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Increased CD4+ T cell infiltrates in rheumatoid arthritisassociated interstitial pneumonitis compared with idiopathic interstitial pneumonitis.

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Vol. 52, No. 1, January 2005, pp 73–79
DOI 10.1002/art.20765
© 2005, American College of Rheumatology
Increased CD4⫹ T Cell Infiltrates in
Rheumatoid Arthritis–Associated Interstitial Pneumonitis
Compared With Idiopathic Interstitial Pneumonitis
Carl Turesson,1 Eric L. Matteson,2 Thomas V. Colby,3 Zvezdana Vuk-Pavlovic,2
Robert Vassallo,2 Cornelia M. Weyand,4 Henry D. Tazelaar,2 and Andrew H. Limper2
Objective. To study lymphocyte markers in rheumatoid arthritis (RA)–associated interstitial pneumonitis (IP) compared with idiopathic IP.
Methods. Paraffin-embedded lung biopsy specimens from patients with RA (n ⴝ 15) and from those
without RA (n ⴝ 16), all of whom had a diagnosis of
either nonspecific IP or usual IP, were studied. Tissue
sections from each patient were reviewed by a pathologist, who was blinded to the clinical data. Age and
pulmonary function test results were similar in RA and
non-RA patients. After high-temperature antigen unmasking, sections were incubated with mouse monoclonal antibodies directed against CD3, CD4, CD8, CD16,
and CD20. All slides were coded, and digital images
(100ⴛ magnification) of the entire tissue area were
obtained. Staining was quantified using computerassisted image analysis.
Results. Staining for CD4 was more prominent in
patients with RA than in the non-RA comparison group
(median 9.3 cells/mm2, interquartile range [IQR] 5.5–
27.3 versus 0.6 cells/mm2, IQR 0.2–1.9; P ⴝ 0.002).
CD4ⴙ cell counts were increased in RA patients with
nonspecific IP as well as in RA patients with usual IP,
with no major difference between these groups. Results
were similar for quantification of CD3 (P ⴝ 0.012).
There was a less striking trend toward more CD8ⴙ cells
in RA patients (P ⴝ 0.27 versus those with non-RA lung
Conclusion. IP lesions in patients with RA are
characterized by an increased number of CD4ⴙ cells, as
compared with that in patients with idiopathic IP. This
finding suggests that CD4ⴙ T cells are critical for the
development of pulmonary manifestations in RA, and
may have implications for the treatment of RAassociated lung disease.
Rheumatoid arthritis (RA) is associated with a
number of pulmonary manifestations, including vascular
disease, pleuritis (1), airway disorders (2,3), and interstitial pneumonitis (IP) (4–6). The frequency of lung
disease in patients with RA depends on the definitions
used for screening (3) and the criteria used for selection
of the patient sample (7). In a survey of a communitybased RA cohort, in which the case definition relied on
clinical diagnosis and the results of pulmonary function
tests (PFTs), the 10-year cumulative incidence of IP
after diagnosis of RA was estimated to be 6% in patients
diagnosed during the period 1975–1995 (8).
Based on histopathologic findings, IP has been
subclassified into categories, which include usual IP and
nonspecific IP (9). A wide variety of pathologic patterns
in RA-associated IP have been reported (6), and IP in
patients with RA has been described as clinically indistinguishable from idiopathic IP (5,6). Some authors have
reported a more stable disease course (10) and a lower
mortality (11–13) in patients with IP in the setting of
connective tissue disease (CTD) compared with those
with idiopathic IP, but this has not been a consistent
finding (14,15). Guidelines issued jointly by the Ameri-
Supported by NIH grant K24-AR-47578-01A1, the Swedish
Rheumatism Association, the Swedish Society for Medicine, and the
Robert N. Brewer Family Foundation.
Carl Turesson, MD, PhD: Mayo Clinic College of Medicine,
Rochester, Minnesota, and Malmö University Hospital, Malmö, Swe2
den; Eric L. Matteson, MD, MPH, Zvezdana Vuk-Pavlovic, PhD,
Robert Vassallo, MD, Henry D. Tazelaar, MD, Andrew H. Limper,
MD, FCCP: Mayo Clinic College of Medicine, Rochester, Minnesota;
Thomas V. Colby, MD, FCCP: Mayo Clinic College of Medicine,
Scottsdale, Arizona; 4Cornelia M. Weyand, MD, PhD: Emory University, Atlanta, Georgia.
Address correspondence and reprint requests to Carl Turesson, MD, PhD, Department of Rheumatology, Malmö University
Hospital, Södra Förstadsgatan 101, S-205 02 Malmö, Sweden. E-mail:
Submitted for publication April 13, 2004; accepted in revised
form September 30, 2004.
can Thoracic Society and the European Respiratory
Society have separated IP in patients with CTD from
idiopathic cases of IP, on the basis of potential differences in etiology and pathogenesis which may affect
management and outcome (16).
Prominent nodular aggregates of lymphocytes in
the parenchymal interstitial tissue have been described
in patients with RA-associated usual IP and in those
with RA-associated nonspecific IP (15). Studies of bronchoalveolar lavage (BAL) samples obtained from RA
patients in comparison with healthy controls have
yielded somewhat contradictory results (17,18), although differences in T cell subpopulations have been
suggested (17). Previous studies of patients with IP with
and without associated CTD have revealed a poor
correlation of CD4⫹ and CD8⫹ cell counts in samples
obtained at BAL with the number of CD4⫹ and CD8⫹
cells in corresponding lung biopsy samples (19). There
have been no quantitative studies of lymphocyte populations in lung biopsy tissue from patients with IP and RA.
T cells are considered to be important in the
pathogenesis of RA (20), and specific T cell abnormalities may be of particular relevance to extraarticular
disease manifestations, including lung disease (21). The
purpose of the present study was to describe T cell
subpopulations in lung biopsy tissue from patients with
RA-associated IP, and to use quantitative data for a
comparison of RA-associated IP with idiopathic IP.
Patients. Samples from patients with a clinical and
histopathologic diagnosis of RA-associated lung disease (n ⫽
23) were obtained from the tissue archives at the Mayo Clinics
in Rochester, Minnesota and Scottsdale, Arizona. The selection of biopsy specimens was based on an ongoing survey of
RA-associated lung disease at the Mayo Clinic and the consultation files of one of the authors (TVC). The basis for
inclusion was a histopathologic diagnosis of inflammatory lung
disease by an experienced lung pathologist (HDT or TVC) in
a patient with documented RA. The medical records were
reviewed in accordance with a structured protocol. One patient
diagnosed with RA did not fulfill the American College of
Rheumatology (formerly, the American Rheumatism Association) 1987 criteria for RA (22), and was therefore excluded.
Slides of hematoxylin and eosin–stained sections from each
patient were reviewed by one of the pathologists (TVC), who
was blinded to the clinical data. Ten of the RA patients were
classified as having nonspecific IP, and 5 as having usual IP.
Seven cases were not classified as IP at either of the 2 reviews.
At the second review, 2 patients originally classified as having
usual IP were reclassified as nonspecific IP, and 1 nonspecific
IP case was relabeled as usual IP.
Patients without RA who had a clinical and histopathologic diagnosis of idiopathic nonspecific IP (n ⫽ 10) or
idiopathic usual IP (n ⫽ 8) were identified from a survey of
Mayo Clinic–Rochester interstitial lung disease cases, and
these were designated as controls. Slides of specimens from
these patients underwent the same review as described above.
Two patients originally classified as having usual IP were not
considered to have IP at the second review, and 1 case of usual
IP was reclassified as nonspecific IP. In total, 11 patients were
classified as having nonspecific IP, and 5 as having usual IP.
Control patients were compared with the RA patients with
nonspecific IP or usual IP.
Most of the patients with nonspecific IP had a histopathologic picture mainly compatible with fibrotic nonspecific IP, with the exception of 2 patients (both non-RA
controls) who had prominent features of cellular nonspecific
IP. All specimens from both groups were obtained by openlung biopsies.
All medical records for the cases and controls were
reviewed, and demographic data, the presence of other autoimmune diseases, and PFT results at the time of diagnosis of
interstitial lung disease were recorded. For patients with RA,
data on rheumatoid factor and antinuclear antibody tests as
well as the presence of rheumatoid nodules and severe extraarticular manifestations, determined according to predefined
criteria (7,23), were noted. The study was approved by the
Mayo Clinic Institutional Review Board.
Immunohistochemical staining. Formalin-fixed,
paraffin-embedded sections of 5-␮m–thick tissue were deparaffinized through 2 exchanges of xylene, each of 5 minutes’
duration. The tissues were then rehydrated using a graded
series of alcohol washes and incubated for 30 minutes in 0.5%
H2O2 to quench endogenous peroxidase activity. Hightemperature antigen unmasking was performed as part of all
staining protocols. Before incubation with antibodies against
CD8, the slides were incubated in preheated Copeland jars
containing 10 mM sodium citrate buffer, pH 6.0, in a 98°C
water bath for 40 minutes. Before incubation with antibodies
against CD3, CD4, CD16, and CD20, slides were heated at
high pressure in 10 mM citrate buffer, pH 6.0 (for CD3, CD16,
and CD20 protocols), or 1 mM EDTA buffer, pH 8.0 (for CD4
protocols), in a pressure cooker for 60 seconds, in accordance
with the recommendations of the antibody manufacturer (Novocastra, Newcastle upon Tyne, UK). Pretreated slides were
incubated for 30 minutes with 1% blocking horse serum before
application of primary antibodies. For all experiments, the
following mouse monoclonal antibodies were used: anti-CD8
(clone C8/144B; Dako, Glostrup, Denmark), anti-CD3 (clone
PS1, dilution 1:100), anti-CD4 (clone 4B12, dilution 1:20),
anti-CD16 (clone 2H7, dilution 1:20), and anti-CD20 (clone
L26, dilution 1:200) (all from Novocastra).
Antibody dilutions and incubation times (60 minutes at
room temperature plus 10 hours at ⫺20°C for anti-CD8; 60
minutes at room temperature for all other antibodies) were
applied uniformly in parallel across all tissues studied. Slides of
specimens from patients with a clinical and histopathologic
diagnosis of nonspecific IP, incubated with a universal mouse
negative reagent containing a cocktail of mouse IgG and IgM
(Dako), were used as negative controls. Primary antibody
binding was detected using the avidin–biotin–immunoperoxidase method (Vectastain Elite ABC Kit; Vector, Burlingame, CA) with 3-amino-9-ethyl-carbazole as the colorimet-
Table 1. Demographic variables and pulmonary function test results
at diagnosis*
Sex, no. female/male
Age, years
Ever smoker, %
Current smoker, %
Current steroid
treatment, %
VC, % of predicted
FVC, % of predicted
FEV1, % of predicted
DLCO, % of predicted
64 (57–72)
64 (57–69)
67 (51–91)
67 (46–80)
69 (51–91)
48 (42–58)
69 (51–89)
66 (53–83)
76 (54–95)
57 (39–75)
* Except where indicated otherwise, values are the median (interquartile range). RA ⫽ rheumatoid arthritis; ILD ⫽ interstitial lung disease;
VC ⫽ vital capacity; FVC ⫽ forced vital capacity; FEV1 ⫽ forced
expiratory volume in 1 second; DLCO ⫽ diffusion capacity of the lung
for carbon monoxide.
† Data available on 13 patients.
ric substrate. The sections were counterstained with 1%
Meyer’s hematoxylin.
Quantification and statistical analysis. All slides were
coded before quantification. Using an Axioplan 2 microscope
and an AxioCam camera connected to KS400 software (all
from Zeiss, Oberkochen, Germany), digital images (⫻100
magnification) of the entire tissue area of each slide were
obtained. A macro specifically designed for the quantification
of these stains was developed using the KS400 software, and a
total of 11,412 images were analyzed in a blinded manner. The
total lung tissue area, the area stained, and the number of
stained cells were quantified for each image, and the proportion of the total area stained and the total number of stained
cells per mm2 were calculated for each slide. Because the
studied variables did not have a normal distribution, the RA
and non-RA groups were compared using the Mann-Whitney
U test. Statistical analysis was performed using SAS software,
version 8.2 (SAS, Chicago, IL).
Figure 1. A, CD4⫹ cells (red stain) in a patient with rheumatoid
arthritis (RA) and nonspecific interstitial pneumonitis (IP). B, Scarcity
of CD4⫹ cells in a patient with nonspecific IP and no RA. C, CD4⫹
cells in a patient with RA and usual IP. D, Scarcity of CD4⫹ cells in
a patient with usual IP and no RA. (Original magnification ⫻ 100.)
In the RA group, 8 of 12 patients for whom
laboratory data were available were seropositive for
rheumatoid factor, and 5 of the 11 patients tested were
positive for antinuclear antibodies. Six patients with RA
had current or previous rheumatoid nodules, and 4 had
a history of nonpulmonary, severe extraarticular disease
manifestations consisting of pericarditis (n ⫽ 2) or major
cutaneous vasculitis (n ⫽ 2). The median duration of RA
was 7.5 years (interquartile range [IQR] 0.5–12.0 years)
Demographic data and PFT results are shown in
Table 1. Age distributions and results of all PFTs were
similar between the 2 groups. The female:male ratio was
1:1 among patients without RA and 1.5:1 among patients
with RA. Of the patients for whom data on smoking at
the time of lung biopsy were available, 4 of 13 in the RA
group and none of 16 in the non-RA group were current
smokers, whereas 7 of 13 in the RA group and 7 of 16 in
the non-RA group had been smokers at any time.
Among the patients without RA, 1 had psoriasis, 1 had
ulcerative colitis, and 1 had a prior diagnosis of extrapulmonary sarcoidosis. However, after a thorough clinical
and histopathologic evaluation, in none of these cases
was the presence of these inflammatory conditions considered to be the cause of the IP.
Figure 2. CD4⫹ cell counts per tissue area in patients with rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) versus
idiopathic ILD. Bars show the median and interquartile range.
Table 2. Quantification of immunohistochemical staining in patients
with RA-associated ILD compared with those with idiopathic ILD*
9.3 (5.5–27.3)
0.6 (0.2–1.9)
% of area stained 0.029 (0.013–0.083) 0.001 (0–0.006)
9.8 (2.9–17.5)
1.5 (0.4–5.2)
% of area stained 0.019 (0.005–0.035) 0.004 (0.001–0.011)
60.4 (10.9–112.5)
23.4 (7.9–53.8)
% of area stained 0.171 (0.029–0.270) 0.049 (0.016–0.148)
* Except where indicated otherwise, values are the median (interquartile range) of measured cell counts per tissue area or measured stained
area as a proportion of the total tissue area, both quantified by
computer-assisted image analysis. See Table 1 for definitions.
Figure 3. CD4⫹ cell counts per tissue area, by rheumatoid arthritis
(RA) diagnosis and nonspecific interstitial pneumonitis (NSIP) or
usual interstitial pneumonitis (UIP) classification. Each circle denotes
an individual patient.
at the time of lung biopsy. Two of the patients had
received treatment with methotrexate before the onset
of pulmonary symptoms. The clinical course and the
histopathologic picture on lung biopsy were not considered compatible with methotrexate-induced pneumonitis in either of these cases. Nine of the 15 patients in the
Figure 4. A, Perifollicular CD3⫹ cells (red stain) in a patient with RA
and nonspecific IP, with most cells in the aggregate being negative for
CD3. B, Subpleural infiltrate of CD8⫹ cells in a patient with RA and
nonspecific IP. C, Scattered peribronchiolar cells positive for CD16 in
a patient with RA and usual IP. D, Aggregate of mononuclear cells
positive for CD20 in a follicular structure, with scattered positive cells
in the surrounding lung tissue. See Figure 1 for definitions. (Original
magnification ⫻ 100.)
RA group were receiving glucocorticosteroids at the
time of the biopsy, as were 5 of 16 in the non-RA group.
Mononuclear cells staining for CD4 were present
in peribronchial infiltrates as well as in fibrotic interstitial lung tissue in patients with RA and IP (Figures 1A
and C). In most sections from patients with idiopathic
IP, only scattered CD4⫹ cells were seen (Figures 1B and
D). When quantified by computer-assisted image analysis, the number of CD4⫹ cells per tissue area was
significantly higher in patients with RA-associated IP
compared with control patients with non-RA IP (Figure
2), with a more than 10-fold increase, on average, in
CD4⫹ cell counts in the RA group. The median number
of CD4⫹ cells/mm2 was 9.3 (IQR 5.5–27.3) in the RA
group compared with 0.6 (IQR 0.2–1.9) in the non-RA
group (P ⫽ 0.002). When subdivided by histopathologic
classification, the increase in CD4⫹ cell counts among
RA patients, compared with controls, was similar between those with nonspecific IP and those with usual IP
(Figure 3).
Major infiltrates of CD3⫹ cells were seen in most
patients with RA-associated IP. Structures resembling
lymphoid follicles were identified, with CD3⫹ cells seen
mainly in a perifollicular distribution (Figure 4A).
CD3⫹ cell counts per tissue area were significantly
increased in patients with RA and IP compared with
non-RA patients with IP (P ⫽ 0.012). CD8⫹ cells,
including prominent peribronchial and subpleural infiltrates (Figure 4B), were also seen, with a trend toward
increased CD8⫹ cell counts in patients with RA. However, in contrast to the scores on CD4 and CD3 image
analysis, the corresponding quantification of CD8⫹ cells
did not reveal a significant difference between interstitial lung disease patients with and those without RA
(P ⫽ 0.27). Staining for CD4, CD3, and CD8 was also
quantified as the proportion of the total tissue area
stained for each of these cell types. These results were
similar to those of cell counts per tissue area (Table 2).
Scattered CD16⫹ cells were seen in tissue sections from patients with RA (Figure 4C) as well as from
patients without RA. Notably, aggregates of mononuclear cells in follicular structures were negative for
CD16, indicating that natural killer cells do not make up
a major part of these cell populations. Staining for CD20
revealed major aggregates of positive cells in structures
resembling lymphoid follicles with germinal centers
(Figure 4D).
In this study of lung biopsy tissue from patients
with RA-associated IP, we found a significantly increased number of CD4⫹ cells when compared with
patients with idiopathic IP. CD3⫹ cells were also significantly increased, whereas there was a less striking
difference for the CD8⫹ subset. The prominent increase
of CD4⫹ cell counts in patients with RA was similar
between those classified as having nonspecific IP and
those classified as having usual IP. These findings may
be of major importance to our understanding of the
nature of RA-associated lung disease.
RA is characterized by increased production of
proinflammatory cytokines of the Th1 subset (24,25).
Based on observations of synovial pathologic patterns
(20) and the strong association between HLA–DRB1
genotypes and RA (26,27), CD4⫹ T cells are considered
important in the pathogenesis of RA, although the role
of T cell antigen recognition in arthritis is unclear (28).
T cell abnormalities in RA include a marked contraction
of the T cell repertoire, with less diversity and emergence of dominant T cell clonotypes (29). In addition,
clonal expansion of CD4⫹ cells lacking the costimulatory molecule CD28 (21,30) is observed most markedly
in patients with severe extraarticular RA manifestations
(31). Associations between some extraarticular manifestations and class II major histocompatibility complex
(MHC) genes (in particular the HLA–DRB1*0401/0401
genotype) (32) and class I MHC genes (in particular
HLA–C3) (33) may be due to effects on the T cell
repertoire and on T cell activation. The observed increased pleural fluid concentrations of soluble
interleukin-2 receptor in patients with RA-associated
pleuritis, compared with patients with pleural exudates
of other origins (34), also support the importance of T
cell activation in RA-associated lung disease.
The present finding of more abundant CD8⫹
cells than CD4⫹ cells in IP lesions is consistent with the
findings in previous studies of idiopathic nonspecific IP
(35). The findings by other authors (35,36) of S100
protein–positive dendritic cells (DCs) in areas of lymphoid aggregates in interstitial lung disease specimens
support a role of T cell activation in interstitial lung
disease. Furthermore, in these studies, DCs were more
abundant in idiopathic nonspecific IP (35) and RAassociated usual IP (36) than in idiopathic usual IP.
Important immunopathologic differences in IP between
patients with RA and patients with idiopathic pulmonary
fibrosis may thus include several interacting cell populations. The role of the B cell aggregates observed in our
patients should also be further explored.
Patients with RA were more likely to be receiving
current treatment with glucocorticosteroids at the time
of lung biopsy than were patients with idiopathic IP.
Steroids would be expected to reduce lymphoid infiltrates, so this would, if anything, tend to diminish
differences in the number of cells positive for CD4 and
other markers between the RA group and the non-RA
group. Thus, treatment differences cannot explain our
Our selection of patients was done without
matching, but the age distribution and PFT results were
similar between the RA group and the control group.
Although our sample size was small, the ratio of women
to men of 1.5:1 in the RA group is compatible with an
overall 2–3-fold increase in the incidence of RA in
women compared with men (37), and is consistent with
a suggested association between male sex and lung
disease in patients with RA (38).
Current smoking was more frequent among patients with RA than among controls. Smoking is a risk
factor for RA (39), and, in patients with established RA,
is a predictor of severe extraarticular manifestations
(40), including IP (41). In transbronchial biopsy specimens from patients with chronic obstructive pulmonary
disease, CD8⫹ cells, but not CD4⫹ cells, were more
abundant in smokers (42–44). Therefore, the observed
increase in CD4⫹ cells in patients with RA cannot be
explained by the frequency of smoking.
There are no effective therapies for idiopathic
pulmonary fibrosis. Although many patients with idiopathic pulmonary fibrosis still receive corticosteroids,
cyclophosphamide, and azathioprine, there are no data
demonstrating efficacy of these agents on lung function
or survival. Randomized controlled trials have failed to
demonstrate a benefit from cyclophosphamide (45) or
azathioprine (46) in idiopathic pulmonary fibrosis.
There are no controlled trials demonstrating a benefit of
immunosuppressive therapies in RA-associated IP, but
studies of case series have suggested that interstitial lung
disease in the setting of RA and other CTDs may
respond better to immunosuppression (47). Individual
cases of RA-associated pulmonary fibrosis (with radiographic characteristics of usual IP) have been reported
to respond to cyclosporine (48–50) and infliximab (51).
The present results, which highlight the importance of
CD4⫹ T cells in RA-associated IP, suggest that treatment with drugs that suppress T cell activation or new
agents that interfere with T cell functions may be useful
in the treatment of RA-associated IP.
Our data also suggest that despite similarities in
the radiographic and histopathologic appearance, there
are fundamental differences in the pathophysiologic
patterns between RA-associated IP and idiopathic usual
and nonspecific IP. Furthermore, the distinction between usual IP and nonspecific IP may not have the
same significance in patients with RA and other CTDs
as it does in patients with idiopathic IP, since we found
markedly increased CD4⫹ cell counts in the RA with
usual IP subset. Although the number of patients with
usual IP in this study is too small for any final conclusions on this subset, our findings are consistent with the
observations by Nakamura et al, who found no difference in survival between usual IP and nonspecific IP
subgroups in a cohort of patients with CTD, in contrast
to a marked decrease of survival in idiopathic IP patients
with usual IP as compared with those with nonspecific IP
The major strength of this study is the thorough
quantification of T cell markers, which was done using
computer-assisted image analysis. This method enables
standardized assessment of all stained tissue, reducing
the risk of sampling error. Differences in the extent of
staining may thus be more reliably assessed than is
possible by semiquantitative methods. In our opinion, a
measure of the total tissue area by computer-assisted
image analysis should be included in any quantification
of immunohistochemical staining, and related to either
manual- or image-analysis–based cell counts in the same
tissue area.
In conclusion, we have demonstrated an increased number of CD4⫹ T cells in lung biopsy tissue
from patients with RA-associated IP compared with
patients having IP without RA. This difference seems to
be independent of the nonspecific versus usual IP classifications, supports the concept that RA-associated lung
disease is different from idiopathic pulmonary fibrosis,
and may have implications for the treatment of these
disorders. Further studies should explore the character-
istics and functional properties of CD4⫹ T cells in
RA-associated IP.
The authors thank James Tarara for excellent technical
help with microscopic photography and image analysis, Drs.
Sean Caples and Jay Ryu for providing access to patients with
RA and ILD, Dr. Karina Keogh for providing access to
patients with idiopathic ILD, and Dr. Jörg Goronzy for helpful
advice on the study.
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idiopathic, increase, cd4, pneumonitis, arthritisassociated, interstitial, compare, rheumatoid, infiltrates, cells
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