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Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade
  1. Terence Rooney1,
  2. Pascale Roux-Lombard2,
  3. Douglas J Veale1,
  4. Oliver FitzGerald1,
  5. Jean-Michel Dayer2,
  6. Barry Bresnihan1
  1. 1Department of Rheumatology, St Vincent's University Hospital, Dublin, Ireland
  2. 2Division of Immunology and Allergy, University Hospital, Geneva, Switzerland
  1. Correspondence to Dr Terence Rooney, Department of Rheumatology, St Vincent's University Hospital, Dublin 4, Ireland; rooneyterence{at}


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

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

Results Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 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 beta (TGFβ) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (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. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGFβ, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II 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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  • Funding This study was supported by research grants from Amgen, Inc.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the St Vincent's University Hospital Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.