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Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular

Chang Xu1, Jacob Selhub2, Paul Jacques2

  • 1Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital, Boston, MA, USA.

Rheumatology (Oxford, England)
|June 18, 2021
PubMed
Abstract

Insights

Higher levels of methotrexate polyglutamates (MTX-PGs) correlate with increased risks of anemia and liver issues, but a decreased risk of thrombocytopenia in patients on low-dose methotrexate (LD-MTX). This finding aids in understanding LD-MTX adverse effects.

Area of Science:

  • Pharmacology
  • Clinical Medicine
  • Toxicology

Background:

  • Low-dose methotrexate (LD-MTX) is frequently prescribed for non-oncologic conditions.
  • Adverse effects (AEs) are common with LD-MTX therapy.
  • The relationship between MTX metabolites and AEs requires further elucidation.

Purpose of the Study:

  • To investigate the correlation between MTX polyglutamates (MTX-PGs) concentrations and adverse events in patients receiving LD-MTX.
  • To identify specific MTX-PG levels associated with particular AEs.

Main Methods:

  • Analysis of data from the LD-MTX arm of the Cardiovascular Inflammation Reduction Trial (CIRT).
  • Measurement of MTX-PGs 1-5 using liquid chromatography-tandem mass spectrometry.
  • Cox proportional hazards regression to assess the relationship between MTX-PGs 3-5 quartiles and AEs.

Main Results:

  • Higher MTX-PG3-5 levels were associated with an increased risk of anemia (HR for Q4: 1.27) and liver abnormalities (HR >134 nmol/l: 1.36).
  • Conversely, higher MTX-PG3-5 levels showed a decreased risk of thrombocytopenia (HR for Q4: 0.52).
  • Data were available for 1319 subjects on LD-MTX (median 16.1 mg/week), followed for a median of 2.2 years.

Conclusions:

  • Elevated MTX-PG3-5 levels are modestly linked to specific LD-MTX adverse events, including anemia and liver function abnormalities.
  • A reduced risk of thrombocytopenia and hemorrhage was observed with higher MTX-PG3-5 levels.
  • These findings contribute to a better understanding of MTX metabolism and its association with AEs.
Keywords:
adverse eventsmethotrexate polyglutamatesrandomized controlled trial

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