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 ! 12). In three patients, ILD
preceded 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 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 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

nterstitial lung disease (ILD) is one of the sysI 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: dskim@amc.seoul.kr
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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 reports57 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 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 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
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 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 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 # 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

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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 1Histopathologic 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).
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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

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Table 2Comparison 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
(0.3180)

15.8 # 17.9
(160)

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
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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
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Table 3Comparison 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
0.336

6
0
47.9 # 88.1
0.7180

2
0
1.5 # 0.7
1.02.0

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

58.7 # 20.5
28.790.0

57.5 # 30.8
4.081.7

59 # 9.9
52.066.0

27.7 # 12.5
9.047.3

37.0 # 29.2
14.488.0

21.5 # 14.9
11.032.0

10.9 # 9.5
1.023.9

4.5 # 2.4
3.07.8

19.3 # 4.6
16.022.5

2.5 # 6.4
017

1.0 # 1.0
02.0

0.3 # 0.4
00.5

2024

Figure 4. A case of UIP, with HRCT showing honeycomb cysts

and traction bronchiectasis predominating in the peripheral and
subpleural regions.
Clinical Investigations

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Table 5Predominant 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

*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.
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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
486

44.5
9188

75.5
19132

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.2324 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.13,2527 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
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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.
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