Genetic predictors of long-term response and trough levels of infliximab in crohn's disease.
Pharmacol Res
; 149: 104478, 2019 11.
Article
in En
| MEDLINE
| ID: mdl-31605784
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 ANDMETHODS:
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⯵g/mL) or infratherapeutic (<3⯵g/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], pâ¯<â¯0.05; HR, 0.39 [95%CI, 0.18-0.88], pâ¯<â¯0.05; and HR, 0.04 [95%CI, 0.18-0.92] pâ¯>â¯0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505â¯T was associated with infratherapeutic levels (pâ¯<â¯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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gastrointestinal Agents
/
Crohn Disease
/
Polymorphism, Single Nucleotide
/
Infliximab
Type of study:
Diagnostic_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adolescent
/
Adult
/
Aged
/
Child
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Pharmacol Res
Journal subject:
FARMACOLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Spain