Author Response: Pulmonary Vasodilators in Sarcoidosis-associated Pulmonary Hypertension

• Sarcoidosis
• Pulmonary hypertension
• Pulmonary vasodilators

Editor – We thank Ho and Kuschner1 for their knowledgeable comments on our case, specifically around the need to individualize therapy for each patient, multimodal therapeutic interventions including immunosuppression, and close follow-up.

Sarcoidosis-associated pulmonary hypertension (SAPH) is often classified as WHO group 5.2,3 However, the pathophysiology of pulmonary hypertension in sarcoidosis is multifactorial and it can also be classified as WHO group 1 (pulmonary arterial hypertension), group 2 (pulmonary hypertension from left heart disease), group 3 (pulmonary hypertension due to lung disease and/or hypoxaemia) or group 4 (pulmonary hypertension due to chronic thromboembolic pulmonary hypertension).4 As the etiology of pulmonary hypertension in sarcoidosis is often multifactorial, the use of vasodilators may prove beneficial in well-selected patients, resulting in improved functional capacity, quality of life and hemodynamics despite its off-label use.4

The treatment of SAPH has not been studied extensively and the best management strategy is currently unknown.3,4 A multidisciplinary approach, including cardiologists, respirologists and radiologists specializing in pulmonary hypertension should be used when treating such patients.4 As Ho and Kuschner1 point out, the cornerstone treatment of sarcoidosis includes immunosuppressive therapies such as corticosteroids; however, these medications are not always effective in isolation in treating SAPH, and long-term use is associated with several unwanted consequences.5,6 The treatment for SAPH therefore can include pulmonary vasodilators, anticoagulants and supplemental oxygen.3

As an example, ambrisentan treats SAPH by blocking endothelin, a vasoconstrictive peptide involved in the development of pulmonary hypertension.3 Endothelin itself is found in higher concentrations in urine, plasma and bronchoalveolar lavage samples from patients with sarcoidosis.3,5 Phosphodiesterase-5 inhibitors such as tadalafil increase nitric oxide in the pulmonary arterial smooth muscle leading to vasodilation reducing pulmonary hypertension.5 The effectiveness of pulmonary vasodilators in the management of SAPH has been demonstrated by numerous studies, which found improved hemodynamics including lower mean pulmonary arterial pressures, pulmonary vascular resistance and brain natriuretic peptide as well as increased cardiac output.7–15 Pulmonary vasodilators have also been associated with increased functionality demonstrated by improved 6-minute walking distances, New York Heart association class and the Borg dyspnea index in patients with sarcoidosis-associated hypertension.7,9,10,12,14–17 This data was compiled in a meta-analysis which confirmed the beneficial aspects of pulmonary vasodilators in patients with SAPH.2

Ho and Kuschner1 note that pulmonary vasodilators may worsen oxygenation in patients with SAPH due to increased shunting.5 However, the use of pulmonary vasodilators, such as phosphodiesterase-5 inhibitors and endothelin receptor antagonists, in patients with SAPH has not been associated with worse outcomes such as increased mortality or the need for lung transplantation.2 Tadalafil has been used in SAPH with no reported major adverse events or clinical worsening.6 Ambrisentan is generally well tolerated and any adverse effects are mostly of mild to moderate intensity and resolve with discontinuation of the medication.16 Other studies in patients with severe parenchymal disease from sarcoidosis and associated SAPH reported no deterioration of oxygen saturation after administration of pulmonary vasodilators.3,10

In order to ensure the safe use of pulmonary vasodilators in patients with sarcoidosis-associated pulmonary hypertension, candidates for these medications should be selected carefully, with particular caution if significant hypoxia or parenchymal disease exists, with follow-ups undertaken regularly. The broad range of responses to these medications reflects the complicated pathophysiologic nature of sarcoidosis and emphasizes the importance of individualizing care to each patient’s presentation and prognosis.3,4

The lack of widespread evidence in support of these drugs may be in relation to small sample sizes of these studies and inappropriate inclusion criteria.5 Specifically, patients at the terminal stage of their disease or those with mild pulmonary vascular dysfunction are least likely to demonstrate a response to therapy.5

There is a clear need for further research into the management of SAPH as current reports are insufficient to guide wide-spread practice but do demonstrate the efficacy of pulmonary vasodilators in select patients.3 The rationale for the use of tadalafil and ambrisentan was explained to our patient and informed consent was obtained prior to the administration of these drugs. The patient experienced rapid recovery on the reported regimen of tadalafil, ambrisentan, methyl-prednisolone and adalimumab and at follow up reported no adverse effects from the medication in addition to continued disease remission.

• Received July 6, 2020.
• Accepted July 6, 2020.