Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system for which more than 20 disease-modifying therapies (DMTs) are currently available. Recent advances in diagnostic criteria, biomarker development, and understanding of disease biology have challenged traditional phenotype-based treatment paradigms and created new opportunities for individualized therapeutic strategies. The 2024 McDonald diagnostic criteria expand the biological definition of MS through incorporation of advanced MRI biomarkers, thereby supporting earlier diagnosis and potentially earlier treatment initiation. Aging influences both disease pathobiology and treatment risk-benefit balance, contributing to reduced focal inflammatory activity, increased progression, diminished regenerative capacity, and greater susceptibility to infections and comorbidities. These observations have important implications for treatment initiation, sequencing, escalation, de-escalation, and discontinuation. Current monitoring strategies remain centered on relapses, disability measures, and MRI lesion activity, but each has important limitations. Emerging imaging and fluid biomarkers, including brain and spinal cord atrophy metrics, neurofilament light chain, glial fibrillary acidic protein, and paramagnetic rim lesions, may improve biological stratification and therapeutic decision making, although further validation is needed. Safety considerations vary substantially across DMT classes. Real-world data have advanced our understanding of long-term risks, particularly with B-cell-depleting therapies. Novel therapeutic approaches in development are intended to more effectively target compartmentalized central nervous system inflammation and progression biology while potentially reducing systemic immunosuppression. As a result of these factors, MS management is evolving.