From the AGA Journals

JAK inhibitors may increase risk of herpes zoster

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.

Dr. Clara Abraham of Yale University

Dr. Clara Abraham

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.



For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

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