Michael Levy

Background: Real-world data are crucial to improving care for patients with rare diseases. Objectives: To develop the first global map of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD) patient registries/databases. Registries/databases were identified through rare disease portals, registry websites, and other sources, and surveyed. Results: Of the respondents ( N = 26), the majority were established within the past 15 years and reported being self-funded. Most collect diagnostic, clinical, and laboratory data. Major objectives included supporting scientific research and advancing disease understanding. Conclusions: Despite cost, time, resource, and data quality challenges, registries/databases provide important insights into addressing unmet needs in MOGAD and NMOSD.

Autoimmune diseases of the central nervous system include multiple sclerosis (MS) and an ever-expanding spectrum of related disorders, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Despite differences in targeted neuroantigens and immune effector mechanisms, these disorders share a common clinical pattern: acute neurological episodes, typically termed attacks at the onset, and relapses during the disease course. Timely recognition of an acute attack or relapse is challenging, not only because of discrepancies between patient-reported and physician-affirmed neurological symptoms, but also due to other confounding factors, such as comorbidities, treatment-related side effects, and transient symptom fluctuations unrelated to underlying disease. Once an attack/relapse is recognized, prompt initiation of treatment is essential, as responsiveness to treatment at the acute stage largely determines the long-term neurological outcomes. In this review, we focus on MS, NMOSD and MOGAD, and discuss the clinical patterns of acute attacks and relapses, including the clinical and para-clinical modalities that are critical for timely recognition and diagnosis. We present the available evidence regarding treatment selection and responsiveness for three categories of therapy: intravenous methylprednisolone (IVMP), intravenous immunoglobulin (IVIG), and plasma exchange/immunoadsorption (PLEX/IA). Notably, we update ongoing clinical trials that incorporate fast-acting, targeted biologic complement inhibitors and neonatal Fc receptor (FcRn) antagonists. We discuss potential drivers of relapses and emerging mechanism-guided interventions for acute management. Finally, we call for international collaborative efforts in this important yet under-investigated area to establish clear criteria for relapse, with the ultimate goal of developing more effective therapies.

Ravulizumab, a complement component 5 inhibitor, was approved for the treatment of adults with anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) based on results of the primary treatment period (PTP) of CHAMPION-NMOSD, a phase 3, open-label, external placebo-controlled trial. Here, we report the final efficacy and safety results of CHAMPION-NMOSD (PTP and the long-term extension [LTE]). Adult patients with AQP4-Ab+ NMOSD received an IV, weight-based loading dose of ravulizumab on day 1 and a maintenance dose on day 15 and every 8 weeks thereafter. After completion of the PTP (up to 2.5 years), patients could enter the LTE. The primary endpoint was time to first adjudicated on-trial relapse. The placebo group of the eculizumab phase 3 trial PREVENT was used as an external comparator because eculizumab availability at CHAMPION-NMOSD initiation precluded the use of concurrent placebo control. Of 58 patients enrolled in the trial, 56 entered and 55 completed the LTE. The overall median (range) follow-up was 170.3 (11.0-243.0) weeks, with 100.8 (53-137) weeks during the LTE. No patient receiving ravulizumab had an adjudicated on-trial relapse throughout the PTP (84.0 patient-years) and LTE (105.7 patient-years); relative reduction in risk of relapse vs placebo (n = 47) was 98.9% (95% CI 91.8-100; p < 0.0001). Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 94.8% and 27.6% of patients, respectively, during the PTP and LTE. Most TEAEs were grade 1 and unrelated to ravulizumab. One patient discontinued ravulizumab because of TEAEs. Two cases of meningococcal infection occurred during the PTP; none occurred in the LTE. One death due to hypertensive heart disease (unrelated to ravulizumab) occurred during the LTE. Long-term ravulizumab treatment (median follow-up, >3 years) continued to show significant relapse risk reduction in patients with AQP4-Ab+ NMOSD, and the safety profile was consistent with the known safety profile for ravulizumab. ClinicalTrials.gov, NCT04201262; EudraCT: 2019-003352-37. Submitted December 11, 2019. First patient enrolled: December 13, 2019. clinicaltrials.gov/study/NCT04201262. This study provides Class III evidence that long-term ravulizumab treatment, as compared with placebo, decreases the probability of clinical relapse in patients with AQP4-Ab+ NMOSD.

Background and ObjectivesMyelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is an inflammatory demyelinating disorder characterized by attacks of optic neuritis, myelitis, and ...

Multiple sclerosis (MS) pathogenesis is linked to Epstein-Barr virus (EBV), but the underlying immune mechanisms remain unclear. Using an optimized T cell assay, we demonstrate that CD4⁺ T cells from individuals with MS predominantly target EBV viral particle components, specifically the late lytic capsid and glycoprotein antigens, rather than latent antigens. In contrast, the Epstein-Barr nuclear antigen 1 (EBNA1) primarily activated CD8⁺ T cells. EBV-specific CD4⁺ T cell responses were twofold higher in individuals with untreated MS compared with healthy controls, whereas responses to other herpesviruses remained similar. Anti-CD20 therapy initiation in treatment-naïve participants reduced these responses, a finding validated in an independent cohort, and eliminated viral shedding in saliva. Our results establish preferential CD4⁺ T cell reactivity to EBV late lytic antigens as a key feature of MS, providing a framework for developing EBV-targeted therapies, including vaccines and antivirals.

Objective: This post hoc analysis of the CHAMPION-NMOSD trial evaluated the safety and efficacy of ravulizumab in patients with aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) previously exposed or naïve to rituximab (RTX). Methods: Patients received weight-based intravenous ravulizumab with a loading dose followed by maintenance dosing every 8 weeks. Patients were stratified by prior RTX exposure: no RTX exposure (RTX-naïve) vs RTX exposure > 3 months before initiating ravulizumab (RTX-exposed). Key outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), relapse rates, and vaccination timing from the last RTX dose. Results: Of the 58 patients enrolled, 89.7% were female, with a mean age of 47.4 years, and 21/58 (36.2%) were RTX-exposed. Relapses occurred in 12/21 (57.1%) RTX-exposed patients between their first RTX dose and study entry. The safety profile of ravulizumab was generally similar between RTX-exposed and RTX-naïve groups. Common TEAEs included COVID-19, headache, urinary tract infection, and upper respiratory tract infection. UTIs were more frequent in RTX-exposed individuals. One patient in each group experienced a meningococcal infection. No adjudicated on-trial relapses were reported while on ravulizumab. Conclusions: Following initiation of ravulizumab, RTX-exposed and RTX-naïve patients with AQP4-Ab+ NMOSD achieved sustained disease control and demonstrated a manageable safety profile. Clinical Trial Information: The CHAMPION-NMOSD Trial; ClinicalTrials.gov identifier: NCT04201262 (registered October 06, 2020).