What are the diagnostic workup and treatment options for a patient with suspected Systemic Lupus Erythematosus (SLE)?

Systemic Lupus Erythematosus: Diagnosis and Treatment

Diagnostic Workup

Begin with ANA testing as the mandatory entry criterion—a positive ANA at titer ≥1:80 by indirect immunofluorescence on HEp-2 cells is required before proceeding with further SLE evaluation. 1

Initial Serological Testing

• ANA testing is the most sensitive screening test for SLE and should be obtained first in patients with unexplained involvement of two or more organ systems 1, 2
• If ANA is negative and symptoms remit, pursue alternative diagnoses 1
• If ANA is negative but symptoms persist, repeat testing in 3-6 months 1

Confirmatory Testing When ANA is Positive

• Order anti-dsDNA antibodies using both a sensitive method (solid phase assay/SPA) and a specific method (Crithidia luciliae immunofluorescence test/CLIFT) to optimize diagnostic accuracy 1
• Test for anti-ENA antibodies, specifically anti-Smith (highly specific for SLE), anti-Ro/SSA, anti-La/SSB, and anti-U1-RNP 1, 3
• Measure complement levels (C3, C4, CH50)—low levels indicate active disease 4, 3

Essential Laboratory Panel

• Complete blood count to detect cytopenias (leukopenia, lymphopenia, thrombocytopenia, hemolytic anemia) 4, 3
• Serum creatinine and eGFR to assess renal function 4, 3
• Urinalysis with microscopy and urine protein-to-creatinine ratio (UPCR) to detect lupus nephritis 4, 3
• Antiphospholipid antibodies (anticardiolipin, anti-β2GP1, lupus anticoagulant) as 30-40% of SLE patients are positive 1

Interpretation Algorithm for Anti-dsDNA Results

• If both SPA and CLIFT are positive: SLE is very likely—proceed with diagnosis in the context of clinical features 1
• If SPA is positive but CLIFT is negative: Evaluate carefully in clinical context; consider anti-nucleosome antibodies (83% sensitivity, 97% specificity for SLE) 1
• If both are negative but clinical suspicion persists: Perform periodic clinical follow-up and repeat testing in 6 months 1

Organ-Specific Evaluation

• For suspected lupus nephritis: Obtain renal biopsy to determine ISN/RPS class (III, IV, V), as histology independently predicts clinical outcome and guides immunosuppressive therapy 4, 3
• Measure blood pressure at every visit, as hypertension predicts worse renal survival 4
• For neuropsychiatric symptoms: Rule out infection first, then consider CSF analysis and brain imaging 5

Disease Activity Monitoring Tools

• Apply validated disease activity indices (SLEDAI-2K, BILAG, or SLE-DAS) to objectively quantify disease activity and detect flares 1, 4, 3

---

Treatment Approach

Hydroxychloroquine is the foundation of SLE treatment and must be prescribed to all patients unless contraindicated, as it reduces disease activity, flares, and mortality. 6, 3, 7

Universal First-Line Therapy

• Hydroxychloroquine at ≤5 mg/kg real body weight daily 3, 7
• Requires ophthalmological screening at baseline, after 5 years, then yearly to monitor for retinal toxicity 6, 3
• Never discontinue hydroxychloroquine unless there is a specific contraindication, as it improves survival even in severe disease 6

Glucocorticoid Management

• For moderate to severe flares: Use short-term systemic glucocorticoids (prednisone or equivalent) 3
• Target chronic maintenance dose of ≤7.5 mg/day prednisone equivalent, with complete withdrawal when possible 6, 3
• For severe organ-threatening disease: Consider pulse IV methylprednisolone 500-1000 mg/day for 3 days 8, 5
• Minimize exposure above 7.5 mg/day to reduce risks of infection, osteoporosis, and cardiovascular disease 6

Immunosuppressive Therapy for Moderate to Severe Disease

Add immunosuppressive agents to facilitate glucocorticoid tapering and achieve disease control:

• Mycophenolate mofetil: Effective for lupus nephritis and refractory cutaneous disease 3, 7
• Azathioprine: Used for maintenance therapy after achieving initial response in organ-threatening disease, or as glucocorticoid-sparing agent 3, 7
• Cyclophosphamide: Reserved for severe organ-threatening disease, particularly Class III/IV lupus nephritis 7, 5

Lupus Nephritis-Specific Treatment

For Class III or IV lupus nephritis:

• Induction: Mycophenolate mofetil (target 2-3 g/day) plus glucocorticoids (IV methylprednisolone followed by oral prednisone taper to ≤2.5 mg/day by Week 16) 8
• Alternative induction: Cyclophosphamide followed by azathioprine for maintenance 8
• Consider adding voclosporin 23.7 mg twice daily to mycophenolate plus glucocorticoids for enhanced complete renal response rates (30% vs 20% with placebo) 8
• Target complete renal response: UPCR ≤0.5 mg/mg and eGFR ≥90 mL/min/1.73 m² or no decrease >10% from baseline 8

Biologic Therapies

For refractory disease or to reduce glucocorticoid burden:

• Belimumab 10 mg/kg IV monthly (after loading doses at Days 0,14,28): Approved for active SLE and lupus nephritis 9, 7
• Belimumab increases primary efficacy renal response in lupus nephritis (43% vs 32% with placebo) 9
• Anifrolumab: Approved for active SLE 7
• Rituximab: Most commonly used for severe neuropsychiatric SLE, though not FDA-approved for this indication 5

Organ-Specific Treatment

For cutaneous manifestations:

• First-line: Topical glucocorticoids plus hydroxychloroquine 3
• Second-line for refractory disease: Methotrexate, mycophenolate mofetil, or dapsone (particularly for bullous lupus) 3
• Retinoids for hyperkeratotic lesions 3

For hematologic manifestations:

• Severe hemolytic anemia: High-dose glucocorticoids first-line, rituximab for refractory cases 6
• Distinguish whether cytopenias are due to lupus activity, medication toxicity, or infection 6

Essential Adjunctive Measures

• Photoprotection with broad-spectrum sunscreen and sun avoidance for all patients with cutaneous manifestations 6, 3
• Low-dose aspirin for patients with antiphospholipid antibodies for primary prevention of thrombosis 3
• Long-term anticoagulation for patients with antiphospholipid-associated thrombosis 3
• Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole) if using high-dose glucocorticoids or multiple immunosuppressants 6

Monitoring During Treatment

• Every 3 months for stable patients: Clinical examination, CBC, serum creatinine, urinalysis with microscopy, C3/C4 levels, and anti-dsDNA antibodies 6, 3
• Do not repeat ANA testing after initial positive result—it is not useful for monitoring disease activity 1
• Use quantitative anti-dsDNA assays (preferably the same method and laboratory used at diagnosis) to monitor disease activity 1
• For lupus nephritis patients who remain anti-dsDNA negative: Use anti-nucleosome antibodies to monitor disease activity 1
• Anti-C1q antibodies have critical negative predictive value—lupus nephritis flares are unlikely in their absence 1

Treatment Goals

Aim for clinical remission or low disease activity state, defined as:

• Minimal symptoms
• Low autoimmune inflammatory markers
• Minimal glucocorticoid requirement (≤7.5 mg/day prednisone) 6, 3
• Prevention of organ damage from both disease activity and treatment toxicity 6, 3

Critical Pitfalls to Avoid

• Never attribute fever or new symptoms to lupus activity alone without first excluding infection, especially in immunosuppressed patients 6, 3
• Do not use ANA titers to monitor disease activity or guide treatment decisions 1
• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day for >3 months) due to substantial toxicity risks 6, 3
• Do not delay renal biopsy when lupus nephritis is suspected—histology guides therapy and predicts outcomes 4, 3
• Mycophenolate mofetil, cyclophosphamide, and methotrexate are contraindicated in pregnancy 3
• Voclosporin requires dose adjustment based on eGFR and blood pressure; do not use if baseline eGFR ≤45 mL/min/1.73 m² 8

Comorbidity Management

• Aggressively manage cardiovascular risk factors (hypertension, dyslipidemia, diabetes) as SLE patients have accelerated atherosclerosis 6, 3
• Screen for and prevent osteoporosis, particularly in patients on chronic glucocorticoids 3
• Monitor for infections systematically, including screening for HIV, HCV, HBV, tuberculosis, and CMV in immunosuppressed patients 6, 3