Current evidence on advances in clinical research and immunotherapy across the major autoimmune CNS disease groups is synthesized, with a particular focus on trial designs, endpoints, and the evolution from observational cohorts to randomized controlled trials.
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.
Introduction. Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterised by neuroinflammation and neurodegeneration leading to progressive disability. Its complex immunopathogenesis involves autoreactive T cells, B cells, and myeloid cells, with growing evidence highlighting the pivotal role of B lymphocytes. B cells contribute through antigen presentation, cytokine secretion, autoantibody production, and formation of ectopic lymphoid structures, making them key therapeutic targets. Current disease-modifying therapies (DMTs), including anti-CD20 monoclonal antibodies such as ocrelizumab, ofatumumab, and recently launched ublituximab, have significantly improved clinical outcomes. However, optimisation of long-term efficacy and safety remains challenging. The novel agent, frexalimab, which targets the CD40–CD40L pathway, aims to refine treatment precision and safety further.Material and methods. A systematic search of PubMed, Scopus, and Web of Science (October–November 2025) was conducted to identify clinical trials and high-quality reviews on emerging MS therapies, with emphasis on anti-CD20 agents, BTK inhibitors, frexalimab, and CAR-T therapy. Eligible studies were critically appraised for mechanisms of action, clinical efficacy, safety, and relevance, with particular focus on recent phase II–III data.Results. This review synthesises current insights into MS immunopathology and recent advances in B-cell-targeted therapies and CAR-T approaches, highlighting an evolving therapeutic landscape focused on improving disease control and long-term outcomes.Conclusions. Continued development of targeted immunotherapies may bring the field closer to sustained remission, effective prevention of progression, and potentially enhanced CNS repair.
Julia Lewtak, Kamil Syga, A. Jamróz-Wiśniewska et al.· Journal of Medical Sciences· 0 citations
The integration of multi-omics data offers a promising conceptual lens through which to understand the intricate immune-neuronal interactions driving AE, though substantial challenges in data standardization, clinical validation, and implementation remain to be addressed.
Xudong Chen, Hui Zhang, Shun Ge et al.· Frontiers in Immunology· 0 citations
Multiple sclerosis (MS) is a chronic autoimmune condition of the central nervous system that links its pathogenesis to immunological dysregulation, genetic predispositions, and environmental triggers. With significant immunology and neuroscience progress in recent years, the treatment of MS has shown remarkable advances. This study summarizes currently approved disease modifying therapies (DMTs) along with innovative therapeutic interventions reaching clinical trial testing and further development. Interferon-beta, glatiramer acetate, and dimethyl fumarate are all FDA-approved therapeutic agents; they exert their immune-regulating actions by lowering rates, inflammation, and progression, yet they also have side effects, lack patient adherence, and are ineffective in progressive MS. As the primary focus of research, the Bruton's Tyrosine Kinase (BTK) Inhibitors have also been shown in recent years to have the potential to bridge chronic neuroinflammation through B cells and myeloid immune cells. Moreover, the newly developed agents promoting myelin repair and neuroprotection will open up new therapeutic options for improved neurological impairment. Some innovative therapeutic approaches have yielded positive results; however, their long-term effectiveness and safety must further be confirmed. From a general perspective, MS treatment is gradually drifting from focusing only on immune-mediated inflammation to also include a general therapeutic approach involving neuroprotection and tissue repair, hence offering patients more favorable treatment onset and opportunities.
Letong Chen· Theoretical and Natural Scie...· 0 citations
This review synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.
Alica M. Goldman, Nora Wong, A. Vezzani et al.· Epilepsy Currents· 0 citations
Autoimmune diseases (ADs) are a broad group of phenotypically heterogeneous conditions characterized by both unique and common clinical and immunological manifestations, with varying rates of progression and responses to pathogenetic therapy. More than 10 per cent of the global population suffers from at least one of ADs, and in recent decades there has been a worldwide trend towards an increase in the number of cooccurring autoimmune conditions, particularly in regions and countries with a high level of socio-demographic development. Given their shared risk factors and immunopathological mechanisms, demyelinating diseases of the central nervous system are associated with an increased likelihood of developing a concomitant ADs, which may unpredictably influence the course of the demyelinating process and the choice of optimal treatment. This review examines the co-occurrence of multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin-4 antibodies (AQP4) with the most common associated ADs, and summarises the evidence regarding the preferred therapeutic approaches in each specific case.
D. V. Samarina, A. A. Belkina, D. A. Ganin et al.· Neurology, neuropsychiatry,...· 0 citations
Immune dysfunction, spanning pathogenic autoimmunity and impaired host defense, represents a convergent mechanism across neurological autoimmune and inflammatory diseases and opportunistic infections. Despite advances in immunomodulatory and anti-infective therapies, many patients remain treatment-refractory, reflecting limitations of conventional agents. Adoptive T-cell therapies introduce dynamic "living drugs" capable of in vivo expansion, adaptation, and persistence. These promising characteristics have led to a rapid proliferation of preliminary reports and clinical trials in inflammatory and infectious diseases of the nervous system, placing neurologists at the forefront of this evolving therapeutic landscape. In this Update, we advance a disease-centred conceptual framework designed to reposition T-cell-based therapies within neurological practice. Rather than adopting a technology-driven perspective, we organize disorders according to major patterns of immune dysfunction. Immune deficiency predisposing to opportunistic infection and immune dysregulation driving autoimmunity constitute the principal axes of neurological immune pathology. Within the autoimmune spectrum, distinct immunopathological archetypes (autoantibody-mediated, mixed B- and T-cell-driven, and disorders at the interface of inflammation and neurodegeneration) provide a pragmatic structure for therapeutic reasoning. Building on this classification, we delineate how adoptive T-cells (chimeric antigen receptor T-cells, virus-specific T-cells, and regulatory T-cells) may be differentially aligned with underlying disease biology, linking mechanistic insight to clinical strategy.
N. Lambert, Irene Cortese· Brain : a journal of neurolo...· 0 citations