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

doi:10.1136/annrheumdis-2013-203725

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 journal › Article › Academic › peer-review

75 Citations (Scopus)

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 language	English
Pages (from-to)	408-414
Number of pages	7
Journal	Annals of the Rheumatic Diseases
Volume	74
Issue number	2
DOIs	https://doi.org/10.1136/annrheumdis-2013-203725
Publication status	Published - 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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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

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10.1136/annrheumdis-2013-203725

http://hdl.handle.net/1765/55171

Cite this

de Rotte, M. C. F. J., den Boer, E., de Jong, P. H. P., Pluijm, S. M. F., Ćalasan, M. B., Weel, A. E., Huisman, A. M., Gerards, A. H., van Schaeybroeck, B., Wulffraat, N. M., Lindemans, J., Hazes, J. M. W., & de Jonge, R. (2015). Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 74(2), 408-414. https://doi.org/10.1136/annrheumdis-2013-203725

@article{3ee27333eb924a299279f457c9c67325,

title = "Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis",

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.",

author = "\{de Rotte\}, \{Maurits C F J\} and \{den Boer\}, Ethan and \{de Jong\}, \{Pascal H P\} and Pluijm, \{Saskia M F\} and {\'C}alasan, \{Maja Bulatovi{\'c}\} and Weel, \{Angelique E\} and Huisman, \{A Margriet\} and Gerards, \{Andreas H\} and \{van Schaeybroeck\}, Barbara and Wulffraat, \{Nico M\} and Jan Lindemans and Hazes, \{Johanna M W\} and \{de Jonge\}, Robert",

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 Bulatovi{\'c} {\'C}alasan 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2015",

month = feb,

doi = "10.1136/annrheumdis-2013-203725",

language = "English",

volume = "74",

pages = "408--414",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "Elsevier",

number = "2",

}

de Rotte, MCFJ, den Boer, E, de Jong, PHP, Pluijm, SMF, Ćalasan, MB, Weel, AE, Huisman, AM, Gerards, AH, van Schaeybroeck, B, Wulffraat, NM, Lindemans, J, Hazes, JMW & de Jonge, R 2015, 'Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis', Annals of the Rheumatic Diseases, vol. 74, no. 2, pp. 408-414. https://doi.org/10.1136/annrheumdis-2013-203725

TY - JOUR

T1 - Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis

AU - de Rotte, Maurits C F J

AU - den Boer, Ethan

AU - de Jong, Pascal H P

AU - Pluijm, Saskia M F

AU - Ćalasan, Maja Bulatović

AU - Weel, Angelique E

AU - Huisman, A Margriet

AU - Gerards, Andreas H

AU - van Schaeybroeck, Barbara

AU - Wulffraat, Nico M

AU - Lindemans, Jan

AU - Hazes, Johanna M W

AU - de Jonge, Robert

N1 - 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

U2 - 10.1136/annrheumdis-2013-203725

DO - 10.1136/annrheumdis-2013-203725

M3 - Article

C2 - 24297383

SN - 0003-4967

VL - 74

SP - 408

EP - 414

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 2

ER -

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

Abstract

Bibliographical note

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