2005 histopathologic pattern and clinical features of rheumatoid arthritis- associated interstitial...

8/17/2019 2005 Histopathologic Pattern and Clinical Features of Rheumatoid Arthritis- Associated Interstitial Lung Disease

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Histopathologic Pattern and ClinicalFeatures of Rheumatoid Arthritis-

Associated 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; andMasanori Kitaichi, MD

Study objectives: To investigate the histopathologic pattern and clinical features of patients withrheumatoid arthritis (RA)-associated interstitial lung disease (ILD) according to the AmericanThoracic Society (ATS)/European Respiratory Society consensus classification of idiopathicinterstitial 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 suspectedILD. 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 organizingpneumonia pattern. RA preceded ILD in the majority of patients (n 12). In three patients, ILDpreceded RA; 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 UIPand 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 RA-ILD was diverse; in our study population, the UIPpattern 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; usualinterstitial pneumonia

Abbreviations: ATS American Thoracic Society; CVD collagen vascular disease; Dlco diffusion capacity of thelung 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

Interstitial lung disease (ILD) is one of the sys-temic manifestations of collagen vascular disease

(CVD), and ILD associated with CVD (CVD-ILD) was reported to have a better prognosis than theidiopathic type of ILD.1 According to the recent

American Thoracic Society (ATS)/European Respi-ratory Society consensus classification, idiopathicinterstitial pneumonias (IIPs) include seven clinico-radiologic-pathologic entities: idiopathic pulmonary

*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 Pathol-ogy (Dr. Kitaichi), Kyoto University Hospital, Kyoto, Japan.

Manuscript received April 16, 2004; revision accepted December9, 2004.Reproduction of this article is prohibited without written permissionfrom 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]

www.chestjournal.org CHEST / 127 / 6 / JUNE, 2005 2019

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fibrosis (IPF), usual interstitial pneumonia (UIP),nonspecific interstitial pneumonia (NSIP), crypto-genic organizing pneumonia, acute interstitial pneu-monia, respiratory bronchiolitis-associated ILD, des-quamative interstitial pneumonia, and lymphoidinterstitial pneumonia.2 Although NSIP was consid-ered to be a provisional diagnosis at that time, it canbe distinguished from UIP by temporal uniformity infibrotic processes, and many reports3–4 have sug-gested a better prognosis for the NSIP pattern thanfor the UIP pattern. Several reports5–7 have sug-gested that NSIP is a major histopathologic patternin CVD-ILD. Bouros et al5 and our group6 reportedthat NSIP was the predominant pathologic pattern inscleroderma (77% and 63%, respectively) on surgicallung biopsy (SLBx). Douglas and colleagues7 alsopublished similar results for dermatomyositis-poly-myositis, and the situation is similar for Sjögrensyndrome.8 Although rheumatoid arthritis (RA) is

the most common type of CVD, there are no reportsof the histopathologic pattern of RA-associated ILD(RA-ILD) after the 1994 description of NSIP.9

Approximately 20 years ago, Yousem and col-leagues10 reported the findings of lung biopsies frompatients with RA. However, only a few patients withILD were included in that study, and the currentclassification system for ILD was not available at thattime. To investigate the histopathologic patterns of RA-ILD and their correlation with clinical featuresand outcome, we reviewed and reclassified SLBxspecimens in the context of the recent classificationof IIPs.2

Materials and Methods

Patients

This is a retrospective study performed at Asan MedicalCenter, a 2,000-bed, university-affiliated, tertiary referral centerin 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 diffuselung diseases to get a definitive diagnosis. The major reason wecould not perform the SLBx was that patients refused to undergothe invasive procedure. All patients met the revised criteria of theAmerican College of Rheumatology for RA.11 Patients withSjögren syndrome or other coexisting CVDs were excluded.Twelve patients attended the pulmonary division due to respira-tory symptoms such as shortness of breath or chronic cough, andothers were first seen by rheumatologists and were then referredto 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 ormore lobes in every patient. This study was approved by theInstitutional Review Board of the Asan Medical Center.

Clinical and Laboratory Test Results

All the clinical data were obtained from medical records, whichincluded the history, physical examination results, laboratory testresults, 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 classifiedaccording to the new ATS/European Respiratory Society consen-sus criteria for IIPs.2 Consensus diagnoses were made by thesepathologists in cases of disagreement. The pattern of UIP wasdistinguished by a temporally heterogeneous pattern of fibrosis( ie, a variation in the age of fibroses, with fibroblastic foci, an areaof spindle cells with plump cytoplasm and little interveningcollagen immediately adjacent to areas of established fibrosis). Inaddition, the subpleural dominant distribution of fibrotic lesionand honeycombing were considered to be important to thehistologic 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 subdividedinto three groups: NSIP group 1, primarily with interstitialinflammation; group 2, with both inflammation and fibrosis; andgroup 3, primarily with fibrosis.

High-Resolution CT of the Chest

High-resolution CT (HRCT) was performed (HiSpeed Advan-tage Scanner; GE Medical Systems; Milwaukee, WI; or SomatomPlus 4 Scanner; Siemens Medical Systems; Erlangen, Germany),and the images were analyzed at a window level of – 700Hounsfield units and a window width of 1,500 Hounsfield units.HRCT of the lungs was reviewed by one radiologist (J.B.S.) andinterpreted without knowledge of the biopsy results or clinicaloutcomes. The HRCT findings were arbitrarily classified into fivegroups according to the predominant features: consolidation,

ground-glass opacity (GGO), GGO with reticular opacity, retic-ular opacity with honeycombing, and nodular opacity.

Pulmonary Function Tests

Results of pulmonary function tests (PFTs) performed usingATS guidelines were expressed as percentage of predicted

values.12 Spirometry was performed with a SensorMedics 2100(SensorMedics; Yorba Linda, CA), diffusion capacity of the lungfor carbon monoxide (Dlco) was measured with a V ˙ max 22(SensorMedics), and total lung capacity was measured using anAuto Box 6200 (SensorMedics). Improvement or deterioration

were defined as more than a 10% change in FVC or total lungcapacity, 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 asmeans SD for continuous variables, percentages for categorical

variables, or medians (ranges). The Mann-Whitney U test wasused to compare the UIP and NSIP groups. In all cases,two-sided tests were used with p values 0.05 to denotestatistical significance.

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Results

Histologic Diagnosis

The coefficient of agreement between the pa-thologists (M.K. and T.V.C. for example) for thedifferentiation 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 fibroticNSIP in two patients, fibrotic NSIP in four patients)[Fig 2], and inflammatory airway disease (IAD)combined with an organizing pneumonia (OP) pat-tern were seen in two patients. One patient with IADexhibited follicular bronchiolitis (FB) [Fig 3], andthe other patient with IAD exhibited chronic non-specific bronchiolitis.

Clinical Features and Laboratory Findings

Clinical Features of the Subjects: Of the 18 pa-

tients, all 8 male patients were current or formersmokers, whereas all 10 female patients were non-smokers (Table 2). The majority of patients com-plained of respiratory symptoms. In the majority of the cases, RA was diagnosed before the detection of ILD; in three patients, ILD preceded the diagnosisof 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 featuresbetween the 24 patients without SLBx and thestudy subjects of 18 patients with SLBx to excludethe possibility of selection bias. Even though thenon-biopsy group was slightly older than the bi-opsy group, no significant difference was found inthe clinical features between these two groups(Table 2).

Comparison of the Clinical Features Between thePatients With UIP and NSIP Patterns at SLBx: Thegender distribution and smoking histories differedsignificantly between two groups (p 0.05) [Ta-ble 3]. All male patients had the UIP pattern, and allpatients in the NSIP group were female. The meanFVC 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 significantdifferences between the two groups.

BAL fluid data were available in 14 patients (UIP,n 7; NSIP, n 5; and IAD, n 2). The meanpercentage of neutrophils, lymphocytes, and eosino-

Figure 2. A case of NSIP, with marked thickening of thealveolar walls by fibrosis and inflammatory cell infiltration. Notethe temporal uniformity without fibrous foci (hematoxylin-eosin,original 20).

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

Histopathologic Diagnosis Subjects, No. (%)

UIP pattern 10 (55.6)NSIP pattern 6 (33.3)

Mixed cellular and fibrotic 2 (11.1)Fibrotic 4 (22.2)

IAD with OP pattern 2 (11.1)FB 1Chronic nonspecific bronchiolitis 1

Figure 1. A case of UIP, with patchy involvement of interstitialfibrosis and inflammation with fibrous foci at the edges of densescar, alternating with relatively normal lung parenchyma (hema-toxylin-eosin, original 40).




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phils in BAL fluid did not differ significantly be-tween these three groups (Table 4). Elevated neu-trophils ( 5%) were found in four of seven patients with the UIP pattern and in two of five patients withthe NSIP pattern, in contrast to increased lympho-cytes ( 20%) in five of seven patients with the UIPpattern and four of five patients with the NSIPpattern.

Radiologic Findings

HRCT findings of all patients were reviewed.Similar to the IPF/UIP, all patients with the UIPpattern had typical reticular opacities with honey-combing predominantly in subpleural area (Fig 4),except one patient who had GGO to the same extentas reticular opacity (Table 5). Patients with the NSIPpattern showed predominant GGO or GGO withsome reticular opacity. One patient with IAD andOP pattern showed mainly multiple patchy consoli-dations, and the other patient showed predominantly

multiple small nodules (Fig 5) in the whole lung fieldin addition to multiple consolidations. A majority (87.5%) of the patients with RA-ILD who did notundergo SLBx showed typical HRCT findings forUIP. According to the ATS statement on IPF,13 if the HRCT findings are typical for IPF/UIP, IPF canbe diagnosed without SLBx in an appropriate clinicalsetting. Therefore, the predominance of typical

HRCT findings for UIP in the non-biopsy groupstrongly supports the finding of higher prevalence of UIP pattern in the biopsy specimens of RA-ILD.

Comparison of Clinical Courses Between PatientsWith UIP and NSIP Patterns

The median durations of follow-up were 4.2 yearsin UIP patients and 3.7 years in NSIP patients. Asshown in Table 6, death occurred only in the UIPgroup (5 of 10 patients). One patient died of acuteexacerbation of pulmonary fibrosis, three patientsdied of steady progression of lung disease, and thelast patient died of presumably infectious pneumoniaduring corticosteroid treatment. One patient withthe UIP pattern had an acute exacerbation withnewly developed diffuse GGOs during steroid taper-ing. All culture findings including BAL examinationfor Pneumocystis carinii and viruses were negative,and the patient died 1 month later. Four patients inthe UIP group initially refused to undergo lungbiopsy or treatment when the clinical and radio-graphic evidence of RA-ILD was apparent first.They revisited the hospital (mean, 28.2 18.8months later) due to aggravation of pulmonary symp-toms. Lung functions were severely reduced (meanFVC change, 31.0 14.5% of predicted), and SLBx was performed at that time. In spite of corticosteroidtherapy, conditions steadily progressed at the samespeed as prior to biopsy, and three patients amongthem died several months (mean, 5 months) afterbiopsy. One remaining patient was in stable condi-tion for 26 months after SLBx. Among the total 10patients with the UIP pattern, lung function im-proved 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 hadstable lung function except one, whose FVC wasslightly reduced (from 67 to 58% predicted). One of nontreated patients had ILD diagnosed 15 yearspreviously, and RA developed 7 years later. Herrespiratory symptoms and pulmonary function didnot change significantly for 15 years.

Discussion

This study shows that the distribution of his-topathologic patterns in RA-ILD was different than

Figure 3. A case of FB, with inflammatory cell infiltration in thebronchial walls and lumens associated with lymphoid follicle

formation ( top: hematoxylin-eosin, original

10; bottom: hema-toxylin-eosin, original 40).




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in other types of CVD-ILD, with the UIP patternbeing more prevalent than NSIP pattern. We alsofound that IAD was one of important manifestationsin RA patents, as reported in previous studies.14–17

Death occurred only in the UIP group, and allpatients with NSIP were alive and improved orstable in this small series.

Our finding of a more prevalent UIP pattern in RAcompared to the NSIP pattern or IAD with the OPpattern contrasted with data suggesting NSIP as themajor histopathologic pattern in CVD-associatedpulmonary fibrosis.5–8 This also suggests that the various CVDs cannot be “lumped together” whenconsidering patterns of lung pathology. In the reportof Bouros et al5 in 2002, NSIP comprised 77.5% of systemic sclerosis-associated pulmonary fibrosis, andNSIP was 68.4% in our series.6 However, previousstudies suggested that UIP was predominant inRA-ILD patients. In the study by Akira et al18 of 29

patients with RA-associated lung disease, threegroups were identified on the basis of the predomi-nant CT pattern; 10 patients had reticulation andhoneycombing and likely had the UIP pattern, al-though histopathologic diagnoses were made for only a few patients. In 1986, Hakala19 reported thatpatients with RA hospitalized for interstitial lung

fibrosis showed a poor prognosis. Twenty-eight of 57patients died due to underlying lung disease, with amedian survival of 3.5 years. Hakala19 suggested thepossibility of at least two different varieties of ILD inRA patients: benign and malignant. These two vari-eties may correspond to NSIP and UIP patterns,respectively, and the poor prognosis of his patientsmay be attributed to the predominance of UIP. Inseveral HRCT-based studies,18–21 a higher percent-age of patients with RA-ILD experienced rapidprogression of their lung disease according to HRCTand pulmonary function. In contrast to the idiopathic

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

Variables Underwent SLBx Did Not Undergo SLBx

Male/female gender, No. 8/10 12/12Mean age, yr 60.3 7.3 65.8 9.3Smoking history, No.

Never 10 13Current/former 8 11

Respiratory symptomExertional dyspnea 16 (88.9) 19 (79.2)Cough 17 (94.4) 20 (83.3)Clubbing 5 (27.8) 2 (8.3)

Duration of symptoms before admission, moMean SD 18.1 44.2 15.8 17.9Range (0.3–180) (1–60)

Sequence of diagnosisRA first, No. (%) 12 (66.7) 16 (66.7)Mean duration of RA, yrs 11.9 9.9 10.4 8.0ILD first 3 (16.7) 0Simultaneously 3 (16.7) 8 (33.3)

Pulmonary function†Restrictive pattern with low Dlco 11 16

Restrictive pattern 0 1Restrictive pattern with normal Dlco 2 0Low Dlco 2 3Obstructive pattern with low Dlco 0 1Normal lung function 3 1FVC (% predicted) 65.3 19.6 67.1 17.3FEV 1 (% predicted) 74.6 20.4 80.5 20.4FEV 1 /FVC (%) 83.6 7.1 85.3 8.7Dlco (% predicted) 62.9 25.3 53.1 17.0

HRCTConsolidation 1 (5.6) 1 (4.1)GGO 3 (16.7) 1 (4.1)Reticulation plus GGO 4 (22.2) 1 (4.1)Reticulation plus honeycombing 9 (50) 21 (87.5)Nodular opacity 1 (5.6) 0

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




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type of interstitial pneumonia or cases of Hakala,19

the prognoses of the patients with the UIP pattern inour study were not uniformly poor. Even though half of the UIP patients died, we had five patients withslightly improved or stable pulmonary function sta-

tus. There was one patient who experienced amarked improvement in respiratory symptoms aftertreatment and was stable for 10 years. However, thenumbers are small, and a study with a larger num-bers of patients is required to determine whether theprognosis for RA-ILD is better than IIP, especially in the same pathologic pattern. Flaherty et al22

demonstrated that patients with CVD-associatedUIP pattern had fewer fibroblastic foci and bettersurvival when compared to patients with the idio-pathic type, which may be related to better prognosisof CVD-associated UIP. However, the number of

patients with the CVD-associated UIP pattern wassmall, and diverse collagen diseases were included.Further study is required for the comparison of CVD-associated UIP with IPF. Because three pa-tients with UIP pattern died shortly after SLBx in

Figure 4. A case of UIP, with HRCT showing honeycomb cystsand traction bronchiectasis predominating in the peripheral andsubpleural regions.

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

Variables UIP NSIP IAD Plus OP

Patients, No. 7 5 2Alveolar macrophages

% 58.7 20.5 57.5 30.8 59 9.9Range 28.7–90.0 4.0–81.7 52.0–66.0

Lymphocytes% 27.7 12.5 37.0 29.2 21.5 14.9Range 9.0–47.3 14.4–88.0 11.0–32.0

Neutrophils% 10.9 9.5 4.5 2.4 19.3 4.6Range 1.0–23.9 3.0–7.8 16.0–22.5

Eosinophils% 2.5 6.4 1.0 1.0 0.3 0.4Range 0–17 0–2.0 0–0.5

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

UIP NSIP IAD With OP

No. of Patients 10 6 2Male/female gender 8/2 0/6 0/2Mean age, yr 61.9 4.9 58.5 9.8 57.5 12Smoking history, No.

Current 2 6 2Former 8 0 0

Duration of respiratory symptoms at biopsy, mo 9.4 11.7 47.9 88.1† 1.5 0.7Range 0.3–36 0.7–180 1.0–2.0

Respiratory symptoms and signsChronic cough 10 5 2Dyspnea on exertion 10 4 2Bibasilar crackles 9 5 2Finger clubbing 3 1 1

Sequence of diagnosisRA first, No. 5 5 2ILD first 2 1 0Simultaneously 3 0 0

Rheumatoid factor 9 5 2Pulmonary function

Restrictive pattern with low Dlco 8 2 1

Restrictive pattern with normal Dlco

0 2 0Low Dlco only 0 2 0Normal lung function 2 0 1

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




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our study, one can suspect the bad influence of SLBxon clinical course. However, four patients (includingthese 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 conditionbefore the biopsy, and three of them died severalmonths later. The other patient improved consider-

ably and lived longer. The remaining six patients whounderwent biopsy in stable condition were dis-charged without significant complications. There-fore, it is unlikely that SLBx had a harmful effect onclinical courses of patients with the UIP pattern.

The composition of the NSIP group was moreuniform: 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 ob-served not only in RA-ILD, but also in IIP. In ourseries of IIP, female nonsmokers were predominant

in NSIP in contrast to predominance of male smok-ers in IPF. Smoking has been known as one of therisk factor of IPF/UIP,13 and an association betweenthe occurrence of ILD among RA patients andcigarette smoking was also suggested in some stud-

ies.23–24 Most of the smokers are male in Korea, andapproximately two thirds of Korean men smoke, incontrast to 5% in women. Therefore, it is possiblethat smoking and/or gender influences the develop-ment of the subtype of interstitial pneumonia, whichrequires further study. The clinical courses of ourRA-NSIP patients were good, and the status of pulmonary function did not change for a long time insome patients. Because the majority of deaths werein men with a smoking history, the contribution of

smoking needs to be considered. However, none hadevidence of obstructive lung diseases in pulmonary function testing or significant amount of emphysemashown on HRCT. Considering the male dominancein UIP, mortality seems to be related to the presenceof the UIP pattern rather than the smoking effect.

In the setting of IIP, the presence of the typicalclinical and HRCT features of UIP are sufficient forconfident diagnosis of IPF, and SLBx may not berequired in these cases.13,25–27 To determine whether these findings for IPF are applicable toRA-ILD, we compared HRCT findings and his-

topathologic diagnoses (Table 5). Even though threepatients with the UIP pattern had an atypical distri-bution of honeycombing on HRCT (patchiness withairway centeredness), most patients with a his-topathologic UIP pattern had typical HRCT findingsfor UIP. None with the NSIP pattern had definitehoneycombing on HRCT, except one patient with 15 years of the illness (Table 5) [p 0.01]; herHRCT showed minimal but definite honeycombingin addition to predominant GGO on HRCT, andbiopsy showed fibrotic NSIP. This suggests that thecharacteristic clinical and HRCT findings of the UIP

Figure 5. A case of nonspecific bronchiolitis, with HRCTobtained at subcarinal level showing diffuse tubular bronchiec-tasis in both lungs. Also noted are multiple centrilobular nodulesand branching opacities, suggesting associated bronchiolar le-sions.

Table 5— Predominant HRCT Findings*

HRCT FindingsUIP Pattern

(n 10)NSIP Pattern

(n 6)IAD With OP

(n 2)

Consolidation 0 0 1GGO 0 3 0Reticulation plus GGO 1 3 0Reticulation plus

honeycombing9† 0† 0

Nodular opacity 0 0 1

*Data are presented as No.†p 0.01.

Table 6—Summary of Outcome*

Variables UIP NSIP IAD With OP

Patients 10 6 2Male/female gender 8/2 0/6 0/2Follow-up duration, mo

Median 50.5 44.5 75.5Range 4–86 9–188 19–132

Outcome

Alive with ILD 5 6 2Death 5 0 0

Cause of deathAcute exacerbation 1Disease progression 3Complication of treatment 1

PFT resultsImproved 2 2 2 Worsened 4 1 0Stable 3 2 0

*Data are presented as No. unless otherwise indicated. Follow upPFT data of one NSIP patient and one UIP patient were notavailable.




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pattern could obviate the need for SLBx in somecases of RA-ILD, as in the setting of IPF. Themajority of SLBx procedures in our patients withtypical UIP pattern on HRCT were done before theATS statement for IPF. Because HRCT findings of the NSIP pattern were also diverse in RA,28–30 SLBxis helpful for the diagnosis when the HRCT findingsare not typical for UIP.

We reviewed the HRCTs of remaining 24 RA-ILDpatients who did not undergo SLBx and found 21patients had typical HRCT features of the UIPpattern. This predominance of typical HRCT fea-tures for UIP in our non-biopsy group support ourassumption that the UIP pattern is a predominantILD in RA.

IADs such as FB, bronchiectasis, and bronchiolitisobliterans were also frequently reported in RA,14–17

and two patients from our series exhibited bronchi-olitis: one FB and one nonspecific bronchiolitis. Thepresence 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 thesepatients had IAD, PFT results showed only a restric-tive pattern, which might be due to the coexistenceof OP in these patients. After corticosteroid treat-ment, the consolidation had almost disappeared, butmultiple small centrilobular nodular lesions sugges-tive of bronchiolitis still remained on follow-upHRCT. Associations between bronchiectasis andRA in the presence or the absence of ILD werereported in several articles.31 Some patients were

found to have bronchiectatic changes not related toILD in HRCTs. But these were not the main HRCTfindings.

The main limitations of our study were the smallnumber of subjects and only symptomatic patients were included. There may be many patients withmilder asymptomatic forms of ILD. All of the pa-tients with RA in our hospital underwent chestradiography at the initial workup at the outpatientclinic, and most patients with chest radiograph ab-normalities, especially interstitial infiltration, underwent further tests, such as a PFT and HRCT;

however, the sensitivity of chest radiography for thelung involvement of RA was rather low (approxi-mately 5%).32 Therefore, many patients with early asymptomatic ILD might be missed, and the distri-bution of histopathologic pattern in these patientsmight be different.

In conclusion, histopathologic patterns among thepatients with RA-ILD were diverse; the UIP patternseems to be more prevalent than the NSIP pattern incontrast to other type of CVD-ILDs. An IAD such asbronchiolitis is an important component of RA-ILD. With typical HRCT findings, UIP could be diag-

nosed without SLBx among RA-ILD patients as inIPF. Although a characteristic histopathologic fea-ture of RA such as lymphoid hyperplasia was foundamong the majority of the patients with RA-ILD,differences between RA-ILD and IIP for basic his-topathologic patterns were not found.

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