Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease.
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.
Hlavaty
T
T
Gastroenterology Unit, University Hospital Gasthuisberg, Leuven, Belgium.
Pierik
M
M
Henckaerts
L
L
Ferrante
M
M
Joossens
S
S
van Schuerbeek
N
N
Noman
M
M
Rutgeerts
P
P
Vermeire
S
S
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
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