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Current Rheumatology Reports

, Volume 12, Issue 1, pp 8–18 | Cite as

Diagnosis and Management of Pulmonary Hypertension in Systemic Sclerosis

  • Nadera J. Sweiss
  • Linda Hushaw
  • Thenappan Thenappan
  • Ray Sawaqed
  • Roberto F. Machado
  • Amit R. Patel
  • Mardi Gomberg-Maitland
  • Aliya N. Husain
  • Stephen L. ArcherEmail author
Article

Abstract

Patients with systemic sclerosis (SSc) can develop pulmonary hypertension (PH; mean pulmonary artery pressure ≥ 25 mm Hg) caused by pulmonary arterial hypertension (PAH), left ventricular disease, or pulmonary fibrosis. PAH is a pulmonary vascular disease, the diagnosis of which requires pulmonary capillary wedge pressure less than 15 mm Hg, pulmonary vascular resistance greater than 3 Wood Units, and exclusion of thromboembolism and parenchymal lung disease. Molecular mechanisms underlying PAH-SSc include activation of inflammatory and fibrogenic pathways in the vasculature and right ventricle. Circulating autoantibodies trigger endothelial damage and fibroblast activation. PAH most commonly occurs as a late complication in patients with limited cutaneous disease and anticentromere antibodies. Although echocardiography is a useful screening tool, heart catheterization is required to diagnose PAH before initiating therapy. Prognosis and therapeutic response are worse in PAH-SSc than in other PAH categories (median survival, 1–3 y). Approved therapies include prostacyclins, endothelin antagonists, and phosphodiesterase type 5 inhibitors. Research is needed to define disease mechanisms and develop effective therapies.

Keywords

Circulating autoantibodies Pulmonary arterial hypertension Connective tissue disease Phosphodiesterase 5 inhibitors Endothelin receptor antagonists Flolan (epoprostenol) 

Notes

Acknowledgement

The authors would like to thank Dr Stuart Rich for his thoughtful review and advice.

Disclosure

Dr. Archer reports no potential conflicts of interest relevant to this article.

[AU: ONLY ARTICLES FROM 2007 TO THE PRESENT CAN BE ANNOTATED -- ANNOTATIONS FOR ARTICLES BEFORE 2007 HAVE THEREFORE BEEN REMOVED]

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Walker UA, Tyndall A, Czirjak L, et al.: Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 2007, 66:754–763. This large European registry provides information on the predictive value of classical risk factors versus antibody profile for organ involvement in scleroderma. It concludes that anticentromere antibody patients are particularly at risk for PAH.CrossRefPubMedGoogle Scholar
  2. 2.
    Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, et al.: Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med 2005, 118:2–10.CrossRefPubMedGoogle Scholar
  3. 3.
    Ranque B, Mouthon L: Geoepidemiology of systemic sclerosis. Autoimmun Rev 2009 Nov 10 (Epub ahead of print).Google Scholar
  4. 4.
    Steen VD, Medsger TA: Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007, 66:940–944.CrossRefPubMedGoogle Scholar
  5. 5.
    •• Hassoun PM: Pulmonary arterial hypertension complicating connective tissue diseases. Semin Respir Crit Care Med 2009, 30:429–439. This article is a well-written review by an expert in pulmonary medicine who has extensive experience with the care and management of patients with SSc and various forms of pulmonary hypertension.CrossRefPubMedGoogle Scholar
  6. 6.
    Kawut SM, Taichman DB, Archer-Chicko CL, et al.: Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003, 123:344–350.CrossRefPubMedGoogle Scholar
  7. 7.
    • Simonneau G, Robbins IM, Beghetti M, et al.: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009, 54:S43–S54. This article reviews the new WHO classification for pulmonary hypertension. The importance of distinguishing category 1 (PAH) from the more common forms of PH is evident.CrossRefPubMedGoogle Scholar
  8. 8.
    Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al.: Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003, 48:2246–2255.CrossRefPubMedGoogle Scholar
  9. 9.
    Cox SR, Walker JG, Coleman M, et al.: Isolated pulmonary hypertension in scleroderma. Intern Med J 2005, 35:28–33.CrossRefPubMedGoogle Scholar
  10. 10.
    Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M: A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J 2007, 30:1103–1110.CrossRefPubMedGoogle Scholar
  11. 11.
    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, 173:1023–1030.CrossRefPubMedGoogle Scholar
  12. 12.
    Steen V, Medsger TA Jr: Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003, 48:516–522.CrossRefPubMedGoogle Scholar
  13. 13.
    Catoggio LJ, Bernstein RM, Black CM, et al.: Serological markers in progressive systemic sclerosis: clinical correlations. Ann Rheum Dis 1983, 42:23–27.CrossRefPubMedGoogle Scholar
  14. 14.
    Steen VD: The lung in systemic sclerosis. J Clin Rheumatol 2005, 11:40–46.CrossRefPubMedGoogle Scholar
  15. 15.
    • Wigley FM: Vascular disease in scleroderma. Clin Rev Allergy Immunol 2009, 36:150–175. This article provides a useful review of the causes and consequences of scleroderma-associated vascular disease by a leader in the field.CrossRefPubMedGoogle Scholar
  16. 16.
    Morse J, Barst R, Horn E, et al.: Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations. J Rheumatol 2002, 29:2379–2381.PubMedGoogle Scholar
  17. 17.
    Liakouli V, Manetti M, Pacini A, et al.: The -670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis. Ann Rheum Dis 2009, 68:584–590.CrossRefPubMedGoogle Scholar
  18. 18.
    Pignone A, Scaletti C, Matucci-Cerinic M, et al.: Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment. Clin Exp Rheumatol 1998, 16:527–532.PubMedGoogle Scholar
  19. 19.
    Chizzolini C, Raschi E, Rezzonico R, et al.: Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 2002, 46:1602–1613.CrossRefPubMedGoogle Scholar
  20. 20.
    Sgonc R, Gruschwitz MS, Boeck G, et al.: Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 2000, 43:2550–2562.CrossRefPubMedGoogle Scholar
  21. 21.
    Bonnet S, Rochefort G, Sutendra G, et al.: The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A 2007, 104:11418–11423.CrossRefPubMedGoogle Scholar
  22. 22.
    Choi JJ, Min DJ, Cho ML, et al.: Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol 2003, 30:1529–1533.PubMedGoogle Scholar
  23. 23.
    Tamby MC, Chanseaud Y, Humbert M, et al.: Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005, 60:765–772.CrossRefPubMedGoogle Scholar
  24. 24.
    Badesch DB, Champion HC, Sanchez MA, et al.: Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009, 54:S55–S66.CrossRefPubMedGoogle Scholar
  25. 25.
    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, 52:3792–3800.CrossRefPubMedGoogle Scholar
  26. 26.
    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, 62:1088–1093.CrossRefPubMedGoogle Scholar
  27. 27.
    • McLaughlin VV, Archer SL, Badesch DB, et al.: ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009, 119:2250–2294. (Published erratum appears in Circulation 2009, 120:e13.) This American Heart Association/American College of Cardiology consensus document on the diagnosis and management of PAH is a useful reference article.Google Scholar
  28. 28.
    Meune C, Avouac J, Wahbi K, et al.: Cardiac involvement in systemic sclerosis assessed by tissue-doppler echocardiography during routine care: a controlled study of 100 consecutive patients. Arthritis Rheum 2008, 58:1803–1809.CrossRefPubMedGoogle Scholar
  29. 29.
    Denton CP, Cailes JB, Phillips GD, et al.: Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997, 36:239–243.CrossRefPubMedGoogle Scholar
  30. 30.
    Mukerjee D, St George D, Knight C, et al.: Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatology (Oxford) 2004, 43:461–466.CrossRefGoogle Scholar
  31. 31.
    Hsu VM, Moreyra AE, Wilson AC, et al.: Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatol 2008, 35:458–465.PubMedGoogle Scholar
  32. 32.
    Tzelepis GE, Kelekis NL, Plastiras SC, et al.: Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study. Arthritis Rheum 2007, 56:3827–3836.CrossRefPubMedGoogle Scholar
  33. 33.
    Steen VD, Graham G, Conte C, et al.: Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992, 35:765–770.CrossRefPubMedGoogle Scholar
  34. 34.
    Chandra S, Shah SJ, Thenappan T, et al.: Carbon monoxide diffusing capacity and mortality in pulmonary arterial hypertension. J Heart Lung Transplant 2009 Sep 25 (Epub ahead of print).Google Scholar
  35. 35.
    Okano Y, Steen VD, Medsger TA Jr: Autoantibody to U3 nucleolar ribonucleoprotein (fibrillarin) in patients with systemic sclerosis. Arthritis Rheum 1992, 35:95–100.CrossRefPubMedGoogle Scholar
  36. 36.
    Allanore Y, Wahbi K, Borderie D, et al.: N-terminal brain natriuretic peptide in systemic sclerosis: a new cornerstone of cardiovascular assessment? Ann Rheum Dis 2009 68:1885–1889.CrossRefPubMedGoogle Scholar
  37. 37.
    Ciurzynski M, Bienias P, Lichodziejewska B, et al.: Non-invasive diagnostic and functional evaluation of cardiac involvement in patients with systemic sclerosis. Clin Rheumatol 2008, 27:991–997.CrossRefPubMedGoogle Scholar
  38. 38.
    Paciocco G, Martinez FJ, Bossone E, et al.: Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J 2001, 17:647–652.CrossRefPubMedGoogle Scholar
  39. 39.
    Shah SJ, Thenappan T, Rich S, et al.: Value of exercise treadmill testing in the risk stratification of patients with pulmonary hypertension. Circ Heart Fail 2009, 2:278–286.CrossRefPubMedGoogle Scholar
  40. 40.
    Halpern SD, Taichman DB: Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest 2009, 136:37–43.CrossRefPubMedGoogle Scholar
  41. 41.
    Fisher MR, Mathai SC, Champion HC, et al.: Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 2006, 54:3043–3050.CrossRefPubMedGoogle Scholar
  42. 42.
    McLaughlin VV, Presberg KW, Doyle RL, et al.: Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004, 126:78 S–92 S.CrossRefPubMedGoogle Scholar
  43. 43.
    Barst RJ, Rubin LJ, Long WA, et al.: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996, 334:296–302.CrossRefPubMedGoogle Scholar
  44. 44.
    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, 132:425–434.PubMedGoogle Scholar
  45. 45.
    •• 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, 36:2244–2249.Google Scholar
  46. 46.
    Oudiz RJ, Schilz RJ, Barst RJ, et al.: Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 2004, 126:420–427.CrossRefPubMedGoogle Scholar
  47. 47.
    Rubin LJ, Badesch DB, Barst RJ, et al.: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002, 346:896–903. (Published erratum appears in N Engl J Med 2002, 346:1258.)Google Scholar
  48. 48.
    Denton CP, Pope JE, Peter HH, et al.: Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis 2008, 67:1222–1228.CrossRefPubMedGoogle Scholar
  49. 49.
    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, 24:1626–1631.CrossRefPubMedGoogle Scholar
  50. 50.
    Archer SL, Michelakis ED: Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med 2009, 361:1864–1871.CrossRefPubMedGoogle Scholar
  51. 51.
    Badesch DB, Hill NS, Burgess G, et al.: Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007, 34:2417–2422.PubMedGoogle Scholar
  52. 52.
    Galie N, Brundage BH, Ghofrani HA, et al.: Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009, 119:2894–2903.CrossRefPubMedGoogle Scholar
  53. 53.
    Avouac J, Wipff J, Kahan A, Allanore Y: Effects of oral treatments on exercise capacity in systemic sclerosis related pulmonary arterial hypertension: a meta-analysis of randomised controlled trials. Ann Rheum Dis 2008, 67:808–814.CrossRefPubMedGoogle Scholar
  54. 54.
    Schachna L, Medsger TA Jr, Dauber JH, et al.: Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum 2006, 54:3954–3961.CrossRefPubMedGoogle Scholar
  55. 55.
    Kowal-Bielecka O, Landewe R, Avouac J, et al.: EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009, 68:620–628.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Nadera J. Sweiss
    • 1
  • Linda Hushaw
    • 1
  • Thenappan Thenappan
    • 2
  • Ray Sawaqed
    • 3
  • Roberto F. Machado
    • 4
  • Amit R. Patel
    • 2
  • Mardi Gomberg-Maitland
    • 2
  • Aliya N. Husain
    • 5
  • Stephen L. Archer
    • 2
    Email author
  1. 1.Section of RheumatologyUniversity of ChicagoChicagoUSA
  2. 2.Section of CardiologyUniversity of ChicagoChicagoUSA
  3. 3.Cardiothoracic SurgeryMethodist HospitalMerrillvilleUSA
  4. 4.Section of Pulmonary and Critical Care MedicineUniversity of ChicagoChicagoUSA
  5. 5.Section of PathologyUniversity of ChicagoChicagoUSA

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