Abstract
Background/Objectives Failure of natalizumab to control disease activity in multiple sclerosis (MS) is an uncommon event. It is currently unknown whether switching to an alternative high-efficacy disease-modifying therapy offers any benefits over persevering with natalizumab.
Methods Patients from the MSBase cohort suffering failure of natalizumab therapy, defined as breakthrough relapses or ≥3 new or gadolinium-enhancing lesions on MRI, were identified. Multivariable Andersen-Gill cumulative hazard models were used to analyse the associations of several variables with the risk of further relapses following natalizumab failure. Subsequent treatment decision was included as a time-dependent exposure. Secondary analyses evaluated the effect of treatment decisions on the risk of subsequent new MRI activity, expanded disability status scale (EDSS) worsening, and disease-activity free survival.
Results 1,131 natalizumab-treated patients fulfilled the inclusion criteria. Of these, 85 de-escalated treatment, 39 switched to anti-CD20 therapy, and 28 switched to alemtuzumab. Following natalizumab failure, switch to an anti-CD20 therapy was associated with a significantly lower risk of relapse (HR=0.51, 95%CI=0.29–0.88) compared to continuing natalizumab. Treatment de-escalation, or cessation, were associated with an increased risk of subsequent relapses (HR=1.40, 95%CI=1.10–1.79; HR=1.89, 95%CI=1.09–3.28, respectively). We did not find any evidence of a difference for switching to alemtuzumab, or outcomes studies in the secondary analyses.
Conclusion We have shown that following natalizumab failure, switching to B-cell depleting agents (ocrelizumab and rituximab), but not alemtuzumab, is associated with a clinically meaningful reduction in the risk of relapses in comparison to continuing natalizumab therapy. Clinicians should consider B-cell depletion following natalizumab failure where appropriate.
