Targeting Bruton's Tyrosine Kinase (BTK) in Autoimmunity: Achievements, Opportunities and Challenges

The selective inhibition of Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic strategy for autoimmune diseases by targeting key signaling pathways in both adaptive and innate immune cells. Initially developed for B cell malignancies, BTK inhibitors are now being evaluated across a range of immune-mediated disorders, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. Beyond B cell receptor signaling, BTK inhibition modulates Fc receptor- and toll-like receptor-dependent activation of myeloid cells, thereby extending its therapeutic relevance. BTK inhibitors comprise a pharmacologically diverse class, including covalent (irreversible) and non-covalent (reversible) inhibitors, which differ in binding mode, selectivity, and pharmacokinetic properties. These differences are increasingly recognized as critical determinants of clinical performance. While early studies demonstrated robust target engagement and anti-inflammatory activity, clinical outcomes have been inconsistent across diseases. In multiple sclerosis, BTK inhibitors have shown promising effects on inflammatory activity and emerging signals on disability progression. In contrast, in rheumatoid arthritis and systemic lupus erythematosus, several compounds failed to meet primary clinical endpoints despite clear pharmacodynamic effects. These divergent outcomes highlight that the efficacy of BTK inhibition depends on disease-specific immune architecture and the relative contribution of BTK-dependent pathways. Safety considerations, including hepatotoxicity signals observed in late-stage trials, and differences between individual compounds further complicate clinical development. In this review, we summarize the mechanistic rationale of BTK inhibition, compare key pharmacological properties across BTK inhibitors, and critically assess clinical trial outcomes. We further discuss key challenges, including patient heterogeneity, trial design constraints, the lack of direct comparative studies, and outline future directions such as biomarker-driven patient selection and the development of BTK degraders.