Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, classification, risk factors, screening, and prognosis
- John Varga, MD
John Varga, MD
- John and Nancy Hughes Professor of Medicine
- Northwestern University Feinberg School of Medicine
- Virginia Steen, MD
Virginia Steen, MD
- Professor of Medicine
- Georgetown University Medical Center
- Section Editors
- Talmadge E King, Jr, MD
Talmadge E King, Jr, MD
- Editor-in-Chief — Pulmonary and Critical Care Medicine
- Section Editor — Interstitial Lung Disease
- Dean, School of Medicine
- Vice Chancellor, Medical Affairs
- University of California San Francisco
- John S Axford, DSc, MD, FRCP, FRCPCH
John S Axford, DSc, MD, FRCP, FRCPCH
- Section Editor — Scleroderma
- Emeritus Professor of Rheumatology
- St George's University of London
Pulmonary complications of systemic sclerosis (SSc) are common, and are the leading cause of SSc-related death. The most common pulmonary manifestations of SSc are pulmonary hypertension (PH), interstitial lung disease (ILD), and any combination thereof.
The classification, definition, risk factors, screening, and prognosis of SSc-associated pulmonary arterial hypertension (PAH), specifically group 1 PAH, are reviewed here. Group 2 PH and group 3 PH are discussed separately. (See "Pulmonary hypertension associated with interstitial lung disease" and "Treatment of pulmonary hypertension in adults", section on 'Group 2 PH' and "Treatment of pulmonary hypertension in adults", section on 'Group 3 PH'.)
The evaluation and diagnosis of lung disease in SSc as well as clinical manifestations, diagnosis, and treatment of SSc-associated pulmonary arterial hypertension are discussed elsewhere. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment" and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)
Many different forms of pulmonary hypertension (PH) occur in systemic sclerosis (SSc). The World Health Organization (WHO) classifies patients with PH into five groups, as shown in the table (table 1) . SSc is most often associated with group 1 pulmonary arterial hypertension (PAH) and group 3 PH, and less commonly with group 2 PH. Due to the varied and sometimes mixed etiology underlying PH in SSc, the precise classification of the type of PH can be challenging.
The following is a brief description of the WHO classification of PH:
- Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54:S43.
- Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:S55.
- Steen V, Chou M, Shanmugam V, et al. Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis. Chest 2008; 134:146.
- Wigley FM, Lima JA, Mayes M, et al. 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; 52:2125.
- Hesselstrand R, Ekman R, Eskilsson J, et al. Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992-2001. Rheumatology (Oxford) 2005; 44:366.
- Codullo V, Caporali R, Cuomo G, et al. Stress Doppler echocardiography in systemic sclerosis: evidence for a role in the prediction of pulmonary hypertension. Arthritis Rheum 2013; 65:2403.
- 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; 52:3792.
- Coghlan JG, Denton CP, Grünig E, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 2014; 73:1340.
- Yang X, Mardekian J, Sanders KN, et al. Prevalence of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review of the literature. Clin Rheumatol 2013; 32:1519.
- Muangchan C, Canadian Scleroderma Research Group, Baron M, Pope J. The 15% rule in scleroderma: the frequency of severe organ complications in systemic sclerosis. A systematic review. J Rheumatol 2013; 40:1545.
- Schachna L, Wigley FM, Chang B, et al. Age and risk of pulmonary arterial hypertension in scleroderma. Chest 2003; 124:2098.
- 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; 62:1088.
- Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken) 2014; 66:489.
- Lefèvre G, Dauchet L, Hachulla E, et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum 2013; 65:2412.
- Hinchcliff M, Fischer A, Schiopu E, et al. Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): baseline characteristics and description of study population. J Rheumatol 2011; 38:2172.
- 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; 179:151.
- Humbert M, Yaici A, de Groote P, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum 2011; 63:3522.
- 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; 182:252.
- Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007; 66:940.
- Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002; 81:139.
- Avouac J, Airò P, Meune C, et al. Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and metaanalysis of 5 studies. J Rheumatol 2010; 37:2290.
- 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. J Rheumatol 2006; 33:269.
- Scorza R, Caronni M, Bazzi S, et al. Post-menopause is the main risk factor for developing isolated pulmonary hypertension in systemic sclerosis. Ann N Y Acad Sci 2002; 966:238.
- Cox SR, Walker JG, Coleman M, et al. Isolated pulmonary hypertension in scleroderma. Intern Med J 2005; 35:28.
- Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35:35.
- Hunzelmann N, Genth E, Krieg T, et al. The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology (Oxford) 2008; 47:1185.
- Shah AA, Wigley FM, Hummers LK. Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol 2010; 37:98.
- Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003; 48:516.
- 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; 58:284.
- Iudici M, van der Goes MC, Valentini G, Bijlsma JW. Glucocorticoids in systemic sclerosis: weighing the benefits and risks - a systematic review. Clin Exp Rheumatol 2013; 31:157.
- Kampolis C, Plastiras S, Vlachoyiannopoulos P, et al. The presence of anti-centromere antibodies may predict progression of estimated pulmonary arterial systolic pressure in systemic sclerosis. Scand J Rheumatol 2008; 37:278.
- Steen VD, Lucas M, Fertig N, Medsger TA Jr. Pulmonary arterial hypertension and severe pulmonary fibrosis in systemic sclerosis patients with a nucleolar antibody. J Rheumatol 2007; 34:2230.
- Aggarwal R, Lucas M, Fertig N, et al. Anti-U3 RNP autoantibodies in systemic sclerosis. Arthritis Rheum 2009; 60:1112.
- Assous N, Allanore Y, Batteux F, et al. Prevalence of antiphospholipid antibodies in systemic sclerosis and association with primitive pulmonary arterial hypertension and endothelial injury. Clin Exp Rheumatol 2005; 23:199.
- Marie I, Jouen F, Hellot MF, Levesque H. Anticardiolipin and anti-beta2 glycoprotein I antibodies and lupus-like anticoagulant: prevalence and significance in systemic sclerosis. Br J Dermatol 2008; 158:141.
- Pasarikovski CR, Granton JT, Roos AM, et al. Sex disparities in systemic sclerosis-associated pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2016; 18:30.
- 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; 35:95.
- Thakkar V, Stevens WM, Prior D, et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther 2012; 14:R143.
- Hummers LK, Hall A, Wigley FM, Simons M. Abnormalities in the regulators of angiogenesis in patients with scleroderma. J Rheumatol 2009; 36:576.
- 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; 63:2790.
- Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum 2013; 65:3194.
- Fischer A, Bull TM, Steen VD. Practical approach to screening for scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 2012; 64:303.
- Gladue H, Steen V, Allanore Y, et al. Combination of echocardiographic and pulmonary function test measures improves sensitivity for diagnosis of systemic sclerosis-associated pulmonary arterial hypertension: analysis of 2 cohorts. J Rheumatol 2013; 40:1706.
- Avouac J, Huscher D, Furst DE, et al. Expert consensus for performing right heart catheterisation for suspected pulmonary arterial hypertension in systemic sclerosis: a Delphi consensus study with cluster analysis. Ann Rheum Dis 2014; 73:191.
- Khanna D, Tan M, Furst DE, et al. Recognition of pulmonary hypertension in the rheumatology community: lessons from a Quality Enhancement Research Initiative. Clin Exp Rheumatol 2014; 32:S.
- 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; 167:735.
- Bae S, Saggar R, Bolster MB, et al. Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry. Ann Rheum Dis 2012; 71:1335.
- MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001; 40:453.
- Valerio CJ, Schreiber BE, Handler CE, et al. Borderline mean pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary hypertension. Arthritis Rheum 2013; 65:1074.
- 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), et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34:1219.
- Gargani L, Pignone A, Agoston G, et al. Clinical and echocardiographic correlations of exercise-induced pulmonary hypertension in systemic sclerosis: a multicenter study. Am Heart J 2013; 165:200.
- Hachulla E, Carpentier P, Gressin V, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study. Rheumatology (Oxford) 2009; 48:304.
- 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; 60:569.
- 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; 140:1016.
- Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 2006; 54:3043.
- Rubenfire M, Huffman MD, Krishnan S, et al. Survival in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern era. Chest 2013; 144:1282.
- Chung L, Farber HW, Benza R, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest 2014; 146:1494.
- Ngian GS, Stevens W, Prior D, et al. Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2012; 14:R213.
- Williams MH, Das C, Handler CE, et al. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart 2006; 92:926.
- Tedford RJ, Mudd JO, Girgis RE, et al. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 2013; 6:953.
- Sobanski V, Giovannelli J, Lynch BM, et al. Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. Arthritis Rheumatol 2016; 68:484.
- WHO CLASSIFICATION
- RISK FACTORS
- - Long-standing SSc
- - Limited cutaneous SSc
- Abnormal pulmonary function (low diffusion)
- Our approach
- Right heart catheterization
- SUMMARY AND RECOMMENDATIONS