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Phenotypic associations of Crohn's disease with antibodies to flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 mutations in a swiss cohort

Schoepfer, Alain M. MD*; Schaffer, Thomas MSc; Mueller, Stefan PhD; Flogerzi, Beatrice; Vassella, Erik PhD; Seibold-Schmid, Beatrice MSc; Seibold, Frank MD*

doi: 10.1002/ibd.20892
Original Article

Background: Distinct Crohn's disease (CD) phenotypes correlate with antibody reactivity to microbial antigens. We examined the association between antibody response to 2 new flagellins called A4-Fla2 and Fla-X, anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (p-ANCA), anti-pancreas antibodies (PAB), NOD2 mutations (R702W, G908R, and L1007fsinsC), and clinical CD phenotypes (according to Vienna criteria).

Methods: All the above-mentioned antibodies as well as NOD2 mutations were determined in 252 CD patients, 53 with ulcerative colitis (UC), and 43 healthy controls (HC) and correlated with clinical data.

Results: A seroreactivity for A4-Fla2/Fla-X/ASCA/p-ANCA/PAB (in percent) was found in 59/57/62/12/22 of CD patients, 6/6/4/51/0 of UC patients, and 0/2/5/0/0 of healthy controls. CD behavior: 37% B1, 36% B2, and 27% B3. In multivariate logistic regression, antibodies to A4-Fla2, Fla-X, and ASCA were significantly associated with stricturing phenotype (P = 0.027, P = 0.041, P < 0.001), negative associations were found with inflammatory phenotype (P = 0.001, P = 0.005, P < 0.001). Antibodies to A4-Fla2, Fla-X, ASCA, and NOD2 mutations were significantly associated with small bowel disease (P = 0.013, P = 0.01, P < 0.001, P = 0.04), whereas ASCA was correlated with fistulizing disease (P = 0.007), and small bowel surgery (P = 0.009). Multiple antibody responses against microbial antigens were associated with stricturing (P < 0.001), fistulizing disease (P = 0.002), and small bowel surgery (P = 0.002).

Conclusions: Anti-flagellin antibodies and ASCA are strongly associated with complicated CD phenotypes. CD patients with serum reactivity against multiple microbes have the greatest frequency of strictures, perforations, and small bowel surgery. Further prospective longitudinal studies are needed to show that antibody-based risk stratification improves the clinical outcome of CD patients.

(Inflamm Bowel Dis 2009)

*Department of Gastroenterology, Inselspital/Bern University Hospital, Switzerland

Department of Clinical Research, University of Bern, Switzerland

Institute of Pathology, University of Bern, Switzerland

Department of Gastroenterology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland (e-mail:

Supported by SNSF grant 3247B0-118112/1 (to F.S.), NIH grant DK64400 (to C.O.E.), SNSF Grant 3347C0-108792/1 (to P.M.) (Swiss IBD Cohort Study), and by

Parts of the results were presented in abstract form (poster) at DDW 2008 in San Diego, USA, 18 May 2008.

The first 2 authors contributed equally.

© Crohn's & Colitis Foundation of America, Inc.
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