title: Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexate-polyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  The objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of methotrexate-polyglutamates (MTX-PGs) in erythrocytes in patients with rheumatoid arthritis and correlate them with the efficacy.
  
  
  METHODS
  MTX-PG concentrations in erythrocytes were measured in 42 MTX-naïve patients repeatedly for 24 weeks by high-performance liquid chromatography. In 56 patients receiving stable MTX doses for at least 12 weeks, the correlation between MTX doses and MTX-PG concentrations was examined. The efficacy was measured by the change of DAS28CRP (ΔDAS28CRP).
  
  
  RESULTS
  There were moderate correlations between MTX dose and MTX-PG 3, 4, and 5. At 24 weeks, MTX-PG2, 3, 4, and 1-5 were higher in patients with ΔDAS28CRP >1.2 than in those with ≤1.2. The cutoff value of MTX-PG1-5 to discriminate ΔDAS28CRP >1.2 from ≤1.2 at 24 weeks was 68.7 nM. Among 20 patients with MTX-PG1-5 > 50.6 nM at 8 weeks, seven already improved at 8 weeks and additional 11 improved at 24 weeks (p < 0.001). On the contrary, among the nine patients with MTX-PG1-5 ≤ 50.6 nM at 8 weeks, none improved at 8 weeks and only one improved at 24 weeks (p = 0.500).
  
  
  CONCLUSIONS
  Erythrocyte MTX-PGs might be a potential indicator and predictor of MTX efficacy.
authors.affiliation: a Division of Rheumatology and Clinical Immunology , Jichi Medical University , Yakushiji , Shimotsuke , Tochigi , Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Murosaki
authors.affiliation: a Division of Rheumatology and Clinical Immunology , Jichi Medical University , Yakushiji , Shimotsuke , Tochigi , Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagatani
authors.affiliation: a Division of Rheumatology and Clinical Immunology , Jichi Medical University , Yakushiji , Shimotsuke , Tochigi , Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Sato
authors.affiliation: a Division of Rheumatology and Clinical Immunology , Jichi Medical University , Yakushiji , Shimotsuke , Tochigi , Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: b Division of Clinical Pharmacology, Department of Pharmacology , Jichi Medical University , Shimotsuke , Tochigi , Japan , and.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ushijima
authors.affiliation: c Department of Surgery , Jichi Medical University , Shimotsuke , Tochigi , Japan.
authors.forename: Alan Kawarai
authors.initials: AK
authors.lastname: Lefor
authors.affiliation: b Division of Clinical Pharmacology, Department of Pharmacology , Jichi Medical University , Shimotsuke , Tochigi , Japan , and.
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
authors.affiliation: a Division of Rheumatology and Clinical Immunology , Jichi Medical University , Yakushiji , Shimotsuke , Tochigi , Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Minota
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000097:blood / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D008875:Middle Aged; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate
keywords: Biomarker; Drug monitoring; Methotrexate; Methotrexate–polyglutamates; Rheumatoid arthritis