Connective tissue diseases (CTDs) can affect the lungs through diseases of the chest wall, pleura, vasculature, airways, and parenchyma. Interstitial lung disease (ILD) is a common complication of CTD associated with increased morbidity and mortality. This article describes the evaluation of respiratory impairment in patients with CTD and summarizes the evidence that guides diagnosis and management of CTD-ILD. Patients with CTD with suspected ILD should undergo clinical, physiologic, and radiologic studies to evaluate for the presence of ILD, and these results should be integrated in a multidisciplinary setting to guide diagnosis and management. Screening for ILD may also be appropriate in asymptomatic patients with high-risk features.
Key points
- •
ILD is a common complication of CTD that has unique management and a poor prognosis.
- •
Patients with CTD without known pulmonary disease should undergo regular symptom assessment and physical examination for findings suggestive of ILD or other respiratory involvement.
- •
A comprehensive evaluation for ILD in patients with high-risk features or suggestive findings should include symptom assessment, physical examination, pulmonary function tests, and chest imaging (plain chest radiography or high-resolution computed tomography).
- •
Clinical, physiologic, and radiologic findings should be integrated in a multidisciplinary setting to guide diagnosis and management.
Introduction
Connective tissue diseases (CTDs) include several systemic disorders that frequently result in pulmonary involvement. CTDs can affect the lungs through diseases of the chest wall, pleura, vasculature, airways, and parenchyma. A large percentage of patients with CTD develop interstitial lung disease (ILD), a group of typically progressive and irreversible diseases that are characterized by inflammation or fibrosis of the lung parenchyma.
A diagnosis of ILD in a patient with CTD is associated with significantly increased morbidity and mortality. Dyspnea, the major symptom of ILD, is an important and independent predictor of physical function and well-being in patients with CTD-associated ILD (CTD-ILD). ILD is the most common cause of death in patients with systemic sclerosis (SSc) and the inflammatory myopathies. In patients with Sjögren syndrome, any respiratory involvement is associated with reduced quality of life and a four-fold increased risk of death. Early recognition of ILD is therefore important to help guide management and improve prognostication.
This article discusses the approach to the evaluation of respiratory impairment in patients with CTD. We focus specifically on the initial evaluation of ILD in patients with CTD, and summarize the evidence that guides the diagnostic work-up of suspected CTD-ILD.
Introduction
Connective tissue diseases (CTDs) include several systemic disorders that frequently result in pulmonary involvement. CTDs can affect the lungs through diseases of the chest wall, pleura, vasculature, airways, and parenchyma. A large percentage of patients with CTD develop interstitial lung disease (ILD), a group of typically progressive and irreversible diseases that are characterized by inflammation or fibrosis of the lung parenchyma.
A diagnosis of ILD in a patient with CTD is associated with significantly increased morbidity and mortality. Dyspnea, the major symptom of ILD, is an important and independent predictor of physical function and well-being in patients with CTD-associated ILD (CTD-ILD). ILD is the most common cause of death in patients with systemic sclerosis (SSc) and the inflammatory myopathies. In patients with Sjögren syndrome, any respiratory involvement is associated with reduced quality of life and a four-fold increased risk of death. Early recognition of ILD is therefore important to help guide management and improve prognostication.
This article discusses the approach to the evaluation of respiratory impairment in patients with CTD. We focus specifically on the initial evaluation of ILD in patients with CTD, and summarize the evidence that guides the diagnostic work-up of suspected CTD-ILD.
Pulmonary involvement in connective tissue disease
Pulmonary symptoms in patients with CTD are nonspecific and can be secondary to pulmonary or nonpulmonary causes. Nonpulmonary causes of dyspnea in patients with CTD include anemia, chest wall disease, and cardiopericardial disease. Pulmonary symptoms can also be related to treatment of the underlying CTD, including drug-induced ILD and opportunistic infections or malignancy that have increased frequency in patients who are chronically immunosuppressed. These nonpulmonary manifestations of CTD and complications of CTD therapy are important to identify because these have unique therapies and often clear benefit from appropriate management.
Dyspnea and cough are also common symptoms of the pulmonary manifestations of CTD, including serositis (eg, pleuritis and associated pleural effusions), vascular disease (eg, thromboembolic disease, pulmonary hypertension), airways disease (eg, follicular or obliterative bronchiolitis), and ILD ( Table 1 ). Each CTD is associated with multiple pulmonary manifestations; however, different CTD subtypes predispose to specific patterns of pulmonary involvement. ILD is most common in patients with rheumatoid arthritis (RA), SSc, the inflammatory myopathies, Sjögren syndrome, and mixed CTD, but occurs at a lower frequency in systemic lupus erythematosus. Similarly, each CTD predisposes to specific ILD subtypes. Nonspecific interstitial pneumonia is the most common pattern in most CTD-ILDs, but other patterns are frequently observed, including usual interstitial pneumonia (UIP), organizing pneumonia, diffuse alveolar damage, and lymphocytic interstitial pneumonia.
| Connective Tissue Disease | Respiratory Involvement | |
|---|---|---|
| Frequent Non-ILD Diseases | Frequent ILD Patterns | |
| Rheumatoid arthritis | Pleuritis/pleural effusion Pulmonary nodules Bronchiolitis | UIP, NSIP, OP, LIP, DAD |
| Systemic sclerosis | Pulmonary hypertension Ventilatory restriction from skin sclerosis Bronchiolitis | NSIP, UIP, OP |
| Sjögren syndrome | Bronchiolitis Pulmonary amyloidosis Pulmonary lymphoma | LIP, NSIP, OP, UIP |
| Inflammatory myopathies | Respiratory muscle weakness Pulmonary hypertension | NSIP, OP, UIP, DAD |
| Mixed connective tissue disease | Pulmonary hypertension Pleuritis/pleural effusion Thromboembolic disease | NSIP, OP, UIP |
| Systemic lupus erythematosus | Pleuritis/pleural effusion Diffuse alveolar hemorrhage Diaphragmatic dysfunction (shrinking lung syndrome) Pulmonary hypertension Thromboembolic disease | NSIP, DAD, OP |
Evaluation for interstitial lung disease in connective tissue disease
The extent of evaluation for ILD in patients with CTD should be based on the pretest likelihood of ILD. In patients with CTD with a high probability of ILD, a comprehensive initial evaluation should include clinical, physiologic, and radiologic evaluations. This can often distinguish between ILD and non-ILD pulmonary involvement ( Table 2 ). Patients with a low probability of ILD should still undergo regular screening including symptom assessment and physical examination, but may not require detailed physiologic or radiologic studies.
| ILD | Non-ILD Respiratory Disease | |||
|---|---|---|---|---|
| Airways Disease | Pleural Disease | Pulmonary Hypertension | ||
| Symptoms and physical examination | Dyspnea Crackles | Dyspnea Wheezing | Dyspnea Pain Decreased breath sounds | Dyspnea Loud P2 Right heart insufficiency |
| Chest imaging | Decreased lung volumes Reticulation Traction bronchiectasis Ground glass opacities Honeycombing | Air trapping Hyperinflation Airway wall thickening Centrilobular nodularity Normal parenchyma | Effusion Pleural thickening Atelectasis | Enlarged pulmonary arteries Dilated right ventricle Mosaic perfusion Centrilobular ground glass nodules |
| PFT | Restrictive pattern Low D l co | Obstructive or mixed pattern Normal or low D l co | Restrictive pattern Normal D l co | Low D l co Normal flow rates and lung volumes |
Symptom Assessment and Physical Examination
Patients with CTD should routinely be questioned regarding the presence of dyspnea, because it is typically the first and predominant symptom of ILD. Dyspnea is a significant predictor of physical function, fatigue, psychological well-being, and global functioning in CTD-ILD, even after adjusting for the severity of lung involvement. Dyspnea can be quantified using detailed questionnaires ; however, these questionnaires are typically time consuming and none are validated in CTD-ILD. In a clinical setting, dyspnea and associated functional limitation can be quickly assessed and quantified using the Modified Medical Research Council scale (ranging from 0 to 4, where 0 is breathless on strenuous exercise, and 4 is too breathless to leave the house). The Modified Medical Research Council scale, initially developed and validated in patients with chronic obstructive pulmonary disease, is associated with activity limitation, anxiety, and depression in ILD. The Modified Medical Research Council scale is not validated in CTD-ILD, but is likely an appropriate screening tool that can be used as a baseline measurement to identify worsening dyspnea and function over time. Other symptoms commonly reported in patients with CTD-ILD include cough, sputum production, and fatigue. Patients that develop these nonspecific symptoms without a clear cause should undergo a detailed evaluation for CTD-ILD.
All patients with CTD should undergo a thorough physical examination for features of ILD at baseline and this should be repeated at regular follow-up visits. The most common examination feature of ILD is crackles on auscultation. Auscultatory crackles can precede the development of clinically apparent symptoms and should prompt further investigations when identified. Tachypnea, hypoxemia, and reduced chest wall expansion can be observed, but are more typical of advanced ILD. Digital clubbing can occur in CTD-ILD, but is less common than in idiopathic pulmonary fibrosis (IPF).
Pulmonary Function Tests
Pulmonary function tests (PFTs) are used to screen patients with CTD for ILD, to support a new diagnosis in patients with suspected CTD-ILD, or to monitor disease activity and progression in patients with an established CTD-ILD diagnosis. PFTs should be performed in all patients with unexplained symptoms or physical examination findings that are consistent with ILD. However, PFTs can be normal in early ILD, and thus the presence of normal physiology does not rule out mild ILD in patients with a high pretest probability. A normal PFT can also indicate the presence of ILD if previous measurements showed supranormal values, illustrating the importance of comparison with previous tests.
Reduced diffusion capacity of the lung for carbon monoxide (D l co) is often the first physiologic manifestation of ILD, but this is not specific for ILD and pulmonary vascular disease can present with similar findings. More advanced ILD is characterized by a restrictive pattern with proportionately reduced flow rates (forced vital capacity [FVC] and forced expiratory volume in 1 second), reduced lung volumes (total lung capacity), and reduced D l co. Once a diagnosis of ILD is established, repeated testing at regular intervals should be performed to quantify the severity of the impairment, assess for disease progression, and monitor response to treatment. A 5% to 10% decline in the FVC is considered clinically important in IPF and this is likely a reasonable threshold to indicate worsening ILD in patients with CTD-ILD.
Functional Assessment
Functional assessment is most often performed in patients with ILD by measuring the six-minute-walk distance (6MWD) or less commonly using a cardiopulmonary exercise test. The 6MWD is a standardized tool that provides a simple measure of functional capacity and may add prognostic information beyond standard PFTs. The 6MWD correlates with ILD severity (PFT measurements) and quality of life in SSc, and both the baseline and change in 6MWD are independent predictors of mortality in IPF. The major limitation of the 6MWD in CTD-ILD is the lack of organ specificity, because abnormalities can also be caused by cardiac disease, pulmonary hypertension, and musculoskeletal disease. In addition, patients with significant peripheral vascular involvement (eg, Raynaud phenomenon) often require pulse oximetry via a forehead or earlobe saturation probe and this equipment can be unreliable and is not universally available. Despite its limitations in identifying ILD in patients with CTD, the 6MWD can be used to monitor disease progression and provide prognostic information in patients with established CTD-ILD.
Cardiopulmonary exercise testing provides a global assessment of the systems involved in exercise and is typically performed in the evaluation of undiagnosed dyspnea. Cardiopulmonary exercise testing can be useful in CTD-ILD to determine if the dyspnea is primarily caused by ILD (ie, ventilatory limitation to exercise with associated hypoxemia), pulmonary vascular disease, cardiac disease, or some other etiology.
Chest Imaging
Plain chest radiography lacks sensitivity and specificity for ILD in a screening setting but may still be useful in the initial evaluation of pulmonary symptoms in CTD because it can identify ILD and other CTD-associated pulmonary manifestations (eg, pleural effusions or pneumonia). High-resolution computed tomography (HRCT) can be used to reliably diagnose or exclude ILD; however, it is costly and associated with nontrivial radiation exposure that increases the risk of malignancy. HRCT is thus not routinely used as a serial screening test in asymptomatic patients with CTD. HRCT of the chest is essential in patients with suspected ILD, and is more sensitive than plain radiography in diagnosing ILD. HRCT can also guide management by suggesting the ILD subtype and providing prognostic information. A radiologic pattern of UIP (subpleural, lower lung–predominant reticulation, traction bronchiectasis, and honeycombing with an absence of ground glass or nodularity) is highly specific for histopathologic UIP in patients with RA, and is associated with a poor prognosis. The extent of fibrosis on HRCT also suggests a poor prognosis in multiple CTD-ILD subtypes, and can provide further evidence of stability or worsening in patients with unclear evidence of progression.
Bronchoscopy and Surgical Lung Biopsy
Bronchoalveolar lavage has no clear role in establishing the diagnosis of CTD-ILD, although it can be helpful to exclude infection, diffuse alveolar hemorrhage, and other causes of ILD in patients with an unclear diagnosis. Transbronchial biopsy has low sensitivity and specificity for diagnosing CTD-ILD and should be discouraged outside of specific situations (eg, patients with suspected sarcoidosis).
Surgical lung biopsy permits a more detailed evaluation of the lung histopathology and is able to identify specific CTD-ILD subtypes. Surgical lung biopsy is particularly useful in cases where the diagnosis of CTD is not yet established, or if a competing diagnosis is possible. Some histopathologic features make the diagnosis of CTD-ILD more likely, including the presence of lymphoid aggregates, interstitial fibrosis with overlapping patterns, bronchiolocentricity, lack of well-formed granulomas, and the presence of rheumatoid nodules. Lung biopsies with any of these findings should prompt a detailed assessment for an occult CTD. Surgical lung biopsy is generally not performed in patients with established CTD given the significant risk of complications and the current lack of evidence that the histopathologic pattern should influence management of CTD-ILD.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
