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Background: Fatigue is common in people with multiple sclerosis (MS). Understanding the relationship between fatigue, physical and neurobehavioural factors is important to inform future research and practice. Few studies explore this explicitly in people with progressive MS (pwPMS)., Objective: To explore relationships between self-reported fatigue, physical and neurobehavioural measures in a large, international progressive MS sample of cognitively impaired people recruited to the CogEx trial., Methods: Baseline assessments of fatigue (Modified Fatigue Impact Scale; MFIS), aerobic capacity (VO 2peak ), time in moderate-vigorous physical activity (MVPA; accelerometery over seven-days), walking performance (6-minute walk test; 6MWT), self-reported walking difficulty (MS Walking Scale; MSWS-12), anxiety and depression (Hospital Anxiety and Depression Scale; HADS and Beck Depression Inventory-II; BDI-II), and disease impact (MS Impact Scale-29, MSIS-29) were assessed. Participants were categorised as fatigued (MFIS Total >=38) or non-fatigued (MFIS Total ≤38)., Statistical Analysis: Differences in individuals categorised as fatigued or non-fatigued were assessed (t-tests, chi square). Pearson's correlation and partial correlations (adjusted for EDSS score, country, sex, and depressive symptoms) determined associations with MFIS Total, MFIS Physical , MFIS Cognitive and MFIS Psychosocial, and the other measures. Multivariable logistic regression evaluated the independent association of fatigue (categorised MFIS Total ) with physical and neurobehavioural measures., Results: The sample comprised 308 pwPMS (62 % female, 27 % primary progressive, 73 % secondary progressive), mean age 52.5 ± 7.2 yrs, median EDSS score 6.0 (4.5-6.5), mean MFIS Total 44.1 ± 17.1, with 67.2 % categorised as fatigued. Fatigued participants walked shorter distances (6MWT, p = 0.043), had worse MSWS-12 scores (p < 0.001), and lower average % in MVPA (p = 0.026). The magnitude of associations was mostly weak between MFIS Total and physical measures (r = 0.13 to 0.18), apart from the MSWS-12 where it was strong (r = 0.51). The magnitude of correlations were strong between the MFIS Total and neurobehavioural measures of anxiety (r = 0.56), depression (r = 0.59), and measures of disease impact (MSIS-physical r = 0.67; MSIS-mental r = 0.71). This pattern was broadly similar for the MSIF subscales. The multivariable model indicated a five-point increase in MSWS-12 was associated with a 14 % increase in the odds of being fatigued (OR [95 %CI]: 1.14 [1.07-1.22], p < 0.0001) CONCLUSION: Management of fatigue should consider both physical and neurobehavioural factors, in cognitively impaired persons with progressive MS., Competing Interests: Declaration of competing interest Luke Connolly has no disclosures to report. Sarah Chatfield has no disclosures to report. Jenny Freeman has been awarded research grants from the NIHR, UK. Amber Salter receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense and is a member of the editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), and Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO). Maria Pia Amato received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Roche, Pharmaceutical Industries and Fondazione Italiana Sclerosi Multipla. Giampaolo Brichetto has been awarded and receives research support from Roche, Fondazione Italiana Sclerosi Multipla, ARSEP, H2020 EU Call. Jeremy Chataway has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society, a local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche. Nancy Chiaravalloti is on an Advisory Board for Akili Interactive and is a member of the Editorial Boards of Multiple Sclerosis Journal and Frontiers in NeuroTrauma. Gary Cutter is a member of Data and Safety Monitoring Boards for Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals,Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). He is on Consulting or Advisory Boards for BioDelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Klein-Buendel Incorporated, Med- immune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. John DeLuca is an Associate Editor of the Archives of Physical Medicine and Rehabilitation, and Neuropsychology Review; received compensation for consulting services and/ or speaking activities from Biogen Idec, Celgene, MedRhythms, and Novartis; and receives research support from Biogen Idec, National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers, and National Institutes of Health. Ulrik Dalgas has received research support, travel grants, and/or teaching honorary from Biogen Idec, Merck-Serono, Novartis, Bayer Schering, and Sanofi Aventis as well as honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. Rachel Farrell has received honoraria and served on advisory panels for Merck, TEVA, Novartis, Gen- zyme, GW pharma (Jazz pharmaceuticals), Allergan, Merz, Ipsen and Biogen. She is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. Peter Feys is editorial board member of NNR and MSJ, provides consultancy to NeuroCompass and was board of advisory board meetings for BIOGEN. Massimo Filippi is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceu tical Industries, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Matilde Inglese is Co-Editor for Controversies for Multiple Sclerosis Journal; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme; and received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. Cecilia Meza has no disclosures to report. Nancy Moore has no disclosures to report. Robert Motl has no disclosures to report. Maria Assunta Rocca received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Brian Sandroff has no disclosures to report. Anthony Feinstein is on Advisory Boards for Akili Interactive and Roche, and reports grants from the MS Society of Canada, book royalties from Johns Hopkins University Press, Cambridge University Press, Amadeus Press and Glitterati Editions, and speaker's honoraria from Novartis, Biogen, Roche and Sanofi Genzyme. Massimo Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The Multiple Sclerosis Walking Scale-12 (MSWS-12) has typically been delivered through paper-and-pencil or computer-based administration., Purpose: This study examined the validity of inferences from scores derived via a telephone administration of the MSWS-12 applied as part of screening of participants with walking dysfunction into a clinical trial of exercise training in MS., Method: The MSWS-12 was administered on two occasions separated by approximately 2 weeks through the telephone and then in-person (i.e., computer-based administration). Participants further completed the Patient Determined Disease Steps (PDDS) scale, timed 25-foot walk (T25FW), six-minute walk (6MW), Modified Fatigue Impact Scale (MFIS), and Multiple Sclerosis Impact Scale-29 (MSIS-29), and underwent a neurological exam for generating an expanded disability status scale (EDSS) score. The primary set of data (Full Sample) for analyses included all persons who passed the telephone screening for inclusion with MSWS-12 scores between 25 and 75 (N = 374). The secondary set of data (Truncated Sample) included only persons with MSWS-12 scores between 25 and 75 for both the telephone and computer administrations of the MSWS-12 (N = 248)., Results: The results in the Full Sample indicated a difference in overall and item levels scores between the telephone and computer data collections, and the computer version had higher internal consistency and stronger unidimensionality. Nevertheless, MSWS-12 scores from both modes of administration had comparable correlations with the T25FW, 6MW, EDSS, PDDS, MFIS, and MSIS-29, but the correlation between the two MSWS-12 administrations did not approach unity. There was a systematic difference in scores between telephone and computer administrations across levels of walking dysfunction based on a Bland-Altman plot, and the difference was predicted by MFIS physical, 6MW, and EDSS scores. The comparison of results between the Full and Truncated Samples suggested that the primary analysis might have been influenced by the larger range of scores on the computer than telephone administrations of the MSWS-12., Conclusion: The telephone administration of the MSWS-12 provides an efficient and cost-effective measure of walking dysfunction in persons with MS., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in the publication of this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cognition is frequently affected in persons with multiple sclerosis (MS). Cognitive impairment (CI) is associated with decreased quality of life (QOL) and employment status. Yet, CI assessed using patient-reported outcome measures is not as well studied and is thought to be influenced by other symptoms. Health Utilities Index 3 (HUI3) is a multi-attribute health-status classification system that assesses 8 different single attributes, including cognition., Methods: The North American Consortium of Multiple Sclerosis (NARCOMS) Registry, a voluntary, self-report registry for persons with MS, Spring 2019 survey collected the HUI3 and self-reported assessment of health-related QOL (RAND-12), cognitive status, depression, fatigue, disability, employment, disease-modifying therapy use, and sociodemographic data. We assessed the relationship between patient-reported cognitive CI from the HUI3 (HUI-C), QOL, and employment while adjusting for factors previously associated with the outcomes. For employment outcomes, the cohort was limited to participants 65 years of age or younger., Results: Of the 6,227 respondents, 56.4 % reported cognitive difficulty with the HUI-C. After adjusting for multiple covariates, cognitive difficulty was associated with 1.2 point lower physical QOL for each 0.1 decrease in HUI-C (p < 0.0001). Mental QOL decreased by 2 points for each 0.1 decrease in HUI-C (p < 0.0001). Cognitive difficulty was associated with a 10 % decreased odds of employment in the multivariable model (p < 0.0001)., Discussion: Patient-reported CI was associated with lower health-related and vocational outcomes for MS patients, even after accounting for age, income, depression, fatigue, and disability associated with cognition. The HUI-C is a single attribute score derived from the HUI3 that may facilitate the evaluation of CI in MS., Competing Interests: Declaration of competing interest Conflicts of interests Samantha Lancia has nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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: The nine-hole peg test (NHPT) is the outcome measure with the least change in secondary and primary progressive MS (SPMS and PPMS) trials. The Standard NHPT is defined as the average of four measurements, two in each hand. Little is known about the performance of alternative NHPT scoring methods as longitudinal outcome measures in progressive MS. Non-ambulatory people with progressive MS are now generally excluded from clinical trials, and there is little information on longitudinal NHPT change in this patient group. In this investigation, we used patient-level data from two large randomized controlled trials in progressive MS to explore alternative NHPT scoring methods and NHPT change in non-ambulatory people with progressive MS., Methods: We used patient-level data from the ASCEND (SPMS, n = 889) and PROMISE (PPMS, n = 943) clinical trials to compare significant change on the Standard NHPT with the alternatives dominant hand (DH), non-dominant hand (NDH), and either hand (EH) NHPT in ambulatory and non-ambulatory trial participants., Results: The Standard NHPT changed slowly and showed few worsening events, as did the DH and NDH alternatives. Using the EH NHPT resulted in a substantial increase of worsening events. Non-ambulatory trial participants with PPMS experienced more NHPT worsening than ambulatory participants, especially when using the EH NHPT., Conclusion: Using the EH NHPT yielded substantially more worsening events in people with progressive MS. Clinical trials in non-ambulatory people may be possible with the NHPT as the primary outcome measure. More research into the precision of these measures in this patient group is necessary., Competing Interests: Declaration of Competing Interest Dr. Koch received consulting fees and travel support from Biogen, Novartis, Roche, Sanofi Genzyme and EMD Serono. Dr. Repovic received consulting and/or speaking honoraria from Alexion, Biogen, Celgene, Roche, Sanofi Genzyme, Viela and EMD Serono. Dr. Mostert reports no disclosures. Dr. Bowen received honoraria from serving on the scientific advisory board and speaker's bureau of Biogen, Celgene, EMD Serono, Genentech and Novartis. He has received research support from AbbVie Inc, Alexion, Alkermes, Biogen, Celgene, Sanofi Genzyme, Genentech, Novartis and TG Therapeutics. Dr. Comtois reports no disclosures. Dr. Strijbis reports no disclosures. Prof. Uitdehaag received consultancy fees and/or research support from Biogen, Sanofi Genzyme, EMD Serono, Novartis, Roche, Teva, and Immunic Therapeutics. Prof. Cutter served on Data and Safety Monitoring Boards: Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee). Consulting or Advisory Boards: Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL., (Copyright © 2022 Elsevier B.V. All rights reserved.)

On 12 September 2019, the global Patient Reported Outcome for Multiple Sclerosis (PROMS) Initiative was launched at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The multi-stakeholder PROMS Initiative is jointly led by the European Charcot Foundation (ECF) and the Multiple Sclerosis International Federation (MSIF), with the Italian Multiple Sclerosis Society (AISM) acting as the lead agency for and on behalf of the global MSIF movement. The initiative has the ambitious mission to (i) maximize the impact of science with and of patient input on the life of people affected by MS, and (ii) to represent a unified view on Patient-Reported Outcomes for MS to people affected by MS, healthcare providers, regulatory agencies and Health Technologies Assessments agencies. Equipped with an innovative participatory governance of an international and interdisciplinary network of different stakeholders, PROMS has the potential to guide future breakthroughs in MS patient-focused research and care. In this paper we present the progresses of the global PROMS Initiative and discuss the open questions that we aim to address., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The Symbol Digit Modalities Test (SDMT) is a common screen of cognitive function for people with Multiple Sclerosis (pwMS) but growing acknowledgement that people with cognitive impairment are a heterogeneous population suggests that a single screen may provide limited information., Objective: To assess the adequacy of the SDMT in capturing impairment across specific cognitive domains as measured by a multi-domain cognitive assessment battery (CAB, NeuroTrax)., Methods: 113 pwMS were assessed with SDMT and the CAB. Cognitive impairment in each CAB domain was defined as ≥1.5 SD below the normalized mean. Logistic regression models were fit for each CAB domain with domain-specific cognitive impairment as the outcome and SDMT as the predictor, and a classifier created by selecting cutpoints using the Youden Index. Model performance was assessed by predicting domain-specific cognitive impairment in an independent data set consisting of 81 pwMS., Results: SDMT was a significant predictor of cognitive impairment in all outcomes considered (Odds Ratio: 0.885-0.950), but prediction metrics such as area under the receiver operating curve (AUC) were modest (0.623-0.778), and the alignment between observed/predicted impairment was less than optimal., Conclusion: The SDMT is not sufficient to differentiate between impaired and non-impaired pwMS across several cognitive domains., (Copyright © 2022. Published by Elsevier B.V.)

Background: The risk of SARS-CoV-2 infection and severity with disease modifying therapies (DMTs) in multiple sclerosis (MS) remains unclear, with some studies demonstrating increased risks of infection with B-cell-depleting (anti-CD20) therapies and severity, while others fail to observe an association. Most existing studies are limited by a reliance on 'numerator' data (i.e., COVID-19 cases) only., Objective: To assess the risks of COVID-19 by DMT, this study aimed to assess both 'numerator' (patients with SARS-CoV-2 infection) and 'denominator' data (all patients treated with DMTs of interest) to determine if any DMTs impart an increased risk of SARS-CoV-2 infection or disease severity., Methods: We systematically reviewed charts and queried patients during clinic encounters in the NYU MS Comprehensive Care Center (MSCCC) for evidence of COVID-19 in all patients who were on the most commonly used DMTs in our clinic (sphingosine-1-phosphate receptor (S1P) modulators (fingolimod/siponimod), rituximab, ocrelizumab, fumarates (dimethyl fumarate/diroximel fumarate), and natalizumab). COVID-19 status was determined by clinical symptoms (CDC case definition) and laboratory testing where available (SARS-CoV-2 PCR, SARS-CoV-2 IgG). Multivariable analyses were conducted to determine predictors of infection and severe disease (hospitalization or death) using SARS-CoV-2 infected individuals per DMT group and all individuals on a given DMT as denominator., Results: We identified 1,439 MS patients on DMTs of interest, of which 230 had lab-confirmed (n = 173; 75.2%) or suspected (n = 57; 24.8%) COVID-19. Infection was most frequent in those on rituximab (35/138; 25.4%), followed by fumarates (39/217; 18.0%), S1P modulators (43/250; 17.2%), natalizumab (36/245; 14.7%), and ocrelizumab (77/589; 13.1%). There were 14 hospitalizations and 2 deaths. No DMT was found to be significantly associated with increased risk of SARS-CoV-2 infection. Rituximab was a predictor of severe SARS-CoV-2 infection among patients with SARS-CoV-2 infection (OR 6.7; 95% CI 1.1-41.7) but did not reach statistical significance when the entire patient population on DMT was used (OR 2.8; 95% CI 0.6-12.2). No other DMT was associated with an increased risk of severe COVID-19., Conclusions: Analysis of COVID-19 risk among all patients on the commonly used DMTs did not demonstrate increased risk of infection with any DMT. Rituximab was associated with increased risk for severe disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes., Methods: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants., Results: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants., Conclusion: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation., (Copyright © 2021. Published by Elsevier B.V.)

Background: The thalamus and the putamen are highly connected hubs implicated in multiple sclerosis (MS) pathology. It remains unclear if white matter (WM) tracts, which pass through them, have a different susceptibility to MS pathology, and if so, if their impact on disability predominates over that exerted by disease in other WM tracts. We hypothesized that WM tracts connected to and passing through these hubs (subsequently termed hub+ tracts) would be more susceptible to MS-related pathology than tracts that do not pass through them (hub- tracts) due to retrograde and anterograde distant degeneration. Thus, we compared the lesion load and neurite orientation dispersion and density imaging (NODDI) derived metrics between hub+ and hub- tracts and assessed the relationship between these MRI metrics and those of physical impairment., Methods: Eighteen patients (mean age of 45.5 years, 12 females) had 3 Tesla MRI consisting of T1-weighted and T2-weighted Fluid Attenuated Inversion Recovery (FLAIR), and NODDI from which the orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (IVF) were derived. Forty-nine WM tracts, i.e., 12 hub+ and 37 hub- tracts, were segmented out. Exploratory analyses of the differences in lesion burden, whole tract and normal appearing WM (NAWM) NODDI metrics were carried out between the two types of tracts using a Mann-Whitney U test. Correlations with physical impairment, quantified using the expanded disability status scale (EDSS) and timed 25-foot walk (T25FW) test were assessed using Spearman correlation analyses., Results: Hub- tracts had larger T1- (p<0.001) and T2-lesion (p<0.001) volumes; lower ODI (p<0.001), NDI (p<0.001) and higher IVF (p = 0.020) in comparison to hub+ tracts. Measures of tissue injury in hub+ tracts correlated with those of clinical disability, though less strongly than in hub- tracts., Conclusions: Contrary to our hypothesis, our exploratory pilot study results suggest that WM tracts that overlap with the thalamus and the putamen have a lower degree of lesional and non-lesional tissue injury, suggesting a protective role of the hubs against MS pathology or a higher degree of vulnerability of those not passing through hub stations. We also show a weaker association between disability impairment and hub+ pathology, compared to that in hub- tracts. Our findings point to a potential role of disease location in relation to hubs as guidance for treatment personalization in MS., (Copyright © 2021. Published by Elsevier B.V.)

Background: This study examined a comprehensive set of demographic, clinical, and symptomatic variables as correlates of subjective sleep quality in adults with multiple sclerosis (MS)., Methods: Participants with MS(N=485) completed the Pittsburgh Sleep Quality Index(PSQI), a demographics and clinical characteristics questionnaire, the Patient Determined Disease Steps Scale(PDDS), the Fatigue Severity Scale, and the Hospital Anxiety and Depression Scale. We conducted bivariate Spearman's rho (ρ) correlation analyses and multiple linear regression analysis for identifying variables associated with PSQI scores., Results: Participants had a mean (standard deviation) age of 55.4 (12.6) years and were mostly female (78%) with a median [interquartile range] PDDS of 2.0[3.0]. Higher levels of fatigue (ρ=0.32), more symptoms of anxiety (ρ=0.39) and depression (ρ=0.36), younger age (ρ=-0.12), lower income status (ρ=-0.13), shorter MS disease duration (ρ=-0.11), being in a minority group (ρ=0.09), and being unemployed (ρ=-0.10) were associated with worse sleep quality. There were no significant associations between gender, marital status, parental status, education level, disability status, or MS disease type and sleep quality. The overall regression model accounted for 26.3% of variance in sleep quality (F[8,229.8]=20.25) and there were significant coefficients for anxiety(β=0.25), fatigue(β=0.18), depression(β=0.16), and employment status(β=-0.12), but not disease duration, age, race, or income level., Discussion: Participants with higher levels of anxiety, fatigue, and depression and who were unemployed reported worse sleep quality in our sample of adults with MS. These results may identify specific subgroups of the MS population that experience more sleep problems, and therefore are in greatest need for interventions designed to improve sleep impairment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic has raised concerns for increased risk of infection in patients with multiple sclerosis (MS) and disrupted their routine MS care. The aim of this study is to characterize the extent of MS patients' perceptions of risk and adherence to care during the pandemic., Methods: A survey was emailed to patients from a large MS center in New York City during the local peak of the pandemic to assess perceptions of infection risk and adherence to MS care including appointments, laboratory studies, MRIs, and taking disease-modifying therapies (DMT)., Results: 529 patients from the MS center responded to the survey during two weeks in April 2020. Patients collectively showed concern about becoming infected with COVID-19 (88%) and perceived a higher infection risk due of having MS (70%) and taking DMTs (68%). Patients frequently postponed appointments (41%), laboratory studies (46%), and MRIs (41%). Noncompliance with DMTs was less common (13%). Decisions to alter usual recommendations for care were made by the patient more often than by the provider regarding adherence to appointments (68%), laboratory studies (70%), MRI (67%), and DMT (65%). Degree of concern for infection was associated with adherence to appointments (p=0.020) and laboratory studies (p=0.016) but not with adherence to MRI and DMTs. Thirty-five patients reported being tested for COVID-19, of whom fourteen reported a positive test., Conclusion: Patients with MS were highly concerned about becoming infected during the local peak of the COVID-19 pandemic. Behaviors that deviated from originally recommended MS care were common and often self-initiated, but patients were overall compliant with continuing DMTs., (Copyright © 2021. Published by Elsevier B.V.)

There remains a pendulum swing to avoid p-values, but the binary, use or don't use p-values may be replacing one problem with another. This paper elaborates on the use of p-values and effect sizes, points out their utility and reminds that the context of the question remains critically important. There is no single measure that provides the sole value of a study. The over or under interpretation of various measures is cautioned. Researchers need to keep in mind there is bio in biostatistics and statistics in biology and medicine. Both are needed to understand results in context., (Copyright © 2020. Published by Elsevier B.V.)

Background: Patient satisfaction with treatment in relapsing-remitting multiple sclerosis (RRMS) has a direct impact on adherence to treatment and, consequently, upon treatment outcomes and costs. Patient-reported outcomes (PROs) are a common method for determining patient satisfaction in MS and other diseases., Methods: The 12-month, open-label, Phase IV CONFIDENCE study assessed patient satisfaction and treatment adherence, using PROs, as well as safety outcomes in patients with RRMS treated with glatiramer acetate (GA). In the previously reported (Cutter et al., 2019) initial 6-month core phase of the study, patients were randomized to receive three-times-weekly (TIW) GA 40 mg/mL (GA40; n = 431) or once-daily GA 20 mg/mL (GA20; n = 430). In the 6-month, single-arm extension phase, 789 patients completing the core phase were treated with GA40 to determine whether benefits observed in the core phase were sustained during the extension phase, to ascertain if switching from GA20 to GA40 resulted in PRO changes, and to assess safety outcomes., Results: Superior PRO scores for patient satisfaction with treatment, patient perception of treatment convenience, and symptomatic changes (fatigue impact and mental health) observed in the GA40 group versus the GA20 group in the core phase were all maintained in the extension phase. Treatment adherence, significantly greater in the GA40 versus the GA20 group in the core phase, was sustained in patients continuing to receive GA40 in the extension phase, while those who switched from GA20 to GA40 increased their adherence during the extension phase. Safety variables remained consistent throughout the study, with no notable changes observed in patients switching from GA20 to GA40., Conclusions: Data from the extension phase of the CONFIDENCE study show that the benefits associated with GA40 treatment in terms of medication satisfaction, treatment convenience perception, symptomatic changes in fatigue impact and mental health status, and treatment adherence were maintained over a 12-month observation period. These results confirm the preferential utility of GA40 versus GA20 in clinical practice, with no additional safety concerns associated with switching from GA20 to GA40., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There is continuing controversy over the excessive reliance on p-values. This paper elaborates on the use of p-values, points out their utility and reminds that there is no single measure that is a universal measure of the value of a study. All measures have their warts and moles, but each has utility. This paper discusses not only p-values but important measures of effect, effect sizes. The over or under interpretation of various measures is cautioned. The p-value is just a function of the summary statistic chosen for the outcome, the sample size and indicates a binary decision about the hypothesis. Using p-values are still OK, but should be coupled with other measures, such as effect sizes. A p-value alone won't get you through an ethics review board, no matter what its value, and it shouldn't get you through a journal review either., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Patients who perceive their medication to be ineffective or inconvenient are less likely to be adherent to treatment, with potentially significant consequences on long-term clinical outcomes. Many patients with multiple sclerosis (MS) are nonadherent to treatment despite demonstrated efficacy of disease-modifying therapies (DMTs). While glatiramer acetate (GA; Copaxone ® , Teva Pharmaceuticals) both 20 mg/mL once daily (GA20) and 40 mg/mL three times weekly (GA40) have demonstrated efficacy in relapsing-remitting MS (RRMS), GA40 has a superior tolerability profile in addition to a more convenient dosing schedule. These characteristics may give rise to greater treatment satisfaction and higher rates of adherence with potentially beneficial effects on clinical outcomes and health-related costs., Methods: CONFIDENCE was a Phase 4, interventional, open-label, randomized, 2-arm, parallel-group, global study with a duration of 6 months. Patients (N = 861) were randomly assigned 1:1 to receive GA20 (n = 430) or GA40 (n = 431) during the core phase. The primary endpoint was patient-reported medication satisfaction using the Medication Satisfaction Questionnaire (MSQ). Secondary endpoints included self-reported convenience perception using the Treatment Satisfaction Questionnaire for Medication-9 convenience component, symptomatic changes (Modified Fatigue Impact Scale, MFIS), and Mental Health Inventory (MHI). Treatment adherence was measured by Multiple Sclerosis Treatment Adherence Questionnaire. Results from the core phase were included., Results: During the core phase, 857 patients received treatments. Patients on GA40 were statistically significantly more satisfied with their medication than those on GA20 (LSM difference in MSQ, 0.3; 95% CI, 0.2, 0.5; p<0.001). Additionally, patients on GA40 found the treatment more convenient (p<0.001), were more adherent (p = 0.002), and reported statistically significant greater improvements in the MFIS Cognitive (p = 0.043) and the MHI Behavior Control (p = 0.014) subscales versus those on GA20. There were no new safety findings., Conclusions: Higher levels of satisfaction, perception of convenience, and adherence were reported by patients on GA40 than those on GA20., Clinical Trial Registration Number: This trial was registered with ClinicalTrials.gov (NCT02499900)., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Fatigue is an important aspect of health-related quality of life and a commonly reported symptom by many persons with multiple sclerosis (MS). There are multiple validated instruments available to assess fatigue in MS with differing benefits for each instrument., Objective: We aimed to assess the relationship between the PROMIS Fatigue instrument and the Fatigue Performance Scale (FPS) in the NARCOMS registry. Additionally, we aimed to examine the association of fatigue with social participation., Methods: The NARCOMS registry is a voluntary, self-report registry, which has enrolled participants with MS who provide semi-annual updates regarding their MS. The Fall 2016 semi-annual survey included the PROMIS Fatigue and Ability to Participate in Social Roles and Activities questionnaires, in addition to demographic and clinical information. We examined the association between instruments using Spearman correlations. Linear and ordinal regression models were used to evaluate associations with fatigue using the PROMIS Fatigue and the FPS., Results: Of the 7,006 Fall 2016 respondents, 6,883 (98.2%) completed the PROMIS instruments. Respondents were mostly female (79.5%) and Caucasian (87.4%), had a mean (SD) age of 59.9 (10.2) years and moderate disability level (median Patient Determined Disease Steps [PDDS] 4 [early cane]). The mean (SD) PROMIS Fatigue T-score was 56.8 (11.0) and median (25th, 75th) FPS was 3 [moderate] (1 [minimal], 4 [severe]). Fatigue measures were strongly correlated (r = 0.83, 95% CI: [0.827, 0.842]). Factors consistently associated with fatigue were PDDS level, depression and pain functionality scales, and symptoms worsening. The ability to participate in social roles and activities was strongly associated with fatigue and had an independent effect on fatigue after adjusting for PDDS, depression and pain levels., Conclusion: A high proportion of respondents experience some level of fatigue and it is independently associated with reduced social participation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Falls are common and impactful in people with multiple sclerosis (MS) but currently there is no accepted standard of care for fall prevention in MS. Evidence supports that the in-person, group-based, Free from Falls (FFF) program is associated with both immediate and six-month sustained improvements in mobility and balance and a reduction in falls, but program attendance is limited by access to the class at a given time and location and by the cost and availability of trained facilitators. Therefore, we developed and evaluated an online, web-based version of FFF, Free from Falls Online (FFFO)., Methods: Thirty people with MS who reported falling at least twice in the previous two months were randomized to FFFO or to a control group. FFFO consists of eight weekly sessions, each with an instructional and exercise component. Subjects in the control group were given a brochure on minimizing fall risk, a letter was sent to their treating physician informing them that the subject reported falling, and these subjects were invited to use the FFFO program at study completion. Outcomes included baseline demographics, falls prospectively reported for the eight weeks of intervention and the following three months, and a program satisfaction survey for the active group. Regression models were used to test for associations between treatment group and fall incidence., Results: Subjects' mean age was 55.8 years, 70% were female, 73% had progressive MS, median Expanded Disability Status Scale (EDSS) score was 6.0, and subjects reported a median of two falls in the month prior to study enrollment. Although, in general, regression models demonstrated trends that those in the intervention group were less likely to fall than those in the control group, statistical significance was only achieved (p = 0.0038) with a post hoc model evaluating the relationship between the square of days and the probability of not falling. This model supported that those in the intervention group were slightly less likely to fall than those in the control group. This difference was most prominent in the first month of the study, less prominent in the following month, and not sustained three months following the intervention. User experience with FFFO was overall positive, with over 75% reporting the web-based program easy to learn and to use, 85% reporting the program was easy to follow, 62% reporting the material to be useful, and 77% finding the exercises to be a useful component of the program., Conclusion: This study supports the viability of online delivery of self-management strategies in MS, suggests that FFFO may help prevent falls in people with MS, and provides the preliminary data needed to verify the findings of this pilot study of FFFO with a fully powered randomized controlled trial in people with MS., (Copyright © 2019. Published by Elsevier B.V.)

Background: People with multiple sclerosis (MS) experience symptoms in multiple domains. High-quality patient-reported outcomes (PROs) that assess multiple domains can aid healthcare providers in assessing these symptoms and may support remote disease monitoring. The "SymptoMScreen" PRO correlates with other PROs in MS; however, whether the SymptoMScreen or its component domains are associated with performance-based or clinician-assessed outcomes is unknown., Objectives: To validate SymptoMScreen and its domains against performance-based, clinician-assessed measures or other well-validated diagnostic tools., Methods: We recruited participants with MS from a large tertiary care center. At routine clinic visits participants completed the MS performance test (MSPT), which is an iPad-based application that objectively assesses walking speed, manual dexterity, processing speed, and low contrast letter acuity. Expanded Disability Status Scale (EDSS) scores were assessed in a subset. Participants also completed an online SymptoMScreen following clinic visits. We assessed criterion and construct validity by calculating Spearman rank correlations between the 12 SymptoMScreen domains and respective clinical outcomes. We evaluated test-retest reliability using intra-class correlation coefficients [ICC], and internal consistency reliability using Cronbach's alpha., Results: The 102 participants were predominantly female (78%), of average age [standard deviation]: 47.6 [12.3] years, with an average disease duration: 13.1 [10.0] years); 60 participants completed the SymptoMScreen and EDSS. Composite SymptoMScreen scores were associated with EDSS (r = 0.71; 95% CI 0.54, 0.83). For individual domains, strong correlations were observed between mobility scores and walking speed (r = 0.63; 95% CI: 0.48, 0.75) and hand function scores with manual dexterity (r = 0.52; 95% CI: 0.36, 0.65). More moderate correlations were detected for the cognition domain with processing speed (r=-0.37; 95% CI: -0.53, -0.18) and for the visual function domain with low contrast letter acuity at 2.5% contrast (r=-0.33; 95% CI -0.54, -0.08). Both test-retest and internal consistency reliability measures for overall SymptoMScreen scores were high (ICC: 0.88; 95% CI: 0.80, 0.93; Cronbach's alpha: 0.93; 95% CI: 0.90, 96)., Conclusions: The SymptoMScreen is practical outcome measure whose subscales may provide a valid assessment of corresponding performance-based and clinician-assessed measures among people with MS with mild-to-moderate disability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Dietary approaches to management of MS has been proposed for several decades, yet very little is known concerning dietary composition or adherence to specialized diets in people with multiple sclerosis (MS)., Methods: We conducted a survey of participants in the North American Research Committee on MS (NARCOMS) registry assessing diet composition and the prevalence of 19 different diets. We characterized prevalence of different diets and compared diet composition with estimated intakes from the National Health and Nutrition Examination Survey (NHANES) survey respondents and across demographics and MS clinical characteristics., Results: Among the 7639 (68%) responders, 6990 provided sufficient information on diet to be included in the analysis. Compared to NHANES participants, responders tended to have comparable intakes of fruit, vegetables and legumes (mean [SD] 2.5 [1.0] servings/day) and whole grains (0.9 [1.3] servings/day) and consume less added sugar (NARCOMS: 9.7 [6.0] vs. NHANES: 18.5[13.5] tsp/day; P < 0.001) and more red meat (NARCOMS: 0.50 [0.47] vs. NHANES: 0.35 [0.97] servings/day; P < 0.001). Of the 3120 (45%) participants who reported any history of following a specific diet, commonly-followed diets were: low-sugar (n = 642), low-carbohydrate (n = 508) and low-calorie (n = 475). Those with no history of following any specific diet were more likely to have progressive MS, be more obese, have worse overall diet quality, not participate in physical activity and smoke (all P < 0.001)., Conclusions: In this large survey, we found that diet composition in MS patients may vary by demographic and disease characteristics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to examine the sociodemographic, clinical, and behavioral factors associated with excessive sitting time in persons with multiple sclerosis (MS)., Methods: Useful data were obtained from 6483 persons with MS who completed the semi-annual survey of the North American Research Committee on Multiple Sclerosis registry conducted in the spring of 2015. Sociodemographic, clinical, and behavioral data were collected using self-report questionnaires. Sitting time per day was determined using the International Physical Activity Questionnaire. We conducted data analyses in May-June 2017 and defined those classified above the 75th percentile of sitting time as excessive sitters. Multivariate binary logistic regression was used to calculate the odds ratios for being an excessive sitter for sociodemographic, clinical, and behavioral variables., Results: The results indicated that participants who were moderately disabled, severely disabled but ambulatory, or severely disabled but non-ambulatory were 1.57, 2.62, and 8.70 times more likely to be excessive sitters than those reporting mild disability. Persons with MS who were insufficiently active were 2.61 times more likely to be excessive sitters than persons who were sufficiently active., Conclusion: This study identified disability status and physical activity levels as two prominent factors associated with the likelihood of being an excessive sitter in MS and this will inform the design of future interventions for reducing sedentary behavior in this population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS)., Objectives: Compare mortality rates and event rates for comorbidities in MS (n=15,684) and non-MS (n=78,420) cohorts from the US Department of Defense (DoD) database., Methods: Comorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios., Results: All-cause mortality was 2.9-fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7-3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2-9.4), diseases of the nervous (5.8, 3.7-9.0), respiratory (5.0, 3.9-6.4) and circulatory (2.1, 1.7-2.7) systems and suicide (2.6, 1.3-5.2). Comorbidities including sepsis (ERR, 95% CI: 5.7, 5.1-6.3), ischemic stroke (3.8, 3.5-4.2), attempted suicide (2.4, 1.3-4.5) and ulcerative colitis (2.0, 1.7-2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9-2.6) and melanoma (1.7, 1.4-2.0)., Conclusions: Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There is little information about risk acceptance of multiple sclerosis (MS) patients to various MS therapies., Objective: To determine MS patients׳ tolerance to risky therapies and identify associated characteristics., Methods: MS patients from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry׳s online cohort were invited to complete questionnaires on decision making and risk tolerance (RT) to two therapeutic scenarios: a theoretical cure for MS [CureMS], with permanent reversal of all MS symptoms but a risk of immediate painless death; and natalizumab [NAT], a real-life scenario with benefits and risks as defined by Phase III trial results., Results: The median RT for both scenarios was 1:10,000; 15-23% of respondents were not willing to take any risk for their MS therapy. Participants with greater disability or not taking any MS therapy showed a greater RT, while females and those caring for dependents had a lower RT. Females and older age were predictors of lower RT, while increasing disability and greater blunting attitude with respect to information seeking behavior were predictors of higher RT., Conclusion: MS patients displayed a wide range of RT for MS therapies. Our study identified gender, age, disability and information seeking behavior to be associated with RT., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: Compare relapse clinical severity, post-relapse residual disability, and the probability of confirmed complete recovery from relapse between patients who relapsed during natalizumab (n=183/627 [29%]) and placebo (n=176/315 [56%]) treatments in the AFFIRM trial., Methods: In this post-hoc analysis, relapse clinical severity and residual disability were defined by change in Expanded Disability Status Scale (EDSS) score occurring between pre-relapse and at-relapse assessment and between pre-relapse and post-relapse assessment, respectively. Patients were considered completely recovered from relapse when their post-relapse EDSS score was less than or equal to their pre-relapse EDSS score, and this was maintained for 12 or 24 weeks., Results: At relapse, an increase in EDSS score of ≥0.5 points occurred in 71% of natalizumab and 84% of placebo patients (P=0.0088); an increase of ≥1.0 point occurred in 49% of natalizumab and 61% of placebo patients (P=0.0349) (mean increase in EDSS at relapse: natalizumab=0.77; placebo=1.09; P=0.0044). After relapse, residual disability of ≥0.5 EDSS points remained in 31% of natalizumab and 45% of placebo patients (P=0.0136) (mean post-relapse residual EDSS increase: natalizumab=0.06; placebo=0.28; P=0.0170). In patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, natalizumab increased the probability of 12-week confirmed complete recovery from relapse by 55% (hazard ratio [HR]=1.554; P=0.0161) and 67% (HR=1.673; P=0.0319) compared to placebo, respectively., Conclusions: In AFFIRM, natalizumab treatment decreased the clinical severity of relapses and improved recovery from disability induced by relapses. These beneficial effects would limit the step-wise accumulation of disability., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Compare survival in patients with multiple sclerosis (MS) from a U.S. commercial health insurance database with a matched cohort of non-MS subjects., Methods: 30,402 MS patients and 89,818 non-MS subjects (comparators) in the OptumInsight Research (OIR) database from 1996 to 2009 were included. An MS diagnosis required at least 3 consecutive months of database reporting, with two or more ICD-9 codes of 340 at least 30 days apart, or the combination of 1 ICD-9-340 code and at least 1 MS disease-modifying treatment (DMT) code. Comparators required the absence of ICD-9-340 and DMT codes throughout database reporting. Up to three comparators were matched to each patient for: age in the year of the first relevant code (index year - at least 3 months of reporting in that year were required); sex; region of residence in the index year. Deaths were ascertained from the National Death Index and the Social Security Administration Death Master File. Subjects not identified as deceased were assumed to be alive through the end of 2009., Results: Annual mortality rates were 899/100,000 among MS patients and 446/100,000 among comparators. Standardized mortality ratios compared to the U.S. population were 1.70 and 0.80, respectively. Kaplan-Meier analysis yielded a median survival from birth that was 6 years lower among MS patients than among comparators., Conclusions: The results show, for the first time in a U.S. population, a survival disadvantage for contemporary MS patients compared to non-MS subjects from the same healthcare system. The 6-year decrement in lifespan parallels a recent report from British Columbia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Interferon-β1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective., Objective: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA., Methods: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio., Results: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions., Conclusion: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

BACKGROUND: Interferon-β1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0 to 5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2 ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.