title: Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study.
abstract: OBJECTIVE
  To assess the utility of erythrocyte methotrexate-polyglutamate (MTX-PG) concentrations in determining the safety and efficacy of MTX in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  79 MTX-naïve patients with RA were enrolled in this prospective 76-week cohort study. MTX was initiated, and a predefined dose-escalation protocol was followed. Erythrocyte MTX-PG concentrations were measured using liquid chromatography. The associations of MTX-PG concentrations with disease activity and adverse events were analysed.
  
  
  RESULTS
  Dose escalation of MTX resulted in increased MTX-PG concentrations and a decrease in the mean Disease Activity Score in 28 joints (DAS28). A significant association was observed between total MTX-PG concentrations and ΔDAS28 at week 12 (β=-0.013, p=0.003) and at week 24 (β=-0.014, p=0.003). The maximum MTX-PG levels were significantly higher in patients presenting with elevated transaminases (≥100 IU/L) than in those without (146 vs 106 nmol/L, p=0.009). Receiver operating characteristic curve analysis revealed that a total MTX-PG concentrations of 83 nmol/L at week 12 was the threshold for a DAS28 improvement of ≥1.2 at week 24, and 105 nmol/L was the threshold for transaminases of ≥50 IU/L and 131 nmol/L for transaminases of ≥100 IU/L. MTX-PG concentrations were strongly influenced by body mass index and a serum albumin level.
  
  
  CONCLUSIONS
  MTX-PG concentrations are a useful biomarker in MTX therapy, in terms of efficacy and safety.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan.
authors.forename: Chihiro
authors.identifier: 0000-0002-6138-770X
authors.initials: C
authors.lastname: Takahashi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Internal Medicine and Center for Arthritis and Rheumatic Disease , Kawasaki Municipal Kawasaki Hospital , Kawasaki , Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okano
authors.affiliation: Department of Internal Medicine and Center for Arthritis and Rheumatic Disease , Kawasaki Municipal Kawasaki Hospital , Kawasaki , Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taguchi
authors.affiliation: Department of Connective Tissue Diseases , Tokyo Medical Center, National Hospital Organization , Tokyo , Japan.
authors.forename: Hisaji
authors.initials: H
authors.lastname: Oshima
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Department of Connective Tissue Diseases, Tokyo Medical Center, National Hospital Organization, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
keywords: Methotrexate; Rheumatoid Arthritis; Treatment