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The treatment of patients with relapsing multiple sclerosis (MS) has advanced tremendously over the past few decades. More efficacious therapies have been approved, which can significantly reduce the inflammatory process of relapsing MS. Neuroprotection by controlling this pathophysiology is important given our current limitations to control progressive MS and induce neurorepair. Here, the authors discuss the current landscape of neurotherapeutics for relapsing MS focusing on newer disease-modifying treatments and their use. Risk mitigation of these medications can greatly improve their safety and improve their benefit-risk balance. The authors discuss treatment strategies for risk mitigation including treatment discontinuation and de-escalation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine the feasibility of low-load resistance training with blood flow restriction (BFR) for people with advanced disability due to multiple sclerosis (MS)., Methods: In this prospective cohort study, 14 participants with MS (Expanded Disability Status Scale [EDSS] score = 6.0 to 7.0; mean age = 55.4 [SD = 6.2] years; 71% women) were asked to perform 3 lower extremity resistance exercises (leg press, calf press, and hip abduction) bilaterally twice weekly for 8 weeks using BFR. Feasibility criteria were as follows: enrollment of 20 participants, ≥80% retention and adherence, ≥90% satisfaction, and no serious adverse events related to the intervention. Other outcomes included knee extensor, ankle plantar flexor, and hip abductor muscle strength, 30-Second Sit-to-Stand Test, Berg Balance Scale, Timed 25-Foot Walk Test, 12-Item MS Walking Scale, Modified Fatigue Impact Scale, Patient-Specific Functional Scale, and daily step count., Results: Sixteen participants consented, and 14 completed the intervention, with 93% adherence overall. All participants were satisfied with the intervention. A minor hip muscle strain was the only intervention-related adverse event. There were muscle strength improvements on the more-involved (16%-28%) and less-involved (12%-19%) sides. There were also changes in the 30-Second Sit-to-Stand Test (1.9 repetitions; 95% CI = 1.0 to 2.8), Berg Balance Scale (5.3 points; 95% CI = 3.2 to 7.4), Timed 25-Foot Walk Test (-3.3 seconds; 95% CI = -7.9 to 1.3), Modified Fatigue Impact Scale (-8.8 points; 95% CI = -16.5 to -1.1), 12-Item MS Walking Scale (-3.6 points; 95% CI = -11.5 to 4.4), Patient-Specific Functional Scale (2.9 points; 95% CI = 1.9 to 3.8), and daily step count (333 steps; 95% CI = -191 to 857)., Conclusion: Low-load resistance training using BFR in people with MS and EDSS scores of 6.0 to 7.0 appears feasible, and subsequent investigation into its efficacy is warranted., Impact: Although efficacy data are needed, combining BFR with low-load resistance training may be a viable alternative for people who have MS and who do not tolerate conventional moderate- to high-intensity training because of more severe symptoms, such as fatigue and weakness., Lay Summary: Low-load strength training with BFR was feasible in people who have advanced disability due to MS. Using BFR may provide an alternative for people with MS who do not tolerate higher intensity training due to more severe symptoms, such as fatigue and weakness., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Disease modifying therapies (DMTs) offer opportunities to improve the course of multiple sclerosis (MS), but decisions about treatment are difficult. People with multiple sclerosis (pwMS) want more involvement in decisions about DMTs, but new approaches are needed to support shared decision-making (SDM) because of the number of treatment options and the range of outcomes affected by treatment. We designed a patient-centered tool, MS-SUPPORT, to facilitate SDM for pwMS. We sought to evaluate the feasibility and impact of MS-SUPPORT on decisions about disease modifying treatments (DMTs), SDM processes, and quality-of-life., Methods: This multisite randomized controlled trial compared the SDM intervention (MS-SUPPORT) to control (usual care) over a 12-month period. English-speaking adults with relapsing MS were eligible if they had an upcoming MS appointment and an email address. To evaluate clinician perspectives, participants' MS clinicians were invited to participate. Patients were referred between November 11, 2019 and October 23, 2020 by their MS clinician or a patient advocacy organization (the Multiple Sclerosis Association of America). MS-SUPPORT is an online, interactive, evidence-based decision aid that was co-created with pwMS. It clarifies patient treatment goals and values and provides tailored information about MS, DMTs, and adherence. Viewed by patients before their clinic appointment, MS-SUPPORT generates a personalized summary of the patient's treatment goals and preferences, adherence, DMT use, and clinical situation to share with their MS clinician. Outcomes (DMT utilization, adherence, quality-of-life, and SDM) were assessed at enrollment, post-MS-SUPPORT, post-appointment, and quarterly for 1 year., Results: Participants included 501 adults with MS from across the USA (84.6% female, 83% white) and 34 of their MS clinicians (47% neurologists, 41% Nurse Practitioners, 12% Physician Assistants). Among the 203 patients who completed MS-SUPPORT, most (88.2%) reported they would recommend it to others and that it helped them talk to their doctor (85.2%), understand their options (82.3%) and the importance of taking DMTs as prescribed (82.3%). Among non-users of DMTs at baseline, the probability ratio of current DMT use consistently trended higher over one-year follow-up in the MS-SUPPORT group (1.30 [0.86-1.96]), as did the cumulative probability of starting a DMT within 6-months, with shorter time-to-start (46 vs 90 days, p=0.24). Among the 222 responses from 34 participating clinicians, more clinicians in the MS-SUPPORT group (vs control) trended towards recommending their patient start a DMT (9 of 108 (8%) vs 5 of 109 (5%), respectively, p=0.26). Adherence (no missed doses) to daily-dosed DMTs was higher in the MS-SUPPORT group (81.25% vs 56.41%, p=.026). Fewer patients forgot their doses (p=.046). The MS-SUPPORT group (vs control) reported 1.7 fewer days/month of poor mental health (p=0.02)., Conclusions: MS-SUPPORT was strongly endorsed by patients and is feasible to use in clinical settings. MS-SUPPORT increased the short-term probability of taking and adhering to a DMT, and improved long-term mental health. Study limitations include selection bias, response bias, social desirability bias, and recall bias. Exploring approaches to reinforcement and monitoring its implementation in real-world settings should provide further insights into the value and utility of this new SDM tool., Competing Interests: Declaration of Competing Interest Funding for this research was provided by EMD Serono Inc., USA, an affiliate of Merck KGaA, Darmstadt, Germany, through MS-LINK, a scientific consortium with a mission to improve patient outcomes by advancing MS science to generate actionable real-world data and patient-centered solutions. Further research supported by MS-LINK is designed to close existing scientific gaps identified by the MS community to advance discovery, care, and outcomes for patients with MS. NC: reports research grants and payment for participation in Advisory Board from EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, during the conduct of the study; grants from Pfizer, grants from Biogen, grants from Edwards Lifesciences, LLC, and grants from MSAA (Multiple Sclerosis Association of America). EA: reports consultation or advisory fees for Alexion, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Horizon, Motric Bio, Novartis, Sanofi, and TG Therapeutics; and funding or grants from: Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Institute, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center, LP: has nothing to disclose. CI: (Carolina) has received research support from Riccio Neuroscience Fund and compensation from Sanofi Genzyme and Bristol Myers Squibb for advisory board participation. IBM: has nothing to disclose. AJS: reports funding by NIH/NINDS K02NS109340; compensation for consulting or advisory boards from EMD Serono, Genentech, Biogen, Alexion, Celgene, Octave Bioscience, and Greenwich Biosciences, compensation for nonpromotional speaking from EMD Serono, and research support from Biogen; and participated in contracted research with Biogen, Novartis, Actelion, and Genentech. CK: Consultant for EMD Serono, Biogen, Genzyme, BMS, Amgen, Teva, and Alexion. TL: is an employee of EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, JC: reports personal fees from EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, Biogen, Allergan, and Biohaven, CIw (Crystal): has nothing to disclose. HC: has nothing to disclose. LN: has nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies., Competing Interests: Declaration of Competing Interest Enrique Alvarez has received compensation for activities such as advisory boards, lectures, and consultancy from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono/Merck, Genentech/Roche, Novartis, Sanofi, and TG Therapeutics; and has received research support from Biogen, Genentech/Roche, National Institutes of Health, National Multiple Sclerosis Society, Novartis, Patient-Centered Outcomes Research Initiative, Rocky Mountain MS Center, and TG Therapeutics. Erin E. Longbrake has received honoraria for consulting from Bristol Myers Squibb, Genentech, NGM Biopharmaceuticals, and TG Therapeutics; and has received research support from Genentech, National Institutes of Health (K23107624, KL2 TR001862), and Patterson Leet Trust. Kottil Rammohan has received speaking, consulting, and advisory fees from Alexion, Biogen, EMD Serono, Genentech, Genzyme, Horizon Therapeutics, Novartis, and TG Therapeutics; and has served as Principal Investigator or Co-investigator for grants to his institutions from Alexion, Biogen, EMD Serono, Genentech, Novartis, Sanofi Genzyme, and TG Therapeutics. James Stankiewicz is an employee and stockholder of Novartis Pharmaceuticals Corporation. Carrie M. Hersh has received speaking, consulting, and advisory board fees from Biogen, Bristol Myers Squibb, DynaMed, EMD Serono, Genentech, Genzyme, Novartis, TG Therapeutics, and Alexion; and has received research support paid directly to her institution by Biogen, Genentech, National Institutes of Health-National Institute of Neurological Disorders and Stroke (1U01NS111678–01A1 sub-award), Novartis, and Patient-Centered Outcomes Research Institute., (Copyright © 2023. Published by Elsevier B.V.)

We recently reported that multiple sclerosis (MS) plasma contains IgG aggregates and induces complement-dependent neuronal cytotoxicity (Zhou et al., 2023). Using ELISA, we report herein that plasma IgG levels in the aggregates can be used as biomarkers for MS. We enriched the IgG aggregates from samples of two cohorts (190 MS and 160 controls) by collecting flow-through after plasma binding to Protein A followed by detection of IgG subclass. We show that there are significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS IgG aggregates, with an AUC >90%; higher levels of IgG1 distinguish secondary progressive MS from relapsing-remitting MS (AUC = 91%). Significantly, we provided the biological rationale for MS plasma IgG biomarkers by demonstrating the strong correlation between IgG antibodies and IgG aggregate-induced neuronal cytotoxicity. These non-invasive, simple IgG-based blood ELISA assays can be adapted into clinical practice for diagnosing MS and SPMS and monitoring treatment responses., Competing Interests: Declaration of Competing Interest We declare that there are no conflicts of interest for all authors., (Copyright © 2023. Published by Elsevier Inc.)

Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS., (© 2023. The Author(s).)

Objective: This study aimed to evaluate safety (infusion-related reactions [IRRs]) and patient satisfaction (patient-reported outcomes [PROs]) for at-home ocrelizumab administration for patients with multiple sclerosis (MS)., Methods: This open-label study included adult patients with an MS diagnosis who had completed a ≥ 600-mg ocrelizumab dose, had a patient-determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600-mg ocrelizumab home-based infusion over 2 h, followed by 24-h and 2-week post-infusion follow-up calls. IRRs and adverse events (AEs) were documented during infusions and follow-up calls. PROs were completed before and 2 weeks post infusion., Results: Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)-similar to other shorter ocrelizumab infusion studies-and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at-home infusion process and confidence in the care provided. Patients also reported a significant preference for at-home infusion compared with prior infusion center experiences., Interpretation: IRRs and AEs occurred at acceptable rates during in-home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home-based ocrelizumab infusion over a shorter infusion period., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Movement slowness is a common and disruptive symptom of multiple sclerosis (MS). A potential cause is that individuals with MS slow down to conserve energy as a behavioral adjustment to heightened metabolic costs of movement. To investigate this prospect, we measured the metabolic costs of both walking and seated arm reaching at five speeds in persons with mild MS (pwMS; n = 13; 46.0 ± 7.7 yr) and sex- and age-matched controls (HCs; n = 13; 45.8 ± 7.8 yr). Notably, the cohort of pwMS was highly mobile and no individuals required a cane or aid when walking. We found that the net metabolic power of walking was approximately 20% higher for pwMS across all speeds ( P = 0.0185). In contrast, we found no differences in the gross power of reaching between pwMS and HCs ( P = 0.492). Collectively, our results suggest that abnormal slowness of movement in MS-particularly reaching-is not the consequence of heightened effort costs and that other sensorimotor mechanisms are playing a considerable role in slowing. NEW & NOTEWORTHY Individuals with multiple sclerosis (MS) often move more slowly than those without the disease. A possible cause is that movements in MS are more energetically expensive and slowing is an adaptation to conserve metabolic resources. Here, we find that while walking is more costly for persons with MS, arm-reaching movements are not. These results bring into question the driving force of movement slowness in MS and implicate other motor-related networks contributing to slowing.

Aim: Evaluate the real-world costs over two years and costs by site of care for ocrelizumab (OCR), natalizumab (NTZ), and alemtuzumab (ATZ) in patients with multiple sclerosis (MS)., Methods: This retrospective study used HealthCore Integrated Research Database and included continuously enrolled adults with MS initiating OCR, NTZ, and ATZ between April 2017 and July 2019 (i.e. patient identification period). Annual total cost of care (pharmacy and medical costs) was evaluated for the first- and second-year of follow-up, further stratified by site of care. Costs were measured using health plan allowed amount and adjusted to 2019 US dollars. Sensitivity analyses were conducted in patients who completed yearly dosing schedule according to Food and Drug Administration approved prescribing information., Results: Overall, 1,058, 166, and 46 patients were included in OCR, NTZ, and ATZ cohorts, respectively. Mean (standard deviation [SD]) total cost of care during first- and second-year follow-up were $125,597 ($72,274) and $109,618 ($75,085) for OCR, $117,033 ($57,102) and $106,626 ($54,872) for NTZ, and $179,809 ($97,530) and $108,636 ($77,973) for ATZ. Infusible drug cost was the main driver in all three cohorts accounting for >78% of the total costs. Annual total cost of care increased substantially after patients started/switched to infusible DMTs. Across site of care, hospital outpatient infusion was common (OCR 58%, NTZ 37%, ATZ 49%) and expensive followed by physician office infusion (OCR 28%, NTZ 40%, ATZ 16%); home infusion was the least common (<10%) and least expensive., Limitations: The results were limited to commercially insured patients (specifically those with Anthem-affiliated health plans)., Conclusions: Real-world costs increased after patients started/switched to infusible DMTs. Drug cost is the main driver for the total costs, which varied substantially by site of care. Controlling drug cost markups and using home setting for infusion can reduce costs in the treatment of MS patients.

Background: Patients with radiologically isolated syndrome (RIS) exhibit CNS lesions suggestive of multiple sclerosis (MS) in the absence of overt neurological symptoms characteristic of the disease. They may have concurrent brain atrophy, subtle cognitive impairment, and intrathecal inflammation. At least half ultimately develop MS, cementing RIS as preclinical MS for many. However, high-quality data, including immunologic biomarkers, to guide treatment decisions in this population are lacking. Early intervention with ocrelizumab, a humanized monoclonal antibody approved for relapsing and primary progressive MS that targets CD20 + B-cells, may affect disease course and improve long-term outcomes. The objective of this study is to describe the protocol for CELLO, a clinical trial assessing the effect of ocrelizumab on RIS., Methods: The CELLO clinical trial, a phase 4, multicenter, randomized, double-blind, placebo-controlled study conducted as an academic-industry collaboration, aims to (1) assess the efficacy of ocrelizumab in patients with RIS and (2) identify biomarkers indicative of emerging autoimmunity as well as immune recovery after transient B-cell depletion. The study will enroll 100 participants across ≥15 sites. Participants will be aged 18 to 40 years, have RIS (defined as meeting 2017 revised McDonald criteria for dissemination in space), and have either been diagnosed with RIS within the last 5 years or have had new brain lesions identified within 5 years of study entry. A screening program of first-degree relatives of patients with MS will be used to boost recruitment. Eligible patients will be randomized 1:1 to receive 3 courses of ocrelizumab or placebo at baseline, week 24, and week 48. Patients will subsequently be followed up for ≥3 years. The primary outcome is time to development of new radiological or clinical evidence of MS. Secondary and exploratory objectives will investigate neuroimaging, serological and immunologic biomarkers, cognitive function, and patient-reported outcomes. A substudy using single-cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS., Conclusion: The CELLO study will improve the understanding of B-cell biology in early MS disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to inform treatment decision-making for individuals with RIS., Clinicaltrials: GOV: NCT04877457., Competing Interests: Declaration of competing interest EEL has received honoraria for consulting for EMD Serono, Biogen, Alexion, Genzyme, Genentech, Janssen, NGM, and TG Therapeutics. She has received honoraria for speaking at Efficient CME, MJH Life Sciences, PRIME education, and DKBmed. She has received travel support for the ACTRIMS Forum meeting. She has participated on the data and safety monitoring board (DSMB) for a fenebrutinib study (Genentech). She serves on a steering committee for Genentech and on the board of directors for ACTRIMS and serves as an assistant editor for Annals of Neurology. She has received research support from National Institutes of Health (NIH) K23107624, Race to Erase MS, Robert Leet and Clara Guthrie Patterson Trust, and UL1 TR001863. LHH has received research funding paid to her institution from Biogen. She has received honoraria for consulting for Novartis, Genzyme, Genentech, EMD Serono, TG Therapeutics, Horizon, Greenwich, Alexion, and Bristol Myers Squibb. She has received honoraria for speaking for Bristol Myers Squibb, Genzyme, and Genentech. She has participated on the advisory boards for Novartis, Genentech, and EMD Serono. EMM has received research support paid to her institution from Biogen, Genentech, and Teva. She has received royalties for editorial duties from UpToDate. She is a DSMB member of the National Institute of Allergy and Infectious Diseases DSMB and TRIM trial. SAG has received research support paid to her institution from Genentech and NIH National Institute of Neurological Disorders and Stroke. EA has received research funding paid to his institution from Genentech, Biogen, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National MS Society, the National Institutes of Health, and the Rocky Mountain MS Center. He has received honoraria for consulting paid to his institution for Actelion, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono, Genentech, Novartis, Sanofi, and TG Therapeutics. AHC has received research support from the Conrad N. Hilton Foundation and Race to Erase MS. She has received honoraria for consulting for Biogen, EMD Serono, Janssen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, Genentech, TG Therapeutics, and Horizon Pharmaceuticals. She has received honoraria for speaking at Neurology Grand Rounds (UCLA, Swedish Medical Center, Washington University School of Medicine, University of New Mexico, University of Miami Miller School of Medicine, Massachusetts General Hospital, and Brigham and Women's Hospital), the Consortium of Multiple Sclerosis Centers Annual meeting, and for the Hillel Panitch Memorial Lecture and the John Jay Dystel Prize lecture. She has also received travel costs for nonvirtual presentations as well as support to attend ACTRIMS Forum 2022, the Consortium of Multiple Sclerosis Centers Annual Meeting 2021, and ECTRIMS 2019. She has a patent issued for 15,060–630 (015,875). She serves on the scientific advisory board for evobrutinib (EMD Serono) and for the OBOE study (Genentech). She serves as the Secretary of the Consortium of Multiple Sclerosis Centers and is the Chair of the Program Committee for ACTRIMS 2020–2022. DAH has received honoraria for consulting for Repertoire Immune Medicines, Biogen, F. Hoffmann-La Roche Ltd, Viela Bio, Compass Therapeutics, Sonoma, Proclara Biosciences, GlaxoSmithKline, EcoR1, EMD Serono, NexImmune, and Biohaven Pharmaceuticals. He has received research support paid to his institution from Genentech. J Pei, J Priest, CR and RWC are employees of Genentech, Inc., and shareholders of F. Hoffmann-La Roche Ltd., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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

Declines in motor function are closely associated with decreases in sensory function in multiple sclerosis (MS). The purpose of our study was to assess the changes in motor function and disability status elicited by transcutaneous electrical nerve stimulation (TENS) to limb muscles of individuals with MS. Fifteen persons with MS and 11 age-matched healthy controls were evaluated before and after receiving 9 treatment sessions during which TENS was applied over the tibialis anterior and rectus femoris muscles of each leg, and over the median nerve and the thenar eminence of each hand. Each evaluation session involved completing two questionnaires (fatigue and walking limitations) and assessing walking performance (2-min test and 25-ft test), dynamic balance (chair-rise test), manual dexterity (grooved pegboard test), and muscle function of hands and legs (strength and force steadiness tests). The MS group exhibited improvements in the 25-ft test (P = 0.001), 2-min test (P = 0.002), chair-rise test (P = 0.008), grooved pegboard test (P = 0.008), and reductions in the self-reported levels of fatigue and walking limitation scores (P = 0.02, d = 0.52; P = 0.008, r = 0.50 respectively). In contrast, there were no statistically significant changes in the Control group. There were no significant changes in either muscle strength or force steadiness for either group. TENS elicited significant improvements in motor function and self-reported disability status in persons with MS. Some improvements reached clinically meaningful levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Fatigue is one of the most common debilitating symptoms reported by persons with multiple sclerosis (MS). It reflects feelings of tiredness, lack of energy, low motivation, and difficulty in concentrating. It can be measured at a specific instant in time as a perception that arises from interoceptive networks involved in the regulation of homeostasis. Such ratings indicate the state level of fatigue and likely reflect an inability to correct deviations from a balanced homeostatic state. In contrast, the trait level of fatigue is quantified in terms of work capacity (fatigability), which can be either estimated (perceived fatigability) or measured (objective fatigability). Clinically, fatigue is most often quantified with questionnaires that require respondents to estimate their past capacity to perform several cognitive, physical, and psychosocial tasks. These retrospective estimates provide a measure of perceived fatigability. In contrast, the change in an outcome variable during the actual performance of a task provides an objective measure of fatigability. Perceived and objective fatigability do not assess the same underlying construct. Persons with MS who report elevated trait levels of fatigue exhibit deficits in interoceptive networks (insula and dorsal anterior cingulate cortex), including increased functional connectivity during challenging tasks. The state and trait levels of fatigue reported by an individual can be modulated by reward and pain pathways. Understanding the distinction between fatigue and fatigability is critical for the development of effective strategies to reduce the burden of the symptom for individuals with MS.

Background: A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression., Objective: The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting., Methods: In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs' overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made., Results: In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice., Conclusions: MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice., (©Tjalf Ziemssen, Gavin Giovannoni, Enrique Alvarez, Virender Bhan, Carrie Hersh, Olaf Hoffmann, Celia Oreja-Guevara, Rene R Robles-Cedeño, Maria Trojano, Patrick Vermersch, Pamela Dobay, Mudeer Khwaja, Bianca Stadler, Benedict Rauser, Thomas Hach, Daniela Piani-Meier, Jason Burton. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.10.2021.)

Background: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs)., Methods: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms., Results: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups., Conclusion: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy., (Copyright © 2021. Published by Elsevier B.V.)

Background: The biomechanical mechanisms underlying stair climbing limitations are poorly understood in people with multiple sclerosis (MS)., Research Questions: Are trunk and pelvis motion and lower extremity joint moments during step ascent different between MS and control groups? Are step ascent biomechanics and stair climbing performance associated in people with MS?, Methods: 20 people with MS (49 ± 12 years, EDSS range: 1.5-5.5) and ten control participants (48 ± 12 years) underwent three-dimensional motion analysis while ascending a 15.2-cm step and also completed a timed Functional Stair Test. Main effects of group (MS vs Control) and limb (Stronger/Dominant vs Weaker/Non-dominant) and interactions were assessed using two-way analyses of variance. Associations between movement patterns during the step ascent and Functional Stair Test performance were performed using Pearson's correlations and backward stepwise linear regression., Results: Significant group main effects were observed in greater sagittal pelvis excursion (p < 0.001), greater sagittal (p = 0.013) and frontal (p = 0.001) trunk excursion, and lower trail limb peak ankle plantar flexion moment (p < 0.001) of the MS group. Significant limb main effects were observed with greater sagittal trunk excursion (p = 0.037) and peak trail limb ankle plantar flexion moment (p = 0.037) in the stronger/dominant limb. A significant interaction was observed in peak knee extensor moment (p = .002). Stair climbing performance in the MS group correlated with sagittal (r = .607, p=<0.001) and frontal pelvis excursions (r = 0.385, p = 0.014), sagittal trunk excursion (r = .411, p = 0.008), and ankle plantar flexion moments (r=-0.415, p = 0.008). Sagittal and frontal pelvis excursion and bilateral handrail use explained a significant amount of variability in stair climbing performance (Adj R 2  = 0.775)., Significance: In conclusion, despite the presence of proximal and distal lower extremity movement pattern compensations during a step ascent task, larger pelvis angular excursions are associated with impaired stair climbing performance in people with MS and may serve as targets for future rehabilitation interventions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Ocrelizumab is an approved MS treatment administered as two 300-mg intravenous infusions 2 weeks apart (Dose 1), each lasting approximately 2.5 hours, followed by single 600-mg infusions every 6 months lasting approximately 3.5 hours. Our objective was to evaluate shorter-duration ocrelizumab infusions in the Phase IIIb open-label SaROD study (NCT03606460)., Methods: Eligible patients received ocrelizumab 600-mg Dose 2 or 3 infused over approximately 2 hours (Cohort 1) or ocrelizumab 300-mg Dose 1, Infusion 2 over approximately 1.5 hours (Cohort 2). The primary endpoint was the number and proportion of patients experiencing Grade 3-4 infusion-related reactions (IRRs) in Cohort 1. Secondary endpoints included Grade 1-4 IRRs in both cohorts and Grade 3-4 IRRs in Cohort 2., Results: Mean infusion times decreased by approximately 1.09 and 0.79 hours in Cohorts 1 and 2, respectively, compared with US prescribing information. IRRs, reported by 36% of 141 patients, were mild-to-moderate, with no observed Grade 3-4 IRRs. No IRR-related discontinuations occurred. No serious AEs, deaths, or new safety signals were observed., Conclusion: The IRR rate with ocrelizumab shorter-duration infusions was similar to that observed in the pivotal Phase III trials. Ocrelizumab can be infused over a shorter time without sacrificing patient safety., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited., Methods: Rituximab-treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow-up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician-reported and laboratory data were retrospectively collected from electronic medical records., Results: One-thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow-up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person-years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair-bound patients had 8.56-fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY., Interpretation: Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B-cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Multiple sclerosis (MS) symptoms reported in the first year of the disease include sensory impairment, fatigue, reduced mobility, and declines in hand function. The progressive reduction in motor function experienced by persons living with MS is invariably preceded by changes in sensory processing, which are strongly associated with the declines in both walking performance and manual dexterity., Aims: To assess the influence of concurrent sensory stimulation using augmented transcutaneous electrical nerve stimulation (aTENS) applied to leg and hand muscles on clinical tests of motor function in individuals whose mobility was compromised by MS., Methods: Thirteen persons with MS (52 ± 8 years; 6 women) and 12 age- and sex-matched healthy adults (52 ± 9 years) met the inclusion criteria. Participants visited the lab on two occasions with one week between visits. Each visit involved the participant performing four tests of motor function and completing two health-related questionnaires (PDDS and MSWS-12). The tests assessed walking performance (6-min test and 25-ft test), dynamic balance (chair-rise tes, and manual dexterity (grooved pegboard test). aTENS was applied through pads attached to the limbs over the tibialis anterior and rectus femoris muscles of the affected leg, and over the median nerve and the thenar eminence of the dominant hand. The pads were attached during both visits, but the current was only applied during the second visit. The stimulation comprised continuous asymmetrical biphasic pulses (0.2 ms) at a rate of 50 Hz and an intensity that elicited slight muscle contractions., Results: At baseline and during both treatment sessions, the performance on all four tests of motor function was worse for the MS group than the Control group. The MS group experienced significant improvements in all outcomes during the aTENS session with medium-to-large effect sizes. PDDS ratings improved (from 2.8 ± 1.3 to 2.0 ± 1.5; effect size d = -0.70) and the MSWS-12 scores declined (from 36 ± 11 to 28 ± 12; effect size d = -1.52). The concurrent application of aTENS enabled the MS group to walk further during the 6-min test (from 397 ± 174 m to 415 ± 172 m; effect size d = 0.81), to complete the 25-ft test in less time (6.7 ± 3.0 s to 6.3 ± 2.9 s; effect size d = -0.76), to increase the counts in the chair-rise test (from 11.2 ± 3.8 to 13.6 ± 4.8; effect size d = 1.52), and to perform the grooved pegboard test more quickly (from 110 ± 43 s to 99 ± 37 s; effect size d = -0.98). The only significant effect for the Control group was a significant increase in the 6-min walk distance (from 725 ± 79 to 740 ± 82 m; effect size d = 0.87)., Conclusions: Stimulation of sensory fibers with aTENS evoked clinically significant improvements in four tests of motor function and the self-reported level of walking limitations in persons who were moderately disabled by MS. Moreover, the improvements in function elicited by the concurrent application of aTENS were immediate., Competing Interests: Deceleration of Competing Interest None, (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rituximab is a chimeric anti-CD20 monoclonal antibody that is an effective therapy for multiple sclerosis. Rituximab has been associated with the development of serum sickness (type III hypersensitivity) characterized by arthralgia, fever, and rash during the treatment of other conditions, such as rheumatoid arthritis. Here we describe serum sickness associated with rituximab in multiple sclerosis patients and discuss both the management of serum sickness itself and implications for utilizing alternative anti-CD20 monoclonal antibodies for disease management in this patient population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Studies suggest cannabis may improve symptoms like pain and muscle spasticity in patients with multiple sclerosis (PwMS). Despite cannabis' new-found legality and availability, few studies have explored the profile of PwMS cannabis users and characteristics of their use, particularly in a state where cannabis is legal both for recreational and medicinal use. The purpose of the current study was to evaluate cannabis use among PwMS at a large academic multiple sclerosis (MS) clinic, specifically: (1) prevalence, (2) products used (e.g., cannabidiol vs Δ 9 -tetrahydocannabinol), (3) symptom treatment, and (4) patient characteristics., Methods: PwMS completed questions assessing personal opinions about cannabis use, characteristics of cannabis use, MS history, and sociodemographic details, as well as the self-reported disability-Patient Determined Disease Steps (PDDS), overall quality of life-the Patient Reported Outcome Measure Information System (PROMIS-10), and cognition-the Neuro-QoL ACGC v1.0 measures., Results: Thirty-eight percent (n = 96) of PwMS were current Cannabis users (CUs). Although there were no sociodemographic or clinical differences (p ≤ 0.05) between CUs and Non-Cannabis users (NUs), CUs had significantly higher median disability compared to NUs (PDDS = 2 vs. 1; p = 0.02). Among CUs, 57% categorized their use as strictly medicinal. CUs reported using cannabis most often for pain and insomnia/poor sleep and experienced greater than 60% benefit/relief from cannabis use. Over 90% of respondents desire more research on cannabis for MS, and 74% indicated they would consider using cannabis for their MS., Conclusion: As cannabis legalization has impacted the variety of cannabis products available, there appears to be growing numbers of PwMS using cannabis, with this study's CUs reporting use of highly efficacious products with minimal side-effects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The effectiveness of fingolimod on clinical and magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis (MS) has been well established in trials and, to a lesser extent, in the real world., Objective: To evaluate clinical and MRI outcomes in patients with relapsing MS receiving fingolimod in US clinical practice., Methods: Clinical and MRI data from 590 patients initiating fingolimod treatment at 33 MS centers in the USA were retrospectively analyzed. Clinical data were obtained from medical records. MRI data were systematically quantified at a centralized imaging facility. Patients had an index (within 6 months before and 1 month after starting fingolimod) and post-index (9-24 months after starting fingolimod) MRI scan; 184 individuals had a pre-index scan (9-24 months before starting fingolimod)., Results: In the index to post-index period, mean annualized relapse rates decreased from 0.36 to 0.13 and disability progression occurred in 18.5% of patients. Median T2, T1 and gadolinium-enhancing lesion volume changed by 1.15%, 2.36%, and -100% between the index and post-index scans, respectively, and median annualized percentage changes in brain volume and lateral ventricular volume were -0.32% and +0.66%, respectively. For patients with pre-index scans, MRI outcomes were unchanged or improved during treatment. Outcomes were generally comparable with those in fingolimod phase 3 trials., Conclusion: This real-world study highlights the effectiveness of fingolimod and the feasibility of quantifying clinical and MRI data collected from multiple centers during routine clinical practice on a group level using a systematic, quantitative methodology., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To compare 2-year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS)., Methods: Patients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician-reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator., Results: A total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85], P  < 0.001) and 2.38 [95% CI: 1.68-3.37], P  < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%)., Interpretation: NTZ appears to be more effective and tolerable than FTY and DMF., Competing Interests: Brandi L. Vollmer reports no disclosures. Dr. Kavita V. Nair receives grants from Novartis, Genentech, Biogen and consulting fees from Biogen, Sanofi‐Genzyme and Astellas. Dr. Stefan Sillau reports no disclosures. Dr. John R. Corboy recieves research support from PCORI, NMSS, Biogen, Novartis and Med Day, has received honorarium for speaking from the Rocky Mountain MS Center and PRIME CME, and has received compensation as editor of Neurology Clinical Practice. Dr. Timothy Vollmer has received compensation for activities such as advisory boards, lectures and consultancy with the following companies and organizations: Academic CME; Alcimed; Anthem Blue Cross; Genentech/Roche; Biogen IDEC; Novartis; CellGene; Seono; Epigene; Rocky Mountain MS Center; GLG Consulting; Ohio Health; TG Therapeutics; Topaz Therapeutics; Dleara Lawyers; and Teva Neuroscience; Biogen Australia & New Zealand. He received research support from the following: Teva Neuroscience; NIH/NINDS; Rocky Mountain MS Center; Biogen; Actelion; Roche/Genentech; UT Southwestern; F. Hoffman‐La Roche, Ltd and TG Therapeutics, Inc. Dr. Enrique Alvarez grants/studies from Genzyme, Biogen, Rocky Mountain MS Center, Novartis, Acorda and consulting for Genzyme, Genentech, Novartis, Acorda and Biogen.

Background: Due to the recurrence of disease activity in multiple sclerosis (MS) patients, a washout period of <3 months has been suggested for the transition from natalizumab (NTZ) to fingolimod (FTY). However, very short transition periods of <1 month may be more beneficial., Methods: Retrospective analysis of patients from the Rocky Mountain MS Center at the University of Colorado who were: a) on NTZ for ≥6 months prior to switching to FTY; b) had a transition period ≤ 6 months; and c) initiated FTY treatment prior to November 2013. Transition periods were grouped as follows: <1 month, 1-2 months, and 3-6 months. Outcomes assessed include clinical and MRI measures within one year of FTY initiation., Results: Thirty-seven, 56 and 24 patients had a transition period < 1 month, 1-2 months and 3-6 months, respectively. Baseline characteristics were well matched: mean age 45-49 years (p = 0.17), disease duration 11-13 years (p = 0.42), and ~70% women (p = 1.00). Following the switch (including transition period), clinical relapses were observed in 0% (<1 month), 12.5% (1-2 months), 37.5% (3-6 month) (p < 0.001) of patients. New gadolinium enhancing lesions occurred in 3.3% (<1 month), 13% (1-2 months), 21.4% (3-6 months) (p = 0.13) patients. New T2 lesions were observed in 11.1% (<1 month), 16.3% (1-2 months), 33.3% (3-6 months) (p = 0.28) of patients. There were no unexpected adverse events or PML observed., Conclusions: Minimizing transition times from NTZ to FTY was beneficial and safe., (Copyright © 2018. Published by Elsevier B.V.)

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: Patients facing a high-stakes clinical decision are often confronted with an overwhelming array of options. High-quality decisions about treatment should reflect patients' preferences as well as their clinical characteristics. Preference-assessment instruments typically focus on pre-selected clinical outcomes and attributes chosen by the investigator., Objective: We sought to develop a patient-centered approach to elicit and compare the treatment goals of patients with multiple sclerosis (MS) and healthcare providers (HCPs)., Methods: We conducted five nominal group technique (NGT) meetings to elicit and prioritize treatment goals from patients and HCPs. Five to nine participants in each group responded silently to one question about their treatment goals. Responses were shared, consolidated, and ranked to develop a prioritized list for each group. The ranked lists were combined. Goals were rated and sorted into categories. Multidimensional scaling and hierarchical cluster analysis were used to derive a visual representation, or cognitive map, of the data and to identify conceptual clusters, reflecting how frequently items were sorted into the same category., Results: Five NGT groups yielded 34 unique patient-generated treatment goals and 31 unique HCP-generated goals. There were differences between patients and HCPs in the goals generated and how they were clustered. Patients' goals tended to focus on the impact of specific symptoms on their day-to-day lives, whereas providers' goals focused on slowing down the course of disease progression., Conclusions: Differences between the treatment goals of patients and HCPs underscore the limitations of using HCP- or investigator-identified goals. This new adaptation of cognitive mapping is a patient-centered approach that can be used to generate and organize the outcomes and attributes for values clarification exercises while minimizing investigator bias and maximizing relevance to patients.

CD40 interacts with CD40L and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared with healthy donors. In this study, we used a multiparameter phosflow approach to analyze the phosphorylation status of NF-κB and three major MAPKs (P38, ERK, and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naive B cells from RRMS and secondary progressive MS patients exhibited a significantly elevated level of phosphorylated NF-κB (p-P65) following CD40 stimulation compared with healthy donor controls. Combination therapy with IFN-β-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyperphosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. Additionally, glatiramer acetate treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease., (Copyright © 2016 by The American Association of Immunologists, Inc.)

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

This review explores the principle features of the immunopathology of multiple sclerosis (MS), particularly relapsing-remitting MS. It highlights the emerging concepts in the pathogenesis of MS in the context of known features of pathology, including the characterization of cytokine networks promoting inflammatory damage of the central nervous system, B-cell involvement, and inflammatory damage of axons and neurons. This article preferentially focuses on MS rather than animal models of the disease, such as experimental autoimmune encephalomyelitis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

BackgroundRecombinant human immunoglobulin M22 (rHIgM22) has promoted remyelination in animal models and was well tolerated in people with clinically stable multiple sclerosis.ObjectiveSafety/tolerability of a single rHIgM22 dose was investigated following an acute relapse and to determine whether this enhanced CNS/CSF concentrations.MethodsAdults (N = 27) with acute relapse were assigned to rHIgM22 (0.5 or 2.0 mg/kg) or placebo. Study included screening/steroid administration periods and 10 study visits over 6 months. rHIgM22 CSF concentrations were assessed on days 2 and 29. Pharmacokinetic and safety samples were taken for up to 60 days. Assessments included adverse events and other clinical measures. Brain magnetic resonance imaging was performed with/without gadolinium.ResultsrHIgM22 CSF levels were consistent with dose-dependent concentration on both days 2 and 29. Infusion was generally well tolerated during an acute relapse. Immunogenicity was mild. Most adverse events did not appear to be dose dependent, were mild/moderate, and were events often associated with multiple sclerosis.ConclusionAlthough limited by high variability and small sample size, the data suggest enhanced CNS uptake associated with a drop in CSF levels. This study demonstrated safety of an antibody directed to myelin and oligodendrocytes in the course of active demyelinating disease. Further research into rHIgM22 is warranted.ClinicalTrials.gov: NCT02398461 https://clinicaltrials.gov/ct2/show/study/NCT02398461?term=M22&draw=2&rank=8.

ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/methodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Ublituximab is a novel anti-CD20 therapy developed for the treatment of patients with multiple sclerosis. It is a glycoengineered chimeric antibody with a novel epitope on CD20, with high antibody-dependent cell-mediated cytotoxicity. Maintenance doses are administered every 6 months over an hour, providing a convenient dosing regimen. The identical phase III randomized, double-blind, active comparator to teriflunomide trials ULTIMATE I and II were completed in early 2022. ULTIMATE I and II, respectively, demonstrated that ublituximab had a strong clinical effect, with annualized relapse rates of 0.08 and 0.09 or reductions of 59% and 49% over teriflunomide. In addition, in ULTIMATE I and II, radiographic efficacy similarly reduced contrast-enhancing lesions by 97% and 96% and new/enlarging T2 lesions by 92% and 90%, respectively. Although ublituximab did not decrease confirmed disability progression in a pooled analysis of both studies, there was an increase in the confirmed disability improvement. Ublituximab was well tolerated, including infusion reactions that were predominantly mild and only seen with the first infusion. Further long-term safety data, as well as relative efficacy compared with current anti-CD20 therapies, will need to be evaluated in the real-world setting if ublituximab is to be approved as expected in December 2022. [ABSTRACT FROM AUTHOR]

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

Background: Strategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation. Objective: To provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients. Methods: We reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation. Results: Younger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity. Conclusion: In a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients. [ABSTRACT FROM AUTHOR]

Background: Ocrelizumab and rituximab are frequently used treatments for multiple sclerosis (MS). Data on switching from rituximab to ocrelizumab is limited. Objectives: To assess the frequency, severity, and factors of infusion related reactions (IRRs) in patients with MS who switch from rituximab to ocrelizumab, compared to those who stay on rituximab. Methods: Prospective study on MS patients aged 18–65, on rituximab for at least 2 cycles, who either switched to ocrelizumab (switch group) or stayed on rituximab (comparator group) (n = 100 each). Participants were followed for IRRs, safety, and tolerability over 12 months. Results: The proportion of IRRs in patients who continue on rituximab (14%) were similar to those who switched to ocrelizumab on Day 1 (14%; p = 1.000) and Week 24 (12%; p = 0.647) but higher than at Day 15 (4%; 0.005). The risk of IRRs for the switch group was associated with the presence of B cells (CD19 and/or CD20 counts ≥1%) increasing by 5.01 (1.49, 16.82) times on Day 1 (p = 0.007). Antidrug antibodies to ocrelizumab were not associated with IRRs. No other safety concerns were identified in switching to ocrelizumab. Conclusion: IRRs are similar between both groups, which suggests that it is safe to switch from rituximab to ocrelizumab. [ABSTRACT FROM AUTHOR]

Background: Clinically stable multiple sclerosis (MS) patients on long-term therapy often have negligible acute inflammation on MRI. Brain atrophy may provide insight into subclinical disease progression in such populations. Objective: This study aims to compare brain atrophy for age- and gender-matched MS patients treated for >2 years with fingolimod (FTY) or glatiramer acetate (GA), examining brain volume, cognition, and patient-reported outcomes (PROs). Methods: Stable relapsing-MS patients, age 18–60, on FTY or GA for >2 years were followed up for 2 years. MRI brain and lesion volumes, cognitive measures, and PROs were collected at baseline and annually. Results: Forty-four FTY and forty-three GA patients completed baseline and year 2 visits. No differences in age, gender, or education were observed. Median EDSS was 2.0GA and 2.5FTY (p = 0.22). Treatment duration was longer for GA, 6.50GA vs. 3.73FTY years (p < 0.001). Baseline geometric mean T2LV were different, GA = 1,009.29 cm3 vs. FTY = 2,404.67 cm3 (p = 0.0071). Baseline brain volumes were similar, GA = 1,508 cm3 vs. FTY = 1,489 cm3 (p = 0.2381). Annualized atrophy rates, adjusted for baseline and at mean baseline value, were GA = −0.2775% vs. FTY = −0.2967% (p = 0.7979). No differences in cognitive measures or PROs were observed. Conclusions: Stable MS patients on long-term treatment with FTY and GA have similar brain volume loss rates. Differences in baseline disease severity may suggest patients with more aggressive disease treated with FTY may achieve similar brain volume loss rates as patients with milder baseline disease on GA. [ABSTRACT FROM AUTHOR]

Introduction: Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist. Methods: Clinician‐reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast‐enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator. Results: A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81–5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67–4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83–2.23), P = 0.216] versus RTX. When examining months 6–24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20–4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88–2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24–3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15–4.97), P < 0.001] had greater odds of discontinuation than RTX. Interpretation: RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6–24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long‐term treatment in a real‐world MS cohort. [ABSTRACT FROM AUTHOR]

Background: Patient-reported outcome (PRO) measures have been shown to be effective for tracking treatment outcomes in multiple sclerosis (MS). However, collecting PROs as part of the clinical standard of care can be time-consuming and examination of their validity for use in an MS sample has been limited. Objective: To determine the discriminant validity of the Quality of Life in Neurological Disorders (Neuro-QoL™) short forms in a real-world MS clinic population. Design/methods: Neuro-QoL is a series of questionnaires for tracking physical function, emotional/cognitive health, and social abilities in clinical populations. Neuro-QoL data from 902 MS patients were analyzed for psychometric properties and factor structure. Results: Neuro-QoL demonstrated acceptable reliability in the moderate-to-good ranges. Moderate support for convergent validity was observed with other measures of MS quality of life, disease severity, and symptoms. However, results from a confirmatory factor analysis suggested poor model fit for most of the 12 domains tested. Conclusions: These findings support the utility of some of the Neuro-QoL questionnaires in evaluating MS-related PROs. However, additional research may help abridge and strengthen these measures for use in this population. [ABSTRACT FROM AUTHOR]

Objective: To compare 2‐year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). Methods: Patients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician‐reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium‐enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator. Results: A total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11–12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium‐enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41–2.85], P < 0.001) and 2.38 [95% CI: 1.68–3.37], P < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%). Interpretation: NTZ appears to be more effective and tolerable than FTY and DMF. [ABSTRACT FROM AUTHOR]

Emerging evidence underlines the importance of micro(mi)RNAs in the pathogenesis of multiple sclerosis (MS). Free-circulating miRNAs were investigated in serum from MS patients compared to controls. Statistically significant decreased levels of miR-15b, miR-23a and miR-223 were observed in MS patients (p < 0.05). Results were validated and replicated in two further independent MS populations. A direct correlation between miRNA levels and the EDSS score was determined in PPMS (p < 0.007). The generalized trend toward miRNA down-regulation could result in over-expression of target genes involved in disease pathogenesis. Circulating miRNA profiling could thus represent a new avenue to identify easily detectable disease biomarkers. [ABSTRACT FROM PUBLISHER]

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica. [ABSTRACT FROM PUBLISHER]

Background: MSProDiscuss is a validated physician-completed tool based on a set of weighted questions that include information on multiple sclerosis (MS) relapses, symptoms, and impacts experienced by the patient within the past 6 months. The tool's traffic light system-linked output is meant as an aid for discussing the signs of MS disease progression. The tool is available online at www.msprodiscuss.com. Objectives: To report physician findings on usability and usefulness testing of the MSProDiscuss tool while discussing disease progression with patients in the real-world setting. Methods: An online qualitative survey was undertaken in 34 countries. Health care practitioners (HCPs) completed individual questionnaires (i) after using MSProDiscuss during face-to-face patient consultations and a final questionnaire (f) to capture the overall experience on the tool. The HCPs also provided general feedback and recommendations for improving the tool. Results: In total, 301 HCPs (including 23 MS nurses and 6 neurology nurse practitioners) tested the tool in 6974 patients with MS. The time taken to complete MSProDiscuss during a regular consultation was 1-4 minutes in 97% (i) to 98% (f) of the time. In 94% (i) to 97% (f ) of cases, HCPs agreed that patients were able to comprehend the questions from the tool. HCPs were willing to use the tool again in the same patient 91% (i) of the time. MSProDiscuss was useful in discussing MS symptoms and its impact on daily activities (88% i / 92% f) and cognitive function (79% both i and f) and in discussing progression in general (88% i / 90% f). While completing the final questionnaire, 95% of HCPs agreed that the questions were similar to those asked in regular consultation. MSProDiscuss was also found helpful for understanding the impact of MS symptoms on daily activities (91%) and cognitive function (80%). Overall, 92% of the HCPs would recommend MSProDiscuss to a colleague. Regarding integration of MSProDiscuss into their clinical practice, 92% of HCPs think that it is feasible and 86% are willing to integrate. Key recommendations were to allow for longitudinal follow-up, expand on cognitive assessments, and provide a patient-completed version; these are considered in the updated version of MSPro- Discuss. Conclusions: The findings from this real-world study suggest that MSProDiscuss is a usable and useful tool to facilitate physician-patient discussion on disease progression in daily clinical practice by capturing structured disease history. [ABSTRACT FROM AUTHOR]