Clin Rheumatol (2016) 35:113116

DOI 10.1007/s10067-015-3139-z

ORIGINAL ARTICLE

Predictive factors of rapidly progressive-interstitial lung disease

in patients with clinically amyopathic dermatomyositis
Y. Xu 1 & C. S. Yang 2 & Y. J. Li 1 & X. D. Liu 1 & J. N. Wang 1 & Q. Zhao 1 & W. G. Xiao 1 &
P. T. Yang 1

Received: 12 August 2015 / Revised: 29 October 2015 / Accepted: 28 November 2015 / Published online: 10 December 2015
# International League of Associations for Rheumatology (ILAR) 2015

Abstract Clinically amyopathic dermatomyositis (CADM) is

a unique subset of dermatomyositis, showing a high incidence
of lung involvements. The aim of this study is to identify risk
factors, other than melanoma differentiation-associated protein (MDA)-5, for developing rapidly progressive-interstitial
lung disease (RP-ILD) in patients with CADM. Forty CADM
patients, in whom 11 patients developed RP-ILD, were enrolled. Clinical features and laboratory findings were compared between the patients with and without RP-ILD. We
found that skin ulceration, CRP, serum ferritin, anti-MDA5
Ab, and lymphocytopenia were significantly associated with
ILD. Multivariate logistic regression analysis indicated that
anti-MDA5 Ab+, elevated CRP, and decreased counts of lymphocyte were independent risk factors for RP-ILD, which can
provide a precise predict for RP-ILD in CADM patients.
When anti-MDA5 Ab+ was removed from the multivariate
regression model, using skin ulcerations, elevated serum ferritin and decreased counts of lymphocyte can also precisely
predict RP-ILD. Except for MDA-5, more commonly available clinical characteristics, such as skin ulcerations, serum
ferritin, and count of lymphocyte may also help to predict
prognosis in CADM.

Y. Xu and C. S. Yang contributed equally to this work.

* P. T. Yang
yangpingtingting@163.com
1

Department of Rheumatology and Immunology, First Affiliated

Hospital, China Medical University, Shenyang 110001, Peoples
Republic of China

Department of 1st Cancer Institute, First Affiliated Hospital, China

Medical University, Shenyang 110001, Peoples Republic of China

Keywords Amyopathic dermatomyositis . Biomarkers .

Comorbidity . Rheumatic diseases

Introduction
Clinically amyopathic dermatomyositis (CADM) is a distinct
subtype of dermatomyositis (DM) that causes the same cutaneous symptoms as classic DM with little or no evidence of
muscular manifestations [13]. It has been reported that
CADM represents an estimated 20 % of all DM patients.
CADM is also characterized by an increased risk of lung disease, such as interstitial lung disease (ILD) [4, 5]. The lung
involvement becomes the most common cause of respiratory
failure and death in CADM. In particular, rapidly progressiveinterstitial lung disease (RP-ILD) in patients with DM is frequently fatal within months [6]. Therefore, predictive factors
for RP-ILD are very important in the management of patients
with CADM.
In 2005, Sato et al. identified a novel autoantibody
rec ognizin g a 14 0-kDa a utoantige n, m elan oma
differentiation-associated protein (MDA)-5, in patients
with DM, particularly in those with CADM [7].
Accumulating evidences have demonstrated that MDA5 is associated with ILD and severe cutaneous vasculopathy in CADM [710]. However, the main barrier is
that the determination of MDA-5 is limited in research
laboratories. On the other hand, we have realized that
there may be some other clinical manifestations associating with the poor outcome in CADM.
In this study, we summarized the clinical data to explore the
risk factors which are related to developing RP-ILD in patients
with CADM. We also evaluated the predicting value of serum
anti-MDA5 antibody and other clinical manifestations to

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Clin Rheumatol (2016) 35:113116

develop RP-ILD in a cohort of CADM patients from a single

center in China.

Materials and methods

Patients
Forty patients with CADM from the First Affiliated Hospital
of China Medical University were retrospectively reviewed.
Diagnosis of CADM was established according to the criteria
of ENMC workshop [11]. Patients were excluded from the
study due to history of neoplasm, recent acute infection, pulmonary infarction, or presence of heart failure. No other connective tissue diseases or malignancy concomitantly were
found in these patients. Systemic treatment of
glucocorticosteroid, cyclophosphamide, and intravenous immunoglobulin started from the date of diagnosis. The diagnosis of ILD was established by the findings of high-resolution
chest computed tomography (HRCT), according to the
International Consensus Statement of Idiopathic Pulmonary
Fibrosis of the American Thoracic Society [12] and the definition proposed by Suda et al. [13]. The RP-ILD was defined
as a progressive deterioration of ILD within 3 months.
Except routine items, arthritis/arthralgia, skin ulcerations,
mechanics hand, Raynauds phenomenon, Gottrons sign, heliotrope rash, as well as fever were specially noted. Serum
levels of creatine kinase (CK), lactate dehydrogenase
(LDH), erythrocyte sedimentation rate (ESR), C-reactive

Table 1 Comparison of clinic

data between the patients with or
without RP-ILD
Age, meanSD years
Male:female
Disease duration (months)
Arthritis/arthralgia
Mechanicss hands
Raynauds phenomenon
Skin ulcerations
ESR >50 mmH2O/1 h
CRP >50 g/L
Serum ferritin >2000 g/L
Lymphocytes <500/L
CD4+ T <200/L
CD8+ T <200/L
ANA+
Anti-Jo-1 Ab+
Anti-MDA-5 Ab+
a

protein (CRP), as well as ferritin were detected. Antinuclear

antibodies (ANA) and antibodies directed against extractable
nuclear antigen (ENA) were also recorded. All data of these
variables were obtained before the initiation of treatment in
order to assess the predictive factors of RP-ILD. All patients
underwent electromyography (EMG) examination and 15 patients underwent muscle biopsy. The whole research was approved by the local ethic commission of the First Affiliated
Hospital of China Medical University.
Anti-MDA5 detection
Anti-MDA5 was determined by our in-house ELISA. Briefly,
96-well ELISA plates were coated with 100 ng of purified
recombinant MDA5 (Abcam, UK), diluted in phosphate buffered saline (PBS), and left to stand overnight at 4 C. Wells
were incubated for 1 h at room temperature with blocking
buffer (10 % nonfat dry milk in PBS). After washing, patient
serum samples diluted 1:100 in blocking buffer were added in
duplicate. Background absorbance was determined by the
MDA5-coated wells in which 100 l PBS, instead of patient
sera, were added in. Plates were incubated at RT for 1 h. After
washing, HRP-labeled goat anti-human IgG antibody
(Abcam, UK) was added to each well and plates were incubated for 1 h at RT and washed again. Color development was
performed with peroxidase reagent TMB Chromogen
(Abcam, UK) and absorbances at 450 nm were determined.
For each sample, the background absorbance from the PBScoated well was subtracted from that of the corresponding

With RP-ILD (n=11)

Without RP-ILD (n=29)

P valueb

53.69.7
5:6
2.93.1
1 (10 %)a
1 (10 %)
1 (10 %)
6 (55 %)
7 (64 %)
6 (55 %)
7 (64 %)
6 (55 %)
7 (64 %)
6 (55 %)
9 (82 %)
0 (0 %)
8 (73 %)

48.813.1
13:16
29.015.9
5 (17 %)
5 (11 %)
3 (10 %)
5 (17 %)
7 (24 %)
4 (14 %)
3 (10 %)
3 (10 %)
4 (14 %)
5 (17 %)
19 (66 %)
3 (10 %)
4 (14 %)

0.28
0.62
0.00
0.46
0.46
0.70
0.04
0.03
0.01
0.00
0.01
0.00
0.03
0.28
0.37
0.00

Values are the number (percentage) unless otherwise indicated

Obtained with Fishers exact test for the comparison of frequencies, Mann-Whitney U test for the comparison of
age and disease duration, and the t test for the comparisons of mean values

Clin Rheumatol (2016) 35:113116

Table 2 Univariate logistic
regression analysis on risk factors
associated with RP-ILD in
CADM patients

115

Wald

OR

95 % CI for OR

P value

Skin ulcerations

1.75

5.04

5.76

1.2526.57

0.03

ESR >50 mmH2O/1 h

1.71

5.00

5.50

1.2324.51

0.03

CRP >50 g/L

Serum ferritin >2000 ng/mL

2.39
2.72

8.38
9.67

10.94
15.17

2.1755.25
2.7384.18

0.00
0.00

Lymphocytes <500/L

2.34

7.43

10.40

1.9356.04

0.01

CD4 <200/L
CD8 <200/L

2.39
1.75

8.38
5.04

10.94
5.76

2.1755.25
1.2526.57

0.00
0.03

Anti-MDA5 antibody (+)

2.81

10.58

16.67

3.0690.82

0.00

B regression coefficient, OR odds ratio, CI credibility interval

MDA5-coated wells. The cutoff value for a positive result on

ELISA was established at 0.212 absorbance units, which
corresponded to 2.5 standard deviations above the mean value
obtained for 15 healthy controls.
Statistical analyses
Data were compared by Students t test or the MannWhitney test for continuous variables. Categorical variables were assessed by the chi-square test or Fishers
exact test. We adopted logistic regression models to identify the risk factors for ILD. Results of the regression
models were shown as the odds ratio (OR) and 95 %
confidence interval (95 % CI). In all of the statistical
tests, the level of significance was set at 5 %.

Results
Forty adult CADM patients were enrolled in the study. The
patients were divided into two groups: CADM + RP-ILD (n=
11) and CADM (n=29), according to having RP-ILD or not.
Six patients had already shown RP-ILD at the initial diagnosis
of CADM. The clinical characteristics of the patients are summarized in Table 1. It should be noted that the disease duration, estimated from the onset of subjective symptoms to the

Table 3 Multivariable logistic

regression analysis on risk factors
for RP-ILD in CADM patient

Including anti-MDA5 Ab+

Anti-MDA5 Ab+
CRP >50 g/L
Lymphocytes <500 L
Excluding anti-MDA5 Ab+
Lymphocytes <500 L
Serum ferritin >2000 ng/mL
Skin ulcerations

establishment of CADM diagnosis, was significantly shorter

in CADM + RP-ILD group than in CADM group (P<0.001,
Mann-Whitney U test). This difference was mainly caused by
the fact that some patients without RP-ILD were not diagnosed in time due to the concealed characteristics of CADM.
Because the disease duration was strongly affected by subjective factors, we excluded it from further regression analysis.
Table 2 shows the results of univariate logistic regression
analysis, indicating that skin ulcerations, elevated ESR, CRP
and serum ferritin, peripheral lymphocytopenia, decreased
peripheral CD4+ and CD8+ T cells, and anti-MDA5 Ab+
were significantly associated with RP-ILD, respectively (all
P<0.05). We then used a multivariable logistic model to predict RP-ILD in the patients. When anti-MDA5 Ab+ was
included in the model, three independent risk factors: antiMDA5+, CRP >50 g/L, and lymphocytes <500/L can
generate an overall correct percentage of 90.0 for predicting
RP-ILD. When anti-MDA5 Ab+ was removed from the multiple regression model, lymphocytes <500/L, serum ferritin
>2000 g/L, and skin ulcerations can also provide a correct
percentage of 87.5 for predicting RP-ILD (Table 3).
Furthermore, ten of the 11 RP-ILD patients died within
3 months after the diagnosis. Such a high mortality rate
(90.9 %) indicates that the predictive factors for PR-ILD
diagnosis are also equivalent to the risk factors for the poor
prognosis.

Wald

OR

95 % CI or OR

P value

2.53
2.31
2.34

5.63
4.38
3.95

12.54
10.09
10.40

1.56101.36
1.1687.93
1.03104.79

0.02
0.04
0.05

2.55
3.78
2.86

3.90
7.12
4.35

12.75
43.97
17.37

1.02159.65
2.73708.80
1.19254.09

0.05
0.01
0.04

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Clin Rheumatol (2016) 35:113116

Discussion
CADM is a unique subset of DM, showing a high incidence of
fatal ILD. It has been established that anti-MDA5 Ab was an
important predictive factor for the poor outcome of ILD
[710]. However, the present problem is that there is no commercial method available for detecting MDA-5 Ab in clinic.
In the present study, we found that except for anti-MDA5 Ab,
routine clinical indexes, including skin ulcerations, serum ferritin level, and lymphocyte counts, may also help predict RPILD in patients with CADM.
Several previous studies have revealed an association between skin ulcer and RP-ILD in the patients with DM [4, 14,
15]. They reported that skin ulcers were observed in 7 of 12
(58 %), 7 of 9 (78 %), and 5 of 15 (33 %) DM patients with
RP-ILD, respectively. In our study, skin ulcer was found in 6
of 11 (55 %) patients with CADM concomitant with RP-ILD,
which is comparable to the previous results. The association
between skin ulcer and ILD may indicate that vasculitis is the
common pathological cause of skin changes and ILD.
Previously, Gono et al. have reported that elevated levels of
serum ferritin were related to the severity of ILD in patients
with DM [16]. They found that the cumulative survival rate
was lower in the subset with ferritin >1500 ng/mL than that in
the subset with ferritin <1500 ng/mL in DM patients. Here, we
found that the presence of serum ferritin >2000 g/L was
statistically more frequent in the CADM patients with RPILD than in those without it (64 versus 10 %). Ferritin is the
major molecule for iron storage, which is mainly secreted by
the activating macrophages and plays a crucial role in sequestration of potentially harmful molecules of reactive iron. High
levels of serum ferritin may reflect aberrant production of
ferritin by activating macrophages in patients with RP-ILD.
In addition, though lymphocytopenia has been reported in
DM patients, our results, for the first time, revealed that
lymphocytopenia is related to RP-ILD.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.
Acknowledgments The work is supported by National Nature Science
Foundation of China of under Grant (No. 81271324) and Liaoning Province Nature Science Funds (201202250) to PT Yang.
Compliance with ethical standards The whole research was approved
by the local ethic commission of the First Affiliated Hospital of China
Medical University.

13.

14.
Disclosures None.

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