Jacqueline Palace

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.

Background and ObjectivesA proportion of patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) experience relapses, but biomarkers predicting which patients are like...

B-cell-depleting therapies in multiple sclerosis (MS) have transformed disease management, yet the immunological mechanisms linking B cells to chronic compartmentalized CNS inflammation, the key pathological driver of disability accrual, remain poorly defined. Here, we leverage anti-CD20 therapy as an in vivo perturbational probe to disentangle MS immunobiology. We combine longitudinal, high-dimensional multimodal immune profiling in patients initiating ocrelizumab with a novel machine learning pipeline to resolve treatment-induced shifts in continuous immune cell states, revealing treatment-associated modulation of shared biological processes that act across the boundaries of discretely partitioned cell types. We identify a distinct chronically activated, proinflammatory–cytotoxic T-cell state with CNS-homing properties that is selectively depleted following B-cell ablation. Importantly, across independent datasets, the same T-cell state is enriched in the circulation of patients with clinically aggressive relapsing disease, in CSF-enriched expanded clonotypes, including a subset with proven Epstein–Barr virus specificity, and in chronically inflamed lesion rims in end-stage MS. Finally, we demonstrate that blockade of lymphocyte trafficking across the blood–brain barrier with the anti-integrin α4 therapy natalizumab leads to enrichment of this cell state in the circulation, demonstrating a mechanistically concordant effect across distinct high-efficacy MS therapies. Together, our findings support a B-cell-dependent pathogenic T-cell state, which links peripheral immune activation to CNS-compartmentalized smouldering neuroinflammation across disease stages. Direct therapeutic manipulation of this T-cell state might represent a key opportunity for targeting chronic neuroinflammation and facilitate a strategic shift away from broad immune cell ablation.

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: The effects of smoking and vascular risk factors (VRF) on relapse activity in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well understood. We aimed to investigate these. Methods: MOGAD patients in the Oxford National Neuromyelitis Optica (NMO) Service with known smoking or VRF (hypertension, hypercholesterolaemia, type 2 diabetes, elevated body mass index) status were considered for inclusion. Outcomes were time-to-relapsing course and relapse rate. Cox and negative binomial regression were utilised. Results: We included 172 patients. Current smokers had a 2.2 times higher relapse rate than never smokers (adjusted rate ratio 2.23 [95% CI = 1.35–3.68], p = 0.0017). Relapse rate was similar between past and never smokers (adjusted rate ratio 0.81 [0.51–1.29], p = 0.38). For time-to-relapsing course, multivariable analysis did not identify smoking as associated although univariable analysis showed a consistent trend with shorter time-to-relapse in current than never smokers (hazard ratio 1.76 [0.97–3.22], p = 0.06). There was no difference in either outcome by VRF status. Conclusion: Relapse rates were doubled in current than never smokers, whereas these were similar between past and never smokers. VRF did not associate with relapse risk. Smoking cessation should be encouraged in current smokers with MOGAD as past smokers were not observed with this poorer outcome.

Background: Predicting relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) when disability is relapse-dependent is crucial to guide treatment decisions including whether to treat from onset. MOG-AR, a relapse risk score, was recently developed in a Chinese cohort from disease onset. This study aimed to externally validate the MOG-AR score. Methods: MOGAD patients seen through the Oxford National NMO Service with ≥ 1-year disease duration and available data for MOG-AR score calculation (variables of age, sex, onset attack phenotype, treatment) were included. MOG-AR score and grade were calculated. Relapse occurrence at 3 years from onset was used as the primary outcome. MOG-AR performance was assessed by measures of discrimination and calibration. Results: We included 284 MOGAD patients with a 4.7-year median disease duration. Relapse occurred in 38% within 3 years of onset. Median MOG-AR score and grade were 11 (IQR 10–12) and 3 (3–3) for those who relapsed and 9 (8–11) and 3 (2–3) for those who did not. Observed proportion with relapse was 27%, 26%, 41%, and 53% for grades 1, 2, 3, and 4, respectively. Discrimination assessment by grade showed an area under the receiver operating characteristic curve of 0.58 (95% CI 0.52–0.63). Calibration assessment was consistent with overestimation of relapse probabilities. Conclusion: In a UK-MOGAD cohort, MOG-AR score showed suboptimal performance in predicting relapse over a 3-year period from onset. Further work to find clinically accessible predictive biomarkers and tools for a relapsing course would facilitate better treatment strategies near disease onset.