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Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate.

Publication ,  Journal Article
Funk, RS; van Haandel, L; Leeder, JS; Becker, ML
Published in: Arthritis Rheumatol
December 2014

OBJECTIVE: Folates exist as a fluctuating pool of polyglutamated metabolites that may serve as a clinical marker of methotrexate (MTX) activity. This study was undertaken to evaluate circulating folate content and folate polyglutamate distribution in juvenile idiopathic arthritis (JIA) patients and in a cell culture model based on MTX exposure and folate supply. METHODS: Blood, plasma, and red blood cell (RBC) measurements of MTX and folates were obtained from previously published data sets and an additional analysis of JIA patients receiving MTX (n = 98) and those not receiving MTX (n = 78). Erythroblastoid cells maintained in culture were exposed to MTX and grown under varying levels of folic acid supplementation. Samples were analyzed for cellular folate and MTX content. RESULTS: Circulating folate levels were lower in JIA patients receiving MTX, with reduced levels of blood, plasma, and RBC 5-methyl-tetrahydrofolate (5mTHF) (P < 0.0001). Average polyglutamate chain length (Gluavg ) of RBC 5mTHF was elevated in JIA patients receiving MTX (median ± interquartile range 5.63 ± 0.15 versus 5.54 ± 0.11 in those not receiving MTX; P < 0.001) and correlated with both RBC MTX accumulation (P = 0.02) and reduced plasma 5mTHF levels (P = 0.008). MTX exposure and folate deprivation in erythroblastoid cells resulted in a depletion of bioactive folate species that was associated with a shift to higher Gluavg values for several species, most notably tetrahydrofolate (THF) and 5,10-methylene-tetrahydrofolate (CH2 THF). Increased Gluavg resulted from the depletion of short-chain and the accumulation of long-chain glutamate species. CONCLUSION: Our findings indicate that folate content and polyglutamate distribution are responsive markers of MTX activity and folate supply in vivo and in vitro, and may provide novel clinical markers of pharmacologic activity of MTX.

Duke Scholars

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Published In

Arthritis Rheumatol

DOI

EISSN

2326-5205

Publication Date

December 2014

Volume

66

Issue

12

Start / End Page

3476 / 3485

Location

United States

Related Subject Headings

  • Tetrahydrofolates
  • Pteroylpolyglutamic Acids
  • Methotrexate
  • Male
  • Humans
  • Folic Acid
  • Female
  • Erythrocytes
  • Child, Preschool
  • Child
 

Citation

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Chicago
ICMJE
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Funk, R. S., van Haandel, L., Leeder, J. S., & Becker, M. L. (2014). Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate. Arthritis Rheumatol, 66(12), 3476–3485. https://doi.org/10.1002/art.38865
Funk, Ryan S., Leon van Haandel, J Steven Leeder, and Mara L. Becker. “Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate.Arthritis Rheumatol 66, no. 12 (December 2014): 3476–85. https://doi.org/10.1002/art.38865.
Funk RS, van Haandel L, Leeder JS, Becker ML. Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate. Arthritis Rheumatol. 2014 Dec;66(12):3476–85.
Funk, Ryan S., et al. “Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate.Arthritis Rheumatol, vol. 66, no. 12, Dec. 2014, pp. 3476–85. Pubmed, doi:10.1002/art.38865.
Funk RS, van Haandel L, Leeder JS, Becker ML. Folate depletion and increased glutamation in juvenile idiopathic arthritis patients treated with methotrexate. Arthritis Rheumatol. 2014 Dec;66(12):3476–3485.
Journal cover image

Published In

Arthritis Rheumatol

DOI

EISSN

2326-5205

Publication Date

December 2014

Volume

66

Issue

12

Start / End Page

3476 / 3485

Location

United States

Related Subject Headings

  • Tetrahydrofolates
  • Pteroylpolyglutamic Acids
  • Methotrexate
  • Male
  • Humans
  • Folic Acid
  • Female
  • Erythrocytes
  • Child, Preschool
  • Child