What is the initial treatment approach for lupus nephritis and how to choose between medications?

Initial Treatment Approach for Lupus Nephritis

For patients with active Class III or IV lupus nephritis, the initial treatment should include glucocorticoids plus any one of the following: mycophenolic acid analogs (MPAA), low-dose intravenous cyclophosphamide, belimumab combined with either MPAA or cyclophosphamide, or MPAA with a calcineurin inhibitor. 1

Treatment Selection Algorithm

First-Line Options Based on Disease Classification:

• Class III/IV Lupus Nephritis (with or without membranous component):

  • Glucocorticoids plus one of the following 1:
    • Mycophenolic acid analogs (MMF target dose: 3 g/day for 6 months) 1
    • Low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) 1
    • Belimumab combined with either MPAA or low-dose cyclophosphamide 1
    • MPAA with calcineurin inhibitor (voclosporin, tacrolimus) if eGFR >45 ml/min/1.73m² 1

• Class V (Pure Membranous) Nephritis with nephrotic-range proteinuria:

  • MMF (target dose 3 g/day for 6 months) with oral prednisone 1
  • Alternative options: cyclophosphamide, calcineurin inhibitors, or rituximab 1

• Class II Lupus Nephritis with proteinuria >1 g/24h:

  • Low-to-moderate doses of glucocorticoids (prednisone 0.25-0.5 mg/kg/day) alone or with azathioprine (1-2 mg/kg/day) as steroid-sparing agent 1

Factors Influencing Treatment Selection:

1. Presence of adverse prognostic factors:

   • For patients with acute deterioration in renal function, substantial cellular crescents, or fibrinoid necrosis, consider higher doses of cyclophosphamide (0.75-1 g/m² monthly for 6 months) 1

2. Fertility considerations:

   • Prefer MMF over cyclophosphamide in women of childbearing age or men planning to father children 1
   • If pregnancy is contemplated, switch from MMF to azathioprine at least 3 months before conception 1

3. Ethnicity:

   • MMF may be more effective than cyclophosphamide in Black and Hispanic patients 2

Glucocorticoid Regimen

• Initial treatment with three consecutive pulses of intravenous methylprednisolone (500-750 mg each) 1
• Follow with oral prednisone 0.5 mg/kg/day for 4 weeks 1
• Taper to ≤10 mg/day by 4-6 months 1
• Consider reduced-dose regimens when using calcineurin inhibitors 1

Adjunctive Treatments

• Hydroxychloroquine for all patients to improve outcomes by reducing renal flares and limiting renal and cardiovascular damage 1, 3
• ACE inhibitors or angiotensin receptor blockers for patients with proteinuria or hypertension 1
• Statins for persistent dyslipidemia (target LDL-cholesterol <100 mg/dl) 1

Monitoring Response to Treatment

• Schedule visits every 2-4 weeks for the first 2-4 months after diagnosis or flare 1
• Monitor: weight, blood pressure, serum creatinine, eGFR, serum albumin, proteinuria, urinary sediment, C3/C4, anti-dsDNA antibodies, and complete blood count 1
• Expect at least 25% reduction in proteinuria by 3 months and 50% by 6 months 4
• Complete response target: UPCR <500-700 mg/g by 12 months 4

Subsequent (Maintenance) Treatment

• For patients improving after initial treatment, continue with either 1:
  • MMF at lower doses (initial target 2 g/day) 1
  • Azathioprine (2 mg/kg/day) 1
• Maintain treatment for at least 3 years 1
• Gradual drug withdrawal (glucocorticoids first) can be attempted after sustained remission 1

Management of Refractory Disease

• For patients failing to improve within 3-4 months or not achieving partial response after 6-12 months 1:
  • Switch from MMF to cyclophosphamide or vice versa 1
  • Consider rituximab as add-on treatment or monotherapy 1
  • Consider calcineurin inhibitors (especially for class V nephritis) 1

Important Considerations and Pitfalls

• Renal biopsy is essential before initiating treatment to guide therapy decisions 4
• Azathioprine has a higher flare risk compared to MMF and should be limited to milder cases with preserved renal function 1
• MMF dose often needs titration to reduce toxicity (doses 1-2 g/day can be effective for long-term treatment) 1
• Monitor MPA blood levels when GFR <30 ml/min 1
• Minimize cumulative cyclophosphamide exposure, especially in women at risk for amenorrhea/infertility 1