Gene Signatures of Early Response to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

Sara Salvador-Martín,Eva Martínez-Ojinaga,Irene Raposo-Gutiérrez,Inés Loverdos,Ana Moreno-Álvarez,Carmen Gallego-Fernández,Rosana Muñoz-Codoceo,Gemma Pujol-Muncunill,Lorena Magallares,Alfonso Solar-Boga,Vicente Merino-Bohórquez,José A Blanca-García,Ruth García-Romero,Ferrán Bossacoma,Víctor Manuel Navas-López,Rafael González De Caldas,Antonio Millán-Jiménez,Óscar Segarra ,C Álvarez Del Vayo ,César Sánchez Sánchez ,Alejandro Rodriguez-Martínez ,Mar Tolín ,Francisco Javier Eizaguirre ,María Sanjurjo‐Sáez ,María José Fobelo ,Luis Andrés López-Fernández

doi:10.3390/ijms21093364

Abstract

Around a 20–30% of inflammatory bowel disease (IBD) patients are diagnosed before they are 18 years old. Anti-TNF drugs can induce and maintain remission in IBD, however, up to 30% of patients do not respond. The aim of the work was to identify markers that would predict an early response to anti-TNF drugs in pediatric patients with IBD. The study population included 43 patients aged <18 years with IBD who started treatment with infliximab or adalimumab. Patients were classified into primary responders (n = 27) and non-responders to anti-TNF therapy (n = 6). Response to treatment could not be analyzed in 10 patients. Response was defined as a decrease in over 15 points in the disease activity indexes from week 0 to week 10 of infliximab treatment or from week 0 to week 26 of adalimumab treatment. The expression profiles of nine genes in total RNA isolated from the whole-blood of pediatric IBD patients taken before biologic administration and after 2 weeks were analyzed using qPCR and the 2−∆∆Ct method. Before initiation and after 2 weeks of treatment the expression of SMAD7 was decreased in patients who were considered as non-responders (p value < 0.05). Changes in expression were also observed for TLR2 at T0 and T2, although that did not reach the level of statistical significance. In addition, the expression of DEFA5 decreased 1.75-fold during the first 2 weeks of anti-TNF treatment in responders, whereas no changes were observed in non-responders. Expression of the SMAD7 gene is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD. TLR2 and DEFA5 need to be validated in larger studies.

Highlights

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is an autoimmune disorder whose pathogenesis genetics and environmental factors play a key role [1,2]
The anti-TNF agents infliximab and adalimumab have revolutionized the treatment of autoimmune diseases, a significant percentage of patients do not respond to this therapy [8]
The genetics of Pediatric IBD (pIBD) differs from adult inflammatory bowel disease (IBD) highlighting the relevance for finding specific biomarkers for children

Summary

Introduction

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is an autoimmune disorder whose pathogenesis genetics and environmental factors play a key role [1,2]. Pediatric IBD (pIBD) is associated with more extensive disease and a more complicated course than adult-onset IBD [3]. These characteristics and the fact that children have to live longer with the existing therapy underline the need for optimization of treatments of pIBD. Biological therapy, mainly anti-TNF agents, has revolutionized the treatment of IBD and other inflammatory diseases. The phenotype of pIBD usually leads to earlier use of biological therapy in children [4]. After 10 weeks of treatment with infliximab in children with moderate-to-severe CD, 11.6% did not respond and 41.1% did not achieve clinical remission [5]. Other biological drugs approved in adults, such as vedolizumab (anti-integrin α4β7) or ustekimumab (an anti-IL-23), are used off-label in children when treatment with infliximab and adalimumab fails [6]

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