Gene signature fingerprints stratify SLE patients in groups with similar biological disease profiles: a multicentre longitudinal study

Abstract

Objectives 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. Results All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC-signature showed the highest association with disease activity. Interestingly 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. Conclusions 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.

Gene Expression and Autoantibody Analysis Revealing Distinct Ancestry‐Specific Profiles Associated With Response to Rituximab in Refractory Systemic Lupus Erythematosus

“…Here, we show that a selected transcriptomic profile associates with organ domain activity and predicts response to rituximab in an ancestry‐specific manner. Although IFN signatures have been previously described as predictors of outcomes in SLE ( 41 ), our present data indicate that these are more informative when evaluated in combination with gene expression scores representing other key areas of the SLE transcriptome, as has also recently been explored in juvenile patients with SLE ( 42 ). Moreover, apparently similar transcriptional profiles yield distinct disease and prognostic associations for rituximab treatment that are dependent on the ancestral group.…”

Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider

“…In this sense, there is a need for more comparative studies using different assays, both in terms of head-to-head analyses to allow direct and indirect comparisons across assays, but also in terms of simultaneous assessments in several RMDs to evaluate if the clinical added value is similar across the RMD spectrum or if, on the contrary, it needs to be regarded as disease-specific. Furthermore, whether this added clinical value may be seen by using combinations of different assays or combinations with other signatures and biomarkers remains to be explored 43 251…”

Targeted multiomics in childhood-onset SLE reveal distinct biological phenotypes associated with disease activity: results from an explorative study

“… 5 These gene modules have been associated with disease features and recently been translated into applicable gene signatures represented by the selected genes. 18 The genes are listed in table 2 .…”

“… *Details can be found in Wahadat et al 18 †Cytokines which were measured in the replication cohort. ‡Cytokines that were positive in less than 20% of the samples patients and thus were excluded from further analysis.…”