Comprehensive Analysis of Real-World Data for NMO Patients Treated
with Eculizumab, Satralizumab, Rituximab, and Inebilizumab: Is it time for a personalized treatMent Approach? (OPTIMA study)

The treatment of neuromyelitis optica (NMO), a debilitating autoimmune disorder characterized by severe and recurrent attacks of optic neuritis and myelitis, has significantly evolved with the advent of targeted therapies. Among the most promising treatments are rituximab, eculizumab, inebilizumab, and satralizumab. These therapies, which target specific immune components, have shown efficacy in reducing relapses and improving clinical outcomes. However, despite their potential, there remains a notable gap in real-world studies evaluating their long-term efficacy and safety. Rituximab, a monoclonal antibody targeting CD20-positive B cells, has been widely used offlabel for NMO. Clinical trials and small-scale studies have demonstrated its effectiveness in reducing relapse rates and stabilizing or improving disability as measured by the Expanded Disability Status Scale (EDSS). Its mechanism involves the depletion of B cells, which play a critical role in the pathogenesis of NMO. Despite promising results, rituximab is associated with potential adverse effects, such as infusion reactions, infections, and progressive multifocal leukoencephalopathy (PML). The real-world data on rituximab are limited, primarily derived from retrospective studies and registries, which often lack the rigor and control of randomized controlled trials (RCTs). Eculizumab is another breakthrough therapy, targeting the complement component C5 and thus inhibiting the formation of the membrane attack complex, which is implicated in NMO pathology. Eculizumab has shown remarkable efficacy in clinical trials, significantly reducing the risk of relapse. However, its safety profile necessitates careful monitoring due to the increased risk of meningococcal infections, necessitating vaccination prior to treatment. Inebilizumab, a monoclonal antibody targeting CD19 on B cells, has demonstrated efficacy in reducing NMO relapses and is generally well-tolerated. The N-MOmentum trial highlighted its effectiveness and safety, showing a significant reduction in relapse risk compared to placebo. Satralizumab targets the interleukin-6 (IL-6) receptor, a key player in the inflammatory process of
NMO. Clinical trials have shown it to be effective in reducing relapses, and it is generally welltolerated with a favorable safety profile. However, long-term real-world data are limited. In summary, while rituximab, eculizumab, inebilizumab, and satralizumab represent significant advancements in the treatment of NMO, the lack of extensive real-world studies is a critical gap. Clinical trials provide essential evidence for efficacy and safety, but real-world studies are necessary to confirm these findings in diverse patient populations and clinical settings. Such studies would help to better understand the long-term safety, effectiveness, and practicality of these treatments, guiding clinicians in making more informed decisions and ultimately improving patient outcomes. The study aims to provide a comprehensive comparison of the efficacy and safety profiles of eculizumab, satralizumab, rituximab, and inebilizumab. By identifying patient-specific factors that predict treatment response, the study will inform clinical guidelines for personalized therapy selection in NMO. This retrospective multicenter study will screen all patients diagnosed with NMO, who were treated with eculizumab, satralizumab, rituximab, and inebilizumab in the period between 1st January 2010 and 31st December 2022. The study will be conducted in the regional authorized centers for the diagnosis and treatment of multiple sclerosis with at least 40 NMO patients referring to each center. We will enroll all NMO patients reporting the first symptoms after age 18, meeting either Poser’s or the McDonald criteria, depending on the current diagnostic criteria at the moment of their first visit.
Objectives:
To provide a detailed comparison of drug efficacy, focusing on relapse reduction, disability progression, and biomarker response.
• To compare the efficacy of eculizumab, satralizumab, rituximab, and inebilizumab in preventing the first relapse of NMO using real-world data from the Italian MS Registry.
• To assess the impact of these treatments on the Expanded Disability Status Scale (EDSS).
• To evaluate the safety profiles of these medications in a real-world setting.
• To identify patient-specific factors (e.g., demographic, clinical, genetic) that predict better responses to each therapy.
Patient inclusion criteria: Patients diagnosed with NMO spectrum disorder according to established criteria; treatment with eculizumab, satralizumab, rituximab, or inebilizumab for at least 6 months; availability of relapses and MRI data; availability of at least 3 years of clinical and radiological followup.
Exclusion criteria: Patients with insufficient follow-up data; patients who received multiple NMOspecific treatments simultaneously; patients with incomplete data on primary outcomes. Statistical analysis: Kaplan-Meier survival analyses will be carried out for time-to-event data (time to first relapse). Cox proportional hazards models will evaluate the impact of different DMTs on relapse risk and disability progression.

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