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

Initial Treatment Approach for Systemic Lupus Erythematosus (SLE)

All patients with SLE should immediately start hydroxychloroquine at ≤5 mg/kg real body weight as foundational therapy, combined with glucocorticoids tailored to disease severity, with the primary goal of achieving remission or low disease activity while minimizing chronic steroid exposure to <7.5 mg/day prednisone equivalent. 1, 2

Foundation Therapy (Universal for All SLE Patients)

Hydroxychloroquine - The Cornerstone

• Hydroxychloroquine is mandatory for all SLE patients unless contraindicated, dosed at ≤5 mg/kg real body weight 1, 2
• This agent reduces disease activity, prevents flares, improves survival, and has been associated with significant mortality reduction 1, 3, 4
• Ophthalmological screening must be performed at baseline, after 5 years, then yearly thereafter using visual fields examination and/or spectral domain-optical coherence tomography to monitor for retinal toxicity 2
• The risk of retinopathy is very low at doses below 5 mg/kg real body weight, but exceeds 10% after 20 years of continuous use 1

Glucocorticoid Strategy - Minimize from the Start

• For non-severe disease: Start oral prednisone at 0.5 mg/kg/day or lower, with rapid tapering toward <7.5 mg/day within weeks to months 2, 5
• For moderate-to-severe disease: Use IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) to provide immediate therapeutic effect, which enables lower starting doses of oral glucocorticoids and faster tapering 1, 2, 6
• Critical principle: Do not use prednisone >1 mg/kg/day or >60 mg/day, as higher doses do not improve outcomes and accelerate damage accrual 6
• The medium to long-term goal is to minimize daily dose to ≤7.5 mg/day prednisone equivalent or discontinue entirely, as continuous GC doses above 7.5 mg/day substantially increase irreversible organ damage 1, 2

Early Immunosuppressive Therapy - Start Promptly

Initiate immunosuppressive agents early to expedite glucocorticoid tapering and eventual discontinuation, as glucocorticoids alone are insufficient for long-term management and lead to prolonged high-dose steroid exposure 2, 6

Selection Algorithm Based on Organ Involvement

For skin and joint manifestations:

• Methotrexate is the preferred immunosuppressive agent 2

For maintenance therapy (especially in women contemplating pregnancy):

• Azathioprine is recommended 2

For renal and non-renal manifestations (except neuropsychiatric disease):

• Mycophenolate mofetil is the preferred agent, typically dosed at 750-1000 mg twice daily 2, 7

For severe organ-threatening or life-threatening disease (especially renal, cardiopulmonary, or neuropsychiatric):

• Cyclophosphamide should be added immediately to the corticosteroid regimen 2, 6
• Low-dose IV cyclophosphamide is preferred over high-dose due to comparable efficacy and lower gonadotoxicity 2

Organ-Specific Treatment Protocols

Lupus Nephritis (Class III-IV)

• Kidney biopsy is essential before initiating therapy to confirm diagnosis and guide treatment planning 2
• Induction therapy: Mycophenolate mofetil OR low-dose IV cyclophosphamide as immunosuppressive agents of choice, combined with high-dose glucocorticoids 2, 6
• Maintenance therapy: Transition to mycophenolate mofetil or azathioprine after controlling acute disease 2, 7
• Aim for at least partial remission (≥50% reduction in proteinuria to subnephrotic levels and serum creatinine within 10% from baseline) by 6-12 months 1

Neuropsychiatric Lupus (NPSLE)

• For inflammatory mechanisms (seizures, psychosis, myelitis, peripheral neuropathy, brain stem disease, optic neuritis): Add cyclophosphamide to high-dose glucocorticoids 2, 6
• For embolic/thrombotic/ischemic mechanisms: Anticoagulant/antithrombotic treatment with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) 2
• When both mechanisms coexist: Combination of immunosuppressive and anticoagulant/antithrombotic therapy 2

Hematological Manifestations

• For severe thrombocytopenia: High-dose glucocorticoids (including IV methylprednisolone pulses) combined with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine) 2
• For severe hemolytic anemia (hemoglobin ≤8 g/dL): High-dose glucocorticoids alone as first-line therapy 6
• IVIG may be considered in the acute phase or with inadequate response to glucocorticoids 2
• Reserve rituximab for refractory cases 2, 6

Biologic Therapies for Inadequate Response to Standard Therapy

Belimumab (anti-BAFF antibody) is FDA-approved and recommended as add-on treatment for active extrarenal SLE and lupus nephritis in patients ≥5 years of age receiving standard therapy. 2, 8, 3, 4

• Belimumab should be considered when patients have inadequate response to hydroxychloroquine, glucocorticoids, and immunosuppressives 2
• Limitation: Efficacy has not been evaluated in severe active CNS lupus; use is not recommended in this situation 8
• Anifrolumab (anti-type 1 interferon receptor) is FDA-approved for moderate-to-severe extrarenal SLE 2, 9
• Rituximab may be considered for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents 2

Treatment Goals and Monitoring

The primary goal is achieving remission (absence of clinical activity) or low disease activity (SLEDAI ≤4, PGA≤1 with GC ≤7.5 mg prednisone and well-tolerated immunosuppressive agents), as these states halt damage accrual and prevent flares 1

• Monitor disease activity using validated indices at each visit 2
• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly 2
• Schedule visits every 2-4 weeks initially after treatment changes to assess response and adjust therapy 7

Critical Pitfalls to Avoid

• Never delay immunosuppressive therapy when indicated, as glucocorticoids alone are insufficient for crisis management and lead to prolonged high-dose steroid exposure 6
• Maintain high index of suspicion for infection in immunosuppressed patients and obtain cultures before initiating immunosuppression when infection cannot be excluded 6
• Counsel about fertility preservation when using cyclophosphamide in reproductive-age patients due to gonadal toxicity 6
• Do not use intravenous cyclophosphamide within 6 months prior to or during belimumab therapy, as this combination was not permitted in clinical trials 8

Additional Preventive Measures

• Photoprotection with sunscreens to prevent cutaneous flares 2
• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 2
• Calcium and vitamin D supplementation for patients on long-term glucocorticoids 2
• Screen for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma), as SLE patients have 5-fold increased mortality risk 2