Publications by authors named "David Laplaud"

42 Publications

Untreated patients with multiple sclerosis: a study of French expert centers.

Eur J Neurol 2021 Mar 1. Epub 2021 Mar 1.

Université Clermont Auvergne, CHU de Clermont-Ferrand, Inserm, Neuro-Dol, F-63000, Clermont-Ferrand, France.

Background: Disease modifying therapies (DMTs), have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (pwMS) remain untreated. The objective of the present study was to determine the proportion of untreated patients with multiple sclerosis (pwMS) followed in expert centers in France and determine the predictive factors of non-treatment.

Methods: Retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on 12/15/2018 and pwMS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. Results Among the 21,189 pwMS (age 47.1±13.1; EDSS 3.4±2.4), 6,631 (31.3%; 95%CI=30.7-31.9) of the patients were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95%CI = 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among relapsing-remitting pwMS, the main factors explaining never having been treated were not having ≥9 lesions on brain MRI (OR = 0.52 [0.44-0.61]) and lower EDSS (OR = 0.78 [0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, 11.6% for secondary and 34.0% for primary progressive MS had never received any DMT.

Conclusion: A significant proportion of pwMS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of pwMS.
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http://dx.doi.org/10.1111/ene.14790DOI Listing
March 2021

The long-term outcome of MOGAD: An observational national cohort study of 61 patients.

Eur J Neurol 2021 Feb 2. Epub 2021 Feb 2.

Department of Neurology, Centre de référence des maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.

Background And Objective: The prognosis in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a matter of debate. Our aim was to assess the long-term outcomes of patients with MOGAD.

Methods: We retrospectively analysed the clinical and paraclinical data of patients from the French nationwide observatory study NOMADMUS who tested positive for MOG antibodies (MOG-IgG) and who had clinical follow-up of at least 8 years from their first episode.

Results: Sixty-one patients (median [range] age at onset 27 [3-69] years), with a median (mean; range) follow-up of 177 (212.8; 98-657) months, were included. Among 58 patients with a relapsing course, 26.3% relapsed in the first year after onset. Of the 61 patients, 90.2% experienced at least one episode of optic neuritis. At last visit, the median (mean; range) Expanded Disability Status Scale (EDSS) score was 1 (2.12; 0-7.5), 12.5% had an EDSS score ≥6 and 37.5% had an EDSS score ≥3. Of 51 patients with final visual acuity (VA) data available, 15.7% had VA ≤0.1 in at least one eye and 25.5% had VA ≤0.5 in at least one eye. Bilateral blindness (VA ≤0.1) was present in 5.9% of patients. Finally, 12.5% of patients presented bladder dysfunction requiring long-term urinary catheterization. No factor associated significantly with a final EDSS score ≥3 or with final VA ≤0.1 was found.

Conclusion: Overall long-term favourable outcomes were achieved in a majority of our patients, but severe impairment, in particular visual damage, was not uncommon.
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http://dx.doi.org/10.1111/ene.14746DOI Listing
February 2021

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Jan 11:1352458520981300. Epub 2021 Jan 11.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia/Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.

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
January 2021

Description of neurotoxicity in a series of patients treated with CAR T-cell therapy.

Sci Rep 2020 11 4;10(1):18997. Epub 2020 Nov 4.

Department of Neurology, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010, Paris, France.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1-2 severity and 34% had grade 3-4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3-4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.
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http://dx.doi.org/10.1038/s41598-020-76055-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642402PMC
November 2020

Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance.

J Clin Invest 2020 11;130(11):6109-6123

OSE Immunotherapeutics, Nantes, France.

T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.
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http://dx.doi.org/10.1172/JCI135528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598080PMC
November 2020

Relapses in Patients Treated with High-Dose Biotin for Progressive Multiple Sclerosis.

Neurotherapeutics 2020 Sep 22. Epub 2020 Sep 22.

CHU de Clermont-Ferrand, F-63000, Clermont-Ferrand, France.

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8 months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (p = 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (p = 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.
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http://dx.doi.org/10.1007/s13311-020-00926-2DOI Listing
September 2020

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients.

Mult Scler Relat Disord 2020 Sep 2;44:102251. Epub 2020 Jun 2.

Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom; Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; Department of Neurology, The Cleveland Clinic Abu Dhabi, United Arab Emirates. Electronic address:

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD).

Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model).

Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses.

Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.
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http://dx.doi.org/10.1016/j.msard.2020.102251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895306PMC
September 2020

G-computation, propensity score-based methods, and targeted maximum likelihood estimator for causal inference with different covariates sets: a comparative simulation study.

Sci Rep 2020 06 8;10(1):9219. Epub 2020 Jun 8.

INSERM UMR 1246 - SPHERE, Université de Nantes, Université de Tours, Nantes, France.

Controlling for confounding bias is crucial in causal inference. Distinct methods are currently employed to mitigate the effects of confounding bias. Each requires the introduction of a set of covariates, which remains difficult to choose, especially regarding the different methods. We conduct a simulation study to compare the relative performance results obtained by using four different sets of covariates (those causing the outcome, those causing the treatment allocation, those causing both the outcome and the treatment allocation, and all the covariates) and four methods: g-computation, inverse probability of treatment weighting, full matching and targeted maximum likelihood estimator. Our simulations are in the context of a binary treatment, a binary outcome and baseline confounders. The simulations suggest that considering all the covariates causing the outcome led to the lowest bias and variance, particularly for g-computation. The consideration of all the covariates did not decrease the bias but significantly reduced the power. We apply these methods to two real-world examples that have clinical relevance, thereby illustrating the real-world importance of using these methods. We propose an R package RISCA to encourage the use of g-computation in causal inference.
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http://dx.doi.org/10.1038/s41598-020-65917-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280276PMC
June 2020

Outcome and risk of recurrence in a large cohort of idiopathic longitudinally extensive transverse myelitis without AQP4/MOG antibodies.

J Neuroinflammation 2020 Apr 23;17(1):128. Epub 2020 Apr 23.

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677, Lyon/Bron, France.

Background: Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy.

Methods: Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS.

Results: Fifty-three patients (median age 38 years (range 16-80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1-8.5), associated to a median EDSS at last follow-up of 4.0 (0-8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%).

Conclusions: A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.
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http://dx.doi.org/10.1186/s12974-020-01773-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178729PMC
April 2020

Evaluation of efficacy and tolerability of first-line therapies in NMOSD.

Neurology 2020 04 13;94(15):e1645-e1656. Epub 2020 Mar 13.

From the Department of Neurology (J.P., J.G., O.O., H.Z.) and U995-LIRIC-Lille Inflammation Research International Center, Inserm, Univ Lille (J.G., H.Z.), CHU Lille; Department of Neurology (R.D.), Fondation Ophtalmologique Adolphe de Rothschild, Paris; CNRS, CRMBM UMR 7339 (B.A.), Aix-Marseille Université; Service de Neurologie (B.A.), Pôle de Neurosciences Cliniques, APHM, Hôpital de la Timone, Marseille; Department of Neurology (J.C.), Hôpital Purpan, CHU de Toulouse; Department of Neurology (E.M., C.P.), Hôpital de la Pitié Salpêtrière, AP-HP, Paris; Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (N.C.), INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg; Département de Neurologie (N.C.) and Centre d'Investigation Clinique, INSERM U1434 (N.C.), Centre Hospitalier Universitaire de Strasbourg; Department of Neurology (B.B.), Hôpital Charles Nicolle, CHU Rouen; Centre de Ressources et Compétences Sclérose en Plaques, Neurologie (M.S.), Université Nice Côte d'Azur, CHU Pasteur 2, Nice; Department of Neurology (S.W., D.L.), CHU Nantes; Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation (S.V., R.M.), Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon; Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (R.M.), Lyon; and INSERM U1028 (R.M.), CNRS UMR 5292, Center for Research in Neuroscience of Lyon, Lyon1 University, France.

Objective: To compare the efficacy and the risk of severe infectious events of immunosuppressive agents used early as first-line therapy in patients with neuromyelitis optica spectrum disorder (NMOSD).

Methods: We retrospectively included patients with NMOSD and a seropositive status for aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies beginning first-line immunosuppressants within 3 years after the disease onset. The main outcome was occurrence of relapse after the initiation of immunosuppressants; the secondary outcome was the annual relapse rate (AAR).

Results: A total of 136 patients were included: 62 (45.6%) were treated with rituximab (RTX), 42 (30.9%) with mycophenolate mofetil (MMF), and 23 (16.9%) with azathioprine (AZA). Compared with RTX-treated patients, the risk of relapse was higher among MMF-treated patients (hazard ratio [HR], 2.74 [1.17-6.40]; = 0.020) after adjusting for age at disease onset, sex, antibody status, disease duration, ARR before treatment, corticosteroid intake, and relapse location. We did not observe any difference between RTX-treated and AZA-treated patients (HR, 2.13 [0.72-6.28]; = 0.17). No interaction was found between the antibody status and immunosuppressive treatments. ARR was lower with RTX than with MMF ( = 0.039), but no difference was observed with AZA. We observed 9 serious infectious events with MMF, 6 with RTX, and none with AZA.

Conclusions: The use of first-line RTX in NMOSD appears more effective than MMF in suppressing clinical activity, independent of the antibody status.

Classification Of Evidence: That study provides Class III evidence that for patients with NMOSD, first-line RTX is superior to MMF to reduce the risk of relapse.
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http://dx.doi.org/10.1212/WNL.0000000000009245DOI Listing
April 2020

Predictive medicine in multiple sclerosis: A systematic review.

Mult Scler Relat Disord 2020 May 2;40:101928. Epub 2020 Jan 2.

SPHERE (methodS in Patient-centered outcomes & HEalth ResEarch) U1246, INSERM, Nantes University, Tours University, Nantes, France; Nantes University Hospital, Nantes, France. Electronic address:

Background: One of the main challenges in multiple sclerosis (MS) is to predict disease progression based on patient characteristics and therapeutic strategies. We therefore performed a systematic review to critically appraise the composite tools available for this purpose.

Methods: We performed electronic database searches in MEDLINE, EMBASE, Web of Science and the Cochrane Library. We included studies in English or French that developed and/or validated a predictive model for MS patients. Two reviewers independently screened articles by title and abstract. Three teams of two reviewers assessed the full text of each relevant study.

Results: Database searches yielded 6,035 studies after deduplication. Among the 42 screened full texts, 15 articles satisfied the eligibility criteria. Of these, six articles examined the development of predictive tools, six articles aimed to validate existing tools and three articles proposed both development and validation. We identified numerous methodological pitfalls, especially the lack of adequate validations in terms of discrimination and calibration. Only two scoring systems were externally validated several times: the Rio and the modified Rio scores. Nevertheless, their accuracies were highly variable, ranging from 65% to 91%.

Conclusions: Overall, there is a lack of validated predictive tools in MS, and further external validation of the existing ones are required. Demonstration of the clinical usefulness is also needed prior to being transferred into clinical practice. Finally, our study illustrates that the MS literature needs to integrate good standards in developing and validating predictive models.
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http://dx.doi.org/10.1016/j.msard.2020.101928DOI Listing
May 2020

Distribution of Bacterial α1,3-Galactosyltransferase Genes in the Human Gut Microbiome.

Front Immunol 2019 13;10:3000. Epub 2020 Jan 13.

Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.

Because of a loss-of-function mutation in the GGTA1 gene, humans are unable to synthetize α1,3-Galactose (Gal) decorated glycans and develop high levels of circulating anti-α1,3-Galactose antibodies (anti-Gal Abs). Anti-Gal Abs have been identified as a major obstacle of organ xenotransplantation and play a role in several host-pathogen relationships including potential susceptibility to infection. Anti-Gal Abs are supposed to stem from immunization against the gut microbiota, an assumption derived from the observation that some pathogens display α1,3-Gal and that antibiotic treatment decreases the level of anti-Gal. However, there is little information to date concerning the microorganisms producing α1,3-Gal in the human gut microbiome. Here, available α1,3-Galactosyltransferase (GT) gene sequences from gut bacteria were selectively quantified for the first time in the gut microbiome shotgun sequences of 163 adult individuals from three published population-based metagenomics analyses. We showed that most of the gut microbiome of adult individuals contained a small set of bacteria bearing α1,3-GT genes. These bacteria belong mainly to the Enterobacteriaceae family, including , but also to Pasteurellaceae genera, and species. α1,3-Gal antigens and α1,3-GT activity were detected in healthy stools of individuals exhibiting α1,3-GT bacterial gene sequences in their shotgun data.
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http://dx.doi.org/10.3389/fimmu.2019.03000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970434PMC
November 2020

Effect of assisted reproductive technology on multiple sclerosis relapses: Case series and meta-analysis.

Mult Scler 2020 10 1;26(11):1410-1419. Epub 2019 Aug 1.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Five case series reported increased relapse risk after assisted reproductive technologies (ART) in women with multiple sclerosis (MS), but small numbers and heterogeneous study design limit broader conclusions.

Objective: To evaluate the risk of relapses after ART in an independent case series and in aggregated analyses of existing studies.

Methods: We compared annualized relapse rate (ARR) in the 3 months after, and 12 months before, ART in (1) an unpublished cohort (Boston: prospectively collected relapses; 22 ART cycles), (2i) data pooled from Boston and five published studies (164 cycles), and (2ii) a meta-analysis of all case series published by 2017 (220 cycles; PRISMA and MOOSE guidelines).

Results: In the Boston cohort, mean ARR was not higher after ART than before (mean: 0.18 ± 0.85 vs 0.27 ± 0.55,  = 0.58). In the pooled analyses, ARR was significantly higher after ART for all clinical scenarios, including varying ART protocols ( ⩽ 0.01 for each). The meta-analysis confirmed an increased ARR after ART (mean difference (MD) = 0.92, 95% confidence interval (CI) = [0.33, 1.51],  = 0.01).

Conclusion: These pooled data support an increase in ARR following ART. Reasons for local variation in ARR after ART, and consideration of MS treatments during conception attempts, will be pursued.
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http://dx.doi.org/10.1177/1352458519865118DOI Listing
October 2020

Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study.

Mult Scler 2020 07 31;26(8):936-944. Epub 2019 May 31.

Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Bron, France; Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle and INSERM U1028, CNRS UMR 5292, Lyon 1 University, Center for Research in Neuroscience of Lyon, Lyon, France.

Objectives: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis.

Material And Methods: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0.

Results: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively),  = 0.007 and  = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group,  = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%),  < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0-4.0)) compared to SM patients (2.0, (1.0-3.0)),  = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01-1.95,  = 0.046).

Conclusion: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.
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http://dx.doi.org/10.1177/1352458519849511DOI Listing
July 2020

Cytotoxic CD8 T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

Proc Natl Acad Sci U S A 2019 02 23;116(6):2312-2317. Epub 2019 Jan 23.

The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, Saint Eloi Hospital, 34090 Montpellier, France;

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) mutant decreased spinal motoneuron loss. Using motoneuron-CD8 T cell coculture systems, we found that mutant SOD1-expressing CD8 T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and CD8 T cells. Activated mutant SOD1 CD8 T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.
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http://dx.doi.org/10.1073/pnas.1815961116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369778PMC
February 2019

Microglial control of astrocytes in response to microbial metabolites.

Nature 2018 05 16;557(7707):724-728. Epub 2018 May 16.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS). Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14 cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
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http://dx.doi.org/10.1038/s41586-018-0119-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422159PMC
May 2018

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

Immuno-Guided Laser-Capture Microdissection of Glial Cells for mRNA Analysis.

Methods Mol Biol 2018 ;1723:261-271

Centre de Recherche en Transplantation et Immunologie, INSERM UMR 1064, Université de Nantes, Nantes, France.

Laser-capture microdissection (LCM) allows for retrieval of specific cell populations in situ. By combining immunofluorescent labeling with LCM, mRNAs can be probed by qRT-PCR for determining in situ gene expression during health and disease. This approach permits obtaining and analyzing histologically enriched cell populations in a tissue that can be hardly obtained from other methods such as white matter astrocytes from rodents or any individual cell population from archival human or rodent brain tissues. Herein, we present our methodology of laser-captured mouse spinal cord white matter astrocytes, which can be adapted for any cell type in CNS tissue and low RNAse containing tissues. The methods presented with an emphasis on tips and advices include the cryostat section preparation from snap-frozen tissue, an adapted immunofluorescent labeling, a brief overview of LCM using a UV-based technology with polyethylene membrane glass slides, procedures for direct use of RNA from lysis buffer vs. column-based purified RNA, RNA quality/quantity assessment, the reverse transcription and preamplification steps used before real-time qPCR analysis.
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http://dx.doi.org/10.1007/978-1-4939-7558-7_15DOI Listing
January 2019

Cost-effectiveness of home telemonitoring in chronic kidney disease patients at different stages by a pragmatic randomized controlled trial (eNephro): rationale and study design.

BMC Nephrol 2017 04 5;18(1):126. Epub 2017 Apr 5.

CHRU de Nancy, Service de Néphrologie, Nancy, France.

Background: Home telemonitoring has developed considerably over recent years in chronic diseases in order to improve communication between healthcare professionals and patients and to promote early detection of deteriorating health status. In the nephrology setting, home telemonitoring has been evaluated in home dialysis patients but data are scarce concerning chronic kidney disease (CKD) patients before and after renal replacement therapy. The eNephro study is designed to assess the cost effectiveness, clinical/biological impact, and patient perception of a home telemonitoring for CKD patients. Our purpose is to present the rationale, design and organisational aspects of this study.

Methods: eNephro is a pragmatic randomised controlled trial, comparing home telemonitoring versus usual care in three populations of CKD patients: stage 3B/4 (n = 320); stage 5D CKD on dialysis (n = 260); stage 5 T CKD treated with transplantation (n= 260). Five hospitals and three not-for-profit providers managing self-care dialysis situated in three administrative regions in France are participating. The trial began in December 2015, with a scheduled 12-month inclusion period and 12 months follow-up. Outcomes include clinical and biological data (e.g. blood pressure, haemoglobin) collected from patient records, perceived health status (e.g. health related quality of life) collected from self-administered questionnaires, and health expenditure data retrieved from the French health insurance database (SNIIRAM) using a probabilistic matching procedure.

Discussion: The hypothesis is that home telemonitoring enables better control of clinical and biological parameters as well as improved perceived health status. This better control should limit emergency consultations and hospitalisations leading to decreased healthcare expenditure, compensating for the financial investment due to the telemedicine system.

Trial Registration: This study has been registered at ClinicalTrials.gov under NCT02082093 (date of registration: February 14, 2014).
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http://dx.doi.org/10.1186/s12882-017-0529-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381043PMC
April 2017

Can we discontinue disease-modifying treatments in multiple sclerosis patients? Yes.

Authors:
David Laplaud

Rev Neurol (Paris) 2017 Jan - Feb;173(1-2):38-40. Epub 2016 Dec 10.

Université de Nantes, 1, rue Gaston-Veil, BP 53508, 44035 Nantes cedex 1, France. Electronic address:

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http://dx.doi.org/10.1016/j.neurol.2016.10.005DOI Listing
September 2017

Effectiveness of mycophenolate mofetil as first-line therapy in AQP4-IgG, MOG-IgG, and seronegative neuromyelitis optica spectrum disorders.

Mult Scler 2017 Sep 25;23(10):1377-1384. Epub 2016 Nov 25.

Service de Neurologie A and Eugène Devic EDMUS Foundation against Multiple Sclerosis, Observatoire Français de la Sclérose en Plaques (OFSEP), Hôpital Neurologique Pierre Wertheimer-GHE, Hospices Civils de Lyon, Bron, France/Lyon's Neuroscience Research Center, Team ONCOFLAM, Inserm U 1028/CNRS 5292, Lyon, France Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

Objective: To evaluate the effectiveness and tolerance of mycophenolate mofetil (MMF) as a first-line treatment in neuromyelitis optica spectrum disorder (NMOSD).

Methods: In all, 67 NMOSD patients treated by MMF as first-line therapy, from the NOMADMUS cohort were included. A total of 65 fulfilled 2015 NMOSD criteria, and 5 were myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) positive. Effectiveness was evaluated on percentage of patients continuing MMF, percentage of patients free of relapse, pre- and post-treatment change in the annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS).

Results: Among 67 patients, 40 (59.7%) continued treatment till last follow-up. A total of 33 (49.3%) were relapse-free. The median ARR decreased from one pre-treatment to zero post-treatment. Of 53 patients with complete EDSS data, the score improved or stabilized in 44 (83%; p < 0.05). Effectiveness was observed in aquaporin-4 (AQP4)-IgG (57.8% continued treatment, 46.7% relapse-free), MOG-IgG (3/5 continued treatment, 4/5 relapse-free), and seronegative NMOSD (64.7% continued treatment, 61.3% relapse-free). In 16 patients with associated steroids, 13 (81.2%) continued MMF till last follow-up versus 15 of 28 (53.6%) in the non-steroid group. Nine patients discontinued treatment for tolerability purpose.

Conclusion: MMF showed effectiveness and good tolerability as a first-line therapy in NMOSD, whatever the AQP4-IgG status. Concomitant use of oral steroids at start could limit the risk of treatment failure.
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http://dx.doi.org/10.1177/1352458516678474DOI Listing
September 2017

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy.

Neurology 2016 12 4;87(23):2491-2494. Epub 2016 Nov 4.

From the CHU Toulouse Purpan (B.P., F.B., D.B., D.A.-P., D.B.), Pôle Neurosciences; INSERM U1043-CNRS UMR 5282 (B.P., F.B., D.B.), Université Toulouse III, Centre de Physiopathologie Toulouse Purpan, France; University of Münster (N.S., T.S.-H., H.W.), Germany; University of Lille (O.O., H.Z., P.V.); Hôpital Civil (J.-C. Ongagna, J.d.S.), Strasbourg; CHU Pellegrin (B.B., J.-C. Ouallet), Bordeaux; CHU Nancy (M.D., S.P.); CHU Caen (G.D., N.D.); CH St Vincent (P.H.), GHICL, Lille; CHU Reims (A.T.); CHU Montpellier (P.L.); CHU Nîmes (G.C., W.C., O.C.); CHRU Clermont Ferrand (P.C.); CHU Besançon (E.B.); Aix Marseille University (J.P., A.R.), APHM, CHU Timone, Marseille; CHU Nantes (D.L., S.W.); CHU Grenoble (E.T.); CHU Dijon (T.M., A.F.); CHU Lyon (S.V.), Bron; Hôpital de la Salpêtrière (C.P.), Paris, France; Centre d'Esclerosi Múltiple de Catalunya (CEMCAT) (M.C.), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; and CHU Nice (C.L.-F.), France.

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http://dx.doi.org/10.1212/WNL.0000000000003401DOI Listing
December 2016

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Neurology 2016 09;87(10):1066

Nantes, France.

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http://dx.doi.org/10.1212/01.wnl.0000497026.62085.8dDOI Listing
September 2016

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Neurology 2016 09;87(10):1065-6

Nantes, France.

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http://dx.doi.org/10.1212/WNL.0000000000003112DOI Listing
September 2016

Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study.

Neurology 2016 Feb 29;86(8):771-8. Epub 2016 Jan 29.

Authors' affiliations are listed at the end of the article.

Objective: To compare natalizumab and fingolimod on both clinical and MRI outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) from 27 multiple sclerosis centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis.

Methods: Patients with RRMS included in the study were aged from 18 to 65 years with an Expanded Disability Status Scale score of 0-5.5 and an available brain MRI performed within the year before treatment initiation. The data were collected for 326 patients treated with natalizumab and 303 with fingolimod. The statistical analysis was performed using 2 different methods: logistic regression and propensity scores (inverse probability treatment weighting).

Results: The confounder-adjusted proportion of patients with at least one relapse within the first and second year of treatment was lower in natalizumab-treated patients compared to the fingolimod group (21.1% vs 30.4% at first year, p = 0.0092; and 30.9% vs 41.7% at second year, p = 0.0059) and supported the trend observed in nonadjusted analysis (21.2% vs 27.1% at 1 year, p = 0.0775). Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1 year (Gd-enhancing lesions: 9.3% vs 29.8%, p < 0.0001; new T2 lesions: 10.6% vs 29.6%, p < 0.0001) and 2 years (Gd-enhancing lesions: 9.1% vs 22.1%, p = 0.0025; new T2 lesions: 16.9% vs 34.1%, p = 0.0010) post treatment initiation.

Conclusion: Taken together, these results suggest the superiority of natalizumab over fingolimod to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years.

Classification Of Evidence: This study provides Class IV evidence that for patients with RRMS, natalizumab decreases the proportion of patients with at least one relapse within the first year of treatment compared to fingolimod.
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http://dx.doi.org/10.1212/WNL.0000000000002395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763805PMC
February 2016

Transcript analysis of laser capture microdissected white matter astrocytes and higher phenol sulfotransferase 1A1 expression during autoimmune neuroinflammation.

J Neuroinflammation 2015 Jul 4;12:130. Epub 2015 Jul 4.

INSERM UMR 1064, CHU Hôtel-Dieu, 30 Bvd Jean Monnet, 44093, Nantes, France.

Background: Astrocytes, the most abundant cell population in mammal central nervous system (CNS), contribute to a variety of functions including homeostasis, metabolism, synapse formation, and myelin maintenance. White matter (WM) reactive astrocytes are important players in amplifying autoimmune demyelination and may exhibit different changes in transcriptome profiles and cell function in a disease-context dependent manner. However, their transcriptomic profile has not yet been defined because they are difficult to purify, compared to gray matter astrocytes. Here, we isolated WM astrocytes by laser capture microdissection (LCM) in a murine model of multiple sclerosis to better define their molecular profile focusing on selected genes related to inflammation. Based on previous data indicating anti-inflammatory effects of estrogen only at high nanomolar doses, we also examined mRNA expression for enzymes involved in steroid inactivation.

Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL6 mice with MOG35-55 immunization. Fluorescence activated cell sorting (FACS) analysis of a portion of individual spinal cords at peak disease was used to assess the composition of immune cell infiltrates. Using custom Taqman low-density-array (TLDA), we analyzed mRNA expression of 40 selected genes from immuno-labeled laser-microdissected WM astrocytes from lumbar spinal cord sections of EAE and control mice. Immunohistochemistry and double immunofluorescence on control and EAE mouse spinal cord sections were used to confirm protein expression in astrocytes.

Results: The spinal cords of EAE mice were infiltrated mostly by effector/memory T CD4+ cells and macrophages. TLDA-based profiling of LCM-astrocytes identified EAE-induced gene expression of cytokines and chemokines as well as inflammatory mediators recently described in gray matter reactive astrocytes in other murine CNS disease models. Strikingly, SULT1A1, but not other members of the sulfotransferase family, was expressed in WM spinal cord astrocytes. Moreover, its expression was further increased in EAE. Immunohistochemistry on spinal cord tissues confirmed preferential expression of this enzyme in WM astrocytic processes but not in gray matter astrocytes.

Conclusions: We described here for the first time the mRNA expression of several genes in WM astrocytes in a mouse model of multiple sclerosis. Besides expected pro-inflammatory chemokines and specific inflammatory mediators increased during EAE, we evidenced relative high astrocytic expression of the cytoplasmic enzyme SULT1A1. As the sulfonation activity of SULT1A1 inactivates estradiol among other phenolic substrates, its high astrocytic expression may account for the relative resistance of this cell population to the anti-neuroinflammatory effects of estradiol. Blocking the activity of this enzyme during neuroinflammation may thus help the injured CNS to maintain the anti-inflammatory activity of endogenous estrogens or limit the dose of estrogen co-regimens for therapeutical purposes.
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http://dx.doi.org/10.1186/s12974-015-0348-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501186PMC
July 2015

Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.

Lancet 2015 Sep 28;386(9997):974-81. Epub 2015 Jun 28.

Clinical Neuroscience Centre, CIC-P 1414 INSERM, Rennes University Hospital, Rennes, France. Electronic address:

Background: High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration.

Methods: We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18-55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov, number NCT00984984.

Findings: Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0·5%, 90% CI -9·5 to 10·4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 [77%]) than in the intravenous group (63 [64%]).

Interpretation: Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month after treatment and had a similar safety profile. This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians.

Funding: French Health Ministry, Ligue Française contre la SEP, Teva.
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http://dx.doi.org/10.1016/S0140-6736(15)61137-0DOI Listing
September 2015

Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis.

Ann Clin Transl Neurol 2015 Jun 28;2(6):609-22. Epub 2015 Apr 28.

INSERM, UMR 1064 Nantes, F-44093, France ; Neurology Department, Nantes Hospital Nantes, F-44093, France ; INSERM 004, Centre d'Investigation Clinique Nantes, F-44093, France.

Objective: In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8(+) T cells. These clones have been assumed - but never demonstrated - to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8(+) T cells in the disease.

Methods: For the first time, TCR Vβ repertoire from paired blood (purified CD8(+) and CD4(+) T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8(+) T cells were characterized by fluorescent staining.

Results: TCR Vβ repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8(+) T cells. In parallel, we showed that blood oligoclonal CD8(+) T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B.

Interpretation: This study highlights the predominant implication of CD8(+) T cells in MS pathophysiology and demonstrates that potentially aggressive CD8(+) T cells can be easily identified and characterized from blood and CSF samples.
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http://dx.doi.org/10.1002/acn3.199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479522PMC
June 2015