What initial laboratory screening should be performed for a patient suspected of systemic lupus erythematosus (SLE)?

Initial Laboratory Screening for Suspected Systemic Lupus Erythematosus

Begin with ANA testing by indirect immunofluorescence on HEp-2 cells as the mandatory first-line screening test, followed immediately by a comprehensive autoantibody panel if positive. 1, 2

First-Line Screening Test

ANA by Indirect Immunofluorescence (IIFA) on HEp-2 Cells:

• This is the reference standard screening method with >95% sensitivity for SLE, making it the most effective test for ruling out the disease 1, 3
• The test should be performed at a screening dilution of 1:80 or 1:160, with titers ≥1:160 considered clinically significant 1, 4
• Both titer and pattern must be reported, as homogeneous patterns correlate with more severe disease activity 1, 5
• Critical caveat: ANA positivity alone is insufficient for diagnosis—it serves only as an entry criterion requiring compatible clinical features and specific autoantibodies 2, 6

Immediate Reflex Testing Panel (If ANA Positive)

Complete the following autoantibody panel without delay: 2, 6

Disease-Specific Antibodies:

• Anti-dsDNA antibodies using dual methodology: solid-phase assay (ELISA/FEIA) for sensitivity plus Crithidia luciliae immunofluorescence test (CLIFT) for specificity 2, 7
• Anti-Sm antibodies (highly specific for SLE, useful for diagnosis but not monitoring) 2, 7
• Complete ENA panel: anti-RNP, anti-Ro/SSA, anti-La/SSB 2, 6
• Antiphospholipid antibodies: anticardiolipin IgG/IgM, anti-β2-glycoprotein I IgG/IgM, and lupus anticoagulant 2, 6

Complement and Inflammatory Markers:

• C3 and C4 complement levels (low levels suggest active disease and correlate with disease activity) 2, 6
• ESR and CRP (ESR typically elevated in SLE; CRP often normal unless infection/serositis present) 2

Essential Baseline Laboratory Tests

Complete Blood Count with Differential: 2

• Screen for cytopenias (leukopenia, lymphopenia, thrombocytopenia, anemia)
• Severe lymphopenia (<500 cells/mm³) or neutropenia (<500 cells/mm³) indicates high infection risk 1

Comprehensive Metabolic Panel: 2, 6

• Serum creatinine and estimated GFR
• Serum albumin (hypoalbuminemia suggests nephrotic syndrome)
• Liver function tests

Urinalysis with Microscopy: 2, 6

• Screen for proteinuria, hematuria, and cellular casts
• If abnormal, immediately add urine protein-to-creatinine ratio 2

Common Pitfalls to Avoid

Do not rely on alternative automated ANA methods (ELISA, multiplex) as the sole screening test 1

• These platforms may miss certain antibodies and have lower sensitivity than IIFA
• If used, the specific platform must be clearly documented and results should not be labeled as "ANA test" 1

Do not order anti-dsDNA or anti-Sm without first confirming ANA positivity 3

• These specific tests have high specificity but lower sensitivity
• Sequential testing (ANA first, then specific antibodies) is the most cost-effective approach 3

Do not assume a single negative ANA rules out SLE indefinitely 8

• ANA can fluctuate and may become negative during disease course or with treatment
• If clinical suspicion remains high despite negative ANA, proceed with specific antibody testing 8, 9

Do not confuse anti-Sm with anti-RNP patterns 7

• Both produce coarse speckled patterns on immunofluorescence
• Anti-Sm is highly specific for SLE, while anti-RNP can occur in multiple conditions 7

Infection Screening Before Immunosuppression

If SLE diagnosis is confirmed and immunosuppressive therapy is planned: 1

• HIV, HCV, HBV based on risk factors
• Tuberculosis screening according to local guidelines (typically interferon-gamma release assay or tuberculin skin test with chest X-ray)
• These should be completed before initiating high-dose glucocorticoids or other immunosuppressive agents 1

Interpretation Algorithm

1. ANA negative by IIFA: SLE is highly unlikely (>95% sensitivity); consider alternative diagnoses 1, 3
2. ANA positive with negative specific antibodies: Monitor every 6-12 months with repeat anti-dsDNA and complement levels, as these can convert over time 2, 6
3. ANA positive with anti-dsDNA and/or anti-Sm positive: Highly suggestive of SLE when combined with compatible clinical features 2, 7
4. Homogeneous ANA pattern: Associated with higher disease activity and worse prognosis compared to speckled patterns 5