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Anti-cyclic citrullinated peptide positivity in non-rheumatoid arthritis disease samples: citrulline-dependent or not?
  1. A Vannini1,
  2. K Cheung2,
  3. M Fusconi3,
  4. J Stammen-Vogelzangs2,
  5. J P H Drenth4,
  6. A C Dall’Aglio1,
  7. F B Bianchi1,
  8. L E Bakker-Jonges5,
  9. W J van Venrooij2,
  10. G J M Pruijn2,
  11. A J W Zendman2
  1. 1Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Bologna, Italy
  2. 2Department of Biomolecular Chemistry, Radboud University Nijmegen, Nijmegen, The Netherlands
  3. 3Department of Internal Medicine, Azienda Ospedaliero-Universitaria S.Orsola-Malpighi, Bologna, Italy
  4. 4Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  5. 5Department of Immunology, Erasmus University Medical Centre, Rotterdam, The Netherlands
  1. Correspondence to:
    Dr A Vannini
    Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Bologna, Italy;antoniovannini{at}


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.

Objectives: 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.

  • AIH-1, Type 1 autoimmune hepatitis
  • AIH, autoimmune hepatitis
  • ANA, antinuclear antibodies
  • Anti-CCP, anti-cyclic citrullinated peptide
  • IAHG, International Autoimmune Hepatitis Group
  • PsA, psoriatic arthritis
  • SjS, Sjögren’s syndrome
  • SLE, systemic lupus erythematosus
  • SMA, smooth muscle antibodies

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  • Published Online First 19 September 2006

  • Funding: This work was financially supported by grants from the “Ordine dei Medici Chirurghi ed Odontoiatri”, Bologna, Italy; “Scuola di Specializzazione in Medicina Interna”, University of Bologna, Bologna, Italy; and the Netherlands Organisation for Health Research and Development grant nr. 916.56.071.

  • Competing interests: None declared.

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