What is the diagnostic approach for Systemic Lupus Erythematosus (SLE)?

How to Diagnose Systemic Lupus Erythematosus (SLE)

Begin with ANA testing at 1:160 dilution as the mandatory entry criterion, then confirm with comprehensive autoantibody profiling and apply the EULAR/ACR 2019 classification criteria requiring involvement of at least two organ systems to establish the diagnosis. 1

Initial Screening Strategy

ANA testing is the absolute first step - use a 1:160 dilution cutoff in unselected populations to minimize false positives. 1 Without positive ANA, you cannot proceed with SLE classification regardless of clinical manifestations. 2 This test has >95% sensitivity in SLE patients. 3

Confirmatory Autoantibody Panel

Once ANA is positive, immediately order:

• Anti-dsDNA antibodies using a double-screening strategy: start with last-generation solid phase assay, then confirm with Crithidia luciliae immunofluorescence test 1
• Anti-Sm antibodies (highly specific for SLE) 1, 4
• Anti-Ro/SSA and anti-La/SSB (associated with neonatal lupus and have prognostic value) 5
• Anti-RNP antibodies (prognostic significance) 5
• Antiphospholipid antibodies (anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant) - these predict thrombotic manifestations, damage development, and pregnancy complications 5

Essential Baseline Laboratory Workup

Order the following tests at initial evaluation:

• Complete blood count - look for cytopenias (anemia, thrombocytopenia, leukopenia, lymphopenia) which have prognostic implications 5, 1
• Complement levels (C3 and C4) - low complement combined with positive anti-dsDNA strongly supports active SLE 1, 5
• Serum creatinine and albumin - provide information on renal involvement and prognosis 5, 1
• Urinalysis with microscopy and urine protein/creatinine ratio - essential for detecting lupus nephritis 5, 1
• ESR and CRP - note that CRP is often normal in SLE; significant elevation (>50 mg/L) suggests superimposed infection 5

Clinical Manifestations to Document

Systematically evaluate these organ systems, as the EULAR/ACR 2019 criteria weight manifestations within each domain:

Mucocutaneous (most common at 82%): 6

• Acute cutaneous lupus (malar rash, photosensitive rash)
• Subacute or chronic cutaneous lupus
• Oral or nasal ulcers
• Non-scarring alopecia
• Consider dermatology referral and skin biopsy for histological confirmation when cutaneous lesions are present 5, 1

Musculoskeletal (59-73%): 6

• Arthritis (typically non-erosive, involving small joints)
• Myalgia and arthralgia 4

Renal (up to 40% develop lupus nephritis): 7

• Proteinuria >0.5 g/24h
• Active urinary sediment (red blood cell casts, hematuria, pyuria)
• Kidney biopsy is mandatory when lupus nephritis is suspected to confirm diagnosis, assess activity versus chronicity, and guide immunosuppressive therapy 1, 8

Hematologic:

• Autoimmune hemolytic anemia 5
• Thrombocytopenia (<100,000/mm³) 5
• Leukopenia (<4,000/mm³) or lymphopenia (<1,000/mm³) 5

Neuropsychiatric (requires comprehensive evaluation):

• Headache, mood disorders, seizures, cognitive impairment, cerebrovascular disease 5
• Use validated attribution models to distinguish primary NPSLE from mimics (infections, malignancy) 5
• Consider neuroimaging and cerebrospinal fluid analysis when NPSLE is suspected 5

Constitutional symptoms:

• Fever (after excluding infection) 7
• Fatigue 4

Apply EULAR/ACR 2019 Classification Criteria

This is the gold standard with 96.1% sensitivity and 93.4% specificity. 1, 7 The criteria use a weighted scoring system:

• Entry criterion: ANA ≥1:80 (mandatory) 1, 2
• Additive weighted criteria across clinical and immunologic domains
• Classification threshold: ≥10 points
• Requirement: At least one clinical criterion must be present 1

Critical Diagnostic Pitfalls to Avoid

Do not diagnose SLE without positive ANA - this is an absolute requirement per current criteria. 2

Rule out SLE mimickers before finalizing diagnosis:

• Rosacea (can mimic malar rash) 9
• Drug-induced lupus 9
• Kikuchi disease, type-1 interferonopathies, Castleman's disease 9
• Infections (especially when CRP is markedly elevated) 5
• Malignancies (lymphoma can present with similar features) 9

Recognize that ANA positivity alone is not diagnostic - ANAs occur in healthy individuals and other conditions; the complete constellation of clinical and laboratory findings is required. 9, 10

In Black/African-American patients, be aware that disease presentation may differ and response to certain treatments may vary. 6

Organ-Specific Diagnostic Procedures

For suspected lupus nephritis:

• Kidney biopsy is essential before initiating immunosuppressive therapy 1, 8
• Classify by ISN/RPS criteria (Class III, IV, V most common) 6

For cutaneous manifestations:

• Skin biopsy with histological analysis and direct immunofluorescence when diagnosis is uncertain 5
• Consider using Cutaneous Lupus Disease Area and Severity Index (CLASI) for patients with predominant skin involvement 5

For neuropsychiatric symptoms:

• Diagnostic evaluation should mirror what would be done in non-SLE patients with the same symptoms 5
• No single test differentiates NPSLE from other causes; use combination of clinical, laboratory, neuropsychological, and imaging tests 5

Post-Diagnosis Monitoring Setup

Once diagnosed, establish baseline monitoring:

• Use validated activity indices (SLEDAI, BILAG, or SLE-DAS) at each visit 1, 8
• Monitor anti-dsDNA and complement levels every 6-12 months even if initially negative/normal 1
• Regular monitoring of CBC, ESR, CRP, serum albumin, creatinine, urinalysis 1
• Anti-C1q antibodies have nearly 100% prevalence during active lupus nephritis and excellent negative predictive value 1
• Ophthalmologic screening at baseline, after 5 years, then yearly for hydroxychloroquine retinal toxicity 8