However, the specific impact of apremilast on the expression of different cytokines and the role of other downstream effectors of cAMP, i.e., Exchange protein directly activated by cAMP (Epac)1 and Epac2, in the mechanism of action of apremilast have not been previously addressed, nor has the interaction of apremilast with other systems that regulate cAMP levels, such as adenosine receptors, in particular with the A2A adenosine receptor (A2AR), which mediates many of the anti-inflammatory actions of methotrexate (MTX), the cornerstone treatment for rheumatoid arthritis [17]. This evidence concerns the gene ADORA2A and rheumatoid arthritis.