title: Anti-cyclic citrullinated peptide positivity in non-rheumatoid arthritis disease samples: citrulline-dependent or not?
abstract: BACKGROUND
  Antibodies directed against citrullinated proteins (eg anti-cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH-1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH-1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti-CCP2 positivity was scored.
  
  
  OBJECTIVE
  To characterise the citrulline-dependence of the observed anti-CCP2 positivity in AIH-1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases).
  
  
  METHODS
  Serum samples of 57 patients with AIH-1 and 66 patients without rheumatoid arthritis, most of them reported as anti-CCP positive, were tested for citrulline-specific reactivity with a second generation anti-CCP kit, with the citrullinated and the corresponding non-citrullinated (arginine-containing) antigen. A subset of AIH-1 sera was also tested with a CCP1 ELISA (and arginine control).
  
  
  RESULTS
  The anti-CCP2 reactivity of most non-rheumatoid arthritis rheumatic diseases samples (87-93%) was citrulline-specific, whereas a relatively high percentage of AIH-1 samples (42-50%) turned out to be reactive in a citrulline-independent manner. The use of citrullinated and non-citrullinated CCP1 peptides confirmed a high occurrence of citrulline-independent reactivity in AIH-1 samples.
  
  
  CONCLUSIONS
  In rheumatoid arthritis and most non-rheumatoid arthritis rheumatologic disease sera, anti-CCP positivity is citrulline-dependent. However in some patients, particularly patients with AIH-1, citrulline-independent reactivity in the anti-CCP2 test can occur. A positive CCP test in a non-rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.
authors.affiliation: Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, and Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. antoniovannini@tiscali.it
authors.forename: A
authors.initials: A
authors.lastname: Vannini
authors.forename: K
authors.initials: K
authors.lastname: Cheung
authors.forename: M
authors.initials: M
authors.lastname: Fusconi
authors.forename: J
authors.initials: J
authors.lastname: Stammen-Vogelzangs
authors.forename: J P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: A C
authors.initials: AC
authors.lastname: Dall'Aglio
authors.forename: F B
authors.initials: FB
authors.lastname: Bianchi
authors.forename: L E
authors.initials: LE
authors.lastname: Bakker-Jonges
authors.forename: W J
authors.initials: WJ
authors.lastname: van Venrooij
authors.forename: G J M
authors.initials: GJ
authors.lastname: Pruijn
authors.forename: A J W
authors.initials: AJ
authors.lastname: Zendman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis / Q000175:diagnosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002648:Child; D002956:Citrulline / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000939:Epitopes; D005260:Female; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D011933:Reagent Kits, Diagnostic; D012216:Rheumatic Diseases / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D000939:Epitopes; D010456:Peptides, Cyclic; D011933:Reagent Kits, Diagnostic; C487763:cyclic citrullinated peptide; D002956:Citrulline