The Art of Sequencing Disease-Modifying Therapies in Multiple Sclerosis

Over the past decade, therapeutic paradigms in multiple sclerosis have shifted toward a "hit-hard-and-early" approach to suppress inflammatory activity and delay progression. However, adverse events, safety concerns, aging, comorbidities, and life circumstances frequently necessitate treatment transitions during the patient journey. Sequencing decisions generally arise from 3 scenarios: insufficient efficacy, tolerability or safety issues, and conceptual considerations such as family planning or exit strategies for discontinuation. Discontinuation or de-escalation of therapy is associated with a significant risk of disease reactivation, particularly after lymphocyte-trafficking inhibitors, underscoring the importance of proactive transition planning to maintain disease control. Evidence suggests that treatment-specific immunologic effects strongly influence optimal sequencing. This narrative review synthesizes mechanistic insights and real-world clinical evidence to guide sequencing strategies for disease-modifying therapies (DMTs) in multiple sclerosis (MS), an increasingly relevant challenge in the era of early high-efficacy treatment. Following natalizumab, anti-CD20 monoclonal antibodies demonstrate superior control of relapse and MRI activity compared with sphingosine-1-phosphate receptor modulators (S1PRMs). Short transition intervals (<30 days) may minimize risk of rebound activity. After S1PRMs, rapid initiation of anti-CD20 therapies or cladribine seems effective, whereas prolonged washout periods increase relapse risk. Anti-CD20 therapies provide sustained suppression of inflammatory activity but are associated with long-term risks, including hypogammaglobulinemia and infections; cladribine may represent a viable exit strategy by enabling durable immune reconstitution. Platform therapies permit straightforward escalation without major rebound concerns, although lymphopenia must be considered when switching from dimethyl fumarate. Emerging Bruton tyrosine kinase inhibitors may further reshape sequencing paradigms, potentially functioning as maintenance therapies targeting compartmentalized inflammation after initial immune-depleting treatment. Future strategies will likely rely on close clinical and biomarker-based monitoring to individualize transitions and identify therapeutic windows. Overall, pragmatic sequencing that anticipates future switches and balances rebound risk against cumulative immunosuppression is essential for optimizing long-term outcomes in MS.