Peter De Cruz1, Michael A Kamm2, Amy L Hamilton3, Kathryn J Ritchie3, Efrosinia O Krejany3, Alexandra Gorelik4, Danny Liew4, Lani Prideaux3, Ian C Lawrance5, Jane M Andrews6, Peter A Bampton7, Peter R Gibson8, Miles Sparrow9, Rupert W Leong10, Timothy H Florin11, Richard B Gearry12, Graham Radford-Smith13, Finlay A Macrae14, Henry Debinski15, Warwick Selby16, Ian Kronborg17, Michael J Johnston18, Rodney Woods18, P Ross Elliott3, Sally J Bell3, Steven J Brown3, William R Connell3, Paul V Desmond3. 1. Department of Gastroenterology, St Vincent's Hospital and Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Austin Health, University of Melbourne, Austin Academic Centre, Heidelberg, VIC, Australia. 2. Department of Gastroenterology, St Vincent's Hospital and Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Medicine, Imperial College London, London, UK. Electronic address: mkamm@unimelb.edu.au. 3. Department of Gastroenterology, St Vincent's Hospital and Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. 4. Melbourne EpiCentre, University of Melbourne and Melbourne Health, Melbourne, VIC, Australia. 5. Centre for Inflammatory Bowel Diseases, Fremantle Hospital and The University of Western Australia, Fremantle, WA, Australia. 6. Department of Gastroenterology and Hepatology, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia. 7. Department of Gastroenterology and Hepatology, Flinders Medical Centre and Flinders University, Adelaide, SA, Australia. 8. Department of Gastroenterology, Alfred Health and Monash University, Melbourne, VIC, Australia. 9. Department of Gastroenterology, Alfred Health, Melbourne, VIC, Australia. 10. Gastroenterology and Liver Services, Concord and Bankstown Hospitals and The University of New South Wales, Sydney, NSW, Australia. 11. Department of Gastroenterology, Mater Health Services, University of Queensland, Brisbane, QLD, Australia. 12. Department of Medicine, University of Otago, Christchurch, New Zealand. 13. QIMR Berghofer Medical Research Institute, University of Queensland School of Medicine, Inflammatory Bowel Diseases Unit, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. 14. Department of Colorectal Medicine and Genetics, and Department of Medicine, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia. 15. Melbourne Gastrointestinal Investigation Unit, Cabrini Hospital, Melbourne, VIC, Australia. 16. AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia. 17. Department of Gastroenterology, Western Hospital, Melbourne, VIC, Australia. 18. Department of Colorectal Surgery, St Vincent's Hospital and Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
Abstract
BACKGROUND: Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS: In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS: Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION: Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING: AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.
RCT Entities:
BACKGROUND: Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS: In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS: Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION: Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING: AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.
Authors: Laura R Glick; Philip H Sossenheimer; Jacob E Ollech; Russell D Cohen; Neil H Hyman; Roger D Hurst; David T Rubin Journal: J Crohns Colitis Date: 2019-09-19 Impact factor: 9.071
Authors: M Fumery; P S Dulai; P Meirick; A M Farrell; S Ramamoorthy; W J Sandborn; S Singh Journal: Aliment Pharmacol Ther Date: 2016-12-08 Impact factor: 8.171
Authors: María Jesús Martínez; Tomás Ripollés; Jose María Paredes; Eduardo Moreno-Osset; Juan Manuel Pazos; Esther Blanc Journal: Dig Dis Sci Date: 2019-01-02 Impact factor: 3.199
Authors: Marisol Luján-Sanchis; Laura Sanchis-Artero; Laura Larrey-Ruiz; Laura Peño-Muñoz; Paola Núñez-Martínez; Génesis Castillo-López; Lara González-González; Carlos Boix Clemente; Cecilia Albert Antequera; Ana Durá-Ayet; Javier Sempere-Garcia-Argüelles Journal: World J Gastrointest Endosc Date: 2016-09-16