O11 Unsupervised machine-learning identifies distinct clusters based on B cell phenotyping and autoantibody profiles in patients with systemic lupus erythematosus

Objective To identify systemic lupus erythematosus (SLE) patient endotypes according to B cell immunophenotyping and serological profile and assess their response to belimumab. Patients and Methods We analysed data from 796 patients with SLE from the phase III BLISS-SC clinical trial of belimumab. Using an unsupervised machine learning algorithm, patients were stratified into distinct clusters based on B cell immunophenotype and autoantibody profile. Analysis of variance was used to compare characteristics across clusters. Cox regression was used to show the effect of belimumab on the attainment of sustained lupus low disease activity state (LLDAS) or DORIS remission across clusters. Results Cluster 1 (n=193) was characterised by significantly higher proportions mean (SD) of CD19+CD24b+CD27+regulatory B cells 35.8%(12.5%), CD19+CD20+CD27+bulk memory B cells 32.0% (9.9%), CD19+CD20+CD69+activated B cells 0.2%(0.3%), CD19+CD20-CD138+ long-lived plasma cells 0.6% (0.9%), and CD19+CD38b+CD27b+ SLE-associated plasma cells 6.6%(7.0%). Cluster 2 (n=358) was predominantly characterised by higher proportions of CD19+CD24b+CD38b+CD27- transitional B cells 6.5% (9.2%), and CD19+CD20+CD27- naïve B cells 85.5%(7.2%), and lower proportions of CD19+CD20-CD138+ peripheral long-lived plasma cells 0.2%(0.3%) and CD19+CD38b+CD27b+ SLE-associated plasma cells 1.6%(6.1%). Cluster 3 was primarily characterised by a higher proportion of CD19+CD20+CD138+ short-lived plasma cells 0.1%(0.1%) and was the most serologically active with respect to low C3 and C4 levels and anti-dsDNA positivity compared to clusters 1 and 2. Cluster 2 was dominated by musculoskeletal manifestations (85.8%) when compared with cluster 1 (75.1%; p2-fold increased probability of sustained LLDAS [HR 2.12 IC 95% (1.1–4.0) p 3-fold increased probability of sustained DORIS remission [HR 3.45 IC 95% (1.2–9.9) pConclusion Three distinct SLE endotypes were identified through an unbiased approach based on B cell immunophenotyping and autoantibody profiles, showing differential benefit from belimumab therapy.