Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis

Maurits C F J de Rotte*, Ethan den Boer, Pascal H P de Jong, Saskia M F Pluijm, Maja Bulatović Ćalasan, Angelique E Weel, A Margriet Huisman, Andreas H Gerards, Barbara van Schaeybroeck, Nico M Wulffraat, Jan Lindemans, Johanna M W Hazes, Robert de Jonge

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

OBJECTIVE: To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events.

METHODS: We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1-5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication.

RESULTS: In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=-0.005), MTX-PG2 (ß=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (ß=-0.004) were associated (p<0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (ß=-0.015), MTX-PG3 (ß=-0.010), MTX-PG4 (ß=-0.008) and total MTX-PG (ß=-0.003) were associated with lower DAS28 over 9 months. None of the MTX-PGs was associated with adverse events.

CONCLUSIONS: In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA.

Original languageEnglish
Pages (from-to)408-414
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume74
Issue number2
DOIs
Publication statusPublished - Feb 2015

Bibliographical note

Funding:
This study was supported by MEDAC GmbH, Germany (unrestricted grant
to NM Wulffraat) and the Dutch Arthritis Association (NR 07-01-402 to NM
Wulffraat; NR 06-2-402 to R de Jonge). M Bulatović Ćalasan is supported by a
Mosaic grant (017.007.025) from the Dutch Organization for Scientific Research
(NWO). The sponsors had no role in the study planning, design, management or
data analysis.
Competing interest None declared.

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Research programs

  • EMC MM-01-25-01
  • EMC MM-02-54-03
  • EMC MUSC-01-31-01

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