Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease

Abstract

Background: The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn's disease in vitro. Aim: To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease. Methods: 99mTechnetium-annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn's disease as assessed by the Crohns Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of > 100 points). Results: Colonic uptake of 99mTc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of 99mTc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic 99mTc-annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41 (0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of 99mTc-annexin V could be detected in 10 of the 14 responding patients (CDAI > 100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis. Conclusions: These in vivo observations support the notion that colonic uptake of 99mTc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.