Publications by authors named "Xavier Montalban"

397 Publications

Effect of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome.

Neurology 2021 Sep 14. Epub 2021 Sep 14.

Centre d'Esclerosi Múltiple de Catalunya (Cemcat). Department of Neurology/Neuroimmunology, Hospital Universitari Vall d'Hebron. Universitat Autònoma de Barcelona. Barcelona, Spain.

Objectives: To explore whether time to diagnosis, time to treatment initiation and age to reach disability milestones has changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS)-diagnostic criteria periods.

Methods: Retrospective study based on data prospective collected from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into five periods according to different MS criteria, and the time to MS diagnosis and treatment initiation were evaluated. The age at which MS patients reached an EDSS ≥3.0 was assessed by Cox regression analysis according to diagnostic criteria periods. Finally, in order to remove the classical "Will Rogers" phenomenon by which the use of different MS criteria over time might result on changes of prognosis, 2017 McDonald criteria were applied and age at EDSS ≥ 3.0 was also assessed by Cox regression.

Results: 1174 patients were included. The median time from CIS to MS diagnosis, and from CIS to treatment initiation showed a 77% and 82 reduction from the Poser to the McDonald 2017 diagnostic criteria periods, respectively. Patients of a given age diagnosed in more recent diagnostic criteria periods had a lower risk of reaching EDSS ≥3.0 than patients of the same age diagnosed in earlier diagnostic periods (reference category Poser period): Adjusted hazard ratio (aHR) 0.47 (95% confidence interval 0.24-0.90) for McDonald 2001, aHR 0.25 (0.12-0.54) for McDonald 2005, aHR 0.30 (0.12-0.75) for McDonald 2010 and aHR 0.07 (0.01-0.45) for McDonald 2017. Early-treatment patients displayed an aHR of 0.53 (0.33-0.85) of reaching age at EDSS ≥3.0 compared to late-treatment. Changes in prognosis together with early-treatment effect were maintained after excluding possible bias derived from the use of different diagnostic criteria over time (so called, "Will Rogers" phenomenon) CONCLUSION: A continuous decrease in the time to MS diagnosis and treatment initiation were observed across diagnostic criteria periods. Overall, patients diagnosed in more recent diagnostic criteria periods displayed a lower risk of reaching disability. Importantly, the prognostic improvement is maintained after discarding the "Will Rogers" phenomenon, and early treatment appears to be the most likely contributing factor.
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http://dx.doi.org/10.1212/WNL.0000000000012726DOI Listing
September 2021

CSF Chitinase 3-Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 8;8(6). Epub 2021 Sep 8.

From the Unitat de Neuroimmunologia Clínica (M.C., J.S.-G., R.P., N.F., A.V.-J., X.M.), Hospital Universitari Vall d´Hebron; Eva Borràs (E.B., E.S.), Proteomics Unit, Universitat Pompeu Fabra, Barcelona; Departments of Neurology and Immunology (L.M.V., L.C.-F.), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion Sanitaria, Madrid; Service of Neurology (A.S., Y.B., S.L.), Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi Sunyer, University of Barcelona; Department of Neurology (S.M.-Y.), Bellvitge University Hospital, Barcelona; and Neuroimmunology Unit (J.A.G.M., A.J.S.L.), Hospital Universitario Puerta de Hierro, Madrid, Spain.

Objective: This study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS).

Methods: CSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years.

Results: Of 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3-like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression ( = 0.03 for NPR and = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%).

Conclusions: Although further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS.

Classification Of Evidence: This study provides Class II evidence that high CSF CHI3L2 levels identified higher disability progression in patients with progressive MS.
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http://dx.doi.org/10.1212/NXI.0000000000001082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428018PMC
November 2021

Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis.

Neurology 2021 Sep 2. Epub 2021 Sep 2.

Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), TX; *R. Hughes was an employee of F. Hoffmann-La Roche Ltd during completion of the work related to this manuscript.** H. Koendgen was an employee of F. Hoffmann-La Roche Ltd during completion of the work related to this manuscript.

ObjectiveTo report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings.MethodsSafety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources.ResultsAt data cut-off (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient years [PY] of exposure) in clinical trials. Rates per 100 PY (95% CI) of AEs (248; 246-251), serious AEs (7.3; 7.0-7.7), infusion-related reactions (25.9; 25.1-26.6), and infections (76.2; 74.9-77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81-2.23) and malignancies (0.46; 0.37-0.57), were consistent with the ranges reported in epidemiologic data.ConclusionContinuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns in a heterogeneous MS population.Classification of evidenceThis analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.
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http://dx.doi.org/10.1212/WNL.0000000000012700DOI Listing
September 2021

Transcriptome and Function of Novel Immunosuppressive Autoreactive Invariant Natural Killer T Cells That Are Absent in Progressive Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 11 12;8(6). Epub 2021 Aug 12.

From the Biotech Research and Innovation Centre (BRIC) (B.C., Y.L., M.H., J.L., S.I.-N.), University of Copenhagen; Danish Multiple Sclerosis Center (J.R.C., C.A., P.S.S.), University of Copenhagen and Department of Neurology, Rigshospitalet; Blood Bank (M.H.D.), Copenhagen University Hospital, Denmark; Centre d'Esclerosi Múltiple de Catalunya (M.C.), Cemcat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d´Hebron (HUVH) - Universitat Autònoma de Barcelona, Barcelona, Spain; and Centre d'Esclerosi Múltiple de Catalunya (X.M.), Cemcat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d´Hebron (HUVH) - Universitat Autònoma de Barcelona, Spain; Danish Multiple Sclerosis Center, University of Copenhagen and Department of Neurology, Rigshospitalet, Denmark.

Background And Objective: The aim of this study was to determine whether natural killer T (NKT) cells, including invariant (i) NKT cells, have clinical value in preventing the progression of multiple sclerosis (MS) by examining the mechanisms by which a distinct self-peptide induces a novel, protective invariant natural killer T cell (iNKT cell) subset.

Methods: We performed a transcriptomic and functional analysis of iNKT cells that were reactive to a human collagen type II self-peptide, hCII707-721, measuring differentially induced genes, cytokines, and suppressive capacity.

Results: We report the first transcriptomic profile of human conventional vs novel hCII707-721-reactive iNKT cells. We determined that hCII707-721 induces protective iNKT cells that are found in the blood of healthy individuals but not progressive patients with MS (PMS). By transcriptomic analysis, we observed that hCII707-721 promotes their development and proliferation, favoring the splicing of full-length AKT serine/threonine kinase 1 (AKT1) and effector function of this unique lineage by upregulating tumor necrosis factor (TNF)-related genes. Furthermore, hCII707-721-reactive iNKT cells did not upregulate interferon (IFN)-γ, interleukin (IL)-4, IL-10, IL-13, or IL-17 by RNA-seq or at the protein level, unlike the response to the glycolipid alpha-galactosylceramide. hCII707-721-reactive iNKT cells increased TNFα only at the protein level and suppressed autologous-activated T cells through FAS-FAS ligand (FAS-FASL) and TNFα-TNF receptor I signaling but not TNF receptor II.

Discussion: Based on their immunomodulatory properties, NKT cells have a potential value in the treatment of autoimmune diseases, such as MS. These significant findings suggest that endogenous peptide ligands can be used to expand iNKT cells, without causing a cytokine storm, constituting a potential immunotherapy for autoimmune conditions, including PMS.
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http://dx.doi.org/10.1212/NXI.0000000000001065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362604PMC
November 2021

CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis.

Mult Scler 2021 Aug 11:13524585211032803. Epub 2021 Aug 11.

Vita-Salute San Raffaele University, Milan, Italy/Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy/Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS).

Objective: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( = 727,  = 732, and  = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study.

Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67-1.31;  = 0.706). Secondary endpoint values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both,  = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg.

Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated.

Clinical Trial Registration Number: ClinicalTrials.gov (NCT01707992).
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http://dx.doi.org/10.1177/13524585211032803DOI Listing
August 2021

Multiple sclerosis is associated with higher comorbidity and health care resource use: A population-based, case-control study in a western Mediterranean region.

Eur J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Neurology-Neuroimmunology Service, Multiple Sclerosis Center of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Background And Purpose: Comorbidities are common in multiple sclerosis (MS), and have been associated with worse outcomes and increased health care resource usage. We studied the frequency of comorbidities and adverse health behaviors (AHBs) in MS patients in the Mediterranean region of Catalonia.

Methods: This population-based, case-control study used primary health care information covering 80% of Catalonia's population. Cases were matched by age/sex with randomly chosen controls (ratio = 1:5). Demographic information, comorbidities, AHBs, annual visits, sick leave days, and medication dispensing were studied. The association of comorbidities with MS and the profile of comorbidities according to sex within MS cases were assessed with multivariate logistic regression models, after adjusting for confounding variables. Health care resource usage was analyzed in MS cases compared to controls, and within MS cases in those with compared to those without comorbidities.

Results: Five thousand five hundred forty-eight MS cases and 27,710 controls (70% female, mean age = 48.3 years) were included. Stroke (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.17-1.99), epilepsy (OR = 2.46, 95% CI = 1.94-3.10), bipolar disorder (OR = 1.67, 95% CI = 1.17-2.36), and depression (OR = 1.83, 95% CI = 1.70-1.98) were more frequent in MS. Cases were more prone to smoking but less to alcohol intake. Among cases, psychiatric comorbidities were more frequent in women, whereas cardiovascular diseases and AHBs were more frequent in men. MS patients, particularly with comorbidities, had higher health care resource usage than controls.

Conclusions: Psychiatric comorbidities, stroke, epilepsy, and AHBs are more common in MS patients than in the general population in the western Mediterranean region of Catalonia. The presence of comorbidities increases the health care resource usage in MS patients.
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http://dx.doi.org/10.1111/ene.15030DOI Listing
July 2021

A smartphone sensor-based digital outcome assessment of multiple sclerosis.

Mult Scler 2021 Jul 14:13524585211028561. Epub 2021 Jul 14.

UCSF Weill Institute for Neurosciences and Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: Sensor-based monitoring tools fill a critical gap in multiple sclerosis (MS) research and clinical care.

Objective: The aim of this study is to assess performance characteristics of the Floodlight Proof-of-Concept (PoC) app.

Methods: In a 24-week study (clinicaltrials.gov: NCT02952911), smartphone-based active tests and passive monitoring assessed cognition (electronic Symbol Digit Modalities Test), upper extremity function (Pinching Test, Draw a Shape Test), and gait and balance (Static Balance Test, U-Turn Test, Walk Test, Passive Monitoring). Intraclass correlation coefficients (ICCs) and age- or sex-adjusted Spearman's rank correlation determined test-retest reliability and correlations with clinical and magnetic resonance imaging (MRI) outcome measures, respectively.

Results: Seventy-six people with MS (PwMS) and 25 healthy controls were enrolled. In PwMS, ICCs were moderate-to-good (ICC(2,1) = 0.61-0.85) across tests. Correlations with domain-specific standard clinical disability measures were significant for all tests in the cognitive ( = 0.82, < 0.001), upper extremity function (|r|= 0.40-0.64, all < 0.001), and gait and balance domains ( = -0.25 to -0.52, all < 0.05; except for Static Balance Test: = -0.20, > 0.05). Most tests also correlated with Expanded Disability Status Scale, 29-item Multiple Sclerosis Impact Scale items or subscales, and/or normalized brain volume.

Conclusion: The Floodlight PoC app captures reliable and clinically relevant measures of functional impairment in MS, supporting its potential use in clinical research and practice.
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http://dx.doi.org/10.1177/13524585211028561DOI Listing
July 2021

Immunosenescence in multiple sclerosis: the identification of new therapeutic targets.

Autoimmun Rev 2021 Sep 5;20(9):102893. Epub 2021 Jul 5.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain; Universitat Autònoma de Barcelona, 08193, Bellaterra, Cerdanyola del Vallès, Spain; Red Española de Esclerosis Múltiple (REEM), Spain. Electronic address:

The number of elderly multiple sclerosis (MS) patients is growing, mainly due to the increase in the life expectancy of the general population and the availability of effective disease-modifying treatments. However, current treatments reduce the frequency of relapses and slow the progression of the disease, but they cannot stop the disability accumulation associated with disease progression. One possible explanation is the impact of immunosenescence, which is associated with the accumulation of unusual immune cell subsets that are thought to have a role in the development of an early ageing process in autoimmunity. Here, we provide a recent overview of how senescence affects immune cell function and how it is involved in the pathogenesis of autoimmune diseases, particularly MS. Numerous studies have demonstrated age-related immune changes in experimental autoimmune encephalomyelitis models, and the premature onset of immunosenescence has been demonstrated in MS patients. Therefore, potential therapeutic strategies based on rejuvenating the immune system have been proposed. Senolytics and regenerative strategies using haematopoietic stem cells, therapies based on rejuvenating oligodendrocyte precursor cells, microglia and monocytes, thymus cells and senescent B and T cells are capable of reversing the process of immunosenescence and could have a beneficial impact on the progression of MS.
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http://dx.doi.org/10.1016/j.autrev.2021.102893DOI Listing
September 2021

Targeting Inflammasomes to Treat Neurological Diseases.

Ann Neurol 2021 Aug 17;90(2):177-188. Epub 2021 Jul 17.

Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Vall d'Hebron University Hospital, Barcelona, Spain.

Inflammasomes are multimeric protein complexes that can sense a plethora of microbe- and damage-associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome-mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1β and IL-18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune-mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021;90:177-188.
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http://dx.doi.org/10.1002/ana.26158DOI Listing
August 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 2021

Serum Neurofilament Levels and PML Risk in Patients With Multiple Sclerosis Treated With Natalizumab.

Neurol Neuroimmunol Neuroinflamm 2021 07 26;8(4). Epub 2021 Apr 26.

From the Servei de Neurologia-Neuroimmunologia (N.F., M.C.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; CRC-SEP Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 CNRS UMR 5282 et Université de Toulouse III, UPS, France; Servei de Neurologia-Neuroimmunologia (J.R., X.M.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain; Univ. Lille (P.V.), Inserm U1172, CHU Lille, FHU Imminent, France; Université (A.R.), Bordeaux; CHU de Bordeaux (A.R.), INSERM-CHU CIC-P 0005, & Services de Neurologie; Neurocentre Magendie (A.R.), INSERM U1215; Department of Neurology (J.dS), Hôpital Civil, Strasbourg; Department of Neurology (P.L.), CHU Montpellier; Department of Neurology CHU Lyon (S.V.); Department of Neurology (C.P.), Hôpital de la Salpétrière, Paris; Chi Aix en Provence (L.M.-A.); Department of Neurology and Faculté de Médecine de Reims (A.T.), CHU de Reims, URCA; LPN EA2027 Université Paris VIII (A.T.), Saint-Denis; Department of Neurology (P.C.), CHRU Clermont Ferrand; Department of Neurology (T.M.), CHU Dijon; Aix-Marseille Univ (J.P.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, CNRS, CRMBM UMR 7339, Marseille; Service de Neurology (C.L.-F.), CHU de Nice Pasteur2, Université Nice Cote d'Azur UR2CA URRIS, Nice; Neurologie (B.B.), CHU Rouen; and Neurologie (G.D.), CHU Caen, France.

Objectives: The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses.

Methods: NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations.

Results: Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses.

Conclusions: These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients.

Classification Of Evidence: This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%.
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http://dx.doi.org/10.1212/NXI.0000000000001003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105883PMC
July 2021

Ozanimod in relapsing multiple sclerosis: Pooled safety results from the clinical development program.

Mult Scler Relat Disord 2021 Jun 15;51:102844. Epub 2021 Feb 15.

Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address:

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data.

Methods: We report pooled incidence and study duration‒adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from an interim data cut (January 31, 2019) of RMS participants treated with ozanimod. Data were pooled from a phase 1 pharmacokinetic/pharmacodynamic trial, a placebo-controlled phase 2 trial with dose-blinded extension, 2 large active-controlled phase 3 trials, and an open-label extension (OLE). Results were compared with pooled phase 3 trial data.

Results: At the data cutoff, 2631 RMS participants had exposure to ozanimod 0.92 mg (mean 32.0 months) and 2787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1000 person-years (PY) for any TEAE (772.2) and serious TEAEs (33.2) in the overall population were similar to those in the phase 3 population (896.1 and 31.2, respectively). There were no serious opportunistic infections. There were no second-degree or higher atrioventricular blocks on electrocardiogram. Hepatic enzyme elevations declined over time. Malignancy rates remained low with longer exposure. Pulmonary function tests showed minimal reductions in lung function. Seven ozanimod-treated participants with comorbid risk factors had confirmed macular edema, including 3 in the ongoing OLE.

Conclusions: Safety results in this larger RMS population with greater ozanimod exposure demonstrated no new safety concerns and were consistent with phase 3 trial results.
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http://dx.doi.org/10.1016/j.msard.2021.102844DOI Listing
June 2021

CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event.

Mult Scler 2021 Apr 19:13524585211010082. Epub 2021 Apr 19.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis.

Objective: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event.

Methods: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (β = 1.41; 95% confidence interval (CI) = 1.10-1.79; < 0.01) and serum NfL levels (β = 2.30; 95% CI = 1.47-3.60; < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (β = 1.45; 95% CI = 1.11-1.90; < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses.

Conclusion: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.
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http://dx.doi.org/10.1177/13524585211010082DOI Listing
April 2021

Selected Clostridia Strains from The Human Microbiota and their Metabolite, Butyrate, Improve Experimental Autoimmune Encephalomyelitis.

Neurotherapeutics 2021 04 7;18(2):920-937. Epub 2021 Apr 7.

Servei de Neurologia-Neuroimmunologia, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Centre d'Esclerosi Múltiple de Catalunya, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain.

Gut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.
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http://dx.doi.org/10.1007/s13311-021-01016-7DOI Listing
April 2021

Scoring the 10-year risk of ambulatory disability in multiple sclerosis: the RoAD score.

Eur J Neurol 2021 08 19;28(8):2533-2542. Epub 2021 Apr 19.

Centre d'Esclerosi Multiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology, Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.

Background And Purpose: Both baseline prognostic factors and short-term predictors of treatment response can influence the long-term risk of disability accumulation in patients with relapsing-remitting multiple sclerosis (RRMS). The objective was to develop and validate a scoring system combining baseline prognostic factors and 1-year variables of treatment response into a single numeric score predicting the long-term risk of disability.

Methods: We analysed two independent datasets of patients with RRMS who started interferon beta or glatiramer acetate, had an Expanded Disability Status Scale (EDSS) score <4.0 at treatment start and were followed for at least 10 years. The first dataset ('training set') included patients attending three MS centres in Italy and served as a framework to create the so-called RoAD score (Risk of Ambulatory Disability). The second ('validation set') included a cohort of patients followed in Barcelona, Spain, to explore the performance of the RoAD score in predicting the risk of reaching an EDSS score ≥6.0.

Results: The RoAD score (ranging from 0 to 8) derived from the training set (n = 1225), was based on demographic (age), clinical baseline prognostic factors (disease duration, EDSS) and 1-year predictors of treatment response (number of relapses, presence of gadolinium enhancement and new T2 lesions). The best cut-off score for discriminating patients at higher risk of reaching the disability milestone was ≥4. When applied to the validation set (n = 296), patients with a RoAD score ≥4 had an approximately 4-fold increased risk for reaching the disability milestone (p < 0.001).

Discussion: The RoAD score is proposed as an useful tool to predict individual prognosis and optimize treatment strategy of patients with RRMS.
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http://dx.doi.org/10.1111/ene.14845DOI Listing
August 2021

Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial.

JAMA Neurol 2021 May;78(5):558-567

Neurology and Research Center for Clinical Neuroimmunology and Neuroscience Basel, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering University Hospital and University of Basel, Basel, Switzerland.

Importance: To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).

Objective: To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.

Design, Setting, And Participants: This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.

Interventions: Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.

Main Outcomes And Measures: The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.

Results: For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

Conclusions And Relevance: In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.

Trial Registration: ClinicalTrials.gov Identifier: NCT02425644.
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http://dx.doi.org/10.1001/jamaneurol.2021.0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008435PMC
May 2021

Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry.

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

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

Background And Purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662).

Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase.

Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years.

Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
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http://dx.doi.org/10.1111/ene.14824DOI Listing
March 2021

Menopause does not modify disability trajectories in a longitudinal cohort of women with clinically isolated syndrome and multiple sclerosis followed from disease onset.

Eur J Neurol 2021 Feb 20. Epub 2021 Feb 20.

Neurology-Neuroimmunology Department, Centro de Esclerosis Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background And Purpose: To evaluate the effect of menopause on disability accumulation in women followed from their clinically isolated syndrome (CIS).

Methods: We examined the longitudinal changes in Expanded Disability Status Scale (EDSS) scores from CIS until the last follow-up in women belonging to the Barcelona CIS prospective cohort, followed through their menopausal transition. The analysis is based on 13,718 EDSS measurements, with an average of 28 EDSS measurements per patient. Differences in EDSS trajectories between menopausal and nonmenopausal women, controlling for age and disease duration, were evaluated. We performed two sensitivity analyses in women with confirmed MS and in those experiencing early menopause.

Results: From 764 eligible women, 496 (65%) responded to the questionnaire, and 74 (14.9%) reached menopause over the follow-up. We did not find a significant inflection point in EDSS trajectories around menopause (slope change -0.009; 95% CI -0.066; 0.046). The annual increase in EDSS over the complete course of the disease was significantly higher in menopausal women (0.049; 95% CI, 0.026-0.074) versus nonmenopausal (0.019; 95% CI, 0.008-0.031; interaction p value 0.025). This difference was lost when controlling for age and disease duration (EDSS annual increase of 0.059; 95% CI, 0.025-0.094 vs. 0.038; 95% CI, 0.021-0.057, respectively; interaction p value 0.321). No inflection point was detected when the analysis was restricted to women with confirmed MS or with earlier menopause.

Conclusions: Menopause is not associated with an increased risk of disability in a CIS population, considering EDSS trajectories throughout the course of the disease together with age and disease duration.
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http://dx.doi.org/10.1111/ene.14782DOI Listing
February 2021

The frequency and characteristics of MS misdiagnosis in patients referred to the multiple sclerosis centre of Catalonia.

Mult Scler 2021 05 10;27(6):913-921. Epub 2021 Feb 10.

Section of Neuroradiology, Radiology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Multiple sclerosis (MS) misdiagnosis may cause physical and emotional damage to patients.

Objectives: The objective of this study is to determine the frequency and characteristics of MS misdiagnosis in patients referred to the Multiple Sclerosis Centre of Catalonia.

Methods: We designed a prospective study including all new consecutive patients referred to our centre between July 2017 and June 2018. Instances of misdiagnosis were identified, and referral diagnosis and final diagnosis were compared after 1 year of follow-up. Association of misdiagnosis with magnetic resonance imaging (MRI) findings, presence of comorbidities and family history of autoimmunity were assessed.

Results: A total of 354 patients were referred to our centre within the study period, 112 (31.8%) with 'established MS'. Misdiagnosis was identified in eight out of 112 cases (7.1%). MRI identified multifocal white matter lesions, deemed non-specific or not suggestive of MS in all misdiagnosed cases. Patients with MS misdiagnosis had more comorbidities in general than patients with MS ( = 0.026) as well as a personal history of autoimmunity ( < 0.001).

Conclusion: A low frequency of MS misdiagnosis was found in our clinical setting. Multifocal non-specific white matter lesions in referral MRI examinations and the presence of comorbidities, including a personal history of autoimmunity, seem to be contributing factors to misdiagnosis.
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http://dx.doi.org/10.1177/1352458520988148DOI Listing
May 2021

Effect of Ozanimod on Symbol Digit Modalities Test Performance in Relapsing MS.

Mult Scler Relat Disord 2021 Feb 10;48:102673. Epub 2020 Dec 10.

Department of Neurology, Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 USA. Electronic address:

Background: Cognitive dysfunction, including slowed cognitive processing speed (CPS), is one of the most disabling symptoms of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a preferred measure of CPS for MS trials and routine screening. Based on encouraging SDMT results in the phase 3 SUNBEAM trial, these post hoc, exploratory analyses were conducted to further compare effects of the sphingosine 1-phosphate receptor modulator ozanimod versus intramuscular interferon β-1a on CPS in participants with relapsing multiple sclerosis (RMS).

Methods: In the phase 3, double-blind, double-dummy, SUNBEAM study, adults (aged 18‒55 years) with RMS (N=1,346) were randomized to once-daily oral ozanimod 0.92 or 0.46 mg, or weekly intramuscular interferon β-1a 30 µg. The study continued until the last participant was treated for 12 months. CPS was measured as part of a secondary endpoint using the SDMT. Exploratory, post hoc analyses evaluated SDMT change and percentages of participants with clinically meaningful (≥4-point) SDMT improvement or worsening at months 6 and 12, and relationship between SDMT and brain volume on magnetic resonance imaging.

Results: Ozanimod improved SDMT scores compared with interferon β-1a at months 6 and 12. At month 12, least squares mean difference in SDMT z-scores for ozanimod 0.92 mg versus interferon β-1a was 0.102 (95% CI, 0.031‒0.174, nominal p = 0.0051; standardized mean difference = 0.1376). A greater percentage of ozanimod 0.92 mg‒treated participants had clinically meaningful improvements in SDMT scores versus interferon β-1a at month 6 (30.0% versus 22.2%) and month 12 (35.6% versus 27.9%). Of those with SDMT improvement at month 6, 66.4% of those treated with ozanimod 0.92 mg and 55.9% of those treated with interferon β-1a had sustained improvement at month 12. Brain volume loss was similar for those with SDMT improvement versus worsening at month 12.

Conclusions: In these exploratory analyses, ozanimod had modestly beneficial effects on CPS in RMS participants. The effects of ozanimod on SDMT are being further evaluated in an ongoing 3-year clinical trial. SUNBEAM is registered on clinicaltrials.gov (NCT02294058) and the European Clinical Trials Database (EudraCT 2014-002320-27).
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http://dx.doi.org/10.1016/j.msard.2020.102673DOI Listing
February 2021

CSF SERPINA3 Levels Are Elevated in Patients With Progressive MS.

Neurol Neuroimmunol Neuroinflamm 2021 03 12;8(2). Epub 2021 Jan 12.

From the Servei de Neurologia-Neuroimmunologia (N.F., C.M.-B., C.C., R.P., V.B., X.M., M.C.L.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; Biotech Research and Innovation Centre (BRIC) (M.O., S.I.-N.), University of Copenhagen, Denmark; Statistics and Bioinformatics Unit (B.M., A.S.), Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain; Genetics, Microbiology and Statistics Department (A.S.), Universitat de Barcelona, Spain; Department of Neurology (I.D.), University of Belgrade School of Medicine, Serbia; Department of Neurology (I.D.), University of North Carolina School of Medicine, Chapel Hill; Department of Neurology (M.V., M.K.), Medical University of Graz, Austria; Proteomics Unit (E.B., E.S.), Centre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), Spain; Proteomics Unit (E.B., E.S.), Universitat Pompeu Fabra, Barcelona, Spain; and Center for Multiple Sclerosis (X.M.), St. Michael's Hospital, University of Toronto, ON, Canada.

Objective: To identify biomarkers associated with progressive phases of MS and with neuroprotective potential.

Methods: Combined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs).

Results: Integrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, = 0.02) and NINCs (1,617 vs 838.6 ng/mL, = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, = 0.01).

Conclusion: These results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS.
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http://dx.doi.org/10.1212/NXI.0000000000000941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105904PMC
March 2021

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Front Neurol 2020 17;11:579438. Epub 2020 Dec 17.

Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.
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http://dx.doi.org/10.3389/fneur.2020.579438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780851PMC
December 2020

COVID-19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response.

Eur J Neurol 2021 Oct 9;28(10):3384-3395. Epub 2021 Jan 9.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background And Purpose: Information regarding multiple sclerosis (MS) patients with the 2019 novel coronavirus disease (COVID-19) is scarce. The study objective was to describe the incidence and characteristics of MS patients with COVID-19, to identify susceptibility and severity risk factors and to assess the proportion of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologies according to disease-modifying treatments.

Methods: This was a retrospective study of an MS cohort analysing data collected between February and May 2020. Cases were identified through an email survey and clinical visits. The relationship of demographic and MS characteristics with COVID-19 and of the disease-modifying treatments with SARS-CoV-2 serostatus were examined.

Results: Data from 48 suspected cases out of 758 valid respondents and from 45 COVID-19 cases identified through clinical visits were collected. Incidence was 6.3%. Nineteen (20.3%) patients were hospitalized and two (2.2%) died. Multivariable models determined that age (odds ratio [OR] per 10 years 0.53, 95% confidence interval [CI] 0.34-0.85), contact with a confirmed case (OR 197.02, 95% CI 56.36-688.79), residence in Barcelona (OR 2.23, 95% CI 1.03-4.80), MS duration (OR per 5 years 1.41, 95% CI 1.09-1.83) and time on anti-CD20 treatment (OR per 2 years 3.48, 95% CI 1.44-8.45) were independent factors for presenting COVID-19 and age (OR per 10 years 2.71, 95% CI 1.13-6.53) for a severe COVID-19. Out of the 79 (84.9%) with serological test, 45.6% generated antibodies, but only 17.6% of those on anti-CD20 therapies. Lymphopaenia or immunoglobulin levels did not relate to COVID-19.

Conclusions: Multiple sclerosis patients present similar incidence, risk factors and outcomes for COVID-19 as the general population. Patients treated with an anti-CD20 therapy for a longer period of time might be at a higher risk of COVID-19 and less than 20% generate an antibody response. Only age was related to severity.
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http://dx.doi.org/10.1111/ene.14690DOI Listing
October 2021

Optic Nerve Topography in Multiple Sclerosis Diagnosis: The Utility of Visual Evoked Potentials.

Neurology 2021 01 16;96(4):e482-e490. Epub 2020 Dec 16.

From the Servicio de Neurología-Neuroinmunología (A V.-J., G.A., S.O.-R., J.R., M.C., C.N., J.C., I.G., S.C., B.R.-A., A.Z., L.M., J.S.-G., X.M., M.T.), Centro de Esclerosis Múltiple de Catalunya (Cemcat), Sección de Neuroradiologia (A.R., C.A.), Servei de Radiologia, Servicio de Medicina Preventiva y Epidemiologia (S.O.-R.), and Servicio de Neurofisiología Clínica (D.M., K.R., V.T.), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; and Division of Neurology (X.M.), St. Michael's Hospital. University of Toronto, Ontario, Canada.

Objective: To assess the added value of the optic nerve region (by using visual evoked potentials [VEPs]) to the current diagnostic criteria.

Methods: From the Barcelona clinically isolated syndrome (CIS) cohort, patients with complete information to assess dissemination in space (DIS), the optic nerve region, and dissemination in time at baseline (n = 388) were selected. Modified DIS (modDIS) criteria were constructed by adding the optic nerve to the current DIS regions. The DIS and modDIS criteria were evaluated with univariable Cox proportional hazard regression analyses with the time to the second attack as the outcome. A subset of these patients who had at least 10 years of follow-up or a second attack occurring within 10 years (n = 151) were selected to assess the diagnostic performance. The analyses were also performed according to CIS topography (optic neuritis vs non-optic neuritis).

Results: The addition of the optic nerve as a fifth region improved the diagnostic performance by slightly increasing the accuracy (2017 DIS 75.5%, modDIS 78.1%) and the sensitivity (2017 DIS 79.2%, modDIS 82.3%) without lowering the specificity (2017 DIS 52.4%, modDIS 52.4%). When the analysis was conducted according to CIS topography, the modDIS criteria performed similarly in both optic neuritis and non-optic neuritis CIS.

Conclusion: The addition of the optic nerve, assessed by VEP, as a fifth region in the current DIS criteria slightly improves the diagnostic performance because it increases sensitivity without losing specificity.
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http://dx.doi.org/10.1212/WNL.0000000000011339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905792PMC
January 2021

Chitinase 3-like 1 is not a target antigen in patients with multiple sclerosis.

Mult Scler 2021 Aug 17;27(9):1455-1457. Epub 2020 Dec 17.

Montalban Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Autoimmunity to chitinase 3-like 1 (CHI3L1) has recently been reported in hepatic and bowel inflammatory conditions. Considering that CHI3L1 plays a role as prognostic biomarker in multiple sclerosis (MS), here we investigated CHI3L1 as potential autoantigenic target in the disease. We determined serum CHI3L1 autoantibodies by enzyme-linked immunosorbent assay (ELISA) in a cohort of 60 untreated MS patients with different clinical forms of the disease and 20 healthy controls (HC). IgG levels to CHI3L1 were similar between patients with relapsing-remitting MS, primary and secondary progressive MS, and HC. These findings do not support a role for CHI3L1 autoantibodies in MS pathogenesis.
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http://dx.doi.org/10.1177/1352458520980141DOI Listing
August 2021

Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review.

JAMA Neurol 2021 Mar;78(3):351-364

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e di Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS.

Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS.

Conclusions And Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.
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http://dx.doi.org/10.1001/jamaneurol.2020.4689DOI Listing
March 2021

U-turn speed is a valid and reliable smartphone-based measure of multiple sclerosis-related gait and balance impairment.

Gait Posture 2021 02 25;84:120-126. Epub 2020 Nov 25.

F. Hoffmann-La Roche Ltd, Basel, 4070, Switzerland; Department of Economics, Baden-Wuerttemberg Cooperative State University, Loerrach, 79539, Germany. Electronic address:

Background: People living with multiple sclerosis (MS) experience impairments in gait and mobility, that are not fully captured with manually timed walking tests or rating scales administered during periodic clinical visits. We have developed a smartphone-based assessment of ambulation performance, the 5 U-Turn Test (5UTT), a quantitative self-administered test of U-turn ability while walking, for people with MS (PwMS).

Research Question: What is the test-retest reliability and concurrent validity of U-turn speed, an unsupervised self-assessment of gait and balance impairment, measured using a body-worn smartphone during the 5UTT?

Methods: 76 PwMS and 25 healthy controls (HCs) participated in a cross-sectional non-randomised interventional feasibility study. The 5UTT was self-administered daily and the median U-turn speed, measured during a 14-day session, was compared against existing validated in-clinic measures of MS-related disability.

Results: U-turn speed, measured during a 14-day session from the 5UTT, demonstrated good-to-excellent test-retest reliability in PwMS alone and combined with HCs (intraclass correlation coefficient [ICC] = 0.87 [95 % CI: 0.80-0.92]) and moderate-to-excellent reliability in HCs alone (ICC = 0.88 [95 % CI: 0.69-0.96]). U-turn speed was significantly correlated with in-clinic measures of walking speed, physical fatigue, ambulation impairment, overall MS-related disability and patients' self-perception of quality of life, at baseline, Week 12 and Week 24. The minimal detectable change of the U-turn speed from the 5UTT was low (19.42 %) in PwMS and indicates a good precision of this measurement tool when compared with conventional in-clinic measures of walking performance.

Significance: The frequent self-assessment of turn speed, as an outcome measure from a smartphone-based U-turn test, may represent an ecologically valid digital solution to remotely and reliably monitor gait and balance impairment in a home environment during MS clinical trials and practice.
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http://dx.doi.org/10.1016/j.gaitpost.2020.11.025DOI Listing
February 2021

Chitinases and chitinase-like proteins as biomarkers in neurologic disorders.

Neurol Neuroimmunol Neuroinflamm 2021 01 8;8(1). Epub 2020 Dec 8.

From the Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.

Chitinases are hydrolytic enzymes widely distributed in nature. Despite their physiologic and pathophysiologic roles are not well understood, chitinases are emerging as biomarkers in a broad range of neurologic disorders, where in many cases, protein levels measured in the CSF have been shown to correlate with disease activity and progression. In this review, we will summarize the structural features of human chitinases and chitinase-like proteins and their potential physiologic and pathologic functions in the CNS. We will also review existing evidence for the role of chitinases and chitinase-like proteins as diagnostic and prognostic biomarkers in inflammatory, neurodegenerative diseases, and psychiatric disorders. Finally, we will comment on future perspectives of chitinase studies in neurologic conditions.
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http://dx.doi.org/10.1212/NXI.0000000000000921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803328PMC
January 2021

Adding brain volume measures into response criteria in multiple sclerosis: the Río-4 score.

Neuroradiology 2021 Jul 25;63(7):1031-1041. Epub 2020 Nov 25.

Servei de Neurologia/Neuroimmunologia, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035, Barcelona, Spain.

Purpose: Brain volume changes (BVC) on therapy in MS are being considered as predictor for treatment response at an individual level. We ought to assess whether adding BVC as a factor to monitor interferon-beta response improves the predictive ability of the (no) evidence of disease activity (EDA-3) and Río score (RS-3) criteria for confirmed disability progression in a historical cohort.

Methods: One hundred one patients from an observational cohort treated with interferon-beta were assessed for different cutoff points of BVC (ranged 0.2-1.2%), presence of active lesions (≥ 1 for EDA/≥ 3 for RS), relapses, and 6-month confirmed disability progression (CDP), measured by the Expanded Disability Status Scale, after 1 year. Sensitivity, specificity, and positive and negative predictive values for predicting confirmed disability progression at 4 years in original EDA (EDA-3) and RS (RS-3) as well as EDA and RS including BVC (EDA-4 and RS-4) were compared.

Results: Adding BVC to EDA slightly increased sensitivity, but not specificity or predictive values, nor the OR for predicting CDP; only EDA-3 showed a trend for predicting CDP (OR 3.701, p = 0.050). Adding BVC to RS-3 (defined as ≥ 2 criteria) helped to improve sensitivity and negative predictive value, and increased OR for predicting CDP using a cutoff of ≤ - 0.86% (RS-3 OR 23.528, p < 0.001; RS-4 for all cutoffs ranged from 15.06 to 32, p < 0.001). RS-4 showed areas under the curve larger than RS-3 for prediction of disability at 4 years.

Conclusion: Addition of BVC to RS improves its prediction of response to interferon-beta.
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http://dx.doi.org/10.1007/s00234-020-02604-8DOI Listing
July 2021

Innovation in resident education - Description of the Neurology International Residents Videoconference and Exchange (NIRVE) program.

J Neurol Sci 2021 01 8;420:117222. Epub 2020 Nov 8.

Division of Neurology, University of Toronto, Toronto, Canada; Division of Neurology, St Michael's Hospital, Toronto, Canada.

There is considerable heterogeneity in residency education around the world. The Neurology International Residents Videoconference and Exchange (NIRVE) program aims to deliver neurology educational content to residents across different resource settings and countries through a monthly videoconferencing platform. Its purpose is to fill gaps in didactic teaching, increase exposure to a variety of cases including various practices and delivery of neurology in multiple countries, as well as integrate global health content into neurology education. NIRVE also facilitates resident exchanges among participating sites. In this descriptive article, we report NIRVE's structure and its cumulative productivity. Since its creation, NIRVE has held more than 90 videoconference rounds and has connected 16 sites in North America, South America, Europe, Asia and Africa. We describe challenges encountered since the inception of the program eleven years ago. NIRVE also fosters a culture of long-term international connection and collaboration. During global disease outbreaks, such as the current COVID-19 pandemic, videoconference rounds serve as a sustainable alternative means to deliver education. Future goals include increasing the number of sites involved, including a focus on Africa and Asia, and fostering resident-led advocacy projects.
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http://dx.doi.org/10.1016/j.jns.2020.117222DOI Listing
January 2021
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