Sara Salvador-Martín1, Beatriz López-Cauce2, Olga Nuñez2, Emilio J Laserna-Mendieta3, María I García1, Elena Lobato1, Judith Abarca-Zabalía1, María Sanjurjo-Saez1, Alfredo J Lucendo4, Ignacio Marín-Jiménez5, Luis A Menchén5, Luis A López-Fernández6. 1. Department of Pharmacy, Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. 2. Department of Gastroenterology, Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. 3. Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain. 4. Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain; Biomedical Research Network Center for liver and Digestive Diseases (CIBEREHD), Madrid, Spain. 5. Department of Gastroenterology, Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Biomedical Research Network Center for liver and Digestive Diseases (CIBEREHD), Madrid, Spain. 6. Department of Pharmacy, Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Spanish Clinical Research Network (SCReN), Spain. Electronic address: Luis.lopez@iisgm.com.
Abstract
INTRODUCTION: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment. OBJECTIVE: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease. PATIENTS AND METHODS: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7 μg/mL) or infratherapeutic (<3 μg/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test. RESULTS: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], p < 0.05; HR, 0.39 [95%CI, 0.18-0.88], p < 0.05; and HR, 0.04 [95%CI, 0.18-0.92] p > 0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505 T was associated with infratherapeutic levels (p < 0.05). CONCLUSION: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab.
INTRODUCTION: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment. OBJECTIVE: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease. PATIENTS AND METHODS: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7 μg/mL) or infratherapeutic (<3 μg/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test. RESULTS: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], p < 0.05; HR, 0.39 [95%CI, 0.18-0.88], p < 0.05; and HR, 0.04 [95%CI, 0.18-0.92] p > 0.05, respectively). In addition, IL6rs10499563 C and IL10rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10rs3024505 T was associated with infratherapeutic levels (p < 0.05). CONCLUSION: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab.
Authors: Sara Salvador-Martín; Irene Raposo-Gutiérrez; Víctor Manuel Navas-López; Carmen Gallego-Fernández; Ana Moreno-Álvarez; Alfonso Solar-Boga; Rosana Muñoz-Codoceo; Lorena Magallares; Eva Martínez-Ojinaga; María J Fobelo; Antonio Millán-Jiménez; Alejandro Rodriguez-Martinez; Concepción A Vayo; Cesar Sánchez; Mar Tolin; Ferrán Bossacoma; Gemma Pujol-Muncunill; Rafael González de Caldas; Inés Loverdos; José A Blanca-García; Oscar Segarra; Francisco J Eizaguirre; Ruth García-Romero; Vicente Merino-Bohórquez; María Sanjurjo-Sáez; Luis A López-Fernández Journal: Int J Mol Sci Date: 2020-05-09 Impact factor: 5.923