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Prediction of anti-TNF clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease
  1. Jan M.H. Van den Brande (j.vandenbrande{at}amc.uva.nl)
  1. Academic Medical Center Amsterdam, Netherlands
    1. Tamara Koehler (t.c.koehler{at}amc.uva.nl)
    1. Academic Medical Center Amsterdam, Netherlands
      1. Zuzana Zelinkova (z.zelinkova{at}amc.uva.nl)
      1. Academic Medical Center Amsterdam, Netherlands
        1. Roelof J Bennink (r.bennink{at}amc.uva.nl)
        1. Academic Medical Center Amsterdam, Netherlands
          1. Anje A te Velde (a.a.tevelde{at}amc.uva.nl)
          1. Academic Medical Center Amsterdam, Netherlands
            1. Fibo Ten Kate (f.j.tenkate{at}amc.uva.nl)
            1. Academic Medical Center Amsterdam, Netherlands
              1. Sander J van Deventer (s.j.vandeventer{at}amc.uva.nl)
              1. Academic Medical Center Amsterdam, Netherlands
                1. Maikel P Peppelenbosch (m.peppelenbosch{at}med.umcg.nl)
                1. Academic Medical Center Amsterdam, Netherlands
                  1. Daan W Hommes (d.w.hommes{at}lumc.nl)
                  1. Academic Medical Center Amsterdam, Netherlands

                    Abstract

                    Background & Aims: The human anti-TNF antibody infliximab binds to membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes from Crohn's disease patients in vitro. We tested if rapid anti-TNF-induced apoptosis in the gut may predict efficacy of anti-TNF therapy in inflammatory bowel disease.

                    Methods: 99mTc-annexin V single photon emission computer tomography (SPECT) was performed in two models of murine experimental colitis and 14 patients with active Crohn's disease as assessed by the Crohn's Disease Activity Index (CDAI) to study the effect of anti-TNF therapy on apoptosis in the intestine during active colitis. Disease activity was evaluated two weeks after infliximab infusion using the CDAI (definition response: drop of > 100 points).

                    Results: Colonic uptake of 99mTc-annexin V significantly increased in TNBS as well as in transfer colitis upon administration of anti-TNF antibodies compared to a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of 99mTc-annexin V significantly increased in active Crohn's disease patients responding to infliximab therapy. Colonic 99mTc-annexin V Uptake Ratio increased from 0.24 (+/- 0.03) to 0.41(+/-0.07) (P<0,01) 24 hours after infliximab (5 mg/kg). A mean increase of 98.7% in colonic uptake of 99mTc-annexin V could be detected in 10 of 14 responding patients (CDAI > 100 points at week 2) compared to 15.2% in non-responding patients (P=0,03). Analysis of mucosal biopsies 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 therapy and might be predictive of therapeutic success.

                    • Crohn's disease
                    • SPECT
                    • annexin V
                    • anti-TNF infliximab
                    • apoptosis

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