Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening

INTRODUCTION — 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 systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH), specifically group 1 pulmonary arterial hypertension (PAH), are reviewed here. Group 2 PH and group 3 PH are discussed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

The evaluation and diagnosis of lung disease in SSc as well as clinical manifestations, diagnosis, and treatment of SSc-PAH 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 arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis" and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

CLASSIFICATION — Many different forms of pulmonary hypertension (PH) occur in systemic sclerosis (SSc). Patients with PH are classified into five groups, as shown in the table (table 1) [1]. SSc is most often associated with group 1 pulmonary arterial hypertension (PAH) and group 3 PH (PH due to chronic lung disease and/or chronic hypoxemia), and less commonly with group 2 PH (pulmonary venous hypertension, which is usually due to left heart disease). Due to the varied and sometimes mixed etiology underlying PH in SSc, the precise classification of the type of PH can be challenging.

When all five groups are described collectively, the term PH is used. When referring to patients in group 1, the term PAH is used (the focus of this topic). A more detailed description of the classification of PH is discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

DEFINITION — Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is defined as a mean pulmonary artery pressure (PAP) greater than 20 mmHg supine and at rest (measured by right heart catheterization [RHC]), a wedge pressure less than or equal to 15 mmHg, and a peripheral pulmonary vascular resistance ≥2 Wood units in a patient who has systemic sclerosis (SSc) without chronic hypoxemia from coexisting interstitial lung disease (ILD) [2]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

EPIDEMIOLOGY — The prevalence of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) is unknown, but estimated on average to range from 10 to 15 percent [3-15]. PAH is the leading cause of death in SSc, with two-year survival rates ranging from 64 to 89 percent [12,16,17]. In addition, a significant proportion of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PAH; approximately 22 percent) are asymptomatic at diagnosis [16,18]. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Prognosis'.)

RISK FACTORS — On average, 10 to 15 percent of patients with systemic sclerosis (SSc) develop pulmonary arterial hypertension (PAH) [3-10,14,15]. SSc patients who are at greatest risk for PAH are those with the following (table 2):

●Long-standing limited cutaneous SSc (lcSSc).

●Low (<80 percent predicted) or progressive decline in the diffusion capacity of carbon monoxide (DLCO), and/or a high forced vital capacity (FVC)/DLCO ratio (FVC/DLCO >1.6).

●Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP).

●Anticentromere, anti-U1-ribonuleoprotein (RNP), and nucleolar pattern antinuclear antibodies (nucleolar-ANA).

●Extensive cutaneous telangiectasia.

Clinical

Long-standing SSc — Long-standing SSc has been associated with the development of PAH in several studies [11,19-21]. One meta-analysis reported longer SSc disease duration correlated positively with the development of PAH [19]. Age has also been identified as a risk factor for the development in PAH in SSc. It is thought that this may be due to an association between age and long-standing disease. A prospective observational study of 709 SSc patients reported a 22 percent increase in the risk of PAH for every 10 years after disease onset [11]. In the same study, patients >60 years had a twofold greater risk of PAH compared with those <60 years.

Limited cutaneous SSc — Limited cutaneous SSc (LcSSc) has historically been associated with an increased risk for the development of PAH [22]. Most series of PAH in scleroderma have significantly more patients with lcSSc. However, subsequent studies have more carefully evaluated patients with the diffuse form of cutaneous SSc (dcSSc) and PAH is more frequent in this population than initially thought [23]. For example one 2008 study reported that the prevalence of PAH was similar in both SSc subsets [24]. Since dcSSc patients are more likely to have pulmonary or cardiac fibrosis, distinguishing PAH from other types of PH in these patients is challenging.

Patients with lcSSc have skin manifestation limited to the hands and frequently have prominent vascular manifestations (eg, Raynaud phenomenon and telangiectasia). The total burden of cutaneous telangiectasias, common in lcSSc, also correlates positively with the risk of PAH [25]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

Abnormal pulmonary function (low diffusion) — Low or progressive decline in the DLCO in patients with SSc is considered a risk factor for the development of PAH [3,26-28]. This was best demonstrated by a case control study of 106 patients with lcSSc with PAH who were matched to patients without PAH according to age, sex, extent of skin involvement, and disease duration [26]. Compared with controls, patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc–PAH), had a lower DLCO (52 versus 81 percent of predicted) that preceded the development of PAH by, on average, five years. In addition, the DLCO declined linearly in patients with PAH over a 10- to 15-year period but remained unchanged in the control group. Other observational studies of patients with SSc have reported a low DLCO/alveolar volume (V_A) ratio (DLCO/V_A <70 percent) or a DLCO that is decreased disproportionately to the forced vital capacity (ie, FVC percent/DLCO percent >1.6) as predictors for the development of SSc-PAH [3,27]. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary function testing'.)

Serology — Autoantibodies that are associated with an increased risk of SSc-PAH include anticentromere antibodies (ACA), RNP, nucleolar pattern of nucleolar-ANA, and rarely, antiphospholipid antibodies [13,23,29-33]. The absence of anti-Scl 70 (also called anti-topoisomerase I) is associated with the development of PAH [26]. By contrast, SSc patients with Scl 70 autoantibodies are more likely to have PH due to interstitial lung disease (ILD) (group 3 PH). Patients with SSc who have anti-ribonucleic acid polymerase III autoantibodies characteristically have extensive skin involvement and increased risk for scleroderma renal crisis, but uncommonly develop PAH [23].

Other — Less well-established risk factors for the development of SSc-PAH include:

●Demographic – Large observational cohort studies report conflicting data on the impact of race on the development of SSc-PAH but do suggest that male sex is a risk factor [16,20,22,26]. In a study of SSc patients, while the frequency of PAH in males was not higher than females, males had a shorter interval between disease onset and PAH development, and were more likely to have diffuse subtype and interstitial lung disease [34]. Additionally, several studies have shown that older age at onset of disease was associated with greater risk for PAH [11,21].

●Exercise-induced PH – Exercise-induced PH on right heart catheterization (RHC) and stress echocardiogram has been reported to be associated with increased risk for developing PAH in patients with SSc [3,35]. For example, in an observational study of patients with SSc in whom exercise-induced PH was identified, nearly 20 percent progressed to PAH over a three-year period [35].

●Biomarkers – Potential biomarkers for the identification of patients with SSc at risk of PAH, such as NT-proBNP and hepatocyte growth factor (HGF), are not yet validated for routine use [36-38]. Similarly, the Cochin risk prediction score that calculates the risk of PAH in SSc patients using a combination of clinical variables (age, FVC, DLCO/V_A) requires validation and is not routinely used [39]. However, it is used investigationally.

SCREENING — The high prevalence rate of pulmonary arterial hypertension (PAH), poor survival, and lack of symptoms, combined with the observation that early treatment of milder disease improves symptoms and may prolong survival, provides a rationale for screening of PAH in patients with systemic sclerosis (SSc) [35,40,41]

Our approach — While there is consensus regarding the need to screen selected patients with SSc for PAH, there is no agreed-upon best approach [1,42,43]. The most commonly used assessment tools are clinical evaluation, pulmonary function testing (PFTs), and echocardiography. The initial screening for both PAH and interstitial lung disease (ILD) in patients newly diagnosed with SSc is described separately. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Evaluation for lung disease at time of SSc presentation'.)

●Initial visits – Most experts agree that screening should be considered at the initial visit with re-evaluation at intervals throughout the disease course [1]. In addition, most clinicians agree that routine screening with echocardiogram and/or right heart catheterization (RHC) is not practical. Consequently, screening algorithms that combine clinical, physiologic, and echocardiographic findings in high-risk SSc patients have been used to identify those in whom RHC is indicated [1,42-46]. Specific algorithm parameters vary among studies and their use is varied. The potential pitfalls of screening with echocardiography include the impact of false positive and false negative results. False-positive results may lead to unnecessary RHC 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, potentially delaying diagnosis and initiation of therapy. False positives are particularly common among patients with SSc who also have ILD [47].

Our practice is the following:

•All patients with SSc are screened for the signs and/or symptoms of PAH (eg, dyspnea, syncope, signs of right heart failure, loud pulmonic [P2] heart sound) at initial presentation and every visit during follow-up. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

•All patients should have a full set of PFTs (spirometry, lung volumes, and DLCO) at the initial visit and annually thereafter. If they have a normal force vitality capacity (FVC) and DLCO, we decrease the frequency of PFTs to every two years in patients with long-standing SSc (more than five years), no dyspnea or exercise intolerance, and in those with PFTs that have remained unchanged over several years (more than three years). (See "Overview of pulmonary function testing in adults".)

•We perform two-dimensional and Doppler echocardiography on the initial visit in patients with SSc who have symptoms (eg, dyspnea on exertion) or are at substantially increased risk for PAH (eg, long-standing disease, limited cutaneous SSc [lcSSc], DLCO <80 percent predicted) or when other SSc-associated complications are suspected (eg, constrictive cardiomyopathy, pericardial effusion). We do not advocate routine echocardiographic PAH screening for patients with SSc who have no suggestive symptoms and have a normal DLCO. When the DLCO is decreased, we assess for concomitant restrictive disease or abnormal high-resolution computed tomography findings that might suggest interstitial lung disease as an alternate explanation for the reduced DLCO. If systemic sclerosis-associated pulmonary arterial hypertension (SSc–PAH) is suspected based on the clinical features, pulmonary function tests, and echocardiogram, then an RHC is performed. (See 'Risk factors' above and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary function testing' and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Imaging' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

Support for this general approach is based upon data from large observational cohort series [7,8,44,48,49]:

•One prospective international multicenter study (Early, Simple, and Reliable Detection of Pulmonary Arterial Hypertension in Systemic Sclerosis [DETECT]) evaluated screening echocardiography in 466 patients with SSc at increased risk of PAH (SSc for >3 years and a DLCO <60 percent predicted) [8]. All patients underwent an RHC. An algorithm based on these observations accurately identified 62 percent of patients who needed RHC and indicated a PAH prevalence of 19 percent in SSc.

•Another cohort analysis of 419 patients with SSc at risk for PAH reported that the use of echocardiography alone failed to diagnose PAH in up to 31 percent of patients, over one-half of whom were captured by PFT [44]. The combination of echocardiography and PFT improved the negative predictive value for diagnosing PAH (97 versus 87 percent).

•Another cohort analysis of 195 consecutive unselected patients with SSc compared several approaches including DETECT criteria with guidelines set forth by the European Society of Cardiology (ESC)/European Respiratory Society (ESC/ERS; recommended screening echocardiography for those with a FVC/DLCO ratio >1.6 and N-terminal pro-brain natriuretic peptide [NT-proBNP] twice the upper limit of normal) and echocardiography alone [48]. The approach with a highest yield was when guidelines and DETECT were implemented together (positive predictive value 23 percent) compared with DETECT (6 percent), guidelines alone (18 percent), or echocardiography alone (11 percent).

•Another study compared several algorithms, DETECT, ESC/ERS, and the Australian Scleroderma Interest Group (ASIG), and did not find significant difference in the sensitivity and specificity, and the positive and negative predictive values of these approaches, although DETECT had more negative RHCs than the other methods [50].

●Follow-up visits – During follow-up, we perform an echocardiogram every one to two years in patients who are at high risk for PAH, and/or develop new or progressive respiratory symptoms or a low DLCO over time, because long-standing disease is a risk factor for the development of SSc-PAH. As an example, in one study, 32 percent of SSc patients at risk of developing PAH who had an initial normal RHC, subsequently developed PAH [51]. In addition, although not every patient develops progressive disease, those with borderline or mild PAH have an increased risk of developing severe PAH within two years [20,52]. These data provide the rationale for yearly evaluation in most patients with clinical examination, PFT, and echocardiogram. Additional prospective studies are needed to confirm that standard echocardiography is the appropriate guide to treatment decisions compared with repeated RHC [53].

The patients with SSc who are at highest risk for the development of PAH during follow-up are those with exercise-induced PAH on stress echocardiography or RHC [6,51,54]. These issues are discussed below. (See 'Echocardiography' below and 'Right heart catheterization' below.)

Echocardiography — Echocardiography is the most widely used noninvasive tool for the identification of SSc-PAH. Two-dimensional echocardiography assesses right ventricle (RV) function. RV dysfunction has a wide variety of etiologies, of which PH is the most common (table 3). Doppler echocardiography is useful because it estimates tricuspid regurgitant jet velocity (TR jet), which is an estimate of the right ventricular systolic pressure (eRSVP)/pulmonary artery systolic pressure (ePASP). Although, exercise echocardiography (EE) detects exercise-induced PH, its use for screening for PAH in patients with SSc remains largely investigational. (See "Transthoracic echocardiography: Normal cardiac anatomy and tomographic views" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Echocardiography' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

●Doppler echocardiography – Several studies of patients with SSc with and without known risk factors for PAH have reported rates of elevated ePASP ranging from 11 to 14 percent [4,5]. However, false positives and in particular, false negatives, exist such that cases of PAH can be missed when echocardiography is used alone for screening [44]. In addition, estimates of TR jet velocity are hampered by high-interobserver variability and poor standardization of threshold cutoff values above and below which PH should be suspected or is unlikely [2]. Suggested values of TR jet velocity and ePASP for probable or likely PH based upon expert opinion are listed in the table (table 4). (See "Echocardiographic assessment of the right heart" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

●Exercise echocardiography (EE) – EE has been used to screen patients for exercise PH [3,6,55,56]. A change in ePASPs with exercise >18 mmHg was reported in one study to predict the development of PH (not necessarily PAH) during follow-up (hazard ratio 3.4) [6].A study of 54 patients with SSc at risk for the development of PAH reported that 44 percent had a ≥20 mmHg increase of the ePASP during exercise, 81 percent of which had RHC-confirmed resting or exercise-induced PAH [3]. In several studies the abnormal exercise response correlated with abnormal lung function, presence of ILD, greater age, and cardiac dysfunction, suggesting that exercise-induced increases in ePASP in SSc are multifactorial and not specific for SSc-PAH [3,55]. In another four-year study of patients with SSc who did not have PAH on initial echocardiography, pulmonary exercise hemodynamics deteriorated over time but only 3 percent developed actual PAH [56]. A prospective, observational cohort of 85 patients found that a positive EE may predict the future development of resting PH. However, a majority of patients had persistently positive EE without progression to resting PH [57]. (See "Overview of stress echocardiography", section on 'Doppler imaging'.)

Right heart catheterization — The workup for suspected PAH in patients with SSc is the same as for other types of PAH, and RHC remains the diagnostic gold standard if SSc–PAH is suspected based on the following features:

●Symptoms and/or signs of PH – Although patients in whom PH is suspected may proceed directly to RHC, we typically perform an echocardiogram prior to catheterization to evaluate for cardiac causes of PH and evaluate the function of the right ventricle and tricuspid valve.

●An echocardiogram with evidence of PH (eg, right ventricular dysfunction, an elevated TR jet, or an increased estimated pulmonary arterial systolic pressure at rest or with exercise). (See "Echocardiographic assessment of the right heart".)

●A low threshold for repeating an RHC is required in patients with exercise-induced PAH at initial RHC.

The diagnosis of PAH in SSc is confirmed when the mean pulmonary artery pressure (PAP) is greater than 20 mmHg at rest (measured by RHC), pulmonary capillary wedge pressure is less than or equal to 15 mmHg, and peripheral pulmonary vascular resistance is ≥2 Wood units in a patient without other etiologies for PH [1]. At the time of RHC, severity of PH and, in some cases, acute responsiveness to vasodilators (which is rare), are measured to guide treatment choices. Suspected SSc-PAH should not be treated without first performing a RHC, preferably in a specialized center with cardiologists and pulmonologists who have expertise in PH. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)' and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary vascular disease'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Pulmonary hypertension (PH) is a significant complication of systemic sclerosis (SSc) and a leading cause of SSc-related death. PH is classified into five groups (table 1). SSc is most often associated with group 1 pulmonary arterial hypertension (PAH) and group 3 PH (due to interstitial lung disease [ILD]), and less commonly with group 2 PH (due to left-sided heart failure). (See 'Classification' above.)

●Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is defined as a mean pulmonary artery pressure (PAP) >20 mmHg at rest (measured by right heart catheterization [RHC]), pulmonary capillary wedge pressure ≤15 mmHg, and peripheral pulmonary vascular resistance ≥2 Wood units in a patient who has SSc without other causes of PH. (See 'Definition' above.)

●The prevalence of unrecognized PAH among patients with SSc is in the range of 10 to 15 percent. Important risk factors include long-standing limited cutaneous SSc (lcSSc), a low (<80 percent predicted) or progressive decline in the diffusion capacity for carbon monoxide (DLCO), and/or a high forced vital capacity (FVC)/DLCO ratio (FVC/DLCO >1.6). Other risk factors are listed in the table (table 2). (See 'Risk factors' above.)

●All patients with SSc should be evaluated for PAH at initial presentation and throughout the course of their disease (see 'Screening' above and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Evaluation for lung disease at time of SSc presentation'):

•All patients should be evaluated for the signs and/or symptoms of PAH (eg, dyspnea, syncope, signs of right heart failure, loud pulmonic second heart sound [P2]) at each visit.

•All patients should have full pulmonary function testing (PFTs; spirometry, lung volumes, and diffusing capacity) at the initial visit and annual PFTs (spirometry and DLCO) thereafter. We decrease the frequency of PFTS to every two years in patients with long-standing SSc (>5 years) who are asymptomatic, a normal DLCO and have stable PFTs (>3 years).

•We perform echocardiography in patients who have symptoms of PAH, and in asymptomatic patients who are at significantly increased risk for PAH, as defined above. Additionally, we perform echocardiography when we suspect other SSc-associated complications such as constrictive cardiomyopathy or pericardial effusion. We do not advocate further evaluation for PAH in patients who do not have pulmonary symptoms and who have a normal DLCO. During follow-up, we perform an echocardiogram every one to two years in patients who are at significantly increased risk for PAH and/or develop symptoms or a low DLCO over time.

•We perform a RHC for patients with SSc who show symptomatic, physiologic and/or echocardiographic evidence of PAH. Algorithms that combine clinical findings, pulmonary function testing and echocardiography in high-risk SSc patients may be used to select those appropriate for RHC (eg, DETECT).