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Finally, an anti-CD20 antibody meeting endpoints in randomized trials

Comment on: “Efficacy and Safety of Obinutuzumab in Active Systemic Lupus Erythematosus” Richard A. Furie et al. NEJM March 2026

Commented by: Karoline Lerang, Department of Rheumatology, Oslo University Hospital- NORWAY

Nearly 15 years after the EXPLORER and LUNAR trials failed in systemic lupus erythematosus (SLE), obinutuzumab—a type II anti-CD20 antibody developed by Roche—has succeeded, meeting both primary and secondary endpoints in randomized controlled trials.

The phase 3 ALLEGORY trial (New England Journal of Medicine, March 2026) randomized 303 patients with active SLE (excluding lupus nephritis and CNS disease) to obinutuzumab or placebo on top of standard therapy. The primary endpoint was SRI-4 response at week 52.

Obinutuzumab showed clear benefit. SRI-4 response was achieved in 76.7% versus 53.5% with placebo. Secondary outcomes also favored treatment: more patients reduced glucocorticoids to ≤7.5 mg/day (80.0% vs. 54.1%), fewer had BILAG flares (33.8% vs. 48.7%), and remission and low disease activity rates were higher (DORIS: 35.1% vs. 13.8%; LLDAS: 57.6% vs. 25.0%). These results address key unmet needs, particularly steroid sparing and flare prevention.

Earlier trials with rituximab showed biological effects but limited clinical benefit, likely due to incomplete B-cell depletion, especially in tissues, along with trial design and glucocorticoid confounding.

Obinutuzumab induces deeper and more sustained B-cell depletion through enhanced cellular cytotoxicity and direct cell death, and appears more effective in tissue.

Emerging evidence suggests that active SLE requires deeper levels of B-cell depletion, a concept supported by the profound remissions observed with CAR-T therapies that induce near-complete B-cell depletion. The ALLEGORY trial supports this concept and positions obinutuzumab as an important advance for patients with active SLE despite standard therapy.

A high burden of SLE risk genes is associated with persistent activation of the interferon system in patients with lupus.

25 May 2026

Comment on: Single-cell RNA-seq reveals a persistent interferon signature in immune cells from  systemic lupus erythematosus patients with high versus low polygenic risk scores despite antimalarial  treatment. J Autoimmun. 2026 May 12:161:103575. doi: 10.1016.  Commented by: Lars Rönnblom, Department of Medical Sciences, Uppsala University, Sweden.    Genome-wide association studies have identified more than 300 loci associated to increased risk for  SLE. For the majority of the gene variants in these loci the functional consequences in the SLE disease  process are unknown. However, a large proportion of identified risk genes are connected to the  interferon signaling pathway and contribute to the interferon signature in SLE. Calculating a polygenic  risk score (PRS) is a method to quantify the cumulative genetic burden in a single patient and studies  have shown that patients with a high PRS have a more severe disease phenotype with increased  organ damage and reduced survival, compared to individuals with a low PRS.   Antimalarial therapy is a well-established treatment of SLE and have shown efficacy in a large  proportion of patients. The therapeutic effect is partly mediated by down regulation of the activated  interferon system, which is connected to clinical response. However, despite therapeutic  concentrations of hydroxychloroquine, many patients still have flares and accumulation of organ  damage. The main objective of the present study was therefore to clarify if antimalarial treatment has  different effects in patients with a high or a low PRS.  SLE patients in remission with a high or a low PRS were compared in gene expression profile at single  cell level on peripheral blood mononuclear cells. A total of 6 healthy controls and 16 matched  patients treated with similar antimalarial doses, but no corticosteroids, were investigated. On  average, 9636 cells were analyzed from each donor and 2724 genes detected per cell. Despite similar  clinical picture, patients with a high PRS had a prominent interferon signature across multiple  immune cell types, compared to patients with a low PRS who had a weak expression of interferon  stimulated genes only in monocytes. Pathway analysis revealed that the interferon signaling pathway 

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