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Early Anti-CD20 and CNS Penetrant BTK Inhibition to Enhance OPC-Driven Remyelination in Multiple Sclerosis
N Vivekanandan1, M V Kumudhavalli2, M Kumar3
1Department of Pharmaceutical Analysis, Vinayaka Mission's College of Pharmacy, Salem, 636 308, Tamilnadu, India.
Abstract:
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.
Insights
Progression Independent of Relapse Activity (PIRA) drives disability in Multiple Sclerosis (MS). This review proposes a dual strategy combining anti-CD20 therapy and Bruton Tyrosine Kinase Inhibition (BTKi) for repair.
Area of Science:
- Neuroimmunology
- Neurodegeneration
- Therapeutic Strategies
Background:
- Multiple Sclerosis (MS) disability often progresses independently of relapses (PIRA).
- Chronic Active Lesions (CALs), including Paramagnetic Rim Lesions (PRLs) and Slowly Expanding Lesions (SELs), drive PIRA through inflammation.
- Current disease-modifying treatments inadequately control PIRA and CALs.
Purpose of the Study:
- To propose a novel two-arm, repair-oriented therapeutic strategy for MS.
- To integrate novel monitoring platforms for assessing treatment efficacy and guiding patient selection.
- To address the unmet need in managing PIRA and CALs in MS.
Main Methods:
- Review of existing data on anti-CD20 therapies and Bruton Tyrosine Kinase Inhibitors (BTKi).
- Proposal of a combined therapeutic approach: early high-efficacy anti-CD20 therapy and CNS-penetrant BTKi.
- Development of a repair-targeted monitoring platform using biomarkers (serum neurofilament light) and advanced MRI techniques (myelin water fraction, magnetization transfer).
Main Results:
- Evidence suggests disability slowing with tolebrutinib in non-relapsing secondary progressive MS.
- BTKi show heterogeneous relapse outcomes and class safety signals favouring add-on therapy.
- Proposed monitoring platform links clinical care with biological markers for repair assessment.
Conclusions:
- A dual therapeutic strategy combining anti-CD20 therapy and CNS-penetrant BTKi offers a promising repair-oriented approach for MS.
- Patient selection should be stratified based on disease activity (relapsing vs. non-relapsing progressive MS).
- Success is defined by reducing CAL burden and promoting remyelination, monitored via integrated biomarkers and imaging.
