Interstitial lung disease (ILD) represents a heterogeneous group of lung disorders of known or unknown cause that affect the lung parenchyma. Most of these disorders involve an infiltrative process that affects the lungs diffusely. Therefore, some authors prefer the term diffuse infiltrative lung diseases or diffuse parenchymal lung disease (1). ILDs can manifest a wide spectrum of histopathologic findings and outcomes. Although most of these disorders are chronic, some ILDs, such as acute interstitial pneumonia (Hamman-Rich syndrome), can progress rapidly (2). The major clinical consequence of ILDs is impaired gas exchange resulting in dyspnea and hypoxemia. Progressive ILD results in respiratory failure and cor pulmonale, a common sequelae of idiopathic pulmonary fibrosis.

ILD is a common manifestation of pulmonary involvement in patients with connective tissue diseases (CTDs), but there is relatively little known regarding its pathogenesis or management. The clinical relevance of various histopathologic patterns of lung injury that are seen in patients with CTDs has not been clarified. The recent evolution of concepts on idiopathic pulmonary fibrosis, the most common form of ILD, may offer some insight.

Traditionally, idiopathic pulmonary fibrosis had been a clinical concept defined by the presence of slowly progressive dyspnea, inspiratory crackles on auscultation of the lungs, and bilateral interstitial infiltrates on chest radiography occurring in the absence of an identifiable cause for the lung disease (3, 4). The advent of high-resolution computed tomography (HRCT) in the evaluation of patients with ILDs allowed recognition of distinct patterns of radiologic abnormalities that were previously unseen by plain chest radiography (5, 6). The correlation of these HRCT findings with underlying histopathologic patterns made it clear that the traditional concept of idiopathic pulmonary fibrosis comprised a broad heterogeneous group of patients with not only differing HRCT and histopathologic findings (various forms of interstitial pneumonias) but also differences in response to therapy and prognosis (3, 4, 7–10). As a result of these insights, an American-European consensus statement (7) was developed, narrowing the definition of idiopathic pulmonary fibrosis to patients with histopathologic findings of usual interstitial pneumonia (UIP) and excluding patients with other forms of idiopathic interstitial pneumonia (IIP), including nonspecific interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia, which are associated with a better prognosis. The application of this revised definition has lead to the realization that traditional treatment using high-dose corticosteroids is ineffective in the management of idiopathic pulmonary fibrosis (4, 7, 8, 11, 12).

Several parallels can be drawn between the concept of idiopathic pulmonary fibrosis and CTD-ILDs. Similar to idiopathic pulmonary fibrosis, initial descriptions of CTD-ILDs were based predominantly on the findings of respiratory symptoms, pulmonary function abnormalities, and parenchymal lung infiltrates detected by chest radiography. Histopathologic confirmation was uncommon, and there have been relatively few studies examining histologic subtypes encountered in the lungs of patients with CTD-ILD and associated clinical relevance. Based on available data and our own clinical experience, it appears likely that histopathologic findings are relevant in predicting response to therapy and prognosis in patients with CTD-ILD. For example, the histopathologic pattern of NSIP is associated with a better prognosis compared with UIP or diffuse alveolar damage in patients with polymyositis/dermatomyositis-associated ILD (13, 14). There may also be important differences in cell types and other immunologic markers among patients with various types of interstitial pneumonias, including UIP and NSIP, as well as in different CTDs, which may have important treatment and outcome implications (15).

In this issue of Arthritis Care & Research, Kocheril et al report a study comparing the survival rates of patients with CTD-ILD with that of patients with IIP (16). The group with CTD-ILD included the full spectrum of CTDs, with rheumatoid arthritis and scleroderma accounting for 50% of the patients. The pulmonary function test results, distribution of HRCT diagnoses (achieved in 60% of all patients by consensus reading), and HRCT fibrotic scores appeared to be similar between the 2 groups. Overall survival was similar for the 2 groups, although it is not known exactly how many deaths were related to progressive lung disease in the respective groups. In addition, both the higher HRCT fibrotic score and the HRCT diagnosis of UIP (compared with the HRCT diagnosis of NSIP) tended to correlate with decreased survival. Other significant predictors of mortality included age at diagnosis and pulmonary function test measurements (forced vital capacity and forced expiratory volume in 1 second).

Although Kocheril and colleagues have demonstrated that overall survival appears to be similar between patients with CTD-ILD and those with IIP, it is unclear how this information should be applied to the management of individual patients with CTD-ILD. The group with CTD-ILD in this study consisted of a heterogeneous mixture of several CTDs and various types of interstitial pneumonias as diagnosed by HRCT. As the authors acknowledged, HRCT has limitations in diagnosing histopathologic patterns of interstitial pneumonias (17, 18). It is also not known how many of the patients in these 2 groups actually had progression of their lung disease. Although the underlying pattern of interstitial pneumonia and the extent of fibrosis (fibrotic score) are likely significant predictors of survival, the clinical context is probably just as important. This clinical context includes the specific CTD and its extrapulmonary manifestations, as well as age and comorbidities of the individual patient.

What are the important questions that need to be answered regarding CTD-ILDs? First, what is the natural history of ILDs occurring in patients with CTDs? Although some information is available, well-designed longitudinal studies are needed to define the long-term clinical course of these patients. Chest radiography and pulmonary function testing are relatively crude tools in the detection and diagnosis of ILDs. HRCT is more sensitive in detecting early ILD as well as in assessing progression and should be helpful in better defining the natural history of CTD-ILDs.

Second, how often does ILD occur in specific CTDs, and what are the risk factors for the development of ILD in patients with CTDs? Some of these risk factors may be disease-specific and peculiar to the particular CTD, whereas others are host-specific and attributable to individual patient factors.

Third, what is the clinical relevance of various interstitial pneumonias in patients with CTDs? For example, it has not been determined whether the presence of UIP in a patient with rheumatoid arthritis confers a worse prognosis compared with the presence of NSIP in such a patient. It is also not known whether a particular histologic subtype of interstitial pneumonia has similar implications in different CTDs. Tansey and colleagues (19) have demonstrated variations in the prevalence of different histologic patterns among various CTDs. Of particular importance to patients and their physicians are the treatment implications of these histopathologic patterns. Is aggressive immunosuppressive therapy appropriate for all patients with CTD-ILD? Corticosteroids and other immunosuppressive agents have been relatively ineffective for treating idiopathic pulmonary fibrosis (idiopathic UIP). If the underlying histopathologic pattern does matter, we need to ask whether an HRCT diagnosis is accurate enough for studying treatment effects and outcomes. Although a surgical lung biopsy is usually the reference standard in the diagnosis of ILDs, it does entail risk of postoperative complications, including death (20).

Fourth, what are the pathogenetic mechanisms leading to the development of CTD-ILDs? These mechanisms may or may not be similar to those operative in the idiopathic versions of these interstitial pneumonias. Lung parenchyma has a relatively limited number of ways in which it can react to injury. The pathogenesis of UIP in rheumatoid arthritis may not be the same as that of UIP occurring in polymyositis. It is intriguing that different patterns of interstitial pneumonias can emerge in association with the same CTD, such as polymyositis. A complex interplay of host- and disease-specific factors is likely to be involved in the initiation and progression of ILD in patients with CTDs.

The study by Kocheril et al has provided data suggesting that patients with CTD-ILD have a poor prognosis that is no better than the prognosis for those with IIP. Their findings are in contrast to earlier studies that reported a more favorable prognosis for patients with CTD-ILD, but these studies had not taken into account the differing spectrum of histopathologic patterns underlying the ILD in these 2 groups of patients (21, 22). Not all ILDs are equal. Patients with CTDs are at risk for harm not only from their lung involvement but from many extrapulmonary manifestations that have significant impacts on disease-related morbidity and mortality. Perhaps, more importantly, the study by Kocheril and colleagues underscores our general lack of knowledge regarding the diagnosis and management of CTD-ILD. Clearly, ILD occurring in a patient with CTDs has major adverse consequences, and, not surprisingly, more data are needed to optimize the management of this manifestation and perhaps eventually lead to its prevention.

  • 1

    Jay H. Ryu, MD, Tim Bongartz, MD, Eric L. Matteson, MD: Mayo Clinic College of Medicine, Rochester, Minnesota.


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