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Cyclic Citrullinated Peptide Antibody 

  • Author: Duane Kirksey, MD, MSc; Chief Editor: Eric B Staros, MD  more...
 
Updated: Dec 04, 2014
 

Reference Range

Citrullination is a normal physiologic process that occurs in many dying cells.[1] Citrulline is a nonstandard amino acid that is produced by diminution of arginine residue present on certain human proteins by the peptidyl arginine-deiminase (PAD) enzyme. The PAD enzyme has several isoforms, of which PAD2 and PAD4 are expressed in inflammatory leukocytes.[2] The release of PAD from dying cells citrullinate extracellular proteins that contain arginine. Production of anticitrullinated protein antibody (ACPA) depends on the genetic background of the patient.

  • < 20 EU/mL - Negative
  • 20-39 EU/mL - Weakly positive
  • 40-59 EU/mL - Moderately positive
  • >60 EU/mL - Strongly positive
  • Normal value - < 20 EU/mL
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Interpretation

Anticyclic citrullinated peptide (anti-CCP) antibody levels are characteristically elevated in rheumatoid arthritis, although they can be elevated in other rheumatologic conditions associated with inflammatory arthritis, such as systemic lupus erythematosus.[3, 4, 5, 6, 7] Anticitrullinated protein antibody (ACPA) level was added to the 2010 American College of Rheumatology(ACR)/European League Against Rheumatism (EULAR) diagnostic criteria for rheumatoid arthritis. These criteria, including ACPA levels, identify more patients with rheumatoid arthritis than the previous 1987 criteria.[8] ACPA can be present in the early presentation of rheumatoid arthritis while the rheumatoid factor is negative. Therefore, if ACPA is identified, the patient likely has rheumatoid arthritis.

The antigen used in most assays is filaggrin, although other antigens are available.[9] ACCP antibodies are a subset of ACPA and are not completely cross-reactive with other citrullinated proteins.[10] The most common test for anti-CCP2 has a sensitivity of 61.6-75.2% for rheumatoid arthritis and specificity of 94-99%.[11] Although multiple assays are available, including antimutated citrullinated vimentin antibody and several generations of anti-CCP, they have all been shown to have comparable diagnostic performance.[1]

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Collection and Panels

Serum anti-CCP antibody

Collection details are as follows:

  • Specimen - 1 mL of serum
  • Container - Plastic screw-cap vial
  • Collection method - Routine venipuncture
  • Transport temperature - Room temperature
  • Reject criteria
    • Gross hemolysis
    • Gross lipemia
    • Plasma
  • Methodology - Immunoassay
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Background

Citrullination is a normal physiologic process that occurs in many dying cells.[1] Citrulline is a nonstandard amino acid that is produced by diminution of arginine residue present on certain human proteins by the peptidyl arginine-deiminase (PAD) enzyme. The PAD enzyme has several isoforms, of which PAD2 and PAD4 are expressed in inflammatory leukocytes.[2] The release of PAD from dying cells citrullinate extracellular proteins that contain arginine. Production of anticitrullinated protein antibody (ACPA) depends on the genetic background of the patient.

Citrulline modified proteins are seen in the keratin layer of the epidermis and the brain. Induction of the expression of citrullinated proteins is seen in various inflammatory states and during apoptosis. Joints under normal states do not contain citrullinated proteins, whereas an array of different citrullinated proteins are present during various types of inflammation.[12] ACPA has been identified in the synovial fluid of patients with rheumatoid arthritis.[13]

Anticyclic citrullinated peptide (anti-CCP) antibody and other autoantibody markers can be helpful in determining which patients with rheumatoid arthritis may have benefit from treatments such as anti–tumor necrosis factor-alfa (TNFa) monoclonal antibodies.[14] Additionally, anti-CCP antibodies have been shown to be predictive of the progression of patients, indicating more erosive disease or increase joint involvement.[15] Anti-CCP was found to be more predictive of erosive arthritis than other measures, such as matrix metalloproteinases-3, erythrocyte sedimentation rate, and C-reactive protein.[16]

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Contributor Information and Disclosures
Author

Duane Kirksey, MD, MSc Physician, Center for Connected Care, Cleveland Clinic

Disclosure: Nothing to disclose.

Chief Editor

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

References
  1. 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. 2007 Mar. 53(3):498-504. [Medline].

  2. Szekanecz Z, Soos L, Szabo Z, Fekete A, Kapitany A, Vegvari A. Anti-citrullinated protein antibodies in rheumatoid arthritis: as good as it gets?. Clin Rev Allergy Immunol. 2008 Feb. 34(1):26-31. [Medline].

  3. Singh U, Singh S, Singh NK, Verma PK, Singh S. Anticyclic citrullinated peptide autoantibodies in systemic lupus erythematosus. Rheumatol Int. 2011 Jun. 31(6):765-7. [Medline].

  4. Genre F, Lopez-Mejias R, Garcia-Bermudez M, Castaneda S, Gonzalez-Juanatey C, Llorca J, et al. Osteoprotegerin CGA Haplotype Protection against Cerebrovascular Complications in Anti-CCP Negative Patients with Rheumatoid Arthritis. PLoS One. 2014. 9(9):e106823. [Medline].

  5. Pedersen JK, Lorenzen T, Ejbjerg B, Szkudlarek M, Voss A, Ostergaard M, et al. Low-field magnetic resonance imaging or combined ultrasonography and anti-cyclic citrullinated peptide antibody improve correct classification of individuals as established rheumatoid arthritis: results of a population-based, cross-sectional study. BMC Musculoskelet Disord. 2014 Aug 7. 15:268. [Medline]. [Full Text].

  6. Budhram A, Chu R, Rusta-Sallehy S, Ioannidis G, Denburg J, Adachi J, et al. Anti-cyclic citrullinated peptide antibody as a marker of erosive arthritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Lupus. 2014 Oct. 23(11):1156-1163. [Medline].

  7. Gonzalez-Lopez L, Rocha-Munoz AD, Ponce-Guarneros M, Flores-Chavez A, Salazar-Paramo M, Nava A, et al. Anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) relation with extra-articular manifestations in rheumatoid arthritis. J Immunol Res. 2014. 2014:536050. [Medline]. [Full Text].

  8. Fautrel B, et al. Level of Agreement of the 1987 ACR and 2010 ACR/EULAR rheumatoid arthritis classification critera: an analysis based on ESPOIR cohort data. Ann Rheum Dis. 2012. 71:386-389.

  9. McPherson RA. Pincus MR. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 22nd Edition. Elsevier Saunders 2012;

  10. Sloan-Facsinay A. Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protein antibodies and contain overlapping and non-overlapping reactivities. Ann Rheum Dis. 2011. 70:188-193.

  11. van Venroolj WJ. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol. 2011. 7:391-398.

  12. Klareskog L, et al. Antibodies ot citrullinated proteins in arthritis: pathology and promise. Curr Opin Rheumatol. 20:300-305.

  13. Snir O, Widhe M, Hermansson M, von Spee C, Lindberg J, Hensen S. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum. 2010 Jan. 62(1):44-52. [Medline].

  14. Lal P, Su Z, Holweg CT, Silverman GJ, Schwartzman S, Kelman A. Inflammation and autoantibody markers identify rheumatoid arthritis patients with enhanced clinical benefit following rituximab treatment. Arthritis Rheum. 2011 Dec. 63(12):3681-91. [Medline].

  15. van der Helm-van Mil, Annette HM, et al. Antibodies to citrulinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Research & Therapy. 2005. 7:R949-R958.

  16. Shovman O, et al. he diagnostic utility of anti-cyclic citrullinated peptide antibodies, matrix metalloproteinases-3, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein in patients with erosive and non-erosive rheumatoid arthritis. Clinical & Developmental Immunology. September 2005. 12(3):197-202.

  17. Mary Lee, ed. Basic Skils in Interpreting Laboratory Data. 4th edition.

 
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