Sildenafil for Early Pulmonary Vascular Disease in Scleroderma
Abstract
Scleroderma is an autoimmune disease that affects the skin and internal organs including the gastrointestinal tract, kidneys, and lungs. While it is a rare disease affecting fewer than 200,000 people in the United States, it is a devastating disease, with an average survival of around 10-12 years after diagnosis. Lung involvement is the most common cause of death as scleroderma patients are prone to develop pulmonary hypertension. Pulmonary hypertension is a disease of the pulmonary blood vessels that leads to strain on the right side of the heart; this ultimately leads to right heart failure and death. About 15% of scleroderma patients develop pulmonary hypertension, which leads to severe shortness of breath that limits their daily activities and to frequent hospitalizations. Unfortunately, despite advances in our understanding of both diseases, average survival for scleroderma patients and pulmonary hypertension is only 4 years from diagnosis. One of the biggest challenges in the evaluation and management of scleroderma patients is identifying pulmonary hypertension in its early stages. Despite guidelines recommending yearly testing for pulmonary hypertension, most patients are diagnosed in advanced stages of disease. While the screening protocols currently employed may be ineffective, the larger issue is that until 2019, the diagnosis pulmonary hypertension was established when the directly measured average pulmonary pressure exceeds 25 mmHg. This pressure threshold actually reflects more severe pulmonary vascular disease; more than 50%-70% of the pulmonary blood vessels have to be affected before the pressure rises to greater than 25 mmHg. Recent studies in various patient populations, including those with scleroderma, demonstrate that mildly elevated pulmonary pressures (from 21-24 mmHg) have significant impact on symptoms, functional capacity, and survival. Based upon these studies, the most recent guidelines for pulmonary hypertension have lowered the pulmonary pressure threshold for pulmonary hypertension to an average pulmonary pressure greater than 20 mmHg. While it intuitively makes sense to treat patients with more mildly elevated pulmonary pressures, there are no clinical trials of therapies for patients with pulmonary pressures in the range of 21-24 mmHg. Further, since scleroderma patients are at high risk for pulmonary hypertension and more than 30% of those with mildly elevated pulmonary pressures will progress to higher pressures within 3 years, this population is an ideal population in which to study new therapies in those with mildly elevated pulmonary pressures. Sildenafil is a medication that dilates blood vessels. It is approved by the Food and Drug Administration (FDA) for the treatment of certain forms of pulmonary hypertension and been safely used in tens of thousands of patients for the treatment of not only pulmonary hypertension, but more commonly for erectile dysfunction. Whether sildenafil helps in scleroderma patients with mildly elevated pulmonary pressures remains unknown. The proposed trial is directly responsive to the Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area of Respiratory Disease and focuses on an area of encouragement, scleroderma. We will conduct a clinical drug trial to determine whether sildenafil is an effective in improving exercise capacity in scleroderma patients and mildly elevated pulmonary pressures. Patients who are interested in participating in the study will be randomized (decided by a flip of a coin) to receive either sildenafil, the investigational drug, or a placebo pill (a sugar pill). We believe that after 4 months, patients who take sildenafil will have significantly improved exercise capacity, heart function, and quality of life compared to patients who take placebo. We will demonstrate these changes by using validated tools and techniques that have been developed by our team and other investigators and employed succe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010768
Entities
People
- Stephen Mathai
Organizations
- Johns Hopkins University
- United States Army