Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that principally affects synovial joints, leading to functional disability and significant morbidity and mortality. The hallmark of RA is the presence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies. Based on the presence of anti-CCP antibodies, RA can be classified into two subsets: anti-CCP positive and anti-CCP negative RA, having distinct genetic and environmental risk factors and different pathogenesis. Early and accurate diagnosis of RA is the key to timely and appropriate management of the disease. Anti-CCP antibodies can be detected at an early stage of RA when symptoms are milder and incomplete or even absent, making these autoantibodies a useful serological marker for early diagnosis. Furthermore, the presence of anti-CCP antibodies can predict the development of joint erosions. Hence, RA patients with a potentially severe course may be selected for early aggressive treatment, which may reduce structural joints damage. In addition, anti-CCP antibodies are considered a useful biomarker for monitoring disease activity and therapy response. On the other hand, several studies in RA patients have focused on the diagnostic performances of second and third generations of anti-CCP antibodies, as well as their cut-off values that considerably differ between available assays, thereby emphasizing the need for harmonization of the cut-off values for low and high anti-CCP levels.
This review aims to discuss the clinical significance of anti-CCP antibodies in RA, with highlights on the diagnostic performances of anti-CCP2 and anti-CCP3 assays.
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References
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094–108. https://doi.org/10.1016/S0140-6736(10)60826-4.
van Delft MAM, Huizinga TWJ. An overview of autoantibodies in rheumatoid arthritis. J Autoimmun. 2020;110:102392. https://doi.org/10.1016/j.jaut.2019.102392.
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358:903–11. https://doi.org/10.1016/S0140-6736(01)06075-5.
Cho J, Pyo JY, Fadriquela A, Uh Y, Lee JH. Comparison of the analytical and clinical performances of four anti-cyclic citrullinated peptide antibody assays for diagnosing rheumatoid arthritis. Clin Rheumatol. 2021;40(2):565–73. https://doi.org/10.1007/s10067-020-05412-w.
Demoruelle MK, Deane K. Antibodies to citrullinated protein antigens (ACPAs): clinical and pathophysiologic significance. Curr Rheumatol Rep. 2011;13(5):421–30. https://doi.org/10.1007/s11926-011-0193-7.
Goëb V, Jouen F, Gilbert D, Le Loët X, Tron F, Vittecoq O. Diagnostic and prognostic usefulness of antibodies to citrullinated peptides. Joint Bone Spine. 2009;76(4):343–9. https://doi.org/10.1016/j.jbspin.2008.12.006.
Van Hoovels L, Studenic P, Sieghart D, Steiner G, Bossuyt X, Rönnelid J. Impact of autoimmune serology test results on RA classification and diagnosis. J Transl Autoimmun. 2022;5:100142. https://doi.org/10.1016/j.jtauto.2022.100142.
Lee AN, Beck CE, Hall M. Rheumatoid factor and anti-CCP autoantibodies in rheumatoid arthritis: a review. Clin Lab Sci. 2008;21(1):15–8.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81. https://doi.org/10.1002/art.27584.
Malher M, Bentow C, Albesa R, Cesana L, Martinez-Prat L, Roux-Lombard P, Nissen MJ, et al. P024 Comparison of CCP2 and CCP3 assays in a large cohort of established rheumatoid arthritis and controls. Annals of the Rheumatic Diseases. 2018;77:A24.
Sokolova MV, Schett G, Steffen U. Autoantibodies in rheumatoid arthritis: historical background and novel findings. Clin Rev Allerg Immunol. 2022;63(2):138–51. https://doi.org/10.1007/s12016-021-08890-1.
Farid SS, Azizi G, Mirshafiey A. Anti-citrullinated protein antibodies and their clinical utility in rheumatoid arthritis. Int J Rheum Dis. 2013;16(4):379–86. https://doi.org/10.1111/1756-185X.12129.
England BR, Thiele GM, Mikuls TR. Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol. 2017;29(1):57–64. https://doi.org/10.1097/BOR.0000000000000356.
Ji M, Hur M, Moon HW, Park M, Yun YM, Lee SH. Comparison of second- and third-generation immunoassays for detection of anti-cyclic citrullinated peptide antibodies. Scand J Clin Lab Invest. 2018;78(6):477–82. https://doi.org/10.1080/00365513.2018.1499957.
Iyengar KP, Vaish A, Nune A. Anti-cyclic citrullinated peptide antibody (ACPA) and Rheumatoid arthritis: Clinical relevance. J Clin Orthop Trauma. 2021;24:101729. https://doi.org/10.1016/j.jcot.2021.101729.
Ten Brinck RM, van Steenbergen HW, van Delft MAM, Verheul MK, Toes REM, Trouw LA, van der Helm-van Mil AHM. The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia. Rheumatology (Oxford). 2017;56(12):2145–53. https://doi.org/10.1093/rheumatology/kex340.
Finckh A, Courvoisier D, Lamacchia C. Recherche clinique en rhumatismes inflammatoires. Measuring ACPA in the general population or primary care: is it useful? RMD Open. 2020;6(1):e001085. https://doi.org/10.1136/rmdopen-2019-001085.
Petrovská N, Prajzlerová K, Vencovský J, Šenolt L, Filková M. The pre-clinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis. Autoimmun Rev. 2021;20(5):102797. https://doi.org/10.1016/j.autrev.2021.102797.
Pedersen M, Jacobsen S, Klarlund M, Pedersen BV, Wiik A, Wohlfahrt J, Frisch M. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res Ther. 2006;8(4):R133. https://doi.org/10.1186/ar2022.
Catrina A, Krishnamurthy A, Rethi B. Current view on the pathogenic role of anti-citrullinated protein antibodies in rheumatoid arthritis. RMD Open. 2021;7:e001228. https://doi.org/10.1136/rmdopen-2020-001228.
Willemze A, Trouw LA, Toes RE, Huizinga TW. The influence of ACPA status and characteristics on the course of RA. Nat Rev Rheumatol. 2012;8(3):144–52. https://doi.org/10.1038/nrrheum.2011.204.
Diaz FJ, Rojas-Villarraga A, Salazar JC, Iglesias-Gamarra A, Mantilla RD, Anaya JM. Anti-CCP antibodies are associated with early age at onset in patients with rheumatoid arthritis. Joint Bone Spine. 2011;78(2):175–8. https://doi.org/10.1016/j.jbspin.2010.07.014.
Källberg H, Ding B, Padyukov L, Bengtsson C, Rönnelid J, Klareskog L, Alfredsson L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70(3):508–11. https://doi.org/10.1136/ard.2009.120899.
Sakkas LI, Daoussis D, Liossis SN, Bogdanos DP. The Infectious Basis of ACPA-Positive Rheumatoid Arthritis. Front Microbiol. 2017;8:1853. https://doi.org/10.3389/fmicb.2017.01853.
Raine C, Giles I. What is the impact of sex hormones on the pathogenesis of rheumatoid arthritis? Front Med (Lausanne). 2022;9:909879. https://doi.org/10.3389/fmed.2022.909879.
Tang MW, Garcia S, Gerlag DM, Tak PP, Reedquist KA. Insight into the Endocrine System and the Immune System: A Review of the Inflammatory Role of Prolactin in Rheumatoid Arthritis and Psoriatic Arthritis. Front Immunol. 2017;8:720. https://doi.org/10.3389/fimmu.2017.00720.
Alghamdi MF, Redwan EM. Advances in the diagnosis of autoimmune diseases based on citrullinated peptides/proteins. Expert Rev Mol Diagn. 2021;21(7):685–702. https://doi.org/10.1080/14737159.2021.1933946.
Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017;39(4):437–46. https://doi.org/10.1007/s00281-017-0627-z.
Mimori T. Clinical significance of anti-CCP antibodies in rheumatoid arthritis. Intern Med. 2005;44(11):1122–6. https://doi.org/10.2169/internalmedicine.44.1122.
Pruijn GJ, Wiik A, van Venrooij WJ. The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis. Arthritis Res Ther. 2010;12(1):203. https://doi.org/10.1186/ar2903.
Burgers LE, van Steenbergen HW, Ten Brinck RM, Huizinga TW, van der Helm-van Mil AH. Differences in the symptomatic phase preceding ACPA-positive and ACPA-negative RA: a longitudinal study in arthralgia during progression to clinical arthritis. Ann Rheum Dis. 2017;76(10):1751–4. https://doi.org/10.1136/annrheumdis-2017-211325.
Ge C, Holmdahl R. The structure, specificity and function of anti-citrullinated protein antibodies. Nat Rev Rheumatol. 2019;15(8):503–8. https://doi.org/10.1038/s41584-019-0244-4.
Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):20–5. https://doi.org/10.1093/rheumatology/kei111.
Vossenaar ER, van Venrooij WJ. Anti-CCP antibodies, a highly specific marker for (early) rheumatoid arthritis. Clinical and Applied Immunology Reviews. 2004;4(4):239–62. https://doi.org/10.1016/j.cair.2003.11.001.
HUA, Charlotte et COMBE, Bernard. The new ACR/EULAR 2010 classification criteria for an earlier rheumatoid arthritis diagnosis. Revue du Rhumatisme Monographies. 2017;84(4):337–42. https://doi.org/10.1016/j.monrhu.2017.07.001.
Zhang WC, Wu H, Chen WX. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide 2 antibody and anti-cyclic citrullinated peptide 3 antibody in rheumatoid arthritis. Clin Chem Lab Med. 2014;52(6):779–90. https://doi.org/10.1515/cclm-2013-0798.
Johnson PM, Faulk WP. Rheumatoid factor: its nature, specificity, and production in rheumatoid arthritis. Clin Immunol Immunopathol. 1976;6(3):414–30. https://doi.org/10.1016/0090-1229(76)90094-5.
Lisse JR. Does rheumatoid factor always mean arthritis? Postgrad Med. 1993;94(6):133–9. https://doi.org/10.1080/00325481.1993.11945749.
Swart A, Burlingame RW, Gürtler I, Mahler M. Third generation anti-citrullinated peptide antibody assay is a sensitive marker in rheumatoid factor negative rheumatoid arthritis. Clin Chim Acta. 2012;414:266–72. https://doi.org/10.1016/j.cca.2012.09.015.
Szekanecz Z, Szabó Z, Zeher M, Soós L, Dankó K, Horváth I, Lakos G. Superior performance of the CCP3.1 test compared to CCP2 and MCV in the rheumatoid factor-negative RA population. Immunol Res. 2013;56(2-3):439–43. https://doi.org/10.1007/s12026-013-8425-8.
Debaugnies F, Servais G, Badot V, Noubouossie D, Willems D, Corazza F. Anti-cyclic citrullinated peptide antibodies: a comparison of different assays for the diagnosis of rheumatoid arthritis. Scand J Rheumatol. 2013;42(2):108–14. https://doi.org/10.3109/03009742.2012.723746.
dos Anjos LM, Pereira IA, d 'Orsi E, Seaman AP, Burlingame RW, Morato EF. A comparative study of IgG second- and third-generation anti-cyclic citrullinated peptide (CCP) ELISAs and their combination with IgA third-generation CCP ELISA for the diagnosis of rheumatoid arthritis. Clin Rheumatol. 2009;28(2):153–8. https://doi.org/10.1007/s10067-008-0999-5.
Shidara K, Inoue E, Tanaka E, Hoshi D, Seto Y, Nakajima A, Momohara S, et al. Comparison of the second and third generation anti-cyclic citrullinated peptide antibody assays in the diagnosis of Japanese patients with rheumatoid arthritis. Rheumatol Int. 2011;31(5):617–22. https://doi.org/10.1007/s00296-009-1336-2.
Wiik AS, van Venrooij WJ, Pruijn GJ. All you wanted to know about anti-CCP but were afraid to ask. Autoimmun Rev. 2010;10(2):90–3. https://doi.org/10.1016/j.autrev.2010.08.009.
Lutteri L, Malaise M, Chapelle JP. Comparison of second- and third-generation anti-cyclic citrullinated peptide antibodies assays for detecting rheumatoid arthritis. Clin Chim Acta. 2007;386(1-2):76–81. https://doi.org/10.1016/j.cca.2007.08.002.
Vos I, Van Mol C, Trouw LA, Mahler M, Bakker JA, Van Offel J, De Clerck L, et al. Anti-citrullinated protein antibodies in the diagnosis of rheumatoid arthritis (RA): diagnostic performance of automated anti-CCP-2 and anti-CCP-3 antibodies assays. Clin Rheumatol. 2017;36(7):1487–92. https://doi.org/10.1007/s10067-017-3684-8.
Correia ML, Carvalho S, Fortuna J, Pereira MH. Comparison of three anti-CCP antibody tests and rheumatoid factor in RA and control patients. Clin Rev Allergy Immunol. 2008;34(1):21–5. https://doi.org/10.1007/s12016-007-8030-5.
Song J, Li M, Li S, Ma J, Liu D, Zhao Q. Diagnostic value of third generation anti-cyclic citrullinated peptide assay in rheumatoid factor negative rheumatoid arthritis. Int. J. Clin. Exp. Pathol. 2016;9(10):10728–33.
Suwannalai P, Trouw LA, Toes RE, Huizinga TW. Anti-citrullinated protein antibodies (ACPA) in early rheumatoid arthritis. Mod Rheumatol. 2012;22(1):15–20. https://doi.org/10.1007/s10165-011-0486-8.
Miriovsky BJ, Michaud K, Thiele GM, O'Dell JR, Cannon GW, Kerr G, Richards JS, et al. Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1292–7. https://doi.org/10.1136/ard.2009.122739.
Mekic M, Hadzigrahic E. Anti-Cyclic Citrullinated Peptide Antibody as a Predictor of Rheumathoid Arthritis Complications. Med Arch. 2020;74(3):183–6. https://doi.org/10.5455/medarh.2020.74.183-186.
Porto LS, Júnior TWC, Costa DA, Lanna CC, Kakehasi AM. Anti-CCP antibodies are not a marker of severity in established rheumatoid arthritis: a magnetic resonance imaging study. Rev Bras Reumatol Engl Ed. 2017;57(1):15–22. https://doi.org/10.1016/j.rbre.2015.07.018.
van Gaalen FA, Visser H, Huizinga TW. A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis. Ann Rheum Dis. 2005;64(10):1510–2. https://doi.org/10.1136/ard.2004.035089.
de Brito RS, Baldo DC, Andrade LEC. Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis. Adv Rheumatol. 2019;59(1):2. https://doi.org/10.1186/s42358-018-0042-8.
Gardette A, Ottaviani S, Tubach F, Roy C, Nicaise-Roland P, Palazzo E, Gill G, et al. High anti-CCP antibody titres predict good response to rituximab in patients with active rheumatoid arthritis. Joint Bone Spine. 2014;81(5):416–20. https://doi.org/10.1016/j.jbspin.2014.06.001.
van Dongen H, van Aken J, Lard LR, Visser K, Ronday HK, Hulsmans HM, Speyer I, et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2007;56(5):1424–32. https://doi.org/10.1002/art.22525.
Visser K, Verpoort KN, van Dongen H, van der Kooij SM, Allaart CF, Toes RE, Huizinga TW, et al. Pretreatment serum levels of anti-cyclic citrullinated peptide antibodies are associated with the response to methotrexate in recent-onset arthritis. Ann Rheum Dis. 2008;67(8):1194–5. https://doi.org/10.1136/ard.2008.088070.
Sieghart D, Konrad C, Swiniarski S, Haslacher H, Aletaha D, Steiner G. The diagnostic and prognostic value of IgG and IgA anti-citrullinated protein antibodies in patients with early rheumatoid arthritis. Front Immunol. 2023;13:1096866. https://doi.org/10.3389/fimmu.2022.1096866.
Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E. Diagnosis and classification of rheumatoid arthritis. J Autoimmun. 2014;48:26–30. https://doi.org/10.1016/j.jaut.2014.01.027.
Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD, Tanasescu R. Extra-articular Manifestations in Rheumatoid Arthritis. Maedica (Bucur). 2010;5(4):286–91.
Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A. Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmun Rev. 2021;20(4):102776. https://doi.org/10.1016/j.autrev.2021.102776.
Arnab B, Biswadip G, Arindam P, Shyamash M, Anirban G, Rajan P. Anti-CCP antibody in patients with established rheumatoid arthritis: Does it predict adverse cardiovascular profile? J Cardiovasc Dis Res. 2013;4(2):102–6. https://doi.org/10.1016/j.jcdr.2012.09.003.
Mackey RH, Kuller LH, Deane KD, Walitt BT, Chang YF, Holers VM, Robinson WH, et al. Rheumatoid Arthritis, Anti-Cyclic Citrullinated Peptide Positivity, and Cardiovascular Disease Risk in the Women's Health Initiative. Arthritis Rheumatol. 2015;67(9):2311–22. https://doi.org/10.1002/art.39198.
Kamiya H, Panlaqui OM. Systematic review and meta-analysis of the risk of rheumatoid arthritis-associated interstitial lung disease related to anti-cyclic citrullinated peptide (CCP) antibody. BMJ Open. 2021;11(3):e040465. https://doi.org/10.1136/bmjopen-2020-040465.
Correia CS, Briones MR, Guo R, Ostrowski RA. Elevated anti-cyclic citrullinated peptide antibody titer is associated with increased risk for interstitial lung disease. Clin Rheumatol. 2019;38(4):1201–6. https://doi.org/10.1007/s10067-018-04421-0.
Khan T, Jose RJ, Renzoni EA, Mouyis M. A Closer Look at the Role of Anti-CCP Antibodies in the Pathogenesis of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Bronchiectasis. Rheumatol Ther. 2021;8(4):1463–75. https://doi.org/10.1007/s40744-021-00362-4.
Eldaly ZH, Saad SA, Hammam N. Ocular surface involvement in patients with rheumatoid arthritis: Relation with disease activity and duration. The Egyptian Rheumatologist. 2020;42(1):5–9.
Vignesh AP, Srinivasan R. Ocular manifestations of rheumatoid arthritis and their correlation with anti-cyclic citrullinated peptide antibodies. Clin Ophthalmol. 2015;9:393–7. https://doi.org/10.2147/OPTH.S77210.
Itty S, Pulido JS, Bakri SJ, Baratz KH, Matteson EL, Hodge DO. Anti-cyclic citrullinated peptide, rheumatoid factor, and ocular symptoms typical of rheumatoid arthritis. Trans Am Ophthalmol Soc. 2008;106:75–81.
Skare TL, Nisihara R, Barbosa BB, da Luz A, Utiyama S, Picceli V. Anti-CCP in systemic lupus erythematosus patients: a cross sectional study in Brazilian patients. Clin Rheumatol. 2013;32(7):1065–70. https://doi.org/10.1007/s10067-013-2213-7.
Amaya-Amaya J, Molano-González N, Franco JS, Rodríguez-Jiménez M, Rojas-Villarraga A, Anaya JM. Anti-CCP antibodies as a marker of rhupus. Lupus. 2015;24(8):892–4. https://doi.org/10.1177/0961203315570165.
Kim SM, Park E, Lee JH, Lee SH, Kim HR. The clinical significance of anti-cyclic citrullinated peptide antibody in primary Sjögren syndrome. Rheumatol Int. 2012;32(12):3963–7. https://doi.org/10.1007/s00296-011-2274-3.
Polimeni M, Feniman D, Skare TS, Nisihara RM. Anti-cyclic citrullinated peptide antibodies in scleroderma patients. Clin Rheumatol. 2012;31(5):877–80. https://doi.org/10.1007/s10067-011-1930-z.
Habib HM, Mosaad YM, Youssef HM. Anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis. Immunol Invest. 2008;37(8):849–57. https://doi.org/10.1080/08820130802438057.
Gupta R, Thabah MM, Vaidya B, Gupta S, Lodha R, Kabra SK. Anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis. Indian J Pediatr. 2010;77(1):41–4. https://doi.org/10.1007/s12098-010-0006-4.
Kim JO, Lee JS, Choi JY, Lee KH, Kim YB, Yoo DH, Kim TH. The relationship between peripheral arthritis and anti-cyclic citrullinated peptide antibodies in ankylosing spondylitis. Joint Bone Spine. 2013;80(4):399–401. https://doi.org/10.1016/j.jbspin.2012.10.002.
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Fatima Zahra Rahali, Maryem Tarmidi, Raja Hazime and Brahim Admou contributed to the literature reviewing, writing and manuscript editing. All authors read and approved the final manuscript.
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Rahali, F., Tarmidi, M., Hazime, R. et al. Clinical significance of anti-cyclic citrullinated peptide (anti-CCP) antibodies in rheumatoid arthritis: Literature review. SN Compr. Clin. Med. 5, 272 (2023). https://doi.org/10.1007/s42399-023-01613-x
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DOI: https://doi.org/10.1007/s42399-023-01613-x