title: Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.
abstract: BACKGROUND
  Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anti-cyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA.
  
  
  OBJECTIVE
  To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed.
  
  
  METHODS
  373 patients with RA were studied. SE, padi4_94C>T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score.
  
  
  RESULTS
  CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C>T genotype (C/C: OR(adj) = 0.93, p(adj) = 0.92; C/T: OR(adj) = 2.92, p(adj) = 0.093; T/T: OR(adj) = 15.3, p(adj) = 0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C>T with ANAs was observed, with noteworthy differences depending on SE status (SE-: OR(adj) = 6.20, p(adj)<0.04; SE+: OR(adj) = 0.36, p(adj) = 0.02) and significant heterogeneity between the two SE strata (p = 0.006).
  
  
  CONCLUSIONS
  PADI4 genotype in combination with anti-CCPs and SE modulates clinical and serological characteristics of RA.
authors.affiliation: Central Institute of Laboratory Medicine and Pathobiochemistry, Charité- Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany. berthold.hoppe@charite.de
authors.forename: B
authors.initials: B
authors.lastname: Hoppe
authors.forename: T
authors.initials: T
authors.lastname: Häupl
authors.forename: K
authors.initials: K
authors.lastname: Egerer
authors.forename: R
authors.initials: R
authors.lastname: Gruber
authors.forename: H
authors.initials: H
authors.lastname: Kiesewetter
authors.forename: A
authors.initials: A
authors.lastname: Salama
authors.forename: G R
authors.initials: GR
authors.lastname: Burmester
authors.forename: T
authors.initials: T
authors.lastname: Dörner
mesh_terms: D000328:Adult; D000974:Antibodies, Antinuclear / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007596:Joints / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010456:Peptides, Cyclic / Q000276:immunology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D012217:Rheumatoid Factor / Q000032:analysis
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases