Identifying lupus Patient Subsets Through Immune Cell Deconvolution of Gene Expression Data in Two Atacicept Phase II Studies

Abstract

Objective: To use cell-based gene signatures to identify patients with systemic lupus erythematous (SLE) in the phase II/III APRIL-SLE and phase IIb ADDRESS II trials most likely to respond to atacicept.

Methods: A published immune cell deconvolution algorithm based on Affymetrix gene array data was applied to whole blood gene expression from patients entering APRIL-SLE. Five distinct patient clusters were identified. Patient characteristics, biomarkers, and clinical response to atacicept were assessed per cluster. A modified immune cell deconvolution algorithm was developed based on RNA sequencing data and applied to ADDRESS II data to identify similar patient clusters and their responses.

Results: Patients in APRIL-SLE (N = 105) were segregated into the following five clusters (P1-5) characterized by dominant cell subset signatures: high neutrophils, T helper cells and natural killer (NK) cells (P1), high plasma cells and activated NK cells (P2), high B cells and neutrophils (P3), high B cells and low neutrophils (P4), or high activated dendritic cells, activated NK cells, and neutrophils (P5). Placebo- and atacicept-treated patients in clusters P2,4,5 had markedly higher British Isles Lupus Assessment Group (BILAG) A/B flare rates than those in clusters P1,3, with a greater treatment effect of atacicept on lowering flares in clusters P2,4,5. In ADDRESS II, placebo-treated patients from P2,4,5 were less likely to be SLE Responder Index (SRI)-4, SRI-6, and BILAG-Based Combined Lupus Assessment responders than those in P1,3; the response proportions again suggested lower placebo effect and a greater treatment differential for atacicept in P2,4,5.

Conclusion: This exploratory analysis indicates larger differences between placebo- and atacicept-treated patients with SLE in a molecularly defined patient subset.

Figure 1

Identification and characterization of patient clusters in APRIL‐SLE by immune cell deconvolution. A, The heatmap shows relative immune cell profiles in the blood of 105 patients (columns) at baseline. The order of the patients in the heatmap is from clustering, and the panel below the heatmap shows which cluster each patient was assigned (P1: n = 37, P2: n = 12, P3: n = 18, P4: n = 16, P5: n = 22). Values are scaled within each cell type. B, Box plots show the distribution of the relative immune cell profiles per patient cluster. NK, natural killer; P1‐P5, patient cluster.

Figure 2

Flare rates and time to BILAG A or B flare by patient clusters according to treatment groups in APRIL‐SLE. The lines represent the percentage of patients with a flare at each time point, and the shaded areas represent confidence intervals. The numbers to the right of the graphs are the number of patients in each treatment group. BILAG, British Isles Lupus Assessment Group; P1‐P5, patient cluster.