How Does Knowledge from Translational Research Impact Our Clinical Care of Pediatric Inflammatory Bowel Disease Patients?
Pediatric Gastroenterology (SR Orenstein, Section Editor)
First Online: 16 March 2012 DOI:
Cite this article as: Denson, L.A. Curr Gastroenterol Rep (2012) 14: 275. doi:10.1007/s11894-012-0258-4 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
• 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
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.
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.
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.
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.
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.
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.
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.
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.
• 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.
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.
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.
• 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
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.
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.
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.
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.
Korzenik JR, Dieckgraefe BK, Valentine JF, et al. Sargramostim for active Crohn’s disease. N Engl J Med. 2005;352(21):2193–201.
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.
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.
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.
• 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.
Schwiertz A, Jacobi M, Frick JS, et al. Microbiota in pediatric inflammatory bowel disease. J Pediatr. 2010;157(2):240–44 e1.
Wine E, Ossa JC, Gray-Owen SD, et al. Adherent-invasive Escherichia coli target the epithelial barrier. Gut Microbes. 2010;1(2):80–4.
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.
Docktor MJ, Paster BJ, Abramowicz S, et al. Alterations in diversity of the oral microbiome in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2011.
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.
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.
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.
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.
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.
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.
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.
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.
• 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
• 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
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.
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.
• 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
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.
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.
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).
© Springer Science+Business Media, LLC 2012