Pulmonary Hypertension Complicating Connective Tissue Disease

Joseph P. Lynch III; John A. Belperio; Rajeev Saggar; Michael C. Fishbein; Rajan Saggar

doi:10.1055/s-0033-1356547

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2013; 34(05): 581-599
DOI: 10.1055/s-0033-1356547

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pulmonary Hypertension Complicating Connective Tissue Disease

Joseph P. Lynch III

¹Division of Pulmonary, Critical Care Medicine, Clinical Immunology, and Allergy, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

,

John A. Belperio

¹Division of Pulmonary, Critical Care Medicine, Clinical Immunology, and Allergy, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

,

Rajeev Saggar

²Division of Pulmonary, Critical Care Medicine, Department of Medicine, St. Joseph Medical Center, Phoenix, Arizona

,

Michael C. Fishbein

³Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

,

Rajan Saggar

¹Division of Pulmonary, Critical Care Medicine, Clinical Immunology, and Allergy, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

› Author Affiliations

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

Full Text

References

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