PURPOSE OF REVIEW: To review novel multiple sclerosis (MS) therapies currently in clinical trials. RECENT FINDINGS: Sixty-seven clinical trials were selected and grouped into the following categories: Bruton's tyrosine kinase inhibitors, remyelinating therapies, immunomodulators, B cell therapies, supplements/microbiome influencers, and cell-directed therapies. Important findings include tolebrutinib's successful trial in nonrelapsing secondary progressive MS that slowed CDP compared to placebo and simvastatin's failure to show an effect on disability in its phase 3 trial. SUMMARY: Multiple strategies are being investigated in MS to address progressive disability, myelin repair, neural protection and treatment refractory disease. Some of these strategies have successfully completed clinical trials giving hope that some of the most vexing aspects of MS will soon have new treatment options.

• Klíčová slova
• Bruton's tyrosine kinase, clinical trials, disease modifying therapies, multiple sclerosis, remyelination,
• MeSH
• imunologické faktory * terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• roztroušená skleróza * terapie   farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• imunologické faktory * MeSH

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), characterized by inflammation and neurodegeneration. The pathophysiology of MS, especially its progressive forms, involves various cellular components, including microglia, the primary resident immune cells of the CNS. This review discusses the role of microglia in neuroinflammation, tissue repair, and neural homeostasis, as well as their involvement in MS and explores potential therapeutic strategies targeting microglial function. METHODS: A literature search conducted in August 2023 and updated in March 2025, using the PubMed database, focused on articles relating to microglia and MS published in 2018-2025. Additionally, ongoing clinical trials of Bruton's tyrosine kinase (BTK) inhibitors were identified through the ClinicalTrials.gov website in November 2023 and updated in March 2025. RESULTS: Microglia are highly adaptive and exhibit various functional states throughout different life stages and play critical roles in neuroinflammation, tissue repair, and neural homeostasis. Their altered activity is a prominent feature of MS, contributing to its pathogenesis. Imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) provide insights into microglial activity in MS. BTK inhibitors and other novel treatments for MS, including masitinib and frexalimab, show promise in modulating microglial function and influencing the disease progression rate. CONCLUSIONS: The multifaceted roles of microglia in CNS development, immune surveillance, and particularly in the pathogenesis of MS highlight the potential of targeting microglial functions in MS treatment. Emerging research on the involvement of microglia in MS pathophysiology offers promising avenues for developing novel therapies, especially for progressive MS, potentially improving patient outcomes in this debilitating disease.

• Klíčová slova
• central nervous system, disease management, microglia, multiple sclerosis, neuroinflammation,
• MeSH
• inhibitory proteinkinas * terapeutické užití   farmakologie   MeSH
• inhibitory tyrosinkinasy MeSH
• lidé MeSH
• mikroglie * účinky léků   imunologie   metabolismus   MeSH
• proteinkinasa BTK * antagonisté a inhibitory   metabolismus   MeSH
• roztroušená skleróza * farmakoterapie   imunologie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• BTK protein, human MeSH Prohlížeč
• inhibitory proteinkinas * MeSH
• inhibitory tyrosinkinasy MeSH
• proteinkinasa BTK * MeSH

Bruton's tyrosine kinase (BTK) is a crucial part of the B-cell receptor signaling pathway that has been extensively studied in various types of malignancies. Recent studies have extended our knowledge on its role in metabolism as well as neurological disorders. It may play an important role in the pathophysiology of neurological diseases, such as multiple sclerosis, Alzheimer's disease, brain injury, and several others. Activation of inflammasomes, mainly NLRP3, is one of the core mechanisms by which it promotes inflammation in the brain related to aging and diseases. In this paper, we provide an overview of the less explored roles of BTK in several brain diseases and discuss the potential of its inhibition to become a therapeutic target for neurological diseases.

• MeSH
• inflamasomy metabolismus   MeSH
• inhibitory proteinkinas * terapeutické užití   farmakologie   MeSH
• lidé MeSH
• nemoci nervového systému * farmakoterapie   enzymologie   metabolismus   MeSH
• proteinkinasa BTK * metabolismus   antagonisté a inhibitory   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• BTK protein, human MeSH Prohlížeč
• inflamasomy MeSH
• inhibitory proteinkinas * MeSH
• proteinkinasa BTK * MeSH

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

A review of Bruton’s tyrosine kinase inhibitors in multiple sclerosis Why was this study done? This study was done to find out about current knowledge on a type of drug, called Bruton’s tyrosine kinase inhibitors, or BTK inhibitors. There are currently six BTK inhibitors being studied as a possible new drug for treating multiple sclerosis (MS). Some of these six drugs are also being studied as a possible new drug for chronic spontaneous urticaria, rheumatoid arthritis and systemic lupus erythematosus. These are all autoimmune conditions, where the immune system mistakenly attacks parts of the body. Clinician scientists wanted to understand what is currently known about BTK inhibitors, how they work in the laboratory and how safe they could be for treating autoimmune conditions. This could help us understand more about BTK inhibitors in MS.What did the scientists do? The scientists assessed existing research on these six BTK inhibitors, through a process known as a literature review. These were results from ongoing clinical trials, and information collected through studying BTK inhibitors in laboratories. The researchers pieced together all these findings, to produce this paper that summarizes the results.What did the scientists find? The scientists found that most studies of BTK inhibitors for MS are still ongoing. So far, BTK inhibitors seem to show reasonable safety in most studies, but it is too early to know. The researchers also found out about how BTK inhibitors work in the lab, about what could happen if the drugs are taken for a long time and how they could impact female reproductive health.What do these findings mean? These findings will help other scientists learn more about BTK inhibitors in MS. Trials with BTK inhibitors for MS are still ongoing, but piecing together all the current findings gives a picture of what we know and what still needs to be done.

• Klíčová slova
• BTK inhibitors, disease-modifying therapies, long-term administration, multiple sclerosis, safety, selectivity,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.

• Klíčová slova
• aging, disease-modifying treatments, management, multiple sclerosis, symptomatic treatment,
• MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• management nemoci MeSH
• roztroušená skleróza * terapie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stárnutí imunologie   MeSH
• věkové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

• Klíčová slova
• central nervous system, cladribine, fingolimod hydrochloride, multiple sclerosis, ozanimod, ponesimod, siponimod, sphingosine 1 phosphate receptor modulators,
• MeSH
• imunosupresiva MeSH
• kladribin MeSH
• lidé MeSH
• nemoci centrálního nervového systému * MeSH
• relabující-remitující roztroušená skleróza * MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• imunosupresiva MeSH
• kladribin MeSH

Cumulative evidence along several lines indicates that B cells play an important role in the pathological course of multiple sclerosis (MS), neuromyelitisoptica spectrum disorders (NMOSD) and related CNS diseases. This has prompted extensive research in exploring the utility of targeting B cells to contain disease activity in these disorders. In this review, we first recapitulate the development of B cells from their origin in the bone marrow to their migration to the periphery, including the expression of therapy-relevant surface immunoglobulin isotypes. Not only the ability of B cells to produce cytokines and immunoglobulins seems to be essential in driving neuroinflammation, but also their regulatory functions strongly impact pathobiology. We then critically assess studies of B cell depleting therapies, including CD20 and CD19 targeting monoclonal antibodies, as well as the new class of B cell modulating substances, Bruton´s tyrosinekinase (BTK) inhibitors, in MS, NMOSD and MOGAD.

• Klíčová slova
• B cell depletion, autoimmune disease of the central nervous system, multiple sclerosis (MS), myelin oligodendrocyte glycoprotein associated autoimmune disease (MOGAD), neuromyelitisoptica spectrum disorders (NMOSD),
• MeSH
• autoimunitní nemoci * farmakoterapie   MeSH
• autoprotilátky MeSH
• B-lymfocyty MeSH
• centrální nervový systém MeSH
• lidé MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• autoprotilátky MeSH