Muhammad Albaab Rehmat

Background: Progressive multiple sclerosis (PMS) is a chronic inflammatory demyelinating CNS disease and the leading driver of irreversible neurological disability among MS patients.^1,2,3 Disability in PMS accumulates independently of relapses, driven by chronic active or “smoldering” lesions with persistently activated microglia that sustain axonal injury through cytokine release, oxidative stress, and impaired remyelination; this is all behind an intact blood-brain barrier (BBB) inaccessible to peripheral immune-targeted therapies.^2,3 Current DMTs primarily target peripheral adaptive immunity and provide only modest benefit on disability progression in PMS, leaving CNS-resident microglial inflammation undertreated. ^1,2,3 Bruton’s tyrosine kinase (BTK), active downstream of B-cell receptors and Fc receptors in both B cells and microglia, has emerged as a candidate target capable of addressing this gap. ^1,2,4

Objective: This narrative review evaluates the evidence supporting BTK inhibition as a therapeutic strategy for attenuating compartmentalized neuroinflammation in progressive MS, with a focus on microglial mechanisms, preclinical model systems, and early human clinical data.

Search Methods: A literature search was conducted using PubMed from 2012 to 2024. Search terms included: “Bruton’s tyrosine kinase,” “BTK inhibitor,” “progressive multiple sclerosis,” “microglia,” “neuroinflammation,” “compartmentalized inflammation,” “remyelination,” and “EAE.” Articles were selected based on direct relevance to BTK biology in CNS immune cells, preclinical MS models, and clinical trial data.

Results: BTK was found to be enriched in microglia and B cells within MS lesions, driving a disease-associated inflammatory transcriptional program in human iPSC-derived microglia.⁴ BTK inhibition shifted microglia toward a homeostatic phenotype, reduced TNF-α and IL-6, and lowered plasma neurofilament heavy chain in EAE, indicating neuroprotective effects beyond inflammation suppression.⁴ In a model that naturally transitions into a secondary progressive phase, BTK inhibition improved disability and motor coordination even when initiated after progression onset, with histological evidence of reduced demyelination and axonal preservation.⁵ Using the cuprizone demyelination model, BTK inhibition was shown to accelerate remyelination, improve myelin-debris phagocytosis, and promote a phenotypic shift from pro-inflammatory iNOS+ to reparative Arginase-1+ microglia, supporting a role for BTK in active CNS repair.⁶ A highly selective, CNS-penetrant BTK inhibitor achieved near-complete brain BTK occupancy and reduced neuroinflammation across three EAE models while sparing T-cell immunity, addressing off-target toxicity concerns of earlier compounds.⁷ In a Phase II randomized controlled trial, oral BTK inhibition produced a 56% reduction in gadolinium-enhancing T1 lesions over 24 weeks in relapsing MS patients, providing proof-of-principle for CNS target engagement in humans.⁸

Conclusion: Convergent evidence from human stem cell models, preclinical systems, and an early-phase clinical trial supports BTK as a key driver of compartmentalized microglial inflammation in PMS. BTK inhibition reduces neuroinflammation, protects axons, and restores reparative microglial function and remyelination; this addresses both the inflammatory and repair deficits of progressive disease. Definitive proof of disability benefit requires dedicated PMS trials with progressive-specific endpoints, including slowly expanding lesion volume and neurofilament levels. Highly selective, CNS-penetrant BTK inhibitors are the most appropriate candidates for this next step.

Works Cited:

1. Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol. 2023;19(5):289-304.
2. Dybowski S, Torke S, Weber MS. Targeting B cells and microglia in multiple sclerosis with Bruton tyrosine kinase inhibitors: a review. JAMA Neurol. 2023;80(4):404-414.
3. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8(11):647-656.
4. Gruber RC, Wirak GS, Blazier AS, et al. BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis. Nat Commun. 2024;15:10116.
5. Evonuk KS, Wang S, Mattie J, et al. Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination. Acta Neuropathol Commun. 2023;11:115.
6. Geladaris A, Torke S, Saberi D, et al. BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair. Acta Neuropathol. 2024;147:175.
7. Nüsslein-Hildesheim B, Ferrero E, Schmid C, et al. Remibrutinib inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. J Neuroinflammation. 2023;20:194.
8. Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. 2019;380(25):2406-2417.