Genetic predictors of long-term response and trough levels of infliximab in crohn’s disease

• Published in: Pharmacological research Vol. 149; p. 104478
• Main 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.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-11-2019
• Subjects: anti-TNF; Drug monitoring; Infliximab; Pharmacogenetics; Tumor necrosis factor-alpha; Pharmacogenetics; Tumor necrosis factor-alpha; Drug monitoring; Infliximab; anti-TNF
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2019.104478

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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.
To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn’s disease.
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.
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).
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.