Histopathologic Pattern and Clinical Features of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Histopathologic Pattern and Clinical Features of Rheumatoid ArthritisAssociated Interstitial Lung Disease* Hyun-Kyung Lee, MD; Dong Soon Kim, MD; Bin Yoo, MD; Joon Beom Seo, MD; Jae-Yoon Rho, MD; Thomas V. Colby, MD; and Masanori Kitaichi, MD

Study objectives: To investigate the histopathologic pattern and clinical features of patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) according to the American Thoracic Society (ATS)/European Respiratory Society consensus classification of idiopathic interstitial pneumonia. Design: Retrospective review. Setting: Two thousand-bed, university-affiliated, tertiary referral center. Patients: Eighteen patients with RA who underwent surgical lung biopsy (SLBx) for suspected ILD. Method: SLBx specimens were reviewed and reclassified by three lung pathologists according to the ATS/European Respiratory Society classification. Clinical features and follow-up courses for the usual interstitial pneumonia (UIP) pattern and the nonspecific interstitial pneumonia (NSIP) pattern were compared. Results: The histopathologic patterns were diverse: 10 patients with the UIP pattern, 6 patients with the NSIP pattern, and 2 patients with inflammatory airway disease with the organizing pneumonia pattern. RA preceded ILD in the majority of patients (n ⴝ 12). In three patients, ILD preceded RA; in three patients, both conditions were diagnosed simultaneously. The majority (n ⴝ 13) of patients had a restrictive defect with or without low diffusion capacity of the lung for carbon monoxide (DLCO) on pulmonary function testing; 2 patients had only low DLCO. The UIP and NSIP groups were significantly different in their male/female ratios (8/2 vs 0/6, respectively; p ⴝ 0.007) and smoking history (current/former or nonsmokers, 8/2 vs 0/6; p ⴝ 0.007). Many of the patients with the UIP pattern had typical high-resolution CT features of UIP. Five patients with the UIP pattern died, whereas no deaths occurred among patients with the NSIP pattern during median follow-up durations of 4.2 years and 3.7 years, respectively. Conclusions: The histopathologic type of RA-ILD was diverse; in our study population, the UIP pattern seemed to be more prevalent than the NSIP pattern. (CHEST 2005; 127:2019 –2027) Key words: bronchiolitis; nonspecific interstitial pneumonia; prognosis; rheumatoid arthritis; surgical lung biopsy; usual interstitial pneumonia Abbreviations: ATS ⫽ American Thoracic Society; CVD ⫽ collagen vascular disease; Dlco ⫽ diffusion capacity of the lung for carbon monoxide; FB ⫽ follicular bronchiolitis; GGO ⫽ ground-glass opacity; HRCT ⫽ high-resolution CT; IAD ⫽ inflammatory airway disease; IIP ⫽ idiopathic interstitial pneumonia; ILD ⫽ interstitial lung disease; NSIP ⫽ nonspecific interstitial pneumonia; OP ⫽ organizing pneumonia; PFT ⫽ pulmonary function test; RA ⫽ rheumatoid arthritis; SLBx ⫽ surgical lung biopsy; UIP ⫽ usual interstitial pneumonia

lung disease (ILD) is one of the sysI nterstitial temic manifestations of collagen vascular disease (CVD), and ILD associated with CVD (CVD-ILD) was reported to have a better prognosis than the idiopathic type of ILD.1 According to the recent *From the Division of Pulmonary and Critical Care Medicine (Drs. Lee and Kim), Rheumatology (Dr. Yoo), the Department of Radiology (Dr. Seo), and the Department of Pathology (Dr. Rho), Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; Department of Pathology (Dr. Colby), Mayo Clinic, Scottsdale, AZ; and Laboratory of Anatomic Pathology (Dr. Kitaichi), Kyoto University Hospital, Kyoto, Japan. www.chestjournal.org

American Thoracic Society (ATS)/European Respiratory Society consensus classification, idiopathic interstitial pneumonias (IIPs) include seven clinicoradiologic-pathologic entities: idiopathic pulmonary Manuscript received April 16, 2004; revision accepted December 9, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Dong Soon Kim, MD, Asan Medical Center, University of Ulsan, College of Medicine, 388-1, Poongnap-dong, Songpa-ku, Seoul, Korea 138-73; e-mail: [email protected] CHEST / 127 / 6 / JUNE, 2005

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fibrosis (IPF), usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, and lymphoid interstitial pneumonia.2 Although NSIP was considered to be a provisional diagnosis at that time, it can be distinguished from UIP by temporal uniformity in fibrotic processes, and many reports3– 4 have suggested a better prognosis for the NSIP pattern than for the UIP pattern. Several reports5–7 have suggested that NSIP is a major histopathologic pattern in CVD-ILD. Bouros et al5 and our group6 reported that NSIP was the predominant pathologic pattern in scleroderma (77% and 63%, respectively) on surgical lung biopsy (SLBx). Douglas and colleagues7 also published similar results for dermatomyositis-polymyositis, and the situation is similar for Sjo¨gren syndrome.8 Although rheumatoid arthritis (RA) is the most common type of CVD, there are no reports of the histopathologic pattern of RA-associated ILD (RA-ILD) after the 1994 description of NSIP.9 Approximately 20 years ago, Yousem and colleagues10 reported the findings of lung biopsies from patients with RA. However, only a few patients with ILD were included in that study, and the current classification system for ILD was not available at that time. To investigate the histopathologic patterns of RA-ILD and their correlation with clinical features and outcome, we reviewed and reclassified SLBx specimens in the context of the recent classification of IIPs.2

Clinical and Laboratory Test Results All the clinical data were obtained from medical records, which included the history, physical examination results, laboratory test results, and clinical outcomes. Histopathologic Diagnosis Three lung pathologists (M.K., T.V.C., and J.Y.R.) reviewed lung biopsy slides independently, and the histology was classified according to the new ATS/European Respiratory Society consensus criteria for IIPs.2 Consensus diagnoses were made by these pathologists in cases of disagreement. The pattern of UIP was distinguished by a temporally heterogeneous pattern of fibrosis (ie, a variation in the age of fibroses, with fibroblastic foci, an area of spindle cells with plump cytoplasm and little intervening collagen immediately adjacent to areas of established fibrosis). In addition, the subpleural dominant distribution of fibrotic lesion and honeycombing were considered to be important to the histologic diagnosis of UIP. In NSIP, fibrosis and inflammation were either patchy or more commonly diffuse, but the pattern of lung injury remained temporally uniform. NSIP was subdivided into three groups: NSIP group 1, primarily with interstitial inflammation; group 2, with both inflammation and fibrosis; and group 3, primarily with fibrosis. High-Resolution CT of the Chest High-resolution CT (HRCT) was performed (HiSpeed Advantage Scanner; GE Medical Systems; Milwaukee, WI; or Somatom Plus 4 Scanner; Siemens Medical Systems; Erlangen, Germany), and the images were analyzed at a window level of – 700 Hounsfield units and a window width of 1,500 Hounsfield units. HRCT of the lungs was reviewed by one radiologist (J.B.S.) and interpreted without knowledge of the biopsy results or clinical outcomes. The HRCT findings were arbitrarily classified into five groups according to the predominant features: consolidation, ground-glass opacity (GGO), GGO with reticular opacity, reticular opacity with honeycombing, and nodular opacity. Pulmonary Function Tests

Materials and Methods Patients This is a retrospective study performed at Asan Medical Center, a 2,000-bed, university-affiliated, tertiary referral center in Seoul, Korea. A computer-aided search revealed 42 patients with an RA-ILD diagnosis from January 1991 to November 2002; 18 of these patients underwent SLBx. We have had a policy of performing SLBx on all patients with clinically significant diffuse lung diseases to get a definitive diagnosis. The major reason we could not perform the SLBx was that patients refused to undergo the invasive procedure. All patients met the revised criteria of the American College of Rheumatology for RA.11 Patients with Sjo¨gren syndrome or other coexisting CVDs were excluded. Twelve patients attended the pulmonary division due to respiratory symptoms such as shortness of breath or chronic cough, and others were first seen by rheumatologists and were then referred to pulmonologists. Follow-up was charted to death or to May 31, 2003. Lung biopsies were performed by thoracotomy or videoassisted thoracoscopy, and specimens were obtained from two or more lobes in every patient. This study was approved by the Institutional Review Board of the Asan Medical Center. 2020

Results of pulmonary function tests (PFTs) performed using ATS guidelines were expressed as percentage of predicted values.12 Spirometry was performed with a SensorMedics 2100 (SensorMedics; Yorba Linda, CA), diffusion capacity of the lung for carbon monoxide (Dlco) was measured with a V˙max 22 (SensorMedics), and total lung capacity was measured using an Auto Box 6200 (SensorMedics). Improvement or deterioration were defined as more than a 10% change in FVC or total lung capacity, and a ⬎ 15% change in Dlco.13 BAL BAL was performed as previously described.6 Statistical Analysis Analyses were performed using software (SPSS for Windows, Release 10.0.7; SPSS; Chicago, IL). Data are expressed as means ⫾ SD for continuous variables, percentages for categorical variables, or medians (ranges). The Mann-Whitney U test was used to compare the UIP and NSIP groups. In all cases, two-sided tests were used with p values ⬍ 0.05 to denote statistical significance. Clinical Investigations

Results Histologic Diagnosis The ␬ coefficient of agreement between the pathologists (M.K. and T.V.C. for example) for the differentiation of UIP and NSIP patterns was 0.63. The most frequent histopathologic pattern was UIP (55.6%) [Table 1; Fig 1]. The NSIP pattern was found in six patients (mixed cellular and fibrotic NSIP in two patients, fibrotic NSIP in four patients) [Fig 2], and inflammatory airway disease (IAD) combined with an organizing pneumonia (OP) pattern were seen in two patients. One patient with IAD exhibited follicular bronchiolitis (FB) [Fig 3], and the other patient with IAD exhibited chronic nonspecific bronchiolitis. Clinical Features and Laboratory Findings Clinical Features of the Subjects: Of the 18 patients, all 8 male patients were current or former smokers, whereas all 10 female patients were nonsmokers (Table 2). The majority of patients complained of respiratory symptoms. In the majority of the cases, RA was diagnosed before the detection of ILD; in three patients, ILD preceded the diagnosis of RA (1.6 years, 2.5 years, and 7 years, respectively). At the time of biopsy, impairment of pulmonary function was a predominantly restrictive type with or without low Dlco (Table 2). The FVC and Dlco were reduced in 13 of 18 patients. Comparison of the Clinical Features Between the Patients With or Without SLBx: Because SLBx was performed in 18 of the 42 RA-ILD patients, we compared the clinical and radiologic features between the 24 patients without SLBx and the study subjects of 18 patients with SLBx to exclude the possibility of selection bias. Even though the non-biopsy group was slightly older than the biopsy group, no significant difference was found in the clinical features between these two groups (Table 2).

Figure 1. A case of UIP, with patchy involvement of interstitial fibrosis and inflammation with fibrous foci at the edges of dense scar, alternating with relatively normal lung parenchyma (hematoxylin-eosin, original ⫻ 40).

Comparison of the Clinical Features Between the Patients With UIP and NSIP Patterns at SLBx: The gender distribution and smoking histories differed significantly between two groups (p ⬍ 0.05) [Table 3]. All male patients had the UIP pattern, and all patients in the NSIP group were female. The mean FVC and Dlco of the UIP group at the time of biopsy were slightly lower than those of NSIP group, but the difference was not statistically significant. Arterial blood gas data did not show significant differences between the two groups. BAL fluid data were available in 14 patients (UIP, n ⫽ 7; NSIP, n ⫽ 5; and IAD, n ⫽ 2). The mean percentage of neutrophils, lymphocytes, and eosino-

Table 1—Histopathologic Diagnosis of the SLBx Specimens From 18 Patients With RA-ILD Histopathologic Diagnosis

Subjects, No. (%)

UIP pattern NSIP pattern Mixed cellular and fibrotic Fibrotic IAD with OP pattern FB Chronic nonspecific bronchiolitis

10 (55.6) 6 (33.3) 2 (11.1) 4 (22.2) 2 (11.1) 1 1

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Figure 2. A case of NSIP, with marked thickening of the alveolar walls by fibrosis and inflammatory cell infiltration. Note the temporal uniformity without fibrous foci (hematoxylin-eosin, original ⫻ 20). CHEST / 127 / 6 / JUNE, 2005

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multiple small nodules (Fig 5) in the whole lung field in addition to multiple consolidations. A majority (87.5%) of the patients with RA-ILD who did not undergo SLBx showed typical HRCT findings for UIP. According to the ATS statement on IPF,13 if the HRCT findings are typical for IPF/UIP, IPF can be diagnosed without SLBx in an appropriate clinical setting. Therefore, the predominance of typical HRCT findings for UIP in the non-biopsy group strongly supports the finding of higher prevalence of UIP pattern in the biopsy specimens of RA-ILD. Comparison of Clinical Courses Between Patients With UIP and NSIP Patterns

Figure 3. A case of FB, with inflammatory cell infiltration in the bronchial walls and lumens associated with lymphoid follicle formation (top: hematoxylin-eosin, original ⫻ 10; bottom: hematoxylin-eosin, original ⫻ 40).

phils in BAL fluid did not differ significantly between these three groups (Table 4). Elevated neutrophils (⬎ 5%) were found in four of seven patients with the UIP pattern and in two of five patients with the NSIP pattern, in contrast to increased lymphocytes (⬎ 20%) in five of seven patients with the UIP pattern and four of five patients with the NSIP pattern. Radiologic Findings HRCT findings of all patients were reviewed. Similar to the IPF/UIP, all patients with the UIP pattern had typical reticular opacities with honeycombing predominantly in subpleural area (Fig 4), except one patient who had GGO to the same extent as reticular opacity (Table 5). Patients with the NSIP pattern showed predominant GGO or GGO with some reticular opacity. One patient with IAD and OP pattern showed mainly multiple patchy consolidations, and the other patient showed predominantly 2022

The median durations of follow-up were 4.2 years in UIP patients and 3.7 years in NSIP patients. As shown in Table 6, death occurred only in the UIP group (5 of 10 patients). One patient died of acute exacerbation of pulmonary fibrosis, three patients died of steady progression of lung disease, and the last patient died of presumably infectious pneumonia during corticosteroid treatment. One patient with the UIP pattern had an acute exacerbation with newly developed diffuse GGOs during steroid tapering. All culture findings including BAL examination for Pneumocystis carinii and viruses were negative, and the patient died 1 month later. Four patients in the UIP group initially refused to undergo lung biopsy or treatment when the clinical and radiographic evidence of RA-ILD was apparent first. They revisited the hospital (mean, 28.2 ⫾ 18.8 months later) due to aggravation of pulmonary symptoms. Lung functions were severely reduced (mean FVC change, 31.0 ⫾ 14.5% of predicted), and SLBx was performed at that time. In spite of corticosteroid therapy, conditions steadily progressed at the same speed as prior to biopsy, and three patients among them died several months (mean, 5 months) after biopsy. One remaining patient was in stable condition for 26 months after SLBx. Among the total 10 patients with the UIP pattern, lung function improved in 2 patients, stabilized in 3 patients, and worsened in 4 patients during follow-up. Of the six patients with the NSIP pattern, four were treated. All patients improved or were had stable lung function except one, whose FVC was slightly reduced (from 67 to 58% predicted). One of nontreated patients had ILD diagnosed 15 years previously, and RA developed 7 years later. Her respiratory symptoms and pulmonary function did not change significantly for 15 years. Discussion This study shows that the distribution of histopathologic patterns in RA-ILD was different than Clinical Investigations

Table 2—Comparison of the Clinical and Radiologic Features Between the Patients Who Underwent SLBx and Those Who Did Not* Variables

Underwent SLBx

Did Not Undergo SLBx

Male/female gender, No. Mean age, yr Smoking history, No. Never Current/former Respiratory symptom Exertional dyspnea Cough Clubbing Duration of symptoms before admission, mo Mean ⫾ SD Range Sequence of diagnosis RA first, No. (%) Mean duration of RA, yrs ILD first Simultaneously Pulmonary function† Restrictive pattern with low Dlco Restrictive pattern Restrictive pattern with normal Dlco Low Dlco Obstructive pattern with low Dlco Normal lung function FVC (% predicted) FEV1 (% predicted) FEV1/FVC (%) Dlco (% predicted) HRCT Consolidation GGO Reticulation plus GGO Reticulation plus honeycombing Nodular opacity

8/10 60.3 ⫾ 7.3

12/12 65.8 ⫾ 9.3

10 8

13 11

16 (88.9) 17 (94.4) 5 (27.8)

19 (79.2) 20 (83.3) 2 (8.3)

18.1 ⫾ 44.2 (0.3–180)

15.8 ⫾ 17.9 (1–60)

12 (66.7) 11.9 ⫾ 9.9 3 (16.7) 3 (16.7)

16 (66.7) 10.4 ⫾ 8.0 0 8 (33.3)

11 0 2 2 0 3 65.3 ⫾ 19.6 74.6 ⫾ 20.4 83.6 ⫾ 7.1 62.9 ⫾ 25.3

16 1 0 3 1 1 67.1 ⫾ 17.3 80.5 ⫾ 20.4 85.3 ⫾ 8.7 53.1 ⫾ 17.0

1 (5.6) 3 (16.7) 4 (22.2) 9 (50) 1 (5.6)

1 (4.1) 1 (4.1) 1 (4.1) 21 (87.5) 0

*Data are presented as No. (%) unless otherwise indicated. †PFT data of two patients of non-biopsy group were not available.

in other types of CVD-ILD, with the UIP pattern being more prevalent than NSIP pattern. We also found that IAD was one of important manifestations in RA patents, as reported in previous studies.14 –17 Death occurred only in the UIP group, and all patients with NSIP were alive and improved or stable in this small series. Our finding of a more prevalent UIP pattern in RA compared to the NSIP pattern or IAD with the OP pattern contrasted with data suggesting NSIP as the major histopathologic pattern in CVD-associated pulmonary fibrosis.5– 8 This also suggests that the various CVDs cannot be “lumped together” when considering patterns of lung pathology. In the report of Bouros et al5 in 2002, NSIP comprised 77.5% of systemic sclerosis-associated pulmonary fibrosis, and NSIP was 68.4% in our series.6 However, previous studies suggested that UIP was predominant in RA-ILD patients. In the study by Akira et al18 of 29 www.chestjournal.org

patients with RA-associated lung disease, three groups were identified on the basis of the predominant CT pattern; 10 patients had reticulation and honeycombing and likely had the UIP pattern, although histopathologic diagnoses were made for only a few patients. In 1986, Hakala19 reported that patients with RA hospitalized for interstitial lung fibrosis showed a poor prognosis. Twenty-eight of 57 patients died due to underlying lung disease, with a median survival of 3.5 years. Hakala19 suggested the possibility of at least two different varieties of ILD in RA patients: benign and malignant. These two varieties may correspond to NSIP and UIP patterns, respectively, and the poor prognosis of his patients may be attributed to the predominance of UIP. In several HRCT-based studies,18 –21 a higher percentage of patients with RA-ILD experienced rapid progression of their lung disease according to HRCT and pulmonary function. In contrast to the idiopathic CHEST / 127 / 6 / JUNE, 2005

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Table 3—Comparison of Clinical Features of RA-ILD Patients in Relation to Histopathologic Patterns on SLBx*

No. of Patients Male/female gender Mean age, yr Smoking history, No. Current Former Duration of respiratory symptoms at biopsy, mo Range Respiratory symptoms and signs Chronic cough Dyspnea on exertion Bibasilar crackles Finger clubbing Sequence of diagnosis RA first, No. ILD first Simultaneously Rheumatoid factor Pulmonary function Restrictive pattern with low Dlco Restrictive pattern with normal Dlco Low Dlco only Normal lung function

UIP

NSIP

10 8/2 61.9 ⫾ 4.9

6 0/6 58.5 ⫾ 9.8

IAD With OP 2 0/2 57.5 ⫾ 12

2 8 9.4 ⫾ 11.7 0.3–36

6 0 47.9 ⫾ 88.1† 0.7–180

2 0 1.5 ⫾ 0.7 1.0–2.0

10 10 9 3

5 4 5 1

2 2 2 1

5 2 3 9

5 1 0 5

2 0 0 2

8 0 0 2

2 2 2 0

1 0 0 1

*Data are presented as No. or mean ⫾ SD. †Including one patient with a 15-year history of respiratory symptoms.

type of interstitial pneumonia or cases of Hakala,19 the prognoses of the patients with the UIP pattern in our study were not uniformly poor. Even though half of the UIP patients died, we had five patients with slightly improved or stable pulmonary function status. There was one patient who experienced a marked improvement in respiratory symptoms after treatment and was stable for 10 years. However, the numbers are small, and a study with a larger numbers of patients is required to determine whether the prognosis for RA-ILD is better than IIP, especially in the same pathologic pattern. Flaherty et al22

demonstrated that patients with CVD-associated UIP pattern had fewer fibroblastic foci and better survival when compared to patients with the idiopathic type, which may be related to better prognosis of CVD-associated UIP. However, the number of patients with the CVD-associated UIP pattern was small, and diverse collagen diseases were included. Further study is required for the comparison of CVD-associated UIP with IPF. Because three patients with UIP pattern died shortly after SLBx in

Table 4 —BAL Cell Differential in Relation to Histopathologic Patterns on SLBx* Variables

UIP

NSIP

IAD Plus OP

Patients, No. Alveolar macrophages % Range Lymphocytes % Range Neutrophils % Range Eosinophils % Range

7

5

2

58.7 ⫾ 20.5 28.7–90.0

57.5 ⫾ 30.8 4.0–81.7

59 ⫾ 9.9 52.0–66.0

27.7 ⫾ 12.5 9.0–47.3

37.0 ⫾ 29.2 14.4–88.0

21.5 ⫾ 14.9 11.0–32.0

10.9 ⫾ 9.5 1.0–23.9

4.5 ⫾ 2.4 3.0–7.8

19.3 ⫾ 4.6 16.0–22.5

2.5 ⫾ 6.4 0–17

1.0 ⫾ 1.0 0–2.0

0.3 ⫾ 0.4 0–0.5

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Figure 4. A case of UIP, with HRCT showing honeycomb cysts and traction bronchiectasis predominating in the peripheral and subpleural regions. Clinical Investigations

Table 5—Predominant HRCT Findings* HRCT Findings

Table 6 —Summary of Outcome*

UIP Pattern NSIP Pattern IAD With OP (n ⫽ 10) (n ⫽ 6) (n ⫽ 2)

Consolidation GGO Reticulation plus GGO Reticulation plus honeycombing Nodular opacity

0 0 1 9†

0 3 3 0†

1 0 0 0

0

0

1

*Data are presented as No. †p ⬍ 0.01.

our study, one can suspect the bad influence of SLBx on clinical course. However, four patients (including these three patients) were already in the process of rapid deterioration at the time of biopsy. In spite of the SLBx, all were discharged in the same condition before the biopsy, and three of them died several months later. The other patient improved considerably and lived longer. The remaining six patients who underwent biopsy in stable condition were discharged without significant complications. Therefore, it is unlikely that SLBx had a harmful effect on clinical courses of patients with the UIP pattern. The composition of the NSIP group was more uniform: all were women and nonsmokers, and all were alive and stable during the follow-up period. This strong gender predilection in the distribution of the pattern of interstitial pneumonia has been observed not only in RA-ILD, but also in IIP. In our series of IIP, female nonsmokers were predominant in NSIP in contrast to predominance of male smokers in IPF. Smoking has been known as one of the risk factor of IPF/UIP,13 and an association between the occurrence of ILD among RA patients and cigarette smoking was also suggested in some stud-

Figure 5. A case of nonspecific bronchiolitis, with HRCT obtained at subcarinal level showing diffuse tubular bronchiectasis in both lungs. Also noted are multiple centrilobular nodules and branching opacities, suggesting associated bronchiolar lesions. www.chestjournal.org

Variables

UIP

NSIP

IAD With OP

Patients Male/female gender Follow-up duration, mo Median Range Outcome Alive with ILD Death Cause of death Acute exacerbation Disease progression Complication of treatment PFT results Improved Worsened Stable

10 8/2

6 0/6

2 0/2

50.5 4–86

44.5 9–188

75.5 19–132

5 5

6 0

2 0

2 1 2

2 0 0

1 3 1 2 4 3

*Data are presented as No. unless otherwise indicated. Follow up PFT data of one NSIP patient and one UIP patient were not available.

ies.23–24 Most of the smokers are male in Korea, and approximately two thirds of Korean men smoke, in contrast to 5% in women. Therefore, it is possible that smoking and/or gender influences the development of the subtype of interstitial pneumonia, which requires further study. The clinical courses of our RA-NSIP patients were good, and the status of pulmonary function did not change for a long time in some patients. Because the majority of deaths were in men with a smoking history, the contribution of smoking needs to be considered. However, none had evidence of obstructive lung diseases in pulmonary function testing or significant amount of emphysema shown on HRCT. Considering the male dominance in UIP, mortality seems to be related to the presence of the UIP pattern rather than the smoking effect. In the setting of IIP, the presence of the typical clinical and HRCT features of UIP are sufficient for confident diagnosis of IPF, and SLBx may not be required in these cases.13,25–27 To determine whether these findings for IPF are applicable to RA-ILD, we compared HRCT findings and histopathologic diagnoses (Table 5). Even though three patients with the UIP pattern had an atypical distribution of honeycombing on HRCT (patchiness with airway centeredness), most patients with a histopathologic UIP pattern had typical HRCT findings for UIP. None with the NSIP pattern had definite honeycombing on HRCT, except one patient with ⬎ 15 years of the illness (Table 5) [p ⬍ 0.01]; her HRCT showed minimal but definite honeycombing in addition to predominant GGO on HRCT, and biopsy showed fibrotic NSIP. This suggests that the characteristic clinical and HRCT findings of the UIP CHEST / 127 / 6 / JUNE, 2005

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pattern could obviate the need for SLBx in some cases of RA-ILD, as in the setting of IPF. The majority of SLBx procedures in our patients with typical UIP pattern on HRCT were done before the ATS statement for IPF. Because HRCT findings of the NSIP pattern were also diverse in RA,28 –30 SLBx is helpful for the diagnosis when the HRCT findings are not typical for UIP. We reviewed the HRCTs of remaining 24 RA-ILD patients who did not undergo SLBx and found 21 patients had typical HRCT features of the UIP pattern. This predominance of typical HRCT features for UIP in our non-biopsy group support our assumption that the UIP pattern is a predominant ILD in RA. IADs such as FB, bronchiectasis, and bronchiolitis obliterans were also frequently reported in RA,14 –17 and two patients from our series exhibited bronchiolitis: one FB and one nonspecific bronchiolitis. The presence of bronchiolitis was suggested in HRCT by the presence of multiple small centrilobular nodules. FB can be related to recent usage of d-penicillamine, which one of our patients received.14 Although these patients had IAD, PFT results showed only a restrictive pattern, which might be due to the coexistence of OP in these patients. After corticosteroid treatment, the consolidation had almost disappeared, but multiple small centrilobular nodular lesions suggestive of bronchiolitis still remained on follow-up HRCT. Associations between bronchiectasis and RA in the presence or the absence of ILD were reported in several articles.31 Some patients were found to have bronchiectatic changes not related to ILD in HRCTs. But these were not the main HRCT findings. The main limitations of our study were the small number of subjects and only symptomatic patients were included. There may be many patients with milder asymptomatic forms of ILD. All of the patients with RA in our hospital underwent chest radiography at the initial workup at the outpatient clinic, and most patients with chest radiograph abnormalities, especially interstitial infiltration, underwent further tests, such as a PFT and HRCT; however, the sensitivity of chest radiography for the lung involvement of RA was rather low (approximately 5%).32 Therefore, many patients with early asymptomatic ILD might be missed, and the distribution of histopathologic pattern in these patients might be different. In conclusion, histopathologic patterns among the patients with RA-ILD were diverse; the UIP pattern seems to be more prevalent than the NSIP pattern in contrast to other type of CVD-ILDs. An IAD such as bronchiolitis is an important component of RA-ILD. With typical HRCT findings, UIP could be diag2026

nosed without SLBx among RA-ILD patients as in IPF. Although a characteristic histopathologic feature of RA such as lymphoid hyperplasia was found among the majority of the patients with RA-ILD, differences between RA-ILD and IIP for basic histopathologic patterns were not found. References 1 Agusti C, Xaubet A, Roca J, et al. Interstitial pulmonary fibrosis with and without associated collagen vascular disease: results of a two-year follow up. Thorax 1992; 47:1035–1040 2 American Thoracic Society and European Respiratory Society. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002; 165:277–304 3 Flaherty KR, Travis WD, Colby TV, et al. Histologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001; 164:1722–1727 4 Daniil Z, Gilchrist F, Nicholson A, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999; 160:899 –905 5 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 6 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 7 Douglas WW, Talezaar HD, Hartman TE, et al. Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 2001; 164:1182–1185 8 Ito I, Nagai S, Kitaichi M, et al. Clinical-radiological-pathological features of lung diseases in patients with primary Sjo¨gren’s syndrome [abstract]. Am J Respir Crit Care Med 2003; 167:A209 9 Katzenstein LA, Fiorelli RB. Nonspecific interstitial pneumonia/fibrosis. Am J Surg Pathol 1994; 18:136 –147 10 Yousem SA, Colby TV, Carrington CB. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis 1985; 131:770 –777 11 Arnett FCS, Edworthy M, Block DA, et al. The American Rheumatism Association revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 32:315–324 12 American Thoracic Society. Standardization of spirometry, 1994 update Am J Respir Crit Care Med 1995; 152:1107– 1136 13 American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement. Am J Respir Crit Care Med 2000; 151:646 – 664 14 Epler FR, Snider GL, Gaensler EA, et al. Bronchiolitis and bronchitis in connective tissue disease. JAMA 1979; 242:528 – 532 15 Yousem SA, Colby TV, Carrington CB, et al. Follicular bronchitis/bronchiolitis. Hum Pathol 1984; 16:700 –706 16 Fortoul TI, Cano-Valle F, Oliva E, et al. Follicular bronchiolitis in association with connective tissue diseases. Lung 1985; 163:305–314 17 Thiel RJ, Burg S, Groote AD, et al. Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Eur Respir J 1991; 4:905–911 18 Akira M, Sakatani M, Hara H. Thin-section CT findings in Clinical Investigations

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