Rheumatoid Arthritis (RA) is one of the most common autoimmune disorders, affecting 1-2% of the population. RA is a connective tissue disorder marked by chronic inflammation of synovial joints with cartilage and bone destruction, progressively disabling the patient. There is increasing emphasis on early and precise diagnosis of RA so that effective therapies may be instituted to prevent this erosive disorder. The American College of Rheumatology (ACR) includes Rheumatoid Factor (RF) as one of the diagnostic criteria of RA. It is anticipated that antibodies against Cyclic Citrullinated Peptides (CCP) will be added to ACR criteria for diagnosis because of their clinical utility. The value of these diagnostic markers lies in their sensitivity and specificity, early presence, ability to predict development of erosive arthritis, and in evaluation of the effectiveness of therapy.

Rheumatoid Factor (RF)
Measurement of RF is important in the diagnosis and prognosis of RA as high titers of RF occur in sera of patients who tend to develop extra-articular complications. The methods used in the diagnostic panel for RA generally include measurement of IgM RF through agglutination of sheep red blood cells, latex, or similar particles coated with IgG. However, studies suggest that other immunoglobulin isotypes of RF are also present in RA and these markers can serve as valuable aids in diagnosis of RF.

RF is present in 70-90% of patients with RA and it is included in the ACR classification criteria. According to the revised ACR criteria, if RF is positive in patients with arthritis of three or more joints, the patient has rheumatoid arthritis. Arthritis in fewer than three joints with RF negative laboratory results excludes diagnosis of RA. This algorithm affords 93.5% sensitivity and 89.3% specificity for RA.

Anti-CCP Antibodies
Recent studies have shown antibodies to citrullinated antigens in the sera of RA patients to be useful for determining diagnosis and prognosis in RA. ELISA methods have been developed to detect autoantibodies targeting CCP in the sera of RA patients. Clinical studies have demonstrated positive anti-CCP ELISA results in a significant number of well-defined RA patient sera with excellent specificity. The diagnostic and prognostic value of the measurement of anti-CCP antibodies has been determined in relation to joint involvement and radiological damage in early RA. Anti-CCP antibodies can be detected years before the development of clinical symptoms. A prospective cohort study showed that 93% of anti-CCP positive patients with undifferentiated arthritis developed rheumatoid arthritis, indicating the strong positive predictive value of these antibodies1.

The anti-CCP test available through the reference laboratory at IMMCO utilizes highly purified synthetic peptides containing citrulline resindues. With this assay anti-CCP antibodies are detected in approximately 80% of established RA patients, in no healthy controls and in less than 5% of non-RA disease controls.2,3 Approximately 40% of RF-seronegative RA patients are positive for antibodies to CCP.4

Anti-Keratin Antibodies (AKA)
Anti-keratin antibodies (AKA), initially described by Young et al5, have been found to be highly specific for RA. AKA can be detected by indirect immunofluorescence (IFA) on rat esophagus substrate, even prior to the onset of joint symptoms.6 AKA occur in approximately 33% of RA patients who are RF negative.

RA and AKA are closely associated. Circulating immune complexes are found in significantly higher concentrations in RA patients positive for AKA. This may explain the association of AKA with severe forms of RA.

1. Van Gaalen et al. Arthur and Rheum. 50 (3): 709-715. 2004.
2. Van Venrooij et al. Neth J Med. 60: 383-388. 2002.
3. Vasishta A. Am Clin Lab. 21: 34-36. 2002.
4. Vossenaar et al. Clin App Imm Rev. 4: 239-262. 2004.
5. Young BJJ et al. Br Med J. ii: 97-99. 1979.
6. Aho K et al. J Rheumatol. 20: 1278-1281. 1993.

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