Rheumatoid arthritis

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. BA preceded ILD in the majority of patients (n = 12). In three patients, ILD preceded BA; in three patients, both conditions were diagnosed simultaneously. The majority (n = 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 = 0.007) and smoking history (current/former or nonsmokers, 8/2 vs 0/6; p = 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 BA-ILD was diverse; in our study population, the UIP pattern seemed to be more prevalent than the NSIP pattern.

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

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Interstitial lung disease (ILD) is one of the systemic 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 American Thoracic Society (ATS)/European Respiratory Society consensus classification, idiopathic interstitial pneumonias (IIPs) include seven clinico-radiologic-pathologic entities: idiopathic pulmonary 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 reports (3-4) have suggested a better prognosis for the NSIP pattern than for the UIP pattern. Several reports (5-7) have suggested that NSIP is a major histopathologic pattern in CVD-ILD. Bouros et al (5) and our group (6) reported that NSIP was the predominant pathologic pattern in scleroderma (77% and 63%, respectively) on surgical lung biopsy (SLBx). Douglas and colleagues (7) also published similar results for dermatomyositis-polymyositis, and the situation is similar for Sjogren 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 colleagues (10) 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)

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 Sjogren 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 video-assisted 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.

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

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 Vmax 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 [+ or -] 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.

RESULTS

Histologic Diagnosis

The [kappa] 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.

[FIGURES 1-3 OMITTED]

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 eases, 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).

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 eosinophils 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 IPFAJIP, 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 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 BA-ILD.

[FIGURES 4-5 OMITTED]

Comparison of Clinical Courses Between Patients With UIP and NSIP Patterns

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 [+ or -] 18.8 months later) due to aggravation of pulmonary symptoms. Lung functions were severely reduced (mean FVC change, 31.0 [+ or -] 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 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 al (5) 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 al (18) of 29 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, Hakala (19) 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. Hakala (19) 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 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 al (22) 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 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 studies. (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 UIPI morality 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 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-penieillamine, 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 diagnosed 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 histopathologie patterns were not found.

* 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.

Manuscript received April 16, 2004; revision accepted December 9, 2004.

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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: dskim@amc.seoul.kr

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