What is the recommended workup, diagnosis, and treatment for a patient suspected of having Systemic Lupus Erythematosus (SLE)?

Systemic Lupus Erythematosus: Workup, Diagnosis, and Treatment

Diagnostic Workup

Begin serological testing with ANA by indirect immunofluorescence on HEp-2 cells at ≥1:80 titer as the mandatory entry criterion, as this is 96.1% sensitive for SLE and effectively rules out the disease when negative. 1, 2

Initial Laboratory Panel

• ANA testing at titer ≥1:80 by indirect immunofluorescence is required before proceeding with further evaluation 1, 2
• Anti-dsDNA antibodies (highly specific for SLE and correlate with lupus nephritis activity) 1
• Anti-Smith antibodies (highly specific confirmatory test) 1
• Complement levels (C3, C4) to detect hypocomplementemia indicating active disease and immune complex consumption 1, 3
• Complete blood count to identify cytopenias (thrombocytopenia, leukopenia, autoimmune hemolytic anemia) 1, 3
• Comprehensive metabolic panel including serum creatinine or eGFR 1, 3
• Urinalysis with microscopy for proteinuria and cellular casts 1, 3
• Urine protein/creatinine ratio (or 24-hour proteinuria) 1
• Antiphospholipid antibody panel (anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant) 1, 3
• Anti-Ro/SSA and anti-La/SSB antibodies for prognostic information regarding neonatal lupus and congenital heart block risk 1

Organ-Specific Investigations

For suspected lupus nephritis (persistently abnormal urinalysis or elevated creatinine): obtain urine protein/creatinine ratio, urine microscopy, renal ultrasound, and proceed directly to kidney biopsy as histological classification is essential for treatment selection and prognosis 1, 3

For neuropsychiatric manifestations (headache, seizures, psychosis, cognitive dysfunction): perform brain MRI and EEG to exclude structural disease, but aggressively exclude infection before attributing symptoms to SLE 1, 3

For mucocutaneous lesions: characterize as LE-specific, LE-nonspecific, LE-mimickers, or drug-related using validated indices like CLASI 1

Diagnosis

The 2019 EULAR/ACR classification criteria require ANA ≥1:80 as entry criterion plus weighted clinical and immunologic criteria totaling ≥10 points, achieving 96.1% sensitivity and 93.4% specificity. 1, 2 However, these are classification criteria for research; clinical diagnosis requires integration of multisystem involvement patterns.

Critical Diagnostic Pitfalls

• Do not order ANA reflexively without clinical suspicion of SLE, as the low prevalence in primary care yields poor predictive value despite high sensitivity 4, 5
• ANA <1:80 effectively rules out SLE in most cases, though rare ANA-negative disease exists with persistent characteristic multisystem involvement 4
• Anti-dsDNA and anti-Sm antibodies are highly specific and have strong confirmatory power even when pretest probability is low 1, 5

Treatment Approach

Foundation Therapy (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, improves survival, and reduces mortality. 1, 3, 6, 2

• Dose must not exceed 5 mg/kg real body weight to minimize retinal toxicity risk (>10% after 20 years) 3, 6
• Ophthalmological screening required at baseline, after 5 years, then yearly using visual fields and/or spectral domain-optical coherence tomography 1, 3, 6

Glucocorticoid Management Algorithm

For acute flares or initial presentation: IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) provides immediate effect and enables lower starting oral doses 1, 3, 6

Chronic maintenance goal: minimize to <7.5 mg/day prednisone equivalent and withdraw when possible to prevent irreversible organ damage 1, 3, 6

Immunosuppressive Therapy Selection

For mild disease (skin and joint manifestations without major organ involvement): add methotrexate if hydroxychloroquine and low-dose glucocorticoids are insufficient 1, 3, 6

For moderate disease requiring glucocorticoid-sparing:

• Azathioprine (particularly suitable for women contemplating pregnancy) 1, 3, 6
• Mycophenolate mofetil for renal and non-renal manifestations (except neuropsychiatric disease) 1, 3, 6

For severe organ-threatening disease (lupus nephritis, cardiopulmonary, neuropsychiatric manifestations): initiate cyclophosphamide or mycophenolate mofetil as induction therapy 1, 3, 6

Lupus Nephritis-Specific Protocol

Induction therapy: Mycophenolate mofetil (1a/A evidence) or low-dose IV cyclophosphamide (Euro-Lupus regimen) as first-line agents with best efficacy/toxicity ratio 3, 6, 7

Maintenance therapy: Mycophenolate mofetil or azathioprine after achieving initial response 3, 6

Treatment goal: achieve at least partial remission (≥50% reduction in proteinuria to subnephrotic levels and serum creatinine within 10% of baseline) by 6-12 months 3, 6

Neuropsychiatric Lupus Treatment

For inflammatory/immune-mediated mechanisms (optic neuritis, acute confusional state, cranial/peripheral neuropathy, psychosis, transverse myelitis): high-dose IV methylprednisolone plus cyclophosphamide (response rate 18/19 vs 7/13 with methylprednisolone alone, p=0.03) 1, 6

For thrombotic/embolic mechanisms: anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) 1, 6

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 3, 6, 7, 2

• In lupus nephritis Trial 5: 43% achieved primary efficacy renal response at Week 104 vs 32% placebo (OR 1.6,95% CI 1.0-2.3, p=0.031) 7

Rituximab should be considered for organ-threatening disease refractory to standard immunosuppressive agents, particularly for hematological manifestations 3, 6

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

Voclosporin is approved for lupus nephritis 2

Adjunctive Therapies

• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 1, 3, 6
• Calcium and vitamin D supplementation for all patients on long-term glucocorticoids to prevent osteoporosis 1, 3, 6
• Photoprotection with sunscreens to prevent cutaneous flares 1, 3, 6

Monitoring Protocol

Disease activity assessment using validated indices (SLEDAI) at each visit 1, 3

Laboratory monitoring at each visit: anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, urine sediment 1, 6

For patients with inactive disease: complete blood count, ESR, CRP, serum albumin, serum creatinine (or eGFR), urinalysis and urine protein/creatinine ratio at 6-12 month intervals 1

For established nephropathy: protein/creatinine ratio, immunological tests (C3, C4, anti-dsDNA), urine microscopy, and blood pressure at least every 3 months for first 2-3 years 1

Cardiovascular risk assessment at baseline and annually: smoking status, vascular events, physical activity, blood cholesterol, glucose, blood pressure, BMI 1

Infection screening: HIV and HCV/HBV based on risk factors, particularly before immunosuppressive drugs; tuberculosis according to local guidelines 1

Critical Pitfalls to Avoid

Do not delay kidney biopsy in suspected lupus nephritis, as histological classification is essential for treatment selection 3, 6

Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate in pregnant or pregnancy-planning women; azathioprine, hydroxychloroquine, and prednisolone are safe alternatives 1, 3, 6

Do not attribute all neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic causes, or medication side effects (steroid-induced psychosis) 3, 6

Do not overlook antiphospholipid antibody syndrome, which requires anticoagulation in addition to immunosuppression 1, 6

Do not use prolonged high-dose glucocorticoids (>7.5 mg/day prednisone equivalent), as this increases risk of irreversible organ damage 3, 6, 8

Comorbidity Management

SLE patients have 5-fold increased mortality risk and require screening for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma) 1, 6

Assess cardiovascular risk in patients with persistent proteinuria, GFR <60 mL/min, and chronic glucocorticoid use 3

Osteoporosis screening according to existing guidelines for postmenopausal women and patients on steroids 1