Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, causing demyelinated lesions that may present as fatigue, visual disturbances, and cognitive decline. Relapsing-remitting MS (RRMS) is the most common form, marked by relapses followed by recovery. In highly active RRMS (HA RRMS), characterized by frequent relapses and higher disability burden, early and sustained disease control is paramount for optimal long-term outcomes.

Therapies with established efficacy in HA RRMS can demonstrate rapid onset of action, significantly reducing relapses and MRI activity compared to platform and other established disease-modifying therapies (DMTs). Earlier treatment initiation offers greater potential to delay disability accrual. Some patients may experience confirmed disability improvement (CDI), a measurable reversal of functional decline. While relapses primarily drive early disability, progression independent of relapse activity (PIRA)—which can occur despite apparent stability—becomes more prominent over time, underscoring the need for timely and sustained intervention.

Vigilant monitoring is crucial. JC virus (JCV) testing is mandated due to progressive multifocal leukoencephalopathy (PML) risk. However, newer assays often classify patients as JCV-positive, which may affect perceived risk assessment. Negative results remain reliable, and PML risk remains low within the first two years of treatment. Risk-mitigation strategies—such as switching to lower-risk DMTs, using extended dosing intervals, or implementing closer MRI monitoring—are especially relevant beyond 12–24 months. Real-world retention on therapy serves as a marker of its tolerability and effectiveness. Shared decision-making is essential, balancing efficacy, risk, and patient quality of life.

How should HCPs approach JCV assay discrepancies when assessing PML risk in HA RRMS? What strategies best support long-term efficacy while minimizing safety concerns in highly active RRMS?