Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome.

OBJECTIVE: The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. METHODS: We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE). RESULTS: Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05-0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). INTERPRETATION: This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604-614.

Cognition and disease characteristics in adult onset versus late onset multiple sclerosis.

BACKGROUND: Cognitive impairment is common sequelae of multiple sclerosis (MS); however, relatively little is known about cognitive impairment in late-onset multiple sclerosis (LOMS). OBJECTIVE: To investigate differences in disease characteristics and cognition in LOMS and adult-onset multiple sclerosis (AOMS) patients. METHODS: Archival medical records and neuropsychological evaluations from an MS specialty center were reviewed. Differences in disease characteristics between 53 LOMS and 124 AOMS were compared using chi-square or analysis of variance (ANOVA). To investigate differences in cognitive functioning, age-adjusted standardized scores were compared via analysis of covariance (ANCOVA), using cardiac risk factors and disease duration as covariates. RESULTS: Compared to AOMS, LOMS patients had significantly more cardiac risk factors, shorter disease duration, and shorter time to diagnosis. LOMS patients had similar Expanded Disability Status Scale scores as AOMS patients. LOMS patients demonstrated significantly more impairment on tasks of visual learning and memory, and working memory than AOMS patients. CONCLUSION: Despite a shorter disease duration, LOMS and AOMS patients had similar levels of physical impairment. However, even after accounting for differences in disease duration and cardiac risk, LOMS patients showed a greater burden of cognitive impairment than AOMS patients, suggesting MS diagnosed later in life may progress faster due to the interaction between MS neuropathology and aging.

Multiple sclerosis management during the COVID-19 pandemic.

BACKGROUND: People with multiple sclerosis (MS) may be at higher risk for complications from the 2019 coronavirus (COVID-19) pandemic due to use of immunomodulatory disease modifying therapies (DMTs) and greater need for medical services. OBJECTIVES: To evaluate risk factors for COVID-19 susceptibility and describe the pandemic's impact on healthcare delivery. METHODS: Surveys sent to MS patients at Cleveland Clinic, Johns Hopkins, and Vall d'Hebron-Centre d'Esclerosi Múltiple de Catalunya in April and May 2020 collected information about comorbidities, DMTs, exposures, COVID-19 testing/outcomes, health behaviors, and disruptions to MS care. RESULTS: There were 3028/10,816 responders. Suspected or confirmed COVID-19 cases were more likely to have a known COVID-19 contact (odds ratio (OR): 4.38; 95% confidence interval (CI): 1.04, 18.54). In multivariable-adjusted models, people who were younger, had to work on site, had a lower education level, and resided in socioeconomically disadvantaged areas were less likely to follow social distancing guidelines. 4.4% reported changes to therapy plans, primarily delays in infusions, and 15.5% a disruption to rehabilitative services. CONCLUSION: Younger people with lower socioeconomic status required to work on site may be at higher exposure risk and are potential targets for educational intervention and work restrictions to limit exposure. Providers should be mindful of potential infusion delays and MS care disruption.

Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60.

BACKGROUND: The risk-benefit ratio of continuing immunomodulating disease-modifying therapy (DMT) in older multiple sclerosis (MS) patients is unknown. OBJECTIVE: To evaluate clinical and patient-reported outcomes after stopping DMT in older MS patients. METHODS: Retrospective, observational study identifying patients from our MS clinics who were aged over 60 and on DMT > 2 years. Cause-specific Cox proportional hazards regression modeled time to discontinuation and time to reinitiation of therapy. Pre- and post-discontinuation comparisons of Performance Scales (PS), Timed 25-Foot Walk, and Patient Health Questionnaire-9 (PHQ9) were analyzed using linear mixed models. RESULTS: A total of 600 patients were included, with 178 (29.7%) discontinuing. Discontinuers were 2.2 years older, had 3.2 years longer disease duration, and 1.6 years lesser treatment exposure. Providers initiated discontinuation more than patients (68.0%). Only one clinical relapse occurred in discontinuers. A proportion (10.7%) reinitiated DMT. Provider-initiated discontinuers restarted less often (hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.12-0.9). In discontinuers, relapsing-remitting patients had lower PS on average than primary progressive. Provider-initiated discontinuation was associated with lower PS than patient- initiated discontinuation. PHQ9 scores appeared higher in those stopping intravenous (IV) therapies than interferons. Lower PS and PHQ9 indicate better outcomes. CONCLUSION: Most patients over age 60, who discontinued DMT, remained off DMT. This study provides real-world data that may guide clinicians considering discontinuing DMT.

Comparing Cognitive Profiles in Older Adults With Multiple Sclerosis and Alzheimer Disease: More Similarities Than Differences.

Background and Objectives: Up to 65% of people with multiple sclerosis (MS) experience disease-related cognitive impairment, but even after decades of research, still very little is known about the cognitive issues among older adults with MS (EwMS; individuals aged 60+). To date, few studies have attempted to characterize cognitive impairment in this group or compare EwMS with those with other neurodegenerative diseases. Our goal was to address this knowledge gap by comparing EwMS with individuals experiencing cognitive impairment due to probable Alzheimer disease (AD) with biomarker confirmation. Methods: We conducted an observational study of individuals seen for routine clinical care at the Cleveland Clinic. After excluding for potential confounding factors, 6 groups were assembled based on the results of their clinical workup and neuropsychological examination: cognitively normal, cognitively normal with MS, mild neurocognitive disorder (due to MS or AD), and major neurocognitive disorder (due to MS or AD). These groups were compared in terms of cognitive test performance, percentage of the group impaired on specific cognitive skills, and rates of cognitive impairment. Results: The sample comprised 140 individuals (64 EwMS and 76 demographically matched individuals from a memory clinic). Among those with mild neurocognitive disorder, differences between MS and AD were marked. However, in those with major neurocognitive disorder, these differences largely disappeared, except persistent performance differences on a measure of rote verbal memory. EwMS outperformed those with AD on memory tests at each level of cognitive impairment. EwMS also exhibited both subcortical and cortical deficits, rather than solely subcortical deficits. Discussion: The overall characterization of the cognitive profile of MS may be different than once described, involving both classically cortical and subcortical functions. Clinically, our results suggest that distinguishing between the cognitive effects of MS and AD at more severe levels of cognitive impairment may be less reliable than once thought. Future work to replicate these findings in other samples and deepen the understanding of cognition in older individuals with MS is needed.

Ageing and multiple sclerosis.

The factor that is most relevant and strongly associated with the clinical course of multiple sclerosis is chronological age. Very young patients exclusively have relapsing remitting disease, whereas those with later onset disease face a more rapid development of permanent disability. For people with progressive multiple sclerosis, the poor response to current disease modifying therapies might be related to ageing in the immune system and CNS. Ageing is also associated with increased risks of side-effects caused by some multiple sclerosis therapies. Both somatic and reproductive ageing processes might contribute to development of progressive multiple sclerosis. Understanding the role of ageing in immune and neural cell function in patients with multiple sclerosis might be key to halting non-relapse-related progression. The growing literature on potential therapies that target senescent cells and ageing processes might provide effective strategies for remyelination and neuroprotection.

Expert opinion on COVID-19 vaccines and cladribine tablets in MS: A plain language summary.

WHAT IS THIS SUMMARY ABOUT?: People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsing-remitting or active secondary progressive disease) taking cladribine tablets. WHAT WERE THE RESULTS?: The committee identified 13 recommendations, which were all agreed upon by at least three-quarters (75%) of the 38 voting MS experts. Generally, they recommended that people with MS taking cladribine tablets should be vaccinated for COVID-19 as soon as possible, because the vaccine is thought to be both safe and effective, and vaccine responses were not likely to be affected by cladribine tablets. WHAT DO THE RESULTS MEAN?: Overall, people with MS taking cladribine tablets should receive the COVID-19 vaccine to protect themselves, unless advised differently by their healthcare provider.

Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

BACKGROUND: Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS. METHODS: This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation. RESULTS: Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND. CONCLUSIONS: In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Effectiveness and safety of switching to teriflunomide in older patients with relapsing multiple sclerosis: A real-world retrospective multicenter analysis.

BACKGROUND: The prevalence of multiple sclerosis (MS) in older people is increasing due to population aging and availability of effective disease-modifying therapies (DMTs). Treating older people with MS is complicated by age-related and MS-related comorbidities, immunologic effects of prior DMTs, and immunosenescence. Teriflunomide is a once-daily oral immunomodulator that has demonstrated efficacy and acceptable safety in clinical trials of adults with relapsing forms of MS (RMS). However, there are limited clinical trial and real-world data regarding teriflunomide use in people with MS aged >55 years. We analyzed real-world data to assess the effectiveness and safety of teriflunomide in older people with RMS who had switched to this agent from other DMTs. METHODS: People with RMS (relapsing remitting and active secondary progressive MS) aged ≥55 years who had switched from other DMTs to teriflunomide (7 mg or 14 mg) for ≥1 year were identified retrospectively by chart review at four sites in the United States. Data were extracted from medical records from 1 year pre-index to 2 years post-index (index defined as the teriflunomide start date). Assessments of effectiveness included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging (MRI) outcomes. Assessments of safety included lymphocyte counts, infections, and malignancies. We examined the effectiveness outcomes and lymphocyte counts within sub-groups defined by age (55-64, ≥65 years), sex, MS type, and prior route of DMT administration (oral, injectable, infusible). RESULTS: In total, 182 patients with RMS aged ≥55 years who switched from other DMTs to teriflunomide were identified (mean [SD] age: 62.5 [5.4] years). Mean ARR decreased from the start of teriflunomide treatment (mean [SD]: 0.43 [0.61]) to year 1 post-index (0.13 [0.65]) and year 2 post-index (0.05 [0.28]). Mean EDSS score remained unchanged from index (mean [SD]: 4.5 [1.8]) to 1 year post-treatment (4.5 [1.8]) and increased slightly at 2 years post-treatment (4.7 [1.7]). MRI scans from index and years 1 and 2 post-index compared with scans from the previous year indicated that most patients had stable or improved MRI outcomes at index (87.7%) and remained stable or improved at years 1 (96.0%) and 2 (93.6%). Lymphopenia decreased at years 1 (21.4%) and 2 post-index (14.8%, compared to index (23.5%). By 1 year post-index, fewer patients had grade 3 or 4 lymphopenia, and at 2 years post-index, there were no patients with grade 3 or 4 lymphopenia. Infection incidence was low (n = 40, 22.0%) and none were related to teriflunomide. The decreases in lymphopenia were driven by decreases among people who switched from a prior oral DMT; there were no notable differences in lymphopenia across the other sub-groups examined. ARR, EDSS score, and MRI outcomes across all sub-groups were similar to the results of the overall population. CONCLUSION: Our multicenter, longitudinal, retrospective study demonstrated that patients with RMS aged 55 or older switching to teriflunomide from other DMTs had significantly improved ARR, stable disability, and stable or improved MRI over up to 2 years' follow up. Safety results were acceptable with fewer patients exhibiting lymphopenia at years 1 and 2 post-index.

The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis.

Siponimod is a selective sphingosine 1-phosphate receptor subtype 1 (S1P1) and 5 (S1P5) modulator approved in the United States and the European Union as an oral treatment for adults with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS). Preclinical and clinical studies provide support for a dual mechanism of action of siponimod, targeting peripherally mediated inflammation and exerting direct central effects. As an S1P1 receptor modulator, siponimod reduces lymphocyte egress from lymph nodes, thus inhibiting their migration from the periphery to the central nervous system. As a result of its peripheral immunomodulatory effects, siponimod reduces both magnetic resonance imaging (MRI) lesion (gadolinium-enhancing and new/enlarging T2 hyperintense) and relapse activity compared with placebo. Independent of these effects, siponimod can penetrate the blood-brain barrier and, by binding to S1P1 and S1P5 receptors on a variety of brain cells, including astrocytes, oligodendrocytes, neurons, and microglia, exert effects to modulate neural inflammation and neurodegeneration. Clinical data in patients with SPMS have shown that, compared with placebo, siponimod treatment is associated with reductions in levels of neurofilament light chain (a marker of neuroaxonal damage) and thalamic and cortical gray matter atrophy, with smaller reductions in MRI magnetization transfer ratio and reduced confirmed disability progression. This review examines the preclinical and clinical data supporting the dual mechanism of action of siponimod in RMS.

The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome.

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.

Curriculum Innovations: Virtual Didactics as a Tool for Harmonizing Education About Rare Topics in Neuroimmunology.

Introduction and Problem Statement: Neuroimmunology is a rapidly evolving subspecialty. At this time, fellowship training is not standardized. Discrepancies exist in fellowship programs across the United States, including in faculty expertise in rarer neuroimmunologic conditions. Many graduating fellows feel uncomfortable managing the full spectrum of diseases within neuroimmunology. Objectives: To evaluate the feasibility and efficacy of a series of live, virtual, interinstitutional seminars educating neuroimmunology fellows on topics that may be infrequently encountered by trainees. Methods and Curriculum Description: A steering committee of 6 neuroimmunology and multiple sclerosis fellowship program directors selected 18 topics felt to be high yield but representing unique areas of expertise. A live, interactive seminar series was organized. Recognized experts on each topic led seminars using a teleconferencing platform over the 2020-2021 academic year. Recordings were subsequently made available for asynchronous learning. Trainees were surveyed before and after the seminar series and comfort levels with each topic were recorded. Results and Assessment Data: An average of 41 trainees participated in each live seminar and an additional average of 17 trainees viewed each seminar on demand. Trainee comfort levels with each topic increased after the seminar series was completed. An average of 72% of trainees self-identified as at least "comfortable" with each topic after the series compared with 26% beforehand (p < 0.0001). Discussion and Lessons Learned: A year-long series of live, interactive, interinstitutional seminars focusing on unique topics within a single subspecialty represents an effective way to increase trainee comfort levels with such topics.

Clinical characteristics of a large multi-center cohort of people with multiple sclerosis over age 60.

BACKGROUND: As the peak prevalence of multiple sclerosis (MS) shifts due to an aging patient population, understanding the characteristics that define this older cohort to improve overall management is critical. We sought to determine the clinical characteristics of people with MS over age 60. METHODS: Demographics, clinical characteristics, MS disease history, and Multiple Sclerosis Performance Test (MSPT) patient-reported outcomes and neuroperformance tests (NPTs) were collected from 10 academic MS centers in the US and Europe participating in the MS Partners Advancing Technology Health Solutions (MS PATHS) system. We characterized demographic and disease characteristics of included participants using descriptive statistics. We characterized prevalence of comorbidities and compared with estimated prevalences from the National Health and Nutrition Examination Survey (NHANES) respondents aged ≥60 years in 2017-2018. RESULTS: We identified 2738 individuals over age 60 from MS PATHS, with 58.1% relapsing-remitting (RR) and 41.9% progressive. Our results showed median age (RR=65.7 years, progressive=66.0 years), age of symptom onset (RR and progressive=40.9 years), and disease duration (RR=22.8 years, progressive=23.3 years). Over two-thirds of individuals in our cohort were treated with DMTs. The most common DMT used in RR patients were interferons (17.6%) and glatiramer acetate (16.3%), while glatiramer acetate was the most common (12.0%) in progressive patients. Progressive patients had higher disability (higher median PDDS scores, worse Neuro-Qol T-scores, and worse NPTs) compared to the RR group. Pain was the most common comorbidity, followed by cardiac disease, depression, hypertension, dyslipidemia, and obesity. Compared to older NHANES participants, older people with MS were more likely to have depression (MS PATHS: 51.5% [95% CI: 49.5% to 53.5%] vs. NHANES: 21.7% [95% CI: 1619.3% to 22.2%]) and osteoporosis (MS PATHS: 12.7% [95% CI: 11.3% to 14.1%] vs. NHANES: 8.2% [95% CI: 6.2% to 10.3%]); they were less likely to be obese (MS PATHS: 29.4% [95% CI: 27.7% to 31.2%] vs. NHANES: 45.1% [95% CI: 38.9% to 51.3%]) and have diabetes (MS PATHS: 12.3% [95% CI: 11.1% to 13.6%] vs. NHANES: 22.5% [95% CI: 18.8% to 25.7%]). CONCLUSIONS: Our study characterizes a large multi-center international cohort of people with MS over age 60. This contemporary cohort appears less disabled than prior studies, which may reflect long term impact of DMT availability on the natural history of MS. The burden of comorbidity in this population was generally high. Information on DMT use, comorbidity, and disability outcome measures will be beneficial in future studies evaluating the impact of therapeutic interventions in older individuals.

Expert opinion on COVID-19 vaccination and the use of cladribine tablets in clinical practice.

BACKGROUND: Gaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination. OBJECTIVE: We describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice. METHODS: A steering committee (SC) of 10 international MS experts identified 7 clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7-9, on a 9-point scale. RESULTS: Consensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e. before and after a treatment course); and the safety of COVID-19 vaccination for these patients. CONCLUSION: These expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice.

Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

Re-Evaluating the Use of IFN-ß and Relapsing Multiple Sclerosis: Safety, Efficacy and Place in Therapy.

The advent of interferon therapy for the treatment of multiple sclerosis (MS) was a massive advancement in the field and changed the course of the disease. While the exact mechanism of interferon therapy in MS is unknown, disease control is likely mediated by reducing Th1 and Th17 cells while increasing regulatory T cells and altering the cytokine profile. Interferon therapy not only gave physicians and patients an evidence-based treatment option to treat MS by decreasing relapses and the accrual of disability but it also provided valuable insight into disease pathophysiology that allowed for the development of further treatments. Currently, there are 18 disease-modifying therapies available for the treatment of MS with varying efficacies, routes of administration, and mechanisms. As treatment options in the field have evolved, interferon therapy is less commonly prescribed as first-line therapy, because the newer therapies are more effective and better tolerated. That being said, interferons still have a place in the field in both clinical practice and clinical trial research. In this review, we will summarize the safety and efficacy of interferon therapy and discuss its current place in MS care.

Effect of switching from natalizumab to moderate- vs high-efficacy DMT in clinical practice.

OBJECTIVE: To assess the real-world comparative effectiveness of switching from natalizumab (NTZ) to a moderate-efficacy (Mod) disease-modifying therapy (DMT) vs high-efficacy therapy (HET) in patients with multiple sclerosis (MS). METHODS: Patients discontinuing NTZ at two MS centers (n = 556) who switched to Mod DMT (n = 270) vs HET (n = 130) were assessed using propensity score (PS) weighting. PS model covariates included demographics and baseline clinical and MRI characteristics. All outcomes were reported as Mod DMT vs HET. RESULTS: Of the patients included in the study, 48.6% switched to Mod DMT (dimethyl fumarate, n = 130; fingolimod, n = 140) vs 23.4% who switched to HET (ocrelizumab, n = 106; rituximab, n = 17; alemtuzumab, n = 7). Within the first 6 months post-NTZ, switchers to Mod DMT experienced comparable relapses (odds ratio [OR] = 1.36, 95% confidence interval [CI] [0.72-1.66], p = 0.724), although they had increased MRI activity on treatment (OR = 2.59, 95% CI [1.09-3.57], p = 0.037). By 24 months post-NTZ, there was no difference in the annualized relapse rate (OR = 1.44, 95% CI [0.69-1.59], p = 0.334) or time to first clinical relapse (HR = 2.12, 95% CI [0.87-5.17], p = 0.090), although switchers to Mod DMT had higher gadolinium-enhancing (GdE) lesions (OR = 3.62, 95% CI [1.56-5.21], p = 0.005), earlier time to first GdE lesion (HR = 6.67, 95% CI [2.06-9.16], p = 0.002), lower proportion with the absence of disease activity (OR = 0.41, 95% CI [0.21-0.71], p = 0.004), and higher risk of disability progression on T25FW (OR = 1.83, 95% CI [1.06-3.02], p = 0.043) and 9-HPT (OR = 1.81, 95% CI [1.05-3.56], p = 0.044). CONCLUSION: Patients switching from NTZ to Mod DMT vs HET were at relatively increased risk of disease activity within the first 6 months of NTZ withdrawal that was sustained at 24 months, yielding greater disability progression.

Disease activity outcomes with different washout periods after switching from natalizumab to an alternative disease-modifying therapy.

BACKGROUND: Washout periods (WPs) are increasingly shortened due to concerns of disease rebound when patients on natalizumab are switched to alternative disease-modifying therapies (DMTs). OBJECTIVE: To characterize disease activity outcomes with different WPs when switching from natalizumab. METHODS: We conducted a retrospective review of patients switching from natalizumab in our MS clinics. Disease activity (relapse, new T2 lesions and/or gadolinium enhancing lesions) between different WPs (days): 0-30, 31-60, and 61-180 were compared, during the first year after switching from natalizumab. To determine predictors of disease activity when switching to any DMT, multivariate logistic regression analysis was used. Post hoc analyses were performed to evaluate the impact of individual DMTs on disease activity. RESULTS: 335 patients discontinued natalizumab with WP: 0-30 (n = 104), 31-60 (n = 113), and 61-180 (n = 136). Disease activity occurred in 44.2% of patients in the 0-30 WP group, 18.6% in the 31-60 WP group, and 27.2% in the 61-180 WP group. There was a significant decrease in odds of disease activity with longer WP when compared to the 0-30 group: 31-60 (OR 0.241, 95% CI 0.108-0.514, p value < 0.001), and 61-180 (OR 0.439, 95% CI 0.218-0.871, p value < 0.05). CONCLUSIONS: Unexpectedly, in our study, patients who had the shortest WP 0-30 days had the most disease activity. Shortening WPs may not be enough to suppress disease activity post-natalizumab switch.

Outcomes and future directions for neuroimmunology/multiple sclerosis fellowship training: Survey of recent trainees.

BACKGROUND: Neuroimmunology/multiple sclerosis is a rapidly evolving, but still poorly defined subspecialty. Fellowship training is not standardized, and there is substantial variability across sites. Outcomes of fellowship training have not yet been studied. We therefore examined early career choices of neuroimmunology/MS fellowship program graduates and solicited the perspective of current and recent trainees on their fellowship experience as well as opportunities to improve neuroimmunology education. METHODS: We developed a questionnaire to collect information about fellowship training experiences and current medical practice. We identified recent graduates based on records from US training programs and the National MS Society and electronically sent the survey to current trainees and recent graduates (within the last 5 years). RESULTS: We identified 179 current/recent trainees and successfully reached 157 with survey distributions. Ninety-five individuals (60.5%) returned surveys. Most graduates assumed an academic practice (68%) focused mostly or exclusively on MS and other CNS neuroimmune diseases (55%), and practiced in regions where there were ≥5 other neuroimmunology specialists (51%). Graduates felt well-prepared to manage diagnoses of MS and neuromyelitis optica spectrum disorders but their comfort with rarer CNS neuroimmune diseases varied substantially. Basic immunology, neuro-rheumatology, grant writing and neuro-rehabilitation were identified as high impact areas for cross-disciplinary didactic training. The majority of recent trainees (57%) favored standardizing a core neuroimmunology curriculum, and 48% favored developing a subspecialty certification. CONCLUSIONS: This is the first study to examine practice outcomes and trainee experiences for neuroimmunology training programs. We anticipate that these data will help educators define a core curriculum for the subspecialty and identify complementary skill sets that enhance the traditional clinic-based model of teaching.

Duration of natalizumab therapy and reasons for discontinuation in a multiple sclerosis population.

OBJECTIVE: To determine multiple sclerosis patient characteristics that predict a shorter duration of natalizumab treatment. METHODS: The Tysabri Outreach: Unified Commitment to Health database was reviewed to identify patients treated with natalizumab at our centers. Cox proportional hazards models were used to evaluate patient characteristics associated with shorter treatment durations on natalizumab. Associations were also assessed with respect to specific reasons for stopping natalizumab. RESULTS: We identified 554 patients who began and stopped natalizumab treatment during the observation period. The average disease duration at natalizumab initiation was 7.6 years, and the average number of infusions was 30. The multivariable Cox proportional hazards model identified greater age (P = 0.035), longer disease duration (P < 0.001), progressive relapsing multiple sclerosis phenotype (P = 0.003), current smoking (P = 0.031), and greater depression (P = 0.026) as significant predictors for natalizumab discontinuation. Greater disability levels (P = 0.022) and gadolinium-enhancing lesions on baseline magnetic resonance imaging (P < 0.001) were significantly associated with longer natalizumab treatment. Individuals with progressive relapsing multiple sclerosis had a 14-fold increased hazard of discontinuing natalizumab due to inflammatory events (P < 0.001) than those with relapsing-remitting multiple sclerosis. Smokers had an 80% increased hazard of discontinuation due to intolerance (P = 0.008). CONCLUSIONS: Our results suggest that smoking, depression, and a progressive relapsing multiple sclerosis phenotype are associated with shorter natalizumab treatment durations.