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Kremer JM, Lawrence DA, Hamilton R, et al. Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures. RMD Open. 2016;2(1):e000287doi: 10.1136/rmdopen-2016-000287.
Kremer, J. M., Lawrence, D. A., Hamilton, R., & McInnes, I. B. (2016). Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures. RMD open, 2(1), e000287. https://doi.org/10.1136/rmdopen-2016-000287
Kremer, Joel M, et al. "Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures." RMD open vol. 2,1 (2016): e000287. doi: https://doi.org/10.1136/rmdopen-2016-000287
Kremer JM, Lawrence DA, Hamilton R, McInnes IB. Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures. RMD Open. 2016 Jun 09;2(1):e000287. doi: 10.1136/rmdopen-2016-000287. eCollection 2016. PMID: 27335660; PMCID: PMC4913203.
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RMD Open. 2016 Jun 09;2(1):e000287. doi: 10.1136/rmdopen-2016-000287. eCollection 2016.

Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures.

RMD open

Joel M Kremer, David A Lawrence, Robert Hamilton, Iain B McInnes

Affiliations

  1. 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.

PMID: 27335660 PMCID: PMC4913203 DOI: 10.1136/rmdopen-2016-000287

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.

DESIGN: Prospective, open-label, long-term mechanism of action study.

SETTING: 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.

Keywords: Cytokines; Disease Activity; Methotrexate; Pharmacokinetics; Rheumatoid Arthritis

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