Efficacy of concurrent administration of cilostazol and methotrexate in rheumatoid arthritis: Pharmacologic and clinical significance

Aims: This study aimed to assess the beneficial effects of the concurrent administration of cilostazol and methotrexate (MTX) on the synovial fibroblasts obtained from patients with rheumatoid arthritis (RA), and in a mouse model of collagen-induced arthritis (CIA). Main methods: Production of TNIF-alpha, IL-1 beta, IL-6 and MCP-1 on synovial fibroblasts from RA patients was determined by RT-PCR. Cell proliferation, viability and apoptosis were measured. Anti-arthritic effects were evaluated in CIA mice. Key finding: Concurrent use of cilostazol and MIX effectively suppressed proliferation and cell viability associated with enhanced apoptosis of synovial fibroblasts and significantly suppressed cytokine production, including TNF-alpha, IL-1 beta, IL-6, and MCP-1 in an additive manner. In line with these findings, LPS-induced increased expression of NURR1 mRNA and protein were suppressed by cilostazol and MIX in accordance with suppression of NF-kappa B p65 activity. These suppressed effects were reversed by KT5720 (cAMP-protein kinase inhibitor) and ZM 241385 (A(2A) receptor antagonist), respectively. In CIA mice, treatment with cilostazol, MIX and their combination significantly decreased clinical signs with improvement of histopathological status in the paw of mice, accompanied by reduced serum cytokine levels. Likewise, following concurrent administration, CD68 (+)-cell recruitment, proteoglycan depletion and osteoclast formation were significantly suppressed in association with repressed RANKL expression in the joints of CIA mice. Significance: In conclusion, a combination of cilostazol and MIX may provide an effective therapeutic strategy for the suppression of inflammation and the prevention of joint damage in RA via activation of the cAMP-dependent protein kinase in the synovial fibroblasts. (C) 2012 Elsevier Inc. All rights reserved.