Articles
Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial

https://doi.org/10.1016/S2468-1253(17)30248-0Get rights and content

Summary

Background

Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life.

Methods

In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18–80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150).

Findings

Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1–185·0) in the resection group versus 172·0 (164·3–179·6) in the infliximab group (mean difference 6·1 points, 95% CI −4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0–116·2) in the resection group versus 106·5 (102·1–110·9) in the infliximab group (mean difference 5·6, 95% CI −0·4 to 11·6), the mean physical component score was 47·7 (45·7–49·7) versus 44·6 (42·5–46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0–52·1) versus 46·1 (43·3–48·9; mean difference 3·5, −0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2–16·8) at baseline versus 17·8 (17·1–18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6–18·6) versus 18·6 (17·6–19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2–6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF.

Interpretation

Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy.

Funding

Netherlands Organisation for Health Research and Development.

Introduction

Crohn's disease is an idiopathic, chronic inflammatory bowel disease that leads to lifelong morbidity and decreased quality of life. It can occur at any site in the gastrointestinal tract. In about a third of patients, the disease is limited to the terminal ileum.1 The most recent 2016 update of the European Crohn's and Colitis Organisation (ECCO) guideline2 on medical management of Crohn's disease recommends that, for mild to moderately active ileocaecal Crohn's disease, a prednisolone course is indicated together with starting an immunomodulator. For severely active disease, the first choice is a biological agent, but prednisolone with an immunomodulator can also be considered.2

Research in context

Evidence before this study

Treatment of patients with ileocaecal Crohn's disease in whom conventional therapy fails is commonly scaled up to biological agents. However, surgery can offer excellent short-term and long-term results. We searched PubMed and Embase from March 14–17, 2017, with the following terms: “laparoscopic ileocaecal resection”, “infliximab”, “anti-TNF”, Crohn's disease”, and “quality of life”. Publications in English between Jan 1, 1990, and Jan 1, 2017, were accepted.

Added value of this study

Effectiveness of laparoscopic ileocaecal resection and infliximab in restoring quality of life has previously been shown, but no randomised controlled trials had compared these strategies directly. We showed that laparoscopic ileocaecal resection did not improve quality-of-life scores to a significantly greater extent than infliximab treatment, but results in similar quality-of-life scores and is not associated with more serious adverse events. Long-term follow-up data indicated that more than a third of the patients who started on infliximab required an ileocaecal resection within a few years, whereas only one in four patients who initially had resection needed anti-TNF therapy later.

Implications of all the available evidence

Based on this trial, we conclude that laparoscopic ileocaecal resection is a reasonable alternative to infliximab in patients with limited, non-stricturing, ileocaecal Crohn's disease in whom conventional therapy fails.

Surgical resection is usually reserved for patients who are refractory or intolerant to medical therapy, or have complications such as clinically relevant fibrostenotic or fistulising disease, as recently expressed in the 2016 guidelines from the ECCO.3 Up to 80% of patients with ileocaecal Crohn's disease undergo surgical resection eventually,3 although the need for surgical resection in general has recently been reported to have declined by 30% since the start of the use of biological agents.4

Following resection, clinically overt Crohn's disease typically recurs in 28–45%5 of patients in population-based studies, which is similar to the reported cumulative 5-year occurrence of infliximab and adalimumab treatment failure.4, 6 About 30% of patients have endoscopic recurrence 1 year after ileocaecal resection, which is similar to the number of recurrences observed in people who initially respond to infliximab.7, 8 Re-resection for recurrent Crohn's disease has been shown to occur in 10–22% of people after 5·0–8·5 years of follow-up.9, 10 This finding suggests that resection can be a valuable alternative to biological agents for inducing and maintaining clinical remission.

Apart from the symptoms associated with Crohn's disease, medication used for maintenance treatment can have a profound effect on quality of life.11, 12 Both anti-tumour necrosis factor (TNF) α antibodies and surgery have been shown to improve quality of life, but the short-term and long-term effects have not yet been compared.13, 14 We hypothesised that laparoscopic resection for ileocaecal Crohn's disease in patients in whom conventional treatment fails could improve quality of life, potentially providing a benefit over biological agents.

Section snippets

Study design

The LIR!C study is a multicentre, randomised controlled, open-label, parallel group trial done at 29 teaching hospitals and tertiary care centres in the Netherlands and the UK (six centres were tertiary referral centres, five of which were in the Netherlands). The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The

Results

Between May 2, 2008, and Oct 14, 2015, 215 patients were assessed for eligibility, of whom 62 were excluded because they did not meet the inclusion criteria, declined to participate, or their data were not reported. 143 patients (47 [33%] male) with a median age of 27 years (IQR 22–40) were enrolled and randomly assigned to either infliximab (n=70) or resection (n=73; figure 1). Baseline characteristics were similar between the two groups, except smoking status, which was higher in the

Discussion

Our study, to our knowledge, is the first randomised controlled trial comparing surgery with infliximab treatment for limited non-stricturing Crohn's disease of the terminal ileum. Although this trial did not show that surgery confers higher IBDQ scores than infliximab treatment at 12 months, and although the trial was not designed to show non-inferiority, the estimated mean difference and corresponding 95% CI suggest that quality of life after surgery is similar to that with infliximab

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  • Cited by (0)

    Study group authors listed in the appendix

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