What is the most common way to test for Systemic Lupus Erythematosus (SLE)?

Testing for Systemic Lupus Erythematosus (SLE)

The most common way to test for lupus is to begin with an Antinuclear Antibody (ANA) test as the initial screening tool, followed by more specific antibody tests such as anti-dsDNA and anti-Sm if the ANA is positive. 1, 2

Initial Screening: ANA Testing

• ANA testing is considered the fundamental screening tool for SLE with nearly 100% sensitivity 2, 3
• The gold standard method for ANA testing uses HEp-2 cells via indirect immunofluorescence (IIF) 2
• A positive ANA is defined as a titer ≥1:80 according to the EULAR/ACR 2019 classification criteria 1, 2
• ANA testing should only be ordered when there is clinical suspicion of SLE (unexplained involvement of two or more organ systems) 4

ANA Patterns and Significance:

• Homogeneous pattern: Associated with dsDNA, histones (suggests SLE) 2
• Coarse speckled: Associated with U1-SnRNP, Sm (suggests SLE, MCTD) 2
• Fine speckled: Associated with SSA/Ro, SSB/La (suggests SLE, Sjögren's) 2

Confirmatory Testing

When ANA is positive, follow-up with more specific antibody tests:

Anti-dsDNA Testing

• Highly specific for SLE (90-97% specificity) 2
• Recommended double-screening strategy: 1
  1. First use a solid phase assay (SPA) like ELISA, FEIA, or CLIA
  2. Then confirm with Crithidia Luciliae Immunofluorescence Test (CLIFT)

Anti-Sm (Smith) Testing

• Highly specific for SLE 2, 3
• Strong confirmatory power even in patients unlikely to have SLE 3

Other Relevant Antibody Tests

• Anti-SSA/Ro and Anti-SSB/La: Associated with SLE and Sjögren's syndrome 2
• Anti-RNP: Associated with mixed connective tissue disease and SLE 2

Testing Algorithm

Clinical suspicion of SLE
    │
    ▼
ANA Testing (IIF on HEp-2 cells)
    │
    ▼
If ANA ≥1:80 → Proceed with specific antibody testing:
    │
    ├── Anti-dsDNA (SPA + CLIFT)
    │       │
    │       ├── If both positive → SLE very likely
    │       │
    │       ├── If SPA+ but CLIFT- → SLE likely (evaluate clinical context)
    │       │
    │       └── If both negative → SLE less likely
    │
    └── Anti-Sm and other specific antibodies (anti-SSA/Ro, anti-SSB/La)

Important Considerations

• Pitfall #1: ANA has low specificity (can be positive in other conditions and even healthy individuals) 1, 4
• Pitfall #2: Anti-dsDNA testing methods vary in sensitivity and specificity; CLIFT is more specific but less sensitive than SPAs 1
• Pitfall #3: Negative ANA usually rules out SLE, but rare cases of ANA-negative SLE exist 4
• Pitfall #4: Anti-dsDNA levels may fluctuate with disease activity and are useful for monitoring, particularly in lupus nephritis 1, 5

Laboratory Recommendations

• Always include clinical information when ordering autoimmunity tests 1
• Laboratory reports should specify which method was used for antibody detection 1
• When multiple methods are used, results from each method should be reported separately 1
• For monitoring disease activity, quantitative anti-dsDNA testing is preferred over repeat ANA testing 2, 5

The combination of ANA screening followed by specific antibody testing (particularly anti-dsDNA and anti-Sm) provides the most rational and cost-effective approach to diagnosing SLE 3.