Unanswered Questions in Treatment-Resistant Pulmonary Sarcoidosis

By Daniel A. Culver, DO

Treatment-resistant pulmonary disease — primarily pulmonary fibrosis and pulmonary hypertension — contributes to pulmonary disease being the most common cause of death in sarcoidosis. Radiologically overt pulmonary fibrosis develops in five to 10 percent of patients with sarcoidosis. Pulmonary hypertension develops in the same percentage; however, the complication is found in more than 50 percent of sarcoid patients with persistent dyspnea.

Although the majority of patients with limited pulmonary fibrosis never develop severe disease, we have no validated markers to help predict which patients will progress to significant fibrosis, and the value of imaging findings in predicting treatment or outcome is unknown. Additionally, how treatment for pulmonary sarcoidosis might mitigate risk is unknown.

A model that combines physiological and radiographic parameters to better predict mortality in these patients has been developed, but requires validation in a large population. While the signs and symptoms suggestive of pulmonary hypertension have been identified, they also require further validation, since many of the individual risk factors are also associated with other lung diseases.

Areas ripe for research

In late 2015, I participated in a National Heart, Lung, and Blood Institute sarcoidosis workshop as part of a multidisciplinary team that reviewed known data on patients with manifestations of high-risk sarcoidosis and suggested where research efforts should be targeted. Our conclusions led us to make the following recommendations in a 2017 article in Annals of the American Thoracic Society:

• Develop a prospective registry of patients with pulmonary fibrotic sarcoidosis by engaging a clinical network of sarcoidosis centers caring for such patients. Such a registry would collect follow-up information, including pulmonary function and clinical outcome, to better characterize common fibrotic lung disease manifestations and to consider subphenotypes.
• Biospecimens for genetics, genomics and other analyses should be obtained to facilitate biomarker development and therapeutic targets.
• Further characterize distinct phenotypes of severe pulmonary disease manifestations by analyzing common radiographic and histopathology patterns and by incorporating newly discovered molecular biomarkers. Validate these initial efforts across other national and international registries to define predictors of differences and similarities in disease outcome. The process should extend to the evaluation and further validation of quality-of-life clinical endpoints that are most impacted by advanced sarcoidosis clinical phenotypes.
• Define new and repurposed therapies to treat severe pulmonary disease and use the clinical networks developed above to evaluate therapies for each severe pulmonary manifestation, most notably fibrotic sarcoidosis and sarcoidosis-associated pulmonary hypertension.
• Develop and validate molecular markers and omics to define mechanisms of disease, and use them to assess response to therapies and disease prognosis longitudinally.

Referring to Cleveland Clinic

Cleveland Clinic’s Sarcoidosis Clinic is a World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) member. In this capacity, we provide multidisciplinary care to patients with all forms of sarcoidosis, while developing new treatment approaches through research.

We encourage you to refer patients with a high suspicion of, or diagnosed with, pulmonary sarcoidosis for a second opinion. Evaluation by our experienced multispecialty team often reveals overlooked aspects of the disease that require attention. We are able to offer a variety of treatments beyond steroids, as well as participation in clinical trials. These are key aspects of care that minimize the degree to which treatment-resistant pulmonary fibrosis affects quality of life.

Dr. Culver directs both the Interstitial Lung Disease and Sarcoidosis Programs the in the Department of Pulmonary Medicine at Cleveland Clinic.