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Published online before print May 27, 2004, 10.1148/radiol.2321030174
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(Radiology 2004;232:81-91.)
© RSNA, 2004

Thoracic Imaging

Rheumatoid Arthritis–related Lung Diseases: CT Findings1

Nobuyuki Tanaka, MD, Jeung Sook Kim, MD, John D. Newell, MD, Kevin K. Brown, MD, Carlyne D. Cool, MD, Richard Meehan, MD, Takuya Emoto, MD, Tsuneo Matsumoto, MD and David A. Lynch, MB

1 From the Depts of Radiology (N.T., J.S.K., D.A.L.) and Pathology (C.D.C.), Univ of Colorado Health Sciences Ctr, Denver; Depts of Radiology (J.D.N.) and Medicine (K.K.B., R.M.), National Jewish Ctr for Immunology and Respiratory Med, Denver, Colo; and Dept of Radiology, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan (N.T., T.E., T.M.). Received Feb 3, 2003; revision requested Apr 22; final revision received Nov 5; accepted Nov 17. Address correspondence to N.T. (e-mail: ntanaka@yamaguchi-u.ac.jp).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate computed tomographic (CT) findings of rheumatoid arthritis–related lung disease and categorize findings according to pathologic features.

MATERIALS AND METHODS: CT scans obtained in 63 patients (27 men, 36 women; mean age, 61.7 years ± 11.2 [SD]; range, 28–81 years) with rheumatoid arthritis were assessed. Mean duration of disease was 7.6 years ± 9.2. Lung parenchymal abnormalities that included airspace consolidation, ground-glass opacity (GGO), reticulation, honeycombing, nodules, bronchiectasis, and air trapping were assessed retrospectively by two chest radiologists. Final decision was reached with consensus of these radiologists and a third radiologist. Patients were classified according to the predominant CT pattern. One of the chest radiologists and a pulmonary pathologist compared CT findings with pathologic findings in 17 patients. Interobserver agreement between the first two radiologists was assessed. Correlation between CT finding extent score and pulmonary function test results was estimated with Spearman rank correlation coefficient.

RESULTS: GGO (57 [90%] patients) and reticulation (62 [98%] patients) were the most common CT features. Four major CT patterns were identified: usual interstitial pneumonia (n = 26), nonspecific interstitial pneumonia (n = 19), bronchiolitis (n = 11), and organizing pneumonia (n = 5). Usual interstitial pneumonia and nonspecific interstitial pneumonia CT patterns overlapped; GGO was more extensive in patients with nonspecific interstitial pneumonia CT pattern (P = .028). In 17 patients who underwent biopsy, CT findings reflected pathologic findings. Exceptions were two patients classified with usual interstitial pneumonia at CT but with nonspecific interstitial pneumonia at pathologic analysis; one patient, with nonspecific interstitial pneumonia at CT but desquamative interstitial pneumonia at pathologic analysis; and one patient, with lymphoid interstitial pneumonia at CT but nonspecific interstitial pneumonia at pathologic analysis.

CONCLUSION: Rheumatoid arthritis is associated with four CT patterns: usual interstitial pneumonia, nonspecific interstitial pneumonia, bronchiolitis, and organizing pneumonia. The most common CT features of rheumatoid arthritis–related lung disease were GGO and reticulation.

© RSNA, 2004

Index terms: Arthritis, rheumatoid, 40.71 • Bronchiolitis, 60.2191 • Lung, CT, 60.1211, 60.12118 • Lung, interstitial disease, 60.611, 60.917 • Pneumonia, interstitial with fibrosis, 60.213


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Rheumatoid arthritis is a common systemic disease that manifests as inflammatory arthritis of multiple joints and produces a wide variety of intrathoracic lesions, including pleural diseases (1–3), rheumatoid nodules (1–5), diffuse interstitial pneumonia (1–10), pulmonary vasculitis (1,2,10,11), and airway disease that includes bronchiectasis, bronchiolitis obliterans, and follicular bronchiolitis (1,4,6,8,12–19). Yousem et al (20) described a broad range of histopathologic features in the lungs of patients with rheumatoid arthritis; these features include rheumatoid nodules, usual interstitial pneumonia, organizing pneumonia, lymphoid hyperplasia, and nonspecific interstitial pneumonia. Therefore, the term rheumatoid lung is of little use as a descriptor, because it encompasses a large spectrum of morphologic changes that are associated with substantially different prognoses.

The purpose of this study was to evaluate the computed tomographic (CT) findings in patients with pulmonary complications of rheumatoid arthritis and to categorize these findings on the basis of pathologic features.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
Between 1991 and 2002, we retrospectively reviewed CT scans obtained in 63 patients with rheumatoid arthritis who underwent a CT examination of the chest at University of Colorado Health Sciences Center, Denver; National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo; and Yamaguchi University School of Medicine, Ube, Japan. These 63 patients were identified from a clinical database. These patients underwent CT examination because they had chest symptoms or abnormal chest radiographic findings. The 63 patients selected for this study fulfilled the revised criteria for rheumatoid arthritis of the American Rheumatism Association (21). Patients who had clinical or laboratory evidence of other collagenous vascular diseases were excluded from this study. Furthermore, patients in whom pulmonary abnormalities were clinically thought to be due to infection or drug toxicity were also excluded. The study was approved by the institutional review boards at our institutions, and informed consent was obtained from the participants.

The study group comprised 27 men who ranged in age from 39 to 77 years (mean, 61.9 years ± 9.4 [SD]) and 36 women who ranged in age from 28 to 81 years (mean, 61.6 years ± 12.4). The total group of 63 patients ranged in age from 28 to 81 years (mean, 61.7 years ± 11.2). Smoking history was not available in nine patients. Of the other 54 patients, eight were current smokers, 22 were ex-smokers, and 24 had never smoked. The respiratory symptoms, which included dyspnea, cough, sputum, wheezing, and fever, were available from the database or medical chart in 54 patients. Dyspnea was present in 31 (57%) patients, cough in 26 (48%), sputum in 17 (31%), wheezing in eight (15%), and fever in five (9%). Several patients had more than two symptoms. Eleven (20%) patients did not have any of these symptoms. Mean duration of disease was 7.6 years ± 9.2.

CT Scanning
CT scans were obtained with one of four units (Somatom Plus 4, Siemens, Erlangen, Germany; TCT-900S, Toshiba Medical Systems, Tokyo, Japan; HiSpeed Advantage or HiSpeed CTi, GE Medical Systems, Milwaukee, Wis). The CT protocol was diverse because of the triinstitutional and retrospective nature of the study. Contiguous scans were obtained with 7- or 10-mm collimation CT through the chest. In 57 of 63 patients, additional thin-section CT scans were obtained with 1- or 2-mm collimation at 10- or 20-mm intervals. Thin-section CT images were reconstructed with a high-spatial-frequency algorithm. CT scans were obtained at suspended end-inspiratory effort with the patients in the supine position and without intravenous contrast material. Additional CT scans were obtained with patients in the prone position (21 patients) and at end expiration (19 patients). All images were obtained at window levels appropriate for lung parenchyma (window width, 1,500 or 1,750 HU; window level, –600 or –700 HU) and mediastinum (window width, 250–400 HU; window level, 40–50 HU).

Interpretation of CT Scans
CT scans were assessed independently in random order by two chest radiologists (N.T., 14 years of experience; J.S.K., 12 years of experience) without knowledge of the patients’ clinical information except that all patients had rheumatoid arthritis. All scans were reviewed by using only hard-copy images. After analysis of interobserver agreement between the two radiologists, the images were reviewed together with a third chest radiologist (D.A.L., 20 years of experience), and the three radiologists reached a final decision with consensus.

Each of the following CT findings was separately coded as present or absent: (a) airspace consolidation; (b) ground-glass opacity (GGO); (c) reticulation (septal lines or nonseptal lines); (d) thickening of bronchovascular bundle; (e) honeycombing; (f) nodules, which included micronodules (<3 mm in diameter), small nodules (3–10 mm in diameter), and large nodules (>10 mm in diameter); (g) emphysema; (h) bullae; (i) bronchiectasis or bronchiolectasis; (j) traction bronchiectasis; (k) crazy-paving appearance (the superimposition of areas of GGO and interlobular or intralobular interstitial thickening); (l) tree-in-bud appearance; (m) mosaic perfusion (a patchwork of regions of inhomogeneous lung attenuation that probably resulted from air trapping or regional differences in lung perfusion); (n) architectural distortion, recognized as the displacement of fissures, bronchi, and vessels; and (o) air trapping, recognized as decreased attenuation of lung parenchyma, which especially manifested as a less than normal increase in attenuation on expiratory images.

Distribution of nodules was recorded as centrilobular, peribronchial, and random. Centrilobular distribution was defined when nodules were identified around peripheral pulmonary arterial branches or 3–5 mm away from the pleura, interlobular septa, or pulmonary veins. Peribronchial distribution was defined when nodules were identified around lobar, segmental, or subsegmental bronchi. Random distribution was defined when nodules did not show either centrilobular or peribronchial distribution and did not show any specific distribution within a secondary pulmonary lobule.

The distribution of pulmonary disease was evaluated according to zones as follows: The upper zones were above the level of the carina, the middle zones lay between the level of the carina and the level of the inferior pulmonary veins, and the lower zones were below the inferior pulmonary veins. The nine CT findings in categories a–i were separately coded as present or absent in the six zones, and thus they defined the vertical distribution of lung changes. The extent of eight CT findings in categories a–h was graded subjectively with a five-point scale within the whole lung field. This scale was as follows: grade 0, the finding was absent; grade 1, the percentage of involvement of the lungs was between 1% and 25%; grade 2, the percentage of involvement was between 26% and 50%; grade 3, the percentage of involvement was between 51% and 75%; and grade 4, the percentage of involvement was more than 76%. The extent of bronchiectasis or bronchiolectasis was graded with a three-point scale, as follows: grade 0, none; grade 1, localized bronchiectasis that affects one bronchopulmonary segment; and grade 2, extensive bronchiectasis that affects two or more segments. The overall distribution of abnormalities in each patient was also defined craniocaudally (as predominance in the upper, middle, or lower zone of the lung and diffuse or indeterminate) and transversely (as peripheral, central, or peribronchial and diffuse or indeterminate).

In each patient, one or two predominant CT patterns (airspace consolidation, GGO, linear-reticular opacity, honeycombing, nodules, emphysema, bronchiectasis or bronchiolectasis, mosaic perfusion, and air trapping) were defined. The most likely CT diagnosis was defined on the basis of previous CT descriptions of these diseases (22–38) (Table 1).


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  		TABLE 1. Summary of CT Features of Interstitial Lung Diseases and Airway Diseases

 
The size of the main pulmonary artery was measured at the widest diameter perpendicular to the long axis of the main pulmonary trunk to detect the presence of pulmonary hypertension, as previously described by Kuriyama et al (39). We regarded the upper limit of normal pulmonary artery diameter as 30 mm. The presence or absence of mediastinal lymph node enlargement was recorded by using criteria defined by Glazer et al (40). Findings of pleural and pericardial effusion or thickening and esophageal dilatation were also recorded.

Pulmonary Function Tests
Spirometry was performed according to American Thoracic Society guidelines (41). Vital capacity, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio, total lung capacity, residual volume, and maximum expiratory flow at 25% of vital capacity were determined, with subjects tested in the seated position within a volume displacement pressure-compensated body plethysmograph. Lung diffusing capacity for carbon monoxide (DLCO) and DLCO corrected for alveolar volume (DLCO/VA) were measured. Except for the FEV1/FVC ratio, all values (eg, vital capacity, total lung capacity, residual volume, maximum expiratory flow at 25% of vital capacity, DLCO, and DLCO/VA) were expressed as a ratio of measured to predicted values (percentage predicted). Measurements were obtained without bronchodilator administration. The patients who did not undergo pulmonary function tests within 2 months of the CT examination were excluded from the evaluation of pulmonary function test results. Vital capacity, FEV1/FVC ratio, total lung capacity, residual volume, maximum expiratory flow at 25% of vital capacity, DLCO, and DLCO/VA were available in 43, 42, 27, 27, 18, 29, and 29 patients, respectively.

Pathologic Findings and Correlation with CT Findings
Seventeen pathologic specimens were available in 16 patients (obtained at 15 surgical biopsies that included open-lung or video-assisted thoracoscopic biopsy and one transbronchial lung biopsy) and in one autopsy case. Correlation between CT findings and pathologic analysis results was possible in these patients. The time from CT examination to pathologic procedure ranged from 6 days to 2 years (median, 27 days). In the five patients in whom the interval between biopsy and CT exceeded 1 month, the main reason was that the CT images obtained at the time of biopsy were not available because those CT images were returned to outside hospitals where patients had undergone CT. In these patients, however, review of the CT reports confirmed that the findings on CT images used for the study were essentially unchanged from those on the images obtained at the time of the biopsy. These CT reports were reviewed by one radiologist (N.T.). CT findings, which included GGO, reticulation, honeycombing, and nodules, were correlated with pathologic findings in 17 patients by the same radiologist and one pulmonary pathologist (C.D.C.).

The pulmonary pathologist assessed the presence, extent, and intensity of findings, which included interstitial inflammation, fibrosis, fibroblastic foci, organization, honeycombing, bronchiolar changes, and vascular changes. She also evaluated the cellularity and spatial or temporal homogeneity of the lesions. The pathologic diagnosis of interstitial pneumonia was made according to the current classification published by the American Thoracic Society and the European Respiratory Society (22). Nonspecific interstitial pneumonia was subclassified according to the classification of Katzenstein and Fiorelli (42): group 1, inflammation without fibrosis; group 2, mixture of inflammation and fibrosis; and group 3, fibrosis alone.

Statistical Analysis
Interobserver agreement between the first two radiologists was assessed by calculating the {kappa} value concerning parenchymal CT findings in categories a–o and other findings including the presence or absence of pulmonary artery enlargement, esophageal dilatation, lymph node enlargement, and pleural and pericardial effusion or thickening. We used the following scale for evaluation of agreement with {kappa} values: 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; greater than 0.81, excellent agreement. Clinical features (age, cigarette consumption), pulmonary function test results (vital capacity, FEV1/FVC ratio, total lung capacity, residual volume, maximum expiratory flow at 25% of vital capacity, DLCO, and DLCO/VA [all except FEV1/FVC ratio expressed as percentage predicted]), and pulmonary artery diameter were compared among groups by using the Fisher protected least significant difference test. Correlation between the extent score of CT findings (airspace consolidation, GGO, reticulation, thickening of bronchovascular bundle, honeycombing, nodules, and bronchiectasis) and results of the same pulmonary function tests just mentioned was estimated with a nonparametric test (Spearman rank correlation coefficient) by using commercially available software (StatView, version 4.5; Abacus Concepts, Berkeley, Calif). A correlation was considered present when there was a difference with a P value of less than .05. These statistical analyses were evaluated after we consulted a statistician at our institution who had 28 years of experience.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
CT Findings
The frequency of CT findings is summarized in Table 2. GGO (91%) and reticulation (98%) were the most frequent findings in patients. Honeycombing (60%), traction bronchiectasis (75%), and architectural distortion (62%) were also frequently seen. Nodules were observed in 31 (49%) patients; these were centrilobular in 23 (37%) patients and indeterminate in eight (13%). There were no cavitated nodules. Interobserver agreement for determination of the CT features was mostly good (moderate to excellent agreement) except for the evaluation of crazy-paving appearance (fair agreement). Four predominant CT patterns were identified: usual interstitial pneumonia (26 patients), nonspecific interstitial pneumonia (19 patients), bronchiolitis (11 patients), and organizing pneumonia (five patients). In the other two patients, imaging diagnoses were diffuse alveolar damage and lymphoid interstitial pneumonia. Enlargement of the pulmonary artery was observed in 26 (46%) of 57 patients in whom the pulmonary artery diameter was measurable. The CT pattern in these 26 patients was usual interstitial pneumonia in 13 patients, nonspecific interstitial pneumonia in 10, organizing pneumonia in one, and bronchiolitis in two.


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  		TABLE 2. Summary of CT Findings according to CT Pattern

 
Usual Interstitial Pneumonia CT Pattern
In the 26 patients with the usual interstitial pneumonia CT pattern, reticulation, honeycombing, and GGO were the most frequent findings. One patient without honeycombing was classified with the usual interstitial pneumonia CT pattern because of subpleural reticulation and the lack of GGO. Reticulation, honeycombing, and areas of GGO were bilateral in most of the cases and showed predominance in the lower zone of the lung (Fig 1). Areas of GGO and reticulation were observed in all lung zones in 11 (42%) and 17 (65%) patients, respectively. The median extent of reticulation and honeycombing was grade 1. The extent of GGO was grade 1 in 22 (85%) patients and grade 2 in two (8%) patients. Traction bronchiectasis and architectural distortion, when present, were always observed concomitantly with reticulation and honeycombing. Consolidation, when present, was minor in extent (grade 1). Nodules were observed in 10 (39%) patients; centrilobular nodules, in four patients; indeterminate nodules, in six patients. Enlargement of the pulmonary artery was seen in 13 (54%) of 24 patients, and the mean diameter of the main pulmonary artery was 30.2 mm ± 4.0. The overall abnormalities were predominant in the lower zone of the lung in 23 (89%) patients. All patients showed peripheral area predominance.



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  		Figure 1a. (a) Transverse thin-section CT scan obtained at level of lower lobe of right lung in 65-year-old man with biopsy-proved usual interstitial pneumonia. Reticulation and honeycombing are seen in posterior subpleural lower lobe of right lung. Small right pneumothorax (*) resulted from video-assisted thoracoscopic biopsy. Both independent chest radiologists classified CT pattern as usual interstitial pneumonia. (b) Photomicrograph of surgical specimen shows extensive interstitial fibrosis with collagen adjacent to large cystic airspace (*). (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 1b. (a) Transverse thin-section CT scan obtained at level of lower lobe of right lung in 65-year-old man with biopsy-proved usual interstitial pneumonia. Reticulation and honeycombing are seen in posterior subpleural lower lobe of right lung. Small right pneumothorax (*) resulted from video-assisted thoracoscopic biopsy. Both independent chest radiologists classified CT pattern as usual interstitial pneumonia. (b) Photomicrograph of surgical specimen shows extensive interstitial fibrosis with collagen adjacent to large cystic airspace (*). (Hematoxylin-eosin stain; original magnification, x40.)

 
Nonspecific Interstitial Pneumonia CT Pattern
In the 19 patients with the nonspecific interstitial pneumonia CT pattern, areas of GGO and reticulation were observed bilaterally in all cases and showed predominance in the lower zone of the lung (Fig 2). However, areas of GGO and reticulation were seen in all lung zones in as many as 13 (68%) and 15 (79%) patients, respectively. The extent of GGO and reticulation were grade 1 in 12 (63%) and 16 (84%) patients, respectively, and grade 2 in seven (37%) and three (16%) patients, respectively. The extent of GGO of a grade higher than grade 2 was more frequent in patients with the nonspecific interstitial pneumonia CT pattern than it was in patients with the usual interstitial pneumonia CT pattern (P = .028, Fisher exact probability test). Honeycombing was seen in 10 (53%) patients, was always bilateral, and showed predominance in the lower zone of the lung. The extent of honeycombing was grade 1 in all 10 patients, which was in keeping with the CT definition of nonspecific interstitial pneumonia. Both traction bronchiectasis and architectural distortion were frequently seen and were bilateral in most of the cases. They were observed concomitantly with reticulation. Nodules were observed in seven (37%) patients: centrilobular nodules in five patients and indeterminate nodules in two patients. Enlargement of the pulmonary artery was seen in 10 (53%) patients. The mean diameter of the main pulmonary artery was 30.0 mm ± 4.7, which was almost identical to that in patients with the usual interstitial pneumonia CT pattern. The abnormalities were predominant in the lower zone of the lung in all cases. Sixteen patients had a predominantly peripheral distribution, and three had a predominantly peribronchial distribution.



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  		Figure 2a. (a) Transverse thin-section CT scan obtained at level of lower lobe of right lung in 64-year-old woman with biopsy-proved nonspecific interstitial pneumonia (Katzenstein and Fiorelli classification group 2). GGO and reticulation are seen in subpleural areas of lower lobe of right lung. Honeycombing is not seen; traction bronchiectasis (arrows) is present. Both independent chest radiologists classified this CT pattern as nonspecific interstitial pneumonia. (b) Photomicrograph of surgical specimen shows thickening of alveolar septa (arrows) with mixture of chronic inflammatory cell infiltrates and fibrosis. Changes appear uniform throughout specimen and indicate spatial homogeneity. (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 2b. (a) Transverse thin-section CT scan obtained at level of lower lobe of right lung in 64-year-old woman with biopsy-proved nonspecific interstitial pneumonia (Katzenstein and Fiorelli classification group 2). GGO and reticulation are seen in subpleural areas of lower lobe of right lung. Honeycombing is not seen; traction bronchiectasis (arrows) is present. Both independent chest radiologists classified this CT pattern as nonspecific interstitial pneumonia. (b) Photomicrograph of surgical specimen shows thickening of alveolar septa (arrows) with mixture of chronic inflammatory cell infiltrates and fibrosis. Changes appear uniform throughout specimen and indicate spatial homogeneity. (Hematoxylin-eosin stain; original magnification, x40.)

 
Bronchiolitis CT Pattern
In the 11 patients with the bronchiolitis CT pattern, nodules and bronchiectasis or bronchiolectasis were the most common findings, which were seen in nine (82%) and 10 (91%) patients, respectively. Nodules were identified as centrilobular micronodules in all nine patients; the nodules were bilateral in eight patients with no zonal predominance and were always seen in patients with bronchiectasis (Fig 3). The extent of nodules was grade 1 in all but one patient. Bronchiectasis was localized in seven patients and extensive in three patients. Bronchiectasis was cylindric in all patients. Bilateral air trapping was observed in all six patients who underwent expiratory CT. The tree-in-bud sign was seen in five (46%) patients. Reticulation, GGO, and airspace consolidation, when present, were typically minor and unilateral. No predominant craniocaudal or transverse distribution was identified.



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  		Figure 3a. Transverse thin-section CT scans obtained at level of lower lobe of right lung in 28-year-old woman with bronchiolitis. (a) Inspiratory scan shows mosaic attenuation (*), centrilobular nodules (arrows), bronchial wall thickening, and cylindric bronchiectasis (arrowheads). FEV1/FVC ratio was 78.7%, and maximum expiratory flow at 25% of vital capacity was 23.3% predicted. Both independent chest radiologists classified CT pattern as bronchiolitis. (b) Expiratory scan shows extensive air trapping (*).

 


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  		Figure 3b. Transverse thin-section CT scans obtained at level of lower lobe of right lung in 28-year-old woman with bronchiolitis. (a) Inspiratory scan shows mosaic attenuation (*), centrilobular nodules (arrows), bronchial wall thickening, and cylindric bronchiectasis (arrowheads). FEV1/FVC ratio was 78.7%, and maximum expiratory flow at 25% of vital capacity was 23.3% predicted. Both independent chest radiologists classified CT pattern as bronchiolitis. (b) Expiratory scan shows extensive air trapping (*).

 
Organizing Pneumonia CT Pattern
In the five patients with the organizing pneumonia CT pattern, airspace consolidation, GGO, reticulation, and centrilobular micronodules were the predominant findings. Airspace consolidation and areas of GGO were bilateral and were located in the subpleural areas in most of the cases and showed no zonal predominance (Fig 4). The extent of airspace consolidation and GGO were grade 1 in two and four patients, respectively, and grade 2 in two patients and one patient, respectively. Thickening of bronchovascular bundle was frequently observed. Centrilobular nodules were observed in all five patients. Four patients showed predominance in the lower lung zone and a craniocaudal distribution. Three patients had a predominantly peripheral distribution, and one had a predominantly peribronchial distribution.



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  		Figure 4a. (a) Transverse thin-section CT scan obtained through lower lung zone in 70-year-old woman with biopsy-proved organizing pneumonia. Multiple patches of consolidation are seen in subpleural area of lung. Both independent chest radiologists classified CT pattern as organizing pneumonia. (b) Photomicrograph of surgical specimen shows numerous polyps (arrows) of granulation tissue within bronchiolar lumina and peribronchiolar airspaces. Interstitial response is observed and consists of thickening of alveolar septa and chronic inflammatory interstitial infiltrates. (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 4b. (a) Transverse thin-section CT scan obtained through lower lung zone in 70-year-old woman with biopsy-proved organizing pneumonia. Multiple patches of consolidation are seen in subpleural area of lung. Both independent chest radiologists classified CT pattern as organizing pneumonia. (b) Photomicrograph of surgical specimen shows numerous polyps (arrows) of granulation tissue within bronchiolar lumina and peribronchiolar airspaces. Interstitial response is observed and consists of thickening of alveolar septa and chronic inflammatory interstitial infiltrates. (Hematoxylin-eosin stain; original magnification, x40.)

 
Other CT Patterns
In one patient who met CT criteria for diffuse alveolar damage, airspace consolidation, GGO, reticulation, and honeycombing were seen in all lung zones. Traction bronchiectasis was also seen bilaterally. The extent of airspace consolidation was grade 2. In one patient with the lymphoid interstitial pneumonia CT pattern, multiple cysts of several centimeters in size were scattered within the lung parenchyma. GGO and reticulation were also seen to a minimal extent.

Pathologic Findings
Pathologic diagnoses in 17 patients included usual interstitial pneumonia in two, nonspecific interstitial pneumonia in 10, organizing pneumonia in two, diffuse alveolar damage in one, desquamative interstitial pneumonia in one, and lymphocytic bronchiolitis in one. Findings of nonspecific interstitial pneumonia were associated with histologic findings of alveolar proteinosis, bronchiolitis obliterans, and lymphocytic bronchiolitis in one, two, and one patient, respectively. Furthermore, the patient with desquamative interstitial pneumonia had associated findings of lymphocytic bronchiolitis. In total, bronchiolitis was seen in five patients.

Pathologic diagnosis was available in four of 26 patients with the usual interstitial pneumonia CT pattern. In two patients, the disease was pathologically diagnosed as usual interstitial pneumonia; in another two patients, the disease was diagnosed as nonspecific interstitial pneumonia (Fig 5). In the two patients with biopsy-proved usual interstitial pneumonia, bandlike dense fibrosis or fibrous thickening of interlobular septa and subpleural cystic airspaces were seen in lung specimens (Fig 1).



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  		Figure 5a. (a) Transverse thin-section CT scan obtained at level of lower lobe of left lung in 67-year-old man with biopsy-proved nonspecific interstitial pneumonia (Katzenstein and Fiorelli classification group 3). Mixed areas of GGO and reticular abnormalities (arrows) are seen extensively. Honeycombing and traction bronchiectasis (arrowheads) are well demonstrated. Both chest radiologists classified CT pattern as usual interstitial pneumonia because of presence of moderate honeycombing. (b) Photomicrograph of surgical specimen shows interstitial thickening with deposition of dense collagen and honeycombing (*). Because of temporal homogeneity and lack of conspicuous fibroblastic foci, pathologic diagnosis was nonspecific interstitial pneumonia. (Hematoxylin-eosin stain; original magnification, x40.)

 


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  		Figure 5b. (a) Transverse thin-section CT scan obtained at level of lower lobe of left lung in 67-year-old man with biopsy-proved nonspecific interstitial pneumonia (Katzenstein and Fiorelli classification group 3). Mixed areas of GGO and reticular abnormalities (arrows) are seen extensively. Honeycombing and traction bronchiectasis (arrowheads) are well demonstrated. Both chest radiologists classified CT pattern as usual interstitial pneumonia because of presence of moderate honeycombing. (b) Photomicrograph of surgical specimen shows interstitial thickening with deposition of dense collagen and honeycombing (*). Because of temporal homogeneity and lack of conspicuous fibroblastic foci, pathologic diagnosis was nonspecific interstitial pneumonia. (Hematoxylin-eosin stain; original magnification, x40.)

 
Pathologic diagnosis was available in eight of 19 patients with the nonspecific interstitial pneumonia CT pattern, and findings in these eight patients were available for pathologic review. Seven of eight patients had histologically proved nonspecific interstitial pneumonia. One patient with the lymphoid interstitial pneumonia CT pattern and two patients with the usual interstitial pneumonia CT pattern proved to have nonspecific interstitial pneumonia at pathologic analysis (surgical biopsy). Therefore, in total, biopsy-proved nonspecific interstitial pneumonia was identified in 10 patients. The nonspecific interstitial pneumonia was graded according to the Katzenstein and Fiorelli classification as follows: group 1, one patient; group 2, five patients; and group 3, four patients. In all patients with biopsy-proved nonspecific interstitial pneumonia, pathologic thickening of alveolar septa caused by interstitial inflammation and/or fibrosis (Fig 2) was observed. GGO and reticulation were observed in all 10 patients. All five patients with honeycombing at CT had subpleural cystic airspaces at biopsy. The diameter of cystic airspaces at biopsy was greater in patients with the group 3 classification than in those with the group 2 classification.

Airspace consolidation was observed at CT in two patients with biopsy-proved nonspecific interstitial pneumonia; both patients had group 2 classification nonspecific interstitial pneumonia, with dense fibrosis or honeycombing containing mucin. Lymphoid follicles were observed histologically in three of four patients with nodules at thin-section CT. Two patients with biopsy-proved nonspecific interstitial pneumonia (one with group 2 classification and the other with group 3 classification) were classified with the usual interstitial pneumonia CT pattern and showed extensive reticulation within areas of GGO and subpleural honeycombing, although areas of GGO were more conspicuous than they were in typical cases of usual interstitial pneumonia (Fig 5).

In patients with histologically proved usual interstitial pneumonia and nonspecific interstitial pneumonia, honeycombing was observed in two (100%) and five (50%) patients, respectively; reticulation was observed in all patients. Areas of GGO were also observed in all patients with histologically proved usual interstitial pneumonia and nonspecific interstitial pneumonia. There was a difference, however, in the extent of GGO between the two groups; GGO was observed in all lung zones in seven patients with histologically proved nonspecific interstitial pneumonia and in none with histologically proved usual interstitial pneumonia. This difference was not significant (P = .152, Fisher exact probability test).

Among 11 patients with the bronchiolitis CT pattern, correlation between CT findings and pathologic findings was available in one patient who received a histologic diagnosis of lymphocytic bronchiolitis. Centrilobular nodules at thin-section CT appeared to reflect marked lymphocyte infiltration without germinal centers surrounding the bronchioles. A pathologic diagnosis was available in two of five patients with the organizing pneumonia CT pattern. Airspace consolidation in one patient was associated with histologic findings of extensive organizing pneumonia and concomitant fibrosis (Fig 4). In another patient in whom the predominant finding was GGO, the histologic findings were patchy organizing pneumonia and fibrotic alveolar septal thickening, with preservation of alveolar spaces. One patient with the CT pattern of diffuse alveolar damage proved to have organizing diffuse alveolar damage at pathologic analysis of a specimen. One patient with the lymphoid interstitial pneumonia CT pattern due to perivascular cysts proved to have cellular nonspecific interstitial pneumonia (group 1 classification) associated with constrictive bronchiolitis. It was unclear whether or not the cystic airspaces identified at CT were caused by bronchial obstruction.

Assessment of Patient Characteristics and Pulmonary Function Test Results
The age distribution according to sex and CT pattern (usual interstitial pneumonia, nonspecific interstitial pneumonia, bronchiolitis, and organizing pneumonia) was evaluated by using the two-factor factorial analysis of variance method. This analysis showed that the differences in sex (P = .445) and CT pattern (P = .095) did not significantly influence the age distribution. In this study, female predominance was seen with the nonspecific interstitial pneumonia and bronchiolitis CT patterns, which contributed to the female predominance in the total cases. In regard to the duration of rheumatoid arthritis, patients with the bronchiolitis CT pattern had longer duration of rheumatoid arthritis than did those with the usual interstitial pneumonia and organizing pneumonia CT patterns (Table 3).


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  		TABLE 3. Patient Characteristics and Pulmonary Function Test Results in Each Group

 
Because of the retrospective nature of the study, the number of patients who underwent each type of physiologic test was variable. The physiologic indices that showed air flow obstruction (FEV1/FVC ratio and maximum expiratory flow at 25% of vital capacity [expressed as percentage predicted]) in patients with the bronchiolitis CT pattern tended to show more impairment than they did in patients with the other CT patterns. The physiologic indices of vital capacity, DLCO, and DLCO/VA (expressed as percentage predicted) in patients with the bronchiolitis CT pattern tended to show less impairment than they did in patients with the other CT patterns. There was no significant difference in physiologic indices among patients with the usual interstitial pneumonia, nonspecific interstitial pneumonia, and organizing pneumonia CT patterns. With regard to the correlation between the extent of CT findings and pulmonary function test results, significant correlations were observed between GGO and FEV1/FVC ratio, between reticulation and vital capacity (expressed as percentage predicted) or the FEV1/FVC ratio, and between bronchiectasis and FEV1/FVC ratio (Table 4).


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  		TABLE 4. Correlation between CT Findings and Pulmonary Function Test Results

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
REFERENCES
 
Since the introduction of the concept of nonspecific interstitial pneumonia by Katzenstein and Fiorelli (42) in 1994, it has been known that nonspecific interstitial pneumonia is frequently associated with collagenous vascular disease. In their article, these authors found collagenous vascular disease in 16% of patients with nonspecific interstitial pneumonia. In a review of pathologic findings in 40 patients with rheumatoid arthritis who underwent open-lung biopsy, Yousem et al (20) found cellular interstitial pneumonia as a primary or secondary lesion, which seemed identical to nonspecific interstitial pneumonia, in 10 patients.

In our study, the nonspecific interstitial pneumonia CT pattern was observed in 19 (30%) patients, whereas the histologic finding of nonspecific interstitial pneumonia was identified in 10 (59%) of the 17 patients in whom biopsy findings were available. Our study findings, therefore, confirm the high prevalence of nonspecific interstitial pneumonia as a histologic and CT finding in rheumatoid disease. The common CT findings of nonspecific interstitial pneumonia are bilateral areas of GGO, with a predominant distribution in the peripheral or subpleural area in the lower zone of the lung (22–25,29,30), and associated reticular abnormalities. These findings are thought to occur in at least 80% of patients (23). Honeycombing is not frequently seen and is sparse when present. In the current study, areas of GGO were more extensive with the nonspecific interstitial pneumonia CT pattern than they were with the usual interstitial pneumonia CT pattern. In our study, the finding of honeycombing was more frequently observed than it was in the previous reports of Remy-Jardin et al (4) and Akira et al (6) (Table 5), which raises the possibility that some patients may have had mixed usual interstitial pneumonia and nonspecific interstitial pneumonia patterns.


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  		TABLE 5. Comparison of CT Findings in Current and Previous Studies of Patients with Rheumatoid Arthritis

 
GGO, reticulation, traction bronchiectasis, and architectural distortion were all more frequently observed than they were in either of the previous studies (Table 5). The higher prevalence of these findings in the current study may be caused by referral bias, since many of the patients in our series were seen at an interstitial lung disease clinic. Remy-Jardin et al (4) and Akira et al (6) stressed that bronchial and bronchiolar changes, which included bronchiectasis, centrilobular nodules, or the tree-in-bud pattern, were the most prevalent lung lesions in patients with rheumatoid arthritis. In the current study, centrilobular micronodules were observed in 23 (37%) of 63 patients, but bronchiectasis and the tree-in-bud sign were less frequent than they were in the patients in the study of Akira et al (Table 5). The reason for the lower frequency of the tree-in-bud pattern in our study is unknown, but it may be related to differing criteria for distinguishing between centrilobular nodules and the tree-in-bud pattern. The lower frequency of bronchiectasis in the patients in our study was probably because the group with bronchiectasis in the study of Akira et al clearly included 13 patients with traction bronchiectasis, as well as two with pure bronchiectasis.

As found in our study, the characteristic CT findings of usual interstitial pneumonia include the reticular pattern and honeycombing with subpleural or peripheral distribution and lower lung zone predominance (22–25). Traction bronchiectasis and architectural distortion are also frequent findings. There was considerable overlap in the frequency of individual CT findings in patients with nonspecific interstitial pneumonia and usual interstitial pneumonia CT patterns in our study. Frequent and characteristic findings in both groups included GGO and reticulation. Honeycombing was also seen in 53% of patients with the nonspecific interstitial pneumonia CT pattern in the current study. The only effective differential point seemed to be the distribution and extent of GGO; GGO was seen more diffusely and extensively in patients with histologically proved nonspecific interstitial pneumonia than they were in patients with usual interstitial pneumonia. There were two discrepant cases, however, in which patients were classified as having the usual interstitial pneumonia CT pattern, but at pathologic analysis of the specimens the cases proved to be nonspecific interstitial pneumonia.

There have been several other reports that showed a difficulty in discrimination between some cases of usual interstitial pneumonia and those of nonspecific interstitial pneumonia at CT because of overlapping findings (30,43). It is speculated that the biopsy-proved cases with the usual interstitial pneumonia CT pattern might have been selected for biopsy because of confusing or overlapping CT findings. Patients with CT features typical of usual interstitial pneumonia rarely undergo surgical biopsy. The discrepancy between the CT pattern and pathologic diagnosis may reflect the difficulty in discrimination between usual interstitial pneumonia and fibrotic nonspecific interstitial pneumonia both on CT images and in pathologic specimens (14,22,24,29,43).

MacDonald et al (30) stressed the difficulty in correct diagnosis of usual interstitial pneumonia and nonspecific interstitial pneumonia because of considerable overlap in thin-section CT appearances. They reported that a misdiagnosis of usual interstitial pneumonia in patients with biopsy-proved nonspecific interstitial pneumonia was associated with coarse fibrosis (honeycombing). Although the frequency of honeycombing in patients with nonspecific interstitial pneumonia has been reported as relatively rare, CT images obtained in patients with it can show honeycombing. This finding was relatively frequent in the current study. The finding of histologic desquamative interstitial pneumonia in one patient with the nonspecific interstitial pneumonia CT pattern is not surprising, as both conditions are characterized at CT by a predominance of GGO. Differentiation between nonspecific interstitial pneumonia and desquamative interstitial pneumonia, however, is usually not critical because the prognosis of both conditions is similar.

Organizing pneumonia shows bilateral areas of airspace consolidation with or without areas of GGO, with a subpleural or peribronchial distribution at CT in the majority of cases (22–28,44). Centrilobular nodules, branching structures, and multiple large nodules have been reported. The current study also showed similar findings. Types of bronchiolitis commonly seen in rheumatoid arthritis are bronchiolitis obliterans and follicular bronchiolitis. The common thin-section CT abnormalities of bronchiolitis obliterans consist of patchy areas of air trapping, bronchial dilatation, and centrilobular nodules with branching linear structures (36–38). Follicular bronchiolitis is characterized by centrilobular micronodules and branching structures at thin-section CT (14). In the current study, it is not clear which histologic pattern was present in 11 patients with the bronchiolitis CT pattern because only one patient underwent surgical biopsy.

In the current study, patients with the usual interstitial pneumonia, nonspecific interstitial pneumonia, and organizing pneumonia CT patterns showed some evidence of airway disease, such as centrilobular micronodules, mosaic perfusion, and air trapping. Conversely, evidence of interstitial disease, such as GGO and reticulation, was seen in patients with the bronchiolitis CT pattern. Also, eight patients with the usual interstitial pneumonia and six patients with the bronchiolitis CT patterns had associated airspace consolidation, a finding that suggested organizing pneumonia. These results show that several kinds of pathologic conditions can coexist in one patient with rheumatoid arthritis. Yousem et al (20) also reported a wide variety of pathologic findings and a multiplicity of lesions in individual cases.

In our study, multiple conditions coexisted in several specimens in the limited number of patients with biopsy-proved cases. The multiplicity of CT patterns in patients with rheumatoid arthritis and other collagenous vascular diseases might help differentiate these patients from those with idiopathic diffuse lung disease. In these patients, CT may be of substantial value in identification of the dominant pattern of abnormality. Enlargement of the pulmonary artery was a rather frequent finding in the current study. This result is different from findings in previous studies that showed that pulmonary hypertension is rare (2,11). Among 26 patients with pulmonary hypertension, however, 10 patients had the nonspecific interstitial pneumonia CT pattern, 13 patients had the usual interstitial pneumonia CT pattern, and one patient had the organizing pneumonia CT pattern. The cause of pulmonary hypertension in these patients might have been interstitial lung disease. Only two patients showed pulmonary hypertension without evidence of interstitial pneumonia, such as honeycombing. Furthermore, pulmonary hypertension is not a rare feature in patients with rheumatoid arthritis.

In regard to the correlation between pulmonary function test results and the extent of CT findings, the extent of reticulation was correlated with vital capacity (expressed as percentage predicted), which suggests that this is a valid reflection of the amount of restrictive physiologic impairment. Conversely, the extent of bronchiectasis was correlated with the FEV1/FVC ratio, which suggests that this reflects airflow impairment. Although rheumatoid arthritis is less common in men than in women, several study results indicate that pulmonary complications are more common in men (1,2). Our study findings indicated an overall predominance of women, which was mainly due to a predominance of women among the patients with the nonspecific interstitial pneumonia and bronchiolitis CT patterns. The reason for the female predominance in those with the nonspecific interstitial pneumonia CT pattern is unclear. Shadick et al (19) reported that severe bronchiectasis predominantly occurs in female patients, and our study results suggest that this female predominance also extends to bronchiolitis.

There were several limitations of this study. The sample size of this study might be too small to allow confident detection of some correlations in the Results section, because we studied all available patients who met the eligibility criteria for rheumatoid arthritis, and a power analysis was not performed. Because pathologic confirmation was not available in all 63 patients, it is unclear whether the classification that was based on CT findings really reflects the pathologic classification. In particular, it is likely that some cases of usual interstitial pneumonia and nonspecific interstitial pneumonia were misclassified. However, it is not practical in clinical medicine to determine the diagnosis in all patients by means of surgical biopsy, especially in those patients who have typical clinical and thin-section CT features of usual interstitial pneumonia. A further limitation was that a precise correlation between radiologic findings and pathologic findings was not possible because the site of biopsy was not identified. Because of the retrospective nature of this study, clinical information, pulmonary function test results, or expiratory CT scans were not available in all patients. More patients with air trapping would have been detected if expiratory CT scans were obtained in all patients.

In conclusion, GGO or reticulation was the most common CT finding in 63 patients with rheumatoid arthritis–related lung disease, and a classification that was based on CT features was largely successful for prediction of the histologic diagnosis; however, a multiplicity of CT patterns is commonly seen in patients with rheumatoid arthritis.


   ACKNOWLEDGMENTS
 
The authors thank Martin E. Wallace, HTBS, National Jewish Center for Immunology and Respiratory Medicine, for his assistance in collecting pathologic specimens, Mario Lujan, Department of Radiology at the National Jewish Center for Immunology and Respiratory Medicine, for his assistance in collecting CT scans, and Noriaki Harada, MD, PhD, for his assistance in statistical data analysis.


   FOOTNOTES
 
Abbreviations: DLCO = lung diffusing capacity for carbon monoxide, DLCO/VA = DLCO corrected for alveolar volume, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, GGO = ground-glass opacity

Author contributions: Guarantors of integrity of entire study, N.T., D.A.L.; study concepts, N.T., D.A.L., J.D.N.; study design, N.T., T.M.; literature research, N.T., T.E.; clinical studies, T.E., R.M., C.D.C., K.K.B., J.S.K.; data acquisition, N.T., T.E., R.M., K.K.B., J.S.K.; data analysis/interpretation, N.T., K.K.B., J.S.K., C.D.C., T.M., D.A.L.; statistical analysis, N.T., D.A.L.; manuscript preparation, N.T.; manuscript definition of intellectual content, D.A.L., J.D.N., T.E., R.M., K.K.B.; manuscript editing, N.T., D.A.L., T.M.; manuscript revision/review and final version approval, all authors


   REFERENCES
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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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