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

Treatment of Systemic Lupus Erythematosus (SLE)

Hydroxychloroquine is the cornerstone of therapy for all SLE patients and should be initiated immediately at diagnosis, as it reduces disease activity, prevents flares, and improves survival. 1, 2, 3, 4

Foundation Therapy (All Patients)

• Hydroxychloroquine (HCQ) is mandatory for all SLE patients unless contraindicated, at a dose not exceeding 5 mg/kg of actual body weight per day (typically 200-400 mg daily). 1, 2, 3

• Ophthalmological screening is required at baseline, after 5 years of therapy, and yearly thereafter to monitor for retinal toxicity. 2

• Low-dose glucocorticoids (GC) (prednisone ≤7.5 mg/day or equivalent) can be added when clinically indicated, but the goal is to minimize to <7.5 mg/day and withdraw when possible to prevent organ damage. 1, 2

• Photoprotection with sunscreens should be used to prevent cutaneous flares. 2

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

• Calcium and vitamin D supplementation is indicated for all patients on long-term glucocorticoids. 1, 2

Treatment Algorithm by Disease Severity

Mild Disease (Musculoskeletal, Mucocutaneous Manifestations)

Step 1: Standard of Care (SOC)

• Start with HCQ plus low-dose GC (if needed). 1
• For acute flares, pulses of intravenous methylprednisolone (500-1000 mg) provide immediate effect and enable lower starting doses of oral GC. 2

Step 2: Add Immunosuppressants if Inadequate Response

• Methotrexate is the preferred first choice due to cost and availability for musculoskeletal and skin manifestations. 1
• Alternatives include azathioprine, mycophenolate mofetil, or cyclosporine. 1

Step 3: Consider Biologics

• Belimumab should be added for patients with inadequate response to standard therapy (HCQ + GC ± immunosuppressants), defined as residual disease activity not allowing GC tapering and/or frequent relapses. 1, 5

Moderate to Severe Disease (Hematologic, Cutaneous, Non-Renal Organ Involvement)

• Add immunosuppressive agents early to enable GC-sparing: methotrexate, azathioprine, or mycophenolate mofetil. 1, 2

• For thrombocytopenia: High-dose GC (including IV methylprednisolone pulses) and/or intravenous immunoglobulin G for acute treatment. 1

• For maintenance of hematologic response: Mycophenolate, azathioprine, or cyclosporine. 1

• For refractory hematologic disease: Rituximab or cyclophosphamide. 1

Severe Organ-Threatening Disease

Lupus Nephritis

Kidney biopsy is essential before initiating therapy to confirm diagnosis and guide treatment planning. 1, 2

Induction Therapy (First 3-6 Months):

• Mycophenolate mofetil (MMF) OR low-dose intravenous cyclophosphamide (CYC) are the first-line options, as they have the best efficacy/toxicity ratio. 1, 2
• Low-dose CYC is preferred over high-dose CYC due to comparable efficacy with lower gonadotoxicity and fewer adverse effects. 1, 2
• For high-risk patients (reduced GFR, fibrous crescents, fibrinoid necrosis, or tubular atrophy/interstitial fibrosis), high-dose IV CYC can be used. 1
• Combine with glucocorticoids (IV methylprednisolone pulses followed by oral prednisone). 1, 2

Maintenance Therapy:

• Mycophenolate mofetil OR azathioprine should be used for long-term maintenance. 1, 2
• In cases of severe nephrotic syndrome or incomplete renal response (persistent proteinuria >0.8-1 g/24 hours after ≥1 year), MMF may be combined with low-dose calcineurin inhibitor (tacrolimus or cyclosporine), provided there is no uncontrolled hypertension, high chronicity index, or reduced GFR. 1

Monitoring:

• Repeat kidney biopsy can distinguish chronic from active lesions in cases with stable/improved renal function but incomplete response. 1

Neuropsychiatric Lupus (NPSLE)

Attribution to SLE is essential and requires neuroimaging, cerebrospinal fluid investigation, consideration of risk factors (timing, patient age, lupus activity, presence of antiphospholipid antibodies), and exclusion of confounding factors. 1

For inflammatory/immune-mediated mechanisms:

• High-dose glucocorticoids (IV methylprednisolone) plus cyclophosphamide is the treatment of choice, with demonstrated superiority (18/19 patients responded vs 7/13 with methylprednisolone alone, p=0.03). 1, 2

For thrombotic/embolic/ischemic mechanisms:

• Anticoagulation with warfarin targeting INR 2.0-3.0 for venous thrombosis or INR 3.0-4.0 for arterial or recurrent thrombosis. 1, 2

When both mechanisms coexist:

• Combination of immunosuppressive and anticoagulant therapy. 2

Life-Threatening Disease

• Cyclophosphamide is reserved for severe organ-threatening or life-threatening SLE and as "rescue" therapy in patients not responding to other immunosuppressive agents. 1

Biologic Therapies for Refractory Disease

Belimumab (anti-BAFF antibody):

• FDA-approved for active extrarenal SLE in patients ≥5 years old receiving standard therapy. 5
• FDA-approved for active lupus nephritis in patients ≥5 years old receiving standard therapy. 5
• Should be considered when standard therapy (HCQ + GC ± immunosuppressants) is inadequate. 1, 2

Rituximab (anti-CD20 antibody):

• Can be considered for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents. 1
• Particularly effective for refractory hematologic manifestations. 1, 2

Anifrolumab (anti-type 1 interferon receptor):

• FDA-approved for moderate-to-severe extrarenal SLE. 2

Voclosporin:

• FDA-approved for lupus nephritis. 2

Critical Monitoring and Comorbidity Management

Disease Activity Monitoring:

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

Comorbidity Screening:

• SLE patients have a 5-fold increased mortality risk compared to the general population. 1, 2
• Screen for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, atherosclerosis, osteoporosis, avascular bone necrosis, and malignancies (especially non-Hodgkin lymphoma, lung cancer, hepatobiliary cancer). 1, 2
• Consider statins and ACE inhibitors in patients with increased cardiovascular risk. 1

Antiphospholipid Antibody Management:

• Low-dose aspirin for primary prevention of thrombosis in patients with antiphospholipid antibodies and at least one traditional cardiovascular risk factor. 1, 2

Special Populations: Pregnancy

Safe medications during pregnancy:

• Hydroxychloroquine, azathioprine, prednisolone, and low-dose aspirin. 2

Contraindicated medications:

• Mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided. 2

Monitoring:

• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring. 6

Common Pitfalls to Avoid

• Never withhold hydroxychloroquine unless there is a clear contraindication—non-adherence is associated with higher flare rates and mortality. 2, 4

• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day prednisone equivalent) as they increase irreversible organ damage risk. 1, 2

• Do not delay immunosuppressive therapy in organ-threatening disease—early aggressive treatment prevents irreversible damage. 1, 2

• Belimumab is not recommended for severe active CNS lupus as efficacy has not been established in this population. 5

• Always perform kidney biopsy before treating lupus nephritis—treatment decisions depend on histological classification. 1, 2