RESEARCH - Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression

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Ann Rheum Dis. Published Online First: 20 May 2009. doi:10.1136/ard.2009.108324

BMJ Publishing Group Ltd & European League Against Rheumatism.

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Extended Report

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

Terence Rooney 1*, Pascale Roux-Lombard 2, J Veale 1, Oliver

FitzGerald 1, Jean-Michel Dayer 2 and Barry Bresnihan 1

1 St 's University Hospital, Republic of Ireland

2 University Hospital Geneva, Switzerland

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 (TGF) 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) / TGF, 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.

http://ard.bmj.com/cgi/content/abstract/ard.2009.108324v1?papetoc

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