What is the recommended management of systemic lupus erythematosus?

Management of Systemic Lupus Erythematosus

Universal Foundation Therapy (All Patients)

Every patient with SLE must receive hydroxychloroquine at ≤5 mg/kg actual body weight (typically 200-400 mg daily) unless contraindicated, as this reduces disease activity, prevents flares, improves survival, and reduces mortality. 1, 2, 3

• Hydroxychloroquine is the cornerstone of therapy and should never be discontinued, even during flares or when adding other agents 2, 4
• The FDA-approved dosing is 200 mg once daily or 400 mg once daily (or in two divided doses) for SLE 5
• Critical safety requirement: 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 detect retinal toxicity 1, 2, 6
• Blood HCQ concentration monitoring can identify non-adherent patients; target levels >0.6 mg/L reduce renal flare rates 6, 7

Treatment Goals (Treat-to-Target Strategy)

The primary objective is achieving complete remission or low disease activity—not merely symptom control—with minimal glucocorticoid exposure. 2, 6

• Complete remission = no clinical activity without glucocorticoids or immunosuppressants 6
• Low disease activity (LLDAS) = SLEDAI ≤4, physician global assessment ≤1, prednisone ≤7.5 mg/day on well-tolerated immunosuppressants 2, 6
• Assess disease activity at every visit using validated indices (SLEDAI, BILAG, ECLAM) 2, 3
• Monitor anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, and urine sediment at each visit 2, 8

Glucocorticoid Management Algorithm

Acute/Severe Disease or Flares

For organ-threatening manifestations, administer IV methylprednisolone 250-1000 mg daily for 1-3 consecutive days as pulse therapy, followed by oral prednisone 0.3-0.5 mg/kg/day (NOT the historical 0.5-1 mg/kg/day). 2, 8, 6

• IV pulses provide immediate therapeutic effect and enable lower oral steroid doses 1, 2, 8
• The lower initial oral dose (0.3-0.5 mg/kg/day) is based on recent evidence showing comparable efficacy with reduced toxicity 2

Tapering Strategy (Critical to Prevent Organ Damage)

Rapidly taper prednisone to ≤7.5 mg/day within 3-6 months, with the ultimate goal of complete withdrawal. 2, 8, 6, 3

• Never maintain chronic prednisone >7.5 mg/day—this is the principal driver of irreversible organ damage, infections, osteonecrosis, and mortality 8, 6
• Target long-term maintenance of <5 mg/day when possible 3
• Prompt initiation of immunosuppressive agents is mandatory to enable rapid steroid tapering 8, 3

Immunosuppressive Therapy Selection

Moderate to Severe Non-Renal SLE

When disease cannot be controlled with hydroxychloroquine and low-dose glucocorticoids alone, add methotrexate, azathioprine, or mycophenolate mofetil as first-line immunosuppressive agents. 2, 8, 3

• Methotrexate: Preferred for cutaneous and articular manifestations 2, 8, 3
• Azathioprine: Suitable for maintenance therapy, particularly in women contemplating pregnancy 2, 8, 3
• Mycophenolate mofetil: Effective for both renal and non-renal manifestations (except neuropsychiatric disease) 2, 8, 3
• Cyclophosphamide: Reserved for severe organ-threatening or life-threatening disease (renal, cardiopulmonary, neuropsychiatric) 2, 8, 3

Lupus Nephritis Treatment Protocol

Induction Therapy (Class III-IV Lupus Nephritis)

First-line induction consists of mycophenolate mofetil 2-3 g/day OR low-dose IV cyclophosphamide (500 mg every 2 weeks × 6 doses) combined with IV methylprednisolone 500-2500 mg total followed by oral prednisone 0.3-0.5 mg/kg/day. 2, 6, 3

• Both mycophenolate and low-dose cyclophosphamide show similar efficacy; mycophenolate may be more effective in African-Americans 2, 6
• High-dose IV cyclophosphamide (0.5-0.75 g/m² monthly × 6 months) is indicated only for patients with adverse prognostic factors: crescents/necrosis in >25% glomeruli OR GFR 25-80 mL/min 2, 6
• Tacrolimus or voclosporin (calcineurin inhibitors) are alternative induction options 6, 3
• Add-on belimumab or voclosporin should be considered for active lupus nephritis 6, 3

Maintenance Therapy

Maintain lupus nephritis patients on mycophenolate mofetil or azathioprine for at least 3 years. 8, 6, 3

• Continue hydroxychloroquine throughout lupus nephritis treatment 6

Treatment Response Targets

Evidence of improvement must be seen by 3 months (decreasing proteinuria, stable/improving GFR). 6

• Partial response by 6 months: ≥50% reduction in proteinuria to subnephrotic levels, creatinine within 10% of baseline 2, 6
• Complete response by 12 months: proteinuria <0.5-0.7 g/24 hours 6
• For nephrotic-range proteinuria at baseline, extend treatment response timeframes by 6-12 months 6

Neuropsychiatric Lupus Management

Treatment depends on the underlying pathophysiological mechanism: for inflammatory/immune-mediated mechanisms, use high-dose IV methylprednisolone plus cyclophosphamide; for thrombotic/embolic mechanisms, use anticoagulation with warfarin. 2, 8, 3

• High-dose glucocorticoids combined with cyclophosphamide showed response in 18/19 patients compared to 7/13 with methylprednisolone alone (p=0.03) 2
• For thrombotic mechanisms, target INR 2.0-3.0 for first venous thrombosis and 3.0-4.0 for arterial or recurrent thrombosis 8
• Exclude infection aggressively before initiating immunosuppressive therapy 8

Biologic Therapies for Refractory Disease

When there is inadequate response to standard therapy, residual disease activity, or frequent relapses, consider adding biologic agents. 8, 6, 3

• Belimumab (anti-BAFF antibody): FDA-approved for active extrarenal SLE (2011) and lupus nephritis (2020); high-quality RCT evidence supports efficacy 8, 6, 4, 3
• Anifrolumab (anti-type 1 interferon receptor): FDA-approved for moderate-to-severe extrarenal SLE; high-quality RCT evidence demonstrates superiority to standard of care 8, 6, 3
• Voclosporin (calcineurin inhibitor): FDA-approved for lupus nephritis; high-quality RCT evidence shows better efficacy in combination with standard of care 8, 6, 3
• Rituximab: Consider for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents 8, 3

Hematological Manifestations

For severe thrombocytopenia, treat with high-dose glucocorticoids (including IV methylprednisolone pulses) and/or IV immunoglobulin G. 8, 3

• First-line treatment includes moderate/high doses of glucocorticoids in combination with immunosuppressive agents (azathioprine, mycophenolate, or cyclosporine) 8
• For refractory cases: rituximab or cyclophosphamide 8

Cutaneous Manifestations

First-line treatment includes topical glucocorticoids, topical calcineurin inhibitors, and hydroxychloroquine. 8

• Methotrexate is preferred for refractory cutaneous disease 2, 8
• Photo-protection with sunscreens is mandatory for all patients to prevent cutaneous flares 2, 8

Comorbidity Management and Prevention

Cardiovascular and Metabolic Risk

SLE patients have a 5-fold increased mortality risk and require systematic screening for infections, cardiovascular disease, hypertension, diabetes, dyslipidemia, osteoporosis, and malignancies (especially non-Hodgkin lymphoma). 2, 8

• Low-dose aspirin should be considered for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 2, 8
• Screen all SLE patients at diagnosis for antiphospholipid antibodies 6

Bone Health

Calcium and vitamin D supplementation is mandatory for all patients on long-term glucocorticoids. 2, 8

Pregnancy Management

Safe medications during pregnancy include prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin; mycophenolate mofetil, cyclophosphamide, and methotrexate are absolutely contraindicated. 2, 8

• Pregnancy may increase lupus disease activity, but flares are usually mild 2
• Patients with lupus nephritis and antiphospholipid antibodies require closer monitoring for pre-eclampsia 2
• Pregnancy should be postponed for 6 months after withdrawal of bisphosphonates 8

Critical Pitfalls to Avoid

• Do NOT maintain chronic oral prednisone >7.5 mg/day—this is the principal driver of steroid-related toxicity and damage accrual 8, 6
• Do NOT delay initiation of immunosuppressive agents—early use is essential for enabling rapid steroid tapering 8
• Do NOT omit hydroxychloroquine—its continued use is critical for all patients regardless of flare status 2, 8
• Do NOT start with high-dose oral prednisone (1 mg/kg/day)—instead, use methylprednisolone pulses followed by lower oral doses (0.3-0.5 mg/kg/day) for better efficacy and lower toxicity 2, 8
• Do NOT crush or divide hydroxychloroquine tablets—administer whole with food or milk 5