Key clinical point: Janus kinase (JAK) inhibitors are generally safe but may increase risk of herpes zoster infection among patients with immune-mediated disease.
Major finding: Patients who received Janus kinase (JAK) inhibitors had a 57% increased relative risk of herpes zoster infection.
Study details: A systematic review and meta-analysis of 82 studies involving 66,159 patients with immune-mediated disease who were treated with JAK inhibitors.
Disclosures: The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
Olivera P et al. Gastro. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
The large number of patients represented in this meta-analysis is a major strength, although not all safety measures could be assessed across this cohort. Because the vast majority of placebo-controlled studies evaluated were of a relatively short duration, safety profiles will need continued assessment over longer periods, taking into account the background risk in patients with these immune-mediated diseases.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.