Tofacitinib in Acute Severe Ulcerative Colitis: Case Series and a Systematic Review–Authors’ Reply

To the Editors, We thank Jena et al1 for their comments and interest in our systematic review with meta-analysis reporting on the real-world effectiveness and safety of tofacitinib for ulcerative colitis (UC).2 Jena et al reported new data from a case series of 4 patients with acute severe ulcerative colitis (ASUC) and performed a systematic review of similar reports.1 Additional evidence further supported the usefulness of tofacitinib in inducing a clinical response and in reducing the need for colectomy in patients with ASUC. Overall, 15 of 21 patients (71%) with ASUC included in the systematic review by Jena et al avoided colectomy over the long term. Tofacitinib may offer additional benefits for the management of ASUC, such as a rapid onset of action. A posthoc analysis of data from phase 3 induction trials in UC reported significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days.3 Furthermore, unlike biologics, tofacitinib has a rapid clearance, which can be an advantage for patients who require urgent colectomy because it can minimize the risk of infections or other postoperative complications. Regarding safety, 1 patient from the Jena et al case series died 1 month after discharge.1 Although the cause of death was not investigated in depth, the diagnosis of pulmonary embolism was considered possible because the patient had sudden-onset shortness of breath. The ORAL postmarketing safety study (ClinicalTrials.gov identifier: NCT02092467) evaluated the long-term risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis who were aged ≥50 years and who had at least 1 additional cardiovascular risk factor. The combined tofacitinib dose arm (5 mg/ or 10 mg/twice daily) showed a quantitative, not significant increased risk of MACE when compared with the anti-tumor necrosis factor arm, and the prespecified noninferiority criteria were not met for the primary comparison.4 These data have not been reproduced in patients with UC, possibly because they constitute a population with a different risk of MACE. In a tofacitinib UC clinical development program, the incidence rate (patients with events/100 patient-years) for deep vein thrombosis (0.04) and for pulmonary embolism (0.16) was comparable to that reported for patients with UC.5 In agreement with Jena et al case series,1 none of the studies included in our systematic review reported MACE or thromboembolic complications, although the evidence was limited by the small sample size and limited drug exposure. We consider linking tofacitinib with pulmonary embolism (without a conclusive objective diagnosis) in a patient who had other known predisposing factors like recent COVID-19 infection to be premature. In conclusion, tofacitinib seems to be useful for reducing the need for colectomy in patients with ASUC. Conflicts of interest: CT has served as a speaker, consultant, and advisory board member for MSD, AbbVie, Pfizer, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillots. CA has served as a speaker for Janssen and has prepared promotional material for Dr. Falk Pharma. These activities were not related to the present work. DO has no conflicts of interest to declare.