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

Criteria for Diagnosis of Systemic Lupus Erythematosus

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, followed by weighted scoring across multiple clinical and immunological domains using the 2019 EULAR/ACR classification criteria. 1

Entry Criterion: ANA Testing

• ANA testing at ≥1:80 titer is the absolute requirement for SLE diagnosis and should only be performed when clinical suspicion exists (unexplained rashes, arthritis, serositis, neurological manifestations, or cytopenias). 2, 1
• In unselected populations, use a 1:160 dilution as the cut-off point to improve specificity and avoid false positives. 3, 2
• If ANA is negative at ≥1:80, SLE is effectively ruled out in most cases. 1
• When ANA is negative but clinical suspicion remains high, anti-dsDNA testing may still be pursued. 2

Confirmatory Immunological Testing

Once ANA is positive (≥1:80), proceed with the following diagnostic algorithm:

Anti-dsDNA Antibodies (Double-Screening Strategy)

• First: Perform solid-phase assay (SPA) such as FEIA, CLIA, or ELISA. 3, 2, 1
• Second: Confirm positive SPA results with Crithidia luciliae immunofluorescence test (CLIFT). 3, 2, 1
• Interpretation hierarchy:
  • SPA positive + CLIFT positive = SLE very likely 1
  • SPA negative + CLIFT negative = SLE diagnosis cannot be established at this time 1
• If SPA is negative but other clinical signs of suspicion exist, perform confirmatory CLIFT; otherwise, report as negative anti-dsDNA. 3

Anti-ENA Panel

• Test anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP antibodies when ANA is positive. 2, 1
• Anti-Sm antibodies provide strong confirmatory evidence for SLE. 2
• Anti-Ro/SSA and anti-La/SSB have prognostic value for neonatal lupus and major organ involvement. 3, 2

Complement Levels

• Measure serum C3 and C4 levels in all suspected SLE cases, as low complement levels correlate with disease activity and major organ involvement. 2, 1

Antiphospholipid Antibodies

• Test for antiphospholipid antibodies as they are associated with thrombotic manifestations, damage development, and pregnancy complications. 3, 1

Routine Laboratory Assessment

Hematologic Tests

• Complete blood count (CBC) is essential for detecting cytopenias (anemia, leukopenia, lymphopenia, thrombocytopenia), which correlate with disease activity and prognosis. 2, 1

Renal Function Assessment

• Perform serum creatinine, urinalysis with microscopy, and quantification of proteinuria (urine protein/creatinine ratio) to provide prognostic information for end-stage renal disease. 3, 2, 1
• Urine sediment analysis has predictive value for the presence and outcome of kidney involvement. 3

2019 EULAR/ACR Classification Criteria

The 2019 criteria are 96.1% sensitive and 93.4% specific for SLE and require: 1, 4

Mandatory Entry Criterion

• ANA ≥1:80 on HEp-2 cells 1, 4

Weighted Scoring Across Multiple Domains

Points are assigned across the following domains (specific clinical and laboratory findings receive weighted scores): 1, 4

• Constitutional domain: Fever 1, 4
• Hematologic domain: Leukopenia, thrombocytopenia, autoimmune hemolysis 1, 4
• Neuropsychiatric domain: Delirium, psychosis, seizures 1, 4
• Mucocutaneous domain: Alopecia, oral ulcers, subacute/chronic cutaneous lupus, acute cutaneous lupus 1, 4
• Serosal domain: Pleural or pericardial effusion, acute pericarditis 1, 4
• Musculoskeletal domain: Joint involvement 1, 4
• Renal domain: Proteinuria >0.5 g/24h, renal biopsy showing lupus nephritis 1, 4
• Immunologic domain: Anti-dsDNA, anti-Sm, antiphospholipid antibodies, low complement (C3, C4), direct Coombs test positive 1, 4

Special Diagnostic Considerations

Lupus Nephritis

• Renal biopsy provides definitive diagnosis and prognostic information for lupus nephritis. 1
• Anti-C1q antibodies are found in almost 100% of patients with active lupus nephritis and have critical negative predictive value (patients are unlikely to flare in their absence). 3, 1

Neuropsychiatric Lupus

• Diagnostic work-up should mirror that used in the general population presenting with the same neuropsychiatric manifestations. 3, 1
• Investigations include cerebrospinal fluid analysis (to exclude CNS infection), EEG (for seizure disorder), neuropsychological tests (for cognitive dysfunction), nerve conduction studies (for peripheral neuropathy), and MRI (T1/T2, FLAIR, diffusion-weighted imaging, enhanced T1). 3

Common Pitfalls to Avoid

• Do not order ANA testing in low-prevalence populations without clinical suspicion, as this leads to false positives. 2
• Do not diagnose SLE based on ANA alone—the weighted scoring system across multiple domains is required. 1
• Do not rely on a single anti-dsDNA method—always use the double-screening strategy (SPA followed by CLIFT confirmation). 3, 2, 1
• Do not ignore negative ANA in the presence of strong clinical suspicion—rare ANA-negative SLE exists, and anti-dsDNA testing may still be warranted. 2
• Laboratories must include the method used in their reports and provide relevant clinical context beyond mere numbers. 1