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Serum pulmonary and activation-regulated chemokineCCL18 levels in patients with systemic sclerosisA sensitive indicator of active pulmonary fibrosis.

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ARTHRITIS & RHEUMATISM
Vol. 52, No. 9, September 2005, pp 2889–2896
DOI 10.1002/art.21257
© 2005, American College of Rheumatology
Serum Pulmonary and Activation-Regulated
Chemokine/CCL18 Levels in Patients With Systemic Sclerosis
A Sensitive Indicator of Active Pulmonary Fibrosis
Masanari Kodera,1 Minoru Hasegawa,1 Kazuhiro Komura,1 Koichi Yanaba,1
Kazuhiko Takehara,1 and Shinichi Sato2
Objective. To clarify the clinical significance of
serum levels of pulmonary and activation-regulated
chemokine (PARC) in the diagnosis and monitoring of
pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc) and to compare PARC levels with KL-6
antigen or surfactant protein D (SP-D) levels.
Methods. Serum PARC levels were determined by
enzyme-linked immunosorbent assay in 123 SSc patients. In a retrospective longitudinal study, correlation
of serum PARC levels with the activity of PF was
assessed in 21 SSc patients with active PF.
Results. PARC levels at the first visit were higher
in patients with SSc than in patients with systemic lupus
erythematosus (SLE) or healthy controls. Increased
serum PARC levels were associated with involvement of
PF, decreased diffusing capacity for carbon monoxide,
and decreased vital capacity in SSc patients. In the
longitudinal study, serum PARC levels were significantly decreased in SSc patients with inactive PF compared with those with active PF.
Conclusion. Elevated serum PARC levels correlated with PF and more sensitively reflected the PF
activity than did serum KL-6 or SP-D levels in SSc.
Serum PARC levels may be a useful new serum marker
for active PF in SSc.
Systemic sclerosis (SSc) is a connective tissue
disease characterized by sclerotic changes in the skin and
internal organs. Pulmonary fibrosis (PF) develops in
more than 50% of SSc patients and is the major cause of
death (1). To assess the activity of PF, previous studies
have identified several important signs, including patchy
areas with a ground-glass or reticular appearance on
high-resolution computed tomography (HRCT) and
neutrophilic alveolitis on analysis of bronchoalveolar
lavage (BAL) fluid (1). However, easier, less-invasive,
and lung-specific serologic markers would be helpful for
closely monitoring the activity of PF in SSc patients.
KL-6 and surfactant protein D (SP-D) may be the
most reliable serum markers at present. KL-6 antigen is
expressed mainly on type II pneumocytes in alveoli and
respiratory bronchiolar epithelial cells (2), whereas
SP-D is produced and secreted by alveolar type II
pneumocytes in alveoli and Clara cells (3). Levels of
KL-6 and SP-D are elevated in the sera of patients with
interstitial lung diseases, including PF related to SSc
(2,4). Recent studies have shown that serum levels of
KL-6 and SP-D are a serologic marker of the severity
and activity of PF in SSc (5–7). However, in some SSc
patients with active PF, we sometimes found discrepancies in the serum levels of these 2 markers, as well as
elevated KL-6 and SP-D levels despite improvements in
clinical symptoms, HRCT findings, and pulmonary function test results after treatment with immunosuppressive
agents. Therefore, another serum marker that more
closely reflects PF activity is needed.
Pulmonary and activation-regulated chemokine
(PARC) might be a candidate marker. Also known as
1
Masanari Kodera, MD, Minoru Hasegawa, MD, PhD, Kazuhiro Komura, MD, PhD, Koichi Yanaba, MD, PhD, Kazuhiko
Takehara, MD, PhD: Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; 2Shinichi Sato, MD, PhD: Kanazawa
University Graduate School of Medical Science, Kanazawa, Japan, and
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Address correspondence and reprint requests to Shinichi
Sato, MD, PhD, Department of Dermatology, Nagasaki University
Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki
852-8501, Japan. E-mail: s-sato@net.nagasaki-u.ac.jp.
Submitted for publication October 7, 2004; accepted in revised form June 3, 2005.
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KODERA ET AL
macrophage inflammatory protein 4 (MIP-4), alternative macrophage activation-associated CC chemokine 1,
dendritic cell chemokine 1, CC chemokine ligand 18,
small secreted cytokine A-18, and chemokine ␤7, PARC
is structurally most closely related to MIP-1␣ (8,9), a
chemotactic factor for T lymphocytes. PARC is constitutively expressed at high levels in the lung (9), particularly by alveolar macrophages (10,11). A recent study
has shown that PARC stimulates collagen messenger
RNA (mRNA) and protein production by dermal and
lung fibroblasts (12). Furthermore, levels of PARC
protein in BAL fluid were found to be highly increased
in SSc patients with active PF compared with those without
PF and compared with healthy controls (12,13). PARC
protein and mRNA levels are also elevated in the lungs of
patients with interstitial lung diseases (10,14,15).
These findings suggest that PARC is an important cause of immune-mediated fibrotic lung diseases.
Therefore, PARC secreted mainly from alveolar macrophages in the lung may be detectable in serum and, if so,
could become a new lung-specific serologic marker in
SSc. To test this possibility, we evaluated serum levels of
PARC and examined their correlation with clinical
features in patients with SSc.
MATERIALS AND METHODS
Serum samples. Serum samples were obtained from
123 Japanese patients with SSc (106 women and 17 men). All
patients fulfilled the criteria proposed by the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) (16). Patients were grouped according to
the degree of skin involvement, based on the classification
system proposed by LeRoy et al (17): 70 patients (67 women
and 3 men) had limited cutaneous SSc (lcSSc), and 53 patients
(39 women and 14 men) had diffuse cutaneous SSc (dcSSc).
The age of the SSc patients was 51 ⫾ 14 years (mean ⫾ SD).
The disease duration in those with lcSSc was 8.8 ⫾ 9.8
(mean ⫾ SD) and the duration in those with dcSSc was 4.4 ⫾
6.6 years. None of the SSc patients received any treatment,
including corticosteroids, D-penicillamine, or other immunosuppressive therapy at their first visit.
Antinuclear antibody was determined by indirect immunofluorescence using HEp-2 cells as the substrate. Autoantibody specificities were further assessed by enzyme-linked
immunosorbent assay (ELISA) and immunoprecipitation. Anticentromere antibody was positive in 50 patients, anti–
topoisomerase I antibody was positive in 42, anti–U1 RNP
antibody was positive in 9, anti–U3 RNP antibody was positive
in 2, anti–RNA polymerases I and III antibody were positive in
4, anti-Th/To antibody was positive in 3, and antinuclear
antibody of unknown specificity was positive in 7. Six patients
were negative for autoantibodies.
Twenty-one patients with systemic lupus erythematosus (SLE) (19 women and 2 men; mean ⫾ SD age 34 ⫾ 9 years)
who fulfilled the ACR criteria (18) were also evaluated as
disease controls. In addition, 37 age- and sex-matched healthy
Japanese persons (32 women and 5 men; mean ⫾ SD age 49 ⫾
10 years) served as normal controls.
Samples of venous blood were drawn, allowed to clot,
and centrifuged shortly after clot formation. Sera were removed, and all samples were stored at –70°C prior to use.
Clinical assessments. Complete medical histories,
physical examinations, and laboratory tests were conducted on
all patients. The degree of skin involvement was determined
according to the modified Rodnan skin thickness score, as
described elsewhere (19). Organ system involvement was defined as described previously (6). Abnormal values for vital
capacity (VC) and diffusing capacity for carbon monoxide
(DLCO) were considered to be ⬍80% and ⬍75%, respectively,
of the predicted normal values.
The activity of the PF was initially determined by
HRCT of the chest, pulmonary function testing, and BAL fluid
analysis. Specifically, PF was considered to be active when the
following 3 criteria were met: a ground-glass appearance or
reticular pattern on HRCT of the chest (20), ⬎10% change in
VC or ⬎15% change in the DLCO within 1 year (21), and
⬎3.0% neutrophils or 2.2% eosinophils on BAL fluid analysis
(22). PF activity was monitored by serial HRCT scans of the
chest (findings scored according to the HRCT scoring system
[23]) and by pulmonary function testing, as previously described (24–26). In the HRCT scoring system (23), each lobe
of the lung was scored separately for the extent of ground-glass
opacity (ground-glass appearance) and reticular opacities and
honeycombing (fibrosis) using a 0–5 scale, where 0 ⫽ absent,
1 ⫽ ⬍5%, 2 ⫽ 5–25%, 3 ⫽ 25–50%, 4 ⫽ 50–75%, and 5 ⫽
⬎75%. A fibrotic score and a ground-glass score were calculated for each patient by determining the mean value for each
feature in all lobes.
The study protocol was approved by the Kanazawa
University Graduate School of Medical Science and the Kanazawa University Hospital. Informed consent was obtained
from all study participants.
Determination of PARC levels. Serum levels of PARC
were measured with a specific ELISA kit (R&D Systems,
Minneapolis, MN), according to the manufacturer’s protocol.
Briefly, 96-well plates were coated overnight at 25°C with
mouse anti-human PARC monoclonal antibodies and were
then blocked with phosphate buffered saline containing 1%
bovine serum albumin and 5% sucrose. Serum samples diluted
to 1:100 were added in duplicate, and the plates were incubated for 2 hours at 20°C. After washing, color was developed
with biotinylated goat anti-human PARC monoclonal antibodies and streptavidin–peroxidase. The detection limit of this
assay was 10 pg/ml.
Determination of KL-6 and SP-D levels. Serum levels
of KL-6 and SP-D were measured with specific ELISA kits
(Eitest KL-6 from Eisai, Tokyo, Japan; SP-D kit from Yamasa,
Chiba, Japan), according to the manufacturers’ protocols.
Briefly, 96-well plates were coated with monoclonal antibodies
to KL-6 or SP-D, and the diluted serum samples were added to
duplicate wells. After washing, the bound antibodies were
detected with peroxidase-conjugated monoclonal antibodies
against KL-6 or SP-D. The cutoff values for positivity were 500
units/ml for KL-6 and 110 ng/ml for SP-D (27,28).
SERUM PARC LEVELS IN SSC
2891
Statistical analysis. Statistical analysis was performed
using the Mann-Whitney U test and Wilcoxon’s signed rank
test for comparison of sample means, Fisher’s exact probability
test for comparison of frequencies, and Bonferroni’s test for
multiple comparisons. Spearman’s rank correlation coefficient
was used to examine the relationship between 2 continuous
variables. P values less than 0.05 were considered statistically
significant. All values are reported as the mean ⫾ SD.
RESULTS
Serum levels of PARC in SSc patients at the first
visit. The 123 SSc patients had significantly higher serum
PARC levels at the first visit (mean ⫾ SD 78.2 ⫾ 34.9
ng/ml) compared with the levels in the normal control
subjects (35.9 ⫾ 17.2) (P ⬍ 0.0001) and in the SLE
control patients (51.4 ⫾ 17.8) (P ⬍ 0.002) (Figure 1).
PARC levels in the sera of dcSSc patients (90.2 ⫾ 36.9)
were significantly increased compared with those in the
normal controls and in the SLE patients (P ⬍ 0.0001 for
both comparisons). Serum PARC levels in the lcSSc
patients (69.2 ⫾ 30.7) were also significantly elevated
relative to those in the normal controls (P ⬍ 0.0001) and
the SLE patients (P ⬍ 0.01). Patients with dcSSc had
higher serum PARC levels than did patients with lcSSc
(P ⬍ 0.01). PARC levels in the SLE control patients
were also significantly increased compared with those in
the normal control subjects (P ⬍ 0.05).
Frequency of elevated serum PARC levels and
correlation with clinical features in SSc. The upper limit
of the normal range of serum PARC levels was determined as the mean ⫹ 2 SD of the levels in the healthy
control subjects (70.3 ng/ml). Elevated serum PARC
levels were observed in 56% of the SSc patients (69 of
123), 66% of the dcSSc patients (35 of 53), and 49% of
lcSSc patients (34 of 70). The levels were not elevated in
the normal controls and were increased in only 14% of
the SLE patient controls (3 of 21) (Figure 1).
With regard to the disease stage, 57% of the SSc
patients with normal levels of PARC (31 of 54 patients)
and 70% of those with elevated levels (48 of 69 patients)
had early disease (disease duration ⬍5 years) (Table 1).
With regard to the disease pattern, 31% of the SSc
patients with normal levels of PARC (17 of 54 patients)
and 52% of those with elevated levels (36 of 69 patients)
had dcSSc. SSc patients with elevated PARC levels had
a significantly increased prevalence of PF and significantly decreased VC and DLCO values (% predicted)
relative to those in SSc patients with normal PARC
levels (P ⬍ 0.005 for all comparisons). Anti–
topoisomerase I antibody was more frequent in SSc
patients with elevated levels of PARC than in those with
Figure 1. Levels of pulmonary and activation-regulated chemokine
(PARC) in serum samples from patients with diffuse cutaneous
systemic sclerosis (dcSSc), limited cutaneous SSc (lcSSc), and systemic
lupus erythematosus (SLE) as well as healthy controls (CTL). Serum
PARC levels were determined by enzyme-linked immunosorbent
assay. Broken line indicates the mean ⫹ 2 SD level of PARC in sera
from normal controls. Bars show the group means.
normal levels (P ⬍ 0.005), whereas anticentromere
antibody was less frequent in SSc patients with elevated
levels of PARC than in those with normal levels (P ⬍
0.05). Furthermore, serum levels of PARC correlated
inversely with DLCO (r ⫽ –0.326, P ⬍ 0.001) and with
VC (r ⫽ –0.244, P ⬍ 0.01) values (Figure 2).
Correlation between serum PARC levels and PF
activity. To determine whether the changes in serum
PARC levels correlated with the activity of PF, we
analyzed serum samples obtained at the time of active
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KODERA ET AL
Table 1.
Clinical and laboratory features of SSc patients, grouped according to serum PARC levels*
Sex, no. males/females
Age, mean ⫾ SD years
Disease duration, mean ⫾ SD years
Disease stage, no. with early/late disease
Disease pattern, no. with dcSSc/lcSSc
Clinical features
MRSS, mean ⫾ SD
Digital pitting scars or ulcers
Contracture of phalanges
Diffuse pigmentation
Organ involvement
Lungs
Pulmonary fibrosis
VC, mean ⫾ SD % predicted
DLCO, mean ⫾ SD % predicted
Pulmonary hypertension
Esophagus
Heart
Kidneys
Joints
Muscles
Laboratory findings
Anti–topoisomerase I antibodies
Anticentromere antibodies
Elevated ESR
Elevated CRP
Elevated IgG
Elevated PARC (n ⫽ 69)
Normal PARC (n ⫽ 54)
10/59
46.4 ⫾ 16.4
6.8 ⫾ 9.4
48/21
36/33†
7/47
43.3 ⫾ 14.4
7.0 ⫾ 8.0
31/23
17/37
12.0 ⫾ 10.6
41
45
51
9.5 ⫾ 8.1
28
42
42
59‡
90.0 ⫾ 21.6‡
54.8 ⫾ 14.6‡
11
49
20
23
23
14
27
102.7 ⫾ 24.7
65.6 ⫾ 16.2
11
49
9
9
28
17
42‡
31†
25
19
46
18
57
36
15
30
* Except where indicated otherwise, values are percentages. SSc ⫽ systemic sclerosis; PARC ⫽ pulmonary
and activation-regulated chemokine; dcSSc ⫽ diffuse cutaneous SSc; lcSSc ⫽ limited cutaneous SSc;
MRSS ⫽ modified Rodnan skin thickness score; VC ⫽ vital capacity; DLCO ⫽ diffusing capacity for
carbon monoxide; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽ C-reactive protein.
† P ⬍ 0.05.
‡ P ⬍ 0.005.
Figure 2. Correlation of serum levels of pulmonary and activation-regulated chemokine (PARC) with vital capacity (VC) and with diffusing
capacity for carbon monoxide (DLCO) (% predicted) in patients with systemic sclerosis (SSc). Serum PARC levels were determined by
enzyme-linked immunosorbent assay.
SERUM PARC LEVELS IN SSC
2893
Figure 3. Changes in serum levels of pulmonary and activation-regulated chemokine (PARC), KL-6 antigen, and surfactant protein D (SP-D)
during active and inactive pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc). Serum samples were obtained during an active phase and
an inactive phase of PF in 21 SSc patients who had anti–topoisomerase I antibodies. PARC, KL-6, and SP-D levels were determined by
enzyme-linked immunosorbent assay. Broken lines indicate cutoff values for normal levels.
and inactive phases of PF in 21 SSc patients who had
anti–topoisomerase I antibody (Figure 3). These patients initially exhibited active PF by HRCT (mean ⫾ SD
fibrosis score 1.9 ⫾ 0.9 and mean ⫾ SD ground-glass
score 2.1 ⫾ 0.8), pulmonary function testing, and BAL
fluid analysis. The disease duration in 17 of these 21
patients was ⬍5 years (mean 2.1 years), and the mean
followup period was 4.9 years (range 2–9 years).
Changes in serum PARC levels in these 21
patients were also compared with changes in serum
KL-6 and SP-D levels. Serum levels of PARC, KL-6, and
SP-D decreased significantly in parallel with an improvement in PF activity (P ⬍ 0.0001, P ⬍ 0.05, and P ⬍ 0.001,
respectively). However, serum PARC levels increased in
only 1 of the 21 patients during inactive PF (fibrosis
score 1.7 ⫾ 0.9; ground-glass score 1.5 ⫾ 1.3), whereas 7
patients and 5 patients had increased KL-6 and SP-D
levels, respectively, during inactive PF.
Two patients (patients 1 and 2) exhibited a
drastic decrease in serum PARC levels in parallel with a
significant improvement in the PF activity. Patient 1
showed a slight increase in KL-6 and SP-D levels in the
presence of mild PF on HRCT of the chest at the first
visit (Figure 4A). Seven months after the first visit, KL-6
and SP-D levels increased in parallel with a subacute
deterioration of the PF activity. On HRCT of the chest,
the ground-glass appearance and reticular shadow were
increased. Like the KL-6 and SP-D levels, the serum
PARC level gradually increased to 83 ng/ml (from 71
ng/ml at the first visit). Intravenous pulse cyclophosphamide treatment was started, followed by an
increase in the oral prednisolone dosage and initiation
of oral cyclosporine. The PF activity stabilized, and the
serum PARC level rapidly decreased to the normal
range. The levels of KL-6 and SP-D, however, increased
during the 5 months following the last cyclophosphamide pulse treatment and finally began to decrease 6 months later.
Patient 2 had high levels of KL-6 and SP-D, a
ground-glass appearance on HRCT of the chest, and
decreased DLCO and VC values at the first visit (Figure
4B). Pulse therapy with cyclophosphamide and oral
prednisolone were initiated. Levels of KL-6 and SP-D
gradually began to decrease, but at 8 months after
cyclophosphamide treatment, when progression of PF
activity had ceased, neither was below the normal range.
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KODERA ET AL
Figure 4. Serial changes in serum levels of pulmonary and activation-regulated chemokine (PARC), KL-6 antigen, and surfactant protein D (SP-D)
during the followup period in 2 patients with diffuse cutaneous systemic sclerosis. PARC, KL-6, and SP-D levels were determined by enzyme-linked
immunosorbent assay. %VC ⫽ vital capacity (% predicted); %DLCO ⫽ diffusing capacity for carbon monoxide (% predicted); HRCT ⫽
high-resolution computed tomography (of the chest; see Patients and Methods for the derivation of the fibrosis and ground-glass scores).
However, the serum PARC level was increased at 108
ng/ml at the first visit, and after the first cyclophosphamide pulse, it rapidly decreased to the normal
range.
DISCUSSION
In the present study, serum PARC levels were
elevated in association with PF activity in patients with
SSc. This study is the first to evaluate serum levels of
PARC in a large number of SSc patients. Recent studies
have shown that levels of PARC protein are increased in
BAL fluid from SSc patients with lung inflammation, as
compared with levels in patients without lung inflammation and in healthy controls (12,13). Although the mechanism of PF in SSc remains unknown, several chemokines are involved in the fibrotic process of PF
associated with SSc by indirectly promoting fibrosis
through attracting and activating the profibrotic activities of inflammatory cells, including alveolar macrophages (29). PARC is produced abundantly by alveolar
macrophages (10,11,13) and slightly by peripheral blood
monocytes, tissue macrophages, and dendritic cells
(10,11). Therefore, the increased levels of PARC in the
serum of SSc patients with PF may be derived from
alveolar macrophages. Since PARC has a chemotactic
effect on lymphocytes and monocyte/macrophages (30),
it may mediate the recruitment of lymphocytes and
monocyte/macrophages into the lung tissues during the
development of PF in SSc.
The current longitudinal study showed that serum PARC levels correlated with the activity of PF.
Many studies have indicated that serum KL-6 and SP-D
levels are useful, sensitive diagnostic markers and indicators of disease activity in patients with pulmonary
interstitial diseases (4–7). Our recent study (5) has
suggested that the combined use of KL-6 and SP-D
measurements is more helpful in the diagnosis and
monitoring of the activity of PF in SSc patients than is
the use of either marker alone. However, the fluctuations in SP-D and KL-6 concentrations are not parallel
and are sometimes still elevated even after treatment
results in an improvement in the PF activity. In this
study, serum levels of PARC, KL-6, and SP-D were all
significantly decreased in parallel with improvement in
PF activity. However, the serum PARC levels most
closely reflected the activity of the PF, since all but 1 of
SERUM PARC LEVELS IN SSC
the patients exhibited a decrease in serum PARC levels
after progression of the PF activity had ceased. Moreover, the serum PARC levels decreased sooner than the
serum KL-6 and SP-D levels after PF progression had
ceased in 2 patients who were treated with intravenous
pulse cyclophosphamide. Although studies with larger
numbers of SSc patients will be needed to confirm our
findings, serum PARC levels may be a new and useful
marker of the activity of PF in SSc.
Serum PARC levels, which probably derive from
activated alveolar macrophages, may reflect the lung
inflammation that precedes fibrotic changes. With serum SP-D levels, however, elevations are induced by the
destruction of the alveolar endothelium, followed by
spillover of SP-D into the bloodstream, so they may
reflect the extent of injury of the alveolar endothelium
(27). KL-6 is abundantly expressed on regenerating and
proliferating type II pneumocytes in patients with pulmonary interstitial diseases (2). With an increase in
epithelial and vascular permeability, KL-6 may flow into
blood vessels in a soluble form. Thus, the increase in
serum SP-D is due to destruction of the alveolar endothelium, whereas the increase in serum KL-6 reflects the
regeneration and proliferation of pneumocytes. In the
process of PF stabilization, infiltration of inflammatory
cells, including activated macrophages, into the lung may
decrease first, and then the permeability of the air–
blood barrier and destruction of alveolar endothelium
may be suppressed. Therefore, it is possible for serum
levels of PARC to decrease more rapidly, in parallel with
a decrease in lung inflammation, since they are derived
from activated alveolar macrophages than for serum
levels of SP-D or KL-6 to decrease, since they are
released by injury of the alveoli or by the regenerative
proliferation of pneumocytes.
Although PARC was more sensitive for assessing
PF activity than was SP-D or KL-6, correlations between
PARC levels and the VC or the DLCO were not strong,
which is also the case for SP-D and KL-6 levels (5). This
is a limitation when evaluating PF activity with the use of
serum markers. Nonetheless, it does not diminish the
clinical significance of serum markers, since they represent simple, easy, and noninvasive techniques and can be
assessed repeatedly. However, it should be noted that
PARC levels must be interpreted in combination with
the findings of other laboratory tests and radiologic
assessments to precisely evaluate the activity of PF.
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