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. 2019 Sep 12;9(9):CD013210.
doi: 10.1002/14651858.CD013210.pub2.

Interventions for maintenance of surgically induced remission in Crohn's disease: a network meta-analysis

Zipporah Iheozor-Ejiofor  1 , Morris Gordon, Andrew Clegg, Suzanne C Freeman, Teuta Gjuladin-Hellon, John K MacDonald, Anthony K Akobeng
Affiliations

Interventions for maintenance of surgically induced remission in Crohn's disease: a network meta-analysis

Zipporah Iheozor-Ejiofor et al. Cochrane Database Syst Rev. .

Abstract

Background: Crohn's disease (CD) is a chronic disease of the gut. About 75% of people with CD undergo surgery at least once in their lifetime to induce remission. However, as there is no known cure for the disease, patients usually experience a recurrence even after surgery. Different interventions are routinely used in maintaining postsurgical remission. There is currently no consensus on which treatment is the most effective.

Objectives: To assess the effects and harms of interventions for the maintenance of surgically induced remission in Crohn's disease and rank the treatments in order of effectiveness.

Search methods: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, and Embase from inception to 15 January 2019. We also searched reference lists of relevant articles, abstracts from major gastroenterology meetings, ClinicalTrials.gov, and the WHO ICTRP. There was no restriction on language, date, or publication status.

Selection criteria: We considered for inclusion randomised controlled trials (RCTs) that compared different interventions used for maintaining surgically induced remission in people with CD who were in postsurgical remission. Participants had to have received maintenance treatment for at least three months. We excluded studies assessing enteral diet, diet manipulation, herbal medicine, and nutritional supplementation.

Data collection and analysis: Two review authors independently selected relevant studies, extracted data, and assessed the risk of bias. Any disagreements were resolved by discussion or by arbitration of a third review author when necessary. We conducted a network meta-analysis (NMA) using a Bayesian approach through Markov Chain Monte Carlo (MCMC) simulation. For the pairwise comparisons carried out in Review Manager 5, we calculated risk ratios (RR) with their corresponding 95% confidence intervals (95% CI). For the NMA, we presented hazard ratios (HR) with corresponding 95% credible intervals (95% CrI) and reported ranking probabilities for each intervention. For the NMA, we focused on three main outcomes: clinical relapse, endoscopic relapse, and withdrawals due to adverse events. Data were insufficient to assess time to relapse and histologic relapse. Adverse events and serious adverse events were not sufficiently or objectively reported to permit an NMA. We used CINeMA (Confidence in Network Meta-Analysis) methods to evaluate our confidence in the findings within networks, and GRADE for entire networks.

Main results: We included 35 RCTs (3249 participants) in the review. The average age of study participants ranged between 33.6 and 38.8 years. Risk of bias was high in 18 studies, low in four studies, and unclear in 13 studies. Of the 35 included RCTs, 26 studies (2581 participants; 9 interventions) were considered eligible for inclusion in the NMA. The interventions studied included 5-aminosalicylic acid (5-ASA), adalimumab, antibiotics, budesonide, infliximab, probiotics, purine analogues, sulfasalazine, and a combination of sulfasalazine and prednisolone. This resulted in 30 direct contrasts, which informed 102 mixed-treatment contrasts.The evidence for the clinical relapse network (21 studies; 2245 participants) and endoscopic relapse (12 studies; 1128 participants) were of low certainty while the evidence for withdrawal due to adverse events (15 studies; 1498 participants) was of very low certainty. This assessment was due to high risk of bias in most of the studies, inconsistency, and imprecision across networks. We mainly judged individual contrasts as of low or very low certainty, except 5-ASA versus placebo, the evidence for which was judged as of moderate certainty.We ranked the treatments based on effectiveness and the certainty of the evidence. For clinical relapse, the five most highly ranked treatments were adalimumab, infliximab, budesonide, 5-ASA, and purine analogues. We found some evidence that adalimumab (HR 0.11, 95% Crl 0.02 to 0.33; low-certainty evidence) and 5-ASA may reduce the probability of clinical relapse compared to placebo (HR 0.69, 95% Crl 0.53 to 0.87; moderate-certainty evidence). However, budesonide may not be effective in preventing clinical relapse (HR 0.66, 95% CrI 0.27 to 1.34; low-certainty evidence). We are less confident about the effectiveness of infliximab (HR 0.36, 95% CrI 0.02 to 1.74; very low-certainty evidence) and purine analogues (HR 0.75, 95% CrI 0.55 to 1.00; low-certainty evidence). It was unclear whether the other interventions reduced the probability of a clinical relapse, as the certainty of the evidence was very low.Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing endoscopic relapse. Whilst there might be some evidence of prevention of endoscopic relapse with adalimumab (HR 0.10, 95% CrI 0.01 to 0.32; low-certainty evidence), no other intervention studied appeared to be effective.Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing withdrawal due to adverse events. Withdrawal due to adverse events appeared to be least likely with sulfasalazine (HR 1.96, 95% Crl 0.00 to 8.90; very low-certainty evidence) and most likely with antibiotics (HR 53.92, 95% Crl 0.43 to 259.80; very low-certainty evidence). When considering the network as a whole, two adverse events leading to study withdrawal (i.e. pancreatitis and leukopenia) occurred in more than 1% of participants treated with an intervention. Pancreatitis occurred in 2.8% (11/399) of purine analogue participants compared to 0.17% (2/1210) of all other groups studied. Leukopenia occurred in 2.5% (10/399) of purine analogue participants compared to 0.08% (1/1210) of all other groups studied.

Authors' conclusions: Due to low-certainty evidence in the networks, we are unable to draw conclusions on which treatment is most effective for preventing clinical relapse and endoscopic relapse. Evidence on the safety of the interventions was inconclusive, however cases of pancreatitis and leukopenia from purine analogues were evident in the studies. Larger trials are needed to further understand the effect of the interventions on endoscopic relapse.

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Conflict of interest statement

  1. Zipporah Iheozor‐Ejiofor: None known.

  2. Morris Gordon has received travel fees from Abbott, Nutricia, BioGaia, Ferring, Allergan, and Tillots to attend international scientific and training meetings such as DDW, Advances in IBD, ESPGHAN, BSPGHAN, and Cochrane‐focused international events. None of these companies has had any involvement in any works completed by Morris Gordon, and he has had no payments for any other activities.

  3. Andrew Clegg: None known.

  4. Suzanne C Freeman: None known

  5. Teuta Gjuladin‐Hellon: None known.

  6. John K MacDonald: None known.

  7. Anthony K Akobeng: None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Network plot ‐ clinical relapse.
5
5
Network plot ‐ endoscopic relapse.
6
6
Network plot ‐ withdrawal due to adverse events.
7
7
Clinical relapse: risk of bias contributions of each piece of study to the network estimate; 21 studies: 8 low, 9 moderate, 4 high. Key: green = low/unclear; yellow = high; red = very high overall risk of bias for the contrast.
8
8
Endoscopic relapse: risk of bias contributions of each piece of study to the network estimate; 12 studies: 4 low, 5 moderate, 3 high. Key: green = low/unclear; yellow = high; red = very high overall risk of bias for the contrast.
9
9
Withdrawal due to adverse events: risk of bias contributions of each piece of study to the network estimate; 15 studies: 7 low, 7 moderate, 1 high. Key: green = low/unclear; yellow = high; red = very high overall risk of bias for the contrast.
10
10
Summary plot of clinical relapse showing network estimates of mean hazard ratios (blue diamonds and squares) and their credible intervals (blue horizontal line). Right‐hand side = favours named treatment; left‐hand side = favours placebo.
11
11
Summary plot of endoscopic relapse showing network estimates of mean hazard ratios (blue diamonds and squares) and their credible intervals (blue horizontal line). Right‐hand side = favours named treatment; left‐hand side = favours placebo.
12
12
Summary plot of withdrawal due to adverse events showing network estimates of mean hazard ratios (blue diamonds and squares) and their credible intervals (blue horizontal line). Right‐hand side favours placebo; left‐hand side favours named treatment.
13
13
Rank ‐ clinical relapse.
14
14
Rank ‐ endoscopic relapse.
15
15
Rank ‐ withdrawal due to adverse events.
16
16
Funnel plot for the clinical relapse network showing comparison‐specific pooled effect sizes; 1 = placebo; 2 = 5‐ASA; 3 = adalimumab; 4 = antibiotics; 5 = budesonide; 6 = infliximab; 7 = probiotics; 8 = purine analogues; 9 = sulfasalazine; 10 = sulfasalazine + prednisolone.
17
17
Funnel plot for the endoscopic relapse network showing comparison‐specific pooled effect sizes; 1 = placebo; 2 = 5‐ASA; 3 = adalimumab; 4 = antibiotics; 5 = infliximab; 6 = probiotics; 7 = purine analogues.
18
18
Funnel plot for the withdrawal due to adverse events network showing comparison‐specific pooled effect sizes; 1 = placebo; 2 = 5‐ASA; 3 = adalimumab; 4 = antibiotics; 5 = budesonide; 6 = infliximab; 7 = probiotics; 8 = purine analogues; 9 = sulfasalazine.
1.1
1.1. Analysis
Comparison 1 Direct evidence: 5‐ASA versus placebo, Outcome 1 Clinical relapse.
1.2
1.2. Analysis
Comparison 1 Direct evidence: 5‐ASA versus placebo, Outcome 2 Adverse events.
1.3
1.3. Analysis
Comparison 1 Direct evidence: 5‐ASA versus placebo, Outcome 3 Serious adverse events.
1.4
1.4. Analysis
Comparison 1 Direct evidence: 5‐ASA versus placebo, Outcome 4 Withdrawal due to adverse events.
1.5
1.5. Analysis
Comparison 1 Direct evidence: 5‐ASA versus placebo, Outcome 5 Endoscopic relapse.
2.1
2.1. Analysis
Comparison 2 Direct evidence: 5‐ASA versus adalimumab, Outcome 1 Clinical relapse.
2.2
2.2. Analysis
Comparison 2 Direct evidence: 5‐ASA versus adalimumab, Outcome 2 Adverse events.
2.3
2.3. Analysis
Comparison 2 Direct evidence: 5‐ASA versus adalimumab, Outcome 3 Endoscopic relapse.
2.4
2.4. Analysis
Comparison 2 Direct evidence: 5‐ASA versus adalimumab, Outcome 4 Withdrawal due to adverse events.
3.1
3.1. Analysis
Comparison 3 Direct evidence: 5‐ASA versus purine analogues, Outcome 1 Clinical relapse.
3.2
3.2. Analysis
Comparison 3 Direct evidence: 5‐ASA versus purine analogues, Outcome 2 Adverse events.
3.3
3.3. Analysis
Comparison 3 Direct evidence: 5‐ASA versus purine analogues, Outcome 3 Serious adverse events.
3.4
3.4. Analysis
Comparison 3 Direct evidence: 5‐ASA versus purine analogues, Outcome 4 Withdrawal due to adverse events.
3.5
3.5. Analysis
Comparison 3 Direct evidence: 5‐ASA versus purine analogues, Outcome 5 Endoscopic relapse.
4.1
4.1. Analysis
Comparison 4 Direct evidence: antibiotics versus placebo, Outcome 1 Clinical relapse.
4.2
4.2. Analysis
Comparison 4 Direct evidence: antibiotics versus placebo, Outcome 2 Adverse events.
4.3
4.3. Analysis
Comparison 4 Direct evidence: antibiotics versus placebo, Outcome 3 Withdrawal due to adverse events.
4.4
4.4. Analysis
Comparison 4 Direct evidence: antibiotics versus placebo, Outcome 4 Endoscopic relapse.
5.1
5.1. Analysis
Comparison 5 Direct evidence: budesonide versus placebo, Outcome 1 Clinical relapse.
5.2
5.2. Analysis
Comparison 5 Direct evidence: budesonide versus placebo, Outcome 2 Adverse events.
5.3
5.3. Analysis
Comparison 5 Direct evidence: budesonide versus placebo, Outcome 3 Withdrawal due to adverse events.
5.4
5.4. Analysis
Comparison 5 Direct evidence: budesonide versus placebo, Outcome 4 Histologic relapse.
6.1
6.1. Analysis
Comparison 6 Direct evidence: infliximab versus adalimumab, Outcome 1 Clinical relapse.
6.2
6.2. Analysis
Comparison 6 Direct evidence: infliximab versus adalimumab, Outcome 2 Adverse events.
6.3
6.3. Analysis
Comparison 6 Direct evidence: infliximab versus adalimumab, Outcome 3 Endoscopic relapse.
6.4
6.4. Analysis
Comparison 6 Direct evidence: infliximab versus adalimumab, Outcome 4 Histologic relapse.
7.1
7.1. Analysis
Comparison 7 Direct evidence: infliximab versus purine analogues, Outcome 1 Clinical relapse.
7.2
7.2. Analysis
Comparison 7 Direct evidence: infliximab versus purine analogues, Outcome 2 Withdrawal due to adverse events.
7.3
7.3. Analysis
Comparison 7 Direct evidence: infliximab versus purine analogues, Outcome 3 Endoscopic relapse.
7.4
7.4. Analysis
Comparison 7 Direct evidence: infliximab versus purine analogues, Outcome 4 Histologic relapse.
8.1
8.1. Analysis
Comparison 8 Direct evidence: probiotics versus placebo, Outcome 1 Clinical relapse.
8.2
8.2. Analysis
Comparison 8 Direct evidence: probiotics versus placebo, Outcome 2 Adverse events.
8.3
8.3. Analysis
Comparison 8 Direct evidence: probiotics versus placebo, Outcome 3 Endoscopic relapse.
9.1
9.1. Analysis
Comparison 9 Direct evidence: purine analogues versus placebo, Outcome 1 Clinical relapse.
9.2
9.2. Analysis
Comparison 9 Direct evidence: purine analogues versus placebo, Outcome 2 Adverse events.
9.3
9.3. Analysis
Comparison 9 Direct evidence: purine analogues versus placebo, Outcome 3 Serious adverse events.
9.4
9.4. Analysis
Comparison 9 Direct evidence: purine analogues versus placebo, Outcome 4 Withdrawal due to adverse events.
9.5
9.5. Analysis
Comparison 9 Direct evidence: purine analogues versus placebo, Outcome 5 Endoscopic relapse.
10.1
10.1. Analysis
Comparison 10 Direct evidence: purine analogues versus adalimumab, Outcome 1 Clinical relapse.
10.2
10.2. Analysis
Comparison 10 Direct evidence: purine analogues versus adalimumab, Outcome 2 Adverse events.
10.3
10.3. Analysis
Comparison 10 Direct evidence: purine analogues versus adalimumab, Outcome 3 Withdrawal due to adverse events.
10.4
10.4. Analysis
Comparison 10 Direct evidence: purine analogues versus adalimumab, Outcome 4 Endoscopic relapse.
11.1
11.1. Analysis
Comparison 11 Direct evidence: sulfasalazine versus placebo, Outcome 1 Clinical relapse.
11.2
11.2. Analysis
Comparison 11 Direct evidence: sulfasalazine versus placebo, Outcome 2 Adverse events.
11.3
11.3. Analysis
Comparison 11 Direct evidence: sulfasalazine versus placebo, Outcome 3 Withdrawal due to adverse events.
12.1
12.1. Analysis
Comparison 12 Direct evidence: sulfasalazine + prednisolone versus placebo, Outcome 1 Clinical relapse.
13.1
13.1. Analysis
Comparison 13 Direct evidence not in network: clinical relapse, Outcome 1 4.0 g/d versus 2.4 g/d mesalazine.
13.2
13.2. Analysis
Comparison 13 Direct evidence not in network: clinical relapse, Outcome 2 Purine analogues versus placebo.
13.3
13.3. Analysis
Comparison 13 Direct evidence not in network: clinical relapse, Outcome 3 Infliximab versus placebo.
13.4
13.4. Analysis
Comparison 13 Direct evidence not in network: clinical relapse, Outcome 4 Antibiotics versus placebo.
13.5
13.5. Analysis
Comparison 13 Direct evidence not in network: clinical relapse, Outcome 5 5‐ASA versus purine analogues.
14.1
14.1. Analysis
Comparison 14 Direct evidence not in network: adverse events, Outcome 1 4.0 g/d versus 2.4 g/d mesalazine.
14.2
14.2. Analysis
Comparison 14 Direct evidence not in network: adverse events, Outcome 2 Probiotics versus placebo.
14.3
14.3. Analysis
Comparison 14 Direct evidence not in network: adverse events, Outcome 3 Infliximab versus placebo.
14.4
14.4. Analysis
Comparison 14 Direct evidence not in network: adverse events, Outcome 4 5‐ASA versus purine analogues.
14.5
14.5. Analysis
Comparison 14 Direct evidence not in network: adverse events, Outcome 5 Purine analogues versus placebo.
15.1
15.1. Analysis
Comparison 15 Direct evidence not in network: serious adverse events, Outcome 1 5‐ASA versus purine analogues.
16.1
16.1. Analysis
Comparison 16 Direct evidence not in network: withdrawal due to adverse events, Outcome 1 4.0 g/d versus 2.4 g/d mesalazine.
16.2
16.2. Analysis
Comparison 16 Direct evidence not in network: withdrawal due to adverse events, Outcome 2 Synbiotic versus placebo.
16.3
16.3. Analysis
Comparison 16 Direct evidence not in network: withdrawal due to adverse events, Outcome 3 Probiotics versus placebo.
16.4
16.4. Analysis
Comparison 16 Direct evidence not in network: withdrawal due to adverse events, Outcome 4 Infliximab versus placebo.
16.5
16.5. Analysis
Comparison 16 Direct evidence not in network: withdrawal due to adverse events, Outcome 5 5‐ASA versus purine analogues.
16.6
16.6. Analysis
Comparison 16 Direct evidence not in network: withdrawal due to adverse events, Outcome 6 Purine analogues versus placebo.
17.1
17.1. Analysis
Comparison 17 Direct evidence not in network: endoscopic relapse, Outcome 1 4.0 g/d versus 2.4 g/d mesalazine.
17.2
17.2. Analysis
Comparison 17 Direct evidence not in network: endoscopic relapse, Outcome 2 Probiotics versus placebo.
17.3
17.3. Analysis
Comparison 17 Direct evidence not in network: endoscopic relapse, Outcome 3 Infliximab versus placebo.
17.4
17.4. Analysis
Comparison 17 Direct evidence not in network: endoscopic relapse, Outcome 4 5‐ASA versus purine analogues.
17.5
17.5. Analysis
Comparison 17 Direct evidence not in network: endoscopic relapse, Outcome 5 Purine analogues versus placebo.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013210

References

References to studies included in this review

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    1. Mowat C, Arnott I, Cahill A, Smith M, Ahmad T, Subramanian S, et al. Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double‐blind, randomised controlled trial. Lancet Gastroenterology and Hepatology 2016;1(4):273‐82. - PMC - PubMed
Prantera 2002 {published data only}
    1. Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial with Lactobacillus GG. Gut 2002;51(3):405‐9. - PMC - PubMed
Regueiro 2009 {published data only}
    1. NCT00688636. Infliximab for the prevention of recurrent Crohn's disease after surgery. clinicaltrials.gov/ct2/show/NCT00688636 (first received 3 June 2008).
    1. Regueiro M, El‐Hachem S, Kip KE, Schraut W, Baidoo L, Watson A, et al. Postoperative infliximab is not associated with an increase in adverse events in Crohn's disease. Digestive Diseases and Sciences 2011;56(12):3610‐5. - PubMed
    1. Regueiro M, Schraut W, Baidoo L, Kip KE, Sepulveda AR, Pesci M, et al. Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology 2009;136(2):441‐50. - PubMed
Regueiro 2016 {published data only}
    1. EUCTR2010‐018431‐18‐DE. A multicenter trial comparing REMICADE (infliximab) and placebo in the prevention of recurrence in Crohn's disease patients undergoing surgical resection who are at an increased risk of recurrence. clinicaltrialsregister.eu/ctr‐search/trial/2010‐018431‐18/GB (first received 6 July 2010).
    1. Regueiro M, Feagan BG, Zou B, Johanns J, Blank MA, Chevrier M, et al. Infliximab reduces endoscopic, but not clinical, recurrence of Crohn's disease after ileocolonic resection. Gastroenterology 2016;150(7):1568‐78. - PubMed
Reinisch 2010 {published data only}
    1. Reinisch W, Angelberger S, Petritsch W, Shonova O, Lukas M, Bar‐Meir S, et al. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double‐blind, double‐dummy, multicentre trial. Gut 2010;59(6):752‐9. - PubMed
    1. Reinisch W, Angelberger S, Petritsch W, Shonova O, Lukas M, Greinwald R, et al. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in Crohn's disease patients with endoscopic recurrence: follow‐up data of a randomised, double‐blind, double‐dummy, 1‐year, multicentre trial. Journal of Crohn's and Colitis 2013;7(1):S254.
Rutgeerts 2005 {published data only}
    1. Rutgeerts P, Assche G, Vermeire S, D'Haens G, Baert F, Noman M, et al. Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double‐blind, placebo‐controlled trial. Gastroenterology 2005;128(4):856‐61. - PubMed
Savarino 2013 {published data only}
    1. Bodini G, Pellegatta G, Giannini EG, Savarino V, Savarino EV. Adalimumab therapy rather than azathioprine and mesalamine is able to halt Crohn's disease progression after resective surgery and a post‐hoc analysis of a prospective randomized study. Gastroenterology 2017;152(5 Suppl 1):S774.
    1. Savarino E, Bodini G, Dulbecco P, Assandri L, Bruzzone L, Mazza F, et al. Adalimumab is more effective than azathioprine and mesalamine at preventing postoperative recurrence of Crohn's disease: a randomized controlled trial. American Journal of Gastroenterology 2013;108:1731‐42. - PubMed
Scapa 2015 {published data only}
    1. Scapa E, Maharshak N, Kariv Y, Ben‐Horin S, White ID, Santo E, et al. Early initiation of adalimumab significantly diminishes post‐operative Crohn's disease recurrence, and is superior to immunomodulator therapy. Preliminary results from the POPART trial. Gastroenterology 2015;148(4 Suppl 1):S240‐1.
Sutherland 1997 {published data only}
    1. Sutherland LR, Martin F, Bailey RJ, Fedorak RN, Poleski M, Dallaire C, et al. A randomized, placebo‐controlled, double‐blind trial of mesalamine in the maintenance of remission of Crohn's disease. The Canadian Mesalamine for Remission of Crohn's Disease Study Group. Gastroenterology 1997;112(4):1069‐77. - PubMed
Tursi 2014 {published data only}
    1. Tursi A, Elisei W, Picchio M, Zampaletta C, Pelecca G, Faggiani R, et al. Comparison of the effectiveness of infliximab and adalimumab in preventing postoperative recurrence in patients with Crohn's disease: an open‐label, pilot study. Techniques in Coloproctology 2014;18(11):1041‐6. - PubMed
Wenckert 1978 {published data only}
    1. Wenckert A, Kristensen M, Eklund AE, Barany F, Jarnum S, Worning H, et al. The long‐term 20 prophylactic effect of salazosulphapyridine (Salazopyrin) in primarily resected patients with 21 Crohn's disease. A controlled double‐blind trial. Scandinavian Journal of Gastroenterology 1978;13(2):161‐7. - PubMed
Yoshida 2012 {published data only}
    1. Yoshida K, Fukunaga K, Ikeuchi H, Kamikozuru K, Hida N, Ohda Y, et al. Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: a 3‐year prospective randomized open trial. Inflammatory Bowel Diseases 2012;18(9):1617‐23. - PubMed

References to studies excluded from this review

Angelberger 2013 {published data only}
    1. Angelberger S, Schaeffeler E, Teml A, Petritsch W, Shonova O, Lukas M, et al. Mucosal improvement in patients with moderate to severe postoperative endoscopic recurrence of Crohn's disease and azathioprine metabolite levels. Inflammatory Bowel Diseases 2013;19(3):590‐8. - PubMed
Armuzzi 2015 {published data only}
    1. Armuzzi A, Felice C, Marzo M, Pugliese D, Andrisani G, Papa A, et al. Infliximab is more effective than azathioprine in the long‐term prevention of postoperative recurrence of Crohn's disease. Gastroenterology 2015;148(4):S856.
Balzola 2010 {published data only}
    1. Balzola F, Bernstein C, Assche G. Impact of infliximab therapy after early endoscopic recurrence following ileocolonic resection of Crohn's disease: a prospective pilot study: Commentary. Inflammatory Bowel Disease Monitor 2010;10(3):102‐3. - PubMed
Bodini 2014a {published data only}
    1. Bodini G, Cassan C, Savarino V, Savarino E. Letter: Biological therapies are effective for prevention of post‐operative Crohn's disease recurrence. Alimentary Pharmacology and Therapeutics 2014;40(3):322. - PubMed
Bodini 2014b {published data only}
    1. Bodini G, Savarino V, Peyrin‐Biroulet L, deCassan C, Dulbecco P, Baldissarro I, et al. Low serum trough levels are associated with post‐surgical recurrence in Crohn's disease patients undergoing prophylaxis with adalimumab. Digestive and Liver Disease 2014;46(11):1043‐6. - PubMed
Bodini 2015 {published data only}
    1. Bodini G, Savarino V, Marabotto E, Savarino E. Anti‐tumor necrosis factor antibodies for prevention of Crohn's disease recurrence after surgery: more than a hope. Clinical Gastroenterology and Hepatology 2015;13(10):1856. - PubMed
Bourreille 2005 {published data only}
    1. Bourreille A. Efficacy of azathioprine and its derivative, 6‐mercaptopurine in the prevention of post operative recurrent Crohn's disease [Efficacité de l’azathioprine et de son dérivé la 6‐mercaptopurine pour la prévention des rechutes post‐opératoires de maladie de Crohn]. Gastroentérologie Clinique et Biologique 2005;29(3):319‐21. [DOI: ]
De Cruz 2012 {published data only}
    1. Cruz P, Kamm MA, Hamilton AL, Ritchie KJ, Gorelik A, Liew D, et al. Adalimumab prevents post‐operative Crohn's disease recurrence, and is superior to thiopurines: early results from the POCER study. Journal of Gastroenterology and Hepatology 2012;4:100.
De Cruz 2013a {published data only}
    1. Cruz P, Kamm M, Hamilton A, Ritchie K, Gearry R (editors). Strategic timing of anti‐TNF therapy in postoperative Crohn's disease: comparison of routine use immediately postoperatively with selective use after demonstrated recurrence at 6 month endoscopy. Results from POCER. Journal of Gastroenterology and Hepatology 2013;28(Suppl 2):92.
De Cruz 2013b {published data only}
    1. Cruz P, Kamm MA, Hamilton AL, Ritchie KJ, Krejany EO, Gorelik A, et al. Smoking is the key risk factor that doubles the risk of postoperative recurrence of Crohn's disease despite preventive drug treatment. Results from the POCER study. United European Gastroenterology Journal 2013;1:A95.
De Cruz 2013c {published data only}
    1. Cruz P, Kamm M, Hamilton A, Ritchie K, Krejany S, Gorelik A, et al. Strategic timing of anti‐TNF therapy in postoperative Crohn's disease: comparison of routine use immediately postoperatively with selective use after demonstrated recurrence at 6 month endoscopy: results from POCER. United European Gastroenterology Journal 2013;1:A16.
De Cruz 2015a {published data only}
    1. Cruz P, Kamm A, Hamilton KJ, Ritchie EO, Krejany A, Gorelik D, et al. Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high‐risk patients ‐ a POCER study analysis. Alimentary Pharmacology & Therapeutics 2015;42(7):867‐79. - PubMed
De Cruz 2015b {published data only}
    1. Cruz P, Kamm MA, Hamilton AL, Ritchie KJ, Krejany EO, Gorelik A, et al. Crohn's disease management after intestinal resection: a randomised trial. Lancet 2015;385(9976):1406‐17. [DOI: 10.1016/S0140-6736(14)61908-5] - DOI - PubMed
Doherty 2009 {published data only}
    1. Doherty GA, Cheifetz AS. Targeting TNF in postoperative recurrence of Crohn's disease: can we extinguish the fire before it starts?. Inflammatory Bowel Diseases 2009;15(12):1925‐6. - PubMed
Dumois 2001 {published data only}
    1. Dumois RA, Herrera JL. Can postoperative relapse of Crohn's disease be prevented?. American Journal of Gastroenterology 2001;96(1):249. - PubMed
Ewe 1976 {published data only}
    1. Ewe K, Holtermuller KH, Baas U, Eckardt V, Kreig H, Kutzner J, et al. Prophylaxis after resection because of Crohn’s disease by Salazosulfapyridin (Azulfidine). A double‐blind study [Rezidivprophylaxenach darmresektion wegen Morbus Crohn durch Salazosulfapyridin (Azulfidine). Eine doppelblindstudie]. Verhandlungen der Deutschen Gesellschaft fur Innere Medizin 1976;82(Pt 1):930‐2. - PubMed
Ewe 1980 {published data only}
    1. Ewe K, Herfarth C, Malchow H. Surgical and internal medicine therapy study of the postoperative prevention of recurrence in Crohn's disease ‐ completion of a partly randomized study. Verhandlungen der Deutschen Gesellschaft fur Innere Medizin 1980;86:1327‐37. - PubMed
Ewe 1981 {published data only}
    1. Ewe K. Effectiveness of Azulfidine/Salazopyrin in the postoperative prevention of recurrence in Crohn disease [Wirksamkeit von Azulfidine/Salazopyrin zur postoperativen rezidivprophylaxe bei Morbus Crohn]. Zeitschrift fur Gastroenterologie ‐ Verhandlungsband 1981;19:41‐4. - PubMed
Ewe 1984 {published data only}
    1. Ewe K, Malchow H, Herfarth C. Radical operation and recurrence prevention with azulfidine in Crohn disease: a prospective multicenter study ‐ initial results. Langenbecks Archiv fur Chirurgie 1984;364:427‐30. - PubMed
Ferrante 2014 {published data only}
    1. Ferrante M, Papamichael K, Duricova D, D'Haens GH, Vermeire S, Archavlis EJ, et al. Systematic versus endoscopy‐driven treatment with azathioprine to prevent postoperative ileal Crohn's disease recurrence: interim results from a randomized, multicenter trial. Gastroenterology 2014;146(5 Suppl 1):S‐592. - PubMed
Ford 2010 {published data only}
    1. Ford AC. Efficacy of azathioprine versus mesalazine in postoperative Crohn's disease. Gut 2010;59(12):1731‐2. - PubMed
Herfarth 2014 {published data only}
    1. Herfarth HH. Anti‐tumor necrosis factor therapy to prevent Crohn's disease recurrence after surgery. Clinical Gastroenterology and Hepatology 2014;12(9):1503‐6. - PubMed
Kamm 2014a {published data only}
    1. Kamm MA, Cruz PP, Wright EK, Hamilton AL, Ritchie KJ, Krejany EO, et al. Optimising post‐operative Crohn's disease management: best drug therapy alone versus colonoscopic monitoring with treatment step‐up. The POCER study. Gastroenterology 2014;1:S164.
Kamm 2014b {published data only}
    1. Kamm MA, Cruz PP, Wright EK, Hamilton AL, Ritchie KJ, Krejany EO. Optimising post‐operative Crohn's disease management: best drug therapy alone versus endoscopic monitoring, disease evolution, and faecal calprotectin monitoring. The POCER study. Journal of Crohn's and Colitis 2014;8:S13.
Kennedy 2015 {published data only}
    1. Kennedy NA, Ennis H, Gaya DR, Mowat C, Arnott IDR. Interobserver agreement in assessment of Rutgeerts' score of endoscopic recurrence of ileal Crohn's disease: a substudy of the TOPPIC trial. Journal of Crohn's and Colitis 2015;9:S231‐2.
Liao 2009 {published data only}
    1. Liao NS, Ren JA, Fan CG, Wang GF, Zhao YZ, Li JS. Efficacy of polyglycosides of Tripterygium wilfordii in preventing postoperative recurrence of Crohn disease. Chinese Journal of Gastrointestinal Surgery 2009;12(2):167‐9. - PubMed
Manship 2015 {published data only}
    1. Manship TA, Ford AC. VSL#3 in postoperative Crohn's disease. Clinical Gastroenterology and Hepatology 2015;13(10):1855. - PubMed
Mardini 2005 {published data only}
    1. Mardini HE. Azathioprine and 6 Mercaptopurine in postoperative maintenance of Crohn's disease remission: is no evidence of effect an evidence of no effect? [3] (multiple letters). Gastroenterology 2005;128(1):246‐9. - PubMed
McLeod 1997 {published data only}
    1. McLeod RS, Wolff BG, Steinhart AH, Carryer PW, O'Rourke K, Andrews DF, et al. Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease. Gastroenterology 1997;113(6):1823‐7. - PubMed
NCT00074542 {published data only}
    1. NCT00074542. An efficacy and safety study of Omega‐3 free fatty acids (Epanova™) for the maintenance of symptomatic remission in subjects with Crohn's disease. clinicaltrials.gov/ct2/show/NCT00074542 (first received 16 December 2003).
NCT01190839 {published data only}
    1. NCT01190839. A multicenter trial comparing REMICADE (Infliximab) and placebo in the prevention of recurrence in Crohn's disease (CD) patients undergoing surgical resection who are at an increased risk of recurrence. clinicaltrials.gov/ct2/show/NCT01190839 (first received 30 August 2010).
NCT01696942 {published data only}
    1. NCT01696942. Cimzia versus mesalamine for Crohn's recurrence. clinicaltrials.gov/show/NCT01696942 (first received 2 October 2012).
NCT02247258 {published data only}
    1. NCT02247258. Azathioprine in the prevention of ileal Crohn's disease postoperative recurrence. clinicaltrials.gov/ct2/show/NCT02247258 (first received 23 September 2014).
NCT02255370 {published data only}
    1. NCT02255370. Curcumin associated with thiopurin in the prevention of post‐op recurrence in Crohn disease. clinicaltrials.gov/ct2/show/NCT02255370 (first received 2 October 2014).
NCT02997059 {published data only}
    1. NCT02997059. Effect of fluconazole on the levels of ASCA after surgical resection for Crohn's disease. clinicaltrials.gov/ct2/show/NCT02997059 (first received 19 December 2016).
Papamichael 2012 {published data only}
    1. Papamichael K, Lariou C, Mantzaris GJ. Adalimumab for the prevention and/or treatment of post‐operative recurrence of Crohn's disease: a prospective, two‐year, single center, pilot study. Journal of Crohn's and Colitis 2012;6(9):924‐31. - PubMed
Regueiro 2013 {published data only}
    1. Regueiro M, Baidoo L, Kip KE, Swoger JM, Binion DG, Hashash JG, et al. Infliximab maintenance beyond one year prevents postoperative Crohn's disease recurrence: long‐term follow‐up from the randomized controlled pilot study. Gastroenterology 2013;144(5 Suppl 1):S173.
Regueiro 2014 {published data only}
    1. Regueiro M, Kip KE, Baidoo L, Swoger JM, Schraut W. Postoperative therapy with infliximab prevents long‐term Crohn's disease recurrence. Clinical Gastroenterology and Hepatology 2014;12(9):1492‐502.e1. - PubMed
Reibetanz 2015 {published data only}
    1. Reibetanz J, Germer CT. Optimal management of Crohn's disease after intestinal resection. Der Chirurg; Zeitschrift fur alle Gebiete der Operativen Medizen 2015;86(11):1070. - PubMed
Ren 2013 {published data only}
    1. Ren J, Wu X, Liao N, Wang G, Fan C, Liu S, et al. Prevention of postoperative recurrence of Crohn's disease: Tripterygium wilfordii polyglycoside versus mesalazine. Journal of International Medical Research 2013;41(1):176‐87. - PubMed
Sandborn 2004 {published data only}
    1. Sandborn WJ, Feagan BG. The efficacy of azathioprine and 6‐mercaptopurine for the prevention of postoperative recurrence in patients with Crohn's disease remains uncertain. Gastroenterology 2004;127(3):990‐3. - PubMed
Steinhart 1992 {published data only}
    1. Steinhart AH, O'Rourke K, Wolff BG, McLeod RS. Application of a stopping rule based on total treatment failures: the postoperative Crohn's disease trial. Journal of Clinical Epidemiology 1992;45(5):495‐504. - PubMed
Tao 2009 {published data only}
    1. Tao QS, Ren JA, Ji ZL, Li JS, Wang XB, Jiang XH. Maintenance effect of polyglycosides of Tripterygium wilfordii on remission in postoperative Crohn disease. Chinese Journal of Gastrointestinal Surgery 2009;12(5):491‐3. - PubMed
Vera‐Mendoza 2017 {published data only}
    1. Vera‐Mendoza I, Domenech E, Taxonera C, Ruiz VV, Marin‐Jimenez I, Guardiola J, et al. Adalimumab vs azathioprine in the prevention of postoperative Crohn's disease recurrence. A GETECCU randomised trial. Journal of Crohn's and Colitis 2017;11(11):1293‐301. - PubMed
Wright 2014 {published data only}
    1. Wright EK, Cruz P, Kamm MA, Hamilton AL, Ritchie KJ, Krejany S, et al. Intestinal resection in Crohn's disease is associated with significant and durable improvement in health related quality of life although to a lesser extent in women and smokers. Results from the POCER study. Gastroenterology 2014;156:S435.
Wright 2015 {published data only}
    1. Wright EK, Kamm MA, Cruz P, Hamilton AL, Ritchie K, Bell SJ, et al. Structured post‐operative treatment and monitoring to prevent Crohn's disease recurrence is cost effective. Results from the POCER study. Journal of Gastroenterology and Hepatology 2015;30:145.
Yamamoto 2009 {published data only}
    1. Yamamoto T, Umegae S, Matsumoto K. Impact of infliximab therapy after early endoscopic recurrence following ileocolonic resection of Crohn's disease: a prospective pilot study. Inflammatory Bowel Diseases 2009;15(10):1460‐6. - PubMed
Yamamoto 2013 {published data only}
    1. Yamamoto T. Adalimumab or infliximab for the prevention or treatment of post‐operative recurrence in Crohn's disease. Journal of Crohn's and Colitis 2013;7(4):157. - PubMed
Zhu 2015 {published data only}
    1. Zhu W, Li Y, Gong J, Zuo L, Zhang W, Cao L, et al. Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn's disease: a randomized clinical trial. Digestive and Liver Disease 2015;47(1):14‐9. - PubMed

References to studies awaiting assessment

NCT00976690 {published data only}
    1. NCT00976690. Comparison azathioprine to mesalazine for the prevention of postoperative recurrence in the Crohn Disease (IMURELPOST). clinicaltrials.gov/ct2/show/NCT00976690 (first received 14 September 2009).
NCT01698970  {published data only}
    1. NCT01698970. Effect of the consumption of a probiotic strain on the prevention of post‐operative recurrence in Crohn's disease. clinicaltrials.gov/ct2/show/NCT01698970 (first received 3 October 2012).

References to ongoing studies

EUCTR2015‐000555‐24‐NL {published data only}
    1. EUCTR2015‐000555‐24‐NL. Randomized, placebo‐controlled, double‐blind, multicenter study to determine the effectiveness and safety of vedolizumab in prevention of recurrence of Crohn's disease of the mucosa in patients with surgical removal of the area between the small and the large bowel. clinicaltrialsregister.eu/ctr‐search/trial/2015‐000555‐24/NL (first received 2 October 2016).
NCT01015391 {published data only}
    1. NCT01015391. Efficacy study of T2 versus AZA to maintain clinical and endoscopic remission in postoperative Crohn's disease. clinicaltrials.gov/show/NCT01015391 (first received 18 November 2009).
NCT02834754 {published data only}
    1. NCT02834754. A randomized, double‐blind, placebo controlled study of vedolizumab for the prevention of post‐operative Crohn's disease recurrence. clinicaltrials.gov/show/NCT02834754 (first received 15 July 2016).
NCT03185611 {published data only}
    1. NCT03185611. Effectiveness of rifaximin combined with thiopurine on preventing postoperative recurrence in Crohn's disease. clinicaltrials.gov/show/NCT03185611 (first received 14 June 2017).
NCT03185624 {published data only}
    1. NCT03185624. Effectiveness of rifaximin on preventing postoperative recurrence in Crohn's disease. clinicaltrials.gov/ct2/show/NCT03185624 (first received 14 June 2017).
NCT03456752 {published data only}
    1. NCT03456752. Perioperative dexamethasone on postoperative outcome in IBD. clinicaltrials.gov/show/NCT03456752 (first received 7 March 2018).
NL6213 (NTR6385) {published data only}
    1. NL6213 (NTR6385). A trial to compare if the diseased area between the colon and the small bowel of patients with Crohn's disease stays free of disease after surgery between a group of patients whom receive no medication versus a group whom receive vedolizumab. https://www.trialregister.nl/trial/6213 (first received 24 April 2017).

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