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Stanley Cohan1,2,3 1Providence Multiple Sclerosis Center, 2Providence Brain and Spine Institute, 3Providence Health & Services, Portland, OR, USA Abstract: Despite the availability of multiple disease-modifying therapies for relapsing multiple sclerosis (MS), there remains a need for highly efficacious targeted therapy with a favorable benefit–risk profile and attributes that encourage a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Daclizumab treatment leads to antagonism of proinflammatory, activated T lymphocyte function and expansion of immunoregulatory CD56bright natural killer cells, and has the potential to, at least in part, rectify the imbalance between immune tolerance and autoimmunity in relapsing MS. The clinical pharmacology, efficacy, and safety of subcutaneous daclizumab have been evaluated extensively in a large clinical study program. In pivotal studies, daclizumab demonstrated superior efficacy in reducing clinical and radiologic measures of MS disease activity compared with placebo or intramuscular interferon beta-1a, a standard-of-care therapy for relapsing MS. The risk of hepatic disorders, cutaneous events, and infections was modestly increased. The monthly subcutaneous self-injection dosing regimen of daclizumab may be advantageous in maintaining patient adherence to treatment, which is important for optimal outcomes with MS disease-modifying therapy. Daclizumab has been approved in the US and in the European Union and represents an effective new treatment option for patients with relapsing forms of MS, and is currently under review by other regulatory agencies. Keywords: daclizumab, disease-modifying therapy, humanized monoclonal antibody, relapsing multiple sclerosis, therapeutic use

A 25 year old man, with a family history of multiple sclerosis in two preceding generations, developed transient sensory changes and incoordination, initially on the left side, and then several months later on the right side in association with an elevated CSF gamma globulin. This was followed by an acute optic neuritis. During the latter episode he developed a positive brain scan which was unaccompanied by any clinical findings explained by a lesion in that area. Cerebral arteriography was normal and the brain scan returned to normal four weeks later, possibly as a result of blood brain barrier restoration. Abnormal brain scans appear to occur only during acute exacerbations of demyelinating disease, and multiple sclerosis should be part of the differential diagnosis of a positive brain scan in a person in the appropriate age range. [ABSTRACT FROM AUTHOR]

The study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF). This was followed by an upregulation of a number of signaling and metabolic pathways at 12 months. Patients with higher baseline brain MRI lesion load demonstrated both higher levels of cytotoxic and structural proteins in plasma at baseline and more pronounced biomarker change trajectories over time. Digital cytometry identified a putative increase in myeloid cells and a pro-inflammatory subset of T-cells. Therapeutic effects of ocrelizumab extend beyond CD20-mediated B-cell lysis and implicate metabolic reprogramming, juxtaposing the early normalization of immune activation, cytokine signaling and metabolite and lipid turnover in periphery with changes in the dynamics of immune cell activation or composition. We identify BAFF increase following CD20 depletion as a tentative compensatory mechanism that contributes to the reconstitution of targeted B-cells, necessitating further research., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Melatonin is an antioxidant and anti-inflammatory agent that modulates the immune system by scavenging free radicals, reducing the upregulation of pro-inflammatory cytokines, and reducing transendothelial cell migration. Therefore, melatonin may play a role in regulating multiple sclerosis (MS) disease activity. However, little is known about how melatonin supplementation effects individuals with MS., Objective: Determine if there was a dose-dependent elevation in urine and serum melatonin concentrations. Determine if melatonin supplementation had an impact on patient reported outcomes., Methods: This was a randomized, dose-blinded exploratory study. Adults (age 18-65) with relapsing forms of multiple sclerosis (RMS) treated with a stable dose of oral disease modifying therapy for at least 6 months were randomized into melatonin 3 mg or 5 mg daily. Urinary and serum melatonin levels and modified fatigue impact scale (MFIS), multiple sclerosis impact scale (MSIS-29), and Pittsburgh sleep quality index (PSQI), patient determined disease steps (PDDS) and performance scales (PS) were measured at baseline, 3, 6, and 12 months. Urinary and serum melatonin analyses was performed to estimate mean concentrations and their differences between treatment arms over time by a repeated measures linear mixed model. The model included treatment, assessment time, and treatment × time interaction., Results: Thirty patients, randomized 1:1, were analyzed in an intent to treat population. Twenty-three completed the study. The repeated measures linear mixed model analysis of all timepoints revealed higher melatonin concentrations in patients on 5 mg compared to 3 mg melatonin for both urinary 6-SMT (p = 0.03) and serum melatonin (p = 0.04). MFIS, MSIS-29, PSQI, and PDSS-PS scores did not significantly change from baseline to month 12. No significant differences in these measures were seen between the two doses. Five patients stopped melatonin (three on 5 mg and two on 3 mg) due to adverse events, including one patient who developed focal spongiotic dermatitis. One patient experienced three consecutive serious adverse events that were unrelated to melatonin supplementation., Conclusions: The 5 mg melatonin supplementation group had higher concentrations of urinary 6-SMT and serum melatonin compared to the 3 mg group over 12 months of treatment. There was a correlation between 6-SMT and serum melatonin concentrations. This suggests that measuring serum melatonin is a reliable alternative to measuring urinary 6-SMT. However, no differences in clinical benefit between the two dosage groups were demonstrated in the patient reported outcomes., Trial Registration Number: NCT03498131., Competing Interests: Declaration of competing interest KS - Consulting and speaking honoraria from Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Roche, Sanofi Genzyme, and TG Therapeutics. Research support from Sanofi Genzyme and Roche Genentech. SC - Research Support from AbbVie, Biogen, Bristol Myers Squibb, EMDSerono, Novartis, Roche Genentech, and Sanofi Genzyme. Consulting and speaking honoraria from Biogen, Bristol Myers Squibb, & EMDSerono. TGF, HM, and CC- no conflicts of interest to report., (Copyright © 2024. Published by Elsevier B.V.)

Can an inclusive test of face cognition meet or exceed the psychometric properties of a prominent less inclusive test? Here, we norm and validate an updated version of the influential Reading the Mind in the Eyes Test (RMET), a clinically significant neuropsychiatric paradigm that has long been used to assess theory of mind and social cognition. Unlike the RMET, our Multiracial Reading the Mind in the Eyes Test (MRMET) incorporates racially inclusive stimuli, nongendered answer choices, ground-truth referenced answers, and more accessible vocabulary. We show, via a series of large datasets, that the MRMET meets or exceeds RMET across major psychometric indices. Moreover, the reliable signal captured by the two tests is statistically indistinguishable, evidence for full interchangeability. We thus present the MRMET as a high-quality, inclusive, normed and validated alternative to the RMET, and as a case in point that inclusivity in psychometric tests of face cognition is an achievable aim. The MRMET test and our normative and validation data sets are openly available under a CC-BY-SA 4.0 license at osf.io/ahq6n., (© 2024. The Author(s).)

Introduction: No validated algorithm exists to identify patients with neuromyelitis optica spectrum disorder (NMOSD) in healthcare claims data. We developed and tested the performance of a healthcare claims-based algorithm to identify patients with NMOSD., Methods: Using medical record data of 101 adults with NMOSD, multiple sclerosis (MS), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), we tested the sensitivity and specificity of claims-based algorithms developed through interviews with neurologists. We tested the best-performing algorithm's face validity using 2016-2019 data from IBM MarketScan Commercial and Medicare Supplemental databases. Demographics and clinical characteristics were reported., Results: Algorithm inclusion criteria were age ≥ 18 years and (≥1 NMO diagnosis [or ≥ 1 transverse myelitis (TM) and ≥ 1 optic neuritis (ON) diagnosis] and ≥ 1 NMOSD drug) or (≥2 NMO diagnoses ≥90 days apart). Exclusion criteria were MS diagnosis or use of MS-specific drug after last NMO diagnosis or NMOSD drug; sarcoidosis diagnosis after last NMO diagnosis; or use of ≥1 immune checkpoint inhibitor. In medical record billing data of 50 patients with NMOSD, 30 with MS, and 21 with MOGAD, the algorithm had 82.0% sensitivity and 70.6% specificity. When applied to healthcare claims data, demographic and clinical features of the identified cohort were similar to known demographics of NMOSD., Conclusions: This clinically derived algorithm performed well in medical records. When tested in healthcare claims, demographics and clinical characteristics were consistent with previous clinical findings. This algorithm will enable a more accurate estimation of NMOSD disease burden using insurance claims datasets., Competing Interests: Declaration of competing interest The authors declare financial and other relationships that may be considered potential competing interests. These are also reflected in the completed ICMJE forms. AP reports support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges) from Genentech, Inc. She reports stock options with Roche/Genentech and reports under other financial or non-financial interests that she is an employee of Genentech, Inc. AE has no declarations of interest. IY, HD, SNG, EC, and MB report support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges) from Genentech, Inc. They are employees of PHAR, which was paid by Genentech, Inc., to conduct the research described in the manuscript. They also report other financial or non-financial interests outside of the submitted work from Akcea, Amgen, Boston Scientific Corporation, Dompé, Eisai, Greenwich Biosciences, Ionis, Jazz, Novartis, Otsuka, Prothena, Pfizer, Recordati, Regeneron, Sanofi US Services, Sunovion, and Takeda Pharmaceuticals USA. SRR and CP report support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges) from Genentech, Inc. They were employees of PHAR for the duration of work described in the manuscript, which was paid by Genentech, Inc., to conduct the research described in the manuscript. They also report other financial or non-financial interests outside of the submitted work while employees at PHAR from Akcea, Amgen, Boston Scientific Corporation, Dompé, Eisai, Greenwich Biosciences, Ionis, Jazz, Novartis, Otsuka, Prothena, Pfizer, Recordati, Regeneron, Sanofi US Services, Sunovion, and Takeda Pharmaceuticals USA. SC reports support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges) from Health Interactions/Nucleus Global. He reports grants or contracts from AbbVie, Biogen, Bristol Myers Squibb, Roche/Genentech, EMD Serono, Icometrix, Novartis, and Sanofi Genzyme. He reports consulting fees from Biogen, Bristol Myers Squibb, EMD Serono, Icometrix, and Novartis. He reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen, Bristol Myers Squibb, EMD Serono, Roche/Genentech, and Sanofi Genzyme. He reports leadership or fiduciary roles in other board, society, committee, or advocacy groups, paid or unpaid, for the National African Americans with MS Registry as an unpaid board member. BG reports support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges) from Genentech, Inc. He was paid by Genentech, Inc., to conduct the research described in the manuscript. He reports grant funding from Regeneron, the National Institutes of Health, Anokion, and Clene Nanomedicine. He reports royalties from UpToDate. He reports consulting fees from Alexion, Novartis, EMD Serono, Horizon, Genentech/Roche, Cycle Pharma, Signant Health, Sandoz, TG Therapeutics, Sanofi/Genzyme, Immunovant, and PRIME Education. He reports participation on a data safety monitoring board for IQVIA. He reports leadership or fiduciary roles in other board, society, committee, or advocacy groups, paid or unpaid, for the Siegel Rare Neuroimmune Association as an unpaid member of the board. He reports stock or stock options from Clene Nanomedicine and GenrAb. ML reports grants or contracts in the form of clinical trial and educational grants from Genentech, UCB, Sanofi, Horizon, and Alexion. He reports consulting fees from Genentech, Horizon, Alexion, UCB, and Sanofi. He reports participation on a data safety monitoring board as an advisory board member for Genentech, Horizon, and Alexion and data safety monitoring board participation for TG Therapeutics., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Multiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing-remitting MS., Methods: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally., Results: Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min-max) months of follow-up was 32 (0-72) for Black, 29 (1-77) for Hispanic, and 41 (0-85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5 years were 0.054 (0.038-0.078) for Black, 0.077 (0.072-0.081) for non-Black, 0.069 (0.043-0.112) for Hispanic, and 0.076 (0.072-0.081) for non-Hispanic populations, representing reductions of 91-92% compared with ARR 12 months before study entry (all p < 0.0001)., Conclusion: The safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients., Trial Registration: ClinicalTrials.gov identifier NCT02047097., (© 2023. The Author(s).)

While age-related decline in face recognition memory is well-established, the degree of decline in face perceptual abilities across the lifespan and the underlying mechanisms are incompletely characterized. In the present study, we used the part-whole task to examine lifespan changes in holistic and featural processing. After studying an intact face, participants are tested for memory of a face part (eyes, nose, mouth) with the target and foil part presented either in isolation or in the context of the whole face. To the extent that parts are encoded into a holistic face representation, an advantage is expected for part recognition when tested in the whole face condition. The task therefore provides measures of holistic processing (whole-over-isolated-part trial advantage) and featural processing for each part when tested in isolation. Using a large sample of 3,341 online participants aged 18-69 years, we found that while discrimination of the eye region decreased beginning in the 50s, both mouth discrimination accuracy and the holistic advantage of whole versus part trial discrimination were stable with age. In separate analyses by gender, we found that age-related declines in eye region accuracy were more pronounced in males than females. We discuss potential mechanistic explanations for this eye region-specific decline with age, including age-related hearing loss directing attention toward the mouth. Further, we discuss how this could be related to the age-related positivity effect, which is associated with reduced sensitivity to eye-related emotions (e.g., anger) but preserved mouth-related emotion sensitivity (e.g., happiness). (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Sustaining concussions has been linked to health issues later in life, yet evidence for associations between contact sports exposure and long-term cognitive performance is mixed. This cross-sectional study of former professional American-style football players tested the association of several measures of football exposure with later life cognitive performance, while also comparing the cognitive performance of former players to nonplayers., Methods: In total, 353 former professional football players (Mage = 54.3) completed both (1) an online cognitive test battery measuring objective cognitive performance and (2) a survey querying demographic information, current health conditions, and measures of past football exposure, including recollected concussion symptoms playing professional football, diagnosed concussions, years of professional play, and age of first football exposure. Testing occurred an average of 29 years after former players' final season of professional play. In addition, a comparison sample of 5,086 male participants (nonplayers) completed one or more cognitive tests., Results: Former players' cognitive performance was associated with retrospectively reported football concussion symptoms (rp = -0.19, 95% CI -0.09 to -0.29; p < 0.001), but not with diagnosed concussions, years of professional play, or age of first football exposure. This association could be due to differences in pre-concussion cognitive functioning, however, which could not be estimated based on available data., Conclusions: Future investigations of the long-term outcomes of contact sports exposure should include measures of sports-related concussion symptoms, which were more sensitive to objective cognitive performance than other football exposure measures, including self-reported diagnosed concussions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Introduction: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear., Objective: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab., Methods: Clinically and radiographically stable RMS patients, ages 18-65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4-6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12., Results: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab., Conclusion: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab., Clinicaltrials.gov Identifier: NCT03157830.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.

Background: Natalizumab (NTZ) is a highly effective disease modifying treatment for relapsing multiple sclerosis (RMS), but it increases risk of progressive multifocal leukoencephalopathy (PML) in patients with serum anti- John Cunningham virus (JCV) antibodies., Objective: To assess the safety and efficacy of rapid transition, from NTZ to teriflunomide (TFM) in RMS patients., Methods: Clinically stable NTZ-treated, anti-JCV antibody positive RMS patients were switched to TFM 28 ± 7 days after their last dose of NTZ. The primary endpoint was proportion of relapse free patients at 24 months., Results: Median [IQR] age of the 55 enrolled patients was 47 [40.7, 56.3] years, 76% were female. The median [IQR] number of prior NTZ treatments was 34 [18, 64]. annualized relapse rate (ARR) was 0.07 and 77% of the patients were relapse free at 24 months. Mean time to first GAD + lesion was 19.6 months, and to new/enlarging T2 lesion was 19.2 months. Mean time to 3 month sustained disability worsening (SDW) was 22 months and proportion free of 3-month SDW was 0.87. There were no cases of PML., Conclusions: The washout-free transition of NTZ to TFM was an efficacious and safe strategy for patients at risk of developing PML.ClinicalTrials.gov Identifier: NCT01970410., Competing Interests: Declaration of conflicting interests: SC has served on advisory boards or steering committees for Biogen, Novartis, Sanofi Genzyme, AbbVie, and EMD Serono and received research support from Biogen, Novartis, Sanofi Genzyme, MedDay, and Roche Genentech, and speaker honoraria from Biogen, Novartis, Sanofi Genzyme, Bristol Myers Squibb, and Roche Genentech. KS has received research support from AbbVie, Biogen, Roche Genentech, and EMD Serono and consulting fees from Bristol Myers Squibb, Janssen, Acorda, Biogen, EMD Serono, Sanofi Genzyme, Roche Genentech, Novartis, and Teva. KE has received honoraria for speaking and consulting from Biogen and EMD Serono and research/grant support from Biogen, Sanofi Genzyme, F. Hoffmann-La Roche and Genentech, EMD Serono, and Novartis. AK, TGF, VK, EB, and CC have no disclosures., (© The Author(s), 2021.)

Background: To monitor long-term outcomes of ocrelizumab treatment., Objective: To evaluate safety and treatment outcomes of ocrelizumab in a community-based multiple sclerosis (MS) population., Methods: Adult patients with MS prescribed ocrelizumab were eligible. Chart reviews were conducted at the start of ocrelizumab treatment and every 6 months thereafter., Results: Of the 355 patients enrolled, 71.9% were female; mean (SD) age was 51.8 (12.5) years; 78.3% had relapsing MS (RMS). Median baseline Expanded Disability Status Scale (EDSS) (IQR) was 3.0 (2.0-4.0) for RMS, 6.5 (6.0-7.5) for secondary progressive MS, and 6.5 (6.0-7.0) for primary progressive MS. Respiratory infections occurred in 40.1% and urinary tract infections in 33.1% of patients. There was no difference in the percentage of infections among patients <55 (68.5%, n=122), and those ≥55 of age (67.5%, n=104) (p=0.94). Twenty-five hospitalisations were due to infections; 69.2% of these patients were ≥55 with a mean EDSS of 5.7 (±1.86). Four patients have died. Serum IgM and IgG levels did not predict infection risk. Annualised relapse rate was 0.34 for the patients with RMS in the preceding 2 years and 0.09 in patients who received ≥2 ocrelizumab 600 mg courses. The first on-treatment MRI was stable in 262 (90.0%) patients, 6.9% had new T2 lesions, 2.7% had enlarging T2 lesions and 1.4% had gadolinium-enhancing lesions. Median EDSS at 12 months was unchanged., Conclusion: Ocrelizumab effectively controlled relapse risk and disability worsening. Although only 12.1% of patients have discontinued ocrelizumab, infections resulting in hospitalisation are a concern, especially in older and disabled patients., Competing Interests: Competing interests: KS has received institutional research support from AbbVie, Biogen, Genentech, EMD Serono, MedDay, and IMS Health and consulting fees from Acorda, Biogen, EMD Serono, Genzyme, Genentech, Novartis, and Teva. SC has served on advisory boards or steering committees for AbbVie, Biogen, Bristol Myers Squibb (Celgene), Novartis, Sanofi Genzyme, and Pear Therapeutics; has received institutional research support from AbbVie, Adamas, Biogen, EMD Serono, Novartis, Sanofi Genzyme, MedDay, and Roche Genentech; has received speaker honoraria from AbbVie, Biogen, Novartis, Sanofi Genzyme, and Roche Genentech., (© 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.)

Background: A growing number of immunomodulating disease-modifying therapies are available for treatment of relapsing multiple sclerosis (RMS). In the absence of randomized head-to-head trials, matching-adjusted indirect comparisons (MAICs) can be used to adjust for cross-trial differences and evaluate the comparative efficacy and safety of these agents. We used MAIC methodology to indirectly compare key outcomes with ozanimod (OZM) and teriflunomide (TERI) in the treatment of RMS., Methods: A systematic literature review was conducted to identify clinical trials evaluating the efficacy and safety of OZM vs TERI. Given the absence of head-to-head trials of OZM vs TERI, we used a matching-adjusted indirect comparison to adjust for potential treatment effect modifiers and prognostic factors while assessing confirmed disability progression (CDP), relapse, and safety outcomes. Individual patient data for OZM (SUNBEAM and RADIANCE Part B trials) and aggregate level data for TERI (ASCLEPIOS I/II, TOWER, OPTIMUM, and TEMSO trials) were used to evaluate the following outcomes: annualized relapse rate (ARR), proportion of patients relapsed, CDP at 3 and 6 months, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs., Results: After matching, baseline patient characteristics were balanced between OZM and TERI. Compared with TERI, OZM demonstrated significant improvements in ARR (rate ratio: 0.73; 95% CI: 0.62-0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44-0.70), overall AEs (OR: 0.35; 95% CI: 0.29-0.43), SAEs (OR: 0.53; 95% CI: 0.37-0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09-0.21). OZM demonstrated statistically significant improvements in CDP at 3 months (hazard ratio [HR]: 0.78; 95% CI: 0.66-0.92) but nonsignificant differences at 6 months (HR: 0.78; 95% CI: 0.60-1.01) compared with TERI., Conclusion: In this indirect treatment comparison of patients with RMS, OZM appeared to have an improved benefit-risk profile over TERI., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Patients with multiple sclerosis (MS) experience relapses and sustained disability progression. Since 2004, the number of disease-modifying therapies (DMTs) for MS has grown substantially. As a result, patients, healthcare providers, and insurers are increasingly interested in comparative efficacy and safety evaluations to distinguish between treatment options, but head-to-head studies between DMTs are limited., Objective: The aim of the current study was to compare efficacy and safety outcomes with the DMTs ozanimod and dimethyl fumarate (DMF) using a matching-adjusted indirect comparison (MAIC) to adjust for cross-trial differences in study design and population., Methods: A systematic literature review was performed to identify clinical studies evaluating the efficacy and safety of ozanimod compared with DMF. Individual patient-level data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate-level patient data (APD) for DMF were obtained from CONFIRM and DEFINE. A MAIC is used to weight IPD to APD based on important baseline patient characteristics considered to be effect modifiers or prognostic factors in order to balance the covariate distribution to establish more homogenous trial populations. Once trial populations are determined to be sufficiently homogenous, outcomes of interest are estimated and used to generate treatment effects between the weighted IPD and APD. We used MAIC methodology to compare efficacy and safety outcomes of interest between ozanimod 1.0 mg once daily (OD) and DMF 240 mg twice daily (BID), including confirmed disability progression (CDP) at 3 and 6 months, annualized relapse rate (ARR), proportion of patients relapsed, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs., Results: After matching patient data, baseline patient characteristics were balanced between patients receiving ozanimod and those receiving DMF. Compared with DMF, ozanimod demonstrated significantly improved CDP at 3 months (hazard ratio 0.67; 95% confidence interval [CI] 0.53-0.86), ARR (rate ratio [RR] 0.80; 95% CI 0.67-0.97), proportion of patients relapsed (odds ratio [OR] 0.66; 95% CI 0.52-0.83), overall AEs (OR 0.11; 95% CI 0.08-0.16), SAEs (OR 0.27; 95% CI 0.19-0.39), and discontinuations (OR 0.11; 95% CI 0.07-0.17). CDP at 6 months did not differ significantly between the two agents (RR 0.89; 95% CI 0.62-1.26)., Conclusions: After adjustment of baseline patient characteristics, the MAIC demonstrated that the efficacy and safety of ozanimod 1.0 mg OD was superior to that of DMF 240 mg BID. Although a MAIC is less likely to produce biased estimates than a naïve or a standard indirect treatment comparison via a common comparator, limitations include potential confounding due to unobserved and thus unaccounted for baseline differences., (© 2021. The Author(s).)

Background: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study., Methods: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors., Results: The total safety population ( N  = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years., Conclusion: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting., Competing Interests: Conflict of interest: LK reports funding to his institution (University Hospital Basel) in the last 3 years used exclusively for research support; steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer, Biogen, Celgene, Genzyme, Merck, Mitsubishi, Novartis, Pfizer, Sanofi, and Santhera; speaker fees from Biogen, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; license fees for Neurostatus products; and grants from Bayer, Biogen, European Union, Innosuisse, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and Swiss National Research Foundation. SC reports speaking honoraria from and/or advisory boards for Biogen, Bristol Myers Squibb, EMD Serono, Novartis, Pear Therapeutics, Roche Genentech, and Sanofi Genzyme; and research support from AbbVie, Acorda, Actelion, Biogen, MedDay, Novartis, Roche Genentech, and Sanofi Genzyme. DLA reports consultant fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Canadian Institutes of Health Research, Celgene, Frequency Therapeutics, Genentech, Genzyme, Immune Tolerance Network, Immunotec, International Progressive MS Alliance, MedDay, Merck Serono, MS Society of Canada, Novartis, Pfizer, Receptos, Roche, and Sanofi and an equity interest in NeuroRx Research. RRR is an employee of and holds stock/stock options in AbbVie. JH was a former employee of and holds stock/stock options in AbbVie. BP was a former employee of and holds stock/stock options in Biogen. SF, SX and WC-B are employees of and hold stock/stock options in Biogen. The EXTEND study and these analyses were funded by Biogen (Cambridge, MA, USA) and AbbVie (Redwood City, CA, USA)., (© The Author(s), 2021.)

Social networks have broad effects on health and quality of life. Biopsychosocial factors may also modify the effects of brain trauma on clinical and pathological outcomes. However, social network characterization is missing in studies of contact sports athletes. Here, we characterized the personal social networks of former National Football League players compared to non-football US males. In 303 former football players and 269 US males, we found that network structure (e.g., network size) did not differ, but network composition (e.g., proportion of family versus friends) did differ. Football players had more men than women, and more friends than family in their networks compared to US males. Black players had more racially diverse networks than White players and US males. These results are unexpected because brain trauma and chronic illnesses typically cause diminished social relationships. We anticipate our study will inform more multi-dimensional study of, and treatment options for, contact sports athletes. For example, the strong allegiances of former athletes may be harnessed in the form of social network interventions after brain trauma. Because preserving health of contact sports athletes is a major goal, the study of social networks is critical to the design of future research and treatment trials.

Background: Nine oral disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) in the United States. Few studies have examined self-reported quality of life (QoL) and functional status outcomes among patients who switch to oral medications from injectable MS therapies. This study compares self-reported QoL and disability status between participants switching from injectable to oral DMTs, to those who stay on injectable DMTs continuously for the same time period., Methods: Longitudinal data were assessed from relapsing MS participants in the Pacific Northwest MS Registry completing a minimum of two surveys between 2012 and 2018 with a maximum of 36 months between surveys. Stayers were defined as those who remained on injectable DMTs continuously from Time 1 to Time 2; switchers were those who switched from injectable to either fingolimod, teriflunomide or dimethyl fumarate during the same time interval. Outcomes of interest were physical and psychological QoL, measured by the Multiple Sclerosis Impact Scale (MSIS-29), and disability, measured by the Patient Determined Disease Steps (PDDS). To analyze the effect of switching to oral DMT on outcomes at Time 2, a one-to-two propensity score matching (PSM) was used to match switchers to stayers. Outcomes at Time 2 were analyzed using paired t-test for QoL scores, and Stuart Maxwell test for PDDS as a categorical variable., Results: Among 2385 participants who returned consecutive yearly surveys, 413 met the inclusion criteria for stayers and 66 for switchers. After one-to-two PSM, 124 stayers were matched to 62 switchers. Paired t-test showed no differences between switchers and stayers for physical (mean difference: - 0.41; [95% confidence interval CI: - 3.3-2.4]; p = 0.78) or psychological (mean difference: - 0.23; [95% CI, - 1.6- 1.1]; p = 0.74) QoL. Additionally, no differences were seen between switchers and stayers in self-reported disability status., Conclusions: MS registry participants who switched to an oral DMT from injectable showed no significant differences in QoL or self-reported disability status compared to those remaining on injectable DMT continuously in the same time period.

Introduction: Black or African American (black/AA) patients with multiple sclerosis (MS) are reported to exhibit greater disease severity compared with non-black or non-AA patients. Whether differences exist in response to MS disease-modifying therapies remains uncertain, as MS clinical trials have included low numbers of non-white patients. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in black/AA patients., Methods: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally., Results: Overall, 4897 non-black/non-AA and 187 black/AA patients were analyzed; median (range) follow-up 18 (2-37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-black/non-AA patients, 0.83 (95% CI 0.80-0.85) versus 0.10 (95% CI 0.09-0.10), 88% lower ARR (P < 0.0001); black/AA patients, 0.68 (95% CI 0.58-0.80) versus 0.07 (95% CI 0.05-0.10), 90% lower ARR (P < 0.0001). In total, 35 (19%) black/AA patients reported adverse events leading to treatment discontinuation; gastrointestinal disorders were most common (7%), consistent with non-black/non-AA patients (8%). Median lymphocyte counts decreased by 22% in the first year (vs 36% in non-black/non-AA patients), then remained stable and above lower limit of normal in most patients., Conclusions: Relapse rates remained low in black/AA patients, consistent with non-black/non-AA patients. The safety profile of DMF in black/AA patients was consistent with that in the non-black/non-AA ESTEEM population, although lymphocyte decrease was less pronounced in black/AA patients.

Background: Multiple sclerosis (MS) is a chronic neurodegenerative disease. Current monitoring practices predominantly rely on brief and infrequent assessments, which may not be representative of the real-world patient experience. Smartphone technology provides an opportunity to assess people's daily-lived experience of MS on a frequent, regular basis outside of episodic clinical evaluations., Objective: The objectives of this study were to evaluate the feasibility and utility of capturing real-world MS-related health data remotely using a smartphone app, "elevateMS," to investigate the associations between self-reported MS severity and sensor-based active functional tests measurements, and the impact of local weather conditions on disease burden., Methods: This was a 12-week, observational, digital health study involving 3 cohorts: self-referred participants who reported an MS diagnosis, clinic-referred participants with neurologist-confirmed MS, and participants without MS (controls). Participants downloaded the elevateMS app and completed baseline assessments, including self-reported physical ability (Patient-Determined Disease Steps [PDDS]), as well as longitudinal assessments of quality of life (Quality of Life in Neurological Disorders [Neuro-QoL] Cognitive, Upper Extremity, and Lower Extremity Function) and daily health (MS symptoms, triggers, health, mobility, pain). Participants also completed functional tests (finger-tapping, walk and balance, voice-based Digit Symbol Substitution Test [DSST], and finger-to-nose) as an independent assessment of MS-related cognition and motor activity. Local weather data were collected each time participants completed an active task. Associations between self-reported baseline/longitudinal assessments, functional tests, and weather were evaluated using linear (for cross-sectional data) and mixed-effects (for longitudinal data) regression models., Results: A total of 660 individuals enrolled in the study; 31 withdrew, 495 had MS (n=359 self-referred, n=136 clinic-referred), and 134 were controls. Participation was highest in clinic-referred versus self-referred participants (median retention: 25.5 vs 7.0 days). The top 5 most common MS symptoms, reported at least once by participants with MS, were fatigue (310/495, 62.6%), weakness (222/495, 44.8%), memory/attention issues (209/495, 42.2%), and difficulty walking (205/495, 41.4%), and the most common triggers were high ambient temperature (259/495, 52.3%), stress (250/495, 50.5%), and late bedtime (221/495, 44.6%). Baseline PDDS was significantly associated with functional test performance in participants with MS (mixed model-based estimate of most significant feature across functional tests [β]: finger-tapping: β=-43.64, P<.001; DSST: β=-5.47, P=.005; walk and balance: β=-.39, P=.001; finger-to-nose: β=.01, P=.01). Longitudinal Neuro-QoL scores were also significantly associated with functional tests (finger-tapping with Upper Extremity Function: β=.40, P<.001; walk and balance with Lower Extremity Function: β=-99.18, P=.02; DSST with Cognitive Function: β=1.60, P=.03). Finally, local temperature was significantly associated with participants' test performance (finger-tapping: β=-.14, P<.001; DSST: β=-.06, P=.009; finger-to-nose: β=-53.88, P<.001)., Conclusions: The elevateMS study app captured the real-world experience of MS, characterized some MS symptoms, and assessed the impact of environmental factors on symptom severity. Our study provides further evidence that supports smartphone app use to monitor MS with both active assessments and patient-reported measures of disease burden. App-based tracking may provide unique and timely real-world data for clinicians and patients, resulting in improved disease insights and management., (©Abhishek Pratap, Daniel Grant, Ashok Vegesna, Meghasyam Tummalacherla, Stanley Cohan, Chinmay Deshpande, Lara Mangravite, Larsson Omberg. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 27.10.2020.)

Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR-1 stimulation led to the development of pharmacological agents which are S1PR antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage of the central nervous system (CNS) in animal models, encouraging their examination of efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated direct protective effects of S1PR antagonists within the CNS, by modulation of S1PRs, particularly S1PR-1 and S1PR-5, and possibly S1PR-2, independent of effects upon lymphocytes. Three of these agents, fingolimod, siponimod and ozanimod have been approved, and ponesimod has been submitted for regulatory approval. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future opportunities in the development of more selective and intracellular S1PR-driven downstream pathway modulators may expand the breadth of agents to treat MS.

Are gender differences in face recognition influenced by familiarity and socio-cultural factors? Previous studies have reported gender differences in processing unfamiliar faces, consistently finding a female advantage and a female own-gender bias. However, researchers have recently highlighted that unfamiliar faces are processed less efficiently than familiar faces, which have more robust, invariant representations. To-date, no study has examined whether gender differences exist for familiar face recognition. The current study addressed this by using a famous faces task in a large, web-based sample of  > 2000 participants across different countries. We also sought to examine if differences varied by socio-cultural gender equality within countries. When examining raw accuracy as well when controlling for fame, the results demonstrated that there were no participant gender differences in overall famous face accuracy, in contrast to studies of unfamiliar faces. There was also a consistent own-gender bias in male but not female participants. In countries with low gender equality, including the USA, females showed significantly better recognition of famous female faces compared to male participants, whereas this difference was abolished in high gender equality countries. Together, this suggests that gender differences in recognizing unfamiliar faces can be attenuated when there is enough face learning and that sociocultural gender equality can drive gender differences in familiar face recognition.

The Football Players Health Study at Harvard University (FPHS) is a unique transdisciplinary, strategic initiative addressing the challenges of former players' health after having participated in American style football (ASF). The whole player focused FPHS is designed to deepen understanding of the benefits and risks of participation in ASF, identify risks that are potentially reversible or preventable, and develop interventions or approaches to improve the health and wellbeing of former players. We are recruiting and following a cohort of former professional ASF players who played since 1960 (current n = 3785). At baseline, participants complete a self-administered standardized questionnaire, including initial reporting of exposure history and physician-diagnosed health conditions. Additional arms of the initiative are addressing targeted studies, including promising primary, secondary, and tertiary interventions; extensive in-person clinical phenotyping, and legal and ethical concerns of the play. This paper describes the components of the FPHS studies undertaken and completed thus far, as well as those studies currently underway or planned for the near future. We present our initiatives herein as a potential paradigm of one way to proceed (acknowledging that it is not the only way). We share what we have learned so that it may be useful to others, particularly in regard to trying to make professional sports meet the needs of multiple stakeholders ranging from players to owners, to fans, and possibly even to parents making decisions for their children., (© 2019 The Authors American Journal of Industrial Medicine Published by Wiley Periodicals, Inc.)

Introduction: Delayed-release dimethyl fumarate (DMF) is an effective treatment for multiple sclerosis (MS). Some patients experience gastrointestinal (GI) adverse events (AEs) that may lead to premature DMF discontinuation. This study characterized the impact of site-specific GI management strategies on the occurrence of GI events and discontinuation patterns., Methods: Data on GI events and DMF persistence were retrospectively abstracted from medical records of patients treated with DMF in routine medical practice in the EFFECT study (NCT02776072). GI management strategies were assessed via a study site questionnaire. Discontinuation rates were analyzed according to counseling patterns., Results: Of 826 DMF-treated patients at 66 sites, 809 from 65 sites were eligible for the GI analysis; of these, 27% experienced GI AEs. Within 1 year of treatment, 14% (118/826) of patients discontinued DMF, 5% (44/809) due to GI events. Most sites (92%) reported that patients were very likely (> 75% of the time) to be counseled about GI events at/before DMF treatment initiation and/or to be recommended that DMF be taken with food (86%); 48% of sites reported to be very likely to recommend using symptomatic therapies for GI AEs. Lower discontinuation rates were reported at sites very likely versus not very likely (≤ 75% of the time) to (1) provide counseling; (2) provide specific details regarding GI events; or (3) recommend taking DMF with food, and/or using symptomatic GI therapies., Conclusion: Counseling and other GI management strategies at initiation of DMF treatment appear to reduce the burden of GI events, and a variety of GI management strategies may improve DMF persistence., Trial Registration: NCT02776072., Funding: Biogen (Cambridge, MA, USA).

Aim: Head-to-head clinical trials of teriflunomide (TFM) versus dimethyl fumarate (DMF) have not been conducted., Objectives: To compare the real-world effectiveness of TFM versus DMF., Methods: Anonymized data were collected from patients with relapsing multiple sclerosis (MS) initiating treatment with teriflunomide (N = 50) or DMF (N = 50)., Results: On follow-up magnetic resonance imaging (MRI) compared with baseline, with TFM versus DMF treatment, the proportion of patients with new/enlarging T2 or gadolinium-enhancing lesions was 30.0 versus 40.0% (p = 0.2752). However, median annualized percent whole brain volume change was -0.1 versus -0.5 (p = 0.0212). There were no significant treatment differences on additional MRI and clinical end points and no unexpected safety signals., Conclusion: The effectiveness of teriflunomide was superior to DMF on whole brain atrophy and similar to DMF on other MRI/clinical end points.

Face-recognition abilities differ largely in the neurologically typical population. We examined how the use of information varies with face-recognition ability from developmental prosopagnosics to super-recognizers. Specifically, we investigated the use of facial features at different spatial scales in 112 individuals, including 5 developmental prosopagnosics and 8 super-recognizers, during an online famous-face-identification task using the bubbles method. We discovered that viewing of the eyes and mouth to identify faces at relatively high spatial frequencies is strongly correlated with face-recognition ability, evaluated from two independent measures. We also showed that the abilities of developmental prosopagnosics and super-recognizers are explained by a model that predicts face-recognition ability from the use of information built solely from participants with intermediate face-recognition abilities ( n = 99). This supports the hypothesis that the use of information varies quantitatively from developmental prosopagnosics to super-recognizers as a function of face-recognition ability.

Background: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments., Objective: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE., Methods: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics., Results: Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55-0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67-0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60-0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures., Conclusion: Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS.

Introduction: This study was designed to assess real-world outcomes of patients with multiple sclerosis (MS) who were stable on interferon (IFN) beta therapy in the year prior to switching to another IFN beta therapy versus those who continued on the initial treatment., Methods: This study used administrative claims from MarketScan Commercial Claims and Encounters Database, from January 1, 2010, to March 31, 2015, to identify MS patients aged 18-64 years who remained relapse free for at least 1 year while continuously treated with an IFN beta therapy. Stable patients remaining on their initial IFN beta therapy (no-switch patients) were matched with stable patients who switched IFN beta therapy (switch patients) using propensity score matching (first claim = index date). Outcome measures included annualized relapse rate (ARR), the percentage of patients who relapsed, medication possession ratio, and the proportion of days covered and were measured during the year following the index date., Results: This study identified 531 patients in the no-switch group and 177 patients in the switch group, with subsets of 270 patients in the no-switch group and 90 patients in the switch group stable on intramuscular (IM) IFN beta-1a therapy. All outcomes during the follow-up year were significantly better in the no-switch group than in the switch group. For all patients, ARR in the switch group was more than twice that in the no-switch group (P = 0.002). For patients stable on IM IFN beta-1a at baseline, ARR was twice as high in the switch group as in the no-switch group (P = 0.012)., Conclusion: Among all patients stable on IFN beta therapy and the subset stable on IM IFN beta therapy in particular, those who remained on therapy had significantly better outcomes than those who switched to another IFN beta therapy., Funding: Biogen (Cambridge, MA, USA).

Background and Purpose: Evidence is needed to understand the effect of fingolimod on slowing down brain atrophy progression in multiple sclerosis (MS) patients in clinical practice. We investigated the effect of fingolimod on brain atrophy in MS patients with active disease (clinically and/or magnetic resonance imaging [MRI]) versus no evidence of active disease (NEAD)., Methods: MS and clinical outcome and MRI in the United States (MS-MRIUS) is a multicenter, retrospective study that included 590 relapsing-remitting MS patients, who initiated fingolimod, and were followed for a median of 16 months. Patients with active disease at baseline (245, 41.5%) were defined as those who had one or more relapses in the year previous starting fingolimod, and/or displayed gadolinium enhancing lesions(s) at baseline MRI scan, whereas patients with NEAD at baseline (345, 58.5%) did not fulfill these criteria. Annualized percentage brain volume change (PBVC) and percentage lateral ventricle volume change (PLVVC) over the follow-up were analyzed in both groups., Results: Over the follow-up, the rate of PBVC was -.38% in active disease and -.25% in NEAD patients (P = .076), whereas PLLVC was 1.76% in active disease and .28% in NEAD patients (P = .046). No changes in timed 25-foot walk (P = .619) and Expanded Disability Status Scale (P = .275) scores or MRI lesion accumulation (P > 0.08) were detected, although the active disease group had a higher proportion of relapses during the follow-up period (P = .02)., Conclusions: The study provides real-world evidence that rate of brain atrophy in MS patients with underlying active disease and NEAD in fingolimod treated patients is below the established pathological cutoff for loss of whole brain volume (>-.4%) or expansion of lateral ventricles (> 3.5%)., (Copyright © 2018 by the American Society of Neuroimaging.)

Background and Objective: The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a patient-reported outcome instrument that quantifies the progressive loss of walking ability from the patient perspective. However, previous psychometric analyses indicated floor and ceiling effects across the multiple sclerosis severity spectrum. This study aimed to address floor effects by creating a gait module that can be used in conjunction with the MSWS-12 for better measurement of treatment benefit in the higher functioning multiple sclerosis population., Methods: We used a step-wise mixed methods study design, with relapsing-remitting multiple sclerosis patients (wave 1, n =88; wave 2, n =30), combining qualitative (concept elicitation and cognitive debriefing interviews) and quantitative (Rasch Measurement Theory) data collection and analytical techniques and consultation interviews with three neurologists specializing in multiple sclerosis., Results: Thirty-seven walking ability concepts were identified, and a five-domain conceptual framework was created. Draft items were generated and refined with patient and neurologist input. Draft items covered gait-related concepts such as dragging, shuffling, limping, tripping and falling. Rasch measurement theory psychometric analysis indicated administering MSWS-12 plus gait items improved measurement precision in targeted populations with better walking ability., Conclusion: Study findings indicate that new gait items could improve sensitivity to detect clinical change in walking ability for higher functioning multiple sclerosis patients.