What are the diagnostic criteria for Systemic Lupus Erythematosus (SLE)?

Diagnostic Criteria for Systemic Lupus Erythematosus

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

Mandatory Entry Criterion: ANA Testing

• 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, 3
• For unselected populations, use 1:160 dilution as the cutoff to reduce false positives 3
• At 1:80 titer, specificity is only 74.7%, meaning approximately 1 in 4 positive results may be false positives 1
• At 1:160 titer, specificity improves to 86.2% while maintaining 95.8% sensitivity 1
• ANA positivity occurs in 13.3% of healthy individuals at 1:80 dilution and 5.0% at 1:160 dilution 1

Weighted Clinical and Immunological Domains

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

Constitutional Domain

• Fever (unexplained, >38.3°C) 1

Hematologic Domain

• Leukopenia, thrombocytopenia, or autoimmune hemolysis 1

Neuropsychiatric Domain

• Delirium, psychosis, or seizures (after excluding other causes such as metabolic derangements, infections, medications) 1

Mucocutaneous Domain

• Acute or subacute cutaneous lupus, oral ulcers, alopecia, or discoid lesions 1
• Skin biopsy is mandatory for histological confirmation when cutaneous lesions are present 3

Musculoskeletal Domain

• Arthritis involving ≥2 joints 1

Serosal Domain

• Pleural or pericardial effusion, or acute pericarditis 1

Renal Domain

• Proteinuria >0.5g/24h or red blood cell casts 1
• Lupus nephritis develops in 40% of SLE patients and progresses to end-stage renal disease in 10% at 10 years 1, 2
• Perform renal biopsy when lupus nephritis is suspected to confirm diagnosis, assess disease activity versus chronicity, and guide immunosuppressive therapy 3

Immunologic Domain (High Specificity)

• Anti-dsDNA antibodies - highly specific for SLE; use double-screening strategy: last-generation solid phase assay first, then Crithidia luciliae immunofluorescence test for confirmation 1, 3
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I) 1
• Low complement (C3, C4) - indicates active disease; measure at baseline as low complement combined with positive anti-dsDNA strongly supports active SLE 1, 3
• Anti-Ro/SSA, anti-La/SSB, anti-RNP antibodies 1
• Anti-Sm antibodies 4

Diagnostic Algorithm in Clinical Practice

Step 1: Screen with ANA when clinical suspicion exists - rash, arthritis, serositis, unexplained cytopenias, renal dysfunction 1

Step 2: If ANA ≥1:80 positive, order comprehensive autoantibody panel including anti-dsDNA, anti-Sm, anti-Ro/SSA, anti-La/SSB, antiphospholipid antibodies 1, 3

Step 3: Assess complement levels (C3, C4) and complete blood count 1, 3

Step 4: Evaluate for organ involvement with urinalysis (proteinuria, hematuria, casts), serum creatinine and albumin, erythrocyte sedimentation rate, and C-reactive protein 3

Step 5: For neuropsychiatric symptoms, perform brain MRI and exclude alternative diagnoses (metabolic, infectious, medication-related) before attributing to SLE 1

Step 6: Apply EULAR/ACR 2019 criteria - calculate weighted score from clinical and immunological domains to reach ≥10 points 1, 3

Critical Pitfalls to Avoid

• Do not rely on ANA alone - the low specificity (74.7% at 1:80) means positive ANA requires confirmation with specific autoantibodies and clinical correlation 1
• Classification criteria are not formal diagnostic criteria - they were developed for research purposes to create homogeneous study populations, though widely used clinically; SLE remains fundamentally a clinical diagnosis after excluding alternatives 5, 6, 7
• For intermediate ANA titers (1:80-1:160), test anti-Ro antibodies as the Ro ribonucleoprotein is clinically important in SLE and related conditions 1
• Do not order ANA testing in patients without unexplained involvement of two or more organ systems, as the low prevalence in primary care populations results in low predictive value 8
• Patients with persistent, characteristic multisystem involvement may have antinuclear antibody-negative disease and require evaluation despite negative ANA 8
• Include detailed clinical information with laboratory requests to help laboratories assess results and determine appropriate follow-up testing 1

Monitoring After Diagnosis

• Repeat anti-dsDNA and complement levels at follow-up visits even if previously negative/normal 3
• Monitor every 6-12 months with CBC, ESR, CRP, serum albumin, creatinine, urinalysis, anti-dsDNA, C3, and C4 levels 3
• Use validated activity indices (SLEDAI, BILAG, or SLE-DAS) to monitor lupus activity and detect flares 3, 7
• Persistent anti-dsDNA antibodies and hypocomplementemia after treatment indicate high risk for renal relapse 3