Pulmonary Manifestations of Scleroderma and Mixed Connective Tissue Disease
Section snippets
Case presentation
A 57-year-old white woman presents to your office with a 3- to 4-year history of progressive dyspnea on exertion. Her dyspnea occurs with walking up 1 flight of stairs. She has a cough that is variably nonproductive or productive of sputum. She has had a 13.6 kg weight loss during the past year, intermittent chest pain, orthopnea, and lower extremity edema. She reports that a recent cardiac workup was normal. Review of systems is notable for arthralgia, gastroesophageal reflux, skin rash, and
SSC
SSc is a rare autoimmune CTD of unknown cause, with an estimated annual incidence of 19.3 new cases per million adults per year.1 SSc is characterized by 3 major processes: disease-specific autoantibodies, organ fibrosis, and small-vessel vasculopathy.2 Organ fibrosis can involve several body systems, including the pulmonary, integument, cardiac, gastrointestinal, and renal systems.2 The American College of Rheumatology classification criteria for SSc include the major criterion of skin
ILD
Inflammation or fibrosis involving the pulmonary interstitium denotes a group of disorders referred to as ILD. Because of the complexity of these disorders, the American Thoracic Society and European Respiratory Society published a consensus on the classification of the idiopathic interstitial pneumonias, and classified parenchymal lung disease related to CTD as diffuse parenchymal lung disease of known association.6 ILD is the most common pulmonary manifestation in SSc, with 40% of patients
Prognostic factors
Restrictive lung disease is common in patients with limited or diffuse SSc. A retrospective cohort study found that patients who reached an FVC <55% predicted were most likely to do so in the first 5 years of disease.9 This highlights the importance of close pulmonary function monitoring early in the course of disease. Although antibodies in SSc are not known to play a role in the pathogenesis of the disease, they may serve as markers of subsets of patients with distinct clinical features.
Clinical features
Patients may present with puffy fingers or sclerodactyly (thickening of skin over the digits), loss of the digital fat pads, pitting or ulceration of the digits, and RP (Fig. 1). Depending on the type of SSc, skin thickening may be limited to the digits and distal extremities (lcSSc), or may be more diffuse and involve most of the integument (dcSSc) (Fig. 2). Calcinosis, telangiectasias, poikiloderma, and other skin manifestations can also be clues to the diagnosis (Fig. 3). A small subset of
Pathogenesis
The pathogenesis of ILD, including SSc-ILD, remains uncertain. There is a complex interplay between inflammatory activation, immunologic phenomena, and vascular injury, although the exact sequence of events remains elusive.
Although the analysis of bronchoalveolar lavage fluid (BALF) in diagnosis and management of SSc-ILD has recently been questioned,16 it has provided insight into pathogenesis. Bronchoalveolar lavage provides an invaluable method of obtaining cultures and cells from the lower
Histopathology
A large retrospective study examined lung biopsies of 80 patients with SSc undergoing open or thoracoscopic lung biopsy.35 The most frequent histopathologic pattern was NSIP (n = 62; 78%), with cellular NSIP (n = 15) and fibrotic NSIP (n = 47) occurring in 24% and 76%, respectively.35 UIP (n = 6) and end-stage lung (ESL) (n = 6) made up 15% of patients, with other patterns comprising the remaining 6 patients.35 Five-year survival did not differ significantly between the NSIP and UIP/ESL groups
PFTs
Patients with SSc-ILD have a restrictive pulmonary physiology. TLC and FVC are used to measure severity of restriction and lung disease in ILD, with percentage of FVC (FVC%) predicted being the most commonly used outcome in clinical trials for SSc. FVC is highly reproducible, but performance of the test is effort dependent, and restriction can also be observed with muscle weakness, space-occupying abnormalities such as effusions and significant cardiomegaly, restricting chest wall or pleural
The 6-minute walk test
Six-minute walk distance (6MWD) is frequently used as an outcome measure in clinical trials in ILD because of its high reproducibility and prognostic value.48, 49 In a multicenter study of 163 subjects with SSc-ILD with mean (±SD) FVC% predicted of 71% (±15.4%) and DLCO 46% (±12.4%) who had limited 6MWD less than 500 m because of dyspnea or walked 500 m or more but had oxygen desaturation during the walk, the mean 6MWD on 2 tests separated by less than 4 weeks was 396.6 (±84.6) m and 399.5
Imaging in scleroderma-related ILD
HRCT is the most frequently used imaging modality for radiologic assessment of ILD. There is a correlation between findings on HRCT scans and chest radiographs; however, HRCT is more sensitive at detecting early ILD and more accurate at quantifying degree of interstitial fibrosis in patients with more progressive lung involvement.53 The HRCT radiographic findings of NSIP can include GGO (increased lung attenuation believed to be associated with an active inflammatory process) and PF (reticular
Biomarkers
There is a critical need for less invasive, clinically applicable biomarkers to improve the prospective evaluation of patients with SSc-ILD. Surfactant protein D (SP-D) and Krebs von den Lungen-6 (KL-6) are glycoproteins secreted by type II pneumocytes that have emerged as possible surrogates for ILD. Serum levels of SP-D increase when there is damage to the alveolar epithelium, such as in the alveolitis of SSc- ILD.60, 61, 62 SP-D levels correlate with the presence of PF in SSc.63 KL-6
Treatment
The treatment of SSc-ILD is complicated by the many phenotypes seen in SSc. As each patient has a unique clinical, serologic, and radiographic picture, there is no single treatment that has been shown to work in all patients, and few randomized trials have been performed in this rare and enigmatic disease.
PAH
The other significant pulmonary complication commonly encountered in patients with SSc is PAH (Box 2). Detection and surveillance for PAH is vital in this patient population at high risk for this potentially fatal complication, especially because newer treatments have led to improved symptoms and function in patients with SSc-PAH.
The true prevalence of PAH in SSc is not known, but is estimated to be between 8% and 12%, when diagnosed by the gold standard, right heart catheterization (RHC).77, 78
Role of PFTs and 6-minute walk testing in PAH
FVC% predicted and DLCO have been observed to be abnormal in PH associated with SSc, with DLCO often out of proportion with the extent of ILD as an indicator of PH. In a study of 114 patients with SSc, PH (defined as a right ventricular systolic pressure [RVSP] >40 mm Hg on echocardiography) was found in 33 (29%) patients, and was associated with higher prevalence of SSc-ILD on HRCT (64% vs 91%, P = .005 with OR 6.78, CI 1.54–29.9). FVC% predicted was lower in patients with PH compared with
Echocardiography and RHC in SSc-PAH
RHC remains the gold standard for the detection of PAH in SSc. Echocardiography cannot measure mean PAP, but estimates RVSP as a measure of the tricuspid valve gradient or velocity of tricuspid regurgitation plus right atrial pressure. Recommendations for screening for SSc-PAH are echocardiographic examination every 6 to 12 months with validation by RHC.92
Estimates of sPAP obtained by echocardiography compared with RHC show that tricuspid valve gradient of 45 mm Hg or more has a low specificity
Treatment
Discussion of therapeutics for PAH in SSc is beyond the scope of this article, but they include drugs that target specific pathways in PAH, namely the prostacylin, nitric oxide, and endothelin pathways. Some therapies exist outside the United States, but these are not discussed in this article. Prostanoids (epoprostenol, iloprost, treprostinil) are administered by a variety of routes, including intravenous, inhaled, and subcutaneous, and their complexity requires close monitoring by a PH
Malignancy
Studies have reported an increased frequency of neoplasm in patients with SSc, with lung carcinoma, especially bronchoalveolar carcinoma, being the most common.96 In the Pittsburgh cohort, 14 of 262 (5%) patients with SSc developed a malignancy, and an increase in lung cancer was observed in the setting of chronic PF even in the absence of tobacco use.97 In a study by Peters-Golden and colleagues,98 71 patients with SSc were followed for a mean of 5 years, and 3 cases of lung cancer were
MCTD
Sharp and colleagues105 in 1972 first described a new clinical entity termed MCTD, a disease process in which patients exhibit a combination of clinical features of SSc, systemic lupus erythematosus (SLE), and an inflammatory myopathy (polymyositis, PM, or dermatomyositis [DM]). Serologically, they often have high titers of speckled ANAs, and autoantibodies to uridine-rich small nuclear ribonucleoprotein (snRNP). These patients present clinically with a myriad of signs and symptoms, notably
Summary
The CTDs, including SSc and MCTD, represent a heterogeneous, complex group of disorders that have important pulmonary manifestations. Patients may present to the pulmonologist initially with only dyspnea as their chief complaint. The astute clinician must recognize the importance of screening for CTD in any patient presenting with ILD or PAH.
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