**Author details**

John W. Swisher1 \* and Shashank Kailash<sup>2</sup>

1 East Tennessee Pulmonary Hypertension Center, Fort Sanders Regional Medical Center, Knoxville, TN, USA

2 Department of Medicine, Brandon Regional Hospital, Brandon, FL, USA

\*Address all correspondence to: jswisher@statcaremed.net

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**27**

2013;**32**:1519-1531

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pulmonary hypertension in patients with systemic sclerosis and mixed connective tissue disease. Medicine.

[10] Coghlan JG, Denton CP, Grunig V, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: The DETECT study. Annals of the Rheumatic Diseases.

[11] Hinchcliff M, Fischer A, Schiopu E,

assessment and recognition of outcomes in scleroderma (PHAROS): Baseline characteristics and description of study population. The Journal of Rheumatology. 2011;**38**(10):2172-2179

[12] Chang B, Schachna L, White B, et al. Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma. The Journal of Rheumatology.

[13] Cox SR, Walker JG, Coleman M, et al. Isolated pulmonary hypertension in scleroderma. Internal Medicine

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[15] Simmoneau G, Gatzoulis M, Adatia I, et al. Updated clinical classification of pulmonary hypertension. Journal of

et al. Pulmonary hypertension

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2003;**48**(2):516-522

[9] Morrisroe K, Stevens W, Sahhar J, et al. Epidemiology and disease characteristics of systemic sclerosis-related pulmonary arterial hypertension: Results from a reallife screening programme. Arthritis Research and Therapy. 2017;**19**:42

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2010;**37**(11):2290-2298

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**26**

**Author details**

John W. Swisher1

Center, Knoxville, TN, USA

provided the original work is properly cited.

\* and Shashank Kailash<sup>2</sup>

\*Address all correspondence to: jswisher@statcaremed.net

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 East Tennessee Pulmonary Hypertension Center, Fort Sanders Regional Medical

2 Department of Medicine, Brandon Regional Hospital, Brandon, FL, USA

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Heart Failure. 2014;**2**:412-421

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Journal. 2005;**19**(9):1178-1180

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and Laboratory Medicine.

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2017;**141**:696-703

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1972-2002. Annals of the Rheumatic

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[135] Arena R, Lavie CJ, Milani RV, et al. Cardiopulmonary exercise testing in patients with pulmonary arterial hypertension: An evidence-based review. The Journal of Heart and Lung Transplantation. 2010;**29**:159-173

[136] Wensel R, Francis DP, Meyer FJ, et al. Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension. International Journal of Cardiology. 2013;**167**:1193-1198

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[144] Lorenzen JM, Nickel N, Kramer R, et al. Osteopontin in patients with idiopathic pulmonary hypertension. Chest. 2011;**139**:1010-1017

[145] Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;**102**:865-870

[146] Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest. 2006;**129**:1313-1321

[147] Williams MH, Handler C, Akram R, et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary

arterial hypertension. European Heart Journal. 2005;**27**:1485-1494

[148] Dimitroulas T, Giannakoulas G, Karvounis H, et al. Natriuretic peptides in systemic sclerosis-related pulmonary arterial hypertension. Seminars in Arthritis and Rheumatism. 2010;**39**:278-284

[149] Leuchte HH, El NM, Tuerpe JC, et al. N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension. Chest. 2007;**131**:402-409

[150] Allanore Y, Borderie D, Meune C, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium channel blockers. Arthritis and Rheumatism. 2003;**48**:3503-3508

[151] Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. The New England Journal of Medicine. 2005;**353**:2148-2157

[152] Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. The Journal of Rheumatology. 2007;**34**:2417-2422

[153] Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;**119**:2894-2903

[154] Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: A randomized, doubleblind, placebo-controlled study. American Journal of Respiratory and Critical Care Medicine. 2011;**183**(12):1723-1729

[155] Ghofrani HA, Galie' N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial

**37**

*Advances in Management of Pulmonary Hypertension Associated with Systemic Sclerosis*

placebo-controlled study. Lancet.

[164] Galie' N, Badesch BD, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. Journal of the American College of Cardiology. 2005;**46**:529-535

[165] Galie' N, Olschewski H, Oudiz R et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebocontrolled, multicenter, efficacy (ARIES) study 1 and 2. Circulation

[166] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. The New England Journal

of Medicine. 2013;**369**:809-818

[167] Galie' N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. American Journal of Respiratory Medicine. 2003;**2**:123-137

[168] Rubin LJ, Mendoza J, Hood M,

[169] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary

pulmonary hypertension. The New England Journal of Medicine.

[170] 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. Annals of Internal Medicine. 2000;**132**:425-434

et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Annals of Internal Medicine.

1990;**112**:485-491

1996;**334**:296-302

2001;**358**:1119-1123

2008; 117: 3010-3019

*DOI: http://dx.doi.org/10.5772/intechopen.86217*

hypertension. The New England Journal

[157] Humbert M, Coghlan JG, Ghofrani HA, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Annals of the Rheumatic

[158] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Annals of Internal

[159] Galie' N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovascular Research.

[160] Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. The New England Journal of Medicine. 2002;**346**:896-903

[161] Galie' N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): A double-blind, randomized controlled trial. Lancet.

[162] Galie' N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: A

[163] Channick RN, Simmoneau G, Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary

hypertension: A randomized

multicenter, double-blind, randomized, placebo-controlled study. Circulation.

of Medicine. 2013;**369**:330-340

pulmonary hypertension. The New England Journal of Medicine.

Diseases. 2017;**76**:422-426

Medicine. 1991;**114**:464-469

2004;**61**:227-237

2008;**371**:2093-2100

2006;**114**:48-54

2013;**369**:319-329

[156] Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic *Advances in Management of Pulmonary Hypertension Associated with Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.86217*

hypertension. The New England Journal of Medicine. 2013;**369**:330-340

*New Insights into Systemic Sclerosis*

2006;**174**:1034-1041

2013;**128**:2005-2015

2008;**32**:503-512

2010;**31**:2291-2300

hypertension. American Journal of Respiratory and Critical Care Medicine. arterial hypertension. European Heart

[148] Dimitroulas T, Giannakoulas G, Karvounis H, et al. Natriuretic peptides in systemic sclerosis-related pulmonary arterial hypertension. Seminars in Arthritis and Rheumatism.

[149] Leuchte HH, El NM, Tuerpe JC, et al. N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension. Chest. 2007;**131**:402-409

[150] Allanore Y, Borderie D, Meune C, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium channel blockers. Arthritis and Rheumatism.

[151] Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. The New England Journal of Medicine.

[152] Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. The Journal of Rheumatology. 2007;**34**:2417-2422

[153] Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;**119**:2894-2903

[154] Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: A randomized, doubleblind, placebo-controlled study. American Journal of Respiratory and Critical Care Medicine. 2011;**183**(12):1723-1729

[155] Ghofrani HA, Galie' N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial

Journal. 2005;**27**:1485-1494

2010;**39**:278-284

2003;**48**:3503-3508

2005;**353**:2148-2157

[140] Grunig E, Tiede H, Enyimayew EO, et al. Assessment and prognostic relevance of right ventricular contractile

pulmonary hypertension. Circulation.

[141] Warwick G, Thomas PS, Yates DH. Biomarkers in pulmonary hypertension. The European Respiratory Journal.

[142] Kumpers P, Nickel N, Lukasz A, et al. Circulating angiopoietins in idiopathic pulmonary arterial hypertension. European Heart Journal.

[143] Quarck R, Nawrot T, Meyns B, et al. C-reactive protein: A new predictor of adverse outcome in pulmonary arterial hypertension. Journal of the American College of Cardiology. 2009;**53**:1211-1218

[144] Lorenzen JM, Nickel N, Kramer R, et al. Osteopontin in patients with idiopathic pulmonary hypertension.

Chest. 2011;**139**:1010-1017

[145] Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation.

[146] Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest.

[147] Williams MH, Handler C, Akram R, et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary

2000;**102**:865-870

2006;**129**:1313-1321

reserve in patients with severe

**36**

[156] Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. The New England Journal of Medicine. 2013;**369**:319-329

[157] Humbert M, Coghlan JG, Ghofrani HA, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Annals of the Rheumatic Diseases. 2017;**76**:422-426

[158] Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Annals of Internal Medicine. 1991;**114**:464-469

[159] Galie' N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovascular Research. 2004;**61**:227-237

[160] Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. The New England Journal of Medicine. 2002;**346**:896-903

[161] Galie' N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): A double-blind, randomized controlled trial. Lancet. 2008;**371**:2093-2100

[162] Galie' N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: A multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;**114**:48-54

[163] Channick RN, Simmoneau G, Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: A randomized

placebo-controlled study. Lancet. 2001;**358**:1119-1123

[164] Galie' N, Badesch BD, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. Journal of the American College of Cardiology. 2005;**46**:529-535

[165] Galie' N, Olschewski H, Oudiz R et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebocontrolled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117: 3010-3019

[166] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. The New England Journal of Medicine. 2013;**369**:809-818

[167] Galie' N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. American Journal of Respiratory Medicine. 2003;**2**:123-137

[168] Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Annals of Internal Medicine. 1990;**112**:485-491

[169] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The New England Journal of Medicine. 1996;**334**:296-302

[170] 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. Annals of Internal Medicine. 2000;**132**:425-434

[171] Simmoneau G, Barst RJ, Galie' N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. American Journal of Respiratory and Critical Care Medicine. 2002;**165**:800-804

[172] Barst RJ, Galie' N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. The European Respiratory Journal. 2006;**28**:1195-1203

[173] McLaughlin V, Rubin L, Benza RL, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. Journal of the American College of Cardiology. 2010;**55**:1915-1922

[174] Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: A randomized, controlled trial. Circulation. 2013;**127**:624-633

[175] Olschewski H, Simmoneau G, Galie' N, et al. Inhaled iloprost in severe pulmonary hypertension. The New England Journal of Medicine. 2002;**347**:322-329

[176] Higenbottam T, Butt AY, McMahon A, et al. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart. 1998;**80**:151-155

[177] Norel X. Prostanoid receptors in the human vascular wall. Scientific World Journal. 2007;**7**:1359-1374

[178] Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;**130**:2189-2208

[179] Mubarak KK. A review of prostaglandin analogues in the management of patients with pulmonary arterial hypertension. Respiratory Medicine. 2010;**104**:9-21

[180] McLaughlin VV, Channick R, Chin KM, et al. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: Results of the GRIPHON study. Journal of the American College of Cardiology. 2015;**65**(Suppl A):A380

[181] Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. The New England Journal of Medicine. 2015;**373**:2522-2533

[182] Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. The European Respiratory Journal. 2017;**50**:1602493

[183] Galie N, Barbara JA, Frost A, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New England Journal of Medicine. 2015;**379**:834-844

[184] Coghlan JG, Galie' N, Barbera JA, et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): Subgroup analysis from the AMBITION trial. Annals of the Rheumatic Diseases. 2017;**76**:1219-1227

[185] Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine. 2015;**192**:1102-1110

[186] Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in

**39**

*Advances in Management of Pulmonary Hypertension Associated with Systemic Sclerosis*

[194] Guillevin L, Armstrong I, Aldrighetti R, et al. Understanding the impact of pulmonary arterial hypertension on patients' and carers' lives. European Respiratory Review.

[195] Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2013;**62**(Suppl):D13-D21

[196] Ramakrishnan G, Sprung J, Ravi BS, et al. Impact of pulmonary hypertension on the outcomes of noncardiac surgery: Predictors of perioperative mobidity and mortality. Journal of the American College of Cardiology. 2005;**45**:1691-1699

[197] McGlothlin D, DeMarco T. Preoperative risk assessment of pulmonary arterial hypertension. Patients undergoing general surgery. Advances in Pulmonary Arterial Hypertension. 2007;**6**(2):66-73

[198] Minai OA, Yared JP, Kaw R, et al. Perioperative risk and management in patients with pulmonary hypertension.

[199] Meyer S, McLaughlin VV, Seyfarth HJ, et al. Outcomes of noncardiac, nonobstetric surgery in patients with PAH: An international prospective survey. The European Respiratory Journal. 2013;**41**:1302-1307

Chest. 2013;**144**:329-340

2013;**22**:535-542

*DOI: http://dx.doi.org/10.5772/intechopen.86217*

[187] Kurzyna M, Dabrowski M, Bielecki D, et al. Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension.

adults. CHEST guideline and expert panel report. Chest. 2014;**146**:449-475

Chest. 2007;**131**:977-983

1998;**32**:297-304

2013;**107**:2081-2087

2006;**114**:1482-1489

Therapy. 2012;**14**:R148

2005;**102**:1133-1137

[188] Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. Journal of the American College of Cardiology.

[189] Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A systematic review. Respiratory Medicine.

[190] deMendonca L, Felix ND, Blanco NG, et al. Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension. Stem Cell Research and Therapy. 2017;**8**:220

[191] Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation.

[192] Grunig E, Maier F, Ehlken N, et al. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Research and

[193] Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology.

*Advances in Management of Pulmonary Hypertension Associated with Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.86217*

adults. CHEST guideline and expert panel report. Chest. 2014;**146**:449-475

*New Insights into Systemic Sclerosis*

2002;**165**:800-804

2006;**28**:1195-1203

2010;**55**:1915-1922

2002;**347**:322-329

[171] Simmoneau G, Barst RJ, Galie' N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. American Journal of Respiratory and Critical Care Medicine.

[179] Mubarak KK. A review of prostaglandin analogues in the management of patients with pulmonary arterial hypertension. Respiratory Medicine. 2010;**104**:9-21

[180] McLaughlin VV, Channick R, Chin KM, et al. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: Results of the GRIPHON study. Journal of the American College of Cardiology.

[181] Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. The New England Journal of Medicine.

[182] Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. The European Respiratory Journal.

[183] Galie N, Barbara JA, Frost A, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New England Journal of Medicine.

[184] Coghlan JG, Galie' N, Barbera JA, et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): Subgroup analysis from the AMBITION trial. Annals of the Rheumatic Diseases.

[185] Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. American

Medicine. 2015;**192**:1102-1110

et al. Pharmacologic therapy for pulmonary arterial hypertension in

Journal of Respiratory and Critical Care

[186] Taichman DB, Ornelas J, Chung L,

2015;**65**(Suppl A):A380

2015;**373**:2522-2533

2017;**50**:1602493

2015;**379**:834-844

2017;**76**:1219-1227

[172] Barst RJ, Galie' N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. The European Respiratory Journal.

[173] McLaughlin V, Rubin L, Benza RL, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: A randomized controlled clinical trial. Journal of the American College of Cardiology.

[174] Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: A randomized, controlled trial. Circulation. 2013;**127**:624-633

[175] Olschewski H, Simmoneau G, Galie' N, et al. Inhaled iloprost in severe pulmonary hypertension. The New England Journal of Medicine.

[176] Higenbottam T, Butt AY, McMahon

prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart. 1998;**80**:151-155

[177] Norel X. Prostanoid receptors in the human vascular wall. Scientific World Journal. 2007;**7**:1359-1374

[178] Humbert M, Lau EM, Montani D,

et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;**130**:2189-2208

A, et al. Long-term intravenous

**38**

[187] Kurzyna M, Dabrowski M, Bielecki D, et al. Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension. Chest. 2007;**131**:977-983

[188] Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. Journal of the American College of Cardiology. 1998;**32**:297-304

[189] Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A systematic review. Respiratory Medicine. 2013;**107**:2081-2087

[190] deMendonca L, Felix ND, Blanco NG, et al. Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension. Stem Cell Research and Therapy. 2017;**8**:220

[191] Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006;**114**:1482-1489

[192] Grunig E, Maier F, Ehlken N, et al. Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. Arthritis Research and Therapy. 2012;**14**:R148

[193] Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology. 2005;**102**:1133-1137

[194] Guillevin L, Armstrong I, Aldrighetti R, et al. Understanding the impact of pulmonary arterial hypertension on patients' and carers' lives. European Respiratory Review. 2013;**22**:535-542

[195] Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2013;**62**(Suppl):D13-D21

[196] Ramakrishnan G, Sprung J, Ravi BS, et al. Impact of pulmonary hypertension on the outcomes of noncardiac surgery: Predictors of perioperative mobidity and mortality. Journal of the American College of Cardiology. 2005;**45**:1691-1699

[197] McGlothlin D, DeMarco T. Preoperative risk assessment of pulmonary arterial hypertension. Patients undergoing general surgery. Advances in Pulmonary Arterial Hypertension. 2007;**6**(2):66-73

[198] Minai OA, Yared JP, Kaw R, et al. Perioperative risk and management in patients with pulmonary hypertension. Chest. 2013;**144**:329-340

[199] Meyer S, McLaughlin VV, Seyfarth HJ, et al. Outcomes of noncardiac, nonobstetric surgery in patients with PAH: An international prospective survey. The European Respiratory Journal. 2013;**41**:1302-1307

**41**

subsets.

**Chapter 2**

**Abstract**

possibilities.

diagnosis, management

vasculitis/glomerulonephritis.

**1. Introduction**

Sclerosis

*and Roman Safranek*

Renal Involvement in Systemic

*Tomas Soukup, Jan Toms, Sabina Oreska, Eva Honsova*

Scleroderma renal crisis (SRC) is classical renal disease in systemic sclerosis (SSc). SRC is a relatively rare manifestation, approximately in 5% of patients. In terms of severity, manifestation in the form of SRC is the most common cause of acute organ failure. In SSc patients, SRC is defined as a new onset of accelerated arterial hypertension and rapidly progressive anuric or oliguric renal failure. SRC is primarily vascular injury with increased activity of the renin-angiotensin activity. These events lead to release or activation of cytokines and growth factors that result in the typical proliferative vascular lesions. Successful approach is routine use of angiotensin-converting enzyme inhibitors in the treatment of SRC (except prevention) and other advances in renal replacement therapy in SSc management. It is crucial to detect manifestations of SRC early and to manage appropriately in collaboration with intensive care medicine, cardiologists, and nephrologists. In contrast to SRC, clinical presentation of interstitial renal disease is poor, often without evidence of renal abnormality. Interestingly, other renal manifestations are glomerulonephritis and vasculitis. These manifestations are associated with overlapping mechanisms. The objective of this chapter is to focus on actual knowledge about the renal involvement in SSc and current treatment principles and

**Keywords:** kidney, systemic sclerosis, scleroderma renal crisis, glomerulonephritis,

Systemic sclerosis (SSc) leads to morbidity and mortality through a combination of inflammation, fibrosis, and vascular damage leading to internal organ complications affecting the heart, lung, bowel, and kidneys. In SSc, we observe kidney

Most often, SSc causes a range of renal manifestations, which occur in both subsets of the disease: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc)

As overlaps are often seen in connective tissue diseases, SSc should be associated with other immunological features of renal disease findings typical for systemic lupus erythematosus (as lupus glomerulonephritis) and ANCA-associated

involvement as three main clinical situations described below.

### **Chapter 2**
