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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. The current standard for diagnosing rheumatoid arthritis is based on the 1987 American College of Rheumatology criteria, which include:

  1. Morning stiffness
  2. Arthritis of 3 or more joints
  3. Arthritis of hand joints
  4. Symmetric arthritis
  5. Rheumatoid nodules
  6. Positive serum rheumatoid factor
  7. Radiographic changes

Five of the criteria are related to clinical assessment, 1 to radiographic examination of the hand and wrist and 1 to the presence or absence of rheumatoid factor. At least 4 of the 7 criteria must be present to diagnose rheumatoid arthritis. Because irreversible joint destruction can be prevented by intervention during the first months of disease, early diagnosis of rheumatoid arthritis is important.

Rheumatoid factor (RF) is an antibody directed against the Fc region of IgG. Although it is 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. Unfortunately, reliable immunoassays for anti-keratin or anti-filaggrin antibodies were never developed. 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, which 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.

Several studies have convincingly demonstrated that anti-CCP antibody has much improved specificity for RA compared to RF. A recent 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 (Ann Inter Med 2007;146:797-808).

Pooled Data

CCP1 or 2

RF

Sensitivity

67

69

Specificity

95

85

Positive LR

12.46

4.86

Negative LR

0.36

0.38

Anti-CCP antibodies were more specific than RF for diagnosing rheumatoid arthritis. 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.

Currently, most rheumatologists measure both anti-CCP antibody and RF to comply with American College of Rheumatology guidelines and to maximize sensitivity. However, RF may become obsolete in the future if the anti-CCP antibody is added to the guidelines and the third generation anti-CCP antibody assay is confirmed to have higher sensitivity than RF.

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

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