Involvement of the respiratory system is common in the collagen vascular diseases and results in significant morbidity and mortality. Many of these diseases are characterized by the presence of a specific type of autoantibody, which may greatly assist specific diagnosis (Table 1). Lung injury from collagen vascular disease can affect each portion of the lung, the pleura, alveoli, interstitium, vasculature, lymphatic tissue, and airways both large and small (Table 2). Commonly, more than 1 compartment is involved (Fig. 1). Most of the parenchymal manifestations of collagen vascular disease are similar to those found in idiopathic interstitial pneumonias3 (see the article by Drs Silva and Muller in this issue), and can be classified using the same system.1 Although there is some overlap, each collagen vascular disease is associated with a characteristic pattern of pulmonary involvement (Table 2). The lung disease associated with collagen vascular disease may precede the clinical presentation of the collagen disease, sometimes by more than 5 years (Fig. 12).
;)
TABLE 1: Autoantibodies Associated With Specific Collagen Vascular Diseases
TABLE 2: Pulmonary Complications of Collagen Vascular Diseases
1,2
Obliterative bronchiolitis and lung fibrosis in a patient with RA. A, CT through the midlungs shows mosaic attenuation indicating obliterative bronchiolitis. B, CT through the lower lungs shows basal ground glass and reticular abnormality suggesting lung fibrosis.
A careful evaluation of the chest radiograph and chest computed tomography (CT) in patients with parenchymal abnormalities can yield some useful clues to the presence of collagen vascular disease. Joint abnormalities (shoulder or acromioclavicular) suggest rheumatoid arthritis (RA). A dilated esophagus should suggest scleroderma or 1 of its variants (Figs. 7, 8). An enlarged pulmonary artery (out of proportion to the extent of lung parenchymal abnormality) may be seen in many types of collagen vascular disease, particularly scleroderma. Soft tissue calcifications may be seen in dermatomyositis or scleroderma. Pleural effusions, pericardial abnormality, or esophageal abnormalities are statistically more common in individuals with lung fibrosis related to collagen vascular disease than in those with idiopathic fibrosing interstitial pneumonia.4
RA
Most patients with RA have abnormalities on high-resolution chest CT. CT-detected abnormalities are often not associated with symptoms. In unselected patients with RA, the most common findings are bronchial wall thickening (12% to 92%), bronchial dilation (30% to 40%), parenchymal micronodules (15% to 20%), reticular abnormality (10% to 20%), pleural opacity (16%), ground glass opacity (15% to 25%), honeycombing (10%), and consolidation (5%).5,6 Pleural effusion may also be identified. Bronchiectasis is usually cylindric in type, and is commonly, although not always, associated with CT and physiologic evidence of small airways disease.7
There is a recognized association between rheumatoid disease and obliterative bronchiolitis (constrictive bronchiolitis)8–12 in which bronchioles are destroyed and replaced by scar tissue. The characteristic CT finding is mosaic perfusion (Fig. 1) with expiratory air trapping (Fig. 2)13–16 often associated with evidence of mild bronchial dilation. Follicular bronchiolitis is a second type of small airway disorder recognized in rheumatoid lung disease.17–21 It is characterized by lymphoid aggregates, with or without germinal centers, lying in the walls of bronchioles and possibly compressing their lumens.22 Follicular bronchiolitis probably produces a reticular or reticulonodular pattern on the chest radiograph.17 The major CT finding is centrilobular nodules, often associated with peribronchial nodules, and with areas of ground glass abnormality.19,22
FIGURE 2.:
Obliterative bronchiolitis in RA. A, Inspiratory CT shows minimal mosaic attenuation. B, Expiratory CT shows moderate multilobular air trapping.
Airways disease seems to be the earliest manifestation of RA in the lung. In a study of 34 patients with early RA (duration<1 y), CT showed expiratory air trapping in 69%, bronchiectasis in 58%, and ground glass opacity in 35%.23 An interesting recent study24 evaluated CT findings in 14 asymptomatic first-degree relatives of individuals with known RA. Six of the 7 individuals who had positive RA-related antibodies (anti-cyclic citrullinated peptide) had expiratory air trapping, compared with none of the 7 antibody-negative subjects. This intriguing finding suggests that the airways or the lung may be involved very early in the evolution of RA. The relatively high prevalence of air trapping in individuals with RA emphasizes the importance of obtaining expiratory images in patients with RA, as inspiratory CT is often normal or near-normal in patients with obliterative bronchiolitis (Fig. 2).
Rheumatoid lung fibrosis is substantially more common in men than in women.25,26 The 2 most common patterns of lung fibrosis in RA are usual interstitial pneumonia (UIP) (Fig. 3) and nonspecific interstitial pneumonia (NSIP).27,28 organizing pneumonia (OP) may also be seen.17,18,29–31 A few cases of desquamative interstitial pneumonia have been described.18,26 CT findings in interstitial pneumonia associated with RA are similar to those of the idiopathic variety.32–34 However, associated nodules, mosaic attenuation, pulmonary arterial enlargement, and pleural abnormality may provide a clue to the underlying diagnosis (Fig. 1). In a study of 63 patients with rheumatoid lung disease,28 26 had a CT pattern suggestive of UIP, 19 had a pattern of NSIP, 11 had a bronchiolitis pattern, and 5 had an OP pattern. These CT patterns were in agreement with the histology in 13 of the 17 who underwent biopsy.
FIGURE 3.:
UIP in RA. A and B, Coronal and axial CT images show typical pattern of basal predominant, peripheral predominant reticular abnormality, and honeycombing.
Necrobiotic nodules, similar to subcutaneous rheumatoid nodules, may uncommonly occur in the lung. They are usually round, well defined, and may cavitate. The entity of Caplan syndrome (multiple, large-rounded nodules seen on the chest radiographs of coal miners with RA) now seems to be very rare, with only 1 published case report since 1965.35,36
Pulmonary hypertension commonly occurs in patients with RA, but is usually mild.37 Other complications of RA include lymphoma, and lung cancer.38 Many of the available treatments for RA, including gold, methotrexate, and D-penicillamine have been implicated in the development of infiltrative lung disease. Low-dose methotrexate may be associated with subacute hypersensitivity pneumonitis in 2% to 5% of cases (Fig. 4).39,40 Preexisting radiographic evidence of interstitial lung disease (ILD) probably predisposes to the development of methotrexate pneumonitis in patients with RA.41
FIGURE 4.:
Methotrexate toxicity in a patient with RA. CT shows patchy basal ground glass and reticular abnormality.
The new generation of biologic agents used to treat RA has resulted in a new array of potential pulmonary side effects. The most important of these is impaired immunity related to the use of anti-tumor necrosis factor-α antibodies (etanercept, infliximab, and adalimumab), which results in a substantially increased incidence of tuberculosis (sometimes disseminated or extra-articular) and nontuberculous mycobacterial infection (Fig. 5).42 Fungal and pneumocystis infection may also occur. Screening chest radiographs are usually obtained when anti-tumor necrosis factor-α antibody treatment is planned. Mycobacterial or fungal infection should be strongly suspected when new parenchymal abnormalities are identified in these patients.
FIGURE 5.:
Mycobacterial infection (Mycobacterium avium complex) in a patient with RA treated with infliximab. CT shows large irregular cavities and 2 noncavitary nodules.
SCLERODERMA (PROGRESSIVE SYSTEMIC SCLEROSIS)
Parenchymal lung involvement is very common in patients with scleroderma. At autopsy, the lungs are abnormal in at least 80% of cases.43 Lung fibrosis is the most common pattern of abnormality, with NSIP being much more common than UIP.44,45 However, pulmonary hypertension is also common, either as an isolated finding or in association with lung fibrosis. Pulmonary hypertension is particularly common in patients with limited scleroderma (CREST syndrome).46 Esophageal dilation is found in up to 80% of cases on CT.47
CT findings in scleroderma reflect the dominant NSIP histology, and are characterized by confluent ground glass opacification and fine reticular pattern, often posterior and subpleural, usually associated with traction bronchiectasis and bronchiolectasis (Fig. 6).48,49 Honeycombing, when present, is usually mild.50 However, patients with honeycombing on initial CT are probably more likely to progress on serial evaluation (Fig. 7).49 The lung fibrosis associated with scleroderma is associated with a much better prognosis than that found in idiopathic lung fibrosis,51–53 most likely due, in part, to the predominant NSIP histology. In a large treatment study, the extent of lung fibrosis identified on baseline CT was an important independent predictor of physiologic progression, and of response to treatment.54
FIGURE 6.:
NSIP pattern in scleroderma. CT through the lower lungs shows basal predominant ground glass abnormality with fine reticular abnormality and marked traction bronchiectasis indicating fibrosis.
FIGURE 7.:
Progressive lung fibrosis in scleroderma. A, Initial CT shows moderate basal reticular abnormality with fine subpleural honeycombing (arrowheads). The esophagus is moderately dilated. B, CT 7 months later shows marked progression of fibrosis, traction bronchiectasis, and honeycombing.
Pulmonary arterial hypertension usually causes enlargement of the main and proximal pulmonary arteries on chest radiograph or CT (Fig. 8A); however, normal-sized pulmonary arteries do not exclude the diagnosis, and the presence of pericardial thickening or fluid in patients with scleroderma is also a strong predictor of echocardiographic pulmonary hypertension (Fig. 8B).55 There is an increased prevalence of lung cancer in scleroderma, with relative risk of malignancy ranging from 1.8 to 6.5.56,57 Lung cancer in this condition often occurs in individuals with lung fibrosis (Fig. 9).
FIGURE 8.:
Pulmonary hypertension in scleroderma. A, CT shows marked dilation of main pulmonary artery, measuring 3.5 cm. B, CT at a lower level shows cardiomegaly, with prominence of the right ventricle, and a small amount of pericardial fluid or thickening (arrowheads). Note the dilated, fluid-filled esophagus on both images (arrows).
FIGURE 9.:
Lung cancer in a patient with lung fibrosis related to scleroderma. CT shows a 4-cm mass in the fibrotic left lower lobe.
SYSTEMIC LUPUS ERYTHEMATOSUS
Pleuritis is the most common pleuropulmonary manifestation of lupus, found in 40% to 60% of patients with systemic lupus erythematosus (SLE),58–60 and may or may not be associated with pleural effusion. Although pulmonary infection is said to be the most common pulmonary complication of lupus,61 acute pulmonary hemorrhage is also an important pulmonary complication of this condition,62 characterized radiologically by diffuse or patchy consolidation and ground glass abnormality (Fig. 10). Acute lupus pneumonitis is a poorly defined entity, characterized by a variable degree of respiratory impairment accompanied by focal or diffuse pulmonary consolidation, occurring in patients with lupus.62 It is now believed that most cases previously identified as lupus pneumonitis probably represented acute interstitial pneumonia with or without pulmonary hemorrhage.63
FIGURE 10.:
Recurrent pulmonary hemorrhage in a patient with systemic lupus erythematosus. A, CT shows bilateral upper lobe consolidation with “acinar” centrilobular nodularity, on account of pulmonary hemorrhage. B, CT 1 year later shows patchy ground glass abnormality, indicating recurrent hemorrhage.
Fibrotic ILD is less common in SLE than in the other collagen vascular diseases.64 UIP or NSIP may occur. CT abnormalities in SLE are often relatively mild and nonspecific, with linear thickened interlobular septa and parenchymal bands being most common.65,66 Other complications of lupus may include diaphragmatic dysfunction (Fig. 11),67 pulmonary hypertension,68 and pulmonary thromboembolism, which may be related to antiphospholipid antibodies.63 Diaphragmatic dysfunction, thought to be due to a diaphragmatic myopathy, is manifested by reduced lung volumes (“shrinking lungs”) (Fig. 11).
FIGURE 11.:
Shrinking lungs in a patient with lupus erythematosis. A, Chest radiograph shows markedly reduced lung volumes. The heart is moderately enlarged. B, Prone CT image shows band-like basal opacity that may represent atelectasis.
POLYMYOSITIS/DERMATOMYOSITIS
The presence of ILD in polymyositis/dermatomyositis (PM/DM) correlates strongly with the presence of anti-Jo-1.69,70 About 50% to 70% of patients who are anti-Jo-1 positive have ILD71 whereas the frequency of ILD falls to about 10% if antibodies are absent. ILD may antedate myositis in patients with anti-Jo-1 antibodies.72 The most common pathologic findings are NSIP73–76 and OP,77–79 often occurring in combination. As with other collagen vascular disease, the occurrence of interstitial pneumonia may precede the development of clinical myositis (Fig. 12). Lung disease associated with PM/DM or with the antisynthetase syndrome, a closely related entity, is often associated with a characteristic CT appearance, characterized by confluent ground glass opacity and consolidation in the lower lobes, superimposed on a background of reticular abnormality with traction bronchiectasis (Fig. 13).77,80,81 This pattern reflects the characteristic histologic combination of organizing pneumonia and fibrotic NSIP.77,81 On serial evaluation, the changes of consolidation, ground glass abnormality, reticular abnormality, and traction bronchiectasis may all be partially reversible with treatment.76,77,80 Consolidation may also progress to reticular abnormality (Fig. 12).
FIGURE 12.:
OP and NSIP in a patient who subsequently developed polymyositis. A, Initial CT shows focal consolidation and ground glass abnormality in the right lower lobe with mild bronchial dilation, compatible with OP. B, CT obtained 1 year later shows bibasal reticular abnormality with traction bronchiectasis, compatible with NSIP. One year later, the patient developed clinical polymyositis.
FIGURE 13.:
Typical findings in lung disease related to polymyositis. Coronal reconstruction from CT shows confluent basal predominant consolidation associated with marked traction bronchiectasis. This combination of findings is quite highly suggestive of polymyositis.
SJÖGREN SYNDROME
CT provides substantial information regarding the pattern of pulmonary involvement by Sjögren syndrome.82 The patterns may be divided into airway abnormality, interstitial fibrosis, pulmonary hypertension, and patterns suggestive of lymphoid interstitial pneumonia (LIP).82 In a study by Franquet et al,83 of 50 consecutive patients with primary Sjögren syndrome, 17 of 50 patients (34%) had CT abnormalities. Overall, changes were the most common in the lower zones. Airway-related abnormalities were common (11 of 17) and consisted of bronchial wall thickening, bronchiectasis (Fig. 14), bronchiolectasis, tree in bud pattern, and air-trapping. Septal or nonseptal lines occurred in a similar number of individuals (11 of 17). Other findings included patchy ground glass opacity (7 of 17), nodules (5 of 17), honeycombing (4 of 17), and consolidation (1 of 17). Nodules more than 10 mm in diameter were caused by lymphoma. Although cysts were not described in this series, cystic abnormality is common in other series.84 Small airway disease was manifest by a mosaic attenuation pattern and expiratory air trapping.83,85
FIGURE 14.:
Cysts and bronchiectasis in a patient with Sjögren syndrome. A and B, CT through the lower lungs shows mild cylindric bronchiectasis, and multiple thin-walled peribronchovascular cysts. The cystic abnormality is strongly suggestive of LIP.
LIP occurring in Sjögren syndrome is characterized by ground glass abnormality on account of the homogenous lymphocytic infiltration.86 Peribronchovascular, centrilobular, and subpleural nodules may also be seen, and cysts measuring 5 to 30 mm are often present (Fig. 14).84 Similar cysts may be found in follicular bronchiolitis.85 These changes are ascribed to bronchiolar obstruction on the basis of lymphocytic wall infiltration. Cysts are helpful in distinguishing LIP from lymphoma.87 Lymphoma should be suspected if consolidation, large nodules (>1 cm) or effusions are present.87 However, similar large “pseudoalveolar” poorly defined nodules were found in 4 patients with combined amyloidosis and LIP.88 In contrast to other cystic lung diseases, such as lymphangioleiomyomatosis, the cysts of LIP show peribronchovascular and lower lung predominance (Fig. 14).
MIXED CONNECTIVE TISSUE DISEASE
Mixed connective tissue disease (MCTD) is an overlap syndrome that is a distinct clinicopathological entity.89 The principal characteristics are the presence of (1) features of SLE, scleroderma, PM/DM, occurring together or evolving sequentially during observation; and (2) antibodies to an extractable nuclear antigen (RNP).89
Pulmonary involvement is common in MCTD. A study of 144 unselected patients found CT evidence of infiltrative lung disease in 67%.90 Many affected patients are asymptomatic.91 The pulmonary abnormalities resemble those seen in SLE, SS, and PM/DM.61 Thus, pleural thickening and pleural and pericardial effusions are common.91 Ground glass attenuation is the most common parenchymal abnormality.90,92 The CT pattern corresponds most closely to NSIP (Fig. 15). Less common findings include honeycombing, consolidation, and poorly defined centrilobular nodules.
FIGURE 15.:
NSIP and bronchiectasis in a patient with mixed connective tissue disease. Coronal CT reconstruction shows basal predominant ground glass abnormality. Focal bronchiectasis is present in the superior segment of left lower lobe.
Other important complications of MCTD include pulmonary arterial hypertension93–95 and esophageal dysmotility.94
ANKYLOSING SPONDYLITIS
Pleuropulmonary involvement is a rare complication of ankylosing spondylitis, found in 1.3% of 2080 patients in 1 series.96 It almost always involves males, with long duration of disease.97 The radiologic changes96 consist of nodular and linear opacity and/or pleural thickening that begin in the lung apices. The apical opacities progress slowly with increasing apical nodularity and pleural thickening, elevation of the hila, and the development of multiple thin-walled or thick-walled cysts or cavities (Fig. 16).96,98,99 These apical changes usually progress slowly,99 but they can remain stable for many years. Pleural calcification may occur. The cavities that develop within the fibrotic lung may be colonized by a variety of fungi and nontuberculous mycobacteria,61,96 most commonly mycetomas containing Aspergillus fumigatus (Fig. 17).99,100 Colonization rates with Aspergillus have varied between 19%96 and 50% to 60%.99,101 Hemoptysis is common in patients with mycetoma, and may be life-threatening.
FIGURE 16.:
Upper lobe fibrosis in ankylosing spondylitis. Chest radiograph (A) and coronal chest CT reconstruction (B) show marked bilateral upper lobe volume loss with dense fibrotic consolidation, and associated air bronchograms. There is dense apical pleural thickening and multifocal pleural calcification. The cystic appearing abnormality seen at the right apex on the chest radiograph represents a dilated, distorted upper esophagus, probably because of the upper lobe fibrosis.
FIGURE 17.:
Mycetoma in ankylosing spondylitis. CT shows bilateral upper lobe cavities, with a filling defect in the left upper lobe cavity.
SUMMARY
In evaluating an individual with suspected or known collagen vascular disease, the radiologist should be aware that specific patterns of lung injury tend to track with specific disease entities. A systematic approach, evaluating each compartment of the lung (airway, interstitium, pleura, pulmonary vasculature) may be helpful. Complications of treatment, including infection, should be specifically considered, particularly in rheumatoid arthritis.
REFERENCES
1. Kim EA, Lee KS, Johkoh T, et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. RadioGraphics. 2002;22:S151–S165.
2. Freemer M, King T. Connective tissue diseases. In: Schwarz M, King T, eds. Interstitial Lung Disease. 4th ed. Toronto: Brian C Decker; 2003: 535–598.
3. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:277–304.
4. Hwang JH, Misumi S, Sahin H, et al. Computed tomographic features of idiopathic fibrosing interstitial pneumonia: comparison with pulmonary fibrosis related to collagen vascular disease. J Comput Assist Tomogr. 2009;33:410–415.
5. Remy-Jardin M, Remy J, Cortet B, et al. Lung changes in rheumatoid arthritis: CT findings. Radiology. 1994;193:375–382.
6. Mori S, Cho I, Koga Y, et al. Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis. J Rheumatol. 2008;35:1513–1521.
7. Perez T, Remy-Jardin M, Cortet B. Airways involvement in rheumatoid arthritis: clinical, functional, and HRCT findings. Am J Respir Crit Care Med. 1998;157:1658–1665.
8. Macfarlane JD, Dieppe PA, Rigden BG, et al. Pulmonary and pleural lesions in rheumatoid disease. Br J Dis Chest. 1978;72:288–300.
9. Geddes DM, Corrin B, Brewerton DA, et al. Progressive airway obliteration in adults and its association with rheumatoid disease. Q J Med. 1977;46:427–444.
10. Herzog CA, Miller RR, Hoidal JR. Bronchiolitis and rheumatoid arthritis. Am Rev Respir Dis. 1981;124:636–639.
11. McCann BG, Hart GJ, Stokes TC, et al. Obliterative bronchiolitis and upper-zone pulmonary consolidation in rheumatoid arthritis. Thorax. 1983;38:73–74.
12. Hakala M, Paakko P, Sutinen S, et al. Association of bronchiolitis with connective tissue disorders. Ann Rheum Dis. 1986;45:656–662.
13. Sweatman MC, Millar AB, Strickland B, et al. Computed tomography in adult obliterative bronchiolitis. Clin Radiol. 1990;41:116–119.
14. Aquino SL, Webb WR, Golden J. Bronchiolitis obliterans associated with rheumatoid arthritis: findings on HRCT and dynamic expiratory CT. J Comput Assist Tomog. 1994;18:555–558.
15. Schwarz MI, Lynch DA, Tuder R. Bronchiolitis obliterans: the lone manifestation of rheumatoid arthritis? Eur Respir J. 1994;7:817–820.
16. Worthy SA, Müller NL. Small airway diseases. Radiol Clin North Am. 1998;36:163–173.
17. Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis. 1985;131:770–777.
18. Hakala M, Paakko P, Huhti E, et al. Open lung biopsy of patients with rheumatoid arthritis. Clin Rheumatol. 1990;9:452–460.
19. Hayakawa H, Sato A, Imokawa S, et al. Bronchiolar disease in rheumatoid arthritis. Am J Respir Crit Care Med. 1996;154:1531–1536.
20. Balagopal VP, da Costa P, Greenstone MA. Fatal pulmonary hypertension and rheumatoid vasculitis. Eur Respir J. 1995;8:331–333.
21. Kinoshita M, Higashi T, Tanaka C, et al. Follicular bronchiolitis associated with rheumatoid arthritis. Intern Med. 1992;31:674–677.
22. Howling SJ, Hansell DM, Wells AU, et al. Follicular bronchiolitis: thin-section CT and histologic findings. Radiology. 1999;212:637–642.
23. Metafratzi ZM, Georgiadis AN, Ioannidou CV, et al. Pulmonary involvement in patients with early rheumatoid arthritis. Scand J Rheumatol. 2007;36:338–344.
24. Deane KD, Simonian PL, Lynch DA, et al. Rheumatoid arthritis (RA)-related autoantibodies are associated with pulmonary airway abnormalities in individuals without RA. 2008.
25. Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997;156:528–535.
26. Turner-Warwick M, Evans R. Pulmonary manifestations of rheumatoid disease. Clin Rheum Dis. 1977;3:549–564.
27. Yoshinouchi T, Ohtsuki Y, Fujita J, et al. Nonspecific interstitial pneumonia pattern as pulmonary involvement of rheumatoid arthritis. Rheumatol Int. 2005;26:121–125.
28. Tanaka N, Kim JS, Newell JD, et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology. 2004;232:81–91.
29. Pommepuy I, Farny M, Billey T, et al. Bronchiolitis obliterans organizing pneumonia in a patient with rheumatoid arthritis. Revue Du Rhumatisme, English Edition. 1998;65:65–67.
30. Gammon RB, Bridges TA, al-Nezir H, et al. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus. Chest. 1992;102:1171–1174.
31. Mroz BJ, Sexauer WP, Meade A, et al. Hemoptysis as the presenting symptom in bronchiolitis obliterans organizing pneumonia. Chest. 1997;111:1775–1778.
32. Steinberg DL, Webb WR. CT appearances of rheumatoid lung disease. J Comput Assist Tomog. 1984;8:881–884.
33. Bergin CJ, Muller NL. CT of interstitial lung disease: a diagnostic approach. AJR Am J Roentgenol. 1987;148:9–15.
34. Fewins HE, McGowan I, Whitehouse GH, et al. High definition computed tomography in rheumatoid arthritis associated pulmonary disease. Br J Rheumatol. 1991;30:214–216.
35. Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax. 1953;8:29–37.
36. Arakawa H, Honma K, Shida H, et al. Computed tomography findings of Caplan syndrome. J Comput Assist Tomogr. 2003;27:758–760.
37. Dawson JK, Goodson NG, Graham DR, et al. Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients. Rheumatology (Oxford). 2000;39:1320–1325.
38. Bouros D, Hatzakis K, Labrakis H, et al. Association of malignancy with diseases causing interstitial pulmonary changes. Chest. 2002;121:1278–1289.
39. Hargreaves MR, Mowat AG, Benson MK. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports. Thorax. 1992;47:628–633.
40. Hilliquin P, Renoux M, Perrot S, et al. Occurrence of pulmonary complications during methotrexate therapy in rheumatoid arthritis. Br J Rheumatol. 1996;35:441–445.
41. Golden MR, Katz RS, Balk RA, et al. The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis. J Rheumatol. 1995;22:1043–1047.
42. Mutlu GM, Mutlu EA, Bellmeyer A, et al. Pulmonary adverse events of anti-tumor necrosis factor-alpha antibody therapy. Am J Med. 2006;119:639–646.
43. D'Angelo WA, Fries JF, Masi AT, et al. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med. 1969;46:428–440.
44. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165:1581–1586.
45. Kim DS, Yoo B, Lee JS, et al. The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:121–127.
46. Hunzelmann N, Genth E, Krieg T, et al. The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology (Oxford). 2008;47:1185–1192.
47. Bhalla M, Silver RM, Shepard J, et al. Chest CT in patients with scleroderma: prevalence of asymptomatic esophageal dilatation and mediastinal lymphadenopathy. Am J Roentgenol. 1993;161:269–272.
48. Schurawitzki H, Stiglbauer R, Graninger W, et al. Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography. Radiology. 1990;176:755–759.
49. Remy-Jardin M, Remy J, Wallaert B, et al. Pulmonary involvement in progressive systemic sclerosis: sequential evaluation with CT, pulmonary function tests, and bronchoalveolar lavage. Radiology. 1993;188:499–506.
50. Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest. 2008;134:358–367.
51. Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 1994;149:1583–1590.
52. Renzoni E, Rottoli P, Coviello G, et al. Clinical, laboratory and radiological findings in pulmonary fibrosis with and without connective tissue disease. Clin Rheumatol. 1997;16:570–577.
53. Muir TE, Tazelaar HD, Colby TV, et al. Organizing diffuse alveolar damage associated with progressive systemic sclerosis. Mayo Clin Proc. 1997;72:639–642.
54. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354:2655–2666.
55. Fischer A, Misumi S, Curran-Everett D, et al. Pericardial abnormalities predict the presence of echocardiographically defined pulmonary arterial hypertension in systemic sclerosis-related interstitial lung disease. Chest. 2007;131:988–992.
56. Pearson JE, Silman AJ. Risk of cancer in patients with scleroderma. Ann Rheum Dis. 2003;62:697–699.
57. Arroliga AC, Podell DN, Matthay RA. Pulmonary manifestations of scleroderma. J Thorac Imaging. 1992;7:30–45.
58. Harvey AM, Shulman LE, Tumulty PA, et al. Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine (Baltimore). 1954;33:291–437.
59. Estes D, Christian CL. The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore). 1971;50:85–95.
60. Murin S, Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med. 1998;19:641–665.
61. Hunninghake GW, Fauci AS. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis. 1979;119:471–503.
62. Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. J Thorac Imaging. 1992;7:1–18.
63. Swigris JJ, Fischer A, Gillis J, et al. Pulmonary and thrombotic manifestations of systemic lupus erythematosus. Chest. 2008;133:271–280.
64. Fraser R, Pare J, Pare P, et al. Diagnosis of Diseases of the Chest. Philadelphia, PA: WB Saunders; 1989.
65. Bankier AA, Kiener HP, Wiesmayr MN, et al. Discrete lung involvement in systemic lupus erythematosus: CT assessment. Radiology. 1995;196:835–840.
66. Fenlon HM, Doran M, Sant SM, et al. High-resolution chest CT in systemic lupus erythematosus. AJR Am J Roentgenol. 1996;166:301–307.
67. Grigor R, Edmonds J, Lewkonia R, et al. Systemic lupus erythematosus. A prospective analysis. Ann Rheum Dis. 1978;37:121–128.
68. Simonson JS, Schiller NB, Petri M, et al. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol. 1989;16:918–925.
69. Friedman AW, Targoff IN, Arnett FC. Interstitial lung disease with autoantibodies against aminoacyl-tRNA synthetases in the absence of clinically apparent myositis. Semin Arthritis Rheum. 1996;26:459–467.
70. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med. 1990;112:682–698.
71. Schwarz MI. Pulmonary and cardiac manifestations of polymyositis-dermatomyositis. J Thorac Imaging. 1992;7:46–54.
72. Bernstein RM, Morgan SH, Chapman J, et al. Anti-Jo-1 antibody: a marker for myositis with interstitial lung disease. Br Med J (Clin Res Ed). 1984;289:151–152.
73. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164:1182–1185.
74. Tazelaar HD, Viggiano RW, Pickersgill J, et al. Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis. 1990;141:727–733.
75. Cottin V, Thivolet-Bejui F, Reynaud-Gaubert M, et al. Interstitial lung disease in amyopathic dermatomyositis, dermatomyositis and polymyositis. Eur Respir J. 2003;22:245–250.
76. Arakawa H, Yamada H, Kurihara Y, et al. Nonspecific interstitial pneumonia associated with polymyositis and dermatomyositis: serial high-resolution CT findings and functional correlation. Chest. 2003;123:1096–1103.
77. Akira M, Hara H, Sakatani M. Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology. 1999;210:333–338.
78. Johkoh T, Ikezoe J, Kohno N, et al. High-resolution CT and pulmonary function tests in collagen vascular disease: comparison with idiopathic pulmonary fibrosis. Eur J Radiol. 1994;18:113–121.
79. Tansey D, Wells AU, Colby TV, et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004;44:585–596.
80. Mino M, Noma S, Taguchi Y, et al. Pulmonary involvement in polymyositis and dermatomyositis: sequential evaluation with CT. AJR Am J Roentgenol. 1997;169:83–87.
81. Ikezoe J, Johkoh T, Kohno N, et al. High-resolution CT findings of lung disease in patients with polymyositis and dermatomyositis. J Thorac Imag. 1996;11:250–259.
82. Taouli B, Brauner MW, Mourey I, et al. Thin-section chest CT findings of primary Sjogren's syndrome: correlation with pulmonary function. Eur Radiol. 2002;12:1504–1511.
83. Franquet T, Gimenez A, Monill JM, et al. Primary Sjogren's syndrome and associated lung disease: CT findings in 50 patients. AJR Am J Roentgenol. 1997;169:655–658.
84. Ichikawa Y, Kinoshita M, Koga T, et al. Lung cyst formation in lymphocytic interstitial pneumonitis: CT features. J Comput Assist Tomog. 1994;18:745–748.
85. Meyer CA, Pina JS, Taillon D, et al. Inspiratory and expiratory high-resolution CT findings in a patient with Sjogren's syndrome and cystic lung disease. AJR Am J Roentgenol. 1997;168:101–103.
86. Johkoh T, Müller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-section CT findings in 22 patients. Radiology. 1999;212:567–572.
87. Honda O, Johkoh T, Ichikado K, et al. Differential diagnosis of lymphocytic interstitial pneumonia and malignant lymphoma on high-resolution CT. AJR Am J Roentgenol. 1999;173:71–74.
88. Jeong YJ, Lee KS, Chung MP, et al. Amyloidosis and lymphoproliferative disease in Sjogren syndrome: thin-section computed tomography findings and histopathologic comparisons. J Comput Assist Tomogr. 2004;28:776–781.
89. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52:148–159.
90. Bodolay E, Szekanecz Z, Devenyi K, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford). 2005;44:656–661.
91. Prakash UB. Respiratory complications in mixed connective tissue disease. Clin Chest Med. 1998;19:733–746.
92. Kozuka T, Johkoh T, Honda O, et al. Pulmonary involvement in mixed connective tissue disease: high-resolution CT findings in 41 patients. J Thorac Imag. 2001;16:94–98.
93. Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis. 2002;45:225–234.
94. Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore). 1984;63:92–107.
95. Wiener-Kronish JP, Solinger AM, Warnock ML, et al. Severe pulmonary involvement in mixed connective tissue disease. Am Rev Respir Dis. 1981;124:499–503.
96. Rosenow E, Strimlan CV, Muhm JR, et al. Pleuropulmonary manifestations of ankylosing spondylitis. Mayo Clin Proc. 1977;52:641–649.
97. Hillerdal G. Ankylosing spondylitis lung disease--an underdiagnosed entity? Eur J Respir Dis. 1983;64:437–441.
98. Wolson AH, Rohwedder JJ. Upper lobe fibrosis in ankylosing spondylitis. Am J Roentgenol Radium Ther Nucl Med. 1975;124:466–471.
99. Davies D. Ankylosing spondylitis and lung fibrosis. Q J Med. 1972;41:395–417.
100. Pamuk ON, Harmandar O, Tosun B, et al. A patient with ankylosing spondylitis who presented with chronic necrotising aspergillosis: report on one case and review of the literature. Clin Rheumatol. 2005;24:415–419.
101. Campbell AH, Macdonald CB. Upper lobe fibrosis associated with ankylosing spondylitis. Br J Dis Chest. 1965;59:90–101.
