What is the recommended initial management for an adult with systemic lupus erythematosus and biopsy‑confirmed Class V (membranous) lupus nephritis?

Management of Class V (Membranous) Lupus Nephritis

Initial Treatment Strategy

For pure Class V lupus nephritis with nephrotic-range proteinuria, mycophenolic acid (MMF target dose 3 g/day for 6 months) combined with oral prednisone (0.5 mg/kg/day) is the recommended first-line treatment based on the best efficacy/toxicity ratio. 1

Defining Treatment Indications

• Immunosuppressive therapy is indicated when proteinuria exceeds 1 g/24 hours despite optimal use of renin-angiotensin-aldosterone system blockers 1
• Patients with nephrotic-range proteinuria are at particular risk for thromboembolic complications, infections, and progressive chronic kidney disease, making treatment more urgent 1
• Unlike primary membranous nephropathy, heavy proteinuria in Class V lupus nephritis does not spontaneously remit, necessitating active immunosuppression 1

Glucocorticoid Regimen

• Start with three consecutive pulses of intravenous methylprednisolone 500-750 mg 1
• Follow with oral prednisone 0.5 mg/kg/day for 4 weeks 1
• Taper to ≤10 mg/day by 4-6 months 1

This approach reduces cumulative glucocorticoid exposure while maintaining efficacy 1

Alternative First-Line Options

When MMF cannot be used or for specific clinical scenarios, several alternatives exist:

Calcineurin Inhibitors (CNIs)

• Tacrolimus or cyclosporine combined with glucocorticoids are recommended alternatives 1
• Tacrolimus may result in faster resolution of proteinuria compared to conventional cytotoxic treatment (76.2% reduction at 12 weeks vs 47.1% with cyclophosphamide/azathioprine) 2
• Voclosporin (a novel CNI) combined with MMF should be considered when heavy proteinuria (well above nephrotic range) requires rapid reduction to avoid nephrotic syndrome complications 3
• Voclosporin can be used for up to 3 years, though long-term administration beyond the first year requires careful monitoring for potential scarring effects 3

Important caveat: CNIs have a higher relapse rate after discontinuation (40% within one year) compared to cyclophosphamide 1

Cyclophosphamide

• Low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) is an alternative option 1
• Cyclophosphamide maintains remission longer than CNIs but carries gonadal toxicity concerns 1

Rituximab

• Rituximab is recommended as an alternative for non-responders to first-line therapy 1

Triple Immunosuppression

• Combination of glucocorticoids, tacrolimus, and low-dose MMF (1-2 g/day) resulted in higher complete remission rates (33.1% vs 7.8%) compared to cyclophosphamide followed by azathioprine in Chinese patients 1

Maintenance Therapy

After Initial Response

• Continue with MMF at lower doses (target 2 g/day) or switch to azathioprine (2 mg/kg/day) for at least 3 years 1
• Patients who responded to initial MMF should remain on MMF unless pregnancy is contemplated 1
• Combine with low-dose prednisone (5-7.5 mg/day) 1
• CNIs can be considered for maintenance in pure Class V nephritis 1

Pre-Pregnancy Planning

• Switch to azathioprine at least 3 months prior to conception 1
• Azathioprine is one of the few safe immunosuppressants in pregnancy 4

Adjunctive Therapies (Essential for All Patients)

Renin-Angiotensin System Blockade

• ACE inhibitors or angiotensin receptor blockers are indicated for all patients with proteinuria (UPCR >50 mg/mmol) or hypertension 1

Hydroxychloroquine

• Hydroxychloroquine is recommended for all patients to reduce renal flares and limit accrual of renal and cardiovascular damage 1
• Dose should not exceed 5 mg/kg/day and must be adjusted for GFR 5

Cardiovascular Protection

• Statins are indicated for persistent dyslipidemia (target LDL-cholesterol <2.58 mmol/L or <100 mg/dL) 1

Thromboprophylaxis

• Consider anticoagulation in nephrotic syndrome with serum albumin <20 g/L, especially if persistent or with anti-phospholipid antibodies present 1

Treatment Goals and Monitoring

Response Targets

• Complete renal response: UPCR <50 mg/mmol with normal or near-normal renal function (within 10% of normal GFR if previously abnormal) 1
• Partial renal response: ≥50% reduction in proteinuria to subnephrotic levels with normal or near-normal renal function 1
• Achieve partial response preferably by 6 months but no later than 12 months 1
• Median time to reduce proteinuria to ≤0.5 mg/mg was 3.6 months with voclosporin 1

Monitoring Schedule

• Visit every 2-4 weeks for the first 2-4 months after diagnosis 1
• Then according to response, but at least every 3-6 months lifelong 1
• At each visit assess: body weight, blood pressure, serum creatinine and eGFR, serum albumin, proteinuria, urinary sediment (microscopic evaluation), serum C3 and C4, anti-dsDNA antibody levels, and complete blood count 1

Management of Refractory Disease

Treatment Failure Definition

• Failure to achieve at least partial response by 12 months 1

Switching Strategy

• For patients failing MMF or cyclophosphamide, switch from MMF to cyclophosphamide or vice versa 1
• Rituximab should be given for refractory cases 1
• Belimumab may be added in cases with inadequate clinical response by 3 months or inability to reduce glucocorticoid dose 3

Critical Pitfalls to Avoid

• Do not delay immunosuppression in nephrotic-range proteinuria: 10-30% of Class V patients progress to kidney failure, with risk directly related to proteinuria severity 1
• Do not use azathioprine as first-line therapy: It is associated with higher flare risk and should only be considered when MMF or cyclophosphamide are contraindicated, not tolerated, or unavailable 1
• Do not discontinue CNIs abruptly: 40% relapse rate within one year of stopping 1
• Do not use leflunomide in women of childbearing potential without proper counseling: It is contraindicated in pregnancy and requires discontinuation at least 2 years before conception 1