O35 B-cell depletion and response in a randomized, controlled trial of obinutuzumab for proliferative lupus nephritis

Abstract

Methods The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN and LN-negative patients. SNPs with a p-value <0.001 in the LN vs LN-negative analysis in the discovery cohort (n SNPs =139) were analyzed in replication cohort 1. Ten SNPs associated to LN (p<0.0002) in the discovery cohort were genotyped in replication cohort 2. A Bonferroni-corrected p-value of <1.0×10-6 correcting for 48,000 independent SNPs was considered significant. Results In the discovery cohort, strong association to LN was found with several highly linked SNPs in BANK1, with the top signal in the intronic SNP rs4699261 (p=9.9×10-5 , OR 0.66). The association was also present in replication cohort 1 (p=9.5×10-4). In a meta-analysis of the discovery and replication cohort 1, a total of 20 SNPs in BANK1 were associated to LN with the highest signal in rs4699261 (p=3.3×10-7). There was a tendency towards association in replication cohort 2 (p=0.05) and in a meta-analysis of all cohorts, the association with BANK1 was strengthened (p=1.7×10-7). Conclusion BANK1 variations are associated with LN in patients with SLE. Upregulated BANK1 expression in renal biopsies from LN patients has previously been shown, however the exact role of BANK1 in LN pathogenesis remains to be elucidated.

Absence of renal remission portends poor long-term kidney outcome in lupus nephritis

“…Taken together, the data presented here strongly suggest that remission is a very appropriate therapeutic goal. In this respect, the results of three recent controlled clinical trials demonstrating a 10%–20% higher rate of renal remission in patients given combination therapy with belimumab, 3 voclosporin 4 or obinutuzumab 5 are most welcome after decades of use of standard immunosuppression with cyclophosphamide, azathioprine or mycophenolate mofetil, which are associated with only a 25% rate of renal remission after 6 months of treatment. 12 …”

What's New in the Treatment of Systemic Lupus Erythematosus

“…Fortunately, two drugs, the orally given voclosporin and the intravenous form of belimumab, have recently been approved from the FDA for the treatment of patients with lupus nephritis on top of standard of care. Another recent report suggests daratumumab, targeting long-lived plasma cells (as well as other cells previously mentioned), as an alternative therapeutic approach in SLE ( 11 ). Daratumumab induced remission in 2 patients with life threatening manifestations including lupus nephritis.…”

“…Serious infections were recorded in 8% in the obinutuzumab group and in 18% in the placebo group, making obinutuzumab not only an efficacious but also a safe choice in the management of lupus nephritis. Flow cytometry measurements at weeks 24 and 52 of obinutuzumab treatment were employed to assess sustained B cell depletion ( 11 ). Obinutuzumab resulted in a remarkable B cell depletion as early as 4 weeks after obinutuzumab treatment.…”

ANCA-Associated Vasculitis: An Update

“…Obinutuzumab is a humanized anti-CD20 monoclonal antibody that has superior antibody-dependent cytotoxicity and direct cell death compared to rituximab, and achieves superior peripheral and tissue B-cell depletion [ 143 ]. Obinutuzumab has recently demonstrated success in lupus nephritis [ 144 ], where autoantibodies play a major role in pathogenesis. B-cell depletion is an attractive treatment strategy in antibody-mediated autoimmune disorders, however, levels of BAFF increase after B-cell depletion, which can preferentially facilitate re-emergence of more autoreactive B-cell populations [ 145 ].…”