Genetic predictors of long-term response and trough levels of infliximab in crohn's disease. (November 2019)

• Record Type: Journal Article
• Authors: Salvador-Martín, Sara; López-Cauce, Beatriz; Nuñez, Olga; Laserna-Mendieta, Emilio J.; García, María I.; Lobato, Elena; Abarca-Zabalía, Judith; Sanjurjo-Saez, María; Lucendo, Alfredo J.; Marín-Jiménez, Ignacio; Menchén, Luis A.; López-Fernández, Luis A.
• Is Part Of: Pharmacological research. Volume 149(2019)
• Publication Date: 2019-11
• Subjects: Pharmacogenetics -- Tumor necrosis factor-alpha -- Infliximab -- anti-TNF -- Drug monitoring; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104478
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.