Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases

Abstract

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.

Keywords: PAH CTD; novel drugs; prognosis; therapy; treatment.

Figure 1

Patients with connective tissue diseases (CTD) may develop pulmonary hypertension (PH) belonging to different groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH secondary to lung disease and/or hypoxia (CTD patients mostly develop interstitial lung disease), and (4) chronic thromboembolic pulmonary hypertension (CTEPH), especially in the setting of antiphospholipid syndrome (APS). A specific treatment for PAH-CTD is currently available and recommended (solid arrows): prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-5 inhibitors (PDE5i: sildenafil, tadalafil) and endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Two other pathways are under intensive investigation (dashed arrows): (1) affecting BMPR2: trapping the ligands of TGF-β and reducing the activity of ACTRIIA (sotatercept, KER-012) or inhibiting PDGFR (imatinib, seralutinib), (2) inhibiting the serotonin pathway by blocking the serotonin-producing enzyme tryptophan hydroxylase 1 (rodatristat ethyl).

Figure 2

In patients with pulmonary arterial hypertension (PAH) BMP signaling is impaired, which leads to the downregulation of anti-proliferative SMAD 1/5/9 and upregulation of pro-proliferative SMAD 2/3 and, in turn, to the proliferation of the smooth muscle cells in pulmonary arterioles. Sotatercept, by trapping the ligands of TGF-β family and reducing the ACTRIIA activity, restores the balance between SMAD2/3 and SMAD 1/5/9. Adapted from Ref. [50].

Figure 3

Seralutinib, by blocking the PDGF receptors located on the fibroblasts and pulmonary arterioles smooth muscle cells (PASMC), promotes the BMPR2 function, in addition, sotatercept, by inhibiting the c-KIT receptors located in the mast cells and endothelial cells as well as CSF-1 receptors located in the macrophages, favors the BMPR2 function and decreases inflammation. Adapted from Ref. [61].

Figure 4

Increased levels of serotonin promote pulmonary arterial smooth muscle cell proliferation and contraction. Rodatristat ethyl blocks the serotonin-producing enzyme tryptophan hydroxylase 1 (TPH1). Adapted from Ref. [62].