SpringerLink
Log in

Treatment of Pulmonary Hypertension

  • Chapter
  • First Online:
Scleroderma

  • 1666 Accesses

Abstract

Pulmonary hypertension (PH) is a significant contributor to the morbidity and mortality associated with systemic sclerosis (SSc). The spectrum of PH in SSc patients includes patients with isolated pulmonary arterial hypertension (SSc-PAH; World Health Organization Group 1) and patients with PH due to pulmonary fibrosis (SSc-ILD-PH; World Health Organization Group 3). In the last 20 years, the combined pulmonary manifestations of SSc have overtaken renal involvement as the primary cause of mortality (Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52:3792–800; Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62:1088–93). accounting for up 60% of the SSc-related deaths (Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62:1088–93). Pulmonary arterial hypertension, independent of other pulmonary manifestations, is the second leading cause of mortality in SSc patients (Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62:1088–93).. All forms of SSc-related PH share a grim prognosis, and the efficacy of currently available PAH-specific therapies in SSc patients has been disappointing when compared to patients with other forms of PAH.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  1. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 2003;29:239–54.

    Article  PubMed  Google Scholar 

  2. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007;66:940–4.

    Article  PubMed  Google Scholar 

  3. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–8.

    Article  PubMed  CAS  Google Scholar 

  4. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477–82.

    Article  PubMed  CAS  Google Scholar 

  5. Williams MH, Das C, Handler CE, et al. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart. 2006;92:926–32.

    Article  PubMed  CAS  Google Scholar 

  6. Chung L, Liu J, Parsons L, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138:1383–94.

    Article  PubMed  Google Scholar 

  7. Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006;54:3043–50.

    Article  PubMed  Google Scholar 

  8. Mukerjee D, George St D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62:1088–93.

    Article  PubMed  CAS  Google Scholar 

  9. Campo A, Mathai SC, Le Pavec J, et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182:252–60.

    Article  PubMed  Google Scholar 

  10. Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest. 2003;123:344–50.

    Article  PubMed  Google Scholar 

  11. Mathai SC, Hummers LK, Champion HC, et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum. 2009;60:569–77.

    Article  PubMed  Google Scholar 

  12. Overbeek MJ, Vonk MC, Boonstra A, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J. 2009;34:371–9.

    Article  PubMed  CAS  Google Scholar 

  13. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121:2045–66.

    Article  PubMed  Google Scholar 

  14. Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J. 2009;33:189–200.

    Article  PubMed  CAS  Google Scholar 

  15. Dorfmuller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38:893–902.

    Article  PubMed  Google Scholar 

  16. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–9.

    PubMed  Google Scholar 

  17. Sandoval J, Bauerle O, Palomar A, et al. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation. 1994;89:1733–44.

    PubMed  CAS  Google Scholar 

  18. van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–7.

    Article  PubMed  Google Scholar 

  19. Hsiao SH, Lee CY, Chang SM, et al. Right heart function in scleroderma: insights from myocardial Doppler tissue imaging. J Am Soc Echocardiogr. 2006;19:507–14.

    Article  PubMed  Google Scholar 

  20. Lee CY, Chang SM, Hsiao SH, et al. Right heart function and scleroderma: insights from tricuspid annular plane systolic excursion. Echocardiography. 2007;24:118–25.

    Article  PubMed  Google Scholar 

  21. Overbeek MJ, Lankhaar JW, Westerhof N, et al. Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. Eur Respir J. 2008;31:1160–6.

    Article  PubMed  CAS  Google Scholar 

  22. Forfia PR, Mathai SC, Fisher MR, et al. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;177:1364–9.

    Article  PubMed  CAS  Google Scholar 

  23. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34:1219–63.

    Article  PubMed  CAS  Google Scholar 

  24. Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114:787–92.

    Article  PubMed  CAS  Google Scholar 

  25. Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation. 1989;80:1198–206.

    Article  PubMed  CAS  Google Scholar 

  26. Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580–7.

    Article  PubMed  CAS  Google Scholar 

  27. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76–81.

    Article  PubMed  CAS  Google Scholar 

  28. Duchini A, Sessoms SL. Gastrointestinal hemorrhage in patients with systemic sclerosis and CREST syndrome. Am J Gastroenterol. 1998;93:1453–6.

    Article  PubMed  CAS  Google Scholar 

  29. Lafyatis R, York M. Innate immunity and inflammation in systemic sclerosis. Curr Opin Rheumatol. 2009;21:617–22.

    Article  PubMed  CAS  Google Scholar 

  30. Dorfmuller P, Perros F, Balabanian K, et al. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22:358–63.

    Article  PubMed  CAS  Google Scholar 

  31. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54:S10–9.

    Article  PubMed  CAS  Google Scholar 

  32. Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144:275–85.

    PubMed  CAS  Google Scholar 

  33. Cool CD, Kennedy D, Voelkel NF, et al. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol. 1997;28:434–42.

    Article  PubMed  CAS  Google Scholar 

  34. Sanchez O, Sitbon O, Jais X, et al. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest. 2006;130:182–9.

    Article  PubMed  CAS  Google Scholar 

  35. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105–11.

    Article  PubMed  CAS  Google Scholar 

  36. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–30.

    Article  PubMed  Google Scholar 

  37. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med. 1990;323:27–36.

    Article  PubMed  CAS  Google Scholar 

  38. Barst RJ, Rubin LJ, Long WA, The Primary Pulmonary Hypertension Study Group, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–302.

    Article  PubMed  CAS  Google Scholar 

  39. McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998;338:273–7.

    Article  PubMed  CAS  Google Scholar 

  40. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112:485–91.

    PubMed  CAS  Google Scholar 

  41. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132:425–34.

    PubMed  CAS  Google Scholar 

  42. Badesch DB, McGoon MD, Barst RJ, et al. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J Rheumatol. 2009;36:2244–9.

    Article  PubMed  CAS  Google Scholar 

  43. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800–4.

    PubMed  Google Scholar 

  44. Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006;129:683–8.

    Article  PubMed  CAS  Google Scholar 

  45. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119–23.

    Article  PubMed  CAS  Google Scholar 

  46. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.

    Article  PubMed  CAS  Google Scholar 

  47. Girgis RE, Mathai SC, Krishnan JA, et al. Long-term outcome of bosentan treatment in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with the scleroderma spectrum of diseases. J Heart Lung Transplant. 2005;24:1626–31.

    Article  PubMed  Google Scholar 

  48. Denton CP, Humbert M, Rubin L, et al. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis. 2006;65:1336–40.

    Article  PubMed  CAS  Google Scholar 

  49. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441–7.

    Article  PubMed  Google Scholar 

  50. Girgis RE, Frost AE, Hill NS, et al. Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis. 2007;66:1467–72.

    Article  PubMed  CAS  Google Scholar 

  51. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010–9.

    Article  PubMed  CAS  Google Scholar 

  52. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–57.

    Article  PubMed  CAS  Google Scholar 

  53. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. 2007;34:2417–22.

    PubMed  Google Scholar 

  54. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894–903.

    Article  PubMed  CAS  Google Scholar 

  55. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006;28:691–4.

    Article  PubMed  CAS  Google Scholar 

  56. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–63.

    Article  PubMed  CAS  Google Scholar 

  57. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521–30.

    PubMed  Google Scholar 

  58. Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24:1007–10.

    Article  PubMed  CAS  Google Scholar 

  59. Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J. 2007;29:469–75.

    Article  PubMed  CAS  Google Scholar 

  60. Adnot S. Lessons learned from cancer may help in the treatment of pulmonary hypertension. J Clin Invest. 2005;115:1461–3.

    Article  PubMed  CAS  Google Scholar 

  61. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation. 2004;109:159–65.

    Article  PubMed  Google Scholar 

  62. Eddahibi S, Humbert M, Sediame S, et al. Imbalance between platelet vascular endothelial growth factor and platelet-derived growth factor in pulmonary hypertension. Effect of prostacyclin therapy. Am J Respir Crit Care Med. 2000;162:1493–9.

    PubMed  CAS  Google Scholar 

  63. Grigoryev DN, Mathai SC, Fisher MR, et al. Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. Transl Res. 2008;151:197–207.

    Article  PubMed  CAS  Google Scholar 

  64. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811–21.

    Article  PubMed  CAS  Google Scholar 

  65. Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics. 2008;33:278–91.

    Article  PubMed  CAS  Google Scholar 

  66. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005;353:1412–3.

    Article  PubMed  CAS  Google Scholar 

  67. Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006;145:152–3.

    PubMed  Google Scholar 

  68. Souza R, Sitbon O, Parent F, et al. Long term imatinib treatment in pulmonary arterial hypertension. Thorax. 2006;61:736.

    Article  PubMed  CAS  Google Scholar 

  69. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182:1171–7.

    Article  PubMed  CAS  Google Scholar 

  70. ten Freyhaus H, Dumitrescu D, Bovenschulte H, et al. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension. Clin Res Cardiol. 2009;98:265–7.

    Article  PubMed  Google Scholar 

  71. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol. 2009;54:S67–77.

    Article  PubMed  Google Scholar 

  72. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update–a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25:745–55.

    Article  PubMed  Google Scholar 

  73. Schachna L, Medsger Jr TA, Dauber JH, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006;54:3954–61.

    Article  PubMed  Google Scholar 

  74. Saggar R, Khanna D, Furst DE, et al. Systemic sclerosis and bilateral lung transplantation: a single centre experience. Eur Respir J. 2010;36:893–900.

    Article  PubMed  CAS  Google Scholar 

  75. Binks M, Passweg JR, Furst D, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001;60:577–84.

    Article  PubMed  CAS  Google Scholar 

  76. Vonk MC, Marjanovic Z, van den Hoogen FH, et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. 2008;67:98–104.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA

    Todd M. Kolb MD, PhD

  2. Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA

    Paul M. Hassoun MD

Authors
  1. Todd M. Kolb MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul M. Hassoun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Todd M. Kolb MD, PhD .

Editor information

Editors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, E. Huron Street 240, Chicago, 60611-2909, Illinois, USA

    John Varga

  2. Royal Free and University College, Medical School, University College London, Rowland Street, London, NW3 2PF, United Kingdom

    Christopher P. Denton

  3. School of Medicine, Div. Rheumatology, Johns Hopkins University, Eastern Avenue 5200, Baltimore, 21224, Maryland, USA

    Fredrick M. Wigley

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Kolb, T.M., Hassoun, P.M. (2012). Treatment of Pulmonary Hypertension. In: Varga, J., Denton, C., Wigley, F. (eds) Scleroderma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-5774-0_37

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-5774-0_37

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4419-5773-3

  • Online ISBN: 978-1-4419-5774-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation