JAK Inhibitors Increases Herpes Zoster Risk in IBD Patients

Pablo A. Olivera

The advent of Janus kinases (JAKs) inhibitors has improved treatment of inflammatory bowel disease (IBD), but may have increased the risk of various adverse events.

A team, led by Pablo A. Olivera, Gastroenterology Section, Department of Internal Medicine, CEMIC, performed a systematic review and meta-analysis investigating the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, or ankylosing spondylitis.

Currently, JAKs inhibitors like tofacitinib are used to treat inflammatory bowel disease and other immune-mediated diseases. While this treatment is effective for ulcerative colitis, there are safety concerns.

The investigators examined various controlled trials that took place between 1990-2019 and performed a manual review of conference databases from 2012-2018.

The investigators sought primary outcomes of incidence rates of adverse events and serious adverse events and estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality.

The team performed a meta-analysis of the available data to assess the relative risk of the adverse events with a random-effect model used to give a more conservative estimate of the effect of individual therapies. This methodology allows for any heterogeneity among studies.

Overall, they identified 973 studies, 82 of which were included in the final analysis. These studies comprised of 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor.

About 66% of the studies included in the final analysis were randomized controlled trials. The incidence rate of adverse events was 42.65 per 100 person-years and 9.88 per 100 person-years for serious adverse events.

The incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events was 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively.

The investigators found mortality was not increased in patients treated with JAK inhibitors when compared to patients given a placebo or active comparator (RR, 0.72; 95% CI, 0.40-1.28). However, they did find a significant increase in the risk of herpes zoster infection for patients who received JAK inhibitors (RR, 1.57; 95% CI, 1.04-2.37).

“In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors,” the authors wrote. “All other [adverse events] were not increased among patients treated with JAK inhibitors.”

Treatment for diseases like ulcerative colitis and Crohn’s disease have changed significantly in the last 20 years when biologics were first introduced. However, available treatment options have limitations in terms of primary nonresponse, secondary loss of response, potentially serious adverse events, and treatment-related costs.

JAK inhibitors are a family of small molecules that block at least 1 of the intracellular tyrosine kinases—JAK1, JAK2, JAK3, and TYK2. Many cytokines exert biological functions by activating the JAK-STAT pathway, which has a crucial role in intracellular cytokine signaling.

These compounds can block several cytokines and inflammatory pathways simultaneously to induce immunosuppression.

The study, “Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis,” was published online in Gastroenterology.