CONTINUING MEDICAL EDUCATION

Dermatomyositis: Clinical features

and pathogenesis
Madeline E. DeWane, BA,a Reid Waldman, MD,b and Jun Lu, MDb
Farmington, Connecticut

Learning objectives
After completing this learning activity, participants should be able to define dermatomyositis and its variants in both adults and children; recognize the clinical features of DM (both
cutaneous and systemic) and potential differences in presentation between adults and children; discuss DM pathogenesis, including genetic, environmental, and immune factors, with
updated review on recently identified auto-antibodies; and recognize common features of DM on cutaneous and muscle biopsy as well as their significance in diagnosis of JDM.

Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).

Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Dermatomyositis (DM) is an idiopathic inflammatory myopathy that is clinically heterogeneous and that
can be difficult to diagnose. Cutaneous manifestations sometimes vary and may or may not parallel myositis
and systemic involvement in time course or severity. Recent developments in our understanding of
myositis-specific antibodies have the potential to change the diagnostic landscape of DM for dermatol-
ogists. Although phenotypic overlap exists, anti-Mi2, -MDA5, -NXP2, -TIF1, and -SAE antibodies may be
correlated with distinct DM subtypes in terms of cutaneous manifestations, systemic involvement, and
malignancy risk. This review highlights new findings on the DM-specific myositis-specific antibodies and
their clinical associations in both adults and children. ( J Am Acad Dermatol 2020;82:267-81.)

Key words: amyopathic dermatomyositis; dermatomyositis; juvenile dermatomyositis; idiopathic inflam-

matory myopathy; interstitial lung disease; malignancy-associated dermatomyositis; Mi2; MDA5; myositis-
specific antibodies; NXP2; SAE; TIF1.

D ermatomyositis (DM) is an idiopathic in- difficult to diagnose. In addition, historical ap-

flammatory myopathy (IIM) that is charac- proaches to the diagnosis of DM have embraced
terized by distinct skin lesions and a the use of ‘‘overlap’’ syndromes to account for
clinically heterogeneous constellation of systemic clinical heterogeneity, making diagnosis even more
manifestations. In the absence of characteristic difficult. The first article in this continuing medical
dermatologic findings or myopathy, DM can be education series discusses the epidemiology, clinical

From the University of Connecticut School of Medicinea and the Scanning this QR code will direct you to the
University of Connecticut Department of Dermatology,b CME quiz in the American Academy of
Farmington. Dermatology’s (AAD) online learning center
Funding sources: None. where after taking the quiz and successfully
Conflicts of interest: None disclosed. passing it, you may claim 1 AMA PRA
Accepted for publication June 6, 2019. Category 1 credit. NOTE: You must have an
Reprint requests: Jun Lu, MD, Department of Dermatology, AAD account and be signed in on your
University of Connecticut, 21 South Rd, Farmington, CT device in order to be directed to the CME
06032. E-mail: [email protected]. quiz. If you do not have an AAD account, you
0190-9622/$36.00 will need to create one. To create an AAD
Ó 2019 by the American Academy of Dermatology, Inc. account: go to the AAD’s website: www.aad.
https://doi.org/10.1016/j.jaad.2019.06.1309 org.
Date of release: February 2020
Expiration date: February 2023

267
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268 DeWane, Waldman, and Lu J AM ACAD DERMATOL
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an area of ongoing research. Traditionally, skin

Abbreviations used:
findings have been divided into pathognomonic
CADM: clinically amyopathic dermatomyositis (Gottron papules, Gottron sign, and heliotrope
CAJDM: clinically amyopathic juvenile
dermatomyositis rash), characteristic, compatible, less common,
DM: dermatomyositis rare, and nonspecific (Table I).12,13 Patients may
IFN: interferon present with 1 or a combination of DM-related skin
IIM: idiopathic inflammatory myopathy
ILD: interstitial lung disease changes (Figs 1-8). The clinical course of DM skin
JDM: juvenile dermatomyositis lesions does not necessarily parallel that of muscle
MDA5: melanoma differentiation associated disease and may precede or follow myositis. Lesions
protein 5
MSA: myositis-specific antibody are often pruritic or burning and are usually photo-
NXP2: nuclear matrix protein 2 sensitive.14 Persistent severe pruritus can signifi-
RP-ILD: rapidly progressive interstitial lung cantly impact patients’ quality of life.15,16 The
disease
cutaneous manifestations of DM associated with
MSAs will be discussed in detail below.

MUSCLE MANIFESTATIONS
characteristics, histopathology, and pathogenesis of Approximately 80% of patients with DM have
DM. Emphasis will be placed on the unique clinical myopathy. The classic muscular manifestation is
manifestations associated with the presence of acute or subacute onset of symmetric, proximal
myositis-specific antibodies (MSAs). muscle weakness. The myopathy is usually painless,
and while elevations of creatine kinase, aspartate
EPIDEMIOLOGY aminotransferase, and alanine aminotransferase are
The epidemiology of DM is difficult to determine common, laboratory indicators of muscle activity
because a variety of classification systems (discussed may also be normal.14,17 Dysphagia, dysphonia, and
in the second article in this continuing medical symptoms of aspiration indicate possible involve-
education series) have historically been used to ment of striated muscle of the pharynx and esoph-
diagnose the condition. Epidemiologic studies agus and are associated with a poor prognosis.18
report incidence rates for the IIMs of 2.47-7.8 per Notably, DM is not associated with sensory loss,
100,000 person-years and prevalence rates of 9.54 to ptosis, involvement of the extraocular muscles, or
32.74 per 100,000 individuals.1-3 DM-specific preva- abnormal reflexes, which can help differentiate it
lence has been estimated at 1 to 6 per 100,000 adults from other neuromuscular disorders.5
in the United States.3 DM is the most common of the Those with DM-consistent skin findings but
IIMs with a recent analysis of 3067 patients in the without myopathy have what is termed CADM.
Euromyositis registry identifying DM in 31% of CADM may by hypomyopathic (no objective weak-
patients.4 DM affects both genders with a 2:1 ness but evidence of subclinical muscle involvement
female:male ratio. All ethnic groups are affected, on laboratory testing, biopsy, or imaging) or amyo-
but it is more common in African Americans.5,6 pathic (no evidence of muscle involvement on
Population-based data suggest that clinically amyo- examination or workup).19
pathic DM (CADM) occurs in $20% of adults with
DM.7 SYSTEMIC MANIFESTATIONS
The average age of diagnosis of DM is bimodal, Table II lists systemic manifestations of DM in
with juvenile DM (JDM) most commonly diagnosed adults and children. Specific manifestations and
between 4 and 14 years of age and adult DM malignancy associations will be discussed in the
diagnosed between 40 and 60 years of age.6 JDM is context of MSAs to best reflect how these manifes-
the most common inflammatory myopathy of child- tations present in clinical practice. The clinical sub-
hood but remains rare, with an estimated incidence sets associated with MSAs will be discussed
of 3.2 cases per million children per year.8 Rates of separately for adult and juvenile DM because the
clinically amyopathic JDM are not well established.9 significance of each antibody depends on the age of
In a recent series of patients with clinically amyo- the affected individual.
pathic JDM, 25% eventually developed muscle
involvement.10 HISTOPATHOLOGY
Skin
CUTANEOUS MANIFESTATIONS Skin biopsy specimens obtained from patients
Cutaneous manifestations of DM may be vari- with DM are characterized by hyperkeratosis,
able,11 and precise skin criteria for DM diagnosis is epidermal atrophy, vacuolar interface dermatitis,

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J AM ACAD DERMATOL DeWane, Waldman, and Lu 269
VOLUME 82, NUMBER 2

Table I. Cutaneous manifestations of adult dermatomyositis

Category Finding Clinical description8,9,12,17,71 Additional features
Pathognomonic Gottron papules Violaceous papules and plaques, Dyspigmentation, atrophy, and
sometimes with subtle scale, scarring possible when lesions
overlying the MCP and ICP joints of resolve106
the hands
Gottron sign Erythematous macules or patches Slight scale may be present13
over extensor surfaces of elbows,
knuckles, knees, and ankles
Heliotrope rash Periorbital erythema with edema, May also involve cheeks and nose12
most often of the upper eyelids
Characteristic Nailfold changes Periungual erythema and Nailfold capillaroscopy may be useful
telangiectasias, dystrophic cuticles, adjunctive tool for monitoring
and hemorrhagic nailfold infarcts disease activity107-109
Shawl sign Violaceous or erythematous macules Poikiloderma may also be present in
and patches over posterior same distribution13
shoulders, neck, upper back, and
possibly lateral upper arms
V sign Erythematous, confluent macules and Skin may also appear atrophic13
patches over lower anterior neck
and upper chest
Holster sign Symmetric poikiloderma of hips and May be reticulated, livedoid, or linear
lateral thighs below the greater and is reported to be highly specific
trochanter for DM13
Scalp involvement Atrophic, erythematous, sometimes May be misdiagnosed as psoriasis or
pruritic scaly plaques seborrheic dermatitis110
Compatible Poikiloderma Hypo- or hyperpigmentation, May be referred to as ‘‘poikiloderma
telangiectasia, and atrophy, usually atrophicans vasculare’’ or
found on upper chest and lateral ‘‘poikilodermatomyositis’’13
upper arms
Periorbital edema Edema with or without erythema
and facial
swelling
Less common Vesiculobullous, Variable Often associated with cutaneous
necrotic, or vasculitis,13 ulceration associated
ulcerative with anti-MDA5 antibodies93
lesions
Cutaneous Variable, but may include petechiae, More common in JDM
vasculitis palpable purpura, livedo reticularis,
and ulceration
Calcinosis cutis Superficial white papules or nodules, Rare in adult DM (estimated 4% of
most commonly over bony surfaces adult DM patients4)
or at sites of inflammation
Rare Mechanic’s hands Hyperkeratotic, scaling, and fissuring More common in patients with anti-
of fingers and/or palms MDA5 antibodies53 and
antisynthetase syndrome53,111
Flagellate Linear erythematous macules and Associated with absence of MSAs on
erythema patches on the back serological testing56 or presence of
anti-Mi2 antibodies70
Deck chair sign Erythematous eruption sparing May be first cutaneous sign preceding
transverse skin folds classic DM skin findings*112
Follicular Follicular, hyperkeratotic papules on Hair follicle destruction and follicular
hyperkeratosis extensor surfaces resembling hyperkeratosis on histopathology
(‘‘wong-type pityriasis rubra pilaris plus interface changes of DM113
DM’’)
Continued

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270 DeWane, Waldman, and Lu J AM ACAD DERMATOL
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Table I. Cont’d
Category Finding Clinical description8,9,12,17,71 Additional features
Panniculitis Painful, indurated nodules of Associated with anti-MDA5
buttocks, arms, thighs, and antibodies93
abdomen
Mucinosis Variable, frequently plaques
appearing in a reticular pattern
Erythroderma Widespread erythema Associated with malignancy12
Oral mucosal Variable, but gingival telangiectasias, Ovoid palatal patch associated with
changes erosions, ulcers, and leukoplakia- anti-TIF1 antibodies80
like lesions reported
Nonspecific Raynaud Episodic vasospasm of fingers and More common in antisynthetase
phenomenon toes in response to cold with syndrome5
triphasic color change114

DM, Dermatomyositis; ICP, intercarpal phalangeal; JDM, juvenile dermatomyositis; MCP, metacarpal phalangeal; MDA5, antiemelanoma
differentiation-associated protein 5; MSA, myositis-specific antibody; TIF1, transcription intermediary factor 1.
*S. Madsen et al, unpublished data, 2019.

Fig 1. A and B, Gottron papules and the Gottron sign on the dorsal surfaces of the hands of
two patients with dermatomyositis.

basement membrane thickening, dermal edema,

pigmentary incontinence, mucin deposits, and a
perivascular infiltrate composed of CD41 lympho-
cytes.6 Endothelial cell damage, loss of capillaries,
and vascular dilatation may also be seen.20

Muscle
Biopsy specimens of muscle from patients with
DM are hallmarked by perifascicular atrophy.14,21
However, atrophy may be patchy,22 which can cause Fig 2. Heliotrope rash on the face of a patient with
false negatives. A 2017 study estimated the sensitivity dermatomyositis.
of perifascicular atrophy to be only 47% (though it is
CD251 plasma cells, and plasmacytoid dendritic
98% specific).23 Recent studies suggest that expres-
cells.5,25 Increased perifascicular expression of major
sion of myxovirus resistance protein A in myofiber
histocompatibility complex class I has also been
cytoplasm may be a better indicator of muscle
reported.14,26
involvement,23,24 with a sensitivity of 71% and
specificity of 98%.23 Other abnormalities observed
in DM muscle include deposition of complement on Special considerations in JDM
endomysial capillaries5 (35% sensitive and 93% spe- There is considerable histologic overlap between
cific6) and decreased capillary density. Inflammatory DM in adults and children, but perifascicular atrophy
infiltrates are both perimysial and perivascular and seen on a biopsy specimen of muscle may be more
consist of macrophages, CD201 B cells, CD41 T cells, reliably identified in JDM.17 In addition, vascular

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J AM ACAD DERMATOL DeWane, Waldman, and Lu 271
VOLUME 82, NUMBER 2

Fig 3. Holster sign on the (A) right lateral thigh and (B) right lateral hip of two patients with
dermatomyositis.

Fig 4. Characteristic nailfold changes of dermatomyositis.

Dermoscopic image shows periungual erythema and
telangiectasias and dystrophic cuticles.

Fig 5. Ulcerative lesion on the antecubital fossa of a

involvement in JDM is often more prominent.27
patient with dermatomyositis.
Specific features of a muscle biopsy specimen and
their associated JDM phenotypes are outlined in
Table III. correlated with autoantibody production in both
adults30,31 and children.32,33 In addition, the
PATHOGENESIS International Genetics Consortium in Myositis has
The pathogenesis of DM is multifactorial, com- identified cytokine and lymphocyte signaling alleles
plex, and incompletely understood. Genetic, envi- associated with disease development, disease
ronmental, and immune mechanisms (including the severity, calcinosis, and ulceration in genome-wide
recently discovered autoantibodies discussed analyses of juvenile IIMs.28 Epigenetic modification,
below), are thought to play a role in both adult DM including DNA methylation, histone modification,
and JDM development. and microRNA activity, may also play a role in DM
pathogenesis.34,35
Genetic risk factors
DM has a strong genetic component. Multiple Environmental risk factors
genotyping studies have demonstrated associations Multiple environmental factors may trigger
between major histocompatibility complex poly- chronic immune activation in genetically susceptible
morphisms and DM development,28,29 and particular individuals.30,36 Proposed triggers for DM include
human leukocyte antigen (HLA) alleles have been ultraviolet radiation, viral infections, medications,

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Fig 6. Characteristic poikiloderma on the lateral arm of a Fig 7. Scalp dark purpuric hyperpigmentation equivalent
patient with dermatomyositis. to erythema and subtle frontal diffuse alopecia in a patient
with Fitzpatrick skin type V and dermatomyositis.

and smoking. Ultraviolet exposure has been linked

with DM and anti-Mi2 antibodies in adult women37
and with JDM and antietranscription intermediary
factor 1 (TIF1) antibodies in children.38 Viral in-
fections may play a role in triggering immune
activation or disrupting immune tolerance,39 but
attempts to isolate viruses from DM muscle samples
have been unsuccessful.14 A 2017 study found that
DM/JDM flares were associated with ultraviolet
exposure, infections, and some medications,
although only sun exposure (odds ratio, 2.2) and
recent nonsteroidal antiinflammatory drug use (odds
ratio, 1.9) remained significant predictors in multi-
variable analysis.40 Smoking has been associated
with DM and the development of interstitial lung
disease (ILD), dysphagia, malignancy, and cardiac
involvement.4 Other potential environmental trig-
gers are less well established, including a recent
report of CADM developing after receiving a tattoo41
and a case series of 3 patients who developed an
acute onset or flare of DM after ingesting the herbal Fig 8. A, V sign with erythema and poikiloderma and (B)
supplement IsaLean.42 shawl sign in a patient with dermatomyositis.

Immune mechanisms
The sequence of immune activation in DM re- from initiation of the classical complement cascade.
mains incompletely understood although it likely Regardless, this activation results in capillary destruc-
results from inappropriate complement activa- tion that leads to ischemia and microinfarction,
tion.43,44 It remains controversial whether this acti- hypoperfusion, and perifascicular atrophy.14
vation is antibody-dependent or whether it results Altered expression of myogenic regulatory factors

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J AM ACAD DERMATOL DeWane, Waldman, and Lu 273
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Table II. Systemic manifestations of dermatomyositis in adults and children

Organ system Adult DM JDM
Pulmonary Varying degrees of ILD most common,17 ILD is ILD rare (6% of cases), associated with anti-MDA5
associated with anti-MDA5 antibodies,19 may antibodies4,71; respiratory muscle weakness
be rapidly progressive, especially in Asian affecting ventilation possible71 and not
populations89; pulmonary hypertension or correlated with other clinical measures of
serositis also possible17 muscle weakness115
Cardiac Cardiovascular risk factors are increased in Clinically significant involvement uncommon,
patients with DM116; subclinical diastolic but systolic and diastolic dysfunction
dysfunction is common116; myocarditis, possible118; increased rates of hypertension,
myocardial fibrosis, arrhythmias, and dyslipidemia,116 and ECG abnormalities116,119;
congestive heart failure are all possible116; decreased heart rate variability116,119;
cardiac involvement does not correlate with pericarditis and myositis occur rarely116
disease severity and may develop at any
time117
Gastrointestinal Dysphagia related to dysfunction of the pharynx GI involvement in 5-37% of JDM cases122;
or esophagus120; gastric and small intestinal dysphagia, dysmotility, vasculitis-related bowel
motility may be affected120; rarely, pathology possible122; weakness affecting
vasculopathy may lead to GI tract infarction or swallowing does not correlate with other
perforation121 clinical measures of muscle weakness123
Endocrine Lipodystrophy in 10-30% of patients124; growth
failure in 10% of cases125; bone mineral density
may be reduced71
Vascular Cutaneous vasculopathy may cause ulcerations, Vasculitis more common in JDM, especially
especially in patients with anti-MDA5 involving the skin and small vessels122; GI
antibodies92,93 involvement may lead to malabsorption,
ulceration, or perforation126; central nervous
system122 and retinal involvement127 also
reported; nailfold capillaroscopy may be useful
tool107-109

DM, Dermatomyositis; ECG, electrocardiographic; GI, gastrointestinal; ILD, interstitial lung disease; JDM, juvenile dermatomyositis; MDA5,
antiemelanoma differentiation-associated protein 5.

(demonstrated in JDM muscle) may also contribute MYOSITIS-SPECIFIC ANTIBODIES

to atrophy because of impaired cell differentiation MSAs are antibodies that are exclusively associ-
and maturation.45 ated with a diagnosis of an IIM.52 DM-specific
In addition, there is considerable evidence that antibodies include anti-Mi2, antiemelanoma
interferons (IFNs) play a role in DM and JDM. differentiation-associated protein 5 (MDA5), anti-
Marked upregulation of the type I IFN pathway has NXP2, anti-TIF1, and antiesmall ubiquitin-like mod-
been demonstrated in the muscle, skin, and blood of ifier activating enzyme (SAE). Except for anti-Jo1,
patients with DM,20,34,46-48 and cutaneous activity in which is present in antisynthetase syndrome, MSAs
adult DM has been shown to correlate with a type I have not yet been incorporated into the diagnostic
IFN gene signature.46 In patients with JDM, type I IFN criteria for IIMs. However, MSAs are potentially
score, type II IFN score, and tumor necrosis helpful to the dermatologist because: 1) they may
factorealpha expression correlate with disease ac- facilitate diagnosis in the absence of a biopsy
tivity.49 A persistent IFN response (perpetuated by specimen of muscle and in clinically atypical DM
chronic stimulation of antigen-presenting cells) has cases53,54; 2) they impact prognosis and can help
been implicated in multiple autoimmune diseases; guide management55-58; and 3) they allow for clinical
the resulting T and B cell activation may be respon- studies to select patients based on serologies, which
sible for autoantibody production.50 In DM and JDM, may help further elucidate the significance of MSAs
however, the pathogenic role of these autoanti- and improve the generalizability of these studies in
bodies remains unclear. The recent identification of clinical practice.54
antiendothelial cell antibodies in the plasma of The current limitations of MSAs are twofold: 1)
children with JDM supports the conceptualization there is still a ‘‘serologic gap,’’ with a significant
of JDM as an antibody-mediated vasculopathy.51 proportion of DM patients presenting without MSAs;

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Table III. Biopsy features and associated severe cutaneous features of DM, such as calcinosis
phenotypes in juvenile dermatomyositis71,128,129 and ulcerative vasculopathy, are not commonly seen
Phenotype Muscle biopsy features
in this clinical subset.
In addition, Mi-2 DM characteristically presents
Severe disease Lymphoid follicles including
with proximal symmetric muscle weakness. Despite
course networks of fDCs and high
endothelial venules; high having clinically mild myopathy, these patients
levels of CXCL13 and frequently have creatine kinase elevations that
lymphotoxins; resident na€ıve are out of proportion to their degree of muscle
CD45RA1 T cells, and involvement. Fortunately, this form of DM is usually
maternally derived B cells responsive to treatment. Mi-2 DM portends a benign
and pDCs prognosis and is not associated with an increased
Chronic disease course Severe arteriopathic changes, risk of development of malignancy or interstitial lung
with ulcerations positive arterial direct disease.58
immunofluorescence, severe Anti-Mi2 antibodies are identified in 4% to 10%
capillary loss, endomysial
of patients with JDM, and the clinical manifesta-
fibrosis, and muscle infarcts
tions and prognostic implications are similar in
Chronic disease Extensive active myopathic
course changes and central nuclei adults and children. Anti-Mi2 antibodies are more
without basophila common in Hispanic children who are older at
disease onset (median age 11 years).71,72 As in
fDC, Follicular dendritic cell; pDC, plasmacytoid dendritic cell. adults, clinical features include symmetric, prox-
imal muscle weakness and pathognomonic cuta-
and 2) clinically available laboratory tests for MSAs neous findings, and these patients tend to respond
can vary in their sensitivity and specificity. Results of well to treatment.71-73
laboratory testing for MSAs vary depending on the
testing technique used, and estimated rates of MSA
positivity in DM range from 20% to 50%.59-61 Using TIF1
commercial laboratories, it is not uncommon for TIF1 (previously p155/140) is a tumor suppres-
MSA testing to be negative, even after a diagnosis of sor protein that is responsible for serving as a
DM has been clinically confirmed61; this may be transcriptional corepressor.24,55 There are 3 sub-
partially attributable to the variability in the accuracy units of the TIF1 protein (alpha, beta, and gamma),
of available commercial testing. Nonetheless, the with each subunit having its own respective auto-
clinical utility of MSA testing is increasing as com- antibodies.74,75 Antibodies to this family of proteins
mercial testing improves and is standardized, espe- were first identified in 200676 and are found in 18% to
cially with recent studies suggesting that MSAs alone 23% of adult patients with DM.55 The primary clinical
can accurately subdivide patients into their appro- significance of anti-TIF1-gamma DM is its strong
priate clinical diagnoses.53 Although laboratory association with underlying malignancy.
testing for MSAs and their use to classify IIMs remain Identification of anti-TIF1 antibodies has a positive
somewhat exploratory, we believe this is a promising predictive value of 58% and a negative predictive
area of research. A summary of MSAs and their value of 95% for cancer-associated DM (odds ratio,
clinical associations in both adults and children is 27.26).77 TIF1 antibodies are associated with the
presented in Table IV. development of both solid and hematologic
malignancies. Tumor rates reported in the
Mi-2 literature are variable but range from 20% to
Anti-Mi2 antibodies are directed against a nuclear 65%.55,78 It has been hypothesized that anti-TIF1
DNA helicase involved in transcription.34 The prev- antibodies are generated during an antitumor
alence of anti-Mi2 antibodies among adult patients immune response.24,55,79
with DM varies based on ethnicity, geographic Anti-TIF1 DM has multiple other key clinical
location, and method of testing,62 but estimates in associations in adults: 1) severe, photosensitive
the literature range from 4% to 35%.34,63-68 These cutaneous disease with heliotrope rash, v sign, and
patients present with ‘‘classic dermatomyositis’’ char- Gottron papules; 2) unique mucocutaneous find-
acterized by the development of pathognomonic ings, such as palmar hyperkeratosis, psoriasiform
cutaneous manifestations.58,69 The cutaneous mani- plaques, ovoid palatal patches, and atrophic hypo-
festations disproportionately associated with Mi-2 pigmented patches with overlying telangiectasias;
DM in adults include facial dermatosis, shawl sign, 3) hypomyopathic disease; 4) gastrointestinal
poikiloderma, and flagellate erythema.70 Other more involvement; and 5) a lack of other systemic

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Table IV. Dermatomyositis-associated myositis-specific antibodies and their associated clinical features
Malignancy
Antibody Target antigen Incidence Associated clinical features association
Anti-Mi2 Nuclear DNA heli- Adult DM ‘‘Classic’’ cutaneous findings, None
case involved in 4-35% facial dermatosis, shawl sign,
transcription poikiloderma, flagellate
erythema; proximal,
symmetric muscle weakness
with highly elevated CK;
treatment responsive
JDM 4-10% More common in Hispanic None
patients, older at disease
onset; clinical features similar
to adults
Anti-TIF1 (previously Tumor suppressor Adult DM Severe, photosensitive Strongly
anti-p155/140) protein that acts 18-23% cutaneous disease, palmar associated with
as transcrip- hyperkeratosis, psoriasiform malignancy
tional plaques, ovoid palatal
corepressor patches, atrophic
hypopigmented patches
with overlying
telangiectasias; often
hypomyopathic; GI
involvement
JDM 18-35% More common in white None
patients, younger at disease
onset; severe, treatment-
refractory cutaneous disease,
ulceration, muscle weakness,
lipodystrophy, chronic
disease course
Anti-MDA5 (previously RNA-specific heli- Adult DM Clinically amyopathic disease; None
CADM140) case involved in 10-30% interstitial lung disease (may
antiviral im- be rapidly progressive);
mune response cutaneous ulceration, painful
palmar papules, panniculitis
JDM 7-50% Ulcerative skin and mucosal None
lesions; interstitial lung
disease; milder muscle
involvement; arthritis
Anti-NXP2 Nuclear protein Adult DM 2- Classic cutaneous findings; Increased risk of
involved in 25% (varies peripheral edema; calcinosis malignancy
regulation of by ethnicity) and ulceration rare
transcription JDM 20-25% Calcinosis cutis; disabling None
and RNA myopathy; GI bleeding
metabolism related to vasculopathy
Anti-SAE Nuclear enzyme Adult DM 8% Strong HLA associations; severe Unknown
involved in (varies by cutaneous disease;
posttranslation ethnicity) progressive muscle disease
modification of with dysphagia; fever and
proteins weight loss
JDM 2-8% Severe cutaneous disease, Unknown
minimal muscle disease

CK, Creatine kinase; DM, dermatomyositis; GI, gastrointestinal; HLA, human leukocyte antigen; ICP, intercarpal phalangeal; JDM, juvenile
dermatomyositis; MCP, metacarpal phalangeal; MDA5, antiemelanoma differentiation-associated protein 5; MSA, myositis-specific antibody;
NXP2, nuclear matrix protein 2; RNA, ribonucleic acid; SAE, small ubiquitin-like modifier activating enzyme; TIF1, antietranscription
intermediary factor 1.

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Table V. Nonedermatomyositis-associated myositis-specific antibodies

Antibody Disease entity Clinical association(s)
Anti-ARS (includes anti-Jo1 Antisynthetase Myositis with ILD, polyarthritis, Raynaud
[histidyl], anti-PL7 [alanyl], syndrome phenomenon, and cutaneous findings (Gottron
anti-PL12 [glycyl], anti-EJ papules, ‘‘mechanic’s hands’’)104; more severe ILD
[isoleucyl], anti-OJ [isoleucyl], and poorer prognosis with non-Jo1 antibodies85
anti-KS [asparaginyl], anti-Zo
[phenylalanyl], and anti-YRS/
HA [tyrosyl])
Anti-SRP Necrotizing myopathy Sudden, severe, and progressive muscle weakness,
(anti-SRP antibody often with cardiac involvement and/or
syndrome) dysphagia59,104; treatment resistant85; no increased
risk of malignancy130
Anti-HMGCR Immune-mediated Increased risk of malignancy compared with the
necrotizing general population130; statin-induced myopathy131
myopathy
CN1A Inclusion body Progressive weakness and functional impairment in
myositis older patients (typically [50 years of age)132

ARS, Aminoacyl tRNA synthetase; CN1A, cytosolic 5’nucleotidase 1A; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; ILD,
interstitial lung disease; SRP, signal recognition particle.

manifestations, such as interstitial lung disease, development of DM-associated RP-ILD.91 The asso-
Raynaud phenomenon, and arthritis.58,80-82 ciated 6-month mortality is approximately 59%.91
In children with JDM, the frequency of anti-TIF1 Anti-MDA5 DM also presents with several unique
antibodies is estimated to be 18% to 35%.71 cutaneous findings in both adults and children that
These antibodies are more common in white are thought to be attributable to the development
patients71,72 with a younger age at disease onset of cutaneous vasculopathy.92,93 These include:
(median 7 years).71 Unlike in adult DM, anti-TIF1 1) cutaneous ulceration frequently at the site of
antibodies in children are not associated with Gottron papules and the lateral nail folds; 2) painful
malignancy.55 Clinical associations include severe, palmar papules (termed inverse Gottron papules);
treatment-refractory, photodistributed cutaneous and 3) panniculitis.19,93-95
disease, cutaneous ulceration, greater muscle Anti-MDA5 antibodies are the third most common
weakness, lipodystrophy, and a chronic disease MSA detected in children with JDM after anti-TIF1
course.71,72 and antienuclear matrix protein 2 (NXP-2).71 The
exact prevalence of anti-MDA5 antibodies in JDM is
unknown, although estimates range from 7.4% per
MDA5 the United Kingdom Juvenile Dermatomyositis
MDA5 (previously CADM140) is a RNA-specific Registry96 to near 50% in Japanese children with
helicase involved in antiviral immune response JDM.96,97 Like their adult counterparts, children with
(including the production of type I IFN).24,83 anti-MDA5 DM have an elevated risk of developing
Autoantibodies against MDA5 are identified in the ILD as well as ulcerative skin and mucosal
majority of adults and children with CADM84,85 and lesions.71,96 RP-ILD is less common in children, but
in 10% to 30% of patients with DM overall.57 This rates of RP-ILM are higher in Asian JDM patients with
subset is identified most frequently in Asian anti-MDA5 antibodies.71,96 Patients with JDM with
patients, with the associated clinical significance these antibodies frequently demonstrate milder
demonstrating some degree of regional/ethnic muscle involvement96 (though less commonly
variability.86-88 Anti-MDA5 DM is associated with an amyopathic disease) and arthritis.71
increased risk of developing ILD, which in some
cases may be rapidly progressive (RP-ILD).24,83,89 NXP-2
RP-ILD is characterized by short-interval (\4 weeks) NXP-2 is a protein involved in multiple nuclear
progression of ILD by subjective symptoms or functions, including regulation of transcription and
objective metrics (eg, ground glass opacity on RNA metabolism.24 Anti NXP-2 antibodies (formerly
computed tomography, worsening PaO2).90 The anti-MJ) are detected in a relatively small percentage
presence of anti-MDA5 antibodies has an estimated of adults with DM, although prevalence varies by
sensitivity of 77% and specificity of 86% for the ethnicity (14-25% in U.S. populations and 2-5% in

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VOLUME 82, NUMBER 2

Japanese populations).58,78,84,98-100 Like anti-TIF1- involvement and minimal muscle disease in a

gamma DM, adults with anti-NXP-2 DM are at an manner analogous to adults.71
elevated risk of underlying malignancy, although the
tumor rate associated with NXP-2 antibodies (37.5%)
is less than that conferred by anti-TIF1-gamma Other MSAs
seropositivity.57 This subset of DM patients typically Other MSAs occur in immune-mediated necro-
presents with classic cutaneous findings. Peripheral tizing myositis, inclusion body myositis, and anti-
edema may be seen in #35% of patients,58,99 and synthetase syndrome. These antibodies may be
calcinosis and distal ulcerations are observed in identified during a work-up of a patient for DM.
adults with anti-NXP-2 DM on occasion.58 Table V lists these other MSAs and their associated
Calcinosis is a much less frequent finding in adults clinical features.
than it is in children with this antibody. In conclusion, the recent discovery of MSAs has
Anti-NXP2 antibodies are the second most revealed that DM is comprised of a heterogenous
common autoantibody in patients with JDM, with a group of closely related clinical subtypes that can be
frequency of 20% to 25%.58,72 Like anti-TIF1 anti- distinguished from one another based on serology.
bodies, anti-NXP2 antibodies are more common in Understanding the clinical implications of MSAs in
younger, white patients (median age at disease onset DM will become increasingly important as more
6 years).71,72 NXP-2 JDM portends a poor prognosis studies are done and autoantibody testing is
and requires more aggressive management than standardized. The first article in this continuing
other forms of JDM. The cutaneous hallmark of this medical education series provided readers with an
subset is the development of calcinosis cutis, which understanding of the clinical significance of MSAs
occurs in [40% of NXP-2 antibodyepositive that will be essential for understanding the
individuals.101,102 This form of JDM also presents approaches to diagnosis, work-up, and management
with severe myopathy that frequently causes discussed in the second article in this series.
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Answers to CME examination

Identification No. JA0220
February 2020 issue of the Journal of the American Academy of Dermatology.

DeWane ME, Waldman R, Lu J. J Am Acad Dermatol 2020;82:267-81.

1. d
2. b
3. d

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