title: Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease.
abstract: BACKGROUND
  Infliximab treatment is effective in 70-80% of patients with refractory luminal and fistulizing Crohn's disease. The effect of infliximab is ascribed to induction of apoptosis.
  
  
  OBJECTIVE
  To study whether polymorphisms in apoptosis genes predict the response to infliximab and whether they interact with clinical predictors.
  
  
  METHODS
  Cohort of 287 consecutive patients treated with infliximab for refractory luminal (n = 204) or fistulizing (n = 83) Crohn's disease was genotyped for 21 polymorphisms in apoptosis genes. Short-term clinical response was assessed at week 4 (luminal Crohn's disease) or 10 (fistulizing Crohn's disease) after the first infliximab infusion.
  
  
  RESULTS
  The response rate was 69% in luminal and 80% in fistulizing Crohn's disease. In luminal Crohn's disease, two genetic predictors were identified: (i) patients with the Fas ligand -843 CC/CT genotype (n = 135) responded in 75%, with the TT genotype (n = 21) in 38% only (P = 0.002; OR = 0.11; 95% CI: 0.08-0.56). (ii) Patients with the caspase-9 93 TT (n = 9) genotype all responded, in contrast with 67% (n = 147) with the CC and CT genotype (P = 0.04; OR = 1.50; 95% CI: 1.34-1.68). Concomitant azathioprine/mercaptopurine therapy overcame the effect of unfavourable genotypes. In the fistulizing Crohn's disease cohort, the same Fas ligand -843 CC/CT genotype was the only predictor of response (P = 0.002; OR = 1.66; 95% CI: 1.21-2.29), interacting with caspase-9 93 polymorphism but not with azathioprine/mercaptopurine.
  
  
  CONCLUSIONS
  We observed that polymorphisms in FasL/Fas system and caspase-9 influence the response to infliximab in luminal and fistulizing Crohn's disease. The strongest association was seen between the Fas ligand -843 TT genotype and non-response. Concomitant mercaptopurine/azathioprine therapy, however, was able to overcome the effect of unfavourable genotypes in luminal disease.
authors.affiliation: Gastroenterology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Hlavaty
authors.forename: M
authors.initials: M
authors.lastname: Pierik
authors.forename: L
authors.initials: L
authors.lastname: Henckaerts
authors.forename: M
authors.initials: M
authors.lastname: Ferrante
authors.forename: S
authors.initials: S
authors.lastname: Joossens
authors.forename: N
authors.initials: N
authors.lastname: van Schuerbeek
authors.forename: M
authors.initials: M
authors.lastname: Noman
authors.forename: P
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: S
authors.initials: S
authors.lastname: Vermeire
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D053453:Caspase 9; D020169:Caspases / Q000235:genetics; D002648:Child; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics*; D053222:Fas Ligand Protein; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D000069285:Infliximab; D007412:Intestinal Fistula / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D048069:Tumor Necrosis Factors / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005765:Gastrointestinal Agents; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D000069285:Infliximab; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases