Serological evidence of increased susceptibility to varicella-zoster virus reactivation or reinfection in natalizumab-treated patients with multiple sclerosis

Abstract

Background: Serious adverse drug reactions of disease-modifying drugs in multiple sclerosis (MS) therapy may include enhanced susceptibility to reactivation of neurotropic herpes viruses like varicella-zoster virus (VZV) and the John Cunningham (JC) polyomavirus. Objective: Because symptomatic reactivation of these viruses are rare events, we determined the incidence of rises in anti-VZV IgG antibody levels as a potential marker for enhanced susceptibility to subclinical and symptomatic reactivation of neurotropic viruses. Methods: Anti-VZV IgG levels were measured in paired serum samples taken 6-8 months apart from natalizumab-treated MS patients, healthy blood donors and human immunodeficiency virus (HIV) infected patients. Results: The incidence of significant rises in anti-VZV IgG levels in natalizumab-treated MS patients was 4.26 per 100 person-years, which was significantly higher than in healthy blood donors. Retrospective evaluation of the available medical records of patients with rises of anti-VZV IgG levels did not reveal herpes zoster (i.e. shingles) manifestations. Conclusions:The increased incidence of significant rises of anti-VZV IgG levels in natalizumab-treated MS patients might indicate an association of natalizumab treatment of MS with an elevated risk of a subclinical VZV reactivation and/or reinfection events. Whether this is predictive of an increased risk of herpes zoster or even symptomatic reactivation of other neurotropic viruses remains to be determined in larger prospective studies.

Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study

“…Mild or moderate herpes zoster infections were reported in 2 of 47 patients (4%) treated with natalizumab. Previous reports have also found a slightly higher rate of herpes infection in natalizumab-treated patients compared with placebo-treated patients or healthy controls (Biogen, 2015;Fine et al, 2013;Kohlmann et al, 2015). However, the frequency of herpes infections does not appear to increase with longer duration of therapy, and the postmarketing reporting rate for herpes infections is consistent with the known safety profile for natalizumab.…”

High cumulative JC virus seroconversion rate during long‐term use of natalizumab

“…This may result in less immunity in the upper gastrointestinal tract and as a consequence a higher risk to get a primary infection with the JCV. In addition Kohlmann et al [23] found an extremely high incidence of rising anti-VZV immunoglobulin G levels in natalizumab-treated MS patients in contrast to age-and gender-matched healthy blood donors and to HIV-infected patients.…”

“…It is not totally excluded that this is (partly) caused by patients who were already infected (i.e. In addition Kohlmann et al [23] found an extremely high incidence of rising anti-VZV immunoglobulin G levels in natalizumab-treated MS patients in contrast to age-and gender-matched healthy blood donors and to HIV-infected patients. Recently, the results of some small studies suggested that patients can have viraemia without anti-JCV antibodies [5][6][7] more often than initially described by Rudick et al [19], who concluded that this was a rare condition.…”

Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis

“…Therefore, vaccination is performed in people who are seronegative for VZV (Singer 2013 ). However, increased rates of VZV/HZ infections have also been reported in MS patients receiving other immunosuppressive drugs, including the anti-integrin VLA-4 monoclonal antibody natalizumab, which blocks activated T cell migration into the CNS (Kohlmann et al 2015 ), and the anti-CD52 monoclonal antibody alemtuzumab, a T cell- and B cell-depleting antibody (Venkatachalapathy et al 2007 ). It appears in fact that the reporting of VZV infections in the post-marketing setting is disproportionate for fingolimod compared to the other disease-modifying treatments, and that the real frequencies may be comparable (Arvin et al 2015 ).…”