In both children and adults, the natural history of Crohn's disease (CD) is characterized by relapsing and remitting bouts of intestinal inflammation, often associated with a progressive shift from inflammatory to complicated stricturing or penetrating disease behavior. The past 2 decades have seen a dramatic shift in therapeutic approach with the increasingly common use of early thiopurine immunomodulation. These maintenance medications were initially introduced primarily as corticosteroid-sparing agents capable of minimizing recurrent flares of inflammatory disease and have proven to be quite efficacious. Increasing evidence suggests, however, that thiopurines may only delay rather than prevent the development of complicated disease behavior. Data from both adult and pediatric CD populations from around the world are reviewed in terms of the effect of early immunomodulation on progression to complicated disease behavior, need for surgery, and prevention of recurrent disease after resection. The effect of thiopurines on the growth of children is also reviewed.

1.
Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R: A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 1995;37:674-678.
2.
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;119:895-902.
3.
Langholz E, Munkholm P, Krasilnikoff, Binder V: Inflammatory bowel diseases with onset in childhood. Clinical features, morbidity, and mortality in a regional cohort. Scand J Gastroenterol 1997;32:139-147.
4.
Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R, Gendre JP: Long-term evolution of disease behavior of Crohn's disease. Inflamm Bowel Dis 2002;8:244-250.
5.
Tarrant KM, Barclay ML, Frampton CMA, Gearry RB: Perianal disease predicts changes in Crohn's disease phenotype - results of a population-based study of inflammatory bowel disease phenotype. Am J Gastroenterol 2008;103:3082-3093.
6.
Vernier-Massouille G, Balde M, Salleron J, Turck D, Dupas JL, Mouterde O, Merle V, Salomez JL, Branche J, Marti R, Lerebours E, Cortot A, Gower-Rousseau C, Colombel JF: Natural history of pediatric Crohn's disease: a population-based cohort study. Gastroenterology 2008;135:1106-1113.
7.
Thia KT, Sandborn WS, 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;139:1147-1155.
8.
Sedgwick DM, Barton JR, Hamer-Hodges DW, Nixon SJ, Ferguson A: Population-based study of surgery in juvenile onset Crohn's disease. Br J Surg 1991;78:171-175.
9.
Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre J-P: Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery. Gut 2005;54:237-241.
10.
Peyrin-Biroulet R, Harmsen WS, Tremaine WJ, Zinsmeister AR, Sandborn WJ, Loftus EV Jr: Surgery in a population-based cohort of Crohn's disease from Olmsted County, Minnesota (1970-2004). Am J Gastroenterol 2012;107:1693-1701.
11.
Picco MF, Zubiaurre I, Adluni M, Cangemi JR, Shelton D: Immunomodulators are associated with a lower risk of first surgery among patients with non-penetrating non-stricturing Crohn's disease. Am J Gastroenterol 2009;104:2754-2759.
12.
Ramada AV, Gunesh S, Thomas GAO, 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;59:1200-1206.
13.
Lakatos PL, Golovics PA, David G, Pandur T, Erdelyi Z, Horvath A, Mester G, Balogh M, Szipocs I, Molnar C, Komaromi E, Veres G, Lovasz BD, Szathmari M, Kiss LS, Lakatos L: 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;107:579-588.
14.
Schaefer ME, Machan JT, Kawatu D, Langton CR, Markowitz J, Crandall W, Mack D, Evans JS, Pfefferkorn MD, Griffiths AM, Otley AR, Bousvaros A, Kugathasan S, Rosh JR, Keljo DJ, Carvalho RS, Tomer G, Mamula P, Kay MH, Kerzner B, Oliva-Hemker M, Kappelman MD, Saeed SA, Hyams JS, Leleiko NS: Factors that determine risk for surgery in pediatric patients with Crohn's disease. Clin Gastroenterol Hepatol 2010;8:789-794.
15.
Punati J, Markowitz J, Lerer T, Hyams J, Kugathasan S, Griffith A, Otley A, Rosh J, Pfefferkorn M, Mack D, Evans J, Bousvaros A, Moyer S, Wyllie R, Oliva-Hemker M, Mezoff A, LeLeiko N, Keljo D, Crandall W: Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008;14:949-954.
16.
Gupta N, Cohen SA, Bostrom AG, Kirschner BS, Baldassano RN, Winter HS, Ferry GD, Smith T, Abramson O, Gold BD, Heyman MB: Risk factors for initial surgery in pediatric patients with Crohn's disease. Gastroenterology 2006;130:1069-1077.
17.
Becker JM: Surgical therapy for ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 1999;28:371-390, viii-ix.
18.
Peyrin-Biroulet L, Deltenre P, Ardizzone S, D'Haens G, Hanauer SB, Herfarth H, Lemann M, Colombel J-F: Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn's disease: a meta-analysis. Am J Gastroenterol 2009;104:2089-2096.
19.
Ardizzone S, Maconi G, Sampietro GM, Russo A, Radice E, Colombo E, Imbesi V, Molteni M, Danelli PG, Taschieri AM, Bianchi Porro G: Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn's disease. Gastroenterology 2004;127:730-740.
20.
D'Haens GR, Vermeire S, Van Assche, Noman GM, Aerden I, Olmen GV, Rutgeerts P: Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn's disease: a controlled randomized trial. Gastroenterology 2008;135:1123-1129.
21.
Hanauer SB, Korelitz BI, Rutgeerts P, Peppercorn MA, Thisted RA, Cohen RD, Present DH: Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004;127:723-729.
22.
Herfarth H, Tjaden C, Lukas M, Obermeier F, Dilger K, Müller R, Schölmerich J; Z T-1 Study Group: Adverse events in clinical trials with azathioprine and mesalamine for prevention of postoperative recurrence of Crohn's disease. Gut 2006;55:1525-1526.
23.
Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M: Predictability of the postoperative course of Crohn's disease. Gastroenterology 1990;99:956-963.
24.
Kanof ME, Lake AM, Bayless TM: Decreased height velocity in children and adolescents before the diagnosis of Crohn's disease. Gastroenterology 1988;95:1523-1527.
25.
Kirschner BS: Growth and development in chronic inflammatory bowel disease. Acta Paediatr Scand Suppl 1990;366:98-104.
26.
Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM: Growth and clinical course of children with Crohn's disease. Gut 1993;34:939-943.
27.
Hildebrand H, Karlberg J, Kristiansson B: Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;18:165-173.
28.
Sawczenko A, Ballinger AB, Savage MO, Sanderson IR: Clinical features affecting final adult height in patients with pediatric-onset Crohn's disease. Pediatrics 2006;118:124-149.
29.
Markowitz J, Grancher K, Rosa J, Aiges H, Daum F: Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993;16:373-380.
30.
Sawczenko A, Ballinger AB, Croft NM, Sanderson IR, Savage MO: Adult height in patients with early onset of Crohn's disease. Gut 2003;52:454-455.
31.
Motil KJ, Grand RJ, Davis-Kraft L, Ferlic LL, Smith EO: Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105:681-691.
32.
Hyams JS, Moore RE, Leichtner AM, Carey DE, Goldberg BD: Relationship of type I procollagen to corticosteroid therapy in children with inflammatory bowel disease. J Pediatr 1988;112:893-898.
33.
Ballinger A: Fundamental mechanisms of growth failure in inflammatory bowel disease. Horm Res 2002;58(suppl 1):7-10.
34.
Sawczenko A, Azooz O, Paraszczuk J, Idestrom M, Croft NM, Savage MO, Ballinger AB, Sanderson IR: Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children. Proc Natl Acad Sci USA 2005;102:13260-13265.
35.
DiFedele LM, He J, Bonkowski EL, Han X, Held MA, Bohan A, Menon RK, Denson LA: Tumor necrosis factor alpha blockade restores growth hormone signaling in murine colitis. Gastroenterology 2005;128:1278-1291.
36.
Pfefferkorn M, Burke G, Griffiths A, Markowitz J, Rosh J, Mack D, Otley A, Kugathasan S, Evans J, Bousvaros A, Moyer MS, Wyllie R, Oliva-Hemker M, Carvalho R, Crandall W, Keljo D, Walters TD, LeLeiko N, Hyams J: Growth abnormalities persist in newly diagnosed children with Crohn disease despite current treatment paradigms. J Pediatr Gastroenterol Nutr 2009;48:168-174.
37.
Malik S, Mason A, Bakhshi A, Young D, Bishop J, Garrick V, McGrogan P, Russell RK, Ahmed SF: Growth in children receiving contemporary disease specific therapy for Crohn's disease. Arch Dis Child 2012;97:698-703.
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