title: Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage.
abstract: BACKGROUND
  The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2.
  
  
  METHODS
  A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia).
  
  
  RESULTS
  The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P<0.001) and also increased significantly after disease onset (P<0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P<0.05, all).
  
  
  CONCLUSIONS
  The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.
authors.affiliation: Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, SE-90185, Sweden. mikael.brink@medicin.umu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brink
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands. M.K.Verheul@lumc.nl.
authors.forename: Marije K
authors.initials: MK
authors.lastname: Verheul
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. johan.ronnelid@igp.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.affiliation: Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, SE-90185, Sweden. Ewa.berglin@vll.se.
authors.forename: Ewa
authors.initials: E
authors.lastname: Berglin
authors.affiliation: Department of Medical Biochemistry and Biophysics, Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden. Rikard.Holmdahl@ki.se.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands. r.e.m.toes@lumc.nl.
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden. Lars.Klareskog@ki.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands. L.A.Trouw@lumc.nl.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, SE-90185, Sweden. solbritt.rantapaa.dahlqvist@umu.se.
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000276:immunology*; D058070:Asymptomatic Diseases; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology*; D016022:Case-Control Studies; D002642:Chick Embryo; D002956:Citrulline / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D011859:Radiography
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007070:Immunoglobulin A; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D002956:Citrulline