Study Identifies SSc, SLE Gene Expression Signatures

Investigators have identified a set of new biomarkers that could help scientists better understand the distinguishing characteristics—as well as the overlap—between systemic sclerosis (SSc) and systemic lupus erythematosus (SLE).

Their findings, which were based on an analysis of RNA sequencing, were published in the International Journal of Rheumatic Diseases.1

The authors noted their research should be seen as a first step into the exploration of transcriptomics in the 2 diseases. | Image credit: Evrymmnt - stock.adobe.com

SSc and SLE are both chronic autoimmune diseases characterized by immune dysregulation, the authors noted. However, there are also important differences between the two. To begin with, SSc is characterized by fibrosis and vascular dysfunction and primarily affects the skin and connective tissues, they noted, while SLE is marked by systemic inflammation, immune complex deposition, and multi-organ damage.

“Furthermore, the underlying immunological pathways differ, with SSc being more associated with fibroblast dysfunction and endothelial damage, while SLE is driven by autoantibody production and immune-mediated tissue destruction,” the authors wrote.

While both diseases have been studied extensively, the investigators said most of the current therapies are non-specific, meaning they lack the kind of specific targeting that might halt the diseases entirely or even reverse their effects.

The investigators said they wanted to conduct a transcriptomic analysis of both diseases in order to better understand both shared and disease-specific molecular mechanisms at play in the diseases. They recruited 10 patients with SSc and 24 patients with SLE, all of whom were off immunosuppressants at the time of their participation in the study. The investigators then used DESeq2 to analyze RNA sequencing data from the patients, with the goal of identifying differentially expressed genes (DEGs).

There were a total of 3895 DEGs between patients with SLE and controls and 2055 DEGs between patients with SSc and controls. They found that expression of the gene RGS5 was significantly downregulated in both diseases, with greater downregulation in SSc. That makes RGS5 a potential biomarker and/or therapeutic target for both diseases, the authors explained.

“Given its known role in vascular homeostasis, the suppression of RGS5 could contribute to the vascular complications observed in both diseases,” they explained.

Previous research into RGS5 found that it is a key regulator of pericyte function during cardiac aging and that its loss can lead to cardiac dysfunction and myocardial fibrosis.2

The transcription factor EGR1 was upregulated in SSc and that BLK, ITGAM, and IFNG were upregulated in SLE.1 RGS5 is involved in vascular regulation, EGR1 is involved in fibrotic remodeling, and BLK is involved in B-cell signaling. The authors said EGR1 and BLK may be potential targets for antifibrotic and B-cell-directed therapies.

The authors noted their research should be seen as a first step into the exploration of transcriptomics in the 2 diseases. Larger cohorts of patients will be needed to confirm their findings, and functional studies will be required to better understand the exact roles these genes play in the diseases.

“To translate findings into treatments, it is essential to validate results through rigorous testing, investigate pathways, develop biomarkers, conduct preclinical trials, advance therapeutic strategies, and design precision clinical trials,” they wrote.

In the meantime, though, the investigators said their work highlights the benefits of transcriptome sequencing as a means to spark new avenues of precision medicine approaches. They said they hope their work proves to be a “foundation for targeted diagnostic tools, precision therapies, and a deeper understanding of these complex autoimmune diseases.”

References

1. Liu AJ, Ciou JR, Wu PC, Chen YP, Chu HT, Chang HH. Unveiling biomarkers and therapeutic targets in systemic sclerosis and lupus erythematosus through transcriptomic profiling. Int J Rheum Dis. 2025;28(6):e70308. doi:10.1111/1756-185X.70308
2. Tamiato A, Tombor LS, Fischer A, et al. Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis. Circ Res. 2024;134(10):1240-1255. doi:10.1161/CIRCRESAHA.123.324183