Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis

Abstract

Background: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity. Objective: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data. Methods: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing–remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients’ clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse. Results: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1–24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9–80% of patients and peaked at 4–7 months, whereas radiological disease activity was observed in 7–87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation ( p ⩽ 0.05). Conclusions: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.

Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation

“…Controversial findings have been reported about the association between the number of NTZ infusions and the risk for reactivation, as some studies have reported higher reactivation rates in patients with shorter exposure to NTZ (Lo Re et al, 2015;Miravalle et al, 2011;Prosperini et al, 2019;Vellinga et al, 2008). In our analysis, we did not detect any correlation between the number of NTZ infusions and the risk for reactivation.…”

“…As expected, reactivation of MS has been shown to occur during the first year after discontinuation of NTZ in some patients (Fox et al, 2014;Gueguen et al, 2014;Havla et al, 2011;Iaffaldano et al, 2015;Kerbrat et al, 2011;Lo Re et al, 2015;O'Connor et al, 2011;Salhofer-Polanyi et al, 2014;West and Cree, 2010). A recent systematic review and meta-analysis of six studies demonstrated that younger age, higher number of relapses, and gadolinium-enhancing lesions before initiation of treatment as well as fewer NTZ infusions were associated with an increased risk for disease reactivation after cessation of treatment (Prosperini et al, 2019).…”

Neurological immunotherapy in the era of COVID-19 — looking for consensus in the literature

“…Most, but not all, international and national recommendations suggest that natalizumab therapy should not increase the risk of severe COVID-19 ( Question 11). Indeed, cessation or interruption of natalizumab treatment carries a considerable risk of MS disease exacerbation or rebound activity in patients with highly active MS 66 , the consequences of which are likely to outweigh the risk of COVID-19. Natalizumab has been suggested as a bridging therapy (a drug that can be used for an immediate effect owing to its fast onset of activity and high efficacy but that is not necessarily considered a long-term option) during the COVID-19 pandemic, and the first reports of SARS-CoV-2 infection in patients receiving natalizumab therapy have suggested no increase in risk 67,68 .…”

Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations

“…The risk of disease reactivation after natalizumab discontinuation may be mitigated somewhat if treatment is switched during a period of relative disease quiescence or if the transition time is < 1-2 months. 145,146 There are limited data that switching from natalizumab to alemtuzumab is more effective than to fingolimod. 147 However, switching from natalizumab to any DMT with a long duration of action may be considered a high-risk approach since treatment could not be withdrawn in such circumstances if the patient had subclinical PML.…”