Anti-Cyclic Citrullinated Peptide Antibody

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 citrullinates extracellular proteins that contain arginine. Production of anti–citrullinated 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

Anti–cyclic 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]} Anti–citrullinated 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 (RF) 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]

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

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 anti–citrullinated 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]

A study by Mouterde et al found that in patients with early arthritis who were seronegative for rheumatoid factor (RF) and ACPA, the disease was less active at baseline and radiographic progression was less severe at 3-year follow-up than in patients who were seropositive for RF and/or ACPA. ^[14]

However, a retrospective study by Murata et al indicated that in patients with newly diagnosed rheumatoid arthritis who are positive for anti–cyclic citrullinated peptide (anti-CCP) antibody, there is no association between a family history of rheumatoid arthritis and high disease activity at baseline. Moreover, the investigators reported that such history does not predict poor outcome at 2 years post-onset of the arthritis in these patients. ^[15]

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. ^[16] Additionally, anti-CCP antibodies have been shown to be predictive of the progression of patients, indicating more erosive disease or increase joint involvement. ^[17] 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. ^[18]

A study by Bettner et al indicated that when present together, elevations in anti-CCP3 antibodies, RF-immunoglobulin M, and serum calprotectin have a positive predictive value of 53.0% for a diagnosis of rheumatoid arthritis within 3 years. ^[19]

A literature review by Kim and Lee found the prevalence of anti-CCP antibody in patients with psoriatic arthritis to be 9.8%, with the antibody being linked to an increased risk of polyarthritis (odds ratio [OR] = 4.390), bone erosion (OR = 2.800), and dactylitis (OR = 1.958). ^[20]

In a study of parenchymal lung disease as a manifestation of rheumatoid arthritis, Esposito et al found that the most commonly detected pulmonary abnormality among the study’s patients was preclinical emphysema, with this condition being associated with higher anti-CCP antibody titers as well as with older age and diffusion abnormalities. ^[21]