Initial Testing for Suspected Systemic Lupus Erythematosus
The antinuclear antibody (ANA) test is the initial screening test that should be ordered when SLE is suspected, as it is the most sensitive test for ruling out the disease. 1, 2, 3
When to Order ANA Testing
ANA testing should be performed specifically when patients present with:
- Unexplained multisystem inflammatory disease involving two or more organ systems 4, 5
- Symmetric joint pain with inflammatory features 6
- Photosensitive rash 6
- Unexplained cytopenias (low blood counts) 6
Do not order ANA testing for nonspecific symptoms alone (such as isolated fatigue or malaise), as this leads to false positives and has limited clinical value 6.
Interpreting ANA Results
If ANA is Negative (< 1:40)
- SLE is highly unlikely and can be ruled out in most cases 4, 5
- Pursue alternative diagnoses to explain the organ system involvement 4
- Important caveat: A small subset of patients (approximately 18% in one study) can have ANA-negative SLE with genuine multisystem disease 7. If clinical suspicion remains very high with persistent multisystem involvement, consider further evaluation despite negative ANA 5, 7
If ANA is Positive (≥ 1:40)
Proceed with a comprehensive autoantibody panel that includes 1, 2:
- Anti-dsDNA antibodies (highly specific for SLE)
- Anti-Sm antibodies (highly specific for SLE)
- Anti-Ro/SSA antibodies
- Anti-La/SSB antibodies
- Anti-RNP antibodies
- Antiphospholipid antibodies
- Complement levels (C3, C4) (often decreased in active SLE)
The 2023 expert panel recommends a double-screening strategy for anti-dsDNA: first use a solid-phase assay (SPA) such as FEIA/ELISA, then confirm positive results with Crithidia luciliae immunofluorescence test (CLIFT) for higher specificity 1.
Additional Baseline Laboratory Tests
Once SLE is suspected based on positive ANA, obtain 2:
- Complete blood count (CBC) to assess for cytopenias
- Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory markers
- Serum creatinine or estimated glomerular filtration rate (eGFR) for renal function
- Urinalysis with urine protein/creatinine ratio to screen for kidney involvement
- Serum albumin
Common Pitfalls to Avoid
- Do not order ANA in low-probability patients: The low prevalence of SLE in primary care means positive ANA results have poor predictive value without appropriate clinical context 5
- Do not stop at ANA alone: A positive ANA requires specific antibody testing to confirm SLE, as ANA can be positive in many other conditions 1, 2
- Do not ignore ANA-negative SLE: While rare, patients with genuine multisystem disease and negative ANA may still have SLE, particularly if they have cutaneous lupus with systemic features 7
- Anti-histone antibodies are NOT part of standard SLE screening: These should only be ordered when drug-induced lupus is specifically suspected 8