For the millions living with multiple sclerosis, suppressing relapses is no longer the finish line — it may not even be the right race. A growing body of evidence now makes clear that disability accumulation in MS increasingly proceeds through pathways entirely independent of the inflammatory flares that current therapies target so effectively, forcing a fundamental rethink of what treatment success actually means.
This comprehensive review synthesizes converging evidence that progressive MS is driven by brain-intrinsic mechanisms distinct from systemic inflammation: compartmentalized central nervous system inflammation that evades peripheral immunosuppression, chronic microglial activation, remyelination failure, and what the authors characterize as accelerated biological aging of neural tissue. Epstein-Barr virus infection is positioned as a critical initiating event, while later-stage disease appears governed by these CNS-autonomous processes. Population-based cohort data confirm that early deployment of high-efficacy therapies meaningfully improves long-term trajectories, yet progression risk climbs substantially after midlife even in patients with well-controlled relapse activity. Emerging biomarkers — serum neurofilament light chain, glial fibrillary acidic protein, paramagnetic rim lesions, and advanced quantitative MRI metrics — now provide granular windows into progressive pathology previously invisible to standard monitoring. Novel therapeutic candidates including brain-penetrant Bruton's tyrosine kinase inhibitors, CD40 ligand-targeting biologics, and CAR-T cell strategies represent mechanistically distinct approaches aimed at CNS-compartmentalized disease.
The conceptual shift here is significant: the field is moving from treating MS as a peripheral immune disorder to recognizing it as a neuro-inflammatory-degenerative continuum requiring layered, precision-stratified interventions. The integration of fluid biomarkers, advanced imaging, genomics, and machine learning for individualized benefit-risk profiling represents a methodologically mature direction, though most candidate therapies remain in early trial phases. For a condition affecting neurological function across decades of adult life, the recognition that midlife marks a biological inflection point has immediate implications for monitoring strategies and long-term care planning. This review is best characterized as a well-synthesized roadmap for a field in active transition rather than a report of singular new findings.