How does sclerosis cause pulmonary hypertension?

From the Guidelines

Sclerosis causes pulmonary hypertension primarily through structural changes in blood vessels that increase resistance to blood flow in the lungs, involving excessive collagen deposition and fibrosis in the walls of pulmonary arteries, as well as endothelial cell dysfunction and inflammatory processes, as noted in the 2023 state-of-the-art evidence in the treatment of systemic sclerosis 1.

Pathophysiology of Sclerosis-Induced Pulmonary Hypertension

The disease process in systemic sclerosis (scleroderma) leads to vessel wall remodeling, narrowing the arterial lumen, and increasing pulmonary vascular resistance. Key factors include:

• Excessive collagen deposition and fibrosis in pulmonary arteries
• Endothelial cell dysfunction, leading to imbalances in vasodilators and vasoconstrictors
• Inflammatory processes damaging vessel walls and promoting fibrosis
• Potential development of plexiform lesions, severely obstructing blood flow

Clinical Implications and Treatment

Pulmonary hypertension in systemic sclerosis is a serious complication with significant impact on prognosis, particularly in limited cutaneous systemic sclerosis, and can develop even without significant interstitial lung disease. Treatment is guided by risk stratification, using the REVEAL 2.0 calculator, and may involve combination oral therapy with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor as first-line treatment, as recommended in the 2023 state-of-the-art evidence 1. The updated EULAR recommendations for the treatment of systemic sclerosis also prioritize a new research agenda for managing vascular manifestations, including pulmonary arterial hypertension, as outlined in the 2025 update 1.

From the FDA Drug Label

The effects of epoprostenol on mean pulmonary arterial pressure (PAPm) were variable and minor Acute intravenous infusions of epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm)

The FDA drug label does not answer the question of how sclerosis causes pulmonary hypertension, it only mentions that epoprostenol is used to treat PAH associated with scleroderma spectrum of diseases (PAH/SSD) and its effects on hemodynamic parameters. Key points:

• The label discusses the treatment of PAH with epoprostenol.
• It mentions PAH associated with scleroderma spectrum of diseases (PAH/SSD) as an indication for epoprostenol.
• The label does not provide information on the mechanism by which sclerosis causes pulmonary hypertension 2

From the Research

Pathophysiology of Sclerosis-Induced Pulmonary Hypertension

• Sclerosis causes pulmonary hypertension through restricted flow in the pulmonary arterial circulation, leading to increased pulmonary vascular resistance and right heart failure 3.
• The condition is a complex clinical situation, and its pathophysiology is not fully understood, but it is known to be a common and life-threatening complication in connective tissue diseases, specifically in systemic sclerosis 3, 4.

Mechanisms and Clinical Implications

• Pulmonary hypertension in systemic sclerosis can result from pulmonary vascular involvement of the disease, categorized as group 1 pulmonary hypertension by the World Health Organization classification system 5.
• The high mortality seen in systemic sclerosis-associated pulmonary arterial hypertension is likely due to the impairment of right ventricular systolic function and the coexistence of other non-group-1 pulmonary hypertension phenotypes 5.
• Patients with systemic sclerosis can suffer from all clinical groups of pulmonary hypertension, particularly pulmonary arterial hypertension and pulmonary hypertension related to interstitial lung disease, with different mechanisms determining a worse prognostic outcome compared to idiopathic pulmonary arterial hypertension 6.

Diagnosis and Treatment

• Early screening and detection of pulmonary hypertension in systemic sclerosis are crucial, but the role of screening with serum biomarkers and noninvasive testing remains controversial 7, 6.
• Right heart catheterization remains the only test that can diagnose pulmonary hypertension and differentiate pulmonary veno-occlusive disease from pulmonary arterial hypertension, which is essential for treatment decisions 7.
• Recent advances in the diagnosis, classification, and management of pulmonary hypertension in systemic sclerosis have led to changes in recommendations for adjunct therapy and selection of pulmonary vasodilators for the treatment of SSc-associated PAH 4.