What is the initial evaluation and diagnostic work‑up for a patient suspected of systemic lupus erythematosus, including history, physical exam, laboratory tests, and classification criteria?

Systemic Lupus Erythematosus: Initial Evaluation and Diagnostic Work-Up

Begin with ANA testing by indirect immunofluorescence on HEp-2 cells at 1:80–1:160 dilution as the first-line screening test, which has >95% sensitivity and effectively rules out SLE when negative. 1

Initial Screening Strategy

ANA Testing (Primary Screening)

• Perform ANA by indirect immunofluorescence (IIFA) on HEp-2 cells at screening dilution of 1:80–1:160; titers ≥1:160 are clinically significant 1
• Report both the titer and immunofluorescence pattern; homogeneous pattern associates with more severe disease activity 1
• A negative ANA makes SLE highly unlikely (negative predictive value >95%) and should prompt consideration of alternative diagnoses 1
• Never use automated ANA platforms (ELISA, multiplex) as the sole screening test due to lower sensitivity and risk of missing relevant antibodies 1
• ANA is positive in >95% of SLE patients, making it the most sensitive screening marker 2, 3

Critical Pitfall: Only order ANA testing in patients with unexplained involvement of two or more organ systems, as the low disease prevalence in primary care yields poor predictive value in patients without typical clinical symptoms 3

Comprehensive Autoantibody Panel (If ANA Positive)

Once ANA is positive, immediately proceed with a complete autoantibody panel including: 4, 1

• Anti-dsDNA antibodies (highly specific for SLE; use double-screening strategy with solid-phase assay followed by Crithidia luciliae immunofluorescence test for confirmation) 1, 5
• Anti-Sm antibodies (highly specific for SLE) 1, 5
• Anti-Ro/SSA antibodies 4, 1
• Anti-La/SSB antibodies 4, 1
• Anti-RNP antibodies 4, 1
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 4, 1
• Complement levels (C3, C4) to assess consumption and disease activity 4, 1, 5

Baseline Laboratory Assessment

Hematologic Evaluation

• Complete blood count with differential to screen for cytopenias 1
  • Severe lymphopenia (<500 cells/mm³) or neutropenia (<500 cells/mm³) signals high infection risk 1
  • Assess for hemolytic anemia, leukopenia, thrombocytopenia 6

Inflammatory Markers

• Erythrocyte sedimentation rate (ESR) 4, 1
• C-reactive protein (CRP) 4, 1

Renal Function Assessment

• Serum creatinine or estimated glomerular filtration rate (eGFR) 4, 1
• Urinalysis with microscopy 4, 1
• Urine protein/creatinine ratio (or 24-hour proteinuria) 4, 1

Additional Baseline Tests

• Serum albumin 4, 1
• Liver function tests 1

Focused Clinical History

Mucocutaneous Symptoms

• Malar rash, discoid lesions, photosensitivity, oral/nasal ulcers, subacute cutaneous lupus lesions 7
• Characterize lesions as LE-specific, LE-nonspecific, LE mimickers, or drug-related 4, 7

Renal Symptoms

• Edema, foamy urine, hematuria, changes in urinary frequency or volume 7
• Hypertension symptoms (headaches, vision changes) 7

Neuropsychiatric Symptoms

• Seizures, headaches, stroke symptoms, peripheral neuropathy 4, 7
• Cognitive dysfunction: problems with multitasking, household tasks, memory, attention/concentration, word-finding difficulties 4, 7
• Mood disorders, depression 4, 7

Thrombotic History

• Arterial thrombosis: stroke, TIA, myocardial infarction at young age 7
• Venous thrombosis: DVT, pulmonary embolism 7
• Any history of blood clots (critical for identifying antiphospholipid syndrome, which significantly increases morbidity and mortality) 7

Obstetric History

• Recurrent miscarriages, preeclampsia, intrauterine growth restriction, stillbirths 7

Drug Exposure

• Medications known to trigger drug-induced lupus (hydralazine, procainamide, isoniazid, minocycline, others) 7

Physical Examination Focus

Organ-Specific Assessment

• Skin examination: document malar rash, discoid lesions, photosensitive rashes, oral/nasal ulcers using validated indices (CLASI) 4
• Musculoskeletal: assess for arthritis, synovitis 8
• Cardiovascular: blood pressure, signs of pericarditis, heart murmurs 7
• Pulmonary: assess for pleuritis, pleural effusion 8
• Neurologic: complete neurologic examination if symptoms present 4

Pre-Treatment Infection Screening

Before initiating immunosuppression, complete the following screens: 1

• HIV, hepatitis C virus (HCV), hepatitis B virus (HBV) based on individual risk factors 1
• Tuberculosis screening per local guidelines (interferon-γ release assay or tuberculin skin test with chest radiography) 1

Cardiovascular Risk Assessment

SLE patients have accelerated atherosclerosis requiring comprehensive cardiovascular screening: 7, 1

• Smoking status 7, 1
• History of vascular events 7, 1
• Physical activity level 7, 1
• Use of oral contraceptives/hormonal therapies 7, 1
• Family history of cardiovascular disease 7, 1
• Blood cholesterol and glucose 1
• Blood pressure 1

Advanced Renal Evaluation (If Indicated)

For patients with persistently abnormal urinalysis or raised serum creatinine: 4

• Urine protein/creatinine ratio (or 24-hour proteinuria) 4
• Urine microscopy 4
• Renal ultrasound 4
• Consider referral for renal biopsy (Level 1b evidence, Grade B recommendation) 4

Diagnostic Interpretation Algorithm

For patients with ANA titer ≥1:160 and characteristic multiorgan involvement: diagnosis can be established without additional testing 3

For patients with ANA titer 1:40 who fail to meet full clinical criteria: proceed with anti-dsDNA and anti-Sm antibody testing 3

For patients with ANA <1:40 but persistent characteristic multisystem involvement: evaluate for possible ANA-negative disease (rare but exists) 3

Critical Caveat: Relying solely on ANA without further specific antibody testing leads to misdiagnosis 1. The presence of anti-dsDNA and anti-Sm antibodies is highly specific for SLE and supports definitive diagnosis 1, 5.