Serological Diagnosis of Lupus
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Serological Diagnosis of Lupus.pdf)
ANA is an Excellent Screen for Systemic Lupus Erythematosus (SLE)
Systemic lupus erythematosus (SLE) is an autoimmune disease featuring inflammatory joint pains, photosensitive rashes, oral ulceration and, less commonly, inflammation of organs such as the kidney and brain. It is characterised by the presence of a positive anti-nuclear antibody (ANA).
The quoted sensitivity of ANA for SLE is around 90-95%. In clinical practice, however, patients often display a combination of features suggestive of autoimmunity that do not meet the strict diagnostic criteria for SLE. Some of these patients may later develop a more "classic" form of SLE, but many will be diagnosed with other conditions, such as scleroderma, polymyositis, CREST, and "overlap" syndromes. In a number of these conditions, the ANA screen can not be relied upon for its negative predictive value. A negative ANA may not exclude these other autoimmune conditions. For example, polymyositis is classically associated with a negative ANA, although cytoplasmic staining may be noted, and testing for antibodies to "Jo-1" (histidyl tRNA synthetase) is the diagnostic test (refer to Table 1). Another important antibody specificity that may be missed on an ANA screen is the ribosomal-P antibody, seen in around 10% of lupus patients, with high specificity (~ 99%) for SLE.
ENA testing (antibodies to "extractable nuclear antigens") assists in defining subsets of autoimmune disease, with the most important antigens and their clinical associations listed below. HAPS performs the ENA screen be enzyme-linked immuno-sorbent assay ( ELISA) and uses the counter-immunoelectrophoresis ( CIE) assay as a confirmatory test. The ELISA results have enhanced sensitivity, especially for SSA, SSB and Scl-70 antibodies but reduced specificity. Results with borderline ELISA positivity should therefore be interpreted with caution and in a clinical context, as low-level false positives may occur.
Table 1: Clinical Associations with ENA Tests |
Sm ("Smith") |
- 95% specificity for lupus, but only seen in 15-30% of patients (predominantly seen in Asiatic and Negroid populations)
|
RNP |
- Seen in a range of autoimmune conditions (rheumatoid, lupus, scleroderma, Sjogren’s)
- In lupus, it is associated with milder, non-renal disease
- Isolated RNP elevation (without other ENAs) is associated with "mixed connective tissue disease" (clinical constellation of Raynaud’s, swollen digits, arthropathy, serositis, myopathy & oesophageal dysfunction)
|
SSA |
- Associated with photosensitive lupus skin disease ("subacute cutaneous lupus"), neonatal lupus syndrome, and Sjogren’s syndrome
|
SSB |
- More specific for Sjogren’s than SSA
|
Ribosomal-P |
- 95% specificity for lupus
- Association with psychosis and renal disease in lupus remains controversial
|
Scl-70 |
- Highly specific for diffuse scleroderma, but only has a sensitivity of 30% for the disease
- Associated with interstitial lung disease as well as severe skin and musculoskeletal involvement in scleroderma
|
Jo-1 |
- Highly specific for polymyositis, but only has a sensitivity of 30%
- Associated with development of interstitial lung disease
|
Pm-Scl |
- Detected in 8% of polymyositis patients, 3% of scleroderma patients, 25% of scleroderma-polymyositis overlap patients
- Associated with milder clinical course compared with Scl-70 positive scleroderma patients
|
Screen for Systemic Autoimmunity with ANA plus ENA
Up to 5% of patients with lupus variants, particularly those with a predominance of photosensitive skin disease, display low-level or negative ANA results but have positive results for SSA or ribosomal P on ENA testing. Therefore, we recommend ANA plus ENA as a screen for suspected lupus and related systemic autoimmune disorders (Figure 1). The paradigm of confining ENA tests to a confirmatory role in ANA-positive patients only should be abandoned.
Figure 1
Ribosomal-P Antibodies
Ribosomal-P antibodies are detected by ENA testing. Like Sm and dsDNA antibodies, seropositivity to ribosomal-P is highly specific for a diagnosis of SLE. The three highly "lupus-specific" antibodies Sm, dsDNA, and ribosomal-P all share a low sensitivity for lupus (15 – 35%). Some studies have suggested that there is an association between ribosomal-P positivity in lupus patients and neuropsychiatric (especially psychotic) disease. This correlation has been questioned by other studies, and the role of this antibody in defining lupus subsets at increased risk of neuropsychiatric complications is currently contentious.
The current routine ENA ELISA screen used by HAPS Immunology does not include ribosomal-P, but can be specifically requested in appropriate clinical circumstances. Indications for requesting ribosomal-P include: suspected SLE; atypical cytoplasmic and/or nucleolar staining on ANA screen; possible autoimmune psychosis or nephritis. PM-Scl (specific for polymyositis-scleroderma overlap syndrome) is also not included on the routine ENA ELISA test.
For assistance with ANA and ENA interpretation, please contact the HAPS Immunology Unit (49214000).
Written by: Dr Glenn Reeves, Immunology HAPS
Written: August 2000
Reviewed: November 2001