Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

Becker, Mara L.; Haandel, Leon van; Gaedigk, Roger; Lasky, Andrew; Hoeltzel, Mark F.; Stobaugh, John F.; Leeder, J. Steven

doi:10.1002/art.27434

Cited by 61 publications

(74 citation statements)

References 23 publications

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“…In approximately 100 JIA patients on stable doses of MTX, RBC MTXGlu 1-7 concentrations and proportions were found to vary 40-100-fold. Dose, route and duration of MTX treatment were clinical variables that contributed to the observed variability, with higher concentrations of long-chain MTXGlu 3-5 in patients dosed subcutaneously, and higher concentrations of short-chain MTXGlu 1+2 observed in patients dosed orally [68]. Although an association with route of administration was noted, there was no association between MTXGlu distribution and active arthritis, in contrast to adult reports [46,65].…”

Section: Predictors Of Variability/ Individualization Of Therapy: Is contrasting

confidence: 70%

Role of methotrexate in juvenile idiopathic arthritis: where we have been and where we are going

Becker¹

2013

International Journal of Clinical Rheumatology

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Section: Predictors Of Variability/ Individualization Of Therapy: Is contrasting

confidence: 70%

Role of methotrexate in juvenile idiopathic arthritis: where we have been and where we are going

Becker¹

2013

International Journal of Clinical Rheumatology

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“…Long-chain MTXGlu concentrations have been associated with improved response in adults with RA (7,8,25), but recently, there have been inconsistencies in the published data (26). In children, we have reported a wide variability in intracellular MTXGlu concentrations in those with JIA, with a strong association between route of administration and MTXGlu chain length (12). To explore factors contributing to this variability and the consequences for clinical response, we herein evaluated the clinical and genetic predictors of MTXGlu patterns, as well as the associations between MTXGlu and outcomes in patients with JIA.…”

Section: Discussionmentioning

confidence: 79%

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

Becker

Gaedigk

Haandel

et al. 2010

Arthritis & Rheumatism

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Objective. The response to and toxicity of methotrexate (MTX) are unpredictable in patients with juvenile idiopathic arthritis (JIA). Intracellular polyglutamation of MTX, assessed by measuring concentrations of MTX polyglutamates (MTXGlu), has been demonstrated to be a promising predictor of drug response. Therefore, this study was aimed at investigating the genetic predictors of MTXGlu variability and associations between MTXGlu and drug response in JIA.Methods. The study was designed as a singlecenter cross-sectional analysis of patients with JIA who were receiving stable doses of MTX at a tertiary care children's hospital. After informed consent was obtained from the 104 patients with JIA, blood was withdrawn during routine MTX-screening laboratory testing. Clinical data were collected by chart review. Genotyping for 34 single-nucleotide polymorphisms (SNPs) in 18 genes within the MTX metabolic pathway was performed. An ion-pair chromatographic procedure with mass spectrometric detection was used to measure MTXGlu 1-7 .Results. Analysis and genotyping of MTXGlu was completed in the 104 patients. K-means clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1 had low red blood cell (RBC) MTXGlu concentrations, cluster 2 had moderately high RBC MTXGlu 1 ؉ 2 concentrations, and cluster 3 had high concentrations of MTXGlu, specifically MTXGlu 3-5 . SNPs in the purine and pyrimidine synthesis pathways, as well as the adenosine pathway, were significantly associated with cluster subtype. The cluster with high concentrations of MTXGlu 3-5 was associated with elevated liver enzyme levels on liver function tests (LFTs), and there were higher concentrations of MTXGlu 3-5 in children who reported gastrointestinal side effects and had abnormal findings on LFTs. No association was noted between MTXGlu and active arthritis.Conclusion. MTXGlu remains a potentially useful tool for determining outcomes in patients with JIA being treated with MTX. The genetic predictors of MTXGlu variability may also contribute to a better understanding of the intracellular biotransformation of MTX in these patients.The response to methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA) is variable, with no identified predictors of response or toxicity (1-3). The mechanism of action of the drug is complex and incompletely understood. However, over the past several decades, we have gained increasing knowledge regarding specific sites of MTX action within the cellular folate cycle. Due to its inhibitory effect on several target enzymes, we know that MTX disrupts the folate cycle, which results in decreased production of DNA precursors, disruption of methyl-dependent reactions, and accumulation of adenosine, the latter of which has antiinflammatory properties (4-6).

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“…The absence of any observed association between long-chain methotrexate polyglutamates levels and improvement in response to methotrexate in the cohort of patients with JRA, seem to indicate that it is important to take into account how individual genetic variability relates to methotrexate polyglutamates concentrations as well as to baseline and adapted folate status, the target of methotrexate treatment [14]. Therefore, considering methotrexate polyglutammates concentrations in the context of the folate pathway may allow, in patients with JRA, optimizing the initial dose of methotrexate on the basis of the folate pathway phenotype [14,108].…”

Section: Pharmacokinetics Of Methotrexatementioning

confidence: 96%

“…In patients with JRA, an association was observed between long chain methotrexate polyglutamates and adverse outcomes, including gastrointestinal side effects and increased occurrence of liver-function test abnormalities [108]; however for patients with JRA, there was no association between the concentration levels of long-chain methotrexate polyglutamates and improved response to methotrexate, association reported in adults with rheumatoid arthritis [100,108]. The absence of any observed association between long-chain methotrexate polyglutamates levels and improvement in response to methotrexate in the cohort of patients with JRA, seem to indicate that it is important to take into account how individual genetic variability relates to methotrexate polyglutamates concentrations as well as to baseline and adapted folate status, the target of methotrexate treatment [14].…”

Section: Pharmacokinetics Of Methotrexatementioning

confidence: 97%

Personalized Therapies in Pediatric Inflammatory and Autoimmune Diseases

Stocco

Iudicibus

Franca

et al. 2012

CPD

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Pediatric inflammatory and autoimmune diseases are a wide array of systemic or organ-specific conditions, characterized by an exaggerated immune reactivity, which generally occurs in immunogenetically predisposed children. Among the most important ones, in terms of their diffusion and morbidity in the population worldwide, pediatric inflammatory bowel disease (IBD) and juvenile rheumatoid arthritis (JRA) have to be considered. The aim of personalized therapy is to give to each patient the most appropriate drug and dose regimen, in order to maximize treatment response and reduce the risk of adverse events. In general, several therapeutic options exist for pediatric inflammatory and autoimmune conditions, therefore the perspective of pharmacological tools that allow identification of patients with increased risk of treatment issues related to a particular medication, in terms of lack of efficacy or increased probability of adverse events, is particularly desirable and promising. The present review will be focused on the personalized therapy approaches already available or in development for pediatric patients with IBD or JRA, comprising pharmacokinetic, pharmacodynamic and pharmacogenetic assays.

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Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

Cited by 61 publications

References 23 publications

Role of methotrexate in juvenile idiopathic arthritis: where we have been and where we are going

Role of methotrexate in juvenile idiopathic arthritis: where we have been and where we are going

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

Personalized Therapies in Pediatric Inflammatory and Autoimmune Diseases

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