Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe form of pulmonary hypertension with poor prognosis. It most commonly arises in systemic sclerosis (SSc), followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Its pathogenesis involves a complex interplay of immune dysregulation, chronic inflammation, endothelial injury, vascular remodeling, and fibrosis. Although vasodilators targeting the endothelin, nitric oxide, and prostacyclin pathways remain the therapeutic backbone, newer agents—including the activin signal inhibitor sotatercept and inhaled treprostinil—have expanded treatment options. Immune-targeted therapies such as glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, and IL-6 receptor inhibitors may benefit inflammation-dominant PAH phenotypes, while fibrotic phenotypes continue to demonstrate limited responsiveness. In addition to brain natriuretic peptide (BNP), N-terminal (NT)-proBNP and disease-specific autoantibodies, emerging biomarkers show promise for early detection, risk stratification, and personalized treatment, though validation in CTD-PAH is lacking. Advances in animal models replicating immune-mediated vascular injury and fibrosis have further improved mechanistic understanding. Despite these developments, substantial unmet needs remain, including the absence of disease-specific therapeutic strategies, limited biomarker integration into clinical practice, and a scarcity of large, well-designed trials targeting individual CTD subtypes. Addressing these gaps will be essential for improving prognosis in patients with CTD-PAH.
Yokoyama et al. (Tue,) studied this question.