title: Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.
authors.affiliation: Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institutet, SE- 141 86, Stockholm, Sweden.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Makrygiannakis
authors.forename: Shankar
authors.initials: S
authors.lastname: Revu
authors.forename: Marianne
authors.initials: M
authors.lastname: Engström
authors.forename: Erik
authors.initials: E
authors.lastname: af Klint
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Nicholas
authors.forename: Ger Jm
authors.initials: GJ
authors.lastname: Pruijn
authors.forename: Anca I
authors.initials: AI
authors.lastname: Catrina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002956:Citrulline / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007150:Immunohistochemistry; D007270:Injections, Intra-Articular; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques; D016896:Treatment Outcome; D014222:Triamcinolone Acetonide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D018501:Antirheumatic Agents; D005938:Glucocorticoids; D010455:Peptides; D002956:Citrulline; D003907:Dexamethasone; D006867:Hydrolases; C000620352:PADI2 protein, human; C000629235:PADI4 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D014222:Triamcinolone Acetonide; C005900:triamcinolone hexacetonide; D008727:Methotrexate