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

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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 (β=-0.005), MTX-PG2 (β=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (β=-0.004) were associated (p<0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (β=-0.015), MTX-PG3 (β=-0.010), MTX-PG4 (β=-0.008) and total MTX-PG (β=-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
Issue number2
Publication statusPublished - 1 Feb 2015

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