Systemic sclerosis is a heterogeneous disease of unknown etiology with limited effective therapies. It is characterized by autoimmunity, vasculopathy, and fibrosis and is clinically manifested by multiorgan involvement. Interstitial lung disease is a common complication of systemic sclerosis and is associated with significant morbidity and mortality. The diagnosis of interstitial lung disease hinges on careful clinical evaluation and pulmonary function tests and high-resolution computed tomography. Effective therapeutic options are still limited. Several experimental therapies are currently in early-phase clinical trials and show promise.
Key points
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Interstitial lung disease is a significant cause of morbidity and mortality in systemic sclerosis.
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Diagnostic modalities to assess interstitial lung disease include pulmonary function tests, which may show decreases in the forced vital capacity and diffusion capacity of the lung for carbon monoxide, and high-resolution computed tomography, which may show patterns consistent with nonspecific interstitial pneumonia or usual interstitial pneumonia.
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Pathogenesis revolves around an interplay of vascular injury, inflammation, and subsequent fibrosis, with transforming growth factor-beta playing a key role in fibrosis.
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Effective treatment modalities are limited, with cyclophosphamide being the most rigorously studied treatment. Therapies that are often used in other autoimmune conditions are not as effective in systemic sclerosis-interstitial lung disease.
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Several alternative treatment approaches are being considered, including rituximab, bosentan, tyrosine kinase inhibitors, pirfenidone, and hematopoietic stem cell transplant.
Introduction
Systemic sclerosis (SSc) is a heterogeneous disease characterized by vasculopathy, autoimmunity, and fibrosis, with multiorgan involvement and no known cure. Pulmonary complications of SSc remain one of the largest causes of morbidity and mortality in the disease. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most common forms of lung disease associated with SSc. This review focuses on SSc-ILD, a leading cause of mortality in SSc. Pulmonary function tests (PFTs) and chest imaging with high-resolution chest tomography (HRCT) remain important tools in the diagnosis and prognosis of SSc-ILD. Although significant advances have been made in the understanding of the pathogenesis of SSc-ILD, current treatment options have limitations in their overall effectiveness. Several treatment modalities are currently under investigation, and novel targeted treatments that have shown promise in idiopathic pulmonary fibrosis (IPF) clinical trials may ultimately be useful in SSc. This review provides a brief overview of SSc-ILD pathogenesis to date, and includes a discussion of key points in the evaluation and management of the disease, including a discussion on novel therapies.
Introduction
Systemic sclerosis (SSc) is a heterogeneous disease characterized by vasculopathy, autoimmunity, and fibrosis, with multiorgan involvement and no known cure. Pulmonary complications of SSc remain one of the largest causes of morbidity and mortality in the disease. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most common forms of lung disease associated with SSc. This review focuses on SSc-ILD, a leading cause of mortality in SSc. Pulmonary function tests (PFTs) and chest imaging with high-resolution chest tomography (HRCT) remain important tools in the diagnosis and prognosis of SSc-ILD. Although significant advances have been made in the understanding of the pathogenesis of SSc-ILD, current treatment options have limitations in their overall effectiveness. Several treatment modalities are currently under investigation, and novel targeted treatments that have shown promise in idiopathic pulmonary fibrosis (IPF) clinical trials may ultimately be useful in SSc. This review provides a brief overview of SSc-ILD pathogenesis to date, and includes a discussion of key points in the evaluation and management of the disease, including a discussion on novel therapies.
Epidemiology
ILD is common in patients with SSc, with up to 90% of patients exhibiting evidence of interstitial changes on HRCT, and between 40% and 75% of patients having PFT abnormalities. Clinically significant lung fibrosis is present in approximately 25% of all SSc patients, but there is significant heterogeneity with regard to the incidence of pulmonary involvement based on several factors, including the SSc subset and antibody profile. In particular, patients with diffuse cutaneous SSc (dcSSc) or Scl-70 (antitopoisomerase) antibodies are at higher risk for ILD development, whereas patients with limited cutaneous SSc or anticentromere antibodies less commonly have ILD. Among 3656 patients in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research database, 60% of patients with positive Scl-70 antibodies had evidence of ILD compared with 21% of patients with anticentromere antibodies. Certain clinical features, such as African-American ethnicity, modified Rodnan Skin Score (mRSS), serum creatinine level, creatine phosphokinase values, and evidence of cardiac involvement are also found to be independent predictors of lung involvement in SSc. In a recent meta-analysis looking at predictors of mortality and progression in SSc-ILD, factors including older age, lower forced vital capacity (FVC), and lower diffusing capacity of the lungs for carbon monoxide (DLCO) predicted mortality. Extent of disease involvement on HRCT predicted both mortality and ILD progression.
Several biomarkers have been studied as possible predictors of the development and progression of ILD in SSc. These markers, which are currently not available for clinical use in the United States, may play a role in prognosis and disease monitoring in the future. Specifically, the glycoproteins Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are found to be elevated in patients with SSc-ILD, and levels may correlate with ILD severity and progression.
Pathogenesis
The pathogenesis of SSc-ILD is multifactorial and incompletely understood. Endothelial cell injury with subsequent vascular damage and alveolar epithelial cell injury are key initial insults that precede fibrosis. At the time of injury, various mediators are released, and fibroblasts are activated. Over time, fibroblasts acquire features of smooth muscle cells and become myofibroblasts, resulting in dysregulated accumulation of collagen and extracellular matrix components and ultimately fibrosis ( Fig. 1 ). Some of the mediators implicated in SSc-ILD include thrombin, transforming growth factor-beta (TGF-β), and the Wnt/β-catenin pathway.
Thrombin
Lung biopsies of SSc-ILD patients show evidence of endothelial and epithelial injury with interstitial edema. Endothelial cell injury results in thrombin production and release of endothelin-1 with elevated levels of thrombin detected in bronchoalveolar lavage fluid of SSc patients compared with healthy controls. Inhibition of thrombin with the oral direct thrombin inhibitor, dabigatran etexilate (Pradaxa), in the mouse bleomycin model of lung injury reduced the number of inflammatory cells in the bronchoalveolar lavage and decreased lung fibrosis. Both thrombin and endothelin-1 also exert direct effects on fibroblasts and play a role in stimulating TGF-β production, a central mediator of SSc fibrosis.
Transforming Growth Factor-beta
TGF-β is a pleiotropic cytokine with a central role in SSc-ILD. Once activated, TGF-β binds to its receptor and leads to the phosphorylation of Smad, a group of intracellular signaling proteins. The Smad proteins subsequently translocate to the nucleus and act as transcription activators for several genes, including type I collagen, fibronectin, plasminogen activator inhibitor-1, and connective tissue growth factor. In mouse models, the conditional knockout of TGF-β receptor type II and Smad3-deficient mice are protected from bleomycin-induced pulmonary fibrosis. Trials of small molecule blockade of Smad phosphorylation and of inhibitors of signaling molecules downstream of TGF-β are currently underway and may provide novel targets to treat SSc-ILD.
Wnt/β-catenin
The Wnt/β-catenin pathway comprises highly conserved growth factors the downstream activity of which leads to the accumulation of β-catenin in the cytoplasm; this then translocates to the nucleus to regulate several genes. Wnt signaling is found to be important in the development of dermal fibrogenesis and the suppression of adipogenesis in a mouse model and in SSc patients. In addition, aberrant expression of components of the Wnt/β-catenin pathway has been implicated in the pathogenesis of IPF. Administration of an antibody to the downstream molecule Wnt1-inducible signaling protein-1 was associated with a decrease in collagen and improved lung function in a mouse model, and further exploration into blockade of the Wnt/β-catenin pathway may provide additional therapeutic strategies for patients with SSc-ILD.
Clinical manifestations
Patients with mild ILD may be asymptomatic during the early stages of the disease. As the extent of pulmonary fibrosis increases, patients often report fatigue and dyspnea on exertion, and physical examination may find dry “velcro” crackles at the lung bases. Of note, patients with PAH may also have exertional dyspnea and fatigue, and the clinician must keep both entities in mind when evaluating an SSc patient for dyspnea. Dry cough is often present and may correlate with DLCO and dyspnea. In the Scleroderma Lung Study, cough severity improved in patients treated with cyclophosphamide, but these improvements disappeared after 2 years of follow-up.
Imaging findings
HRCT plays an important role in determining the pattern and extent of involvement of ILD in SSc patients. The most common pattern seen on HRCT is nonspecific interstitial pneumonia (NSIP), although usual interstitial pneumonia (UIP) can also be seen in 25% to 40% of cases. The NSIP pattern on HRCT is evident by ground glass opacities in a peripheral distribution with subpleural and basilar predominance ( Fig. 2 A). In more severe disease, volume loss with a reticular pattern and traction bronchiectasis can also be seen. In UIP, HRCT findings include reticulonodular opacities, traction bronchiectasis, and honeycomb cysts (see Fig. 2 B). A normal chest computed tomography scan at baseline is generally reassuring; in one study, 85% of SSc patients who had a normal HRCT at baseline still had a normal HRCT at 5 years.
Pulmonary function tests
PFTs are a key component in the diagnosis and long-term follow-up of SSc-ILD. The FVC and DLCO are important parameters for the assessment of lung function in SSc patients, and the FVC can help stratify patients for treatment. Reduced DLCO is sensitive for early ILD but can also be an indicator of pulmonary hypertension and needs to be interpreted in the context of the overall lung volumes. FVC and DLCO should be greater than 80% predicted to be considered normal. In a study of 890 SSc patients who had PFTs, 60% had no or minimal restrictive disease (FVC >75%), 27% had moderate disease (FVC 50%–75%), and 14% had severe disease (FVC ≤50%). Both FVC and DLCO are prognostic factors in patients with SSc-ILD. Among 80 patients who underwent lung biopsy for SSc with fibrosing alveolitis, lower initial DLCO and FVC were associated with mortality.
In general, the authors recommend close clinical follow-up of SSc patients to monitor for a change in cardiopulmonary symptoms, usually every 3 to 6 months. In the absence of a clinical change, PFTs should be done annually. If there is progression of symptoms, such as dyspnea or cough, PFTs should be done every 6 months and should be followed with an HRCT if there are abnormalities on the PFTs. Others have suggested that HRCT be performed in all SSc patients as a screening examination and, if mildly abnormal, be followed by PFTs every 3 to 6 months. Both HRCT and PFTs are well-accepted methods for the diagnosis of SSc-ILD, with 100% and 99% consensus among 117 SSc experts for the use of HRCT and PFTs, respectively. The first 5 years after diagnosis of SSc are critical for the development of ILD, and patients should be monitored closely during this time. The clinician should also keep in mind the role that gastroesophageal reflux (GER) may play in worsening fibrosis and clinical symptoms. Patients with SSc-ILD are found to have more severe GER than SSc patients without ILD, and this may contribute to worsening respiratory symptoms.
6-minute walk test
The 6-minute walk test (6MWT) is an easy and noninvasive tool used for the assessment of lung function in pulmonary disease. Its utility in SSc-ILD is, however, limited primarily because of functional impairment of patients. In a study of 163 patients with SSc-ILD, the 6MWT did not correlate well with other parameters such as FVC, DLCO, or dyspnea index scores despite its reproducibility. It may play a more important role in SSc patients with PAH.
Histopathology
Histologically, SSc-ILD is characterized by early pulmonary infiltration of inflammatory cells and subsequent fibrosis of the lung parenchyma. The most common patterns seen on histologic examination are NSIP and UIP. NSIP is characterized by varying degrees of inflammation and fibrosis. In contrast, UIP is characterized by dense patchy fibrosis with “honeycombing,” primarily in a subpleural distribution. NSIP is the more common pattern seen in SSc-ILD and is present in 64% to 77% of cases. Lung biopsy is not necessary to confirm the histopathologic diagnosis, as the patterns of ILD are usually readily distinguishable on HRCT. Biopsy may play a role when other diagnoses, such as infection or malignancy, are suspected based on HRCT.
Treatment
Approach to Treatment
Multiple treatment modalities have been used in SSc-ILD with only some having modest benefit. Drug development for ILD has expanded dramatically and several investigational approaches are currently in early-phase clinical trials. The decision of which patients to treat must be considered carefully given the potential toxicities of many of the medications. An algorithm for determining the severity of disease has been proposed by Goh and colleagues, and use of this algorithm may aid in treatment decisions for a patient with SSc-ILD. In this algorithm, lung involvement on HRCT of greater than 20% and FVC less than 70% were associated with increased mortality risk, and these parameters may help determine which patients would benefit the most from treatment.
Current Treatment Modalities
Cyclophosphamide (Cytoxan)
Cyclophosphamide (Cytoxan) has been the most rigorously studied medication in the treatment of SSc-ILD ( Table 1 ). The 2009 EULAR recommendations for the treatment of SSc suggest the use of cyclophosphamide for the treatment of SSc-ILD despite its known potential toxicities. This recommendation was based on 2 randomized, controlled trials (RCTs) comparing cyclophosphamide with placebo. In a small study of patients with SSc-ILD, monthly intravenous cyclophosphamide for 6 months, in addition to prednisolone followed by azathioprine, was compared with placebo. There was a trend toward improvement in FVC, but this did not reach statistical significance likely in part because of the small study size. In the first multicenter RCT to look at the role of cyclophosphamide in SSc-ILD, the Scleroderma Lung Study found that patients with early SSc-ILD treated with oral cyclophosphamide for 1 year had improvement in FVC, dyspnea index scores, chest imaging, and skin scores, but not in DLCO. By 2 years, the positive effect of cyclophosphamide on lung function had disappeared, but the improvement in dyspnea scores was still present. Based on these results, cyclophosphamide should be strongly considered as first-line treatment in patients with SSc-ILD. The optimal duration of therapy is not known given the risk of adverse effects; typical protocols suggest treatment up to a year followed by a switch to another agent for maintenance therapy (see later discussion).
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