ORIGINAL ARTICLE

Skin ulcer is a predictive and prognostic factor of acuteor subacute interstitial lung disease in dermatomyositis

Kazuyoshi Ishigaki • Junko Maruyama • Noboru Hagino •

Atsuko Murota • Yasunobu Takizawa • Ran Nakashima •

Tsuneyo Mimori • Keigo Setoguchi

Received: 23 May 2011 / Accepted: 24 March 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract The aim of this study was to determine whether

skin ulcer can be used as a predictive and prognostic factor

of acute/subacute interstitial lung disease (ILD) in Japanese

patients with dermatomyositis (DM). We reviewed the

medical records of 39 consecutive DM patients who were

admitted to Tokyo Metropolitan Komagome Hospital from

January 2000 to December 2009. The mean follow-up

period was 63.9 ± 51.6 months. Fifteen patients had acute/

subacute ILD and 11 patients had chronic ILD. Seven out

of 15 acute/subacute ILD led to respiratory failure and 3 of

them died due to ILD. Skin ulcers were observed in 5 out

of 15 patients with acute/subacute ILD (33.3 %) and in 2

out of 24 patients without acute/subacute ILD (8.3 %). The

presence of skin ulcers was revealed to be a significant

predictive factor for acute/subacute ILD among various

parameters by multivariate analysis. In the 15 patients with

acute/subacute ILD, the presence of skin ulcers was a

significant poor prognostic factor (p = 0.0231) and the

cumulative survival rate of patients with skin ulcers was

53.3 % for 12 months. Skin ulcer is a significant predictive

and prognostic factor of acute/subacute ILD in patients

with DM.

Keywords Dermatomyositis � Interstitial lung disease �Skin ulcer � Prognostic factor

Introduction

Dermatomyositis (DM) is a systemic inflammatory disease

of unknown etiology that affects skin, skeletal muscles, and

other internal organs. About 5–65 % of inflammatory

myositis cases are complicated with interstitial lung disease

(ILD) [1–4]. ILD is one of the major poor prognostic factors

of PM and DM. Chen et al. [3] reported that the survival rate

of patients with ILD was 56.7 % at 1 year and was signif-

icantly worse than in patients without ILD in cases with PM

and DM. Many reports have investigated poor prognostic

factors of ILD in PM and DM until now. They have included

features of amyopathic dermatomyositis, high ferritin levels,

low forced vital capacity (FVC), low diffusing capacity of

carbon monoxide (DLco), neutrophil alveolitis, and histol-

ogy of usual interstitial pneumonitis [1, 2, 5, 6]. In partic-

ular, acute/subacute ILD in patients with DM is frequently

fatal within months despite high-dose prednisolone (PSL)

therapy [7]. Therefore, predictive factors and prognostic

factors for acute/subacute ILD are very important in the

management of patients with DM.

We recently experienced several DM patients who

presented with skin ulcers and suffered from intractable

ILD. In the patient profile of the article published by Ideura

et al. [8], skin ulcers in DM were observed in 7 of 9 rapidly

progressive ILD patients (77.8 %), while they were

observed in only 3 of 9 patients with slowly progressive

ILD (33.3 %). Ye et al. [9] reported that 7 of 12 DM

patients (58.3 %) with necrotic skin lesions died mainly

due to ILD during the follow-up period. Mimori et al. [10]

also reported 2 DM cases with ILD complicated with skin

K. Ishigaki (&) � J. Maruyama � A. Murota � Y. Takizawa �K. Setoguchi

Department of Allergy and Immunological Diseases,

Tokyo Metropolitan Komagome Hospital, 3-18-22,

Honkomagome, Bunkyo-ku, Tokyo, Japan

e-mail: kazuyoshi@mbe.nifty.com

K. Ishigaki � N. Hagino

Department of Allergy and Rheumatology, Graduate School

of Medicine, University of Tokyo, Bunkyo, Japan

R. Nakashima � T. Mimori

Department of Rheumatology and Clinical Immunology,

Kyoto University Graduate School of Medicine, Kyoto, Japan

123

Rheumatol Int

DOI 10.1007/s00296-013-2735-y

ulcers who subsequently died of ILD. Although several

reports have suggested that skin ulcer is a potential prog-

nostic factor of ILD in DM, there have been no reports

clearly demonstrating this relation.

The purpose of this study was to determine whether skin

ulcer can be used as a predictive and prognostic factor of

acute/subacute ILD in Japanese patients with DM. We also

assessed the clinical significance of anti-CADM-140 anti-

body, which is reportedly associated with DM complicated

with severe ILD [11, 12].

Methods

Patients

We retrospectively analyzed the data from medical records

of Tokyo Metropolitan Komagome Hospital. We included

all DM patients who were admitted to our hospital between

January 2000 and December 2009. All patients had active

problems of skin rash, myopathy, respiratory symptoms, or

a combination of these. We excluded cases who were

admitted primarily for infections, fractures, or any other

conditions not related to DM or ILD. We also excluded

juvenile onset DM and cases with overlap syndrome who

met classification criteria of systemic lupus erythematosus

(SLE), systemic sclerosis (SSc), or mixed connective tissue

disease (MCTD). The diagnosis of DM was made

according to the Bohan and Peter criteria. We also diag-

nosed patients with DM who had hallmark cutaneous

manifestations of classical DM with no clinical evidence of

muscle weakness and divided them into amyopathic DM

(ADM), hypomyopathic DM (HDM), and premyopathic

DM according to the definition of Sontheimer et al. [13].

The study was approved by the ethical committee in our

institution, according to the Declaration of Helsinki. All

patients gave their informed consent.

Interstitial lung disease

Screening methods for ILD included review of patient

history, lung auscultation, and chest radiography findings.

Patients with abnormalities underwent high-resolution

chest computed tomography (HRCT). Patients were diag-

nosed with ILD if they had HRCT findings consistent with

ILD (reticulonodular, ground-glass attenuation or opacities,

consolidations, irregularity of the interfaces between

peripheral pleura and aerated lung parenchyma, or honey-

combing or traction bronchiectasis). All HRCTs were

judged by 2 radiologists.

Patients with ILD were classified into two categories

according to clinical presentations: acute/subacute or

chronic ILD. The acute/subacute ILD was defined as

rapidly progressive ILD showing deterioration within

3 months. According to the International Consensus

Statement of Idiopathic Pulmonary Fibrosis of the Ameri-

can Thoracic Society [14] and the definition proposed by

Suda et al. [15], the deterioration was defined by two or

more of the following: 1) symptomatic exacerbation

(dyspnea on exertion); 2) an increase in opacities on HRCT

scan; and 3) physiological change defined by one of the

following, [10 % decrease in vital capacity (VC) or

worsening of O2 saturation ([4 percentage point decrease

in the measured saturation). The chronic form was defined

as a slowly progressive ILD that gradually deteriorated over

[3 months.

Clinical and laboratory data

Skin ulcers were defined by the disintegration of the skin

with the loss of epidermis. Underlying calcinosis was

excluded by physical examination and plain film radiog-

raphy. Respiratory failure was defined as hypoxia requiring

chronic oxygen therapy and death primarily due to ILD.

We obtained all clinical data from the medical charts of

the period between the admission and the initiation of

treatment. In one referral case where the patient had

already been treated before admission to our hospital, we

obtained the clinical data of the period before the initiation

of the treatment from the previous hospital.

All patients underwent a detailed medical history and

physical examination. Blood tests included C-reactive

protein (CRP), erythrocyte sedimentation rate (ESR), fer-

ritin, creatine phosphokinase (CPK), lactate dehydrogenase

(LDH), aspartate transaminase (AST), alanine transami-

nase (ALT), c-glutamyl transpeptidase (c-GTP), sialylated

carbohydrate antigen KL-6 (KL-6), surfactant protein D

(SP-D), rheumatoid factor (RF), and antinuclear antibody

(ANA), using standard methods. MRI muscle scan, elec-

tromyography, muscle biopsy, and pulmonary function

tests (PFTs) were performed as routine evaluations, but

could not be obtained in several cases owing to the poor

general condition of patients.

Autoantibody determination

All serum samples were tested for anti-Jo1 antibody

activity at SRL, Tokyo, where enzyme-linked immuno-

sorbent assay (ELISA) was used. Anti-CADM-140 anti-

body was assayed in 8 cases by immunoprecipitation using

extracts of HeLa cells and recombinant human IFN

induced with helicase C domain protein 1 (IFIH1). Details

of this assay were previously reported by Nakashima et al.

[12].

Rheumatol Int

123

Statistical analysis

Univariate and multivariate logistic regression analyses

were used to study the predictive factors for acute/subacute

ILD. We included the whole variables for the initial anal-

ysis. Variables found significant at p \ 0.15 by univariate

analysis were then subjected to multivariate analysis.

Patients with missing values for the variables used were

excluded. The cumulative survival rate was calculated

using Kaplan–Meier test. The log-rank test was also used to

compare survival. A p value of less than or equal to 0.05

was considered to be significant. Data were analyzed using

SPSS 19 statistical software (SPSS, Chicago, IL, USA).

Results

Epidemiological and clinical data

The clinical data are summarized in Table 1. Thirty-nine

DM patients were included in this study. Mean follow-up

period was 63.9 ± 51.6 months. Twenty-five patients had

apparent muscle involvement. Out of the 14 DM patients

without muscle weakness, 8 patients were categorized as

premyopathic DM, 5 patients were categorized as HDM,

and 1 patient was categorized as ADM according to the

definition of Sontheimer et al. [13]. In 8 patients, we

detected underlying malignant disease before the initiation

of the treatments and an additional 3 patients developed

malignancies after the initiation of the treatments. In total,

11 patients had malignancies. Fifteen patients had acute/

subacute ILD and 11 patients had chronic ILD. Out of 15

acute/subacute ILD patients, 7 patients developed respira-

tory failure and 3 of them died due to ILD.

Seven patients had skin ulcers. Table 2 summarizes the

sites of the ulcers, the appearance, and other clinical data of

the cases with skin ulcers. Six of them (case 2–7, Table 2)

had ulcers at the extensor surfaces of joints, that is, to say

the same distribution as Gottron’s signs. Four cases had

superficial shallow ulcers partially covered by crusts, and 2

cases had round and sharply circumscribed punched-out

ulcers and 1 case had ulcers with intractable skin necrosis.

Figure 1 shows encrusted superficial ulcers on the extensor

surface of elbow in case 5. None of them had anti-

phospholipid syndrome (APS). Pathological examination

of the lesions before the initiation of the treatment was

available only in one patient, which detected no signs of

vasculitis and only showed perivascular dermatitis consis-

tent with DM.

Predictive factors for acute/subacute ILD

Table 3 shows the comparison between clinical findings of

DM with and without acute/subacute ILD. All data of these

variables were obtained before the initiation of treatment in

order to assess the predictive factors of acute/subacute ILD.

Number of cases with missing values was shown in the

table. The 3 patients who had malignancies after the ini-

tiation of treatment were not included here. In order to

assess predictive factors for acute/subacute ILD, we per-

formed univariate analysis in the first place followed by

multivariate analysis. The presence of malignancy, fever,

skin ulcer, DLco, VC, CRP, RF, ANA, and anti-Jo1 anti-

body was found significant at p \ 0.15 by univariate

analysis and was then subjected to multivariate analysis.

ESR and ferritin were excluded in multivariate analysis due

to strong correlation with CRP (the Spearman correlation

coefficient was 0.716 and 0.71, respectively). The presence

of skin ulcers, fever, lower DLco, and positive rheumatoid

factor revealed to be significant predictive factors for acute/

subacute ILD by multivariate analysis.

Prognostic factors for acute/subacute ILD

Aside from the 3 patients who died of ILD as mentioned

above, there were 6 additional deaths due to other causes.

Three of them were due to malignancy and the other 3 were

due to gastrointestinal perforation, congestive heart failure,

and accident. Figure 2 shows the cumulative survival and

cumulative survival without respiratory failure, where we

counted death not related to ILD as censored cases.

Although not significant, cumulative survival rate was

lower in cases with acute/subacute ILD than without it

Table 1 Summary of clinical data

Classification

Subjects, n 39

Age, years 59.6 ± 13.6

Female, n (%) 27 (69.2)

Muscle weakness, n (%) 25 (64.1)

Skin ulcer, n (%) 7 (17.9)

Malignancya, n (%) 11 (28.2)

Interstitial lung disease, n (%)

None 13 (33.3)

Chronic ILD 11 (28.2)

Acute/subacute ILD 15 (38.4)

Respiratory failure due to ILD, n (%) 7 (17.9)

Cause of death, n (%)

ILD 3 (7.6)

Malignancy 3 (7.6)

Other causeb 3 (7.6)

Data of age are mean ± SDa Out of 11 patients, 3 patients developed malignancies after the

initiation of the treatmentb Gastrointestinal perforation, congestive heart failure and suicide

Rheumatol Int

123

(p = 0.073, 80 vs. 100 % at 12 months, Fig. 1a). Cumu-

lative survival rate without respiratory failure was signifi-

cantly lower in cases with acute/subacute ILD than without

it (p = 0.0023, 66.6 vs. 100 % at 12 months, Fig. 1b). Of

the 15 DM patients with acute/subacute ILD patients, the

presence of skin ulcers was a significant poor prognostic

factor (p = 0.0231) and the cumulative survival rate was

53.3 % at 12 months (Fig. 1c) and the cumulative survival

rate without respiratory failure was 40 % at 12 months

(Fig. 1d). The other factors listed on Table 3 were not

significantly associated with survival.

A/S ILD: acute/subacute ILD. (A), (B): cumulative

survival rate and cumulative survival rate without respira-

tory failure, respectively, in cases with/without acute/sub-

acute ILD. (C), (D): cumulative survival rate and

cumulative survival rate without respiratory failure,

respectively, in acute/subacute ILD cases with/without skin

ulcers.

Anti-CADM-140 antibody

Eight serum samples were assayed for anti-CADM-140

antibodies. Out of 4 cases with this antibody, 3 cases had

respiratory failure and 2 of them died due to ILD. Out of 4

patients without this antibody, 2 cases had respiratory

failure, but none of them died due to ILD. These clinical

data are shown in Table 4.

Treatment

The details of treatment are summarized in Table 5. Cor-

ticosteroids were used in every case, except 4 cases without

acute/subacute ILD. Immunosuppressants were adminis-

tered in 8 cases with acute/subacute ILD (53.3 %) and 5

cases without it (20.8 %). Intravenous cyclophosphamide

(IVCY) was the most frequently used immunosuppressant

Table 2 Characteristics of cases with skin ulcers

Case Site Appearance Biopsy A/S ILDa Death Malignancy APS RPb Weaknessc CRPd Ferritine

1 Fingertips, lateral

side of fingers

Punched-out ulcer - ? – – – – – 1.2 573

2 Elbows, shoulders,

buttocks

Encrusted superficial

ulcer

- ? ? - - ND - 5.4 862

3 Shoulders, back,

ears

Necrotic ulcer - - ?# Lung cancer - - ? 2.1 575

4 MCPsf, face Encrusted superficial

ulcer

- - - - - - - 0.3 682

5 MCPsf, elbows,

shoulders

Encrusted superficial

ulcer

? ? ? - - - - 12.6 2,601

6 MCPsf Punched-out ulcer - ? ?## - - - - 0.6 92.7

7 Back Encrusted superficial

ulcer

- ? ?# Gastric cancer - - ? 4.1 ND

a Acute/subacute ILDb Raynaud phenomenonc Muscle weaknessd mg/dle ng/mlf Metacarpophalangeal joints# death due to malignancy, ## Death due to suicide

Fig. 1 Encrusted superficial ulcers on the extensor surface of elbow

in case 5

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123

in acute/subacute ILD, whereas no cases were treated with

IVCY in cases without acute/subacute ILD.

The 2 deceased patients, out of 5 cases with skin ulcers

and acute/subacute ILD, were treated with glucocorticoid

and IVCY and one of them was also given cyclosporine

simultaneously. These treatments started several days

before their respiratory conditions deteriorated and both

cases were intubated. Out of the other 3 cases who sur-

vived, 1 case was treated with glucocorticoid alone and

survived without respiratory failure. Another case was

treated with glucocorticoid, IVCY and cyclosporine, and

also survived without respiratory failure. The other case

was treated with glucocorticoid, IVCY and tacrolimus, and

these combination treatments started when she began to be

dependent on a small amount of oxygen therapy with nasal

cannula.

Discussion

Many data support the theory that DM patients with acute/

subacute ILD have a worse prognosis than patients without

it [1, 6, 8, 15]. We also demonstrated the same trend in the

DM cases with acute/subacute ILD in terms of cumulative

survival rate and cumulative survival rate without respira-

tory failure, although our results were not significant for the

cumulative survival rate. It is meaningful to predict which

cases will develop acute/subacute ILD in order to deter-

mine a prognosis in the early phase. However, just know-

ing the predictive factor of acute/subacute ILD is not

enough to determine the treatment strategy, because the

treatment responsiveness varied significantly and some

cases had a more severe course than others, despite

intensive treatment in our DM cases with acute/subacute

Table 3 Clinical characteristics and predictive factors of acute/subacute ILD in DM

Variables Missing valuec DM with A/S ILD DM without A/S ILD Univariate

analysis

Multivariate analysis

p value OR p value

Subjects, n 15 24

Age 0 63.5 ± 10.6 57.2 ± 14.9 0.304

Female, n (%) 0 11 (73.3) 16 (66.6) 0.572

Malignancy, n (%)a 0 0 (0) 8 (100) 0.072 0.874

Smoking, n (%) 4 5 (38.4) 5 (20.8) 0.462

Muscle weakness, n (%) 0 8 (53.3) 17 (70.8) 0.16

Fever, n (%)b 1 8 (53.3) 6 (25.0) 0.004* 9.958 (1.048–94.609) 0.045*

Arthritis, n (%) 2 11 (73.3) 17 (70.8) 0.257

Skin ulcer, n (%) 0 5 (33.3) 2 (8.3) 0.043* 71.459 (1.358–3761.544) 0.035*

%DLco, % 11 44 (23–116) 79 (32–169) 0.013* 0.937 (0.891–0.986) 0.013*

%VC, % 6 66 (47–107) 88 (51–131) 0.007* 0.961

CRP, mg/dl 1 3.9 (0.1–12.6) 0.3 (0.1–4.3) 0.005* 0.062

ESR, mm/hr 7 54 (18–113) 39 (10–87) 0.032*

Ferritin, ng/ml 14 489 (30.2–3,000) 151 (5.5–682) 0.065

CPK, IU/l 0 413 (32–6,035) 916.5 (28–26,100) 0.542

LDH, IU/l 0 519 (224–801) 394.5 (174–3,643) 0.534

AST, IU/l 0 74 (18–241) 56 (21–807) 0.481

ALT, IU/l 0 64 (15–142) 39.5 (12–548) 0.337

c-GTP, IU/l 7 21 (15–112) 17 (5–43) 0.974

KL-6, U/ml 17 646 (211–2,118) 520 (192–4,020) 0.586

SP-D, ng/ml 21 107 (17–276) 182 (17.3–364) 0.606

RF, n (%) 2 5 (33.3) 2 (8.3) 0.06 61.939 (2.447–1567.821) 0.012*

ANA, n (%) 0 2 (13.3) 11 (45.8) 0.034* 0.135

Anti-Jo1, n (%) 0 5 (33.3) 5 (20.8) 0.125 0.138

A/S ILD acute/subacute ILD. Categorical data are n (%), data of age are mean ± S.D, and other continuous values are median (range)

* p value less than 0.05. p-values were obtained with logistic regression analysisa The 3 patients who developed malignancies after the initiation of treatment were not includedb Fever was defined as a temperature above 38 degrees centigradec Number of cases with missing values

Rheumatol Int

123

ILD. The heterogeneous nature of acute/subacute ILD of

DM is consistent with previous reports [1, 6, 8, 15]. From a

practical point of view, the knowledge of prognostic factors

associated with acute/subacute ILD in the early stage of the

disease is crucial for the early initiation of intensive

treatments. Because all clinical data used in this analysis

were obtained from the period before the initiation of the

treatment, they were appropriate candidates of predictive

and prognostic factors of acute/subacute ILD.

We have demonstrated for the first time that skin ulcer is

a significant predictive and prognostic factor of acute/

subacute ILD in DM. Because the sites of skin ulcers in this

Fig. 2 The cumulative rate of

all survival and survival without

respiratory failure for

12 months

Table 4 Clinical characteristics of patients with or without anti-CADM-140 antibody

Case CADM140 A/S ILDa Respiratory

failure

Deathb Skin

ulcer

Weaknessc Fever Arthritis CRPd Ferritine CPKf RF ANA Jo1

1 ? ? ? ? ? - ? ? 5.4 862 32 - - -

2 ? ? ? ? ? - - ? 12.6 2,601 1,529 - - -

3 ? ? ? - - - ? ? 4.3 489 138 ? - -

4 ? - - - - - - ? 0.1 5.5 28 - - -

5 - ? 1 - ? - - ? 0.6 92 37 - - -

6 - ? 1 - - ? ? ? 3.9 3,000 3,476 ? - -

7 - - - - - - - ? 1.0 117 594 - - ?

8 - - - - - - - - 0.2 93 51 NA ? -

a Acute/subacute ILDb Death due to ILDc Muscle weaknessd mg/dle ng/mlf IU/l

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123

study had a similar distribution to Gottron’s signs, and no

cases had APS or Raynaud’s phenomena, we determined

that the underlying pathophysiology of skin ulcers was not

simply due to circulatory insufficiency. Based on the

background that several investigators showed pathological

evidence of vasculitis in their case reports of DM with skin

ulcers [16–19], we speculate some vasculitic components

might exist in our cases with skin ulcers and this might

have contributed to the refractoriness to intensive therapy

and poor prognosis of ILD. Historically, skin ulcers in DM

had been related to malignancy [10, 20–22]. Although 2 of

7 cases with skin ulcers (28.5 %) had malignancy and died

from this condition during the follow-up periods, the fre-

quency of malignancy was about the same as that of all

patients in this study (28.2 %), which is higher than pre-

viously reported, probably because our hospital specialized

in malignant diseases [23].

Although some articles discuss the predictive factors of

ILD without sorting them into acute/subacute and chronic

ILD, it is more clinically meaningful to investigate spe-

cifically the predictive factors of acute/subacute ILD,

separating from chronic ILD, because evidence supports

that acute/subacute ILD is a distinct type of ILD with a

worse prognosis than others as discussed above. Gono et al.

[6] recently reported that high ferritin levels predict the

occurrence of acute/subacute ILD. Although our data

indicate high ferritin levels might also be another predic-

tive factor of acute/subacute ILD in univariate analysis

(p = 0.065, Table 3), it was excluded in multivariate

analysis due to strong correlation with CRP. Several

reports demonstrated that ILD, especially acute/subacute

ILD, in clinically amyopathic dermatomyositis (CADM)

had a worse prognosis than ILD in classical DM [9, 15, 24].

However, we showed that the absence of muscle weakness

was not a statistically significant predictive or prognostic

factor of acute/subacute ILD. The absence of muscle

weakness might be a useful indicator of ILD in DM, but

there are several weak points. The examination of muscle

weakness can be subjective, with some interobserver var-

iability, and it might be hard to assess muscle weakness

precisely in cases with impending respiratory failure and

poor general conditions. The presence of skin ulcers could

serve as an alternative factor.

Anti-CADM-140 autoantibody has been shown to be a

marker of DM and intractable ILD, and Nakashima et al.

[11, 12] recently reported that IFIH1/MDA5 was the

autoantigen identified by the anti-CADM-140 antibody.

Two cases out of the 4 DM patients with anti-CADM-140

antibody subsequently died due to ILD. Both of these

patients had CADM and skin ulcers, high ferritin levels and

high CRP levels (Table 4). Anti-CADM-140 antibody may

be informative to predict the prognosis of DM, although it

is hard to conclude the clinical usefulness of anti-CADM-

140 antibody from our study because patients who were

tested for this antibody were selected arbitrarily and the

sample size was small.

As show in Table 5, 3 cases with skin ulcers and acute/

subacute ILD were treated with glucocorticoid, IVCY, and

calcineurin inhibitor. Two of them survived and 1 of them

died of ILD. The treatment delay seemed to be one of the

reasons for the poor outcome. Although we cannot con-

clude the optimal treatment regimen and timing of

Table 5 Comparison of

treatment between cases with or

without skin ulcers and acute/

subacute ILD

HD high dose, PSLprednisolone, mPSLmethylprednisolone, IVCYintravenous cyclophosphamide,

IVIG intravenous

immunoglobulina One case in each group died

due to ILD

Treatments DM with acute/subacute

ILD, with skin ulcers

DM with acute/subacute

ILD, without skin ulcers

DM without

acute/subacute

ILD

Number of patients 5 10 24

No treatment 0 0 4

HD PSL alone 0 2 7

HD PSL ? mPSL pulse 1 4a 8

HD PSL ? immunosuppressant 0 2 3

HD PSL ? mPSL pulse ?

immunosuppressant

4 2 2

Immunosuppressant

IVCY 1a 3 0

IVCY ? tacrolimus 1 0 0

IVCY ? cyclosporine 2a 0 0

Tacrolimus 0 1 0

Methotrexate 0 0 2

Azathioprine 0 0 2

IVIG ? cyclosporine 0 0 1

Rheumatol Int

123

treatment initiation from these limited data, several other

reports also suggested the effectiveness of early adminis-

tration of glucocorticoid and immunosuppressant, espe-

cially the combination of IVCY and calcineurin inhibitor

[7, 25]. We conclude that it is important to consider initi-

ating a combination therapy of glucocorticoid, IVCY, and

calcineurin inhibition in the early phase of acute/subacute

ILD before respiratory conditions deteriorate in cases with

skin ulcers or other poor prognostic factors.

The prevalence of ILD might be underestimated as only

patients with abnormal findings on physical examination,

past medical history, or chest X-Ray proceeded to HRCT.

However, the chances of missing the cases with acute/

subacute ILD must be significantly low because those cases

must have abnormal findings on those screening test. We

focused on only the predictive and prognostic factors of

acute/subacute ILD, not chronic ILD. Therefore, our

approach did not create a significant problem in our study.

There are several limitations in this study. First, the

retrospective nature and small sample size of this study

allows for a selection bias that limits firm conclusions.

Secondly, we could not clearly demonstrate the underlying

pathophysiology of skin ulcers, which can explain the

association with poor prognosis of acute/subacute ILD

because of insufficient pathological data. Thirdly, the

radiologists were not blinded to the clinical background

and that might produce another bias.

In conclusion, we have demonstrated that skin ulcer is a

significant predictive and prognostic factor of acute/suba-

cute ILD in DM patients. Combination immunosuppressive

therapy should be considered to prevent respiratory failure

in DM patients presenting with skin ulcers and acute/sub-

acute ILD from the early phase of their disease course.

Conflict of interest The authors have declared no conflicts of

interest.

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