Background: Systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) displays significant clinical heterogeneity; More than twenty risk genes have been identified to be closely linked to the pathogenesis of idiopathic and familial PAH. However, the role of rare variants of PAH risk genes in SLE-associated PAH remains largely unknown.

Objectives: To investigate the contribution of rare variants of known PAH risk genes to the phenotypes, therapeutic responses and outcomes of SLE-associated PAH.

Methods: Based on the Chinese SLE Treatment and Research Group (CSTAR)-PAH cohort, 241 patients with SLE-associated PAH were recruited and screened for rare deleterious variants in 28 known PAH risk genes by whole exome sequencing. Clinical features, hemodynamic characteristics and outcomes were compared between variant carriers and noncarriers. Another 87 patients with SLE-associated PAH were included as genetic replication cohort.

Results: 51 patients (21.5%) carried rare variants of PAH risk genes, which is significantly higher than control group (13.9%, P=0.009). This finding was replicated in the independent validation cohort. Compared to noncarriers, carriers had a shorter PAH duration from SLE onset, a higher proportion of PAH as the onset symptom of SLE and lower SLE disease activity. Carrying rare variants of PAH risk genes was identified as an independent prognostic factor of mortality (hazard ratio [HR]=3.13, 95% CI, 1.10-8.97; P=0.005) and of poor treatment response to immunosuppressants, defined as the proportion of patients reaching a low risk profile of PAH (HR=0.56, 95% CI 0.34-0.94, P=0.027).

Conclusion: We showed for the first time that rare variants of PAH risk genes associated with a distinct vasculopathy phenotype and worse outcomes in patients with SLE-associated PAH, highlighting the significant clinical value in molecular classification.

REFERENCES: NIL.

Acknowledgements: We appreciated Shunyi Study, for sharing the sequencing data of non-SLE disease control for this project. We also thank Dr. Jieying Wang, Dr. Min Hui, Dr. Ziwei Liu, Dr. Jingge Qu and Dr. Yue Shi from Peking Union Medical College Hospital for their work in collecting samples and clinical information from patients with SLE-associated PAH. We also thank the physicians, research nurses, and coordinators from Peking Union Medical College Hospital involved in this study.

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.