DMARD activity of methotrexate is thought to be due to its polyglutamated form and several mechanisms have been proposed to explain the clinical efficacy in RA, including generation of reactive oxygen species, antagonism of folate-dependent processes, inhibition of methyl-donor production, downregulation of adhesion-molecule, eicosanoids and matrix metalloproteinases (MMPs) expression, modification of cytokine profiles, stimulation of adenosine signaling, inhibition of RANKL/RANK/OPG and JAK/STAT pathways (26–28). This evidence concerns the gene TNFRSF11B and rheumatoid arthritis.