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. 2019 Mar 29:12:1756286419837809.
doi: 10.1177/1756286419837809. eCollection 2019.

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

Luca Prosperini  1 , Revere P Kinkel  2 , Augusto A Miravalle  3 , Pietro Iaffaldano  4 , Simone Fantaccini  5
Affiliations

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

Luca Prosperini et al. Ther Adv Neurol Disord. .

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.

Keywords: discontinuation; meta-analysis; natalizumab; relapsing–remitting multiple sclerosis.

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Conflict of interest statement

Conflict of interest statement: LP has received research grant from Genzyme and Italian MS Society (Associazione Italiana Sclerosi Multipla); consulting fees from Biogen, Genzyme, and Novartis; speaking honoraria from Almirall, Biogen, Genzyme, Merck Serono, Novartis, Roche and Teva; and travel grants from Biogen, Genzyme, and Teva. He is also a member of the steering committee AIFA (Italian Medicine Agency) on natalizumab. RPK has been a scientific consultant for CorTech, Genentech, ImStem, and Novoron and has received speaking honoraria from Acorda, Biogen, Genentech, and Genzyme. AAM has received consulting fees from Bayer, Biogen, the Consortium of MS Centers, Genentech, Genzyme, Questcor/Mallinckrodt, and the Rocky Mountain MS Center. PI has received consulting fees from Bayer-Schering, Biogen, and Genzyme; speaking honoraria from Biogen, Genzyme, Merck Serono, Novartis, and Teva; and travel grants from Biogen, Genzyme, Merck Serono, Novartis, and Teva. SF had equity interests in Biogen and was employeed by Biogen at the time of manuscript development.

Figures

Figure 1.
Figure 1.
Flowchart of evaluation process for the systematic review and meta-analysis.
Figure 2.
Figure 2.
Forest plots showing main results of the meta-analysis on six articles.,,,,, The study by Cohen et al., Iaffaldano et al. Kerbrat et al., and Rossi et al. were not included in all subanalyses given lack of data on disease duration and Gd+ lesions,, at natalizumab start, and number of natalizumab infusions before interruption., CI, confidence interval; IV, inverse variance; MS: multiple sclerosis; SD: standard deviation.
See this image and copyright information in PMC

References

    1. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910. - PubMed
    1. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–923. - PubMed
    1. O’Connor P, Goodman A, Kappos L, et al. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS study. Neurology 2014; 83: 78–86. - PMC - PubMed
    1. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880. - PubMed
    1. Bozic C, Richman S, Plavina T, et al. Anti-John Cunningham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol 2011; 70: 742–750. - PubMed