What are the current classification criteria for systemic lupus erythematosus (SLE)?

Current Classification Criteria for Systemic Lupus Erythematosus

The 2019 EULAR/ACR classification criteria are the current gold standard for SLE, requiring positive ANA (≥1:80 titer) as an absolute entry criterion, followed by weighted scoring across 7 clinical and 3 immunologic domains to reach a threshold of ≥10 points, achieving 96.1% sensitivity and 93.4% specificity. 1, 2

Mandatory Entry Criterion

ANA positivity at titer ≥1:80 by indirect immunofluorescence on HEp-2 cells is absolutely required - without this, SLE classification cannot proceed regardless of other clinical manifestations. 1, 2 This represents a fundamental shift from previous criteria sets that did not require ANA as an entry point. 2

Critical Caveat About ANA Specificity

• At the 1:80 titer threshold, specificity is only 74.7%, meaning approximately 1 in 4 positive results may be false positives for SLE. 1, 3
• At 1:160 titer, specificity improves substantially to 86.2% while maintaining 95.8% sensitivity. 1, 3
• ANA positivity occurs in 13.3% of healthy individuals at 1:80 dilution and 5.0% at 1:160 dilution. 1

Weighted Scoring System

After confirming positive ANA, evaluate the following domains with their assigned point values to reach ≥10 points for SLE classification: 1, 2

Clinical Domains (7 domains)

Constitutional Domain:

• Fever (unexplained, >38.3°C): 2 points 1, 2

Hematologic Domain:

• Leukopenia (<4,000/mm³): 3 points 2
• Thrombocytopenia (<100,000/mm³): 4 points 2
• Autoimmune hemolysis: 4 points 1, 2

Neuropsychiatric Domain:

• Delirium: 2 points 2
• Psychosis: 3 points 2
• Seizures: 5 points 1, 2

Mucocutaneous Domain:

• Non-scarring alopecia: 2 points 2
• Oral ulcers: 2 points 1, 2
• Subacute cutaneous OR discoid lupus: 4 points 2
• Acute cutaneous lupus: 6 points 1, 2

Serosal Domain:

• Pleural or pericardial effusion: 5 points 1, 2
• Acute pericarditis: 6 points 1, 2

Musculoskeletal Domain:

• Joint involvement (≥2 joints with synovitis OR tenderness with ≥30 minutes morning stiffness): 6 points 1, 2

Renal Domain:

• Proteinuria >0.5g/24h: 4 points 2
• Renal biopsy showing Class II or V lupus nephritis: 8 points 2
• Renal biopsy showing Class III or IV lupus nephritis: 10 points 2

Immunologic Domains (3 domains)

Complement Proteins:

• Low C3 OR low C4: 3 points 1, 2
• Low C3 AND low C4: 4 points 1, 2

SLE-Specific Antibodies:

• Anti-dsDNA antibody OR anti-Smith antibody: 6 points 1, 2

Antiphospholipid Antibodies:

• Anticardiolipin antibodies OR anti-β2GP1 antibodies OR lupus anticoagulant: 2 points 1, 2

Essential Attribution Rule

Each criterion must be attributed to SLE and not have a more likely alternative explanation. 4 This attribution rule is critical for maintaining specificity - failure to properly apply it leads to overdiagnosis and reduced specificity in external validation studies. 4

Diagnostic Algorithm in Clinical Practice

1. Screen with ANA testing when clinical suspicion exists (unexplained rash, arthritis, serositis, cytopenias, renal dysfunction). 1

2. If ANA ≥1:80 positive, order comprehensive autoantibody panel:

   • Anti-dsDNA 1, 5
   • Anti-Smith (Sm) 5
   • Anti-Ro/SSA and anti-La/SSB 5
   • Anti-RNP 5
   • Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2GP1) 5, 1

3. Assess complement levels (C3, C4) and complete blood count. 5, 1

4. Evaluate for organ involvement:

   • Urinalysis with microscopy for proteinuria, hematuria, and red blood cell casts 5, 1
   • Urine protein/creatinine ratio or 24-hour proteinuria 5
   • Serum creatinine or eGFR 5
   • Consider renal biopsy if nephritis suspected (persistently abnormal urinalysis or elevated creatinine) 5

5. For neuropsychiatric symptoms, perform brain MRI and rigorously exclude alternative diagnoses before attributing to SLE. 1

Critical Pitfalls to Avoid

Do not rely on ANA alone for diagnosis - the low specificity (74.7% at 1:80) mandates confirmation with specific autoantibodies and clinical correlation. 1, 6

Classification criteria are not formal diagnostic criteria - they were developed for research purposes to create homogeneous patient populations for clinical trials, though they are widely used clinically. 5, 1 SLE remains fundamentally a clinical diagnosis after excluding alternatives. 1

For intermediate ANA titers (1:80-1:160), provide detailed clinical information to laboratories to guide appropriate reflex testing and interpretation. 1

Do not repeat ANA testing for monitoring disease activity once diagnosis is established - instead, use quantitative anti-dsDNA assays and complement levels consistently with the same method. 5

Performance Characteristics

The 2019 EULAR/ACR criteria demonstrate superior performance compared to previous criteria sets: 2, 7

• Sensitivity: 96.1% 2, 7
• Specificity: 93.4% 2, 7
• ACR 1997 criteria: 82.8% sensitivity, 93.4% specificity 2
• SLICC 2012 criteria: 96.7% sensitivity, 83.7% specificity 2

External validation studies confirm these performance characteristics across diverse populations, with variation in specificity primarily related to incomplete application of the attribution rule. 4, 8