Rheumatoid arthritis (RA) is an autoimmune disease characterized by autoantibodies against citrullinated antigens. The importance of citrulline for the epitopes bound by these autoantibodies, referred to as ACPA (anti-citrullinated peptide/protein antibodies), was first described in 1998. In addition to citrullinated proteins, cyclic citrullinated peptides (CCP) can also be used as test substrates for detecting ACPA. The standard test for these antibodies is the second-generation CCP (CCP2) test, which is one of the best in terms of sensitivity and specificity. The generation of ACPA is an early event in the disease course, and is dependent on the presence of certain MHC class II alleles. ACPA in the inflamed synovium have been shown to associate with citrullinated antigens to form immune complexes, resulting in progression of the inflammatory process. The involvement of ACPA in the chronicity of RA is probably the reason why ACPA-positive patients have a more erosive disease course than ACPA-negative patients. The presence of ACPA has been included in the 2010 RA classification criteria. Thus, it is important to further standardize ACPA testing, for example by including an internal serum standard, which may lead to a better distinction between low and high ACPA levels.
Anti-citrullinated peptide/protein antibodies (ACPA) are present in early disease, and are highly specific for rheumatoid arthritis (RA)
Data from the literature show that the second-generation anti-cyclic citrullinated peptide antibody (CCP2) test is one of the best tools for detecting ACPA
The CCP2 test enables the clinician to distinguish two subclasses of patients with early RA (ACPA-positive and ACPA-negative), each with their own genetic background and future disease course
ACPA have recently been added to the RA classification criteria jointly developed by the American College of Rheumatology and the European League Against Rheumatism
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schellekens, G. A., de Jong, B. A., van den Hoogen, F. H., van de Putte, L. B. & van Venrooij, W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998).
Schellekens, G. A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000).
van Gaalen, F. A. et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 50, 709–715 (2004).
Rantapaa-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).
van Venrooij, W. J., Zendman, A. J. & Pruijn, G. J. Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun. Rev. 6, 37–41 (2006).
Avouac, J., Gossec, L. & Dougados, M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann. Rheum. Dis. 65, 845–851 (2006).
Pruijn, G. J., Wiik, A. & van Venrooij, W. J. The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis. Arthritis Res. Ther. 12, 203 (2010).
van der Woude, D. et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann. Rheum. Dis. 69, 1554–1561 (2010).
Aletaha, D. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 62, 2569–2581 (2010).
Neogi, T. et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum. 62, 2582–2591 (2010).
van der Linden, M. P., Knevel, R., Huizinga, T. W. & van der Helm-van Mil, A. H. Classification of rheumatoid arthritis—comparison of the 1987 ACR and 2010 ACR/EULAR criteria. Arthritis Rheum. 63, 37–42 (2011).
Nienhuis, R. L. & Mandema, E. A new serum factor in patients with rheumatoid arthritis: the antiperinuclear factor. Ann. Rheum. Dis. 23, 302–305 (1964).
Dale, B. A., Holbrook, K. A., Kimball, J. R., Hoff, M. & Sun, T. T. Expression of epidermal keratins and filaggrin during human fetal skin development. J. Cell Biol. 101, 1257–1269 (1985).
Hoet, R. M., Boerbooms, A. M., Arends, M., Ruiter, D. J. & van Venrooij, W. J. Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin. Ann. Rheum. Dis. 50, 611–618 (1991).
Hoet, R. M., Voorsmit, R. A. & van Venrooij, W. J. The perinuclear factor, a rheumatoid arthritis-specific autoantigen, is not present in keratohyalin granules of cultured buccal mucosa cells. Clin. Exp. Immunol. 84, 59–65 (1991).
Simon, M. et al. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called “antikeratin antibodies,” autoantibodies specific for rheumatoid arthritis. J. Clin. Invest. 92, 1387–1393 (1993).
Sebbag, M. et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 95, 2672–2679 (1995).
Girbal-Neuhauser, E. et al. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J. Immunol. 162, 585–594 (1999).
Vossenaar, E. R. & van Venrooij, W. J. Anti-CCP antibodies, a highly specific marker for (early) rheumatoid arthritis. Clin. Applied Immunol. Rev. 4, 239–262 (2004).
Wiik, A. S., van Venrooij, W. J. & Pruijn, G. J. All you wanted to know about anti-CCP but were afraid to ask. Autoimmun. Rev. 10, 90–93 (2010).
van Beers, J. J. B. C., Zendman, A. J. W., van Venrooij, W. J. & Pruijn, G. J. M. in From Etiopathogenesis to the Prediction of Autoimmune Diseases: Relevance of Autoantibodies: Report on the 8th Dresden Symposium on Autoantibodies held in Dresden on September 12–15, 2007. Ch. 7 (eds Conrad, K. et al.) 378–388 (Pabst Science Publishers, Lengerich, 2007).
Vossenaar, E. R. et al. The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum. 50, 3485–3494 (2004).
Klareskog, L., Catrina, A. I. & Paget, S. Rheumatoid arthritis. Lancet 373, 659–672 (2009).
Hill, J. A. et al. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J. Immunol. 171, 538–541 (2003).
Hill, J. A. et al. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J. Exp. Med. 205, 967–979 (2008).
van der Woude, D. et al. Protection against anti-citrullinated protein antibody-positive rheumatoid arthritis is predominantly associated with HLA-DRB1*1301: a meta-analysis of HLA-DRB1 associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in four European populations. Arthritis Rheum. 62, 1236–1245 (2010).
James, E. A. et al. HLA-DR1001 presents “altered-self” peptides derived from joint-associated proteins by accepting citrulline in three of its binding pockets. Arthritis Rheum. 62, 2909–2918 (2010).
Gyetvai, A. et al. New classification of the shared epitope in rheumatoid arthritis: impact on the production of various anti-citrullinated protein antibodies. Rheumatology (Oxford) 49, 25–33 (2010).
Berglin, E. et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res. Ther. 6, R303–R308 (2004).
Klareskog, L., Wedren, S. & Alfredsson, L. On the origins of complex immune-mediated disease: the example of rheumatoid arthritis. J. Mol. Med. 87, 357–362 (2009).
Bang, S. Y. et al. Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regardless of anti-cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis: a case control study. Arthritis Res. Ther. 12, R115 (2010).
van Venrooij, W. J. & Pruijn, G. J. An important step towards completing the rheumatoid arthritis cycle. Arthritis Res. Ther. 10, 117 (2008).
Klareskog, L., Ronnelid, J., Lundberg, K., Padyukov, L. & Alfredsson, L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu. Rev. Immunol. 26, 651–675 (2008).
Bang, H. et al. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 56, 2503–2511 (2007).
Mathsson, L. et al. Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum. 58, 36–45 (2008).
Vander Cruyssen, B. et al. Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays. Arthritis Res. Ther. 8, R122 (2006).
Bizzaro, N., Tonutti, E., Tozzoli, R. & Villalta, D. Analytical and diagnostic characteristics of 11 2nd- and 3rd-generation immunoenzymatic methods for the detection of antibodies to citrullinated proteins. Clin. Chem. 53, 1527–1533 (2007).
Coenen, D., Verschueren, P., Westhovens, R. & Bossuyt, X. Technical and diagnostic performance of 6 assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of rheumatoid arthritis. Clin. Chem. 53, 498–504 (2007).
Dejaco, C. et al. Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis. Arthritis Res. Ther. 8, R119 (2006).
Mutlu, N. et al. Comparative performance analysis of 4 different anti-citrullinated protein assays in the diagnosis of rheumatoid arthritis. J. Rheumatol. 36, 491–500 (2009).
Damjanovska, L. et al. Diagnostic value of anti-MCV antibodies in differentiating early inflammatory arthritis. Ann. Rheum. Dis. 69, 730–732 (2010).
Innala, L. et al. Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides. J. Rheumatol. 35, 1002–1008 (2008).
Soos, L. et al. Clinical evaluation of anti-mutated citrullinated vimentin by ELISA in rheumatoid arthritis. J. Rheumatol. 34, 1658–1663 (2007).
Vander Cruyssen, B. et al. Do all anti-citrullinated protein/peptide antibody tests measure the same? Evaluation of discrepancy between anti-citrullinated protein/peptide antibody tests in patients with and without rheumatoid arthritis. Ann. Rheum. Dis. 67, 542–546 (2008).
van der Linden, M. P. et al. Towards a data-driven evaluation of the 2010 ACR/EULAR criteria for rheumatoid arthritis: is it sensible to look at levels of rheumatoid factor? Arthritis Rheum. 63, 1190–1199 (2011).
Jansen, L. M. et al. The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis. J. Rheumatol. 30, 1691–1695 (2003).
Snir, O. et al. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Ann. Rheum. Dis. 68, 736–743 (2009).
Snir, O. et al. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum. 62, 44–52 (2010).
Ioan-Facsinay, A. et al. Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protein antibodies and contain overlapping and non-overlapping reactivities. Ann. Rheum. Dis. 70, 188–193 (2011).
Andrade, F. et al. Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation. Arthritis Rheum. 62, 1630–1640 (2010).
Halvorsen, E. H. et al. Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity. Ann. Rheum. Dis. 67, 414–417 (2008).
Halvorsen, EH. et al. Serum IgG antibodies to peptidylarginine deiminase 4 predict radiographic progression in patients with rheumatoid arthritis treated with tumour necrosis factor-alpha blocking agents. Ann. Rheum. Dis. 68, 249–252 (2009).
Kolfenbach, J. R. et al. Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis. Arthritis Rheum. 62, 2633–2639 (2010).
Ioan-Facsinay, A. et al. Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease. Arthritis Rheum. 58, 3000–3008 (2008).
Schuerwegh, A. J. et al. Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 107, 2586–2591 (2010).
Kokkonen, H. et al. Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res. Ther. 13, R13 (2011).
Vannini, A. et al. Anti-cyclic citrullinated peptide positivity in non-rheumatoid arthritis disease samples: citrulline-dependent or not? Ann. Rheum. Dis. 66, 511–516 (2007).
Kakumanu, P. et al. Citrulline dependence of anti-cyclic citrullinated peptide antibodies in systemic lupus erythematosus as a marker of deforming/erosive arthritis. J. Rheumatol. 36, 2682–2690 (2009).
Elkayam, O. et al. The anti-cyclic citrullinated peptide response in tuberculosis patients is not citrulline-dependent and sensitive to treatment. Arthritis Res. Ther. 12, R12 (2010).
Kakumanu, P. et al. Patients with pulmonary tuberculosis are frequently positive for anti-cyclic citrullinated peptide antibodies, but their sera also react with unmodified arginine-containing peptide. Arthritis Rheum. 58, 1576–1581 (2008).
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
Berglin, E. et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann. Rheum. Dis. 65, 453–458 (2006).
Kallberg, H. et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80, 867–875 (2007).
van Beers, J. J. B. C., van Venrooij, W. J. & Pruijn, G. J. M. in From Pathogenesis to Therapy of Autoimmune Diseases: Autoantigens, Autoantibodies, Autoimmunity (eds Conrad, K. et al.) 265–278 (Pabst Science Publishers, Lengerich, 2009).
van der Helm-van Mil, A. H. & Huizinga, T. W. Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. Arthritis Res. Ther. 10, 205–212 (2008).
Cader, M. Z., Filer, A. D., Buckley, C. D. & Raza, K. The relationship between the presence of anti-cyclic citrullinated peptide antibodies and clinical phenotype in very early rheumatoid arthritis. BMC. Musculoskelet. Disord. 11, 187–191 (2010).
Pedersen, M. et al. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res. Ther. 8, R133 (2006).
López-Longo, F. J., Sánchez-Ramón, S. & Carreño, L. The value of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: do they imply new risk factors? Drug News Perspect. 22, 543–548 (2009).
van Dongen, H. et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 56, 1424–1432 (2007).
Mikuls, T. R. et al. Anti-citrullinated protein antibody (ACPA) in rheumatoid arthritis: influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione S-transferase in a cross-sectional study. Arthritis Res. Ther. 12, R213 (2010).
Kallberg, H. et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann. Rheum. Dis. 70, 508–511 (2011).
Bang, S. Y. et al. Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status. Arthritis Rheum. 62, 369–377 (2010).
Vossenaar, E. R. & van Venrooij, W. J. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res. Ther. 6, 107–111 (2004).
Bos, W. H., Dijkmans, B. A., Boers, M., van de Stadt, R. J. & van Schaardenburg, D. Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial. Ann. Rheum. Dis. 69, 571–574 (2010).
Mjaavatten, M. D. et al. The likelihood of persistent arthritis increases with the level of anti-citrullinated peptide antibody and immunoglobulin M rheumatoid factor: a longitudinal study of 376 patients with very early undifferentiated arthritis. Arthritis Res. Ther. 12, R76 (2010).
Kuhn, K. A. et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J. Clin. Invest. 116, 961–973 (2006).
Uysal, H. et al. Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis. J. Exp. Med. 206, 449–462 (2009).
Ho, P. P. et al. Autoimmunity against fibrinogen mediates inflammatory arthritis in mice. J. Immunol. 184, 379–390 (2010).
Clavel, C. et al. Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 58, 678–688 (2008).
van Oosterhout, M. et al. Differences in synovial tissue infiltrates between anti-cyclic citrullinated peptide-positive rheumatoid arthritis and anti-cyclic citrullinated peptide-negative rheumatoid arthritis. Arthritis Rheum. 58, 53–60 (2008).
Trouw, L. A. et al. Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways. Arthritis Rheum. 60, 1923–1931 (2009).
Sokolove, J., Zhao, X., Chandra, P. E. & Robinson, W. H. Immune complexes containing citrullinated fibrinogen co-stimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 63, 53–62 (2010).
Mahdi, H. et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis. Nat. Genet. 41, 1319–1324 (2009).
Visser, K. et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the BeSt study. Ann. Rheum. Dis. 69, 1333–1337 (2010).
Wegner, N. et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 62, 2662–2672 (2010).
Mangat, P., Wegner, N., Venables, P. J. & Potempa, J. Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis? Arthritis Res. Ther. 12, 209–217 (2010).
Edwards, J. C. & Cambridge, G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford) 40, 205–211 (2001).
Cambridge, G. et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 48, 2146–2154 (2003).
Vossenaar, E. R., Zendman, A. J., van Venrooij, W. J. & Pruijn, G. J. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25, 1106–1118 (2003).
Our work was supported in part by the Dutch Arthritis Association and the Dutch Technology Foundation (STW).
The authors declare no competing financial interests.
About this article
Cite this article
van Venrooij, W., van Beers, J. & Pruijn, G. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol 7, 391–398 (2011). https://doi.org/10.1038/nrrheum.2011.76
The Journal of Nutritional Biochemistry (2020)
Effect of Porphyromonas gingivalis infection on gut dysbiosis and resultant arthritis exacerbation in mouse model
Arthritis Research & Therapy (2020)
Autophagy promotes citrullination of VIM (vimentin) and its interaction with major histocompatibility complex class II in synovial fibroblasts
Inhibitory Effect of Tetramerized Single-Chain Variable Fragment of Anti-Cyclic Citrullinated Peptide Antibodies on the Proliferation, Activation, and Secretion of Cytokines of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis In Vitro Co-Culture System
International Journal of Molecular Sciences (2020)