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Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression. analysis of a proof-of-concept randomized clinical trial of cytokine blockade.
  1. Terence Rooney (rooneyterence{at}gmail.com)
  1. St Vincent's University Hospital, Republic of Ireland
    1. Pascale Roux-Lombard (pascale.roux-lombard{at}hcuge.ch)
    1. University Hospital Geneva, Switzerland
      1. Douglas J Veale (douglas.veale{at}ucd.ie)
      1. St Vincent's University Hospital, Republic of Ireland
        1. Oliver FitzGerald (oliver.fitzgerald{at}ucd.ie)
        1. St Vincent's University Hospital, Republic of Ireland
          1. Jean-Michel Dayer (jean-michel.dayer{at}medecine.unige.ch)
          1. University Hospital Geneva, Switzerland
            1. Barry Bresnihan (barry.bresnihan{at}gmail.com)
            1. St Vincent's University Hospital, Republic of Ireland

              Abstract

              Objectives: To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biologic therapy for rheumatoid arthritis (RA).

              Methods: Patients with active RA entered a randomized study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800μg/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline and 2 further time-points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis (DIA). Selected mediators were also measured in serum.

              Results: Twenty-two patients were randomized: 11 received monotherapy and 11 combination therapy. American College of Rheumatology (ACR) 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy, and 36%, 9%, and 0% with monotherapy, respectively.

              In synovial tissue, T-cell infiltration, vascularity and transforming growth factor β (TGFβ) expression demonstrated significant utility as biomarkers of disease activity and the therapeutic response. In serum, interleukin-6 (IL-6), matrix metalloproteinase -1 (MMP-1), MMP-3 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pre-treatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor (VEGF) / TGFβ, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII and IL-18 correlated with radiographic progression.

              Conclusions: Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.

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