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Pulmonary vascular disease in systemic sclerosis (scleroderma): Definition, classification, risk factors, screening, and prognosis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Mar 21, 2012.

INTRODUCTION — Pulmonary complications of systemic sclerosis (SSc) are both frequent and the leading cause of SSc-related death [1,2]. The most common pulmonary manifestations of SSc are the following:

  • Pulmonary arterial hypertension (PAH)
  • Interstitial lung disease (ILD)
  • Pulmonary hypertension (PH) due to ILD
  • A combination of ILD and PAH

The classification, definition, risk factors, screening, and prognosis of SSc-associated PAH are reviewed here, while the clinical manifestations, diagnosis, and treatment of SSc-associated PAH are discussed elsewhere. (See "Clinical manifestations of systemic sclerosis (scleroderma) lung disease", section on 'Pulmonary arterial hypertension' and "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment".)

The other types of SSc-related lung disease are also discussed separately, including ILD and ILD-associated PH. (See "Clinical manifestations of systemic sclerosis (scleroderma) lung disease", section on 'Interstitial lung disease' and "Prognosis and treatment of interstitial lung disease in systemic sclerosis (scleroderma)" and "Pulmonary hypertension associated with interstitial lung disease".)

CLASSIFICATION — The World Health Organization (WHO) classifies patients with pulmonary hypertension into five groups, as shown in the table (table 1) [3]. (See "Overview of pulmonary hypertension", section on 'Classification'.)

Patients in the first group are considered to have pulmonary arterial hypertension (PAH). In contrast, patients in the remaining four groups are considered to have pulmonary hypertension (PH):

  • Group 2 PH consists of patients who have pulmonary venous hypertension, which is usually due to left heart disease
  • Group 3 PH includes patients who have PH due to lung disease and/or chronic hypoxemia (ie, interstitial lung disease, chronic obstructive airways disease, and obstructive sleep apnea)
  • Group 4 PH consists of patients with chronic thromboembolic pulmonary hypertension
  • Group 5 PH includes patients whose PH is of uncertain cause and likely multifactorial

When all five groups are described collectively, the term PH is used.

Systemic sclerosis (SSc) is unique among the different forms of PH because it can be associated with group 1 PAH or group 3 PH. In addition, patients with SSc frequently have diastolic dysfunction and group 2 PH. As a result, the precise classification of the type of PH can be challenging in patients with SSc.

Group 1 PAH is the focus of this review. Group 2 PH and group 3 PH are discussed separately. (See "Pulmonary hypertension associated with interstitial lung disease" and "Treatment of pulmonary hypertension", section on 'Group 2 PH' and "Treatment of pulmonary hypertension", section on 'Group 3 PH'.)

DEFINITION — Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest (measured by right heart catheterization) with a wedge pressure less than or equal to 15 mmHg in a patient who has systemic sclerosis without significant coexisting interstitial lung disease and chronic hypoxemia [4].

RISK FACTORS — It is important to recognize patients who are at increased risk for developing systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH). Vigilant monitoring and early detection facilitates the timely initiation of therapy, which improves symptoms and may prolong survival. (See "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment", section on 'Directed therapy'.)

The following risk factors for PAH have been identified in patients with SSc:

  • Long-standing limited cutaneous SSc with a positive anti-centromere antibody. The total burden of cutaneous telangiectasias correlates positively with the risk of PAH [5].
  • Patients with diffuse cutaneous SSc tend to develop PAH less commonly; however, those with a nucleolar pattern of anti-nuclear antibody (ANA) are at increased risk [6].
  • Progressive decrease of the diffusion capacity (DLCO) over serial measurements. This was demonstrated by a case control study of 212 patients with limited cutaneous SSc [7]. Patients with PAH were matched to patients without PAH according to age, gender, extent of skin involvement, and disease duration. The mean DLCO was 52 percent of predicted five years before PAH developed. A linear decline of 50 percent was found over a 10 to 15 year period among patients who developed PAH. In contrast, the DLCO remained unchanged in patients who did not develop PAH.
  • Exercise-induced PH on right heart catheterization [8,9]. Nearly 20 percent of patients with SSc and exercise-induced PH may progress to PAH, according to an observational study [9].

In contrast to these risk factors, patients with Scl 70 autoantibodies are more likely to have PH associated with interstitial lung disease (group 3 PH). Patients with SSc who have anti-RNA polymerase III autoantibodies characteristically have extensive skin involvement and increased risk for scleroderma renal crisis, but uncommonly develop PAH [6].

SCREENING — Patients with systemic sclerosis (SSc) who have never been diagnosed with pulmonary vascular disease have been screened for pulmonary arterial hypertension (PAH) in numerous observational studies. Doppler echocardiography was the most common screening method, but exercise echocardiography and diagnostic algorithms were also used:

  • Doppler echocardiography – In a study that included 669 patients with SSc or mixed connective tissue disease, 13 percent had an elevated right ventricular systolic pressure (an indicator of PAH) [10]. In another study of 227 patients with SSc, serial Doppler echocardiograms found a high tricuspid gradient (also an indicator of PAH) in 11 percent of patients during the initial echocardiogram and 17 percent during a subsequent echocardiogram [11].
  • Exercise echocardiography – A study of 54 patients with SSc found that 44 percent had an abnormal response to exercise (defined as a ≥20 mmHg increase of the estimated pulmonary arterial systolic pressure during exercise, as measured echocardiographically) [8]. Right heart catheterization confirmed the presence of resting or exercise induced PAH in 81 percent of these patients. Thus, resting PAH was identified in nearly 36 percent of the study population. Of note, the abnormal response to exercise strongly correlated with a very low diffusion capacity (DLCO) and a high forced vital capacity to DLCO ratio (FVC/DLCO).
  • Diagnostic algorithms – A study of 709 patients who had SSc identified PAH in 8 percent of the patients using an algorithm that included Doppler echocardiography and right heart catheterization [12].

Taken together, the studies have estimated that the prevalence of PAH is 8 to 37 percent among patients with SSc who have never been diagnosed with pulmonary vascular disease range [8,10-12]. This high prevalence, combined with the high mortality rate of SSc-associated PAH and the observation that early detection of milder disease is associated with better survival [9,13], has been used as an argument to screen patients who have SSc for PAH.

These factors must be weighed against the potential pitfalls of screening, which include the impact of false positive and false negative results. False positive results may lead to unnecessary right heart catheterization and related complications, as well as unnecessary patient anxiety. False negative results may lead to false reassurance and decreased vigilance in the clinical assessment of symptoms and signs of PAH, ultimately delaying diagnosis and therapy. False positive and false negative results are most common among patients who have interstitial lung disease [14].

We believe that all patients with SSc should be monitored for the development of PAH as follows:

  • Patients should be evaluated regularly and thoroughly for symptoms and/or signs of PAH. The symptoms and signs of PAH are described separately. (See "Overview of pulmonary hypertension", section on 'Clinical manifestations'.)
  • Patients should have a baseline and yearly pulmonary function tests (PFTs) to look for changes in the diffusion capacity (DLCO) [15,16]. Patients who have no dyspnea or exercise tolerance, and who have had a persistently normal DLCO over ten years of disease, may have the frequency of their PFTs decreased to every two years [16].
  • Patients should have an echocardiogram performed every two years [16].

A diagnostic evaluation should be initiated if any symptoms or signs of pulmonary vascular disease develop, the DLCO is reduced (<70 percent of predicted), the DLCO is decreased disproportionately to the FVC (ie, FVC percent/DLCO percent >1.6), or an echocardiogram has evidence of pulmonary vascular disease (eg, right ventricular dysfunction, an elevated tricuspid regurgitant velocity, or an increased estimated pulmonary arterial systolic pressure). The diagnostic evaluation of suspected SSc-associated PAH is the same as that for other types of PAH, which is discussed in detail elsewhere. Suspected SSc-associated PAH should not be treated without first performing a right heart catheterization. (See "Diagnostic evaluation of pulmonary hypertension".)

PROGNOSIS — Pulmonary arterial hypertension (PAH) is an independent risk factor for mortality among patients with systemic sclerosis (SSc) [17]. The severity of the PAH and the presence of coexisting interstitial lung disease (ILD) directly correlate with mortality [9,18-20]:

  • A prospective cohort study of 794 patients with SSc found a prevalence of PAH of 12 percent, which was confirmed by right heart catheterization [19]. The two year mortality rates among patients with mean pulmonary artery pressures of <32 mmHg and >45 mmHg were 22 and 61 percent, respectively. A high right atrial pressure (indicative of right ventricular failure) was the strongest hemodynamic predictor of mortality.
  • A prospective cohort study of 59 patients with SSc and pulmonary hypertension (confirmed by right heart catheterization) compared patients with coexisting ILD to patients without ILD [20]. Survival was significantly worse among patients with coexisting ILD (46 versus 79 percent). Most of the deaths among the patients with ILD were due to respiratory failure, whereas most of the deaths among patients without ILD were due to right heart failure [20]. These findings were supported by a subsequent retrospective cohort study of 97 patients, which found that patients with SSc-associated ILD and pulmonary hypertension (confirmed by right heart catheterization) had a worse three-year survival than patients with SSc-associated PAH (47 versus 71 percent) [21].

Progression of SSc-associated PAH is not inevitable. In one observational study of patients with SSc, 30 percent of those who had an estimated pulmonary artery pressure of >30 mmHg on an echocardiogram were found to have an estimated pulmonary artery pressure <30 mmHg two years later.

The prognosis for patients with SSc-associated PAH is worse than that for patients with idiopathic pulmonary arterial hypertension (IPAH). This was suggested by a retrospective cohort study of 91 patients that found that patients with SSc-associated PAH had one-, two-, and three-year survival rates of 87, 64, and 64 percent, respectively [22]. In contrast, patients with IPAH had one-, two-, and three-year survival rates of 91, 88, and 78 percent, respectively. Patients with SSc-associated PAH also had higher serum levels of N-terminal brain natriuretic peptide (NT-BNP) than patients with IPAH [22,23]. NT-BNP is an index of cardiac strain.

Survival among patients with SSc-associated PAH appears to have improved modestly over the past decade. This is most likely the consequence of earlier diagnosis and more effective supportive and directed therapies. A prospective cohort study of 92 patients with SSc-associated PAH (confirmed by right heart catheterization) compared the survival of patients prior to 2002 with that of patients in the current treatment era [24]. Two year survival was significantly better in the current era (71 versus 47 percent). Therapy generally consisted of diuretics, digoxin, oxygen, warfarin, and prostanoids prior to 2002, but the endothelin-1 antagonists became the most frequently used first-line therapy during the current era.

Despite its improvement, the mortality rate of SSc-associated PAH remains unacceptably high, particularly when associated with ILD. Treatment of SSc-associated PAH is reviewed separately. (See "Pulmonary vascular disease in systemic sclerosis (scleroderma): Treatment".)

SUMMARY AND RECOMMENDATIONS

  • Pulmonary hypertension is a common and serious complication of systemic sclerosis (SSc). (See 'Introduction' above.)
  • Pulmonary hypertension is classified into five groups by the World Health Organization (WHO) (table 1). SSc can be associated with group 1 pulmonary arterial hypertension (PAH) or group 3 pulmonary hypertension (PH) secondary to interstitial lung disease. In addition, patients with SSc frequently have diastolic dysfunction and group 2 PH. (See 'Classification' above.)
  • SSc-associated PAH is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest (measured by right heart catheterization), with a wedge pressure less than or equal to 15 mmHg in a patient who has SSc without significant coexisting interstitial lung disease causing chronic hypoxia. (See 'Definition' above.)
  • Risk factors for PAH among patients with SSc include the following: long-standing limited cutaneous SSc with a positive anti-centromere antibody, numerous cutaneous telangiectasia, diffuse cutaneous SSc associated with a nucleolar pattern of antinuclear antibody (ANA), an isolated decrease in the diffusion capacity (DLCO) less than 60 percent predicted or a progressive decrease of the diffusion capacity (DLCO), and exercise-induced PH on right heart catheterization. (See 'Risk factors' above.)
  • Estimates of the prevalence of unrecognized PAH among patients with SSc range from 8 to 37 percent. (See 'Screening' above.)
  • We believe that all patients with SSc should be evaluated regularly and thoroughly for symptoms and/or signs of PAH, as well as having regular pulmonary function tests (PFTs) to look for changes in the diffusion capacity (DLCO). We do not advocate routine screening for PAH in patients who do not have pulmonary symptoms and who have a normal DLCO. However, yearly PFTs and echocardiograms should be considered if the DLCO is decreased (<70 percent of predicted). Clinicians should maintain a low threshold to initiate a diagnostic evaluation if any symptoms or signs of pulmonary vascular disease develop. (See 'Screening' above.)
  • PAH is an independent risk factor for mortality among patients with SSc. The severity of the PAH and the presence of coexisting interstitial lung disease each directly correlate with mortality. (See 'Prognosis' above.)

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REFERENCES

  1. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007; 66:940.
  2. 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.
  3. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54:S43.
  4. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:S55.
  5. Shah AA, Wigley FM, Hummers LK. Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol 2010; 37:98.
  6. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35:35.
  7. Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003; 48:516.
  8. Steen V, Chou M, Shanmugam V, et al. Exercise-induced pulmonary arterial hypertension in patients with systemic sclerosis. Chest 2008; 134:146.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Schreiber BE, Valerio CJ, Keir GJ, et al. Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests. Arthritis Rheum 2011; 63:3531.
  16. Fischer A, Bull TM, Steen VD. Practical approach to screening for scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 2012; 64:303.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 2006; 54:3043.
  23. 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.
  24. Williams MH, Das C, Handler CE, et al. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart 2006; 92:926.
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