What is the approach to diagnose systemic lupus erythematosus (SLE) in a patient, particularly in women of childbearing age or those with a family history of autoimmune disorders, presenting with symptoms such as joint pain, skin rashes, kidney problems, or fever?

Diagnosing Systemic Lupus Erythematosus

Diagnose SLE using the 2019 EULAR/ACR classification criteria, which require a positive ANA (≥1:80 titer) as an entry criterion, followed by weighted scoring of clinical and immunologic domains to reach a threshold of ≥10 points, achieving 96.1% sensitivity and 93.4% specificity. 1

Entry Criterion: ANA Testing

• ANA positivity (≥1:80 titer) is mandatory before applying classification criteria 1
• Without a positive ANA, alternative diagnoses should be strongly considered 1
• ANA testing serves as the immunologic gatekeeper for SLE diagnosis 2

Clinical Domain Assessment

Constitutional and Mucocutaneous Features

• Fever (unexplained, >38.3°C): Document presence as it contributes to diagnostic scoring 1
• Lupus-specific rashes: Distinguish between acute cutaneous lupus (malar rash), subacute cutaneous lupus, and chronic cutaneous lupus (discoid lesions) 3, 2
• Oral ulcers (palate, buccal, tongue) and non-scarring alopecia should be documented 3, 2
• Skin biopsy may be required when clinical morphology is unclear or mimics other conditions 4

Musculoskeletal Manifestations

• Arthritis: Document joint pain, swelling, and morning stiffness affecting multiple joints 4
• Serositis: Assess for pleuritic chest pain, pericardial pain, or pleural/pericardial effusions 4

Renal Involvement

• Proteinuria: Quantify with spot urine protein-to-creatinine ratio (nephrotic range >3.5 g/day indicates severe disease) 5
• Urine sediment analysis: Look for red blood cell casts, white blood cell casts, or acanthocytes (≥5%) 5
• Serum creatinine and blood pressure: Elevated creatinine (e.g., >150 μmol/L) indicates impaired glomerular filtration 5
• Kidney biopsy should be performed to classify lupus nephritis according to ISN/RPS criteria when renal involvement is suspected 5

Neuropsychiatric Manifestations

• Seizures, psychosis, acute confusional state: Document these major neuropsychiatric features 4, 3
• Cognitive dysfunction: Specifically assess memory, attention, concentration, multitasking ability, and word-finding difficulties 4, 3
• Headaches, mood disorders, peripheral neuropathy, stroke symptoms: Include in systematic evaluation 3
• Diagnostic workup (neuropsychological testing, brain MRI) should mirror that used in the general population with similar symptoms 4

Hematologic Abnormalities

• Complete blood count: Document cytopenia (anemia, thrombocytopenia, leukopenia) 4, 1
• Thrombosis history: Any arterial (stroke, TIA, MI) or venous (DVT, PE) thrombotic events 3

Immunologic Testing

Essential Autoantibodies

• Anti-dsDNA antibodies: Highly specific for SLE and correlates with disease activity, particularly renal involvement 4, 1
• Anti-Smith (anti-Sm) antibodies: Highly specific for SLE 1, 2
• Antiphospholipid antibodies (anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant): Critical for identifying antiphospholipid syndrome 4, 3
• Anti-Ro/SSA and anti-La/SSB antibodies: Provide prognostic information 4
• Anti-RNP antibodies: May indicate overlap syndromes 4

Complement Levels

• Low C3 and C4: Strongly associated with active disease, particularly lupus nephritis 4, 5
• C3 <0.9 g/L and C4 <0.1 g/L suggest active renal disease 5
• Anti-C1q antibodies: Associated with lupus nephritis 4

Diagnostic Algorithm

1. Screen with ANA: If negative at ≥1:80 titer, SLE is unlikely 1
2. If ANA positive: Obtain specific autoantibody panel (anti-dsDNA, anti-Sm, antiphospholipid antibodies, anti-Ro/SSA, anti-La/SSB) 4, 1
3. Measure complement levels: C3 and C4 to assess disease activity 4, 5
4. Assess organ involvement systematically:
   • Renal: Urinalysis, urine protein-to-creatinine ratio, serum creatinine 5
   • Hematologic: CBC with differential 4
   • Neuropsychiatric: Clinical history and targeted testing based on symptoms 4, 3
   • Mucocutaneous: Clinical examination, consider biopsy if unclear 4, 3
5. Apply 2019 EULAR/ACR classification criteria: Weight clinical and immunologic features to reach ≥10 points 1
6. Consider kidney biopsy when renal parameters are abnormal to guide treatment 5
7. Exclude alternative diagnoses: Drug-induced lupus, infections, malignancies 3, 6

Critical Pitfalls to Avoid

• Do not rely solely on classification criteria for diagnosis: These were developed for research, not clinical diagnosis, and strict adherence may delay treatment 7
• Recognize that SLE remains primarily a clinical diagnosis: Classification criteria support but do not replace clinical judgment 7
• Early SLE may not meet full criteria: Patients with inadequate features at presentation may still require treatment 7
• CRP elevation is uncommon in SLE: If CRP >50 mg/L, strongly suspect superimposed infection 4
• Drug-induced lupus mimics SLE: Inquire about medications known to trigger lupus-like syndromes (hydralazine, procainamide, minocycline) 3

Special Populations

Women of Childbearing Age

• Document obstetric history: Recurrent miscarriages, preeclampsia, intrauterine growth restriction, stillbirths suggest antiphospholipid syndrome 3
• Test for antiphospholipid antibodies: Essential for pregnancy planning and management 3

Patients with Family History of Autoimmune Disease

• Lower threshold for investigation: Genetic predisposition increases SLE risk 6
• Screen for other autoimmune conditions: Overlap syndromes are common 6