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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.

Publication ,  Journal Article
Becker, ML; van Haandel, L; Gaedigk, R; Lasky, A; Hoeltzel, M; Stobaugh, J; Leeder, JS
Published in: Arthritis Rheum
June 2010

OBJECTIVE: Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. METHODS: Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. RESULTS: Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). CONCLUSION: In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5).

Duke Scholars

Published In

Arthritis Rheum

DOI

EISSN

1529-0131

Publication Date

June 2010

Volume

62

Issue

6

Start / End Page

1803 / 1812

Location

United States

Related Subject Headings

  • Severity of Illness Index
  • Polyglutamic Acid
  • Patient Selection
  • Methotrexate
  • Infant
  • Humans
  • Drug Administration Routes
  • Cluster Analysis
  • Chromatography, Reverse-Phase
  • Child, Preschool
 

Citation

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Chicago
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MLA
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Becker, M. L., van Haandel, L., Gaedigk, R., Lasky, A., Hoeltzel, M., Stobaugh, J., & Leeder, J. S. (2010). Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations. Arthritis Rheum, 62(6), 1803–1812. https://doi.org/10.1002/art.27434
Becker, Mara L., Leon van Haandel, Roger Gaedigk, Andrew Lasky, Mark Hoeltzel, John Stobaugh, and J Steven Leeder. “Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations.Arthritis Rheum 62, no. 6 (June 2010): 1803–12. https://doi.org/10.1002/art.27434.
Journal cover image

Published In

Arthritis Rheum

DOI

EISSN

1529-0131

Publication Date

June 2010

Volume

62

Issue

6

Start / End Page

1803 / 1812

Location

United States

Related Subject Headings

  • Severity of Illness Index
  • Polyglutamic Acid
  • Patient Selection
  • Methotrexate
  • Infant
  • Humans
  • Drug Administration Routes
  • Cluster Analysis
  • Chromatography, Reverse-Phase
  • Child, Preschool