Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)

INTRODUCTION — Interstitial lung disease (ILD) is one of the major forms of lung involvement in patients with systemic sclerosis (SSc). SSc-associated ILD consists of various histopathologic subtypes, most commonly nonspecific interstitial pneumonitis and usual interstitial pneumonitis. Affected patients have a worse prognosis than patients with SSc who are free of pulmonary involvement.

The clinical manifestations, evaluation, and diagnosis of SSc-associated ILD are discussed here. The treatment of SSc-associated ILD, the evaluation and management of pulmonary arterial hypertension and other pulmonary complications of SSc are discussed separately. (See "Overview of pulmonary complications of 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".)

EPIDEMIOLOGY — The reported prevalence of ILD in patients with SSc varies based upon population studied and definition of ILD [1-4]. In one study of 779 patients with SSc, 48 percent of those with diffuse cutaneous SSc and 26 percent of those with limited cutaneous SSc were found on HRCT to have ILD [1]. In separate studies that identified ILD by HRCT, the prevalence of ILD in SSc was 50 to 60 percent [5,6].

RISK FACTORS FOR ILD — Diffuse cutaneous SSc, which is characterized by extensive skin involvement and extension of skin sclerosis proximal to the elbows, is a risk factor for developing ILD early in the course of SSc [7,8]. Patients with limited cutaneous SSc, in which skin sclerosis is generally restricted to the hands, distal extremities, and, to a lesser extent, the face and neck, are less likely to develop ILD early in the course of disease, but may develop ILD as a late manifestation [7,9,10]. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Influence of diffuse cutaneous and limited cutaneous disease' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Background'.)

Other features that may predict early development of ILD in patients with SSc include African-American ethnicity, higher skin score and serum creatine phosphokinase (CPK) levels, hypothyroidism, and cardiac involvement [2,11]. Anticentromere antibodies appear protective against ILD, whereas the presence of anti-topoisomerase I (antiScl-70) antibodies increases the likelihood of ILD [2,3,8,10,12].

CLINICAL MANIFESTATIONS — Early ILD is frequently asymptomatic. The most common symptoms of SSc-associated ILD are fatigue, breathlessness (ie, exertional dyspnea initially), and dry cough. Chest pain is infrequent, and hemoptysis is rare.

While most patients have cutaneous manifestations of SSc at the time ILD is identified, occasional patients present first with ILD and are subsequently found to have SSc based on the presence of findings such as Raynaud phenomenon, sclerodactyly, positive autoantibodies (eg, antinuclear antibody, antitopoisomerase [anti-Scl70]), or abnormal nailfold capillary microscopy (figure 1). (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Nailfold capillary microscopy'.)

The most characteristic finding of ILD on physical examination is bibasilar fine inspiratory crackles (ie, "Velcro" rales) at the lung bases [13]. Finger clubbing is uncommon. Signs of cor pulmonale can be seen with advanced ILD, but are more commonly associated with pulmonary hypertension, which may occur in SSc as a separate process or in association with ILD.

EVALUATION — SSc-associated ILD is usually suspected when a patient with known SSc develops exertional dyspnea, cough, auscultatory crackles, or abnormalities on pulmonary function testing (PFTs) or the chest radiograph. The evaluation of suspected ILD in a patient with SSc is similar to that of other patients with suspected ILD. However, a lung biopsy is almost never required to secure a diagnosis of SSc-ILD. A general diagnostic approach to the patient with ILD is discussed in detail separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

Investigations evaluating suspected SSc-associated ILD are designed to characterize the type and severity of ILD and to exclude the possibility that another lung disease or extra-pulmonary process is etiologic, such as infection, heart failure, drug-induced lung disease, or recurrent aspiration.

Laboratory findings — The presence of characteristic autoantibodies supports the diagnosis of systemic sclerosis and may indicate an increased likelihood of specific clinical manifestations, such as ILD, but none are diagnostic of ILD. As an example, anti-topoisomerase I (also known as anti-Scl-70) antibody, which is typically determined as part of the diagnostic evaluation of patients with suspected SSc, is associated with an increased risk for SSc-associated ILD (sensitivity 45 percent, specificity 81 percent) [14]. The role and availability of specific laboratory tests in the diagnosis and management of SSc is discussed separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Laboratory testing'.)

Additional SSc-related autoantibodies have also been associated with an increased risk for ILD, including anti-U3 ribonucleoprotein (RNP), anti-U11/U12 RNP, and anti-Th/To [15-21]. However, these tests might not be commercially available, and their clinical utility in the evaluation and management of SSc-associated ILD is currently still uncertain.

Anticentromere antibodies (ACA), which are common among patients with limited cutaneous SSc and can be associated with pulmonary arterial hypertension, are rarely associated with significant ILD [20].

Pulmonary function testing — PFTs are performed in patients with SSc at the time of initial diagnosis to determine the presence and extent of SSc-associated lung involvement. Subsequently, PFTs are generally performed annually or more frequently to evaluate new onset of dyspnea, cough, or radiographic abnormality. The pattern of abnormalities on PFTs can help to differentiate among the various types of SSc lung involvement. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Types of pulmonary involvement'.)

●Spirometry – A proportional reduction of the forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC; ie, a normal FEV₁/FVC ratio) suggests a restrictive defect and may be present in patients with ILD. However, early ILD in SSc patients cannot be excluded by normal spirometry. One study found that 62 percent of SSc patients with normal FVC had clinically important ILD identified by HRCT (false negative rate) [5]. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary function testing' and "Overview of pulmonary function testing in adults".)

●Lung volumes – The FVC, total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) may be decreased in ILD. Patients with SSc who have a near-normal FVC at initial presentation have low risk for progression to severe ILD [22]. However, normal lung volumes cannot be used to exclude early ILD [5]. (See "Overview of pulmonary function testing in adults".)

●Diffusing capacity – The single breath diffusion capacity for carbon monoxide (DLCO) is a sensitive screening test for ILD, although rarely patients with SSc will have a normal DLCO despite radiographic evidence of ILD [5,23]. A decrease in the DLCO may be the earliest PFT abnormality seen in patients with SSc-associated ILD but is nonspecific; other processes (eg, pulmonary hypertension, cigarette smoking, thromboembolic disease, as well as anemia) can also cause a decrease in DLCO. Among patients with SSc-associated ILD, the decrease in DLCO is usually proportionate to the decrease in lung volumes. Furthermore, the decrease in DLCO correlates with the severity of ILD detected by high-resolution computed tomography (HRCT) and is a predictor of poor outcome [24,25]. (See "Diffusing capacity for carbon monoxide".)

●Six-minute walk test – The six-minute walk test (6MWT) assesses both the distance walked (meters) and the degree of oxygen desaturation. It is used as a measure of submaximal exercise performance in a variety of pulmonary diseases (eg, idiopathic pulmonary fibrosis and pulmonary arterial hypertension). Assessment of pulse oxygen desaturation can be problematic in patients with SSc due to Raynaud phenomenon and poor finger perfusion. If the appropriate attachment is available, measurement of pulse oxygen saturation using an earlobe clip may be more reliable. Desaturation on ambulation is common to both ILD and pulmonary hypertension.

The value of the 6MWT is somewhat limited in SSc, as the distance walked does not discriminate well between patients with lung involvement and those without [26]. This may be due to musculoskeletal and peripheral vascular complications.

Imaging

Chest radiograph — Chest radiographs are relatively insensitive for the detection of early ILD and may be omitted if the patient has chest computed tomography instead. The classic radiographic features of established SSc-associated ILD consist of symmetric, reticular, or ground glass opacities. These are usually most pronounced at the lung bases.

HRCT scanning — All patients with suspected SSc-ILD should undergo chest HRCT at initial evaluation. Imaging in both supine and prone positions is important because early radiologic changes of SSc-associated ILD are usually found in the dependent lung areas; scanning in the prone position is used to exclude the possibility of dependent atelectasis. (See "High resolution computed tomography of the lungs", section on 'Clinical application of HRCT'.)

The HRCT patterns found in SSc-associated ILD mirror the common histopathological patterns of the idiopathic interstitial pneumonias (eg, fibrotic nonspecific interstitial pneumonia [NSIP], usual interstitial pneumonia [UIP], and centrilobular fibrosis). (See "Idiopathic interstitial pneumonias: Classification and pathology".)

●Among patients with SSc-associated ILD, the most common pathologic pattern, NSIP, is associated with the HRCT finding of ground glass opacities in a peripheral distribution (image 1 and picture 1) [9,27,28]. 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. As the disease progresses, there is volume loss associated with a reticular appearance and traction bronchiectasis. The honeycomb pattern is rarely seen with NSIP.

●In the subset of patients with a histologic UIP pattern, the HRCT appearance is usually similar to that of fibrotic NSIP. However, sometimes the HRCT pattern is more consistent with that of UIP with bibasilar reticular opacities (image 2), associated with traction bronchiectasis and the development of subpleural honeycomb air spaces, which ultimately coalesce into large cystic air spaces (image 3 and picture 2) [9,27,29,30].

●Centrilobular fibrosis is a rare pattern that is associated with patchy ground glass or consolidative opacities with a central distribution on HRCT scanning. In a series of 28 patients with SSc-associated ILD, six had centrilobular fibrosis on biopsy. In these patients, centrilobular fibrosis was associated with pathologic evidence of recurrent aspiration [28]. Centrilobular nodules and “tree-in-bud” pattern are other features of recurrent aspiration. (See "High resolution computed tomography of the lungs", section on 'Centrilobular nodules'.)

The extent of ILD seen on HRCT is negatively correlated with FVC and is a powerful predictor of survival [27,31,32]. In a prospective study of 215 patients with SSc, increasing extent of interstitial changes on HRCT was highly predictive of mortality [31]. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

Bronchoalveolar lavage — Bronchoscopy and bronchoalveolar lavage (BAL) in patients with SSc and suspected ILD are rarely indicated. Their main role is to exclude other causes of ILD. However, for SSc patients with atypical features, such as fever, productive cough, hemoptysis, peripheral blood eosinophilia, or focal consolidation on chest imaging, bronchoscopy with BAL may be indicated. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Patients with SSc-associated ILD typically have elevated numbers of granulocytes in their BAL fluid, particularly neutrophils and eosinophils, and may sometimes have an increase in lymphocytes and mast cells [33-35]. However, the clinical significance of these findings is controversial. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Some centers have used BAL in SSc-associated ILD to assess the degree of alveolitis and predict the response to immunosuppressive therapy [27,36,37]. However, the results from a multicenter clinical trial argue against the routine use of BAL to identify active or progressive ILD (ie, alveolitis). In this trial of 158 patients with early SSc-associated ILD, there was no difference in the change in FVC after 12 months when patients with BAL-defined alveolitis were compared to patients who had a normal BAL [38].

Lung biopsy — Lung biopsy is seldom warranted in the evaluation of SSc-associated ILD. Biopsy may be indicated in patients with imaging findings that are atypical for SSc-associated lung disease or are suggestive of granulomatous disease, a malignant process, or pulmonary infection, particularly in patients receiving immunosuppressive drugs. When needed, a lung biopsy is typically obtained via video-assisted thoracoscopic surgery. Since SSc-associated ILD is predominantly subpleural, significant histologic changes are more likely to be found in peripheral lung biopsy than from tissue sampling of other locations [24]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Surgical lung biopsy'.)

Pathology — The most frequently noted histopathologic finding on lung biopsy in SSc is fibrotic NSIP (picture 1)[25,30,39-42]. Within the classification of NSIP, variable amounts of mononuclear cell infiltration and alveolar septal fibrosis can be seen. In SSc-associated NSIP, the pattern is more fibrotic and less inflammatory, thus leading to the designation fibrotic NSIP, rather than cellular NSIP. Additional characteristics of NSIP are temporal homogeneity and absence of fibroblast foci. (See "Treatment and prognosis of nonspecific interstitial pneumonia" and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology'.)  

In addition to the type of interstitial pneumonia, lung biopsy may reveal other histopathologic findings. In a series of lung biopsies from 34 patients with SSc, lymphocyte and plasma cell infiltration of the alveolar walls and interstitial fibrosis were noted, and approximately a fourth of the biopsies had focal lymphoid hyperplasia (also known as germinal centers or follicular bronchiolitis) [43]. Intimal thickening of pulmonary arteries with resultant luminal narrowing is often found in postmortem lung specimens [44].

A pattern consistent with UIP is occasionally seen in SSc [9]. When compared with lung biopsies from patients with idiopathic pulmonary fibrosis, biopsies of SSc-associated UIP have a lower number of fibroblast foci and a higher number of germinal centers [45]. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology'.)

Rarely, histopathologic patterns consistent with other interstitial pneumonias are seen. In one series, four cases of respiratory bronchiolitis-associated interstitial lung disease were seen in patients who were cigarette smokers [25]. Organizing pneumonia was seen in a patient taking penicillamine [25]. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology' and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Cryptogenic organizing pneumonia'.)

DIAGNOSIS — The diagnosis of SSc-associated ILD is generally based on the presence of the characteristic chest high-resolution computed tomography (HRCT) features of ILD in a patient with known SSc and exclusion of other etiologies of pulmonary parenchymal disease, such as heart failure, drug-induced lung toxicity, recurrent aspiration, or pulmonary vascular disease. (See 'HRCT scanning' above.)

Once ILD is identified on HRCT, the radiographic pattern can generally be used to determine whether it is typical of the most common type of SSc-associated ILD, fibrotic nonspecific interstitial pneumonia, or another type of ILD, such as usual interstitial pneumonia. (See 'Pathology' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SSc-associated ILD includes ILD due to another rheumatic disease (eg, mixed connective tissue disease), ILD complicated by pulmonary arterial hypertension, heart failure, fluid overload, drug toxicity, recurrent aspiration, and rarely, pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease. Other types of ILD may need to be considered based on any history of exposures, such as medications, cigarette smoking (respiratory bronchiolitis-associated interstitial disease), silica, or organic dusts (hypersensitivity pneumonitis).

●Mixed connective tissue disease (MCTD) – MCTD is characterized by the presence of high titers of the autoantibody anti-U1 ribonucleoprotein (RNP, previously called antibody to extractable nuclear antigen) in a patient with overlapping features of systemic lupus erythematosus, SSc, and polymyositis. ILD occurs in about 50 to 66 percent of patients with MCTD. Differentiation of ILD due to SSc or MCTD is based on the pattern of other clinical manifestations and the presence of dominant autoantibodies to U1 RNP. The clinical manifestations and diagnosis of MCTD are discussed separately. (See "Mixed connective tissue disease".)

●ILD with pulmonary hypertension (PH) – Among patients with SSc-associated ILD, some may have concomitant pulmonary arterial hypertension (PAH) that is indistinguishable from idiopathic PAH and others with advanced ILD can develop PH due to hypoxemia. Either of these processes can present with a reduction in diffusion capacity for carbon monoxide (DLCO) that appears greater than what would be expected based in the reduction in lung volume or high-resolution computed tomography (HRCT) abnormalities. Identification of PH contributor to dyspnea or a low DLCO is dependent on finding elevated pulmonary artery pressures on Doppler echocardiography followed by confirmation on right heart catheterization. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Right heart catheterization'.)

Rare cases have been reported of patients with SSc who have pulmonary hypertension due to pulmonary capillary hemangiomatosis or veno-occlusive disease [46-48]. The HRCT findings of pulmonary capillary hemangiomatosis (PCH) include a centrilobular pattern of ground-glass opacities, septal lines, pleural effusion, pericardial effusion, and/or mediastinal lymphadenopathy [46]. The HRCT features of pulmonary veno-occlusive disease (PVOD) are similar with mediastinal lymph node involvement, centrilobular ground glass opacities, and septal thickening [48]. It is important to distinguish these HRCT findings from SSc-associated ILD with PAH, as these patients are at increased risk for pulmonary edema associated with pulmonary vasodilator therapy. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

●Heart failure and fluid overload – Heart failure can develop in SSc due to myocardial fibrosis which can lead to systolic or more often diastolic ventricular dysfunction. The diagnosis may be suspected on the basis of myositis, evidence of volume overload, or abnormal findings on transthoracic echocardiography. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

●Drug toxicity – Several drugs used to treat SSc are associated with drug-induced pulmonary disease, such as cyclophosphamide, methotrexate, and angiotensin converting enzyme inhibitors. Drug-induced lung toxicity should always be in the differential diagnosis of new respiratory signs, symptoms, and radiographic abnormalities. (See "Cyclophosphamide pulmonary toxicity" and "Methotrexate-induced lung injury" and "Pulmonary disease induced by cardiovascular drugs", section on 'Angiotensin-converting enzyme inhibitors'.)

●Recurrent aspiration – Patients with SSc have a high rate of gastroesophageal reflux due to impaired esophageal peristalsis and, often, reduced tone of the lower esophageal sphincter (image 2). Thus, they are at increased risk for recurrent aspiration. Studies have found that presence of a dilated (patulous) esophagus on HRCT of the chest is associated with more severe radiographic ILD, lower lung volumes, and possibly greater progression of ILD [49]. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Esophageal involvement'.)

INVESTIGATIONAL TESTS — Several investigational biomarkers have shown a correlation with the presence of ILD in patients with SSc but are not clinically available [11]. Krebs von den Lungen-6 (KL-6), a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, is elevated in the serum of patients with SSc-associated ILD and may correlate with the presence of pneumonitis and the radiological fibrosis score in patients with SSc [50,51]. Serial measurements of serum KL-6 may eventually find a role in the diagnosis and monitoring of ILD in SSc [11].

Similar prognostic roles have been proposed for surfactant proteins A and D, which also are elevated in the serum of most patients with SSc-associated lung disease [52,53], and for CCL18, a chemokine that is abundantly expressed by pulmonary macrophages [54].

Genetic factors might influence susceptibility to ILD in patients with SSc. As an example, one study found an association between SSc-associated ILD and the presence of human leukocyte antigen (HLA)-B*62 and HLA-Cw*0602, whereas PAH was associated with HLA-B*13 and HLA-B*65 [55]. Other studies have demonstrated a strong association of SSc-associated ILD with variants of the interferon regulatory factor 5 (IRF5) gene [56]. In contrast, genetic polymorphisms in MUC5B that are strongly associated with idiopathic pulmonary fibrosis do not appear to be a risk factor for SSc-associated ILD [57].

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)" and "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Definition and epidemiology – Interstitial lung disease (ILD) is one of the major forms of lung involvement in patients with systemic sclerosis (SSc). The prevalence of ILD approaches 50 percent of patients with diffuse cutaneous SSc (extensive skin involvement proximal to the wrists, particularly over the proximal limbs and trunk). (See 'Epidemiology' above and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Types of pulmonary involvement'.)

●Clinical manifestations – Early SSc-associated ILD may be asymptomatic. When symptoms develop, fatigue, breathlessness (ie, exertional dyspnea initially), and dry cough are most commonly reported. Chest pain is infrequent, and hemoptysis is rare. Bibasilar, fine inspiratory crackles (ie, "Velcro" rales) are the most characteristic finding of ILD; clubbing is uncommon. (See 'Clinical manifestations' above.)

●Evaluation – The evaluation of suspected ILD in a patient with SSc is similar to that of other patients with suspected ILD and is designed to characterize the type and severity of ILD and to exclude the possibility that another lung disease or extra-pulmonary process is etiologic. Most patients will require pulmonary function testing and high-resolution computed tomography (HRCT) of the chest. (See 'Evaluation' above and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

•Pulmonary function testing – Reduced lung volumes and a reduced diffusing capacity for carbon monoxide (DLCO) are hallmarks of ILD and are usually proportionate in terms of changes from the percent predicted values. A decreased DLCO without a concomitant decrease in lung volumes is more typical of pulmonary arterial hypertension. (See 'Pulmonary function testing' above.)

•Imaging – All patients with suspected SSc-ILD should undergo HRCT with supine and prone images. The typical HRCT finding is a peripheral, bibasilar distribution of ground glass opacities, consistent with nonspecific interstitial pneumonia (NSIP). With more advanced disease, reticular opacities increase and traction bronchiectasis becomes apparent, suggesting volume loss. The HRCT pattern in patients with the less common usual interstitial pneumonia (UIP) pattern is similar and may include honeycombing. Centrilobular fibrosis is a rare pattern that is associated with patchy ground glass or consolidative opacities with a central distribution on HRCT scanning. HRCT imaging in SSc might reveal the presence of ILD even in patients with no respiratory symptoms and normal PFTs (See 'HRCT scanning' above.)

•Bronchoscopy with BAL, in select patients – Bronchoscopy with bronchoalveolar lavage (BAL) is rarely necessary in the evaluation of patients with suspected SSc-ILD. However, for patients with atypical features, such as fever, productive cough, hemoptysis, peripheral blood eosinophilia, or focal consolidation on chest imaging, bronchoscopy with BAL may be indicated. (See 'Bronchoalveolar lavage' above.)

●Diagnosis – The diagnosis of SSc-associated ILD is based on the presence of the characteristic chest HRCT features of ILD in a patient with known SSc and exclusion of other causes of ILD and does not usually require a lung biopsy. (See 'Lung biopsy' above and 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of ILD in SSc includes ILD due to another rheumatic disease (eg, mixed connective tissue disease when the diagnosis of underlying SSc is not definitive), ILD in combination with pulmonary arterial hypertension, heart failure, drug toxicity, recurrent aspiration, and rarely, pulmonary capillary hemangiomatosis or pulmonary veno-occlusive disease. (See 'Differential diagnosis' above.)