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

Hdl Handle:
http://hdl.handle.net/10147/207544
Title:
Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.
Authors:
Rooney, Terence; Edwards, Carl K 3rd; Gogarty, Martina; Greenan, Laura; Veale, Douglas J; FitzGerald, Oliver; Dayer, Jean-Michel; Bresnihan, Barry
Affiliation:
Department of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland., rooneyterence@gmail.com
Citation:
Rheumatol Int. 2010 Nov;30(12):1571-80. Epub 2009 Oct 22.
Journal:
Rheumatology international
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207544
DOI:
10.1007/s00296-009-1191-1
PubMed ID:
19847430
Abstract:
The 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.
Language:
eng
MeSH:
Antirheumatic Agents/therapeutic use; Arthritis, Rheumatoid/drug therapy/metabolism/*physiopathology; Biological Markers/metabolism; Biopsy; Disease Progression; Drug Therapy, Combination; Female; Health Status; Humans; Image Processing, Computer-Assisted; Interleukin 1 Receptor Antagonist Protein/therapeutic use; Knee Joint/drug effects/*physiopathology/radiography; Male; Middle Aged; Osteoprotegerin/metabolism; RANK Ligand/*metabolism; Severity of Illness Index; Synovial Membrane/drug effects/metabolism/*physiopathology
ISSN:
1437-160X (Electronic); 0172-8172 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorRooney, Terenceen_GB
dc.contributor.authorEdwards, Carl K 3rden_GB
dc.contributor.authorGogarty, Martinaen_GB
dc.contributor.authorGreenan, Lauraen_GB
dc.contributor.authorVeale, Douglas Jen_GB
dc.contributor.authorFitzGerald, Oliveren_GB
dc.contributor.authorDayer, Jean-Michelen_GB
dc.contributor.authorBresnihan, Barryen_GB
dc.date.accessioned2012-02-01T10:30:52Z-
dc.date.available2012-02-01T10:30:52Z-
dc.date.issued2012-02-01T10:30:52Z-
dc.identifier.citationRheumatol Int. 2010 Nov;30(12):1571-80. Epub 2009 Oct 22.en_GB
dc.identifier.issn1437-160X (Electronic)en_GB
dc.identifier.issn0172-8172 (Linking)en_GB
dc.identifier.pmid19847430en_GB
dc.identifier.doi10.1007/s00296-009-1191-1en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207544-
dc.description.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.en_GB
dc.language.isoengen_GB
dc.subject.meshAntirheumatic Agents/therapeutic useen_GB
dc.subject.meshArthritis, Rheumatoid/drug therapy/metabolism/*physiopathologyen_GB
dc.subject.meshBiological Markers/metabolismen_GB
dc.subject.meshBiopsyen_GB
dc.subject.meshDisease Progressionen_GB
dc.subject.meshDrug Therapy, Combinationen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshHealth Statusen_GB
dc.subject.meshHumansen_GB
dc.subject.meshImage Processing, Computer-Assisteden_GB
dc.subject.meshInterleukin 1 Receptor Antagonist Protein/therapeutic useen_GB
dc.subject.meshKnee Joint/drug effects/*physiopathology/radiographyen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshOsteoprotegerin/metabolismen_GB
dc.subject.meshRANK Ligand/*metabolismen_GB
dc.subject.meshSeverity of Illness Indexen_GB
dc.subject.meshSynovial Membrane/drug effects/metabolism/*physiopathologyen_GB
dc.titleSynovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.en_GB
dc.contributor.departmentDepartment of Rheumatology, St. Vincent's University Hospital, Dublin 4, Ireland., rooneyterence@gmail.comen_GB
dc.identifier.journalRheumatology internationalen_GB
dc.description.provinceLeinster-

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