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Pulmonary Hypertension Associated with Connective Tissue Disease

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Pulmonary Manifestations of Rheumatic Disease

Abstract

Pulmonary hypertension (PH) commonly complicates connective tissue disease and is associated with increased morbidity and mortality in this population. The incidence of PH varies widely between connective tissue diseases; patients with systemic sclerosis are most likely to develop PH. Several different types of PH can present in CTD, including PH related to left heart disease, respiratory disease such as interstitial lung disease or chronic obstructive lung disease, chronic thromboembolic disease, and renal disease. Importantly, CTD patients are at risk for developing pulmonary arterial hypertension (PAH), in which PH is present without any of the aforementioned co-morbidities. However, despite this increased risk of development of PH, patients with PAH may benefit from specific pulmonary vasodilator therapy and thus, are an important group to identify. Unfortunately, response to pulmonary vasodilator therapy in general is less robust and survival is worse in CTD-associated PAH than in other patient populations with PAH. Still, early diagnosis and treatment of PH, if indicated, may allow for institution of pulmonary vasodilator therapy and for appropriate referral for lung transplantation.

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References

  1. Chin KM, Kim NH, Rubin LJ. The right ventricle in pulmonary hypertension. Coron Artery Dis. 2005;16(1):13–8.

    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(25 Suppl):D34–41.

    Google Scholar 

  3. Mathai SC, Hassoun PM. Pulmonary arterial hypertension in connective tissue diseases. Heart Fail Clin. 2012;8(3):413–25.

    PubMed Central  PubMed  Google Scholar 

  4. Barnett CF, De MT. Pulmonary hypertension associated with left-sided heart disease. Heart Fail Clin. 2012;8(3):447–59.

    PubMed  Google Scholar 

  5. Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: part 1: epidemiology, pathophysiology, and definitions. Circ Heart Fail. 2013;6(2):344–54.

    PubMed  Google Scholar 

  6. Hatano S, Strasser T. Primary pulmonary hypertension. Report on a WHO meeting. Geneva: World Health Organization; 1975.

    Google Scholar 

  7. Ghofrani HA, Distler O, Gerhardt F, Gorenflo M, Grunig E, Haefeli WE, et al. Treatment of pulmonary arterial hypertension (PAH): updated recommendations of the Cologne Consensus Conference 2011. Int J Cardiol. 2011;154 Suppl 1:S20–33.

    PubMed  Google Scholar 

  8. Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg. 2003;76(5):1457–62.

    PubMed  Google Scholar 

  9. Mayer E, Jenkins D, Lindner J, D'Armini A, Kloek J, Meyns B, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg. 2011; 141(3):702–10.

    PubMed  Google Scholar 

  10. Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension. Circulation. 2008;118(21):2190–9.

    PubMed  Google Scholar 

  11. Launay D, Mouthon L, Hachulla E, Pagnoux C, de Groote P, Remy-Jardin M, et al. Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J Rheumatol. 2007;34(5):1005–11.

    PubMed  Google Scholar 

  12. Mathai SC, Hummers LK, Champion HC, Wigley FM, Zaiman A, Hassoun PM, et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum. 2009;60(2):569–77.

    PubMed  Google Scholar 

  13. de Groote P, Gressin V, Hachulla E, Carpentier P, Guillevin L, Kahan A, et al. Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis. 2008;67(1):31–6.

    PubMed  Google Scholar 

  14. Launay D, Hachulla E, Hatron PY, Jais X, Simonneau G, Humbert M. Pulmonary arterial hypertension: a rare complication of primary Sjogren syndrome: report of 9 new cases and review of the literature. Medicine (Baltimore). 2007;86(5):299–315.

    Google Scholar 

  15. Gunnarsson R, Andreassen AK, Molberg O, Lexberg AS, Time K, Dhainaut AS, et al. Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature. Rheumatology (Oxford). 2013;52(7):1208–13.

    CAS  Google Scholar 

  16. Chow SL, Chandran V, Fazelzad R, Johnson SR. Prognostic factors for survival in systemic lupus erythematosus associated pulmonary hypertension. Lupus. 2012;21(4):353–64.

    CAS  PubMed  Google Scholar 

  17. 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. 2010;138(6):1383–94.

    PubMed Central  PubMed  Google Scholar 

  18. Minai OA. Pulmonary hypertension in polymyositis-dermatomyositis: clinical and hemodynamic characteristics and response to vasoactive therapy. Lupus. 2009;18(11):1006–10.

    CAS  PubMed  Google Scholar 

  19. Chung SM, Lee CK, Lee EY, Yoo B, Lee SD, Moon HB. Clinical aspects of pulmonary hypertension in patients with systemic lupus erythematosus and in patients with idiopathic pulmonary arterial hypertension. Clin Rheumatol. 2006;25(6):866–72.

    PubMed  Google Scholar 

  20. Hatron PY, Tillie-Leblond I, Launay D, Hachulla E, Fauchais AL, Wallaert B. Pulmonary manifestations of Sjogren’s syndrome. Presse Med. 2011;40(1 Pt 2):e49–64.

    PubMed  Google Scholar 

  21. Szodoray P, Hajas A, Kardos L, Dezso B, Soos G, Zold E, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus. 2012;21(13):1412–22.

    CAS  PubMed  Google Scholar 

  22. Lin DF, Yan SM, Zhao Y, Zhang W, Li MT, Zeng XF, et al. Clinical and prognostic characteristics of 573 cases of primary Sjogren’s syndrome. Chin Med J (Engl). 2010;123(22):3252–7.

    Google Scholar 

  23. Le PJ, Launay D, Mathai SC, Hassoun PM, Humbert M. Scleroderma lung disease. Clin Rev Allergy Immunol. 2011;40(2):104–16.

    Google Scholar 

  24. Voelkel NF, Mizuno S, Bogaard HJ. The role of hypoxia in pulmonary vascular diseases: a perspective. Am J Physiol Lung Cell Mol Physiol. 2013;304(7):L457–65.

    CAS  PubMed  Google Scholar 

  25. Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ, Nicolls MR. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J. 2012;40(6):1555–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol. 2007;2:369–99.

    CAS  PubMed  Google Scholar 

  27. Farkas L, Gauldie J, Voelkel NF, Kolb M. Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol. 2011;45(1):1–15.

    CAS  PubMed  Google Scholar 

  28. Stewart S, Rassl D. Advances in the understanding and classification of pulmonary hypertension. Histopathology. 2009;54(1):104–16.

    PubMed  Google Scholar 

  29. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips III JA, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med. 2001;345(5):319–24.

    CAS  PubMed  Google Scholar 

  30. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001;345(5):325–34.

    CAS  PubMed  Google Scholar 

  31. Nasim MT, Ogo T, Ahmed M, Randall R, Chowdhury HM, Snape KM, et al. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat. 2011;32(12):1385–9.

    CAS  PubMed  Google Scholar 

  32. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001;68(1):92–102.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Morse J, Barst R, Horn E, Cuervo N, Deng Z, Knowles J. Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations. J Rheumatol. 2002;29(11):2379–81.

    PubMed  Google Scholar 

  34. Tew MB, Arnett FC, Reveille JD, Tan FK. Mutations of bone morphogenetic protein receptor type II are not found in patients with pulmonary hypertension and underlying connective tissue diseases. Arthritis Rheum. 2002;46(10):2829–30.

    PubMed  Google Scholar 

  35. Wipff J, Kahan A, Hachulla E, Sibilia J, Cabane J, Meyer O, et al. Association between an endoglin gene polymorphism and systemic sclerosis-related pulmonary arterial hypertension. Rheumatology (Oxford). 2007;46(4):622–5.

    CAS  Google Scholar 

  36. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.

    CAS  PubMed  Google Scholar 

  37. Price LC, Wort SJ, Perros F, Dorfmuller P, Huertas A, Montani D, et al. Inflammation in pulmonary arterial hypertension. Chest. 2012;141(1):210–21.

    CAS  PubMed  Google Scholar 

  38. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144(2):275–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Perros F, Dorfmuller P, Montani D, Hammad H, Waelput W, Girerd B, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185(3):311–21.

    PubMed  Google Scholar 

  40. Dorfmuller P, Humbert M, Perros F, Sanchez O, Simonneau G, Muller KM, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38(6):893–902.

    PubMed  Google Scholar 

  41. Steen VD. The many faces of scleroderma. Rheum Dis Clin North Am. 2008;34(1):1–15.

    PubMed  Google Scholar 

  42. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360(19):1989–2003.

    CAS  PubMed  Google Scholar 

  43. Tamby MC, Humbert M, Guilpain P, Servettaz A, Dupin N, Christner JJ, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J. 2006;28(4):799–807.

    CAS  PubMed  Google Scholar 

  44. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 2005;26(6):1110–8.

    CAS  PubMed  Google Scholar 

  45. Riemekasten G, Philippe A, Nather M, Slowinski T, Muller DN, Heidecke H, et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis. 2011;70(3):530–6.

    CAS  PubMed  Google Scholar 

  46. Negrini D, Passi A, De LG, Miserocchi G. Pulmonary interstitial pressure and proteoglycans during development of pulmonary edema. Am J Physiol. 1996;270(6 Pt 2):H2000–7.

    CAS  PubMed  Google Scholar 

  47. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996;98(3):785–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Ebina M, Shimizukawa M, Shibata N, Kimura Y, Suzuki T, Endo M, et al. Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2004;169(11):1203–8.

    PubMed  Google Scholar 

  49. Burdick MD, Murray LA, Keane MP, Xue YY, Zisman DA, Belperio JA, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med. 2005;171(3):261–8.

    PubMed  Google Scholar 

  50. Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal BD. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol. 2000;279(1):L143–51.

    CAS  PubMed  Google Scholar 

  51. Lewandowska K, Ciurzynski M, Gorska E, Bienias P, Irzyk K, Siwicka M, et al. Antiendothelial cells antibodies in patients with systemic sclerosis in relation to pulmonary hypertension and lung fibrosis. Adv Exp Med Biol. 2013;756:147–53.

    CAS  PubMed  Google Scholar 

  52. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.

    CAS  PubMed  Google Scholar 

  53. Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24(2):165–70.

    PubMed  Google Scholar 

  54. Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. 2010;9(5):A311–8.

    PubMed  Google Scholar 

  55. Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res. 1991;283(6):366–71.

    CAS  PubMed  Google Scholar 

  56. Silman A, Jannini S, Symmons D, Bacon P. An epidemiological study of scleroderma in the West Midlands. Br J Rheumatol. 1988;27(4):286–90.

    CAS  PubMed  Google Scholar 

  57. Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology (Oxford). 2004;43(5):596–602.

    CAS  Google Scholar 

  58. Mayes MD, Lacey Jr JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48(8):2246–55.

    PubMed  Google Scholar 

  59. Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52(12):3792–800.

    PubMed  Google Scholar 

  60. Mukerjee D, St GD, Coleiro B, Knight C, Denton CP, Davar J, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62(11):1088–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Battle RW, Davitt MA, Cooper SM, Buckley LM, Leib ES, Beglin PA, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest. 1996;110(6):1515–9.

    CAS  PubMed  Google Scholar 

  62. Stupi AM, Steen VD, Owens GR, Barnes EL, Rodnan GP, Medsger Jr TA. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum. 1986;29(4):515–24.

    CAS  PubMed  Google Scholar 

  63. MacGregor AJ, Canavan R, Knight C, Denton CP, Davar J, Coghlan J, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford). 2001;40(4):453–9.

    CAS  Google Scholar 

  64. Sacks DG, Okano Y, Steen VD, Curtiss E, Shapiro LS, Medsger Jr TA. Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody. J Rheumatol. 1996;23(4):639–42.

    CAS  PubMed  Google Scholar 

  65. Murata I, Takenaka K, Yoshinoya S, Kikuchi K, Kiuchi T, Tanigawa T, et al. Clinical evaluation of pulmonary hypertension in systemic sclerosis and related disorders. A Doppler echocardiographic study of 135 Japanese patients. Chest. 1997;111(1):36–43.

    CAS  PubMed  Google Scholar 

  66. Fisher MR, Forfia PR, Chamera E, Housten-Harris T, Champion HC, Girgis RE, et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(7):615–21.

    PubMed Central  PubMed  Google Scholar 

  67. Mathai SC, Sibley CT, Forfia PR, Mudd JO, Fisher MR, Tedford RJ, et al. Tricuspid annular plane systolic excursion is a robust outcome measure in systemic sclerosis-associated pulmonary arterial hypertension. J Rheumatol. 2011;38(11):2410–8.

    PubMed  Google Scholar 

  68. Hinchcliff M, Fischer A, Schiopu E, Steen VD. Pulmonary hypertension assessment and recognition of outcomes in scleroderma (PHAROS): baseline characteristics and description of study population. J Rheumatol. 2011;38(10):2172–9.

    PubMed Central  PubMed  Google Scholar 

  69. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–30.

    PubMed  Google Scholar 

  70. Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179(2):151–7.

    PubMed  Google Scholar 

  71. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry. Chest. 2010;137(2):376–87.

    PubMed  Google Scholar 

  72. Chung L, Domsic RT, Lingala B, Alkassab F, Bolster M, Csuka ME, et al. Survival and predictors of mortality in systemic sclerosis associated pulmonary arterial hypertension: outcomes from the PHAROS registry. Arthritis Care Res (Hoboken). 2013. [Epub ahead of print].

    Google Scholar 

  73. Blanco I, Mathai SC, Shafiq M, Boyce D, Kolb TM, Chami H, Hummers LK, Housten T, Chaisson N, Zaiman AL, Wigley FM, Tedford RJ, Kass DA, Damico R, Girgis RE, Hassoun PM. Severity of scleroderma-associated pulmonary arterial hypertension in African Americans. Medicine 2014. (Accepted for publication).

    Google Scholar 

  74. Schachna L, Wigley FM, Chang B, White B, Wise RA, Gelber AC. Age and risk of pulmonary arterial hypertension in scleroderma. Chest. 2003;124(6):2098–104.

    PubMed  Google Scholar 

  75. Scorza R, Caronni M, Bazzi S, Nador F, Beretta L, Antonioli R, et al. Post-menopause is the main risk factor for developing isolated pulmonary hypertension in systemic sclerosis. Ann N Y Acad Sci. 2002;966:238–46.

    PubMed  Google Scholar 

  76. Beretta L, Caronni M, Origgi L, Ponti A, Santaniello A, Scorza R. Hormone replacement therapy may prevent the development of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Scand J Rheumatol. 2006;35(6):468–71.

    CAS  PubMed  Google Scholar 

  77. Avouac J, Airo 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 Rheumatol. 2010;37(11):2290–8.

    PubMed  Google Scholar 

  78. Cox SR, Walker JG, Coleman M, Rischmueller M, Proudman S, Smith MD, et al. Isolated pulmonary hypertension in scleroderma. Intern Med J. 2005;35(1):28–33.

    CAS  PubMed  Google Scholar 

  79. 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 Rheum. 2009;60(6):1831–9.

    PubMed  Google Scholar 

  80. Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La MG, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore). 2002;81(2):139–53.

    Google Scholar 

  81. Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48(2):516–22.

    PubMed  Google Scholar 

  82. Shah AA, Wigley FM, Hummers LK. Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol. 2010;37(1):98–104.

    PubMed Central  PubMed  Google Scholar 

  83. Allanore Y, Borderie D, Avouac J, Zerkak D, Meune C, Hachulla E, et al. High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheum. 2008;58(1):284–91.

    CAS  PubMed  Google Scholar 

  84. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219–63.

    CAS  PubMed  Google Scholar 

  85. Black WC, Welch HG. Screening for disease. AJR Am J Roentgenol. 1997;168(1):3–11.

    CAS  PubMed  Google Scholar 

  86. 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(11):3522–30.

    PubMed  Google Scholar 

  87. Humbert M, Gerry CJ, Khanna D. Early detection and management of pulmonary arterial hypertension. Eur Respir Rev. 2012;21(126):306–12.

    PubMed  Google Scholar 

  88. Coghlan JG, Denton CP, Grunig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2013. [Epub ahead of print].

    Google Scholar 

  89. 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 Rheum. 2013;65(12):3194–201.

    PubMed  Google Scholar 

  90. Kawut SM, Taichman DB, Archer-Chicko CL, Palevsky HI, Kimmel SE. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest. 2003;123(2):344–50.

    PubMed  Google Scholar 

  91. 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 Rheum. 2006;54(9):3043–50.

    PubMed  Google Scholar 

  92. Hachulla E, Carpentier P, Gressin V, Diot E, Allanore Y, Sibilia J, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinerAIR-Sclerodermie study. Rheumatology (Oxford). 2009;48(3):304–8.

    Google Scholar 

  93. Campo A, Mathai SC, Le PJ, Zaiman AL, Hummers LK, Boyce D, et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(2):252–60.

    PubMed Central  PubMed  Google Scholar 

  94. Rubenfire M, Huffman MD, Krishnan S, Seibold JR, Schiopu E, McLaughlin VV. Survival in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern era. Chest. 2013;144(4):1282–90.

    PubMed  Google Scholar 

  95. Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le PJ, et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J. 2010;35(1):95–104.

    CAS  PubMed  Google Scholar 

  96. Overbeek MJ, Lankhaar JW, Westerhof N, Voskuyl AE, Boonstra A, Bronzwaer JG, et al. Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. Eur Respir J. 2008;31(6):1160–6.

    CAS  PubMed  Google Scholar 

  97. Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, et al. Right ventricular dysfunction in systemic sclerosis associated pulmonary arterial hypertension. Circ Heart Fail. 2013;6(5):953–63.

    CAS  PubMed  Google Scholar 

  98. Launay D, Humbert M, Berezne A, Cottin V, Allanore Y, Couderc LJ, et al. Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease. Chest. 2011;140(4):1016–24.

    PubMed  Google Scholar 

  99. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease—an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52(2):148–59.

    CAS  PubMed  Google Scholar 

  100. Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Kinoshita M, Sumiya M. Increase of cytokine production by pulmonary artery endothelial cells induced by supernatants from monocytes stimulated with autoantibodies against U1-ribonucleoprotein. Clin Exp Rheumatol. 1999;17(6):705–12.

    CAS  PubMed  Google Scholar 

  101. Bodolay E, Csipo I, Gal I, Sipka S, Gyimesi E, Szekanecz Z, et al. Anti-endothelial cell antibodies in mixed connective tissue disease: frequency and association with clinical symptoms. Clin Exp Rheumatol. 2004;22(4):409–15.

    CAS  PubMed  Google Scholar 

  102. Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum. 1998;41(5):768–77.

    CAS  PubMed  Google Scholar 

  103. Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42(5):899–909.

    CAS  PubMed  Google Scholar 

  104. Lundberg I, Hedfors E. Clinical course of patients with anti-RNP antibodies. A prospective study of 32 patients. J Rheumatol. 1991;18(10):1511–9.

    CAS  PubMed  Google Scholar 

  105. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum. 2005;52(7):2125–32.

    PubMed  Google Scholar 

  106. Sullivan WD, Hurst DJ, Harmon CE, Esther JH, Agia GA, Maltby JD, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore). 1984;63(2):92–107.

    CAS  Google Scholar 

  107. Gunnarsson R, Aalokken TM, Molberg O, Lund MB, Mynarek GK, Lexberg AS, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis. 2012;71(12):1966–72.

    PubMed  Google Scholar 

  108. Johnson SR, Granton JT. Pulmonary hypertension in systemic sclerosis and systemic lupus erythematosus. Eur Respir Rev. 2011;20(122):277–86.

    CAS  PubMed  Google Scholar 

  109. Perez HD, Kramer N. Pulmonary hypertension in systemic lupus erythematosus: report of four cases and review of the literature. Semin Arthritis Rheum. 1981;11(1):177–81.

    CAS  PubMed  Google Scholar 

  110. Quismorio Jr FP, Sharma O, Koss M, Boylen T, Edmiston AW, Thornton PJ, et al. Immunopathologic and clinical studies in pulmonary hypertension associated with systemic lupus erythematosus. Semin Arthritis Rheum. 1984;13(4):349–59.

    PubMed  Google Scholar 

  111. Badui E, Garcia-Rubi D, Robles E, Jimenez J, Juan L, Deleze M, et al. Cardiovascular manifestations in systemic lupus erythematosus. Prospective study of 100 patients. Angiology. 1985;36(7):431–41.

    CAS  PubMed  Google Scholar 

  112. Simonson JS, Schiller NB, Petri M, Hellmann DB. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol. 1989;16(7):918–25.

    CAS  PubMed  Google Scholar 

  113. Asherson RA, Higenbottam TW, Dinh Xuan AT, Khamashta MA, Hughes GR. Pulmonary hypertension in a lupus clinic: experience with twenty-four patients. J Rheumatol. 1990;17(10):1292–8.

    CAS  PubMed  Google Scholar 

  114. Ong ML, Veerapen K, Chambers JB, Lim MN, Manivasagar M, Wang F. Cardiac abnormalities in systemic lupus erythematosus: prevalence and relationship to disease activity. Int J Cardiol. 1992;34(1):69–74.

    CAS  PubMed  Google Scholar 

  115. Winslow TM, Ossipov MA, Fazio GP, Simonson JS, Redberg RF, Schiller NB. Five-year follow-up study of the prevalence and progression of pulmonary hypertension in systemic lupus erythematosus. Am Heart J. 1995;129(3):510–5.

    CAS  PubMed  Google Scholar 

  116. Shen JY, Chen SL, Wu YX, Tao RQ, Gu YY, Bao CD, et al. Pulmonary hypertension in systemic lupus erythematosus. Rheumatol Int. 1999;18(4):147–51.

    CAS  PubMed  Google Scholar 

  117. Johnson SR, Gladman DD, Urowitz MB, Ibanez D, Granton JT. Pulmonary hypertension in systemic lupus. Lupus. 2004;13(7):506–9.

    CAS  PubMed  Google Scholar 

  118. Fois E, Le Guern V, Dupuy A, Humbert M, Mouthon L, Guillevin L. Noninvasive assessment of systolic pulmonary artery pressure in systemic lupus erythematosus: retrospective analysis of 93 patients. Clin Exp Rheumatol. 2010;28(6):836–41.

    CAS  PubMed  Google Scholar 

  119. Goupille P, Fauchier L, Babuty D, Fauchier JP, Valat JP. Precapillary pulmonary hypertension dramatically improved with high doses of corticosteroids during systemic lupus erythematosus. J Rheumatol. 1994;21(10):1976–7.

    CAS  PubMed  Google Scholar 

  120. Asherson RA, Oakley CM. Pulmonary hypertension and systemic lupus erythematosus. J Rheumatol. 1986;13(1):1–5.

    CAS  PubMed  Google Scholar 

  121. Kim WU, Min JK, Lee SH, Park SH, Cho CS, Kim HY. Causes of death in Korean patients with systemic lupus erythematosus: a single center retrospective study. Clin Exp Rheumatol. 1999;17(5):539–45.

    CAS  PubMed  Google Scholar 

  122. Pope J. An update in pulmonary hypertension in systemic lupus erythematosus—do we need to know about it? Lupus. 2008;17(4):274–7.

    CAS  PubMed  Google Scholar 

  123. Mavragani CP, Moutsopoulos HM. Sjogren’s syndrome. Annu Rev Pathol. 2014;9:273–85.

    Google Scholar 

  124. Kokosi M, Riemer EC, Highland KB. Pulmonary involvement in Sjogren syndrome. Clin Chest Med. 2010;31(3):489–500.

    PubMed  Google Scholar 

  125. Vassiliou VA, Moyssakis I, Boki KA, Moutsopoulos HM. Is the heart affected in primary Sjogren’s syndrome? An echocardiographic study. Clin Exp Rheumatol. 2008;26(1):109–12.

    CAS  PubMed  Google Scholar 

  126. Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(3):633–9.

    PubMed Central  PubMed  Google Scholar 

  127. Turesson C, McClelland RL, Christianson TJ, Matteson EL. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66(1):70–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Balbir-Gurman A, Yigla M, Nahir AM, Braun-Moscovici Y. Rheumatoid pleural effusion. Semin Arthritis Rheum. 2006;35(6):368–78.

    PubMed  Google Scholar 

  129. Marigliano B, Soriano A, Margiotta D, Vadacca M, Afeltra A. Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis. Autoimmun Rev. 2013;12(11):1076–84.

    PubMed  Google Scholar 

  130. Dawson JK, Goodson NG, Graham DR, Lynch MP. Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients. Rheumatology (Oxford). 2000;39(12):1320–5.

    CAS  Google Scholar 

  131. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Ollier WE, et al. Echocardiographic and Doppler findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin Arthritis Rheum. 2004;33(4):231–8.

    PubMed  Google Scholar 

  132. Kay JM, Banik S. Unexplained pulmonary hypertension with pulmonary arthritis in rheumatoid disease. Br J Dis Chest. 1977;71(1):53–9.

    CAS  PubMed  Google Scholar 

  133. Lehrman SG, Hollander RC. Severe pulmonary hypertension in a patient with rheumatoid arthritis—response to nifedipine. West J Med. 1986;145(2):242–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Eaton AM, Serota H, Kernodle Jr GW, Uglietta JP, Crawford J, Fulkerson WJ. Pulmonary hypertension secondary to serum hyperviscosity in a patient with rheumatoid arthritis. Am J Med. 1987;82(5):1039–45.

    CAS  PubMed  Google Scholar 

  135. Morikawa J, Kitamura K, Habuchi Y, Tsujimura Y, Minamikawa T, Takamatsu T. Pulmonary hypertension in a patient with rheumatoid arthritis. Chest. 1988;93(4):876–8.

    CAS  PubMed  Google Scholar 

  136. Young ID, Ford SE, Ford PM. The association of pulmonary hypertension with rheumatoid arthritis. J Rheumatol. 1989;16(9):1266–9.

    CAS  PubMed  Google Scholar 

  137. Sharma S, Vaccharajani A, Mandke J. Severe pulmonary hypertension in rheumatoid arthritis. Int J Cardiol. 1990;26(2):220–2.

    CAS  PubMed  Google Scholar 

  138. Balagopal VP, da Costa P, Greenstone MA. Fatal pulmonary hypertension and rheumatoid vasculitis. Eur Respir J. 1995;8(2):331–3.

    CAS  PubMed  Google Scholar 

  139. Keser G, Capar I, Aksu K, Inal V, Danaoglu Z, Savas R, et al. Pulmonary hypertension in rheumatoid arthritis. Scand J Rheumatol. 2004;33(4):244–5.

    CAS  PubMed  Google Scholar 

  140. Castro GW, Appenzeller S, Bertolo MB, Costallat LT. Isolated pulmonary hypertension secondary to rheumatoid arthritis. Clin Rheumatol. 2006;25(6):901–3.

    PubMed  Google Scholar 

  141. Shariff N, Kumar A, Narang R, Malhotra A, Mukhopadhyaya S, Sharma SK. A study of pulmonary arterial hypertension in patients with rheumatoid arthritis. Int J Cardiol. 2007;115(1):75–6.

    PubMed  Google Scholar 

  142. Udayakumar N, Venkatesan S, Rajendiran C. Pulmonary hypertension in rheumatoid arthritis–relation with the duration of the disease. Int J Cardiol. 2008;127(3):410–2.

    CAS  PubMed  Google Scholar 

  143. Bernatsky S, Joseph L, Pineau CA, Belisle P, Boivin JF, Banerjee D, et al. Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences. Ann Rheum Dis. 2009;68(7):1192–6.

    CAS  PubMed  Google Scholar 

  144. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84(3):223–43.

    CAS  PubMed  Google Scholar 

  145. Mammen AL. Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. Nat Rev Neurol. 2011;7(6):343–54.

    CAS  PubMed  Google Scholar 

  146. Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest. 2013;143(3):814–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Adnot S. Lessons learned from cancer may help in the treatment of pulmonary hypertension. J Clin Invest. 2005;115(6):1461–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–38.

    CAS  PubMed  Google Scholar 

  149. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182(9):1171–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005;353(13):1412–3.

    CAS  PubMed  Google Scholar 

  151. Godinas L, Guignabert C, Seferian A, Perros F, Bergot E, Sibille Y, et al. Tyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword? Semin Respir Crit Care Med. 2013;34(5):714–24.

    PubMed  Google Scholar 

  152. Girgis RE, Frost AE, Hill NS, Horn EM, Langleben D, McLaughlin VV, et al. Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis. 2007;66(11):1467–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Oudiz RJ, Schilz RJ, Barst RJ, Galie N, Rich S, Rubin LJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest. 2004;126(2):420–7.

    CAS  PubMed  Google Scholar 

  154. Denton CP, Humbert M, Rubin L, Black CM. 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(10):1336–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Denton CP, Pope JE, Peter HH, Gabrielli A, Boonstra A, van den Hoogen FH, 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(9):1222–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galie N, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. 2007;34(12):2417–22.

    PubMed  Google Scholar 

  157. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93(3):391–8.

    Google Scholar 

  158. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet 1981;1(8222):681–6.

    Google Scholar 

  159. Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006;114(14):1482–9.

    PubMed  Google Scholar 

  160. Grunig E, Maier F, Ehlken N, Fischer C, Lichtblau M, Blank N, et al. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Res Ther. 2012;14(3):R148.

    PubMed Central  PubMed  Google Scholar 

  161. Jais X, Launay D, Yaici A, Le PJ, Tcherakian 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 Rheum. 2008;58(2):521–31.

    PubMed  Google Scholar 

  162. Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest. 2006;130(1):182–9.

    CAS  PubMed  Google Scholar 

  163. Kato M, Kataoka H, Odani T, Fujieda Y, Otomo K, Oku K, et al. The short-term role of corticosteroid therapy for pulmonary arterial hypertension associated with connective tissue diseases: report of five cases and a literature review. Lupus. 2011;20(10):1047–56.

    CAS  PubMed  Google Scholar 

  164. Miyamichi-Yamamoto S, Fukumoto Y, Sugimura K, Ishii T, Satoh K, Miura Y, et al. Intensive immunosuppressive therapy improves pulmonary hemodynamics and long-term prognosis in patients with pulmonary arterial hypertension associated with connective tissue disease. Circ J. 2011;75(11):2668–74.

    CAS  PubMed  Google Scholar 

  165. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301.

    CAS  PubMed  Google Scholar 

  166. 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(6):425–34.

    CAS  PubMed  Google Scholar 

  167. Farber HW, Graven KK, Kokolski G, Korn JH. Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma. J Rheumatol. 1999;26(5):1195–6.

    CAS  PubMed  Google Scholar 

  168. Palmer SM, Robinson LJ, Wang A, Gossage JR, Bashore T, Tapson VF. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest. 1998;113(1):237–40.

    CAS  PubMed  Google Scholar 

  169. Farber HW, Miller DP, Meltzer LA, McGoon MD. Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL registry. J Heart Lung Transplant. 2013;32(11):1114–22.

    PubMed  Google Scholar 

  170. Caravita S, Wu SC, Secchi MB, Dadone V, Bencini C, Pierini S. Long-term effects of intermittent iloprost infusion on pulmonary arterial pressure in connective tissue disease. Eur J Intern Med. 2011;22(5):518–21.

    CAS  PubMed  Google Scholar 

  171. Hoeper MM, Gall H, Seyfarth HJ, Halank M, Ghofrani HA, Winkler J, et al. Long-term outcome with intravenous iloprost in pulmonary arterial hypertension. Eur Respir J. 2009;34(1):132–7.

    CAS  PubMed  Google Scholar 

  172. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347(5):322–9.

    CAS  PubMed  Google Scholar 

  173. 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: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915–22.

    CAS  PubMed  Google Scholar 

  174. Shao D, Park JE, Wort SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacol Res. 2011;63(6):504–11.

    CAS  PubMed  Google Scholar 

  175. Shetty N, Derk CT. Endothelin receptor antagonists as disease modifiers in systemic sclerosis. Inflamm Allergy Drug Targets. 2011;10(1):19–26.

    CAS  PubMed  Google Scholar 

  176. Girgis RE, Mathai SC, Krishnan JA, Wigley FM, Hassoun PM. 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(10):1626–31.

    PubMed  Google Scholar 

  177. Tingey T, Shu J, Smuczek J, Pope J. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken). 2013;65(9):1460–71.

    CAS  Google Scholar 

  178. Galie 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(23):3010–9.

    CAS  PubMed  Google Scholar 

  179. Oudiz RJ, Galie N, Olschewski H, Torres F, Frost A, Ghofrani HA, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(21):1971–81.

    PubMed  Google Scholar 

  180. Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736–45.

    CAS  PubMed  Google Scholar 

  181. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.

    CAS  PubMed  Google Scholar 

  182. McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2009;135(1):122–9.

    CAS  PubMed  Google Scholar 

  183. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188(6):239–46.

    Google Scholar 

  184. Galie 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(20):2148–57.

    CAS  PubMed  Google Scholar 

  185. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract. 2006;60(8):967–75.

    CAS  PubMed  Google Scholar 

  186. Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894–903.

    CAS  PubMed  Google Scholar 

  187. Wirostko BM, Tressler C, Hwang LJ, Burgess G, Laties AM. Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension. BMJ. 2012;344:e554.

    PubMed Central  PubMed  Google Scholar 

  188. Ghofrani HA, Grimminger F. Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. Eur Respir Rev. 2009;18(111):35–41.

    CAS  PubMed  Google Scholar 

  189. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006;5(9):755–68.

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40.

    CAS  PubMed  Google Scholar 

  191. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24(3):353–9.

    CAS  PubMed  Google Scholar 

  192. Mathai SC, Girgis RE, Fisher MR, Champion HC, Housten-Harris T, Zaiman A, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J. 2007;29(3):469–75.

    CAS  PubMed  Google Scholar 

  193. Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005;60(1):107–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115(10):2811–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation. 2008;118(20):2081–90.

    CAS  PubMed  Google Scholar 

  196. Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006;145(2):152–3.

    PubMed  Google Scholar 

  197. Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax. 2006;61(8):736.

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Overbeek MJ, van Nieuw Amerongen GP, Boonstra A, Smit EF, Vonk-Noordegraaf A. Possible role of imatinib in clinical pulmonary veno-occlusive disease. Eur Respir J. 2008;32(1):232–5.

    CAS  PubMed  Google Scholar 

  199. ten Freyhaus H, Dumitrescu D, Bovenschulte H, Erdmann E, Rosenkranz S. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension. Clin Res Cardiol. 2009;98(4):265–7.

    PubMed  Google Scholar 

  200. Montani D, Bergot E, Gunther S, Savale L, Bergeron A, Bourdin A, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128–37.

    CAS  PubMed  Google Scholar 

  201. Nagaraj C, Tang B, Balint Z, Wygrecka M, Hrzenjak A, Kwapiszewska G, et al. Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. Eur Respir J. 2013;41(1):85–95.

    CAS  PubMed  Google Scholar 

  202. McMahan ZH, Wigley FM. Novel investigational agents for the treatment of scleroderma. Expert Opin Investig Drugs. 2014;23(2):183–98.

    CAS  PubMed  Google Scholar 

  203. 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(8):2456–64.

    PubMed  Google Scholar 

  204. Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, Kirk R, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult lung and heart-lung transplant report—2011. J Heart Lung Transplant. 2011;30(10):1104–22.

    PubMed  Google Scholar 

  205. Schachna L, Medsger Jr 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 Rheum. 2006;54(12):3954–61.

    PubMed  Google Scholar 

  206. 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. 2010;36(4):893–900.

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Shitrit D, Amital A, Peled N, Raviv Y, Medalion B, Saute M, et al. Lung transplantation in patients with scleroderma: case series, review of the literature, and criteria for transplantation. Clin Transplant. 2009;23(2):178–83.

    PubMed  Google Scholar 

  208. 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(6):808–14.

    CAS  PubMed  Google Scholar 

  209. Distler O, Behrens F, Pittrow D, Huscher D, Denton CP, Foeldvari I, et al. Defining appropriate outcome measures in pulmonary arterial hypertension related to systemic sclerosis: a Delphi consensus study with cluster analysis. Arthritis Rheum. 2008;59(6):867–75.

    PubMed  Google Scholar 

  210. Denton CP, Avouac J, Behrens F, Furst DE, Foeldvari I, Humbert M, et al. Systemic sclerosis-associated pulmonary hypertension: why disease-specific composite endpoints are needed. Arthritis Res Ther. 2011;13(3):114.

    PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, 5th Floor, Baltimore, MD, 21205, USA

    Stephen C. Mathai M.D., M.H.S.

  2. Department of Medicine/Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Suite 4000, Mason F. Ford Building, Center Tower, Baltimore, MD, 21224, USA

    Laura K. Hummers M.D., Sc.M.

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  1. Stephen C. Mathai M.D., M.H.S.
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  2. Laura K. Hummers M.D., Sc.M.
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Correspondence to Stephen C. Mathai M.D., M.H.S. .

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Editors and Affiliations

  1. Harvard Medical School, Department of Medicine, Division of Rheumatology Brigham and Women’s Hospital, Boston, Massachusetts, USA

    Paul F. Dellaripa

  2. Division of Rheumatology, Autoimmune and Interstitial Lung Disease Program, Department of Medicine, National Jewish Health, Denver, Colorado, USA

    Aryeh Fischer

  3. Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Kevin R. Flaherty

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Mathai, S.C., Hummers, L.K. (2014). Pulmonary Hypertension Associated with Connective Tissue Disease. In: Dellaripa, P., Fischer, A., Flaherty, K. (eds) Pulmonary Manifestations of Rheumatic Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0770-0_11

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