Publications by authors named "Jérôme De Seze"

204 Publications

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

Ann Clin Transl Neurol 2021 Apr 8. 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
April 2021

Microglial Cell Morphology and Phagocytic Activity Are Critically Regulated by the Neurosteroid Allopregnanolone: A Possible Role in Neuroprotection.

Cells 2021 Mar 21;10(3). Epub 2021 Mar 21.

Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Centre de Recherche en Biomédecine de Strasbourg (CRBS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 1 rue Eugène Boeckel, 67000 Strasbourg, France.

Microglial cells are key players in neural pathogenesis and microglial function regulation appears to be pivotal in controlling neuroinflammatory/neurological diseases. Here, we investigated the effects and mechanism of action of neurosteroid allopregnanolone (ALLO) on murine microglial BV-2 cells and primary microglia in order to determine ALLO-induced immunomodulatory potential and to provide new insights for the development of both natural and safe neuroprotective strategies targeting microglia. Indeed, ALLO-treatment is increasingly suggested as beneficial in various models of neurological disorders but the underlying mechanisms have not been elucidated. Therefore, the microglial cells were cultured with various serum concentrations to mimic the blood-brain-barrier rupture and to induce their activation. Proliferation, viability, RT-qPCR, phagocytosis, and morphology analyzes, as well as migration with time-lapse imaging and quantitative morphodynamic methods, were combined to investigate ALLO actions on microglia. BV-2 cells express subunits of GABA-A receptor that mediates ALLO activity. ALLO (10µM) induced microglial cell process extension and decreased migratory capacity. Interestingly, ALLO modulated the phagocytic activity of BV-2 cells and primary microglia. Our results, which show a direct effect of ALLO on microglial morphology and phagocytic function, suggest that the natural neurosteroid-based approach may contribute to developing effective strategies against neurological disorders that are evoked by microglia-related abnormalities.
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http://dx.doi.org/10.3390/cells10030698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004004PMC
March 2021

Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study.

Ther Adv Neurol Disord 2021 19;14:1756286421993999. Epub 2021 Mar 19.

Washington University School of Medicine, St. Louis, MO, USA.

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing-remitting MS who received DRF or DMF in EVOLVE-MS-2.

Methods: A analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 [ClinicalTrials.gov identifier: NCT03093324] study of DRF DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work.

Results: In total, 504 patients (DRF,  = 253; DMF,  = 251) received study drug and 502 (DRF,  = 253; DMF,  = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere 'quite a bit' or 'extremely' with regular daily activities [IGISIS: DRF, 9.5% (24/253) DMF, 28.9% (72/249)] or work productivity [GGISIS: DRF, 6.1% (10/165) DMF, 11.3% (18/159)]. DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days,  = 20 DMF, 88 days,  = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2-3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations [58.3% (7/12)]. GI tolerability AEs [DRF, 34.8% (88/253); DMF, 48.2% (121/251)], concomitant symptomatic medication use [DRF, 19.3% (17/88) DMF, 30.6% (37/121)], and GI-related discontinuations (DRF, 0.8% DMF, 4.8%) were lower with DRF DMF.

Conclusions: The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use.

Trial Registration: [ClinicalTrials.gov identifier: NCT03093324].
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http://dx.doi.org/10.1177/1756286421993999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985943PMC
March 2021

Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies.

Nat Med 2021 Mar 26. Epub 2021 Mar 26.

Virus & Immunity Unit, Department of Virology, Institut Pasteur, Paris, France.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals.
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http://dx.doi.org/10.1038/s41591-021-01318-5DOI Listing
March 2021

Time to walking aid after 6.5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials.

Eur J Neurol 2021 Mar 16. Epub 2021 Mar 16.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background: Requiring a walking aid is a fundamental milestone in MS, represented by Expanded Disability Status Scale (EDSS) score ≥6.0. Here we assess the effect of ocrelizumab on time to EDSS≥6.0 in relapsing MS.

Methods: Time to EDSS≥6.0 confirmed for ≥24 and ≥48 weeks was assessed over 6.5 years (336 weeks) in the double-blind and open-label extension periods of OPERA I (NCT01247324) and OPERA II (NCT01412333).

Results: Time to reach EDSS≥6.0 was significantly delayed in those initially randomized to ocrelizumab versus interferon. Over 6.5 years, the risk of requiring a walking aid confirmed for ≥24 weeks was 34% lower among those who initiated ocrelizumab earlier vs. delayed treatment (average HR DBP+OLE [95%CI]: 0.66 [0.45-0.95]; P = 0.024); the risk of requiring a walking aid confirmed for ≥48 weeks was 46% lower (average HR DBP+OLE [95%CI]: 0.54 [0.35-0.83]; P = 0.004).

Conclusion: The reduced risk of requiring a walking aid in earlier initiators of ocrelizumab demonstrates the long-term implications of earlier highly effective treatment.
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http://dx.doi.org/10.1111/ene.14823DOI Listing
March 2021

Sex differences in the evolution of neutralizing antibodies to SARS-CoV-2.

J Infect Dis 2021 Mar 7. Epub 2021 Mar 7.

CHU de Strasbourg, Laboratoire de virologie, F-67091 Strasbourg, France.

We measured Anti-Spike (S), Nucleoprotein (N) and neutralizing antibodies (NAbs) in sera from 308 RT-qPCR + healthcare workers with mild disease, collected at two time-points up to 6 months after symptom onset. At Month 1 (M1), anti-S and N antibody levels were higher in males > 50 years or with a body mass index (BMI) > 25. At M3-6, anti-S and anti-N antibodies were detected in 99% and 59% of individuals, respectively. Anti-S antibodies and NAbs declined faster in males than in females, independently of age and BMI, suggesting an association of sex with evolution of the humoral response.
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http://dx.doi.org/10.1093/infdis/jiab127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989436PMC
March 2021

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

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

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

Background And Purpose: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment.

Methods: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included.

Results: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) 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 patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 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, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT.

Conclusion: A significant proportion of patients with MS 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 patients with MS.
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http://dx.doi.org/10.1111/ene.14790DOI Listing
March 2021

Pregnancy in Patients With AQP4-Ab, MOG-Ab, or Double-Negative Neuromyelitis Optica Disorder.

Neurology 2021 04 24;96(15):e2006-e2015. Epub 2021 Feb 24.

From the Department of Neurology (N.C., C.A.D.R., J.D.S.), CHU de Strasbourg; Department of Neurology (B.B.), Rouen University Hospital; Department of Neurology (D.B.), CRC-SEP, CHU Toulouse; Service de Neurologie Sclérose en Plaques, Pathologies de La Myéline et Neuro-inflammation (R.M.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; Department of Neurology (A.M.d.S., E.S.), Centro Hospitalar Universitario do Porto, Hospital de Santo Antonio, Oporto, Portugal; Department of Neurology (E.M., C.P.), Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Pitié-Salpétrière Hospital, Paris, France; and Department of Clinical Neurology (J.P., M.I.S.L.), John Radcliffe Hospital, Oxford University Hospitals Trust, UK.

Objective: To analyze the effects of pregnancy on neuromyelitis optica spectrum disorder (NMOSD) according to patients' serostatus and immunosuppressive therapy (IST).

Methods: We performed a retrospective multicenter international study on patients with NMOSD. Patients were tested for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Informative pregnancies were reported when NMOSD onset occurred before or during pregnancy or up to 12 months postpartum. The mean annualized relapse rate (ARR) was calculated for the 12 months before conception, for each trimester of pregnancy, and postpartum. Events such as miscarriage, abortion, and preeclampsia were reported. IST was considered if taken in the 3 months before or during pregnancy.

Results: We included 89 pregnancies (46 with AQP4-Ab, 30 with MOG-Ab, and 13 without either Ab) in 58 patients with NMOSD. Compared to the prepregnancy period, the ARR was lower during pregnancy in each serostatus group and higher during the postpartum period in patients with AQP4-Ab ( < 0.01). Forty-eight percent (n = 31) of pregnancies occurred during IST and these patients presented fewer relapses during pregnancy and the 12 months postpartum than untreated patients (26% vs 53%, = 0.04). Miscarriages occurred in 10 (11%) pregnancies, and were mainly in patients with AQP4-Ab (with or without IST) and a previous history of miscarriage. Preeclampsia was reported in 2 (2%) patients who were AQP4-Ab-positive.

Conclusion: We found a rebound in the ARR during the first postpartum trimester that was higher than the prepregnancy period only in AQP4-Ab-positive patients. Taking IST just before or during pregnancy reduces the risk of relapses in these conditions.
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http://dx.doi.org/10.1212/WNL.0000000000011744DOI Listing
April 2021

Multiplex assays for the identification of serological signatures of SARS-CoV-2 infection: an antibody-based diagnostic and machine learning study.

Lancet Microbe 2021 Feb 21;2(2):e60-e69. Epub 2020 Dec 21.

Malaria: Parasites and Hosts Unit, Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France.

Background: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces an antibody response targeting multiple antigens that changes over time. This study aims to take advantage of this complexity to develop more accurate serological diagnostics.

Methods: A multiplex serological assay was developed to measure IgG and IgM antibody responses to seven SARS-CoV-2 spike or nucleoprotein antigens, two antigens for the nucleoproteins of the 229E and NL63 seasonal coronaviruses, and three non-coronavirus antigens. Antibodies were measured in serum samples collected up to 39 days after symptom onset from 215 adults in four French hospitals (53 patients and 162 health-care workers) with quantitative RT-PCR-confirmed SARS-CoV-2 infection, and negative control serum samples collected from healthy adult blood donors before the start of the SARS-CoV-2 epidemic (335 samples from France, Thailand, and Peru). Machine learning classifiers were trained with the multiplex data to classify individuals with previous SARS-CoV-2 infection, with the best classification performance displayed by a random forests algorithm. A Bayesian mathematical model of antibody kinetics informed by prior information from other coronaviruses was used to estimate time-varying antibody responses and assess the sensitivity and classification performance of serological diagnostics during the first year following symptom onset. A statistical estimator is presented that can provide estimates of seroprevalence in very low-transmission settings.

Findings: IgG antibody responses to trimeric spike protein (S) identified individuals with previous SARS-CoV-2 infection with 91·6% (95% CI 87·5-94·5) sensitivity and 99·1% (97·4-99·7) specificity. Using a serological signature of IgG and IgM to multiple antigens, it was possible to identify infected individuals with 98·8% (96·5-99·6) sensitivity and 99·3% (97·6-99·8) specificity. Informed by existing data from other coronaviruses, we estimate that 1 year after infection, a monoplex assay with optimal anti-S IgG cutoff has 88·7% (95% credible interval 63·4-97·4) sensitivity and that a four-antigen multiplex assay can increase sensitivity to 96·4% (80·9-100·0). When applied to population-level serological surveys, statistical analysis of multiplex data allows estimation of seroprevalence levels less than 2%, below the false-positivity rate of many other assays.

Interpretation: Serological signatures based on antibody responses to multiple antigens can provide accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. This provides potential solutions to two pressing challenges for SARS-CoV-2 serological surveillance: classifying individuals who were infected more than 6 months ago and measuring seroprevalence in serological surveys in very low-transmission settings.

Funding: European Research Council. Fondation pour la Recherche Médicale. Institut Pasteur Task Force COVID-19.
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http://dx.doi.org/10.1016/S2666-5247(20)30197-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837364PMC
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

First line treatment failure: Predictive factors in a cohort of 863 Relapsing Remitting MS patients.

Mult Scler Relat Disord 2021 Feb 13;48:102686. Epub 2020 Dec 13.

CRC SEP, Montpellier University Hospital, INSERM, Univ Montpellier, Montpellier. Electronic address:

Background: The advent of new, potent, disease-modifying therapies has dramatically changed the management of multiple sclerosis (MS). Along with these possibilities, it is crucial to better recognize patients who are at risk of first line treatment (FLT) failure and switch to highly effective therapies (HET).

Objectives: To identify baseline prognostic factors associated with FLT failure in relapsing remitting MS (RR-MS) patients.

Methods: We included recently diagnosed RR-MS patients starting an FLT identified from 3 French MS centers databases. Baseline characteristics were included in a multivariable Cox analysis to identify the main factors associated with FLT failure.

Results: Eight hundred sixty-three patients were included. We observed an overall rate of treatment failure of 23.5%. The main baseline characteristics associated with treatment failure were age <26 years at treatment start (HR= 2.1, p<0.001), EDSS ≥2 (HR=2.1, p<0.001) and ≥2relapses in the previous year (HR=1.5, p=0.04). The association with the presence of gadolinium enhancement on MRI was not statistically significant. EDSS progression was only significantly associated with age at treatment start and treatment failure.

Conclusion: Our series demonstrates that some clinical and imaging factors are associated with treatment failure, and should be considered when planning treatment strategy in patients with recently diagnosed RR-MS.
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http://dx.doi.org/10.1016/j.msard.2020.102686DOI Listing
February 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 Mar 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

Biomarkers of treatment response in patients with progressive multiple sclerosis treated with high-dose pharmaceutical-grade biotin (MD1003).

Brain Behav 2021 Feb 13;11(2):e01998. Epub 2020 Dec 13.

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

Background: High-dose pharmaceutical-grade biotin (MD1003) has positive effects on disability in progressive multiple sclerosis (PMS), but its mechanism of action remains unclear. The objective of our study was to quantify the effect of MD1003 in patients with PMS, using clinical response, plasma neurofilament light chain (pNfL) levels, and brain (BV) or cervical spinal cord volume (CSCV).

Materials And Methods: Forty-eight patients with PMS newly treated with MD1003 were followed during one year. Patients were assessed clinically using the Expanded Disability Status Scale (EDSS), the nine-hole peg test (9HPT), and the 25-foot walk time (25FWT). CSCV was quantified using CORDIAL software and BV using SIENA or SIENAX. We measured pNfL level using SIMOA at several time points. Bayesian linear and logistic regressions were used to evaluate potential prognostic factors.

Results: Treatment response, defined as a significant decrease of EDSS, 25FWT, or 9HPT at 1 year, was observed in 13 patients (27%). A gain of volume was noted in 7/24 patients for brain and in 10/19 patients for cervical spinal cord. The strongest predictors of poor treatment response were a high pNfL level at MD1003 onset (OR 0.96; 95% CI [0.91; 1]), high age at MS onset (OR 0.95; 95% CI [0.89; 1.01]), and an increase in brain lesion load during MD1003 treatment (OR 0.81; 95% CI [0.55; 1.05]).

Conclusions: MD1003 treatment was associated with clinical, BV, and CSCV improvement at 1 year. The correlation between the levels of pNfL at baseline, the age at multiple sclerosis onset, and a treatment response at M12 is consistent with a better effect in less disabled patients.
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http://dx.doi.org/10.1002/brb3.1998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882156PMC
February 2021

Fatigue in teriflunomide-treated patients with relapsing remitting multiple sclerosis in the real-world Teri-FAST study.

Mult Scler Relat Disord 2021 Jan 28;47:102659. Epub 2020 Nov 28.

Sanofi, Gentilly, France.

Background: Fatigue is a frequent and disabling symptom of multiple sclerosis (MS) often associated with impaired quality of life (QoL) in patients. Teriflunomide is a once-daily oral immunomodulator used for the treatment of relapsing remitting forms of MS. However, its effect on fatigue is not well known in real life practice. We evaluated the impact of teriflunomide on fatigue in patients with relapsing remitting MS (RRMS) after 2 years of treatment in the real-world Teri-FAST study.

Methods: Teri-FAST was a 2-year, prospective, observational study conducted in France in RRMS patients treated with teriflunomide 14 mg. Fatigue was assessed using the French version of the modified fatigue impact scale (EMIF-SEP). The primary endpoint was the change from baseline in EMIF-SEP score after 2 years of treatment. Secondary endpoints included evaluation of depression (Beck Depression Inventory [BDI]), health-related QoL (Two-Life Scale TLS-QoL 10), self-reported physical activity, and adverse events.

Results: 210 eligible patients were included in the study with a mean age of 45.4 years and a mean ± SD Expanded Disability Status Scale score of 1.76 ± 1.43 at baseline. About half (52.4%) of patients had no previous treatment for MS. In the 163 patients who completed at least 1 follow-up visit, the mean change in EMIF-SEP score at Year 2 was -1.54 (95% CI: -4.02, 0.94) indicating that fatigue remained stable. Similarly, there were no changes in depression level and QoL after 2 years of treatment. Physical activity slightly improved with 57% of patients reporting being physically active after 2 years as compared to 46% at baseline. The safety profile of teriflunomide was consistent with that seen during clinical development, and compliance with treatment was high.

Conclusion: Fatigue scores remained stable in RRMS patients treated with teriflunomide 14 mg over 2 years in real-life setting. Teriflunomide did not negatively impact depression or QoL.
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http://dx.doi.org/10.1016/j.msard.2020.102659DOI Listing
January 2021

Inadequate Immune Humoral Response against JC Virus in Progressive Multifocal Leukoencephalopathy Non-Survivors.

Viruses 2020 12 2;12(12). Epub 2020 Dec 2.

Virology Laboratory, Strasbourg University Hospitals, 67000 Strasbourg, France.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization "blind spot" was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients' humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.
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http://dx.doi.org/10.3390/v12121380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761562PMC
December 2020

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

Mult Scler 2020 Dec 3:1352458520978218. 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
December 2020

Living with secondary progressive multiple sclerosis in Europe: perspectives of multiple stakeholders.

Neurodegener Dis Manag 2021 02 25;11(1):9-19. Epub 2020 Nov 25.

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland.

The transition from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS) remains a clinical challenge owing to the heterogeneous course of the disease, indistinct disease progression and lack of availability of validated biomarkers and diagnostic tools. This article summarizes the outcomes from an international expert group meeting conducted to validate the preliminary research findings gathered through interviews with primary healthcare stakeholders and pharmaceutical representatives, and to understand the current and future patient journey of SPMS across seven European countries. We highlight the uncertainty in SPMS diagnosis and management and, consequently, the need for uniform assessment guidelines, enhanced awareness and a collaborative effort between the stakeholders associated with SPMS patient care and the pharmaceutical industry.
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http://dx.doi.org/10.2217/nmt-2020-0054DOI Listing
February 2021

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

Eur Radiol 2021 May 6;31(5):2944-2955. Epub 2020 Nov 6.

Hôpitaux Universitaires de Strasbourg, Service d'imagerie 2, Hôpital de Hautepierre, Strasbourg, France.

Objectives: To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection.

Materials And Methods: In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement.

Results: The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response.

Conclusion: Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML.

Key Points: • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution "the milky way," and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.
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http://dx.doi.org/10.1007/s00330-020-07362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644389PMC
May 2021

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

Mult Scler 2020 Oct 30:1352458520969145. 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
October 2020

Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO).

BMJ Open 2020 10 29;10(10):e035397. Epub 2020 Oct 29.

Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Purpose: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD.

Participants: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices.

Findings To Date: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline.

Future Plans: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.
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http://dx.doi.org/10.1136/bmjopen-2019-035397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597491PMC
October 2020

Outcomes of coronavirus disease 2019 in patients with neuromyelitis optica and associated disorders.

Eur J Neurol 2020 Oct 26. Epub 2020 Oct 26.

Service de Neurologie and CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

Background: Outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), often treated with immunosuppressive therapies, are still unknown.

Methods: We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID-19 between 1 March 2020 and 30 June 2020. Main outcome was COVID-19 severity score assessed on a seven-point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).

Results: Fifteen cases (mean [SD] age: 39.3 [14.3] years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24-year-old patient with positive aquaporine-4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti-CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean [SD] age: 37.0 [13.4] years), with a longer disease duration (mean [SD]: 8.3 [6.3] years) and had a lower expanded disability severity score (EDSS) score (median [range] EDSS: 2.5 [0-4]) relative to patients requiring hospitalization (mean [SD] age: 44.0 [16.4] years, mean [SD] disease duration: 5.8 [5.5] years, median [range] EDSS: 4 [0-6.5]).

Conclusions: COVID-19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID-19; however, we recommend personal protective measures to reduce risk of SARS-CoV-2 infection in this immunocompromised population.
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http://dx.doi.org/10.1111/ene.14612DOI Listing
October 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

Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Ann Neurol 2021 01 15;89(1):30-41. Epub 2020 Oct 15.

Department of Neurology, Multiple Sclerosis and Neuroinflammation, Pierre Wertheimer Neurological Hospital, Lyon Civil Hospices, Lyon, France.

Objective: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD).

Methods: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives.

Results: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280).

Interpretation: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2021;89:30-41.
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http://dx.doi.org/10.1002/ana.25909DOI Listing
January 2021

Evaluation of the performance of SARS-CoV-2 serological tools and their positioning in COVID-19 diagnostic strategies.

Diagn Microbiol Infect Dis 2020 Dec 21;98(4):115181. Epub 2020 Aug 21.

Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; INSERM, UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. Electronic address:

Rapid and accurate diagnosis is crucial for successful outbreak containment. During the current coronavirus disease 2019 (COVID-19) public health emergency, the gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis is the detection of viral RNA. Additional diagnostic methods õenabling the detection of current or past SARS-CoV-2 infection would be highly beneficial. We assessed 2 immunochromatographic lateral flow assays (LFA-1, LFA-2) and 2 enzyme-linked immunosorbent assay kits (IgA/IgG ELISA-1, IgM/IgG ELISA-2) using 325 samples: serum samples from polymerase chain reaction-confirmed COVID-19 hospitalized patients (n = 55) and healthcare workers (n = 143) and 127 samples from negative controls. Diagnostic performances were assessed according to days after symptom onset (dso) and the antigenic format used by manufacturers. Clinical sensitivities varied greatly among the assays, showing poor mutual agreement. After 15 dso, ELISA-1 (Euroimmun) and LFA-1 (Biosynex) combining IgM and IgG detection showed the best performances. A thorough selection of serological assays for the detection of ongoing or past infections is advisable.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441068PMC
December 2020

Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology.

Neurol Neuroimmunol Neuroinflamm 2020 09 20;7(5). Epub 2020 Aug 20.

From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.
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http://dx.doi.org/10.1212/NXI.0000000000000841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455314PMC
September 2020

Ofatumumab versus Teriflunomide in Multiple Sclerosis.

N Engl J Med 2020 08;383(6):546-557

From the UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco (S.L.H.); the Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.B.-O.); the Department of Neurology, Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland (J.A.C.); the Institute of Experimental Neurology and Multiple Sclerosis Center IRCCS, San Raffaele Hospital, Milan (G.C.); the Department of Neurology, Fleni, Buenos Aires (J.C.); the Department of Neurology, Stony Brook University, Stony Brook, NY (P.K.C.); Washington University School of Medicine, St. Louis (A.H.C.); the University Hospital of Strasburg and Clinical Investigation Center INSERM 1434, Strasburg, France (J.S.); University Hospital Basel (D.L.), Novartis Pharma (C.K., R.W., A.K., D.T., D.A.H., K.R., M.M.), and the Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel (L.K.) - all in Basel, Switzerland; the Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona (X.M.); the University of Warmia and Mazury, Olsztyn, and the Center of Neurology, Lodz - both in Poland (K.S.); the Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany (H.W.); and Novartis Pharmaceuticals, East Hanover, NJ (B.L., A.G., R.P.).

Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.

Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.

Conclusions: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).
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http://dx.doi.org/10.1056/NEJMoa1917246DOI Listing
August 2020

Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France.

EBioMedicine 2020 Sep 31;59:102915. Epub 2020 Jul 31.

Institut Pasteur, Emerging Diseases Epidemiology Unit, Paris, France; Conservatoire National des Arts et Métiers, PACRI Unit, Paris, France.

Background: The serologic response of individuals with mild forms of SARS-CoV-2 infection is poorly characterized.

Methods: Hospital staff who had recovered from mild forms of PCR-confirmed SARS-CoV-2 infection were tested for anti-SARS-CoV-2 antibodies using two assays: a rapid immunodiagnostic test (99.4% specificity) and the S-Flow assay (~99% specificity). The neutralizing activity of the sera was tested with a pseudovirus-based assay.

Findings: Of 162 hospital staff who participated in the investigation, 160 reported SARS-CoV-2 infection that had not required hospital admission and were included in these analyses. The median time from symptom onset to blood sample collection was 24 days (IQR: 21-28, range 13-39). The rapid immunodiagnostic test detected antibodies in 153 (95.6%) of the samples and the S-Flow assay in 159 (99.4%), failing to detect antibodies in one sample collected 18 days after symptom onset (the rapid test did not detect antibodies in that patient). Neutralizing antibodies (NAbs) were detected in 79%, 92% and 98% of samples collected 13-20, 21-27 and 28-41 days after symptom onset, respectively (P = 0.02).

Interpretation: Antibodies against SARS-CoV-2 were detected in virtually all hospital staff sampled from 13 days after the onset of COVID-19 symptoms. This finding supports the use of serologic testing for the diagnosis of individuals who have recovered from SARS-CoV-2 infection. The neutralizing activity of the antibodies increased overtime. Future studies will help assess the persistence of the humoral response and its associated neutralization capacity in recovered patients.

Fundings: The funders had no role in study design, data collection, interpretation, or the decision to submit the work for publication.
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http://dx.doi.org/10.1016/j.ebiom.2020.102915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502660PMC
September 2020

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

Mult Scler 2020 09 14;26(10):1157-1162. Epub 2020 Jul 14.

MS International Federation, London, UK.

Background: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale.

Objectives: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible.

Methods: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale.

Results: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process.

Conclusions: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.
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http://dx.doi.org/10.1177/1352458520941485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361123PMC
September 2020

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

Mult Scler 2021 Apr 9;27(5):729-741. Epub 2020 Jul 9.

Department of Neurology, Centre Hospitalier Universitaire de Lille, Lille, France/Department of Neuroradiology, Centre Hospitalier Universitaire de Lille, Lille, France.

Background: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS).

Objectives: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors.

Methods: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0.

Results: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor.

Conclusion: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.
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http://dx.doi.org/10.1177/1352458520936239DOI Listing
April 2021

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