title: A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis patients receiving methotrexate.
abstract: OBJECTIVE
  Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Although in general MTX is very effective, the major drawback is the large inter-patient variability in clinical response. The circulating levels of MTX polyglutamates (MTXPGs) are supposed to correlate with clinical efficacy, therefore having a potential role in drug monitoring. However, there is a controversial discussion about the importance of methotrexate polyglutamates as outcome parameters in the therapy of rheumatoid arthritis. The aim of the present study was to investigate the formation and pharmacokinetics of MTXPGs and to correlate their concentration with clinical response in MTX-naïve patients.
  
  
  METHODS
  The pharmacokinetics of erythrocyte MTXPGs was determined in samples of nineteen MTX-naïve patients by high pressure liquid chromatography (HPLC) using post-column photo-oxidation and fluorimetric detection. The relationship between erythrocyte concentrations of MTXPGs and the primary outcome parameter DAS-28 was assessed using the Spearman's correlation coefficient.
  
  
  RESULTS
  The short-chain polyglutamate MTXPG2 revealed to be a potential marker for clinical outcome in rheumatoid arthritis with a statistically significant positive correlation of MTXPG2 Cmax levels and improvement in DAS-28 (+0.518, p=0.023) over 16 weeks. Furthermore, Cmax levels of MTXPG2 negatively correlated with basophils (-0.478, p=0.038) and eosinophils (-0.531, p=0.019), both pro-inflammatory cells involved in the disease.
  
  
  CONCLUSIONS
  MTXPG2 seems to be a potential indicator for clinical response and may serve as a marker for drug monitoring.
authors.affiliation: Medical University of Vienna, Department of Clinical Pharmacology, Waehringer Guertel 18-20, 1090 Vienna, Austria. eva-luise.hobl@meduniwien.ac.at
authors.forename: Eva-Luise
authors.initials: EL
authors.lastname: Hobl
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.forename: Ludwig
authors.initials: L
authors.lastname: Erlacher
authors.forename: Bernhard
authors.initials: B
authors.lastname: Duhm
authors.forename: Monika
authors.initials: M
authors.lastname: Mustak
authors.forename: Hans
authors.initials: H
authors.lastname: Bröll
authors.forename: Petra
authors.initials: P
authors.lastname: Högger
authors.forename: Blanka
authors.initials: B
authors.lastname: Rizovski
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mader
mesh_terms: D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D001317:Austria; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004185:Disability Evaluation; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005470:Fluorometry; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008875:Middle Aged; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D008727:Methotrexate