Review articleAnti-CCP antibodies, a highly specific marker for (early) rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is a common, systemic autoimmune disease affecting 0.5–1% of the population [1], [2]. It is characterized by chronic inflammation of the synovial joints, which commonly leads to progressive joint destruction and consequent disability and reduction of quality of life [3]. Disease outcome may vary from mild symptoms to severe systemic disease when joint destruction is accompanied by extraarticular manifestations (i.e., rheumatoid nodules, vasculitis). Mortality in the latter group is significantly increased compared to the former group and the general population [4], [5].
With more sophisticated and effective therapies becoming available (reviewed in [6]) and with the understanding that early intervention is crucial in preventing irreversible joint damage [7], [8], [9], it is more and more important to diagnose RA at a very early stage in the disease. Although the 1987 American College of Rheumatology (ACR; formerly, American Rheumatism Association) classification criteria for RA [10] are often used in clinical practice as diagnostic tool for RA, they are not very well suited for the diagnosis of early RA [11], [12], [13]. The ACR criteria rely heavily on the expression of clinical symptoms of RA, but in early RA these clinical parameters are often not (yet) manifest. Therefore, a specific and sensitive (serological) marker, which is present very early in the disease, is needed. Rheumatologists need to be able to target the use of potentially toxic and expensive drugs to those patients where the benefits clearly outweigh the risks [13], [14]. Therefore a good marker should ideally be able to predict the erosive or nonerosive progression of the disease. Fortunately, the anti-CCP (cyclic citrullinated peptide) antibodies meet the demands for a good and useful marker for early RA and this will be the focus of this review.
Section snippets
RA-associated antibodies
The serum of RA patients contains a large repertoire of antibodies directed against self-proteins. Most of these autoantibodies, however, can also be detected in patients with other (autoimmune) conditions, and are therefore not specific for RA. Even the well known rheumatoid factor (RF) antibodies, directed against the Fc domain of IgG molecules (reviewed in [15]), which are part of the ACR criteria [10] have only moderate specificity for RA. They can be found in patients with other autoimmune
The original systems: APF and AKA
In 1964 the antiperinuclear factor (APF) was described for the first time [48]. These autoantibodies are specific for RA (reviewed in [49]) and can be detected by indirect immunofluorescence using human buccal mucosa cells as the antigenic substrate. Light and immunoelectron microscopy revealed that the perinuclear factor is localized in the keratohyalin granules [50], [51]. These granules are 0.5–4 μm amorphous structures of densely packed proteins located in the cytoplasm of epithelial cells.
The CCP1 and CCP2 systems
To increase the sensitivity of the citrulline-containing peptide ELISA [63], peptides were modified to adopt a structure in which the citrulline moiety is optimally exposed for antibody binding ([76] and our unpublished 3D-NMR observations). With a single cyclic citrullinated peptide (CCP), antibodies could be detected in 68% of RA sera with a very high specificity (98%) [76]. This filaggrin-derived cyclic peptide was used as the antigenic substrate in the CCP1 test (results described below).
CCP for the clinician
A good serological marker should be:
- 1.
Sensitive and highly specific for the disease
- 2.
Detectable very early in the disease
- 3.
Able to prognose disease outcome
Local presence of citrullinated autoantigens at the site of inflammation in RA
The anti-CCP antibodies are probably produced locally in the synovium as they constitute a higher proportion of IgG in synovial fluid and synovial tissue compared to serum (1.4 and 7.5-fold, respectively) [66], [67]. Furthermore anti-CCP producing plasma cells have been isolated from the synovium of RA patients [66], [68]. This local antibody production requires the existence of citrullinated antigens in the inflamed synovium and consequently also the presence of PAD enzymes. Five isotypes of
For the researcher: possible pathoimmunological role in RA
Many animal models are being used to study the mechanisms of inflammation in RA (for an overview see [138]). We recently showed that synovial proteins are citrullinated during inflammation in both an acute (streptococcal cell wall arthritis) and a chronic destructive (collagen-induced arthritis) mouse model for arthritis [139]. One of the citrullinated proteins in the inflamed mouse synovium could be identified as fibrin. However, in contrast with the human disease, the mice did not produce
The future of CCP
The current second generation CCP system meets many of the requirements of a useful serological marker for RA. It is highly specific for the disease, can be detected early in the disease and because of its prognostic potential, it may provide an indication for aggressive treatment. With regard to the sensitivity of anti-CCP, there still is some room for improvement. The ideal marker would have a sensitivity of 100%, but because RA is such a complex and diverse condition, absolute sensitivity is
Conclusion
Anti-CCP antibodies meet all the requirements of a good serological marker for RA. Their high specificity and prognostic value make them a valuable diagnostic tool. Furthermore, all the available experimental data is compatible with a possible role in the disease process.
Currently, the revised 1987 ACR criteria are considered the gold standard for the classification of RA. Incorporation of anti-CCP positivity as an extra criterion would improve the accuracy of the ACR criteria [99], [107].
Acknowledgements
The authors wish to thank Dr. Han Zendman (Nijmegen, The Netherlands), Dr. Floris van Gaalen (Leiden, The Netherlands), Dr. Roberto Manetti (Florence, Italy), Dr. Anil Vasishta (Dundee, Scotland), Dr. Mark Nielen (Amsterdam, The Netherlands), Dr. Olivier Meyer (Paris, France), Dr. Solbritt Rantapää-Dahlqvist (Umea, Sweden), Dr. Guido Valesini (Rome, Italy), and Dr. Leen De Rycke (Ghent, Belgium) for providing valuable information and critical reading of the manuscript.
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