What is the management of systemic lupus erythematosus (SLE)?

Management of Systemic Lupus Erythematosus

All patients with SLE should receive hydroxychloroquine as the foundation of therapy (unless contraindicated), combined with strict photoprotection, smoking cessation, regular physical activity, and aggressive cardiovascular risk factor management, with additional immunosuppressive agents added based on organ involvement and disease severity. 1, 2, 3

Core Pharmacological Management

Universal Foundation Therapy

• Hydroxychloroquine is mandatory for all SLE patients at a dose not exceeding 5 mg/kg real body weight, as it reduces disease activity, flares, organ damage, and mortality. 1, 2, 4, 3
• Ophthalmological screening must be performed at baseline, after 5 years, and yearly thereafter to monitor for retinal toxicity. 1, 2
• Never discontinue hydroxychloroquine unless there is a specific contraindication, as it improves survival even in severe disease. 4

Glucocorticoid Strategy

• For moderate-to-severe flares, initiate methylprednisolone pulses followed by low-to-moderate doses of oral prednisone with rapid tapering to ≤5 mg/day (ideally ≤7.5 mg/day) for chronic maintenance. 5, 1, 4
• Chronic glucocorticoid exposure above 7.5 mg/day prednisone equivalent substantially increases risks of infection, osteoporosis, and cardiovascular disease. 1, 4
• Promptly add immunosuppressive agents to facilitate glucocorticoid tapering and discontinuation. 5, 2

Immunosuppressive Agents

• For moderate-to-severe disease or as steroid-sparing agents, use azathioprine, mycophenolate mofetil, or methotrexate based on organ involvement. 3, 5, 2
• For organ-threatening or life-threatening disease, initiate high-intensity immunosuppressive therapy (cyclophosphamide or high-dose mycophenolate) to control disease activity, followed by maintenance therapy. 6, 3
• Azathioprine is used for maintenance therapy after achieving initial response in organ-threatening disease, not as initial therapy in stable SLE. 2

Biologic Therapies

• Belimumab is indicated for active SLE refractory to standard therapy and for lupus nephritis (Class III, IV, and/or V) in combination with standard immunosuppression. 7, 3
• Belimumab demonstrated significant improvement in renal response rates: 43% achieved Primary Efficacy Renal Response at Week 104 versus 32% with placebo (OR 1.6, p=0.031). 7
• Rituximab should be reserved for refractory cases, particularly severe hematologic manifestations or cases unresponsive to standard therapies. 5, 2
• Anifrolumab is FDA-approved for active SLE and represents an additional biologic option. 3

Organ-Specific Management

Cutaneous Manifestations

• Start with topical glucocorticoids or calcineurin inhibitors plus hydroxychloroquine for localized disease. 2
• For widespread or severe disease, add short-term systemic glucocorticoids (prednisone equivalent). 2
• For refractory cutaneous disease, escalate to methotrexate, dapsone (particularly effective for bullous lupus and urticarial vasculitis), retinoids (for hyperkeratotic lesions), or mycophenolate mofetil. 2

Lupus Nephritis

• For active proliferative and/or membranous lupus nephritis (Class III, IV, V), use corticosteroids combined with either mycophenolate for induction followed by mycophenolate maintenance, or cyclophosphamide for induction followed by azathioprine maintenance. 7
• Add belimumab 10 mg/kg IV to standard therapy, as it significantly improves complete renal response rates (30% vs 20%, OR 1.7, p=0.017). 7
• Renal biopsy, urine sediment analysis, proteinuria, and renal function have independent predictive value for clinical outcome. 2
• Voclosporin is FDA-approved for lupus nephritis and represents an additional treatment option. 3

Hematologic Manifestations

• For severe hemolytic anemia, initiate high-dose glucocorticoids as first-line therapy, reserving rituximab for refractory cases. 4
• Evaluate whether cytopenias are due to lupus activity, medication toxicity, or infection before escalating immunosuppression. 4

Essential Non-Pharmacological Management

Photoprotection

• Use SPF 60+ broad-spectrum sunscreen daily, avoid sun exposure during peak hours, and wear protective clothing to prevent cutaneous flares and systemic disease activity. 1, 2
• Photoprotection prevents development of new skin lesions and is beneficial for all patients with cutaneous manifestations. 1, 2

Lifestyle Modifications

• Achieve complete smoking cessation immediately, as smoking impairs response to antimalarial therapy, increases disease activity, and accelerates cardiovascular damage. 1, 2
• Engage in regular physical activity to reduce disease activity and improve outcomes. 8, 1, 2
• Assess smoking status at baseline and annually during follow-up. 1

Cardiovascular Risk Management

• Assess and aggressively manage all modifiable cardiovascular risk factors at baseline and annually: blood pressure, LDL cholesterol, fasting glucose, and body mass index. 1, 4
• Consider low-dose aspirin for primary prevention in patients with antiphospholipid antibodies, those on chronic glucocorticoids, or those with multiple traditional cardiovascular risk factors. 1, 2

Bone Health

• Ensure adequate calcium intake (1000-1200 mg daily) and vitamin D supplementation (800-1000 IU daily) for all patients, particularly those on glucocorticoids. 1, 2
• Assess calcium and vitamin D intake, weight-bearing exercise habits, and smoking status at baseline and annually. 1

Monitoring and Disease Activity Assessment

Regular Monitoring Schedule

• For stable patients, monitor every 3 months with clinical examination, complete blood count, serum creatinine, urinalysis with microscopy, C3/C4 levels, and anti-dsDNA antibodies. 4, 2
• Use validated disease activity indices (SLEDAI, BILAG, or ECLAM) to objectively track disease activity and detect flares early. 4, 2

Baseline and Annual Assessments

• Initial evaluation should include clinical signs (skin lesions, arthritis, serositis, neurological manifestations), laboratory tests (complete blood count, serum creatinine, proteinuria, urine sediment), and immunological tests (C3, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, antiphospholipids, anti-RNP). 2

Infection Prevention and Management

Screening and Prophylaxis

• Screen for latent infections at baseline: HIV, hepatitis B and C, tuberculosis, and CMV in immunosuppressed patients. 1, 4
• Vaccinate according to guidelines for immunocompromised patients: annual influenza, pneumococcal, and COVID-19 vaccines. 1
• Consider Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole) if using high-dose glucocorticoids or multiple immunosuppressants. 4
• Live vaccines are contraindicated in patients receiving belimumab and other immunosuppressive therapies. 7

Fever Management Algorithm

• Always exclude infection first before attributing fever to lupus activity alone - this is the most critical differential diagnosis. 2, 4
• Screen systematically for common and opportunistic infections, assess infection risk factors (severe neutropenia, lymphopenia, low IgG). 2, 4
• Evaluate new clinical manifestations correlating with disease activity and obtain laboratory markers of lupus activity. 2
• Treat infection aggressively with appropriate antimicrobials; consider temporarily holding or reducing immunosuppression during severe infection. 2

Management of Comorbidities

High-Risk Conditions

• Patients with SLE have increased risk for infections, atherosclerosis, hypertension, dyslipidemias, diabetes, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin lymphoma). 2
• Minimize risk factors with high index of suspicion, immediate evaluation, and diligent follow-up. 2

Antiphospholipid Antibody Management

• Consider low-dose aspirin for primary prevention of thrombosis and pregnancy loss in patients with antiphospholipid antibodies. 2
• Estrogen-containing contraceptives are absolutely contraindicated in patients with antiphospholipid antibodies due to dramatically increased thrombosis risk. 1, 2
• For non-pregnant patients with antiphospholipid-associated thrombosis, use long-term anticoagulation with oral anticoagulants for secondary prevention. 2

Treatment Goals

• Aim for clinical remission or low disease activity state, defined as minimal symptoms, low autoimmune inflammatory markers, and minimal glucocorticoid requirement (≤7.5 mg/day prednisone). 4, 6, 9
• Prevent organ damage accrual from both disease activity and treatment toxicity. 4, 6
• Optimize health-related quality of life and prolong survival. 5, 6

Critical Pitfalls to Avoid

• Never escalate immunosuppression empirically for fever alone without comprehensive infectious workup. 2, 4
• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day for >3 months) without implementing steroid-sparing strategies. 1, 4
• Do not overlook cumulative cardiovascular damage from inadequately controlled traditional risk factors, as it compounds the inflammatory burden of SLE. 1
• Never discontinue hydroxychloroquine without specific contraindication. 4

Special Populations: Pregnancy

• Pregnancy can increase SLE disease activity, but flares are usually mild. 2
• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring. 2
• Safe medications during pregnancy: prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin. 2
• Contraindicated during pregnancy: mycophenolate mofetil, cyclophosphamide, and methotrexate. 2