Finite depletion, sustained control: can impulse therapy prevent rebound activity in multiple sclerosis?

In JNNP, Konen et al provide real-world evidence that, in carefully selected stable patients with multiple sclerosis (MS), discontinuation of ocrelizumab after about 30 months was not associated with a statistically significant increase in inflammatory disease activity over a median follow-up of 28.5 months¹, a relevant finding given that, although anti-CD20 therapies are highly effective in suppressing focal inflammatory activity, prolonged continuous B-cell depletion raises increasing concerns about hypogammaglobulinaemia, recurrent infections and impaired humoral vaccine responses.² However, the CIs were wide, and disease activity showed a numerical increase beyond 24 months off treatment, arguing less for ‘safety’ than for cautious feasibility under structured surveillance.¹ The next clinical question is therefore not only whether anti-CD20 therapy can be stopped, but how. Here, de-escalation may be more attractive than simple withdrawal in selected patients at higher infectious risk.

In a second Konen-led multicentre retrospective analysis, the group examined bidirectional switching between anti-CD20 therapies and cladribine among patients with active disease under current treatment.³ Following the switch, the proportion of patients with recurrent disease activity was markedly reduced in both directions, accompanied by clinical stabilisation and broadly stable short-term serum biomarker trajectories (including neurofilament light chain). Notably, hypogammaglobulinaemia appeared less prevalent after switching from anti-CD20 therapy to cladribine, in line with the hypothesis that a move away from continuous depletion may mitigate its cumulative immunological sequelae while allowing more preserved vaccine responses and peripheral and central immune surveillance.³

Together, these reports support the emerging concept of ‘exit strategies’ after anti-CD20 therapy discontinuation. For selected patients, particularly those developing hypogammaglobulinaemia, recurrent infections or age-related vulnerability due to immunosenescence, a maintenance to immune reconstitution therapy sequence (IRT, eg, transitioning to cladribine) could represent a pragmatic de-escalation bridging approach. Mechanistically, the sustained effects of cladribine on memory B-cell compartments, in particular its ability to cross the blood–brain barrier and target central nervous system-resident B-cells, provide biological plausibility for maintaining disease control while potentially reducing the long-term immunosuppressive burden.⁴

Future studies will play a crucial role in prospectively validating these observations by defining patient profiles most suitable for a finite number of anti-CD20 courses, identifying biomarkers and monitoring intervals that best anticipate delayed reactivation, and comparing ‘stop-and-monitor’ strategies with planned maintenance-IRT switching with respect to clinically meaningful endpoints. Another important question to address is the timing of the switch from an anti-CD20 therapy to cladribine. If the switch is due to loss of efficacy of the anti-CD20 therapy, the transition should be made as soon as possible, provided all baseline checks have been completed to ensure safe use of cladribine. If the switch is for de-risking infectious complications, it would make sense to allow for B-cell reconstitution and the administration of vaccines.⁴ In our experience, B-cell reconstitution happens in most patients at about 9 months after the last course of ocrelizumab. In the case of hypogammaglobulinaemia, we would not advise waiting for immunoglobulin levels to return to normal, as this typically takes several years and would put the patient at risk of MS disease reactivation.