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

Rituximab for Lupus

Rituximab should be reserved for refractory lupus nephritis that has failed to respond to standard first-line therapies (mycophenolate or cyclophosphamide with glucocorticoids) after 6 months of treatment. It is not approved as first-line therapy and should not be used as initial treatment for lupus or lupus nephritis.

Role in Lupus Nephritis

First-Line Treatment

• Do not use rituximab as initial therapy for active lupus nephritis 1, 2
• Standard first-line options remain mycophenolic acid analogs (MMF) with glucocorticoids, or cyclophosphamide with glucocorticoids 2
• The LUNAR randomized controlled trial failed to demonstrate superiority of rituximab over placebo when added to standard therapy (MMF and glucocorticoids) 1

Refractory Disease

Rituximab is appropriate when lupus nephritis fails to improve or worsens after 6 months of standard induction therapy 1, 2

Before adding rituximab, verify the following 1:

• Confirm medication adherence - non-adherence exceeds 60% in SLE patients 1
• Check drug levels (mycophenolic acid) or infusion records (cyclophosphamide) to ensure adequate dosing 1
• Consider repeat kidney biopsy to exclude chronicity or alternative diagnoses like thrombotic microangiopathy 1

Expected Response Rates

When used for refractory lupus nephritis, rituximab achieves complete or partial response in 50-80% of patients 1:

• A meta-analysis of 31 studies with 1,112 patients showed complete response in 46% and partial response in 32% 1
• European pooled data from 164 patients demonstrated 30% complete response and 37% partial response at 12 months 3
• Significant improvement in proteinuria (from 4.41g to 1.31g at 12 months) and serum albumin 3

Predictors of Response

Better outcomes occur with 3:

• Class III lupus nephritis (compared to Class IV or V)
• Absence of nephrotic syndrome at treatment initiation
• Absence of renal failure at time of rituximab administration

Worse response predicted by 3:

• Nephrotic syndrome at baseline (p<0.001)
• Renal failure at time of administration (p=0.024)

Treatment Protocol

Administration

• Rituximab is typically given as 1000mg IV on days 1 and 15 (rheumatoid arthritis protocol) 1
• Alternative lymphoma protocol uses 375mg/m² weekly for 4 weeks, though the RA protocol is preferred due to cost considerations with similar efficacy 1

Combination Therapy

Rituximab should be combined with glucocorticoids and/or immunosuppressive agents 1, 3:

• In the European cohort, 99% received concomitant corticosteroids and 76% received additional immunosuppressants (cyclophosphamide or mycophenolate) 3
• Consider dose reduction of adjuvant immunosuppressants to decrease infection risk 1

Role in Non-Renal Lupus

Rituximab is used off-label for severe organ involvement in systemic lupus erythematosus 1, but:

• It is not FDA-approved for non-renal SLE manifestations
• Evidence is primarily from observational studies and case series 4, 5
• Two large randomized controlled trials for non-renal lupus failed to meet primary endpoints 5

Safety Considerations

Common adverse events include 4, 6:

• Infusion reactions (most common)
• Infections - one fatal case of invasive histoplasmosis reported in a cohort of 22 patients 6
• Risk increases with concurrent immunosuppression 1

Alternative Options for Refractory Disease

When rituximab fails or is not appropriate, consider 1, 2:

• Switching between cyclophosphamide and MMF if not previously tried
• Extended course of IV pulse cyclophosphamide 1
• Other biologics: obinutuzumab, belimumab (though data are limited) 1, 2
• Calcineurin inhibitors (tacrolimus or cyclosporine) combined with glucocorticoids and/or MMF 1
• Clinical trial enrollment for emerging therapies like CAR-T cell therapy 1, 2

Critical Pitfalls to Avoid

• Do not use rituximab as first-line therapy - it has not demonstrated superiority over standard treatments in controlled trials 1, 5
• Always verify adherence before declaring treatment failure - non-adherence is the most common cause of apparent refractory disease 1
• Do not delay switching therapy - waiting beyond 6 months of failed treatment increases risk of irreversible kidney damage 1
• Monitor for infections closely - particularly when combining rituximab with other immunosuppressants 6