Title: Assessing and predicting disease progression in inflammatory bowel diseases: a combined clinical and molecular approach
Other Titles: Vaststellen en voorspellen van ziekteprogressie bij inflammatoire darmziekten: een gecombineerde klinische en moleculaire aanpak.
Authors: Ferrante, Marc
Issue Date: 13-Dec-2007
Abstract: Inflammatory bowel diseases are complex heterogenic disorders characterized by chronic relapsing and remitting intestinal inflammation. The twomain entities are CrohnÂ’s disease (CD) and ulcerative colitis (UC). Disease progression and post-operative recurrence remain challenging problems, and predictive markers have been ill defined. The aim of this thesis, was to define clinical, serological, genetic, endoscopic, surgical andhistological parameters associated with and/or predictive of complicated disease behaviour, need for surgery and post-operative disease outcomein both CD and UC. The majority of patients with CD will develop a complicated disease behaviour with strictures and/or fistula during the course of their disease. We found an increased frequency of complicated disease behaviour and CD-related abdominal surgery in patients with a higher cumulative number of positive antibodies and higher antibody responses towards ASCA, ALCA, ACCA, AMCA and anti-Omp (Ferrante M et al, Gut 2007;56:1394-1403). The predictive role of these serological markers is unclear, since increasing antibody responses were present in patients with a longer disease duration. Fibrostenosis is a common complication leading to repeated surgery in CD. Both infliximab (IFX) exposure and vascular endothelial growth factor(VEGF) have been linked to stenotic events. We observed increased TGF-β1, CTGF, collagen-1α and BMP-7 expression in the intestinal tissue of CD patients compared to non-IBD controls, but were unable to demonstrate a profibrogenetic role for pre-operative IFX exposure (Burke JP/Ferrante M et al, submitted). However, our data suggest a pro-fibrogenetic role for corticosteroids. Concerning VEGF, we measured significantlyhigher serum VEGF levels in CD compared to healthy controls, but this probably resembles ongoing inflammation since comparable serum levels were found in patients with other inflammatory conditions (Ferrante M et al, Inflamm Bowel Dis 2006;12:870-878). We did not find different VEGF genotypes or serum VEGF levels in CD patients to coincide with a stricturing behaviour. Up to 50% of patients with CD will need an intestinal resection, but most of them will encounter a post-operative relapse. We found a significant association between presence of myenteric plexitis at the proximal resection margin and early postoperative endoscopic CD recurrence (Ferrante M et al, Gastroenterology 2006;130:1595-1606). Furthermore, we found apositive correlation between the severity of the inflammatory infiltrate and the severity of postoperative endoscopic recurrence. Recently, infliximab has been introduced for the treatment of UC. We reported a short-term clinical response rate of 63 percent (Ferrante M et al, Inflamm Bowel Dis 2007;13:123-128). On the long-term, we observed a sustained clinical response and a colectomy-free survival in, respectively, 69% and 82% of patients (Ferrante M et al, submitted). Independent predictors of colectomy were absence of short-term clinical response, a baseline CRP ≥5 mg/L and any previous IV treatment with corticosteroids and/or cyclosporine. Finally, we evaluated the post-operative outcome in UC patients undergoing proctocolectomy with ileal pouch-anal anastomosis. Early post-operative complications were seen in 27% of patients, while 35% developed lateseptic and/or obstructive complications and 46% developed at least one episode of pouchitis (Ferrante M/Declerck S et al, Inflamm Bowel Dis accepted). Extra-intestinal manifestations, a GT/TT genotype at Toll Like Receptor-1 S87I, anti-chitobioside carbohydrate antibodies and a young age at diagnosis were independently associated with pouchitis (Ferrante M et al, JCC accepted). Factors associated with chronic pouchitis, diagnosed in 33 patients (19%), were extra-intestinal manifestations, backwash ileitis, outer-membrane porin antibodies and a young age at proctocolectomy. This doctoral thesis draws attention to several new variables which areassociated with complicated disease behaviour, need for surgery and post-operative disease outcome. To conclude on the predictive role of all these variables replication is needed in a prospective situation.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Translational Research in GastroIntestinal Disorders

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