Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.
Edwards, Carl K 3rd
Veale, Douglas J
AffiliationDepartment of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland., email@example.com
MeSHAntirheumatic Agents/therapeutic use
Arthritis, Rheumatoid/drug therapy/metabolism/*physiopathology
Drug Therapy, Combination
Image Processing, Computer-Assisted
Interleukin 1 Receptor Antagonist Protein/therapeutic use
Knee Joint/drug effects/*physiopathology/radiography
Severity of Illness Index
Synovial Membrane/drug effects/metabolism/*physiopathology
MetadataShow full item record
CitationRheumatol Int. 2010 Nov;30(12):1571-80. Epub 2009 Oct 22.
AbstractThe objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-kappabeta 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 mug/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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