Rheumatoid Arthritis (RA) is the most prevalent inflammatory joint disease, affecting roughly 1% of the global adult population. It is characterized by persistent synovial inflammation, which frequently leads to progressive joint degeneration, disability, and a loss in quality of life. Although the exact cause of RA is unknown, autoimmunity is strongly linked to the illness, as evidenced by the presence of numerous autoantibodies. Apart from rheumatoid factor (RF), another class of autoantibodies has recently been discovered in the serum of RA patients: anti-cyclic citrullinated peptide antibodies (anti CCP).

Antibodies directed against self-antigens are seen in the serum of RA patients. The rheumatoid factor (RF) antibody, which targets the constant domain of IgG molecules, is the most well-known of these autoantibodies. The presence of RF is one of the criteria used by the American College of Rheumatology (ACR) to classify RA. Although the RF test has a high sensitivity for RA, it is not highly specific since it can also be found in the blood of patients with other rheumatic or inflammatory disorders, as well as a significant proportion of the healthy (elderly) population.

Antibodies to anti-perinuclear factor (APF) and anti-keratin (AKA) have been known to be highly specific for RA for some years. Both of these antibodies were later discovered to react with native filaggrin and are now known as anti-filaggrin antibodies (AFA). All of these antibodies are directed to citrulline-containing epitopes, according. Citrulline is a non-standard amino acid since it is not integrated in the protein synthesis.

Limitation of Rheumatoid Factor (RF)

  • RF antibodies target the Fc region of IgG immunoglobulins and are detected in 70-80% of RA patients.
  • IgM RF is the most common isotype seen in RA, as well as other autoimmune disorders, infections, and up to 5%-10% of healthy people.
  • The presence of both IgM and IgA RFs in a blood sample indicates that the patient has RA. In contrast, IgA RFs are not readily available.

Anti-CCP pathogenic role

Deimination (Citrullination) of arginine residues in various proteins by the enzyme peptidylarginine deiminase produces citrulline (PAD). PAD 2 and PAD 4 isoenzymes are prevalent in the inflammatory synovium of RA patients and produce local citrullination of synovial proteins including fibrin. The finding of anti-CCP and anti-citrullinated filaggrin antibodies in the RA synovium reveals that citrullinated extracellular fibrin is one of the key autoantigens driving the local immune response.

Citrullinated peptides also fit better in the antigen binding grooves of HLA DR4 (DRB1*0401 or *0404) than arginine-containing peptides. The development of anti-CCP antibodies has been linked to HLA class II RA susceptibility alleles. Furthermore, RA patients with both anti-CCP antibodies and shared epitope alleles had a more severe disease progression.

Anti-CCP as diagnostics

Diagnosis of early Rheumatoid Arthritis

Clinical symptoms in many early episodes of RA are milder and vague, and patients will not meet ACR classification criteria for RA. As a result, detecting a disease-specific autoantibody such as anti-CCP is critical. Anti-CCP antibodies can be found in 50-60% of people with early RA. Anti-CCP has a specificity of 95-98 percent for undifferentiated types of arthritis that do not progress to RA. IgM RF are frequently identified in the same individuals, although they have a substantially lower RA specificity. Anti-CCP antibodies might be several years prior to the onset of arthritis.

Prediction of Severe disease

Anti-CCP positive early RA patients may have a more erosive illness than those who do not have anti-CCP, according to several studies. Anti-CCP has been found to be a reliable predictor of radiation injury. Another study found that using anti-CCP and IgM RF together improved the capacity to predict erosive and progressive illness.

Differentiation from other diseases

Due to the lack of particular blood indicators, distinguishing between elderly onset rheumatoid arthritis (EORA) and polymyalgia rheumatica (PMR) is problematic in a considerable proportion of individuals. Anti-CCP antibodies must be considered as strongly indicative of EORA in a patient with clinical signs of PMR. Anti-CCP antibodies may help doctors distinguish between RA and erosive SLE. Anti-RA33 antibodies as well as RF are ineffective.

Therapeutic interventions

AntiTNF alpha therapy in RA has been shown to reduce blood titers of RF and anti-CCP antibodies in patients who have improved clinically, suggesting that these assays might be a valuable adjuvant in determining therapy effectiveness.

Reference Range:

  • <20.0 U (negative)
  • 20.0-39.9 U (weak positive)
  • 40.0-59.9 U (positive)
  • or =60.0 U (strong positive)


  • Some individuals with systemic lupus erythematosus or other autoimmune connective tissue disorders may test positive for cyclic citrullinated peptide (CCP) antibodies.
  • Antirheumatic therapy should not be started simply on the basis of a positive CCP antibody test, nor should treatment be changed based on CCP antibody levels.


  1. M. Herold, V. Boeser, E. Russe, W. Klotz, “Anti-CCP: History and its Usefulness”, Journal of Immunology Research, vol. 12, Article ID 194583, 5 pages, 2005.
  2. Anti-CCP antibodies in Rheumatoid Arthitis, Indian Rheumatol Assoc 2004 : 12 : 143 -46
  3. Mayoclinic website

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