Bruton’s Tyrosine Kinase Inhibitors and Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis: A Review of Complementary Paradigms for a Divergent Disease

Multiple sclerosis (MS) is a heterogeneous autoimmune disease driven by peripheral immune dysregulation and compartmentalized central nervous system (CNS) inflammation. Despite more than 20 approved disease-modifying therapies, disability accrual remains common, particularly in patients with highly active relapsing disease and progressive phenotypes characterized by silent progression and smoldering neuroinflammation. Two emerging therapeutic strategies address these unmet needs: Bruton’s tyrosine kinase (BTK) inhibitors and autologous haematopoietic stem cell transplantation (HSCT). Although mechanistically distinct, both aim to overcome limitations of conventional immunosuppression by intervening more deeply in the autoimmune cascade. This narrative review synthesized mechanistic, clinical, and translational evidence identified through a comprehensive search of PubMed, Scopus, Web of Science, and ClinicalTrials.gov from January 2010 to August 2025. BTK inhibitors are oral, CNS-penetrant therapies that selectively modulate B-cell signaling and CNS-resident myeloid cells without broad lymphocyte depletion, enabling continuous immunomodulation. Phase II–III trials of evobrutinib, tolebrutinib, and fenebrutinib show consistent MRI activity suppression but variable effects on relapses and disability, suggesting relevance in microglial-driven, relapse-independent disease. HSCT is a one-time immune reconstitution therapy that eradicates autoreactive immune clones and restores immune tolerance. Randomized and real-world studies demonstrate profound suppression of inflammatory activity, stabilization or improvement of disability, and durable treatment-free remission in selected patients with highly active relapsing–remitting MS, although procedure-related risks require strict eligibility criteria and experienced centers. Together with BTK inhibitors, HSCT represents a complementary strategy within an increasingly personalized MS treatment paradigm, emphasizing biomarker-guided patient selection and optimized therapeutic sequencing.