What is the initial workup and treatment for systemic lupus erythematosus (SLE)?

Initial Workup for Systemic Lupus Erythematosus

All patients suspected of having SLE require serological testing for antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), anti-Smith antibodies, complement levels (C3, C4), complete blood count, comprehensive metabolic panel including creatinine, urinalysis with microscopy for proteinuria and cellular casts, and antiphospholipid antibody testing. 1, 2

Diagnostic Approach

Essential Laboratory Testing

• Autoantibody profile must include ANA (screening test), anti-dsDNA, anti-Smith, and antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I), as these are weighted heavily in the 2019 EULAR/ACR classification criteria with 96.1% sensitivity and 93.4% specificity 3, 4

• Complement levels (C3 and C4) should be measured at baseline and monitored regularly, as hypocomplementemia indicates active disease and immune complex consumption 1

• Complete blood count to detect cytopenias (thrombocytopenia, leukopenia, autoimmune hemolytic anemia), which are common hematological manifestations requiring specific management 1, 2

• Renal function assessment with serum creatinine, urinalysis for proteinuria (quantified as protein-to-creatinine ratio), and urine microscopy for cellular casts, since 40% of SLE patients develop lupus nephritis and 10% progress to end-stage renal disease within 10 years 3, 4

Clinical Manifestations to Document

• Mucocutaneous findings: malar rash, discoid lesions, photosensitivity, oral ulcers, and alopecia, which are among the earliest presenting symptoms and carry diagnostic weight 3, 4, 5

• Musculoskeletal symptoms: arthralgia, myalgia, and non-erosive arthritis affecting small and large joints 3, 4

• Constitutional symptoms: fever (after excluding infection), fatigue, and weight loss 3, 4

• Neuropsychiatric manifestations: headache (excluding other causes like aseptic meningitis or sinus thrombosis), seizures, psychosis, or cognitive dysfunction require MRI and EEG to exclude structural brain disease 1

Organ-Specific Workup

For suspected lupus nephritis (proteinuria >0.5 g/24 hours or active urine sediment), kidney biopsy is essential before initiating immunosuppressive therapy to determine histological class and guide treatment selection 1, 2

For neuropsychiatric symptoms, obtain brain MRI and EEG to exclude structural lesions, inflammatory conditions, or metabolic causes, and perform lumbar puncture for CSF analysis if infection is suspected 1

For hematological abnormalities, distinguish autoimmune cytopenias from drug-induced causes and assess severity (platelets <30,000/mm³ require urgent treatment) 1, 2

Monitoring Parameters

• Disease activity indices should be assessed at each visit using validated tools like SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) 1, 2

• Regular monitoring every 3 months for high-risk patients (males, juvenile onset, serologically active including anti-C1q antibodies) to detect early organ involvement 1

• Serial measurements of anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment at each visit to track disease activity 1, 2

Treatment Initiation

Foundation Therapy for All Patients

Hydroxychloroquine at ≤5 mg/kg real body weight is mandatory for all SLE patients unless contraindicated, as it reduces disease activity, prevents flares, and improves survival. 1, 2, 6, 3

• The dose should not exceed 5 mg/kg real body weight to minimize retinal toxicity risk, which exceeds 10% after 20 years of continuous use 1, 2

• Ophthalmological screening is required at baseline, after 5 years, then yearly using visual fields examination and/or spectral domain-optical coherence tomography 1, 2, 6

Glucocorticoid Strategy

• Intravenous methylprednisolone pulses (250-1000 mg daily for 1-3 days) provide immediate therapeutic effect for acute flares and enable lower starting doses of oral glucocorticoids 1, 2

• Oral prednisone dosing depends on disease severity, but the medium to long-term goal is to minimize to ≤7.5 mg/day or discontinue entirely, as chronic use above this threshold substantially increases irreversible organ damage risk 1, 2

Immunosuppressive Agent Selection

For mild disease (skin and joint manifestations without major organ involvement), add methotrexate if hydroxychloroquine and low-dose glucocorticoids are insufficient 2

For moderate disease requiring glucocorticoid-sparing, add azathioprine (particularly suitable for women contemplating pregnancy) or mycophenolate mofetil for renal and non-renal manifestations 1, 2

For severe organ-threatening disease (lupus nephritis, cardiopulmonary, or neuropsychiatric manifestations), initiate cyclophosphamide or mycophenolate mofetil as induction therapy 1, 2

Lupus Nephritis-Specific Protocol

• Induction therapy: Mycophenolate mofetil or low-dose cyclophosphamide (Euro-Lupus regimen) are first-line agents with the best efficacy/toxicity ratio 1, 2

• Low-dose cyclophosphamide is preferred over high-dose regimens due to comparable efficacy and lower gonadotoxicity 1

• Maintenance therapy: Mycophenolate mofetil or azathioprine after achieving initial response 1, 2

• Treatment goals include at least partial remission (≥50% reduction in proteinuria to subnephrotic levels and serum creatinine within 10% of baseline) by 6-12 months 1

Adjunctive Therapies

• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 2

• Calcium and vitamin D supplementation for all patients on long-term glucocorticoids to prevent osteoporosis 2

• Photoprotection with sunscreens to prevent cutaneous flares 2

Biologic Therapies for Refractory Disease

• Belimumab (anti-BAFF antibody) is FDA-approved as add-on treatment for active extrarenal SLE and lupus nephritis when standard therapy is insufficient 2, 3

• Rituximab should be considered for organ-threatening disease refractory to standard immunosuppressive agents, particularly for hematological manifestations 1, 2

• Anifrolumab (anti-type 1 interferon receptor) is approved for moderate-to-severe extrarenal SLE 2, 3

Critical Pitfalls to Avoid

• Do not delay kidney biopsy in suspected lupus nephritis, as histological classification is essential for treatment selection and prognosis 1, 2

• Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate in women who are pregnant or contemplating pregnancy; azathioprine, hydroxychloroquine, and prednisolone are safe alternatives 2

• Do not attribute all neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic causes, or medication side effects (steroid-induced psychosis) 1

• Do not overlook antiphospholipid antibody syndrome, which requires anticoagulation (warfarin with target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) in addition to immunosuppression 1, 2

Comorbidity Screening

• Screen for infections (5-fold increased mortality risk), cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma) at regular intervals 2, 3

• Assess cardiovascular risk in patients with persistent proteinuria, GFR <60 mL/min, and chronic glucocorticoid use, as these are major risk factors 1