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

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Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Department of Rheumatology, St. Vincent’s University Hospital, Dublin 4, Ireland

    Terence Rooney, Martina Gogarty, Laura Greenan, Douglas J. Veale, Oliver FitzGerald & Barry Bresnihan

  2. Division of Immunology and Allergy, University Hospital, Geneva, Switzerland

    Jean-Michel Dayer

  3. Department of Inflammation Drug Discovery Research, Amgen Inc., Thousand Oaks, CA, 91360, USA

    Carl K. Edwards III

Authors
  1. Terence Rooney
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  2. Carl K. Edwards III
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  3. Martina Gogarty
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  4. Laura Greenan
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  6. Oliver FitzGerald
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Correspondence to Terence Rooney.

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Rooney, T., Edwards, C.K., Gogarty, M. et al. Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade. Rheumatol Int 30, 1571–1580 (2010). https://doi.org/10.1007/s00296-009-1191-1

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  • DOI: https://doi.org/10.1007/s00296-009-1191-1

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