Jul 2026· Journal of Medical Sciences· Vol 95, pp. e1565· 0 citations· 14 references
TL;DR
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.
Abstract
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.
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.
Multiple sclerosis (MS) is a complex, progressive neurodegenerative autoimmune disease and a major cause of neurological disability worldwide. MS affects approximately 2.8-3 million people, predominantly presenting as relapsing–remitting MS (RRMS) that frequently converts to secondary progressive disease, while effective options for progressive phenotypes remain limited. This review reframes MS immunotherapy through a tolerance-centric paradigm, distinguishing continuous maintenance disease-modifying therapies (DMTs) from immune reconstitution therapies (IRTs) and emerging antigen-specific tolerance strategies. Classical immune reconstitution therapies, including alemtuzumab, cladribine, and autologous hematopoietic stem cell transplantation (aHSCT), have demonstrated durable disease control and prolonged periods of no evidence of disease activity (NEDA) in appropriately selected patients. This is accomplished through a finite course of lymphocyte depletion followed by qualitative immune repopulation that favors tolerogenic regulatory T (Treg) and regulatory B (Breg) cells over pathogenic Th1/Th17 clones. In contrast, maintenance DMTs (interferons, sphingosine-1-phosphate modulators, anti-CD20 monoclonals, natalizumab) suppress inflammation activity during continuous administration but lack durable immune reset. Building on IRT principles, next-generation cell-based therapies (tolerogenic dendritic cells (tolDCs), autologous Tregs, and mesenchymal stromal cells/extracellular vesicles (MSCs/EVs)), aim to induce precision, antigen-specific tolerance while minimizing systemic immunosuppression. These approaches hold promise for overcoming the limitations of chronic immunosuppression, providing durable disease control, and improving long-term patient outcomes. Collectively, immune reconstitution and tolerance-inducing therapies represent an emerging shift from lifelong disease control toward durable immune resetting and the possibility of sustained drug-free remission in MS.
Alireza Beheshti Maal, M. Arki, Seyed Massood Nabavi et al.· Neurological Sciences· 0 citations
Uveitis associated with demyelinating diseases, particularly multiple sclerosis (MS), has gained increasing attention in recent years. Advances in diagnostic modalities, such as the widespread use of brain magnetic resonance imaging, have facilitated deeper investigation into the pathophysiology of uveitis and revealed stronger associations with MS. Additionally, recent genome-wide association studies and progress in immunology have further expanded our understanding of the complex relationship between these conditions. Of particular interest is the emerging recognition of drug-induced MS, especially linked to tumor necrosis factor-alpha (TNF-α) inhibitors. While TNF-α inhibitors are commonly employed in the treatment of uveitis, accumulating evidence suggests they may carry risks of inducing or exacerbating central nervous system demyelination. This evolving landscape necessitates a careful review of current literature to identify new associations, evaluate the strength of existing evidence, and guide clinical decision-making. Special focus is needed on the optimal use of biological therapies and management strategies for refractory uveitis in the context of MS when conventional treatments fail. This narrative review aims to synthesize recent findings, highlight emerging challenges, and provide practical insights for clinicians managing this complex interplay between uveitis and demyelinating diseases.
Aniruddha Agarwal, A. Mubashir, S. Mittal· Indian Journal of Ophthalmol...· 0 citations
Background: Autoimmune rheumatic diseases (ARDs) are characterized by a failure of immune tolerance, leading to chronic inflammation, autoantibody production, and progressive organ damage. Conventional therapies often fail to induce long-term, drug-free remission in refractory patients. Chimeric antigen receptor (CAR) T-cell therapy, originally developed for hematological malignancies, has appeared as a promising strategy to achieve the sustained depletion of pathogenic immune cells in rheumatology.
Objective: This review critically synthesizes current evidence regarding the pathophysiological mechanisms, molecular designs, clinical efficacy, and toxicity profiles of CAR-T therapy across systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), and adult-onset Still's disease (AOSD).
Methods: 77 peer-reviewed sources, including clinical trials, preclinical models, and case series, were analyzed and objectively categorized by target antigens, cellular modifications, and clinical endpoints.
Results: CD19-directed CAR-T cells successfully penetrate inflamed tissues and deplete the autoreactive B-cell compartment, resulting in measurable clinical remission in highly refractory SLE, SSc, and IIM cohorts.This enables the complete discontinuation of concurrent immunosuppressive drugs. Due to a complex, hypoxic synovial microenvironment, targeted RA treatment needs advanced approaches, such as fourth-generation CARs and in vivo generation techniques. Therapy-associated toxicities, primarily cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), generally present with significantly lower clinical severity in ARD patients compared to heavily pre-treated oncological cohorts.
Conclusion: CAR-T cell therapy represents a fundamental paradigm shift in the management of severe ARD, shifting the objective from chronic immunosuppression to definitive immune reconstitution. Despite logistical, financial, and safety challenges, clinical efficacy in treatment-refractory cases remains exceptionally high.
Mateusz Miluski, D. Szydłowska, Mikołaj Jońca et al.· International Journal of Inn...· 0 citations
Progressive multiple sclerosis (PMS) represents a severe and disabling form of MS characterized by a gradual accumulation of neurological impairment and limited responsiveness to conventional disease-modifying therapies. Unlike the relapsing forms of the disease, progressive MS is driven not only by peripheral immune dysregulation but also by persistent neuroinflammation, microglial activation, mitochondrial dysfunction, and progressive neurodegeneration within the central nervous system. These complex and overlapping pathogenic mechanisms contribute to irreversible axonal loss and pose significant challenges for therapeutic intervention. Although recent advances in immunomodulatory treatments have improved outcomes for some patients, currently available therapies provide only limited benefits in slowing disease progression. Consequently, the identification of novel molecular pathways and therapeutic targets has become a major focus in the development of more effective strategies for progressive MS. Rapid progress in understanding the cellular and molecular basis of disease progression has facilitated the exploration of innovative therapeutic approaches, including targeted immunotherapies, neuroprotective agents, remyelination-promoting strategies, and emerging cell-based interventions. Here, in this review, we summarize current advances in the therapeutic landscape of progressive MS, highlighting recently approved treatments as well as promising agents under clinical investigation. Particular emphasis is placed on the underlying mechanisms of action of these therapies and their potential to modify disease progression, restore neural function, and support the development of personalized treatment strategies for patients with PMS.
Patients with central nervous system demyelinating disease (ICI-CDD) should be suspected in patients receiving ICI therapy who present with unexplained paraparesis, sensory deficits, sphincter dysfunction, visual loss, or visual field defects, thereby improving clinical outcomes.
