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See detailPredictors of severe Crohn's disease
Loly, Catherine ULg; Belaiche, Jacques ULg; Louis, Edouard ULg

in Scandinavian Journal of Gastroenterology (2008), 43(8), 948-54

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See detailSensitivity of intestinal fibroblasts to TNF-related apoptosis-inducing ligand-mediated apoptosis in Crohn's disease
Reenaers, Catherine ULg; Franchimont, Nathalie; Oury, Cécile ULg et al

in Scandinavian Journal of Gastroenterology (2008), 43

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See detailA positive response to infliximab in Crohn disease: Association with a higher systemic inflammation before treatment but not with-308 TNF gene polymorphism
Louis, Edouard ULg; Vermeire, S.; Rutgeerts, P. et al

in Scandinavian Journal of Gastroenterology (2002), 37(7), 818-824

Background: Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over ... [more ▼]

Background: Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over time. Biological characteristics and/or genetic background can influence the response to treatment. The aim was to assess the value of C-reactive protein and TNF-alpha serum levels before treatment as well as the TNF -308 gene polymorphism in the prediction of response to infliximab treatment in Crohn disease. Methods: Two-hundred-and-twenty-six Crohn disease patients treated in the setting of an expanded access programme to infliximab in Belgium were studied. There were 136 refractory luminal diseases and 90 refractory fistulizing diseases. Luminal diseases were treated with one single infusion; fistulizing diseases with three infusions at weeks 0, 2 and 6. A clinical response to treatment was defined as either a Crohn disease activity index <150 (complete) or a drop of 70 points (partial) at week 4, for luminal disease, and as either complete fistula healing (complete) or a decrease of at least 50% of the number of draining fistulas on two consecutive visits between weeks 0 and 18, for fistulizing disease. CRP and serum TNF-α levels were measured at week 0 before treatment and were compared between responders and non- responders. Patients were genotyped for the -308 TNF gene polymorphism, and allelic as well as genotype frequencies were compared between responders and non- responders. Results: There were 73.2% responders (46.4% complete and 26.8% partial) and 26.8% non- responders. Response rates were similar in luminal and fistulizing diseases. CRP level before treatment was significantly higher in responders than in non-responders (16.8 mg/l (5-160) versus 9.6 mg/l (5-143); P = 0.02). Furthermore, response rate was significantly higher in patients with elevated CRP (> 5 mg/l) than in patients with a normal CRP value (< 5 mg/l) before treatment (76% versus 46%; P = 0.004; OR: 0.26 (0.11-0.63)). Allelic and genotype frequencies for -308 TNF gene polymorphis m were not significantly different between responders and non- responders - with the exception of a slightly higher TNF2 frequency in nonresponders in luminal disease (22.1% versus 11.6%; P = 0.04). However, this was not associated with a significant difference in genotype frequencies. Conclusion: A positive clinical response to infliximab was associated with a higher CRP level before treatment in our population of Crohn disease patients, but there was no relevant association with -308 TNF gene polymorphism. We therefore suggest that CRP level may help to identify better candidates for infliximab treatment. [less ▲]

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See detailIncreased Response of Blood Eosinophils to Various Chemotactic Agents in Quiescent Crohn Disease
Denis, M. A.; Louis, Renaud ULg; Malaise, Michel ULg et al

in Scandinavian Journal of Gastroenterology (2001), 36(2), 190-5

BACKGROUND: The number of eosinophils is increased in the mucosae of the digestive and the respiratory tracts in Crohn disease, even clinically quiescent. The mechanisms underlying this panmucosal ... [more ▼]

BACKGROUND: The number of eosinophils is increased in the mucosae of the digestive and the respiratory tracts in Crohn disease, even clinically quiescent. The mechanisms underlying this panmucosal eosinophilia are unknown. METHODS: The response of blood eosinophils to various chemotactic agents was assessed in 15 patients with clinically quiescent Crohn disease. The results were compared with 15 healthy controls. After purification, eosinophils were placed in Boyden microchambers and the chemotactic effect of PAF (10(-7) M), RANTES (50 ng/ml), IL-5 (0-20 ng/ml), IL-8 (0-50 ng/ml), Eotaxin (0-50 ng/ml) was evaluated. The number of eosinophils in induced sputum of these Crohn disease patients and controls was also assessed and the correlation between chemotaxis and eosinophil count in induced sputum was studied. RESULTS: PAF and RANTES induced a chemotactic effect both in Crohn disease patients and controls. The chemotactic index was significantly higher in Crohn than controls for PAF (2.09+/-0.24 versus 1.37+/-0.14; P < 0.05) but not RANTES. With IL-5, IL-8 and Eotaxin, there was no detectable chemotactic effect in controls while in Crohn, we observed a significant dose-dependent chemotactic effect. Furthermore, with Eotaxin 50 ng/ml, the chemotactic index was significantly higher in Crohn disease patients than controls (2.42+/-0.18 versus 1.56+/-0.28; P < 0.05). A significant increase in sputum eosinophil count and a significant decrease in sputum macrophage count in Crohn disease were observed. However, there was no correlation between eosinophil chemotaxis and sputum eosinophil count in individual patients. CONCLUSION: There is an increased response of blood eosinophils to various chemotactic agents, mainly PAF and Eotaxin, in clinically quiescent Crohn disease. This may participate in the mucosal infiltration by eosinophils in this disease. [less ▲]

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See detailTherapeutic Drug Monitoring of Azathioprine and 6-Mercaptopurine Metabolites in Crohn Disease
Belaiche, Jacques ULg; Desager, J. P.; Horsmans, Y. et al

in Scandinavian Journal of Gastroenterology (2001), 36(1), 71-6

BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the ... [more ▼]

BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and haematological parameters. METHODS: Twenty-eight CD patients treated for at least 3 months with AZA/6-MP were prospectively studied. Patients were separated into three main groups: group 1 (n = 19), corresponding to quiescent CD receiving AZA (dose: 2.05 +/- 0.4 mg/kg/day for a mean of 28.6 +/- 25 months) or 6-MP (dose: 1.4 +/- 01 mg/kg/day for a mean of 7.5 +/- 3.5 months) alone; group 2 (n = 6), corresponding to quiescent CD treated by AZA (dose: 2.14 +/- 0.5 mg/kg/day for a mean of 29.5 +/- 22 months) with oral steroids; and group 3 (n = 3), corresponding to active CD on AZA (dose: 1.94 +/- 0.6 mg/kg/day for a mean of 31.3 +/- 35 months) as the only treatment. An assessment was also made by merging groups 1 and 2 forming a larger group of patients (n = 25) defined by clinical remission and groups 2 and 3 forming a larger group of patients (n = 9), non-complete responders with AZA/6-MP alone. Crohn disease index activity (CDAI), blood samples for full blood count and differential white cell count and measurement of RBC 6TGN and 6-MMP concentrations were evaluated at inclusion and at 6 months (n = 17). RBC 6TGN were measured using high performance liquid chromatography (HPLC) on heparinized blood. RESULTS: The baseline characteristics of the three groups of patients were similar. There was no significant difference among the three groups of patients regarding the dose and the duration of immunosuppressive treatment. There was no significant difference between groups according to various parameters tested. Particularly, the median RBC 6TGN concentration at inclusion was similar in the three groups of patients (166 (105-688), 183 (90-261) and 160 (52-194) pmol/8 x 10(8) RBC, respectively). The majority of patients had no detectable level of 6-MMP metabolite, except for 3 patients. There was also no difference between merging groups. Furthermore, there was no significant correlation between RBC 6TGN concentrations and the various biological parameters tested except for the mean erythrocyte volume. At 6 months, all patients of group 1 remained in remission and median RBC 6TGN concentration remained stable. No side effects were observed. CONCLUSIONS: There is, contrary to preliminary studies, a broad overlap in RBC 6TGN levels as well as for haematological parameters in patients in remission or not and responders or not to AZA/6-MP therapy. This suggests, beside a variability in the metabolism of these drugs, the existence of complex mechanisms of action. Nevertheless, beside the use of RBC 6TGN determination to confirm compliance to therapy, this dosage could be useful in non-responding patients, allowing, in absence of leukopenia, to increase the dose of AZA/6-MP safely. [less ▲]

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