Pulmonary Hypertension Complicating Connective Tissue Disease

Abstract

Pulmonary hypertension (PH) may complicate connective tissue disease (CTD), particularly systemic sclerosis (SSc, scleroderma), and markedly increases mortality. More than 70% of cases of PH complicating CTD occur in SSc, which is the major focus of this article. Pulmonary complications (i.e., interstitial lung disease [ILD] and PH) are the leading causes of scleroderma-related deaths. “Isolated” PH (i.e., without ILD) complicates SSc in 7.5 to 20% of cases; secondary PH may also occur in patients with SSc-associated ILD. Several clinical markers and specific autoantibody profiles have been associated with PH in SSc. The role of PH-specific therapy is controversial, as prognosis and responsiveness to therapy are worse in SSc-associated PH compared with idiopathic pulmonary arterial hypertension. We discuss medical therapies for CTD-associated PH and the role of lung transplantation for patients failing medical therapy.

Keywords

systemic sclerosis - scleroderma - pulmonary hypertension - pulmonary arterial hypertension - connective tissue disease

• References

• 1 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 (6) 425-434
• 2 Kuhn KP, Byrne DW, Arbogast PG, Doyle TP, Loyd JE, Robbins IM. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med 2003; 167 (4) 580-586
• 3 Trad S, Amoura Z, Beigelman C , et al. Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. Arthritis Rheum 2006; 54 (1) 184-191
• 4 Launay D, Sitbon O, Le Pavec J , 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 (Oxford) 2010; 49 (3) 490-500
• 5 Condliffe R, Kiely DG, Peacock AJ , et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009; 179 (2) 151-157
• 6 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) 2125-2132
• 7 Sanchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006; 130 (1) 182-189
• 8 Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Hara M, Kamatani N. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol 2002; 29 (2) 282-287
• 9 Li EK, Tam LS. Pulmonary hypertension in systemic lupus erythematosus: clinical association and survival in 18 patients. J Rheumatol 1999; 26 (9) 1923-1929
• 10 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) 866-872
• 11 Simonson JS, Schiller NB, Petri M, Hellmann DB. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol 1989; 16 (7) 918-925
• 12 Hunzelmann N, Genth E, Krieg T , et al; Registry of the German Network for Systemic Scleroderma. The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology (Oxford) 2008; 47 (8) 1185-1192
• 13 Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009; 360 (19) 1989-2003
• 14 Ferri C, Valentini G, Cozzi F , et al; Systemic Sclerosis Study Group of the Italian Society of Rheumatology (SIR-GSSSc). Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002; 81 (2) 139-153
• 15 Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980; 23 (5) 581-590
• 16 LeRoy EC, Black C, Fleischmajer R , et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988; 15 (2) 202-205
• 17 Denton CP, Hachulla E. Risk factors associated with pulmonary arterial hypertension in patients with systemic sclerosis and implications for screening. Eur Respir Rev 2011; 20 (122) 270-276
• 18 Steen VD, Conte C, Owens GR, Medsger Jr TA. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994; 37 (9) 1283-1289
• 19 Meyer OC, Fertig N, Lucas M, Somogyi N, Medsger Jr TA. Disease subsets, antinuclear antibody profile, and clinical features in 127 French and 247 US adult patients with systemic sclerosis. J Rheumatol 2007; 34 (1) 104-109
• 20 Mayes MD, Lacey Jr JV, Beebe-Dimmer J , et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003; 48 (8) 2246-2255
• 21 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 (11) 1088-1093
• 22 Steen V. Advancements in diagnosis of pulmonary arterial hypertension in scleroderma. Arthritis Rheum 2005; 52 (12) 3698-3700
• 23 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 (12) 3792-3800
• 24 Hachulla E, de Groote P, Gressin V , et al; Itinér AIR-Sclérodermie Study Group. 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) 1831-1839
• 25 Launay D, Mouthon L, Hachulla E , 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) 1005-1011
• 26 Vonk MC, Broers B, Heijdra YF , et al. Systemic sclerosis and its pulmonary complications in The Netherlands: an epidemiological study. Ann Rheum Dis 2009; 68 (6) 961-965
• 27 Hachulla E, Carpentier P, Gressin V , et al; ItinérAIR-Sclérodermie Study Investigators. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study. Rheumatology (Oxford) 2009; 48 (3) 304-308
• 28 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 (1) 2-10
• 29 Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007; 66 (7) 940-944
• 30 Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J Dermatol 2010; 37 (1) 42-53
• 31 Sato H, Lagan AL, Alexopoulou C , et al. The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma. Arthritis Rheum 2004; 50 (2) 558-564
• 32 Weiner ES, Earnshaw WC, Senécal JL, Bordwell B, Johnson P, Rothfield NF. Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients. Arthritis Rheum 1988; 31 (3) 378-385
• 33 Joyal F, Choquette D, Roussin A, Levington C, Senécal JL. Evaluation of the severity of systemic sclerosis by nailfold capillary microscopy in 112 patients. Angiology 1992; 43 (3 Pt 1) 203-210
• 34 Maricq HR, Spencer-Green G, LeRoy EC. Skin capillary abnormalities as indicators of organ involvement in scleroderma (systemic sclerosis), Raynaud's syndrome and dermatomyositis. Am J Med 1976; 61 (6) 862-870
• 35 LeRoy EC, Medsger Jr TA. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001; 28 (7) 1573-1576
• 36 Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol 2011; 40 (2) 78-83
• 37 Steen VD, Medsger Jr TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43 (11) 2437-2444
• 38 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) 639-642
• 39 Penn H, Howie AJ, Kingdon EJ , et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007; 100 (8) 485-494
• 40 Poormoghim H, Lucas M, Fertig N, Medsger Jr TA. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 2000; 43 (2) 444-451
• 41 Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990; 21 (5) 467-474
• 42 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 2003; 29 (2) 239-254
• 43 Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008; 37 (4) 223-235
• 44 Le Guern V, Mahr A, Mouthon L, Jeanneret D, Carzon M, Guillevin L. Prevalence of systemic sclerosis in a French multi-ethnic county. Rheumatology (Oxford) 2004; 43 (9) 1129-1137
• 45 Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol 2012; 24 (2) 165-170
• 46 Satoh M, Akizuki M, Kuwana M , et al. Genetic and immunological differences between Japanese patients with diffuse scleroderma and limited scleroderma. J Rheumatol 1994; 21 (1) 111-114
• 47 Nishioka K, Katayama I, Kondo H , et al; Scleroderma Research Committee Japan. Epidemiological analysis of prognosis of 496 Japanese patients with progressive systemic sclerosis (SSc). J Dermatol 1996; 23 (10) 677-682
• 48 Hashimoto A, Endo H, Kondo H, Hirohata S. Clinical features of 405 Japanese patients with systemic sclerosis. Mod Rheumatol 2012; 22 (2) 272-279
• 49 Reveille JD, Fischbach M, McNearney T , et al; GENISOS Study Group. Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 2001; 30 (5) 332-346
• 50 Agarwal SK, Tan FK, Arnett FC. Genetics and genomic studies in scleroderma (systemic sclerosis). Rheum Dis Clin North Am 2008; 34 (1) 17-40 , v
• 51 Loubière LS, Lambert NC, Madeleine MM , et al. HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women. Rheumatology (Oxford) 2005; 44 (3) 318-322
• 52 Bryan C, Knight C, Black CM, Silman AJ. Prediction of five-year survival following presentation with scleroderma: development of a simple model using three disease factors at first visit. Arthritis Rheum 1999; 42 (12) 2660-2665
• 53 Simeón CP, Armadans L, Fonollosa V , et al. Mortality and prognostic factors in Spanish patients with systemic sclerosis. Rheumatology (Oxford) 2003; 42 (1) 71-75
• 54 Lee P, Langevitz P, Alderdice CA , et al. Mortality in systemic sclerosis (scleroderma). Q J Med 1992; 82 (298) 139-148
• 55 Jacobsen S, Ullman S, Shen GQ, Wiik A, Halberg P. Influence of clinical features, serum antinuclear antibodies, and lung function on survival of patients with systemic sclerosis. J Rheumatol 2001; 28 (11) 2454-2459
• 56 Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis 1998; 57 (11) 682-686
• 57 Bryan C, Howard Y, Brennan P, Black C, Silman A. Survival following the onset of scleroderma: results from a retrospective inception cohort study of the UK patient population. Br J Rheumatol 1996; 35 (11) 1122-1126
• 58 Nagy Z, Czirják L. Predictors of survival in 171 patients with systemic sclerosis (scleroderma). Clin Rheumatol 1997; 16 (5) 454-460
• 59 Scussel-Lonzetti L, Joyal F, Raynauld JP , et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore) 2002; 81 (2) 154-167
• 60 Steen VD, Costantino JP, Shapiro AP, Medsger Jr TA. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990; 113 (5) 352-357
• 61 Tyndall AJ, Bannert B, Vonk M , et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69 (10) 1809-1815
• 62 Bond C, Pile KD, McNeil JD , et al. South Australian Scleroderma Register: analysis of deceased patients. Pathology 1998; 30 (4) 386-390
• 63 Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 1994; 37 (1) 75-83
• 64 Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol 1988; 15 (2) 276-283
• 65 Kuwana M, Kaburaki J, Arnett FC, Howard RF, Medsger Jr TA, Wright TM. Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti-DNA topoisomerase I antibody. Arthritis Rheum 1999; 42 (3) 465-474
• 66 Steen VD, Medsger Jr TA, Osial Jr TA, Ziegler GL, Shapiro AP, Rodnan GP. Factors predicting development of renal involvement in progressive systemic sclerosis. Am J Med 1984; 76 (5) 779-786
• 67 Steen VD, Powell DL, Medsger Jr TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988; 31 (2) 196-203
• 68 Reveille JD, Solomon DH. American College of Rheumatology Ad Hoc Committee of Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 2003; 49 (3) 399-412
• 69 Fanning GC, Welsh KI, Bunn C, Du Bois R, Black CM. HLA associations in three mutually exclusive autoantibody subgroups in UK systemic sclerosis patients. Br J Rheumatol 1998; 37 (2) 201-207
• 70 Dick T, Mierau R, Bartz-Bazzanella P , et al. Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis. Ann Rheum Dis 2002; 61 (2) 121-127
• 71 Hesselstrand R, Scheja A, Shen GQ, Wiik A, Akesson A. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology (Oxford) 2003; 42 (4) 534-540
• 72 Okano Y, Steen VD, Medsger Jr TA. Autoantibody to U3 nucleolar ribonucleoprotein (fibrillarin) in patients with systemic sclerosis. Arthritis Rheum 1992; 35 (1) 95-100
• 73 Mitri GM, Lucas M, Fertig N, Steen VD, Medsger Jr TA. A comparison between anti-Th/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement. Arthritis Rheum 2003; 48 (1) 203-209
• 74 Ho KT, Reveille JD. The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003; 5 (2) 80-93
• 75 Dagher JH, Scheer U, Voit R , et al. Autoantibodies to NOR 90/hUBF: longterm clinical and serological followup in a patient with limited systemic sclerosis suggests an antigen driven immune response. J Rheumatol 2002; 29 (7) 1543-1547
• 76 Franceschini F, Cavazzana I, Generali D , et al. Anti-Ku antibodies in connective tissue diseases: clinical and serological evaluation of 14 patients. J Rheumatol 2002; 29 (7) 1393-1397
• 77 Rozman B, Cucnik S, Sodin-Semrl S , et al. Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: a European EUSTAR-initiated multi-centre case-control study. Ann Rheum Dis 2008; 67 (9) 1282-1286
• 78 Fertig N, Domsic RT, Rodriguez-Reyna T , et al. Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 2009; 61 (7) 958-965
• 79 Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol 1998; 25 (3) 462-466
• 80 Wusirika R, Ferri C, Marin M , et al. The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis. A study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma. Am J Clin Pathol 2003; 120 (4) 596-606
• 81 Pope JE, Thompson A. The frequency and significance of anticardiolipin antibodies in scleroderma. J Rheumatol 2000; 27 (6) 1450-1452
• 82 Baroni SS, Santillo M, Bevilacqua F , et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006; 354 (25) 2667-2676
• 83 Hietarinta M, Lassila O, Hietaharju A. Association of anti-U1RNP- and anti-Scl-70-antibodies with neurological manifestations in systemic sclerosis (scleroderma). Scand J Rheumatol 1994; 23 (2) 64-67
• 84 Walker UA, Tyndall A, Czirják 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 (6) 754-763
• 85 Silman AJ. Scleroderma and survival. Ann Rheum Dis 1991; 50 (4) 267-269
• 86 Okano Y, Steen VD, Medsger Jr TA. Autoantibody reactive with RNA polymerase III in systemic sclerosis. Ann Intern Med 1993; 119 (10) 1005-1013
• 87 Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35 (1) 35-42
• 88 Marguerie C, Bunn CC, Copier J , et al. The clinical and immunogenetic features of patients with autoantibodies to the nucleolar antigen PM-Scl. Medicine (Baltimore) 1992; 71 (6) 327-336
• 89 Dib H, Tamby MC, Bussone G , et al. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 2012; 39 (6) 1405-1414
• 90 Antonioli CM, Danieli E, Airò P, Cattaneo R, Tincani A. More on anticardiolipin and anti-beta2 glycoprotein I in systemic sclerosis. Ann Rheum Dis 2003; 62 (6) 589-590
• 91 Hasegawa M, Sato S, Yanaba K, Komura K, Yamazaki M, Takehara K. Autoantibodies against phosphatidylserine-prothrombin complex in patients with systemic sclerosis. Ann Rheum Dis 2004; 63 (11) 1514-1517
• 92 Koschik II RW, Fertig N, Lucas MR, Domsic RT, Medsger Jr TA. Anti-PM-Scl antibody in patients with systemic sclerosis. Clin Exp Rheumatol 2012; 30 (2, Suppl 71): S12-S16
• 93 Hudson M, Mahler M, Pope J , et al. Clinical Correlates of CENP-A and CENP-B Antibodies in a Large Cohort of Patients with Systemic Sclerosis. J Rheumatol 2012;
• 94 Fritzler MJ, Hart DA, Wilson D , et al. Antibodies to fibrin bound tissue type plasminogen activator in systemic sclerosis. J Rheumatol 1995; 22 (9) 1688-1693
• 95 Grigolo B, Mazzetti I, Meliconi R , et al. Anti-topoisomerase II alpha autoantibodies in systemic sclerosis-association with pulmonary hypertension and HLA-B35. Clin Exp Immunol 2000; 121 (3) 539-543
• 96 Tamby MC, Chanseaud Y, Humbert M , et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005; 60 (9) 765-772
• 97 Okawa-Takatsuji M, Aotsuka S, Fujinami M, Uwatoko S, Kinoshita M, Sumiya M. Up-regulation of intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1) and class II MHC molecules on pulmonary artery endothelial cells by antibodies against U1-ribonucleoprotein. Clin Exp Immunol 1999; 116 (1) 174-180
• 98 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 (6) 1602-1613
• 99 Tamby MC, Humbert M, Guilpain P , et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 2006; 28 (4) 799-807
• 100 Arnett FC, Howard RF, Tan F , et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum 1996; 39 (8) 1362-1370
• 101 Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 1996; 22 (4) 751-764
• 102 Austin ED, Loyd JE, Phillips III JA. Genetics of pulmonary arterial hypertension. Semin Respir Crit Care Med 2009; 30 (4) 386-398
• 103 Newman JH, Wheeler L, Lane KB , 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) 319-324
• 104 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) 2379-2381
• 105 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) 2829-2830
• 106 Wipff J, Kahan A, Hachulla E , et al. Association between an endoglin gene polymorphism and systemic sclerosis-related pulmonary arterial hypertension. Rheumatology (Oxford) 2007; 46 (4) 622-625
• 107 Dorfmüller P, Humbert M, Perros F , et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007; 38 (6) 893-902
• 108 Overbeek MJ, Vonk MC, Boonstra A , et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J 2009; 34 (2) 371-379
• 109 McGuire F, Kennelly T, Tillack T, Robbins M. Pulmonary capillary hemangiomatosis associated with CREST syndrome: a case report and review of the literature. Respiration 2010; 80 (5) 435-438
• 110 Gugnani MK, Pierson C, Vanderheide R, Girgis RE. Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma: a case of pulmonary capillary hemangiomatosis. Arthritis Rheum 2000; 43 (3) 699-703
• 111 Le Pavec J, Humbert M, Mouthon L, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 181 (12) 1285-1293
• 112 Hassoun PM. Therapies for scleroderma-related pulmonary arterial hypertension. Expert Rev Respir Med 2009; 3 (2) 187-196
• 113 Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G. Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 2000; 43 (11) 2550-2562
• 114 Cerinic MM, Valentini G, Sorano GG , et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum 2003; 32 (5) 285-295
• 115 Choi JJ, Min DJ, Cho ML , et al. Elevated vascular endothelial growth factor in systemic sclerosis. J Rheumatol 2003; 30 (7) 1529-1533
• 116 Riccieri V, Stefanantoni K, Vasile M , et al. Abnormal plasma levels of different angiogenic molecules are associated with different clinical manifestations in patients with systemic sclerosis. Clin Exp Rheumatol 2011; 29 (2, Suppl 65): S46-S52
• 117 Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 2005; 26 (6) 1110-1118
• 118 Meadows CA, Risbano MG, Zhang L , et al. Increased expression of growth differentiation factor-15 in systemic sclerosis-associated pulmonary arterial hypertension. Chest 2011; 139 (5) 994-1002
• 119 Saggar R, Saggar R, Aboulhosn J, Belperio JA, Zisman DA, Lynch III JP. Diagnosis and hemodynamic assessment of pulmonary arterial hypertension. Semin Respir Crit Care Med 2009; 30 (4) 399-410
• 120 Galiè N, Hoeper MM, Humbert M , et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34 (6) 1219-1263
• 121 D'Alonzo GE, Barst RJ, Ayres SM , et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115 (5) 343-349
• 122 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351 (14) 1425-1436
• 123 Fisher MR, Mathai SC, Champion HC , et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 2006; 54 (9) 3043-3050
• 124 Williams MH, Handler CE, Akram R , et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 2006; 27 (12) 1485-1494
• 125 Allanore Y, Borderie D, Avouac J , 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) 284-291
• 126 Bezante GP, Rollando D, Sessarego M , et al. Cardiac magnetic resonance imaging detects subclinical right ventricular impairment in systemic sclerosis. J Rheumatol 2007; 34 (12) 2431-2437
• 127 Hachulla AL, Launay D, Gaxotte V , et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis 2009; 68 (12) 1878-1884
• 128 Galiè N, Torbicki A, Barst R , et al; Task Force. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. Eur Heart J 2004; 25 (24) 2243-2278
• 129 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 (4) 461-466
• 130 Arcasoy SM, Christie JD, Ferrari VA , et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167 (5) 735-740
• 131 Tei C, Dujardin KS, Hodge DO , et al. Doppler echocardiographic index for assessment of global right ventricular function. J Am Soc Echocardiogr 1996; 9 (6) 838-847
• 132 Miller D, Farah MG, Liner A, Fox K, Schluchter M, Hoit BD. The relation between quantitative right ventricular ejection fraction and indices of tricuspid annular motion and myocardial performance. J Am Soc Echocardiogr 2004; 17 (5) 443-447
• 133 Forfia PR, Fisher MR, Mathai SC , et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006; 174 (9) 1034-1041
• 134 Kiatchoosakun S, Wongvipaporn C, Nanagara R, Hoit BD. Right ventricular systolic pressure assessed by echocardiography: a predictive factor of mortality in patients with scleroderma. Clin Cardiol 2011; 34 (8) 488-493
• 135 Grünig E, Janssen B, Mereles D , et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000; 102 (10) 1145-1150
• 136 Alkotob ML, Soltani P, Sheatt MA , et al. Reduced exercise capacity and stress-induced pulmonary hypertension in patients with scleroderma. Chest 2006; 130 (1) 176-181
• 137 Condliffe R, Radon M, Hurdman J , et al. CT pulmonary angiography combined with echocardiography in suspected systemic sclerosis-associated pulmonary arterial hypertension. Rheumatology (Oxford) 2011; 50 (8) 1480-1486
• 138 Schreiber BE, Valerio CJ, Keir GJ , et al. Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests. Arthritis Rheum 2011; 63 (11) 3531-3539
• 139 Meune C, Avouac J, Airò P , et al. Prediction of pulmonary hypertension related to systemic sclerosis by an index based on simple clinical observations. Arthritis Rheum 2011; 63 (9) 2790-2796
• 140 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 (6) 1803-1809
• 141 de Groote P, Gressin V, Hachulla E , et al; ItinerAIR-Scleroderma Investigators. Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis 2008; 67 (1) 31-36
• 142 Mathai SC, Bueso M, Hummers LK , et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 2010; 35 (1) 95-104
• 143 Luo YF, Robbins IM, Karatas M, Brixey AG, Rice TW, Light RW. Frequency of pleural effusions in patients with pulmonary arterial hypertension associated with connective tissue diseases. Chest 2011; 140 (1) 42-47
• 144 Tang KJ, Robbins IM, Light RW. Incidence of pleural effusions in idiopathic and familial pulmonary arterial hypertension patients. Chest 2009; 136 (3) 688-693
• 145 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) 808-814
• 146 Pamidi S, Mehta S. Six-minute walk test in scleroderma-associated pulmonary arterial hypertension: are we counting what counts?. J Rheumatol 2009; 36 (2) 216-218
• 147 Garin MC, Highland KB, Silver RM, Strange C. Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma. J Rheumatol 2009; 36 (2) 330-336
• 148 Schoindre Y, Meune C, Dinh-Xuan AT, Avouac J, Kahan A, Allanore Y. Lack of specificity of the 6-minute walk test as an outcome measure for patients with systemic sclerosis. J Rheumatol 2009; 36 (7) 1481-1485
• 149 Vogel-Claussen J, Skrok J, Shehata ML , et al. Right and left ventricular myocardial perfusion reserves correlate with right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension. Radiology 2011; 258 (1) 119-127
• 150 Skrok J, Shehata ML, Mathai S , et al. Pulmonary arterial hypertension: MR imaging-derived first-pass bolus kinetic parameters are biomarkers for pulmonary hemodynamics, cardiac function, and ventricular remodeling. Radiology 2012; 263 (3) 678-687
• 151 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 (3) 458-465
• 152 MacGregor AJ, Canavan R, Knight C , et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001; 40 (4) 453-459
• 153 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 (9) 1023-1030
• 154 Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007; 30 (1) 104-109
• 155 Sackner MA, Akgun N, Kimbel P, Lewis DH. The Pathophysiology of Scleroderma Involving the Heart and Respiratory System. Ann Intern Med 1964; 60: 611-630
• 156 Salerni R, Rodnan GP, Leon DF, Shaver JA. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977; 86 (4) 394-399
• 157 Ungerer RG, Tashkin DP, Furst D , et al. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983; 75 (1) 65-74
• 158 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) 515-524
• 159 Murata I, Kihara H, Shinohara S, Ito K. Echocardiographic evaluation of pulmonary arterial hypertension in patients with progressive systemic sclerosis and related syndromes. Jpn Circ J 1992; 56 (10) 983-991
• 160 Battle RW, Davitt MA, Cooper SM , et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest 1996; 110 (6) 1515-1519
• 161 Yamane K, Ihn H, Asano Y , et al. Clinical and laboratory features of scleroderma patients with pulmonary hypertension. Rheumatology (Oxford) 2000; 39 (11) 1269-1271
• 162 Chang B, Schachna L, White B, Wigley FM, Wise RA. Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma. J Rheumatol 2006; 33 (2) 269-274
• 163 D'Alto M, Ghio S, D'Andrea A , et al. Inappropriate exercise-induced increase in pulmonary artery pressure in patients with systemic sclerosis. Heart 2011; 97 (2) 112-117
• 164 Hachulla E, Coghlan JG. A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism. Ann Rheum Dis 2004; 63 (9) 1009-1014
• 165 Plastiras SC, Karadimitrakis SP, Kampolis C, Moutsopoulos HM, Tzelepis GE. Determinants of pulmonary arterial hypertension in scleroderma. Semin Arthritis Rheum 2007; 36 (6) 392-396
• 166 Cox SR, Walker JG, Coleman M , et al. Isolated pulmonary hypertension in scleroderma. Intern Med J 2005; 35 (1) 28-33
• 167 Steen V. Predictors of end stage lung disease in systemic sclerosis. Ann Rheum Dis 2003; 62 (2) 97-99
• 168 Ong YY, Nikoloutsopoulos T, Bond CP, Smith MD, Ahern MJ, Roberts-Thomson PJ. Decreased nailfold capillary density in limited scleroderma with pulmonary hypertension. Asian Pac J Allergy Immunol 1998; 16 (2-3) 81-86
• 169 Steen VD, Graham G, Conte C, Owens G, Medsger Jr TA. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992; 35 (7) 765-770
• 170 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) 344-350
• 171 Mathai SC, Hummers LK, Champion HC , et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum 2009; 60 (2) 569-577
• 172 Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996; 35 (10) 989-993
• 173 Chung L, Liu J, Parsons L , et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 2010; 138 (6) 1383-1394
• 174 Hachulla E, Launay D, Yaici A , et al; French PAH-SSc Network. Pulmonary arterial hypertension associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but severe outcome. Rheumatology (Oxford) 2010; 49 (5) 940-944
• 175 Thompson AE, Pope JE. A study of the frequency of pericardial and pleural effusions in scleroderma. Br J Rheumatol 1998; 37 (12) 1320-1323
• 176 Campo A, Mathai SC, Le Pavec J , et al. Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 182 (2) 252-260
• 177 Forfia PR, Mathai SC, Fisher MR , et al. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 177 (12) 1364-1369
• 178 Williams MH, Das C, Handler CE , et al. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart 2006; 92 (7) 926-932
• 179 Fernandes F, Ramires FJ, Arteaga E, Ianni BM, Bonfá ES, Mady C. Cardiac remodeling in patients with systemic sclerosis with no signs or symptoms of heart failure: an endomyocardial biopsy study. J Card Fail 2003; 9 (4) 311-317
• 180 Hinderliter AL, Willis IV PW, Long W , et al. Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. PPH Study Group. Primary pulmonary hypertension. Am J Cardiol 1999; 84 (4) 481-484 , A10
• 181 Overbeek MJ, Lankhaar JW, Westerhof N , et al. Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. Eur Respir J 2008; 31 (6) 1160-1166
• 182 Launay D, Humbert M, Berezne A , et al. Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease. Chest 2011; 140 (4) 1016-1024
• 183 Olschewski H, Ghofrani HA, Walmrath D , et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999; 160 (2) 600-607
• 184 Le Pavec J, Girgis RE, Lechtzin N , et al. Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis Rheum 2011; 63 (8) 2456-2464
• 185 Hinchcliff M, Fischer A, Schiopu E, Steen VD. PHAROS Investigators. Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): baseline characteristics and description of study population. J Rheumatol 2011; 38 (10) 2172-2179
• 186 Fischer A, Bull TM, Steen VD. Practical approach to screening for scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 2012; 64 (3) 303-310
• 187 Sitbon O, Humbert M, Jaïs X , et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111 (23) 3105-3111
• 188 Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327 (2) 76-81
• 189 Galiè N, Ussia G, Passarelli P, Parlangeli R, Branzi A, Magnani B. Role of pharmacologic tests in the treatment of primary pulmonary hypertension. Am J Cardiol 1995; 75 (3) 55A-62A
• 190 Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70 (4) 580-587
• 191 Kawut SM, Horn EM, Berekashvili KK , et al. New predictors of outcome in idiopathic pulmonary arterial hypertension. Am J Cardiol 2005; 95 (2) 199-203
• 192 Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Hawker GA, Feldman BM. Effect of warfarin on survival in scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and idiopathic PAH. Belief elicitation for Bayesian priors. J Rheumatol 2011; 38 (3) 462-469
• 193 Humbert M, Simonneau G. Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases. Nat Clin Pract Rheumatol 2005; 1 (2) 93-101
• 194 Joglekar A, Tsai FS, McCloskey DA, Wilson JE, Seibold JR, Riley DJ. Bosentan in pulmonary arterial hypertension secondary to scleroderma. J Rheumatol 2006; 33 (1) 61-68
• 195 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) 1626-1631
• 196 Badesch DB, Hill NS, Burgess G , et al; SUPER Study Group. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007; 34 (12) 2417-2422
• 197 Oudiz RJ, Schilz RJ, Barst RJ , et al; Treprostinil Study Group. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 2004; 126 (2) 420-427
• 198 Kowal-Bielecka O, Landewé R, Avouac J , et al; EUSTAR Co-Authors. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009; 68 (5) 620-628
• 199 McLaughlin VV, Archer SL, Badesch DB , et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. 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. J Am Coll Cardiol 2009; 53 (17) 1573-1619
• 200 Clements PJ, Tan M, McLaughlin VV , et al; Pulmonary Arterial Hypertension Quality Enhancement Research Initiative (PAH-QuERI) Investigators. 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 (2) 249-252
• 201 Barst RJ, Rubin LJ, Long WA , et al; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334 (5) 296-301
• 202 Simonneau G, Barst RJ, Galie N , et al; Treprostinil Study Group. 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 (6) 800-804
• 203 McLaughlin VV, Gaine SP, Barst RJ , et al; Treprostinil Study Group. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003; 41 (2) 293-299
• 204 Strauss WL, Edelman JD. Prostanoid therapy for pulmonary arterial hypertension. Clin Chest Med 2007; 28 (1) 127-142 , ix
• 205 Tapson VF, Gomberg-Maitland M, McLaughlin VV , et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest 2006; 129 (3) 683-688
• 206 Kallen AJ, Lederman E, Balaji A , et al. Bloodstream infections in patients given treatment with intravenous prostanoids. Infect Control Hosp Epidemiol 2008; 29 (4) 342-349
• 207 Hoeper MM, Galiè N, Simonneau G, Rubin LJ. New treatments for pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (9) 1209-1216
• 208 Launay D, Hachulla E, Hatron PY , et al. Aerosolized iloprost in CREST syndrome related pulmonary hypertension. J Rheumatol 2001; 28 (10) 2252-2256
• 209 Channick RN, Simonneau G, Sitbon O , et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358 (9288) 1119-1123
• 210 Rubin LJ, Badesch DB, Barst RJ , et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346 (12) 896-903
• 211 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) 1336-1340
• 212 Galiè N, Olschewski H, Oudiz RJ , et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. 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) 3010-3019
• 213 Barst RJ, Langleben D, Frost A , et al; STRIDE-1 Study Group. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004; 169 (4) 441-447
• 214 Benza RL, Mehta S, Keogh A, Lawrence EC, Oudiz RJ, Barst RJ. Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan. J Heart Lung Transplant 2007; 26 (1) 63-69
• 215 Benza RL, Barst RJ, Galie N , et al. Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival. Chest 2008; 134 (4) 775-782
• 216 Valerio CJ, Handler CE, Kabunga P, Smith CJ, Denton CP, Coghlan JG. Clinical experience with bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension. Rheumatology (Oxford) 2010; 49 (11) 2147-2153
• 217 Rosato E, Molinaro I, Borghese F, Rossi C, Pisarri S, Salsano F. Bosentan improves skin perfusion of hands in patients with systemic sclerosis with pulmonary arterial hypertension. J Rheumatol 2010; 37 (12) 2531-2539
• 218 Korn JH, Mayes M, Matucci Cerinic M , et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50 (12) 3985-3993
• 219 Jain M, Varga J. Bosentan for the treatment of systemic sclerosis-associated pulmonary arterial hypertension, pulmonary fibrosis and digital ulcers. Expert Opin Pharmacother 2006; 7 (11) 1487-1501
• 220 Matucci-Cerinic M, Denton CP, Furst DE , et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011; 70 (1) 32-38
• 221 Galiè N, Ghofrani HA, Torbicki A , et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20) 2148-2157
• 222 Galiè N, Brundage BH, Ghofrani HA , et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119 (22) 2894-2903
• 223 O'Callaghan DS, Gaine SP. Combination therapy and new types of agents for pulmonary arterial hypertension. Clin Chest Med 2007; 28 (1) 169-185 , ix
• 224 Mathai SC, Girgis RE, Fisher MR , et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007; 29 (3) 469-475
• 225 Simonneau G, Rubin LJ, Galiè N , et al; PACES Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008; 149 (8) 521-530
• 226 Keogh A, Strange G, Kotlyar E , et al. Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: an Australian collaborative report. Intern Med J 2011; 41 (3) 235-244
• 227 Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006; 61 (8) 736
• 228 Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005; 353 (13) 1412-1413
• 229 Christie JD, Edwards LB, Kucheryavaya AY , 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) 1104-1122
• 230 Saggar R, Khanna D, Furst DE , et al. Systemic sclerosis and bilateral lung transplantation: a single centre experience. Eur Respir J 2010; 36 (4) 893-900
• 231 Schachna L, Medsger Jr TA, Dauber JH , et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum 2006; 54 (12) 3954-3961
• 232 Shitrit D, Amital A, Peled N , et al. Lung transplantation in patients with scleroderma: case series, review of the literature, and criteria for transplantation. Clin Transplant 2009; 23 (2) 178-183
• 233 Tanoue LT. Pulmonary hypertension in the collagen vascular diseases. Semin Respir Crit Care Med 2003; 24 (3) 287-296
• 234 Jais X, Launay D, Yaici A , 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) 521-531
• 235 Launay D, Hachulla E, Hatron PY, Jais X, Simonneau G, Humbert M. Pulmonary arterial hypertension: a rare complication of primary Sjögren syndrome: report of 9 new cases and review of the literature. Medicine (Baltimore) 2007; 86 (5) 299-315