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Background Circular RNAs (circRNAs) are possible biomarkers for many diseases, but the knowledge of circRNAs in the peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE) remains limited. This study aimed to assess the expression of circRNAs in PBMCs from patients with SLE and healthy individuals by RNA sequencing (RNA-seq). Methods In total, 128 circRNAs were significantly differentially expressed including 39 upregulated and 89 downregulated circRNAs in four new-onset SLE patients compared with three healthy controls. After verification of the four candidate circRNAs in 49 patients with SLE and 37 controls using quantitative real-time polymerase chain reaction (qRT-PCR) assays, a previously undescribed circRNA with potential translation activity, circPTPN22, was selected to confirm its clinical significance. Results Bioinformatics analysis demonstrated that the parent gene of circPTPN22 was protein tyrosine phosphatase non-receptor type 22 (PTPN22), a potent regulator of T cell activation. The downregulation of circPTPN22 in patients with SLE was strongly negatively correlated with their Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores. circRNA-miRNA-mRNA co-expression network analysis indicated a correlation between circPTPN22 and the miRNAs and mRNAs related to immunological regulation including the development of SLE. Patients with higher SLEDAI scores had lower circPTPN22 expression levels, and long-term hormone treatment significantly increased circPTPN22 levels. Receiver operating characteristic curve analysis indicated that circPTPN22 has good diagnostic value for SLE. Conclusion Our data demonstrated the aberrant expression of circRNAs in patients with SLE compared with healthy controls; circPTPN22 might function as a diagnostic and disease severity indicator in SLE. [ABSTRACT FROM AUTHOR]