New Review Offers Framework for Sequencing Disease-Modifying Therapies in MS

Switching disease-modifying therapies (DMTs) in multiple sclerosis (MS) has become an increasingly common, and increasingly complex, clinical decision as the field moves further into the “hit-hard-and-early” treatment era, according to a new narrative review published in Neurology: Neuroimmunology & Neuroinflammation. The review combines mechanistic and real-world evidence to guide health care professionals through 3 common scenarios that prompt a treatment switch: insufficient efficacy, tolerability or safety concerns, and conceptual considerations (eg, family planning or long-term exit strategies).¹

Sequencing After Sequestration Therapies

Natalizumab (Tysabri; Biogen) and the sphingosine-1-phosphate receptor modulators (S1PRMs) both work by trapping lymphocytes outside the central nervous system rather than depleting them, which sets up a distinct rebound risk once therapy stops. The authors found that switching to an anti-CD20 monoclonal antibody after either agent had produced better control of relapses and MRI activity than switching to another S1PRM. Importantly, keeping the transition interval under 30 days was associated with the lowest rates of breakthrough disease, whereas waits of 30 days or longer were linked to relapse rates as high as 16%.¹

Cladribine (Mavenclad; EMD Serono) also emerged as a reasonable option after an S1PRM, particularly for patients prioritizing a favorable pregnancy-planning profile; however, the authors caution that delaying cladribine to await lymphocyte recovery may do more harm than good because S1PRM-associated lymphopenia is largely a sequestration effect rather than true depletion.¹

Anti-CD20 and Cladribine as Exit Strategies

For patients who are well controlled on anti-CD20 therapy but develop hypogammaglobulinemia or recurrent infections, the review points to cladribine as a promising off-ramp that may normalize immunoglobulin levels and lymphocyte counts, offering an alternative to simply extending dosing intervals. Conversely, patients who experience breakthrough activity within a cladribine treatment cycle are generally better served by escalating to a monoclonal antibody instead of repeating cladribine, because recurrence within the 4-year cycle suggests the immune reconstitution approach has not achieved its goal.¹

Looking Ahead to BTK Inhibitors

The review also looks forward to Bruton tyrosine kinase inhibitors (BTKis), an emerging class with distinct efficacy profiles across agents such as tolebrutinib (Cenrifki; Sanofi) and fenebrutinib (Roche). Because BTKis lack the immune-depleting properties needed to counter rebound activity, the authors suggest they are unlikely to work well as a direct switch from sequestration agents. Instead, current evidence points toward BTKis functioning as maintenance therapy layered on after an initial depleting agent, targeting the smoldering, compartmentalized inflammation that drives disability progression independent of relapse.¹

Why This Matters for Pharmacists

The review’s emphasis on transition timing, immune monitoring, and individualized risk-benefit tradeoffs lands squarely in pharmacists’ scope of practice. Neurology and specialty pharmacists are frequently the team members who are tracking infusion schedules, lymphocyte and immunoglobulin trends, and John Cunningham virus antibody index results that inform exactly the kind of switching decisions this review addresses.² Further, a recent analysis of a health-system specialty pharmacy found that pharmacists themselves initiated more than a third of DMT switches identified in the study, emphasizing the pharmacist’s role both supporting a neurologist’s decision and flagging the need for one.³

Pharmacists are also positioned to counsel patients through the anxiety that can accompany a therapy switch, particularly around infection risk during washout periods, the practical logistics of infusion versus oral regimens, and family-planning timelines that intersect with teratogenicity windows for certain agents.²

As MS treatment increasingly relies on sequencing strategies that anticipate future switches from the outset, pharmacists’ ongoing relationships with patients—paired with their expertise in pharmacokinetics, monitoring parameters, and drug interactions—make them essential partners in translating evidence like this review into individualized care plans.

REFERENCES

1. Dersch RS, Pfeuffer S, Bsteh G, Wiendl H. The art of sequencing disease-modifying therapies in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2026;13(5):e200621. doi:10.1212/NXI.0000000000200621

2. Clark D, Jones S. Multiple sclerosis: disease-modifying therapies. The Pharmaceutical Journal. Accessed July 22, 2026. https://pharmaceutical-journal.com/article/ld/multiple-sclerosis-disease-modifying-therapies

3. Kozlicki MZ, Markley B, Shah NB, DeClercq J, Choi L, Zuckerman AD. A cross-sectional analysis of persistence to disease-modifying therapies in treatment naïve and experienced patients with relapsing multiple sclerosis at a health-system specialty pharmacy. Mult Scler Relat Disord. 2022;63:103860. doi:10.1016/j.msard.2022.103860