Annals of Thoracic Medicine
REVIEW ARTICLE
Year
: 2014  |  Volume : 9  |  Issue : 4  |  Page : 193--202

Pictorial review of intrathoracic manifestations of progressive systemic sclerosis


Hamdan AL-Jahdali1, Prabhakar Rajiah2, Carolyn Allen3, Shyam Sunder Koteyar3, Ali Nawaz Khan3,  
1 Department of Medicine, King Saud University For Health Sciences, Riyadh, Saudi Arabia
2 Cardiothoracic Imaging Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA
3 North Manchester General Hospital and Clinical Director, Acute Pennine NHS Trust, Crumpsal, Manchester, United Kingdom

Correspondence Address:
Ali Nawaz Khan
Consultant Radiologist and Professor (Hon), North Manchester General Hospital, Acute Pennine NHS Trust, Crumpsal, Manchester M8 6RB
United Kingdom

Abstract

Intra-thoracic manifestations of progressive systemic sclerosis (PSS) are not well known particularly the imaging features, which forms the basis of accurate and timely diagnosis. The aim of this study is to familiarize the physicians and radiologists with these features. The diagnosis can remain elusive because of the non-specific nature of symptoms which mimic many common conditions. Thus, the diagnosis of PSS can be missed leading to continuous morbidity if the correct imaging is not pursued. The authors examined the records of rheumatology patient referrals of over a 5 year period. A hundred and seventy patients with systemic sclerosis and mixed connective tissue disorders were chosen for detailed study of the imaging available, which form the basis of this review. The images included conventional chest radiographs, digital radiographs computed radiography (CT) and high resolution computed tomography (HRCT). Where applicable computed pulmonary angiography (CTPA) and radionuclide scans were also interrogated.



How to cite this article:
AL-Jahdali H, Rajiah P, Allen C, Koteyar SS, Khan AN. Pictorial review of intrathoracic manifestations of progressive systemic sclerosis.Ann Thorac Med 2014;9:193-202


How to cite this URL:
AL-Jahdali H, Rajiah P, Allen C, Koteyar SS, Khan AN. Pictorial review of intrathoracic manifestations of progressive systemic sclerosis. Ann Thorac Med [serial online] 2014 [cited 2021 Jun 22 ];9:193-202
Available from: https://www.thoracicmedicine.org/text.asp?2014/9/4/193/140121


Full Text

 Introduction



Progressive systemic sclerosis (PSS) is a connective tissue disease associated with small vessel arterial vasculopathy, inflammatory and immunological processes. The peak incidence is between 45 and 64 years of age. [1] Women are predominantly affected. The cause of PSS is not known. Black Americans suffer from more severe disease as compared to White Americans. [1]

The original name of scleroderma was coined because of the hard skin that accompanies the disorder. The disease is termed limited when the hands and face only are involved. Limited disease is at lower risk of visceral involvement although pulmonary hypertension is more common. [2],[3],[4],[5] PSS is diffuse disease with multiorgan involvement associated with skin, and inflammatory changes. Three subgroups are described:

Classical type;CREST syndrome; and Overlap syndromes associated with other connective tissue disorders such as rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis. [6]

The lungs are commonly involved in PSS with a frequency second only to the skin. Esophageal dismotility is common. Respiratory symptoms occur, in a very few cases, as a presenting manifestation. Clinical signs of pulmonary involvement are non-specific and include shortness of breath on exertion and subsequently also at rest. Other symptoms reported are non-productive cough, atypical chest pain, fatigue, and dyspnea. [7]

Abnormalities of lung function include a restrictive ventilatory defect, airflow obstruction, and reduced carbon monoxide diffusion, which may be an isolated early finding. Interstitial lung fibrosis associated with honeycombed lung is the most common lung parenchymal abnormality on a chest radiographs. Heart enlargement and pulmonary artery dilatation are a common finding on imaging. High-resolution computed tomography (HRCT) can detect asymptomatic disease in PSS. Bronchoalveolar lavage shows an increase in total cell count; there are predominantly lymphocytic cells in alveolitis. The two distinct lung disease patterns on studies on live subjects and autopsy studies:

Interstitial lung disease andPulmonary vascular disease.

Pulmonary hypertension may occur in the absence of interstitial lung disease, particularly in patients with limited disease. The overall mortality is reported as 50% at 7 years, with pulmonary complications as the major cause of death. [8] PSS carries the highest mortality among patients with collagen vascular disease, with pulmonary arterial hypertension the leading cause of death. Among patients with PSS, the prevalence of confirmed pulmonary arterial hypertension is around 10-16%. [9]

Interstitial lung fibrosis

The incidence of lung involvement in PSS is 74-95% on autopsy series. [10] Lung involvement is less common in CREST syndrome than other types of systemic scleroses [Figure 1]. Interstitial fibrosis occurs in 20-65% of PSS (8, 10). Restrictive pulmonary function tests with a decreased diffusing capacity may precede clinical or radiographic changes. [11],[12] Restrictive ventilatory defect, airflow obstruction, and reduced carbon monoxide diffusion may predate lung fibrosis. [11],[12] Interstitial lung fibrosis associated with honeycombed lung is the most common lung parenchymal abnormality on a chest radiographs. [Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7],[Figure 8],[Figure 9],[Figure 10],[Figure 11] and [Figure 12] show different patterns of lung fibrosis. High-resolution computed tomography (HRCT) can detect asymptomatic disease in PSS. [8] {Figure 1}{Figure 2}{Figure 3}{Figure 4}{Figure 5}{Figure 6}{Figure 7}{Figure 8}{Figure 9}{Figure 10}{Figure 11}{Figure 12}

Oesophageal dysmotility

Esophageal dysmotility is a common finding and occurs in 74% of cases and may be associated with aspiration pneumonia. [13],[14] Recent work indicates that pulmonary fibrosis and gastroesophageal reflux associated with PSS has more extensive esophageal involvement compared with patients with PSS without pulmonary fibrosis. [15],[16],[17] It has been postulated that increased episodes of gastroesophageal reflux in these patients could be responsible for the development of pulmonary fibrosis. Although the exact mechanism, of pulmonary fibrosis, remains elusive the authors go on to suggest that these patients with gastroesophageal reflux should be considered for anti-reflux therapy. [Figure 2],[Figure 4],[Figure 5] and [Figure 6],[Figure 9] and [Figure 11] showing dilated oesophagus with recurrent aspiration and lung fibrosis.

Pulmonary hypertension

Pulmonary hypertension (PH) is common and affects 50% of patients with CREST and 33% patients with PSS at angiography. [18] PH is usually secondary to lung parenchymal disease, but primary PH may occur. [19],[20] Although large pulmonary arteries and cardiomegaly may be seen on the chest radiographs the, finding is non- specific. [18],[21],[22] [Figure 4]d and [Figure 8]

Infections

Tyndall et al.[23] studied the causes and predictors of mortality in systemic sclerosis (SSc). They obtained questionnaires on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes. Amongst the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Shalev et al.[24] reviewed the medical records of nine patients with diagnosis of scleroderma (8 female, 1 male), admitted to the intensive care unit between 1991 and 2002. They concluded that the outcome of scleroderma patients admitted to the ICU was extremely poor. Infectious complication was the most common cause of death in these patients. A major contributory factor to this poor outcome was dependent on the severity of the underlying visceral organ involvement, particularly severe pulmonary fibrosis. The severity of this involvement is a poor outcome predictor. [24]

Mediastinal lymphadenopathy

Gordonson J and associates, [25] first described a patient with mediastinal lymphadenopathy and undifferentiated connective tissue disease. The histology of the lymph node showed follicular hyperplasia with plasmacytosis, a finding seen in rheumatoid arthritis. The lymphadenopathy resolved 10 months after the patient was first seen, but the mixed connective tissue disease persisted [Figure 13] and [Figure 14].{Figure 13}{Figure 14}

Lymphadenopathy is prevalent in patients with SSc and interstitial lung disease regardless of clinical subtype or interstitial pattern. Wechsler et al, [26] found mediastinal lymphadenopathy in 50% of patients with diffuse cutaneous SSc and 40% in patients with limited cutaneous SSc. The authors also describe a significant association of between lymphadenopathy and interstitial lung disease. 2% patients had a ground-glass parenchymal pattern of interstitial disease and 74% had honeycomb pattern. Warrick and associates [27] studied 17 patients with early systemic sclerosis (SSc) that underwent HRCT of the chest to evaluate dyspnea and/or abnormal pulmonary function tests. Mediastinal lymphadenopathy was detected in 41% of the patients. The authors postulate that ground glass opacities on HRCT may reflect active alveolitis, and mediastinal lymphadenopathy associated with SSc lung disease may be a consequence of pulmonary inflammation. [27] Bhalla and associates, [28] found asymptomatic esophageal dilatation in 80% and mediastinal adenopathy in 60% patients in, scleroderma. The results of their study suggest that CT is useful in the detection of mediastinal adenopathy and asymptomatic esophageal involvement in patients with scleroderma. The findings can help to narrow the differential diagnosis in patients in whom CT shows diffuse interstitial lung disease. [28]

Garber and associates [29] found that mediastinal lymphadenopathy occurs frequently in patients with SSc, at HRCT particularly if lung involvement is extensive. Their study found mediastinal lymphadenopathy in in 32% patients with lung involvement but in only 8% patients no lung parenchymal disease. The prevalence of mediastinal lymphadenopathy increase with more extensive lung involvement, but there is a poor correlation with the CT appearance and concurrent erythrocyte sedimentation rate. Yoshioka [30] reports a case SSc a 77-year old woman with general fatigue that presented with and mediastinal lymphadenopathy preceding skin changes and lung fibrosis. Mediastinal lymphadenopathy was diagnosed by chest computed tomography before the skin and lung involvements of SSc were discovered. The mediastinal lymphadenopathy resolved with the development of lung fibrosis. [30]

Pericardial effusions/myocardial disease

The radiological features of scleroderma pericarditis with effusion were first described by Steinberg and Rothbard [31] and later by Nasser WK and associates. [32] Thompson, Pope [33] using a case-control format, recruited 37 patients with scleroderma and no known cardiac disease to determine the frequency of pericardial and pleural effusions in scleroderma. Echocardiograms and chest radiographs were performed patients. Age- and gender-matched controls had echocardiograms performed which were read by a cardiologist, blinded to the diagnosis. Pleural effusions were identified in 7% (4/58) of the cohort of scleroderma patients and were more frequent in diffuse disease (10%). A total of 17% (4/23) of diffuse and 4% (1/23) of limited scleroderma patients had evidence of pericardial effusions. [31] The authors concluded that pericardial effusions do occur in scleroderma without evidence of clinical cardiac dysfunction and are more common in diffuse scleroderma. Pericardial effusion associated with scleroderma is usually asymptomatic. The incidence of pericardial involvement in scleroderma is about 50% on autopsy series. Asymptomatic pericarditis occurs in 16% of patients with diffuse disease and 30% of patients with limited scleroderma. A case of scleroderma associated large pericardial effusion, which antedated the other clinical and serologic features of scleroderma. [34] Pleural effusions in scleroderma occur in 70%. [31] Abu-Shakra and associates [35] describe a case of diffuse scleroderma associated with a large pleural effusions, pericardial effusion and subsequent renal failure. Histology of the pericardium and pleura revealed the presence of leukocytoclastic vasculitis. [35] The authors suggest pleuropericarditis in systemic sclerosis may occur as a consequence of vasculitis and large pericardial effusions may predispose to oliguric renal failure. [35] [Figure 15],[Figure 16] and [Figure 17].{Figure 15}{Figure 16}{Figure 17}

Cardiac tamponade

Inoue et al.[36] describe, a 42-year old Japanese woman with mixed connective tissue disease who developed fulminant hepatic failure and hepatic encephalopathy. Echocardiography revealed a massive pericardial effusion associated with cardiac tamponade. Bezerra et al.[37] also described a case of fulminant hepatic failure due to cardiac tamponade associated with mixed connective tissue disease. An extremely rare case of cardiac tamponade as an initial manifestation of undifferentiated connective tissue diseases has been reported. [38] The report described a case of a middle-aged man who presented with symptoms of fatigue, exertional dyspnea and orthopnea. His physical exam was significant for anasarca, elevated JVP and pulsus paradoxus. Chest X-ray showed pleural effusions and cardiomegaly the EKG revealed pulses alternans and a transthoracic echocardiography showed a large pericardial effusion associated with circulatory compromise. [36] Right heart catheter study revealed features of cardiac tamponade. Once diagnosed these patients carry the risk developing CDT within 5 years of disease onset and should be followed up in clinic periodically. [36] Briasoulis and associates, [39] report a case of a 24-year old woman admitted with a new onset heart failure and features of cardiac tamponade. Further investigations revealed progressive mixed connective tissue disease associated with severe hypothyroidism. Despite early recognition prompt recognition and prompt treatment with glucocorticoids, thyroxin, metoprolol, lisinopril, furosemide, and milrinone, the patient deteriorated and died within 4 weeks.

Pleural disease

Pleuritis/pleural effusion/thickening is a general finding in PSS. Pleuritic chest pain occurs in 40% patients. This is common, with pleuritic chest pain in 40%, but radiographic signs of thickening and effusions are less common. [13],[14] Diffuse pleural thickening is seen in 20% on HRCT significant effusions are uncommon. [11],[12],[14],[21] There is no pattern to the pleural thickening in mixed connective tissue disease [Figure 10] and [Figure 11].

Pleural effusions

Taormina and associates [21] analyzed the chest film manifestations of 73 PSS patients which were sub-grouped on the basis of previously described criteria. Radiographic abnormalities, either interstitial lung disease or pleural effusion, were present as follows: Pleural effusions were found in 18% (8/44); CRST/CREST, 0% (0/9); and PSS-overlap syndromes, 75% (15/20). Pericardial effusion associated with scleroderma is usually asymptomatic. The incidence of pericardial involvement in scleroderma is about 50% on autopsy series. Asymptomatic pericarditis occurs in 16% of patients with diffuse disease and 30% of patients with limited scleroderma. A case of scleroderma associated large pericardial effusion, which antedated the other clinical and serologic features of scleroderma. [34] Pleuropulmonary disease and pleural effusions is a common feature of several connective tissue diseases. Pleural effusions in connective tissue disease are non-specific and require exclusion of other causes such as infection. In particular, rheumatoid nodules may mimic infectious and neoplastic lung diseases. In rheumatoid pleural effusions, a needle biopsy may reduce the likelihood of infection or malignancy. Pleural effusions caused in SLE and rheumatoid arthritis (RA) has characteristics on pleural fluid analysis that aid in diagnosis, [40],[41] but other causes of effusion may complicate the issue and must be excluded. Moreover, drugs used in connective tissue disease may cause interstitial disease, increase susceptibility to infection, or both. This complicates differential diagnosis. Acute lupus pneumonitis and SLE-related alveolar hemorrhage are usually fulminant processes, often associated with fever. [40],[41] Highland, Heffner [42] reviewed the association of pleural effusions and interstitial parenchymal lung disease and the recent reports of occurrence of effusions to include systemic sclerosis, polymyositis-dermatomyositis, several drugs, and several miscellaneous causes of interstitial lung disease. [42] The effusions require a clinical evaluation to exclude complications of therapy and coexisting conditions unrelated to the underlying interstitial lung disease. Pulmonary hypertension is an independent risk factor for pleural effusion irrespective of connective tissue disease. Pleural effusions frequently occur with pulmonary hypertension. A study by Luo et al.[43] in patients with idiopathic and heritable PH demonstrated that pleural effusions frequently occur in patients with isolated right-sided heart failure. [43] The authors found 39.3% patients with PAH associated with CTD had pleural effusions, 45.1% with scleroderma and 27.8% with mixed connective tissue disease.

The elevation of tumor markers in SLE, RA, or diabetes mellitus has been reported recently. Kimura and associates [41] report a female patient with PSS and pleuritis that demonstrated a high level of CA125 in her pleural effusion and blood serum. The authors measured the serum levels of CA125 and CA19-9 in 27 female patients with collagen diseases including SLE, PSS, dermatomyositis and Sjögren syndrome, and 11 healthy females as controls. All 27 patients showed no elevation CA125 and CA19-9 as compared with the healthy controls, there was any evident elevation of CA19-9 or CA125 levels in collagen diseases except in the reported case. Elevated serum CA125 may be one of the indicators of pleural effusion in collagen disease.

Diffuse alveolar hemorrhage

Diffuse alveolar haemorrhage is a rare but potentially serious complication of PSS and may occur with a systemic vasculitis or rarely with isolated pulmonary capillaritis. [44-47] Griffin and co-workers, [44] have described a case of a 41-year-old man with PSS that developed severe diffuse alveolar haemorrhage and died. The authors emphasize the importance of diffuse alveolar haemorrhage as a rare but potentially serious complication of connective tissue disease that should not be overlooked. Chaer and co-workers [45] report a 38-year-old woman with limited cutaneous systemic sclerosis and pulmonary fibrosis with diffuse alveolar hemorrhage during the course of her disease. The patient responded to steroids.

Pulmonary thromboemboli in systemic sclerosis

Mizoguchi et al.[48] employed ELISA and VDRL tests in order to detect Anticardiolipin antibodies (ACL) antibodies in sera samples obtained from 105 patients with SLE, RA, scleroderma, dermatomyositis, primary Sjögren's syndrome, vasculitis and pulmonary thromboemboli. ACL antibodies were detected in 4 patients out of 11 scleroderma, 1 patient out of 7 vasculitis, 2 patients out of 5 primary Sjögren's syndrome, and 3 patients out of 6 pulmonary thromboemboli. Mizoguchi and co-workers [49] have reported a case of recurrent pulmonary embolism due to intracardiac thrombi in systemic sclerosis. Pulmonary endothelium plays an important role in the mechanism of PAH. A study by Peled and co-workers [50] postulates that a systemic component of endothelial dysfunction might be involved in idiopathic, scleroderma-associated and chronic thromboembolic PAH that is correlated with disease severity [Figure 18].{Figure 18}

Lung neoplasms

Houser and Jonsson SM(50) reported a case of lung cancer associated with PSS and conducted a brief review. Richards RL & Miline JA [51] reported two cases in which cancer was associated with PSS. The authors reviewed 4 other cases previously reported. They found no evidence of an intimate association between malignant disease in general and PSS such as found dermatomyositis. In only one of the six patients, a bronchial carcinoma and the cutaneous and vascular changes of PSS develop together in a patient with previously normal lungs. In the other 5 patients, the lung manifestations of PSS preceded the lung cancer by a number of years, and in these pathological changes of the primary disease were present in parts of the lungs unaffected by tumour. The authors concluded that there was good evidence that PSS may predispose to the development of cancer of the lung. Adziæ et al. [52] reviewed 375 patients; with CTD six of these (25%) had PSS. The authors analysed lung cancer (LC) stage, clinical presentation, histological type, patients' smoking status, method of diagnosis, treatment applied, and disease outcome. The majority of CTD patients who developed lung cancer were diagnosed at an advanced stage and had poor survival. Efforts for early detection of LC in CTD patients' group are warranted.

Lung cancer is the most frequent cancer seen in patients with PSS, followed by breast cancer. Cancer is associated with PSS in between 3.6 and 10.7% of patients. [53] The diagnosis of PSS may occur before, concurrent with, or after the diagnosis of malignancy. Risk factors for the development of malignancy in patients with PSS are female gender, increased age, and diffuse systemic sclerosis. There is no consistent relationship with autoantibodies such as anticentromere and antitopoisomerase and the risk of developing cancer in PSS. [54]

In a study by Colaci et al.[55] in which two thousand and 40 patients with PSS were reviewed and concluded that systemic sclerosis is a risk factor for cancer, particularly smoking- and alcohol-related cancers. Men with systemic sclerosis is at a higher cancer risk than women. Both primary and secondary cancer preventive measures are needed in the care of patients with systemic sclerosis. In their study results from an Italian rheumatologic center and review of the literature Colaci et al.[56] confirmed the higher frequency of lung cancer among PSS patients compared to the general population, particularly within patients' subset with serum anti-Scl70 antibodies and lung involvement. [Figure 12],[Figure 19],[Figure 20],[Figure 21],[Figure 22],[Figure 23],[Figure 24] and [Figure 25]{Figure 19}{Figure 20}{Figure 21}{Figure 22}{Figure 23}{Figure 24}{Figure 25}

Neuromuscular respiratory failure in PSS

Peripheral neuropathy may be a cause of ventilatory muscle weakness found in MCTD and systemic lupus. Martyn and co-workers [57] reported a 34-year-old female patient with MCTD who developed severe pulmonary and neuromuscular complications. She presented initially with myasthenia gravis and then polymyositis, profound peripheral neuropathy, and respiratory muscle failure. Eventually she died despite aggressive immunosuppressive therapy and plasmapheresis. Autopsy revealed spinal cord changes secondary to a peripheral neuropathy and signs of neurogenic atrophy confined to the respiratory muscles. [57] [Figure 26].{Figure 26}

Bronchiectasis and bronchiolitis obliterans organizing pneumonia (BOOP)

Bronchiectasis has been reported in 14% in, association with MCTD on HRCT usually secondary to traction of the airway secondary to from fibrosis or due to recurrent aspiration and infection [58] [Figure 2],[Figure 3],[Figure 4] and [Figure 5].

There is an ever growing list of pathologies associated with BOOP. Bridges and co-workers [58] described two cases associated with PSS with rapidly evolving pulmonary infiltrates, which upon biopsy showed histologic findings of BOOP. As BOOP responds to steroid therapy it is important to differentiate BOOP from SSC and other connective tissue disorders. [58],[59] Taylor JG and Bolster MB [59] presented three cases of biopsy-proven BOOP in patients with PSS and MCTD. BOOP and PSS alveolitis have similar findings on spirometry, radiographs, and BAL; the definitive diagnosis of BOOP was made by open lung biopsy. As PSS alveolitis and BOOP are treated differently, histological diagnosis of BOOP is required.

 Summary



Intra-thoracic manifestations of PSS are not well known. Imaging features are the key to diagnosis and the basis of accurate and timely intervention. The study illustrates the whole spectrum of intrathoracic manifestations of PSS and aims to familiarize the physician and radiologist with these features.

Declaration of Patient Consent

"The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed."

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