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

Treatment of 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, 3

Foundation Therapy (Mandatory for All Patients)

• Hydroxychloroquine is the cornerstone of SLE treatment and must be prescribed to all patients at ≤5 mg/kg real body weight, as it reduces disease activity, prevents flares, improves survival, and reduces mortality 1, 2, 3, 4

• Ophthalmological screening is mandatory 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

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

• Calcium and vitamin D supplementation is required for all patients on long-term glucocorticoids 2

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, 5

• Initial oral prednisone dosing ranges from 0.5-1 mg/kg/day depending on severity, followed by aggressive tapering 2

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7.5 mg/day prednisone equivalent and withdrawn when possible to prevent organ damage 1, 2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

Immunosuppressive Therapy Selection

Add immunosuppressive agents when patients fail to respond to hydroxychloroquine alone or in combination with glucocorticoids, or when unable to reduce glucocorticoids below acceptable doses for chronic use: 1, 2

• Methotrexate for skin and joint manifestations 1, 2

• Azathioprine for maintenance therapy, particularly suitable for women contemplating pregnancy 1, 2

• Mycophenolate mofetil for renal and non-renal manifestations (except neuropsychiatric disease) 1, 2

• Cyclophosphamide for severe organ-threatening or life-threatening disease, especially renal, cardiopulmonary, or neuropsychiatric manifestations 1, 2

Organ-Specific Treatment Protocols

Lupus Nephritis

Kidney biopsy is essential before initiating therapy 1, 2

Induction therapy (choose one):

• Mycophenolate mofetil (preferred, highest quality evidence) 1, 2
• Low-dose IV cyclophosphamide (preferred over high-dose due to comparable efficacy and lower gonadotoxicity) 1

Maintenance therapy (choose one):

• Mycophenolate mofetil (preferred) 1, 2
• Azathioprine 1, 2

Treatment target: Achieve at least partial remission (≥50% reduction in proteinuria to subnephrotic levels) by 6-12 months 2

Neuropsychiatric Lupus (NPSLE)

Treatment depends on the underlying pathophysiological mechanism: 1

• For inflammatory/immune-mediated mechanisms: High-dose IV methylprednisolone plus cyclophosphamide (response rate 18/19 patients vs 7/13 with methylprednisolone alone, p=0.03) 1, 2

• 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/antithrombotic therapy 1

Hematological Manifestations (Significant Thrombocytopenia)

• Initial pulse IV methylprednisolone followed by moderate/high-dose glucocorticoids combined with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine) 1, 2

• IVIG may be considered in the acute phase or with inadequate response to glucocorticoids 1

• For refractory cases: rituximab or cyclophosphamide 1

Cutaneous Manifestations

• First-line therapy includes topical glucocorticoids, topical calcineurin inhibitors, and hydroxychloroquine 1, 2

SLE with Interstitial Lung Disease

• First-line therapy: mycophenolate, azathioprine, rituximab, or cyclophosphamide 6

• For rapidly progressive ILD: pulse IV methylprednisolone 6

Biologic Therapies for Refractory Disease

Consider biologics when there is inadequate response to standard therapy, residual disease activity, or frequent relapses: 1, 2

• Belimumab (anti-BAFF antibody) is FDA-approved for active extrarenal SLE in patients ≥5 years receiving standard therapy, and for active lupus nephritis in patients ≥5 years receiving standard therapy 7, 2, 8, 4

• Anifrolumab (anti-type 1 interferon receptor) is FDA-approved for moderate-to-severe extrarenal SLE and was superior to standard of care in high-quality randomized controlled trials 7, 2, 4

• Voclosporin (novel calcineurin inhibitor) is FDA-approved for lupus nephritis, with high-quality evidence showing better efficacy in combination with standard of care 7, 2, 4

• Rituximab may be considered for organ-threatening, refractory disease, particularly for hematological manifestations 1, 2, 5

Monitoring and Comorbidity Prevention

Regular monitoring is crucial as SLE patients have 5-fold increased mortality risk: 1, 2

• Use validated activity indices at each visit 1, 2

• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment regularly 1, 2

• Screen aggressively for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin lymphoma) 1, 2

Pregnancy Considerations

Safe medications during pregnancy: 2

• Prednisolone
• Azathioprine
• Hydroxychloroquine
• Low-dose aspirin

Contraindicated medications: 2

• Mycophenolate mofetil
• Cyclophosphamide
• Methotrexate

Critical Pitfalls to Avoid

• Never treat lupus nephritis without kidney biopsy - this leads to suboptimal therapy selection 1, 2

• Avoid chronic glucocorticoid doses ≥7.5 mg/day - this is the primary driver of long-term organ damage 1, 2, 9

• Do not delay immunosuppressive therapy in severe disease - early introduction prevents organ damage accrual, particularly in the first 5 years after diagnosis 9

• NSAIDs should only be used judiciously for limited periods in patients at low risk for complications 2

• Belimumab is not recommended for severe active CNS lupus as efficacy has not been evaluated in this population 8