Hot Topics in Multiple Sclerosis and Related Autoimmune Disorders

A Special Issue of Brain Sciences (ISSN 2076-3425) belonging to the section "Neuropharmacology and Neuropathology".

Deadline for manuscript submissions: 15 February 2027 | Viewed by 1697

Editor


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Guest Editor
Department of Neurology, Jackson T. Stephens Spine and Neuroscience Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Interests: neuroimmunology; BTKI; fenebrutinib; multiple sclerosis; progressive multiple sclerosis; relapsing multiple sclerosis; microglia; B cells; neuroinflammation

Special Issue Information

Dear Colleagues,

Bruton’s tyrosine kinase (BTK) inhibition is a promising strategy in multiple sclerosis (MS), targeting peripheral B-cell–driven immunity and central nervous system (CNS) myeloid cells, specifically microglia. Microglia are primary drivers of chronic inflammation and disease progression. While current therapies reduce relapses, they have a limited impact on compartmentalized CNS inflammation. In contrast, BTK inhibitors address smoldering lesions, meningeal inflammation, and progression independent of relapse activity. This field spans BTK biology, immune signaling, and the roles of B cells and microglia in MS pathogenesis. Clinical trial data for drugs like fenebrutinib, tolebrutinib, and evobrutinib show reduced recurrence rates and MRI lesion activity, demonstrating potential in progressive MS phenotypes. However, hepatotoxicity and CNS penetration remain important considerations. Ultimately, this study is significant as it could alter treatment for relapsing and progressive MS by bridging the gap between immunobiology, neuroinflammation, and clinical translation.

This Special Issue of Brain Sciences seeks to bring together cutting-edge work on multiple sclerosis and related autoimmune disorders, with an emphasis on advances that connect basic immunology, neuroinflammation, and clinical practice. We invite submissions spanning disease mechanisms, B-cell and myeloid cell biology, neuroinflammation, progressive disease processes, imaging and biomarker studies, and emerging therapeutic strategies. Original research articles, reviews, perspectives, and other contributions that advance understanding of disease pathophysiology and pharmacology or inform patient care are particularly encouraged. These broader themes also provide an important foundation for focused discussion of Bruton’s tyrosine kinase as an emerging target in MS and neuroinflammatory disease.

Dr. Shitiz Sriwastava
Guest Editor

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Keywords

  • Bruton’s tyrosine kinase inhibitors (BTKi)
  • multiple sclerosis
  • progressive multiple sclerosis
  • relapsing multiple sclerosis
  • microglia
  • B cells
  • neuroinflammation
  • fenebrutinib
  • tolebrutinib
  • evobrutinib

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Published Papers (1 paper)

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15 pages, 1196 KB  
Systematic Review
Emerging Role of BTK Inhibitors in Multiple Sclerosis: From Immunobiology to Clinical Translation
by Aashray Raj, Vansh Patel, Mehak Dang, Aken Kayastha, Yusuf Kagzi, Praveen Nandha Kumar Pitchan Velammal, Nidhi Agrawal, Kushagra Sharma, Nicholas Hansen, Sijin Wen, Shruti Jaiswal and Shitiz Sriwastava
Brain Sci. 2026, 16(6), 634; https://doi.org/10.3390/brainsci16060634 - 12 Jun 2026
Viewed by 1317
Abstract
Background: Multiple sclerosis (MS), an autoimmune disease, involves peripheral immune activation followed by CNS inflammation in a compartmentalized manner. Although high-efficacy disease-modifying therapies (HE-DMTs) have been effective in suppressing relapses in MS patients, they fail to effectively target chronic microglial activation and smoldering [...] Read more.
Background: Multiple sclerosis (MS), an autoimmune disease, involves peripheral immune activation followed by CNS inflammation in a compartmentalized manner. Although high-efficacy disease-modifying therapies (HE-DMTs) have been effective in suppressing relapses in MS patients, they fail to effectively target chronic microglial activation and smoldering lesions in MS patients. Bruton’s tyrosine kinase inhibitors (BTKis), which are orally active and capable of crossing the blood–brain barrier, have been found to be effective in modulating B cells and CNS-resident myeloid cells. Objective: The objective was to assess the efficacy and safety of Bruton’s tyrosine kinase inhibitors in patients with relapsing, secondary, and primary progressive MS. Methods: We performed a systematic review and meta-analysis according to the Cochrane and PRISMA guidelines (PROSPERO registration number: 1323474). We included randomized controlled trials (RCTs) that assessed fenebrutinib, evobrutinib, or tolebrutinib in adult MS patient populations. The main outcome measures were annualized relapse rate, MRI lesion activity, disability progression (EDSS), and hepatotoxicity. The quality of the included trials was assessed for bias by the RoB2 tool. Results: Six RCTs with 3616 participants were included. BTK inhibitors significantly reduced ARR compared with control therapy (pooled RR 0.24; 95% CI 0.15–0.39). MRI activity was reduced (mean difference −1.45 new/enlarging T2 lesions; 95% CI −2.08 to −0.82). Disability progression was unchanged in short-term relapsing MS trials. Serious hepatotoxicity was reported in 11.0% of BTKi-treated patients compared with 13.7% of control patients (pooled RR 0.80; 95% CI 0.66–0.96). However, increased transaminase elevations were reported in placebo-controlled trials, which indicates that hepatotoxicity remains a clinically relevant safety concern for the class. Conclusions: BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning. Full article
(This article belongs to the Special Issue Hot Topics in Multiple Sclerosis and Related Autoimmune Disorders)
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