CCP Antibodies for Rheumatoid Arthritis

Rheumatoid arthritis, which causes chronic inflammation of joint synovium, is the most common autoimmune disease, affecting approximately 1% of the world population. As the disease progresses, joints are gradually destroyed, leading to pain, reduced range of motion and disability. 

A classical feature of rheumatoid arthritis is the presence of rheumatoid factor in the blood. Rheumatoid factor (RF) is an antibody directed against the Fc region of IgG.  Although it has been included as one of the diagnostic criteria, it is not very sensitive or specific for rheumatoid arthritis. Approximately 3% of the general population has low level RF. The incidence increases with age, up to 20% in persons over 65 years old. High titered RF is present in other autoimmune diseases such as Sjogren's syndrome and essential mixed cryoglobulinemia. RF is present in low titers in a variety of chronic infections and inflammatory disorders that are associated with intense stimulation of the immune system and hypergammaglobulinemia.  

For more than 20 years, anti-keratin antibodies have been known to be specifically associated with rheumatoid arthritis. Subsequent research demonstrated that the antigen for anti-keratin antibody is the epithelial protein filaggrin. More recent studies determined that filaggrin is rich in the amino acid, arginine. The oxidation that occurs in an inflamed joint results in the deamidation of arginine to form citrulline. This is the immunodominant group responsible for the antigenicity of filaggrin. Conversion of arginine to citrulline results in the loss of a positive charge on proteins, which can alter protein conformation and disrupt protein to protein interactions that are necessary for normal function. Citrullinated peptides are also present in inflamed synovial tissues of non-RA patients, but they do not stimulate production of anti-citrullinated peptide antibodies. An aberrant immune response in RA is most likely responsible for the production of these autoantibodies. 

Three generations of assays for cyclic citrullinated peptide (CCP) antibody assays have been developed. The first generation assay, CCP1, used synthetic peptides that were based on the filaggrin molecule, but was not widely marketed. The second generation assay, CCP2, used synthetic cyclic citrullinated peptides that had higher specificity for RA than RF. The third generation assay, CCP3, incorporated additional citrullinate epitopes that increased sensitivity for RA an additional 5% while maintaining high specificity.  

Citrullinated autoantigens are more specific than RF to patients with rheumatoid arthritis, occurring in less than 2% of healthy individuals. They only occur at low concentrations in other inflammatory diseases. 

Several studies have convincingly demonstrated that anti-CCP antibody has much improved specificity for RA compared to RF. A  meta-analysis compared the sensitivities, specificities, and positive and negative likelihood ratios (LR) from 37 studies of first and second generation anti-CCP antibody and 50 studies of RF.

Anti-CCP antibodies were more specific than RF for distinguishing rheumatoid arthritis from other autoimmune diseases. CCP antibody was more often negative in patients with Sjogren’s syndrome, systemic lupus erythematosis with erosive arthritis, polymyalgia rheumatica and hepatitis C infection presenting with joint complaints than RF. RF is detectable in 40 to 70% of patients with these conditions, but CCP is detectable in <10%. The current CCP3 assay has higher sensitivity than the first and second generation assays that were included in this meta-analysis. 

Another conclusion of the meta-analysis was that the risk for radiographic progression was greater with anti-CCP antibody positivity than with RF positivity. Earlier diagnosis of rheumatoid arthritis facilitates earlier treatment with disease-modifying antirheumatic drugs (DMARDS). The authors of the meta-analysis concluded that positivity for anti-CCP antibodies should be added to the American College of Rheumatology criteria for diagnosis of rheumatoid arthritis. 

Case series have reported that 30 to 50% of patients with rheumatoid arthritis develop interstitial lung disease. Patients with rheumatoid arthritis who test positive for anti-CCP have the highest risk for developing interstitial lung disease.  The level of anti-CCP antibody in the serum correlates with the severity of disease. Patients with levels greater than 125 units are more likely to have pulmonary fibrosis with honeycomb changes. 

Specimen requirement is one red top tube of blood.  Reference range is 0–30 units.  

References

Nishimura K, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007 Jun 5;146(11):797-808. doi: 10.7326/0003-4819-146-11-200706050-00008.

Correia CS et al. Elevated anti-cyclic citrullinated peptide antibody titer is associated with increased risk for interstitial lung disease. Clin Rheumatol. 2019;38(4):1201-1206.

Malmstrom V et al. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting, Nat Rev Immunology 2016; doi:10.1038/nri.2016.124