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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

Abstract

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.

Methods

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.

Results

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.

Conclusion

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

Keywords

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

Abbreviations

CARD

Caspase-activation recruitment domain

CD

Crohn’s disease

CI

Confidence interval

DC

Dendritic cells

fs

Frameshift

HD

Human defensin

IBD

Inflammatory bowel disease

IL

Interleukin

IL23R

Interleukin 23 receptor (gene)

MFP

Multivariable fractional polynomials

MRE

MRI enteroclysma

MRI

Magnetic resonance imaging

NOD

Nucleotide-binding oligomerization domain

NPV

Negative predictive value

OR

Odds ratio

PCR

Polymerase chain reaction

PPV

Positive predictive value

ROC

Receiver-operating characteristic

SNP

Single nucleotide polymorphism

TLR

Toll-like receptor

UC

Ulcerative colitis

wt

Wild-type

Notes

Acknowledgments

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)

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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

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