Multiple sclerosis: New immunomodulatory strategies and biomarkers

Introduction and purpose: Multiple Sclerosis (MS) disability accumulation is driven primarily by compartmentalized, subclinical neuroinflammation and diffuse neurodegeneration, termed smouldering MS. While traditional disease-modifying therapies (DMTs) control peripheral relapses and focal MRI activity, halting this progression remains a major challenge. Consequently, the therapeutic landscape is shifting toward novel central nervous system-targeting strategies to prevent Progression Independent of Relapse Activity (PIRA). The clinical utility of these interventions relies on highly sensitive fluid biomarkers, including serum neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and kappa free light chains (kFLC), to track neuroaxonal injury, astrogliosis, and intrathecal immunoglobulin synthesis. This review evaluates the latest clinical evidence for next-generation immunomodulatory therapies, specifically autologous hematopoietic stem cell transplantation, Bruton’s tyrosine kinase inhibitors, and anti-CD20 monoclonal antibodies, alongside the diagnostic and prognostic roles of these emerging biomarkers.