Background/Purpose: Pulmonary hypertension (PH) is prominent as a vascular involvement of systemic sclerosis (SSc), which remains a leading cause of death in spite of current best treatments. The definition of PH was updated from mPAP≥25mmHg to mPAP >20mmHg and PVR≥3WU (G. Simonneau et al. Eur Respir J 2019, 53). Although it may enable to improve the prognosis of PH associated with SSc, it seems be still insufficient because more than 2/3 of the pulmonary circulation is already impaired before meeting the definition. Therefore, the ideal therapeutic intervention should be started at the subclinical stage of PH in SSc patients, but little is known about underlying pathological mechanisms. Recently, it was reported that TNFα drives PH by suppressing the BMP type-II receptor and altering NOTCH signalling (LA. Hurst et al., Nat Commun 2017. 13;8:14079). In this study, we try to detect the gene expressions in peripheral blood involved in the progression to exercise-induced PH (exPH), considered as subclinical PH, in the prospective registry of high-risk population for developing PH associated with SSc.

Methods: Total of 180 patients who had not met PH criteria with Raynaud phenomenon, skin sclerosis or SSc-related autoantibody was registered. To detect the early pulmonary vessel disease (PVD), exercise Doppler echocardiography (exDE) was carried out every 6 or 12 months for up to 6 years. The definition of exPH was maximum sPAP >40mmHg or increase in sPAP >20mmHg estimated by exDE during exercise (R. Naeije et al., Am J resp and critical care med 2013, 187, 576-583). For gene expression analysis, total RNAs from whole peripheral blood cells were extracted and then multiplex sequencing was done. To identify candidate genes involved in the progression to exPH, random forest machine learning method was employed. Volcano plots, a scatter plots to visualize fold-changes and p-values of differentially expressed genes (DEGs) between exPH and others (exN), were also used for seeking the important genes for disease progression.

Results: At the time of registration, 34.4% of patients met exPH criteria, and 15.6% of patients developed exPH during follow-up period (35.0±18.1 months). Expression of TNF gene was selected as the most useful genes to predict progression to exPH by random forest, and the accuracy of the model was about 87%. Volcano plots indicated that expressions of TMEM176A and TMEM176B were prominent (fold-change >2.4 and -log10 p-value >3.5) in exPH patients. The accuracy was improved to 90% if the expression of TNF and TMEMA/B were used for the prediction of progression to exPH. We found that the statistically significant increase in expression of TNF was eliminated at the time of fulfilling the exPH criteria, while the increase in expressions of TMEM A/B were still kept.

Conclusion: Our findings suggest that TNFα plays important role only in the period of pre-exPH. On the other hand, increase in expressions of TMEM A/B were observed through the period of pre-exPH to post-exPH. It suggests that there are multiple phases before developing PH associated with SSc. It is very important to understand the phases for the precise treatment to arrest the progression of PVD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/up-regulation-of-tnf%ce%b1-gene-in-peripheral-blood-is-useful-for-predicting-the-development-of-exercise-induced-pulmonary-hypertension-which-is-early-stage-of-pulmonary-vascular-disease-associated-w/