Immunomodulators: Friends or Enemies in Surgery for Crohn’s Disease?

Kalle      Landerholm; Disa      Kalman; Conny      Wallon; Pär      Myrelid
Abstract

Crohn’s disease may severely impact the quality of life and being a chronic disease it requires both medical and surgical treatment aimed at induction and maintenance of remission to prevent relapsing symptoms and the need for further surgery. Surgery in Crohn’s disease often has to be performed in patients with well-known risk factors of post-operative complications, particularly intraabdominal septic complications. This review will look at the current knowledge of immunomodulating therapies in the peri-operative phase of Crohn’s disease. The influence of immunomodulators on postoperative complications is evaluated by reviewing available clinical reports and data from animal studies. Furthermore, the effect of immunomodulators on preventing or deferring primary as well as repeat surgery in Crohn’s disease is reviewed with particular consideration given to high-risk cohorts and timing of prophylaxis.
Keywords: Crohn's disease, inflammatory bowel disease, surgery, immunomodulators, thiopurines, azathioprine, mercaptopurine.
Graphical Abstract

[1] 
Podolsky DK. Inflammatory bowel disease. N Engl J Med  2002; 347(6): 417-29.
[http://dx.doi.org/10.1056/NEJMra020831] [PMID:  12167685] 
[2] 
Vind I, Riis L, Jess T, et al. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: A population-based study from the Danish Crohn colitis database. Am J Gastroenterol  2006; 101(6): 1274-82.
[http://dx.doi.org/10.1111/j.1572-0241.2006.00552.x] [PMID:  16771949] 
[3] 
Lindgren A, Wallerstedt S, Olsson R. Prevalence of Crohn’s disease and simultaneous occurrence of extraintestinal complications and cancer. An epidemiologic study in adults. Scand J Gastroenterol  1996; 31(1): 74-8.
[http://dx.doi.org/10.3109/00365529609031630] [PMID:  8927944] 
[4] 
Tang LY, Rawsthorne P, Bernstein CN. Are perineal and luminal fistulas associated in Crohn’s disease? A population-based study. Clin Gastroenterol Hepatol  2006; 4(9): 1130-4.
[http://dx.doi.org/10.1016/j.cgh.2006.06.021] [PMID:  16905369] 
[5] 
Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology  2002; 122(4): 875-80.
[http://dx.doi.org/10.1053/gast.2002.32362] [PMID:  11910338] 
[6] 
Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol  2001; 96(4): 1116-22.
[http://dx.doi.org/10.1111/j.1572-0241.2001.03756.x] [PMID:  11316157] 
[7] 
Pimentel M, Chang M, Chow EJ, et al. Identification of a prodromal period in Crohn’s disease but not ulcerative colitis. Am J Gastroenterol  2000; 95(12): 3458-62.
[http://dx.doi.org/10.1111/j.1572-0241.2000.03361.x] [PMID:  11151877] 
[8] 
Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology  2004; 126(6): 1518-32.
[http://dx.doi.org/10.1053/j.gastro.2004.02.072] [PMID:  15168364] 
[9] 
Keller J, Panter H, Layer P. Management of the short bowel syndrome after extensive small bowel resection. Best Pract Res Clin Gastroenterol  2004; 18(5): 977-92.
[http://dx.doi.org/10.1016/S1521-6918(04)00060-5] [PMID:  15494290] 
[10] 
Agwunobi AO, Carlson GL, Anderson ID, Irving MH, Scott NA. Mechanisms of intestinal failure in Crohn’s disease. Dis Colon Rectum  2001; 44(12): 1834-7.
[http://dx.doi.org/10.1007/BF02234463] [PMID:  11742170] 
[11] 
Thompson JS, Iyer KR, DiBaise JK, Young RL, Brown CR, Langnas AN. Short bowel syndrome and Crohn’s disease. J Gastrointest Surg  2003; 7(8): 1069-72.
[http://dx.doi.org/10.1016/j.gassur.2003.08.007] [PMID:  14675717] 
[12] 
Fazio VW, Marchetti F, Church M, et al. Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg  1996; 224(4): 563-71.
[http://dx.doi.org/10.1097/00000658-199610000-00014] [PMID:  8857860] 
[13] 
Post S, Herfarth C, Böhm E, et al. The impact of disease pattern, surgical management, and individual surgeons on the risk for relaparotomy for recurrent Crohn’s disease. Ann Surg  1996; 223(3): 253-60.
[http://dx.doi.org/10.1097/00000658-199603000-00005] [PMID:  8604905] 
[14] 
Raab Y, Bergström R, Ejerblad S, Graf W, Påhlman L. Factors influencing recurrence in Crohn’s disease. An analysis of a consecutive series of 353 patients treated with primary surgery. Dis Colon Rectum  1996; 39(8): 918-25.
[http://dx.doi.org/10.1007/BF02053992] [PMID:  8756849] 
[15] 
Poggioli G, Pierangeli F, Laureti S, Ugolini F. Review article:
Indication and type of surgery in crohn's disease. Aliment Pharmacol
Ther  16(4): 59-64.2002; 
[16] 
Yamamoto T, Bain IM, Allan RN, Keighley MR. An audit of strictureplasty for small-bowel Crohn’s disease. Dis Colon Rectum  1999; 42(6): 797-803.
[http://dx.doi.org/10.1007/BF02236939] [PMID:  10378605] 
[17] 
Yamamoto T, Allan RN, Keighley MR. Long-term outcome of surgical management for diffuse jejunoileal Crohn’s disease. Surgery  2001; 129(1): 96-102.
[http://dx.doi.org/10.1067/msy.2001.109497] [PMID:  11150039] 
[18] 
Yamamoto T, Fazio VW, Tekkis PP. Safety and efficacy of strictureplasty for Crohn’s disease: a systematic review and meta-analysis. Dis Colon Rectum  2007; 50(11): 1968-86.
[http://dx.doi.org/10.1007/s10350-007-0279-5] [PMID:  17762967] 
[19] 
Bernklev T, Jahnsen J, Lygren I, Henriksen M, Vatn M, Moum B. Health-related quality of life in patients with inflammatory bowel disease measured with the short form-36: psychometric assessments and a comparison with general population norms. Inflamm Bowel Dis  2005; 11(10): 909-18.
[http://dx.doi.org/10.1097/01.mib.0000179467.01748.99] [PMID:  16189421] 
[20] 
Canavan C, Abrams KR, Hawthorne B, Drossman D, Mayberry JF. Long-term prognosis in Crohn’s disease: factors that affect quality of life. Aliment Pharmacol Ther  2006; 23(3): 377-85.
[http://dx.doi.org/10.1111/j.1365-2036.2006.02753.x] [PMID:  16422997] 
[21] 
Blondel-Kucharski F, Chircop C, Marquis P, et al. Health-related quality of life in Crohn’s disease: a prospective longitudinal study in 231 patients. Am J Gastroenterol  2001; 96(10): 2915-20.
[http://dx.doi.org/10.1111/j.1572-0241.2001.04681.x] [PMID:  11693326] 
[22] 
Casellas F, Vivancos JL, Sampedro M, Malagelada JR. Relevance of the phenotypic characteristics of Crohn’s disease in patient perception of health-related quality of life. Am J Gastroenterol  2005; 100(12): 2737-42.
[http://dx.doi.org/10.1111/j.1572-0241.2005.00360.x] [PMID:  16393228] 
[23] 
Andersson P, Olaison G, Bendtsen P, Myrelid P, Sjödahl R. Health related quality of life in Crohn’s proctocolitis does not differ from a general population when in remission. Colorectal Dis  2003; 5(1): 56-62.
[http://dx.doi.org/10.1046/j.1463-1318.2003.00407.x] [PMID:  12780929] 
[24] 
Tillinger W, Mittermaier C, Lochs H, Moser G. Health-related quality of life in patients with Crohn’s disease: influence of surgical operation--a prospective trial. Dig Dis Sci  1999; 44(5): 932-8.
[http://dx.doi.org/10.1023/A:1026600428484] [PMID:  10235600] 
[25] 
Larsson K, Lööf L, Rönnblom A, Nordin K. Quality of life for patients with exacerbation in inflammatory bowel disease and how they cope with disease activity. J Psychosom Res  2008; 64(2): 139-48.
[http://dx.doi.org/10.1016/j.jpsychores.2007.10.007] [PMID:  18222127] 
[26] 
Casellas F, Rodrigo L, Niño P, Pantiga C, Riestra S, Malagelada JR. Sustained improvement of health-related quality of life in Crohn’s disease patients treated with infliximab and azathioprine for 4 years. Inflamm Bowel Dis  2007; 13(11): 1395-400.
[http://dx.doi.org/10.1002/ibd.20205] [PMID:  17567874] 
[27] 
Casellas F, López-Vivancos J, Badia X, Vilaseca J, Malagelada JR. Influence of inflammatory bowel disease on different dimensions of quality of life. Eur J Gastroenterol Hepatol  2001; 13(5): 567-72.
[http://dx.doi.org/10.1097/00042737-200105000-00017] [PMID:  11396538] 
[28] 
Silverstein MD, Loftus EV, Sandborn WJ, et al. Clinical course and costs of care for Crohn’s disease: Markov model analysis of a population-based cohort. Gastroenterology  1999; 117(1): 49-57.
[http://dx.doi.org/10.1016/S0016-5085(99)70549-4] [PMID:  10381909] 
[29] 
Andrews HA, Keighley MR, Alexander-Williams J, Allan RN. Strategy for management of distal ileal Crohn’s disease. Br J Surg  1991; 78(6): 679-82.
[http://dx.doi.org/10.1002/bjs.1800780614] [PMID:  2070232] 
[30] 
Andersson P, Olaison G, Bodemar G, et al. Low symptomatic load in Crohn’s disease with surgery and medicine as complementary treatments. Scand J Gastroenterol  1998; 33(4): 423-9.
[http://dx.doi.org/10.1080/00365529850171062] [PMID:  9605265] 
[31] 
Casellas F, López-Vivancos J, Badia X, Vilaseca J, Malagelada JR. Impact of surgery for Crohn’s disease on health-related quality of life. Am J Gastroenterol  2000; 95(1): 177-82.
[http://dx.doi.org/10.1111/j.1572-0241.2000.01681.x] [PMID:  10638579] 
[32] 
Ponsioen CY, de Groof EJ, Eshuis EJ, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol  2017; 2(11): 785-92.
[http://dx.doi.org/10.1016/S2468-1253(17)30248-0] [PMID:  28838644] 
[33] 
Rhodes J, Bainton D, Beck P. Azathioprine in Crohn’s disease. Lancet  1970; 2(7683): 1142.
[http://dx.doi.org/10.1016/S0140-6736(70)92347-0] [PMID:  4097954] 
[34] 
Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut  2002; 50(4): 485-9.
[http://dx.doi.org/10.1136/gut.50.4.485] [PMID:  11889067] 
[35] 
Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med  1995; 123(2): 132-42.
[http://dx.doi.org/10.7326/0003-4819-123-2-199507150-00009] [PMID:  7778826] 
[36] 
Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol  1993; 88(8): 1198-205.
[PMID:  8338087] 
[37] 
Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in crohn’s disease. Cochrane Database Syst Rev 2009.
[38] 
D’Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology  1997; 112(5): 1475-81. [see comments].
[http://dx.doi.org/10.1016/S0016-5085(97)70027-1] [PMID: 9136824] 
[39] 
D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endosc  1999; 50(5): 667-71.
[http://dx.doi.org/10.1016/S0016-5107(99)80017-0] [PMID:  10536324] 
[40] 
Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre JP. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut  2005; 54(2): 237-41.
[http://dx.doi.org/10.1136/gut.2004.045294] [PMID:  15647188] 
[41] 
Myrelid P, Olaison G, Sjödahl R, Nyström P-O, Almer S, Andersson P. Thiopurine therapy is associated with postoperative intra-abdominal septic complications in abdominal surgery for Crohn’s disease. Dis Colon Rectum  2009; 52(8): 1387-94.
[http://dx.doi.org/10.1007/DCR.0b013e3181a7ba96] [PMID:  19617749] 
[42] 
Frøslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology  2007; 133(2): 412-22.
[http://dx.doi.org/10.1053/j.gastro.2007.05.051] [PMID:  17681162] 
[43] 
Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology  2000; 119(4): 895-902.
[http://dx.doi.org/10.1053/gast.2000.18144] [PMID:  11040176] 
[44] 
Etchevers MJ, Aceituno M, Sans M. Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease. World J Gastroenterol  2008; 14(36): 5512-8.
[http://dx.doi.org/10.3748/wjg.14.5512] [PMID:  18810768] 
[45] 
Treton X, Bouhnik Y, Mary JY, et al. Azathioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol  2009; 7(1): 80-5.
[http://dx.doi.org/10.1016/j.cgh.2008.08.028] [PMID:  18849016] 
[46] 
Almer SH, Hjortswang H, Hindorf U. 6-Thioguanine therapy in Crohn’s disease--observational data in Swedish patients. Dig Liver Dis  2009; 41(3): 194-200.
[http://dx.doi.org/10.1016/j.dld.2008.07.314] [PMID:  18799369] 
[47] 
Teml A, Schaeffeler E, Herrlinger KR, Klotz U, Schwab M. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet  2007; 46(3): 187-208.
[http://dx.doi.org/10.2165/00003088-200746030-00001] [PMID:  17328579] 
[48] 
Teml A, Schaeffeler E, Herrlinger KR, Klotz U, Schwab M. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet  2007; 46(3): 187-208.
[http://dx.doi.org/10.2165/00003088-200746030-00001] [PMID:  17328579] 
[49] 
Pierik M, Rutgeerts P, Vlietinck R, Vermeire S. Pharmacogenetics in inflammatory bowel disease. World J Gastroenterol  2006; 12(23): 3657-67.
[http://dx.doi.org/10.3748/wjg.v12.i23.3657] [PMID:  16773681] 
[50] 
Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther  2002; 16(10): 1743-50.
[http://dx.doi.org/10.1046/j.1365-2036.2002.01353.x] [PMID:  12269967] 
[51] 
Hindorf U, Johansson M, Eriksson A, Kvifors E, Almer SH. Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther  2009; 29(6): 654-61.
[http://dx.doi.org/10.1111/j.1365-2036.2008.03925.x] [PMID:  19183142] 
[52] 
Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi Porro G. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study. Dig Liver Dis  2003; 35(9): 619-27.
[http://dx.doi.org/10.1016/S1590-8658(03)00372-4] [PMID:  14563183] 
[53] 
Hassard PV, Vasiliauskas EA, Kam LY, Targan SR, Abreu MT. Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn’s disease. Inflamm Bowel Dis  2000; 6(1): 16-20.
[http://dx.doi.org/10.1097/00054725-200002000-00003] [PMID:  10701145] 
[54] 
Tan T, Lawrance IC. Use of mycophenolate mofetil in inflammatory bowel disease. World J Gastroenterol  2009; 15(13): 1594-9.
[http://dx.doi.org/10.3748/wjg.15.1594] [PMID:  19340901] 
[55] 
Baumgart DC, Wiedenmann B, Dignass AU. Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease. Aliment Pharmacol Ther  2003; 17(10): 1273-81.
[http://dx.doi.org/10.1046/j.1365-2036.2003.01534.x] [PMID:  12755840] 
[56] 
Ierardi E, Principi M, Francavilla R, et al. Oral tacrolimus long-term therapy in patients with Crohn’s disease and steroid resistance. Aliment Pharmacol Ther  2001; 15(3): 371-7.
[http://dx.doi.org/10.1046/j.1365-2036.2001.00938.x] [PMID:  11207512] 
[57] 
Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med  1995; 332(5): 292-7.
[http://dx.doi.org/10.1056/NEJM199502023320503] [PMID:  7816064] 
[58] 
Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory crohn’s disease. Cochrane Database Syst Rev 2005.
[59] 
Srinivasan R, Akobeng AK. Thalidomide and thalidomide analogues for induction of remission in crohn’s disease. Cochrane Database Syst Rev 2009.
[http://dx.doi.org/10.1002/14651858.CD007350.pub2] 
[60] 
McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. Cyclosporine for induction of remission in crohn’s disease. Cochrane Database Syst Rev 2005.
[http://dx.doi.org/10.1002/14651858.CD000297.pub2] 
[61] 
Reinisch W, Panés J, Lémann M, et al. A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn’s disease. Am J Gastroenterol  2008; 103(9): 2284-92.
[http://dx.doi.org/10.1111/j.1572-0241.2008.02024.x] [PMID:  18671816] 
[62] 
Vandeputte L, D’Haens G, Baert F, Rutgeerts P. Methotrexate in refractory Crohn’s disease. Inflamm Bowel Dis  1999; 5(1): 11-5.
[http://dx.doi.org/10.1097/00054725-199902000-00002] [PMID:  10028444] 
[63] 
Korelitz BI. Is there any remaining role for methotrexate for Crohn’s disease? Dig Liver Dis  2003; 35(9): 610-1.
[http://dx.doi.org/10.1016/S1590-8658(03)00374-8] [PMID:  14563181] 
[64] 
van Dieren JM, Kuipers EJ, Samsom JN, Nieuwenhuis EE, van der Woude CJ. Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil: their mechanisms of action and role in the treatment of IBD. Inflamm Bowel Dis  2006; 12(4): 311-27.
[http://dx.doi.org/10.1097/01.MIB.0000209787.19952.53] [PMID:  16633053] 
[65] 
Akobeng AK, Stokkers PC. Thalidomide and thalidomide analogues for maintenance of remission in crohn’s disease. Cochrane Database Syst Rev  2009; 2: CD007351.
[http://dx.doi.org/10.1002/14651858.CD007351.pub2] 
[66] 
Mao EJ, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with meta-analysis: comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn’s disease and ulcerative colitis. Aliment Pharmacol Ther  2017; 45(1): 3-13.
[http://dx.doi.org/10.1111/apt.13847] [PMID:  27862107] 
[67] 
Markowitz J. Can we change the natural history of Crohn’s disease with early immunomodulation? Dig Dis  2014; 32(4): 345-50.
[http://dx.doi.org/10.1159/000358134] [PMID:  24969278] 
[68] 
Chatu S, Subramanian V, Saxena S, Pollok RC. The role of thiopurines in reducing the need for surgical resection in Crohn’s disease: a systematic review and meta-analysis. Am J Gastroenterol  2014; 109(1): 23-34.
[http://dx.doi.org/10.1038/ajg.2013.402] [PMID:  24322839] 
[69] 
Chhaya V, Pollok RC, Cecil E, et al. Impact of early thiopurines on surgery in 2770 children and young people diagnosed with inflammatory bowel disease: a national population-based study. Aliment Pharmacol Ther  2015; 42(8): 990-9.
[http://dx.doi.org/10.1111/apt.13361] [PMID:  26271196] 
[70] 
Kariyawasam VC, Selinger CP, Katelaris PH, et al. Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn’s disease. Inflamm Bowel Dis  2014; 20(8): 1382-90.
[http://dx.doi.org/10.1097/MIB.0000000000000119] [PMID:  24991785] 
[71] 
Lakatos PL, Golovics PA, David G, et al. Has there been a change in the natural history of Crohn’s disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009. Am J Gastroenterol  2012; 107(4): 579-88.
[http://dx.doi.org/10.1038/ajg.2011.448] [PMID:  22233693] 
[72] 
Chatu S, Saxena S, Subramanian V, et al. The impact of timing and duration of thiopurine treatment on first intestinal resection in Crohn’s disease: national UK population-based study 1989-2010. Am J Gastroenterol  2014; 109(3): 409-16.
[http://dx.doi.org/10.1038/ajg.2013.462] [PMID:  24469612] 
[73] 
Ramadas AV, Gunesh S, Thomas GA, Williams GT, Hawthorne AB. Natural history of Crohn’s disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates. Gut  2010; 59(9): 1200-6.
[http://dx.doi.org/10.1136/gut.2009.202101] [PMID:  20650924] 
[74] 
Qiu Y, Chen BL, Mao R, et al. Early thiopurines versus conventional step-care therapy for modifying the disease course of early crohn’s disease: A tertiary referral center cohort study. Medicine (Baltimore)  2015; 94(31): e1148.
[http://dx.doi.org/10.1097/MD.0000000000001148] [PMID:  26252273] 
[75] 
Qiu Y, Chen BL, Mao R, et al. Endoscopy assessment at 1-year identifies long-term responders to thiopurines maintenance therapy in patients with crohn’s disease. Medicine (Baltimore)  2015; 94(31): e1204.
[http://dx.doi.org/10.1097/MD.0000000000001204] [PMID:  26252278] 
[76] 
Alexakis C, Saxena S, Chhaya V, Cecil E, Curcin V, Pollok R. Do thiopurines reduce the risk of surgery in elderly onset inflammatory bowel disease? A 20-year national population-based cohort study. Inflamm Bowel Dis  2017; 23(4): 672-80.
[http://dx.doi.org/10.1097/MIB.0000000000001031] [PMID:  28151735] 
[77] 
Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs conventional management of crohn’s disease: A randomized controlled trial. A randomized controlled trial. Gastroenterology  2013; 145(4): 758-74.
[http://dx.doi.org/10.1053/j.gastro.2013.04.048] 
[78] 
Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine
therapy is no more effective than placebo for newly diagnosed
crohn's disease  2013; 145(4): 766-4.e1.
[http://dx.doi.org/10.1053/j.gastro.2013.06.009] ; Early azathioprine therapy is no more effective than placebo for newly diagnosed crohn's disease Gastroenterology 2013; 145(4): 766-4.
[79] 
Magro F, Rodrigues-Pinto E, Coelho R, et al. Is it possible to change phenotype progression in Crohn’s disease in the era of immunomodulators? Predictive factors of phenotype progression. Am J Gastroenterol  2014; 109(7): 1026-36.
[http://dx.doi.org/10.1038/ajg.2014.97] [PMID:  24796767] 
[80] 
Zhu Z, Mei Z, Guo Y, et al. Reduced risk of inflammatory bowel disease-associated colorectal neoplasia with use of thiopurines: A systematic review and meta-analysis. J Crohn’s Colitis  2018; 12(5): 546-58.
[http://dx.doi.org/10.1093/ecco-jcc/jjy006] [PMID:  29370346] 
[81] 
Rieder F, Reinisch W. Thiopurines and the natural course of Crohn’s disease: did we finally find the right therapeutic target? Am J Gastroenterol  2014; 109(7): 1037-40.
[http://dx.doi.org/10.1038/ajg.2014.162] [PMID:  24989094] 
[82] 
Jones DW, Finlayson SR. Trends in surgery for Crohn’s disease in the era of infliximab. Ann Surg  2010; 252(2): 307-12.
[http://dx.doi.org/10.1097/SLA.0b013e3181e61df5] [PMID:  20585239] 
[83] 
Thia KT, Sandborn WJ, Harmsen WS, Zinsmeister AR, Loftus EV Jr. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology  2010; 139(4): 1147-55.
[http://dx.doi.org/10.1053/j.gastro.2010.06.070] [PMID:  20637205] 
[84] 
Gerdin L, Eriksson AS, Olaison G, et al. The swedish crohn trial: A prematurely terminated randomized controlled trial of thiopurines or open surgery for primary treatment of ileocaecal crohn’s disease. J Crohn’s Colitis  2016; 10(1): 50-4.
[http://dx.doi.org/10.1093/ecco-jcc/jjv184] [PMID:  26507858] 
[85] 
Ponsioen CY, de Groof EJ, Eshuis EJ, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol  2017; 2(11): 785-92.
[http://dx.doi.org/10.1016/S2468-1253(17)30248-0] [PMID:  28838644] 
[86] 
Iesalnieks I, Kilger A, Glass H, Obermeier F, Agha A, Schlitt HJ. Abdominal abscess in crohn’s disease: Multidisciplinary management. Dig Dis  2010; 32(1): 103-9.
[http://dx.doi.org/10.1002/ibd.21303] [PMID:  20848506] 
[87] 
de Groof EJ, Carbonnel F, Buskens CJ, Bemelman WA. Perforating Crohn’s ileitis: delay of surgery is associated with inferior postoperative outcome. Inflamm Bowel Dis  2010; 16(12): 2125-30.2014; 
[88] 
Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Current management. J Crohn’s Colitis  2010; 4(1): 28-62.
[http://dx.doi.org/10.1016/j.crohns.2009.12.002] [PMID:  21122489] 
[89] 
Farmer RG, Hawk WA, Turnbull RB Jr. Indications for surgery in Crohn’s disease: analysis of 500 cases. Gastroenterology  1976; 71(2): 245-50.
[http://dx.doi.org/10.1016/S0016-5085(76)80196-5] [PMID:  1084841] 
[90] 
Latchis KS, Rao CS, Colcock BP. The complications of enterocolitis. Am J Surg  1971; 121(4): 418-25.
[http://dx.doi.org/10.1016/0002-9610(71)90233-9] [PMID:  5581477] 
[91] 
Young S, Smith IS, O’Connor J, Bell JR, Gillespie G. Results of surgery for Crohn’s disease in the Glasgow region, 1961-70. Br J Surg  1975; 62(7): 528-34.
[http://dx.doi.org/10.1002/bjs.1800620707] [PMID:  1174782] 
[92] 
Alves A, Panis Y, Bouhnik Y, et al. Risk factors for intra-abdominal septic complications after a first ileocecal resection for Crohn’s disease: a multivariate analysis in 161 consecutive patients. Dis Colon Rectum  2007; 50(3): 331-6.
[http://dx.doi.org/10.1007/s10350-006-0782-0] [PMID:  17252288] 
[93] 
Post S, Betzler M, von Ditfurth B, Schurmann G, Kuppers P, Herfarth C. Risks of intestinal anastomoses in crohn's disease. Ann Surg  213(1): 37-42.1991; 
[94] 
Yamamoto T, Allan RN, Keighley MR. Risk factors for intra-abdominal sepsis after surgery in Crohn’s disease. Dis Colon Rectum  2000; 43(8): 1141-5.
[http://dx.doi.org/10.1007/BF02236563] [PMID: 10950014] 
[95] 
Aberra FN, Lewis JD, Hass D, Rombeau JL, Osborne B, Lichtenstein GR. Corticosteroids and immunomodulators: postoperative infectious complication risk in inflammatory bowel disease patients. Gastroenterology  2003; 125(2): 320-7.
[http://dx.doi.org/10.1016/S0016-5085(03)00883-7] [PMID:  12891531] 
[96] 
Lim M, Sagar P, Abdulgader A, Thekkinkattil D, Burke D. The impact of preoperative immunomodulation on pouch-related septic complications after ileal pouch-anal anastomosis. Dis Colon Rectum  2007; 50(7): 943-51.
[http://dx.doi.org/10.1007/s10350-007-0246-1] [PMID:  17525860] 
[97] 
Myrelid P, Olaison G, Sjödahl R, Nyström PO, Almer S, Andersson P. Thiopurine therapy is associated with postoperative intra-abdominal septic complications in abdominal surgery for Crohn’s disease. Dis Colon Rectum  2009; 52(8): 1387-94.
[http://dx.doi.org/10.1007/DCR.0b013e3181a7ba96] [PMID:  19617749] 
[98] 
Tjandra JJ, Fazio VW, Milsom JW, Lavery IC, Oakley JR, Fabre JM. Omission of temporary diversion in restorative proctocolectomy--is it safe? Dis Colon Rectum  1993; 36(11): 1007-14.
[http://dx.doi.org/10.1007/BF02047291] [PMID:  8223051] 
[99] 
Subramanian V, Saxena S, Kang JY, Pollok RC. Preoperative steroid use and risk of postoperative complications in patients with inflammatory bowel disease undergoing abdominal surgery. Am J Gastroenterol  2008; 103(9): 2373-81.
[http://dx.doi.org/10.1111/j.1572-0241.2008.01942.x] [PMID:  18616660] 
[100] 
Bruewer M, Utech M, Rijcken EJ, et al. Preoperative steroid administration: effect on morbidity among patients undergoing intestinal bowel resection for Crohńs disease. World J Surg  2003; 27(12): 1306-10.
[http://dx.doi.org/10.1007/s00268-003-6972-1] [PMID:  14716499] 
[101] 
Simi M, Leardi S, Minervini S, et al. Early complications after surgery for Crohn’s disease. Neth J Surg  1990; 42(4): 105-9.
[PMID:  2216004] 
[102] 
Alves A, Panis Y, Trancart D, et al. Factors associated with clinically significant anastomotic leakage after large bowel resection: multivariate analysis of 707 patients. World J Surg  2002; 26(4): 499-502.
[http://dx.doi.org/10.1007/s00268-001-0256-4] [PMID:  11910487] 
[103] 
Yamamoto T, Bain IM, Mylonakis E, Allan RN, Keighley MR. Stapled functional end-to-end anastomosis versus sutured end-to-end anastomosis after ileocolonic resection in Crohn disease. Scand J Gastroenterol  1999; 34(7): 708-13.
[http://dx.doi.org/10.1080/003655299750025921] [PMID:  10466883] 
[104] 
Schrock TR, Deveney CW, Dunphy JE. Factor contributing to leakage of colonic anastomoses. Ann Surg  1973; 177(5): 513-8.
[http://dx.doi.org/10.1097/00000658-197305000-00002] [PMID:  4540874] 
[105] 
Fasth S, Hellberg R, Hultén L, Magnusson O. Early complications after surgical treatment for Crohn’s disease with particular reference to factors affecting their development. Acta Chir Scand  1980; 146(7): 519-26.
[PMID:  7223290] 
[106] 
Golub R, Golub RW, Cantu R Jr, Stein HD. A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg  1997; 184(4): 364-72.
[PMID:  9100681] 
[107] 
Alexander-Williams J. Reducing the risk of operationCrohn’s disease and ulcerative colitis - surgical management.  London: Springer-Verlag 1993; pp. 51-66.
[http://dx.doi.org/10.1007/978-1-4471-3296-7_8] 
[108] 
Colombel JF, Loftus EV Jr, Tremaine WJ, et al. Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol  2004; 99(5): 878-83.
[http://dx.doi.org/10.1111/j.1572-0241.2004.04148.x] [PMID:  15128354] 
[109] 
Mahadevan U, Loftus EV Jr, Tremaine WJ, et al. Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not associated with increased postoperative complications. Inflamm Bowel Dis  2002; 8(5): 311-6.
[http://dx.doi.org/10.1097/00054725-200209000-00001] [PMID:  12479645] 
[110] 
Schroll S, Sarlette A, Ahrens K, Manns MP, Göke M. Effects of azathioprine and its metabolites on repair mechanisms of the intestinal epithelium in vitro. Regul Pept  2005; 131(1-3): 1-11.
[http://dx.doi.org/10.1016/j.regpep.2005.03.001] [PMID:  16122821] 
[111] 
Karukonda SR, Flynn TC, Boh EE, et al. The effects of drugs on wound healing--part II. Specific classes of drugs and their effect on healing wounds. Int J Dermatol  2000; 39(5): 321-33.
[http://dx.doi.org/10.1046/j.1365-4362.2000.00949.x] [PMID:  10849120] 
[112] 
Myrelid P, Svärm S, Andersson P, et al. Azathioprine as a postoperative prophylaxis reduces symptoms in aggressive Crohn’s disease. Scand J Gastroenterol  2006; 41(10): 1190-5.
[http://dx.doi.org/10.1080/00365520600587378] [PMID:  16990204] 
[113] 
Tay GS, Binion DG, Eastwood D, Otterson MF. Multivariate analysis suggests improved perioperative outcome in Crohn’s disease patients receiving immunomodulator therapy after segmental resection and/or strictureplasty. Surgery  2003; 134(4): 565-72.
[http://dx.doi.org/10.1016/S0039-6060(03)00298-8] [PMID:  14605616] 
[114] 
Selvasekar CR, Cima RR, Larson DW, et al. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis. J Am Coll Surg  2007; 204(5): 956-62.
[http://dx.doi.org/10.1016/j.jamcollsurg.2006.12.044] [PMID:  17481518] 
[115] 
Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for induction of remission in crohn’s disease. Cochrane Database Syst Rev  2002; 2.
[116] 
Kanazawa A, Yamana T, Okamoto K, Sahara R. Risk factors for postoperative intra-abdominal septic complications after bowel resection in patients with Crohn’s disease. Dis Colon Rectum  2012; 55(9): 957-62.
[http://dx.doi.org/10.1097/DCR.0b013e3182617716] [PMID:  22874602] 
[117] 
Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. BMJ  1955; 2(4947): 1041-8.
[http://dx.doi.org/10.1136/bmj.2.4947.1041] [PMID:  13260656] 
[118] 
Øresland T, Bemelman WA, Sampietro GM, et al. European evidence based consensus on surgery for ulcerative colitis. J Crohn’s Colitis  2015; 9(1): 4-25.
[http://dx.doi.org/10.1016/j.crohns.2014.08.012] [PMID:  25304060] 
[119] 
Mantzoros I, Kanellos I, Demetriades H, et al. Effects of steroid on the healing of colonic anastomoses in the rat. Tech Coloproctol  8(1): 180-3.2004; 
[http://dx.doi.org/10.1007/s10151-004-0150-9] 
[120] 
Polat A, Nayci A, Polat G, Aksöyek S. Dexamethasone down-regulates endothelial expression of intercellular adhesion molecule and impairs the healing of bowel anastomoses. Eur J Surg  2002; 168(8-9): 500-6.
[http://dx.doi.org/10.1080/110241502321116532] [PMID:  12549693] 
[121] 
Del Rio JV, Beck DE, Opelka FG. Chronic perioperative steroids and colonic anastomotic healing in rats. J Surg Res  1996; 66(2): 138-42.
[http://dx.doi.org/10.1006/jsre.1996.0385] [PMID:  9024825] 
[122] 
Furst MB, Stromberg BV, Blatchford GJ, Christensen MA, Thorson AG. Colonic anastomoses: bursting strength after corticosteroid treatment. Dis Colon Rectum  1994; 37(1): 12-5.
[http://dx.doi.org/10.1007/BF02047207] [PMID:  8287740] 
[123] 
Roberts AB, Sporn MB. Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors  1993; 8(1): 1-9.
[http://dx.doi.org/10.3109/08977199309029129] [PMID:  8448037] 
[124] 
Wicke C, Halliday B, Allen D, et al. Effects of steroids and retinoids on wound healing. Arch Surg  2000; 135(11): 1265-70.
[http://dx.doi.org/10.1001/archsurg.135.11.1265] [PMID:  11074878] 
[125] 
Lima O, Cooper JD, Peters WJ, et al. Effects of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation. J Thorac Cardiovasc Surg  1981; 82(2): 211-5.
[PMID:  7019582] 
[126] 
Myrelid P, Salim SY, Darby T, et al. Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis. Scand J Gastroenterol  2015; 50(8): 991-1001.
[http://dx.doi.org/10.3109/00365521.2014.964760] [PMID:  25861827] 
[127] 
Stolzenburg T, Ljungmann K, Christensen H. The effect of azathioprine on anastomotic healing: an experimental study in rats. Dis Colon Rectum  2007; 50(12): 2203-8.
[http://dx.doi.org/10.1007/s10350-007-9010-9] [PMID:  17653797] 
[128] 
Schäffer M, Fuchs N, Völker J, Schulz T, Kapischke M, Viebahn R. Differential effect of tacrolimus on dermal and intestinal wound healing. J Invest Surg  2005; 18(2): 71-9.
[http://dx.doi.org/10.1080/08941930590926294] [PMID:  16036775] 
[129] 
Schäffer MR, Fuchs N, Proksch B, Bongartz M, Beiter T, Becker HD. Tacrolimus impairs wound healing: a possible role of decreased nitric oxide synthesis. Transplantation  1998; 65(6): 813-8.
[http://dx.doi.org/10.1097/00007890-199803270-00008] [PMID:  9539093] 
[130] 
Petri JB, Schurk S, Gebauer S, Haustein UF. Cyclosporine A delays wound healing and apoptosis and suppresses activin beta-A expression in rats. Eur J Dermatol  1998; 8(2): 104-13.
[PMID:  9649703] 
[131] 
Fishel R, Barbul A, Wasserkrug HL, Penberthy LT, Rettura G, Efron G. Cyclosporine A impairs wound healing in rats. J Surg Res  1983; 34(6): 572-5.
[http://dx.doi.org/10.1016/0022-4804(83)90112-9] [PMID:  6855226] 
[132] 
Zeeh J, Inglin R, Baumann G, et al. Mycophenolate mofetil impairs healing of left-sided colon anastomoses. Transplantation  2001; 71(10): 1429-35.
[http://dx.doi.org/10.1097/00007890-200105270-00013] [PMID:  11391231] 
[133] 
Egger B, Tolmos J, Procaccino F, et al. Keratinocyte growth factor promotes healing of left-sided colon anastomoses. Am J Surg  1998; 176(1): 18-24.
[http://dx.doi.org/10.1016/S0002-9610(98)00104-4] [PMID:  9683126] 
[134] 
Zeeh JM, Procaccino F, Hoffmann P, et al. Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats. Gastroenterology  1996; 110(4): 1077-83.
[http://dx.doi.org/10.1053/gast.1996.v110.pm8612996] [PMID:  8612996] 
[135] 
Egger B, Procaccino F, Sarosi I, Tolmos J, Büchler MW, Eysselein VE. Keratinocyte growth factor ameliorates dextran sodium sulfate colitis in mice. Dig Dis Sci  1999; 44(4): 836-44.
[http://dx.doi.org/10.1023/A:1026642715764] [PMID:  10219846] 
[136] 
Di Sebastiano P, di Mola FF, Artese L, et al. Beneficial effects of Batimastat (BB-94), a matrix metalloproteinase inhibitor, in rat experimental colitis. Digestion  2001; 63(4): 234-9.
[http://dx.doi.org/10.1159/000051895] [PMID:  11435723] 
[137] 
Medina C, Santana A, Paz MC, et al. Matrix metalloproteinase-9 modulates intestinal injury in rats with transmural colitis. J Leukoc Biol  2006; 79(5): 954-62.
[http://dx.doi.org/10.1189/jlb.1005544] [PMID:  16478919] 
[138] 
Syk I, Agren MS, Adawi D, Jeppsson B. Inhibition of matrix metalloproteinases enhances breaking strength of colonic anastomoses in an experimental model. Br J Surg  2001; 88(2): 228-34.
[http://dx.doi.org/10.1046/j.1365-2168.2001.01649.x] [PMID:  11167872] 
[139] 
Kiyama T, Onda M, Tokunaga A, Efron DT, Barbul A. Effect of matrix metalloproteinase inhibition on colonic anastomotic healing in rats. J Gastrointest Surg  2001; 5(3): 303-11.
[http://dx.doi.org/10.1016/S1091-255X(01)80052-4] [PMID:  11360054] 
[140] 
Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol  2005; 20(8): 1149-57.
[http://dx.doi.org/10.1111/j.1440-1746.2005.03832.x] [PMID:  16048561] 
[141] 
Myrelid P, Marti-Gallostra M, Ashraf S, et al. Complications in surgery for Crohn’s disease after preoperative antitumour necrosis factor therapy. Br J Surg  2014; 101(5): 539-45.
[http://dx.doi.org/10.1002/bjs.9439] [PMID:  24615529] 
[142] 
Smedh K, Andersson M, Johansson H, Hagberg T. Preoperative management is more important than choice of sutured or stapled anastomosis in Crohn’s disease. Eur J Surg  2002; 168(3): 154-7.
[http://dx.doi.org/10.1080/110241502320127766] [PMID:  12182240] 
[143] 
Myrelid P, Söderholm JD, Olaison G, Sjödahl R, Andersson P. Split stoma in resectional surgery of high-risk patients with ileocolonic Crohn’s disease. Colorectal Dis  2012; 14(2): 188-93.
[http://dx.doi.org/10.1111/j.1463-1318.2011.02578.x] [PMID:  21689286] 
[144] 
Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn’s disease. Ann Surg  2000; 231(1): 38-45.
[http://dx.doi.org/10.1097/00000658-200001000-00006] [PMID:  10636100] 
[145] 
Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn’s disease. Relationship between the clinical pattern and prognosis. Gastroenterology  1985; 88(6): 1818-25.
[http://dx.doi.org/10.1016/0016-5085(85)90006-X] [PMID:  3922845] 
[146] 
Vester-Andersen MK, Prosberg MV, Jess T, et al. Disease course and surgery rates in inflammatory bowel disease: a population-based, 7-year follow-up study in the era of immunomodulating therapy. Am J Gastroenterol  2014; 109(5): 705-14.
[http://dx.doi.org/10.1038/ajg.2014.45] [PMID:  24642581] 
[147] 
Olaison G, Smedh K, Sjödahl R. Natural course of Crohn’s disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms. Gut  1992; 33(3): 331-5.
[http://dx.doi.org/10.1136/gut.33.3.331] [PMID:  1568651] 
[148] 
Riss S, Schuster I, Papay P, et al. Surgical recurrence after primary ileocolic resection for Crohn’s disease. Tech Coloproctol  2014; 18(4): 365-71.
[http://dx.doi.org/10.1007/s10151-013-1061-4] [PMID:  23982768] 
[149] 
Renna S, Cammà C, Modesto I, et al. Meta-analysis of the placebo rates of clinical relapse and severe endoscopic recurrence in postoperative Crohn’s disease. Gastroenterology  2008; 135(5): 1500-9.
[http://dx.doi.org/10.1053/j.gastro.2008.07.066] [PMID:  18823987] 
[150] 
Ferrante M, Papamichael K, Duricova D, et al. International Organization for Study of Inflammatory Bowel D: Systematic versus endoscopy-driven treatment with azathioprine to prevent postoperative ileal crohn’s disease recurrence. J Crohn’s Colitis  2015; 9(8): 617-24.
[http://dx.doi.org/10.1093/ecco-jcc/jjv076] [PMID:  25926532] 
[151] 
Hellers G, Cortot A, Jewell D, et al. Oral budesonide for prevention of postsurgical recurrence in Crohn’s disease. Gastroenterology  1999; 116(2): 294-300.
[http://dx.doi.org/10.1016/S0016-5085(99)70125-3] [PMID:  9922309] 
[152] 
D’Haens GR, Vermeire S, Van Assche G, et al. Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn’s disease: a controlled randomized trial. Gastroenterology  2008; 135(4): 1123-9.
[http://dx.doi.org/10.1053/j.gastro.2008.07.010] [PMID:  18727929] 
[153] 
Lochs H, Mayer M, Fleig WE, et al. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology  2000; 118(2): 264-73. [see comments].
[http://dx.doi.org/10.1016/S0016-5085(00)70208-3] [PMID: 10648454] 
[154] 
Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology  2004; 127(3): 723-9.
[http://dx.doi.org/10.1053/j.gastro.2004.06.002] [PMID:  15362027] 
[155] 
Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology  1990; 99(4): 956-63.
[http://dx.doi.org/10.1016/0016-5085(90)90613-6] [PMID:  2394349] 
[156] 
Mowat C, Arnott I, Cahill A, et al. Mercaptopurine versus placebo to prevent recurrence of Crohn’s disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial. Lancet Gastroenterol Hepatol  2016; 1(4): 273-82.
[http://dx.doi.org/10.1016/S2468-1253(16)30078-4] [PMID:  28404197] 
[157] 
McLeod RS, Wolff BG, Steinhart AH, et al. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology  1995; 109(2): 404-13.
[http://dx.doi.org/10.1016/0016-5085(95)90327-5] [PMID:  7615189] 
[158] 
Borley NR, Mortensen NJ, Jewell DP. Preventing postoperative recurrence of Crohn’s disease. Br J Surg  1997; 84(11): 1493-502.
[http://dx.doi.org/10.1002/bjs.1800841104] [PMID:  9393267] 
[159] 
Michelassi F, Balestracci T, Chappell R, Block GE. Primary and recurrent Crohn’s disease. Experience with 1379 patients. Ann Surg  1991; 214(3): 230-8.
[http://dx.doi.org/10.1097/00000658-199109000-00006] [PMID:  1929605] 
[160] 
Myrelid P, Svärm S, Andersson P, et al. Azathioprine as a postoperative prophylaxis reduces symptoms in aggressive Crohn’s disease. Scand J Gastroenterol  2006; 41(10): 1190-5.
[http://dx.doi.org/10.1080/00365520600587378] [PMID:  16990204] 
[161] 
Domènech E, Garcia V, Iborra M, et al. Incidence and management of recurrence in patients with crohn’s disease who have undergone intestinal resection: The practicrohn study. Inflamm Bowel Dis  2017; 23(10): 1840-6.
[http://dx.doi.org/10.1097/MIB.0000000000001180] [PMID:  28644182] 
[162] 
Papay P, Reinisch W, Ho E, et al. The impact of thiopurines on the risk of surgical recurrence in patients with Crohn’s disease after first intestinal surgery. Am J Gastroenterol  2010; 105(5): 1158-64.
[http://dx.doi.org/10.1038/ajg.2009.673] [PMID:  20010925] 
[163] 
van Loo ES, Vosseberg NW, van der Heide F, et al. Thiopurines are associated with a reduction in surgical re-resections in patients with Crohn’s disease: a long-term follow-up study in a regional and academic cohort. Inflamm Bowel Dis  2013; 19(13): 2801-8.
[http://dx.doi.org/10.1097/01.MIB.0000435758.97952.a8] [PMID:  24189041] 
[164] 
Li Y, Zhu W, Zuo L, et al. Frequency and risk factors of postoperative recurrence of Crohn’s disease after intestinal resection in the Chinese population. J Gastrointest Surg  2012; 16(8): 1539-47.
[http://dx.doi.org/10.1007/s11605-012-1902-x] [PMID:  22555673] 
[165] 
Orlando A, Mocciaro F, Renna S, et al. Early post-operative endoscopic recurrence in Crohn’s disease patients: data from an Italian Group for the study of inflammatory bowel disease (IG-IBD) study on a large prospective multicenter cohort. J Crohn’s Colitis  2014; 8(10): 1217-21.
[http://dx.doi.org/10.1016/j.crohns.2014.02.010] [PMID:  24630485] 
[166] 
De Cruz P, Kamm MA, Hamilton AL, et al. Crohn’s disease management after intestinal resection: a randomised trial. Lancet  2015; 385(9976): 1406-17.
[http://dx.doi.org/10.1016/S0140-6736(14)61908-5] [PMID:  25542620] 
[167] 
Reese GE, Nanidis T, Borysiewicz C, et al. The effect of smoking after surgery for Crohn’s disease: a meta-analysis of observational studies. Int J Colorectal Dis  2008; 23(12): 1213-21.
[http://dx.doi.org/10.1007/s00384-008-0542-9] [PMID:  18762954] 
[168] 
Yamamoto T, Watanabe T. Strategies for the prevention of postoperative recurrence of Crohn’s disease. Colorectal Dis  2013; 15(12): 1471-80.
[http://dx.doi.org/10.1111/codi.12326] [PMID:  23809911] 
[169] 
Gionchetti P, Dignass A, Danese S, et al. 3rd European evidence-based consensus on the diagnosis and management of crohn’s disease 2016: Part 2: Surgical management and special situations. J Crohn’s Colitis  2017; 11(2): 135-49.
[http://dx.doi.org/10.1093/ecco-jcc/jjw169] [PMID:  27660342] 
[170] 
Simillis C, Yamamoto T, Reese GE, et al. A meta-analysis comparing incidence of recurrence and indication for reoperation after surgery for perforating versus nonperforating Crohn’s disease. Am J Gastroenterol  2008; 103(1): 196-205.
[http://dx.doi.org/10.1111/j.1572-0241.2007.01548.x] [PMID:  17900320] 
[171] 
Simillis C, Jacovides M, Reese GE, Yamamoto T, Tekkis PP. Meta-analysis of the role of granulomas in the recurrence of Crohn disease. Dis Colon Rectum  2010; 53(2): 177-85.
[http://dx.doi.org/10.1007/DCR.0b013e3181b7bfb0] [PMID:  20087093] 
[172] 
Ferrante M, de Hertogh G, Hlavaty T, et al. The value of myenteric plexitis to predict early postoperative Crohn’s disease recurrence. Gastroenterology  2006; 130(6): 1595-606.
[http://dx.doi.org/10.1053/j.gastro.2006.02.025] [PMID:  16697723] 
[173] 
Sokol H, Polin V, Lavergne-Slove A, et al. Plexitis as a predictive factor of early postoperative clinical recurrence in Crohn’s disease. Gut  2009; 58(9): 1218-25.
[http://dx.doi.org/10.1136/gut.2009.177782] [PMID:  19625280] 
[174] 
Borley NR, Mortensen NJ, Chaudry MA, et al. Recurrence after abdominal surgery for Crohn’s disease: relationship to disease site and surgical procedure. Dis Colon Rectum  2002; 45(3): 377-83.
[http://dx.doi.org/10.1007/s10350-004-6186-0] [PMID:  12068198] 
[175] 
Reese GE, Purkayastha S, Tilney HS, von Roon A, Yamamoto T, Tekkis PP. Strictureplasty vs resection in small bowel Crohn’s disease: an evaluation of short-term outcomes and recurrence. Colorectal Dis  2007; 9(8): 686-94.
[http://dx.doi.org/10.1111/j.1463-1318.2006.01114.x] [PMID:  17854290] 
[176] 
Domènech E, Mañosa M, Bernal I, et al. Impact of azathioprine on the prevention of postoperative Crohn’s disease recurrence: results of a prospective, observational, long-term follow-up study. Inflamm Bowel Dis  2008; 14(4): 508-13.
[http://dx.doi.org/10.1002/ibd.20359] [PMID:  18183602] 
[177] 
Ardizzone S, Maconi G, Sampietro GM, et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn’s disease. Gastroenterology  2004; 127(3): 730-40.
[http://dx.doi.org/10.1053/j.gastro.2004.06.051] [PMID:  15362028] 
[178] 
Herfarth H, Tjaden C, Lukas M, et al. Adverse events in clinical trials with azathioprine and mesalamine for prevention of postoperative recurrence of Crohn’s disease. Gut  2006; 55(10): 1525-6.
[PMID:  16966711] 
[179] 
Peyrin-Biroulet L, Deltenre P, Ardizzone S, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn’s disease: a meta-analysis. Am J Gastroenterol  2009; 104(8): 2089-96.
[http://dx.doi.org/10.1038/ajg.2009.301] [PMID:  19568226] 
[180] 
Reinisch W, Angelberger S, Petritsch W, 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.
[http://dx.doi.org/10.1136/gut.2009.194159] [PMID:  20551460] 
[181] 
Savarino E, Bodini G, Dulbecco P, et al. Adalimumab is more effective than azathioprine and mesalamine at preventing postoperative recurrence of Crohn’s disease: a randomized controlled trial. Am J Gastroenterol  2013; 108(11): 1731-42.
[http://dx.doi.org/10.1038/ajg.2013.287] [PMID:  24019080] 
[182] 
Armuzzi A, Felice C, Papa A, et al. Prevention of postoperative recurrence with azathioprine or infliximab in patients with Crohn’s disease: an open-label pilot study. J Crohn’s Colitis  2013; 7(12): e623-9.
[http://dx.doi.org/10.1016/j.crohns.2013.04.020] [PMID:  23810678] 
[183] 
Gordon M, Taylor K, Akobeng AK, Thomas AG. Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in crohn’s disease. Cochrane Database Syst Rev  2014; 1(8): CD010233.
[184] 
López-Sanromán A, Vera-Mendoza I, Domènech E, et al. Adalimumab vs azathioprine in the prevention of postoperative crohn’s disease recurrence. A geteccu randomised trial. J Crohn’s Colitis  2017; 11(11): 1293-301.
[http://dx.doi.org/10.1093/ecco-jcc/jjx051] [PMID:  28402454] 
[185] 
Hansen LF, Jakobsen C, Paerregaard A, Qvist N, Wewer V. Surgery and postoperative recurrence in children with Crohn disease. J Pediatr Gastroenterol Nutr  2015; 60(3): 347-51.
[http://dx.doi.org/10.1097/MPG.0000000000000616] [PMID:  25373863] 
[186] 
Splawski JB, Pffefferkorn MD, Schaefer ME, et al. Naspghan clinical report on postoperative recurrence in pediatric crohn disease. J Pediatr Gastroenterol Nutr  2017; 65(4): 475-86.
[http://dx.doi.org/10.1097/MPG.0000000000001606] [PMID:  28937552] 
[187] 
Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn’s disease: risk factors for postoperative recurrence. Am J Gastroenterol  2001; 96(7): 2169-76.
[http://dx.doi.org/10.1111/j.1572-0241.2001.03876.x] [PMID:  11467649] 
[188] 
Bordeianou L, Stein SL, Ho VP, et al. Immediate versus tailored prophylaxis to prevent symptomatic recurrences after surgery for ileocecal Crohn’s disease? Surgery  2011; 149(1): 72-8.
[http://dx.doi.org/10.1016/j.surg.2010.03.009] [PMID:  20434748] 
[189] 
Guo Z, Cai C, Liu R, et al. Immediate prophylactic versus endoscopic or symptomatic driven azathioprine treatment to prevent surgical recurrence after intestinal resection in crohn’s disease. Colorectal Dis  In press)
[190] 
Moran GW, Dubeau MF, Kaplan GG, et al. Clinical predictors of thiopurine-related adverse events in Crohn’s disease. World J Gastroenterol  2015; 21(25): 7795-804.
[http://dx.doi.org/10.3748/wjg.v21.i25.7795] [PMID:  26167079] 
[191] 
Ananthakrishnan AN, Hur C, Juillerat P, Korzenik JR. Strategies for the prevention of postoperative recurrence in Crohn’s disease: results of a decision analysis. Am J Gastroenterol  2011; 106(11): 2009-17.
[http://dx.doi.org/10.1038/ajg.2011.237] [PMID:  21788991] 
[192] 
Doherty GA, Miksad RA, Cheifetz AS, Moss AC. Comparative cost-effectiveness of strategies to prevent postoperative clinical recurrence of Crohn’s disease. Inflamm Bowel Dis  2012; 18(9): 1608-16.
[http://dx.doi.org/10.1002/ibd.21904] [PMID:  21905173] 
[193] 
Bordeianou L. In flux on infliximab: conflicting studies on surgical outcomes. Inflamm Bowel Dis  2009; 15(10): 1605-6.
[http://dx.doi.org/10.1002/ibd.20891] [PMID:  19177548] 
[194] 
Scarpa M, Ruffolo C, Bertin E, et al. Surgical predictors of recurrence of Crohn’s disease after ileocolonic resection. Int J Colorectal Dis  2007; 22(9): 1061-9.
[http://dx.doi.org/10.1007/s00384-007-0329-4] [PMID:  17534633] 
[195] 
Welsch T, Hinz U, Löffler T, et al. Early re-laparotomy for post-operative complications is a significant risk factor for recurrence after ileocaecal resection for Crohn’s disease. Int J Colorectal Dis  2007; 22(9): 1043-9.
[http://dx.doi.org/10.1007/s00384-007-0309-8] [PMID:  17390141] 
[196] 
Sartini A, Scaioli E, Belluzzi A. Is early endoscopy-based therapy the best strategy to prevent all crohn’s disease postoperative recurrence? Gastroenterology  2016; 151(5): 1040-1.
[http://dx.doi.org/10.1053/j.gastro.2016.08.058] [PMID:  27702633] 
Cite As
Current Drug Targets

Immunomodulators: Friends or Enemies in Surgery for Crohn’s Disease?

Abstract

Graphical Abstract
