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


OBJECTIVE
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
(99m)Technetium-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 (99m)Tc-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 (99m)Tc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic (99m)Tc-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 (99m)Tc-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 (99m)Tc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.
Van den Brande
Jan M H
JM
Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.vandenbrande@amc.uva.nl
Koehler
Tamara C
TC
Zelinkova
Zuzana
Z
Bennink
Roelof J
RJ
te Velde
Anje A
AA
ten Cate
Fibo J W
FJ
van Deventer
Sander J H
SJ
Peppelenbosch
Maikel P
MP
Hommes
Daniël W
DW
D000328:Adult; D000818:Animals; D017304:Annexin A5; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D003424:Crohn Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008875:Middle Aged; D015609:Organotechnetium Compounds; D012720:Severity of Illness Index; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D017304:Annexin A5; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D015609:Organotechnetium Compounds; D014409:Tumor Necrosis Factor-alpha; C417036:technetium Tc 99m annexin V; D014302:Trinitrobenzenesulfonic Acid; D000069285:Infliximab