Objectives To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response.Methods RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions.Results We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p