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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Medicine II, Grosshadern, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany

    Matthias Jürgens, Stephan Brand, Julia Seiderer, Jürgen Glas, Johanna Wagner, Simone Pfennig, Cornelia Tillack, Florian Beigel, Maria Weidinger, Fabian Schnitzler, Burkhard Göke & Thomas Ochsenkühn

  2. Institute for Medical Informatics, Biometry and Epidemiology (IBE), Ludwig-Maximilians-University Munich, Munich, Germany

    Rüdiger P. Laubender

  3. Clinic for Preventive Dentistry and Parodontology, Ludwig-Maximilians-University Munich, Munich, Germany

    Jürgen Glas

  4. Department of Human Genetics, RWTH Aachen University, Aachen, Germany

    Jürgen Glas

  5. Department of Pediatrics, Medical School Hannover, Hannover, Germany

    Martin Wetzke

  6. Department of Surgery, Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany

    Martin E. Kreis

  7. Department of Clinical Chemistry, Ludwig-Maximilians-University Munich, Munich, Germany

    Peter Lohse

  8. Department of Radiology, Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany

    Karin Herrmann

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  1. Matthias Jürgens
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  2. Stephan Brand
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Corresponding author

Correspondence to Stephan Brand.

Additional information

M. Jürgens and S. Brand contributed equally to this work.

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Jürgens, M., Brand, S., Laubender, R.P. et al. The presence of fistulas and NOD2 homozygosity strongly predict intestinal stenosis in Crohn’s disease independent of the IL23R genotype. J Gastroenterol 45, 721–731 (2010). https://doi.org/10.1007/s00535-010-0231-7

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