Current Gastroenterology Reports

, Volume 14, Issue 3, pp 275–281 | Cite as

How Does Knowledge from Translational Research Impact Our Clinical Care of Pediatric Inflammatory Bowel Disease Patients?

Pediatric Gastroenterology (SR Orenstein, Section Editor)

Abstract

Recent translational studies have provided new insights into pathogenesis, disease behavior, and treatment responses in pediatric Inflammatory Bowel Disease (IBD). Registry studies have identified distinct clinical phenotypes with increasing age of onset; this has led to a revision of the clinical phenotyping system, now termed the Paris classification system. It is recognized that there are infantile (age <2 years), very early onset (VEO, age 2–10), and early onset (EO, age 10–17) forms of disease. Rare genetic mutations affecting anti-microbial and anti-inflammatory pathways have been discovered in infantile and VEO forms, while genetic pathways identified in EO disease have been similar to adult-onset IBD. Genetic and serologic patterns measured soon after diagnosis have been shown to be associated with more aggressive stricturing behavior; these patterns may now be used clinically to help predict disease course. More recently, clinical and genetic models have been developed that, if validated, could be used to predict treatment responses.

Keywords

ASCA ANCA OmpC I2 CBir1 NOD2 Infantile Very early onset Early onset Crohn disease Ulcerative colitis Microbiome Dysbiosis Serology Diagnosis Prognosis Stricture Paris 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011;17(6):1314–21. This study establishes the current standard for clinical phenotyping of pediatric IBD patients for translational studies.PubMedCrossRefGoogle Scholar
  2. 2.
    Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361(21):2033–45.PubMedCrossRefGoogle Scholar
  3. 3.
    Begue B, Verdier J, Rieux-Laucat F, et al. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol. 2011;106(8):1544–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117(5):1522–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Jyonouchi S, Forbes L, Ruchelli E, et al. Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum—a single-center pediatric experience. Pediatr Allergy Immunol. 2011;22(3):313–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Imielinski M, Baldassano RN, Griffiths A, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet. 2009;41(12):1335–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Kugathasan S, Baldassano RN, Bradfield JP, et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet. 2008;40(10):1211–5.PubMedCrossRefGoogle Scholar
  10. 10.
    • Muise AM, Xu W, Guo CH, et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 2011. This study established the utility of candidate gene discovery in VEO pediatric IBD, and highlighted the importance of the neutrophil oxidative pathway in this setting. Google Scholar
  11. 11.
    Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007;356(6):567–79.PubMedCrossRefGoogle Scholar
  12. 12.
    Uchida K, Nakata K, Suzuki T, et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood. 2009;113(11):2547–56.PubMedGoogle Scholar
  13. 13.
    • Han X, Uchida K, Jurickova I, et al. Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn’s disease. Gastroenterology. 2009;136(4):e1–3. This study showed for the first time that cytokine auto-antibodies play a role in immune regulation and clinical outcomes in pediatric IBD.CrossRefGoogle Scholar
  14. 14.
    Nylund CM, D’Mello S, Kim MO, et al. Granulocyte macrophage-colony-stimulating factor autoantibodies and increased intestinal permeability in Crohn disease. J Pediatr Gastroenterol Nutr. 2011;52(5):542–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Samson CM, Jurickova I, Molden E, et al. Granulocyte-macrophage colony stimulating factor blockade promotes ccr9(+) lymphocyte expansion in Nod2 deficient mice. Inflamm Bowel Dis 2011.Google Scholar
  16. 16.
    Walters MJ, Wang Y, Lai N, et al. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. J Pharmacol Exp Ther. 2010;335(1):61–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Kelsen JR, Rosh J, Heyman M, et al. Phase I trial of sargramostim in pediatric Crohn’s disease. Inflamm Bowel Dis. 2010;16(7):1203–8.PubMedGoogle Scholar
  18. 18.
    Korzenik JR, Dieckgraefe BK, Valentine JF, et al. Sargramostim for active Crohn’s disease. N Engl J Med. 2005;352(21):2193–201.PubMedCrossRefGoogle Scholar
  19. 19.
    McGovern DP, Jones MR, Taylor KD, et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum Mol Genet. 2010;19(17):3468–76.PubMedCrossRefGoogle Scholar
  20. 20.
    Morrow AL, Meinzen-Derr J, Huang P, et al. Fucosyltransferase 2 non-secretor and low secretor status predicts severe outcomes in premature infants. J Pediatr. 2011;158(5):745–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Perminow G, Beisner J, Koslowski M, et al. Defective paneth cell-mediated host defense in pediatric ileal Crohn’s disease. Am J Gastroenterol. 2010;105(2):452–9.PubMedCrossRefGoogle Scholar
  22. 22.
    • Negroni A, Costanzo M, Vitali R, et al. Characterization of adherent-invasive Escherichia coli isolated from pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2011. This study characterized in detail pathogenic features of AIEC in isolated from pediatric IBD patients. This is an important emerging pathway of disease pathogenesis. Google Scholar
  23. 23.
    Schwiertz A, Jacobi M, Frick JS, et al. Microbiota in pediatric inflammatory bowel disease. J Pediatr. 2010;157(2):240–44 e1.PubMedCrossRefGoogle Scholar
  24. 24.
    Wine E, Ossa JC, Gray-Owen SD, et al. Adherent-invasive Escherichia coli target the epithelial barrier. Gut Microbes. 2010;1(2):80–4.PubMedCrossRefGoogle Scholar
  25. 25.
    Lodes MJ, Cong Y, Elson CO, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004;113(9):1296–306.PubMedGoogle Scholar
  26. 26.
    Docktor MJ, Paster BJ, Abramowicz S, et al. Alterations in diversity of the oral microbiome in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2011.Google Scholar
  27. 27.
    Edwards LA, Lucas M, Edwards EA, et al. Aberrant response to commensal Bacteroides thetaiotaomicron in Crohn’s disease: an ex vivo human organ culture study. Inflamm Bowel Dis. 2011;17(5):1201–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Jyonouchi H, Geng L, Cushing-Ruby A, et al. Aberrant responses to TLR agonists in pediatric IBD patients; the possible association with increased production of Th1/Th17 cytokines in response to candida, a luminal antigen. Pediatr Allergy Immunol. 2010;21(4 Pt 2):e747–55.PubMedGoogle Scholar
  29. 29.
    Verdier J, Begue B, Cerf-Bensussan N, et al. Compartmentalized expression of Th1 and Th17 cytokines in pediatric inflammatory bowel diseases. Inflamm Bowel Dis 2011.Google Scholar
  30. 30.
    Rosen MJ, Frey MR, Washington MK, et al. STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm Bowel Dis. 2011;17(11):2224–34.PubMedCrossRefGoogle Scholar
  31. 31.
    Mannon PJ, Hornung RL, Yang Z, et al. Suppression of inflammation in ulcerative colitis by interferon-beta-1a is accompanied by inhibition of IL-13 production. Gut. 2011;60(4):449–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Dubinsky MC, Kugathasan S, Mei L, et al. Increased immune reactivity predicts aggressive complicating Crohn’s disease in children. Clin Gastroenterol Hepatol. 2008;6(10):1105–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Davis MK, Valentine JF, Weinstein DA, et al. Antibodies to CBir1 are associated with glycogen storage disease type Ib. J Pediatr Gastroenterol Nutr. 2010;51(1):14–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Yu JE, De Ravin SS, Uzel G, et al. High levels of Crohn’s disease-associated anti-microbial antibodies are present and independent of colitis in chronic granulomatous disease. Clin Immunol. 2011;138(1):14–22.PubMedCrossRefGoogle Scholar
  35. 35.
    • Kobayashi K, Qiao SW, Yoshida M, et al. An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice. Gastroenterology. 2009;137(5):1746–56 e1. This study provided evidence in an animal model that anti-flagellin antibodies may drive disease severity in IBD, and not simply function as biomarkers.PubMedCrossRefGoogle Scholar
  36. 36.
    • Markowitz J, Kugathasan S, Dubinsky M, et al. Age of diagnosis influences serologic responses in children with Crohn’s disease: a possible clue to etiology? Inflamm Bowel Dis. 2009;15(5):714–9. This study showed that AMS serology titers vary with age of onset in pediatric IBD, and so this will need to be accounted for in validating prognostic panels in children.PubMedCrossRefGoogle Scholar
  37. 37.
    Lacher M, Helmbrecht J, Schroepf S, et al. NOD2 mutations predict the risk for surgery in pediatric-onset Crohn’s disease. J Pediatr Surg. 2010;45(8):1591–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Lichtenstein GR, Targan SR, Dubinsky MC, et al. Combination of genetic and quantitative serological immune markers are associated with complicated Crohn’s disease behavior. Inflamm Bowel Dis. 2011;17(12):2488–96.PubMedCrossRefGoogle Scholar
  39. 39.
    • Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease. Inflamm Bowel Dis. 2011;17(1):30–8. This study developed a statistical model to predict disease course in pediatric CD, including the effects of the timing of specific therapies. Importantly, a software application was also developed to display this information to individual patients, for the purpose of decision making.PubMedCrossRefGoogle Scholar
  40. 40.
    Thayu M, Denson LA, Shults J, et al. Determinants of changes in linear growth and body composition in incident pediatric Crohn’s disease. Gastroenterology. 2010;139(2):430–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Dubinsky MC, Mei L, Friedman M, et al. Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(8):1357–66.PubMedGoogle Scholar
  42. 42.
    Kabakchiev B, Turner D, Hyams J, et al. Gene expression changes associated with resistance to intravenous corticosteroid therapy in children with severe ulcerative colitis. PLoS One 2010;5(9).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Pediatric Gastroenterology, Department of PediatricsCincinnati Children’s Hospital Medical Center and the University of Cincinnati College of MedicineCincinnatiUSA

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