In an adult with newly diagnosed or flaring proliferative lupus nephritis (class III, IV, or mixed), what is the appropriate high‑dose intravenous methylprednisolone pulse regimen and the recommended induction immunosuppressive therapy?

Pulse Therapy for Proliferative Lupus Nephritis

For adults with newly diagnosed or flaring class III/IV lupus nephritis, initiate treatment with intravenous methylprednisolone 500–1000 mg daily for 3 consecutive days, followed by oral prednisone 0.5–1.0 mg/kg/day (maximum 80 mg/day) tapered to <5 mg/day by week 25, combined with either low-dose intravenous cyclophosphamide (500 mg every 2 weeks × 6 doses) or mycophenolate mofetil as first-line induction immunosuppression. 1, 2, 3

Methylprednisolone Pulse Regimen

Dosing Protocol:

• Induction pulse: 500–1000 mg IV methylprednisolone daily for 3 consecutive days at treatment initiation 1
• The dose should be tailored to disease severity, with 250–500 mg/day acceptable for less severe presentations 2, 3
• This recommendation is based primarily on expert opinion (Level C evidence), as some prospective trials used pulse steroids while others achieved similar outcomes without them 1

Oral Glucocorticoid Continuation:

• Start oral prednisone at 0.5–1.0 mg/kg/day (maximum 80 mg/day) immediately following pulse therapy 2, 3
• Taper aggressively to <5 mg/day by week 25 to minimize toxicity while maintaining efficacy 2, 3
• The reduced-dose glucocorticoid protocol maintains therapeutic efficacy while minimizing steroid-related adverse effects 2

Critical Pitfall: Never use glucocorticoids as monotherapy—they must always be combined with immunosuppressive agents, as 16 mg methylprednisolone alone results in inadequate disease control 3

Induction Immunosuppressive Therapy

The KDIGO 2024 guidelines identify four equally effective first-line options 2:

Option 1: Low-Dose Intravenous Cyclophosphamide (Euro-Lupus Regimen)

• Dosing: 500 mg IV every 2 weeks for 6 doses (total ≈3 g over 3 months) 1, 2
• This regimen has replaced the older NIH high-dose protocol (500–1000 mg/m² monthly × 6) due to lower cumulative dose and improved safety profile 2
• Racial considerations: The low-dose regimen was validated in Caucasian patients with Western/Southern European backgrounds and shows equivalent efficacy to high-dose with fewer serious infections and less leukopenia 1
• The low and high-dose regimens have not been compared in non-Caucasian racial groups 1
• Ten-year follow-up data show similar rates of lupus nephritis flares, end-stage renal disease, and serum creatinine doubling between low and high-dose regimens 1

Mandatory cyclophosphamide co-interventions:

• Mesna with each IV dose to prevent hemorrhagic cystitis 2
• GnRH agonists (e.g., leuprolide) for women to preserve fertility 2
• Sperm banking for men before treatment 2
• Pneumocystis jirovecii prophylaxis 2
• Monthly neutrophil count monitoring 2

Option 2: Mycophenolate Mofetil

• Dosing: 1.0–1.5 g twice daily (target 3 g/day for 6 months) 2, 3
• Alternative: Mycophenolic acid sodium 0.72–1.08 g twice daily 2
• Preferred when: Fertility preservation is a major concern, as cyclophosphamide causes permanent infertility in both sexes 1

Option 3: Belimumab + Mycophenolate or Cyclophosphamide

• Belimumab 10 mg/kg IV every 2 weeks × 3 doses, then every 4 weeks, combined with either mycophenolate or cyclophosphamide 2

Option 4: Mycophenolate + Calcineurin Inhibitor

• Only when eGFR >45 mL/min/1.73 m² 2
• Voclosporin 23.7 mg twice daily plus mycophenolate 2
• Particularly effective for class III+V disease with heavy proteinuria, as it directly addresses podocyte dysfunction 4

Treatment Selection Algorithm

Choose cyclophosphamide when:

• Adherence to oral regimens is a concern (IV administration ensures compliance) 2
• Severe nephritic features present (rapid GFR decline, >25% glomeruli with crescents/necrosis) 2
• Prior documented failure of mycophenolate 2

Choose mycophenolate when:

• Patient desires future fertility without prior cyclophosphamide exposure 2
• Moderate-to-high cumulative prior cyclophosphamide exposure exists 2

Avoid azathioprine for induction: It is less effective than cyclophosphamide combined with glucocorticoids and inferior at preventing long-term flares and delaying chronic lesion progression 1

Monitoring and Response Assessment

Early monitoring (first 3 months):

• If renal function worsens (rising creatinine or increasing proteinuria) within 3 months, promptly switch to alternative therapy or obtain repeat kidney biopsy 2
• At 8 weeks, ≥25% reduction in proteinuria and/or normalization of C3/C4 predicts good clinical response 1

Standard assessment timeline:

• Continue induction therapy for 6 months before making major treatment changes (other than glucocorticoid adjustments) unless clear worsening occurs 1
• Approximately 50% show definite improvement by 6 months, increasing to 65–80% by 12–24 months 1

Response definitions:

• Complete response: Proteinuria <0.5 g/g with stable/improved kidney function 2, 4
• Partial response: ≥50% reduction in proteinuria to <3 g/g with stable/improved kidney function 2, 4

Maintenance Therapy (After 6-Month Induction)

• Switch to mycophenolate mofetil 750–1000 mg twice daily or mycophenolic acid 540–720 mg twice daily 2
• Continue for ≥36 months total 2, 4
• Azathioprine 1–2 mg/kg/day is an alternative for patients intolerant of mycophenolate 2
• Taper glucocorticoids to lowest possible dose 2

Mandatory Adjunctive Therapies for All Patients

• Hydroxychloroquine unless contraindicated, to reduce flares and improve long-term outcomes 2, 4
• ACE inhibitor or ARB for proteinuria control and blood pressure management 2, 4
• Infection prophylaxis: Screen for hepatitis B, hepatitis C, HIV, tuberculosis; vaccinate non-immune individuals; provide PCP prophylaxis 2
• Bone protection: Calcium and vitamin D supplementation; bisphosphonates when indicated 2

Safety Considerations

• Limit total lifetime cyclophosphamide exposure to <36 g to reduce malignancy risk; the 3 g Euro-Lupus course stays well below this threshold 2
• Most frequent complications are infections, particularly in patients with hypoalbuminemia 5
• Transient post-pulse elevation of serum creatinine may occur with return to baseline by 1 month 6
• Exacerbation of hypertension can occur during pulse therapy 6