Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis

We read with interest the article by Berinstein et al1Berinstein J.A. et al.Clin Gastroenterol Hepatol. 2019; 17: 988-990Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar regarding the use of tofacitinib for the management of acute severe ulcerative colitis (UC). Janus kinase inhibitors in UC targeting multiple inflammatory pathways may offer advantages over monoclonal antibodies targeting specific cytokines;2Pérez-Jeldres T. et al.Front Pharmacol. 2019; 10: 212Crossref PubMed Scopus (40) Google Scholar however, studies regarding the safety and effectiveness of combination biologic and small molecule therapies in UC are limited.3Glassner K. et al.J Dig Dis. 2020; PubMed Google Scholar,4Le Berre C. et al.Clin Gastroenterol Hepatol. 2019; 17: 794-796Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar We herein describe the use of tofacitinib in combination with infliximab for the management of UC. Five patients receiving tofacitinib combined with infliximab for a minimum of 90 days were identified from a prospectively maintained database. All 5 patients demonstrated partial response to intensified infliximab dosing following a median total of 8 doses (range, 4–11), over a median duration of 8 months (range, 4–21 months) with optimized thiopurine therapy. All had been hospitalized previously with at least 1 episode of acute severe UC. One patient had failed vedolizumab before infliximab. Tofacitinib induction using 10 mg twice daily (apart from 1 patient who received 10 mg three times a day for acute severe UC) was initiated in combination with infliximab and thiopurine was discontinued. Tofacitinib dosing was de-escalated to 5 mg twice daily after 8 weeks. Disease was assessed clinically, biochemically, and endoscopically before tofacitinib initiation. Patients had a median Mayo score of 10 (range, 6–11), and a Mayo Endoscopic Score ≥2. Median duration of combination therapy was 9 months (range, 4–12 months). At 90 days, all patients had a reduction in Mayo score of ≥3. Four patients improved clinically and biochemically (Table 1), with 3 patients achieving steroid-free remission. At endoscopic evaluation, 3 patients had an improvement in Mayo Endoscopic Score, with 2 achieving endoscopic remission. One patient was admitted within 90 days of initiation with a moderate disease flare, which responded to tofacitinib 10-mg oral twice daily escalation with a short course of oral prednisolone (weaned over 6 weeks). All patients avoided colectomy.Table 1Baseline Patient, Treatment, Clinical, Biochemical, and Endoscopic Characteristics Before Tofacitinib Followed by Treatment Response Following 90 Days of Combination Tofacitinib and InfliximabBaseline characteristicsTreatment responseCaseAgeSexInfliximab dosingFCP (μg/mL)CRP (mg/L)MESTotal Mayo ScoreFCP (μg/mL)CRP (mg/L)MESTotal Mayo Score142M5 mg/kg4-weekly28105631080.312216F10 mg/kg4-weekly68231391061.735325M5 mg/kg4-weekly344062310421.413434F10 mg/kg4-weekly4599265097.023518M5 mg/kg4-weekly22306.531117910.028CRP, C-reactive protein; FCP, fecal calprotectin; MES, Mayo Endoscopic Score. Open table in a new tab CRP, C-reactive protein; FCP, fecal calprotectin; MES, Mayo Endoscopic Score. One patient developed varicella zoster, which was treated successfully with a course of oral valaciclovir, with a 2-week break in tofacitinib. No major adverse reactions (including venous thromboembolism, hypercholesterolemia, or significant infection requiring hospitalization) have occurred. Our study is the largest to date supporting a role for tofacitinib as an adjunctive induction agent in combination with infliximab for those in need of rapid induction of remission of UC. The trend for benefit observed in this cohort may have been caused by the effect of tofacitinib alone via targeting of non–tumor necrosis factor pathways, a synergistic effect of tofacitinib with infliximab, or via a reduction of immunogenicity. Although it is unknown whether a similar benefit may have been derived from tofacitinib monotherapy, the rate of response to tofacitinib can vary from days to months. Given the aggressive disease phenotype and partial response to infliximab, it was considered safer to continue with tofacitinib while minimizing concurrent steroids until clinical remission was achieved. Combination biologic and small molecule therapy may be an appropriate approach in patients with aggressive disease and partial response to biologic therapy. Such an approach has the potential to minimize steroid exposure, induce remission, and avoid colectomy by facilitating a safe transition to maintenance therapy. Future studies should explore the extent to which combination therapy with tofacitinib augments response to anti–tumor necrosis factor, the duration of therapy required to confer such benefit, and whether tofacitinib can be used as an alternative to immunomodulator therapy. Efficacy of Induction Therapy With High-Intensity Tofacitinib in 4 Patients With Acute Severe Ulcerative ColitisClinical Gastroenterology and HepatologyVol. 17Issue 5PreviewAs many as 25% of patients diagnosed with ulcerative colitis are hospitalized with an episode of acute severe ulcerative colitis (ASUC).1 The standard of care for patients hospitalized with ASUC relies on rapid induction with intravenous (IV) corticosteroids. Up to 30% of patients do not respond to corticosteroids alone.2 Rescue therapy with infliximab or cyclosporine has been shown to reduce rates of colectomy to 20% by 90 days.3,4 This still represents a significant rate of treatment failure, which leads to an unplanned and irreversible surgery. In recent years, increasing numbers of patients admitted with ASUC have already failed infliximab therapy, highlighting the need for additional treatment options for these patients. Tofacitinib is a rapidly acting, oral, small-molecule Janus kinase inhibitor that was recently approved by the Food and Drug Administration for treatment of ulcerative colitis.5 We present the first reported use of off-label, high-intensity tofacitinib in 4 patients admitted to our institution with ASUC predicted to fail medical management. Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 19Issue 6PreviewWe thank Gilmore et al1 for their comments on our case series.2 The case series by Gilmore et al1 adds to the growing literature regarding positioning Janus kinase inhibitors in the management of ulcerative colitis. Despite numerous therapeutic advancements, the management of those admitted to the hospital with acute severe ulcerative colitis (ASUC) remains limited. Full-Text PDF