Therapeutic Strategies for Multiple Sclerosis: Approved and Investigational Treatments

Emerging Therapies in Multiple Sclerosis Management – Can We Stop the Demyelinating Process?

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.

Pathobiology-guided diagnostic advances, biomarker discovery, and emerging therapeutic strategies in progressive multiple sclerosis.

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.

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

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.

Immune reconstitution and tolerance-inducing therapies as promising therapeutic approaches in multiple sclerosis

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.

Clinical Medicine and Integrative Therapies

PATHOGENESIS, DIAGNOSIS, AND TREATMENT OF SYSTEMIC SCLEROSIS – AN INTEGRATIVE REVIEW OF THE CURRENT APPROACHES

Systemic sclerosis is a rare autoimmune connective tissue disorder marked by immunological dysregulation, vasculopathy, and progressive fibrosis of the skin and internal organs, resulting in considerable morbidity and mortality. The disease results from a complex interaction between genetic susceptibility, epigenetic modifications, environmental triggers, endothelial dysfunction, and aberrant immune responses. These mechanisms promote persistent inflammation, stimulation of fibroblasts and abundant extracellular matrix deposition, eventually causing irreversible tissue fibrosis and organ dysfunction. The diagnosis is based on clinical manifestations, supported by specific antibodies detection, capillaroscopy, and appropriate functional and imaging tests. To facilitate diagnosis, the American College of Rheumatology/European League Against Rheumatism issued guidelines in 2013, enabling earlier diagnosis and more accurate prognostic assessment. Although no curative therapy is currently available, treatment has advanced considerably and focuses on suppressing disease activity, slowing fibrosis, and preventing organ complications. Current therapeutic strategies include immunosuppressive agents, biologic therapies, antifibrotic drugs, and targeted vasodilator treatments tailored to individual organ involvement. Emerging approaches, such as JAK-STAT pathway inhibitors, CAR-T cell therapy, and stem cell transplantation, may further improve long-term outcomes in selected patients. Despite substantial progress in understanding disease mechanisms and expanding therapeutic options, systemic sclerosis remains a clinically heterogeneous disorder requiring early diagnosis, multidisciplinary management, and individualized treatment to optimize survival and quality of life.