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P419 Concentrations of anti-TNF agents in non-inflamed intestinal tissue are associated with the long-term outcome of patients with Crohn's disease

Yoshihara T., Shinzaki S., Kawai S., Iwatani S., Yamaguchi T., Araki M., Hiyama S., Inoue T., Hayashi Y., Watabe K., Iijima H., Takehara T.

Osaka university, Gastroenterology and Hepatology, Suita, Osaka, Japan

Background

Many reports show that high serum trough levels of anti-tumor necrosis factor (TNF) agents are required for the sustained remission in patients with Crohn's disease (CD). However, the pharmacokinetics of anti-TNF agents in intestinal mucosa was poorly investigated. The aim of our study was to investigate the correlation between the tissue concentration of anti-TNF agents and long-term disease outcome.

Methods

This was a prospective single center study and 25 patients with CD administered infliximab or adalimumab as a maintenance therapy were enrolled. All participants received colonoscopy or balloon-assisted small bowel endoscopy two weeks after the administration of anti-TNF agents. Biopsy samples obtained from the inflamed and non-inflamed intestinal tissue were immersed in distilled water in the concentration of 0.1 mg/ μl. Tissue concentrations of anti-TNF agents were evaluated by enzyme-linked immunosorbent assay and the correlation with serum trough levels was compared. Moreover, we investigated the association between tissue concentrations of anti-TNF agents and the time to therapeutic interventions defined as no additional medical, endoscopic, and surgical treatment for 24 months.

Results

Concentrations of anti-TNF agents in the inflamed tissue were significantly higher than that in the non-inflamed tissue (1.7 versus 1.0 μg/g, median, p=0.0011). Crohn's Disease Activity Index score and modified Rutgeerts score were not associated with the levels of anti-TNF agents in either inflamed or non-inflamed tissue. Serum trough concentrations of infliximab and adalimumab were 2.3 μg/ml (median, range [0.2–7.0]) and 10.4 μg/ml (0.8–22.8), respectively. When the patients were divided by median serum trough levels of each anti-TNF agent, patients with high serum trough concentrations of anti-TNF agents had significantly higher anti-TNF agents levels in the non-inflamed tissue than those with low serum trough concentrations (1.2 versus 0.0 μg/g, median, p=0.0346), but the difference was not observed in the inflamed tissue. Patients with high concentrations of anti-TNF agents in the non-inflamed tissue (>1.3 μg/g) had significantly longer time to therapeutic interventions than those with low concentrations of anti-TNF agents (15.5 versus 3.0 months, HR 0.33; 95% CI: 0.09–0.93).

Conclusion

The concentrations of anti-TNF agents in the non-inflamed mucosa can reflect sustained remission and be a biomarker for monitoring therapeutic intensity in CD patients receiving anti-TNF agents.