A. Ruffa

High Expression of the “A Disintegrin And Metalloprotease” 19 (ADAM19), a Sheddase for TNF-α in the Mucosa of Patients with Inflammatory Bowel Diseases

Background:Tumor necrosis factor &agr; (TNF-&agr;) plays a major role in the tissue-damaging immune response in inflammatory bowel diseases (IBDs). The tissue concentration of TNF-&agr; is related to the activity of “A Disintegrin And Metalloprotease” (ADAMs), enzymes that process membrane-bound TNF-&agr; and liberate the TNF-&agr; trimer into the extracellular environment. Although IBD-related inflammation is associated with high ADAM17 levels, the contribution of other members of the ADAMs family is not known. In this study, we characterized the expression of other TNF-&agr; convertases (i.e., ADAM9, ADAM10, and ADAM19) in IBD. Methods:Normal and IBD biopsies were examined for the content of ADAMs by real-time polymerase chain reaction, Western blotting and immunohistochemistry. ADAM19 was also analyzed in intestinal epithelial cells and normal colonic explants stimulated with inflammatory cytokines and in ex vivo biopsies taken from IBD patients before and after a successful infliximab treatment. Results:ADAM19 RNA transcripts and protein were upregulated in patients with ulcerative colitis and, to a lesser extent, in patients with Crohns disease compared with normal controls. In contrast, ADAM9 and ADAM10 expression did not differ between patients with IBD and controls. Immunohistochemical analysis showed that epithelial cells were the major source of ADAM19 in IBD. ADAM19 expression was increased in colonic epithelial cell lines and normal colonic explants by TNF-&agr;, interleukin 21 and interleukin 6, and was downregulated in IBD tissue by infliximab. Conclusions:These findings suggest the existence of a positive feedback mechanism involving cytokines and ADAM19 that can amplify cytokine production in IBD.

Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease

BACKGROUND Crohns disease and ulcerative colitis are inflammatory bowel diseases involving a genetically determined inappropriate mucosal immune response towards luminal antigens, including resident bacterial flora. Recent studies identified susceptibility genes involved in autophagy. AIMS We analyzed known autophagic loci (IRGM, ULK1 and AMBRA1) previously described as associated with inflammatory bowel diseases or with other autoimmune and/or inflammatory disorders in a sample of Italian inflammatory bowel diseases patients in order to confirm their possible involvement and relative contribution in the disease. METHODS We performed a case-control association study, a sub-phenotype correlation and a haplotype analysis. The analysis included 263 Crohns disease, 206 ulcerative colitis patients and 245 matched healthy controls. Five polymorphisms were genotyped by allelic discrimination assays. RESULTS IRGM was the most strongly associated with Crohns disease susceptibility [rs13361189: P=0.011, OR=1.66 [95% CI: (1.12-2.45)]; rs4958847: P=0.05, OR=1.43 [95% CI: (1-2.03)]. The SNP rs13361189 was also found to increase the risk of Crohns disease clinical sub-phenotype (fibrostricturing behaviour, ileal disease, perianal disease, intestinal resection). These findings suggest that IRGM variants may modulate clinical characteristics of Crohns disease. CONCLUSIONS Our study confirms IRGM rs13361189 and rs4958847 polymorphisms to be important for Crohns disease susceptibility and phenotype modulation, in accordance with previous findings.

Inflammatory Bowel Disease Phenotype as Risk Factor for Cancer in a Prospective Multicentre Nested Case-Control IG-IBD Study

BACKGROUND AND AIMS Cancer risk in inflammatory bowel disease [IBD] is still debated. In a prospective, multicentre, nested case-control study, we aimed to characterise incident cases of cancer in IBD. The role of immunomodulators vs clinical characteristics of IBD as risk factors for cancer was also investigated. MATERIALS AND METHODS From January 2012 to December 2014, each IBD patient with incident cancer was matched with two IBD patients without cancer for: IBD type, gender, and age. Risk factors were assessed by multivariate regression analysis. RESULTS IBD patients considered numbered 44619: 21953 Crohns disease [CD], 22666 ulcerative colitis [UC]. Cancer occurred in 174 patients: 99 CD [CD-K], 75 UC [UC-K]. Controls included 198 CD [CD-C], 150 UC [UC-C]. Cancer incidence in IBD was 3.9/1000, higher in CD (4.5/1000 [99/21,953]) than in UC (3.3/1000 [75/22,666]; p = 0.042). Cancers involved: digestive system [36.8%], skin [13.2%], urinary tract [12.1%], lung [8.6%], breast [8%], genital tract [6.9%], thyroid [4.6%], lymphoma [3.5%], others [6.3%]. In CD, penetrating behaviour and combined thiopurines and tumour necrosis factor alpha [TNFα] antagonists were risk factors for cancer overall: odds ratio [OR] (95% confidence interval [CI] 2.33 [1.01-5.47]); 1.97 [1.1-3.5]; and for extracolonic cancers 3.9 [1.56-10.1]; 2.15 [1.17-4.1], respectively. In UC, risk factors were pancolitis and disease-related surgery for cancer overall (OR: 2.52 [1.26-5.1]; 5.09 [1.73-17.1]); disease-related surgery for colorectal cancer [CRC] (OR 3.6 [1.0-12]); and extensive and left-sided vs distal UC for extracolonic cancers (OR: 2.55 [1.15-5.9]; 2.6 [1.04-6.6]), respectively. CONCLUSIONS In a multicentre study, penetrating CD and extensive UC were risk factors for cancer overall. Cancer incidence was higher in CD than in UC.

P.04.4 SCREENING FOR MELANOMA AND NON MELANOMA SKIN CANCER IN IBD PATIENTS BEFORE TREATMENT WITH THIOPURINES AND ANTI-TNFs: A PROSPECTIVE COHORT STUDY

P352 Screening for melanoma and non melanoma skin cancer in IBD patients before treatment with thiopurines and anti-TNFs: A prospective cohort study E. Lolli1 *, R. Saraceno2, C. Petruzziello1, G. Condino1, M. Ascolani1, A. Ventura2, A. Capanna1, A. Ruffa1, S. Onali1, E. Calabrese1, S. Chimenti2, F. Pallone1, L. Biancone1. 1Universita di Roma Tor Vergata, Medicina dei sistemi, cattedra di Gastroenterologia, Roma, Italy, 2Dermatology Unit, University of Rome Tor Vergata, Systems Medicine, Rome, Italy