SAT0508 Lack of a clear disease modifying activity of celecoxib in treatment of end-stage knee osteoarthritis: a randomized observer blinded clinical trial
Authors: EM Van Helvoort, K Coeleveld, TN de Boer, AM Huisman, AA Polak, JWJ Bijlsma, JM van Laar, FJPG Lafeber, SC Mastbergen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Several studies suggest that celecoxib has beneficial effects on degenerated cartilage (1, 2). Together with effects on synovial tissue and bone, celecoxib was postulated to have disease modifying osteoarthritic drug (DMOAD) activity. <h3>Objectives</h3> This study evaluated the DMOAD activity of celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor compared to no treatment and naproxen, treating end-stage knee osteoarthritis (OA), after in vivo exposure using detailed <i>ex vivo</i> tissue analyses. <h3>Methods</h3> 172 patients with end-stage knee OA were randomized to 4 groups and treated for 4 weeks prior to knee replacement surgery: celecoxib 2dd200g, naproxen 3dd250mg, celecoxib 2dd200mg stopped 3 days prior to surgery, or no treatment. To determine if treatment had reached the joint, intra-articular COX-2 expression was determined by Western Blot analysis in the celecoxib until surgery and no treatment group, considering these as most extremes. Proteoglycan release, as primary outcome and content were determined by staining and precipitation of glycosaminoglycans (GAGs) with Alcian Blue. Release of newly formed proteogylcans, as a measure of proteoglycan retention, was determined by loss of <sup>35</sup>SO<sub>4</sub><sup>2</sup>-labeled GAGs in culture medium by precipitation of GAGs and subsequent liquid scintillation analysis. Synovial tissue inflammation markers interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were determined by Enzyme Linked Immuno Sorbet Assay (ELISA) and nitric oxide (NO) production by standard Griess reaction. Western Ontario and McMaster University (WOMAC) questionnaire was used to evaluate clinical parameters. <h3>Results</h3> Intra-articular COX-2 expression was significantly decreased in both cartilage and synovial tissue (figure 1) indicating proper in vivo exposure of the treatment. Despite this reduction, no significant effect on proteoglycan release, retention or content was found for none of the treatment groups (table 1). Synovial tissue showed only a small decrease in nitric oxide levels in celecoxib treated patients. No clear clinical effects could be observed as indicated by the WOMAC scores. <h3>Conclusions</h3> No effect of a 4-week in vivo celecoxib treatment on joint tissue in knee OA patients could be detected, although decreased expression of COX-2 confirmed its intra-articular availability. Effects on synovial inflammatory mediators and clinical outcome were very limited. No adverse effects were found either. As such the previous reported disease modifying effects of celecoxib in <i>in vitro</i> and pilot clinical studies could not unambiguously be confirmed in this randomized trial. <h3>References</h3> de Boer TN, Huisman AM, Polak AA, Niehoff AG, van Rinsum AC, Saris D, et al. The chondroprotective effect of selective COX-2 inhibition in osteoarthritis: ex vivo evaluation of human cartilage tissue after in vivo treatment. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2009;17(4):482–8. Mastbergen SC, Jansen NW, Bijlsma JW, Lafeber FP. Differential direct effects of cyclo-oxygenase-1/2 inhibition on proteoglycan turnover of human osteoarthritic cartilage: an in vitro study. Arthritis research &amp; therapy. 2006;8(1):R2. <h3>Disclosure of Interest</h3> E. Van Helvoort: None declared, K. Coeleveld: None declared, T. de Boer: None declared, A. Huisman: None declared, A. Polak: None declared, J. Bijlsma Grant/research support from: J.W.J. Bijlsma received a consultancy fee from Pfizer (&lt;5.000 US$). J. van Laar: None declared, F. Lafeber: None declared, S. Mastbergen: None declared