DOI: 10.1056/NEJMoa2410965Key Points:- Phase 3 trial testing obinutuzumab (anti-CD20 monoclonal antibody) + standard therapy vs placebo + standard therapy for lupus nephritis- Primary endpoint: Complete renal response at week 76- Notable finding: 46.4% response with obinutuzumab vs 33.1% with placebo (13.4% improvement, p=0.02)Trial Design:- 271 adult patients with active lupus nephritis - Randomized 1:1 to receive obinutuzumab or placebo- All patients received standard therapy (mycophenolate mofetil + prednisone)- Target prednisone dose: 7.5mg/day by week 12, 5mg/day by week 24Key Results:1. Primary Endpoint:- Complete renal response at week 76 significantly better with obinutuzumab- Lower intercurrent events with obinutuzumab (treatment failure 3.7% vs 17.6%)2. Secondary Endpoints:- Better complete response with prednisone ≤7.5mg/day (42.7% vs 30.9%)- More patients achieved UPCR <0.8 (55.5% vs 41.9%)- Less death/renal events with obinutuzumab (18.9% vs 35.6%)Safety Findings:- More serious adverse events with obinutuzumab (32.4% vs 18.2%)- Main issues: infections including COVID-19- 4 deaths total (3 in obinutuzumab group, 1 in placebo)- When excluding COVID-19, serious infection rates were 11% vs 7.6%Clinical Implications:- First successful phase 3 trial showing benefit of B-cell depletion in lupus nephritis- Results support the role of B-cells in disease pathogenesis- Safety concerns need to be balanced against efficacy- COVID-19 vaccination important for patients receiving this therapyStudy Limitations:- COVID-19 pandemic affected safety outcomes- Trial started before widespread vaccination- Relatively short follow-up period (76 weeks)- Need more data on long-term outcomesNext Steps:- Longer follow-up needed- Study impact of vaccination on safety- Identify optimal patient selection- Evaluate combination with other therapiesThe trial represents a significant advance in lupus nephritis treatment while highlighting important safety considerations that need to be addressed in clinical practice.

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