Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Pulmonary arterial hypertension (PAH) is prominent as a vascular involvement in systemic sclerosis (SSc), which remains a leading cause of death in spite of current best treatments. As the pulmonary vascular disease (PVD) can be well compensated for, more than a half of the pulmonary circulation is impaired before early PAH is detected. Although recent studies focused on molecular basis of the PVD, the underlying mechanisms have not been fully elucidated, especially at early stage of SSc. In this study, we try to detect the subclinical PVD and to detect a gene co-expression network involved in the pathogenesis of exercise-induced PAH at early stage of SSc.
Methods: Total of 93 cases without PAH symptoms (NYHA I) with either Raynaud phenomenon (RP: n=80), skin sclerosis (n=51) or SSc-related autoantibody (anti-RNP: n=15, centromere: n=50, topoisomerase-1: n=3, RNA polymerase III: n=3) were enrolled. To detect the latent PAH, exercise DE with Master’s two-step stress was carried out. Systolic PAP (sPAP) was determined by maximum velocities of tricuspid regurgitation jets, and exercise induced pulmonary hypertension (exPH) group was segregated from normal response group (exN) with using the definition of a sPAP greater than 40 mm Hg during exercise, or a exercise increase in sPAP by greater than 20 mm Hg1). Meanwhile, genome-wide gene expression analysis was performed with using whole peripheral blood from some of these patients (n=74). Total RNAs were extracted and multiplex sequencing was done. After quantifying the expressions of transcripts, co-expression modules were identified by weighted gene co-expression network analysis (WGCNA). And then, pathway enrichment analysis (PathVisio) was performed to investigate the module.
Results: In clinical test items, the level of serum BNP was high in exPH group, whereas there were no significant differences between exPH and exN group in the results of total skin score, pulmonary function and thermography after 0°C-stress test. The SSc-related autoantibody positive was a risk factor for exPH (odds ratio=1.62); especially, anti-RNP positive seems to be prominent (odds ratio=2.10). Based on the gene expression analysis, 19 co-expression modules were identified by WGCNA. Pathway enrichment analysis revealed that modules related with the titer of anti-RNP antibody were enriched with genes of type2 interferon signaling pathway.
Conclusion: The paradigm of SSc-PAH management should ideally be aimed at detecting early PVD and starting treatment prior to fulfilling the criteria for PAH. Although it remains a major challenge, individuals who require early therapeutic intervention are possible to be segregated by the follow-up with exercise DE. By this study, the crucial genes involved in the pathogenesis of exercise-induced PAH have not been completely elucidated. However, it is noteworthy that anti-RNP autoantibody, shown as an important risk factor for exercise-induced PAH, seemed to be related with type 2 interferon signaling pathway. It may show a hint for therapeutic intervention at the early stage of the disease to prevent the aggravation of PVD.
References: 1)R. Naeije et al., American journal of respiratory and critical care medicine 187, 576-583 (2013).
To cite this abstract in AMA style:Koyama Y, Fuke S, Sato Y, Higuchi T. Focusing on Pulmonary Vascular Disease at Early Stage of Systemic Sclerosis: Exercise-Induced Pulmonary Arterial Hypertension and Gene Co-Expression Networks Involved in Its Pathogenesis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/focusing-on-pulmonary-vascular-disease-at-early-stage-of-systemic-sclerosis-exercise-induced-pulmonary-arterial-hypertension-and-gene-co-expression-networks-involved-in-its-pathogenesis/. Accessed October 27, 2021.
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