What is the role of Rituximab (rituximab) in the treatment of lupus nephritis?

Rituximab in Lupus Nephritis

Primary Recommendation

Rituximab should be reserved for refractory lupus nephritis that has failed to respond to standard first-line therapies (mycophenolate mofetil or cyclophosphamide with glucocorticoids) after 6 months of treatment. 1, 2

First-Line Treatment Hierarchy

Rituximab is not recommended as initial therapy for active lupus nephritis. 1 Standard first-line options remain:

• Mycophenolate mofetil (2-3 g/day) with glucocorticoids 3
• Low-dose intravenous cyclophosphamide (500 mg every 2 weeks × 6) with glucocorticoids 3
• Calcineurin inhibitors (especially tacrolimus) in specific cases with preserved kidney function and nephrotic-range proteinuria 3, 4

Glucocorticoid dosing should be minimized: intravenous methylprednisolone (500-2500 mg total over 1-3 days) followed by oral prednisone (0.3-0.5 mg/kg/day), tapering to ≤7.5 mg/day by 3-6 months. 3

When to Consider Rituximab

Indications for Rituximab Use

Rituximab becomes appropriate when: 1, 2

• Lupus nephritis fails to improve or worsens after 6 months of standard induction therapy (either MMF or cyclophosphamide with glucocorticoids)
• Switching between cyclophosphamide and MMF has been attempted without adequate response 4, 2
• Patient has reached maximum cumulative cyclophosphamide dose and remains refractory 4

Expected Response Rates

When used for refractory disease, rituximab achieves:

• Complete or partial response in 50-80% of patients 1
• Complete response in 46% and partial response in 32% based on meta-analysis of 31 studies with 1,112 patients 1
• Complete or partial renal remission in 53-77% at 6-12 months in observational studies 5, 6

Treatment Protocol

Dosing Regimens

Two standard approaches exist: 1

• 1000 mg IV on days 1 and 15 (most commonly used)
• 375 mg/m² IV weekly for 4 weeks (lymphoma protocol)

Rituximab must be combined with glucocorticoids and/or immunosuppressive agents—it should not be used as monotherapy. 1

Critical Evidence Limitations

The LUNAR Trial Paradox

Despite extensive clinical experience supporting rituximab efficacy, the LUNAR randomized controlled trial failed to demonstrate superiority of rituximab over placebo when added to standard therapy. 1, 7 This creates a significant evidence gap where:

• Observational data strongly supports efficacy 7, 5, 6
• The only large RCT was negative 1, 7
• Trial design flaws (high steroid doses, trial size, endpoints) likely explain the negative result 7, 6

This explains why rituximab remains widely used off-label despite lack of FDA approval for lupus nephritis. 7, 6

Factors Predicting Response

B-Cell Depletion is Critical

Achievement of complete B-cell depletion at 1 month after rituximab strongly correlates with renal response. 8 Factors associated with incomplete depletion include:

• Black ethnicity 8
• Hypoalbuminemia 8

Incomplete B-cell depletion may contribute to treatment failure and clinical deterioration. 9

Disease Characteristics

• Rapidly progressive glomerulonephritis does not respond well to rituximab 8
• Both proliferative (Class III/IV) and membranous (Class V) lupus nephritis can respond 8, 6

Safety Considerations and Risks

Common Adverse Events

• Infections (most common serious adverse event) 1, 8
• Infusion reactions 6
• Moderate neutropenia 8

Risk of Clinical Deterioration

A critical caveat: some patients experience transient worsening of renal function and/or nephrotic syndrome following rituximab. 9 In one case series:

• 5 of 7 patients had clinical deterioration following rituximab 9
• Manifestations included worsening renal function, increased proteinuria, or rapidly progressive renal failure 9
• Some patients subsequently improved, but others required rescue therapy with high-dose steroids and cyclophosphamide 9

Patients must be informed of this risk before treatment initiation. 9

Alternative Options for Refractory Disease

When rituximab fails or is inappropriate, consider: 1, 2

• Belimumab (FDA-approved for lupus nephritis; achieved 43% vs 32% primary efficacy renal response compared to placebo at 2 years) 3, 4
• Extended course of IV pulse cyclophosphamide 2
• Clinical trial enrollment for emerging therapies (e.g., obinutuzumab, anifrolumab) 4, 2

Guideline Positioning

KDIGO 2024 Guidelines

Recommend addition of rituximab for patients with inadequate response to initial therapy after attempting switching between cyclophosphamide and MMF. 4, 2

American College of Rheumatology

Recommends rituximab for refractory lupus nephritis that has failed standard first-line therapies after 6 months. 1, 2

EULAR/ERA-EDTA 2019

Reserves rituximab for non-responders in both Class III/IV and Class V lupus nephritis. 3

Practical Algorithm

1. Start with MMF or cyclophosphamide + glucocorticoids 3
2. Assess response at 6 months 1, 2
3. If inadequate response: switch from cyclophosphamide to MMF, or MMF to cyclophosphamide 4, 2
4. If still refractory after 6 months of second regimen: add rituximab 1, 2
5. Monitor for B-cell depletion at 1 month (predictor of response) 8
6. Watch for transient clinical deterioration in first weeks to months 9
7. If rituximab fails: consider belimumab, extended cyclophosphamide, or clinical trials 4, 2