Background/Purpose: Raynaud phenomenon (RP) is known to precede other disease manifestations of systemic sclerosis (SSc), and classically viewed as reversible vasospasm due to functional changes in the digital arteries of the hands. However, progressive structural changes were found in the small blood vessels in many patients with SSc. Pulmonary arterial hypertension (PAH) is also prominent as a vascular involvement in 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. Recently, it has been reported that stress testing with exercise Doppler echocardiography (DE) may facilitate early diagnosis of PVD. In this study, we tried to detect the specific changes at the stage of subclinical PVD of SSc in patients with RP


Methods: Total of 46 cases without PAH symptoms (NYHA I) with RP were investigated. To detect the involvement of pulmonary vessels, mean pulmonary artery pressure-cardiac output (mPpa-Q) response was estimated by exercise DE with Master’s two-step stress, which reflects the elasticity of pulmonary artery. Then, the expressed genes in peripheral blood were explored with using next-generation sequencing. The differences between SSc-related autoantibody negative (R group=19) and positive group (S group) consisting of with (S1 group; n=22) and without (S2 group; n=7) scleroderma were investigated. The SSc-related autoantibodies include anti-RNP (n=4), topoisomerase-1 (n=1), centromere (n=23) and RNA polymerase III antibodies (n=0).


Results: The estimated mPpa-Q (mmHg•min/L) by exercise DE was significantly elevated in S group as compared with R group (6.54±5.31 vs. 4.49±2.39, p<0.05). In the S group, the average of estimated mPpa-Q in S1 group was higher than that in S2 group (6.70±5.97 vs. 6.01±2.60). Based on the differences in gene expression between S group and R group by ANOVA, 30 differentially expressed genes (DEGs) were selected, and then subjected to a hierarchical clustering with assessment of the statistical robustness. The hierarchical clustering showed major 2 clusters, and one of them consisted of only cases in S group, which included one case in S2 group. When we focused on 117 genes reported to be directly implicated in the development of PAH (Parikh VN et al., Circulation. 2012;125:1520-1532.), it is noteworthy that 11 of them were differentially expressed in S2 group (p<0.05 by Student’s t-test) as compared with R group.


Conclusion: Although detection of early PVD in SSc patients remains a major challenge, we have shown that estimated mPpa-Q which reflects elasticity of pulmonary arteries were significantly increased in S group. As S2 group is considered as very early SSc, it is notable that the average of mPpa-Q in S2 group was located between established SSc (S1) and Raynaud only (R) group. Moreover, some of genes involved in PAH development were differentially expressed in S2 group as compared with R group. It means that the changes toward PVD had already started at the very early stage of SSc. In order to detect crucial factors for PAH development, it is very important to follow up the clinical courses of these cases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/detecting-the-pulmonary-vascular-involvement-and-the-changes-in-gene-activation-profiles-at-early-stage-of-systemic-sclerosis-in-patients-with-raynaud-phenomenon/