Gene Signature Fingerprints Stratify SLE Patients in Groups with Similar Biological Disease Profiles: A Multicenter Longitudinal Study

Background: Clinical phenotyping and predicting treatment responses in Systemic Lupus Erythematosus (SLE) patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising for stratification of SLE patients. We aimed to translate existing transcriptomic data into simpler gene signatures suitable for daily clinical practice. Methods: RT-PCR of multiple genes from the Interferon M1·2, Interferon M5·12, neutrophil (NPh) and plasma cell (PLC) modules followed by a principle component analysis, was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood onset SLE cohorts (n=101 and n=34, respectively) and associated with clinical features. Disease activity was measured using SELENA-SLEDAI. Cluster analysis subdivided patients into three mutually exclusive fingerprint-groups termed 1) all-signatures-low, 2) only IFN high (M1·2 and/or M5·12) and 3) high NPh and/or PLC. Findings: All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC-signature showed the highest association with disease activity. Also, in longitudinally collected samples, the PLC signature was associated with disease activity and showed a decrease over time. When patients were divided into fingerprints, the highest disease activity was observed in the high NPh and/or PLC group. The lowest disease activity was observed in the all-signatures-low group. The same distribution was reproduced in samples from an independent SLE cohort. Interpretation: The identified gene signatures are associated with disease activity and suitable tools to stratify SLE patients into groups with similar activated immune pathways that may guide future treatment choices. Funding: Sophia Children’s Hospital Fund, NVLE (Dutch patient organization for Lupus, APS, Scleroderma and MCTD) and Dutch Arthritis Society Declaration of Interest: SK received funding from GlaxoSmithKline outside the submitted work. All other authors declare no competing interests. Ethical Approval: Written informed consent was obtained from all participants in compliance with the Declaration of Helsinki. The study was approved by the ethics committee of each institution.