Anti-citrullinated protein antibodies (ACPAs) are
autoantibodies (
antibodies to an individual's own proteins) that are directed against
peptides and
proteins that are
citrullinated. They are present in the majority of patients with
rheumatoid arthritis. Clinically, cyclic citrullinated peptides (CCP) are frequently used to detect these antibodies in patient serum or plasma (then referred to as anti–citrullinated peptide antibodies).[1]
ACPAs have proved to be powerful
biomarkers that allow the diagnosis of
rheumatoid arthritis (RA) to be made at a very early stage.[1]
In July 2010, the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria were introduced.[3] These new classification criteria include ACPA testing, and overruled the "old"
ACR criteria of 1987 and are adapted for early RA diagnosis.
History
The presence of autoantibodies against citrullinated proteins in rheumatoid arthritis patients was first described in the mid-1970s when the biochemical basis of antibody reactivity against
keratin and
filaggrin was investigated.[4][5] Subsequent studies demonstrated that autoantibodies from RA patients react with a series of different citrullinated antigens, including fibrinogen, deiminated Epstein-Barr Virus Nuclear Antigen 1 and
vimentin,[6][7][8] which is a member of the intermediate filament family of proteins. Several assays for detecting ACPAs were developed in the following years, employing mutated citrullinated Vimentin (MCV-assay), filaggrin-derived peptides (CCP-assay)[9][10] and viral citrullinated peptides (VCP-assay).
A 2006 clinical study showed that anti viral citrullinated peptide (VCP) antibodies of the
IgG and
IgAisotypes represent a discriminating specific marker of rheumatoid arthritis from other chronic arthritides and disease controls, suggesting an independent production of each isotype.[11]
In 2010, ACPA testing has become substantial part of The 2010 ACR-EULAR classification criteria for rheumatoid arthritis.[3]
Clinical significance
In a comparative study (in 2007), various detection kits had a
sensitivity between 69.6% and 77.5% and a
specificity between 87.8% and 96.4%.[12] Despite the excellent performance of these
immunoassays, for example CCP-assays, they only provide a sensitivity comparable with that of
rheumatoid factor (RF). Moreover, analysis of the correlation of anti-CCP antibody titre with RA disease activity yielded conflicting results.[13][14] Unfortunately, these artificial antigens are not expressed in the affected tissue, and therefore are probably not directly involved in the pathogenesis of RA.[citation needed]
However, novel test systems utilizing ACPA have been developed. Citrullinated vimentin is a very promising autoantigen in RA, and a suitable tool for studying this systemic
autoimmune disease. Vimentin is secreted and citrullinated by macrophages in response to apoptosis, or by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha).[15][16]
A newly developed
ELISA system utilises genetically modified citrullinated vimentin (
MCV), a naturally occurring isoform of vimentin to optimize the performance of the test.[6][17] Noteworthy are the findings of a recently published study that highly valuates anti-MCV test systems for diagnosing rheumatoid arthritis in anti-CCP-negative patients. However, data from all around the world vary substantially.[18] Anti-CCP is also very useful in the early diagnosis of rheumatoid arthritis in high-risk groups, such as relatives of RA patients,[19] although Silman and co-workers found that the concordance rate of developing RA was 15.4% among identical (monozygotic) twins and was 3.6% among fraternal (dizygotic) twins.[20]
Given that ACPA are more specific than rheumatoid factor, they are used to distinguish various causes of arthritis.[21] Novel assays may be useful for monitoring disease activity and effects of RA therapy.[22]
Anti-CCP is part of the 2010 ACR/EULAR classification criteria for
Rheumatoid Arthritis. Anti-CCP positivity is also a good prognostic marker for future radiographic damage, and possibly a marker to B-cell therapy responses including
rituximab.[24]
Combination of anti-CCP with other serological markers like
rheumatoid factor, 14-3-3η (
YWHAH) not only enhances the diagnostic capture rate but together with acute phase reactants either in early disease or at the time of diagnosis may be useful in predicting future outcomes.
Other ACPAs and citrullinated targets in RA
Vimentin, fibrin, filaggrin, enolase and keratin are common citrullination targets. The list of proteins that undergo
citrullination and make up the citrullinome continues to increase. The RA associated citrullinome has been reported to include targets from synovial fluid and tissue that range from proteases, receptors, and carrier proteins. These proteins are components of complement, proteolytic activity, cell recognition, endocytosis, and response to biotic stimuli amongst others.[25] 14-3-3η (
YWHAH) is also another synovial derived protein that has been reported as a citrullination target.[26]
^Pratesi F, Tommasi C, Anzilotti C, Chimenti D, Migliorini P (March 2006). "Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis". Arthritis Rheum. 54 (3): 733–41.
doi:
10.1002/art.21629.
PMID16508937.
^Bang H, Egerer K, Gauliard A, et al. (August 2007). "Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis". Arthritis Rheum. 56 (8): 2503–11.
doi:
10.1002/art.22817.
PMID17665451.
^Greiner A, Plischke H, Kellner H, Gruber R (June 2005). "Association of anti-cyclic citrullinated peptide antibodies, anti-citrullin antibodies, and IgM and IgA rheumatoid factors with serological parameters of disease activity in rheumatoid arthritis". Ann. N. Y. Acad. Sci. 1050: 295–303.
doi:
10.1196/annals.1313.031.
PMID16014545.
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^Asaga H, Yamada M, Senshu T (February 1998). "Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages". Biochem. Biophys. Res. Commun. 243 (3): 641–6.
doi:
10.1006/bbrc.1998.8148.
PMID9500980.
^Mor-Vaknin N, Punturieri A, Sitwala K, Markovitz DM (January 2003). "Vimentin is secreted by activated macrophages". Nat. Cell Biol. 5 (1): 59–63.
doi:
10.1038/ncb898.
PMID12483219.
S2CID30850762.
^Iwaszkiewicz C, Puszczewicz M, Białkowska-Puszczewicz G (January 2015). "Diagnostic value of the anti-Sa antibody compared with the anti-cyclic citrullinated peptide antibody in rheumatoid arthritis". International Journal of Rheumatic Diseases. 18 (1): 46–51.
doi:
10.1111/1756-185X.12544.
PMID25488711.
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^Gardette A, Ottaviani S, Tubach F, Roy C, Nicaise-Roland P, Palazzo E, Gill G, Meyer O, Dieudé P. High anti-CCP antibody titres predict good response to rituximab in patients with active rheumatoid arthritis. Joint Bone Spine. 2014 Oct;81(5):416–20. doi: 10.1016/j.jbspin.2014.06.001. Epub 2014 Jul 3. PMID 24998790.
^Tilvawala R, Nguyen SH, Maurais AJ, Nemmara VV, Nagar M, Salinger AJ, Nagpal S, Weerapana E, Thompson PR. The Rheumatoid Arthritis-Associated Citrullinome. Cell Chem Biol. 2018 Jun 21;25(6):691–704.e6. doi: 10.1016/j.chembiol.2018.03.002. Epub 2018 Apr 5. PMID 29628436; PMCID: PMC6014894.
^Maksymowych WP, Marotta A. 14-3-3η: a novel biomarker platform for rheumatoid arthritis. Clin Exp Rheumatol. 2014 Sep-Oct;32(5 Suppl 85):S-35-9. Epub 2014 Oct 30. PMID 25365087.