Abstract
IntroductionProtein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity. As a result, the present study examined the possibility that effective antirheumatic treatment will decrease the level of synovial citrullination.MethodsSynovial 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.ResultsThe 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.ConclusionSynovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.
Highlights
Protein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity
15 Rheumatoid arthritis (RA) patients (11 women and four men; median age, 63 years; range, 34 to 83 years) with active knee arthritis independent of disease duration received an intraarticular injection of 40 mg of triamcinolone hexacetonide, and synovial biopsy samples were obtained with arthroscopy before and after 2 weeks after intraarticular treatment
We analyzed the immunohistochemical expression of citrullinated peptides and the PAD2 and PAD4 enzymes in baseline RA samples obtained before initiation of treatment, as compared with healthy synovial biopsies
Summary
Protein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity. 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. Protein citrullination enhances the HLA binding capacity of synovial-derived proteins and promotes NFB and tumor necrosis factor (TNF) production in the presence ACPA [7]. This suggests that local synovial citrullination might be essential in a later phase of the disease process, contributing to occurrence and perpetuation of chronic synovitis in the presence of specific anti-citrulline antibodies. The present study aimed to investigate any direct effect of these drugs on protein citrullination
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