and 2010 McDonald criteria. These findings deserve to be confirmed prospectively.
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http://dx.doi.org/10.1007/s00415-019-09212-4DOI Listing
April 2019

Observatoire Français de la Sclérose en Plaques (OFSEP): A unique multimodal nationwide MS registry in France.

Mult Scler 2020 01 13;26(1):118-122. Epub 2018 Dec 13.

Department of Neurology, CHU de Toulouse, Toulouse, France.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.
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http://dx.doi.org/10.1177/1352458518815602DOI Listing
January 2020

MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study.

CNS Drugs 2018 07;32(7):661-672

Department of Ophthalmology, Faculty of Medicine, CHU de Reims, URCA, Reims, France.

Background: Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS.

Objective: The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss.

Methods: The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed.

Results: Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (- 0.061 logMAR, + 3.1 letters) than with placebo (- 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (- 0.058 logMAR) with MD1003 and worsened by - 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo.

Conclusions: MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated.

Trial Registration: EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 FUNDING: MedDay Pharmaceuticals.
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http://dx.doi.org/10.1007/s40263-018-0528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061426PMC
July 2018

Efficacy of rituximab in refractory RRMS.

Mult Scler 2019 05 3;25(6):828-836. Epub 2018 May 3.

Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France/CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France.

Objective: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT).

Methods: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts.

Results: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001).

Conclusion: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.
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http://dx.doi.org/10.1177/1352458518772748DOI Listing
May 2019

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study.

Neurology 2018 05 25;90(21):e1858-e1869. Epub 2018 Apr 25.

Objective: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis.

Methods: Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included.

Results: Median age at onset was 36.46 (range 18.0-76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26-0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22-0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07-0.72). Finally, MOG-Ab titers were higher at relapse than in remission ( = 0.009).

Conclusion: In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.
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http://dx.doi.org/10.1212/WNL.0000000000005560DOI Listing
May 2018

Generational changes in multiple sclerosis phenotype in North African immigrants in France: A population-based observational study.

PLoS One 2018 27;13(3):e0194115. Epub 2018 Mar 27.

Nancy University Hospital, Department of Neurology, Nancy, France.

Background: The incidence of multiple sclerosis (MS) changes from generation to generation in ethnically different immigrants compared with native-born people. We aimed to determine whether there are generational changes in MS phenotypes among North African immigrants in France.

Methods: Cohort study with data from a population-based MS registry to compare the clinical characteristics of 80 first (NAG1) and 167 second (NAG2) generation North Africans with MS living in France with 5200 native-born Europeans. Adjusted Cox models were used to test the association between scores of 3 and 6 on the expanded disability status scale (EDSS) and the "origin/generation" variable.

Results: Cox models for EDSS scores 3 and 6 showed a higher risk of score 3 (hazard ratio = 1.738, 95% confidence interval 1.237 to 2.444; P = .002) and 6 (hazard ratio = 2.372, 95% confidence interval 1.626 to 3.462; P<.0001) for NAG1 than Europeans. Being NAG2 was not significantly associated with higher hazards of scores 3 and 6.

Conclusions: We found two different phenotypes among NAG1 and NAG2 MS patients in France. NAG1, but not NAG2, have a higher risk of disability than Europeans. This raises the question of environmental factors in MS expression, and advocates appropriate patient management according to generation in immigrants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194115PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870962PMC
July 2018

Quantitative and qualitative normative dataset for intraepidermal nerve fibers using skin biopsy.

PLoS One 2018 25;13(1):e0191614. Epub 2018 Jan 25.

Fédération de Médecine Translationnelle de Strasbourg (FMTS), University Hospital of Strasbourg, Strasbourg, France.

Background: Skin biopsy is the most relevant tool to diagnose small-fiber neuropathy. A well-documented normal dataset for intraepidermal nerve fiber in the distal leg is required to improve its diagnostic value.

Methods: Three hundred healthy subjects were enrolled in the study, after clinical and biological screening to exclude neurological and systemic pathologies. A distal leg biopsy was taken and intraepidermal nerve fiber density after protein gene product-9.5 immunocytochemistry with brightfield microscopy was determined. Morphological variations of intraepidermal nerve fibers, previously described in small-fiber neuropathies, were analyzed. One hundred biopsies were also analyzed at the ultrastructural level.

Findings: The median number of fibers was lower in men compared to women and decreased with age. Using statistical modeling taking into account age and gender, we calculated the 5th percentile of intraepidermal nerve fiber density as follows: 7.6156-0.0769 x age (years) + 1.5506 x gender (woman = 1; man = 0). We observed a low frequency of large swellings or horizontal branchings but an increasing frequency of small swellings of intraepidermal nerve fibers and irregular distribution along the dermal-epidermal junction with age. Axonal diameter of unmyelinated fibers of the papillary dermis did not vary with age or gender. Ultrastructural analysis also showed that fiber endings in close apposition to Merkel cells should not be mistaken for small-fiber swellings.

Conclusions: Our dataset allows accurate calculation of the normal density of intraepidermal nerve fibers for each year of age and provides original morphological observations that improve the diagnostic value of skin biopsy in the distal leg for small-fiber neuropathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784950PMC
March 2018

Implementation and Evaluation of an Economic Model for Telestroke: Experience from , France.

Front Neurol 2017 20;8:613. Epub 2017 Nov 20.

Department of Neurology, Stroke Unit, University Hospital of Nancy, Nancy, France.

Background: Telestroke is recognized as a safe and time-efficient way of treating stroke patients. However, admission centers (spokes) are subject to financial charges which can make them reluctant to join the system. We implemented and assessed an economic model supporting our telestroke system, , France, which includes one expert center (hub) and six spokes.

Methods: The model is based on payment for the expertise provided by the hub, distribution of charges related to telemedicine according to the fees perceived by the spokes, and transfer of patients between the spokes and the hub. We performed a cost-benefit analysis for all patients included in from January 2014 to December 2015 to assess the economic balance in each center.

Results: 321 patients were prospectively included in the study. Application of the economic model resulted in overall financial balance with funding of a dedicated medical service in the hub, and reduced costs directly related to telestroke by an average of 10% in the spokes. The conditions generating the highest costs for the spokes were: a patient returning from the hub for re-hospitalization (mean cost of $1,995/patient); management of patients treated by intravenous thrombolysis without transfer to the hub (mean cost of $2,075/patient). The most favorable financial condition for the spokes remained simple transfer of patients to the hub and no return (mean cost of $329/patient).

Conclusion: We describe an economic model which can be applied to any telestroke system to ensure the optimal balance between hub and spoke centers.
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http://dx.doi.org/10.3389/fneur.2017.00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701923PMC
November 2017
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