What are the diagnostic tests for a patient suspected of having systemic lupus erythematosus (SLE)?

Diagnostic Testing for Systemic Lupus Erythematosus

Begin with ANA testing using a 1:160 dilution cutoff, and if positive, confirm with anti-dsDNA antibodies, complement levels (C3/C4), and comprehensive clinical evaluation requiring involvement of at least two organ systems, then apply the EULAR/ACR 2019 classification criteria for final diagnosis. 1

Initial Screening Strategy

Step 1: ANA Testing

• Order ANA testing when patients present with unexplained multisystem inflammatory disease, symmetric joint pain with inflammatory features, photosensitive rash, or cytopenias 2
• Use 1:160 dilution as the cutoff point in unselected populations to minimize false positives 1
• ANA negative (<1:40) makes SLE highly unlikely and other diagnoses should be pursued 3, 4
• ANA titers ≥1:40 warrant further evaluation for SLE 3, 4

Critical Caveat: Do not order ANA testing in patients with only nonspecific symptoms like isolated malaise or fatigue, as the test has limited value in these contexts 2. Only test when at least two organ systems are involved 3, 4.

Confirmatory Autoantibody Testing

Step 2: When ANA is Positive

• Measure anti-dsDNA antibodies using a double-screening strategy: perform last-generation solid phase assay first, then confirm with Crithidia luciliae immunofluorescence test 1
• Test for anti-Sm antibodies (highly specific for SLE) 4
• Measure complement levels (C3 and C4) at baseline—low complement combined with positive anti-dsDNA strongly supports active SLE 1, 5
• Consider testing for anti-Ro/SSA and anti-La/SSB antibodies, particularly in women of childbearing age due to association with neonatal lupus 5
• Measure antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) due to associations with thrombosis and pregnancy complications 5

Important Note: Anti-C1q antibodies have nearly 100% prevalence during active lupus nephritis and excellent negative predictive value 1.

Essential Laboratory Workup

Step 3: Baseline Laboratory Panel

• Complete blood count (CBC) to detect anemia, thrombocytopenia, leukopenia, and lymphopenia—all associated with disease activity and worse prognosis 5, 6
• Serum creatinine and albumin for renal function assessment 5, 1
• Urinalysis with microscopy and urine protein-to-creatinine ratio to detect renal involvement 5, 1
• Erythrocyte sedimentation rate (ESR) for inflammatory activity 1, 6
• C-reactive protein (CRP)—note that SLE patients rarely have elevated CRP, and values >50 mg/L suggest superimposed infection 5, 6

Clinical Evaluation Requirements

Step 4: Multi-System Assessment

• Mucocutaneous: Document number and type of skin lesions (acute, subacute, or chronic cutaneous lupus); consider CLASI scoring for predominant cutaneous disease 5, 6
• Musculoskeletal: Assess for active arthritis and serositis 5, 6
• Renal: Monitor blood pressure, proteinuria, hematuria, and serum creatinine 5, 1
• Hematologic: Evaluate for cytopenias (anemia, thrombocytopenia, leukopenia, lymphopenia) 5, 6
• Neuropsychiatric: Screen for seizures, psychosis, cognitive impairment, headache, mood disorders, and cerebrovascular disease 5, 6
• Constitutional: Document fever and fatigue 6

Tissue Biopsy When Indicated

Step 5: Histological Confirmation

• Skin biopsy is mandatory when cutaneous lesions are present for histological confirmation 1
• Renal biopsy should be performed when lupus nephritis is suspected to confirm diagnosis, assess disease activity versus chronicity, and guide immunosuppressive therapy 1

Final Diagnostic Confirmation

Step 6: Apply Classification Criteria

• Use the EULAR/ACR 2019 classification criteria as the standard for diagnosis (96.1% sensitive, 93.4% specific) 1, 7
• Patients fulfilling four or more of the American College of Rheumatology criteria are highly likely to have SLE 3
• Diagnosis requires positive ANA (entry criterion), involvement of at least two organ systems, and sufficient weighted criteria points 1, 7

Common Diagnostic Pitfalls

• Do not rely on ANA alone: ANA is positive in nearly every case of SLE but is not specific and must be interpreted in appropriate clinical context 2, 7
• Beware of lupus mimickers: Conditions like rosacea, Kikuchi disease, type-1 interferonopathies, Castleman's disease, and Evans' syndrome can mimic SLE 8
• Consider ANA-negative SLE: In rare cases (<5%), patients with persistent characteristic multisystem involvement may have ANA-negative disease and require evaluation by a rheumatologist 4
• Repeat testing when initially negative: If anti-dsDNA and complement levels are initially negative or normal, repeat them at follow-up visits as they may become positive with disease activity 6