EXTENDED REPORT

Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac

M A Álvarez-Soria^1,*, R Largo^1,*, J Santillana², O Sánchez-Pernaute¹, E Calvo¹, M Hernández², J Egido¹, G Herrero-Beaumont¹

¹ Joint and Bone Research Unit, Fundación Jiménez Díaz, Autonomous University, Madrid, Spain
² Orthopaedic Surgery Department, Hospital Virgen de la Cinta, Tortosa, Tarragona, Spain

Correspondence to:
Dr G Herrero-Beaumont
Servicio de Reumatología, Fundación Jiménez Díaz Avenida Reyes Católicos 2, 28040 Madrid, Spain; gherrero{at}fjd.es

Objective: To compare the effect of celecoxib with that of a classic non-steroidal anti-inflammatory drug (NSAID) on synovial inflammation and on the synovial expression of proinflammatory genes in patients with knee osteoarthritis (OA).

Methods: 30 patients with severe knee OA scheduled for total knee replacement surgery were included in a 3 month clinical trial. They were randomised to two groups: patients treated with celecoxib (CBX) (200 mg/24 h) and patients treated with aceclofenac (ACF) (100 mg/12 h). Those patients with OA who did not want to be treated with NSAIDs served as a control group. During knee surgery, synovial fluid (SF) and synovial membrane (SM) were collected. A SM specimen was fixed and embedded in paraffin and another part was frozen for molecular biology studies.

Results: At the end of study both CBX and ACF treated patients showed a significant improvement in pain and knee function compared with controls. Both drugs significantly reduced prostaglandin E₂ (PGE₂) SF concentration and down regulated COX-2 mRNA and protein expression at the SM. However, synovial macrophage infiltration (CD68 antigen staining) and expression of proinflammatory mediators, such as interleukin 1ß and tumour necrosis factor , were decreased only by CBX treatment.

Conclusion: Both drugs improved joint pain and function, inhibited SF PGE₂ concentration, and induced a decrease in synovial COX-2 expression and synthesis not related to the tissue inflammatory status. These data suggest that PGE₂ blocking agents may decrease PGE₂ production not only by direct COX-2 inhibition but also by down regulating COX-2 expression and synthesis. However, CBX and ACF appear to have different anti-inflammatory profiles in controlling OA synovial macrophage infiltration and proinflammatory expression.

Abbreviations: ACF, aceclofenac; CBX, celecoxib; COX, cyclo-oxygenase; IL, interleukin; NSAIDs, non-steroidal anti-inflammatory drugs; OA, osteoarthritis; PCR, polymerase chain reaction; PG, prostaglandin; SF, synovial fluid; SM, synovial membrane; TNF, tumour necrosis factor; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Keywords: osteoarthritis; COX-2; synovial membrane; non-steroidal anti-inflammatory drugs; celecoxib

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