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Open Access Highly Accessed Research article

Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis

Dimitrios Makrygiannakis1, Shankar Revu1, Marianne Engström1, Erik af Klint1, Anthony P Nicholas2, Ger JM Pruijn3 and Anca I Catrina1*

Author affiliations

1 Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institutet, SE- 141 86, Stockholm, Sweden

2 University of Alabama at Birmingham and Birmingham Veterans Administration Medical Center, S. 19th Street, Birmingham, AL 35233, USA

3 Department of Biomolecular Chemistry, Radboud University Nijmegen, PO Box 9102, 6500 HC, Nijmegen, The Netherlands

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Citation and License

Arthritis Research & Therapy 2012, 14:R20  doi:10.1186/ar3702

Published: 27 January 2012

Abstract

Introduction

Protein 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.

Methods

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.

Results

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.

Conclusion

Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.