Sarcoidosis Associated Pulmonary Hypertension: An exploratory journey

Pulmonary hypertension (PH) is a rare but serious complication of sarcoidosis, with a prevalence between 3-20%, dependent on the ethnicity and severity of sarcoidosis. This thesis showed a PH prevalence around 3% in a mainly Caucasian cohort of sarcoidosis patients newly referred to a tertiary centre (PULSAR cohort).

The cause sarcoidosis associated pulmonary hypertension (SAPH) is heterogenic and sometimes multifactorial. Most patients fit a parenchymal phenotype with hypoxemia as main mechanism for the development of PH. Other mechanisms in sarcoidosis, often with a worse hemodynamic profile, include compression of the pulmonary vasculature, chronic thromboembolic disease, left heart disease and suspected vasculopathy. A study assessing the pulmonary vasculature by intravascular ultrasound showed changes in wall thickness and vascular properties predominantly in the upper lobes, similar to sarcoidosis related abnormalities, suggesting a vascular component. Phenotyping is valuable in order to evaluate possible treatment options.

The diagnosis of PH is established by measuring the mean pulmonary artery pressure during right heart catheterisation. Since symptoms and signs of sarcoidosis and PH overlap, it can be challenging to identify patients with suspected PH. Besides thorough history taking and patterns in pulmonary function tests, measurement of the pulmonary artery diameter on chest-CT can be helpful. As shown in this thesis, the diameter corrected for the body surface area gives the most accurate prediction. Echocardiography is used as a screening tool to assess the likelihood of PH before performing a right heart catheterisation. The ESC/ERS PH guideline classifies patients into a low, intermediate or high PH probability based on echocardiographic measurements. This thesis shows that in patients with a low PH probability and high PH probability, PH can be ruled out or diagnosed accurately. However in patients with intermediate PH probability, discrimination for the presence of PH is difficult. Furthermore, echocardiographic measurement of the right ventricular systolic pressure has a strong correlation with invasively measured systolic pulmonary artery pressure, however it tends to overestimate the actual pressures in mild PH and underestimates in severe PH. New echocardiographic imaging techniques are arising to assess right ventricular dimension and function. In this thesis knowledge based reconstruction, using three-dimensional coordinates, was investigated but showed no additional value to determine right ventricular dimensions in sarcoidosis patients.

Treatment of SAPH consist of supportive heart failure and/or oxygen treatment and, if possible, treating the underlying cause. In carefully selected patients the use of PH targeted therapy can be considered. This thesis investigated a case series of macitentan in SAPH, and showed it was safe and mostly well tolerated with improvement in functional capacity. Survival of the PULSAR cohort was relatively good with a 1, 2, 3 and 4-year survival of 100%, 99.0%, 98.2% and 94.6%. Predictors for mortality were elevated right ventricular systolic pressure, presence of PH on echocardiography and progressive fibrotic disease.

The thesis concludes with recommendations based on expert opinion of a task force established by the World Association of Sarcoidosis and Other Granulomatous disease (WASOG) to provide guidance for the diagnosis and management of SAPH.