Overview of pulmonary complications of systemic sclerosis (scleroderma)

INTRODUCTION — 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 [1]. 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, risk factors, and screening".)

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 "Clinical manifestations and diagnosis 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].

●Limited cutaneous SSc is characterized by skin sclerosis restricted to the hands, distal extremities, and, to a lesser extent, to the face and neck. Patients with limited cutaneous SSc generally have prominent vascular manifestations and may have CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). A subset may develop ILD [2].

TYPES OF PULMONARY INVOLVEMENT — The most common forms of SSc lung involvement, which may occur separately or together, are interstitial lung disease and pulmonary vascular disease. Other pulmonary complications include pulmonary thromboembolic disease, pleural disease, aspiration pneumonitis, airways disease, drug-induced pneumonitis, and lung cancer. More than one of these processes may be present in a given patient.

Interstitial lung disease — Interstitial lung disease (ILD) is a common complication of diffuse cutaneous SSc (approximately 50 percent), but can also occur in patients with limited cutaneous SSc (approximately 25 percent) [2,3]. ILD may be apparent at the time of or soon after the diagnosis of SSc or, less commonly, may develop many years after the onset of skin disease; rarely does it precede the recognition of SSc. SSc-associated ILD typically presents with the subacute onset of dyspnea on exertion and sometimes nonproductive cough. The radiographic, and pathologic features of SSc-associated ILD are typically those of fibrotic nonspecific interstitial pneumonia (NSIP) or, less commonly, usual interstitial pneumonia (UIP) or pleuroparenchymal fibroelastosis [2,5,6]. The clinical and laboratory features and diagnosis of ILD in patients with SSc are discussed in detail separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Idiopathic interstitial pneumonias: Classification and pathology".)

Pulmonary vascular disease — Pulmonary hypertension (PH) is the most common pulmonary vascular disease in SSc, but patients can also develop thromboembolic disease, pulmonary capillary hemangiomatosis, or pulmonary veno-occlusive disease.

Pulmonary hypertension — Several different forms of PH occur in SSc, and the classification is based on the cause of elevated pulmonary artery pressures. Pulmonary arterial hypertension (PAH) that is due to diseases that localize to the small muscular pulmonary arterioles is classified as group 1 (includes idiopathic and rheumatic disease-associated); PH caused by myocardial dysfunction is group 2; and PH due to hypoxemia from advanced ILD is group 3 (table 1). SSc-associated PAH is pathologically indistinguishable from idiopathic PAH. PAH is the most common of the types of PH in SSc. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Classification' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

The exact prevalence of PAH in patients with SSc is unknown, but is estimated to be 10 to 15 percent. Patients with long-standing SSc are at greatest risk for developing PAH; limited cutaneous disease has long been thought to be a risk factor for PAH, particularly in association with the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). However, PAH also occurs in patients with diffuse cutaneous disease. Anticentromere antibodies are associated with a higher likelihood of PAH. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Risk factors'.)

Among patients with SSc and PAH, dyspnea on exertion is the most common initial symptom, but early PAH can be asymptomatic. Patients with advanced PAH may have chest pain due to right ventricular angina, and near-syncope or syncope on exertion due to reduced cardiac reserve. Patients with PH due to ILD typically have profound dyspnea on exertion and a history of ILD. Those with PH due to left heart dysfunction may have other features of myocardial dysfunction such as peripheral edema, palpitations, or syncope. The clinical features of PH associated with SSc are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations' and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

Thromboembolic disease — The risk of pulmonary thromboembolism appears to be increased in patients with SSc compared with the healthy adult population. In a population-based cohort study that included 1895 patients with SSc and 7580 healthy controls, the risk of developing pulmonary thromboembolism was significantly higher in SSc (hazard ratio 7.00; 95% CI 2.64-18.5) after adjusting for age, sex, and comorbidities [7].

Pulmonary capillary hemangiomatosis and veno-occlusive disease — Rare cases have been reported of pulmonary capillary hemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD) in patients with SSc [8-11]. PCH and PVOD may actually be part of a spectrum of one disease rather than two separate entities. A retrospective, histopathologic analysis of explanted lungs showed a frequent finding of PVOD in patients (15 of 18 subjects) with SSc-PH-ILD [12]. The clinical and imaging manifestations of PVOD are discussed separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

PVOD and/or PCH should be suspected in a patient with elevated pulmonary artery pressures and normal or low pulmonary capillary wedge pressure (PCWP) when imaging studies suggest pulmonary edema. In general, pulse oxygen saturation is lower during a six-minute walk test and pulmonary artery systolic pressure (PASP) is higher (typically >45 mmHg) in PVOD than PAH. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Pleural effusion — Pleural effusions have been reported in both diffuse and limited cutaneous scleroderma, but are uncommon (less than 10 percent) and often asymptomatic [13,14]. Among patients with SSc, potential causes of a pleural effusion include pleuritis, heart failure, pericarditis (with tamponade), pneumonia, PCH-PVOD and cancer. Depending on the etiology, the presentation varies from acute onset of pleuritic chest pain (pleuritis) to progressive shortness of breath (heart failure) to an asymptomatic pleural effusion discovered on imaging or at autopsy [13,14]. On physical examination, a pleural friction rub may be heard in patients with SSc-associated pleuritis.

SSc-associated pleuritis is typically associated with an exudative, lymphocytic effusion [14,15]. No particular association with autoantibodies has been identified [15]. When both pleuritis and pericarditis are present, other potential causes include overlap with another rheumatic disease such as systemic lupus erythematosus and drug-induced pleuritis. (See "Pleural fluid eosinophilia", section on 'Drugs' and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Chest wall pain'.)

Spontaneous pneumothorax — Spontaneous pneumothorax is rare in SSc and usually occurs in patients with ILD [16]. Rupture of a subpleural bleb is the suspected cause [17]. As is typical for secondary spontaneous pneumothorax, the onset of symptoms (eg, shortness of breath, pleuritic chest pain) is acute and the diagnosis is made by a chest radiograph. The management of SSc-associated spontaneous pneumothorax is determined by the size of the pneumothorax, response to initial drainage, and the type and severity of underlying lung disease. (See "Treatment of secondary spontaneous pneumothorax in adults".)

Recurrent aspiration — Esophageal dysmotility and chronic gastroesophageal reflux, which are present in the majority of patients with SSc, can lead to aspiration of pharyngeal and gastric contents [18,19]. The exact role of recurrent episodes of aspiration in lung disease in SSc is not known, but such episodes may contribute to centrilobular fibrosis and possibly worsening of SSc-associated ILD. One series described six patients with SSc and centrilobular fibrosis (ground glass or consolidative opacities in a patchy centrilobular distribution on high-resolution computed tomography [HRCT]) that was associated with intrabronchial basophilic material consistent with aspirated food or medication; coexisting esophageal abnormalities were noted in all patients [20]. In case series, the severity of esophageal disease, assessed by symptoms, pH monitoring, or esophageal manometry, as well as the widest esophageal diameter [21] correlated with abnormalities in pulmonary function tests and/or HRCT, suggesting that recurrent episodes of micro-aspiration may contribute to lung injury in SSc-associated ILD [19,22,23]. Similarly, it is hypothesized that chronic micro-aspiration may contribute to progression of idiopathic pulmonary fibrosis. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Oropharyngeal involvement' and "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Esophageal involvement' and "Aspiration pneumonia in adults" and "Treatment of idiopathic pulmonary fibrosis", section on 'Empiric treatment for asymptomatic gastroesophageal reflux'.)

Drug-associated pneumonitis — Some drugs used to treat SSc and associated conditions, such as methotrexate, cyclophosphamide, penicillamine, and angiotensin converting enzyme inhibitors, may cause pneumonitis. A partial listing of drugs reported to cause lung toxicity is provided in the table (table 2), and a more complete listing is available on the Pneumotox website. (See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'Prior medication use and irradiation'.)

Airways disease — Airway involvement is a less common manifestation of SSc, but can contribute to dyspnea and pulmonary function test abnormalities.

●Airflow limitation – Airflow limitation has been noted on pulmonary function testing in a small portion of patients with SSc, and cigarette smoking is thought to be a contributing factor [24,25]. However, nonsmokers can also manifest airflow limitation. In a series of 46 patients with SSc, airflow limitation (decreased forced expiratory volume in one second/forced vital capacity [FEV₁/FVC] with a reduction in FEV₁ below 80 percent predicted) was noted in 5 of 34 nonsmokers (15 percent) and 4 of 12 current or ex-smokers (33 percent) [24]. The cause of airflow limitation in these patients is not known.

●Bronchiolitis obliterans – Bronchiolitis obliterans has rarely been described in association with limited or systemic sclerosis, but is most likely due to treatment with penicillamine rather than the underlying disease [26,27].

●Follicular bronchiolitis – Follicular bronchiolitis is characterized by hyperplasia of bronchus-associated lymphoid tissue (BALT) and is usually a minor feature seen in the context of an interstitial pneumonia, such as NSIP or lymphocytic interstitial pneumonia. The prevalence of follicular bronchiolitis in SSc is not known, but in a review of lung biopsy specimens obtained from 34 patients with SSc, eight had follicular bronchiolitis often in association with an NSIP pattern [28]. (See "Overview of bronchiolar disorders in adults", section on 'Follicular bronchiolitis'.)

●Bronchiectasis – Cylindrical bronchiectasis is a common finding on chest HRCT scanning of patients with SSc. In one study of 22 patients, bronchiectasis was present in 59 percent [29]. Bronchiectasis may be caused by recurrent aspiration or traction due to fibrosis in patients with ILD. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Clinically apparent bronchiectasis may increase the risk of serious infection and warrants careful evaluation when the use of immunosuppressive drugs is considered [30].

Lung cancer — The risk of lung cancer appears to be increased in patients with SSc, especially those with ILD, and can occur independently of cigarette smoking. In a series of 17 patients with SSc and lung cancer, 13 had adenocarcinoma, 12 had underlying ILD, 11 were current or former cigarette smokers, and 8 had antibodies to topoisomerase [31]. In addition, 13 had other pulmonary nodules noted on CT prior to the diagnosis of lung cancer, although the nature of the noncancerous lung nodules was not further specified. The evaluation of lung nodules is discussed separately. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

The potential association of SSc and cancer is discussed separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Other disease associations'.)

Respiratory muscle weakness — Respiratory muscle weakness is a rare cause of hypercapnic respiratory failure in systemic sclerosis and may reflect an overlap syndrome with polymyositis or mixed connective tissue disease [32,33]. Patients with SSc can develop an inflammatory myopathy clinically and histologically similar to classic polymyositis. Typical findings of respiratory muscle weakness on pulmonary function testing (PFTs) include a restrictive pattern with reductions in forced vital capacity and total lung capacity, and also reduced maximum inspiratory and expiratory pressures. The chest radiograph may show small lung volumes. (See "Tests of respiratory muscle strength" and "Neuromuscular manifestations of systemic sclerosis (scleroderma)", section on 'Myopathy' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

EVALUATION FOR LUNG DISEASE AT TIME OF SSC PRESENTATION — All patients with SSc should be screened for interstitial lung disease (ILD) and pulmonary hypertension (PH) at presentation and periodically thereafter. The rationale for screening is based on the frequent occurrence of these lung diseases and their high morbidity; studies to show improved outcomes among screened patients are lacking [34,35].

In concert with current guidelines, we typically screen for these processes with a clinical assessment, N-terminal pro-brain natriuretic peptide (NT-proBNP) or BNP, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT). While some guidelines also include a Doppler echocardiogram, we reserve this test for selected patients [35]. Further testing is based on the results of these initial tests.

Clinical assessment — The clinical assessment for lung involvement should include the following: inquiry about symptoms such as cough, sputum production, dyspnea on exertion, exertional presyncope, syncope, ankle swelling, and chest pain; a complete history regarding cigarette smoking, medication use, and occupational and domiciliary exposures to fumes and chemicals.

Patients are examined for physical signs of lung involvement, including tachypnea, crackles (rales), pleural friction rub, an increased A wave in the jugular venous pulse, increased pulmonic component of the second heart sound or a right ventricular S4, a right ventricular heave, a pulmonary arterial "tap," a murmur suggestive of tricuspid regurgitation, and peripheral edema.

Worsening dyspnea and/or cough in a patient with SSc should also arouse suspicion for aspiration due to gastroesophageal reflux and/or esophageal dysmotility. Additional considerations include infection, thromboembolism, or superimposed left heart failure. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Esophageal involvement' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

Laboratory testing — Measurement of plasma levels of BNP and/or NT-proBNP is a useful component of screening for pulmonary arterial hypertension (PAH) in SSc [35]. Further study is needed to clarify the role of these tests in identifying PAH in SSc. (See "Natriuretic peptide measurement in non-heart failure settings", section on 'Pulmonary hypertension'.)

In one study, elevated NT-proBNP levels in SSc patients had a sensitivity and specificity of 90 percent for the presence of PAH [36]. This has been confirmed by several studies that have also demonstrated a correlation between NT-proBNP levels and the tricuspid gradient, mean pulmonary arterial pressure, pulmonary vascular resistance, and survival [34,37-39]. However, patients with SSc can also have myocardial dysfunction that could contribute to the elevation of BNP.

The role of antibody testing in assessing an individual patient’s risk for pulmonary complications is not well-established. The antibodies associated with SSc are discussed separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Laboratory testing'.)

Pulmonary function testing — All patients should have PFTs (spirometry, lung volumes, and a single breath diffusion capacity for carbon monoxide [DLCO]) performed at the time of their initial presentation [35,40,41]. These tests assess for a restrictive pattern on lung volumes (forced vital capacity [FVC] and/or total lung capacity <80 percent of predicted) and reduced gas transfer. In addition, a six minute walk test with or without ambulatory oximetry can be helpful for monitoring lung function over time. (See "Overview of pulmonary function testing in adults".)

The combination of reduced lung volumes and a reduced DLCO suggests ILD, although a reduced DLCO with normal lung volumes can be seen in early ILD. On the other hand, a DLCO less than 65 percent of predicted in the absence of significant lung volume abnormalities or a decrease in DLCO ≥20 percent in a year suggests PH, particularly in a patient with long standing limited cutaneous SSc. The FVC/DLCO ratio is another way to assess whether the degree of impairment of gas transfer is greater than what would be expected on the basis of ILD. A ratio of FVC/DLCO percent predicted >1.6 suggests pulmonary hypertension [35].

Analysis of the combination of all PFT parameters is necessary to minimize the risk of false negative results [42-44]. As an example, in a series of 102 patients with SSc, 40 of 64 (62 percent) patients with ILD by HRCT had a normal FVC, including patients with radiographically advanced ILD [42]. However, combining the all the PFT parameters and using a DLCO threshold of 80 percent, the rate of false negative results was reduced to under 25 percent. These data support the inclusion of HRCT in screening SSc patients for ILD.

Imaging — For virtually all patients with a new diagnosis of SSc, we obtain chest imaging to screen for the presence of ILD. We obtain an HRCT scan rather than a conventional chest radiograph due to the greater sensitivity of the HRCT [42,45]. We include prone images to evaluate for dependent atelectasis that can mimic ILD and expiratory images to assess air trapping. (See "High resolution computed tomography of the lungs", section on 'Clinical application of HRCT'.)

The HRCT scan of the chest is examined for the presence and distribution of ground glass opacities (image 1), reticular opacities, "honeycombing" (image 2), bronchiectasis, and emphysematous blebs or bullae. The most common pathologic pattern in SSC-associated ILD, nonspecific interstitial pneumonia (NSIP), is associated with the HRCT finding of ground glass opacities in a peripheral distribution, while the earliest HRCT change is usually a narrow, often ill-defined, subpleural crescent of increased density in the posterior (dependent) segments of the lower lobes. The evaluation of patients with HRCT evidence of ILD is discussed separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

The prognostic utility of HRCT screening for SSc-ILD is supported by several studies [43,46-48]. As an example, in a prospective study of 305 patients with SSc, absence of changes suggestive of ILD on baseline HRCT predicted continued absence on repeat HRCT and minimal worsening of FVC three years later, while the presence of such changes correlated with progression of lung disease [43]. It has been suggested that the presence of ILD at baseline appears to have an adverse impact on patient outcome in SSc [45].

The finding of centrilobular fibrosis (ground glass or consolidative opacities in a patchy centrilobular distribution) may suggest recurrent aspiration, especially in patients with esophageal disease related to SSc. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

Radiographic imaging studies are often normal in SSc patients with early PH, so they are not helpful for screening. However, an enlarged pulmonary artery and attenuation of the smaller pulmonary vessels may be seen with more advanced disease. Right ventricular enlargement (diminished retrosternal space) and right atrial dilatation (prominent right heart border) can also be seen. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Imaging'.)

Echocardiography — Two-dimensional transthoracic and Doppler echocardiography provides a noninvasive assessment of pulmonary artery pressures. In addition to assessing pulmonary artery pressures, the transthoracic echocardiogram can assess for left ventricular systolic or diastolic dysfunction or pericardial effusion to look for causes of elevated pulmonary artery pressures other than pulmonary hypertension [35]. (See "Echocardiographic assessment of the right heart".)

●Two-dimensional and Doppler echocardiography – We perform two-dimensional and Doppler echocardiography on the initial visit in patients who have symptoms or are at substantially increased risk for PAH (eg, elevated BNP, low DLCO) or when other SSc-associated complications are suspected (eg, constrictive cardiomyopathy, pericardial effusion). We do not advocate routine echocardiographic screening for patients with SSc who have no suggestive symptoms and have a normal DLCO. However, other SSc experts prefer to obtain Doppler echocardiography as part of routine screening for PH, rather than just in patients with symptoms or abnormalities on these other tests. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Our approach'.)

The echocardiographic features of PH are summarized in the figures (figure 1). The results of Doppler echocardiography may be expressed as the pulmonary artery systolic pressure (PASP) or the tricuspid regurgitant jet velocity (TRV), where PASP = 4 (TRV)². In general, an echocardiographically-estimated PASP exceeding 35 to 40 mmHg should be considered elevated, which would correlate approximately with a tricuspid regurgitant velocity >2.9 m/sec (figure 1 and image 3). However, the sensitivity and specificity of Doppler echocardiography for detecting PAH varies with the estimated PASP or right ventricular pressure (another method to estimate PASP) chosen as a threshold [49]. As an example, Doppler echocardiography with a threshold of an estimated right ventricular systolic pressure >35 mmHg has a sensitivity of 94 percent and a specificity of 73 percent. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

When PH is suggested by Doppler echocardiography, right heart catheterization is necessary for confirmation of an elevated pulmonary artery systolic pressure and to exclude occult left ventricular dysfunction.

●Exercise echocardiography – Exercise echocardiography has been proposed as a method to screen patients for early pulmonary hypertension. However, exercise-induced increases in Doppler estimates of PASP in SSc are multifactorial and not specific for SSc-PAH. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Echocardiography' and "Overview of stress echocardiography".)

SUBSEQUENT MONITORING — Patients with no evidence of lung involvement at the time of the initial evaluation (described above) remain at risk for developing interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) in the future, and thus need periodic re-evaluation. Patients with diffuse skin involvement are particularly at an increased risk for development of ILD during the first three to five years after the onset of systemic sclerosis (SSc). In contrast, while patients with limited skin involvement have a lower risk for early ILD, they are more likely to develop PAH, even in later stages of their disease.

We typically follow patients with SSc at three to six month intervals to assess changes in symptoms (eg, dyspnea or reduced exercise tolerance) or physical examination (eg, crackles).

For the first several years after the initial diagnosis, we obtain annual pulmonary function tests (spirometry, diffusing capacity [DLCO], exertional pulse oxygen saturation). We decrease the frequency of pulmonary function tests (PFTs) to every two years in patients with long-standing SSc (more than five years) if they have a normal DLCO, no dyspnea or exercise intolerance, and in those with PFTs that have remained unchanged over several years (more than three years).

The timing of repeat chest high-resolution computed tomography (HRCT) is based on the clinical findings and results of PFTs. Re-evaluation is performed if new symptoms or signs develop or a decline in lung volumes or DLCO occurs.

We obtain a plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) or BNP and perform a Doppler echocardiogram every one to two years in patients who are at high risk for PAH (eg, long-standing disease, limited skin involvement with prominent vascular manifestations) or at the time of new or progressive respiratory symptoms and/or a decrease in DLCO. We do not advocate routine echocardiographic PAH screening for patients with SSc who have no suggestive symptoms and have a normal DLCO. However, other experts obtain a Doppler echocardiogram annually [35].

Patients receiving a combination of glucocorticoids and cyclophosphamide or another immunosuppressive agent are also at risk for opportunistic infection and drug-induced lung toxicity. They should be assessed at three month intervals or sooner if new symptoms or signs emerge. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)

DIAGNOSIS OF LUNG DISEASE IN SYSTEMIC SCLEROSIS — The diagnosis of interstitial lung disease (ILD) and pulmonary vascular disease requires careful clinical assessment in SSc, because the presenting symptoms and pulmonary function test abnormalities overlap and because they can occur independently and in combination. In a series of 93 patients with SSc-ILD, 29 (31 percent) had right heart catheterization-proven pulmonary hypertension and of these, 7 had group I PH/PAH, 6 had group II PH (left heart disease), and 16 had group III PH (due to ILD) [50]. Salient features of the evaluation are described below.

Interstitial lung disease — The diagnosis of SSc-associated ILD is generally based on the presence of the characteristic high-resolution computed tomography (HRCT) features of ILD (eg, bibasilar ground glass or reticular opacities) in a patient with known SSc and exclusion of other causes of ILD, such as heart failure, drug-induced toxicity, or recurrent aspiration. Supportive findings include dyspnea on exertion, a normal brain natriuretic peptide, and the proportionately reduced lung volumes and diffusing capacity for carbon monoxide (DLCO). A bronchoscopy and/or lung biopsy is rarely needed in this setting, unless the clinical picture is atypical (eg, fever, rapid onset of dyspnea, unilateral radiographic findings, nodular pattern to opacities). The diagnosis and differential diagnosis of ILD in patients with SSc are discussed separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Diagnosis' and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Differential diagnosis' and 'Drug-associated pneumonitis' above and 'Recurrent aspiration' above.)

If the DLCO is decreased substantially more than the reduction in lung volumes (eg, the forced vital capacity [FVC]/DLCO ratio >1.6), the possibility of concomitant pulmonary hypertension (PH) should be explored, as described below.

Pulmonary hypertension — When PH is suspected on the basis of the screening evaluation that shows an elevated brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP), a low DLCO with relatively normal lung volumes, elevated pulmonary artery pressures (eg, greater than 35 to 40 mmHg on Doppler echocardiography), we proceed to right-heart catheterization (RHC). As Doppler echocardiography is associated with occasional false negative results, patients with well-documented dyspnea on exertion and decreased DLCO (<60 percent predicted) and no other explanation for the findings should also undergo RHC. (See 'Echocardiography' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

The diagnosis of PH depends on identification of an elevated mean pulmonary artery pressure (greater than 20 mmHg at rest) and exclusion of left ventricular dysfunction (pulmonary capillary wedge pressure [pcwp] ≤15 mmHg) and pericardial disease (equalization of average intracardiac diastolic pressures). The diagnosis and classification of PH in general and in SSc are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis' and "Pericardial effusion: Approach to diagnosis", section on 'Cardiac catheterization'.)

For patients with a diagnosis of PH by RHC, we pay particular attention to the differentiation of the following scenarios:

●No evidence of pulmonary parenchymal disease on HRCT – These patients likely have SSc-associated PAH (group 1).

●SSc-associated ILD based on HRCT scan results – The combination of ILD and PH needs to be further classified (table 1).

•Patients with SSc associated ILD and PH may have pulmonary arterial hypertension (PAH, group 1) and SSc-associated ILD as independent, but simultaneous processes [51,52]. In these patients, the severity of ILD is not sufficient to cause pulmonary vasoconstriction due to hypoxemia. Pulse oxygen saturation (SpO₂) may decrease on exertion, but generally not below 88 percent. (See 'Pulmonary hypertension' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Group 1: Pulmonary arterial hypertension'.)

•Patients with advanced SSc-associated ILD may have PH due to the vasoconstricting effects of chronic hypoxemia (group 3 PH). These patients have HRCT evidence of advanced ILD, moderate to severe reductions in lung volumes, and hypoxemia (eg, SpO₂ <89 percent) at rest or on exertion. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Group 3: PH due to chronic lung disease and/or hypoxemia'.)

•Patients with PH in association with centrilobular nodular ground glass opacities may have pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH), which are categorized as group 1’ PH (table 1). As noted above, these patients tend to have more severe PH and also have HRCT abnormalities (eg, centrilobular, nodular ground glass opacities, septal thickening, pleural effusion, mediastinal lymph node enlargement). While PVOD and PCH are rare disorders, it is important to identify this possibility as pulmonary vasodilator therapy may result in pulmonary edema. (See 'Pulmonary capillary hemangiomatosis and veno-occlusive disease' above and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Once the diagnosis of SSc-associated PAH is confirmed, the assessment of the severity of pulmonary hypertension and, in some cases, acute responsiveness to vasodilators is used to guide treatment choices. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis".)

Other pulmonary complications — The evaluation and diagnosis of the other pulmonary complications of SSc are discussed separately:

●Pleural effusion and pneumothorax (see "Pleural fluid analysis in adults with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion" and "Treatment of secondary spontaneous pneumothorax in adults")

●Thromboembolic disease (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism")

●Recurrent aspiration is suspected in patients with cough, report of choking during ingestion, and in those with widely dilated (patulous) esophagus or centrilobular fibrosis on HRCT (see "Gastrointestinal manifestations of systemic sclerosis (scleroderma)")

●Airflow limitation (see "Overview of pulmonary function testing in adults")

●Bronchiolitis (see "Overview of bronchiolar disorders in adults")

●Bronchiectasis (see "Clinical manifestations and diagnosis of bronchiectasis in adults")

●Respiratory muscle weakness (see "Neuromuscular manifestations of systemic sclerosis (scleroderma)" and "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation")

●Lung cancer (see "Overview of the initial treatment and prognosis of lung cancer")

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: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●Types of pulmonary involvement – In patients with systemic sclerosis (SSc), the most common forms of pulmonary involvement, interstitial lung disease (ILD) and pulmonary hypertension (PH), can occur in isolation or they can coexist. Less common pulmonary complications include pulmonary thromboembolism, pleural effusion, spontaneous pneumothorax, airways disease, aspiration pneumonia, lung cancer, drug-induced pneumonitis, respiratory muscle weakness, and rarely, pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. (See 'Types of pulmonary involvement' above.)

●Influence of cutaneous involvement on lung disease – Diffuse cutaneous SSc (extensive skin involvement with extension of skin sclerosis proximal to the wrists) is more typically associated with ILD, while limited cutaneous SSc (changes confined to the fingers, distal portion of the extremities, and the face) is more likely associated with PH. (See 'Influence of diffuse cutaneous and limited cutaneous disease' above.)

●Timing of evaluation – Early pulmonary involvement in SSc is often asymptomatic. In view of the potentially ominous prognosis of ILD and PH and the availability of treatment, we evaluate virtually all newly diagnosed patients with SSc for ILD and PH. (See 'Evaluation for lung disease at time of SSc presentation' above.)

●Typical evaluation – The initial evaluation for SSc lung disease includes a review of respiratory symptoms, physical examination, measurement of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) or BNP, pulmonary function testing, and noncontrast chest CT. (See 'Evaluation for lung disease at time of SSc presentation' above.)

•Additional testing, in those at risk for PH – We perform echocardiography in patients felt to be at greater risk for PH based on the screening evaluation (eg, low DLCO, elevated NT-pro-BNP). (See 'Echocardiography' above.)

•Subsequent monitoring in those without initial lung involvement – We typically follow patients with SSc at three- to six-month intervals to assess changes in symptoms (eg, dyspnea or reduced exercise tolerance) or physical examination (eg, crackles). In addition, we obtain annual pulmonary function tests (spirometry, DLCO). Additional laboratory tests and imaging may be needed depending on the results. (See 'Subsequent monitoring' above.)

●Features of SSc-associated ILD – SSc-associated ILD is suggested by the presence of respiratory symptoms, crackles on lung auscultation, reduction in both lung volumes and DLCO, and ground-glass or reticular opacities on CT. The diagnosis of SSc-associated ILD is based on CT-imaging features and exclusion of other causes of pulmonary parenchymal disease (eg, heart failure, recurrent aspiration, drug-induced pneumonitis). Lung biopsy is reserved for atypical cases. (See 'Interstitial lung disease' above and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

●Features of SSc-associated PH – PH is suggested by exertional dyspnea, chest pain, presyncope, or syncope, especially in patients with long-standing limited cutaneous scleroderma. Pulmonary arterial hypertension (PAH) is typically associated with a reduced DLCO (<60 percent predicted) that is decreased out of proportion to the lung volumes (eg, ratio of FVC/DLCO percent predicted >1.6) or a fall in DLCO ≥20 percent in one year. (See 'Influence of diffuse cutaneous and limited cutaneous disease' above and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening".)

●Diagnosis and classification of PH – When PH is suspected after screening evaluation including elevated estimated pulmonary artery pressures (eg, greater than 35 to 40 mmHg) on Doppler echocardiography, we proceed to right-heart catheterization (RHC) for formal diagnosis and classification. The PH classification and subsequent treatment is influenced by the presence, imaging characteristics, and severity of concomitant ILD. (See 'Pulmonary hypertension' above and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)