doi: 10.2169/internalmedicine.9553-17
Intern Med 57: 1039-1043, 2018
http://internmed.jp【 CASE REPORT 】

Successful Treatment of Rapidly Progressive Unclassifiable
Idiopathic Interstitial Pneumonia with Anti-melanoma
Differentiation-associated Gene-5 Antibody by Intensive
Immunosuppressive Therapy
Takuma Koga 1, Shinjiro Kaieda 1, Masaki Okamoto 1, Ken Masuda 1, Kyoko Fujimoto 1,
Satoshi Sakamoto 1, Masayuki Nakamura 1, Masaki Tominaga 1, Tomotaka Kawayama 1,Kiminori Fujimoto 2, Tomoaki Hoshino 1 and Hiroaki Ida 1

Abstract:
We describe a case of a woman who presented with a persistent cough, general fatigue, and a fever. Interstitial lung disease was rapidly progressive and resistant to high-dose steroid therapy. She tested positive forthe presence of anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, although she had no skinmanifestations of dermatomyositis. She was eventually diagnosed with unclassifiable idiopathic interstitial
pneumonia and was successfully treated with intensive immunosuppressive therapy including intravenous cyclophosphamide. To our knowledge, this is the first report of anti-MDA-5 antibody in a patient with idiopathic interstitial pneumonia.
Key words: anti-MDA-5 antibody, idiopathic pneumonia with autoimmune features (IPAF), rapidly
progressive interstitial lung disease, unclassifiable idiopathic interstitial pneumonia (UCIP)(Intern Med 57: 1039-1043, 2018)(DOI: 10.2169/internalmedicine.9553-17)

Introduction
Anti-melanoma differentiation-associated gene 5 (MDA-5)
antibody has a close relationship with rapidly progressive interstitial lung disease (RP-ILD) in East Asian patients withclinically amyopathic dermatomyositis (CADM) and is associated with increased mortality (1-3). Anti-MDA-5 antibody
has been reported to be a diagnostic marker for classic dermatomyositis (DM) and CADM and it is not detected inpolymyositis (PM), non-PM/DM connective tissue disease(CTD), or idiopathic interstitial pneumonia (IIP) (2, 4). Nevertheless, we encountered a patient with anti-MDA-5 antibody positive-RP-ILD who lacked typical skin manifestations of DM. She was diagnosed with unclassifiable idiopathic interstitial pneumonia (UCIP) according to theglobal classification of IIP (5). UCIP is the term used forcases that cannot be classified into the major subtypes ofIIP. The patient had an autoimmune-featured ILD, and she
did not meet the criteria for a defined CTD.
To our knowledge, the presence of anti-MDA-5 antibody
in a patient with IIP has not been reported previously.

Case Report
A 61-year-old woman presented at another institution
with a persistent cough, general fatigue, and fever in August
2016. She had no history of smoking. No skin alterations,
including heliotrope rash and Gottron’s sign, were observed.
Chest radiographs showed consolidations and ground-glass
opacities (GGOs), predominantly in the bilateral lower lungfields, as well as a decrease in basal lung volume (Fig. 1a).
Chest high-resolution computed tomography (HRCT) revealed patchy consolidation and GGOs with dilated air

１

Department of Medicine, Division of Respirology, Neurology, and Rheumatology, Kurume University School of Medicine, Japan and ２ Department of Radiology, Kurume University School of Medicine, Japan
Received: May 24, 2017; Accepted: August 8, 2017; Advance Publication by J-STAGE: December 21, 2017
Correspondence to Dr. Shinjiro Kaieda, kaieda@med.kurume-u.ac.jp1039

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Figure 1. Pulmonary manifestations at the initial diagnosis (a, b, and c) and on the 106th day ofhospitalization (d, e, and f). Chest radiograph (a) shows consolidations and GGOs in the bilateral lungfields and decrease in the basal lung volume at the initial diagnosis of interstitial lung disease. HRCT(b, right middle lung zone and c, left lower lung zone) shows patchy consolidations and GGOs (arrowhead) with dilated air bronchogram (white arrows). Lung volume loss in the bilateral lung fields
at the 106th day of hospitalization is indicated on chest radiography (d). Bilateral consolidations andGGOs are shown to be reduced on chest HRCT (e and f). GGOs: ground-glass opacities, HRCT: highresolution computed tomography

bronchogram, predominantly in the bilateral middle andlower lung zones, suggesting ILD with a radiologic patternof non-specific interstitial pneumonia (NSIP) with organizing pneumonia (OP) (Fig. 1b and c). Pleural effusion was
not detected. A transbronchial lung biopsy demonstrated
non-specific inflammatory changes. A predominance of lymphoid cells was confirmed in bronchopulmonary lavage (total cell count, 530/μL; lymphocytes, 57%; neutrophils, 9%;monocytes, 31%; eosinophils 3%). Infectious lung disease
was excluded by the bronchoscopy results, and the patient
was diagnosed with IIP. The subtype of IIP was classified
according to the global classification of IIP as UCIP (5). A

surgical lung biopsy was not performed because of hypoxia.
Steroid pulse therapy was initiated in mid August, followedby oral prednisolone 60 mg/day (1 mg/kg). High-dose steroid therapy did not improve ILD. She was transferred to ourdepartment for further therapy in late August.
On admission to our hospital, a physical examination revealed no skin alterations, including heliotrope rash, Gottron’s sign, palmar papules, or skin ulcers (Fig. 2). In addition, we did not observe Koebner phenomenon around thejoint, periungual erythema, or nail fold bleeding. Furthermore, Raynaud’s phenomenon, arthralgia, and myalgia werenot present. Manual muscle testing (MMT) by a neurologist

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Figure 2. Clinical presentation on admission to our hospital.
Gottron’s sign, periungual erythema, and mechanic’s hands
were not observed.

revealed mild weakness of the gluteus maximus muscle on
both sides (MMT score, 4/4). On chest auscultation, heartsounds were clear, but fine crackles were audible over bilateral lower lung fields. A laboratory evaluation revealed
slight elevation of aldolase at 11.1 U/L (normal range: 2.16.1 U/L), whereas creatinine phosphokinase and myoglobin
were within normal range. In addition, levels of C-reactive
protein, lactate dehydrogenase, aspartate aminotransferase,
and alanine aminotransferase were slightly elevated (0.35mg/dL, 264 U/L, 48 U/L, and 95 U/L, respectively), andlevels of serum ferritin and KL-6 were elevated (344 ng/mL
and 822 U/mL, respectively). Results of immunologic tests
were negative for antinuclear antibodies, anti-aminoacyltRNA synthetase antibodies and anti-neutrophil cytoplasmic
antibodies. An arterial blood gas analysis on 0.5 L/min oxygen showed hypoxia (PaO2, 80.5 Torr). The percentage vital
capacity predicted (%VC) was very low, 35.4% on admission, and because of this, the percentage diffusing capacityof the lung for carbon monoxide predicted was not evaluated.
Chest radiograph indicated an exacerbation of volume loss
via lung fibrosis (Fig. 1, 3). Cardiac ultrasonography revealed that left ventricular function was well-maintained,and pulmonary hypertension was excluded. Myopathy was
not detected in the iliopsoas, gluteus, or femoral muscles bymagnetic resonance imaging (MRI). Myogenic alterations ofthe iliopsoas and the quadriceps muscles were not observed
by electromyography. A muscle biopsy was not performed
because myopathy was not detected by MRI or electromyography. Although the patient did not meet the Japanesecriteria for a diagnosis of DM (revised in 2015), anti-MDA5 antibody was detected by an enzyme-linked immunosorbent assay (MESACUP anti-MDA-5 ELISA kit; Medical &Biological Laboratories, Nagoya, Japan) with a high titer(index 147, normal range: <32). We noted that lung involvement progressed rapidly, and the patient’s hypoxia worsened. PaO2 was 58.6 torr under 1 L/min oxygen on the 50thday of hospitalization (Fig. 3). The patient met the diagnostic criteria of RP-ILD because of the severe and rapidly progressing condition of ILD, as previously reported (6).
Her ILD was resistant to steroid therapy and showed asimilar pathophysiology to RP-ILD complicated by antiMDA-5 antibody-positive DM. Intravenous cyclophosphamide [IVCY; 840 mg (500 mg/mm2)] and tacrolimus
therapy was initiated. The dose of tacrolimus was started at
0.025 mg/kg twice a day, and the trough was adjusted to 10ng/mL. A dose of 3 mg of tacrolimus elevated the troughlevel to 13.8 ng/mL, and nephrotic syndrome was induced.
The dose of tacrolimus was decreased to 2.4 mg, but thenephrotic syndrome did not improve, and tacrolimus wasdiscontinued. After the nephrotic syndrome improved,
tacrolimus was resumed, and the trough was adjusted to 510 ng/mL. We repeated IVCY every 2 weeks and increased
the IVCY dosage to 900 mg. High-dose intravenous immunoglobulin was also given. Levels of serum ferritin were elevated to a maximum of 893 ng/mL on the 50th day of hospitalization.
After the fourth cycle of IVCY therapy, hypoxia began toimprove, and the serum levels of ferritin were decreased to767 ng/mL on the 64th day of hospitalization and reachedthe lowest values, 226 ng/mL, before discharge from ourhospital. The titer of anti-MDA-5 antibodies was also decreased. Although a loss of volume in the bilateral lungfields was indicated on chest radiography, the bilateral consolidations and GGOs were reduced on chest HRCT on the106th day of hospitalization (Fig. 1d-f). We recorded a %VC ranging from 34% to 40.7%. The clinical course is summarized in Fig. 3.

Discussion
The presence of anti-MDA-5 antibodies identifies a population of patients with CADM who have an increased risk
for RP-ILD. The 5-year survival rate of patients with antiMDA-5 antibodies has been reported to be 56% (2). Serum
ferritin levels !
450 ng/mL on admission have been reported
to be poor prognostic markers (3, 7, 8). Furthermore, rightmiddle lobe GGO involving >5% of the lobe on HRCT has
also been indicated as a poor prognostic factor in anti
MDA-5 antibody-positive DM-ILD patients (7). While serum ferritin levels were elevated only slightly (344 ng/mL)in the present case, the GGO areas in the right middle lobe
on HRCT accounted for 10%, representing a poor prognostic factor.
The administration of intensive immunosuppressive therapy, including high-dose corticosteroids, oral calcineurin inhibitor, and IVCY, prior to the onset of irreversible pulmonary changes might lead to an improved prognosis (9). In
the present case, UCIP was rapidly progressive and resistant
to high-dose steroid therapy. Repeated IVCY inhibited theacute exacerbation of ILD and decreased the serum ferritin
and anti-MDA-5 antibody titer.
While the patient had mild muscle weakness with a slightelevation of serum aldolase, myopathy was not confirmed on
MRI or electromyography. We could not exclude the possibility of polymyositis because a muscle biopsy was not performed. However, a diagnosis of CADM or DM was ruled1041

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Figure 3. The clinical course of the patient. IVCY: intravenous pulse cyclophosphamide, IVIG:
intravenous immunoglobulin, PSL: prednisolone, Tac: tacrolimus, %VC: percentage vital capacity
predicted

out because our patient lacked the typical skin manifestations observed with DM. A multicenter cross-sectional study
indicated that a subset of anti-CADM-140 (MDA-5)
antibody-positive patients develop lung disease without skinor muscle manifestation as initial symptoms (2). ILD may
precede skin involvement, and high-dose steroid therapy
may mask the development of skin and muscle damage.
However, the patient was diagnosed with UCIP because theunderlying disorder did not meet the classification criteria ofa given CTD.
Many patients with IIPs have subtle features suggestive ofan autoimmune etiology; however, these patients are classified as having UCIP because they do not meet the diagnostic criteria for CTD. Recently, classification criteria for interstitial pneumonia with autoimmune features (IPAF) wereproposed (10). These criteria are organized around three
central domains: a clinical domain consisting of specific extrathoracic features such as arthritis, Raynaud’s phenome-non, and Gottron’s sign; a serologic domain consisting ofspecific circulating autoantibodies, including anti-MDA-5
antibody; and a morphologic domain consisting of specificchest imaging features. In addition to the typical skin manifestations, which include Gottron’s sign, minor skin alterations such as periungual erythema and nail fold bleeding
should be noted. To be classified as having IPAF, an individual must present with at least one feature from at least twodomains. Our patient was classified as having IPAF due tothe presence of anti-MDA-5 antibody in the serologic domain and NSIP with an OP pattern on HRCT in the morphologic domain. If patients develop RP-ILD with autoimmune features and demonstrate a pathology similar to antiMDA-5 antibody-positive DM-ILD, the presence of antiMDA-5 antibody should be suspected. Thus, knowledge ofthe clinical features of anti-MDA-5 antibody-positive DMILD, including skin alterations, radiological findings, andchanges in pulmonary function, is crucial. In addition, the1042

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collaboration of dermatologists, rheumatologists, radiologists, and respiratory medicine specialists might be requiredin order to identify all of these clinical features.
If a patient develops RP-ILD with autoimmune features
and anti-MDA-5 antibody is detected, intensive immunosuppressive therapy including IVCY should be considered.
The authors state that they have no Conflict of Interest (COI).
Shinjiro Kaieda and Masaki Okamoto contributed equally tothis work.

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Ⓒ 2018 The Japanese Society of Internal Medicine
Intern Med 57: 1039-1043, 20181043