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Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis
  1. Maurits C F J de Rotte1,
  2. Ethan Den Boer1,
  3. Pascal H P de Jong2,
  4. Saskia M F Pluijm3,
  5. Maja Bulatović Ćalasan4,
  6. Angelique E Weel5,
  7. A Margriet Huisman6,
  8. Andreas H Gerards7,
  9. Barbara van Schaeybroeck8,
  10. Nico M Wulffraat4,
  11. Jan Lindemans1,
  12. Johanna M W Hazes2,
  13. Robert de Jonge1
  1. 1Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, Netherlands
  2. 2Department of Rheumatology, Erasmus University Medical Center, Rotterdam, Netherlands
  3. 3Department of Pediatric Hemato-Oncology, Erasmus University Medical Center, Rotterdam, Netherlands
  4. 4Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children's hospital, Utrecht, Netherlands
  5. 5Department of Rheumatology, Maasstad Hospital, Rotterdam, Netherlands
  6. 6Interne Specialismen Rijnmond Noord, Sint Franciscus Hospital, Rotterdam and IJsselland Hospital, Capelle aan de IJssel, Netherlands
  7. 7Department of Rheumatology, Vlietland Hospital, Schiedam, Netherlands
  8. 8Department of Rheumatology, Albert Schweitzer Hospital, Dordrecht, Netherlands
  1. Correspondence to Maurits C F J de Rotte, Department of Clinical Chemistry, Erasmus University Medical Center, ‘s-Gravendijkwal 230, Rotterdam 3015 CE, The Netherlands; m.derotte{at}erasmusmc.nl

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.

  • DMARDs (synthetic)
  • Rheumatoid Arthritis
  • Pharmacokinetics

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