Tofacitinib as Salvage Therapy for 55 Patients Hospitalised With Refractory Severe Ulcerative Colitis

A GETAID Cohort

Mathieu Uzzan; Clément Bresteau; David Laharie; Carmen Stefanescu; Christophe Bellanger; Franck Carbonnel; Mélanie Serrero; Stéphanie Viennot; Maria Nachury; Aurélien Amiot; Romain Altwegg; Laurence Picon; Stéphane Nahon; Lucine Vuitton; Philippe Ah Soune; Julien Kirchgesner; Laurent Peyrin-Biroulet; Yoram Bouhnik

Disclosures

Aliment Pharmacol Ther. 2021;54(3):312-319. 

In This Article

Discussion

In the present study, we report a large cohort of patients that received tofacitinib as a rescue therapy for a flare of UC that required hospitalization in tertiary centres. While all patients included in the study did not meet the acute severe colitis (ASUC) criteria (i.e., Lichitiger of 10 or more or Truelove and Witts criteria) many had features of severe disease with almost three quarter with a Lichtiger of 10 or more at inclusion. In addition, although most of them did not receive usual salvage treatment of ASUC (ciclosporin and/or infliximab) during the current hospitalization, all but one patient already failed antiTNF and 89% were already exposed to infliximab. Incidence estimates of colectomy at month 3 were similar to previously published rates in ASUC. In particular, in the randomised controlled trial comparing the efficacy of ciclosporin and infliximab in steroid-refractory ASUC, incidences of colectomy were 21% at 90 days for the ciclosporin arm and 17% in the infliximab-treated arm.[2] The incidence of colectomy at 3 months was estimated at 21.1% in our study. This rate appears encouraging for further evaluation of tofacitinib in ASUC considering both severity and refractoriness of the patients evaluated in our cohort.

Three small cohorts were previously published, specifically evaluating safety and effectiveness of tofacitinib as a therapeutic option in patients hospitalised for severe acute colitis.[5–7] Berinstein et al reported four patients, aged 19–51, hospitalised with acute severe colitis. Two were anti-TNF-exposed and 2 were naïve of biologic treatments. Three patients received 60 mg of concomitant intravenous methylprednisolone and all were initiated with a 10 mg three times daily regimen. Among the four patients, one required urgent colectomy, one withdrew tofacitinib for truncal maculopapular rash after initial remission and one underwent an elective colectomy at 6 months.[5] Kotwani et al described four refractory patients (from 23 to 46 years old) with previous failure of two or more biologics including infliximab. One patient escalated 15 mg twice daily and no colectomy was reported within 90 days.[7] Honap et al reported seven anti-TNF-experienced patients treated with tofacitinib. Among the seven patients, three required a colectomy within 3 months, including 2 at week 2 and 1 at week 12, and a fourth patient had a colectomy at week 26.

Overall, 11 patients who were hospitalised with acute severe ulcerative colitis and/or active and refractory UC and were initiated with tofacitinib, were reported in the literature so far. The oldest patient was 57 years old. Six of the 11 patients underwent a colectomy, including four within 3 months of tofacitinib initiation. Two severe adverse events were reported: a CMV infection and an extensive unspecific rash.

Safety is a critical concern in patients severely ill and hospitalised for acute severe colitis. It is well established that a delayed colectomy is strongly associated with increased morbidity and mortality.[9] In our study, two withdrawals occurred in patients due to viral infections. One was a severe herpes zoster infection in a 60-year-old patient, the second was recurrent pulmonary viral infections in a patient with a chronic lung condition. Additionally, in our cohort, an 81-year-old patient with multiple chronic conditions died in the context of delayed colectomy.

A recent preliminary report in rheumatoid arthritis patients aged over 50 years old with at least one cardiovascular risk factor, suggested an increased risk of major cardiovascular adverse event associated with tofacitinib use as compared to anti-TNF. The study including 4362 patients presented a trend for an increase in major cardiovascular risk events associated with tofacitinib treatment as compared to antiTNF (HR = 1.33, 95 CI [0.91–1.94]). In addition, there was an increased association with tofacitinib and the occurrence of malignancies excluding non-melanoma skin cancers (HR = 1.48, 95 CI [1.04–2.09]).[10]

Of note, no arterial cardiovascular event and/or pulmonary embolism occurred in our study despite the increased risk conferred by severe active inflammatory bowel disease.[11]

We acknowledge several limitations in the present study including its partially retrospective nature, a relatively small-sized cohort and short follow-up duration, as well as the absence of standardised follow-up and clinical management with few endoscopic assessments.

In conclusion, tofacitinib appears as a promising option as rescue therapy in patients hospitalised with a severe flare of refractory UC. However, it should not delay colectomy in aged patients and/or with increased susceptibility to infections. Further prospective and controlled studies are warranted to validate and position the use of tofacitinib in severe colitis as compared to already validated treatments.

processing....