Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis.
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.
['de Rotte|Maurits C F J|MC|', 'den Boer|Ethan|E|', 'de Jong|Pascal H P|PH|', 'Pluijm|Saskia M F|SM|', 'Ćalasan|Maja Bulatović|MB|', 'Weel|Angelique E|AE|', 'Huisman|A Margriet|AM|', 'Gerards|Andreas H|AH|', 'van Schaeybroeck|Barbara|B|', 'Wulffraat|Nico M|NM|', 'Lindemans|Jan|J|', 'Hazes|Johanna M W|JM|', 'de Jonge|Robert|R|']
D018501:Antirheumatic Agents D001172:Arthritis, Rheumatoid D002853:Chromatography, Liquid D015331:Cohort Studies D004912:Erythrocytes D005260:Female D006801:Humans D008137:Longitudinal Studies D008297:Male D008727:Methotrexate D008875:Middle Aged D011099:Polyglutamic Acid D053719:Tandem Mass Spectrometry
Rheumatoid Arthritis DMARDs (synthetic) Pharmacokinetics