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

Jan M. H. Van den Brande; Tamara C. Koehler; Zuzana Zelinkova; Roelof J. Bennink; Anje A. te Velde; Fibo J. W. ten Cate; Sander J. H. van Deventer; Maikel P. Peppelenbosch; Daniel W. Hommes

doi:10.1136/gut.2006.105379

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

Jan M. H. Van den Brande^*
, Tamara C. Koehler
, Zuzana Zelinkova
, Roelof J. Bennink
, Anje A. te Velde
, Fibo J. W. ten Cate
, Sander J. H. van Deventer
, Maikel P. Peppelenbosch
, Daniel W. Hommes

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

165 Citations (Scopus)

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: (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 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 Tc-99m-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 T-99m-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.

Original language	English
Pages (from-to)	509-517
Number of pages	9
Journal	Gut
Volume	56
Issue number	4
DOIs	https://doi.org/10.1136/gut.2006.105379
Publication status	Published - Apr-2007

Keywords

CHIMERIC MONOCLONAL-ANTIBODY
RADIOLABELED ANNEXIN-V
INFLIXIMAB INDUCES APOPTOSIS
CASPASE-DEPENDENT PATHWAY
PROPRIA T-LYMPHOCYTES
IN-VIVO DETECTION
FACTOR-ALPHA CA2
TNF-ALPHA
RHEUMATOID-ARTHRITIS
CELL-DEATH

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Van den Brande, J. M. H., Koehler, T. C., Zelinkova, Z., Bennink, R. J., Velde, A. A. T., ten Cate, F. J. W., van Deventer, S. J. H., Peppelenbosch, M. P., & Hommes, D. W. (2007). Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease. Gut, 56(4), 509-517. https://doi.org/10.1136/gut.2006.105379

@article{58f3eefa10af4271ad1ac19ceed6c628,

title = "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: (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 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 Tc-99m-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 T-99m-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.",

keywords = "CHIMERIC MONOCLONAL-ANTIBODY, RADIOLABELED ANNEXIN-V, INFLIXIMAB INDUCES APOPTOSIS, CASPASE-DEPENDENT PATHWAY, PROPRIA T-LYMPHOCYTES, IN-VIVO DETECTION, FACTOR-ALPHA CA2, TNF-ALPHA, RHEUMATOID-ARTHRITIS, CELL-DEATH",

author = "\{Van den Brande\}, \{Jan M. H.\} and Koehler, \{Tamara C.\} and Zuzana Zelinkova and Bennink, \{Roelof J.\} and Velde, \{Anje A. te\} and \{ten Cate\}, \{Fibo J. W.\} and \{van Deventer\}, \{Sander J. H.\} and Peppelenbosch, \{Maikel P.\} and Hommes, \{Daniel W.\}",

year = "2007",

month = apr,

doi = "10.1136/gut.2006.105379",

language = "English",

volume = "56",

pages = "509--517",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "4",

}

TY - JOUR

T1 - Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease

AU - Van den Brande, Jan M. H.

AU - Koehler, Tamara C.

AU - Zelinkova, Zuzana

AU - Bennink, Roelof J.

AU - Velde, Anje A. te

AU - ten Cate, Fibo J. W.

AU - van Deventer, Sander J. H.

AU - Peppelenbosch, Maikel P.

AU - Hommes, Daniel W.

PY - 2007/4

Y1 - 2007/4

N2 - 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: (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 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 Tc-99m-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 T-99m-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.

AB - 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: (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 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 Tc-99m-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 T-99m-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.

KW - CHIMERIC MONOCLONAL-ANTIBODY

KW - RADIOLABELED ANNEXIN-V

KW - INFLIXIMAB INDUCES APOPTOSIS

KW - CASPASE-DEPENDENT PATHWAY

KW - PROPRIA T-LYMPHOCYTES

KW - IN-VIVO DETECTION

KW - FACTOR-ALPHA CA2

KW - TNF-ALPHA

KW - RHEUMATOID-ARTHRITIS

KW - CELL-DEATH

U2 - 10.1136/gut.2006.105379

DO - 10.1136/gut.2006.105379

M3 - Article

SN - 0017-5749

VL - 56

SP - 509

EP - 517

JO - Gut

JF - Gut

IS - 4

ER -

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

Abstract

Keywords

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