Background: Systemic sclerosis (SS) is a complex autoimmune disease characterized by progressive skin fibrosis and multiorgan involvement, particularly in the diffuse cutaneous subtype. Among its systemic manifestations, interstitial lung disease (ILD) is the leading cause of mortality in SS patients [1]. The lack of reliable biomarkers for early pulmonary involvement delays treatment until advanced fibrosis is evident [2]. Furthermore, the inaccessibility of lung tissue poses significant challenges for early screening and diagnosis of pulmonary complications.

Advances in gene expression profiling have provided critical insights into the molecular mechanisms underlying autoimmune diseases, enabling the identification of potential diagnostic and therapeutic targets. Previously, our team identified 10 key genes involved in the pathogenesis of SS, demonstrating their diagnostic potential in peripheral blood samples. This study focuses on the expression of these genes in skin tissue and their correlation with skin thickness and pulmonary function to uncover their role in the shared molecular pathways of cutaneous and pulmonary involvement in SS.

Objectives: This study aimed to compare the expression profiles of the previously identified key genes in SS patients with and without ILD and investigate their correlation with cutaneous thickness and pulmonary function.

Methods: The transcriptomic dataset GSE47162, obtained from the Gene Expression Omnibus platform, was analyzed. This dataset includes gene expression profiles from 59 patients with systemic sclerosis (SS), of whom 23 had pulmonary involvement (ILD) and 36 did not. The study focused on 10 previously identified key genes: SFRP4 , COL4A4 , IL6 , SERPINE1 , COMP , NOX4 , COL11A1 , MMP1 , COL8A1 , and LTF . Mean fluorescence intensity (MFI) values for these genes were retrieved, and differences between the ILD and non-ILD groups were evaluated using either parametric Student’s t-test for normally distributed data and nonparametric Mann-Whitney U test for non-normally distributed data. To assess the relationship between gene expression, skin fibrosis, and pulmonary function, a Spearman correlation analysis was conducted. The variables included the MFI values of the key genes, the modified Rodnan skin score (a measure of skin fibrosis), the lung diffusion capacity for carbon monoxide (DLCO), and the forced vital capacity (FVC), which are indicators of pulmonary function. Statistical significance was set at p < 0.05 for all tests. This approach aimed to determine the molecular link between cutaneous and pulmonary involvement in systemic sclerosis.

Results: No significant differences were observed in the MFIs of the hub genes between the non-ILD and ILD groups, as shown in Table 1. However, correlation analysis revealed significant relationships between the expression levels of these genes and clinical parameters of systemic sclerosis. The Rodnan Skin Score showed positive correlations with the expression levels of most hub genes, including SFRP4 , COL4A4 , IL6 , SERPINE1 , COMP , NOX4 , COL11A1 , and COL8A1 . Conversely, DLCO (diffusion lung capacity for carbon monoxide) exhibited significant negative correlations with SFRP4 , COMP , COL11A1 , and COL8A1 . Interestingly, the forced vital capacity (FVC) correlated negatively only with SFRP4.

Conclusion: These findings highlight the molecular links between cutaneous and pulmonary involvement in systemic sclerosis, suggesting that gene expression profiles in the skin may reflect underlying pulmonary dysfunction. Further validation and research on peripheral blood markers are needed to improve early detection and management.

REFERENCES: [1] Perelas, Apostolos et al. “Systemic sclerosis-associated interstitial lung disease.” The Lancet. Respiratory medicine vol. 8,3 (2020): 304-320. doi:10.1016/S2213-2600(19)30480-1.

[2] Tashkin, Donald P et al. “Cyclophosphamide versus placebo in scleroderma lung disease.” The New England journal of medicine vol. 354,25 (2006): 2655-66. doi:10.1056/NEJMoa055120.

Acknowledgements: We’d like to thank the Mexican National Council of Humanities, Science and Technology (CONAHCYT) for providing the academic grant that made this research possible. Grant ID: PCC-2022-320697.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.