Infliximab Induction Regimens in Steroid-Refractory Acute Severe Colitis

A Multicentre Retrospective Cohort Study With Propensity Score Analysis

Shaji Sebastian; Sally Myers; Konstantinos Argyriou; Gayle Martin; Louis Los; Joseph Fiske; Ravi Ranjan; Benjamin Cooper; Vivek Goodoory; Hey-Long Ching; NishaniLalanthika Jayasooriya; Johanne Brooks; Anjan Dhar; Achut H. Shenoy; Jimmy K. Limdi; Jeffrey Butterworth; Patrick B. Allen; Sunil Samuel; Gordon W. Moran; Richard Shenderey; Gareth Parkes; Alan Lobo; Nicholas A. Kennedy; Sreedar Subramanian; Tim Raine

Disclosures

Aliment Pharmacol Ther. 2019;50(6):330-335. 

In This Article

Abstract and Introduction

Abstract

Background: Accelerated induction regimens of infliximab have been proposed to improve response rates in patients with steroid-refractory acute severe colitis.

Aim: To determine the differences in outcome for acute severe ulcerative colitis between accelerated and standard-dose infliximab

Methods: We collected data on hospitalised patients receiving differing regimens of rescue therapy for steroid-refractory acute severe ulcerative colitis. Our primary outcome was 30-day colectomy rate. Secondary outcomes were colectomy within index admission, and at 90 days and 12 months. We used propensity score analysis with optimal calliper matching using high risk covariates defined a priori to reduce potential provider selection bias.

Results: We included 131 patients receiving infliximab rescue therapy; 102 received standard induction and 29 received accelerated induction. In the unmatched cohort, there was no difference by type of induction in the 30-day colectomy rates (18% vs 20%, P = .45), colectomy during index admission (13% vs 20%, P = .26) or overall colectomy (20% vs 24%, P = .38). In the propensity score-matched cohort of 52 patients, 30-day colectomy (57% vs 27%, P = .048) and index admission colectomy (53% vs 23%, P = .045) rates were higher in those receiving standard induction compared to accelerated induction but there was no difference in overall colectomy rates (57% vs 31%, P = .09). There was no significant difference in length of stay or in complication and infection rates.

Conclusion: In a propensity score-matched cohort, steroid-refractory acute severe ulcerative colitis patients, short-term, but not long-term, colectomy rates appear to be lower in those receiving an accelerated induction regimen.

Introduction

Acute severe ulcerative colitis (ASUC) is a medical emergency with up to 30% of patients requiring colectomy during their index admission[1,2] and is associated with a mortality of up to 2.9% in peripheral centres and about 1% in specialist IBD units.[3] ASUC is traditionally defined by the Truelove and Witt's criteria,[4] which combine frequency of bloody stools (≥6 per day) with at least one marker of systemic toxicity: pulse rate > 90 bpm, temperature > 37.8°C, haemoglobin < 105 g/L and/or an ESR > 30 mm/h. ASUC requiring hospitalisation occurs in 10%-25% at diagnosis and in 20%-30% during the disease course of ulcerative colitis.[5,6]

Intravenous corticosteroids remain the cornerstone of first-line therapy for ASUC. A meta-analysis of cohort studies and randomised trials, published in 2007, examined the response to corticosteroids in ASUC. The authors reported a pooled response rate to intravenous steroids of 67%, indicating that up to 40% of patients fail to respond.[7] Over the last decade, in patients failing corticosteroids, rescue therapies, including ciclosporin and infliximab,[1–3] have been used as an option to avoid colectomy. While there is no difference in response rates between infliximab and ciclosporin,[8–10] a majority of clinicians now appear to favour infliximab mainly citing convenience and safety.[11]

Despite the use of rescue therapies, a significant proportion of patients still undergo colectomy.[12] The data on rescue therapies indicate that the rates of nonresponse to infliximab rescue vary from 40%-55%.[8–10] Reasons for nonresponse may include patient and disease factors or treatment factors such as timing of rescue and dosing schedules. A key and unanswered question remains the optimal dosing strategy of infliximab in steroid-refractory ASUC. Current regimens have extrapolated dosing schedules for management of moderate-to-severe disease in an out-patient clinic setting to the hospitalised in-patient, and use a standard induction regimen of 5 mg/kg intravenously at week 0, 2 and 6. However, there are multiple reasons why ASUC may be associated with increased clearance of infliximab. These include hypoalbuminaemia, leakage of infliximab itself into the stool, activation of the reticuloendothelial system and higher circulating TNF levels.[13–15] This enhanced clearance of infliximab may also be associated with worse clinical outcomes.

This has led to the concept of 'accelerated induction rescue therapy,' where higher dosages or increased frequency of induction dosing have been proposed.[15] There are no published randomised controlled trials on the efficacy and safety of accelerated induction. Although there is increasing use of accelerated induction in clinical practice, the data from the published small cohort studies are conflicting.[16–18] Our recent meta-analysis of the available cohort studies showed no conclusive evidence for benefit of accelerated induction in reducing colectomy rates in steroid-refractory disease.[19] However, the majority of existing studies are single-centre cohorts with significant limitations including small sample sizes. Furthermore, such studies did not take into account provider bias, which could be an important determinant in selection of the type of rescue therapy.[20]

We have now performed a multicentre retrospective cohort study in 11 centres in the United Kingdom to compare the outcomes of using accelerated induction to standard induction regimens for ASUC in the real-world setting. We have used propensity score matching method to reduce the impact of provider bias in treatment selection.

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