A comprehensive review of varicella-zoster virus, herpes simplex virus and cryptococcal infections associated with sphingosine-1-phosphate receptor modulators in multiple sclerosis patients

Abstract

Sphingosine-1-phosphate (S1P) receptor modulators are a new class of oral disease-modifying therapies used for Multiple Sclerosis (MS). These are immunomodulatory drugs and can thus increase the risk of certain infections in these patients. This paper summarizes the existing data on the most common opportunistic infections associated with the drugs in this class: Varicella Zoster Virus (VZV), Herpes Simplex Virus (HSV), and Cryptococcus neoformans. A literature review and descriptive analysis of reported cases and clinical phase III study findings on the incidences of these infections were conducted using PubMed and Google Scholar. Results regarding fingolimod, siponimod, ozanimod, and ponesimod were obtained. Overall, the incidence of these infections was found to be extremely low in MS patients treated with S1P receptor modulators. Among the four drugs in this class, the incidence rates of VZV, HSV, and cryptococcal infections were either similar or slightly higher than placebo, with some infections not reported in cases of ozanimod and ponesimod. Most of these resulted in favorable outcomes, with very few disabilities or fatalities. However, this paper highlights the increasing relevance of assessing infectious risk factors to promote the early identification of serious complications related to these drugs. Opportunistic infections should be considered in the differential diagnosis of an MS relapse in the setting of disease-modifying treatment.

Keywords: Cryptococcal infections and S1PR modulators; DMTs and opportunistic infections; Herpesvirus infections and S1PR modulators; S1PR modulators; VZV infections and S1PR modulators.