Elsevier

Autoimmunity Reviews

Volume 4, Issue 7, September 2005, Pages 468-474
Autoimmunity Reviews

Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: Specificity and relation with rheumatoid factor

https://doi.org/10.1016/j.autrev.2005.04.018Get rights and content

Abstract

Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific and sensitive markers for rheumatoid arthritis (RA). For instance, for the anti-CCP2 assay, sensitivities ranging from 55% to 80% and specificities ranging from 90% to 98% have been reported. Despite their high specificity, recent reports have suggested that ACPA may be found in some patients with other rheumatic autoimmune diseases, including psoriatic arthritis, systemic lupus erythematosus and Sjögren's syndrome. Also, the differences between the classical rheumatoid factor (RF) and ACPA, as well as the complementarity between both tests have recently been demonstrated more clearly. Indeed, both antibody systems have a different association with specific RA features like extra-articular manifestations, a different association with the HLA shared epitope and, behave differently following anti-TNF therapy.

Section snippets

Introduction and short history of ACPA

Autoantibody formation is a common manifestation of rheumatoid arthritis (RA). The oldest and best-known antibody is the rheumatoid factor (RF), which constitutes one of the revised American College of Rheumatology (ACR) criteria for RA. In 1964, a new antibody was described: the antiperinuclear factor (APF). This factor was the first of a new group of antibodies, which we currently know to be directed against citrullinated residues and known as anti-citrullinated protein/peptide antibodies

ACPA as a highly specific marker for rheumatoid arthritis

In general, all recent ACPA assays have a good diagnostic performance for the diagnosis of RA. Anti-CCP2 assays have a sensitivity of 55% to 80% and a specificity of 90% to 98% for established RA [4], [5], [6]. Sensitivities and specificities can differ between studies, due to the use of different patient populations, different control populations [7], different assays, and the use of different cut-offs. In general, tests are validated in established disease. From a clinical point of view,

Reports on appearance of ACPA in non-RA rheumatic diseases

Despite the high specificity of ACPA for RA, there are several reports about the occurrence of ACPA in non-RA rheumatic diseases.

Phenotypic correlations with RF and ACPA

It is generally accepted that patients with extra-articular manifestations such as rheumatic nodules are more frequently RF positive. This is in contrast with ACPA. Indeed, RF positivity and not ACPA positivity seemed to be more frequent in patients with compared to patients without such extra-articular manifestations [12]. Similar results were previously found with AFA [29]. Both RF and ACPA have been associated with more severe and more erosive disease [7], [25], [30].

Associations of RF and ACPA with the HLA shared epitope

In RA patients, there is an association between ACPA and the HLA shared epitope. This is in contrast to RF, which seems to be less associated with the HLA shared epitope. This is reflected by higher odds ratios (OR) for the association between ACPA and the HLA shared epitope than for the association between RF and the HLA shared epitope [31], [32]. Three studies directly compared these associations. In a study with longstanding RA patients, ACPA, and not RF, were significantly more frequent

Evolutions of RF and ACPA concentrations following biological therapy

Four studies evaluated the effect of ACPA and RF concentrations after infliximab treatment. All studies found a significant decrease in RF titers. Two of them found no decrease in ACPA concentrations [35], [36] after 22 and 30 weeks; another study described a decrease of ACPA levels at week 24 [37]; the fourth study found a decrease of ACPA levels at week 30; however at week 52 and week 78 there was an evolution towards baseline levels [38]. The discrepant behavior between ACPA and RF following

Future use of RF and ACPA

In general, ACPA are superior to RF for diagnosing RA. In view of the reduced costs of RF versus ACPA, it is relevant to identify situations where the diagnostic performance of RF equals that of ACPA. This is the case if RF reaches very high levels or if intermediately high RF levels occur in patients with a high pretest probability for RA [14]. A guideline for clinicians might thus be a two-step testing model. One can start with RF: when there is a high pretest probability for RA (based on the

Conclusions

ACPA and RF are distinct antibody systems yielding different information. They also differ in their association with the HLA shared epitope and with extra-articular manifestations, and behave differently following therapy. It can be stated that ACPA have better diagnostic properties than RF, which is reflected by a higher sensitivity at a preset high specificity level. However, the presence of ACPA does not exclude other rheumatic diseases and should always be interpreted in the full clinical

Acknowledgments

Bert Vander Cruyssen was supported by a concerted action grant GOA 2001/12051501 of the Ghent University, Belgium. The work of Leen De Rycke is supported by the “Vlaams instituut voor de bevordering van het wetenschappelijk technologisch onderzoek in de industrie” (IWT/ISB/11127).

Tineke Cantaert is supported by a research grant form the ‘Bijzonder Onderzoeksfonds' (B/04608) Ghent University.

Take-home messages

  • ACPA are highly specific markers for rheumatoid arthritis; yet, they do not exclude the

References (40)

  • M. Sebbag et al.

    Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis

    Joint Bone Spine

    (2004)
  • A. Union et al.

    Identification of citrullinated rheumatoid arthritis-specific epitopes in natural filaggrin relevant for antifilaggrin autoantibody detection by line immunoassay

    Arthritis Rheum

    (2002)
  • I. Peene et al.

    History and diagnostic value of antibodies to citrullinated proteins in rheumatoid arthritis

    Int J Immunopathol Pharmacol

    (2004)
  • S. Dubucquoi et al.

    Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the diagnosis of rheumatoid arthritis

    Ann Rheum Dis

    (2004)
  • G.C. Pinheiro et al.

    Anti-cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis

    Ann Intern Med

    (2003)
  • D.M. Lee et al.

    Clinical utility of the anti-CCP assay in patients with rheumatic diseases

    Ann Rheum Dis

    (2003)
  • I. Vallbracht et al.

    Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis

    Ann Rheum Dis

    (2004)
  • A.L.M.A. Jansen et al.

    Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis

    J Rheumatol

    (2002)
  • M.K. Söderlin et al.

    Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity

    Scand J Rheumatol

    (2004)
  • A. Kastbom et al.

    Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)

    Ann Rheum Dis

    (2004)
  • M. Zweig et al.

    Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine

    Clin Chem

    (1993)
  • L. De Rycke et al.

    Rheumatoid factor and anti-citrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations

    Ann Rheum Dis

    (2004)
  • M. Nielen et al.

    Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis

    Ann Rheum Dis

    (2005 (January))
  • I.E.A. Hoffman et al.

    Diagnostic performance and predictive value of rheumatoid factor, anti-citrullinated peptide antibodies and the HLA shared epitope for the diagnosis of rheumatoid arthritis

    Clin Chem

    (2005)
  • I.E. Hoffman et al.

    Presence of rheumatoid factor and antibodies to citrullinated peptides in systemic lupus erythematosus

    Ann Rheum Dis

    (2005)
  • R. Mediwake et al.

    Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis

    Ann Rheum Dis

    (2001)
  • J.E. Gottenberg et al.

    Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjögren's syndrome

    Ann Rheum Dis

    (2005)
  • B. Vander Cruyssen et al.

    Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis

    Ann Rheum Dis

    (2005 (Feb 4))
  • L. Bogliolo et al.

    Antibodies to cyclic citrullinated peptides in psoriatic arthritis

    J Rheumatol

    (2005)
  • T. Avcin et al.

    Prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

    Ann Rheum Dis

    (2002)
  • Cited by (67)

    • Autoantibodies in psoriatic disease

      2023, Advances in Clinical Chemistry
    • Heightened autoantibody immune response to citrullinated calreticulin in bronchiectasis: Implications for rheumatoid arthritis

      2017, International Journal of Biochemistry and Cell Biology
      Citation Excerpt :

      There is credence in both neuronal signals (Sakane and Suzuki, 2000) and activation of inflammatory pathways by microorganisms (van Heemst et al., 2015) participating in immune tolerance breakdown. A clue to the origins of RA may be found in the serological profile that often precedes individuals developing the disease, namely the formation of rheumatoid factor (RF) comprised of IgM autoantibodies to IgG (Corper et al., 1997; Hutchinson et al., 2016) and anti-citrullinated peptide antibodies (ACPAs) (Vander Cruyssen et al., 2005). There is evidence to suggest that chronic and persistent infections precede and contribute to the development of RA through the generation of enzymes e.g. peptidyl arginine deiminase (PAD) (Maresz et al., 2013).

    • Comparative analysis of novel autoantibody isotypes against citrullinated-inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3)<sup>542–556</sup> peptide in serum from Taiwanese females with rheumatoid arthritis, primary Sjögren's syndrome and secondary Sjögren's syndrome in rheumatoid arthritis

      2016, Journal of Proteomics
      Citation Excerpt :

      Arlestig et al. reported that the diagnostic sensitivity and specificity of ACPA isotypes (IgG, IgA, and IgM) were higher than rheumatoid factors for RA detection, and that the diagnostically most important anti-CCP isotype was IgG, followed by IgA and IgM [43]. The anti-CCP2, a second-generation CCP test, is for the RA assay, and sensitivities ranging 55%–80% and specificities ranging 90%–98% were reported [44]. Nielen et al. reported that most isotypes of ACPA-positive RA patients appeared to be ACPA-positive already years before the onset of disease, which was up to 10 years before in RA patients [45].

    • B cell depletion with rituximab in patients with rheumatoid arthritis: Multiplex bead array reveals the kinetics of IgG and IgA antibodies to citrullinated antigens

      2016, Journal of Autoimmunity
      Citation Excerpt :

      Smoking and periodontitis, now known to be environmental risk factors for the development of Rheumatoid arthritis (RA), both promote protein citrullination in mucosa. Autoantibodies directed against citrullinated moieties on a number of proteins or their derived peptide antigens (ACPA), are present in the majority of patients with RA and have a higher specificity than Rheumatoid factor (RhF) for the disease [3,4]. The ACPA response in RA patients comprises a mixture of antibodies recognizing over-lapping but also discrete citrullinated epitopes [5].

    View all citing articles on Scopus
    View full text