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Current Approaches to the Treatment of Systemic-Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

  • Scleroderma (J Varga, Section Editor)
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Abstract

Pulmonary arterial hypertension (PAH) is a severe condition causing significant morbidity and mortality in patients with systemic sclerosis (SSc). Despite the use of specific treatments, SSc-PAH survival remains poorer than in idiopathic PAH (IPAH). Recent therapeutic advances in PAH show a lower magnitude of response in SSc-PAH and a higher risk of adverse events, as compared to IPAH. The multifaceted underlying mechanisms and the multisystem nature of SSc probably explain part of the worse outcomes in SSc-PAH compared to IPAH. This review describes the current management of SSc-PAH with an emphasis on the impact of the different organ involvements in the prognosis and treatment response. An earlier detection of PAH and a better characterization of the clinical phenotypes of SSc-PAH are warranted in clinical practice and future trials. Determinants of prognosis, surrogate markers of clinical improvement or worsening, and relevance of the common endpoints used in clinical trials should be evaluated in this specific population. A multidisciplinary approach in expert referral centers is mandatory for SSc-PAH management.

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References

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

  1. Komocsi A, Vorobcsuk A, Faludi R, Pinter T, Lenkey Z, Kolto G, et al. The impact of cardiopulmonary manifestations on the mortality of SSc: a systematic review and meta-analysis of observational studies. Rheumatology. 2012;51:1027–36.

    Article  PubMed  Google Scholar 

  2. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.

    Article  PubMed  Google Scholar 

  3. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42–50.

    Article  PubMed  Google Scholar 

  4. Lefèvre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M, et al. Survival and prognostic factors in systemic sclerosis–associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013;65:2412–23. This meta-analysis confirmed the poor prognosis of SSc-PAH. Baseline hemodynamics including right atrial pressure were associated with survival, but not the period of time during which patients were included in the studies.

    Article  PubMed  Google Scholar 

  5. Clements PJ, Tan M, McLaughlin VV, Oudiz RJ, Tapson VF, Channick RN, et al. The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH. Ann Rheum Dis. 2012;71:249–52. This US multicenter study compared clinical characteristics between IPAH and SSc-PAH and confirmed a worse prognosis in SSc-PAH.

    Article  CAS  PubMed  Google Scholar 

  6. Launay D, Sitbon O, Le Pavec J, Savale L, Tcherakian C, Yaici A, et al. Long-term outcome of systemic sclerosis-associated pulmonary arterial hypertension treated with bosentan as first-line monotherapy followed or not by the addition of prostanoids or sildenafil. Rheumatology. 2010;49:490–500.

    Article  CAS  PubMed  Google Scholar 

  7. McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D73–81. Provides multiple treatment goals with specific values of the relevant parameters. Will need validation on the specific SSc-PAH population.

    Article  PubMed  Google Scholar 

  8. McGoon MD, Benza RL, Escribano-Subias P, Jiang X, Miller DP, Peacock AJ, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol. 2013;62:D51–9.

    Article  PubMed  Google Scholar 

  9. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903–75. 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH.

    Article  PubMed  Google Scholar 

  10. Avouac J, Airò P, Meune C, Beretta L, Dieude P, Caramaschi P, et al. Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and metaanalysis of 5 studies. J Rheum J Rheum. 2010;37:2290–8.

    Article  PubMed  Google Scholar 

  11. Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Annals of the Rheumatic Diseases. BMJ Publishing Group Ltd and European League Against Rheumatism; 2014;73:1340–9. Provides a novel evidence-based algorithm for PAH detection in SSc. Two steps are proposed using non-echocardiographic and echocardiographic variables.

  12. Hachulla E, De Groote P, Gressin V, Sibilia J, Diot E, Carpentier P, et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis & Rheumatism. Wiley Subscription Services, Inc., A Wiley Company; 2009;60:1831–9

  13. Overbeek MJ, Vonk MC, Boonstra A, Voskuyl AE, Vonk-Noordegraaf A, Smit EF, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J Eur Respir Soc. 2009;34:371–9.

    Article  CAS  Google Scholar 

  14. Dorfmuller P, Humbert M, Perros F, Sanchez O, Simonneau G, Müller K-M, 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 

  15. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65:1976–97. The management of PAH is reviewed, especially the cardiac evaluation using echocardiography and RHC (differentiation between PAH and PH-LHD, evaluation of RV function).

    Article  PubMed  Google Scholar 

  16. Kherbeck N, Tamby MC, Bussone G, Dib H, Perros F, Humbert M, et al. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clinical Reviews in Allergy \& Immunology. Humana Press Inc; 2013;44:31–8

  17. Bussone G, Tamby MC, Calzas C, Kherbeck N, Sahbatou Y, Sanson C, et al. IgG from patients with pulmonary arterial hypertension and/or systemic sclerosis binds to vascular smooth muscle cells and induces cell contraction. Ann Rheum Dis. 2012;71:596–605.

    Article  CAS  PubMed  Google Scholar 

  18. Becker MO, Kill A, Kutsche M, Guenther J, Rose A, Tabeling C, et al. Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am J Respir Crit Care Med Am Thorac Soc. 2014;190:808–17. Vascular receptor autoantibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

    Article  CAS  Google Scholar 

  19. Muangchan C. Canadian Scleroderma Research Group, Baron M, Pope J. The 15% rule in scleroderma: the frequency of severe organ complications in systemic sclerosis. A systematic review. The Journal of rheumatology. J Rheum. 2013;40:1545–56.

    Article  PubMed  Google Scholar 

  20. Hachulla E, Launay D, Mouthon L, Sitbon O, Berezne A, Guillevin L, et al. Is pulmonary arterial hypertension really a late complication of systemic sclerosis? Chest. 2009;136:1211–9.

    Article  PubMed  Google Scholar 

  21. Nihtyanova SI, Schreiber BE, Ong VH, Rosenberg D, Moinzadeh P, Coghlan JG, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheum. 2014;66:1625–35.

    Article  Google Scholar 

  22. Le Pavec J, Girgis RE, Lechtzin N, Mathai SC, Launay D, Hummers LK, et al. Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis Rheum. 2011;63:2456–64.

    Article  PubMed  Google Scholar 

  23. Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JSR, Vrapi F, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179:151–7.

    Article  PubMed  Google Scholar 

  24. Le Pavec J, Girgis RE, Lechtzin N, Mathai SC, Launay D, Hummers LK, et al. Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis & Rheumatism. Wiley Subscription Services, Inc., A Wiley Company; 2011;63:2456–64

  25. Günther S, Jais X, Maitre S, Bérezné A, Dorfmüller P, Seferian A, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis & Rheumatism. Wiley Subscription Services, Inc., A Wiley Company; 2012;64:2995–3005. HRCT signs of PVOD are frequently observed in SSc patients with pre-capillary PH and are associated with a high risk of pulmonary edema.

  26. Montani D, O'Callaghan DS, Savale L, Jaïs X, Yaici A, Maitre S, et al. Pulmonary veno-occlusive disease: recent progress and current challenges. Respir Med. 2010;104 Suppl 1:S23–32.

    Article  PubMed  Google Scholar 

  27. Kahan A, Coghlan G, McLaughlin V. Cardiac complications of systemic sclerosis. Rheumatology (Oxford, England). Oxford University Press; 2009;48 Suppl 3:iii45–8.

  28. Hachulla A-L, Launay D, Gaxotte V, de Groote P, Lamblin N, Devos P, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis. 2009;68:1878–84.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Fisher MR, Mathai SC, Champion HC, Girgis RE, Housten-Harris T, Hummers L, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis & Rheumatism. Wiley Subscription Services, Inc., A Wiley Company; 2006;54:3043–50.

  30. Fox BD, Shimony A, Langleben D, Hirsch A, Rudski L, Schlesinger R, et al. High prevalence of occult left heart disease in scleroderma-pulmonary hypertension. Eur Respir J: Off J Eur Soc Clin Respir Physiol. 2013;42:1083–91. PH-LHD is frequent in SSc-PH population. The authors propose an additional testing with fluid challenge during left heart catheterization to diagnose PH-LHD in misclassified PAH patients.

    Article  Google Scholar 

  31. Vachiery J-L, Adir Y, Barbera JA, Champion H, Coghlan JG, Cottin V, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62:D100–8.

    Article  PubMed  Google Scholar 

  32. Schoenfeld SR, Choi HK, Sayre EC, Aviña-Zubieta JA. The risk of pulmonary embolism and deep venous thrombosis in systemic sclerosis: A general population-based study. Arthritis Care \& Research. 2015;:n/a–n/a.

  33. Morrisroe KB, Stevens W, Nandurkar H, Prior D, Thakkar V, Roddy J, et al. The association of antiphospholipid antibodies with cardiopulmonary manifestations of systemic sclerosis. Clin Exp Rheumatol. 2014;32:S–133–7.

    PubMed  Google Scholar 

  34. Meier FMP, Frommer KW, Dinser R, Walker UA, Czirjak L, Denton CP, et al. Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Annals of the Rheumatic Diseases. BMJ Publishing Group Ltd and European League Against Rheumatism; 2012;71:1355–60.

  35. Ruiter G, Lankhorst S, Boonstra A, Postmus PE, Zweegman S, Westerhof N, et al. Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur Respir J Eur Respir Soc. 2011;37:1386–91.

    Article  CAS  Google Scholar 

  36. Ruiter G, Lanser IJ, de Man FS, van der Laarse WJ, Wharton J, Wilkins MR, et al. Iron deficiency in systemic sclerosis patients with and without pulmonary hypertension. Rheumatology (Oxford, England). Oxford University Press; 2014;53:285–92.

  37. Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing Z-C, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60–72.

    Article  PubMed  Google Scholar 

  38. Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. Lippincott Williams & Wilkins; 2014;129:57–65. This analysis of a European PAH registry suggested a survival benefit with oral anticoagulation for IPAH. In SSc-PAH, there was a trend toward a worse survival in patients receiving anticoagulants.

  39. Ngian G-S, Stevens W, Prior D, Gabbay E, Roddy J, Tran A, et al. Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. Arthritis Research \& Therapy. BioMed Central Ltd; 2012;14:R213.

  40. Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Le T, Lee P, et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheum J Rheum. 2012;39:276–85.

    Article  PubMed  Google Scholar 

  41. Preston IR, Roberts KE, Miller DP, Hill NS, Farber HW. Effect Of Warfarin Treatment On Survival of Patients With Pulmonary Arterial Hypertension (PAH) In The Registry To Evaluate Early And Long-Term PAH Disease Management (REVEAL). American Thoracic Society International Conference Abstracts. American Thoracic Society; 2014. pp. A2464–4.

  42. Kuwana M, Watanabe H, Matsuoka N, Sugiyama N. Pulmonary arterial hypertension associated with connective tissue disease: meta-analysis of clinical trials. BMJ Open. 2013;3:e003113–3. This meta-analysis suggested that ERAs bosentan and ambrisentan may be less effective in patients with CTD-PAH than in those with PAH generally. However there were limitations due to the limited number of studies dedicated to CTD-PAH and the small number of CTD-PAH patients included in others.

    Article  Google Scholar 

  43. Montani D, Savale L, Natali D, Jaïs X, Herve P, Garcia G, et al. Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. European heart journal. The Oxford University Press; 2010;31:1898–907.

  44. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study. Lancet. 2001;358:1119–23.

    Article  CAS  PubMed  Google Scholar 

  45. Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.

    Article  CAS  PubMed  Google Scholar 

  46. Galiè N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093–100.

    Article  PubMed  Google Scholar 

  47. Denton CP. 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  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Annals of the Rheumatic Diseases. BMJ Publishing Group Ltd and European League Against Rheumatism; 2011;70:32–8.

  49. Badesch DB. Ambrisentan therapy for pulmonary arterial hypertension: a comparison by PAH etiology. Chest Am Coll Chest Phys. 2007;132:488b–9b.

    Google Scholar 

  50. Badesch DB, Feldman J, Keogh A, Mathier MA, Oudiz RJ, Shapiro S, et al. ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension. Cardiovascular Therapeutics. Blackwell Publishing Ltd; 2012;30:93–9.

  51. Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Int Med Am Coll Phys. 2013;158:641–9.

    Article  Google Scholar 

  52. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani H-A, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–18.

    Article  CAS  PubMed  Google Scholar 

  53. Channick RN, Delcroix M, Ghofrani H-A, Hunsche E, Jansa P, Le Brun F-O, et al. Effect of macitentan on hospitalizations: results from the SERAPHIN trial. JACC Heart Fail. 2015;3:1–8.

    Article  PubMed  Google Scholar 

  54. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–57.

    Article  PubMed  Google Scholar 

  55. Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil Therapy for Pulmonary Arterial Hypertension. Circulation. 2009;119:2894–903.

    Article  PubMed  Google Scholar 

  56. Jing Z-C, Yu Z-X, Shen J-Y, Wu B-X, Xu K-F, Zhu X-Y, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med Am Thorac Soc. 2011;183:1723–9.

    Article  CAS  Google Scholar 

  57. Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galiè N, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheum. 2007;34:2417–22.

    PubMed  Google Scholar 

  58. Ghofrani H-A, Galiè N, Grimminger F, Grünig E, Humbert M, Jing Z-C, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–40.

    Article  CAS  PubMed  Google Scholar 

  59. Galiè N, Müller K, Scalise A-V, Grünig E. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J. 2015;45:1314–22.

    Article  PubMed  Google Scholar 

  60. Simonneau G, Barst RJ, Galiè N, Naeije R, Rich S, Bourge RC, 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.

    Article  PubMed  Google Scholar 

  61. Olschewski H, Simonneau G, Galiè N, Higenbottam T, Naeije R, Rubin LJ, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–9.

    Article  CAS  PubMed  Google Scholar 

  62. Galiè N, Humbert M, Vachiery J-L, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–502.

    Article  PubMed  Google Scholar 

  63. Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2119–25.

    Article  CAS  PubMed  Google Scholar 

  64. Tapson VF. Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study). Chest. 2012;142:1383–8.

    Article  CAS  PubMed  Google Scholar 

  65. Tapson VF. Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients Receiving Background Endothelin Receptor Antagonist and Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C2 Study). Chest. 2013;144:952–7.

    Article  CAS  PubMed  Google Scholar 

  66. Jing Z-C, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. Lippincott Williams & Wilkins; 2013;127:624–33

  67. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, 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.

    Article  CAS  PubMed  Google Scholar 

  68. Oudiz RJ, Schilz RJ, Barst RJ, Galiè N, Rich S, Rubin LJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest Am Coll Chest Physicians. 2004;126:420–7.

    CAS  Google Scholar 

  69. Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlócai K, Galiè N, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J Eur Respir Soc. 2012;40:874–80.

    Article  CAS  Google Scholar 

  70. McLaughlin VV, Channick R, Chin K, Frey A, Gaine S, Ghofrani A, et al. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: results of the Griphon Study. J Am Coll Cardiol Am Coll Cardiol Found. 2015;65:A1538.

    Article  Google Scholar 

  71. Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2004;24:353–9.

    CAS  Google Scholar 

  72. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, 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  CAS  PubMed  Google Scholar 

  73. Simonneau G, Rubin LJ, Galiè N, Barst RJ, Fleming TR, Frost AE, 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.

    Article  PubMed  Google Scholar 

  74. McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, et al. Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension. Journal of the American College of Cardiology. Elsevier Inc; 2010;55:1915–22.

  75. McLaughlin V, Channick RN, Ghofrani H-A, Lemarié J-C, Naeije R, Packer M, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46:405–13.

    Article  PubMed  Google Scholar 

  76. Galiè N, Barberà JA, Frost AE, Ghofrani H-A, Hoeper MM, McLaughlin VV, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–44.

    Article  PubMed  Google Scholar 

  77. Hassoun PM, Zamanian RT, Damico R, Lechtzin N, Khair R, Kolb TM, et al. Ambrisentan and Tadalafil Upfront Combination Therapy in Scleroderma-Associated PAH. Am J Respir Crit Care Med. 2015;:rccm.201507–1398OC–43.

  78. Johnson SR, Brode SK, Mielniczuk LM, Granton JT. Dual therapy in IPAH and SSc-PAH. A qualitative systematic review. Respiratory Medicine. Elsevier Ltd; 2012;106:730–9. A systematic review suggesting a beneficial effect of dual therapy in IPAH and SSc-PAH

  79. Saggar R, Khanna D, Furst DE, Belperio JA, Park GS, Weigt SS, et al. Systemic sclerosis and bilateral lung transplantation: a single centre experience. Eur Respir J Eur Respir Soc. 2010;36:893–900.

    Article  CAS  Google Scholar 

  80. Schachna L, Medsger TA, Dauber JH, Wigley FM, Braunstein NA, White B, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis & Rheumatism. Wiley Subscription Services, Inc., A Wiley Company; 2006;54:3954–61.

  81. Launay D, Savale L, Berezne A, Le Pavec J, Hachulla E, Mouthon L, et al. Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary Working Group. Presse Médicale (Paris, France: 1983). 2014;43:e345–63.

  82. Bournia V-K, Evangelou K, Sfikakis PP. Therapeutic inhibition of tyrosine kinases in systemic sclerosis: a review of published experience on the first 108 patients treated with imatinib. Semin Arthritis Rheum. 2013;42:377–90.

    Article  CAS  PubMed  Google Scholar 

  83. Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galiè N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. Lippincott Williams & Wilkins; 2013;127:1128–38.

  84. Sanchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest Am Coll Chest Physicians. 2006;130:182–9.

    CAS  Google Scholar 

  85. Jaïs X, Launay D, Yaici A, Le Pavec J, Tchérakian C, Sitbon O, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis & Rheumatism. Wiley Subscription Services, Inc., A Wiley Company; 2008;58:521–31.

  86. Sobanski V, Giovannelli J, Lynch BM, Schreiber BE, Nihtyanova SI, Harvey J, et al. Characteristics and survival of patients with anti-U1RNP antibodies in connective tissue disease associated pulmonary arterial hypertension. Arthritis & Rheumatology. 2015;:n/a–n/a.

  87. Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH) - Full Text View - ClinicalTrials.gov.

  88. Sanges S, Launay D, Rhee RL, Sitbon O, Hachulla E, Mouthon L, et al. A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension. Annals of the Rheumatic Diseases. 2015;:annrheumdis–2015–207336. The authors showed within two cohorts that non-hemodynamic factors could have an impact on the 6MWD in SSc-PAH. There was no association between the changes in 6MWD and hemodynamic parameters during follow-up suggesting that 6MWD may not be an appropriate surrogate marker of hemodynamic outcomes in treated SSc-PAH.

  89. Savarese G, Paolillo S, Costanzo P, D'Amore C, Cecere M, Losco T, et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol. 2012;60:1192–201.

    Article  PubMed  Google Scholar 

  90. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest Am Coll Chest Physicians. 2010;138:1383–94.

    Google Scholar 

  91. Denton CP, Avouac J, Behrens F, Furst DE, Foeldvári I, Humbert M, et al. Systemic sclerosis-associated pulmonary hypertension: why disease-specific composite endpoints are needed. Arthritis Research \& Therapy. BioMed Central Ltd; 2011;13:114.

  92. Simonneau G, Galiè N, Jansa P, Meyer GMB, Hiti Al H, Kusic-Pajic A, et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol. 2014;172:332–9.

    Article  PubMed  Google Scholar 

  93. Khanna D, Gladue H, Channick R, Chung L, Distler O, Furst DE, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis & Rheumatism. 2013. pp. 3194–201. Consensus-based, evidence-driven recommendations for screening and early detection of CTD-PAH

  94. Humbert M, Yaici A, De Groote P, Montani D, Sitbon O, Launay D, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63:3522–30.

    Article  PubMed  Google Scholar 

  95. Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirják L, 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;68:620–8.

    Article  CAS  PubMed  Google Scholar 

  96. Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, 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  Google Scholar 

  97. Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292–7.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. U995 Lille Inflammation Research International Center, University Lille, Lille, France

    Vincent Sobanski, David Launay & Eric Hachulla

  2. Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France

    Vincent Sobanski, David Launay & Eric Hachulla

  3. Centre National de Référence Maladies Systémiques et Auto-Immunes Rares (Sclérodermie Systémique), Lille, France

    Vincent Sobanski, David Launay & Eric Hachulla

  4. FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies (IMMINeNT), Lille, France

    Vincent Sobanski, David Launay & Eric Hachulla

  5. Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France

    Marc Humbert

  6. Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France

    Marc Humbert

  7. INSERM UMR S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France

    Marc Humbert

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  1. Vincent Sobanski
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  2. David Launay
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  3. Eric Hachulla
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  4. Marc Humbert
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Correspondence to Marc Humbert.

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Conflicts of interest

Vincent Sobanski declares that he has no conflicts of interest. David Launay reports grants and personal fees from Actelion, GSK, and Pfizer, outside the submitted work; Eric Hachulla reports personal fees from Actelion, GlaxoSmithKline, Pfizer, United Therapeutics, and Bayer-Schering during the conduct of the study, outside the submitted work; Marc Humbert reports grants and personal fees from Actelion, GSK, and Pfizer and personal fees from Novartis during the conduct of the study, outside the submitted work.

Human and animal rights and informed consent

With regard to the authors’ research cited in this paper, all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. In addition, all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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This article is part of the Topical Collection on Scleroderma

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Sobanski, V., Launay, D., Hachulla, E. et al. Current Approaches to the Treatment of Systemic-Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH). Curr Rheumatol Rep 18, 10 (2016). https://doi.org/10.1007/s11926-015-0560-x

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  • DOI: https://doi.org/10.1007/s11926-015-0560-x

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