Response to Infliximab in Crohn's Disease: Genetic Analysis Supporting Expression Profile.

Luz María Medrano,Antonio López-Sanromán,Juan Luis Mendoza,Carlos Taxonera,José L Pérez-Calle,Elena Urcelay,María Gómez-García,Manuel Barreiro-De Acosta,Concepción Núñez,Virginia Pascual,Dolores Martín Arranz,Fernando Bermejo,Javier P Gisbert,Javier Martín,Cristina González-Artacho

doi:10.1155/2015/318207

Abstract

Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276*G/rs3014866*C/rs724781*C/rs3006488*A; P = 0.05); G0S2 (rs4844486*A/rs1473683*T; P = 0.15); TNFAIP6 (rs11677200*C/rs2342910*A/rs3755480*G/rs10432475*A; P = 0.10); and IL11 (rs1126760*C/rs1042506*G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

Highlights

Crohn’s disease (CD) is one of the clinical forms of inflammatory bowel disease (IBD) resulting from a defective regulation of mucosal immune responses to commensal microbiota in genetically susceptible individuals [1]
Since 1998, when the US Food and Drug Administration approved infliximab (IFX) for treatment of moderate or severe CD that does not respond to a conservative treatment, monoclonal antibodies to tumor necrosis factor alpha (TNF-α) have become the hallmark treatment for refractory CD
One haplotype in the IL11 region showed a marginal significant association with the response to the anti-TNF treatment (P = 0.068; Odds ratios (ORs) = 1.72 (0.91–3.21)), and trends for association could be observed for haplotypes within the other two chromosomal regions explored (G0S2: P = 0.15; OR = 2.92 (0.45– 15.23) and TNFAIP6: P = 0.10; OR = 0.71 (0.46– 1.09))

Summary

Introduction

Crohn’s disease (CD) is one of the clinical forms of inflammatory bowel disease (IBD) resulting from a defective regulation of mucosal immune responses to commensal microbiota in genetically susceptible individuals [1]. A lack of response or a partial response to IFX has been consistently observed and a growing need exists to identify biomarkers of response in order to achieve a more efficacious use of this expensive and potentially toxic therapy. Data from clinical trials of IFX suggest that high-risk patients and patients with active inflammation may benefit from earlier use of this drug [5]. Clinical parameters such as concurrent therapies, smoking habits, or previous surgery seem to account for only a small amount of the variance in response to anti-TNF therapies [6]

Objectives

Methods

Results

Conclusion