ABSTRACT & COMMENTARY
By Joseph E. Safdieh, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Safdieh reports no financial relationships relevant to this field of study.
Synopsis: The risk of varicella-zoster virus infections in patients treated with fingolimod is slightly higher than placebo, but is overall quite low.
Source: Arvin AM, et al. Varicella-zoster virus in patients treated with fingolimod: Risk assessment and consensus recommendations for management. JAMA Neurol 2014;Nov 24 doi:10.1001/jamaneurol.2014.3065 [Epub ahead of print].
The rapidly evolving field of novel therapies for multiple sclerosis (MS) has led to FDA approval of a number of oral therapies. Fingolimod, the first oral therapy approved for MS, sequesters certain types of T lymphocytes in the lymph nodes by modulating sphingosine 1-phosphate receptors. Fingolimod lowers lymphocyte counts by 20-30% and, therefore, does increase the risk of infections. FDA labeling for fingolimod specifically notes a death from disseminated zoster infection and states that patients should be assessed for prior varicella infection or vaccination, or have varicella-zoster virus (VZV) serum antibodies assessed prior to initiation of therapy to ensure prior immunity. Nonimmune patients should be vaccinated prior to initiation of therapy. VZV is a herpesvirus that causes varicella (chickenpox) during initial infection and shingles (herpes zoster) during reactivation. Risk factors for reactivation (shingles) increase in settings of reduced T-cell immunity, including age, HIV infection, and immunosuppression by medications.
In this study, the authors calculated the rates of VZV infection in patients with MS treated with fingolimod. The rates were derived from a number of cohorts, including the patients enrolled in the completed Phase 2 and 3 trials for fingolimod and postmarketing reports since approval in 2010. It is important to note that the clinical trial included a cohort of patients receiving 1.25 mg/day, much higher than the eventual FDA-approved dose of 0.5 mg/day. Rates of VZV were calculated in patient-years.
Analysis of the data revealed that the rate of VZV infection in the fingolimod-treated patients in clinical trials was 11 per 1000 patient-years. The placebo rate was 6 per 1000 patient-years. In postmarketing data, the reported rate of VZV infection was 7 per 1000 patient-years, lower than the clinical trial patients but higher than postmarketing reports for all other disease-modifying MS therapies. Of note, two fatal cases of VZV were reported, one during the clinical trial in a patient receiving the high dose and another with standard dosing reported in postmarketing data. That patient was previously treated with natalizumab and was receiving 10 days of concomitant corticosteroid therapy. The majority of cases of VZV were uncomplicated, involving one or two dermatomes. Eight percent of cases involved more than two dermatomes. Non-cutaneous dissemination was extremely rare. Rates of serious VZV infections were not higher in fingolimod groups compared to other MS disease-modifying therapies.
Based on these results, the authors conclude that while the risk of VZV in fingolimod-treated patients is higher than placebo, the absolute numbers (11 per 1000 patient-years in the clinical trial and 7 per 1000 patient-years in postmarketing) are quite low and the vast majority of cases involved one or two dermatomes only. However, the authors do propose consensus guidelines to most effectively mitigate the risk of VZV in patients who are being considered for treatment or who are being treated with fingolimod. These include testing for VZV antibodies in patients with no clear history of varicella, vaccinating non-immune patients with varicella vaccination at least 1 month before initiating therapy, avoiding varicella vaccination during fingolimod therapy as it is a live-attenuated vaccine, limiting corticosteroid treatment for MS relapses to 3-5 days in patients receiving fingolimod, and having high vigilance for recognizing and treating zoster in patients on fingolimod therapy. Patients should be educated about signs and symptoms of shingles and told to report them to their physician if they suspect shingles. The consensus is to stop fingolimod in the setting of zoster only if disseminated and to treat VZV infections with antiviral therapy as per CDC guidelines.