What is the current treatment guideline for Class 4 lupus nephritis?

Current Treatment Guideline for Class IV Lupus Nephritis

For Class IV lupus nephritis, initiate treatment with glucocorticoids PLUS one of four equally recommended options: mycophenolic acid analogs (MPAA), low-dose IV cyclophosphamide, belimumab combined with either MPAA or cyclophosphamide, or MPAA plus a calcineurin inhibitor (CNI) when eGFR >45 mL/min/1.73 m² 1.

Initial (Induction) Therapy

Glucocorticoid Regimen

All patients require glucocorticoids as the foundation 1:

• IV methylprednisolone pulses: 0.25-0.5 g/day for 1-3 days initially (optional but often included based on disease severity) 1
• Oral prednisone: Start at 0.5-1.0 mg/kg/day (maximum 80 mg/day), then taper over 6 months 1
  • Reduced-dose regimen (0.5-0.6 mg/kg/day max 40 mg) can be considered when both renal and extrarenal manifestations show satisfactory improvement 1
  • Target <5 mg/day by week 25 or beyond 1

Immunosuppressive Options (Choose ONE)

Option 1: Mycophenolic Acid Analogs (MPAA) - First-line for most patients 1

• Mycophenolate mofetil (MMF): 1.0-1.5 g twice daily 1
• OR Mycophenolic acid sodium: 0.72-1.08 g twice daily 1
• Preferred for: Patients at high risk of infertility or those with moderate-to-high prior cyclophosphamide exposure 1
• Evidence: As effective as cyclophosphamide with significantly lower risk of ovarian failure (RR 0.15,95% CI 0.03-0.80) and alopecia 2

Option 2: Low-dose IV Cyclophosphamide 1

• 500 mg every 2 weeks × 6 doses 1
• OR oral 1.0-1.5 mg/kg/day for 3 months 1
• Preferred for: Patients with adherence concerns to oral regimens 1
• Critical caveat: Minimize lifetime exposure to <36 grams to reduce cancer risk 1

Option 3: Belimumab + MPAA or Cyclophosphamide (Triple Therapy) 1

• Belimumab IV: 10 mg/kg every 2 weeks × 3 doses, then every 4 weeks 1
• Combined with either MPAA (doses above) OR IV cyclophosphamide 500 mg every 2 weeks × 6 1
• Preferred for: Patients with repeated kidney flares or high risk for progression to kidney failure due to severe CKD 1
• FDA evidence: Achieved 43% Primary Efficacy Renal Response at Week 104 vs 32% with placebo (OR 1.6, p=0.031) 3
• Duration up to 2.5 years 1

Option 4: MPAA + Calcineurin Inhibitor 1

• Voclosporin 23.7 mg twice daily + MPAA (doses above) 1
• OR Tacrolimus or cyclosporine when voclosporin unavailable 1
• Critical restriction: Only when eGFR >45 mL/min/1.73 m² due to nephrotoxicity risk 1
• Preferred for: Relatively preserved kidney function with nephrotic-range proteinuria (extensive podocyte injury) or intolerance to standard-dose MPAA 1
• CNI duration up to 3 years 1

Alternative Agents (Second-line)

• Azathioprine or leflunomide with glucocorticoids may be considered when standard drugs are unavailable, unaffordable, or not tolerated, but expect inferior efficacy with increased flare rates 1
• Rituximab for persistent disease activity or inadequate response to initial therapy 1

Maintenance Therapy

After completing induction (typically 3-6 months), transition to maintenance therapy 1:

• MPAA is the recommended maintenance agent 1

  • MMF: 750-1000 mg twice daily 1
  • MPA: 540-720 mg twice daily 1

• Azathioprine is an alternative for patients who cannot tolerate MPAA, lack access, or are considering pregnancy 1

  • Important caveat: Azathioprine has significantly higher renal relapse risk compared to MMF (RR 1.83,95% CI 1.24-2.71) 2

• Glucocorticoid tapering: Reduce to lowest possible dose during maintenance; discontinuation can be considered after ≥12 months of complete clinical renal response 1

• Total duration: Initial immunosuppression plus maintenance should be ≥36 months 1

• Triple therapy continuation: Patients on belimumab or CNI-based regimens can continue these as maintenance 1

Adjunctive Therapies (All Patients)

Implement these protective measures for all Class IV lupus nephritis patients 1:

• Renal protection: ACE inhibitors or ARBs, SGLT2 inhibitors 1
• Infection prophylaxis: Screen for HBV, HCV, HIV; vaccinate for hepatitis B; Pneumocystis jirovecii prophylaxis; consider recombinant zoster vaccine 1
• Bone protection: Assess bone mineral density; calcium and vitamin D supplementation; bisphosphonates when appropriate 1
• Fertility preservation: Gonadotropin-releasing hormone agonists (leuprolide); sperm/oocyte cryopreservation before cyclophosphamide 1
• Contraception counseling: Individualized based on thrombosis risk 1
• UV protection: Broad-spectrum sunscreen, limit exposure 1

Treatment Response Monitoring

Complete response (target outcome for best long-term prognosis) 1:

• Proteinuria <0.5 g/g (PCR from 24-hour collection) 1
• Stabilization or improvement in kidney function (±10-15% of baseline) 1
• Achieved within 6-12 months (may take >12 months) 1

Partial response 1:

• ≥50% reduction in proteinuria to <3 g/g 1
• Stabilization or improvement in kidney function 1