Early Anti-CD20 and CNS Penetrant BTK Inhibition to Enhance OPC-Driven Remyelination in Multiple Sclerosis

Disability in Multiple Sclerosis (MS) increasingly accrues through Progression Independent of Relapse Activity (PIRA), driven by compartmentalized inflammation in Chronic Active Lesions (CALs) such as Paramagnetic Rim Lesions (PRLs) and Slowly Expanding Lesions (SELs), which are poorly controlled by disease-modifying treatments. This review proposes a two-arm, repair-oriented strategy: (1) early high-efficacy anti-CD20 therapy to preserve axons and myelin (substrate preservation) while acknowledging residual on-treatment PIRA, and (2) central nervous system penetrant Bruton Tyrosine Kinase Inhibition (BTKi) to modulate B cell and microglial networks that sustain rim and meningeal pathology. Supporting data include disability slowing with tolebrutinib in non-relapsing secondary progressive MS, heterogeneous relapse outcomes across BTKi molecules, and class safety signals that favour BTKi as an add-on rather than a replacement for anti-CD20 therapy. This study outlines a repair-targeted monitoring platform that links care with biology, combining serum neurofilament light for axonal injury, brain volumetrics for structural protection, and myelin-sensitive MRI metrics, such as myelin water fraction and magnetization transfer, to quantify lesion-level remyelination. Functional readouts for trials, including visual evoked potential latency, offer complementary measures of repair. Patient selection bifurcates into active relapsing MS, suited to upfront anti-CD20 therapy to maximise salvageable substrate, and non-reversing SPMS or PPMS, enriched for PRL and SEL burden, where CNS-penetrant BTKi is prioritised. Success is defined as a decrease in CAL burden and an increase in rem.