What is the usual treatment for Systemic Lupus Erythematosus (SLE)?

Treatment of Systemic Lupus Erythematosus (SLE)

All patients with SLE should receive hydroxychloroquine at ≤5 mg/kg real body weight as foundational therapy unless contraindicated, combined with glucocorticoids tailored to disease severity, with the primary goal of minimizing chronic steroid exposure to <7.5 mg/day prednisone equivalent. 1, 2, 3

Foundation Therapy (Mandatory for All Patients)

• Hydroxychloroquine is non-negotiable for all SLE patients at doses not exceeding 5 mg/kg real body weight (typically 200-400 mg daily), as it reduces disease activity, prevents flares, improves survival, and reduces mortality. 1, 2, 4, 3

• Ophthalmological screening must be performed at baseline, after 5 years of therapy, then yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography to monitor for retinal toxicity. 2, 4, 5

• Photoprotection with sunscreens prevents cutaneous flares and should be used consistently. 4, 5

• Low-dose aspirin should be given to patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors. 2, 4, 5

• Calcium and vitamin D supplementation is required for all patients on long-term glucocorticoids to prevent osteoporosis. 4, 5

Glucocorticoid Management Algorithm

The critical principle is aggressive minimization—glucocorticoids are necessary evils that must be tapered rapidly. 1, 2

• For acute flares or initial presentation, administer intravenous methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days), which provides immediate therapeutic effect and enables lower starting doses of oral glucocorticoids. 2, 4, 5

• Initial oral prednisone dosing ranges from 0.5-1 mg/kg/day depending on severity, followed by aggressive tapering. 5

• Chronic maintenance glucocorticoid therapy must be minimized to <7.5 mg/day prednisone equivalent and withdrawn when possible to prevent irreversible organ damage. 1, 2, 4, 5

• Prompt initiation of immunomodulatory agents expedites glucocorticoid tapering and discontinuation. 2

Immunosuppressive Therapy Selection by Manifestation

When patients fail to respond to hydroxychloroquine alone or in combination with glucocorticoids, or cannot taper glucocorticoids below 7.5 mg/day, add immunosuppressive agents based on the following algorithm: 1, 2

Musculoskeletal and Cutaneous Manifestations

• Methotrexate is the preferred first choice due to cost and availability for skin and joint manifestations. 1, 2, 4, 5

• Topical glucocorticoids and topical calcineurin inhibitors can be added for cutaneous disease. 2, 5

Maintenance Therapy (Non-Organ-Threatening Disease)

• Azathioprine is recommended for maintenance therapy, particularly suitable for women contemplating pregnancy as it is safe during pregnancy. 2, 4, 5

Renal and Non-Renal Manifestations (Except Neuropsychiatric)

• Mycophenolate mofetil is the agent of choice for renal and non-renal manifestations except neuropsychiatric disease. 2, 4, 5

Severe Organ-Threatening Disease

• Cyclophosphamide is reserved for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations. 2, 4, 5

Organ-Specific Treatment Protocols

Lupus Nephritis (Requires Aggressive Approach)

Kidney biopsy is absolutely essential before initiating therapy to confirm diagnosis and guide treatment planning—failure to perform biopsy leads to suboptimal therapy selection. 1, 2, 4, 5

Induction therapy (first 6 months):

• Mycophenolate mofetil (first-line) or low-dose intravenous cyclophosphamide are the immunosuppressive agents of choice. 1, 2, 4, 5
• Low-dose cyclophosphamide is preferred over high-dose cyclophosphamide due to comparable efficacy and lower gonadotoxicity. 1
• Combine with high-dose glucocorticoids (IV methylprednisolone pulses followed by oral prednisone). 1, 2

Maintenance therapy (after induction):

• Mycophenolate mofetil (first-line) or azathioprine for long-term maintenance. 1, 2, 4, 5

Treatment target:

• Achieve at least partial remission (≥50% reduction in proteinuria to subnephrotic levels) by 6-12 months. 2, 5

Neuropsychiatric Lupus (NPSLE)

Treatment depends on the underlying pathophysiological mechanism—always exclude infection aggressively before initiating immunosuppressive therapy. 2, 5

For inflammatory/immune-mediated mechanisms:

• High-dose intravenous methylprednisolone plus cyclophosphamide is the recommended regimen, with response rates of 18/19 patients compared to 7/13 with methylprednisolone alone (p=0.03). 2, 5

For thrombotic/embolic mechanisms:

• Anticoagulation with warfarin is required, with target INR of 2.0-3.0 for first venous thrombosis and 3.0-4.0 for arterial or recurrent thrombosis. 2

When both mechanisms coexist:

• Combination of immunosuppressive and anticoagulant/antithrombotic therapy. 2

Hematological Manifestations (Thrombocytopenia)

For significant thrombocytopenia:

• Initial pulse IV methylprednisolone followed by moderate/high-dose glucocorticoids combined with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine). 2, 5
• IVIG may be added in the acute phase or with inadequate response to glucocorticoids. 2
• For refractory cases: rituximab or cyclophosphamide. 2

Biologic Therapies for Refractory Disease

When standard therapy (hydroxychloroquine + glucocorticoids ± immunosuppressants) is inadequate, residual disease activity persists, or frequent relapses occur, add biologic agents. 2, 4, 5

FDA-Approved Biologics

• Belimumab (anti-BAFF antibody) is FDA-approved for active extrarenal SLE in patients ≥5 years receiving standard therapy, and for active lupus nephritis. 2, 4, 5, 6

• Anifrolumab (anti-type 1 interferon receptor) is FDA-approved for moderate-to-severe extrarenal SLE, with high-quality randomized controlled trials showing superiority to standard of care. 2, 4, 5

• Voclosporin (novel calcineurin inhibitor) is FDA-approved for lupus nephritis, with high-quality evidence showing better efficacy in combination with standard of care. 2, 4, 5

Off-Label Biologic

• Rituximab may be considered for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents, particularly for hematological manifestations. 2, 4, 5

Critical Monitoring and Comorbidity Prevention

SLE patients have a 5-fold increased mortality risk compared to the general population—aggressive screening for comorbidities is mandatory. 2, 4, 5

Disease Activity Monitoring

• Use validated activity indices (SLEDAI, BILAG, or ECLAM) at each visit. 2, 4, 5
• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly. 2, 4, 5

Infection Prevention

• Screen for HIV, HCV/HBV, tuberculosis, and CMV before immunosuppression. 4
• Vaccinate with inactivated vaccines (influenza, pneumococcus) when SLE is inactive. 4
• Monitor for severe neutropenia, severe lymphopenia, and low IgG levels. 4

Cardiovascular Disease Prevention

• Screen aggressively for hypertension, diabetes, dyslipidemia, and atherosclerosis. 2, 4, 5

Osteoporosis Prevention

• Assess calcium and vitamin D intake, encourage regular exercise, and promote smoking cessation. 4
• Screen and follow up according to guidelines for postmenopausal women and patients on steroids. 4

Malignancy Screening

• Screen for non-Hodgkin lymphoma, lung cancer, hepatobiliary cancer, and cervical cancer according to guidelines for the general population. 2, 4, 5

Special Populations: Pregnancy

Safe medications during pregnancy:

• Hydroxychloroquine, azathioprine, prednisolone, and low-dose aspirin are safe. 2, 4, 5

Contraindicated medications:

• Mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided during pregnancy. 2, 4, 5

Additional considerations:

• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring. 4
• Pregnancy should be postponed for 6 months after withdrawal of bisphosphonates. 2

Common Pitfalls to Avoid

• Never withhold hydroxychloroquine unless there is a clear contraindication—non-adherence is associated with higher flare rates and mortality. 4

• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day prednisone equivalent) as they increase irreversible organ damage risk. 2, 4

• Do not delay immunosuppressive therapy in organ-threatening disease—early aggressive treatment prevents irreversible damage. 4

• Always perform kidney biopsy before treating lupus nephritis—treatment decisions depend on histological classification. 4, 5

• NSAIDs should only be used judiciously for limited periods in patients at low risk for complications. 5