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Anti-melanoma differentiation–associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features
Accepted Manuscript Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features Drew JB. Kurtzman, MD, Ruth Ann Vleugels, MD, MPH PII:
S0190-9622(17)32764-0
DOI:
10.1016/j.jaad.2017.12.010
Reference:
YMJD 12168
To appear in:
Journal of the American Academy of Dermatology
Received Date: 21 May 2017 Revised Date:
27 November 2017
Accepted Date: 2 December 2017
Please cite this article as: Kurtzman DJ, Vleugels RA, Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2017.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise
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review with an emphasis on distinctive clinical features
3 Authors and Affiliations
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Drew JB Kurtzman, MD1 and Ruth Ann Vleugels, MD, MPH2
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Division of Dermatology, The University of Arizona, Tucson, Arizona
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Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School,
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Boston, Massachusetts
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Drew Kurtzman, MD, FAAD
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Assistant Professor of Medicine (Dermatology)
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Director, Connective Tissue Disease Clinic
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Director, Psoriasis and Psoriatic Arthritis Clinic
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Director, Immunobullous Disease Clinic
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1515 N Campbell Ave
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PO Box 245024
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Tucson, Arizona 85724
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[email protected]
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[email protected]
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Phone: 520-626-6024
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Fax: 520-626-6033
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ACCEPTED MANUSCRIPT 2 Word Counts
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Abstract: 116
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Capsule Summary: 50
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Text: 2448
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Figure Count: 6
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Table Count: 2
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References: 67
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Statement of Funding Sources: No funding was obtained for the preparation, synthesis, or
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submission of this manuscript. Dr. Vleugels’ career has been supported by a Medical
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Dermatology Career Development Award from the Dermatology Foundation.
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Conflicts of Interest: The authors have no conflicts of interest or other financial disclosures to
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report.
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ACCEPTED MANUSCRIPT 3 Abstract
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Melanoma differentiation-associated gene 5 (MDA5) is a recently described autoantigen target in
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a subset of patients with dermatomyositis (DM). Anti-MDA5 DM is characterized by a unique
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mucocutaneous and systemic phenotype that includes cutaneous and oral ulceration, painful
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palmar papules, alopecia, panniculitis, arthritis, a lower incidence of myositis, and, importantly,
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an elevated risk of interstitial lung disease, with a potentially fatal course. Because the clinical
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features may differ substantially from those typically observed in cutaneous DM, the diagnosis is
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often overlooked, which may negatively affect patient outcomes. This review aims to familiarize
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the clinician with the distinctive clinical features of anti-MDA5 DM in order to enhance its
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recognition and to facilitate an appropriate screening and management strategy.
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57 Key Words
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Dermatomyositis; interstitial lung disease; MDA5; melanoma differentiation-associated gene 5;
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myositis; palmar papule; ulceration.
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•
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lung disease.
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Anti-MDA5 dermatomyositis exhibits unique clinical features including mucocutaneous ulceration, palmar papules, non-scarring alopecia, panniculitis, arthritis, and interstitial
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Early intervention may reduce disease-related morbidity and improve survival in affected
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Knowledge of the salient features of anti-MDA5 dermatomyositis enhances its recognition and facilitates treatment.
ACCEPTED MANUSCRIPT 4 70 Introduction
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Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a recently
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described subtype of DM that is characterized by distinctive mucocutaneous features, some of
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which may develop as a result of an occlusive vasculopathy. Because the clinical presentation
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may differ substantially from that of typical cutaneous DM, the diagnosis may be overlooked,
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leading to a delay in treatment. Importantly, individuals with anti-MDA5 DM have a significant
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risk of developing interstitial lung disease (ILD) with a rapidly progressive course, and therefore
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correctly identifying the condition in its earliest stages is critical, as early intervention appears to
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improve patient outcomes. The objectives of this review are to acquaint the reader with the most
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salient clinical features of anti-MDA5 DM and to provide a brief framework for appropriate
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screening and management.
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History and Putative Function of MDA5
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Anti-MDA5 DM was first described in a Japanese cohort by Sato et al in 2005.1 Among the 42
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patients studied, sera from 8 (19%) had antibodies directed against an unknown 140 kd protein.
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Because each patient had clinically amyopathic DM (CADM), the antibody was originally
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designated anti-CADM-140.1 Subsequent studies demonstrated that the autoantigen target for
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anti-CADM-140 antibodies was MDA5 (also known as IFIH1), a cytoplasmic RIG-I like
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receptor that functions in innate immunity.2,3 Specifically, MDA5 recognizes intracellular viral
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nucleic acids (e.g., double stranded RNA) and triggers type I interferon (IFN) production that
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leads to suppression of viral particle replication.2,4 The elucidation of the antiviral function of
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MDA5 supports the hypothesis that viral infection may be a critical antecedent event in the
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ACCEPTED MANUSCRIPT 5 pathogenesis of DM. According to this paradigm, loss of self-tolerance and pathogenic tissue
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injury may develop after innate pathogen sensors (e.g., MDA5) interact with viral RNA and are
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released from damaged cells, which may expose privileged antigens and culminate in the
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generation of cryptic epitopes, creating a self-perpetuating autoimmune cycle.2,3,5,6 The
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observation that type I IFNs correlate with DM disease activity further substantiates this
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hypothesis, as these cytokines are regarded as major constituents of the innate immune system.7-9
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Anti-MDA5 antibodies were first discovered using immunoprecipitation.1 Enzyme-linked
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immunosorbent assays (ELISAs) that use a recombinant MDA5 antigen were subsequently
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developed,2,10,11 and, recently, line blot immunoassays have been partially validated for detecting
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MDA5 antibodies.12 Testing for MDA5 antibodies by ELISA has two advantages over
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immunoprecipitation: faster detection times and the provision of a quantitative measure of
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antibody titers, which has prognostic implications.13 The highest sensitivity and specificity
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performance for anti-MDA5 antibody detection is obtained by using a combination of
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immunoprecipitation and ELISA.3,14,15 While ELISAs and line blot immunoassays are available
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in Japan, China, and certain European countries, neither are currently available in the United
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States. Furthermore, in the US, immunoprecipitation is largely restricted to research centers,
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although a few commercial immunoprecipitation assays are available.16 The lack of widely
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accessible methods for detecting anti-MDA5 antibodies, coupled with the slow turnaround times
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inherent to performing immunoprecipitation, represent major practice gaps facing clinicians in
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the US, which further highlight the critical need for clinicians to be familiar with the
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characteristic phenotype associated with anti-MDA5 DM.
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Anti-MDA5 antibodies are DM-specific and are not found in other connective tissue disorders or inflammatory myopathies, including polymyositis.1,3,14,17,18 Furthermore, anti-MDA5
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antibodies appear to be mutually exclusive of other MSAs, such as anti-Mi-2 and anti-155/TIF-
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1γ.14 In other words, DM patients with anti-MDA5 antibodies do not test positive for other
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MSAs, suggesting that a specific immune response governs the distinct clinical phenotype of this
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DM subtype.19 Importantly, anti-MDA5 antibody titers correlate with disease activity, and during
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periods of remission or after adequate disease control has been achieved, antibodies may become
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undetectable.10,13,20-22 This finding has led some investigators to use anti-MDA5 antibody titers
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as a tool for monitoring therapeutic response and predicting disease relapse.20,23
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Unique Mucocutaneous Features of Anti-MDA5 Dermatomyositis (Table 1)
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Individuals with anti-MDA5 DM have a distinctive mucocutaneous phenotype, which may
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reflect a severe underlying vasculopathy. A seminal retrospective study delineating these unique
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features was first reported by Fiorentino et al in 2011,24 and their findings were validated by
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several subsequent studies.17,25-31 Although typical cutaneous DM features often accompany the
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distinctive anti-MDA5 phenotype, the anti-MDA5 phenotype may dominate the clinical picture,
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which may lead to diagnostic confusion and a delay in screening and treatment.
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ulceration. Ulcers develop in up to 82% of cases and are usually deep and appear punched out or
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exhibit thick, hyperkeratotic crusts (Figure 1). Cutaneous ulcers show a predilection for certain
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sites—e.g., overlying Gottron papules, involving the digital pulp and nailfolds (Figure 2), and
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overlying Gottron sign on the elbows and/or knees. Less commonly, ulcers may occur on sun-
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exposed sites such as the chest, back, and arms (Figure 3). Importantly, ulcers that are located on
ACCEPTED MANUSCRIPT 7 the digital pulp or periungual area are highly correlated with anti-MDA5 antibody positivity in
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individuals with DM.25 Furthermore, in patients with anti-MDA5 antibodies, the presence of
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cutaneous ulceration is the strongest predictor of developing ILD.25 In other words, anti-MDA5
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antibody positive patients with cutaneous ulcers have a significantly increased risk of developing
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ILD. Cutaneous ulcers are frequently a source of substantial morbidity and disability for patients,
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as these lesions are often associated with severe pain. Gangrene or osteomyelitis may supervene
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and lead to more serious complications, such as digital amputation. Cutaneous ulcers may
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represent the convergence of several independent pathogenic processes including vasculopathy,
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severe interface dermatitis, and vasculitis, although the precise pathogenic mechanisms of their
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development are unknown.24
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Palmar papules represent another unique feature of anti-MDA5 DM (Figure 4). Although the moniker ‘palmar papule’ is the most widely adopted, these lesions may also present as
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macules and patches. They invariably occur on the palms and palmar aspects of the fingers,
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particularly over the metacarpophalangeal or interphalangeal joint creases. Although palmar
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papules are typically inflammatory, they may also appear pale and atrophic, develop on a purple
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or livedoid background, or may ulcerate (Figure 5). Palmar papules are frequently painful and
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can cause substantial morbidity. Importantly, lesional biopsies of palmar papules
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characteristically demonstrate an occlusive vasculopathy that affects the small- and medium-
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sized dermal vasculature.17,24 Biopsies show intravascular fibrin deposition, which may be pauci-
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inflammatory or accompanied by a mononuclear inflammatory infiltrate.17,24 The discovery that
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palmar papules were associated with an occlusive vasculopathy provided important insight into
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the possible pathogenic mechanisms involved in this subset of DM patients.
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Several other mucocutaneous features are associated with anti-MDA5 DM (Table 1). Although non-scarring alopecia frequently develops in patients with DM, the alopecia seen in
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anti-MDA5 DM tends to be diffuse and more pronounced. Once disease activity has been
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controlled, this complication typically improves. Painful oral ulcers may also occur in anti-
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MDA5 DM and can affect any site within the oral cavity including the gingiva, buccal mucosa,
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tongue, or palate. Panniculitis, which is otherwise a rare finding in DM, also occurs with a higher
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frequency in anti-MDA5 DM.24 Although once regarded as a pathognomonic sign of the anti-
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synthetase syndrome,32,33 mechanic hands, which are characterized by fissured, scaly, and
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hyperkeratotic plaques along the thenar, radial, and ulnar aspects of the fingers, may also be seen
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in other subtypes of DM including classic disease, CADM, and anti-MDA5 DM (Figure 6).24,28,34
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Systemic Features of Anti-MDA5 Dermatomyositis (Table 2)
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Systemic disease is common in anti-MDA5 DM, and despite the morbidity associated with the
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typical mucocutaneous phenotype, systemic involvement represents a critical consideration for
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this population, as it constitutes the major cause of mortality. Interstitial lung disease is the most important systemic complication in anti-MDA5 DM
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because it may have a rapidly progressive and fatal course. Interstitial lung disease develops as a
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result of inflammation and fibrosis of the lung parenchyma and is defined by fibrosis or ground-
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glass opacification seen on computed tomography (CT). High-resolution CT (HRCT) of the
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chest is the preferred imaging modality because of its high sensitivity for detecting ILD. Notably,
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some studies have shown that anti-MDA5 DM HRCT patterns differ from those seen in anti-
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MDA5 negative patients, and that these patterns may be useful for predicting patient
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survival.35,36 Although diagnosing ILD is contingent on CT findings, it may also be screened for
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ACCEPTED MANUSCRIPT 9 by pulmonary function testing (PFT) with diffusing capacity of the lung for carbon monoxide
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(DLCO)—the presence of both restriction (FVC<80% of predicted levels in the absence of
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obstruction) and a decreased DLCO (<80% predicted) may suggest ILD.28 Abnormalities in PFT
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with DLCO alone cannot reliably detect ILD, however, and therefore an abnormal result should
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be confirmed with a high-resolution chest CT.37
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The prevalence of ILD in anti-MDA5 DM has been estimated to be between 42–100%, which is higher than the observed prevalence in typical DM.3,14,17,18,24,27-29,38-42 Some ethnic
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groups appear to have an increased propensity to develop this complication compared to others.
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For example, large Asian cohort studies estimate the prevalence of ILD to be between 92–
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100%,3,14,17,27 while European and US cohort studies have recorded slightly lower rates, between
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50–73%.24,28,30,39,43 That said, ILD is highly associated with anti-MDA5 antibodies, regardless of
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ethnicity, and therefore screening for ILD is warranted in all suspected cases.1,17,24,29,38,43 Rapidly
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progressive ILD (RP-ILD) with a fatal outcome is seen in a substantial proportion of anti-MDA5
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DM patients, also irrespective of ethnicity.17,43 A meta-analysis found that the odds ratio of
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developing RP-ILD was more than 20-fold higher for anti-MDA5 positive patients compared to
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anti-MDA5 negative patients.18 While the majority of deaths can be attributed to RP-
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ILD,14,18,27,44 some investigators have found that a positive anti-MDA5 antibody status alone is
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an independent predictor of poor survival.29,43 It is unclear why anti-MDA5 DM patients develop
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ILD, but vasculopathy of the pulmonary vasculature, endothelial injury caused by anti-MDA5
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antibodies, and increased expression of profibrotic cytokines may contribute to this
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phenomenon.17,24,45-47 Histopathologic examination of lung tissue from anti-MDA5 DM patients
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with confirmed ILD has shown two distinct patterns of injury—diffuse alveolar damage and
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interstitial fibrosis.48,49 The latter feature provides evidence that supports a fibrosis-mediated
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process.
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While ILD is the major pulmonary manifestation of anti-MDA5 DM, pneumomediastinum, which is characterized by free air surrounding the mediastinal structures, is
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another complication seen in this patient group. Pneumomediastinum has been associated with
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RP-ILD, cutaneous ulcers, and poor survival in anti-MDA5 DM patients.50
Several other systemic features may develop in anti-MDA5 DM. Arthritis and arthralgias
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occur frequently. The arthritis is typically symmetric and affects the small joints of the hands,
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resembling rheumatoid arthritis. Rheumatoid factor and cyclic citrullinated peptides are typically
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negative.28 Erosive joint injury may result in permanent deformity. Hand swelling without overt
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arthritis or arthralgias may also occur. Fever, fatigue, and non-specific constitutional symptoms
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are also very common and may be the presenting signs of anti-MDA5 DM.51 There are mixed data regarding the association between CADM and anti-MDA5 antibody
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status. Certain ethnic groups with anti-MDA5 DM, such as those from China and Japan, clearly
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have a lower rate of myositis (i.e., more likely to be clinically amyopathic), whereas others,
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including Korean populations, appear to have a normal prevalence of myositis, irrespective of
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anti-MDA5 antibody status.1-3,14,17,28,38,43 Two cohort studies from the US, both of which were
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largely comprised of Caucasian subjects, have shown conflicting results regarding myositis in
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anti-MDA5 DM—one suggested a decreased prevalence of myositis, while the other showed a
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prevalence more consistent with typical DM.24,43 Despite these incongruent data, most experts
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consider anti-MDA5 DM patients to have a lower incidence of myositis when compared to
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typical DM patients in the US. Regardless, the authors screen all newly diagnosed cases of DM
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for myositis. Future prospective studies will ideally clarify the true incidence of myositis in anti-
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MDA5 DM in various populations.
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The association between DM and malignancy is well established.52 In up to 25% of new cases, a cancer is detected a year prior to or up to 3 years following the diagnosis.53 With respect
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to the anti-MDA5 subtype, most reports indicate a reduced risk of malignancy,24,25 and some
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studies have even demonstrated an inverse correlation between the presence of ILD and the risk
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of malignancy in all forms of DM.54 However, there are rare reports of malignancy occurring in
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anti-MDA5 DM patients.14,17,29,55,56 For this reason, similar to screening for myositis, the
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authors’ approach is to evaluate all new DM patients for malignancy, irrespective of anti-MDA5
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antibody status.
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Laboratory Evaluation in Anti-MDA5 Dermatomyositis
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The diagnosis of anti-MDA5 DM is contingent upon the detection of anti-MDA5 antibodies
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using immunoprecipitation or ELISA in the appropriate clinical setting. In the US, a reliable
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immunoprecipitation assay from the Oklahoma Medical Research Foundation is commercially
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available.16
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Apart from directly testing for anti-MDA5 antibodies, other laboratory investigations may provide useful clinical and prognostic information in suspected cases of anti-MDA5 DM,
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particularly in instances in which testing for antibodies is unavailable or the results are delayed.
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Serum ferritin levels are commonly elevated in individuals with anti-MDA5 DM and appear to
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correlate with disease activity, particularly ILD, with higher levels signifying greater disease
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activity.3,22,57 Importantly, in a cohort of anti-MDA5 DM patients, elevated serum ferritin levels
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(≥500 ng/mL) portended decreased survival, and the strength of this association increased with
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ACCEPTED MANUSCRIPT 12 increasing ferritin levels (≥1600 ng/mL).58 Some investigators have advocated that individuals
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with anti-MDA5 DM who have hyperferritinemia should receive more aggressive treatment,
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given their worse prognosis.59 As with anti-MDA5 antibody titers, serum ferritin levels decrease
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in response to successful treatment.20 Other laboratory abnormalities seen in anti-MDA5 DM
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include lymphopenia, elevated erythrocyte sedimentation rate (ESR), and elevated peripheral
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blood concentrations of interleukin (IL)-18.22,44 The lack of availability of an IL-18 assay may
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limit its clinical utility. Notably, while around a third to half of DM patients test positive for
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antinuclear antibody (ANA), anti-MDA5 DM patients test positive less frequently. In one cohort,
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nearly 90% of anti-MDA5 DM patients were ANA negative.24 This finding is not unexpected
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because MDA5 is a cytoplasmic protein, and anti-MDA5 antibodies occur exclusively of other
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MSAs.
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Management of Anti-MDA5 Dermatomyositis
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While a complete discussion of the management of DM and the anti-MDA5 subtype is beyond
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the scope of this review, there are several important points to consider when evaluating and
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treating the patient with anti-MDA5 DM. First, screening for pulmonary disease is mandatory for
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each suspected or confirmed case. While HRCT of the chest is the gold standard for diagnosing
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ILD, its use may be limited by high cumulative radiation exposure. Therefore, PFT with DLCO
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may be a prudent initial screening test, with a low threshold to perform a HRCT if any
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abnormalities are discovered. The habit of the authors is to repeat screening with PFT and DLCO
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at pre-specified intervals in patients with anti-MDA5 DM (e.g., every 3 to 6 months for the first
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year from diagnosis) to ensure early detection of ILD, should it develop, and to take a detailed
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history of pulmonary symptoms at each patient encounter. Second, diagnosing anti-MDA5 DM
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ACCEPTED MANUSCRIPT 13 early in its course and treating it aggressively has been shown to improve patient
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outcomes.10,13,17,20,57,60-62 Even after ILD has developed, further lung injury can be prevented and,
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to some degree, reversed by aggressive intervention.17,60 For these reasons, recognition of the
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characteristic clinical phenotype of anti-MDA5 DM as well as its systemic complications is
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paramount.
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The treatment of anti-MDA5 DM should be guided by the degree of disease severity and whether or not extracutaneous disease (e.g., ILD) is present. In many cases, a combination of
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immunomodulators and immunosuppressants is needed, although it is important to keep in mind
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that a single treatment algorithm may not be suitable for all patients, and that not every patient
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with anti-MDA5 DM will respond uniformly to a specific therapeutic regimen. Therefore, the
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specific treatment regimen will depend on the organ systems involved and the severity of
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involvement. The authors prefer to use mycophenolate mofetil as the initial corticosteroid-
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sparing agent in patients with anti-MDA5 DM. Mycophenolate mofetil has been shown to be
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effective for treating anti-MDA5 DM in case reports and small series.57,61 Moreover,
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mycophenolate mofetil reduces the expression of profibrotic cytokines,63 and it appears to
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attenuate the progression of lung disease in individuals with ILD associated with connective
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tissue disease, including dermatomyositis.64-66 Therefore, in the authors’ opinion, mycophenolate
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mofetil represents a rational choice for treating individuals with anti-MDA5 DM, given their
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inherent predisposition to develop ILD. Because the cutaneous disease in anti-MDA5 DM may
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be difficult to manage, we often also use intravenous immunoglobulin (IVIG) in conjunction
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with mycophenolate mofetil, as it appears to be effective for treating refractory cutaneous DM.67
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In some patients, additional immunosuppressive agents are needed for refractory cutaneous
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disease. In patients with severe or recalcitrant pulmonary disease, rituximab, cyclophosphamide,
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ACCEPTED MANUSCRIPT 14 or other agents may be needed. Ancillary therapies aimed at ameliorating the underlying
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vasculopathy (e.g., vasodilators such as nifedipine and sildenafil) as well as agents that improve
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peripheral circulation (e.g., aspirin and pentoxifylline) may also be helpful for treating anti-
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MDA5 DM. In the authors’ experience, these therapies may enhance the healing of cutaneous
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ulcers and reduce morbidity. Finally, a multidisciplinary approach is often needed to adequately
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address the various complications of anti-MDA5 DM. These patients benefit from the care
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provided by colleagues in pulmonology, rheumatology, and wound care.
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304 Conclusion
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Anti-MDA5 DM is a unique subtype of DM that exhibits distinctive mucocutaneous and
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systemic features. The disorder carries a significant risk of ILD and RP-ILD, with a potentially
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fatal course. For this reason, it is imperative that the clinician recognizes its unique clinical
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presentation in order to appropriately screen for and manage the complications of this condition.
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310 Abbreviations
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ANA: antinuclear antibody; CADM: clinically amyopathic dermatomyositis; DLCO: diffusion
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capacity of the lung for carbon monoxide; DM: dermatomyositis; CT: computed tomography;
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ELISA: enzyme-linked immunosorbent assay; ESR: erythrocyte sedimentation rate; HRCT: high
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resolution computed tomography; IL: interleukin; ILD: interstitial lung disease; IVIG:
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intravenous immunoglobulin; MDA5: melanoma differentiation-associated gene 5; MSA:
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myositis specific antibody; PFT: pulmonary function testing; RP-ILD: rapidly progressive
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interstitial lung disease.
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ACCEPTED MANUSCRIPT 25 542 Figure Legends
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Figure 1. Cutaneous ulceration overlying Gottron papules in an individual with anti-MDA5
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dermatomyositis.
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Figure 2. Cutaneous ulceration on the proximal and lateral nailfolds of several fingers in a patient
547
with anti-MDA5 dermatomyositis.
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Figure 3. Deep, punched out-appearing ulcers on the arm and elbow of a woman with anti-
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MDA5 dermatomyositis.
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Figure 4. Typical painful palmar papules involving the palms and palmar creases of the fingers in
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a patient with anti-MDA5 dermatomyositis. Fingertip ulcerations are also present.
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Figure 5. Ulcerated palmar papules and necrotic fingertips occurring on a purple and livedoid
553
background in a patient with severe anti-MDA5 dermatomyositis.
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Figure 6. Lateral digit hyperkeratosis and fissuring on the radial aspects of the first and second
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fingers in an individual with anti-MDA5 dermatomyositis.
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Table 1. Distinctive Mucocutaneous Features of Anti-MDA5 Dermatomyositis
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Lesion
Distribution
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Cutaneous ulceration
Overlying MCP/IP joints, elbows, knees, nailfold**
40–82%
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Alopecia
Scalp, typically diffuse, non-scarring
78%
560
Lateral digit hyperkeratosis and/or scaling
Thenar and lateral aspects of the fingers
67%
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Palmar papules
Palms and palmar creases of fingers
20–60%
562
Oral ulcers
Gingiva, buccal mucosa, tongue, palate
50%
563
Panniculitis
Upper arms, thighs, breasts, buttocks
20%
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Estimated Prevalence*
564 565
*
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one study (reference 23) was the lead investigator a dermatologist. Furthermore, the results were obtained from tertiary centers, and
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therefore the generalizability of these estimates is unknown.
568
**
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IP, interphalangeal; MCP, metacarpophalangeal.
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Cutaneous ulceration may occur anywhere on the skin, but these locations represent the most commonly involved sites.
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Represents estimates from three studies (references 23, 27, and 29) that systematically described these features. Importantly, in only
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Feature
Estimated Prevalence
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Interstitial lung disease
42–100%*
574
Rapidly progressive interstitial lung disease
39–92%**
575
Arthritis/arthralgia
13–82%***
576
Fever
46%–69%****
577
Clinically amyopathic
46–50%***
578
Hand swelling
25–40%***
579
Pneumomediastinum
unknown
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580 581
*
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Features).
583
**
584
***
585
and 29). The results were obtained from tertiary centers, and therefore the generalizability of
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these estimates is unknown.
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****
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(references 3 and 27).
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Aggregated estimates from references 1, 3, 12, 16, 17, 19, 26, 35, 39.
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Estimated from three studies that systematically described these features (references 23, 27,
Estimated from two studies that systematically characterized and reported this feature
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A full list of references can be found in the manuscript’s text (see section on Systemic
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S0190-9622(17)32764-0
DOI:
10.1016/j.jaad.2017.12.010
Reference:
YMJD 12168
To appear in:
Journal of the American Academy of Dermatology
Received Date: 21 May 2017 Revised Date:
27 November 2017
Accepted Date: 2 December 2017
Please cite this article as: Kurtzman DJ, Vleugels RA, Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise review with an emphasis on distinctive clinical features, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2017.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: a concise
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review with an emphasis on distinctive clinical features
3 Authors and Affiliations
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Drew JB Kurtzman, MD1 and Ruth Ann Vleugels, MD, MPH2
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1
Division of Dermatology, The University of Arizona, Tucson, Arizona
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2
Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School,
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Boston, Massachusetts
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9 Corresponding Author:
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Drew Kurtzman, MD, FAAD
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Assistant Professor of Medicine (Dermatology)
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Director, Connective Tissue Disease Clinic
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Director, Psoriasis and Psoriatic Arthritis Clinic
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Director, Immunobullous Disease Clinic
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1515 N Campbell Ave
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PO Box 245024
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Tucson, Arizona 85724
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[email protected]
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[email protected]
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Phone: 520-626-6024
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Fax: 520-626-6033
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Abstract: 116
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Capsule Summary: 50
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Text: 2448
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Figure Count: 6
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Table Count: 2
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References: 67
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Statement of Funding Sources: No funding was obtained for the preparation, synthesis, or
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submission of this manuscript. Dr. Vleugels’ career has been supported by a Medical
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Dermatology Career Development Award from the Dermatology Foundation.
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Conflicts of Interest: The authors have no conflicts of interest or other financial disclosures to
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report.
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ACCEPTED MANUSCRIPT 3 Abstract
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Melanoma differentiation-associated gene 5 (MDA5) is a recently described autoantigen target in
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a subset of patients with dermatomyositis (DM). Anti-MDA5 DM is characterized by a unique
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mucocutaneous and systemic phenotype that includes cutaneous and oral ulceration, painful
51
palmar papules, alopecia, panniculitis, arthritis, a lower incidence of myositis, and, importantly,
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an elevated risk of interstitial lung disease, with a potentially fatal course. Because the clinical
53
features may differ substantially from those typically observed in cutaneous DM, the diagnosis is
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often overlooked, which may negatively affect patient outcomes. This review aims to familiarize
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the clinician with the distinctive clinical features of anti-MDA5 DM in order to enhance its
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recognition and to facilitate an appropriate screening and management strategy.
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57 Key Words
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Dermatomyositis; interstitial lung disease; MDA5; melanoma differentiation-associated gene 5;
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myositis; palmar papule; ulceration.
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•
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lung disease.
•
67 68 69
Anti-MDA5 dermatomyositis exhibits unique clinical features including mucocutaneous ulceration, palmar papules, non-scarring alopecia, panniculitis, arthritis, and interstitial
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Early intervention may reduce disease-related morbidity and improve survival in affected
individuals. •
Knowledge of the salient features of anti-MDA5 dermatomyositis enhances its recognition and facilitates treatment.
ACCEPTED MANUSCRIPT 4 70 Introduction
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Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a recently
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described subtype of DM that is characterized by distinctive mucocutaneous features, some of
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which may develop as a result of an occlusive vasculopathy. Because the clinical presentation
75
may differ substantially from that of typical cutaneous DM, the diagnosis may be overlooked,
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leading to a delay in treatment. Importantly, individuals with anti-MDA5 DM have a significant
77
risk of developing interstitial lung disease (ILD) with a rapidly progressive course, and therefore
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correctly identifying the condition in its earliest stages is critical, as early intervention appears to
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improve patient outcomes. The objectives of this review are to acquaint the reader with the most
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salient clinical features of anti-MDA5 DM and to provide a brief framework for appropriate
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screening and management.
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History and Putative Function of MDA5
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Anti-MDA5 DM was first described in a Japanese cohort by Sato et al in 2005.1 Among the 42
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patients studied, sera from 8 (19%) had antibodies directed against an unknown 140 kd protein.
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Because each patient had clinically amyopathic DM (CADM), the antibody was originally
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designated anti-CADM-140.1 Subsequent studies demonstrated that the autoantigen target for
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anti-CADM-140 antibodies was MDA5 (also known as IFIH1), a cytoplasmic RIG-I like
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receptor that functions in innate immunity.2,3 Specifically, MDA5 recognizes intracellular viral
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nucleic acids (e.g., double stranded RNA) and triggers type I interferon (IFN) production that
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leads to suppression of viral particle replication.2,4 The elucidation of the antiviral function of
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MDA5 supports the hypothesis that viral infection may be a critical antecedent event in the
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ACCEPTED MANUSCRIPT 5 pathogenesis of DM. According to this paradigm, loss of self-tolerance and pathogenic tissue
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injury may develop after innate pathogen sensors (e.g., MDA5) interact with viral RNA and are
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released from damaged cells, which may expose privileged antigens and culminate in the
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generation of cryptic epitopes, creating a self-perpetuating autoimmune cycle.2,3,5,6 The
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observation that type I IFNs correlate with DM disease activity further substantiates this
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hypothesis, as these cytokines are regarded as major constituents of the innate immune system.7-9
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Anti-MDA5 antibodies were first discovered using immunoprecipitation.1 Enzyme-linked
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immunosorbent assays (ELISAs) that use a recombinant MDA5 antigen were subsequently
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developed,2,10,11 and, recently, line blot immunoassays have been partially validated for detecting
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MDA5 antibodies.12 Testing for MDA5 antibodies by ELISA has two advantages over
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immunoprecipitation: faster detection times and the provision of a quantitative measure of
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antibody titers, which has prognostic implications.13 The highest sensitivity and specificity
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performance for anti-MDA5 antibody detection is obtained by using a combination of
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immunoprecipitation and ELISA.3,14,15 While ELISAs and line blot immunoassays are available
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in Japan, China, and certain European countries, neither are currently available in the United
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States. Furthermore, in the US, immunoprecipitation is largely restricted to research centers,
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although a few commercial immunoprecipitation assays are available.16 The lack of widely
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accessible methods for detecting anti-MDA5 antibodies, coupled with the slow turnaround times
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inherent to performing immunoprecipitation, represent major practice gaps facing clinicians in
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the US, which further highlight the critical need for clinicians to be familiar with the
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characteristic phenotype associated with anti-MDA5 DM.
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Anti-MDA5 antibodies are DM-specific and are not found in other connective tissue disorders or inflammatory myopathies, including polymyositis.1,3,14,17,18 Furthermore, anti-MDA5
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antibodies appear to be mutually exclusive of other MSAs, such as anti-Mi-2 and anti-155/TIF-
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1γ.14 In other words, DM patients with anti-MDA5 antibodies do not test positive for other
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MSAs, suggesting that a specific immune response governs the distinct clinical phenotype of this
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DM subtype.19 Importantly, anti-MDA5 antibody titers correlate with disease activity, and during
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periods of remission or after adequate disease control has been achieved, antibodies may become
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undetectable.10,13,20-22 This finding has led some investigators to use anti-MDA5 antibody titers
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as a tool for monitoring therapeutic response and predicting disease relapse.20,23
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Unique Mucocutaneous Features of Anti-MDA5 Dermatomyositis (Table 1)
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Individuals with anti-MDA5 DM have a distinctive mucocutaneous phenotype, which may
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reflect a severe underlying vasculopathy. A seminal retrospective study delineating these unique
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features was first reported by Fiorentino et al in 2011,24 and their findings were validated by
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several subsequent studies.17,25-31 Although typical cutaneous DM features often accompany the
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distinctive anti-MDA5 phenotype, the anti-MDA5 phenotype may dominate the clinical picture,
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which may lead to diagnostic confusion and a delay in screening and treatment.
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ulceration. Ulcers develop in up to 82% of cases and are usually deep and appear punched out or
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exhibit thick, hyperkeratotic crusts (Figure 1). Cutaneous ulcers show a predilection for certain
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sites—e.g., overlying Gottron papules, involving the digital pulp and nailfolds (Figure 2), and
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overlying Gottron sign on the elbows and/or knees. Less commonly, ulcers may occur on sun-
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exposed sites such as the chest, back, and arms (Figure 3). Importantly, ulcers that are located on
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individuals with DM.25 Furthermore, in patients with anti-MDA5 antibodies, the presence of
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cutaneous ulceration is the strongest predictor of developing ILD.25 In other words, anti-MDA5
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antibody positive patients with cutaneous ulcers have a significantly increased risk of developing
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ILD. Cutaneous ulcers are frequently a source of substantial morbidity and disability for patients,
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as these lesions are often associated with severe pain. Gangrene or osteomyelitis may supervene
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and lead to more serious complications, such as digital amputation. Cutaneous ulcers may
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represent the convergence of several independent pathogenic processes including vasculopathy,
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severe interface dermatitis, and vasculitis, although the precise pathogenic mechanisms of their
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development are unknown.24
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Palmar papules represent another unique feature of anti-MDA5 DM (Figure 4). Although the moniker ‘palmar papule’ is the most widely adopted, these lesions may also present as
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macules and patches. They invariably occur on the palms and palmar aspects of the fingers,
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particularly over the metacarpophalangeal or interphalangeal joint creases. Although palmar
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papules are typically inflammatory, they may also appear pale and atrophic, develop on a purple
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or livedoid background, or may ulcerate (Figure 5). Palmar papules are frequently painful and
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can cause substantial morbidity. Importantly, lesional biopsies of palmar papules
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characteristically demonstrate an occlusive vasculopathy that affects the small- and medium-
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sized dermal vasculature.17,24 Biopsies show intravascular fibrin deposition, which may be pauci-
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inflammatory or accompanied by a mononuclear inflammatory infiltrate.17,24 The discovery that
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palmar papules were associated with an occlusive vasculopathy provided important insight into
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the possible pathogenic mechanisms involved in this subset of DM patients.
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Several other mucocutaneous features are associated with anti-MDA5 DM (Table 1). Although non-scarring alopecia frequently develops in patients with DM, the alopecia seen in
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anti-MDA5 DM tends to be diffuse and more pronounced. Once disease activity has been
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controlled, this complication typically improves. Painful oral ulcers may also occur in anti-
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MDA5 DM and can affect any site within the oral cavity including the gingiva, buccal mucosa,
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tongue, or palate. Panniculitis, which is otherwise a rare finding in DM, also occurs with a higher
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frequency in anti-MDA5 DM.24 Although once regarded as a pathognomonic sign of the anti-
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synthetase syndrome,32,33 mechanic hands, which are characterized by fissured, scaly, and
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hyperkeratotic plaques along the thenar, radial, and ulnar aspects of the fingers, may also be seen
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in other subtypes of DM including classic disease, CADM, and anti-MDA5 DM (Figure 6).24,28,34
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Systemic Features of Anti-MDA5 Dermatomyositis (Table 2)
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Systemic disease is common in anti-MDA5 DM, and despite the morbidity associated with the
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typical mucocutaneous phenotype, systemic involvement represents a critical consideration for
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this population, as it constitutes the major cause of mortality. Interstitial lung disease is the most important systemic complication in anti-MDA5 DM
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because it may have a rapidly progressive and fatal course. Interstitial lung disease develops as a
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result of inflammation and fibrosis of the lung parenchyma and is defined by fibrosis or ground-
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glass opacification seen on computed tomography (CT). High-resolution CT (HRCT) of the
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chest is the preferred imaging modality because of its high sensitivity for detecting ILD. Notably,
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some studies have shown that anti-MDA5 DM HRCT patterns differ from those seen in anti-
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MDA5 negative patients, and that these patterns may be useful for predicting patient
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survival.35,36 Although diagnosing ILD is contingent on CT findings, it may also be screened for
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ACCEPTED MANUSCRIPT 9 by pulmonary function testing (PFT) with diffusing capacity of the lung for carbon monoxide
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(DLCO)—the presence of both restriction (FVC<80% of predicted levels in the absence of
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obstruction) and a decreased DLCO (<80% predicted) may suggest ILD.28 Abnormalities in PFT
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with DLCO alone cannot reliably detect ILD, however, and therefore an abnormal result should
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be confirmed with a high-resolution chest CT.37
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The prevalence of ILD in anti-MDA5 DM has been estimated to be between 42–100%, which is higher than the observed prevalence in typical DM.3,14,17,18,24,27-29,38-42 Some ethnic
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groups appear to have an increased propensity to develop this complication compared to others.
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For example, large Asian cohort studies estimate the prevalence of ILD to be between 92–
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100%,3,14,17,27 while European and US cohort studies have recorded slightly lower rates, between
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50–73%.24,28,30,39,43 That said, ILD is highly associated with anti-MDA5 antibodies, regardless of
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ethnicity, and therefore screening for ILD is warranted in all suspected cases.1,17,24,29,38,43 Rapidly
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progressive ILD (RP-ILD) with a fatal outcome is seen in a substantial proportion of anti-MDA5
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DM patients, also irrespective of ethnicity.17,43 A meta-analysis found that the odds ratio of
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developing RP-ILD was more than 20-fold higher for anti-MDA5 positive patients compared to
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anti-MDA5 negative patients.18 While the majority of deaths can be attributed to RP-
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ILD,14,18,27,44 some investigators have found that a positive anti-MDA5 antibody status alone is
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an independent predictor of poor survival.29,43 It is unclear why anti-MDA5 DM patients develop
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ILD, but vasculopathy of the pulmonary vasculature, endothelial injury caused by anti-MDA5
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antibodies, and increased expression of profibrotic cytokines may contribute to this
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phenomenon.17,24,45-47 Histopathologic examination of lung tissue from anti-MDA5 DM patients
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with confirmed ILD has shown two distinct patterns of injury—diffuse alveolar damage and
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interstitial fibrosis.48,49 The latter feature provides evidence that supports a fibrosis-mediated
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process.
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While ILD is the major pulmonary manifestation of anti-MDA5 DM, pneumomediastinum, which is characterized by free air surrounding the mediastinal structures, is
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another complication seen in this patient group. Pneumomediastinum has been associated with
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RP-ILD, cutaneous ulcers, and poor survival in anti-MDA5 DM patients.50
Several other systemic features may develop in anti-MDA5 DM. Arthritis and arthralgias
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occur frequently. The arthritis is typically symmetric and affects the small joints of the hands,
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resembling rheumatoid arthritis. Rheumatoid factor and cyclic citrullinated peptides are typically
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negative.28 Erosive joint injury may result in permanent deformity. Hand swelling without overt
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arthritis or arthralgias may also occur. Fever, fatigue, and non-specific constitutional symptoms
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are also very common and may be the presenting signs of anti-MDA5 DM.51 There are mixed data regarding the association between CADM and anti-MDA5 antibody
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status. Certain ethnic groups with anti-MDA5 DM, such as those from China and Japan, clearly
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have a lower rate of myositis (i.e., more likely to be clinically amyopathic), whereas others,
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including Korean populations, appear to have a normal prevalence of myositis, irrespective of
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anti-MDA5 antibody status.1-3,14,17,28,38,43 Two cohort studies from the US, both of which were
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largely comprised of Caucasian subjects, have shown conflicting results regarding myositis in
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anti-MDA5 DM—one suggested a decreased prevalence of myositis, while the other showed a
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prevalence more consistent with typical DM.24,43 Despite these incongruent data, most experts
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consider anti-MDA5 DM patients to have a lower incidence of myositis when compared to
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typical DM patients in the US. Regardless, the authors screen all newly diagnosed cases of DM
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for myositis. Future prospective studies will ideally clarify the true incidence of myositis in anti-
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MDA5 DM in various populations.
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The association between DM and malignancy is well established.52 In up to 25% of new cases, a cancer is detected a year prior to or up to 3 years following the diagnosis.53 With respect
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to the anti-MDA5 subtype, most reports indicate a reduced risk of malignancy,24,25 and some
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studies have even demonstrated an inverse correlation between the presence of ILD and the risk
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of malignancy in all forms of DM.54 However, there are rare reports of malignancy occurring in
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anti-MDA5 DM patients.14,17,29,55,56 For this reason, similar to screening for myositis, the
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authors’ approach is to evaluate all new DM patients for malignancy, irrespective of anti-MDA5
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antibody status.
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Laboratory Evaluation in Anti-MDA5 Dermatomyositis
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The diagnosis of anti-MDA5 DM is contingent upon the detection of anti-MDA5 antibodies
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using immunoprecipitation or ELISA in the appropriate clinical setting. In the US, a reliable
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immunoprecipitation assay from the Oklahoma Medical Research Foundation is commercially
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available.16
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Apart from directly testing for anti-MDA5 antibodies, other laboratory investigations may provide useful clinical and prognostic information in suspected cases of anti-MDA5 DM,
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particularly in instances in which testing for antibodies is unavailable or the results are delayed.
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Serum ferritin levels are commonly elevated in individuals with anti-MDA5 DM and appear to
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correlate with disease activity, particularly ILD, with higher levels signifying greater disease
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activity.3,22,57 Importantly, in a cohort of anti-MDA5 DM patients, elevated serum ferritin levels
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(≥500 ng/mL) portended decreased survival, and the strength of this association increased with
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ACCEPTED MANUSCRIPT 12 increasing ferritin levels (≥1600 ng/mL).58 Some investigators have advocated that individuals
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with anti-MDA5 DM who have hyperferritinemia should receive more aggressive treatment,
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given their worse prognosis.59 As with anti-MDA5 antibody titers, serum ferritin levels decrease
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in response to successful treatment.20 Other laboratory abnormalities seen in anti-MDA5 DM
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include lymphopenia, elevated erythrocyte sedimentation rate (ESR), and elevated peripheral
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blood concentrations of interleukin (IL)-18.22,44 The lack of availability of an IL-18 assay may
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limit its clinical utility. Notably, while around a third to half of DM patients test positive for
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antinuclear antibody (ANA), anti-MDA5 DM patients test positive less frequently. In one cohort,
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nearly 90% of anti-MDA5 DM patients were ANA negative.24 This finding is not unexpected
260
because MDA5 is a cytoplasmic protein, and anti-MDA5 antibodies occur exclusively of other
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MSAs.
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Management of Anti-MDA5 Dermatomyositis
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While a complete discussion of the management of DM and the anti-MDA5 subtype is beyond
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the scope of this review, there are several important points to consider when evaluating and
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treating the patient with anti-MDA5 DM. First, screening for pulmonary disease is mandatory for
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each suspected or confirmed case. While HRCT of the chest is the gold standard for diagnosing
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ILD, its use may be limited by high cumulative radiation exposure. Therefore, PFT with DLCO
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may be a prudent initial screening test, with a low threshold to perform a HRCT if any
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abnormalities are discovered. The habit of the authors is to repeat screening with PFT and DLCO
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at pre-specified intervals in patients with anti-MDA5 DM (e.g., every 3 to 6 months for the first
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year from diagnosis) to ensure early detection of ILD, should it develop, and to take a detailed
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history of pulmonary symptoms at each patient encounter. Second, diagnosing anti-MDA5 DM
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ACCEPTED MANUSCRIPT 13 early in its course and treating it aggressively has been shown to improve patient
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outcomes.10,13,17,20,57,60-62 Even after ILD has developed, further lung injury can be prevented and,
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to some degree, reversed by aggressive intervention.17,60 For these reasons, recognition of the
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characteristic clinical phenotype of anti-MDA5 DM as well as its systemic complications is
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paramount.
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The treatment of anti-MDA5 DM should be guided by the degree of disease severity and whether or not extracutaneous disease (e.g., ILD) is present. In many cases, a combination of
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immunomodulators and immunosuppressants is needed, although it is important to keep in mind
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that a single treatment algorithm may not be suitable for all patients, and that not every patient
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with anti-MDA5 DM will respond uniformly to a specific therapeutic regimen. Therefore, the
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specific treatment regimen will depend on the organ systems involved and the severity of
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involvement. The authors prefer to use mycophenolate mofetil as the initial corticosteroid-
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sparing agent in patients with anti-MDA5 DM. Mycophenolate mofetil has been shown to be
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effective for treating anti-MDA5 DM in case reports and small series.57,61 Moreover,
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mycophenolate mofetil reduces the expression of profibrotic cytokines,63 and it appears to
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attenuate the progression of lung disease in individuals with ILD associated with connective
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tissue disease, including dermatomyositis.64-66 Therefore, in the authors’ opinion, mycophenolate
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mofetil represents a rational choice for treating individuals with anti-MDA5 DM, given their
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inherent predisposition to develop ILD. Because the cutaneous disease in anti-MDA5 DM may
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be difficult to manage, we often also use intravenous immunoglobulin (IVIG) in conjunction
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with mycophenolate mofetil, as it appears to be effective for treating refractory cutaneous DM.67
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In some patients, additional immunosuppressive agents are needed for refractory cutaneous
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disease. In patients with severe or recalcitrant pulmonary disease, rituximab, cyclophosphamide,
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ACCEPTED MANUSCRIPT 14 or other agents may be needed. Ancillary therapies aimed at ameliorating the underlying
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vasculopathy (e.g., vasodilators such as nifedipine and sildenafil) as well as agents that improve
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peripheral circulation (e.g., aspirin and pentoxifylline) may also be helpful for treating anti-
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MDA5 DM. In the authors’ experience, these therapies may enhance the healing of cutaneous
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ulcers and reduce morbidity. Finally, a multidisciplinary approach is often needed to adequately
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address the various complications of anti-MDA5 DM. These patients benefit from the care
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provided by colleagues in pulmonology, rheumatology, and wound care.
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304 Conclusion
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Anti-MDA5 DM is a unique subtype of DM that exhibits distinctive mucocutaneous and
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systemic features. The disorder carries a significant risk of ILD and RP-ILD, with a potentially
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fatal course. For this reason, it is imperative that the clinician recognizes its unique clinical
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presentation in order to appropriately screen for and manage the complications of this condition.
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310 Abbreviations
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ANA: antinuclear antibody; CADM: clinically amyopathic dermatomyositis; DLCO: diffusion
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capacity of the lung for carbon monoxide; DM: dermatomyositis; CT: computed tomography;
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ELISA: enzyme-linked immunosorbent assay; ESR: erythrocyte sedimentation rate; HRCT: high
315
resolution computed tomography; IL: interleukin; ILD: interstitial lung disease; IVIG:
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intravenous immunoglobulin; MDA5: melanoma differentiation-associated gene 5; MSA:
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myositis specific antibody; PFT: pulmonary function testing; RP-ILD: rapidly progressive
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interstitial lung disease.
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Figure 1. Cutaneous ulceration overlying Gottron papules in an individual with anti-MDA5
545
dermatomyositis.
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Figure 2. Cutaneous ulceration on the proximal and lateral nailfolds of several fingers in a patient
547
with anti-MDA5 dermatomyositis.
548
Figure 3. Deep, punched out-appearing ulcers on the arm and elbow of a woman with anti-
549
MDA5 dermatomyositis.
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Figure 4. Typical painful palmar papules involving the palms and palmar creases of the fingers in
551
a patient with anti-MDA5 dermatomyositis. Fingertip ulcerations are also present.
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Figure 5. Ulcerated palmar papules and necrotic fingertips occurring on a purple and livedoid
553
background in a patient with severe anti-MDA5 dermatomyositis.
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Figure 6. Lateral digit hyperkeratosis and fissuring on the radial aspects of the first and second
555
fingers in an individual with anti-MDA5 dermatomyositis.
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Table 1. Distinctive Mucocutaneous Features of Anti-MDA5 Dermatomyositis
557
Lesion
Distribution
558
Cutaneous ulceration
Overlying MCP/IP joints, elbows, knees, nailfold**
40–82%
559
Alopecia
Scalp, typically diffuse, non-scarring
78%
560
Lateral digit hyperkeratosis and/or scaling
Thenar and lateral aspects of the fingers
67%
561
Palmar papules
Palms and palmar creases of fingers
20–60%
562
Oral ulcers
Gingiva, buccal mucosa, tongue, palate
50%
563
Panniculitis
Upper arms, thighs, breasts, buttocks
20%
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Estimated Prevalence*
564 565
*
566
one study (reference 23) was the lead investigator a dermatologist. Furthermore, the results were obtained from tertiary centers, and
567
therefore the generalizability of these estimates is unknown.
568
**
569
IP, interphalangeal; MCP, metacarpophalangeal.
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Cutaneous ulceration may occur anywhere on the skin, but these locations represent the most commonly involved sites.
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Represents estimates from three studies (references 23, 27, and 29) that systematically described these features. Importantly, in only
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Feature
Estimated Prevalence
573
Interstitial lung disease
42–100%*
574
Rapidly progressive interstitial lung disease
39–92%**
575
Arthritis/arthralgia
13–82%***
576
Fever
46%–69%****
577
Clinically amyopathic
46–50%***
578
Hand swelling
25–40%***
579
Pneumomediastinum
unknown
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580 581
*
582
Features).
583
**
584
***
585
and 29). The results were obtained from tertiary centers, and therefore the generalizability of
586
these estimates is unknown.
587
****
588
(references 3 and 27).
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Aggregated estimates from references 1, 3, 12, 16, 17, 19, 26, 35, 39.
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Estimated from two studies that systematically characterized and reported this feature
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A full list of references can be found in the manuscript’s text (see section on Systemic
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