What is the preferred treatment regimen for an adult with biopsy‑proven class III, IV, or mixed class III/IV + V lupus nephritis, including induction and maintenance therapy?

Treatment of Class III, IV, or Mixed Class III/IV + V Lupus Nephritis

For adults with biopsy-proven class III, IV, or mixed class III/IV + V lupus nephritis, initiate induction therapy with glucocorticoids (IV methylprednisolone pulses followed by oral prednisone) combined with either mycophenolate mofetil (MMF) or low-dose intravenous cyclophosphamide, then transition to maintenance therapy with MMF or azathioprine for at least 3-5 years. 1, 2

Induction Therapy (First 3-6 Months)

Glucocorticoid Regimen

• Administer intravenous methylprednisolone 500-1000 mg daily for 3 consecutive days at treatment initiation 1, 2
• Follow immediately with oral prednisone 0.5-1.0 mg/kg/day (maximum 80 mg/day) 1, 2
• Taper aggressively to <5 mg/day by week 25, with the ultimate goal of complete withdrawal when possible 1, 2, 3

Immunosuppressive Options (Choose One)

Mycophenolate Mofetil (Preferred for Most Patients)

• Dose: 2-3 g/day divided into two doses (1.0-1.5 g twice daily) 1, 2
• MMF is particularly preferred for African-American and Hispanic patients, who show superior response rates compared to cyclophosphamide 1
• MMF is the first choice for patients concerned about fertility preservation, as it avoids gonadotoxicity 1, 2
• MMF has a better safety profile than high-dose cyclophosphamide regarding infections and leukopenia 1

Low-Dose Intravenous Cyclophosphamide (Euro-Lupus Regimen)

• Dose: 500 mg IV every 2 weeks for 6 doses (total ≈3 g over 3 months) 1, 2
• Choose cyclophosphamide when adherence to oral medications is a concern, as IV administration ensures compliance 1, 2
• Preferred for patients with severe nephritic features (rapid GFR decline, >25% glomeruli showing crescents/necrosis) 2
• The Euro-Lupus regimen is superior to the older NIH high-dose protocol due to comparable efficacy with markedly reduced toxicity 1, 2
• Validated primarily in Caucasian (Western/Southern European) populations; no comparative data exist for non-Caucasian racial groups 1, 2
• Cost considerations may favor cyclophosphamide in resource-limited settings where MMF access is restricted 1

Alternative: Tacrolimus (Calcineurin Inhibitor)

• Consider tacrolimus in combination with MMF when eGFR >45 mL/min/1.73 m² 2
• Evidence is limited primarily to Asian populations 1
• May be used for refractory nephrotic syndrome despite standard therapy within 3-6 months 1

Mandatory Adjunctive Therapy During Induction

• Hydroxychloroquine: Prescribe to every patient unless contraindicated, at ≤5 mg/kg actual body weight/day (typically 200-400 mg daily) 1, 3
• ACE inhibitor or ARB: Required for proteinuria control and blood pressure management 1, 2, 3
• Pneumocystis jirovecii prophylaxis: Provide during high-dose immunosuppression 2
• Mesna: Co-administer with each IV cyclophosphamide dose to prevent hemorrhagic cystitis 2
• Calcium and vitamin D supplementation: Mitigate glucocorticoid-induced osteoporosis 2, 3

Fertility Preservation Measures

• Women: Administer gonadotropin-releasing hormone agonists (e.g., leuprolide) during cyclophosphamide exposure 2
• Men: Offer sperm banking before cyclophosphamide therapy 2
• High-dose cyclophosphamide causes sustained amenorrhea in 12% of women <25 years, 27% of women <30 years, and 62% of women ≥31 years 1

Response Assessment and Treatment Adjustment

Early Monitoring Milestones

• At 8 weeks: ≥25% reduction in proteinuria and/or normalization of complement C3/C4 predicts favorable response 1, 2
• At 3 months: If clear worsening occurs (≥50% increase in proteinuria or serum creatinine), switch to alternative therapy or obtain repeat kidney biopsy 1, 2
• At 6 months: Continue induction therapy for full 6 months before major treatment changes unless clear deterioration occurs 1, 2
• Approximately 50% of patients achieve definite improvement by 6 months, increasing to 65-80% by 12-24 months 1, 2

Target Response Definitions

• Complete response: Proteinuria <0.5 g/24 hours (or uPCR <0.5 g/g), eGFR ≥90 mL/min/1.73 m² or no decrease >10% from baseline 2, 3, 4
• Partial response: ≥50% reduction in proteinuria to <3 g/24 hours, stabilization or improvement in kidney function 2
• Optimal target at 12 months: Proteinuria <0.7-0.8 g/24 hours is most predictive of good long-term renal outcome 4

Maintenance Therapy (After Achieving Response)

Duration and Agent Selection

• Continue maintenance therapy for minimum 3-5 years 3, 5
• Most renal flares occur within 5-6 years, justifying extended maintenance 3

Mycophenolate Mofetil (Preferred)

• Dose: 1.5-2 g/day divided into two doses (750-1000 mg twice daily) 1, 2, 3
• MMF is associated with fewer relapses compared to azathioprine 1, 5
• MMF and azathioprine have superior safety profiles compared to continued cyclophosphamide, particularly regarding gonadotoxicity and blood pressure control 1

Azathioprine (Alternative)

• Dose: 1-2 mg/kg/day 1, 2, 3
• Choose azathioprine when pregnancy is planned (MMF is teratogenic and must be discontinued ≥3 months before conception) 3
• Cost and availability issues may favor azathioprine in resource-limited settings 1
• Efficacy is equivalent to MMF regarding long-term renal function preservation, though relapse rates may be slightly higher 1, 5

Glucocorticoid Management During Maintenance

• Taper to ≤5-7.5 mg/day prednisone 1, 3
• Aim for complete withdrawal when disease control permits 1, 3

Continued Adjunctive Therapy

• Hydroxychloroquine: Continue indefinitely unless contraindicated 1, 3
• ACE inhibitor or ARB: Maintain for proteinuria and blood pressure control 1, 2, 3
• SGLT2 inhibitors: Consider for additional renal protection 2
• Statins: Prescribe for persistent dyslipidemia 3
• Low-dose aspirin: Use in patients with antiphospholipid antibodies 3
• Anticoagulation: Consider if nephrotic syndrome with albumin <20 g/L, especially with antiphospholipid antibodies 3

Management of Refractory or Relapsing Disease

Before Switching Therapy

• Verify medication adherence (nonadherence is the most common cause of apparent treatment failure, particularly in young women experiencing corticosteroid side effects) 1
• Confirm adequate dosing and rule out concurrent infection or other complications 3

Second-Line Options

• Switch from MMF to cyclophosphamide (or vice versa) if inadequate response by 6-12 months 3
• Add rituximab for refractory disease after failure of standard immunosuppression 1, 3
• Belimumab: FDA-approved add-on therapy to standard immunosuppression (10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks) 2, 6
  • In the pivotal lupus nephritis trial, 43% of patients receiving belimumab plus standard therapy achieved primary efficacy renal response at Week 104 versus 32% with placebo (OR 1.6,95% CI 1.0-2.3, p=0.031) 6
  • Complete renal response was achieved in 30% versus 20% (OR 1.7,95% CI 1.1-2.7, p=0.017) 6

Common Pitfalls and How to Avoid Them

• Premature treatment switching: Continue induction therapy for full 6 months unless clear worsening occurs; 65-80% of responders emerge by 12-24 months 1, 2
• Inadequate glucocorticoid tapering: Failure to reduce steroids below 7.5 mg/day by 3-6 months drives organ damage accumulation 1, 3
• Assuming treatment failure without checking adherence: Young women experiencing corticosteroid side effects frequently modify or abandon therapy; explore adherence before switching regimens 1
• Using high-dose cyclophosphamide unnecessarily: The Euro-Lupus low-dose regimen (3 g total) has equivalent efficacy with superior safety compared to NIH high-dose protocol 1, 2
• Forgetting hydroxychloroquine: This foundational therapy reduces flares, prevents organ damage, and significantly reduces mortality in all SLE patients 1, 3
• Stopping maintenance therapy too early: Continue for minimum 3-5 years, as most relapses occur within 5-6 years 3, 5