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Background: The long-term disease trajectory of people living with multiple sclerosis (MS) can be improved by initiating efficacious treatment early. More quantitative evidence is needed on factors that affect a patient's risk of disability worsening or possibility of improvement to inform timely treatment decisions., Methods: We developed a multistate model to quantify the influence of demographic, clinical, and imaging factors on disability worsening and disability improvement simultaneously across the disability spectrum as measured by the Expanded Disability Status Scale (EDSS). We used clinical trial data from the Novartis-Oxford MS database including ~130,000 EDSS assessments from ~8000 patients, spanning all MS phenotypes., Results: Higher brain volume was positively associated with disability improvement at all disability levels (hazard ratio (HR) = 1.09-1.19; 95% credible interval (CI) = 1.02-1.27). Higher T2 lesion volume was negatively associated with disability improvement up to EDSS 6 (HR = 0.80-0.89; 95% CI = 0.75-0.94). Older age, time since first symptoms, and the number of relapses in the past year were confirmed as predictors of future disability worsening., Conclusions: Brain damage was identified as the most consistent factor limiting the patient's probability for improvements from the earliest stages and across the whole course of MS. Protecting brain integrity early in MS should have greater weight in clinical decision-making., 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: F.H. is currently employee of Exact Sciences, which was not involved in the study. D.L.A. has received personal compensation for serving as a Consultant for Alexion, Biogen, Celgene, Eli Lilly, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi, and Shionogi, and holds an equity interest in NeuroRx. T.E.N received consulting fees from Perspectum Ltd. H.W. has received honoraria for acting as a member of scientific advisory boards for Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, and Sanofi-Aventis, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, Teva, and WebMD Global. H.W is acting as a paid consultant for AbbVie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, Sanofi-Aventis, and the Swiss Multiple Sclerosis Society. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, the European Union, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme. R.A.B. has served as a consultant for Astra Zeneca, Biogen, EMD Serono, Genzyme, Genentech, Novartis, and VielaBio. He receives research support from Biogen, Genentech, and Novartis. D.A.H., A.O., J.Č., G.G., W.S., M-C.M., P.A., and B.C.K. are employees of Novartis. H.G., Y.S., S.G., S.C.P., and T.E.N. are current employees of the Big Data Institute (Oxford, UK) which received funding from Novartis to collaborate on AI in Medicine including the work presented here.

Purpose of Review: Despite availability of high-efficacy therapies for multiple sclerosis (MS), many patients experience significant disability worsening due to limited effects of currently available drugs on central nervous system (CNS)-compartmentalized inflammation. Bruton tyrosine kinase (BTK) is an intracellular signaling molecule involved in regulation of maturation, survival, migration, and activation of B cells and microglia, which are central players in the immunopathogenesis of progressive MS. Therefore, CNS-penetrant BTK inhibitors may better prevent disease progression by targeting immune cells on both sides of the blood-brain barrier. This review gives an overview on the preliminary results of clinical trials., Recent Findings: Currently, the efficacy and safety of six BTK inhibitors are being evaluated in clinical trials in patients with relapsing and progressive MS. Evobrutinib, tolebrutinib and fenebrutinib have shown efficacy and safety in relapsing MS in phase 2 studies, and evobrutinib and tolebrutinib in their extension studies up to 3-5 years. However, evobrutinib failed to distinguish itself from the comparator drug teriflunomide in reduction of relapse rate (primary end point) in two phase 3 studies in relapsing MS., Summary: Inhibition of BTK has emerged as a promising therapeutic approach to target the CNS-compartmentalized inflammation. Results from phase 3 clinical trials will shed light on differences in efficacy and safety of BTK inhibitors and its potential role in the future MS landscape., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS)., Methods: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods., Results: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change., Conclusions: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis ( n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-β on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient's blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.

Background and Objectives: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression., Methods: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient., Results: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001)., Discussion: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Modulation of immune cell trafficking across the blood-brain barrier has not only introduced a therapeutic avenue for multiple sclerosis (MS) but also represents an example of reverse translational medicine. Data from clinical trials of drugs such as natalizumab and fingolimod have revealed the involvement of different compartments in relapsing versus non-relapsing MS immune biology, contributed to our understanding of central nervous system (CNS) immune surveillance, and stimulated new fields of research. Here, we discuss the results of these trials, as well as patient biomaterial-based scientific projects, and how both have informed our understanding of CNS immunopathology.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease causing axonal degeneration and demyelination. Exercise in mice with active monophasic experimental autoimmune encephalomyelitis (EAE) attenuates disease severity associated with diverse impacts on T cell-mediated immunity. However, studies have so far focused on preventive approaches. In this study, we investigated the impact of endurance exercise on established EAE disease in a model of secondary progressive MS. When the exercise program on motorized running wheels was started at disease manifestation, the disease course was significantly ameliorated. This was associated with a significant decrease in B cell, dendritic cell, and neutrophil cell counts in the central nervous system (CNS). Furthermore, we observed an increased expression of major histocompatibility complex class II (MHC-II) as well as alterations in costimulatory molecule expression in CNS B cells and dendritic cells. In contrast, T cell responses were not altered in the CNS or periphery. Thus, exercise training is capable of attenuating the disease course even in established secondary progressive EAE, potentially via modulation of the innate immune compartment. Further studies are warranted to corroborate our findings and assess the potential of this lifestyle intervention as a complementary therapeutic strategy in secondary progressive MS patients.

Background and Objectives: Immune responses in the central nervous system (CNS) are highly compartmentalized and cerebrospinal fluid (CSF) in particular often reflects CNS pathology better than peripheral blood. While CSF leukocytes are known to be distinct from blood, the immediate effects of peripheral leukocyte depletion on CSF leukocytes have not been studied in humans., Methods: We here analyzed CSF and blood from two relapsing-remitting multiple sclerosis (RRMS) patients early after peripheral leukocyte depletion with the anti-CD52 antibody alemtuzumab compared to untreated RRMS and control patients using single cell RNA-sequencing., Results: As expected for alemtuzumab, most leukocyte lineages including T cells were synchronously depleted from CSF and blood, while - surprisingly - pDCs were maintained in CSF but depleted from blood by alemtuzumab. Transcriptionally, genes associated with migration were elevated only in the CSF after alemtuzumab. Predicted cellular interactions indicated a central role of pDCs and enhanced migration signaling in the CSF after alemtuzumab., Discussion: The CSF and blood compartments are thus partially uncoupled, emphasizing that the CNS is only partially accessible even for treatments profoundly affecting the blood., Competing Interests: Declaration of Competing Interest GMzH received compensation for serving on scientific advisory boards (LFB) and speaker honoraria (Alexion). HW is acting as a paid consultant for AbbVie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, Sanofi-Aventis, and the Swiss Multiple Sclerosis Society. The remaining authors declare no financial interests or conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials., (© 2023. Springer Nature Limited.)

Background: Natalizumab (TYSABRI®) 300 mg administered intravenously every-4-weeks (Q4W) is approved for treatment of relapsing-remitting multiple sclerosis but is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Extended natalizumab dosing intervals of approximately every-6-weeks (Q6W) are associated with a lower risk of PML. Primary and secondary clinical outcomes from the NOVA randomized clinical trial (NCT03689972) suggest that effective disease control is maintained in patients who were stable during treatment with natalizumab Q4W for ≥12 months and who then switched to Q6W dosing. We compared additional exploratory clinical and patient-reported outcomes (PROs) from NOVA to assess the efficacy of Q6W dosing., Methods: Prespecified exploratory clinical efficacy endpoints in NOVA included change from baseline in Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), dominant- and nondominant-hand 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). Exploratory patient-reported outcome (PRO) efficacy endpoints included change from baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM), Neuro-QoL fatigue questionnaire, Multiple Sclerosis Impact Scale (MSIS-29), EuroQol 5 Dimensions (EQ-5D-5 L) index score, Clinical Global Impression (CGI)-Improvement (patient- and clinician-assessed) and CGI-Severity (clinician-assessed) rating scales. Estimated proportions of patients with confirmed EDSS improvement were based on Kaplan-Meier methods. Estimates of mean treatment differences for Q6W versus Q4W in other outcomes were assessed by least squares mean (LSM) and analyzed using a linear mixed model of repeated measures or ordinal logistic regression (CGI-scale)., Results: Exploratory clinical and patient-reported outcomes were assessed in patients who received ≥1 dose of randomly assigned study treatment and had ≥1 postbaseline efficacy assessment (Q6W group, n = 247, and Q4W group, n = 242). Estimated proportions of patients with EDSS improvement at week 72 were similar for Q6W and Q4W groups (11.7% [19/163] vs 10.8% [17/158]; HR 1.02 [95% confidence interval [CI], 0.53-1.98]; P = 0.9501). At week 72, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for T25FW (0.00, P = 0.975), 9HPT (dominant [0.22, P = 0.533] or nondominant [0.09, P = 0.862] hand), or SDMT (-1.03, P = 0.194). Similarly, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for any PRO (TSQM, -1.00, P = 0.410; Neuro-QoL fatigue, 0.52, P = 0.292; MSIS-29 Psychological, 0.67, P = 0.572; MSIS-29 Physical, 0.74, P = 0.429; EQ-5D-5 L, 0.00, P = 0.978). For the EQ-5D-5 L, a higher proportion of Q6W patients than Q4W patients demonstrated worsening (≥0.5 standard deviation increase in the EQ-5D-5 L index score; P = 0.0475). From baseline to week 72 for Q6W versus Q4W, odds ratio (ORs) of LSM change in CGI scores did not show meaningful differences between groups (CGI-Improvement [patient]: OR [95% CI] 1.2 [0.80-1.73]; CGI-Improvement [physician]: 0.8 [0.47-1.36]; CGI-Severity [physician]: 1.0 [0.71-1.54])., Conclusions: No significant differences were observed in change from baseline to week 72 between natalizumab Q6W and Q4W groups for all exploratory clinical or PRO-related endpoints assessed. For the EQ-5D-5 L, a higher proportion of Q6W than Q4W patients demonstrated worsening., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background and Objectives: With the increasing use of visually evoked potentials (VEPs) as quantitative outcome parameters for myelin in clinical trials, an in-depth understanding of longitudinal VEP latency changes and their prognostic potential for subsequent neuronal loss will be required. In this longitudinal multicenter study, we evaluated the association and prognostic potential of VEP latency for retinal neurodegeneration, measured by optical coherence tomography (OCT), in relapsing-remitting MS (RRMS)., Methods: We included 293 eyes of 147 patients with RRMS (age [years, median ± SD] 36 ± 10, male sex 35%, F/U [years, median {IQR} 2.1 {1.5-3.9}]): 41 eyes had a history of optic neuritis (ON) ≥6 months before baseline (CHRONIC-ON), and 252 eyes had no history of ON (CHRONIC-NON). P100 latency (VEP), macular combined ganglion cell and inner plexiform layer volume (GCIPL), and peripapillary retinal nerve fiber layer thickness (pRNFL) (OCT) were quantified., Results: P100 latency change over the first year predicted subsequent GCIPL loss (36 months) across the entire chronic cohort ( p = 0.001) and in (and driven by) the CHRONIC-NON subset ( p = 0.019) but not in the CHRONIC-ON subset ( p = 0.680). P100 latency and pRNFL were correlated at baseline (CHRONIC-NON p = 0.004, CHRONIC-ON p < 0.001), but change in P100 latency and pRNFL were not correlated. P100 latency did not differ longitudinally between protocols or centers., Discussion: VEP in non-ON eyes seems to be a promising marker of demyelination in RRMS and of potential prognostic value for subsequent retinal ganglion cell loss. This study also provides evidence that VEP may be a useful and reliable biomarker for multicenter studies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS)., Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression., Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab)., Exposures: Patients received standard immunotherapies or were untreated., Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally., Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001)., Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Objective: Multiple sclerosis (MS) is associated with cognitive impairment (CI) such as slowed information processing speed (IPS). Currently, no immunocellular or molecular markers have been established in cerebrospinal fluid and serum analysis as surrogate biomarkers with diagnostic or predictive value for the development of CI. This systematic review and meta-analysis aims to sum up the evidence regarding currently discussed markers for CI in MS., Methods: A literature search was conducted on molecular biomarkers of CI in MS, such as neurofilament light chain, chitinases, and vitamin D., Results: 5543 publications were screened, of which 77 entered the systematic review. 13 studies were included in the meta-analysis. Neurofilament light chain (CSF: r p = -0.294, p = 0.003; serum: r p = -0.137, p = 0.001) and serum levels of vitamin D (r p = 0.190, p = 0.014) were associated with IPS outcomes., Conclusions: Neurofilament light chain and vitamin D are promising biomarkers to track impairments in IPS in MS. Further longitudinal research is needed to establish the use of molecular biomarkers to monitor cognitive decline., Competing Interests: Conflict of Interest TDR and NCL have nothing to disclose. HW receives honoraria for acting as a member of Scientific Advisory Boards from Abbvie, Alexion, Argenx, Bristol Myers Squibb/Celgene, Janssen, Merck, and Novartis. He receives speaker honoraria and travel support from Alexion, Biogen, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd., Genzyme, Merck, Neurodiem, Novartis, Roche Pharma AG, TEVA, and WebMD Global. He is acting as a paid consultant for Abbvie, Actelion, Argenx, Biogen, Bristol Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen, Lundbeck, Merck, NexGen, Novartis, PSI CRO, Roche, Sanofi, Swiss Multiple Sclerosis Society, UCB, and Worldwide Clinical Trials. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics Inc., Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis Pharma, Roche Pharma, UCB Biopharma. SGM receives honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Healthcare, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, Quintiles/MS und Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutschen Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen Idec, Diamed, Fresenius Medical Care, Genzyme, Merck Healthcare, Novartis, ONO Pharma, Roche, und Teva. AJ received honoraria and travel-reimbursements for acting as a speaker for Biogen., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Neurological manifestations of autoimmune connective tissue diseases (CTD) are poorly understood and difficult to diagnose. We here aimed to address this shortcoming by studying immune cell compositions in CTD patients with and without neurological manifestation., Methods: Using flow cytometry, we retrospectively investigated paired cerebrospinal fluid (CSF) and blood samples of 28 CTD patients without neurological manifestation, 38 CTD patients with neurological manifestation (N-CTD), 38 non-inflammatory controls, and 38 multiple sclerosis (MS) patients, a paradigmatic primary neuroinflammatory disease., Results: We detected an expansion of plasma cells in the blood of both N-CTD and CTD compared to non-inflammatory controls and MS. Blood plasma cells alone distinguished the clinically similar entities N-CTD and MS with high discriminatory performance (AUC: 0.81). Classical blood monocytes indicated higher disease activity in systemic lupus erythematosus (SLE) patients. Surprisingly, immune cells in the CSF did not differ significantly between N-CTD and CTD, while CD4 + T cells and the CD4 + /CD8 + ratio were elevated in the blood of N-CTD compared to CTD. Several B cell-associated parameters partially overlapped in the CSF in MS and N-CTD. We built a machine learning model that distinguished N-CTD from MS with high discriminatory power using either blood or CSF., Conclusion: We here find that blood flow cytometry alone surprisingly suffices to distinguish CTD with neurological manifestations from clinically similar entities, suggesting that a rapid blood test could support clinicians in the differential diagnosis of N-CTD., (© 2023. The Author(s).)

What Is This Summary About?: This is a summary of an article originally published in the Multiple Sclerosis Journal . Cladribine tablets (MAVENCLAD ® ) are an oral (taken by mouth) medication, approved for the treatment of people with relapsing forms of multiple sclerosis (MS, with episodes of new or worsening symptoms). They are administered for a maximum of 10 days per year, over a period of 2 years. Cladribine tablets work by temporarily reducing the number of lymphocytes, which are immune cells that help to fight off infections. Because of this, people with MS (also called PwMS) may have concerns about the effect of cladribine tablets on vaccines, as these work via immune cells to build protection against infection., What Happened in the Magnify-Ms Study?: A study called MAGNIFY-MS investigated how long it takes for cladribine tablets to begin to work in people with a type of MS called highly active relapsing MS. During the study, some participants received their usual vaccinations against flu (influenza) and against the chickenpox virus (also called varicella zoster virus) as part of their routine medical care. The MAGNIFY-MS study gave the researchers an opportunity to look at how cladribine tablets affect the way the flu and chickenpox virus vaccines work in the body., What Were the Results?: Cladribine tablets do not affect how well the body responds to flu and chickenpox vaccines., What Do the Results Mean?: PwMS taking cladribine tablets who are vaccinated against chickenpox, flu or both can be protected against these diseases.

Background and Purpose: Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease-modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain., Methods: A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon-beta therapy (n = 84) and untreated patients (n = 45)., Results: Patients treated with interferon-beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year., Conclusions: These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon-beta treatment., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, brain endothelial barrier impairment, and oligodendrocyte damage via induction of apoptotic pathways. This is accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT-treated patients. Notably, Th17 cells derived from NAT-treated patients, who later developed a disease rebound upon treatment cessation, displayed a distinct transcriptional pathogenicity profile associated with altered migratory properties. Accordingly, increased brain infiltration of patient Th17 cells was illustrated in a humanized mouse model and brain histology from a rebound patient. Therefore, peripheral blood-accumulated MCAM+CCR6+Th17 cells might be involved in rebound pathophysiology, and monitoring of changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk assessment in the future.

Background: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation., Methods: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m 2 ) and non-obese (BMI <30 kg/m 2 ) patients and correlated with individual BMI values., Results: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m 2  and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m 2 compared with patients with BMI <30 kg/m 2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up., Conclusions: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS., Competing Interests: Competing interests: SB has received honoraria from Biogen Idec, Bristol Meyer Squibbs, Merck Serono, Novartis, Sanofi-Genzyme, Roche and Teva. His research is funded by the Deutsche Forschungsgemeinschaft (DFG) and Hertie Foundation. FL has served on the advisory board of Roche and received travel funding from Teva. AS has received speaker honoraria and/or travel compensation for activities with Bristol Myers Squibb, CSL Behring, Novartis and Roche, and research support by the Swiss MS Society and Baasch Medicus Foundation, not related to this manuscript. LK has received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis and Roche. She has received speaker honoraria and travel support from Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She has received research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. CK has received speaker fees, travel support and/or served on advisory boards by Biogen, Merck, Roche and Sanofi. BW has received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, and personal fees from Alexion, Bayer, Biogen, Teva; none related to this work. AB has received personal compensation from Merck Serono, Biogen, Novartis, Teva, Roche, Sanofi/Genzyme, Celgene/BMS and Janssen; he has received grants for congress travel and participation from Biogen, Teva, Novartis, Sanofi/Genzyme, Merck Serono and Celgene. None related to this report. HT has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Celgene, GSK, Jannssen, Merck, Novartis, Roche, Sanofi Genzyme and Teva. SM has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche and Teva. CT has received honoraria for consultation and expert testimony from Alexion Pharma Germany, Chugai Pharma Germany and Roche Pharma. None of this interfered with the current report. UKZ has received speaking fees, travel support and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Bristol-Myers-Squibb, Janssen, Merck-Serono, Novartis, Octapharm, Roche, Sanofi-Genzyme and Teva as well as EU, BMBF, BMWi. CH has received speaker honoraria from Merck and Roche. He has received grant support from Merck, Novartis and Roche. TK has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma, Alexion and Biogen as well as grant support from Novartis and Chugai Pharma in the past. None of this interfered with the current report. RG has received speaker and board honoraria from Baxter, Bayer Schering, Biogen Idec, Bristol Meyer Squibb, CSL Behring, Eisai, Genzyme, Janssen, Merck Serono, Novartis, Stendhal, Talecris and Teva. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis and Teva. All of RG’s declarations are unrelated to the content of this manuscript. BH has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Polpharma, Sandoz and TG therapeutics; he or his institution has received speaker honoraria from Desitin; his institution has received research grants from Regeneron for multiple sclerosis research. He holds part of two patents: one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralising antibodies to interferon. FZ has recently received research grants and/or consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol-Meyers-Squibb, Celgene, German Research Foundation (DFG), Janssen, Max-Planck-Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sanofi Genzyme and Sandoz. HW has received honoraria for acting as a member of Scientific Advisory Boards for Janssen, Merck and Novartis as well as speaker honoraria and travel support from Alexion, Amicus Therapeuticus, Biogen, Biologix, Bristol Myers Squibb, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Medison, Merck, Novartis, Roche Pharma AG, Genzyme, Teva and WebMD Global. HW is acting as a paid consultant for Biogen, Bristol Myers Squibb, EMD Serono, Idorsia, Immunic, Novartis, Roche, Sanofi, the Swiss Multiple Sclerosis Society and UCB. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics, Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis Pharma, Roche Pharma and UCB Biopharma. JDL has received speaker fees, research support, travel support, and/or served on advisory boards by Abbvie, Alexion, Argenx, Biogen, Merck, Novartis, Roche, Sanofi and Takeda. JDL has received speaker fees, research support, travel support, and/or served on advisory boards by Abbvie, Alexion, Argenx, Biogen, Merck, Novartis, Roche, Sanofi and Takeda., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT., Methods: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question., Results: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided., Conclusions: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Multiple sclerosis (MS) is a chronic and often disabling autoimmune disease of the central nervous system (CNS). Cerebrospinal fluid (CSF) surrounds and protects the CNS. Analysis of CSF can aid the diagnosis of CNS diseases, help to identify the prognosis, and underlying mechanisms of diseases. Several recent studies have leveraged single-cell RNA-sequencing (scRNA-seq) to identify MS-associated changes in CSF cells that are considerably more altered than blood cells in MS. However, not all alterations were replicated across all studies. We therefore integrated multiple available scRNA-seq datasets of CSF cells from MS patients with early relapsing-remitting (RRMS) disease. We provide a searchable and interactive resource of this integrated analysis ( https://CSFinMS.bxgenomics.com ) facilitating diverse visualization and analysis methods without requiring computational skills. In the present joint analysis, we replicated the known expansion of B lineage and the recently described expansion of natural killer (NK) cells and some cytotoxic T cells and decrease of monocytes in the CSF in MS. The previous observation of the abundance of Th1-like Th17 effector memory cells in the CSF was not replicated. Expanded CSF B lineage cells resembled class-switched plasmablasts/-cells (e.g., SDC1/CD138, MZB1) as expected. Our integrative analysis thus validates increased cell type diversity and B cell maturation in the CSF in MS and improves accessibility of available data., (© 2022. The Author(s).)

Peripheral central nervous system (CNS)-infiltrating lymphocytes are a hallmark of relapsing-remitting multiple sclerosis. Tissue-resident memory T cells (T RM ) not only populate the healthy CNS parenchyma but also are suspected to contribute to multiple sclerosis pathology. Because cerebrospinal fluid (CSF), unlike CNS parenchyma, is accessible for diagnostics, we evaluated whether human CSF, apart from infiltrating cells, also contains T RM cells and CNS-resident myeloid cells draining from the parenchyma or border tissues. Using deep generative models, we integrated 41 CSF and 14 CNS parenchyma single-cell RNA sequencing (scRNAseq) samples from eight independent studies, encompassing 120,629 cells. By comparing CSF immune cells collected during multiple sclerosis relapse with cells collected during therapeutic very late antigen-4 blockade, we could identify immune subsets with tissue provenance across multiple lineages, including CNS border-associated macrophages, CD8 and CD4 T RM cells, and tissue-resident natural killer cells. All lymphocytic CNS-resident cells shared expression of CXCR6 but showed differential ITGAE expression (encoding CD103). A common signature defined CD4 and CD8 T RM cells by expression of ZFP36L2 , DUSP1 , and ID2 . We further developed a user interface-driven application based on this analysis framework for atlas-level cell identity transfer onto new CSF scRNAseq data. Together, these results define CNS-resident immune cells involved in multiple sclerosis pathology that can be detected and monitored in CSF. Targeting these cell populations might be promising to modulate immunopathology in progressive multiple sclerosis and other neuroinflammatory diseases.

Background and Objectives: Cladribine tablets cause a reduction in lymphocytes with a predominant effect on B-cell and T-cell counts. The MAGNIFY-MS substudy reports the dynamic changes on multiple peripheral blood mononuclear cell (PBMC) subtypes and immunoglobulin (Ig) levels over 12 months after the first course of cladribine tablets in patients with highly active relapsing multiple sclerosis (MS)., Methods: Immunophenotyping was performed at baseline (predose) and at the end of months 1, 2, 3, 6, and 12 after initiating treatment with cladribine tablets. Assessments included lymphocyte subtype counts of CD19 + B cells, CD4 + and CD8 + T cells, CD16 + natural killer cells, plasmablasts, and Igs. Immune cell subtypes were analyzed by flow cytometry, and serum IgG and IgM were analyzed by nephelometric assay. Absolute cell counts and percentage change from baseline were assessed., Results: The full analysis set included 57 patients. Rapid reductions in median CD19 + , CD20 + , memory, activated, and naive B-cell counts were detected, reaching nadir by month 2. Thereafter, total CD19 + , CD20 + , and naive B-cell counts subsequently reconstituted, but memory B cells remained reduced by 93%-87% for the remainder of the study. The decrease in plasmablasts was slower, reaching nadir at month 3. Decrease in T-cell subtypes was also slower and more moderate compared with B-cell subtypes, reaching nadir between months 3 and 6. IgG and IgM levels remained within the normal range over the 12-month study period., Discussion: Cladribine tablets induce a specific pattern of early and sustained PBMC subtype dynamics in the absence of relevant Ig changes: While total B cells were reduced dramatically, T cells were affected significantly less. Naive B cells recovered toward baseline, naive CD4 and CD8 T cells did not, and memory B cells remained reduced. The results help to explain the unique immune depletion and repopulation architecture regarding onset of action and durability of effects of cladribine tablets while largely maintaining immune competence., Trial Registration Information: ClinicalTrials.gov Identifier: NCT03364036. Date registered: December 06, 2017., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen-specific TCRβ sequences. We detected more MHC-I-restricted EBV-specific TCRβ sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti-VLA-4 treatment amplified this observation, while interferon β- or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8+ T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS., (© 2022 Schneider-Hohendorf et al.)

Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins and the extent to which multiple sclerosis therapies delay disability accumulation. Using the Novartis-Oxford multiple sclerosis (NO.MS) data pool spanning all multiple sclerosis phenotypes and paediatric multiple sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 000 patients with ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (n = 27 328); (ii) all phase 3 clinical trials (n = 8346); and (iii) all placebo-controlled phase 3 clinical trials (n = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models and observed the impact of the mechanism of worsening and disease-modifying therapies on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in the disease process, occurred in all phenotypes and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events; following a year in which relapses occurred (versus a year without relapses), the hazard increased by 31-48% (all P < 0.001). Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease-modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and 3.09 years (2.60, 3.72), respectively. In patients with relapsing-remitting multiple sclerosis, those who worsened exclusively due to RAW events took a similar length of time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses. Our data confirm that relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA begins in relapsing-remitting multiple sclerosis and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. The use of disease-modifying therapies delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing., Methods: In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030)., Results: 42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes ("full/best" vs. "average" vs. "worse/none"). Upon discharge, the adjusted odds ratio for any treatment response ("full/best" + "average" vs. "worse/none") was 10.697 favouring immunoadsorption (p = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response ("full/best" vs. "average" + "worse/none") was 103.236 favouring IA patients (p = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors., Interpretation: Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement., (© 2022. The Author(s).)

Background: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile., Objective: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years., Methods: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide., Results: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections., Conclusion: In patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

The cerebrospinal fluid (CSF) features a unique immune cell composition and is in constant contact with the brain borders, thus permitting insights into the brain to diagnose and monitor diseases. Recently, the meninges, which are filled with CSF, were identified as a neuroimmunological interface, highlighting the potential of exploring central nervous system (CNS) immunity by studying CNS border compartments. Here, we summarize how single-cell transcriptomics of such border compartments advance our understanding of neurological diseases, the challenges that remain, and what opportunities novel multi-omic methods offer. Single-cell transcriptomics studies have detected cytotoxic CD4 + T cells and clonally expanded T and B cells in the CSF in the autoimmune disease multiple sclerosis; clonally expanded pathogenic CD8 + T cells were found in the CSF and in the brain adjacent to β-amyloid plaques of dementia patients; in patients with brain metastases, CD8 + T cell clonotypes were shared between the brain parenchyma and the CSF and persisted after therapy. We also outline how novel multi-omic approaches permit the simultaneous measurements of gene expression, chromatin accessibility, and protein in the same cells, which remain to be explored in the CSF. This calls for multicenter initiatives to create single-cell atlases, posing challenges in integrating patients and modalities across centers. While high-dimensional analyses of CSF cells are challenging, they hold potential for personalized medicine by better resolving heterogeneous diseases and stratifying patients., (© 2022. The Author(s).)

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis., Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972., Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07-0·63) in the once every 6 weeks group and 0·05 (0·01-0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86-20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12-0·82) and 0·06 (0·01-0·31; mean lesion ratio 4·93 [95% CI 1·05-23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic., Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab., Funding: Biogen., Competing Interests: Declaration of interests JFF reports personal compensation for consulting activities from Biogen and Octave; and compensation (paid to institution) for data safety monitoring or advisory boards from Biogen, Genentech, and Novartis. GD reports personal compensation for scientific advisory boards and funding for travel or speaker honoraria from Biogen, Bristol-Myers Squibb, Merck Serono, Novartis, Sanofi Genzyme, and Teva Pharmaceuticals; and research grants (paid to institution) from Biogen, Merck Serono, Novartis, and Sanofi Genzyme. LZR reports personal compensation for advisory board activities from Biogen, Genentech, and Novartis; and research support from Biogen, Celgene, and Genentech. JAC reports personal compensation for consulting from Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; for speaking from H3 Communications; and for serving as an Editor of Multiple Sclerosis Journal. DLA reports consulting fees from Albert Charitable Trust, Alexion Pharma, Biogen, Celgene, Frequency Therapeutics, Genentech, Med-Ex Learning, Merck, Novartis, Population Council, Receptos, Roche, and Sanofi Aventis; grants from Biogen, Immunotec, and Novartis; and equity interest in NeuroRx. HB reports personal compensation for consulting from Oxford Health Policy Forum; compensation (paid to institution) for advisory board membership or speaker bureaus from Biogen, Merck, Novartis, Roche, and UCB Pharma; research support (paid to institution) from Biogen, Merck, Novartis, and Roche; and honorarium (paid to institution) for serving on NOVA trial steering committee. GC reports serving on data and safety monitoring boards for AstraZeneca, Avexis, Biolinerx, Brainstorm Cell Therapeutics, Bristol-Myers Squibb–Celgene, CSL Behring, Galmed, GreenValley Pharma, Mapi, Merck, Merck–Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Orphazyme, Sanofi, Reata, Teva Pharmaceuticals, VielaBio, Vivus, the National Heart, Lung, and Blood Institute (Protocol Review Committee), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric Pharmacology Research Unit oversight committee); consulting or advisory boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel, MedDay, MedImmune, Neurogenesis, Novartis, Osmotica, Perception Neurosciences, Recursion–Cerexis, Rekover, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham, Birmingham, AL, USA; and is president of Pythagoras, a private consulting company located in Birmingham, AL, USA. GG reports consulting or speaker fees from AbbVie, Aslan, Atara Bio, Biogen, Bristol-Myers Squibb–Celgene, GlaxoSmithKline, GW Pharma, Janssen–Actelion, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA–EMD Serono, Novartis, Sanofi Genzyme, Roche–Genentech, and Teva Pharmaceuticals. JK reports speaker and consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharmaceuticals. HW reports honoraria for consulting or speaking from AbbVie, Actelion, Alexion, Argenx, Biogen, Bristol-Myers Squibb, Cognomed, EMD Serono, Evgen, F Hoffmann-La Roche, Idorsia, IGES, Immunic, Immunovant, Janssen, Johnson & Johnson, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, the Swiss Multiple Sclerosis Society, Teva Pharmaceuticals, and UCB; travel support from Alexion, Biogen, Biologix, Cognomed, F Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Genzyme, Merck, Novartis, Roche Pharma, Teva Pharmaceuticals, and WebMD Global; and research support from Biogen, GlaxoSmithKline, Roche, and Sanofi Genzyme. KS, GK, RK, and NC report support from Biogen as employees; and hold stock or stock options in Biogen. SX is a former employee of Biogen., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The impact of distinct disease-modifying therapies (DMTs) on severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination efficacy in patients with multiple sclerosis (MS) is still enigmatic. In this prospective comparative study, we investigated humoral and cellular immune-responses in patients with MS receiving interferon beta, natalizumab, and ocrelizumab pre-vaccination and 6 weeks post second SARS-CoV-2 vaccination. Healthy individuals and interferon beta-treated patients generated robust humoral and cellular immune-responses. Although humoral immune responses were diminished in ocrelizumab-treated patients, cellular immune-responses were reduced in natalizumab-treated patients. Thus, both humoral and cellular immune responses should be closely monitored in patients on DMTs. Whereas patients with a poor cellular immune-response may benefit from additional vaccination cycles, patients with a diminished humoral immune-response may benefit from a treatment with SARS-CoV-2 antibodies in case of an infection., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Inhibition of dihydroorotate dehydrogenase suppresses magnetic resonance imaging brain lesions and disease activity in multiple sclerosis but has limiting tolerability. We assessed the safety and efficacy of vidofludimus calcium, a novel, selective dihydroorotate dehydrogenase inhibitor, in patients with relapsing-remitting multiple sclerosis., Methods: This double-blind, 24 weeks, placebo-controlled, phase 2 trial (EMPhASIS) enrolled patients 18-55 years with relapsing-remitting multiple sclerosis. Eligible patients were randomly assigned (1:1:1) to once-daily vidofludimus calcium (30 mg or 45 mg) or placebo. The primary endpoint was the cumulative number of combined unique active lesions to week 24 between vidofludimus calcium 45 mg and placebo (clinicalTrials.gov number NCT03846219; EudraCT 2018-001896-19)., Results: After 24 weeks, the mean cumulative number of combined unique active lesions was 6.4 (95% CI: 2.8-13.9) with placebo compared to 2.4 (95% CI: 1.1-4.9) with vidofludimus calcium 45 mg (rate ratio 0.38, 95% CI: 0.22-0.64; p = 0.0002); the rate ratio between vidofludimus calcium 30 mg and placebo was 0.30 (95% CI: 0.17-0.53; p < 0.0001). Treatment-emergent adverse events occurred in 30 (44%) of patients assigned placebo and 60 (43%) of patients assigned vidofludimus calcium. Serious adverse events occurred in one (1%) assigned placebo and two (1%) assigned vidofludimus calcium. No increased incidence of infectious, hepatic, or renal treatment-emergent adverse events or serious adverse events was observed., Interpretation: Treatment with vidofludimus calcium led to a reduction in new magnetic resonance imaging lesions in patients with relapsing-remitting multiple sclerosis and was well tolerated with a favorable safety profile. Assessment in longer, larger trials is justified., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: The onset of action for high-efficacy immunotherapies in multiple sclerosis (MS) is an important parameter. This study (MAGNIFY-MS) evaluates the onset of action of cladribine tablets by observing changes in combined unique active (CUA) MRI lesion counts during the first 6 months of treatment in patients with highly active relapsing MS., Methods: MRI was performed at screening, baseline, and at months 1, 2, 3, and 6 after initiating treatment with cladribine tablets 3.5 mg/kg. CUA lesion counts, defined as the sum of T1 gadolinium-enhancing (Gd+) lesions and new or enlarging active T2 lesions (without T1 Gd+), were compared between postbaseline and the baseline period and standardized to the period length and the number of MRIs performed., Results: Included in this analysis were 270 patients who received ≥1 dose of cladribine tablets. After treatment initiation, significant reductions in mean CUA lesion counts were observed from month 1 onward compared with the baseline period (-1.193 between month 1 and month 6, -1.500 between month 2 and month 6, and -1.692 between month 3 and month 6; all p < 0.0001). Mean T1 Gd+ lesion counts were decreased from month 2 onward compared with baseline (-0.857 at month 2, -1.355 at month 3, and -1.449 at month 6; all p < 0.0001), whereas the proportion of patients without any CUA lesions increased from 52.0% between month 1 and month 6 to 80.5% between month 3 and month 6., Discussion: Findings suggest an early onset of action for cladribine tablets, with an increasing reduction in active MRI lesions over time., Trial Registration Information: NCT03364036; Date registered: December 06, 2017., Classification of Evidence: Using frequent MRI assessments of the brain over the first 6 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets 3.5 mg/kg in adult patients with highly active relapsing MS. This study provides Class IV evidence that, in such patients, treatment with cladribine tablets is associated with an early onset of action with reductions in active MRI lesion counts from month 2 (day 60) onward, with an increasing reduction in such lesions over time., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: The anti-CD20 antibody ofatumumab is an efficacious therapy for multiple sclerosis (MS) through depletion of B cells. The purpose of this study was to examine the derivative effects of B cell depletion on the peripheral immune system and a direct treatment effect on T cells expressing CD20., Methods: Frequency and absolute numbers of peripheral leukocytes of treatment-naive patients with relapsing-remitting MS (RRMS) and patients treated with ofatumumab for a mean of 482 days were assessed in this observational study by flow cytometry. In addition, effector function and CNS migration of T cells using a human in vitro blood-brain barrier (BBB) assay were analyzed., Results: This study showed that ofatumumab treatment of patients with RRMS increased the control of effector T cells and decreased T cell autoreactivity. It also showed that ofatumumab reduced the level of peripheral CD20 + T cells and that the observed decrease in CNS-migratory capacity of T cells was caused by the depletion of CD20 + T cells. Finally, our study pointed out a bias in the measurement of CD20 + cells due to a steric hindrance between the treatment antibody and the flow cytometry antibody., Discussion: The substantial ofatumumab-induced alteration in the T cell compartment including a severely decreased CNS-migratory capacity of T cells could partly be attributed to the depletion of CD20 + T cells. Therefore, we propose that depletion of CD20 + T cells contributes to the positive treatment effect of ofatumumab and suggests that ofatumumab therapy should be considered a B cell and CD20 + T cell depletion therapy., Classification of Evidence: This study provides Class IV evidence that compared with treatment-naive patients, ofatumumab treatment of patients with RRMS decreases peripheral CD20 + T cells, increases effector T cell control, and decreases T cell autoreactivity., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Since the beginning of the COVID-19 pandemic and development of new vaccines, the issue of post-vaccination exacerbation or manifestation of demyelinating central nervous system (CNS) disorders has gained increasing attention., Case Presentation: We present a case of a 68-year-old woman previously diagnosed with multiple sclerosis (MS) since the 1980s who suffered a rapidly progressive severe sensorimotor paraparesis with loss of bladder and bowel control due to an acute longitudinal extensive transverse myelitis (LETM) after immunization with the mRNA Pfizer-BioNTech COVID-19 vaccine. Detection of Aquaporin-4-antibodies (AQP4) in both serum and CSF led to diagnosis of AQP4-antibody positive neuromyelitis optica spectrum disorder (NMOSD). Treatment with intravenous corticosteroids and plasmapheresis led to a slight improvement of the patient's symptoms., Conclusions: Pathogenic mechanisms of post-vaccination occurrence of NMOSD are still unknown. However, cases like this should make aware of rare neurological disorders manifesting after vaccination and potentially contribute to improvement of management of vaccinating patients with inflammatory CNS disorders in the future. So far two cases of AQP4-antibody positive NMOSD have been reported in association with viral vector COVID-19 vaccines. To our knowledge, we report the first case of AQP4-antibody positive NMOSD after immunization with an mRNA COVID-19-vaccine., (© 2022. The Author(s).)

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS)., Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion., Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUC τ ) and maximum plasma concentration ( C max ) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed., Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUC τ , 487.7 vs 474.1 h × µg/mL (ratio 1.03); C max , 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated., Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II-III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these 'negative' experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte 'outside-in' traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood-brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for 'proof of concept', time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs., (© 2022. The Author(s).)

Background and Purpose: Using the treatment goal of "no evidence of disease activity" (NEDA) incorporating magnetic resonance imaging (MRI) re-baselining, we aimed to assess the efficacy of ocrelizumab in patients with relapsing-remitting multiple sclerosis with a prior suboptimal response, defined by MRI or relapse criteria, to one or two disease-modifying therapies (DMTs)., Methods: CASTING was a prospective, international, multicenter, single-arm, open-label phase 3 trial (NCT02861014). Patients (Expanded Disability Status Scale [EDSS] score ≤ 4.0, with discontinued prior DMT of ≥6 months duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint was NEDA (defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified MRI re-baselining at Week 8) over 96 weeks., Results: A total of 680 patients were enrolled, 167 (24.6%) based on MRI activity only. At Week 96, 74.8% (95% confidence interval [CI] 71.3-78.0, n/N = 492/658) of patients had NEDA. NEDA was highest among patients enrolled due to MRI activity alone (80.6% [95% CI 68.6-89.6], n/N = 50/62) versus those enrolled for relapse (75.1% [95% CI 69.0-80.6], n/N = 172/229) or for relapse with MRI (70.5% [95% CI 60.0-79.0], n/N = 74/105). NEDA across subgroups was highest in patients with a baseline EDSS score <2.5 (77.2% [95% CI 72.8-81.2], n/N = 315/408). NEDA was higher in patients receiving one prior DMT (77.6% [95% CI 73.2-81.6], n/N = 312/402) versus two prior DMTs (70.3% [95% CI 64.3-75.8], n/N = 180/256)., Conclusions: In patients switching therapy due to suboptimal disease control, treatment with ocrelizumab led to an overall high NEDA rate across a wide range of disease-related and demographic subgroups, regardless of prior treatment background, with no new safety signals detected., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM)., Methods: This multicenter cohort study included 601 treatment-naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow-up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis., Results: Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient] = 0.763, p = 0.003 [left]; s = 0.755, p = 0.006 [right]), putamen (s = 0.614, p = 0.002 [left]; s = 0.606, p = 0.003 [right]) and pallidum (s = 0.606, p = 0.012 [left]; s = 0.606, p = 0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 [left]; p = 0.007 [right]) and pons (p = 0.0001)., Interpretation: We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192-202., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Oral cladribine has been approved for the treatment of relapsing multiple sclerosis (MS) yet real-world evidence regarding its effectiveness and safety remains scarce., Objective: To evaluate efficacy and safety outcomes of MS patients following induction of cladribine., Methods: We evaluated our prospective cohort of cladribine-treated MS patients from two tertiary centres in Germany. Relapses, disability worsening and occurrence of new or enlarging T2-hyperintense magnetic resonance imaging (MRI) lesions were assessed as well as lymphocyte counts and herpes virus infections., Results: Among 270 patients treated with cladribine, we observed a profound reduction of both relapses and new or enlarging MRI lesions. Treatment appeared more efficacious, especially in patients without previous therapy or following platform substances. Patients switching from natalizumab were prone to re-emerging disease activity. Among patients following dimethyl fumarate pre-treatment, severe lymphopenia was common and associated with increased rates of herpes virus manifestations., Conclusion: Overall, we observed an efficacy and safety profile of cladribine consistent with data from the phase 3 clinical trial. However, patients switching from natalizumab experienced suboptimal disease control beyond rebound activity following cessation of natalizumab. Furthermore, dimethyl fumarate pre-treatment was associated with a profound risk of developing severe lymphopenia and subsequent herpes virus infections.

Background: Therapeutic inertia (TI) is a worldwide phenomenon that affects 60 to 90% of neurologists and up to 25% of daily treatment decisions during management of multiple sclerosis (MS) patients. A large volume of MS patients are women of childbearing age, and desire for pregnancy is a complex variable often affecting MS care. The objective of this study was to determine the effect of desire for pregnancy on decisions to escalate treatment during management of MS patients., Methods: 300 neurologists with expertise in MS from 20 countries were invited to participate in the study. Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. Disaggregated discrete choice experiments were used to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. An excel calculator that provides estimates as the percentage of participants that would escalate treatment for a simulated case-scenario was constructed., Results: 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per month by each neurologist was 18 (±16). Non-MS specialists were significantly less likely to escalate treatment than MS specialists across mild, moderate, and severe patient cases. These differences were accentuated when case scenarios introduced a desire for pregnancy. The findings were consistent when MRI-lesions, severity of symptoms, and number of relapses were included., Conclusions: Desire for pregnancy differentially influences decisions to escalate treatment, suggesting knowledge-to-action gaps between MS and non-MS specialists. Our findings indicate the need for educational strategies to overcome these gaps and improve clinical outcomes for MS patients who desire pregnancy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set., Objective: The objective of this study is to describe the Novartis-Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes., Methods: We report key characteristics of NO.MS. We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients' baseline age, using phase III study data (≈8000 patients)., Results: NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up. (1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (<25%) of disability worsening over 2 years while risk is higher (25%-75%) in older, disabled or progressive MS patients. Young patients benefit most from treatment., Conclusion: NO.MS will illuminate questions related to MS characterisation, progression and prognosis. Age modulates relapse frequency and, thus, the phenotypic presentation of MS. Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity.

Coronavirus disease (COVID-19) appeared in December 2019 in the Chinese city of Wuhan and has quickly become a global pandemic. The disease is caused by the severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2), an RNA beta coronavirus phylogenetically similar to SARS coronavirus. To date, more than 132 million cases of COVID19 have been recorded in the world, of which over 2.8 million were fatal ( https://coronavirus.jhu.edu/map.html ). A huge vaccination campaign has started around the world since the end of 2020. The availability of vaccines has raised some concerns among neurologists regarding the safety and efficacy of vaccination in patients with multiple sclerosis (MS) taking immunomodulatory or immunosuppressive therapies., (© 2021. The Author(s).)

Objective: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening., Methods: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG IF and IgM IF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models., Results: By categorical analysis, in patients with IgM IF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM IF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG IF . Furthermore, quantitative analyses revealed that in patients with IgM IF  ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM IF  < median. Dose-dependent associations were also found for IgM IF but not for IgG IF with magnetic resonance imaging-defined disease activity and sNfL., Interpretation: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Alemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified., Methods: We retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity., Results: The regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.534; p<0.001). Additionally, patients pretreated with fingolimod were more likely to experience spinal relapses (55% vs 10% among previously naïve patients; p<0.001) and had an increased risk of secondary autoimmunity (HR 5.875, 95% CI 2.126 to 16.27; p<0.001)., Conclusion: In the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management., Competing Interests: Competing interests: SP: received travel grants from Sanofi Genzyme and Merck Serono, lecturing honoraria from Sanofi Genzyme, Mylan Healthcare, and Biogen, and research support from Diamed, Merck Serono, and the German Multiple Sclerosis Society Northrhine-Westphalia. TR: received travel grants and financial research support from Genzyme and Novartis and received honoraria for lecturing from Roche, Merck, Genzyme, Biogen and Teva. RP: received honoraria for lecturing and travel expenses for attending meetings from Alexion, Bayer Health Care, Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva; has received research funding from Novartis. LR: received travel grants from Merck Serono and Sanofi-Genzyme. MP: received speaker honoraria and travel reimbursements from Novartis. CK: received travel grants from TEVA, compensation for serving on Scientific Advisory Boards for Novartis, and speaker honoraria from Biogen, Genzyme, and Merck Serono. BW: received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck Serono, Sanofi Genzyme, Novartis pharmaceuticals, and personal fees from Bayer, Biogen, Teva Pharma. LK: received compensation for serving on Scientific Advisory Boards for Genzyme, Janssen, Novartis, and Roche. She received speaker honoraria and travel support from Biogen, Genzyme, Merck Serono, Novartis, Roche and TEVA. She receives research support from the German Ministry for Education and Research, the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Novartis, and Merck Serono. CK: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Merck Serono, Desitin, Sanofi-Genzyme, Biogen, Teva, Bayer, Novartis, Boehringer Ingelheim, Pfizer, Bristol Myers-Squibb, Daiichi Sankyo, Siemens, Eisai, Biotronik, Roche, Stago, Ever Pharma, CSL Behring, Mylan, MedDay Pharmaceuticals, Amgen. HW: received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Sanofi Genzyme, Merck Serono, and Novartis. He received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck Serono, Omniamed, Novartis, and Sanofi Aventis. He received compensation as a consultant from Biogen Idec, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. HW also received research support from Bayer Healthcare, Bayer Vital, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Sanofi US and Teva. SGM: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)