Rheumatoid arthritis (RA) involves multiple compartments and cellular systems, including lymphocyte subsets, activated monocytes / macrophages and aggressive synovial fibroblasts. Our hypothesis is that chronicity is associated with cellular memory, leading to stably activated and/or hyperreactive cells. This involves epigenetic mechanisms in a defined genetic background. These cells communicate through an network of interactions, resulting at end in destruction of the joint. To cure the disease, it will be essential to disrupt the mechanisms leading to these activated phenotypes. In monocytes, this could be possible by interfering with epigenetic effector mechanisms, e.g. TET enzymes and DNA hydroxymethylation (which is a sign of gene activation), whereas in RA synovial fibroblasts, a possibly would be to reverse global DNA hypomethylation using methyl donors and inhibitors of the polyamine backconversion, a pathway regulated by permidine / spermine N1 acethyltransferase (SSAT1).