For biologic-experienced patients hospitalized with acute severe ulcerative colitis, off-label, high-intensity doses of tofacitinib (Xeljanz) given with intravenous corticosteroids may have reduced their chances of undergoing a colectomy, a small retrospective study found.
Within 90 days, 15% of patients receiving tofacitinib at standard or more frequent dosing and 20% of patients in the control group underwent a colectomy, with a multivariate model finding that tofacitinib reduced the risk of colectomy (HR 0.28, 95% CI 0.10-0.81, P=0.018), reported Jeffrey A. Berinstein, MD, MSc, and colleagues from the University of Michigan in Ann Arbor.
Giving hospitalized patients 10 mg of tofacitinib three times per day for a total of nine doses (an off-label approach) was significantly protective against a colectomy (HR 0.11, 95% CI 0.02-0.56, P=0.008), but giving 10 mg of tofacitinib to patients twice daily was not significantly protective (HR 0.66, 95% CI 0.21-2.09), the authors wrote in Clinical Gastroenterology and Hepatology.
The group noted that while the study was not powered for safety, “we did not observe any increased risk of infection, venous thromboembolic events, or cardiovascular events with inpatient tofacitinib.”
Safety with the JAK inhibitor has been a particular concern of late, with the FDA issuing an alert after a post-marketing safety study in rheumatoid arthritis patients turned up a significantly higher risk of malignancy and a numerical increase in major adverse cardiovascular events versus other available treatments.
It is estimated that 30% of patients with acute severe ulcerative colitis will not benefit from the current standard of care, which includes rapid IV corticosteroids. Cyclosporine or infliximab (Remicade or Inflectra) have been used previously to benefit steroid-resistant acute severe ulcerative colitis, and both have shown similar comparative rates at reducing colectomy risk, but treatment failure still persists leaving patients to require a colectomy.
Selected study participants were adults with severe acute ulcerative colitis who were hospitalized from January 2010 to December 2020, and were given IV corticosteroids. Patients were excluded if they had been prescribed infliximab followed by tofacitinib while hospitalized, or if prescribed tofacitinib before being admitted. Patients who were given tofacitinib were matched to controls (1:3, respectively).
The primary outcome was to estimate the risk of patients requiring a colectomy at 90 days. The secondary outcomes included steroid dependence and complication rates.
Overall, 40 patients received tofacitinib and 113 did not. The average age of participants was 34 in the tofacitinib group and 38 in the control group. The tofacitinib group had 60% women, while the control group had 51% women and most were white. Patients had an average inflammatory bowel disease duration of 10 years in the tofacitinib group and 8 years in the control group. Over 77% of patients in the tofacitinib group presented with extensive colitis than compared to just over 70% in the control group.
All patients in the tofacitinib group had prior experience with biologics compared to less than 40% of the control group. Other notable differences included fewer patients with outside hospital transfers (3.2% vs 6.2%, respectively), and tofacitinib patients were taking steroids for a longer period of time (51 days vs 9 days). In the tofacitinib group, 40% of participants were given 10 mg doses of the drug twice daily, while 60% of participants were given an off-label approach of 10 mg three times daily. The average length of patient hospital stays was about 9 days in the tofacitinib group and 7 days in the control group.
The authors noted albumin nadir, number of failed target therapies, colonic dilation, and endoscopic Mayo score were all significant predictors of colectomy in an adjusted analysis.
There was no significant decrease in the rate of postoperative infections in patients given tofacitinib.
“This is the first and largest case-control study to evaluate the efficacy and safety of rapid acting JAK inhibitor therapy for ASUC [acute severe ulcerative colitis] in comparison to matched controls,” Berinstein and colleagues stated, “Up until now, we have relied on small, uncontrolled, case-series to guide management of our sickest patients hospitalized with ASUC and at high risk for requiring urgent surgical rescue for uncontrolled disease.”
The authors noted tofacitinib is more affordable than infliximab rescue therapy, as “tofacitinib costs $1,444 for nine 10 mg doses ($160 per 10 mg dose)” while infliximab “costs $3,220 for a single infusion of 700 mg ($460 per 100 mg at a dose of 10 mg/kg in a 70 kg individual).”
They cited the possibility for tofacitinib to be used as a future monotherapy to potentially target ulcerative colitis flares instead of corticosteroids.
The authors reported a common limitation of having a small study size, which resulted in the difficulty of identifying minimal variations observed in safety and efficacy data. Furthermore, data was obtained from a large single tertiary care center, thus not generalizable to all centers.
In addition, since this study was not randomized, the reduction in colectomy rates reported cannot be definitively attributed to the administration of tofacitinib. More trials will be necessary to identify the optimal dose, safety, duration, and frequency tofacitinib can be given to patients with acute severe ulcerative colitis, the authors added.
Berinstein and colleagues stated, “this study raises the possibility that tofacitinib induction at 10 mg [given 3 times per day] for nine doses in addition to intravenous corticosteroids may be an effective therapeutic strategy for the treatment of high-risk biologic-experienced patients admitted with ASUC.”
This study was supported by an NIH-funded grant for clinical research.
Berinstein disclosed no conflicts of interest. One co-author reportedly received consulting fees from Lycera, Genentech, AbbVie, JBR Pharma, and Amgen. No additional conflicts of interest were reported.