Patients with multiple sclerosis acquire disability either through: (1) Relapse-associated worsening (RAW), or (2) progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins, and the extent to which multiple sclerosis therapies delay disability accumulation. Using the Novartis-Oxford MS (NO.MS) data pool spanning all multiple sclerosis phenotypes and pediatric multiple sclerosis, we evaluated ∼200,000 EDSS transitions from >27,000 patients with ≤15 years follow-up. We analyzed three datasets: (A) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (N = 27,328); (B) All phase 3 clinical trials (N = 8364); and (C) All placebo-controlled phase 3 clinical trials (N = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models, and observed the impact of the mechanism of worsening and disease modifying therapies (DMTs) on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in multiple sclerosis, occurred in all phenotypes, and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events: Following a year in which relapses occurred (vs a year without relapses), the hazard increased by 31–48%; all p < 0.001. Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1) it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with DMTs delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and by 3.09 years (2.60, 3.72), respectively. In relapsing-remitting multiple sclerosis (RRMS), patients who worsened exclusively due to RAW events took a similar time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses. Our data confirm relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA starts already in RRMS and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. Using DMTs delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.

Background: The impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on SARS-CoV-2 vaccination response is uncertain. Methods: Post-SARS-CoV-2 vaccination blood samples across multiple DMTs were tested for SARS-CoV-2 immunoglobulin G (IgG) response. Results: Three hundred twenty-two people with MS were included; 91.9% received an mRNA vaccine. Post-vaccination reactive IgG rates (IgG index > 1) were 40% for anti-CD20 (32/80 patients); 41% for sphingosine 1-phosphate receptor modulators (S1PRM, 16/39); and 100% for all other classes, including the no DMT group. Conclusion: Anti-CD20 therapies and S1PRMs reduce IgG response to SARS-CoV-2 vaccination; IgG response is preserved with other DMTs.

Background Several studies have demonstrated reduced serological response to vaccines in patients treated with anti-CD20 agents. However, limited data exist surrounding the clinical effect of disease modifying therapy (DMT) use on vaccine efficacy. Objectives To investigate breakthrough coronavirus disease 2019 (COVID-19) in vaccinated people with multiple sclerosis (PwMS) on DMT. Methods PwMS on DMT diagnosed with COVID-19 after full vaccination were identified from an existing Cleveland Clinic COVID-19 registry, supplemented by provider-identified cases. Demographics, disease history, DMTs, comorbidities, exposures, vaccination status, and COVID-19 outcomes were confirmed by review of the electronic medical record. Results Thirteen (3.8%) of 344 fully vaccinated people with multiple sclerosis on disease modifying therapy were diagnosed with COVID-19 after vaccination. Ten patients (76.9%) were on an anti-CD20 therapy, the remaining 3 (23.1%) on fingolimod. Only 2 patients (15.4%), both on anti-CD20 therapy, required hospitalization and steroid treatment. Neither required Intensive Care Unit admission. Conclusion Patients treated with anti-CD20 agents and sphingosine 1-phosphate receptor modulators may still be at risk for COVID-19 despite vaccination. While still at risk for hospitalization, intubation and death from COVID-19 appear rare. Larger studies analyzing how this may differ in the setting of emerging variants are needed.

Background: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). Objective: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. Methods: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. Results: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population ( n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. Conclusion: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.