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The immune system attacking self tissue is the basis of the immune process. The overlap of clinical features in many of the rheumatic and connective tissue diseases has always complicated the task of segregating disease entities. Autoantibody tests can help classification, though clinical assessment remains the cornerstone of diagnosis.
FRACP FRCPA
Daman is a head of immunology at the Sonic Brisbane laboratory. He trained in rheumatology and immunology in Perth and Brisbane. Daman’s expertise is in auto-immune disease, allergy and immune deficiency.
Immune system attacking own body forms the basis of the autoimmune disease process, the end result being target organ damage. Most laboratory investigations are based on antibody detection as markers of autoimmune tissue damage, analogous to high blood pressure and vascular disease. Other basic investigations are also useful in the diagnosis and monitoring of disease activity such as CRP levels in rheumatoid arthritis (RA), though they are less useful in systemic lupus erythematosus (SLE).
Investigations
Rheumatoid Factor (RF): Rheumatoid factors are auto-antibodies directed against antigenic determinants on the Fc portion of IgG. Agglutination tests using IgG-coated particles (latex or erythrocytes) form the basis of most diagnostic tests.
Interpretation: RF assays are not specific for RA. RF may be found in a variety of acute and chronic inflammatory diseases, most of which are associated with a broadly elevated level of gamma globulin. RFs are also found in low titre (5%) in normal individuals, with titre and incidence increasing with age. Positive RF is, however, a highly sensitive diagnostic tool for RA, with 80% of RA patients having positive results, though only 50% will be positive at time of diagnosis. The frequency of positive results increases with the duration of the disease.
Cyclic citrullinated peptide (CCP) antibodies: The importance of antibodies directed against citrullinated peptides in the development of RA has allowed the subsequent production of commercial assays. Citrulline is a non- standard amino acid formed during cellular aging. CCP antibodies are present in a significant number (up to 70%) of RA patients. The antibodies may be present in those with a negative rheumatoid factor and are useful in combination with the RF assay. At present, tests for CCP antibodies are performed via an ELISA-based test and reported in numeric terms. The magnitude of the antibody level has not been reliably associated with clinical markers of severity.
Antinuclear antibodies: Autoantibodies to a variety of cellular components are a frequent finding in connective tissue diseases. Antinuclear antibodies (ANA) were first detected when the LE cell phenomenon was discovered. This test was superseded by the ANA indirect immunofluorescence test. Human epithelial cell line cells are used for screening for ANA. This is a modification of the previous HEp2-based ANA test so that SSA is also detected. In general, a negative ANA excludes active SLE.
Interpretation: Standard testing for ANA provides a rapid screening for SLE and related connective tissue disorders with a very high negative predictive value. A low titre (<1:160) ANA may have little or no clinical relevance, occurring in a wide range of diseases, and a percentage of healthy individuals. The ANA is positive, however, in 100% of patients with active SLE, in up to 90% of patients with RA, and in 50% of patients with systemic sclerosis.
Conclusion
Despite the lack of definitive tests for the diagnosis of rheumatic and connective tissue diseases, there are many pointers to their diagnosis. Rheumatoid factor assays, although moderately sensitive for RA, lack specificity. The use of CCP antibodies is a valuable tool.
The ANA test remains a sensitive but not specific screening test for many connective tissue diseases. In combination, ANA for screening, and more specific anti-ds DNA and anti-ENA tests are helpful in the diagnosis of connective tissue diseases. A negative ANA, anti-ds DNA and anti-ENA excludes the diagnosis of SLE. Tests for antihistone antibodies are useful in diagnosis of drug- induced SLE. Testing for ANCA is useful in the investigation of patients with suspected small vessel necrotising vasculitis.
Some connective tissue diseases commonly associated with RF
- Rheumatoid arthritis
- Systemic lupus erythematosus (SLE)
- Sjögren’s syndrome
- Systemic sclerosis
- Mixed connective tissue disease
Queries to Dr Mina John, Head of Immunology at Clinipath Pathology.
Questions? Contact the editor.
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