Overview

  • PAH, which impairs the heart’s ability to pump blood throughout the body, is a chronic, progressive, and often fatal lung disease1
  • Approximately 30% of patients with PAH have an underlying CTD, such as scleroderma or lupus erythematosus2
  • In the US, the 5-year survival for CTD-PAH is approximately 44%, while the survival of PAH from other causes is substantially greater 3
  • Patients with CTD-PAH represent a subset of the PAH population with a significant unmet medical need
  • The FDA has granted orphan drug status to bardoxolone methyl, Reata’s novel candidate for the treatment of PAH
  • Reata is currently conducting a study of bardoxolone methyl for the treatment of CTD-PAH

PAH is a chronic, progressive, and incurable condition in which high blood pressure causes the small vessels of the lung to narrow and stiffen. This decreases blood flow and makes the right side of the heart work harder. As the disease progresses, the stress on the blood vessels causes the heart to enlarge and become even less able to pump blood throughout the body.1

Diagnosis and Prognosis

The most common symptoms of PAH are fatigue, shortness of breath, and feeling faint.4 The diagnosis of PAH in patients with CTD is often delayed because these symptoms are mistaken for the worsening of their underlying disease, such as lupus erythematosus.5,6

While there are several types and causes of PAH, CTD-PAH is often fatal. Overall, CTD-PAH occurs in approximately 30% of people with PAH.2 Between 10% and 15% of patients with scleroderma or lupus erythematosus, for example, have CTD-PAH.6-9 Patients with CTD-PAH do more poorly than those with PAH from other causes. In the US, the 5-year survival for CTD-PAH is approximately 44%, while the survival of PAH from other causes is substantially greater.3 As a result, patients with CTD-PAH represent a subset of the PAH population with a significant unmet medical need.

Pathophysiology

Mitochondrial dysfunction and inflammation due to increased activation of NF-κB, a transcription factor, contribute to the pathophysiology of CTD-PAH.10

chronic-inflammation-in-PAH

NF-κB, a transcription factor, controls several genes involved in many critical functions, including the body’s immune response and inflammation, as well as stress responses.16 NF-κB has been shown to be markedly increased in the pulmonary arteries of patients with PAH10 and induces dysregulation of nitric oxide (NO)-based signaling and activates endothelin-1 (ET-1). These vasoconstrictive factors, together with inflammation-mediated growth factors, promote vascular proliferation, and ultimately, chronic cardiac remodeling in PAH.7

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PAH is now recognized as a systemic disease affecting tissues beyond the cardiopulmonary system. Inflammation and oxidative stress contribute to metabolic dysfunction in the skeletal muscles of patients with PAH. These processes promote bioenergetic deficits and mitochondrial dysfunction, including reduced glucose uptake, decreased lipid oxidation, and reduced cellular energy production, which translate clinically to dyspnea, fatigue, and impaired functional activity in patients with PAH despite optimal vasodilator therapy. Mitochondrial dysfunction is also associated with a phenotype in pulmonary arterial smooth muscle cells that can promote structural remodeling and disease progression in PAH.17

References
  1. Pulmonary Hypertension Association. Types of pulmonary hypertension. http://phassociation.org/patients/aboutph/types-of-ph/. Accessed November 9, 2018.
  2. McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary arterial hypertension: Epidemiology and registries. J Am Coll Cardiol. 2013;62(25 suppl):D51-D59.
  3. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL registry. Chest. 2012;142(2):448-456.
  4. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537.
  5. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65(18):1976-1997.
  6. Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective-tissue disease associated pulmonary arterial hypertension. Arthritis Rheum. 2013;65(12):3194-3201.
  7. Galiè N, Manes A, Farahani KV, et al. Pulmonary arterial hypertension associated to connective tissue diseases. Lupus. 2005;14(9):713-717.
  8. Hsu VM, Chung L, Hummers LK, et al. Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study. Semin Arthritis Rheum. 2014;44(1):55-62.
  9. Pérez-Peñate GM, Rúa-Figueroa I, Juliá-Serdá G, et al. Pulmonary arterial hypertension in systemic lupus erythematosus: Prevalence and predictors. J Rheumatol. 2016;43(2):323-329.
  10. Price LC, Caramori G, Perros F, et al. Nuclear factor k-B is activated in the pulmonary vessels of patients with end-stage idiopathic pulmonary arterial hypertension. PLoS One. 2013;8(10):e75415.
  11. Bello-Klein A, Mancardi D, Araujo AS, Schenkel PC, Turck P, de Lima Seolin BG. Role of redox homeostasis and inflammation in the pathogenesis of pulmonary arterial hypertension. Curr Med Chem. 2018;25(11):1340-1351.
  12. Scott TE, Kemp-Harper BK, Hobbs AJ. Inflammasomes: A novel therapeutic target in pulmonary hypertension [published online May 30, 2018] Br J Pharmacol. doi:10.1111/bph.14375.
  13. Cho JG, Lee A, Chang W, Lee MS, Kim J. Endothelial to mesenchymal transition represents a key link in the interaction between inflammation and endothelial dysfunction. Front Immunol. 2018;9:294.
  14. Plecitá-Hlavatá A, D’Alessandro A, El Kasmi K, et al. Metabolic reprogramming and redox signaling in pulmonary hypertension. Adv Exp Med Biol. 2017;967:241-260.
  15. Liu N, Parry S, Xiao Y, Zhou S, Liu Q. Molecular targets of the Warburg effect and inflammatory cytokines in the pathogenesis of pulmonary artery hypertension. Clin Chim Acta. 2017;466:98-104.
  16. Park MH, Hong JT. Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells. 2016;5(2):pii:E15.
  17. Freund-Michel V, Khoyrattee N, Savineau JP, Muller B, Guibert C. Mitochondria: Roles in pulmonary hypertension. Int J Biochem Cell Biol. 2014;55:93-97.
View References