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P481. Failure of infliximab treatment in Crohn's disease is associated with the presence of fibrosis

J. de Bruyn1,2, S. Meijer3, M. Wildenberg2, G. van den Brink1,2, G. D'Haens1, 1Academic Medical Center, Gastroenterology & Hepatology, Amsterdam, Netherlands, 2Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands, 3Academic Medical Center, Pathology, Amsterdam, Netherlands

Background

Intestinal fibrosis in Crohn's disease (CD) is a process stimulated by chronic inflammation leading to an increased presence of myofibroblasts and collagen deposition in all layers of the intestinal wall. However, once the fibrotic process has been initiated it may progress independently of inflammation. Infliximab (IFX) is a highly effective anti-inflammatory treatment in CD. Despite initial good response, considerable proportions of patients lose response during maintenance treatment. We aimed to investigate if this phenomenon could be explained by the presence of pre-existing fibrosis.

Methods

We collected ileocecal resection specimens from patients operated between 2005 and 2012 who had failed IFX treatment (at least 3 gifts IFX), and from patients operated without previous IFX treatment. Demographics and pre-operative C-reactive protein (CRP) were recorded. Inflammation was scored on H&E stains by an experienced IBD pathologist (range 0–13 points). Sirius Red and collagen I immunohistochemistry stainings were performed for collagen deposition, and α-smooth muscle (αSMA) for detection of myofibroblasts and smooth muscle cells. Staining intensity was measured using image analysis software (Image J, NIH).

Results

We examined 12 specimens from patients operated after IFX failure, and 20 specimens of IFX-naive patients. Median duration of IFX treatment was 77 (IQR 21–189) weeks. CRP levels did not differ between treated and non-treated patients (respectively 17 (3–51) mg/L vs 6 (3–24) mg/L). Both IFX-failure and IFX-naïve groups had significant inflammation but this did not differ significantly (11 (IQR 6–12) vs 10 (IQR 7–12) points).

More collagen I deposition in the IFX-failure group was found in the submucosa (number of collagen I positive cells versus total number of cells; respectively 71% vs 57%, p = 0.03), with a trend to more collagen I deposition in the mucosa and muscularis externa (respectively 50% vs 30%, p = 0.069 and 46% vs 23%, p = 0.067).

IFX-naïve patients had more αSMA expression in the muscularis externa (39% vs 34%, p = 0.01).

There was a strong negative correlation between inflammation and submucosal αSMA positivity in patients who had failed IFX (R=-0.84, p = 0.001). No correlation between IFX duration and inflammation or collagen deposition was found.

Conclusion

In our series of ileocoecal resection specimens, there is more collagen I deposition in the submucosa with a trend in the mucosa and muscularis externa. Moreover there is a strong negative correlation between inflammation and submucosal αSMA positivity in these patients. Fibrotic deposition could be a cause for IFX failure in CD patients.