A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation

Silvia Rossi, Caterina Motta, Valeria Studer, Fabrizia Monteleone, Valentina De Chiara, Fabio Buttari, Francesca Barbieri, Giorgio Bernardi, Luca Battistini, Gary Cutter, Olaf Stüve, Marco Salvetti, Diego Centonze

Research output: Contribution to journalArticle

Abstract

Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation. Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation. Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade. Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation. Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.

Original languageEnglish
Pages (from-to)59-68
Number of pages10
JournalMultiple Sclerosis Journal
Volume19
Issue number1
DOIs
Publication statusPublished - 2013

Keywords

  • Apoptosis
  • CIRIS
  • lymphocytosis
  • rebound
  • relapse

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

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