4.4  tsDMARDs
The overall risk of serious and opportunistic infections observed with Janus Kinase (JAK) inhibitors in RA patients is roughly comparable with bDMARDs [64,65], although these early years of tofacitinib and baricitinib use have raised the issue of an increased risk of Herpes Zoster virus (HZV) infections [66]. Data from tofacitinib pooled population enrolled in RCTs showed an HZV incidence rate of 4.0 per 100 patient-years (with greater incidence in geographic area with high HZV endemicity), doubling the rates of RA patients not receiving JAKis [67]. A similar picture has also been observed in the overall development program of baricitinib, with an incidence rate of 3.2 cases per patient-years [68]. The subsequent real-life experience from US claim databases revealed that the risk of HZV was higher in patients receiving tofacitinib compared to those treated with abatacept (aHR 2.01 (95% CI 1.40; 2.88) [69], and the risk of serious hospitalized HZV infection is 2-fold higher versus all bDMARDs [70]. Older age, female sex, prednisone >7.5 mg/day, prior infection, and greater number of hospitalizations were associated with increased HZV risk, whereas vaccination was associated with a lower risk [71]. More recent reports from RCTs conducted with novel JAK-1 selective inhibitors upadacitinib and filgotinib have basically confirmed the same trend, suggesting that the increase in HZV infections can be considered as a class effect of JAKis [72,73]. Although the exact mechanism by which HZV reactivation occurs in the context of JAK inhibition is unclear, the downregulation of both cell-mediated immunity and innate antiviral signaling through type I and II interferons (IFN) is likely to be involved [74].
Currently, no data are available on the risk of respiratory virus infections carried by JAK inhibitors.