Overview of pulmonary complications of systemic sclerosis (scleroderma)
- John Varga, MD
John Varga, MD
- John and Nancy Hughes Professor of Medicine
- Northwestern University Feinberg School of Medicine
- 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 involvement occurs in over 80 percent of patients with systemic sclerosis (SSc) and is second in frequency only to esophageal involvement as a visceral complication . It has surpassed renal involvement as the most common cause of death.
Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most frequent major types of lung involvement. Affected patients have a poorer prognosis than those with SSc who are free of pulmonary involvement.
The spectrum of pulmonary complications of SSc and an approach to their evaluation will be reviewed here. The clinical manifestations, diagnosis, therapy, and prognosis of SSc-associated ILD and PAH are discussed separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, classification, risk factors, screening, and prognosis".)
INFLUENCE OF DIFFUSE CUTANEOUS AND LIMITED CUTANEOUS DISEASE
Two major types of SSc are commonly recognized and are based on whether the extent of skin involvement is limited or diffuse. The type of cutaneous involvement correlates with the risk for different types of lung involvement, although substantial overlap exists. (See "Overview and classification of scleroderma disorders" and "Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults".)
●Diffuse cutaneous SSc is characterized by extensive skin involvement with extension of skin sclerosis proximal to the wrists (particularly over the proximal limbs and trunk but commonly sparing the upper back). Approximately one third of patients with SSc have diffuse skin involvement. Patients with diffuse skin involvement due to SSc have a greater likelihood of developing interstitial lung disease (ILD; and also cardiac and renal disease), compared with those who have limited cutaneous SSc [2-4].
- 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.
- Fischer A, Swigris JJ, Groshong SD, et al. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest 2008; 134:601.
- Gilson M, Zerkak D, Wipff J, et al. Prognostic factors for lung function in systemic sclerosis: prospective study of 105 cases. Eur Respir J 2010; 35:112.
- Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35:35.
- Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002; 165:1581.
- Chung WS, Lin CL, Sung FC, et al. Systemic sclerosis increases the risks of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Rheumatology (Oxford) 2014; 53:1639.
- 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; 80:435.
- Humbert M, Maître S, Capron F, et al. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am J Respir Crit Care Med 1998; 157:1681.
- Günther S, Jaïs X, Maitre S, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64:2995.
- 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; 38:893.
- Thompson AE, Pope JE. A study of the frequency of pericardial and pleural effusions in scleroderma. Br J Rheumatol 1998; 37:1320.
- King TE Jr, Kim EJ, Kinder BW. Connective tissue diseases. In: Interstitial Lung Disease, 5th, Schwartz MI, King TE Jr. (Eds), People's Medical Publishing House, Shelton, CT 2011. p.689.
- Gómez Carrera L, Bonilla Hernan G. Pulmonary manifestations of collagen diseases. Arch Bronconeumol 2013; 49:249.
- Yoon J, Finger DR, Pina JS. Spontaneous pneumothorax in scleroderma. J Clin Rheumatol 2004; 10:207.
- Zeuner M, Müller-Ladner U, Mohr VD, Lang B. Spontaneous pneumothorax in a patient with systemic sclerosis. Clin Rheumatol 1996; 15:211.
- Johnson DA, Drane WE, Curran J, et al. Pulmonary disease in progressive systemic sclerosis. A complication of gastroesophageal reflux and occult aspiration? Arch Intern Med 1989; 149:589.
- Savarino E, Bazzica M, Zentilin P, et al. Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring. Am J Respir Crit Care Med 2009; 179:408.
- de Souza RB, Borges CT, Capelozzi VL, et al. Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis. Respiration 2009; 77:389.
- Richardson C, Agrawal R, Lee J, et al. Esophageal dilatation and interstitial lung disease in systemic sclerosis: A cross-sectional study. Semin Arthritis Rheum 2016; 46:109.
- Marie I, Dominique S, Levesque H, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum 2001; 45:346.
- Zhang XJ, Bonner A, Hudson M, et al. Association of gastroesophageal factors and worsening of forced vital capacity in systemic sclerosis. J Rheumatol 2013; 40:850.
- Quadrelli SA, Molinari L, Ciallella LM, et al. Patterns of pulmonary function in smoking and nonsmoking patients with progressive systemic sclerosis. Rheumatol Int 2009; 29:995.
- Bjerke RD, Tashkin DP, Clements PJ, et al. Small airways in progressive systemic sclerosis (PSS). Am J Med 1979; 66:201.
- Boehler A, Vogt P, Speich R, et al. Bronchiolitis obliterans in a patient with localized scleroderma treated with D-penicillamine. Eur Respir J 1996; 9:1317.
- Alekperov RT, Avdeev SN, Kotovskaia MA. [Obliterating bronchiolitis induced by D-penicillamine in the female patient with systemic scleroderma]. Ter Arkh 2004; 76:74.
- Bruguera-Àvila N, Sánchez-Martínez E, Garcia-Olivé I, et al. Obliterating bronchiolitis in a patient treated with (D)-penicillamine. Arch Bronconeumol 2013; 49:411.
- Harrison NK, Myers AR, Corrin B, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis 1991; 144:706.
- Andonopoulos AP, Yarmenitis S, Georgiou P, et al. Bronchiectasis in systemic sclerosis. A study using high resolution computed tomography. Clin Exp Rheumatol 2001; 19:187.
- Lavie F, Rozenberg S, Coutaux A, et al. Bronchiectasis in a patient with CREST syndrome. Joint Bone Spine 2002; 69:515.
- Katzen JB, Raparia K, Agrawal R, et al. Early stage lung cancer detection in systemic sclerosis does not portend survival benefit: a cross sectional study. PLoS One 2015; 10:e0117829.
- Pugazhenthi M, Cooper D, Ratnakant BS, et al. Hypercapnic respiratory failure in systemic sclerosis. J Clin Rheumatol 2003; 9:43.
- Chausow AM, Kane T, Levinson D, Szidon JP. Reversible hypercapnic respiratory insufficiency in scleroderma caused by respiratory muscle weakness. Am Rev Respir Dis 1984; 130:142.
- 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.
- 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.
- 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 Rheum 2003; 48:3503.
- Mukerjee D, Yap LB, Holmes AM, et al. Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension. Respir Med 2003; 97:1230.
- 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; 27:1485.
- Cavagna L, Caporali R, Klersy C, et al. Comparison of brain natriuretic peptide (BNP) and NT-proBNP in screening for pulmonary arterial hypertension in patients with systemic sclerosis. J Rheumatol 2010; 37:2064.
- Behr J, Furst DE. Pulmonary function tests. Rheumatology (Oxford) 2008; 47 Suppl 5:v65.
- Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003; 48:516.
- Suliman YA, Dobrota R, Huscher D, et al. Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease. Arthritis Rheumatol 2015; 67:3256.
- Roth MD, Tseng CH, Clements PJ, et al. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum 2011; 63:2797.
- 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.
- Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. J Rheumatol 2003; 30:2398.
- 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.
- INFLUENCE OF DIFFUSE CUTANEOUS AND LIMITED CUTANEOUS DISEASE
- TYPES OF PULMONARY INVOLVEMENT
- Interstitial lung disease
- Pulmonary vascular disease
- - Pulmonary hypertension
- - Thromboembolic disease
- - Pulmonary capillary hemangiomatosis and veno-occlusive disease
- Pleural effusion
- Spontaneous pneumothorax
- Recurrent aspiration
- Drug-associated pneumonitis
- Airways disease
- Lung cancer
- Respiratory muscle weakness
- EVALUATION FOR LUNG DISEASE AT TIME OF SSC PRESENTATION
- Clinical assessment
- Laboratory testing
- Pulmonary function testing
- SUBSEQUENT MONITORING
- DIAGNOSIS OF LUNG DISEASE IN SYSTEMIC SCLEROSIS
- Interstitial lung disease
- Pulmonary hypertension
- Other pulmonary complications
- SUMMARY AND RECOMMENDATIONS