Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: Specificity and relation with rheumatoid factor
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
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ACPA are highly specific markers for rheumatoid arthritis; yet, they do not exclude the
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2017, International Journal of Biochemistry and Cell BiologyCitation 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 ProteomicsCitation 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].
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2016, Journal of AutoimmunityCitation 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].