From the AGA Journals

Tofacitinib upped herpes zoster risk in ulcerative colitis

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How safe is tofacitinib?

As new mechanisms of action become available for ulcerative colitis (UC) drugs, clinicians must weigh the risks versus benefits (i.e., safety vs. efficacy). In this article, Sandborn and colleagues provide additional information on the safety profile of tofacitinib. They report an increased risk of herpes zoster that was dose dependent (sixfold increase on 10 mg twice daily). The overall safety profile was reassuring, is similar to the rheumatoid arthritis population treated with tofacitinib, and is in line with the safety profile of anti-TNF antibodies (excluding the increase risk of zoster). With a nonlive zoster vaccine now available, some have advocated vaccinating all patients being started on tofacitinib. However, there is a theoretical risk of disease exacerbation and ongoing studies that will hopefully answer this important question.

Dr. David A. Schwartz is professor of medicine, division of gastroenterology, hepatology and nutrition, Inflammatory Bowel Disease Center, Vanderbilt University, Nashville.

Dr. David A. Schwartz

Another emerging safety concern with tofacitinib involves venous thromboembolism (VTE). The Food and Drug Administration recently issued a warning based on the findings of a safety trial in rheumatoid arthritis in which they found an increased risk of PE and death in those on 10-mg twice-daily dose. The exact details of the risk have yet to be released. Enrollment in the trial required patients aged over 50 years with at least one cardiovascular risk factor. The European regulatory body (EMA) recently forbade the use of the 10-mg dose of tofacitinib for anyone at increased risk for VTE. It is unclear if this risk applies to those younger than 50 years without cardiovascular risk factors or the UC population. In the current study of UC patients, the rate of a major cardiovascular event was rare (n = 4; IR, 0.2). In the short term, it may be prudent to restrict the 10-mg twice-daily dose to those who do not fall into the high-risk category, or try to reduce the dose to 5 mg twice daily if possible.

David A. Schwartz, MD, professor of medicine, division of gastroenterology, hepatology and nutrition, Inflammatory Bowel Disease Center, Vanderbilt University, Nashville.



Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.

Herpes zoster is a significant contributor to morbidity, disability and chronic pain. clsgraphics/iStockphoto

Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).

With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.

Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.

Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.

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