Pulmonary Arterial Hypertension – A Rare Disease with a High Mortality Rate
Over 250,000 people have been diagnosed with PAH in the US1 and this disease is almost twice as common in women than men.2 PAH is a rapidly progressive disease with an approximate 50% five-year mortality rate.3 The disease is characterized by vascular remodeling in the pulmonary arterial bed. This pathology leads to decreased vessel elasticity, increased arterial blood and resistance in the lungs, and an increased workload for the heart. Individuals with PAH typically succumb to right ventricular heart failure.
PAH is currently treated with vasodilators, which offer some benefit but fail to address the underlying vessel remodeling believed to be responsible for the disease’s high morbidity and mortality rates. Reducing peripheral serotonin production is a novel approach for the treatment of PAH and has the potential to halt or reverse pulmonary remodeling. Rodatristat is being developed as an adjunctive treatment for PAH as its mechanism of action is thought to be complementary to the current standard of care.
Pulmonary Vasculature Remodels as PAH Progresses10
Bronchiolitis Obliterans Syndrome (BOS)
Immunosuppression therapy after lung transplantation is often inadequate at preventing bronchiolitis obliterans syndrome (BOS), a life-threatening form of chronic lung allograft dysfunction (CLAD). Registry data from the International Society of Heart and Lung Transplantation (ISHLT) reports a median BOS-free survival of only ~3.2 and ~3.8 years for recipients of unilateral and bilateral lung transplants, respectively; with overall 5-year survival rates at 55.8% and 66.2%12.
BOS is driven by inadequate suppression of cytotoxic mediators, following for example an infection, that leads to prolonged upregulation of various inflammatory cytokines and chemokines that promote inflammatory cell infiltration into the transplanted lung 13, 14, 15. This inflammatory process leads to recruitment of fibroblasts and myofibroblasts with resulting deposition of airway subepithelial extracellular matrix and fibrosis of non-cartilaginous smaller airways (membranous and respiratory bronchioles). This fibrosis leads to the characteristic luminal obstruction or total occlusion of BOS.
Other predisposing conditions for BOS include: allogeneic hematopoietic stem cell transplantation (HSCT) which develops in 4-6% of patients likely as a form of chronic graft versus host disease (cGVHD)16, pulmonary complications of rheumatologic diseases (e.g. rheumatoid arthritis and scleroderma), noxious irritant gas inhalation (e.g. chlorine and ammonia) and food flavoring chemical dust inhalation (diacetyl).
BOS is considered an irreversible condition with poor responses reported for the limited treatment options available. Current therapies may reduce the decline in pulmonary function, but are not expected to halt or reverse the progression of BOS.