Anti-CCP Antibodies (ACPA) Dx

Synonyms:  CCP (cyclic citrullinated peptides), ACPA (anti-citrullinated protein antibodies)

CPT Code:  86200 

Description: Anti-CCP antibodies bind to proteins containing the amino acid citrulline, which is formed by a post-translational modification of the non-traditional amino acid  arginine by the enzyme peptidyl arginine deiminase PADI). Since the late 1960s various autoantibodies distinct from rheumatoid factor (RF) were described in the sera of patients with RA. These autoantibodies included antiperinuclear factor, antifilaggrin, antikeratin, and anti-Sa. It was suggested that these antibodies might be more specific than RF for the diagnosis of rheumatoid arthritis (RA). In 1998, it was recognized that these various  antibodies all targeted citrullinated peptides. Citrullination of several  synovial proteins such as fibrinogen, fibronectin and filaggrin, which happens to a greater extent in inflammatory sites, may  be relevant to the immunopathogenesis of RA.

Methods: Anti-CCP antibodies are detected using enzyme-linked immunosorbent assay (ELISA). Cyclization of citrullinated peptides in the ELISA was found to more closely mimic natural conformational epitopes and thereby optimized performance characteristics of the assay. The second generation (CCP-2) assay is commonly used but has been replaced by the third generation (CCP3.1) assay, as this has shown greater sensitivity compared with CCP-2.  At least 0.3 ml of serum is necessary to do the assay.  Antibody levels are stable and maintained for 7 days at room temperature

Normal Values:    Most ELISA assays define a normal or negative value as being less than 20 U. Up to 2% of normal blood donors will have low titer positive results.

Abnormal Values:  Although the greatest value of the ACPA test is its specificity for RA, it is also positive in other disorders, including psoriatic arthritis (7-14%) patients with more severe arthritis. Few patients with lupus and arthritis will be CCP positive. Lastly, a subset of interstitial lung disease patients (without RA) will be CCP positive.  Unlike RF, which may be positive in patients with hepatitis B or C, anti-CCP antibodies are uncommon with hepatitis B or C infection, but have been reported in patients with tuberculosis.

Clinical Associations: Compared with RF, anti-CCP antibodies may have higher specificity for the diagnosis of RA (88%–95%) with similar sensitivity (70%–80%). It has been noted that patients who ultimately have gone on to develop RA may develop anti-CCP antibodies before the onset of any symptoms, in some cases years prior.  Anti-CCP antibodies have useful in the diagnosis of patients with early RA, and have been incorporated into the 2010 ACR/EULAR classification criteria for RA.  Similar to RF, patients with RA with high titers of anti-CCP antibodies are more likely to have aggressive disease and with a greater likelihood of poor outcomes, such as radiographic joint damage. It has been suggested that patients positive for both anti-CCP and RF may have a worse prognosis that those positive for either antibody.  Up to 60% of RA patients who are seronegative for IgM RF may be CCP antibody positive.  The association between cigarette smoking and both the development and severity of  RA derives from anti-CCP positive patients.

Cost: Approximately $80–95.

Comment:  CCP titers may vary over time and with treatment.  However, once positive, CCP levels are not expected to significantly change with effective therapy.  Hence, there is little value in serial assessment of CCP titers in patients known to be positive.

BIBLIOGRAPHY

Vossenaar ER, VanVenrooij WJ. Citrullinated proteins sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res 2004;6:107–111. PMID: 15142259 

Wiik A, van Venrooij WJ. ACR Hotline October 2003 (available at www.rheumatology.org/publications/hotline/1003anticcp.asp).

Lundström E1, Källberg H, Alfredsson L, Klareskog L, Padyukov L. Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important. Arthritis Rheum. 2009;60:1597-603. PMID: 19479873

Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580-8. PMID: 20699241