What are the diagnostic criteria and initial work‑up for systemic lupus erythematosus?

Diagnosis of Systemic Lupus Erythematosus

Begin with ANA testing by indirect immunofluorescence on HEp-2 cells at a titer ≥1:80, which serves as the mandatory entry criterion and effectively rules out SLE when negative (>95% sensitivity). 1, 2

Initial Screening Strategy

ANA Testing (First-Line)

• Order ANA by indirect immunofluorescence on HEp-2 cells at a screening dilution of 1:80–1:160; titers ≥1:160 are clinically significant and improve specificity in unselected populations 1, 2
• Report both the titer and immunofluorescence pattern; a homogeneous pattern correlates with more severe disease activity 1
• A negative ANA at ≥1:80 makes SLE highly unlikely (negative predictive value >95%) and should prompt consideration of alternative diagnoses 1, 2
• Do not use automated ANA platforms (ELISA, multiplex) as the sole screening test—they have lower sensitivity and may miss relevant antibodies 1, 2

Critical pitfall: Repeating ANA testing after an initial positive result provides no clinical benefit and is not cost-effective for monitoring disease activity 1

Comprehensive Autoantibody Panel (When ANA Positive)

Specific Autoantibodies

• Anti-dsDNA: Use a double-screening strategy—initial solid-phase assay (ELISA/FEIA) followed by Crithidia luciliae immunofluorescence test (CLIFT) confirmation for higher specificity 3, 1, 2
  • Both SPA and CLIFT positive = very high likelihood of SLE 1, 2
  • SPA positive but CLIFT negative = interpret cautiously in clinical context and repeat in 6 months 1, 2
• Anti-Sm antibodies: Highly specific for SLE 3, 1, 2
• Anti-Ro/SSA and anti-La/SSB: Essential baseline testing, particularly before pregnancy 3, 1, 2
• Anti-RNP antibodies 3, 1, 2
• Antiphospholipid antibodies: Lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I 3, 1

Complement Levels

• Measure C3 and C4 at baseline; low levels support the diagnosis and track disease activity 3, 1, 2
• Serial measurement at every clinical encounter is recommended even when previously normal 1

Baseline Laboratory Assessment

Hematologic and Metabolic Tests

• Complete blood count with differential to screen for cytopenias; severe lymphopenia (<500 cells/mm³) or neutropenia (<500 cells/mm³) signals high infection risk 3, 1
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as baseline inflammatory markers 3, 1
• Serum albumin to identify hypoalbuminemia related to disease activity or renal loss 3, 1
• Liver function tests as part of the baseline metabolic panel 1

Renal Function Assessment

• Serum creatinine or estimated glomerular filtration rate (eGFR) 3, 1
• Urinalysis with microscopy 3, 1
• Urine protein/creatinine ratio (or 24-hour proteinuria) to detect renal involvement 3, 1

For patients with persistently abnormal urinalysis or raised serum creatinine: Obtain repeat urine protein/creatinine ratio, urine microscopy, renal ultrasound, and strongly consider renal biopsy (Level 1b evidence, Grade B recommendation) 3, 1

Organ-Specific Clinical Assessment

Mucocutaneous Evaluation

• Document history of malar rash, discoid lesions, photosensitivity, oral/nasal ulcers, and subacute cutaneous lesions 3, 1
• Classify lesions as LE-specific, LE-nonspecific, LE mimickers, or drug-related 3, 1
• Use the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) for standardized severity scoring 3, 1

Neuropsychiatric Assessment

• Query specifically for seizures, headaches, stroke-like symptoms, peripheral neuropathy, cognitive dysfunction (memory, attention, multitasking difficulties), and mood disorders (depression) 3, 1
• Assess cognitive impairment by evaluating attention, concentration, word finding, and memory difficulties 3, 1

Ophthalmologic Assessment

• Baseline eye examination is recommended, especially for patients who will receive glucocorticoids or antimalarials 3, 1

Pre-Treatment Infection Screening

• Screen for HIV, hepatitis C, and hepatitis B based on individual risk factors before starting high-dose glucocorticoids or immunosuppressive agents 1
• Tuberculosis screening (interferon-γ release assay or tuberculin skin test with chest radiography) according to local guidelines before immunosuppression 1

Diagnostic Criteria Application

2019 EULAR/ACR Classification Criteria

• Mandatory entry criterion: Positive ANA at titer ≥1:80 by indirect immunofluorescence on HEp-2 cells 2, 4
• Classification threshold: Accumulation of ≥10 points across 7 clinical domains (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic domains (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) 2, 4
• Criteria are weighted from 2 to 10 points; only the highest-weighted item within each domain is counted 2, 4
• Attribution rule: Count criteria only if there is no more likely alternative explanation 4, 5
• Sensitivity 96.1%, specificity 93.4% 2, 4

Important nuance: While these are classification criteria designed for research, they are widely used clinically and reflect current diagnostic thinking about SLE 3, 6, 4

Special Diagnostic Considerations

ANA-Negative SLE

• In patients with negative ANA at 1:160 who exhibit multisystem involvement, consider rare ANA-negative SLE and repeat ANA testing in 3–6 months 1
• Anti-dsDNA testing may be performed despite negative ANA if strong clinical features suggest lupus nephritis 1

Direct Coombs Test

• Not recommended as routine first-line testing in the initial SLE evaluation (uncertain appropriateness) 1
• Order only when peripheral blood smear shows spherocytes or schistocytes 1