Inhibiting citrullination in rheumatoid arthritis: taking fuel from the fire

this issue, Makrygiannakis and colleagues study the eff ect on synovial citrullination of treatment with two commonly used drugs in the treatment of rheumatoid arthritis (RA) [1]. Th ey found by immuno histo chemistry that intracellular citrullination, as deter mined by F95 antibody staining, as well as peptidyl arginine deiminase (PAD) expression were correlated with measures of synovial infl ammation. Intra-articular injection of gluco-corticoid, but not oral methotrexate, was associated with a reduction in synovial infl ammation, intracellular citrul-li nation, and PAD expression. Based on cultures of syno-vial fl uid mononuclear cells and synovial explants, they also make the interesting proposal that gluco corticoids may suppress citrullination independent of infl ammation by inhibiting PAD enzyme expression. Th ere are a number of caveats to this proposition, including the specifi city of anti-PAD antibodies. In our laboratory we have found a number of these antibodies to be cross-reactive with other proteins, which could confound immuno histochemistry fi ndings unless specifi city is confi rmed or the results are corroborated by other techniques. Neverthe less, given the dearth of information on the regulation of citrullination in RA, their paper is welcome. Th e presence of anti-citrullinated protein/peptide anti-bodies (ACPA) defi nes a major subset of RA that is associated with distinctive genetic and environmental risk factors and with a more severe clinical phenotype [2]. Frequently cited evidence to support the importance of ACPA in pathogenesis includes their appearance years before clinical diagnosis, their production within the joint, the ability of ACPA immune complexes to activate macrophages, and some animal model data [2]. Th e actual role of ACPA in pathogenesis is still a matter for investigation. A widely-held hypothesis for this patho-genesis comprises two hits [2]. Th e fi rst hit follows accelerated citrulli nation of proteins in an extra-articular site – due to smoking or infection, for example – which in the context of a permissive HLA type gives rise to ACPA. Th e second hit, which may occur years later, would be an unrelated episode of otherwise self-limiting synovial infl ammation. Since citrullination of proteins is a feature of infl am matory tissue, the presence of pre-existing ACPA would exacerbate and perpetuate the synovitis. If this was to be the case, one might predict that inhibiting citrullination would ameliorate disease – the fi ndings of Makry giannakis and colleagues suggest this may be a previously unappreciated mechanism of action of …