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Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn's disease
Author(s) -
HLAVATY T.,
PIERIK M.,
HENCKAERTS L.,
FERRANTE M.,
JOOSSENS S.,
SCHUERBEEK N.,
NOMAN M.,
RUTGEERTS P.,
VERMEIRE S.
Publication year - 2005
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/j.1365-2036.2005.02635.x
Subject(s) - infliximab , medicine , gastroenterology , genotype , crohn's disease , azathioprine , concomitant , disease , mercaptopurine , refractory (planetary science) , cohort , fas ligand , immunology , apoptosis , gene , biology , biochemistry , programmed cell death , astrobiology
Summary 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. Aim : 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. Conclusion : 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.