What is the initial evaluation and first‑line therapy for a patient with suspected systemic lupus erythematosus?

Initial Evaluation and First-Line Therapy for Suspected Systemic Lupus Erythematosus

Begin with ANA testing by indirect immunofluorescence on HEp-2 cells at 1:80–1:160 dilution; if positive (≥1:160), proceed with a comprehensive autoantibody panel, renal assessment, and complete blood count, then initiate hydroxychloroquine 5 mg/kg/day as first-line therapy for all patients without contraindications. 1, 2

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Initial Laboratory Workup

ANA Screening (Mandatory First Step)

• ANA by indirect immunofluorescence on HEp-2 cells is the reference-standard screening test, providing >95% sensitivity for SLE and effectively ruling out the disease when negative. 1
• Screen at 1:80–1:160 dilution; titers ≥1:160 are clinically significant. 1
• Report both titer and immunofluorescence pattern (homogeneous pattern associates with more severe disease). 1
• A negative ANA makes SLE highly unlikely (negative predictive value >95%) and should prompt alternative diagnoses. 1, 3
• Never use automated ANA platforms (ELISA, multiplex) as the sole screening test—they have lower sensitivity and may miss relevant antibodies. 1

Comprehensive Autoantibody Panel (If ANA Positive)

• Order anti-dsDNA, anti-Sm, anti-Ro/SSA, anti-La/SSB, anti-RNP, and antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I). 1, 2
• Use a double-screening strategy for anti-dsDNA: initial solid-phase assay (ELISA/FEIA) followed by Crithidia luciliae immunofluorescence test (CLIFT) for confirmation. 1
• When both solid-phase and CLIFT are positive, the likelihood of SLE is very high. 1
• If solid-phase is positive but CLIFT is negative, interpret cautiously and repeat in 6 months. 1

Complement and Inflammatory Markers

• Measure C3 and C4 complement levels (low levels indicate active disease and help monitor flares). 1, 2
• Obtain ESR and CRP; markedly elevated CRP (>50 mg/L) should trigger urgent evaluation for superimposed bacterial infection, as lupus activity alone rarely produces such high CRP. 4, 1

Baseline Hematologic and Metabolic Assessment

• Complete blood count with differential to screen for cytopenias (lymphopenia <500 cells/mm³ or neutropenia <500 cells/mm³ signals high infection risk). 1, 2
• Serum creatinine or eGFR to assess renal function. 1, 2
• Serum albumin (hypoalbuminemia may reflect disease activity or renal loss). 1, 4
• Liver function tests as part of baseline metabolic panel. 1

Renal Evaluation (Critical for All Patients)

• Urinalysis with microscopy and urine protein-to-creatinine ratio are essential to detect lupus nephritis. 1, 2
• For patients with abnormal urinalysis or rising creatinine, obtain repeat urine protein-to-creatinine ratio, urine microscopy, renal ultrasound, and consider renal biopsy when there is uncertainty about the nature or severity of renal involvement (Level 1b evidence, Grade B recommendation). 1

Infection Screening Before Immunosuppression

• Screen for HIV, hepatitis C, hepatitis B, and tuberculosis (interferon-γ release assay or tuberculin skin test with chest radiography) according to local guidelines before initiating high-dose glucocorticoids or immunosuppressive agents. 1

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Clinical Assessment

Mucocutaneous Manifestations

• Document malar rash, discoid lesions, photosensitivity, oral/nasal ulcers, and subacute cutaneous lesions; classify as LE-specific, LE-nonspecific, mimickers, or drug-related. 1
• Perform skin biopsy of any suspicious lesion to confirm cutaneous lupus or vasculitis and differentiate from mimicking conditions. 4
• Use the Cutaneous Lupus Disease Area and Severity Index (CLASI) to quantify disease activity and damage at each visit. 4, 1

Neuropsychiatric Symptoms

• Systematically screen for seizures, headaches, stroke-like symptoms, peripheral neuropathy, cognitive dysfunction (memory, attention, word-finding difficulties), and mood disorders (depression). 1, 5
• The diagnostic workup for neuropsychiatric manifestations should mirror that in the general population presenting with the same symptoms. 5

Musculoskeletal and Constitutional Symptoms

• Assess for arthritis, serositis, fatigue, and fever—these are often the earliest complaints. 5, 6

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First-Line Therapy

Hydroxychloroquine (Cornerstone of Treatment)

• All SLE patients should receive hydroxychloroquine unless contraindicated, at a target dose of 5 mg/kg real body weight/day. 2, 7
• Hydroxychloroquine reduces disease flares, improves long-term outcomes, and is associated with significant reduction in mortality. 2, 8
• Baseline ophthalmologic examination is recommended before starting hydroxychloroquine, especially for patients who will also receive glucocorticoids. 1

Glucocorticoids (Bridging Therapy Only)

• Use glucocorticoids as "bridging therapy" during periods of disease activity to achieve rapid symptom control. 7, 5
• For maintenance, minimize to ≤5 mg/day prednisone equivalent and, when possible, withdraw completely. 7
• Low-dose glucocorticoids may be used for mild disease without major organ involvement. 2, 5

NSAIDs (Judicious Use)

• NSAIDs may be used judiciously for limited periods in patients at low risk for complications (renal, cardiovascular, gastrointestinal). 5

Immunosuppressive Agents (For Non-Responsive or Steroid-Dependent Disease)

• In patients who do not respond to hydroxychloroquine and low-dose glucocorticoids, or who cannot taper steroids below acceptable doses for chronic use, consider azathioprine, mycophenolate mofetil, or methotrexate. 5, 7
• For moderate-to-severe disease or specific organ involvement, higher-dose glucocorticoids and immunosuppressive agents are indicated. 2

Biologic Agents (Add-On Therapy)

• Belimumab or anifrolumab should be considered as add-on therapy to control disease and facilitate glucocorticoid tapering/discontinuation. 7
• Rituximab should be considered in refractory disease. 7

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Adjunctive Therapies and Preventive Measures

Photoprotection and Lifestyle Modifications

• Photoprotection is essential for all patients with skin manifestations. 5, 4
• Encourage smoking cessation, weight control, and regular exercise. 5, 2

Bone Health and Cardiovascular Protection

• Calcium and vitamin D supplementation, particularly for patients on glucocorticoids, to prevent osteoporosis. 5, 2
• Low-dose aspirin may be recommended for patients with specific cardiovascular risk factors or antiphospholipid antibodies. 5, 2
• Assess cardiovascular risk factors annually. 2

Antiphospholipid Antibody Follow-Up

• Repeat antiphospholipid antibody testing at 12 weeks to confirm persistent positivity and establish a diagnosis of antiphospholipid syndrome. 4
• Re-evaluate anti-Ro/SSA and anti-La/SSB antibodies before pregnancy due to risk of neonatal lupus and congenital heart block. 4, 1

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Monitoring and Follow-Up

Disease Activity Assessment

• Use validated indices (SLEDAI or BILAG) at each visit to evaluate disease activity. 2, 1
• For patients with inactive disease, no organ damage, and no comorbidities, evaluate SLEDAI every 6–12 months. 1
• Patients with established nephropathy require more frequent monitoring (every 3 months for the first 2–3 years) including proteinuria, immunological tests (C3, C4, anti-dsDNA), urinalysis, and blood pressure. 1

Laboratory Monitoring

• CBC, renal function, urinalysis, and immunological tests (C3, C4, anti-dsDNA) should be performed every 3–6 months in stable patients. 2, 1
• Organ damage assessment using a validated index (SLICC Damage Index) should be done annually. 2, 1

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Critical Pitfalls to Avoid

• Do not rely solely on ANA without further specific antibody testing—this can lead to misdiagnosis. 1
• Do not use automated ANA platforms as the sole screening test—they have lower sensitivity. 1
• Do not overlook infection screening before starting immunosuppression—SLE patients are at high risk for infections. 5, 1
• Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate in pregnancy. 4
• In ANA-negative patients with persistent multisystem involvement, consider rare ANA-negative SLE and repeat ANA testing in 3–6 months. 1