Lung involvement in Scleroderma

Lung Involvement in Scleroderma SAMUEL N. BREIT, PhD STEPHEN C. THORNTON, RONALD PENNY, MD

DSc, MD

I?

ulmonary involvement occurs frequently in a number of connective tissue diseases. In scleroderma in particular, clinical involvement of the lung occurs frequently and is a major determinant of morbidity and mortality. There are three major manifestations of pulmonary disease, reflecting the anatomical localization of lung involvement: interstitial pneumonitis, bronchiolitis, and pulmonary vascular disease. Increasingly sensitive methods suggest that some degree involvement occurs in most, if not all, patients. In order to ascribe disease associations correctly, accurate diagnosis is essential. Although the diagnosis of scleroderma is usually not difficult, Sjiigren’s syndrome, with which scleroderma is co-associated in many patients, is less often considered. Most studies fail to consider the possible relevance of disease manifestation due to Sjiigren’s syndrome. This is of particular importance in lung disease, because of the propensity of Sjogren’s syndrome to involve both the pulmonary airways and interstitium.‘-’ We believe that some aspects of the lung pathology traditionally ascribed to scleroderma may actually be due to the associated Sjiigren’s syndrome.

Major Techniques for the Assessment of Pulmonary Disease The aim of pulmonary assessment in scleroderma is to determine its presence, severity, activity, and anatomical

From the Centre for Immunology, Faculty of Medicine, St. Vincent’s Hospital and University of New South Wales, Sydney, Australia. Address correspondence to Samuel N. Breit, MD, Centre of Immunology, St. Vincent’s Hospital and University of New South Wales, Sydney 2010, Australia. Supported by grants from the National Health and Medical Research Council, Scleroderma Foundation of New South Wales, the Arthritis Foundation of Australia, and St. Vincent’s Hospital.

0 1994 by Elsevier Science Inc.

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localization to either interstitium, ture, or small airways.

pulmonary

vascula-

interstitial Lung Disease The gold standard for assessment of interstitial lung disease is the open lung biopsy. Even with the advent of minithoracotomy and biopsy using a thoracoscope, this technique is difficult to justify as a routine clinical tool, except in seriously ill patients. Lung samples can also be obtained by transbronchial biopsies, but, unfortunately, because of sample size, biopsies are not a useful diagnostic tool for most interstitial lung diseases. Thus, of necessity, indirect measures of pulmonary pathology have been used. Multiple techniques are available, but all have substantial limitations. Chest X rays are insensitive and do not allow differentiation between fibrotic and active inflammatory processes. Respiratory function studies, especially the gas diffusion (DLCO), is much more sensitive but still does not differentiate between inflammatory and burned-out fibrotic processes, nor between pulmonary vascular and interstitial disease. A newer generation of tests that include bronchoalveolar lavage, gallium lung scanning, and, more recently, high-resolution computerized tomography have increased sensitivity and the capacity to identify ongoing inflammatory processes. Bronchoalveolar lavage has been particularly useful for both detecting and characterizing the presence of an inflammatory response, and in a research setting, determining the local production of bioactive substances.5 However, there are substantial problems with its standardization. The most important variable is the method used for estimation of the cell differential, a process that is more complex than obtaining a differential from a blood count.5 Most groups use the cytocentrifuge method for this purpose because of its great simplicity, and because there is a large body of data already available using this technique. Although the cytocentrifuge method appears

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to be relatively accurate for enumeration of neutrophils, it markedly underestimates lymphocyte numbers.6 Furthermore, the error is not predictable, obviating the use of any correction factor.6-* Our own data strongly support this observation and suggest that in normal nonsmoking individuals the percentage of lymphocytes is about 31% f 12%,9-11 rather than the 5% - 10% frequently quoted in other publications. The use of cytocentrifuge data has led to the commonly held but inaccurate view that normal bronchoalveolar lavages contain very low lymphocyte numbers. Although these methods are of great value, there are often considerable overlaps in results between normal and disease populations and different tests reflect different aspects of the disease process.9 This is made even more complicated by the substantial confounding effect of smoking.59,12 One approach that has been used to overcome these limitations has been to use statistical modeling methods to derive scores for patients based on the pooled and weighted results of a combination of these investigations.9

Small Airways Disease Small airways disease is best assessed with respiratory flow studies, such as the maximal mid-expiratory flow rate (MMEFR). Smoking is a common cause of a depressed MMEFR, but this test is not affected to a marked extent by pure interstitial pulmonary pathology. Unlike interstitial disease, small airways pathology can be examined successfully by transbronchial biopsy methods.

Pulmonary Vascular Disease Primary pulmonary vascular pathology in scleroderma is currently not easy to detect, except at a relatively advanced stage. It is most often suggested by a markedly depressed DLCO (less than 50% of predicted) in the absence of major interstitial pathology. In some instances echocardiography may provide further evidence of pulmonary vascular disease, but direct measurement of pulmonary artery pressure by cardiac catheterization is required for unequivocal confirmation.

Clinical Recommendafions For scleroderma lung disease, the investigations of most value in the clinical setting include respiratory function studies, high-resolution computerized tomography, and gallium lung scanning. The bronchoalveolar lavage is particularly useful, but only where there is experience both in performance and sample analysis.

Interstitial Lung Disease GeneralFeatures This is the most frequent serious manifestation of lung involvement in this disorder. The most common symptoms are a nonproductive cough, shortness of breath, and reduced exercise capacity. Patients, especially at an early stage, may be asymptomatic. Progression in dyspnoea suggests the presence of an ongoing inflammatory process. It must be remembered, however, that these symptoms may also be due to other conditions including bronchiolitis, pulmonary vascular disease, or cardiac disease. There has, as yet, not been any large unselected population based study to determine the prevalence of respiratory disease. Nonetheless, respiratory symptoms are frequently present in scleroderma. In a recent study of 31 scleroderma patients, unselected as to the presence of respiratory disease, 58% had significant shortness of breath of grade I or greater on the MRC scale.” Most had also noted deterioration in these symptoms over the prior 12-month period. It is interesting to note that respiratory symptoms were found more frequently in those who had associated Sjogren’s syndrome. Many investigators have attempted to identify the presence of lung disease using respiratory function studies, particularly the DLCO, which, despite some limitations (see above), is a reasonably sensitive and simple test. A decreased DLCO has been identified in 29% - 77% of patients. 13-20 There is also a general trend toward slow deterioration.15J9 Not surprisingly, smoking has substantial additional deleterious effects.‘s There are no difference in lung volumes between patients with limited and diffuse variants of scleroderma. However, the limited variant is more frequently associated with a depressed DLCO, which may be due to the increased prevalence of pulmonary vascular disease.‘*,16 In one large university hospital review of pulmonary function in 165 nonsmoking subjects with scleroderma, only 28% and 38% of patients with the limited and diffuse forms of scleroderma respectively had normal respiratory function.‘* The most common abnormality was a restrictive pattern, and the least common was an isolated depressed MMEFR indicative of small airways disease.‘* Stratification according to respiratory function showed substantial differences in life expectancy. The 5-year survival of those with a restrictive defect was 58% compared with greater than 90% in those with no respiratory abnormalities.“’ There was no clear predictor of deterioration in pulmonary function,21,22 and it is important to note that in those who died, the cause was frequently nonpulmonary.1s~21 A somewhat different perspective on survival of this population group has recently been obtained in a multi-

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center study of 48 patients who presented within the first year of disease. 23 This study is unique because it is not biased by the selection of long-term survivors (studies of longstanding scleroderma may exclude those who die early due to severe disease). The estimated 5-year survival of this group was 68% and 8 of the 15 deaths were due to cardiac or respiratory failure. Parameters indicative of ongoing inflammatory responses but not the DLCO were significantly associated with outcome.23 This implies the likely presence of a subgroup of those with a low DLCO who have a poor prognosis. This subgroup cannot be detected by mechanical and physiological studies of lung function but might be detected with investigation such as bronchoalveolar lavage, which directly samples the inflammatory response in the lung. Some genetic and immunological factors can predict the risk of interstitial lung disease in scleroderma. The anti-Scl-70 antibody (topoisomerase I antibody) is associated with diffuse scleroderma and pulmonary fibrosis.** The HLA haplotype DR3/DRW52a represents a significant genetic risk factor for the development of pulmonary fibrosis.= The effects of the anti-Scl-70 antibody and HLA DR3/DRW52a are additive being associated with a relative risk of 16.7 for the development of pulmonary fibrosis.25

Histopathology The most direct information about the nature of pulmonary abnormalities can be obtained by histopathological examination of lung biopsy or autopsy material. United numbers of reports suggest the majority of patients with scleroderma demonstrate pulmonary histopathological abnormalities consisting of oedema, increased alveolar wall cellularity, fibrosis, and, less frequently, pulmonary vascular abnormalities.26-31 There has been only one comprehensive biopsy study of scleroderma lung histopathology.32 Selection criteria for open lung biopsy was the presence of an abnormal chest X ray or high-resolution computerized tomograph. There was an intentional bias toward early and interstitial lung disease and lung function studies were normal in some patients. Interstitial pulmonary changes were found in all subjects, although they could be patchy in nature. These consisted of increased intraalveolar macrophages with occasional neutrophils and lymphocytes and an interstitial infiltrate with lymphocytes and plasma cells. Lymphoid aggregates were sometimes also seen adjacent to bronchioles. A variable amount of fibrosis was also present and any pulmonary vascular changes were confined to parts of the lung affected by the interstitial process. These appearances were indistinguishable from those of cryptogenic fibrosing alveolitis.

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The unaffected regions or lobes, when examined by electron microscopy were all found to be ultrastructurally abnormal.32 In evidence was patchy epithelial and endothelial swelling and focal cell loss, as well as increased interstitial collagen and elastin. There were no electron dense deposits suggestive of immune complexes. Histopathology studies of scleroderma lung, therefore, support epidemiological studies suggesting the high prevalence of pulmonary abnormalities.

BronchoalveolarLavageStudies Bronchoalveolar lavage is an easily performed procedure that samples the fluid and cellular milieux of the pulmonary interstitium, which has provided valuable diagnostic and pathogenetic information in scleroderma. A number of studies has been carried out in scleroderma over the last 10 years utilizing this approach.4J0J1#33-43 In general, these studies all support the notion that interstitial pulmonary pathology is associated with bronchoalveolar lavage abnormalities that may occur in the absence of X-ray changes, and sometimes in asymptomatic subjects. Where subjects were unselectedas to respiratory symptoms or abnormalities, the bronchoalveolar lavage was abnormal in about 50% - 75% of subjects.10~37~42 In general, two types of abnormalities occur commonly and have been identified by bronchoalveolar lavage: a lymphocytosis or a neutrophil leukocytosis. These types of alveolitis rarely if ever coexist.lOJ1 Most authors note both these patterns but probably underestimate the lymphocytic abnormalities both in magnitude and extent because of the use of the cytocentrifuge method for undertaking cell differentials (discussed earlier). Patients with an increased number of lymphocytes on bronchoalveolar lavage may have an alveolotis or a bronchiolitis.1° In the absence of pulmonary infection, patients having lavage neutrophil leukocytosis have an alveolitis. In patients having an alveolitis, the bronchoalveolar lavage lymphocytosis and the neutrophil leukocytosis are associated with different patterns of pulmonary abnormalities. Neutrophilic and lymphocytic alveolitis probably represent two different disease processes and, in all likelihood, carry different prognostic implications (Fig. 1).10,11*39The neutrophilic alveolitis (lavage neutrophils usually 5% - 10%) is similar to the alveolitis of idiopathic pulmonary fibrosis probably represents the alveolitis directly attributable to scleroderma. It is associated with greater depression of DLCO but a less marked increase in gallium index.10s36 The lymphocytic alveolitis (lavage lymphocytes usually 40% - 60%) may well be associated with Sjiigren’s syndrome and not with the scleroderma per se.10J1,39It is generally felt to carry a somewhat better

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Sjijgren’s Syndrome pGizzq DLCO Gallium BAL lymphocytes BAL neutrophils Fibrosis Response

to therapy

Very Normal

High

Normal

Normal

High

No

Yes

Better

Bronchiolitis

Figure 1. Pattern syndrome.

Low High

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respiratory changesin sclerodermaand Sjogren’s

prognosis and there is less impairment of the DLCO but a more marked increased in the gallium index.“rM The gallium scan generally appears to be more sensitive to the detection of lymphocytic alveolitis rather than neutrophilic alveolitis.39*U Lavage studies all support the growing belief that respiratory involvement in scleroderma may be far more common than previously suspected. These studies have detected a number of different patterns of abnormalities in subjects with scleroderma, which may carry different prognostic implications (Fig. 1). This may be due in part to the propensity for fibrosis in the neutrophilic alveolitis and the general absence of fibrosis in many disorders characterized by a marked lymphocytosis.

Pathogenesis Fibrosis is the end result of many chronic inflammatory processes, including the interstitial lung disease of scleroderma and is largely irreversible. Although therapy has been able to modulate inflammatory responses in many situations, fibrosis has been largely unaltered by treatment. Studies of pathogenic mechanisms underlying the interstitial lung disease in scleroderma are quite scarce. However, as the histological features of interstitial lung disease in scleroderma are largely indistinguishable from those in idiopathic pulmonary fibrosis, it is likely the overall inflammatory and fibrotic circuits will be similar, even if not identical (see Fig. 2). The fibrotic response contains three major components: chemotaxis of fibroblasts to the site of inflammation, local fibroblast replication (Fig. 3), and stimulation of synthesis of matrix proteins such as collagen (Fig. 4). The latter is also modulated by the balance between enzymes capable of degrading collagen and the inhibitors of these enzymes (Fig. 4). These three processes are mediated largely by cytokines, growth factors, and other bioactive compounds. A major source of these compounds is the macrophage, with which the lung is highly

endowed. Other important sources include cells of nonimmune origin such as endothelial cells and fibroblasts. Antiinflammatory therapy has largely been directed at immune cells. The production of cytokines and growth factors by cells of nonimmune origin may be one of the reasons why the induction of fibrosis has been so resistant to treatment. Local fibroblast replication is of particular importance, not only because it increases local fibroblast numbers, but also because of evidence that this replicative response results in the overgrowth of an important fibroblast subpopulation .45-50 This subpopulation produces much larger amounts of collagen and other matrix proteins than normal skin fibroblasts.45-50 This increase in cell number must be mediated by fibroblast growth factors, the most important of which are platelet-derived growth factor A or B (PDGF A or B), insulin-like growth factor 1 (IGF-l), and, to a lesser extent, tumor necrosis factor alpha (TNFa), acid or basic fibroblast growth factor (aFGF or bFGF), and endothelin.51 In some circumstances interleukin 1 (IL-l) and transforming growth factor beta (TGF-P) can also act as fibroblast growth factors. There is, however, evidence that PDGF and IGF-1 are the major-if not only-growth factors for fibroblasts, as all other growth factors act by stimulating fibroblasts to secrete PDGF and IGF-1, which then act in an autocrine manner.52 In the context of scleroderma PDGF also assumes major importance because of evidence (discussed later) for its local production in scleroderma lung and ~kix-t.~~-~~ Our laboratory has had a major interest in fibrotic mechanisms generally, and their applicability to scleroderma lung disease specifically. In order to determine what fibroblast growth factors are locally produced by immune cells in scleroderma lung, we have studied bronchoalveolar lavage cells from sclerodenna patients with and without interstitial lung disease.53 Freshly isolated lavage cells spontaneously secreted fibroblast growth factor activity into tissue culture medium. The secretion of PDGF-B and slightly increased amounts of fibronectin

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Figure 2. Major mechanisms underlying the interstitial lung diseaseof scleroderma.

appeared to be specifically associated with subjects with interstitial lung disease. 53No other growth factors such as FGF or IGF-1 were contributing to the fibroblast growth factor activity detected in the cell supernatants, strongly suggesting that PDGF-B is the major fibroblast growth factor of immune origin, involved in the interstitial lung disease of scleroderma. PDGF is a dimeric molecule whose individual polypeptide chains are synthesized by two closely related genes (PDGF-A or PDGF-B) located on separate chromosomes. The biologically active product is either a homoor heterodimer. Macrophages secrete PDGF-B, fibroblasts PDGF-A, while endothelium probably secretes both PDGF-A and B. As PDGF-B appeared to be the dominant fibroblast growth factor secreted locally in

scleroderma lung we then sought to understand the processes that modulate its synthesis and secretion in macrophages5’ It appears that macrophage secretion of PDGFB can be divided into two phases. Interferon gamma (IFN-y) induces synthesis of this molecule that is retained in a cell associated form. A second signal is required for secretion of PDGF-B from the macrophage, and this can be delivered by a any of a number of different cytokines including IL-2, TGF$, IL-la, IL-6, or endothelin-1. There appears to be at least two additional levels of control of the local action of this potent cytokine. Interleukin 10 (IL-lo) inhibits the synthesis of cell associated PDGF-B. Even if PDGF-B is present within the macrophage, interleukin 4 (IL-4) can prevent its secretion from the cell. In the context of chronic inflammation, these studies imply

Figure 3, Regulation of fibroblast replication. This diagram outlines the factors involved in the regulation of production of PDGF from different cell sourcesand their inferraction to induce fibroblast replication. THl

(IFN-g

TH2 (IL-4

IL-IO)

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IL-~)

Cflokines (N m-1 IL.6T0F.bGM-CSFI

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. Fibroblast

Redication

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Interferon-g Interferon-a

+ Fibroblast

Collagen

Figure 4. Regulation

of

@o&last collagen production.

that T cells, through the secretion of cytokines with opposing actions, are of great importance in the regulation of connective tissue cell proliferation. (Fig. 3). A number of cells other than the macrophage are known to produce PDGF, including the endothelium and the fibroblast itself. Because of the marked vascular abnormalities in scleroderma, this needs to be seriously considered as another source of this cytokine. Fibrosis in scleroderma is preceded by a perivascular inflammatory stage, characterized by an infiltration of lymphocytes and macrophages and accompanied by endothelial injury.5*-60 In skin, the cellular reaction starts around the capillaries and affects the dermis and subcutaneous tissue.54 PDGF has been detected immunohistochemically in that location in scleroderma54,55 and PDGF-b receptors have been found in dermal vessels and stromal fibroblast-like cells close to these vessels in scleroderma skin56 In-situ hybridization studies and antibodies specific to newly synthesized collagen both suggest that the major site for synthesis of collagen is in fibroblasts adjacent to blood vessels in the deep dermis.61-63 It is, therefore, quite possible that both vascular injury, and locally produced cytokines could act on the vascular endothelium to induce secretion of PDGF. With these studies in mind, we decided to determine the factors which may regulate production of endothelial cell PDGF.a Human endothelial cells were stimulated with a number of cytokines and PDGF production estimated by specific bioassay. Nonreplicating cells were unable to produce PDGF. Replicating cells however, could be induced to synthesise PDGF by a number of cytokines including IL2, IL-l/3, TGF-P, IFN-y, and TNF-a (Fig. 3).

The only form of PDGF present was PDGF-B. More material was synthesized by cytokine combinations than by any single cytokine, with the most potent combination being IL-2 and IFN-y. IL-4 could inhibit PDGF-B production, provided it was added with the activating agent. Essentially similar results were obtained regardless of whether umbilical vein or human capillary endothelium were the target cells.6” These results indicate that PDGF-B synthesis is also under stringent control with the coincidence of two signals (replication and one exogenous cytokine) being necessary prior to any synthesis, and three different signals (replication and two different cytokines) for maximal production. 64 Endothelial replication, as would presumably be induced in vivo by the local cell injury known to occur in scleroderma, appeared to be the most important prerequisite for cytokine-stimulated PDGF-B synthesis. This work suggests that endothelial PDGF-B synthesis and release, an important contributor to the fibrotic response in scleroderma, is regulated by endothelial injury in combination with local cytokine production. One other important site for PDGF synthesis is the fibroblast itself. It is known to produce both PDGF-A and IGF-1, the two most potent fibroblast growth factors. When fibroblasts are stimulated by a wide range of different fibroblasts growth factors including TNF-a, aFGF, bFGF endothelin and PDGF and IGF-1 themselves, they respond by synthesizing IGF-1 and PDGF-A52 (Fig. 3). This autocrine pathway is important in efficient fibroblast replication.52 One of the challenges of scleroderma is to determine how or if endothelial changes may be linked to fibrosis. Two endothelial-derived molecules would appear to be important candidates in such a process are PDGF (discussed above) and endothelin. Endothelin is released from activated and injured endothelium and plasma levels are elevated in scleroderrna subjects.65tti Elevated levels are not only more marked in those with pulmonary and renal vascular disease, but also in a subset with diffuse cutaneous disease and interstitial lung pathology.66 In idiopathic pulmonary fibrosis, a disorder with similar pathology to the interstital lung disease of scleroderma, diffuse staining for endothelin is present in many pulmonary structures. 67 Through its capacity to induce fibroblast replication, probably through autocrine pathways involving release of PDGF-A and IGF-1,62 endothelin may be an important link between the endothelium and fibroblast replication.

Therapy Evaluation and performance of clinical therapeutic studies in scleroderma is fraught with difficulty. One of the

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greatest problems is the effect of time from onset of disease. A disease very early in its course with a major inflammatory component is likely to respond differently to a longstanding disorder with widespread fibrosis. Therefore, studies should ideally be performed on patients with early disease, but it is difficult for many centers to collect large numbers of such patients. Until studies such as this are undertaken, it will be difficult to be certain if negative response to approaches such as immunosuppression68 are simply due to a preponderance of patients with longstanding disease. Therapy of scleroderma generally is largely unsatisfactory. The only therapy thus far of demonstrable benefit in scleroderma lung disease is penicillamine. Two studies suggest that its prolonged use is associated with improvement in the DLCO, but not in any other parameters of respiratory function. 6~‘~ Other agents of current therapeutic interest, but not as yet proven to be of therapeutic benefit, include methotrexate, IFN-y, cyclosporin, and photophoresis.

Bronchiolitis Involvement of the small airways at both the pathological and physiological level has been recognized for quite some time in scleroderma.7*-73 Histopathologically, the bronchiolitis is characterized by a chronic submucosal inflammatory infiltrate affecting mainly the terminal and respiratory bronchioles. 3* There may be bronchiolar metaplasia, fibrous scarring, and variable luminal constriction. It is difficult to estimate the proportion of patients with scleroderma who may have bronchiolitis, but it is probably between 13% and 25%.10,20 The typical respiratory function abnormality is that of a decrease in the MMEFR. In our studies there was also a strong association with a lavage lymphocytosis, presumably because of flushing of these cells from the terminal airway.‘O As the majority of patients with scleroderma also have Sjogren’s syndrome, we believe that at least in a sign&ant proportion of patients, the dominant association of bronchiolitis may well be with Sjogren’s syndrome rather than scleroderma.4J0 A decrease in the MMEFR is associated with small airways disease in smokers, thus in an individual smoking patient with scleroderma, this may obscure the diagnosis. However, this abnormality is frequently seen in nonsmoking scleroderma subjects and thus cannot account for this l?nding. Drugs, especially penicillamine, have also been suggested as contributing factors in the pathogenesis of bronchiolitis.” Again, although this might conceivably account for some, it cannot account for most patients with this abnormality. It is probable that bronchiolitis is a common Rnding in

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scleroderma subjects and is most usually asymptomatic. Severe bronchiolitis in the absence of other pulmonary manifestations appears to be quite unusual. When treatment is necessary, there is some evidence that it may be steroid responsive.73

Pulmonary Hypertension Pulmonary hypertension in scleroderma may occur secondary to severe interstitial lung disease or as a disorder in which the pulmonary vasculature is primarily affected. It is only the latter category that will be considered in this section. Pulmonary vascular changes were noted on lung histopathology, in the absence of fibrosis, and in 30% of 17 autopsies of subjects with scleroderma.31 Interestingly, the histopathology was associated with mononuclear infiltration of the fibroelastotic plaque of the arterioles.3* This suggests the possibility of underlying inflammatory mechanisms in the pulmonary vascular disease of scleroderma. An isolated marked depression in the DLCO has been suggested as an early sign of pulmonary hypertension. In the largest published analysis of respiratory function studies in scleroderma (815 subjects), only 27% had normal respiratory function and an isolated depression in the DLCO was found in 19%.*O Of these, 5% had clinical pulmonary hypertension at presentation and 11% had developed it by a mean follow-up period of 7.2 years. Clinical pulmonary hypertension seemed to be particularly associated with a DLCO of less than 48% predicted. All had limited forms of scleroderma and died within 2 years of the diagnosis of pulmonary hypertension.*O The etiology of pulmonary hypertension is uncertain, but the recent identification of a family of extremely potent endothelial derived vasospastic and smooth muscle proliferative compounds, the endothelins, has suggested a role for them in this disorder as well as the more generalized vascular disease of scleroderma.65*66*67 Although raised endothelin levels were seen in scleroderma generally, they were more elevated in those with pulmonary (or renal) vascular disease. 66 The strongest evidence for the role of endothelin comes from a recent study of paired pulmonary arterial and peripheral venous samples in scleroderma patients with pulmonary hypertension.7s In patients with secondary pulmonary hypertension, there was essentially no difference between the endothelial levels at these two sites. However, in scleroderma patients with isolated pulmonary hypertension the pulmonary arterial level was a mean of 2.2 times the peripheral venous level. This suggests substantial local production of endothelin within the lung. Another recent study, not done in patients with scleroderma, also demonstrated local synthesis of endothelin-1 in pulmonary vascular

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endothelial cells in pulmonary hypertension.76 In patients who have primary pulmonary hypertension, the intensity of endothelin-1 staining was highly correlated with the pulmonary vascular resistance, further suggesting a causal link.76 This support a model in which endothelin release from the pulmonary vasculature causes pulmonary vasoconstriction and eventual proliferation of arterial smooth muscle cells leading to pulmonary hypertension. As indicated earlier, the life expectancy of a patient with pulmonary hypertension is quite short, with most patients dying within 2 years of diagnosis. A number of therapeutic strategies have been proposed and tied on a limited basis in scleroderma, including continuous ambulatory oxygen therapy, ” calcium channel blockers,7*,79 or continuous intravenous prostacyclin infusion.*0 Although some patients may respond at least with transient improvement in pulmonary vascular hemodynamics, there is no evidence to suggest that any alter the abysmal prospects for survival of patients with this complication.

Conclusions The evidence suggests that pulmonary involvement, even at a subclinical level, may well occur in most subjects with scleroderma. Clinical involvement is also frequent and is a major determinant of morbidity and mortality. For this reason, pulmonary assessment should be undertaken in all subjects with this disease. Although technical improvements now make it much easier to determine the degree of involvement and the presence of inflammatory changes, studies of its pathogenesis and treatment are limited. The challenge of the next decade will be to address these issues and develop more effective therapeutic strategies.

References 1. Vaughan Strimlan C, Rosenow EC, Divertie MB, et al. Pulmonary manifestations of Sjogren’s syndrome. Chest 1976;70:354-61. 2. Vitali C, Tavoni A, Viegi G, et al. Lung Involvement in Sjogrens’s syndrome: A comparison between patients with primary and with secondary syndrome. Anna1 Rheum Dis 1985;44:455-61. 3. Constantopoulos SH, Papadimitriou CS, Moutsopoulos HM. Respiratory manifestations in primary Sjogren’s syndrome. Chest 1985;88:226-9. 4. Hatron P-Y, Wallaert B, Gosset D, et al. Subclinical lung inflammation in primary Sjogren’s syndrome. Arthritis Rheum 1987;30:1226-31. 5. Gibson PG, Bryant DH, Robinson B, et al. The role of bronchoalveolar lavage in the assessment of diffuse lung diseases. Aust N Z J Med 1989;19:281-91.

Clinics in Dermatology 1994;12:243-252 6. Saltini C, Hance AJ, Ferrans VJ, et al. Accurate quantification of cells recovered by bronchoalveolar lavage. Am Rev Resp Dis 1984;130:650-8. 7. Merchant RR, Schwartz DA, Helmers RA, et al. Bronchoalveolar lavage cellularity. The distribution in normal volunteers. Am Rev Respir Dis 1992;146:448-53. 8. Breit SN. Comment on bronchoalveolar lavage cellularity: The distribution in normal volunteers. Am Rev Respir Dis 1993;147:1607. 9. Cairns D, Shelley L, Burke WMJ, et al. Interstitial lung disease associated with connective tissue diseases: The use of statistical structure analysis in model development. Amer Rev Respir Dis 1991;143:1235-40. 10. Cairns D, Shelley L, Burke W, et al. The differing patterns of interstitial lung involvment in connective tissue diseases. J Rheumatol 1992;19:1089-95. 11. Breit SN, Cairns D, Szentirmay A, et al. The presence of Sjogren’s syndrome is a major determinant of the pattern of interstitial lung disease in scleroderma and other connective tissue diseases. J Rheumatol 1989;16:1043-9. 12. Burke WMJ, Roberts CM, Bryant DH, et al. Smoking induced changes in epithelial lining fluid volume, cell density and protein. Eur Respir J 1992;5:780-4. 13. Peters-Golden M, Wise RA, Hochberg MC, et al. Carbon monoxide diffusing capacity as a predictor of outcome in systemic sclerosis. Am J Med 1984;77:1027-33. 14. Guttadauria M, Ellman H, Emmanuel G, et al. Pulmonary function in scleroderma. Arthritis Rheum 1977;20:107179. 15. Bagg LR, Hughes DTD. Serial pulmonary function tests in progressive systemic sclerosis. Thorax 1979;34:224 - 8. 16. Owens GR, Fino GJ, Herbert DL, et al. Pulmonary function in progressive systemic sclerosis. Comparison of CREST syndrome variant with diffuse scleroderma. Chest 1983; 84:546-50. 17. Peters-Golden M, Wise RA, Hochberg MC, et al. Clinical and demographic predictors of loss of pulmonary function in systemic sclerosis. Medicine (Baltimore) 1984;63:22131. 18. Steen VD, Owens GR, Fino GJ, et al. Pulmonary irtvolvement in systemic sclerosis (scleroderma). Arthritis Rheum 1985;28:759-67. 19. Schneider PD, Wise RA, Hochberg MC, Wigley FM. Serial pulmonary function in systemic sclerosis. Am J Med 1982;73:385-94. 20. Steen VD, Graham G, Conte C, et al. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992;35:765-70. 21. Altman RD, Medsger TA, Bloch DA, et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991;34:403-13. 22. Greenwald GI, Tashkin DP, Gong H, et al. Longitudinal changes in lung function and respiratory symptoms in progressive systemic sclerosis. Am J Med 1987;83:83-92.

Clinics in Dermatology 1994;12:243-252 23. Bulpitt KJ,Clements PJ,Lachenbruch PA, et al. Early undifferentiated connective tissue disease: III. Outcome and prognostic indicators in early scleroderma (systemic sclerosis). Ann Intern Med 1993;118:602-9. 24. Steen VD, Powell DL, Medsger TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis.Arthritis Rheum 1988;31:196-203. 25. Briggs DC, Vaughan RW, Welsh KI, et al. Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis.Lancet 1991;338:661-2. 26. D’Angelo WA, Fries JF,Masi AT, Shulman LE. Pathological observations in systemic sclerosis(scleroderma): a study of Sfty eight autopsy cases and fifty eight matched controls. Am J Med 1969;46:428-40. 27. Weaver AL, Divertie MB, Titus JL. Pulmonary scleroderma. Dis Chest 1968;54:4- 12. 28. Sackner MA, Akgun N, Kimbel P, et al. The pathophysiology of scleroderma involving the heart and respiratory system. Ann Intern Med 1964;60:611-30. 29. Enson Y, Thomas HM, Bosken CH, et al. Pulmonary hypertension in interstitial lung disease: relation of vascular resistance to lung structure. Trans Assoc Am Phys 1969;88:248-55. 30. Young RH, Mark GJ. Pulmonary vascular changes in scleroderma. Am J Med 1978;64:998-1004. 31. Yousem SA. The pulmonary pathological manifestations of the CREST syndrome. Human Pathology 1990:21:467- 74. 32. Harrison NK, Myers AR, Corrin B, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis 1991;144:706-13. 33. Pesci A, Bertorelli G, Manganelli P, et al. Bronchoalveolar lavage analysis of interstitial lung disease in CREST syndrome. Clin Exp Rheum 1986;4:121-4. 34. Rossi GA, Bitterman PB, Rennard SI, et al. Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis. Am Rev Respir Dis 1985;131:612-7. 35. Owens GR, Paradis IL, Gryzan S, et al. Role of inflammation in the lung disease of systemic sclerosis: Comparison with idiopathic pulmonary fibrosis. J Lab Clin Med 1986;107:253-60. 36. Silver RM, Metcalf JF, Stanley JH, et al. Interstitial lung disease in scleroderma. Analysis by bronchoalveolar lavage. Arthritis Rheum 1984;27:1254-62. 37. Konig G, Luderschmidt C, Hammer C, et al. Lung involvment in scleroderma. Chest 1984;85:318-24. 38. Silver RM, Metcalf JF, LeRoy EC. Interstitial lung diseasein scleroderma. Immune Complexes in sera and bronchoalveolar lavage fluid. Arthritis Rheum 1986;29:525-31. 39. Wallaert B, Hatron P-Y, Grosbois J-M, et al. Subclinical pulmonary involvement in collagen vascular diseases assessed by bronchoalveolar lavage. Am Rev Respir Dis 1986;133:574-80.

BREIT ET AL 251 LUNG INVOLVEMENT IN SCLERODERMA 40. Frigieri L, Mormile F, Grilli N, et al. Bilateral bronchoalveolar lavage in progressive systemic sclerosis: Interlobar variability, lymphocyte subpopulations and functional correlations. Respiration 1991;58:132-40. 41. Harrison NK, Glanville AR, Strickland B, et al. Pulmonary involvement in systemic sclerosis: the detection of early changes by thin section CT scan, bronchoalveolar lavage and 99”Tc-DTPA clearance. Respir Med 1989;83:403-14. 42. Miller KS, Smith EA, Kinsella M, et al. Lung disease associated with progressive systemic sclerosis. Am Rev Respir Dis 1990;141:301-6. 43. Cairns D, Bryant DH, Yeates M, et al. Epithelial fluid albumin concentrations in normals and patients with interstitial lung disease. Eur J Respir Dis 1993;6:110-5. 44. Ramsay S, Yeates M, Burke WMJ, et al. Quantitative pulmonary lung scanning in interstitial lung diseases. Eur J Nut Med 1992;19:80-5. 45. LeRoy EC. Connective tissue biosynthesis by scleroderma skin fibroblasts in cell culture. J Esp Med 1972;135:135162. 46. LeRoy EC, McGuire M, Chen N. Increased collagen biosynthesis by scleroderma skin fibroblasts in vitro. J Clin Invest 1974;54:880-9. 47. Botstein GR, Sherer GK, Leroy EC. Fibroblast selection in scleroderma: An alternative model of fibrosis. Arthritis Rheum 1982;25:189-95. 48. Yamakage A, Kikuchi K, Smith EA, et al. Selective upregulation of platelet derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts. J Exp Med 1992;175:1227-34. 49. Needleman SW, Ordonez JV, Taramelli D, et al. In vitro identification of a subpopulation of fibroblasts that produce high levels of collagen in scleroderma patients. Arthritis Rheum 1990;33:842-52. 50. Goldring SR, Stephenson ML, Downie E, et al. Heterogeneity in hormone responses and patterns of collagen synthesis in cloned dermal fibroblasts. J Clin Invest 1990;85:798803. 51 Thornton SC, Por SB, Walsh B, et al. The interaction of immune and connective tissue cells: 1. The effect of lymphokines and monokines on fibroblast growth. J Leukocyte Biol 1990;47:312-20. 52. Thornton SC, Robbins J,Penny R, et al. Autocrine synthesis of PDGF and IGF-1 are responsible for fibroblast replication J Cell Biol (submitted). 53. Thornton SC, Robbins JM, Shelley L, et al. Fibroblast growth factors in connective tissue disease associated interstitial lung disease: Association with disease activity and identification as TNF-a, PDGF and fibronectin. Clin Exp Immunol 1992;90:447-52. 54. Harlan JM, Thompson PJ, Ross RR, et al. cr-Thrombin induces release of platelet-derived growth factor-like molecule(s) by cultured human endothelial cells. J Cell Biol 1986;103:1129-33.

252

BREIT ET AL

55. Gay S, Jones RE, Huang GQ, et al. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J Invest Dermatol 1989;92:301-3. 56. Klareskog L, Gustafsson R, Scheynius A, et al. Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis. Arthritis Rheum 1990;33:1534-41. 57. Thornton SC, Bennett S, Por SB, et al. Cytokine regulators of macrophage PDGF production J Immunol (submitted). 58. Fleischmajer R, Perlish JS. Capillary alterations in scleroderma. J Am Acad Dermatol 1980;2:161170. 59. Kazandjian S, Fiessinger JN, Cammilleri JP, et al. Endothelial cell renewal in skin of patients with progressive systemic sclerosis (PSS): An in vitro autoradiographic study. Acta Derm Venereol (Stockh) 1982;62:425-9. 60. Kahaleh MB, Sherer GK, LeRoy EC. Endothelial injury in scleroderma. The myth of the “uninvolved skin.” J Exp Med 1979;149:1326-35. 61. Fleischrnajer R, Perlish JS, Reeves JRT. Cellular infiltrates in scleroderma skin. Arthritis Rheum 1977;20:975 -84. 62. Scharfetter K, Lankat-Buttgereit B, Krieg T. Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Invest 1988;18:9-17. 63. Claman HN, Giomo RC, Seibold JR. Endothelial and fibroblastic activation in scleroderma. Arthritis Rheum 1991;34:1495-1501. 64. Thornton SC, Magoulas T, Por SB, et al. Cytokine action on endothelium releases platelet derived growth factor J Leucocyte Biol (submitted). 65. Kahaleh MB. Endothelin, an endothelial-dependent vasoconstrictor in scleroderma. Arthritis Rheum 1991;34:97882. 66. Vancheeswaran R, Magoulas T, Efrat G, et al. Circulating endotherm-1 levels suggest different pathogenic mechanisms in systemic sclerosis (SSc) subsets Lancet (submitted). 67. Giaid A, Michel RP, Stewart DJ, et al. Expression of endothelm-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet 1993;341:1550-4.

Clinics in Dermatology 1994;12:243-252 68. Furst DE, Clements PJ, Hiilis S, et al. Immunosuppression with chlorambucil, versus placebo, for scleroderma. Arthritis Rheum 1989;32:584-93. 69. Steen VD, Owens CR, Redmond C, et al. The effect of d-penicillamine on pulmonary findings in systemic sclerosis. Arthritis Rheum 1985;28:882-8. 70. de Clerck LS, Dequeker J, Francx L, et al. d-Penicillamine therapy and interstitial lung disease in scleroderma. A long term follow up study. Arthritis Rheum 1987;30:643-50. 71. Guttadauria M, Ellman H, Emmanuel G, et al. Pulmonary function in scleroderma. Arthritis Rheum 1977;20:1071-9. 72. Bjerke RD, Tashkin DP, Clements PJ, et al. Small airways in progressive systemic sclerosis. American J Med 1979; 66:201- 8. 73. Bridges AJ, Hsu K-C, Dias-Arias AA, et al. Bronchiolitis obliterans organizing pneumonia and scleroderma. J Pheumatol 1992;19:1136-40. 74. Murphy KC, Atkins CJ, Offer RC, et al. Obliterative bronchiolitis in two rheumatoid arthritis patients treated with penicillamine. Arthritis Rheum 1981;24:557-60. 75. Stewart DJ, Levy RD, Cemacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464-9. 76. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Eng J Med 1993;328:1732-9. 77. Morgan JM, Griffiths M, du Bois RM, et al. Hypoxic pulmonary vasoconstriction in systemic sclerosis and primary pulmonary hypertension. Chest 1991;99:551-6. 78. Ocken S, Reinitz E, Strom J. Nifedipine treatment for pulmonary hypertension in a patient with systemic sclerosis. Arthritis Rheum 1983;26:794-6. 79. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium channel blockers on survival in primary pulmonary hypertension, N Eng J Med 1992;327:76-81. 80. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (Epoprostenol). Ann Intern Med 1990; 112:485-91.