Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis

Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intraarticular glucocorticoid injection, and eight healthy volunteers. Synovial inflammation was assessed with double-blind semiquantitative analysis of lining thickness, cell infiltration, and vascularity by using a 4-point scale. Expression of citrullinated proteins (CPs) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically with double-blind semiquantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB), mononuclear cells (MCs), and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed with immunohistochemistry for expression of CP as well as PAD2 and PAD4 enzymes.The presence of synovial CP was almost exclusive in RA compared with healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination, as demonstrated by the decrease in the level of citrullination and PAD expression after incubation of SFMC and synovial explants with dexamethasone.Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the presence of highly specific anti-citrullinated protein antibodies (ACPAs) [1]. These antibodies recognize several different proteins that are citrullinated. Citrullination is the conversion of peptidylarginine to peptidylcitrulline through a calcium-dependent process catalyzed by the peptidylarginine deiminase (PAD) enzymes. Five PAD isotypes have been described in humans (PAD1, PAD2, PAD3,