The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response

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The effect of genotype on methotrexate polyglutamate variability in juvenile

idiopathic arthritis and association with drug response

http://onlinelibrary.wiley.com/doi/10.1002/art.30080/abstract

Abstract

Objective:

Response and toxicity to methotrexate (MTX) are unpredictable in Juvenile

Idiopathic Arthritis (JIA). Intracellular MTX polyglutamates (MTXGlu) have

shown promise as a predictor of drug response. We investigated genetic

predictors of MTXGlu variability and associations between MTXGlu and drug

response in JIA.

Methods:

This is a single center cross-sectional study evaluating JIA patients on

stable doses of MTX at a tertiary care children's hospital. After obtaining

informed consent, blood was drawn from 104 JIA patients during routine MTX

screening labs. Clinical data was collected by chart review. Genotyping for

34 SNPs in 18 genes within the MTX metabolic pathway was performed. An

ion-pairing chromatographic procedure with mass spectrometric detection

measured MTXGlu1-7.

Results:

MTXGlu analysis and genotyping was completed in 104 patients. K-means

clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1

had low RBC MTXGlu concentrations, cluster 2 had moderately high RBC

MTXGlu1+2 concentrations, and cluster 3 had high concentrations of MTXGlu,

specifically MTXglu3-5. SNPs in the purine and pyrimidine synthesis pathway,

as well as the adenosine pathway were significantly associated with cluster

subtype. The cluster with high concentrations of MTXGlu3-5 was associated

with elevated liver function studies (LFTs), and there were higher

concentrations of MTXGlu3-5 in children who reported GI side effects and LFT

elevation. No association was noted between MTXGlu and active arthritis.

Conclusions:

MTXGlu remains a potentially useful tool for determining outcomes of JIA

patients on MTX. The genetic predictors of MTXGlu variability may also

contribute to the better understanding of MTX intracellular

biotransformation.