Varicella-zoster virus reactivation and cardiovascular risk: implications for patients receiving JAK inhibitors

Varicella-zoster virus (VZV) is a neurotropic herpesvirus responsible for varicella and herpes zoster. Beyond its classical clinical manifestations, recent evidence shows that VZV reactivation may contribute to acute cardiovascular events. Vaccination reduces the incidence of herpes zoster and may confer cardiovascular benefits, although causality remains unproven. To summarise current evidence linking VZV infection to cardiovascular risk, evaluate the impact of VZV vaccination in the general and immune-mediated inflammatory disease (IMID) populations, and discuss the hypothesis that increased VZV reactivation under Janus kinase inhibitor (JAKi) therapy may partially explain the major adverse cardiovascular event (MACE) signal observed in the ORAL Surveillance trial. Epidemiologic studies show a consistent association between herpes zoster and a transient increase in MACEs. Mechanistic insights support VZV's ability to infect vascular tissues, induce inflammation, destabilise atherosclerotic plaques, and enhance thrombogenicity. Vaccination with the recombinant zoster vaccine (RZV) effectively prevents herpes zoster and is associated with reduced MACEs in large observational cohorts, although randomised trials powered for cardiovascular endpoints are lacking. In IMID populations, vaccination reduces herpes zoster incidence but has not consistently demonstrated cardiovascular benefit. JAKis, which increase VZV reactivation risk by impairing antiviral immunity, may create episodic vascular insults that contribute to the elevated MACE rates observed with tofacitinib in the ORAL Surveillance trial. VZV reactivation is a plausible and potentially preventable contributor to cardiovascular risk, particularly in older and immunosuppressed individuals. While vaccination shows promise in reducing zoster-associated cardiovascular risk, definitive causal evidence remains lacking. The hypothesised JAKi-VZV-vascular pathway warrants prospective evaluation.