Rheumatoid arthritis (RA) appears to be a complicated disease as its etiology still remains elusive despite the numerous advances and knowledge concerning its progression. Soluble tumor necrosis factor (TNF) receptors are mainly found in high concentration in synovial fluid and serum of patients with rheumatoid arthritis. Thus excess of TNF-α relative to this high level of soluble TNF receptors amplify joint inflammation. Therapies currently employed for RA treatment include the administration of non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatics drugs (DMARDs) including other newer classes of drugs which antagonize specific markers involved in the pathogenesis of RA. Since Infliximab has been approved by the United States Food and Drug Administration (FDA) in 1992, anti-cytokines therapy has continually been proven efficient and effective despite its high cost. The use of phosphodiesterase (PDE4) inhibitors is an emerging therapy in the class of anti-cytokines drug therapies and it is increasingly being demonstrated to be the promising treatment strategy for rheumatoid joint with a safer side effect profile compared to some of the currently approved medications. The discovery of C-terminal regulatory element CR3 (Control Region 3) in PDE4 structure has further brought advanced insight into the treatment of inflammatory joint disease. PDE4 inhibition affects the regulatory role of p38 MAPKs in cytokine production and suppresses the overexpression of cytokines through cAMP, PKA and NF-κB route. Indeed, current research demonstrates PDE4 as an important, although under-exploited, molecular target for anti-rheumatoid arthritis. Therefore, in this review we provide a comprehensive overview of PDE4 activity and show how its inhibition is crucial in the treatment of rheumatoid arthritis (RA) and how this class of drugs can be further developed for enhanced effectiveness.
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