What is the recommended treatment and management approach for a patient with a known history of systemic lupus erythematosus (SLE)?

Management of Systemic Lupus Erythematosus

Core Treatment Foundation

Hydroxychloroquine is mandatory for all SLE patients at ≤5 mg/kg actual body weight unless contraindicated, as it reduces disease activity, prevents flares, and improves survival. 1, 2, 3, 4

• Typical dosing is 200-400 mg daily, with the dose not exceeding 5 mg/kg real body weight to minimize retinal toxicity risk (>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
• This medication serves as the cornerstone of therapy and should not be discontinued unless there is a specific contraindication. 1, 5

Initial Evaluation and Monitoring Protocol

At diagnosis and each follow-up visit, obtain clinical assessment (skin lesions, arthritis, serositis, neurological manifestations), complete blood count, serum creatinine, proteinuria with urine sediment, serum C3/C4, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, antiphospholipid antibodies, and anti-RNP. 6, 1, 2

• Use validated disease activity indices (SLEDAI) at each visit to monitor lupus activity and detect flares. 1, 2
• High-risk patients (males, juvenile onset, serologically active including anti-C1q antibodies) require monitoring every 3 months to detect early organ involvement. 2
• Hypocomplementemia (low C3/C4) indicates active disease and immune complex consumption. 2, 3

Treatment Algorithm by Disease Severity

Mild Disease (Skin and Joint Manifestations Without Major Organ Involvement)

Add methotrexate if hydroxychloroquine and low-dose glucocorticoids are insufficient. 2

• For cutaneous manifestations, initiate topical glucocorticoids as first-line for localized disease. 1
• For widespread or severe cutaneous disease, add short-term systemic glucocorticoids (prednisone equivalent). 1
• For refractory cutaneous cases, add immunomodulatory agents (methotrexate, azathioprine, or mycophenolate mofetil). 1
• NSAIDs may be used judiciously for limited periods in patients at low risk for complications. 6

Moderate Disease Requiring Glucocorticoid-Sparing

Add azathioprine (particularly suitable for women contemplating pregnancy) or mycophenolate mofetil for renal and non-renal manifestations. 6, 2

• Azathioprine is used for maintenance therapy after achieving initial response in organ-threatening disease, or as a glucocorticoid-sparing agent—not as initial therapy in stable, non-active SLE. 1
• Mycophenolate mofetil is effective for refractory cutaneous disease and moderate systemic manifestations. 1, 2
• Prompt initiation of immunomodulatory agents expedites the tapering/discontinuation of glucocorticoids. 1

Severe Organ-Threatening Disease

For lupus nephritis, cardiopulmonary, or neuropsychiatric manifestations, initiate mycophenolate mofetil or low-dose cyclophosphamide (Euro-Lupus regimen) as induction therapy. 2

Lupus Nephritis-Specific Protocol:

• Do not delay kidney biopsy in suspected lupus nephritis, as histological classification is essential for treatment selection and prognosis. 2
• Induction therapy: Mycophenolate mofetil (first-line) or low-dose intravenous cyclophosphamide combined with glucocorticoids. 5, 2
• Maintenance therapy: Mycophenolate mofetil or azathioprine after achieving initial response. 5, 2
• Treatment goal: At least partial remission (≥50% reduction in proteinuria to subnephrotic levels and serum creatinine within 10% of baseline) by 6-12 months. 2

Glucocorticoid Management

Minimize chronic oral glucocorticoids to <7.5 mg/day prednisone equivalent for chronic maintenance and, when possible, withdraw completely. 1, 5

• Risks substantially increase above 7.5 mg/day continuous dosing. 1
• In adolescents, minimize to <7.5 mg/day to limit growth impairment. 5
• Short-term higher doses may be used for acute flares, but rapid taper is essential. 1

Biologic Therapies for Refractory Disease

Belimumab (10 mg/kg IV at 2-week intervals for first 3 doses, then every 4 weeks) is FDA-approved as add-on treatment for active extrarenal SLE and lupus nephritis when standard therapy is insufficient. 7, 3

• In lupus nephritis (Trial 5), belimumab plus standard therapy achieved 43% Primary Efficacy Renal Response at Week 104 versus 32% with placebo (OR 1.6, p=0.031). 7
• Complete Renal Response was achieved in 30% versus 20% with placebo (OR 1.7, p=0.017). 7
• Belimumab is FDA-approved for patients ≥5 years of age with active SLE or lupus nephritis. 7
• Consider rituximab for organ-threatening disease refractory to standard immunosuppressive agents, particularly for hematological manifestations. 2
• Anifrolumab is approved for moderate-to-severe extrarenal SLE. 2, 3

Antiphospholipid Antibody Management

For patients with antiphospholipid antibodies, prescribe low-dose aspirin for primary prevention of thrombosis and pregnancy loss. 1, 2

• For non-pregnant patients with antiphospholipid-associated thrombosis, long-term anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) is required. 1, 2
• Estrogen-containing medications increase thrombosis risk and should be avoided. 1
• Evaluate other thrombosis risk factors systematically. 1

Pregnancy Considerations

Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin may be used in pregnancies with lupus. 1

• Mycophenolate mofetil, cyclophosphamide, and methotrexate are contraindicated during pregnancy and must be avoided. 1, 2
• Pregnancy can increase SLE disease activity, but flares are usually mild. 1
• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring. 1
• SLE can affect the fetus, especially if the mother has lupus nephritis history, antiphospholipid antibodies, anti-Ro, and/or anti-La. 1
• Females of reproductive potential should use effective contraception during belimumab treatment and for at least 4 months after final dose. 5

Comorbidity Screening and Prevention

Screen for infections (5-fold increased mortality risk), cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma) at regular intervals. 6, 1, 2

• Provide calcium and vitamin D supplementation for all patients on long-term glucocorticoids to prevent osteoporosis. 2
• Photoprotection with sunscreens prevents cutaneous flares. 1, 2
• Assess cardiovascular risk in patients with persistent proteinuria, GFR <60 mL/min, and chronic glucocorticoid use. 2
• Minimization of risk factors together with high index of suspicion, prompt evaluation, and diligent follow-up is essential. 6, 1

Critical Pitfalls to Avoid

Never attribute all neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic causes, or medication side effects (steroid-induced psychosis). 2

• Neuropsychiatric manifestations require MRI and EEG to exclude structural brain disease. 2
• Do not assume fever is solely due to lupus activity without excluding infection first. 1
• Do not escalate immunosuppression empirically for fever alone without comprehensive infectious workup. 1
• Do not use prolonged high-dose glucocorticoids, as risks substantially increase above 7.5 mg/day. 1

Treatment Goals

Aim for remission or low disease activity state, prioritizing prevention of organ damage and minimization of medication side effects. 1, 3

• Remission is defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while on maintenance immunomodulatory therapy. 3
• Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage from disease or treatment toxicity. 3