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

How to Diagnose Lupus (Systemic Lupus Erythematosus)

Essential Entry Criterion

A positive antinuclear antibody (ANA) test at a titer ≥1:80 by indirect immunofluorescence on HEp-2 cells is the mandatory entry criterion for diagnosing SLE, as established by the 2019 EULAR/ACR classification criteria. 1 Without a positive ANA, SLE diagnosis cannot be established in the vast majority of cases, though rare ANA-negative disease exists in patients with persistent, characteristic multisystem involvement. 2

Diagnostic Algorithm

Step 1: Initial Screening

• Order ANA testing only when patients present with unexplained involvement of two or more organ systems 2
• In unselected populations, use a 1:160 dilution as the cut-off point for ANA detection to improve specificity 1
• If ANA is negative at ≥1:80, SLE is effectively ruled out in most cases 1, 2
• If symptoms persist despite negative ANA, repeat testing in 3-6 months 1

Step 2: Confirmatory Testing When ANA is Positive

When ANA is positive (≥1:80), proceed with the following laboratory tests 1:

Anti-dsDNA Testing (Double-Screening Strategy):

• First: Perform a solid-phase assay (SPA) such as FEIA 1
• Second: Confirm with Crithidia luciliae immunofluorescence test (CLIFT) 1
• If SPA is negative but clinical suspicion remains high, still perform CLIFT 1

Additional Autoantibody Panel:

• Anti-Sm (Smith) antibodies 3
• Anti-Ro/SSA antibodies 1
• Anti-La/SSB antibodies 1
• Anti-RNP antibodies 1
• Antiphospholipid antibodies 1, 3

Complement Levels:

• C3 and C4 levels (low levels support diagnosis) 1, 3

Hematologic Tests:

• Complete blood count (CBC) for cytopenias 1
• Serum creatinine 1
• Urinalysis with proteinuria quantification and urinary sediment 1

Step 3: Interpretation of Anti-dsDNA Results

The interpretation follows this hierarchy 1:

• SPA positive + CLIFT positive: SLE very likely - proceed with clinical correlation
• SPA positive + CLIFT negative: Evaluate in context of clinical characteristics; if diagnosis unclear, repeat in 6 months
• SPA negative + CLIFT positive: SLE likely - evaluate clinical features
• SPA negative + CLIFT negative: SLE diagnosis cannot be established at this time; perform clinical follow-up periodically

Step 4: Clinical Criteria Assessment

The 2019 EULAR/ACR classification criteria require:

• Positive ANA (≥1:80) as entry criterion 1
• Weighted scoring across multiple domains 1, 3:
  • Constitutional (fever)
  • Hematologic (leukopenia, thrombocytopenia, autoimmune hemolysis)
  • Neuropsychiatric (seizures, psychosis, delirium)
  • Mucocutaneous (acute cutaneous lupus, chronic cutaneous lupus, oral ulcers, alopecia)
  • Serosal (pleural or pericardial effusion, acute pericarditis)
  • Musculoskeletal (joint involvement)
  • Renal (proteinuria >0.5 g/24h, renal biopsy showing lupus nephritis)
  • Immunologic (anti-dsDNA, anti-Sm, antiphospholipid antibodies, low complement, direct Coombs test positive)

The criteria achieve 96.1% sensitivity and 93.4% specificity for SLE 4

Critical Diagnostic Pitfalls

Avoid these common errors:

• Do not order ANA in patients without multisystem involvement - the low prevalence of SLE in primary care populations results in poor predictive value 2
• Do not rely on a single anti-dsDNA method - non-correlation between methods reflects differences in antigenic specificity; always use the double-screening strategy (SPA + CLIFT) 1
• Do not assume all positive anti-dsDNA indicates active disease - some patients exhibit "serologically active, clinically quiescent" SLE with elevated anti-dsDNA but no clinical symptoms 1, 5
• Do not exclude lupus nephritis based solely on negative anti-dsDNA - some patients with biopsy-proven lupus nephritis remain anti-dsDNA negative long-term; consider anti-nucleosome or anti-histone antibodies in these cases 1
• Do not use ANA titer of 1:40 as diagnostic threshold - while the ACR criteria historically used 1:40, the 2019 EULAR/ACR criteria require ≥1:80, and unselected populations should use 1:160 for better specificity 1, 2

Special Diagnostic Considerations

For lupus nephritis specifically:

• Renal biopsy provides definitive diagnosis and prognostic information 1
• Anti-C1q antibodies are found in almost 100% of patients with active lupus nephritis and have critical negative predictive value 1
• Proteinuria >0.5 g/24h is a key diagnostic feature 3

For neuropsychiatric lupus:

• Diagnostic work-up (clinical, laboratory, neuropsychological, imaging tests) should mirror that used in the general population presenting with the same neuropsychiatric manifestations 1
• Brain MRI may provide prognostic information 1

Laboratory Reporting Requirements

Laboratories must:

• Include the method used in their reports 1
• Provide relevant clinical context beyond mere numbers 1
• Use international units (IU) when available for anti-dsDNA quantification to ensure comparability across assays 1
• Validate results with clinical information when available 1