Modern Rheumatology
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Anti-MDA-5 antibody-positive bullous dermatomyositis with palmar papules complicating rapidly progressive interstitial lung disease Noriki Fujimoto, Shinichiro Honda, Makiko Wakabayashi, Yasuhito Hamaguchi, Manabu Fujimoto & Toshihiro Tanaka To cite this article: Noriki Fujimoto, Shinichiro Honda, Makiko Wakabayashi, Yasuhito Hamaguchi, Manabu Fujimoto & Toshihiro Tanaka (2014): Anti-MDA-5 antibody-positive bullous dermatomyositis with palmar papules complicating rapidly progressive interstitial lung disease, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2014.908811
Published online: 20 May 2014.
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Date: 05 November 2015, At: 18:10
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–3 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.908811
CASE REPORT
Anti-MDA-5 antibody-positive bullous dermatomyositis with palmar papules complicating rapidly progressive interstitial lung disease Noriki Fujimoto1, Shinichiro Honda1, Makiko Wakabayashi1, Yasuhito Hamaguchi2, Manabu Fujimoto3, and Toshihiro Tanaka1 1Department of Dermatology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga, Japan, 2Department of Dermatology, Graduate School
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of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan, and 3Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan Abstract
Keywords
We present the first case of dermatomyositis showing both vesicle formation and palmar papules. The association of bullous formation and internal malignancy, and palmar papules and interstitial lung disease (ILD) is well known in dermatomyositis, respectively. This patient presented with vesicles; however, the immunoprecipitation assays detected anti-MDA-5 antibody and the patient complicated rapidly progressive ILD, but no malignancy. We propose that palmar papules might be regarded as more critical than blister formation.
Blister formation, Bullous dermatomyositis, MDA-5, Palmar papules, Vesicle
Introduction Dermatomyositis (DM) is known to present with many types of eruption. The characteristic cutaneous manifestations include heliotrope eruption on eyelids and Gottron’s sign on the dorsal fingers. In addition, periungual telangiectasia, poikiloderma, subcutaneous calcinosis, panniculitis, mucinosis, and seborrheic dermatitis-like facial erythema are occasionally seen [1]. Ulceration and palmar papules are unusual [2], and vesicle or bulla formation is very rare [3]. The link with cutaneous manifestations and complications regarding DM such as bullous formation and internal malignancy, and palmar papules and interstitial lung disease (ILD) has been reported. We present the first case of bullous DM with palmar papules, which complicated rapidly progressive ILD, but not malignancy.
Case report A 50-year-old woman noticed erythema on the dorsum of her hands one month previously, and she was referred to our hospital for the eruption and general malaise. Physical examination showed heliotrope rash on the bilateral eyelids, Gottron’s sign on the dorsum of her hands (Figure 1a) and elbows, periungual erythema, erythematous papules without pain on the palmar surfaces of the metacarpal and interphalangeal joints (Figure 1b), and multiple, small, tense vesicles on the bilateral forearms (Figure 1c). She did not show clinical muscle weakness or pharyngeal dysphagia. Laboratory investigations showed raised aspartate aminotransferase (45 IU/L), lactate dehydrogenase (350 IU/L), and creatine kinase (288 IU/L) levels. No other abnormalities, including KL-6 (220 U/ml) and ferritin (28.0 ng/ml)
Correspondence to: Noriki Fujimoto, Department of Dermatology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan. Tel: ⫹ 81-77-548-2233. Fax: ⫹ 81-77-548-2154. E-mail: noriki@ belle.shiga-med.ac.jp
History Received 13 February 2014 Accepted 19 March 2014 Published online 16 May 2014
levels, were observed. The anti-nuclear antibody titer was 1:40, and circulating autoantibodies against Jo-1, SS-A/Ro, and SS-B/ La were not detected using the enzyme-linked immunosorbent assay. Immunoprecipitation assays [4] revealed the presence of anti-melanoma differentiation–associated gene 5 (MDA-5) antibody and absence of anti-transcription intermediary factor 1γ (TIF-1γ) antibody. Histopathological findings in a cutaneous biopsy specimen from an erythematous lesion on the dorsal surface of the hand revealed acanthosis, slight basal vacuolar change, and sparse perivascular lymphocyte infiltration. A biopsy specimen from a forearm vesicle showed subepidermal blister formation without basal vacuolar change and marked edema of the superficial dermis (Figure 2a). A deltoid muscle biopsy showed myositis (Figure 2b). Direct immunofluorescence studies of a biopsy specimen from a vesicle demonstrated no deposition of immunoglobulin or complement in the basement membrane zone. Electromyography showed myogenic abnormalities. Screening for internal malignancy using upper and lower gastrointernal endoscopy, abdominal echography, and total body computerized tomography (CT) was negative. High-resolution CT of the chest demonstrated slight ground-glass opacities of the bilateral lower lung lobes and consolidations in the S6 area on the left side. We diagnosed this patient with bullous DM having ILD, and administered oral prednisolone at 60 mg a day. The vesicles on forearms healed in about 1 week with the treatments; however, only palmar papules partially improved and did not disappear throughout the course. The serum creatine kinase level decreased within 1 month; however, ground-glass opacities gradually extended and pneumomediastinum occurred. We added cyclosporine at 200 mg a day. Although additional treatment including intravenous cyclophosphamide and intravenous immunoglobulin were performed, hypoxia worsened and ground-glass opacities extended. KL-6 levels increased to 2940 U/ml. The patient died from respiratory failure 3 months after the initial visit. Autopsy revealed diffuse alveolar damage, but no malignancy.
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Figure 1. Clinical presentation at the initial visit. (a) Gottron’s sign on the dorsum of the hands. (b) Palmar papules on the surfaces of the metacarpal and interphalangeal joints. (c) Multiple, small, and tense vesicles on the forearms.
Discussion
Figure 2. Histological findings in a biopsy specimen from a vesicle and deltoid muscle. (a) Subepidermal blister formation and marked edema of the superficial dermis are observed (hematoxylin & eosin staining (H-E), original magnification ⫻ 100). (b) Mononuclear cell infiltration is observed around vessels and through muscle fibers (H-E, original magnification ⫻ 100).
A close association between blister formation and internal malignancy in DM, especially gynecologic, was first reported in 1996 [5]. Then, DM with vesicles or bullas has been described as several terms of diagnosis such as DM with vesicle formation [5], vesiculo-bullous DM [1], and bullous DM [6]. A recent report revealed internal malignancy in 68% of bullous DM [3]. Autoantibodies against a 155-kD protein and a 155-/140-kD doublet were described in DM patients several years ago, which was reported to have association with internal malignancy. To date, it is revealed that the 155-kD protein recognized by anti-155/140 antibodies is TIF-1γ, and the TIF-1 family is target of anti-155/140 antibodies [7]. The TIF-1 family is a subgroup of the tripartite motif-containing (TRIM) proteins consisting of at least three members, TIF-1α, TIF-1β, and TIF-1γ. TIF-1 family plays important positive and/or negative roles in carcinogenesis. Therefore, it is speculated that the autoantibodies to these proteins develop through anti-tumor immune responses in cancer-associated DM. High sensitivity and specificity for the association with internal malignancy and antiTIF-1γ antibody has been revealed [7]. In our case, both screening examination and autopsy revealed no internal malignancy, and anti-TIF-1γ antibody was not found using immunoprecipitation assays. We speculate that anti-TIF-1γ antibody is present in most bullous DM; however, the rate of anti-TIF-1γ antibody among bullous DM has not been evaluated. The presence of anti-MDA-5 antibody, also referred to as anticlinically amyopathic dermatomyositis 140 (CADM)-140 antibody, was first detected in sera of Japanese CADM patients [4]. MDA-5 is a 140-kD cytoplasmic RNA-specific helicase that recognizes singlestrand RNA viruses. The protein is one of a family of retinoic acidinducible gene I-like receptors that recognizes pathogen-associated molecular patterns within viral RNA and produce type-I interferon [2]. Anti-MDA-5 antibody has been shown to be associated with CADM complicating rapidly progressive ILD, especially in Asians [8]. Furthermore, anti-MDA-5 antibody is not detected in CADM or DM without ILD or in polymyositis [9]. Although palmar papules are not so rare in DM, this is the first case report of DM showing both vesicles and palmar papules. The definite nomenclature of palmar papules has not been established;
Bullous DM with rapidly progressive ILD 3
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DOI 10.3109/14397595.2014.908811
however, erythematous papules or macules on the palmar surfaces of the metacarpal and interphalangeal joints are regarded as palmar papules [10]. The intense correlation between palmar papules and the risk of development of acute/subacute interstitial pneumonia in patients with DM was reported form Japan in 2005 [11]. Then, significant association between palmar papules and the presence of anti-MDA-5 antibody was shown in 2011 [10]. Palmar papules in DM patients with anti-MDA-5 antibody often accompany pain unlike Gottron’s sign, which histologically show vasculopathy on small to medium dermal vessels [10]. In our case, only anti-MDA-5 antibody was detected, and rapidly progressive ILD was found in spite of multiple vesicles; however, no malignancy was detected. Significant observation about the clinical course was that multiple vesicles responded well, but palmar papules did not disappear with the treatments. Palmar papules and skin ulcers show associations with anti-MDA-5 antibody [2], and autoantibodies against MDA-5 and TIF-1γ do not coexist in DM [12]. Since the analysis of autoantibodies such as anti-MDA-5 and anti-TIF-1γ antibodies is not always possible in all institutes, we should still predict the types of autoantibody according to the clinical presentation. Palmar papules might be regarded as more critical than blister formation, and we must note the possibility of anti-MDA-5 antibody presence in DM with palmar papules, even if vesicles are observed.
Acknowledgments
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Conflict of interest
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References 1. Nishigori K, Yamamoto T, Yokozeki H. Vesiculo-bullous dermatomyositis: report of three cases. Dermatol Online J. 2009;15(4):6. 2. Chaisson NF, Paik J, Orbai AM, Casciola-Rosen L, Fiorentino D, Danoff S, Rosen A. A novel dermato-pulmonary syndrome associated
12.
with MDA-5 antibodies: report of 2 cases and review of the literature. Medicine (Baltimore). 2012;91(4):220–8. Mitsuya J, Hara H, Hattori A, Matsunaga A, Terui T. Vesicle formation in dermatomyositis associated with colon carcinoma. Clin Exp Dermatol. 2009;34(7):e221–2. Sato S, Hirakata M, Kuwana M, Suwa A, Inada S, Mimori T, et al. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum. 2005;52(5):1571–6. Kubo M, Sato S, Kitahara H, Tsuchida T, Tamaki K. Vesicle formation in dermatomyositis associated with gynecologic malignancies. J Am Acad Dermatol. 1996;34(2 pt 2):391–4. Zangrilli A, Papoutsaki M, Bianchi L, Teoli M, Chimenti S. Bullous dermatomyositis: a marker of poor prognosis and aggressive internal malignancy? Acta Derm Venereol. 2008;88(4):393–4. Fujimoto M, Hamaguchi Y, Kaji K, Matsushita T, Ichimura Y, Kodera M, et al. Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum. 2012;64(2):513–22. Betteridge ZE, Gunawardena H, McHugh NJ. Novel autoantibodies and clinical phenotypes in adult and juvenile myositis. Arthritis Res Ther. 2011;13(2):209. Gono T, Kawaguchi Y, Kuwana M, Sugiura T, Furuya T, Takagi K, et al. Brief report: association of HLA-DRB1*0101/*0405 with susceptibility to anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis in the Japanese population. Arthritis Rheum. 2012;64(11):3736–40. Fiorentino D, Chung L, Zwerner J, Rosen A, Casciola-Rosen L. The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol. 2011;65(1):25–34. Kameda H, Nagasawa H, Ogawa H, Sekiguchi N, Takei H, Tokuhira M, et al. Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis. J Rheumatol. 2005; 32(9):1719–26. Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa M, Kaji K, Matsushita T, et al. Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study. Arch Dermatol. 2011;147(4): 391–8.