Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease

Abstract

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. To study whether polymorphisms in apoptosis genes predict the response to infliximab and whether they interact with clinical predictors. 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. 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. 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.