Robert T. Naismith

Background: Modifiable factors that contribute to racial disparities in healthcare have been highlighted in multiple clinical settings; however, the role of these factors in individuals with multiple sclerosis has not been well examined. Objectives: In this study, we quantify disparities in multiple sclerosis care among non-Hispanic Black and non-Hispanic White patients. Methods: Longitudinal data across four encounters obtained via retrospective chart review were analyzed for non-Hispanic Black and non-Hispanic White patients across two multiple sclerosis centers. Variables included demographics, multiple sclerosis characteristics, and clinical care factors. Results: In total, 150 non-Hispanic Black and 150 non-Hispanic White patients were included (mean age = 49.3 vs 53.6). Non-Hispanic Black patients had longer time gaps between encounters with their multiple sclerosis clinician versus non-Hispanic White (mean months = 10.3 vs 8.8; adjusted mean difference = 1.53 months (95% confidence interval = 0.59, 2.47; p = 0.001)). Non-Hispanic Black patients less frequently received comprehensive/longer encounters, evaluations for a recent relapse, or had magnetic resonance imaging findings discussed during encounters relative to non-Hispanic White, although these findings were not statistically significant. Conclusions: Gaps in multiple sclerosis care metrics, including lower levels of care and greater time between encounters, were observed for non-Hispanic Black compared to non-Hispanic White patients with multiple sclerosis, all of which may contribute to disparities in multiple sclerosis. Further research is needed to assess contributing clinician, patient, and systemic factors.

Central nervous system injury causes motor deficits through derangement of excitatory, inhibitory, and/or neuromodulatory inputs to motoneurons, the three fundamental components of motor commands. Typically, study of pathologic neural control in humans is restricted to only one of the three. Chardon et al. (2024) presented a fundamentally new approach to comprehensively study all components by reverse engineering motor unit firing patterns. We apply their framework to motor unit firing patterns from 89 people with multiple sclerosis (MS) and 34 controls to study excitatory, inhibitory, and neuromodulatory contributions to pathologic motor output. Disruptions to all components are plausible in MS, a disease hallmarked by heterogeneity in nearly all aspects. Accordingly, we found abnormalities in MS for all three components. Notably, neuromodulation included both high and low extremes. Our results suggest that pathophysiology of motor commands in MS varies among patients, a finding fundamentally different from other studied populations showing relative consistency.

Growing evidence suggests that first-line (1L) treatment with high-efficacy disease-modifying therapies (HE-DMTs) may have greater clinical benefit in multiple sclerosis (MS) than delaying HE-DMTs to second- or subsequent-line (2L+) therapy. However, MS treatment is often initiated using an escalation approach, involving initial treatment with low- to moderate-efficacy DMTs followed by escalation to HE-DMTs in the presence of new disease activity or disability worsening. Ocrelizumab is a HE-DMT approved for the treatment of relapsing and primary progressive MS, but real-world outcomes of ocrelizumab as a 1L vs 2L+ therapy are not well characterized. Real-world data from people with MS (pwMS) receiving treatment at four centers in the USA were analyzed. The effectiveness of ocrelizumab when administered as 1L or 2L+ treatment was compared for up to 60 months in follow-up. The primary outcome was time to confirmed disability worsening (based on Patient-Determined Disease Steps [PDDS]). Secondary outcomes were time to requiring a walking aid (PDDS ≥ 4), annualized patient-reported relapse rate, and magnetic resonance imaging measures (e.g., brain volume and number and volume of new T2 lesions). A total of 403 pwMS (1L n = 309, 2L+ n = 94) were identified. Overall, pwMS who received 1L ocrelizumab experienced less confirmed disease worsening (25.8% vs 42.6%; P = 0.03) and requirement for a walking aid (6.5% vs 27.4%; P < 0.01) compared with the 2L+ cohort. The 1L group also had a significantly lower change in T2 lesion volume (mean difference - 0.797 mL; P < 0.05) and a lower risk of developing new T2 lesions than the 2L+ group (incidence rate ratio 0.88 [95% CI 0.78-0.99]; P = 0.04). Relapse rate and brain volume outcomes were not significantly different between groups. This study contributes to the growing pool of evidence that 1L treatment with HE-DMTs such as ocrelizumab can improve clinical outcomes for pwMS compared with delaying HE-DMT to 2L+ .

Background: Opicinumab, a human monoclonal antibody against LINGO-1, is hypothesized to promote remyelination by enhancing the differentiation of oligodendrocyte progenitor cells. Objective: The objective of the study is to investigate the efficacy and safety of opicinumab as an add-on therapy to anti-inflammatory disease-modifying therapies (DMTs) in participants with relapsing multiple sclerosis (RMS). Methods: Participants with RMS aged 18–58 years, with disease duration up to 20 years, were randomized 1:1 to receive intravenous infusions of placebo or opicinumab every 4 weeks for 72 weeks. Primary endpoint was Overall Disability Response Score (ODRS) over 72 weeks. Results: The study enrolled 263 participants. Adjusted mean difference (95% confidence interval (CI)) on ODRS was 0.15 (−0.05 to 0.35; p = 0.148) over 72 weeks, favoring opicinumab versus placebo. Numerically larger differences in favor of opicinumab were observed in participants aged ⩾ 40 years with Expanded Disability Status Scale ⩾ 3.0, with disease duration ⩾ 6 years, and receiving dimethyl fumarate as the background DMT. 85% participants in placebo group and 86% in opicinumab group had adverse events. Conclusion: Although the AFFINITY study did not show significant difference in mean ODRS between opicinumab and placebo groups, data from AFFINITY interpreted with the previous SYNERGY study may inform the design of future remyelination trials. Clinicaltrials.gov identifier: (NCT03222973).

Multiple sclerosis (MS) is a progressive inflammatory neurodegenerative disease that degrades neural transmission between the brain and spinal α-motoneurons. These voluntary motor commands contain excitatory, inhibitory, and neuromodulatory components that must be appropriately balanced for skilled motor control. Unlike other clinical populations, in MS we have no knowledge about how voluntary motor commands are disrupted. MS is a clinically heterogeneous population, with sensorimotor impairments that vary widely and unpredictably across patients. Our overall scientific hypothesis is that the voluntary motor command in the MS population varies accordingly, with multiple “phenotypes” evident. Here, we explore this idea by identifying pathological aspects of the voluntary motor command in 59 participants with MS with a range of sensorimotor symptoms and disability, compared with 38 age-/sex-matched controls. We recorded motor unit discharge from the tibialis anterior and soleus muscles during isometric dorsiflexion/plantarflexion contractions. We then calculated geometric and temporal features in their firing patterns to characterize their excitatory, inhibitory, and neuromodulatory inputs according to a recently developed “reverse engineering” paradigm. MS values for many of our parameters were highly variable, with some participants with abnormally values and others with abnormally low values. In addition to this variability, MS group means for most parameters reflecting the balance of neuromodulation and inhibition were significantly lower than those of controls. These initial findings support the idea that there may be different phenotypes of voluntary motor command pathology among patients with MS, indicating the potential need to personalize the selection of mechanistically targeted rehabilitation therapies.

Background: A digital adaptation of the nine-hole peg test (9HPT) was developed with the potential to provide novel disability features for patients with multiple sclerosis (PwMS). Objectives: The objectives were to evaluate the 9HPT features based on reliability, prognosis, and discrimination between treatment groups. Methods: The MS partners Advancing Technology and Health Solutions (MS PATHS) cohort data were used to derive new features including completion time and speed. Association and reliability between features and clinical outcomes were tested by intraclass correlation coefficients (ICCs) with repeated measures. The added prognostic value of the features for a clinically meaningful decline was assessed by time-to-event analyses with likelihood ratio tests. The estimated effect size between treatment efficacy groups was acquired from linear mixed-effects models. Sample size was calculated for a hypothetical randomized clinical trial. Results: For the 10,843 PwMS, speed and completion time were associated with MS disability. Compared with time, speed showed higher reliability (ICC = 0.78 vs 0.74), added benefits in predicting disability worsening ( p < 0.001), better discrimination between high- and low-efficacy groups (effect size: 0.035 vs 0.015), and an 18% reduction in required sample size for a 1-year clinical trial. Conclusion: Integrating horizontal hand distances traveled over the 9HPT pegboard can be a more reliable measure of hand function.

Background: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS.Method: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time.Results: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease −6.98 µg/dL, 95% CI: −28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO⁺regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks.Conclusions: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS.Trial registration number: NCT03539094.

Background: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. Objective: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). Methods: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. Results: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). Conclusion: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.

Objectives: To examine the agreement between published reference resources for neurofilament light chain applied to a large population of people with multiple sclerosis (MS). Methods: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score > 1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for four of six reference resources. Results: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean±SD age was 47.1±11.7 years, 72.1% of participants were female, disease duration was 15.0±10.6 years, body mass index was 28.6±6.9kg/m2, and sNfL was 12.87±12.86pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the six reference resources utilized was 0.576 (95% CI: 0.571 to 0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89. Discussion: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multi-modal predictive algorithms) for prediction of disease-specific outcomes.

Background: Diroximel fumarate (DRF) is approved for adults with relapsing–remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. Objective: To report final outcomes from EVOLVE-MS-1. Methods: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. Results: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0–2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11–0.15). Conclusion: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.