title: Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity.
abstract: BACKGROUND
  Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients.
  
  
  METHODS
  A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables.
  
  
  RESULTS
  Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants.
  
  
  CONCLUSIONS
  Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4. The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.
authors.affiliation: Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, 0027 Oslo, Norway. eirikhha@medisin.uio.no
authors.forename: E H
authors.initials: EH
authors.lastname: Halvorsen
authors.forename: S
authors.initials: S
authors.lastname: Pollmann
authors.forename: I-M
authors.initials: IM
authors.lastname: Gilboe
authors.forename: D
authors.initials: D
authors.lastname: van der Heijde
authors.forename: R
authors.initials: R
authors.lastname: Landewé
authors.forename: S
authors.initials: S
authors.lastname: Ødegård
authors.forename: T K
authors.initials: TK
authors.lastname: Kvien
authors.forename: Ø
authors.initials: Ø
authors.lastname: Molberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D005470:Fluorometry; D006801:Humans; D006867:Hydrolases / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011859:Radiography; D011994:Recombinant Proteins / Q000276:immunology; D012217:Rheumatoid Factor / Q000097:blood; D012720:Severity of Illness Index
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases