What is the initial management for patients with systemic lupus erythematosus (SLE)?

Initial Management of Systemic Lupus Erythematosus

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

Foundation Therapy (Mandatory for All Patients)

• Hydroxychloroquine is non-negotiable for all SLE patients unless contraindicated, dosed at ≤5 mg/kg real body weight, as it reduces disease activity, prevents flares, improves survival, and reduces mortality 1, 2, 3
• 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 1
• Photoprotection with sunscreens to prevent cutaneous flares 1
• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 1
• Calcium and vitamin D supplementation for patients on long-term glucocorticoids 1

Glucocorticoid Management Algorithm

For acute flares or moderate-to-severe disease:

• Administer IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) to provide immediate therapeutic effect and enable lower starting doses of oral glucocorticoids 1, 4, 5
• Follow with oral prednisone 0.5-1 mg/kg/day depending on severity 4
• Never exceed prednisone >1 mg/kg/day or >60 mg/day, as higher doses do not improve outcomes and accelerate damage accrual 4

For chronic maintenance:

• Aggressively taper glucocorticoids with a goal of <7.5 mg/day prednisone equivalent 1, 5
• Withdraw glucocorticoids completely when possible 1
• Avoid delayed immunosuppressive therapy, as glucocorticoids alone are insufficient and lead to prolonged high-dose steroid exposure 4

Immunosuppressive Therapy Selection by Clinical Presentation

Prompt initiation of immunomodulatory agents is essential to expedite glucocorticoid tapering and discontinuation 1

For Skin and Joint Manifestations:

• Methotrexate is the recommended agent 1
• Topical glucocorticoids and topical calcineurin inhibitors for cutaneous disease 1

For Lupus Nephritis (Class III-IV):

• Kidney biopsy is essential before initiating therapy 6, 1
• Induction therapy: Mycophenolate mofetil OR low-dose IV cyclophosphamide in combination with glucocorticoids 6, 1
• Low-dose cyclophosphamide is preferred over high-dose due to comparable efficacy and lower gonadotoxicity 1
• Maintenance therapy: Mycophenolate mofetil OR azathioprine for at least 3 years 6, 1
• If initial treatment was mycophenolate, continue mycophenolate for maintenance 6

For Pure Class V Lupus Nephritis with Nephrotic-Range Proteinuria:

• Mycophenolate mofetil in combination with oral glucocorticoids 6

For Severe Organ-Threatening Disease:

• Cyclophosphamide for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations 1, 4
• Consider gonadal toxicity in reproductive-age patients and counsel about fertility preservation options 4

For Neuropsychiatric Lupus:

• For inflammatory mechanisms: High-dose glucocorticoids plus cyclophosphamide 1, 4
• For thrombotic/embolic mechanisms: Anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) 1
• When both mechanisms coexist: Combination of immunosuppressive and anticoagulant therapy 1

For Severe Thrombocytopenia (Hemoglobin ≤8 g/dL):

• High-dose glucocorticoids (including IV methylprednisolone pulses) 1, 4
• IV immunoglobulin G may be added in the acute phase or with inadequate response 1
• Reserve rituximab for refractory cases 1, 4

Biologic Therapies for Refractory Disease

• Belimumab (anti-BAFF antibody) is FDA-approved for active extrarenal SLE and lupus nephritis as add-on treatment 1, 7, 2
• In lupus nephritis trials, belimumab plus standard therapy achieved 43% primary efficacy renal response at Week 104 versus 32% with placebo (OR 1.6, p=0.031) 7
• Rituximab for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents 1, 5
• Anifrolumab (anti-type 1 interferon receptor) for moderate-to-severe extrarenal SLE 1, 2
• Voclosporin for lupus nephritis 1, 2

Treatment Goals and Monitoring

Primary treatment goals:

• Achieve complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function) for lupus nephritis 6
• Achieve remission or low disease activity in all organ systems 1, 3
• Prevent disease flares and organ damage 6, 2
• Minimize glucocorticoid exposure to reduce adverse effects 1, 8

Monitoring requirements:

• Use validated activity indices (such as BILAG) at each visit 1
• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment 1
• Screen for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma), as SLE patients have a 5-fold increased mortality risk 1

Critical Pitfalls to Avoid

• Never delay immunosuppressive therapy in moderate-to-severe disease—glucocorticoids alone are insufficient 4
• Never use prednisone >60 mg/day—higher doses cause harm without benefit 4
• Never omit hydroxychloroquine unless contraindicated—it is the backbone of all SLE therapy 1, 2
• Never skip kidney biopsy before treating lupus nephritis—clinical findings cannot predict histology 6
• Maintain high suspicion for infection in immunosuppressed patients 4

Special Populations

During pregnancy:

• Safe medications include prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin 1
• Contraindicated: Mycophenolate mofetil, cyclophosphamide, and methotrexate 1
• Switch to appropriate medications without reducing treatment intensity in anticipation of pregnancy 6