Journal of Gastroenterology

, Volume 45, Issue 7, pp 721–731 | Cite as

The presence of fistulas and NOD2 homozygosity strongly predict intestinal stenosis in Crohn’s disease independent of the IL23R genotype

  • Matthias Jürgens
  • Stephan BrandEmail author
  • Rüdiger P. Laubender
  • Julia Seiderer
  • Jürgen Glas
  • Martin Wetzke
  • Johanna Wagner
  • Simone Pfennig
  • Cornelia Tillack
  • Florian Beigel
  • Maria Weidinger
  • Fabian Schnitzler
  • Martin E. Kreis
  • Burkhard Göke
  • Peter Lohse
  • Karin Herrmann
  • Thomas Ochsenkühn
Original Article—Alimentary Tract


Background and aims

We analyzed the prevalence of concomitant intestinal stenosis in patients with fistulizing Crohn’s disease (CD), including the NOD2/CARD15 and IL23R genotype status.


Medical records of n = 1,110 patients with inflammatory bowel diseases were screened for patients with fistulizing and stricturing CD. Study inclusion required diagnosis of stenosis made within 6 months of diagnosing fistulas. CD-associated NOD2 and IL23R variants were genotyped. Similarly, we prospectively investigated 42 patients presenting with fistulizing CD.


In the retrospective study (n = 333 CD patients), fistulas were found in 145 (43.5%) patients and stenoses in 223 (67.0%) patients. Concomitant stenosis was diagnosed in 125 patients with fistulas resulting in a positive predictive value (PPV) of 86.2% for fistulas predicting intestinal stenosis (p = 5.53 × 10−11; OR 5.74, 95% CI 3.22–10.50). In logistic regression analysis, presence of fistulas (OR 4.51; 95% CI 2.54–8.01, p = 2.68 × 10−7) and disease duration (OR 1.09; 95% CI 1.05–1.13; p = 3.19 × 10−6) were strongly associated with intestinal stenosis. NOD2 genotype information, but not IL23R status, increased the PPV for the correct diagnosis of stenosis (PPV = 89.9%). All homozygous carriers (100%) of NOD2 variants with fistulizing CD were diagnosed with stenosis; 1007fs homozygotes were found more often among patients with fistulas and stenoses than in patients without stenoses and fistulas (p = 0.00037). Similar results were found in the prospective analysis, in which 83.3% of the patients with fistulizing CD had concomitant stenosis.


Fistulizing CD is strongly associated with concomitant intestinal stenosis, particularly in homozygous carriers of NOD2 mutations.


Crohn’s disease Inflammatory bowel disease Fistula Stenosis NOD2/CARD15 IL23R 



Caspase-activation recruitment domain


Crohn’s disease


Confidence interval


Dendritic cells




Human defensin


Inflammatory bowel disease




Interleukin 23 receptor (gene)


Multivariable fractional polynomials


MRI enteroclysma


Magnetic resonance imaging


Nucleotide-binding oligomerization domain


Negative predictive value


Odds ratio


Polymerase chain reaction


Positive predictive value


Receiver-operating characteristic


Single nucleotide polymorphism


Toll-like receptor


Ulcerative colitis





This manuscript contains parts of the unpublished degree thesis of J. Wagner. S. Brand was supported by grants from Deutsche Forschungsgemeinschaft (DFG; BR 1912/5-1), the Else Kröner-Fresenius-Stiftung (Else Kröner Fresenius Memorial Stipendium 2005; P50/05/EKMS05/62), the Ludwig-Demling Grant 2007 from DCCV e.V. and by grants from the Ludwig-Maximilians-University Munich (Excellence Initiative, Investment Funds 2008 and FöFoLe program). M. Jürgens and T. Ochsenkühn were supported by a grant from Centocor, Inc. J. Seiderer was supported by grants from the Ludwig-Maximilians-University (FöFoLe 422), Robert-Bosch-Stiftung and Else Kröner-Fresenius-Stiftung (Else Kröner-Fresenius Memorial Grant 2008; P81/08//EKMS08/01).

Conflict of interest statement

None of the authors and co-authors have a conflict of interest related to this manuscript.

Supplementary material

535_2010_231_MOESM1_ESM.doc (144 kb)
Supplemental Tables (DOC 144 kb)


  1. 1.
    Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.CrossRefPubMedGoogle Scholar
  2. 2.
    Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8:458–66.CrossRefPubMedGoogle Scholar
  4. 4.
    Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: A pathologic and clinical entity. JAMA. 1932;99:1323–9.Google Scholar
  5. 5.
    Penner A, Crohn B. Perianal fistulae as a complication of regional ileitis. Ann Surg. 1938;108:867–73.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis. 2002;8:244–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA, Belaiche J. Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut. 2001;49:777–82.CrossRefPubMedGoogle Scholar
  10. 10.
    Brand S, Staudinger T, Schnitzler F, Pfennig S, Hofbauer K, Dambacher J, et al. The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn’s disease. Inflamm Bowel Dis. 2005;11:645–52.CrossRefPubMedGoogle Scholar
  11. 11.
    Seiderer J, Schnitzler F, Brand S, Staudinger T, Pfennig S, Herrmann K, et al. Homozygosity for the CARD15 frameshift mutation 1007 fs is predictive of early onset of Crohn’s disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis. Scand J Gastroenterol. 2006;41:1421–32.CrossRefPubMedGoogle Scholar
  12. 12.
    Seiderer J, Brand S, Herrmann KA, Schnitzler F, Hatz R, Crispin A, et al. Predictive value of the CARD15 variant 1007fs for the diagnosis of intestinal stenoses and the need for surgery in Crohn’s disease in clinical practice: results of a prospective study. Inflamm Bowel Dis. 2006;12:1114–21.CrossRefPubMedGoogle Scholar
  13. 13.
    Schnitzler F, Brand S, Staudinger T, Pfennig S, Hofbauer K, Seiderer J, et al. Eight novel CARD15 variants detected by DNA sequence analysis of the CARD15 gene in 111 patients with inflammatory bowel disease. Immunogenetics. 2006;58:99–106.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Glas J, Seiderer J, Wetzke M, Konrad A, Torok HP, Schmechel S, et al. rs1004819 is the main disease-associated IL23R variant in German Crohn’s disease patients: combined analysis of IL23R, CARD15, and OCTN1/2 variants. PLoS ONE 2007;2:e819.Google Scholar
  16. 16.
    Herrmann KA, Michaely HJ, Seiderer J, Ochsenkuehn T, Reiser MF, Schoenberg SO. The “star-sign” in magnetic resonance enteroclysis: a characteristic finding of internal fistulae in Crohn’s disease. Scand J Gastroenterol. 2006;41:239–41.CrossRefPubMedGoogle Scholar
  17. 17.
    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;314:1461–3.CrossRefPubMedGoogle Scholar
  18. 18.
    Sauerbrei W, Royston P. Building multivariable prognostic and diagnostic models: transformation of the predictors by using fractional polynomials. J R Statist Soc (Ser A). 1999;162:71–94.CrossRefGoogle Scholar
  19. 19.
    Sauerbrei W, Royston P. Corrigendum: building multivariable prognostic and diagnostic models: transformation of the predictors by using fractional polynomials. J R Statist Soc (Ser A). 2002;162:399–400.CrossRefGoogle Scholar
  20. 20.
    Sauerbrei W, Meier-Hirmer C, Benner A, Royston P. Multivariable regression model building by using fractional polynomials: description of SAS, STATA and R programs. Comput Stat Data Anal. 2006;50:3464–85.CrossRefGoogle Scholar
  21. 21.
    Hosmer DW, Lemeshow S. Applied logistic regression (Wiley Series in probability and statistics). New York: Wiley-Interscience; 2000.Google Scholar
  22. 22.
    Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc Ser B (Methodol). 1995;57:289–300.Google Scholar
  23. 23.
    Hamilton LC. Regression with graphics. A second course in applied statistics. USA: Duxbury Press; 1992.Google Scholar
  24. 24.
    Brand S, Hofbauer K, Dambacher J, Schnitzler F, Staudinger T, Pfennig S, et al. Increased expression of the chemokine fractalkine in Crohn’s disease and association of the fractalkine receptor T280 M polymorphism with a fibrostenosing disease phenotype. Am J Gastroenterol. 2006;101:99–106.CrossRefPubMedGoogle Scholar
  25. 25.
    Seiderer J, Dambacher J, Leistner D, Tillack C, Glas J, Niess JH. et al. Genotype-phenotype analysis of the CXCL16 p.Ala181Val polymorphism in inflammatory bowel disease. Clin Immunol. 2008;127:49–55.CrossRefPubMedGoogle Scholar
  26. 26.
    Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C. et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn’s disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis. 2008;14:437–45.CrossRefPubMedGoogle Scholar
  27. 27.
    Glas J, Konrad A, Schmechel S, Dambacher J, Seiderer J, Schroff F, et al. The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn’s disease in the German population. Am J Gastroenterol. 2008;103:682–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Seiderer J, Dambacher J, Kuhnlein B, Pfennig S, Konrad A, Torok HP, et al. The role of the selenoprotein S (SELS) gene −105G > A promoter polymorphism in inflammatory bowel disease and regulation of SELS gene expression in intestinal inflammation. Tissue Antigens. 2007;70:238–46.CrossRefPubMedGoogle Scholar
  29. 29.
    Thalmaier D, Dambacher J, Seiderer J, Konrad A, Schachinger V, Pfennig S, et al. The +1059G/C polymorphism in the C-reactive protein (CRP) gene is associated with involvement of the terminal ileum and decreased serum CRP levels in patients with Crohn’s disease. Aliment Pharmacol Ther. 2006;24:1105–15.CrossRefPubMedGoogle Scholar
  30. 30.
    Torok HP, Glas J, Tonenchi L, Lohse P, Muller-Myhsok B, Limbersky O, et al. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn’s disease. Gut. 2005;54:1421–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Mirow L, Hauenschild L, Hildebrand P, Kleemann M, Keller R, Franke C, et al. Recurrence of Crohn’s disease after surgery–causes and risks. Zentralbl Chir. 2008;133:182–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Vermeire S, Van Assche G, Rutgeerts P. Perianal Crohn’s disease: classification and clinical evaluation. Dig Liver Dis. 2007;39:959–62.CrossRefPubMedGoogle Scholar
  33. 33.
    Bataille F, Rohrmeier C, Bates R, Weber A, Rieder F, Brenmoehl J, et al. Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn’s disease. Inflamm Bowel Dis. 2008;14:1514–27.CrossRefPubMedGoogle Scholar
  34. 34.
    Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, et al. Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation? Gut. 2006;55:342–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006;290:G827–38.CrossRefPubMedGoogle Scholar
  36. 36.
    Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, Paschos E, et al. Linking genetic susceptibility to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis. 2008;14:204–12.CrossRefPubMedGoogle Scholar
  37. 37.
    Dambacher J, Beigel F, Zitzmann K, de Toni E, Goke B, Diepolder HM, et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 2009;58:1207–17.CrossRefPubMedGoogle Scholar
  38. 38.
    Brand S, Olszak T, Beigel F, Diebold J, Otte JM, Eichhorst ST, et al. Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells. J Cell Biochem. 2006;97:709–23.CrossRefPubMedGoogle Scholar
  39. 39.
    Brand S. Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut. 2009;58:1152–67.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Matthias Jürgens
    • 1
  • Stephan Brand
    • 1
    Email author
  • Rüdiger P. Laubender
    • 2
  • Julia Seiderer
    • 1
  • Jürgen Glas
    • 1
    • 3
    • 4
  • Martin Wetzke
    • 5
  • Johanna Wagner
    • 1
  • Simone Pfennig
    • 1
  • Cornelia Tillack
    • 1
  • Florian Beigel
    • 1
  • Maria Weidinger
    • 1
  • Fabian Schnitzler
    • 1
  • Martin E. Kreis
    • 6
  • Burkhard Göke
    • 1
  • Peter Lohse
    • 7
  • Karin Herrmann
    • 8
  • Thomas Ochsenkühn
    • 1
  1. 1.Department of Medicine II, GrosshadernLudwig-Maximilians-University MunichMunichGermany
  2. 2.Institute for Medical Informatics, Biometry and Epidemiology (IBE)Ludwig-Maximilians-University MunichMunichGermany
  3. 3.Clinic for Preventive Dentistry and ParodontologyLudwig-Maximilians-University MunichMunichGermany
  4. 4.Department of Human GeneticsRWTH Aachen UniversityAachenGermany
  5. 5.Department of PediatricsMedical School HannoverHannoverGermany
  6. 6.Department of Surgery, GrosshadernLudwig-Maximilians-University MunichMunichGermany
  7. 7.Department of Clinical ChemistryLudwig-Maximilians-University MunichMunichGermany
  8. 8.Department of Radiology, GrosshadernLudwig-Maximilians-University MunichMunichGermany

Personalised recommendations