Rheumatology International

, Volume 30, Issue 12, pp 1571–1580 | Cite as

Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade

  • Terence RooneyEmail author
  • Carl K. EdwardsIII
  • Martina Gogarty
  • Laura Greenan
  • Douglas J. Veale
  • Oliver FitzGerald
  • Jean-Michel Dayer
  • Barry Bresnihan
Original Article


The objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-κβ ligand (RANKL) and osteoprotegerin (OPG) as biomarkers of disease activity, progressive joint damage, and therapeutic response, during cytokine blockade in rheumatoid arthritis (RA). Patients with active RA entered a randomized open-label 12-month study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 μg/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline, at 4 weeks and at the final time point. Following immunohistochemical staining, RANKL and OPG expression was quantified using digital image analysis. Radiographic damage was evaluated using the van der Heijde modification of the Sharp scoring system. Twenty-two patients were randomized. Baseline expression of RANKL, but not OPG, correlated significantly with baseline CRP levels (r = 0.61, P < 0.01). While a significant reduction in OPG expression following treatment was observed in clinical responders at the final time point (P < 0.05 vs. baseline), RANKL levels did not change, and the RANKL:OPG ratio remained unaltered, even at the highest levels of clinical response. When potential predictors of radiographic outcome were evaluated, baseline RANKL expression correlated with erosive progression at 1 year (r = 0.71, P < 0.01). Distinct, though related, pathophysiologic processes mediate joint inflammation and destruction in RA. Elevated synovial tissue RANKL expression is associated with progressive joint erosion, and may be independent of the clinical response to targeted therapy. The potential therapeutic importance of modulating RANKL in RA is highlighted, if radiographic arrest is to be achieved.


Rheumatoid Arthritis Synovial Tissue Anakinra Radiographic Progression RANKL Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by research grants from Amgen Inc. The authors would like to thank Evelyn Murphy and Ann Madigan for laboratory advice and assistance and for data collection.

Conflict of interest statement

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Terence Rooney
    • 1
    Email author
  • Carl K. EdwardsIII
    • 3
  • Martina Gogarty
    • 1
  • Laura Greenan
    • 1
  • Douglas J. Veale
    • 1
  • Oliver FitzGerald
    • 1
  • Jean-Michel Dayer
    • 2
  • Barry Bresnihan
    • 1
  1. 1.Department of RheumatologySt. Vincent’s University HospitalDublin 4Ireland
  2. 2.Division of Immunology and AllergyUniversity HospitalGenevaSwitzerland
  3. 3.Department of Inflammation Drug Discovery ResearchAmgen Inc.Thousand OaksUSA

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