A regimen of three daily doses of tofacitinib (Xeljanz, Pfizer) slashed rates of colectomy by nearly 90% in patients admitted to the hospital for acute severe ulcerative colitis, researchers have found.
In addition to its marked efficacy, the high-dose therapy did not cause serious side effects or complications, and none of the patients who required colectomy had postsurgical infections, according to the study.
“If these findings are validated in large, randomized controlled studies, administering high-dose tofacitinib could be a practical and cost-effective alternative strategy for medical salvage in acute severe UC, with strikingly low rates of colectomy compared to current standards of care,” said Dana Lukin, MD, PhD, the clinical director of translational research at the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine, in New York City. He was not involved in the research.
The standard medical protocol for patients admitted for acute severe UC is IV corticosteroids for 72 hours before considering IV cyclosporine A or infliximab.
“Given the rapid action of Janus kinase inhibitors, like tofacitinib, and the questionable wisdom of waiting 72 hours before moving from IV corticosteroids to another treatment in high-risk acute severe UC, we investigated a short course of high-dose tofacitinib initiated at the same time as IV steroids,” said Peter Higgins, MD, PhD, the director of the IBD program at the University of Michigan’s Department of Internal Medicine, in Ann Arbor, and the senior investigator on the new study.
His team’s analysis included 40 patients admitted with acute severe UC and given IV corticosteroids with either 10 mg of tofacitinib twice or three times daily for three days, followed by 10 mg of tofacitinib twice daily. The investigators matched these patients with a control group of 228 patients with varying levels of UC severity. All patients in the control group had received IV corticosteroids, and some were given cyclosporine A or infliximab after initial corticosteroid treatment.
Dr. Higgins said patients who received tofacitinib had more severe endoscopic disease, on average, than controls. All recipients of tofacitinib were previously treated with one or more biologic agents, compared with 39% of controls.
According to Dr. Higgins, whose group presented the findings during a talk at the virtual 2021 Digestive Disease Week and published them in Clinical Gastroenterology and Hepatology (2021 May 24. doi:10.1016/j.cgh.2021.05.038), rates of colectomy at 90 days among all recipients of tofacitinib were 72% lower than in the control group (hazard ratio, 0.28). However, analyzing the data by dose of tofacitinib showed that only the triple-dose regimen was associated with the reduction in colectomy (Table).
Rates of infection with high-dose tofacitinib were statistically similar to the number of infections in the control group, and none of the patients who took the drug and ultimately required colectomy experienced infections after surgery. In contrast, 39% of controls who underwent colectomy developed postsurgical infections (P=0.065), Dr. Higgins reported.
Although the difference was just short of statistical significance, Dr. Higgins said results showing that 50% of tofacitinib recipients followed for 90 days were still using corticosteroids at that time, compared with 31% of controls (P=0.051), should be taken seriously.
“Given the small sample size, and the near significance of the finding, we should be cautious about ignoring this possible signal,” he said, adding that the patients taking tofacitinib may have had more severe disease at baseline and required a longer course of corticosteroids.
Despite the exciting results, Dr. Higgins said the retrospective nature of the study and the small patient population mean the data “should be taken with a grain of salt. That said, the effect size of tofacitinib looks impressive, and this could be an important development in the treatment of acute severe UC if it’s validated in further studies.”
Another recently published observational study with a similar sample size also indicated tofacitinib could be effective in this group of patients, albeit the frequency of colectomy was closer to historical rates (Aliment Pharmacol Ther 2021 Jun 20. doi:10.1111/apt.16463).
Dr. Lukin called the results “very provocative,” but urged clinicians “to be very cautious and consider the potential cardiovascular risk of high-dose tofacitinib as well as the risk of infection, bowel perforation or malignancy when initiating therapy with this drug. We should remember that this is a small, uncontrolled study that requires further validation in larger, randomized controlled trials.”