The Controlled Trial of Apremilast for Rheumatoid Arthritis Treatment (CARAT)

Many manifestations associated with RA result from, or are significantly influenced by, the effects of pro-inflammatory cytokines (e.g., TNF, IL-1, IL-6). Specific inhibition of these cytokines with newer, parenterally administered biologic agents has revolutionized the treatment of RA. Apremilast is a novel, orally administered drug which approaches the reduction of pro-inflammatory cytokines via inhibition of phosphodiesterase type 4 (PDE4). Apremilast, Acetamide, N-\[2-\[ (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl\]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl\] is a phosphodiesterase type 4 (PDE4) inhibitor under development for use in the treatment of inflammatory conditions. PDE4 is one of the major phosphodiesterases expressed in leukocytes. Inhibitors of PDE4 cause accumulation of intracellular cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A and other downstream effectors, resulting in inhibition of pro-inflammatory cytokine transcription and other cellular responses such as neutrophil degranulation, chemotaxis, and adhesion to endothelial cells. In human cellular models, apremilast inhibited production of inflammatory mediators such as TNF-α, IL-12, IL-2, IFN-γ, IL-5, IL-8, leukotriene B4 (LTB4), and the adhesion molecule CD18/CD11b (Mac-1). Apremilast has also been shown to be a potent anti-inflammatory agent in several animal models of inflammation.