Search

Background Uric acid ( UA) could act as a natural peroxynitrite scavenger with antioxidant properties. It has been proposed that hyperuricemia might protect against multiple sclerosis ( MS). Methods Patients with relapsing-remitting MS starting treatment with interferon beta-1a 44 µg sc 3/week were randomly assigned to receive either inosine 3 g/day or placebo in a double-blind manner. Follow-up was 12 months. Outcome measures were adverse events and UA laboratory results. Secondary end point was clinical and radiological activity of MS. Relapse rates, percentage of patients without relapses, and progression to secondary MS ( SPMS) were assessed. Results Thirty six patients were included. Two patients in the inosine group showed UA serum level above 10 mg/ml, and symptoms derived from renal colic not leading to hospital admission. Ten additional patients had asymptomatic hyperuricemia (>7 mg). Efficacy parameters (clinical and radiological) were similar between groups. No patient progressed to SPMS Conclusions Inosine administration was associated with hyperuricemia and renal colic with no additional effect on MS. We cannot conclude inosine is a safe and well-tolerated drug. Doses of around 2 g/day may be more appropriate for future trials. [ABSTRACT FROM AUTHOR]

Background: Infection by cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) play a prognostic role in multiple sclerosis (MS)., Objectives: To explore whether humoral immune responses to HCMV and EBV at disease onset were associated with changes in serum and cerebrospinal fluid (CSF) levels of inflammatory and neurodegeneration biomarkers., Methods: Ninety-eight MS patients with a median follow-up of 20 years were included in the study. The levels of a panel of nine biomarkers were measured in serum ( N = 60) and CSF ( N = 61) samples of patients at the time of the first demyelinating event., Results: Immune responses to HCMV inversely correlated with serum neurofilament light chain (sNfL) levels (rho = -0.367; p = 0.039). sNfL levels were reduced in patients with high immune responses to HCMV ( p = 0.006). Elevated sNfL levels were associated with higher risk of Expanded Disability Status Scale (EDSS) 3.0 ( p = 0.016), 4.0 ( p = 0.009) and 6.0 ( p = 0.003), and with higher risk of developing secondary progressive MS ( p = 0.003) and to receive treatment ( p = 0.032). Serum soluble CD21 levels were increased in patients with high immune responses to EBV nuclear antigen 1 ( p = 0.020)., Conclusions: High immune responses to HCMV are associated with limited disease progression and central nervous system (CNS) injury in MS patients. These findings reinforce the protective role of HCMV infection in MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: The combination of anatomical MRI and deep learning-based methods such as convolutional neural networks (CNNs) is a promising strategy to build predictive models of multiple sclerosis (MS) prognosis. However, studies assessing the effect of different input strategies on model's performance are lacking., Purpose: To compare whole-brain input sampling strategies and regional/specific-tissue strategies, which focus on a priori known relevant areas for disability accrual, to stratify MS patients based on their disability level., Study Type: Retrospective., Subjects: Three hundred nineteen MS patients (382 brain MRI scans) with clinical assessment of disability level performed within the following 6 months (~70% training/~15% validation/~15% inference in-house dataset) and 440 MS patients from multiple centers (independent external validation cohort)., Field Strength/sequence: Single vendor 1.5 T or 3.0 T. Magnetization-Prepared Rapid Gradient-Echo and Fluid-Attenuated Inversion Recovery sequences., Assessment: A 7-fold patient cross validation strategy was used to train a 3D-CNN to classify patients into two groups, Expanded Disability Status Scale score (EDSS) ≥ 3.0 or EDSS < 3.0. Two strategies were investigated: 1) a global approach, taking the whole brain volume as input and 2) regional approaches using five different regions-of-interest: white matter, gray matter, subcortical gray matter, ventricles, and brainstem structures. The performance of the models was assessed in the in-house and the independent external cohorts., Statistical Tests: Balanced accuracy, sensitivity, specificity, area under receiver operating characteristic (ROC) curve (AUC)., Results: With the in-house dataset, the gray matter regional model showed the highest stratification accuracy (81%), followed by the global approach (79%). In the external dataset, without any further retraining, an accuracy of 72% was achieved for the white matter model and 71% for the global approach., Data Conclusion: The global approach offered the best trade-off between internal performance and external validation to stratify MS patients based on accumulated disability., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS)., Objectives: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials., Methods: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis., Results: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder., Conclusion: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.P. has received funding travel from Roche and speaking honoraria from Novartis; he developed this project during a 2021 ECTRIMS Clinical Training Fellowship program and is currently performing an MSIF-ARSEP Fellowship program. R.C. has received consulting services and speaking honoraria from Roche, Novartis, BIIB-Colombia, Merck, Sanofi, and was funded by an ECTRIMS Clinical Training Fellowship program. C.T. is currently being funded by a Junior Leader La Caixa Fellowship; she has also received the 2021 Merck’s Award for the Investigation in Multiple Sclerosis (Spain) and a grant (PI/01860) from Instituto de Salud Carlos III, Spain; and she has also received speaker honoraria from Roche and Novartis. A.C.C. has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007. P.C.M.’s yearly salary is supported by a grant from Biogen to Fundació Privada Cemcat for statistical analysis. N.B. has received travel expenses for scientific meetings and speaking honoraria from Roche, Novartis, Biogen, and Merck, and is currently being funded by ECTRIMS Fellowship. A.V.J. receives support for contracts Juan Rodes (JR16/00024) from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain; and has received speaking honoraria and travel expenses from Novartis, Roche, Teva, Biogen, and Sanofi-Genzyme. G.A. has received speaking honoraria, compensation for consulting services or participation in advisory boards from Sanofi, Merck, Roche, and Horizon Therapeutics; travel support for scientific meetings from Novartis, Roche, and ECTRIMS; is editor for Europe of the Multiple Sclerosis Journal—Experimental, Translational and Clinical; is a member of the International Women in Multiple Sclerosis (iWiMS) network executive committee; and is a member of the European Biomarkers in MS (BioMS-eu) consortium steering committee. N.M.O. has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (Spain). C.N. has received funding for travel from Biogen Idec and F. Hoffmann-La Roche, and speaker honoraria from Novartis. B.R.A. has received honoraria for consulting services from Wellspect. A.Z. has received travel expenses for scientific meetings from Biogen Idec, Merck Serono, and Novartis; speaking honoraria from Eisai; and a study grant from Novartis. M.C. has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merck Serono, Biogen Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis. J.S.G. has received compensation for participating on Advisory Boards, speaking honoraria, and travel expenses for scientific meetings, consulting services, or research support from Celgene, Novartis, Biogen, Teva, Merck, Almirall, and Genzyme. M.T. has received compensation for consulting services, speaking honoraria from Almirall, Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva Pharmaceuticals, and is co-editor of Multiple Sclerosis Journal—ETC. A.R. serves on scientific advisory boards for Novartis, Sanofi Genzyme, Icometrix, SyntheticMR, Bayer, Biogen, and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi Genzyme, Bracco, Merck Serono, Teva Pharmaceutical Industries Ltd., Novartis, Roche, and Biogen. X.M. has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, MedDay, Merck, Mylan, NervGen, Novartis, Sandoz, Sanofi Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF, and NMSS. J.R. has received speaking honoraria and personal compensation for participating on Advisory Boards from Almirall, Bayer Schering Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis, Teva, and Sanofi Aventis. C.A., A.S.A., J.C.J., L.B., L.M., A.S., I.G., and M.R.B. report no disclosures.

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay., Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment., Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023., Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year)., Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed., Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment., Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Background and Purpose: The aim was to evaluate whether magnetic resonance imaging (MRI) phenotypes defined by inflammation and neurodegeneration markers correlate with serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in relapsing-remitting multiple sclerosis (RRMS) patients; and to explore the role of radiological phenotypes and biomarker levels on treatment response and long-term prognostic outcomes., Methods: Magnetic resonance imaging scans from 80 RRMS patients were classified at baseline of interferon-beta (IFNβ) treatment into radiological phenotypes defined by high and low inflammation and high and low neurodegeneration, based on the number of contrast-enhancing lesions, brain parenchymal fraction and the relative volume of non-enhancing black holes on T1-weighted images. Serum levels of NfL and GFAP were measured at baseline with single molecule array (Simoa) assays. MRI phenotypes and serum biomarker levels were investigated for their association with IFNβ response, and times to second-line therapies, secondary-progressive MS (SPMS) conversion and Expanded Disability Status Scale (EDSS) 6.0., Results: Mean (SD) follow-up was 17 (2.9) years. Serum NfL levels and GFAP were higher in the high inflammation (p = 0.04) and high neurodegeneration phenotypes (p = 0.03), respectively. The high inflammation phenotype was associated with poor response to IFNβ treatment (p = 0.04) and with shorter time to second-line therapies (p = 0.04). In contrast, the high neurodegeneration phenotype was associated with shorter time to SPMS (p = 0.006) and a trend towards shorter time to EDSS 6.0 (p = 0.09). High serum NfL levels were associated with poor response to IFNβ treatment (p = 0.004)., Conclusions: Magnetic resonance imaging phenotypes defined by inflammation and neurodegeneration correlate with serum biomarker levels, and both have prognostic implications in treatment response and long-term disease outcomes., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Mumps-Measles-Rubella (MMR) and Varicella zoster vaccines (VAR) are live attenuated vaccines, usually administered in a two-dose scheme at least 4 weeks apart. However, single-dose immunization schemes may also be effective and can reduce delays in immunosuppressive treatment initiation in patients with multiple sclerosis (pwMS) who need to be immunized., Objectives: To evaluate the immunogenicity of a single-dose attempt (SDA) versus the standard immunization scheme (SIS) with VAR and/or MMR in pwMS., Methods: Retrospective observational study in pwMS vaccinated against VAR and/or MMR. We compared seroprotection rates and antibody geometric mean titers (GMTs) between the two strategies., Results: Ninety-six patients were included. Thirty-one patients received VAR and 67 MMR. In the SDA group, the seroprotection rate was 66.7% (95% confidence interval (CI): 53.3-78.3) versus 97.2% (95% CI: 85.5-99.9) in the SIS ( p  < 0.001). For the seroprotected patients, GMTs were similar for both schemes., Conclusion: An SDA of VAR and/or MMR vaccines could be sufficient to protect almost two-thirds of patients. Testing immunogenicity after a single dose of VZ and/or MMR could be included in routine clinical practice to achieve rapid immunization., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R. Carvajal is currently being funded by ‘Vall d’Hebron Institut de Recerca’ grand, this project was supported by ECTRIMS Fellowship training performed during 2021–2022, he has also received speaking honoraria and personal compensation for participating on Advisory Boards and from Roche, Novartis, BIIB-Colombia, Merck, and Sanofi. C. Tur is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by ‘la Caixa’ Foundation (ID 100010434), she has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (PI21/01860); in 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society, she is a member of the Editorial Board of Neurology and Multiple Sclerosis Journal, she has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group. X. Martínez-Gómez has received research support fees from GlaxoSmithKline, Sanofi Pasteur MSD, Statens Serum Institut & Janssen Vaccine, as well as travel expenses fees from GlaxoSmithKline and Sanofi Pasteur MS. L. Bollo is supported by a 1-year stipend endowed by the NMSS/AAN John Dystel Prize for Multiple Sclerosis Research awarded to Prof. Xavier Montalban in 2022. J. Esperalba reports no disclosures. M. Rodríguez reports no disclosures. A. Pappolla has received funding travel from Roche and speaking honoraria from Novartis. He developed this project during a 2021 ECTRIMS Clinical Training Fellowship programme, and is currently performing an MSIF-ARSEP Fellowship programme. A. Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain; JR19/00007. P. Carbonell yearly salary is supported by a grant from Biogen to Fundació privada Cemcat for statistical analysis. B. Borras-Bermejo has received travel expenses for scientific meetings from GlaxoSmithKline J. Rio has received speaking honoraria and personal compensation for participating on Advisory Boards from Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Teva, Roche, and Sanofi-Aventis. J. Castilló reports no disclosures. N. Braga has received travel expenses for scientific meetings and speaking honoraria from Roche, Novartis, Biogen, Merck and was funded by ECTRIMS Fellowship in 2022–2023. N. Mongay-Ochoa has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III (CM21/00018), she also has received speaking honoraria and travel expenses from Merck and Roche. J.A. Rodigo-Pendás has received research support fees from GlaxoSmithKline, Sanofi Pasteur MSD, Statens Serum Institut, Janssen Vaccines & Prevention B.V. and Spanish Clinical Research Network—SCReN and travel expenses fees from Sanofi Pasteur MSD. A. Vidal-Jordana has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck, and Sanofi. G. Arrambide has received speaking honoraria and consulting services or participation in advisory boards from Sanofi, Merck, Roche, and Horizon Therapeutics; travel expenses for scientific meetings from Novartis, Roche, and ECTRIMS. I. Galán reports no disclosures. B. Rodríguez-Acevedo has received speaking honoraria from Merck and honoraria for consulting services from Novartis. A. Zabalza has a predoctoral grant Rio Hortega, from the Instituto de Salud Carlos III, Spain (CM22/00237), received travel expenses for scientific meetings from Biogen-Idec, Merck Serono and Novartis, speaking honoraria from Eisai and a study grant from Novartis. L. Midaglia reports no disclosures. M. Comabella has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merck Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. J. Sastre-Garriga serves as co-Editor for Europe on the editorial board of Multiple Sclerosis Journal and as Editor-in-Chief in Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950) and has served as a consultant/speaker for Biogen, Celgene/Bristol Meyers Squibb, Sanofi, Novartis and Merck. X. Montalbán has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF, and NMSS. M. Tintore has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma. S. Otero-Romero has received speaking and consulting honoraria from Genzyme, Biogen-Idec, Novartis, Roche, Excemed, and MSD; as well as research support from Novartis.

Background: The development of touchscreen-based assessments of upper extremity function could benefit people with multiple sclerosis (MS) by allowing convenient, quantitative assessment of their condition. The Pinching Test forms a part of the Floodlight smartphone app (F. Hoffmann-La Roche Ltd, Basel, Switzerland) for people with MS and was designed to capture upper extremity function., Objective: This study aimed to evaluate the Pinching Test as a tool for remotely assessing upper extremity function in people with MS., Methods: Using data from the 24-week, prospective feasibility study investigating the Floodlight Proof-of-Concept app for remotely assessing MS, we examined 13 pinching, 11 inertial measurement unit (IMU)-based, and 13 fatigability features of the Pinching Test. We assessed the test-retest reliability using intraclass correlation coefficients [second model, first type; ICC(2,1)], age- and sex-adjusted cross-sectional Spearman rank correlation, and known-groups validity (data aggregation: median [all features], SD [fatigability features])., Results: We evaluated data from 67 people with MS (mean Expanded Disability Status Scale [EDSS]: 2.4 [SD 1.4]) and 18 healthy controls. In this cohort of early MS, pinching features were reliable [ICC(2,1)=0.54-0.81]; correlated with standard clinical assessments, including the Nine-Hole Peg Test (9HPT) (|r|=0.26-0.54; 10/13 features), EDSS (|r|=0.25-0.36; 7/13 features), and the arm items of the 29-item Multiple Sclerosis Impact Scale (MSIS-29) (|r|=0.31-0.52; 7/13 features); and differentiated people with MS-Normal from people with MS-Abnormal (area under the curve: 0.68-0.78; 8/13 features). IMU-based features showed similar test-retest reliability [ICC(2,1)=0.47-0.84] but showed little correlations with standard clinical assessments. In contrast, fatigability features (SD aggregation) correlated with 9HPT time (|r|=0.26-0.61; 10/13 features), EDSS (|r|=0.26-0.41; 8/13 features), and MSIS-29 arm items (|r|=0.32-0.46; 7/13 features)., Conclusions: The Pinching Test provides a remote, objective, and granular assessment of upper extremity function in people with MS that can potentially complement standard clinical evaluation. Future studies will validate it in more advanced MS., Trial Registration: ClinicalTrials.gov NCT02952911; https://clinicaltrials.gov/study/NCT02952911., (©Jennifer S Graves, Marcin Elantkowski, Yan-Ping Zhang, Frank Dondelinger, Florian Lipsmeier, Corrado Bernasconi, Xavier Montalban, Luciana Midaglia, Michael Lindemann. Originally published in JMIR Formative Research (https://formative.jmir.org), 02.10.2023.)

Objective: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) distinguish multiple sclerosis (MS) from MOG-associated disease in most cases. However, studies analyzing MOG-Ab at the time of a first demyelinating event suggestive of MS in adults are lacking. We aimed to (1) evaluate the prevalence of MOG-Ab in a first demyelinating event suggestive of MS and (2) compare clinical and paraclinical features between seropositive (MOG-Ab+) and seronegative (MOG-Ab-) patients., Methods: Six hundred thirty adult patients with available serum samples obtained within 6 months from the first event were included. MOG-Ab were analyzed using a live cell-based assay. Statistical analyses included parametric and nonparametric tests, logistic regression, and survival models., Results: MOG-Ab were positive in 17 of 630 (2.7%). Fourteen out of 17 (82.4%) MOG-Ab+ patients presented with optic neuritis (ON) compared to 227of 613 (37.0%) MOG-Ab- patients (p = 0.009). Cerebrospinal fluid-restricted oligoclonal bands (CSF-OBs) were found in 2 of 16 (12.5%) MOG-Ab+ versus 371 of 601 (61.7%) MOG-Ab- subjects (p < 0.001). Baseline brain magnetic resonance imaging (MRI) was normal in 9 of 17 (52.9%) MOG-Ab+ versus 153 of 585 (26.2%) MOG-Ab- patients (p = 0.029). Absence of CSF-OBs and ON at onset were independently associated with MOG-Ab positivity (odds ratio [OR] = 9.03, 95% confidence interval [CI] = 2.04-53.6, p = 0.009; and OR = 4.17, 95% CI = 1.15-19.8, p = 0.042, respectively). Of MOG-Ab+ patients, 22.9% (95% CI = 0.0-42.7) compared to 67.6% (95% CI = 63.3-71.3) of MOG-Ab- patients fulfilled McDonald 2017 criteria at 5 years (log-rank p = 0.003)., Interpretation: MOG-Ab are infrequent in adults with a first demyelinating event suggestive of MS. However, based on our results, we suggest to determine these antibodies in those patients with ON and absence of CSF-OBs, as long as the brain MRI is not suggestive of MS. ANN NEUROL 2023., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. A polymorphism in the CYP24A1 gene, rs2762943, was recently identified that was associated with an increased MS risk. CYP24A1 encodes a protein involved in the catabolism of the active form of vitamin D. The immunological effects of carrying the rs2762943 risk allele were investigated, as well as its role as genetic modifier., Methods: Serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) were measured in a cohort of 167 MS patients. In a subgroup of patients, expression levels of major histocompatibility complex class II and co-stimulatory molecules were determined by flow cytometry, and serum levels of pro-inflammatory (interferon gamma, granulocyte macrophage colony-stimulating factor, C-X-C motif chemokine ligand 13) and anti-inflammatory (interleukin 10) cytokines and neurofilament light chain were measured by single-molecule array assays. The effect of the rs2762943 polymorphism on disease activity and disability measures was evaluated in 340 MS patients., Results: Compared to non-carriers, carriers of the rs2762943 risk allele were characterized by reduced levels of 1,25(OH) 2 D (p = 0.0001) and elevated levels of interferon gamma (p = 0.03) and granulocyte macrophage colony-stimulating factor (p = 0.008), whereas no significant differences were observed for the other markers. The presence of the rs2762943 risk allele had no significant impact on disease activity and disability outcomes during follow-up. However, risk allele carriers were younger at disease onset (p = 0.04)., Conclusions: These findings suggest that the CYP24A1 rs2762943 polymorphism plays a more important role in MS susceptibility than in disease prognosis and is associated with lower 1,25(OH) 2 D levels and a heightened pro-inflammatory environment in MS patients., (© 2023 European Academy of Neurology.)

Introduction: Cerebral vasculitides are often devastating conditions that require immediate diagnosis and treatment., Case Report: We report a pathologically proven clinical case of primary central nervous system vasculitis in a 50-year-old man with a diagnosis of relapsing-remitting multiple sclerosis after alemtuzumab therapy, which required additional immunosuppression to control this life-threatening condition., Conclusion: In patients presenting subacute neurological deterioration after alemtuzumab therapy, primary central nervous system vasculitis should be considered as a differential diagnosis among other autoimmune conditions., Competing Interests: A. Pappolla has received speaking honoraria from Novartis, travel expenses by Roche, and has performed an ECTRIMS Clinical Training Fellowship. M. Tintoré has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. À. Rovira serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, SyntheticMR, Bayer, Roche, Biogen, Icometrix and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd., Novartis, Roche and Biogen. The remaining authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests., Methods: In a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55 years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis., Results: Worse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ - 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ - 0.41), and pons (r = 0.35/ - 0.35)., Conclusions: Multiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments., (© 2022. The Author(s).)

Importance: Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS)., Objective: To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA., Design, Setting, and Participants: This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments., Exposures: Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA)., Main Outcomes and Measures: Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0., Results: Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009)., Conclusions and Relevance: Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.

Introduction: Multiple sclerosis mainly affects women of childbearing age, and the pregnancy and postpartum period is of special interest because of the peculiarities of the disease course and the therapeutic consequences that derive from it. During the period of breastfeeding (BF), the choice of treatment strategy must weigh up the well-established benefits of BF for both the newborn and the mother against the safety profile and potential adverse effects on the infant resulting from exposure to disease-modifying drugs transferred through breast milk., Development: The study reviews the current evidence on the safety of disease-modifying drugs available for the treatment of multiple sclerosis during the BF period, and gathers data on the transfer of the different drugs into breast milk, as well as the potential adverse effects described in the infant. The drugs of first choice during this period are interferon beta and glatiramer acetate. The rest of the disease modifying drugs are not accepted for use in the BF period according to their summary of product characteristics. However, in recent years, data from studies of clinical practice and case series have been published suggesting that some of these drugs could be used safely during this period., Conclusions: Given the recognised health benefits of BF for both mother and infant, exclusive breastfeeding is recommended whenever possible. It is essential to carry out an individualised assessment prior to pregnancy and to evaluate the different treatment options depending on each patient.

Intrathecal production of kappa free light chains occurs in multiple sclerosis and can be measured using the kappa free light chain index. Kappa free light chain index values can be determined more easily than oligoclonal bands detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of oligoclonal bands, kappa free light chain index cut-offs 5.9, 6.6 and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome inception cohort. We selected patients with sufficient data to determine oligoclonal bands positivity, MRI dissemination in space and time, IgG index and sufficient quantities of paired CSF and blood samples to determine kappa free light chain indexes (n = 214). We used Kendall's Tau coefficient to estimate concordance, calculated the number of additional diagnoses when adding each positive index to dissemination in space and positive oligoclonal bands, performed survival analyses for oligoclonal bands and each index with the outcomes second attack and 2017 MRI dissemination in space and time and estimated the diagnostic properties of oligoclonal bands and the different indexes for the previously mentioned outcomes at 5 years. Oligoclonal bands were positive in 138 patients (64.5%), kappa free light chain-5.9 in 136 (63.6%), kappa free light chain-6.6 in 135 (63.1%), kappa free light chain-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between oligoclonal bands and kappa free light chain-6.6 (τ = 0.727) followed by oligoclonal bands and kappa free light chain-5.9 (τ = 0.716). Combining dissemination in space plus oligoclonal bands or kappa free light chain-5.9 increased the number of diagnosed patients by 11 (5.1%), with kappa free light chain-6.6 by 10 (4.7%), with kappa free light chain-10.61 by 9 (4.2%) and with IgG index by 3 (1.4%). Patients with positive oligoclonal bands or indexes reached second attack and MRI dissemination in space and time faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [adjusted hazard ratio (95% confidence interval)], the risk for second attack was very similar between kappa free light chain-5.9 [2.0 (0.9-4.3), P = 0.068] and kappa free light chain-6.6 [2.1 (1.1-4.2), P = 0.035]. The highest risk for MRI dissemination in space and time was demonstrated with kappa free light chain-5.9 [4.9 (2.5-9.6), P < 0.0001], followed by kappa free light chain-6.6 [3.4 (1.9-6.3), P < 0.0001]. Kappa free light chains-5.9 and -6.6 had a slightly higher diagnostic accuracy than oligoclonal bands for second attack (70.5, 71.1 and 67.8) and MRI dissemination in space and time (85.7, 85.1 and 81.0). Kappa free light chain indexes 5.9 and 6.6 performed slightly better than oligoclonal bands to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between oligoclonal bands and these indexes, we suggest using dissemination in space plus positive oligoclonal bands or positive kappa free light chain index as a modified criterion to diagnose multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The effect of disease-modifying therapies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response is unclear., Objectives: We aim to determine the immunological responses to SARS-CoV-2 in multiple sclerosis (MS) and anti-CD20-treated patients with other autoimmune diseases (AID)., Methods: Humoral and cellular responses we determined before and 30-90 days after vaccination in patients with MS and anti-CD20-treated patients with other AID in two Catalan centers., Results: 457 patients were enrolled. Findings showed that humoral response decreased under anti-CD20s or sphingosine 1-phosphate receptor modulators (S1PRM) and with longer treatment duration and increased after 4.5 months from the last anti-CD20 infusion. Cellular response decreased in S1PRM-treated. Patients on anti-CD20 can present cellular responses even in the absence of antibodies., Conclusion: Anti-CD20s and S1PRM modify the immunological responses to SARS-CoV-2 vaccines.

Objective: To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis (MS)., Methods: Reproductive information from women included in the Barcelona CIS prospective cohort was collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity score models., Results: A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI) = 0.33-1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17-3.76). Sensitivity analyses confirmed these results., Conclusion: OC use does not modify the risk of second attack or disability accrual in patients with CIS and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders.

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., (© 2021 European Academy of Neurology.)

Introduction: To evaluate the impact of the COVID-19 pandemic on (1) number of clinical visits, (2) magnetic resonance (MR) scans, and (3) treatment prescriptions in a multiple sclerosis (MS) referral centre., Methods: Retrospective study covering January 2018 to May 2021., Results: The monthly mean (standard deviation [SD]) of visits performed in 2020 (814[137.6]) was similar to 2018 (741[99.7]; p = 0.153), and 2019 (797[116.3]; p = 0.747). During the COVID-19 period (2020 year), 36.3% of the activity was performed through telemedicine. The number of MR scans performed dropped by 76.6% during the "first wave" (March 14 to June 21, 2020) compared to the mean monthly activity in 2020 (183.5[68.9]), with a recovery during the subsequent two months. The monthly mean of treatment prescriptions approved in 2020 (24.1[7.0]) was lower than in 2019 (30[7.0]; p = 0.049), but similar to 2018 (23.8[8.0]; p = 0.727). Natalizumab prescriptions increased in the "first wave" and onwards, whereas anti-CD20 prescriptions decreased during the COVID-19 period., Conclusion: Maintenance of the number of clinical visits was likely due to telemedicine adoption. Although the number of MR dramatically dropped during the "first wave", an early recovery was observed. Treatment prescriptions suffered a slight quantitative decrease during 2020, whereas substantial qualitative changes were found in specific treatments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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 ( r = 0.82, p < 0.001), upper extremity function (|r|= 0.40-0.64, all p < 0.001), and gait and balance domains ( r = -0.25 to -0.52, all p < 0.05; except for Static Balance Test: r = -0.20, p > 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.

Background and Objectives: Information about humoral and cellular responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and antibody persistence in convalescent (COVID-19) patients with multiple sclerosis (PwMS) is scarce. The objectives of this study were to investigate factors influencing humoral and cellular responses to SARS-CoV-2 and its persistence in convalescent COVID-19 PwMS., Methods: This is a retrospective study of confirmed COVID-19 convalescent PwMS identified between February 2020 and May 2021 by SARS-CoV-2 antibody testing. We examined relationships between demographics, MS characteristics, disease-modifying therapy (DMT), and humoral (immunoglobulin G against spike and nucleocapsid proteins) and cellular (interferon-gamma [IFN-γ]) responses to SARS-CoV-2., Results: A total of 121 (83.45%) of 145 PwMS were seropositive, and 25/42 (59.5%) presented a cellular response up to 13.1 months after COVID-19. Anti-CD20-treated patients had lower antibody titers than those under other DMTs ( p < 0.001), but severe COVID-19 and a longer time from last infusion increased the likelihood of producing a humoral response. IFN-γ levels did not differ among DMT. Five of 7 (71.4%) anti--CD20-treated seronegative patients had a cellular response. The humoral response persisted for more than 6 months in 41/56(81.13%) PwMS. In multivariate analysis, seropositivity decreased due to anti-CD20 therapy (OR 0.08 [95% CI 0.01-0.55]) and increased in males (OR 3.59 [1.02-12.68]), whereas the cellular response decreased in those with progressive disease (OR 0.04 [0.001-0.88]). No factors were associated with antibody persistence., Discussion: Humoral and cellular responses to SARS-CoV-2 are present in COVID-19 convalescent PwMS up to 13.10 months after COVID-19. The humoral response decreases under anti-CD20 treatment, although the cellular response can be detected in anti-CD20-treated patients, even in the absence of antibodies., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Sex hormones play a role in both the risk and the prognosis of multiple sclerosis (MS). Considering all stages of women's reproductive life, data regarding the influence of menopause on MS and vice versa are scarce., Objective: The aim of this study was to review the evidence addressing the relationship between menopause and MS., Methods: A literature search through PubMed was conducted, selecting studies that assessed (1) the influence of menopause in the MS course, (2) the influence of MS and disease-modifying drugs (DMD) on the development of menopause and (3) the effect of hormone replacement therapy (HRT) on symptoms of menopausal MS patients., Results: (1) Most studies suggest menopause may transitorily aggravate MS symptoms. Two studies found an inflexion point on the Expanding Disability Status Scale (EDSS) with clinical worsening during the menopausal transition. Another study considering full EDSS trajectories from clinically isolated syndrome to postmenopause did not find such an EDSS inflection; (2) MS and DMD do not seem to alter the age of menopause onset; and (3) HRT in menopausal MS patients has not shown consistent benefits., Conclusion: Menopause seems to be associated with transient symptom worsening, but the existence of an inflection in disability progression is still controversial. Properly designed studies are necessary to achieve conclusive results.

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4 + T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST , IL31RA , and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4 + T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4 + T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo-DC) differentiation as a process potentially influenced by MS risk SNPs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mena, Alloza, Tulloch Navarro, Aldekoa, Díez García, Villanueva Etxebarria, Lindskog, Antigüedad, Boyero, Mendibe-Bilbao, Álvarez de Arcaya, Sánchez Menoyo, Midaglia, Villarrubia, Malhotra, Montalban, Villar, Comabella and Vandenbroeck.)

Background and Objectives: Different treatment response scoring systems in treated MS patients exist. The objective was to assess the long-term predictive value of these systems in RRMS patients treated with self-injectable DMTs., Methods: RRMS-treated patients underwent brain MRI before the onset of therapy and 12 months thereafter, and neurological assessments every 6 months. Clinical and demographic characteristics were collected at baseline. After the first year of treatment, several scoring systems [Rio score (RS), modified Rio score (MRS), MAGNIMS score (MS), and ROAD score (RoS)] were calculated. Cox-Regression and survival analyses were performed to identify scores predicting long-term disability., Results: We included 319 RRMS patients. Survival analyses showed that patients with RS > 1 and RoS > 3 had a significant risk of reaching an EDSS of 4.0 and 6.0 The score with the best sensitivity (61%) was the RoS, while the MRS showed the best specificity (88%). The RS showed the best positive predictive value (42%) and the best accuracy (81%)., Conclusions: The combined measures integrated into different scores have an acceptable prognostic value for identifying patients with long-term disability. Thus, these data reinforce the concept of early treatment optimization to minimize the risk of long-term disability., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: To explore whether time to diagnosis, time to treatment initiation, and age to reach disability milestones have changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS) diagnostic criteria periods., Methods: This retrospective study was based on data collected prospectively from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into 5 periods according to different MS criteria, and the times to MS diagnosis and treatment initiation were evaluated. The age at which patients with MS reached an Expanded Disability Status Scale (EDSS) score ≥3.0 was assessed by Cox regression analysis according to diagnostic criteria periods. Last, to remove the classic Will Rogers phenomenon by which the use of different MS criteria over time might result in a changes of prognosis, the 2017 McDonald criteria were applied, and age at EDSS score ≥3.0 was assessed by Cox regression., Results: In total, 1,174 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 an EDSS score ≥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. Patients in the early-treatment group displayed an aHR of 0.53 (0.33-0.85) of reaching age at EDSS score ≥3.0 compared to those in the late-treatment group. Changes in prognosis together with early-treatment effect were maintained after the exclusion of possible bias derived from the use of different diagnostic criteria over time (Will Rogers phenomenon)., Discussion: A continuous decrease in the time to MS diagnosis and treatment initiation was observed across diagnostic criteria periods. Overall, patients diagnosed in more recent diagnostic criteria periods displayed a lower risk of reaching disability. The prognostic improvement is maintained after the Will Rogers phenomenon is discarded, and early treatment appears to be the most likely contributing factor., (© 2021 American Academy of Neurology.)

Objective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment., Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases., Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058)., Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​., Competing Interests: EM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme. SS received payment for lecturing or travel expenses from Almirall, Biogen, Merck-Serono, Novartis Roche, Sanofi-Genzyme, and Teva. MC has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. LR-T has received speaking honoraria and travel expenses for scientific meetings and has participated in advisory boards in the past years with Bayer Schering Pharma, Biogen, EMD Merck Serono, Sanofi Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, Merck KGaA, Darmstadt Germany, Mylan, Nervgen, Novartis, Roche, Sanofi-Genzyme, Teva MSIF and NMSS. LM has received travel funding from Genzyme, Roche, Biogen Idec and Novartis, and personal fee for lectures from Roche. JM-L received grants and consulting or speaking fees from Almirall, Biogen, Celgene, Genzyme, Merck, Novartis, Roche and Teva. RA-L reports grants and personal fees from Merck Serono, personal fees and non-financial support from Biogen IDEC, grants, personal fees and non-financial support from Novartis Pharmaceuticals S.A., grants and personal fees from Genzyme, non-financial support from TEVA Pharma, S.L. LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall. LV received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Bristol-Myers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Walo-Delgado, Monreal, Medina, Quintana, Sainz de la Maza, Fernández-Velasco, Lapuente, Comabella, Ramió-Torrentà, Montalban, Midaglia, Villarrubia, Carrasco-Sayalero, Rodríguez-Martín, Roldán, Meca-Lallana, Alvarez-Lafuente, Masjuan, Costa-Frossard and Villar.)

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., (© 2020 European Academy of Neurology.)

There is increasing interest in the development and deployment of digital solutions to improve patient care and facilitate monitoring in medical practice, e.g., by remote observation of disease symptoms in the patients' home environment. Digital health solutions today range from non-regulated wellness applications and research-grade exploratory instruments to regulated software as a medical device (SaMD). This paper discusses the considerations and complexities in developing innovative, effective, and validated SaMD for multiple sclerosis (MS). The development of SaMD requires a formalised approach (design control), inclusive of technical verification and analytical validation to ensure reliability. SaMD must be clinically evaluated, characterised for benefit and risk, and must conform to regulatory requirements associated with device classification. Cybersecurity and data privacy are also critical. Careful consideration of patient and provider needs throughout the design and testing process help developers overcome challenges of adoption in medical practice. Here, we explore the development pathway for SaMD in MS, leveraging experiences from the development of Floodlight™ MS, a continually evolving bundled solution of SaMD for remote functional assessment of MS. The development process will be charted while reflecting on common challenges in the digital space, with a view to providing insights for future developers.

Introduction: Despite the great advances that have occurred in the diagnosis and treatment of ? multiple sclerosis (MS), few changes have taken place in terms of clinical monitoring. The lack of time and space in clinical practice limits the assessment of invisible symptoms and certain motor symptoms as manual dexterity and walking ability, which have a clear impact on the patient functional situation., Objective: To review the potential role of technological tools in the clinical monitoring of MS patients., Development: A bibliographic search was carried out through PubMed, selecting those studies focused on biosensors and digital tools aimed at evaluating the general functional situation, and specific aspects of the disease or certain functional systems., Results: Different digital tools such as biosensors, mobile or web applications, both for remote and hospital use, self-completed or administered by healthcare personnel, seem to offer a more 'complete and real' picture of the functional situation of patients. Some studies have shown that digital technology could detect subclinical disability progression, which traditional tests, including the EDSS, fail to reflect, favouring the adoption of appropriate therapeutic measures and actions in an early and personalized manner., Conclusions: Digital tools, capable of collecting detailed and extensive clinical information, could play an important role in decision-making and clinical monitoring of patients with MS.