Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade
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.
KeywordsRheumatoid Arthritis Synovial Tissue Anakinra Radiographic Progression RANKL Expression
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.
- 3.Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR et al (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with Concomitant Therapy Study Group. N Engl J Med 343(22):1594–1602CrossRefPubMedGoogle Scholar
- 5.Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50(5):1400–1411CrossRefPubMedGoogle Scholar
- 6.Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54(9):2793–2806CrossRefPubMedGoogle Scholar
- 8.Goldring SR (2003) Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology (Oxford) 42(suppl 2):ii11–ii16Google Scholar
- 12.Zwerina J, Hayer S, Tohidast-Akrad M, Bergmeister H, Redlich K, Feige U et al (2004) Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. Arthritis Rheum 50(1):277–290CrossRefPubMedGoogle Scholar
- 14.Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT et al (2008) Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum 58(5):1299–1309CrossRefPubMedGoogle Scholar
- 15.Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M et al (2002) Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61(12):1047–1054CrossRefPubMedGoogle Scholar
- 22.Haynes D, Crotti T, Weedon H, Slavotinek J, Au V, Coleman M et al (2008) Modulation of RANKL and osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis in response to disease-modifying antirheumatic drug treatment and correlation with radiologic outcome. Arthritis Rheum 59(7):911–920CrossRefPubMedGoogle Scholar
- 23.Rooney T, Roux-Lombard P, Veale DJ, FitzGerald O, Dayer JM, Bresnihan B (2009) 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. Ann Rheum Dis. 20 May 2009 [Epub ahead of print]Google Scholar
- 28.Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38(1):44–48CrossRefPubMedGoogle Scholar
- 32.Rooney T, Bresnihan B, Andersson U, Gogarty M, Kraan M, Schumacher HR et al (2007) Microscopic measurement of inflammation in synovial tissue: inter-observer agreement for manual quantitative, semiquantitative and computerised digital image analysis. Ann Rheum Dis 66(12):1656–1660CrossRefPubMedGoogle Scholar
- 36.Skoumal M, Kolarz G, Haberhauer G, Woloszczuk W, Hawa G, Klingler A (2005) Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis. Rheumatol Int 26(1):63–69CrossRefPubMedGoogle Scholar
- 38.Yano K, Nakagawa N, Yasuda H, Tsuda E, Higashio K (2001) Synovial cells from a patient with rheumatoid arthritis produce osteoclastogenesis inhibitory factor/osteoprotegerin: reciprocal regulation of the production by inflammatory cytokines and basic fibroblast growth factor. J Bone Miner Metab 19(6):365–372CrossRefPubMedGoogle Scholar
- 39.Scott DL (2000) Prognostic factors in early rheumatoid arthritis. Rheumatology (Oxford) 39(suppl 1):24–29Google Scholar
- 40.Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D et al (2005) Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum 52(4):1020–1030CrossRefPubMedGoogle Scholar