Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: retrospective long-term follow-up of the LIR!C trial.

BACKGROUND: The LIR!C trial showed that laparoscopic ileocaecal resection is a cost-effective treatment that has similar quality-of-life outcomes to treatment with infliximab, an anti-tumour necrosis factor (TNF) drug. We aimed to compare long-term outcomes of both interventions and identify baseline factors associated with the duration of treatment effect in each group. METHODS: In this retrospective follow-up study, we collected data from patients who participated in the LIR!C trial, a multicentre randomised controlled trial that compared quality of life after surgical resection versus infliximab in adult patients with non-stricturing and immunomodulator-refractory ileocaecal Crohn's disease. From Jan 1 to May 1, 2018, we collected follow-up data from the time from enrolment in the LIR!C trial until the last visit at either the gastrointestinal surgeon or gastroenterologist. In this study, outcomes of interest were need for surgery or repeat surgery or anti-TNF therapy, duration of treatment effect, and identification of factors associated with the duration of treatment effect. Duration of treatment effect was defined as the time without need for additional Crohn's disease-related treatment (corticosteroids, immunomodulators, biologics, or surgery). FINDINGS: We collected long-term follow-up data for 134 (94%) of 143 patients included in the LIR!C trial, of whom 69 were in the resection group and 65 were in the infliximab group. Median follow-up was 63·5 months (IQR 39·0-94·5). In the resection group, 18 (26%) of 69 patients started anti-TNF therapy and none required a second resection. 29 (42%) patients in the resection group did not require additional Crohn's disease-related medication, although 14 (48%) of these patients were given prophylactic immunomodulator therapy. In the infliximab group, 31 (48%) of 65 patients had a Crohn's disease-related resection, and the remaining 34 patients maintained, switched, or escalated their anti-TNF therapy. Duration of treatment effect was similar in both groups, with a median time without additional Crohn's disease-related treatment of 33·0 months (95% CI 15·1-50·9) in the resection group and 34·0 months (0·0-69·3) in the infliximab group (log-rank p=0·52). In both groups, therapy with an immunomodulator, in addition to the allocated treatment, was associated with duration of treatment effect (hazard ratio for resection group 0·34 [95% CI 0·16-0·69] and for infliximab group 0·49 [0·26-0·93]). INTERPRETATION: These findings further support laparoscopic ileocaecal resection as a treatment option in patients with Crohn's disease with limited (affected segment ≤40 cm) and predominantly inflammatory terminal ileitis for whom conventional treatment is not successful. FUNDING: None.

Cost-effectiveness of laparoscopic ileocaecal resection versus infliximab treatment of terminal ileitis in Crohn's disease: the LIR!C Trial.

OBJECTIVE: Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy. DESIGN: A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty. RESULTS: In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score. CONCLUSION: Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015).

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

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.

Screening prior to biological therapy in Crohn's disease: adherence to guidelines and prevalence of infections. Results from a multicentre retrospective study.

BACKGROUND: Screening for opportunistic infections prior to starting biological therapy in patients with inflammatory bowel disease is recommended. AIMS: To assess adherence to screening for opportunistic infections prior to starting biological therapy in Crohn's disease patients and its yield. METHODS: A multicentre retrospective study was conducted in Crohn's disease patients in whom infliximab or adalimumab was started between 2000 and 2010. Screening included tuberculin skin test, interferon-gamma release assay or chest X-ray for tuberculosis. Extended screening included screening for tuberculosis and viral infections. Patients were followed until three months after ending treatment. Primary endpoints were opportunistic and serious infections. RESULTS: 611 patients were included, 91% on infliximab. 463 (76%) patients were screened for tuberculosis, of whom 113 (24%) underwent extended screening. Screening for tuberculosis and hepatitis B increased to, respectively, 90-97% and 36-49% in the last two years. During a median follow-up of two years, 64/611 (9%, 3.4/100 patient-years) opportunistic infections and 26/611 (4%, 1.6/100 patient-years) serious infections were detected. Comorbidity was significantly associated with serious infections (hazard ratio 3.94). CONCLUSIONS: Although screening rates for tuberculosis and hepatitis B increased, screening for hepatitis B was still suboptimal. More caution is required when prescribing biologicals in patients with comorbid conditions.

Adalimumab for Crohn's disease: long-term sustained benefit in a population-based cohort of 438 patients.

BACKGROUND AND AIMS: Adalimumab is an effective therapy for induction and maintenance of Crohn's disease. However, results in clinical trials don't necessarily reflect daily clinical practice. Therefore, we assessed real-life long-term clinical response to adalimumab in a large population-based cohort and identified clinical parameters affecting response METHODS: All consecutive patients in North-Holland that started adalimumab between 2003 and 2011 were included, of which medical charts were reviewed. Response to induction therapy was assessed after 3months. Sustained benefit of maintenance therapy was calculated from Kaplan-Meier survival tables depicting ongoing adalimumab treatment. Regression analyses were performed to identify factors predicting response to adalimumab therapy. RESULTS: In total 438 Crohn's patients started adalimumab with 92.5% response to the induction phase. After 1year 83.3% showed sustained benefit of maintenance treatment, followed by 74.0% after 2years. Nevertheless, one third of patients were in steroid-free remission at the end of their follow-up. Response to induction was negatively affected by longer disease duration (OR 1.05; p<0.01) and strictures (OR 3.73; p=0.04). Increased CRP levels predicted higher rates of initial response (OR 0.31; p<0.01). Concomitant thiopurines in the first 6months of adalimumab treatment decreased the risk to fail maintenance therapy (HR 0.69, p=0.05). Previous infliximab therapy did not affect response to adalimumab, however dose escalation was more often deemed necessary (p<0.01). CONCLUSION: Adalimumab was successful in the majority of patients, with 10% loss of response per subsequent year. Concomitant thiopurines might improve adalimumab maintenance treatment.

Effects of infliximab retreatment after consecutive discontinuation of infliximab and adalimumab in refractory Crohn's disease.

BACKGROUND: Switches between anti-tumor necrosis factor agents in the treatment of Crohn's disease (CD) occur in case of treatment failure, intolerance, or patient preference. No data are currently available on the usefulness of a second infliximab treatment after earlier discontinuation and previous switch to an alternative anti-tumor necrosis factor agent. In this study, we evaluated the clinical benefit of infliximab retreatment in patients with CD after sequential use of both infliximab and adalimumab. METHODS: Twenty-nine patients with CD who had received earlier treatments with sequential infliximab and adalimumab and were then restarted on infliximab were retrieved from a multicenter registry designed for the follow-up of adalimumab treatment for CD. Short-term and sustained effects of infliximab retreatment were evaluated retrospectively by reviewing clinical records. Follow-up was 18 months for all patients. RESULTS: In 13/29 (45%) patients, infliximab was reintroduced at intensified dosing schedule (>5 mg/kg or <8 wk) for 23/29 (79%) of patients similar to the schedule who were on at time of previous discontinuation. During the second infliximab treatment course, dosing was further intensified in 11 out of 29 (38%) patients. After 18 months 18/29 (62%), patients were still on continued therapy of their second infliximab treatment. Infliximab was discontinued (after a median of 7 mo) in 11 out of 29 patients for loss of response (n = 7 [24%]), intolerance (n = 3 [10%]), or non-compliance (n = 1 [3%]). Use of induction schedule or concomitant immunomodulators were not significantly associated with treatment benefit. CONCLUSIONS: The majority of patients with CD benefit from a second treatment with infliximab after previous treatment with infliximab and adalimumab, which offer a meaningful therapeutic option in often highly refractory patients.

Ten years of infliximab for Crohn's disease: outcome in 469 patients from 2 tertiary referral centers.

BACKGROUND: Aim was to assess the long-term clinical efficacy of infliximab therapy in patients with Crohn's disease treated in a cohort of 2 tertiary referral centers in the Netherlands. METHODS: All consecutive patients with Crohn's disease treated with infliximab were assessed. Endpoints were primary clinical efficacy, sustained benefit, efficacy of retreatment, surgical intervention rates, and safety. Sustained benefit was determined by Kaplan-Meier analysis. The estimated 5-year benefit was calculated. RESULTS: A total of 469 patients were included. Median follow-up length was 4.5 years (interquartile range, 2.7-6.8). Seventy patients (15%) had unsuccessful remission induction, and 316 patients received maintenance therapy. Scheduled maintenance regimen was successful in 169 of 276 (61%). Episodic maintenance therapy was successful in 19 of 40 patients (48%). Estimated 5-year sustained benefit was 55.7% (95% confidence interval, 48.8-62.6). Concomitant thiopurines were associated with improved sustained benefit. A second course of infliximab after previous discontinuation was prescribed in 131 patients with similar efficacy rates. Abdominal surgical intervention rate per 100 patient-years was significantly reduced after infliximab initiation in patients with a scheduled maintenance regime (reduction, 2.70; 95% confidence interval, -4.82 to -0.35; P = 0.018). Mortality and malignancy rates were 1.9% (0.39/100 patient-years) and 3.4% (0.70/100 patient-years), respectively. CONCLUSIONS: The present study shows an estimated 5-year sustained benefit of 55.7% in patients with Crohn's disease treated with infliximab maintenance therapy. Remission induction and maintenance were equally successful in patients starting infliximab and patients who temporarily stopped and were retreated. Long-term use of infliximab was safe and reduced the need for surgery in patients on scheduled maintenance therapy.

Previous infliximab therapy and postoperative complications after proctocolectomy with ileum pouch anal anastomosis.

BACKGROUND AND AIMS: It is unclear whether infliximab treatment induces increased complication rates after surgery for ulcerative colitis. Aim was to compare complication rates after pouch surgery in refractory ulcerative colitis patients with versus without previous infliximab therapy. METHODS: We performed a retrospective study evaluating all patients who underwent an ileoanal J-pouch for refractory ulcerative colitis over a four-year period. Postoperative complications, infliximab use and time between last infliximab administration and restorative surgery were assessed. 1-stage procedures (proctocolectomy with pouch, with or without temporary diversion) and 2-stage procedures (emergency colectomy and subsequent completion proctectomy with pouch, with or without temporary diversion) were analyzed separately. RESULTS: Seventy-two patients were included; 33 underwent 1-stage procedure and 39 had 2-stage surgery. In the 1-stage group, 21 patients (64%) had previous infliximab therapy (median time between last infusion and surgery: 7.1 months (IQR 2.6-8.3)). Infliximab-treated patients had higher incidence of pelvic sepsis (5/21 vs. 0/12; risk difference 24%; 95% CI: 6 to 42, p=0.067) and non-infectious complications (8/21 vs. 1/12; risk difference 30%; 95% CI: 4 to 56, p=0.065). In the 2-stage group, 17 (44%) had previous infliximab therapy (median time between last infusion and surgery: 11.8 months (IQR 7.3-15.5)). Total, infectious, non-infectious complication rates and pelvic sepsis rates were similar for infliximab and non-infliximab patients in the 2-stage group. CONCLUSIONS: This small study suggests that infliximab use prior to 1-stage restorative proctocolectomy in patients with UC is associated with increased incidence of pelvic sepsis. A 2-stage procedure in these patients should be considered.

Alternative specimen extraction techniques after laparoscopic emergency colectomy in inflammatory bowel disease.

BACKGROUND: Omitting the extraction site incision potentially further decreases the abdominal wall trauma in laparoscopic surgery. The purpose of this study was to report the results of alternative specimen extraction techniques after laparoscopic emergency colectomy in patients with inflammatory bowel disease (IBD). METHODS: Ten consecutive patients with IBD underwent (sub)acute emergency colectomy for refractory disease from October 2009 until December 2010. The specimen was retrieved via the stoma site in three and transrectally in seven patients. Patient data were prospectively collected. In case of later completion proctectomy and pouch procedure, adhesions were systematically scored. RESULTS: The extraction techniques were all feasible. Median operative time was 219 (interquartile range (IQR), 197-232) min. The pain scores and morphine requirement in patients decreased quickly after surgery. No infectious complications occurred. In five patients, a completion proctectomy was performed at a median time of 7 (IQR, 3.8-9.3) months after colectomy. All patients showed absence of any adhesions in the pelvis. In two patients, limited adhesions of the cut side of the mesentery were present. CONCLUSIONS: Specimen extraction via the rectum or stoma site is a safe, alternative way to extract the specimen after laparoscopic colectomy. No infectious complications were observed postoperatively and no pelvic adhesions were found during completion proctectomy.

Decision-making in ileocecal Crohn's disease management: surgery versus pharmacotherapy.

Ileocecal Crohn's disease (CD) can be treated medically as well as surgically. Both treatment modalities have been improved markedly in the last two decades, making CD more manageable. However, multidisciplinary research, addressing issues such as timing of surgery or medical treatment versus surgery, is scarce. Particularly in limited ileocecal CD, ileocolic resection might be a good alternative to long-term medical therapy. This review discusses the evidence on medical and surgical treatment options for ileocecal CD. It provides an aid in decision-making by discussing a treatment algorithm that can be used until further evidence on treatment is available.

Infliximab for the treatment of ulcerative colitis.

Infliximab (IFX), an anti-TNF biologic agent, has been demonstrated to offer benefits for the treatment of autoimmune disorders, such as rheumatoid arthritis and Crohn's disease. Several trials have also investigated the efficacy of IFX for the treatment of ulcerative colitis (UC). IFX was found to be well tolerated. In most trials, IFX treatment was more effective than placebo for patients with moderate, moderate-to-severe or severe UC. However, its place in the treatment algorithms for UC remains to be defined and, to this end, clinical trials comparing IFX treatment to conventional therapies are needed.

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial).

BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction. The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.

Long-term surgical recurrence, morbidity, quality of life, and body image of laparoscopic-assisted vs. open ileocolic resection for Crohn's disease: a comparative study.

PURPOSE: Several studies have compared conventional open ileocolic resection with a laparoscopic-assisted approach. However, long-term outcome after laparoscopic-assisted ileocolic resection remains to be determined. This study was designed to compare long-term results of surgical recurrence, quality of life, body image, and cosmesis in patients who underwent laparoscopic-assisted or open ileocolic resection for Crohn's disease. METHODS: Seventy-eight consecutive patients who underwent ileocolic resection during the period 1995 to 1998 were analyzed; 48 underwent a conventional open approach in the Academic Medical Centre (Amsterdam, The Netherlands) and 30 underwent a laparoscopic-assisted approach in the Leiden University Medical Centre (Leiden, The Netherlands). Primary outcome parameters were reoperation and readmission rate. Secondary outcome parameters were quality of life, body image, and cosmesis. RESULTS: The two groups were comparable for characteristics of sex, age, and immunosuppressive therapy. Seventy-one patients had a complete follow-up of median 8.5 years. Resection for recurrent Crohn's disease was performed in 6 of 27 (22 percent) and 10 of 44 (23 percent) patients in the laparoscopic and open groups, respectively. Reoperations for incisional hernia were only performed after conventional open ileocolic resection (3/44 = 6.8 percent). Quality of life and body image were comparable, but cosmesis scores were significantly higher in the laparoscopic group. CONCLUSIONS: Despite small numbers, we found that surgical recurrence and quality of life after laparoscopic-assisted and open ileocolic resection were comparable. Incisional hernias occurred only after open ileocolic resection, and laparoscopic-assisted ileocolic resection resulted in a significantly better cosmesis.