What is the diagnostic approach for a patient suspected of having Systemic Lupus Erythematosus (SLE), considering their age, sex, ethnicity, and past medical history?

ANA Diagnosis for Lupus

Begin with ANA testing by indirect immunofluorescence (IIF) on HEp-2 cells as the mandatory entry criterion—a positive ANA is now required for SLE diagnosis per the 2019 ACR/EULAR criteria, and a negative ANA essentially rules out SLE unless there is exceptionally high clinical suspicion. 1

Initial Screening Approach

Step 1: ANA Testing

• Order ANA by IIF on HEp-2 cells as the primary screening test due to its high sensitivity for ruling out SLE 2, 1
• A negative ANA makes SLE diagnosis highly unlikely and further autoantibody testing is generally not recommended unless there is strong clinical suspicion with characteristic multisystem involvement (unexplained cytopenias, proteinuria, or typical rashes) 3, 4
• If ANA is positive, proceed immediately to comprehensive autoantibody panel 2

Step 2: Comprehensive Autoantibody Panel (if ANA positive)

When ANA is positive, order the following specific antibodies simultaneously 5, 2:

• Anti-dsDNA antibodies using double-screening strategy:

  • First: Solid-phase assay (FEIA, CLIA, or ELISA) for sensitivity
  • Second: Crithidia luciliae immunofluorescence test (CLIFT) for confirmation and specificity 3
  • This combination minimizes false positives while maintaining diagnostic accuracy 3

• Anti-Sm antibodies (highly specific for SLE) 2, 1

• Anti-Ro/SSA and anti-La/SSB antibodies (important for neonatal lupus risk and subacute cutaneous lupus) 3, 5

• Anti-RNP antibodies 3, 2

• Antiphospholipid antibodies (anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant) 5, 1

Step 3: Complement Levels and Inflammatory Markers

• C3 and C4 complement levels—low levels strongly correlate with active disease, particularly lupus nephritis 3, 5, 1
• ESR and CRP—note that CRP >50 mg/L in SLE should raise suspicion for superimposed infection rather than lupus activity 3, 5

Organ-Specific Assessment Based on Clinical Presentation

Renal Evaluation (Critical—40% develop lupus nephritis)

Perform the following tests in all suspected SLE patients 5, 1:

• Urinalysis with microscopy looking for red blood cell casts, white blood cell casts, or acanthocytes
• Spot urine protein-to-creatinine ratio (more practical than 24-hour collection)
• Serum creatinine and eGFR
• Renal ultrasound if abnormalities detected
• Consider renal biopsy if persistent proteinuria >500 mg/day, abnormal sediment, or unexplained decline in eGFR 1

Hematologic Assessment

• Complete blood count to identify cytopenias: leukopenia, lymphopenia, thrombocytopenia, or hemolytic anemia 3, 2, 1
• Serum albumin as part of baseline assessment 3, 2

Mucocutaneous Evaluation

Document and classify skin lesions as 3, 5:

• LE-specific lesions: acute cutaneous LE (malar rash), subacute cutaneous LE, chronic cutaneous LE (discoid)
• LE-nonspecific lesions
• LE mimickers
• Drug-related lesions
• Consider skin biopsy when clinical morphology is unclear or mimics other conditions 5

Neuropsychiatric Assessment

Screen by focused history for 3, 5:

• Seizures, psychosis, acute confusional state
• Cognitive dysfunction (attention, concentration, word-finding, memory difficulties)
• Headaches, paresthesias, numbness, weakness
• Depression

Interpreting Anti-dsDNA Double-Screening Results

The combination of solid-phase assay (SPA) and CLIFT produces four possible outcomes 3:

SPA Result	CLIFT Result	Interpretation
Negative	Negative	SLE diagnosis cannot be established at this time
Positive	Positive	SLE very likely—proceed with diagnosis
Positive	Negative	Evaluate in clinical context; if diagnosis unclear, repeat in 6 months
Negative	Positive	Inconsistent result—repeat testing; clinical follow-up periodically

Special Population Considerations

Women of Childbearing Age

• Document obstetric history including recurrent miscarriages, preeclampsia, intrauterine growth restriction, stillbirths 5
• Test anti-Ro and anti-La antibodies before pregnancy due to neonatal lupus risk 1
• Confirm antiphospholipid antibodies with repeat testing >12 weeks apart if initially positive 1

High-Risk Populations

Asian, African/Caribbean, and Hispanic descent patients require heightened clinical suspicion due to higher incidence and more severe disease manifestations 1

Common Diagnostic Pitfalls

• Do not rely solely on ANA without specific antibody testing—this leads to misdiagnosis due to low positive predictive value in primary care populations 2, 4
• ANA titer of 1:40 alone is insufficient—requires characteristic multiorgan involvement or additional specific antibodies (anti-dsDNA, anti-Sm) 4
• Do not order ANA in patients without multisystem involvement—per ACR guidelines, only order when unexplained involvement of two or more organ systems is present 4
• Beware of drug-induced lupus—inquire about hydralazine, procainamide, and minocycline exposure 5
• Elevated CRP is uncommon in SLE—if present, suspect infection rather than disease activity 3, 5

Clinical Context Integration

The diagnosis requires integration of 3, 5, 6:

• Clinical manifestations: fever, rash (malar, discoid, photosensitive), arthritis, serositis, neuropsychiatric symptoms
• Laboratory findings: cytopenias, proteinuria, positive specific autoantibodies, low complement
• Exclusion of mimickers: infections, malignancies, other autoimmune diseases

The 2019 ACR/EULAR classification criteria are 96.1% sensitive and 93.4% specific for SLE and require positive ANA as entry criterion plus weighted scoring of clinical and immunologic features 6