Autoimmune inflammatory diseases of the central nervous system: advances in clinical trials and immunotherapeutic strategies

Abstract

Autoimmune inflammatory diseases of the central nervous system (CNS), including autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), have emerged over the last two decades as distinct nosological entities with specific autoantibody targets, clinical phenotypes, and treatment responses. Recognition of their autoimmune basis has transformed management from largely supportive and empiric approaches toward mechanism-based immunotherapy. However, these conditions remain rare, clinically heterogeneous, and frequently severe, posing substantial challenges for the design and conduct of robust clinical trials. This review synthesizes current evidence on advances in clinical research and immunotherapy across the major autoimmune CNS disease groups, with a particular focus on trial designs, endpoints, and the evolution from observational cohorts to randomized controlled trials. In AE, first-line immunotherapies (high-dose glucocorticoids, intravenous immunoglobulin, and plasma exchange) remain based mainly on observational data, while second-line therapies such as rituximab and cyclophosphamide are increasingly used despite limited comparative trial data. Recent systematic reviews and individual patient data meta-analyses have highlighted both the potential and the limitations of existing observational evidence, and several randomized phase II–III trials are now underway evaluating agents including bortezomib, satralizumab, and inebilizumab. In NMOSD, the therapeutic landscape has advanced more rapidly, with multiple pivotal randomized controlled trials of targeted biologics (e.g. complement inhibition with eculizumab, B-cell depletion with inebilizumab, interleukin 6 [IL-6] receptor blockade with satralizumab) demonstrating large reductions in relapse risk and leading to regulatory approvals. For MOGAD, most data still derive from retrospective cohorts and extrapolation from NMOSD and multiple sclerosis, but several disease-specific trials are ongoing that investigate IL 6 receptor inhibitors, neonatal Fc receptor (FcRn) antagonists, and purine synthesis inhibitors. Across these disorders, key challenges for clinical research include small and geographically dispersed patient populations, variable access to diagnostic antibody testing, limited validation of outcome measures that capture cognitive and psychiatric morbidity, and underrepresentation of pediatric, elderly, and low-resource populations. Emerging strategies include use of adaptive and basket trial designs, registry-based and pragmatic trials, and increased reliance on international collaborative networks. Addressing these methodological and equity-related issues will be essential to translate immunopathological insights into broadly accessible, evidence-based care for patients with autoimmune CNS disease.