Pharmacogenetics of infliximab in Crohn's disease: 5q31/Haplotype predicts response

Abstract

BACKGROUND: Infliximab is effective in two thirds of patients with Crohn's disease (CD) who do not respond to standard therapy. Inherited variants in genes regulating tumour necrosis factor (TNF) expression, metabolism or signal transduction might influence therapeutic response, Aims: To assess genetic and phenotypic predictors of response to infliximab. METHODS: We obtained genotypes for polymorphisms in LTA (A720C, C365G and G249A), the TNF promoter (T1031C, C863A, C857A, G308A G238A), TNFR1 G201A, TG230A, G845A, G839A, Cl 135T), TNFR2 (A1663G, T1668G, C1690T, ex-6 T676G), TACE (G2928A) and IBD5 (IGR2060al) in 144 patients with Crohn's disease from a single Belgian centre. This comprised both refractory Crohn's (RD) and fistulating disease (FD). A positive response was defined as fall in CDAI >70 or a post-treatment CDAI of <150 in RD and closure of more than 50% of the fistula in FD. RESULTS: Overall positive response rate of 77.1% to infliximab was observed. Patients who carried the IBD5 risk haplotype were significantly less likely to respond than non-carriers (72.1 % vs. 90.0%; P=0.02). As previously reported in this cohort, the minor-308 allele predicted a poor response (Vermeire Set at Gastroenterology Suppl 2000; 118: A654). No other polymorphism in genes regulating TNF expression, metabolism, signal transduction or LTA predicted response to infliximab. CONCLUSION: Non-possession of the IBD5/5q31 risk haplotype predicted a good response to infliximab. This might prove a clinically useful parameter to predict response, but this finding first requires confirmation in an independent cohort.