title: Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures.
abstract: OBJECTIVE
  To describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters.
  
  
  METHODS
  Prospective, open-label, long-term mechanism of action study.
  
  
  METHODS
  University clinic.
  
  
  METHODS
  MTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6-36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation.
  
  
  RESULTS
  Cytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=-0.63, p=0.007).
  
  
  CONCLUSIONS
  MTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion.
authors.affiliation: Division of Rheumatology, Department of Medicine , Albany Medical College, and The Center for Rheumatology (JMK), The New York State Department of Health (DAL) the Albany College of Pharmacy (RH), and The University of Glasgow (IBM) , Albany, New York , USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Kremer
authors.affiliation: Division of Rheumatology, Department of Medicine , Albany Medical College, and The Center for Rheumatology (JMK), The New York State Department of Health (DAL) the Albany College of Pharmacy (RH), and The University of Glasgow (IBM) , Albany, New York , USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Division of Rheumatology, Department of Medicine , Albany Medical College, and The Center for Rheumatology (JMK), The New York State Department of Health (DAL) the Albany College of Pharmacy (RH), and The University of Glasgow (IBM) , Albany, New York , USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hamilton
authors.affiliation: Division of Rheumatology, Department of Medicine , Albany Medical College, and The Center for Rheumatology (JMK), The New York State Department of Health (DAL) the Albany College of Pharmacy (RH), and The University of Glasgow (IBM) , Albany, New York , USA.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
keywords: Cytokines; Disease Activity; Methotrexate; Pharmacokinetics; Rheumatoid Arthritis