Multiple Sclerosis and Related Disorders

BackgroundUncertainties remain about the benefit of a 3rd COVID-19 vaccine for people with attenuated response to earlier vaccines. This is of particular relevance for people with multiple sclerosis (pwMS) treated with anti-CD20 therapies and fingolimod, who have substantially reduced antibody responses to initial vaccine course. MethodsPwMS taking part in a seroprevalence study without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/-venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. The relationship between evidence of prior COVID-19 infection and immune response to COVID-19 vaccine 3 was evaluated using Fishers exact test. ResultsOf 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There no association between laboratory evidence of prior COVID-19 infection and anti-spike seroconversion following COVID-19 vaccine 3. ConclusionsApproximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine. Key messagesO_ST_ABSWhat is already knownC_ST_ABSThe benefits of COVID vaccination are well described. It is unknown whether there is additional benefit afforded from a third COVID-19 vaccination in those people who have failed to mount a serological response to their initial vaccine course. What this study addsApproximately one third of people with MS in our study, all of whom had failed to response to initial vaccine course, developed anti-spike antibodies following a third COVID-19 vaccine. Two-thirds of participants had T cell response to vaccination. No people taking fingolimod appeared to mount a T cell response to vaccination. How this study might influence practiceThese findings highlight potential benefits of booster vaccinations to a substantial proportion of immunosuppressed people who have failed to respond to initial vaccination course. The clinical correlates of antibody and T-cell responses to COVID-19 remain uncertain but they are almost certainly associated with milder subsequent disease in the general population.

BackgroundCD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown. MethodsRelapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal. ResultsOnly 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab. ConclusionsFew people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

ObjectiveOcrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval. MethodsInternet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600mg treatment cycles (week 0-72), followed by an 18 month treatment-free period. ResultsCD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events. ConclusionsOcrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression. Further studies are now clearly required to determine whether this data is robust, as few people seemed to complete the study.

In January 2024, all persons with multiple sclerosis (pwMS) treated with natalizumab (NTZ) at Oslo University Hospital switched from originator to biosimilar NTZ. We prospectively monitored 39 pwMS during the first year of treatment with biosimilar NTZ and evaluated change in disease activity, side effects, serum NTZ levels, anti-drug antibodies (ADAb), and anti-John Cunningham virus (JCV) antibody levels. Serum NTZ levels and ADAb were measured using in-house assays, while JCV antibody levels were evaluated using Stratify (Biogen) and Immunowell (Sandoz) platforms. One new relapse occurred during the first year and 11 pwMS (28%) reported new side effects after switching to the biosimilar; whereof fatigue, headache, and muscle pain were most frequent. Serum NTZ levels were similar between pwMS on originator (15.1 mg/L, SD 8.9) and biosimilar NTZ (14.9 mg/L, SD 9.0; p = 0.63). We identified ADAb in one pwMS, present both before and after switching. The proportion of pwMS with positive JCV antibody levels increased from 13% in 2023 (Stratify) to 52% in 2024 (Immunowell). Four pwMS discontinued NTZ due to high anti-JCV antibody levels (in the Immunowell assay) in the first 10 months.

BackgroundThere is increasing evidence that Epstein-Barr virus (EBV) plays a causal role in MS. No treatments have been shown to reduce EBV turnover. We studied the effect of famciclovir on salivary EBV shedding in people with MS (NCT05283551). MethodsPeople with MS receiving natalizumab provided weekly saliva samples for 12 weeks before starting Famciclovir 500mg bd. 12 saliva samples were provided on treatment and 12 following treatment. A real-time quantitative PCR Taqman assay targeted to a non-repeated sequence of the EBV polymerase gene was used to detect EBV DNA in saliva. The proportion of saliva samples containing EBV DNA was compared using the Friedman test. Results30 patients were recruited (19F; mean age 41 years; median EDSS 3.5). 29 patients received famciclovir, 24 completed the 12-week course. 21 participants provided at least one usable saliva sample in all 3 epochs. 10/21 participants had shedding in at least one sample pre-drug; 7/21 when taking famciclovir (not significant). No difference in EBV DNA copy number was seen. There were no drug-related serious adverse events. ConclusionsNo significant effect of famciclovir on EBV shedding was seen. Salivary EBV shedding in this natalizumab-treated cohort was lower than in previous studies; this requires replication.

ObjectiveReport outcomes on patients with Multiple Sclerosis (MS) and related disorders with COVID-19 illness. MethodsFrom March 16 to April 30th, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center (MSCC) were identified with laboratory-confirmed or suspected COVID-19. The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records. ResultsWe identified 76 patients (55 with relapsing MS of which 9 had pediatric-onset;17 with progressive MS; and 4 with related disorders). 37 underwent PCR testing and were confirmed positive. Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n=34, 44.7%) and sphingosine 1-phosphate receptor modulators (n=10, 13.5%). The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection. A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death. Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a non-ambulatory status. No DMT class was associated with an increased risk of hospitalization or fatal outcome. ConclusionsMost MS patients with COVID-19 do not require hospitalization despite being on DMTs. Factors associated with critical illness were similar to the general at risk patient population. DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample.

BackgroundThere are already numerous B-cell depleting monoclonal anti-CD20 antibodies which have been used to reduce the inflammatory burden associated with multiple sclerosis (MS). We describe here our experience of treating MS-patients with B-cell depleting rituximab. Patients and methodsAll MS-patients (n=72) who had received rituximab treatment for at least six months by January 2019 were identified from the patient charts at the Turku University Hospital. Information about MS disease subtype, disease severity, MR-imaging outcomes and B-cell counts were collected from the charts. ResultsRituximab was well received and well tolerated by the patients. There were no serious infusion-related side effects. The most serious adverse event that led to treatment discontinuation was neutropenia. Our study confirms the usability of rituximab treatment for MS in the Finnish health care environment. ConclusionsOff-label rituximab-treatment can be successfully used to reduce MS disease burden for the benefit of MS patients.

BackgroundCalorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) through reduction of inflammation. The aim of this trial was to study the effects of 12-week iCR on metabolic, immunological and clinical outcomes in people with MS (pwMS). MethodsParticipants with relapsing-remitting MS were randomly assigned to intermittent CR (iCR) or a control group for 12 weeks. Primary outcome was change in leptin levels; secondary outcomes included changes in anthropometric and body composition measures, peripheral blood metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate differences. ResultsForty-two pwMS were randomized, 34 completed the study (17 iCR and 17 control). Leptin levels decreased in the iCR group and were significantly lower in the iCR than the control group at 6 (mean difference 11.49 mg/dL, 95% CI 32.54, 9.54; P=0.01) and 12 weeks (6.97 mg/dL, 95% CI 28.02, 14.06; P=0.03). We observed a significant reduction of weight, body mass index and body adiposity measures over the 6 and 12-weeks in the iCR group. Immune profiling showed a significant increase in CD45RO+ regulatory T cell numbers after 6 weeks of iCR. Lysophosphatidylcholine, lysophophatidylethanolamine and phosphatidylinositol lipid species were significantly increased after 12 weeks in the iCR group compared to baseline, and all three were higher at 12 weeks compared to controls. Exploratory cognitive testing demonstrated improvement in the symbol digit modality test score in the iCR group. ConclusionsShort term iCR is safe, feasible and can benefit metabolic and immunologic profiles in pwMS. ClinicalTrial.gov number: NCT03539094 (first patient screened on 11/14/17; first patient recruited on 1/29/2018; last patient recruited on 11/24/2021).

BackgroundClinically defined relapses are the traditional primary endpoint of randomized control trials (RCTs) in multiple sclerosis (MS), yet a substantial proportion lack new inflammatory lesions. Confirming relapses with brain and spinal cord MRI to distinguish relapses with active MRI (RAM) from acute clinical events with stable MRI (ACES) may provide a more sensitive primary outcome for future trials. ObjectiveTo estimate RAM and ACES rates in MS trials and evaluate the impact on statistical power of using RAM. MethodsWe used two approaches: an aggregated data (AD) approach, combining population-level data from RCTs with observational data from the French MS registry, and an individual patient data (IPD) approach from the PRIMUS platform. Trials were selected if they evaluated DMTs sufficiently represented in the OFSEP ancillary study or were available in PRIMUS. Eleven pivotal RCTs were included, evaluating natalizumab, cladribine, dimethyl fumarate, teriflunomide, fingolimod, or ocrelizumab; 7 were analyzed with AD only, 1 with IPD only, and 3 with both. For the AD approach, population-level characteristics were extracted from published reports; expected RAM probabilities were then derived from a RAM model fitted on OFSEP observational data, applied to each RCT arm population. For the IPD approach, clinically defined relapses were directly classified as RAM/ACES according to radiological activity on subsequent brain MRI. Main outcomes were the treatment effect on RAM and ACES rates, compared with the effect on clinically defined relapses. ResultsAcross 11 RCTs, treatment effects were consistently equal or greater for RAM than for clinically defined relapses, with both AD and IPD approaches. No DMT significantly reduced ACES rates, which remained stable at approximately 0.08 events/year across arms. The IPD approach yielded systematically lower RAM probabilities than the AD approach. Using RAM as the endpoint improved statistical power in most scenarios: e.g. a trial with annualized relapse rates of 0.15/year (active arm) vs 0.30 (control arm) requires one-third fewer participants. ConclusionAdopting RAM as the primary outcome could substantially enhance the power of future MS trials and better target the effect of treatment on inflammatory activity.

BackgroundOcrelizumab and natalizumab are commonly prescribed high-effectiveness disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). However, no randomized clinical trial and few real-world studies have directly compared their effectiveness in reducing disability progression. Subtype classification and disability status are critical for multiple sclerosis (MS) research, but these data are often missing in electronic health records (EHRs), limiting robust real-world evidence generation. ObjectiveTo compare the effectiveness of ocrelizumab and natalizumab in two-year clinician-rated disability progression among RRMS patients using longitudinal registry-linked EHR data. DesignRetrospective cohort study. SettingA large healthcare system that includes both academic and community practices. ParticipantsPatients diagnosed with MS who initiated ocrelizumab or natalizumab between 2012 and 2020, with at least 6-month EHR data before treatment initiation and no prior exposure to other high-effectiveness DMTs. ExposuresTreatment with ocrelizumab vs natalizumab. MeasurementsWe developed an ensemble machine learning model to impute RRMS subtype and disability outcomes using structured and narrative EHR data. The primary outcome was moderate/severe clinician-rated disability at 2 years (observed or imputed Expanded Disability Status Scale [EDSS][≥]4) after treatment initiation. We estimated the average treatment effects using semi-supervised doubly robust approach with comprehensive confounder adjustment and calibration to mitigate imputation bias. Covariates included standard demographic and clinical features such as baseline disability as well as knowledge graph-selected features. Sensitivity analyses used observed EDSS scores in registry-derived RRMS patients. Exploratory analyses included rituximab, another B-cell-depleting therapy, with adjustments for differences in patient profiles. ResultsAmong RRMS patients, those treated with ocrelizumab (n=543) had a significantly lower two-year risk of moderate/severe disability compared with those treated with natalizumab (n=205) based on imputed outcomes (risk difference, -5.87%; 95% CI: -11.28% to -0.46%; p=0.033) after confounder adjustment. Sensitivity analyses yielded consistent findings using imputed or observed EDSS outcomes in registry-derived RRMS patients. Conclusion and relevanceIn this real-world comparative effectiveness study using a novel semi-supervised doubly-robust framework, ocrelizumab was associated with a lower risk of disability progression than natalizumab among RRMS patients. This approach provides a roadmap for generating robust large-scale real-world evidence in settings of missing key inclusion features and outcomes.

ImportanceThe identification of a prodrome in multiple sclerosis (MS) is the key to early prevention and the targeting of new interventions. ObjectiveTo assess the associations between health conditions diagnosed in primary care and the risk of incident MS relative to other autoimmune inflammatory diseases. DesignA case-control study in the UK and France was conducted from Jan 1, 1996 to March 28, 2022 in the UK and from Jan 4, 1998 to March 28, 2022 in France. SettingData were obtained from electronic health records from the Health Improvement Network database. ParticipantsWe included all individuals with at least two years of history in the database and a recorded diagnosis of either MS, lupus or Crohns disease. Three controls matched for sex, age at index date and year at index date were randomly assigned to each individual with a diagnosis of MS. Main outcome measuresWe agnostically tested the associations between 113 different diagnoses and multiple sclerosis diagnosis during the five years before or the five years after the diagnosis of MS. Unadjusted odds ratios (ORs) and 95% CIs were estimated, and p values were corrected for multiple comparisons. We also stratified for sex, age at diagnosis, and year of diagnosis. A logistic regression analysis (adjusted for sex and age at diagnosis) was performed to compare MS patients with lupus and Crohns disease patients. ResultsThe study population consisted of patients with MS (UK: 15,808; and France: 4,366), Crohns disease (UK: 20,872; and France: 9,605) or lupus (UK: 5,296; and France: 2,041). We identified twelve health conditions as significantly positively associated with the risk of MS. After considering health conditions suggestive of demyelinating events as the first diagnosis of MS, five health conditions remained significantly associated with MS: depression (UK OR 1.22 [95%CI 1.11-1.34]), sexual dysfunction (1.47 [1.11-1.95]), constipation (1.5 [1.27-1.78]), cystitis (1.21 [1.05-1.39]), and urinary tract infections (1.38 [1.18-1.61]). However, none of these conditions was selectively associated with MS in comparisons with both lupus and Crohns disease. During the five years after MS diagnosis, all five health conditions identified here were still associated with MS. Conclusion and relevanceThe identified symptoms may be considered to be not only prodromal, but also early-stage symptoms, albeit not specific to MS. Key pointsO_ST_ABSQuestionC_ST_ABSWhat prediagnostic manifestations of multiples sclerosis (MS) occur in primary care settings and how do they differ from those of other autoimmune diseases? ResultsIn this agnostic study of 15,808 MS patients from the UK and 4,366 MS patients from France, we identified five health conditions as positively associated with the risk of MS when recorded in the five years preceding MS diagnosis. We show that most of these health conditions were also present in the early presentations of lupus and Crohns disease. MeaningOur findings suggest that the prodromal phase of MS is largely similar to the prediagnostic manifestations of other autoimmune diseases.

BackgroundNatalizumab is a high-efficacy therapy for RRMS. While EID may reduce PML risk, critical gaps persist in understanding post-cessation outcomes, posing urgent clinical challenges for neurologists discontinuing treatment. ObjectivesTo compare efficacy/safety of natalizumab SID vs. EID and quantify relapse/disability risk after cessation in adults with RRMS. MethodsWe conducted a systematic review/meta-analysis (PROSPERO: CRD420251103014) following PRISMA guidelines. We searched MEDLINE, Cochrane Library, ClinicalTrials.gov, and other sources (2015-2025) for RCTs and observational studies. Primary outcomes: ARR and disability progression; secondary: PML incidence and post-cessation relapse. Risk of bias was assessed using Cochrane RoB 2.0 and ROBINS-I. Data were synthesized narratively or via meta-analysis, with evidence certainty graded (GRADE). ResultsTwenty-eight studies (n=45,803) were included. The key finding was a substantial 41.7% (95% CI 30.8-53.6%) pooled relapse risk within 12 months of cessation (4 studies, n=857) using a random-effects model. Sensitivity analysis excluding the outlier study (Weinstock-Guttman 2016) showed a relapse risk of 36.9% (95% CI 33.7-40.3%). Narrative synthesis of ARR (9 studies) showed no consistent SID vs. EID difference (median difference 0.00). Meta-analysis of PML risk (3 studies) found no significant difference (RR 0.70, 95% CI 0.20-2.54). Disability outcomes were too heterogeneous for meta-analysis. Evidence certainty was low for most outcomes. ConclusionThis review demonstrates a substantial 41.7% relapse risk within 12 months of natalizumab cessation, representing the most critical clinical implication. While EID may maintain efficacy comparable to SID, the high withdrawal relapse rate necessitates prompt therapy transition and patient counseling. Treatment decisions must encompass the entire continuum from initiation to discontinuation.

BackgroundTreatment strategy for relapsing multiple sclerosis (RMS) is increasingly shifting towards first-line use of high-efficacy DMT (H-DMT). However, DMT efficacy declines with increasing age and the benefit of first line H-DMT at higher age remains unclear. Here, we aimed to investigate whether the superiority of H-DMT over moderate-efficacy DMT (M-DMT) depends on age. MethodsUsing the Austrian MS database, we included previously DMT-naive RMS patients aged [&ge;]18 years, who i) initiated a DMT continuing it for [&ge;]12 months, ii) had MRI at baseline, and iii) had clinical follow-up for [&ge;]24 months. Cox regression analyses including age and DMT strategy (H-DMT vs. M-DMT) plus an interaction effect were employed to predict time to relapse. ResultsA total of 215 RMS patients (median age of 41 years [25th-75th percentiles: 32-53], 66% females) were observed over a median of 42 (28-58) months. During this period, eighty-one (38%) patients had a relapse. While increasing age was associated with decreased risk of relapse (hazard ratio (HR) 0.95 per year, 95% confidence interval [CI]: 0.93-0.98, p<0.001), the use of H-DMT lowered the risk of relapse compared to M-DMT (HR 0.06, 95%-CI: 0.01-0.45, p=0.007). In patients with H-DMT, the benefit of treatment was reduced by increasing age (HR: 1.06, 95%-CI: 1.01-1.11, per year, p=0.031). Superiority of H-DMT over M-DMT was estimated to be lost at the age of approximately 50 years. ConclusionThe benefit of H-DMT over M-DMT as first-line treatment decreases with increasing age and seems to vanish in patients above approximately 50 years. What is already known on this topicHigh-efficacy disease-modifying treatments (H-DMTs) are increasingly used as first-line therapy in relapsing multiple sclerosis (RMS) due to their superior effectiveness in reducing inflammatory disease activity. However, both clinical and radiological disease activity naturally decline with age, and prior meta-analyses suggest that the relative benefit of H-DMT over moderate-efficacy DMTs (M-DMTs) diminishes in older patients. These findings have largely been derived from clinical trials with restricted age ranges and enriched disease activity, limiting their generalizability to real-world, treatment-naive populations across the full adult age spectrum. What this study addsIn a real-world, national cohort of DMT-naive RMS patients across a wide range of age, this study shows that while H-DMTs significantly reduce the risk of relapse compared to M-DMTs, their superiority is progressively attenuated with advancing age. Notably, the benefit of initiating H-DMTs as first-line therapy becomes statistically indistinguishable from M-DMTs around the age of 50 years. These findings were independent of baseline disease duration and other covariates, emphasizing age as a key modifier of treatment effect. How this study might affect research, practice or policyThese findings support the integration of age as a critical factor in guiding first-line DMT decisions for RMS. For patients over 50 years, M-DMTs may offer a more appropriate initial treatment option, minimizing exposure to the higher risk profiles of H-DMTs in the absence of clearly superior efficacy. This study underscores the importance of personalized treatment approaches and highlights the need for future clinical trials to include broader age ranges, facilitating evidence-based, age-adjusted treatment strategies in multiple sclerosis.

The introduction of a third dose vaccination along with new variants of concerns raises questions regarding serology and T-cell responses in patients with MS (pwMS) treated with B-cell depletion who develop attenuated humoral response to vaccines. The aim of this study is to longitudinally evaluate humoral and cellular response to SARS-CoV-2 mRNA vaccine in ocrelizumab-treated pwMS before and following third vaccine dose. Following the third vaccine dose, patients who are low or non-responders following initial vaccination did not increase antibody titers. In HCs and ocrelizumab-treated pwMS, cellular response decreased 6 months following initial vaccination and increased significantly after the third booster.

IntroductionPsychological distress is a major issue in multiple sclerosis (MS), having a significant impact on quality of life. Antidepressants are generally unhelpful for subsyndromal symptomatology, and psychological treatment approaches often not accessible or too cognitively demanding for some patients. There is an urgent need for low-cost interventions to improve wellbeing in MS. MethodsThis was a pilot randomised controlled trial (RCT) of Positive Mental Training (PosMT), a low intensity intervention providing training in positivity, optimism and resilience previously shown to improve anxious and depressive symptomotology. 28 patients with MS were randomised to the intervention and 30 to the control group. ResultsFollow-up data was obtained from 39 patents. The majority of participants receiving PosMT reported that they had used the intervention, with few reporting side effects. The intervention group reported a significant improvement in self-rated health as measured by the EuroQual visual analogue scale, F(4,34) = 3.204, p = 0.025, R2 = 0.274. DiscussionThis preliminary RCT found that PosMT in its current form could be used by patients with MS with little difficulty. Despite the small size of the study, allocation to the intervention was found to be associated with a significant improvement in self-rated health. Given the low cost of PosMT and its easy availability (it can simply be downloaded from a website), this pilot RCT suggests it could be a useful tool for MS patients. We believe this intervention warrants further study, ideally in a large multi-centre RCT.

Patient-reported outcomes importantly reflect the lived experiences of persons with multiple sclerosis (MS); however, given the broad array of MS symptoms, comprehensive evaluation can be burdensome, especially with lengthy questionnaires. The MS Impact Scale queries twenty different physical difficulties (MSIS-20). In 1150 patients with MS, evaluation of internal consistency indicated redundancy in the MSIS-20 (Cronbachs alpha: 0.96), but optimal internal consistency (0.90) of a six-item short form (MSIS-SF; first six MSIS items). The MSIS-20 and MSIS-SF showed comparably strong associations with objective physical disability. The MSIS-SF provides a psychometrically robust, less burdensome, and time-efficient option for assessing patient-reported physical disturbance.

SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases. Here we investigated the induction and stability of vaccine-specific antibodies, B cells, and T cells in multiple sclerosis (MS) patients on different DMTs in a prospective cohort study up to 6 months after homologous prime-boost mRNA vaccination. We analysed 103 MS patients of which 86 received anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-{beta}, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and compared them to 17 untreated MS patients. In contrast to all other DMTs and untreated patients, treatment with aCD20-BCD or fingolimod significantly reduced anti-S1 IgG, serum neutralizing activity, and RBD- and S2-specific B cells. MS patients receiving fingolimod additionally lacked S1- and S2-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether patients successfully developed humoral immune responses. Fingolimod blocks the ability of immune cells to recirculate and migrate within secondary lymphoid organs demonstrating that functional immune responses require not only immune cells themselves but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses in fingolimod-treated MS patients suggests that these patients are at risk for severe SARS-CoV-2 infections despite vaccination, which is highly relevant for clinical decision-making and adapted protective measures, particularly in light of additional recently approved S1P receptor antagonists for MS treatment.

BackgroundProgression independent of relapses (PIRA) is a major therapeutic challenge in multiple sclerosis (MS). Nasal anti-CD3 treats animal models of progressive MS by inducing regulatory T cells (Tregs) that suppress central nervous system (CNS) inflammation and lessen clinical disease. MethodsTen patients with non-active secondary progressive MS (naSPMS) that continued to progress on B cell therapy were treated with nasal anti-CD3 (foralumab) for a minimum of six months in an open label study. Safety monitoring included otolaryngology evaluation and neurologic assessments including Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC-4), Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test (CVLT-II) and Low Contract Visual Acuity (LCVA). MRI and microglial translocator protein (TSPO)-PET imaging with [F-18]PBR06 were conducted. Serum and cerebrospinal fluid (CSF) proteomic biomarkers and single cell RNA sequencing of blood was performed to evaluate foralumab-induced immunomodulation. The endpoints of our study were safety, clinical effects, microglial signal and immune measures. ResultsAll patients stabilized on EDSS scores and three of four patients treated continuously for 12 months had improvement on EDSS. Six of 10 patients had improvement in fatigue on the MFIS scale. There were no treatment-related serious adverse events (SAEs) or severe AEs and no new T2 lesions were observed on MRI. There was a reduction in TSPO-PET signal over six months (p<0.05). Changes in peripheral blood gene expression occurred as early as three months and affected antigen presentation, interferon responses and regulatory pathways in multiple cell types including FoxP3+ Tregs, CD4+ Tcm cells, CD8+ Tem cells, CD14+ and CD16+ monocytes and B cells. TGF{beta} expression was increased across cell multiple subsets. InterpretationThese findings identify a novel, non-toxic immune based therapy for the treatment for PIRA that acts by the induction of a regulatory immune responses and dampens microglial inflammation. Double blind placebo-controlled trials are warranted to explore nasal foralumab for the treatment of naSPMS.

Background and ObjectivesPatients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses and reach irreversible disability at a younger age than adult-onset patients. There have been few randomized placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. MethodsThis retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021 (N=1218). The primary outcome was the time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years post baseline; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. ResultsPatients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMT (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; P=0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMT (HR, 0.15; 95% CI, 0.07-0.31; P<0.001) or fingolimod (HR, 0.37; 95% CI, 0.14-1.00; P=0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DiscussionOur results suggest that natalizumab and fingolimod have broadly equivalent therapeutic efficacies in patients with POMS, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. However, analyses of relapse outcomes suggest natalizumab is superior to fingolimod in the control of relapses in this population with high rates of new inflammatory activity. Classification of EvidenceThis study provides Class III evidence that natalizumab may provide better disease control than fingolimod in patients with POMS.

BackgroundB-cell depletion (BCD) therapies (e.g., ocrelizumab, ofatumumab, rituximab) and natalizumab (NTZ) are highly effective disease-modifying therapies (DMTs) for multiple sclerosis (MS). However, no randomized clinical trial and only limited observational studies compared the two DMT classes. ObjectiveWe compared BCD and NTZ in managing MS patient-reported disability progression using registry-linked electronic healthcare record (EHR) data. MethodsThe study population of an EHR cohort of MS patients included a subset enrolled in a clinic-based MS registry that provided gold-standard outcome labels. To estimate average treatment effects, we applied a doubly-robust semi-supervised approach to analyze all (not only registry) patients and comprehensively adjusted for confounders that included not only a priori standard features but also knowledge graph-derived EHR features. While gold-standard disability outcomes were available in registry patients, we imputed the baseline pre-treatment and post-treatment disability status for non-registry patients. We categorized patient-reported disability progression status as "sustained worsening", "sustained improvement", or "no sustained change" based on 3 or more observations or imputations of Patient Determined Disease Steps (PDDS) scores within 3 years after target treatment initiation as the primary endpoint. ResultsIn this MS cohort (n=1,738, Age=46{+/-}13 years, Non-Hispanic White=86.71%), there was no significant difference between BCD (n=1,245, 71.63%) and NTZ (n=495, 28.37%) in mitigating sustained worsening (ATE=-0.020, 95% CI [-0.149, 0.076], p=.755) or promoting sustained improvement (ATE=-0.073, 95% CI [-0.187, 0.009], p=.114) of patient-reported disability. Sensitivity analyses using a 2-year window after treatment initiation confirmed no difference in sustained worsening (ATE=-0.013, 95% CI [-0.069, 0.074], p=.819) or sustained improvement (ATE=-0.187, 95% CI [-0.264, 0.008], p=.135) between BCD and NTZ. In power analysis, the semi-supervised approach increased statistical power compared to the standard approach of using gold-standard data alone. ConclusionThis real-world comparative effectiveness analysis based on a novel doubly-robust semi-supervised approach found no difference between BCD and NTZ in managing MS disability progression. Key Messages{blacksquare} Evaluation of sustained disability accumulation requires long-term follow-up beyond the typical clinical trials, while the scarcity of patient-reported and certainly rater-assessed disability outcomes in routine clinical care hinders analysis using real-world clinical data. {blacksquare}Using a large registry-linked electronic healthcare record cohort and a novel semi-supervised, doubly-robust method that incorporates knowledge graph-derived clinically relevant covariates from EHR, we conducted a causal inference study to compare sustained change in patient-reported disability in people with MS. {blacksquare}The semi-supervised approach effectively leverages additional data from patients without observed outcome information and increases the statistical power of the comparative effectiveness study while retaining robustness properties and achieving more consistent treatment effect estimation in the causal analysis. {blacksquare}There was no statistically significant difference between B-cell depletion therapy and natalizumab in sustained patient-reported disability outcomes up to 3-years after treatment initiation.