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

How to Treat Systemic Lupus Erythematosus (SLE)

All patients with SLE must 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 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 is mandatory at ≤5 mg/kg real body weight for all patients unless contraindicated, as it reduces disease activity, prevents flares, improves survival, and reduces mortality 1, 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, 2
• Photoprotection with sunscreens prevents cutaneous flares 2, 4
• Low-dose aspirin should be given to patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 2, 4
• Calcium and vitamin D supplementation is required for all patients on long-term glucocorticoids 2, 4

Glucocorticoid Management Algorithm

For acute flares or initial presentation:

• IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) provides immediate therapeutic effect and enables lower starting doses of oral glucocorticoids 1, 2
• Initial oral prednisone dosing ranges from 0.5-1 mg/kg/day depending on severity, with a maximum of 60 mg/day 5
• Never exceed 1 mg/kg/day or 60 mg/day, as higher doses provide no additional benefit and accelerate damage accrual 5

For chronic maintenance:

• Glucocorticoids must be minimized to <7.5 mg/day prednisone equivalent and withdrawn when possible to prevent organ damage 1, 2
• Prompt initiation of immunomodulatory agents expedites glucocorticoid tapering/discontinuation 1, 2

Immunosuppressive Therapy Selection (When Hydroxychloroquine ± Glucocorticoids Are Insufficient)

Add immunosuppressive agents when:

• Patients fail to respond to hydroxychloroquine alone or in combination with glucocorticoids 1
• Patients are unable to reduce glucocorticoids below 7.5 mg/day 1
• Organ-threatening disease is present at initial presentation 1

Agent selection by indication:

• Methotrexate: Recommended for skin and joint manifestations 1, 2, 4
• Azathioprine: Recommended for maintenance therapy, particularly suitable for women contemplating pregnancy 1, 2, 4
• Mycophenolate mofetil: Recommended for renal and non-renal manifestations except neuropsychiatric disease 1, 2, 4
• Cyclophosphamide: Reserved for severe organ-threatening or life-threatening SLE, especially renal, cardiopulmonary, or neuropsychiatric manifestations 1, 2, 4

Organ-Specific Treatment Protocols

Lupus Nephritis

• Kidney biopsy is essential before initiating therapy to guide treatment selection 2, 4
• Induction therapy: Mycophenolate mofetil (first-line) or low-dose IV cyclophosphamide (alternative) as they have the best efficacy/toxicity ratio 1, 2
• Maintenance therapy: Mycophenolate mofetil (first-line) or azathioprine (alternative) 1, 2
• Target at least partial remission within 6-12 months 4

Neuropsychiatric Lupus (NPSLE)

Critical first step: Attribution to SLE-related versus non-SLE neuropsychiatric manifestations is essential before initiating immunosuppressive therapy 1, 2

• Perform comprehensive diagnostic workup including neuroimaging, cerebrospinal fluid investigation, and assessment of risk factors (type and timing of manifestation relative to lupus onset, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies) 1
• Exclude infection aggressively by obtaining cultures before initiating immunosuppression 5

Treatment algorithm based on mechanism:

• For inflammatory/immune-mediated mechanisms (seizures, psychosis, myelitis, peripheral neuropathy, brain stem disease, optic neuritis): High-dose IV methylprednisolone plus cyclophosphamide 1, 2, 5
• For atherothrombotic/antiphospholipid-related manifestations: Antiplatelet agents or anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) 1, 2
• When both mechanisms coexist: Combination of immunosuppressive and anticoagulant/antithrombotic therapy 1, 2

Hematological Manifestations (Thrombocytopenia)

• Acute treatment: High-dose glucocorticoids including IV methylprednisolone pulses and/or IV immunoglobulin G 1, 2
• Maintenance therapy: Mycophenolate, azathioprine, or cyclosporine 1, 2
• Refractory cases: Rituximab or cyclophosphamide 2

Cutaneous Manifestations

• First-line therapy: Topical glucocorticoids, topical calcineurin inhibitors, and hydroxychloroquine 1, 2
• Non-responsive cases or cases requiring high-dose glucocorticoids: Add methotrexate, retinoids, dapsone, or mycophenolate 1

Musculoskeletal Manifestations

• Initial approach: Hydroxychloroquine and glucocorticoids (standard of care) 1
• Failing standard of care: Add methotrexate (preferred due to cost and availability), azathioprine, mycophenolate, or belimumab 1

Biologic Therapies for Refractory Disease

When to consider biologics:

• Inadequate response to standard therapy (combinations of hydroxychloroquine and glucocorticoids with or without immunosuppressive agents) 1
• Residual disease activity not allowing tapering of glucocorticoids 1
• Frequent relapses 1

Agent selection:

• Belimumab (anti-BAFF antibody): FDA-approved for active extrarenal SLE in patients ≥5 years receiving standard therapy, and for active lupus nephritis 1, 2, 6

  • Dosing for IV administration: 10 mg/kg at 2-week intervals for first 3 doses, then at 4-week intervals thereafter 6
  • Dosing for subcutaneous administration (adults with SLE): 200 mg once weekly 6
  • Dosing for subcutaneous administration (adults with lupus nephritis): 400 mg (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter 6
  • Consider prophylactic premedication for infusion reactions and hypersensitivity reactions 6

• Rituximab: May be considered for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents, particularly for hematological manifestations 1, 2

• Anifrolumab (anti-type 1 interferon receptor): FDA-approved for moderate-to-severe extrarenal SLE, with particular efficacy for cutaneous manifestations 2, 7

• Voclosporin: FDA-approved for lupus nephritis 2

Monitoring and Comorbidity Prevention

Disease activity monitoring:

• Use validated activity indices at each visit 2, 4
• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly 2, 4

Comorbidity screening (SLE patients have 5-fold increased mortality risk):

• Screen aggressively for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin lymphoma) 2, 4

Pregnancy Considerations

Safe medications during pregnancy:

• Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin 2, 4

Contraindicated medications:

• Mycophenolate mofetil, cyclophosphamide, and methotrexate 2, 4
• Consider gonadal toxicity when using cyclophosphamide in reproductive-age patients and counsel about fertility preservation options 5

Critical Pitfalls to Avoid

• Never delay immunosuppressive therapy in severe disease, as glucocorticoids alone are insufficient for crisis management and lead to prolonged high-dose steroid exposure 5
• NSAIDs should only be used judiciously for limited periods in patients at low risk for complications 4
• Failure to perform kidney biopsy before treating lupus nephritis leads to suboptimal therapy selection 2, 4
• Maintain high suspicion for infection throughout treatment, as immunosuppressed SLE patients have substantially elevated infection risk 5
• Live vaccines should not be given concurrently with belimumab or other immunosuppressive agents 6
• Belimumab efficacy has not been evaluated in patients with severe active CNS lupus; use is not recommended in this situation 6