Background: Systemic sclerosis (SSc) is a connective tissue disease characterized by microvascular alterations and fibrosis. Morbidity and mortality are substantially associated with interstitial lung disease and/or pulmonary hypertension. However, more than 80% of patients with SSc suffer from gastrointestinal involvement, for which therapy is only symptomatic. To the best of our knowledge, the understanding of molecular signatures at the level of gene expression in the upper gastrointestinal tract of patients with SSc are limited and findings associated with microRNA (miRNA) expression are altogether lacking.

Objectives: To identify genes and miRNA associated with the pathogenesis of upper gastrointestinal tract involvement of SSc.

Methods: This single-centre pilot study prospectively included adult patients fulfilling the 2013 ACR-EULAR criteria for SSc and who required gastroscopy as part of a regular medical workup. Control subjects were patients that met the Rome IV criteria for dyspepsia. Gastrointestinal forceps biopsies were obtained at five different levels (upper, middle, and lower thirds of the esophagus, the antrum, and the duodenum). Total RNA and miRNA were isolated after extraction for sequencing. Histological analysis was followed by immunostaining and RNA fluorescence in situ hybridization (RNA-FISH).

Results: Data from 6 patients with SSc were compared with those from 2 control subjects (limitations related to the COVID-19 period). Differential gene expression analysis revealed changes suggestive of abnormal tissue repair involving macrophages, fibroblasts, and endothelial cells, with activation of signaling pathways associated with inflammation and neoangiogenesis. In scleroderma patients, increased differential gene expression was significative for alarmins IL-33 and S100A7. Overexpression at the mRNA level of MUC4 and LRG1 was validated by FISH. Among candidate miRNA implicated in autoimmune and fibrotic diseases, only miR-21-5p was expressed at all three levels of the esophagus and in the antrum, unlike miR-199a-5p (expressed only in the thoracic section of the esophagus) and miR-142 (expressed in the lower esophagus and in the antrum).

Conclusions: This pilot study demonstrates the feasibility of analyzing tissue-RNAs from standard digestive mucosal forceps-biopsies and suggests their potential roles as biomarkers in SSc. To the best of our knowledge, it is also the first meta-transcriptomic study to analyze the expression of coding and non-coding RNA in relation to specific segments of the gastrointestinal tract and provides an insight into the identification of candidate biomarkers associated with the upper gastrointestinal involvement of this disease.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.