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

• Published in: Gut 2007-04, Vol.56 (4), p.509-517
• Main Authors: Van den Brande, Jan M H, Koehler, Tamara C, Zelinkova, Zuzana, Bennink, Roelof J, te Velde, Anje A, ten Cate, Fibo J W, van Deventer, Sander J H, Peppelenbosch, Maikel P, Hommes, Daniël W
• Format: Article
• Language: English
• Subjects: 7-amino-actinomycin D; 7AAD; 99mTc-HYNIC; Adult; Animals; Annexin A5; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Apoptosis; Apoptosis - drug effects; AZA; azathioprine; C reactive protein; CD4-Positive T-Lymphocytes - drug effects; CDAI; chimaeric rat anti-mouse control antibody; Cloning; Colitis - chemically induced; Colitis - pathology; Colon; colon uptake ratio; Crohn Disease - diagnostic imaging; Crohn Disease - drug therapy; Crohn Disease - pathology; Crohn's disease; Crohn’s Disease Activity Index; CRP; CUR; cVAM; Disease Models, Animal; FACS; Female; fluorescence-activated cell sorting; Gangrene; Gastrointestinal Agents - pharmacology; Gastrointestinal Agents - therapeutic use; Heart attacks; Humans; Inflammation; Inflammatory bowel disease; Infliximab; Intestinal Mucosa - immunology; lamina propria mononuclear cell; LPMNC; Lymphocytes; mAb; Male; Medical imaging; Mice; Mice, Inbred BALB C; Mice, SCID; Middle Aged; monoclonal antibody; Organotechnetium Compounds; PBS; phosphate-buffered saline; Rheumatoid arthritis; Rodents; SCID; severe combined immunodeficiency; Severity of Illness Index; single-photon emission computer tomography; SPECT; technetium-hydrazinonicotinamide; TNBS; TNF; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; trinitrobenzene sulphonic acid; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-TNF; tumour necrosis factor
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2006.105379

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 Crohńs 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) (p100 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.