title: Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in juvenile idiopathic arthritis patients.
abstract: OBJECTIVE
  To determine association of erythrocyte methotrexate polyglutamates (MTX-PG) with disease activity and adverse effects in a prospective juvenile idiopathic arthritis (JIA) cohort.
  
  
  METHODS
  One hundred and thirteen JIA patients were followed from MTX start until 12 months. Erythrocyte MTX-PGs with 1-5 glutamate residues were measured at 3 months with tandem mass spectrometry. The outcomes were Juvenile Arthritis Disease Activity Score (JADAS)-27 and adverse effects. To determine associations of MTX-PGs with JADAS-27 at 3 months and during 1 year of MTX treatment, linear regression and linear mixed-model analyses were used. To determine associations of MTX-PGs with adverse effects during 1 year of MTX treatment, logistic regression was used. Analyses were corrected for JADAS-27 at baseline and co-medication.
  
  
  RESULTS
  Median JADAS-27 decreased from 12.7 (IQR: 7.8-18.2) at baseline to 2.9 (IQR: 0.1-6.5) at 12 months. Higher concentrations of MTX-PG3 (β: -0.006, p=0.005), MTX-PG4 (β: -0.015, p=0.004), MTX-PG5 (β: -0.051, p=0.011) and MTX-PG3-5 (β: -0.004, p=0.003) were associated with lower disease activity at 3 months. Higher concentrations of MTX-PG3 (β: -0.005, p=0.028), MTX-PG4 (β: -0.014, p=0.014), MTX-PG5 (β: -0.049, p=0.023) and MTX-PG3-5 (β: -0.004, p=0.018) were associated with lower disease activity over 1 year. None of the MTX-PGs was associated with adverse effects.
  
  
  CONCLUSIONS
  In the first prospective study in JIA, long-chain MTX-PGs were associated with lower JADAS-27 at 3 months and during 1 year of MTX treatment. Erythrocyte MTX-PG could be a plausible candidate for therapeutic drug monitoring of MTX in JIA.
authors.affiliation: Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Maja Bulatović
authors.initials: MB
authors.lastname: Ćalasan
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Ethan
authors.initials: E
authors.lastname: den Boer
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Maurits C F J
authors.initials: MC
authors.lastname: de Rotte
authors.affiliation: Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Sebastiaan J
authors.initials: SJ
authors.lastname: Vastert
authors.affiliation: Department of Paediatric Rheumatology, Erasmus University Medical Centre Rotterdam, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kamphuis
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: de Jonge
authors.affiliation: Department of Paediatric Immunology, University Medical Centre Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Nico M
authors.initials: NM
authors.lastname: Wulffraat
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000032:analysis; D053719:Tandem Mass Spectrometry
chemical_list: D018501:Antirheumatic Agents; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate
keywords: DMARDs (synthetic); Disease Activity; Juvenile Idiopathic Arthritis; Methotrexate; Treatment