Multiple sclerosis

Abstract

Multiple sclerosis (MS) is increasingly recognized not merely as a disorder of acute inflammation but as a condition driven by underlying neurodegeneration and chronic inflammation, known as progression independent of relapse activity (PIRA). PIRA occurs from the early stages of the disease and is a major driver of long–term disability. This review discusses the evolving therapeutic landscape and diagnostic criteria in the context of these pathophysiological insights.

While current disease–modifying therapies (DMTs) primarily target acute inflammation, real–world evidence and clinical trials demonstrate that the early introduction of high–efficacy DMTs (HE–DMTs), such as anti–CD20 monoclonal antibodies, is superior to escalation therapy. Early intensive treatment significantly delays the conversion to secondary progressive MS and suppresses PIRA more effectively than traditional approaches. Furthermore, emerging Bruton's tyrosine kinase (BTK) inhibitors show promise in targeting the innate immune mechanisms associated with smoldering inflammation.

Reflecting accumulating evidence supporting the superiority of early induction therapy, the 2024 revisions to the McDonald diagnostic criteria aim to facilitate earlier diagnosis. Key updates include the incorporation of radiologically isolated syndrome (RIS) into the diagnostic framework, the addition of the optic nerve as a site for dissemination in space, and the utilization of novel biomarkers such as kappa free light chains, the central vein sign, and paramagnetic rim lesions to increase specificity and sensitivity. Ultimately, while early intervention with HE–DMTs is essential to mitigate disability accumulation, developing therapies that effectively target the neurodegenerative component of MS remains a critical unmet need.