Pediatric Inflammatory Bowel Disease (IBD): Phenotypic, Genetic and Therapeutic Differences between Early-Onset and Adult-Onset IBD

소아기에 발병하는 염증성장질환(IBD)은 성인 IBD와 다른 질환인가? - 조기발병 소아 IBD의 역학적, 임상적, 유전학적 특성 및 치료 시 고려 사항-

  • Seo, Jeong-Kee (Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Seoul National University College of Medicine)
  • 서정기 (서울대학교 의과대학 소아과학교실, 소아소화기 영양분과)
  • Received : 2011.03.02
  • Accepted : 2011.03.25
  • Published : 2011.03.30


Inflammatory bowel disease (IBD) develops during childhood or adolescence in approximately 25% of patients with IBD. Recent studies on pediatric IBD have revealed that early-onset IBD has distinct phenotype differences compared to adult onset IBD. Pediatric early-onset IBD differs in many aspects including disease type, location of the lesions, disease behavior, gender preponderance and genetically attributable risks. This review examines the currently published data on the clinical, epidemiological and genetic differences between early-onset and adult-onset IBD. And finally, therapeutic considerations in the management of pediatric-onset IBD are also discussed.


  1. Seo JK, Yeon KM, Chi JG. Inflammatory bowel disease in children: clinical, endoscopic, radiologic and histopathologic investigation. J Korean Med Sci 1992;7: 221-35.
  2. Suh HA, Kim SE, Jang JY, Kim BJ, Kim JS, Lee SY, et al. Efficacy of nutritional therapy in children with crohn disease. Korean J Pediatr Gastroenterol Nutr 2006;9:210-7.
  3. Lee NY, Park JH. Clinical features and course of crohn disease in children. Korean J Gastrointest Endosc 2007; 34:193-9.
  4. Lee JH, Lee HJ, Park SE, Choe YH. Infliximab: the benefit for refractory Crohn disease and top-down induction therapy in severe Crohn disease. Korean J Pediatr Gastroenterol Nutr 2008;11:28-35.
  5. Abramson O, Durant M, Mow W, Finley A, Kodali P, Wong A, et al. Ncidence, prevalence, and time trends of pediatric inflammatory bowel disease in Northern California, 1996 to 2006. J Pediatr 2010;157:233-9.
  6. Turunen P, Kolho KL, Auvinen A, Iltanen S, Huhtala H, Ashorn M. Incidence of inflammatory bowel disease in Finnish children, 1987-2003. Inflamm Bowel Dis 2006; 12:677-83.
  7. Ruyssers NE, De Winter BY, De Man JG, Loukas A, Pearson MS, Weinstock JV, et al. Therapeutic potential of helminth soluble proteins in TNBS-induced colitis in mice. Inflamm Bowel Dis 2009;15:491-500.
  8. Thompson N, Pounder R, Wakefield A, Montgomery S. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet 1995;345:1071-4.
  9. Hafner S, Timmer A, Herfarth H, Rogler G, Scholmerich J, Schaffler A, et al. The role of domestic hygiene in inflammatory bowel diseases: hepatitis A and worm infestations. Eur J Gastroenterol Hepatol 2008;20:561-6.
  10. Summers R, Elliott D, Urban J, Thompson R, Weinstock J. Trichuris suis therapy in Crohn's disease. Gut 2005; 54:87.
  11. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N Engl J Med 2001;344:808-14.
  12. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn's disease. Gastroenterology 2003;124:40-6.
  13. Jowett S, Seal C, Pearce M, Phillips E, Gregory W, Barton J, et al. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut 2004;53:1479-84.
  14. Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a metaanalysis. Mayo Clin Proc 2006;81:1462-71.
  15. McGilligan VE, Wallace JM, Heavey PM, Ridley DL, Rowland IR. Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis. Inflam Bowel Dis 2007;13:108-15.
  16. Rubin DT, Hanauer SB. Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12:855-62.
  17. Gasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ, et al. A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000;6:8-15.
  18. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. oward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19(Suppl A):5-36.
  19. Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, et al. Pediatric modification of the montreal classification for inflammatory bowel disease: the paris classification. Inflamm Bowel Dis 2010 Nov 8. [Epub ahead of print]
  20. Levine A, Kugathasan S, Annese V, Biank V, Leshinsky Silver E, Davidovich O, et al. Pediatric onset Crohn's colitis is characterized by genotype dependent age related susceptibility. Inflamm Bowel Dis 2007;13:1509-15.
  21. Meinzer U, Ideström M, Alberti C, Peuchmaur M, Belarbi N, Bellaïche M, et al. Ileal involvement is age dependent in pediatric Crohn's disease. Inflamm Bowel Dis 2005;11:639-44.
  22. Markowitz J, Kugathasan S, Dubinsky M, Mei L, Crandall W, LeLeiko N, et al. Age of diagnosis influences serologic responses in children with Crohn's disease: a possible clue to etiology? Inflamm Bowel Dis 2009;15:714-9.
  23. Ruemmele FM, El Khoury MG, Talbotec C, Maurage C, Mougenot JF, Schmitz J, et al. Characteristics of inflammatory bowel disease with onset during the first year of life. J Pediatr Gastroenterol Nutr 2006;43:603-9.
  24. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, et al. Inflammatory bowel disease and mutation affecting the interleukin-10 receptor. N Engl J Med 2009;361:2033-45.
  25. Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135: 1114-22.
  26. Vernier-Massouille G, Balde M, Salleron J, Turck D, Dupas JL, Mouterde O, et al. Natural history of pediatric Crohn's disease: a population-based cohort study. Gastroenterology 2008;135:1106-13.
  27. Heyman MB, Kirschner BS, Gold BD, Ferry G, Baldassano R, Cohen SA, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35-40.
  28. Kappelman MD, Rifas-Shiman SL, Kleinman K, Ollendorf D, Bousvaros A, Grand RJ, et al. The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007;5:1424-9.
  29. Kugathasan S, Judd RH, Hoffmann RG, Heikenen J, Telega G, Khan F, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 2003;143:525-31.
  30. Sawczenko A, Sandhu BK, Logan RF, Jenkins H, Taylor CJ, Mian S, et al. Prospective survey of childhood inflammatory bowel disease in the British isles. Lancet 2001;357:1093-4.
  31. Newby EA, Croft NM, Green M, Hassan K, Heuschkel RB, Jenkins H, et al. Natural history of paediatric inflammatory bowel diseases over a 5-year follow-up: a retrospective review of data from the register of paediatric inflammatory bowel diseases. J Pediatr Gastroenterol Nutr 2008;46:539.
  32. Sagiv-Friedgut K, Karban A, Weiss B, Shaoul R, Shamir R, Bujanover Y, et al. Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter. J Pediatr Gastroenterol Nutr 2010;50:22-6.
  33. Sauer CG, Kugathasan S. Pediatric inflammatory bowel disease: Highlighting pediatric differences in IBD. Med Clin North Am 2010;94:35-52.
  34. Henriksen M, Jahnsen J, Lygren I, Sauar J, Kjellevold, Schulz T, et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006;12:543-50.
  35. Hyams J, Markowitz J, Lerer T, Griffiths A, Mack D, Bousvaros A, et al. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006;4:1118-23.
  36. Gupta N, Bostrom AG, Kirschner BS, Cohen SA, Abramson O, Ferry GD, et al. Presentation and disease course in early- compared to later-onset pediatric Crohn's disease. Am J Gastroenterol 2008;103:2092-8.
  37. Keljo DJ, Markowitz J, Langton C, Lerer T, Bousvaros A, Carvalho R, et al. Course and treatment of perianal disease in children newly diagnosed with Crohn's disease. Inflamm Bowel Dis 2009;15:383-7.
  38. Karban A, Itay M, Davidovich O, Leshinsky-Silver E, Kimmel G, Fidder H, et al. Risk factors for perianal Crohn's disease: the role of genotype, phenotype, and ethnicity. Am J Gastroenterol 2007;102:1702-8.
  39. Romano C, Famiani A, Gallizzi R, Comito D, Ferrau' V, Rossi P. Indeterminate colitis: a distinctive clinical pattern of inflammatory bowel disease in children. Pediatrics 2008;122:e1278-81.
  40. Martland GT, Shepherd NA. Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity. Histopathology 2007;50:83-96.
  41. Wells AD, McMillan I, Price AB, Ritchie JK, Nicholls RJ. Natural history of indeterminate colitis. Br J Surg 1991;78:179-81.
  42. Moum B, Vatn MH, Ekbom A, Fausa O, Aadland E, Lygren I, et al. Incidence of inflammatory bowel disease in southeastern Norway: evaluation of methods after 1 year of registration. Southeastern Norway IBD Study Group of Gastroenterologists. Digestion 1995;56:377-81.
  43. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. A long-term follow-up of 1116 patients. Dig Dis Sci 1993;38:1137-46.
  44. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005;19(Suppl A):5-36.
  45. Cucchiara S, Iebba V, Conte MP, Schippa S. The microbiota in inflammatory bowel disease in different age groups. Dig Dis 2009;27:252-8.
  46. Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol 2008;24: 4-10.
  47. Taurog JD, Richardson JA, Croft J, Simmons WA, Zhou M, Fernandez-Sueiro JL, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994; 180:2359-64.
  48. Fabia R, Ar'Rajab A, Johansson M, Andersson R, Willen R, Jeppsson B, et al. Impairment of bacterial flora in human ulcerative colitis and experimental colitis in the rat. Digestion 1993;54:248-55.
  49. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, et al. Mucosal flora in inflammatory bowel disease. Gastroenterology 2002;122: 44-54.
  50. Sartor RB. Review article: role of the enteric microflora in the pathogenesis of intestinal inflammation and arthritis. Aliment Pharmacol Ther 1997;11(Suppl 3):17-22.
  51. Seksik P, Rigottier-Gois L, Gramet G, Sutren M, Pochart P, Marteau P, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon. Gut 2003;52:237-42.
  52. Mylonaki M, Langmead L, Pantes A, Johnson F, Rampton DS. Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol 2004;16:775-8.
  53. Meyer AM, Ramzan NN, Loftus Jr EV, Heigh RI, Leighton JA. The diagnostic yield of stool pathogen studies during relapses of inflammatory bowel disease. J Clin Gastroenterol 2004;38:772-5.
  54. Swidsinski A, Loening-Baucke V, Vaneechoutte M, Doerffel Y. Active Crohn's disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis 2008;14:147-61.
  55. Conte MP, Schippa S, Zamboni I, Penta M, Chiarini F, Seganti L, et al. Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut 2006;55:1760-7.
  56. Schippa S, Conte MP, Borrelli O, Iebba V, Aleandri M, Seganti L, et al. Dominant genotypes in mucosa associated Escherichia coli strains from pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2009;15:661-72.
  57. Kirsner JB, Spencer JA. Family occurrences of ulcerative colitis, regional enteritis, and ileocolitis. Ann Intern Med 1963;59:133.
  58. Yang H, McElree C, Roth M, Shanahan F, Targan S, Rotter J. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993;34:517-24.
  59. Halme L, Paavola-Sakki P, Turunen U, Lappalainen M, Farkkila M, Kontula K. Family and twin studies in inflammatory bowel disease. World J Gastroenterol 2006;12:3668-72.
  60. Orholm M, Binder V, Sorensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins: results of a nationwide study. Scand J Gastroenterol 2000;35:1075-81.
  61. Abreu MT, Taylor KD, Lin YC, Hang T, Gaiennie J, Landers CJ, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. Gastroenterology 2002;123:679-88.
  62. Chamaillard M, Iacob R, Desreumaux P, Colombel JF. Advances and perspectives in the genetics of inflammatory bowel diseases. Clin Gastroenterol Hepatol 2006;4:143-51.
  63. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005;307:731-4.
  64. Fiocchi C. Susceptibility genes and overall pathogenesis of inflammatory bowel disease: where do we stand? Dig Dis 2009;27:226-35.
  65. Biank V, Broeckel U, Kugathasan S. Pediatric inflammatory bowel disease: clinical and molecular genetics. Inflamm Bowel Dis 2007;13:1430-8.
  66. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2006;39:207-11.
  67. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596-604.
  68. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 2007;39:830-2.
  69. Kugathasan S, Baldassano RN, Bradfield JP, Sleiman PM, Imielinski M, Guthery SL, et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 2008;40:1211-5.
  70. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006;314:1461.
  71. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447: 661-73.
  72. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008;40:955-62.
  73. Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 2008;40:713-5.
  74. Anderson CA, Massey DCO, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, et al. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 2009;136:523-9.
  75. Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, Mayr G, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 2008;40:1319-23.
  76. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rious JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn disease. Nat Genet 2008;40:955-62.
  77. McGovern DPB, Gardet A, Torkvist L, Goyette P, Essers J, Taylor KD, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 2010;42:332-7.
  78. Latella G, Fiocchi C, Caprili R. News from the "5th international meeting on inflammatory bowel disease" CAPRI 2010. J Crohn Colitis 2010;4:690-702.
  79. Peterson N, Guthery S, Denson L, Lee J, Saeed S, Prahalad S, et al. Genetic variants in the autophagy pathway contribute to paediatric Crohn's disease. Gut 2008;57:1336-7.
  80. Essers JB, Lee JJ, Kugathasan S, Stevens CR, Grand RJ, Daly MJ. Established genetic risk factors do not distinguish early and later onset Crohn's disease. Inflamm Bowel Dis 2009;15:1508-14.
  81. Scherr R, Essers J, Hakonarson H, Kugathasan S. Genetic determinants of pediatric inflammatory bowel disease: is age of onset genetically determined? Dig Dis 2009;27: 236-9.
  82. Ridder L, Weersma RK, Dijkstra G, Van der Steege G, Benninga MA, Nolte IM, et al. Genetic susceptibility has a more important role in pediatric onset Crohn disease than in adult-onset Crohn disease. Inflamm Bowel Dis 2007;13:1083-92.
  83. Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V, Dubinsky M, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 2009;41:1335-40.
  84. Henderson P, Van Limbergen JE, Wilson DC, Satsangi J, Russell RK. Genetics of childhood-onset inflammatory bowel disease. Inflamm Bowel Dis 2011;17:346-61.
  85. Sagiv-Friedgut K, Karban A, Weiss B, Shaoul R, Shamir R, Bujanover Y, et al. Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter. J Pediatr Gastroenterol Nutr 2010;50:22-6.
  86. Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease. Cochrane Database Syst Rev 2005;(1): CD003715.
  87. Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2003;(3):CD000543.
  88. Turner D, Travis SPL, Griffiths AM, Ruemmele FM, Levine A, Benchimol EI, et al. Consensus for managing acute severe ulcerative colitis in children: A systemic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol 2011;Jan 11 (in press)
  89. Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev 2005;(1):CD003459.
  90. Uhlen S, Belbouab R, Narebski K, Goulet O, Schmitz J, Cezard J, et al. Efficacy of methotrexate in pediatric Crohn's disease: a French multicenter study. Inflamm Bowel Dis 2006;12:1053-7.
  91. Turner D, Grossman AB, Rosh J, Kugathasan S, Gilman AR, Baldassano R, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol 2007;102:2804-12.
  92. Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, et al. Induction and maintenance infliximab therapy for the treatment of moderateto- severe Crohn's disease in children. Gastroenterology 2007;132:863-73.
  93. Hyams JS, Lerer T, Griffiths A, Pfefferkorn M, Kugathasan S, Evans J, et al. Long term outcome of maintenance infliximab therapy in children with Crohn's disease. Inflamm Bowel Dis 2009;15:816-22.
  94. D'Haens G, Baert F, Van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371:660-7.
  95. Hyams JS. Risk/benefit Strategies must be employed pediatric Crohn's disease. Dig Dis 2009;27:291-6.
  96. Thayu M, Markowitz JE, Mamula P, Russo PA, Muinos WI, Baldassano RN. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005;40:220-2.
  97. Drini M, Prichard PJ, Brown GJ, Macrae FA. Hepatosplenic T-cell lymphoma following infliximab therapy for Crohn's disease. Med J Aust 2008;189: 464-5.
  98. Sandborn W, Rutgeerts P, Reinisch W, Kornbluth A, Lichtiger S, D'Haens G, et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn's disease naive to immunomodulators and biologic therapy. Am J Gastroenterol 2008;103(Suppl 1):S436.
  99. Lichtenstein G, Diamond R, Wagner C, Olson A, Hegedus R, Bala M, et al. Infliximab administered as 3-dose induction followed by scheduled maintenance therapy in IBD: comparable clinical outcomes with or without concomitant immunomodulators. Gastroenterology 2007;132(Suppl 2):A146.
  100. Van Assche G, Magdelaine-Beuzelin C, D'Haens G, Baert F, Noman M, Vermeire S, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008;134:1861-8.
  101. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, et al. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991;12:439-47.
  102. Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007; 133:423-32.
  103. Griffiths AM. Growth retardation in early-onset inflammatory bowel disease: should we monitor and treat these patients differently? Dig Dis 2009;27:404-11.
  104. Walters TD, Griffiths AM. Mechanisms of growth impairment in pediatric Crohn's disease. Nat Rev Gastroenterol Hepatol 2009;6:513-23.
  105. De Benedetti F, Meazza C, Oliveri M, Pignatti P, Vivarelli M, Alonzi T, et al. Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. Endocrinology 2001;142:4818-26.