SYMPOSIUM ON NEUROSCIENCES

Diagnosis and Management of

From the Neuromuscular
Medicine Division, Depart-
ment of Neurology, Mayo
Clinic, Rochester, MN.
Immune-Mediated Myopathies
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antibodies with specific immune-mediated myopathies, and (3) differentiate
muscle pathologic features of common immune-mediated myopathies.
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Abstract

Immune-mediated myopathies (IMMs) are a heterogeneous group of acquired muscle disorders charac-
terized by muscle weakness, elevated creatine kinase levels, and myopathic electromyographic findings.
Most IMMs feature the presence of inflammatory infiltrates in muscle. However, the inflammatory exudate
may be absent. Indeed, necrotizing autoimmune myopathy (NAM), also called immune-mediated
necrotizing myopathy, is characterized by a necrotizing pathologic process with no or minimal inflam-
mation in muscle. The recent discovery of antibodies associated with specific subtypes of autoimmune
myopathies has played a major role in characterizing these diseases. Although diagnostic criteria and
classification of IMMs currently are under revision, on the basis of the clinical and muscle histopathologic
findings, IMMs can be differentiated as NAM, inclusion body myositis (IBM), dermatomyositis, poly-
myositis, and nonspecific myositis. Because of recent developments in the field of NAM and IBM and the
controversies around polymyositis, this review will focus on NAM, IBM, and dermatomyositis.
ª 2017 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2017;92(5):826-837

I
mmune-mediated myopathies (IMMs) are levels, and myopathic electromyographic
a heterogeneous group of acquired mus- findings. Because of the frequent presence
cle disorders characterized by muscle of inflammatory infiltrates on muscle biopsy,
weakness, elevated creatine kinase (CK) IMMs are often referred to as idiopathic

826 Mayo Clin Proc. n May 2017;92(5):826-837 n http://dx.doi.org/10.1016/j.mayocp.2016.12.025

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IMMUNE-MEDIATED MYOPATHIES
inflammatory myopathies (IIMs). However,
the inflammatory exudate may be absent in
the muscle in some IMMs. Indeed, muscle
biopsy of necrotizing autoimmune myopathy
(NAM), also called immune-mediated necro-
tizing myopathy, often reveals prominent
muscle fiber necrosis and regeneration with
minimal or no inflammation.1,2 Since the
1975 classification of polymyositis (PM)
and dermatomyositis (DM) by Bohan and
Peter,3 there has been a constant effort to
define diagnostic criteria and reclassify the
IMMs, but to date, no diagnostic criteria
or classification has found unanimous
consensus.
On the basis of the clinical and muscle
histopathologic findings, IMMs can be
distinguished as DM, PM, inclusion body
myositis (IBM), NAM, and nonspecific
myositis.2 The entity PM is controversial,
and although still recognized as a specific
IIM, it seems to be overdiagnosed.4,5 Many
patients with PM have been later diagnosed
as having IBM or overlapping myositis.6,7
The distinction of DM, PM, IBM, NAM,
and nonspecific myositis does not entirely
reflect the true spectrum of IMMs. Indeed,
a subset of IIM can have extramuscular
involvement consisting of lung, skin, or
joint involvement (overlap myositis). In
addition, the recently discovered myositis-
associated antibodies link to specific clinical
and pathologic phenotypes and may even
guide treatment.8 These antibodies comple-
ment the clinical and myopathologic find-
ings and contribute to the characterization
of the IMMs. Therefore, these antibodies
could be of tremendous value in the reclas-
sification of IMMs.
This article will discuss NAM, IBM, and
DM as defined by clinical and myopathologic
features.
NEEDS IN THE FIELD
In light of the knowledge on noninflammatory
IMMs, the rarity of PM, and the discovery of
myositis-associated antibodies, it has become
evident that the old Bohan and Peter classifi-
cation,3 as well as the more recently proposed
classifications of IMMs, are in need of verifi-
cation and revision.2,9,10 Diagnostic criteria
for each subtype require definition and
consensus.
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NECROTIZING AUTOIMMUNE MYOPATHY
Clinical Features
Necrotizing autoimmune myopathy manifests
with subacute proximal limb muscle weakness
and persistently elevated CK levels. In contrast
to immune-mediated inflammatory myopa-
thies, NAM muscle biopsies often reveal no or
minimal inflammation but prominent muscle
fiber necrosis and regeneration (Figure 1,
Table 1).1,11 Necrotizing autoimmune myop-
athy most frequently affects adults but can
also occur in children.12,13 The weakness is
predominantly proximal and more prominent
in the lower limbs. In a recent Mayo Clinic
study, coexisting distal weakness involving
foot dorsiflexors and finger extensors was
documented in more than 40% of patients.11
Neck muscle weakness and dysphagia
are common. Occasionally, head drop and
camptocormia are the predominant clinical fea-
tures.11,14 Myalgia may or may not be present.
Respiratory muscle weakness is common as
suggested by dyspnea, a restrictive pattern on
pulmonary function tests, and abnormal find-
ings on overnight oximetry. The respiratory
muscle weakness can result in hypercapnic res-
piratory failure and the need for mechanical
ventilation,11,15 not only in the setting of gener-
alized weakness but also at disease onset.16
Cardiac involvement is infrequent and occurs
in the form of left ventricular wall motion
abnormalities or takotsubo cardiomyopa-
thy.11,17 Necrotizing autoimmune myopathy
can be associated with cancer; therefore, cancer
screening is needed.11,18,19 Although NAM is
commonly a subacute myopathy, it can also
manifest with slowly progressive weakness
mimicking muscular dystrophies, clinically
and pathologically.20
Diagnosis
The diagnosis of NAM relies on the combina-
tion of clinical and pathologic features and the
exclusion of other etiologies that can result in
a similar muscle histopathologic pattern. The
histologic features of NAM (necrotizing myop-
athy with minimal or no inflammation) are
nonspecific and also compatible with early
muscular dystrophy or toxic myopathies.21
The subacute onset of the weakness makes
hereditary myopathy unlikely. The presence
of serologic markers (see “Necrotizing
827

FIGURE 1. Muscle biopsy specimens from a patient with necrotizing
autoimmune myopathy and antie3-hydroxy-3-methylglutaryl coenzyme
A reductase antibodies. A, There are numerous scattered necrotic
muscle fibers (asterisks), fewer regenerating fibers (arrow), and no
inflammatory exudate; few fibers have internalized nuclei (arrowhead)
(hematoxylin-eosin). B, Macrophages invading necrotic fibers appear red
(acid phosphatase stain).
Autoimmune Myopathy,” “Serologic Markers”
section) and clinical response to immuno-
therapy support the autoimmune nature of
the disease. Often, biopsy specimens from
patients with NAM exhibit C5b9 deposits on
the sarcolemma of nonnecrotic muscle fibers
and diffuse major histocompatibility complex
(MHC) class 1 up-regulation.2,21,22 However,
the latter finding is nonspecific because it
can be observed in muscular dystrophies,
especially in those frequently associated
with an inflammatory exudate in muscle.23-25
Although muscle fiber necrosis and
regeneration are the main histologic features
of NAM, approximatly 20% of patients with
antie3-hydroxy-3-methylglutaryl coenzyme
A reductase (HMGCR) antibody have minor
TABLE 1. Pathologic Hallmarks of Immune-Mediated Myopathies
Myopathy Muscle histologic features Inflammatory cells
NAM Necrotic and regenerating Only about 20% of patients have
muscle fibers an inflammatory exudate on
muscle biopsy
IBM Inflammatory infiltrate invading CD 8þ T cells
nonnecrotic muscle fibers Macrophages
Rimmed vacuoles
Congophilic inclusions
DM Perifascicular muscle fiber atrophy CD4þ T cells
Focal capillary depletion Plasmacytoid dendritic cells
DM ¼ dermatomyositis; IBM ¼ inclusion body myositis; NAM ¼ necrotizing autoimmune
myopathy.
n n
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MAYO CLINIC PROCEEDINGS
inflammatory infiltrates.26 When present, the
inflammatory cells are located in the endomy-
sium and perivascular sites (CD8þ T cells
invading nonnecrotic muscle fibers, as
observed in PM, are not a feature of NAM)
and consist predominantly of macrophages.
These macrophages are likely involved in
tissue repair and not destruction, as sug-
gested by their M2 polarization.22 More con-
spicuous T-cell infiltrates have been
described in antiesignal recognition particle
(SRP) antibodyepositive NAM.8
Serologic Markers
Levels of CK are always elevated in NAM, to
the order of several thousands.
The 2 main antibodies associated with
NAM are the anti-HMGCR and anti-SRP anti-
bodies (Table 2). Approximately a third of
patients with NAM have no detectable
HMGCR or SRP antibodies.
3-Hydroxy-3-methylglutaryl coenzyme A
reductase is the enzyme that catalyzes the
rate-limiting step of cholesterol synthesis.
Antibodies directed against HMGCR are
present in patients with NAM who have
been exposed to statins but also in statin-
naive patients.11,26,27 Up to one-third of
anti-HMGCR antibodyepositive patients
with NAM are statin naive and tend to have
myopathy that is more resistant to treat-
ment.27 However, statins are also contained
in dietary constituents, and therefore, indi-
viduals may not actually be statin naive.
This factor has created confusion about the
possible role of statins as a trigger for NAM.
The duration of exposure to statins does
not seem to affect the development of
NAM, and in some patients, the myopathy
has developed after discontinuation of the
statins. In addition, statin discontinuation
does not arrest the progression of the anti-
HMGCReassociated myopathy.26 In general,
anti-HMGCR antibody titers correlate with
CK levels and disease activity.13,26,28 Howev-
er, in a large cohort of Chinese patients with
low prevalence of statin exposure, serum
levels of anti-HMGCR antibody did not
match disease activity.29 Atorvastatin and
simvastatin were the most common statins
in the Mayo Clinic NAM cohort.11 Atorvasta-
tin was the statin most frequently associated
with anti-HMGCR antibodies in a more
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IMMUNE-MEDIATED MYOPATHIES

recent study.30 The anti-HMGCR antibodies

TABLE 2. Antibodies and Clinical Associationsa,b
are quite specific for NAM. A large interna-
tional study of approximately 1900 sera Antibody Phenotype Additional clinical features
detected anti-HMGCR antibodies in NAM AntieMi-2 DM NA
and in only a few cases of inflammatory AntieTIF-1g DM [ Risk of cancer
myopathies associated with muscle fiber ILD
Severe skin disease
necrosis (PM and DM) but not in the serum
Anti-MDA5 DM ILD
of patients with muscular dystrophy.31
Amyopathic DM
Patients with self-limiting statin intolerance Anti-SAE DM
and self-limiting cerivastatin-related rhabdo- Anti-NXP2 DM [ Risk of cancer (in adults)
myolysis had no anti-HMGGCR antibodies, Calcinosis (in juvenile DM)
suggesting that the early detection of the Anti-Jo1 Antisynthetase syndrome, ILD
anti-HMGCR antibodies could distinguish myositis-predominant
statin-associated NAM from the statin self- Anti-HMGCR NAM [ Risk of cancer
limiting myopathy.26,32 Essentially, the Anti-SRP NAM [ vs unchanged risk of cancer
detection of anti-HMGCR antibodies would Anti-cN1A IBM NA
allow the early diagnosis and treatment of a
cN1A ¼ cytosolic 50 -nucleotidase 1A; DM ¼ dermatomyositis; Jo1 ¼ histidyletransfer RNA
NAM. However, the measurement of anti- synthetase; IBM ¼ inclusion body myositis; ILD ¼ interstitial lung disease; MDA5 ¼ melanoma
HMGCR antibodies in the cohort of patients differentiationeassociated gene 5; NAM ¼ necrotizing autoimmune myopathy; NA ¼ not
available; NXP2 ¼ nuclear matrix protein 2; SAE ¼ small ubiquitinlike modifier activating enzyme;
with self-limiting cerivastatin-related rhabdo-
SRP ¼ signal recognition particle; TIF-1g ¼ transcriptional intermediary factor 1-g.
myolysis was performed years after the b
Dermatomyositis and NAM are associated with an increased risk of cancer compared
diagnosis of rhabdomyolysis. Therefore, the with age- and sex-matched controls. Risk of cancer is higher in the presence of certain
possibility that these patients had circulating antibodies.
antibodies at the time of the myopathy or
“seronegative” NAM cannot be excluded. In
addition, cerivastatin was removed from the
market in early 2000 because of renal failure In comparison with the general population,
secondary to rhabdomyolysis.33 Therefore, patients who have NAM with anti-HMGCR
the observation that cerivastatin-related rhab- antibodies, as well as those without anti-
domyolysis is not associated with anti- HMGCR or anti-SRP antibodies, have a higher
HMGCR antibodies cannot be generalized to incidence of malignant disease, which was not
all the statins. observed in a cohort of anti-SRP antibodye
Signal recognition particle is a complex positive patients with NAM.39 Cancers of
consisting of 6 polypetides and a 7S RNA various types seem to occur mainly within 3
molecule that is important for the transloca- years of NAM diagnosis and in patients older
tion of newly formed proteins to the endo- than 50 years.39 However, malignant
plasmic reticulum. Similar to anti-HMGCR, disorders have also been documented in
anti-SRP antibody titers also correlate with anti-SRP antibodyepositive NAM.15 There-
CK levels and degree of muscle weakness, fore, independent from the coexisting sero-
raising the possibility of a pathogenic role for logic markers, broad screening for cancer is
such antibodies in NAM.34 The specificity of appropriate.
anti-SRP antibodies is controversial because
these antibodies have also been reported in Pathogenesis
other autoimmune disorders.35,36 Moreover, The role of anti-HMGCR and anti-SRP anti-
the use of the terms NAM, PM, and myositis bodies and their pathogenicity in NAM
interchangeably in some studies limits the remain unknown. It has been suggested
assessment of the diagnostic specificity of that the HMGCR up-regulation induced
anti-SRP antibodies. by statins may contribute to the develop-
Comparing anti-HMGCR antibodye ment of the disease in immunogenetically
positive and anti-SRP antibodyepositive pa- predisposed individuals (only 2-3 per
tients with NAM, the latter seem to have 100,000 statin-treated patients per year
more severe weakness and susceptibility to have development of NAM27). The HMGCR
development of interstitial lung disease.37,38 overexpression in regenerating muscle tissue

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 MAYO CLINIC PROCEEDINGS

FIGURE 2. Features of inclusion body myositis. Note weakness of the finger flexors (A) but spared
strength of finger extensors (B) in the same patient and weakness of the orbicularis oculi (C), as suggested
by inability to close the eyes, in another patient.

could perpetuate the muscle insult by driving
the autoimmune response.26 A similar mech-
anism may apply to NAM-associated cancer,
as HMGCR is up-regulated in some
malignant cells.40 In regard to anti-SRP
antibodies, their potential pathogenicity in
NAM is indirectly suggested by the correla-
tion of the antibody titer with the CK
values34 and demonstration of anti-SRP
antibodyedependent complement-mediated
muscle cell lysis in culture.41
Treatment
No randomized clinical trials have been per-
formed in patients with NAM, and treatment
is based on expert opinion and data from case
series. Although therapy should be individual-
ized, it appears that corticosteroids alone are
often not sufficient to treat the disease, and
most patients require at least 2 immuno-
suppressant drugs. In the Mayo Clinic cohort,
patients who received 2 or more immunothera-
peutic agents (corticosteroids, intravenous
immunoglobulin [IVIG], and a steroid-sparing
immunosuppressant agent) in the first 3
months of treatment were more likely to
experience significant improvement.11 In
addition, early treatment with IVIG seems to
be associated with a more significant
improvement in strength.8,11,13,42-44 Intrave-
nous immunoglobulin as monotherapy has
also been successful in treating rare cases of
anti-HMGCR antibodyepositive NAM.27
Rituximab may be especially beneficial in
n n
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anti-SRP antibodyepositive NAM.37,45 Corti-
costeroid weaning or discontinuation of immu-
notherapy is associated with a high relapse
rate.11,45
INCLUSION BODY MYOSITIS
Clinical Features
Inclusion body myositis is often indicated as
sporadic IBM to distinguish it from hereditary
IBM, which has a genetic etiology. The term
IBM will be used here to indicate the acquired
form. Inclusion body myositis is the most
common acquired muscle disease in patients
older than 50 years.46 It has a mild male
predominance and is characterized by early
development of quadriceps and finger flexor
weakness and atrophy (Figure 2, A and B).
The weakness is frequently asymmetric.
When present, quadriceps weakness greater
than that in the hip flexors favors the diagnosis
of IBM over other inflammatory myopathies.
Dysphagia and weakness of the foot dorsiflex-
ors are also common. Facial weakness occurs
in up to 55% of cases (Figure 2, C), and axial
weakness may occur in the advanced stage of
the disease.47,48 Occasionally, facial weakness,
dysphagia, and camptocormia secondary to
paraspinal muscle weakness can be the mani-
festing feature of IBM.49,50 Asymptomatic
impairment of respiratory function is common
in IBM, as well as sleep-disordered breathing,
independent from daytime respiratory func-
tion.51,52 Diaphragmatic weakness has been
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IMMUNE-MEDIATED MYOPATHIES

FIGURE 3. Muscle biopsy specimens from a patient with inclusion body myositis. A, Autoaggressive in-
flammatory infiltrates invading a nonnecrotic muscle fiber (arrow) (hematoxylin-eosin, original
magnification 40). B, Rimmed vacuoles (arrow) (trichrome stain, original magnification 40). C, Con-
gophilic inclusions within a muscle fiber appear bright red (arrow) (Congo redestained section viewed
under rhodamine optics, original magnification 40).

described occasionally.53 Although muscle
weakness slowly progresses and may result
in severe disability, life expectancy is not
affected, although death can be related to aspi-
ration pneumonia secondary to dysphagia.54
There is no evidence that IBM affects cardiac
tissue, and the prevalence of cardiac abnor-
malities in IBM seems similar to that observed
in the general population with similar age
distribution.55
Diagnosis
Muscle biopsy remains the criterion standard
for the diagnosis of IBM. Patients with the
classic pathologic features of IBM (Figure 3,
Table 1)dautoaggressive CD8þ T cells
invading nonnecrotic muscle fibers, rimmed
vacuoles, congophilic inclusions, protein
aggregates, and histologic signs of mitochon-
drial dysfunctiondare diagnosed with definite
IBM.56 However, all the pathologic features of
IBM may not be present in the muscle biopsy
specimen, especially in the early stage of the
disease. Therefore, researchers and clinicians
have emphasized the relevance of clinical
findings (eg, quadriceps weakness and flexor
digitorum profundus weakness) in the diag-
nosis of IBM.2,57
A recent study identified T-cell large gran-
ular lymphocytic leukemia in more than half
of a cohort of 38 patients with IBM and mus-
cle invasion by large granular lymphocytes.58
These findings led to the hypothesis that
transformation of T-cell expansion into a
neoplastic disorder might contribute to IBM
refractoriness to immunotherapy. This study
was criticized because of the unknown
chronology of the IBM and T-cell large gran-
ular lymphocytic leukemia (which of the 2
diseases manifested first?) and lack of coexist-
ing hematologic abnormalities (anemia or
neutropenia) in IBM.59
Serologic Markers
In IBM, the CK value is normal or increased
less than 10-fold above the upper limit of
normal.
Antiecytosolic 50 -nucleotidase 1A (cN1A)
autoantibodies are a serologic marker of IBM
(Table 2).60,61 Cytosolic 50 -nucleotidase 1A
catalyzes the conversion of adenosine mono-
phosphate into adenosine and phosphate.
Moderate and high reactivity of anti-cN1A
antibodies has been reported to be 92% and
98% specific for the diagnosis of IBM, respec-
tively.61 In a small group of patients with IBM,
the anti-cN1A antibody seropositivity was
associated with more severe motor disability
and respiratory involvement.62 However,
anti-cN1A antibodies have also been detected
in other autoimmune diseases, mainly
systemic lupus erythematosus and Sjögren
syndrome, and occasionally in nonautoim-
mune neuromuscular diseases.2,63 Therefore,
anti-cN1A positivity should be interpreted in
relationship to the patient’s clinical and myo-
pathologic findings. Anti-cN1A antibodies
can be supportive of the diagnosis of IBM
when the canonical myopathologic features
of IBM are missing.
Because amyloidogenic proteins accumu-
late in IBM muscle, investigators have studied
amyloidogenic molecules as possible bio-
markers of IBM. An increase of amyloid

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precursor protein b, b-secretase-1 (b-site amy-
loid precursor proteinecleaving enzyme 1)
and g-secretase (both enzymes process amy-
loid precursor protein), was demonstrated in
the plasma from patients with IBM when
compared with controls and other inflamma-
tory myopathies.64 However, the low sensi-
tivity of these amyloidogenic biomarkers
(despite the high specificity of w90%) limits
their use in clinical practice.65
Pathogenesis
The pathogenesis of IBM remains unclear.
The disease is thought to be the result of a
combined inflammatory and degenerative
process. The autoaggressive inflammatory
infiltrates mainly consisting of CD8þ T cells,
sarcolemmal overexpression of MHC-1 and
II,66 regulatory T-cell down-regulation in
blood,67 association with other autoimmune
diseases,68 and the recently discovered anti-
cN1A antibodies suggest an autoimmune
etiology.60,61 The rimmed vacuoles, abnormal
protein aggregates, and lack of response to
immunosuppressant therapy have pointed to
a defect in protein degradation and a degener-
ative process as mechanisms contributing to
the disease. Recently, a genetic contribution
to the pathogenesis of IBM has emerged.
Rare cases of sporadic IBM fulfilling diag-
nostic criteria for IBM were found to
have sequence variants in genes causing he-
reditary IBM (eg, valosin containing protein,
VCP; sequestosome 1, SQSTM1; slow/b car-
diac myosin heavy chain 7, MYH7).69,70
Moreover, association studies have suggested
a genetic susceptibility to IBM (eg, strong as-
sociation with HLA-DRB*03:01 or disease-
modifying effect of a specific polymorphism
in translocase of outer mitochondrial mem-
brane 40, TOMM40).48,69
Treatment
To date, there is no evidence that immunosup-
pressant drugs are beneficial in IBM. A
long-term observational study found that
immunosuppressive treatment did not
improve the disease course and may have
exacerbated the progression of the disability.54
A recent clinical trial with placebo vs bimagru-
mab, an activin receptor II inhibitor antibody,
provided class I evidence that bimagrumab
increases thigh muscle volume measured by
n n
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MAYO CLINIC PROCEEDINGS
magnetic resonance imaging (MRI).71 Howev-
er, a phase 2b/3 study found no evidence for
beneficial effect of bimagrumab, leading to
discontinuation of the study. Nevertheless,
some physicians would consider a trial of
treatment with corticosteroids and a steroid-
sparing agent in patients with IBM who have
rapidly progressive disease or associated
autoimmune disease.48 At the present time,
treatment of IBM is largely supportive.
DERMATOMYOSITIS
Clinical Features
Dermatomyositis is an inflammatory disease
with prominent muscle and skin involvement.
It causes subacute or insidiously progressive
proximal muscle weakness, sometimes accom-
panied by myalgia. Dysphagia occurs and is
more frequent in patients with severe weakness
of sternomastoid muscles.72 Skin manifesta-
tions in DM include heliotrope rash, malar
rash, Gottron papules, erythematous derma-
titis, and photosensitivity. Nail beds can have
dilated capillary loops. Oral features of DM are
well characterized, such as lichen planus,
gingival telangiectasia, desquamative gingivitis,
and ovoid palatal patch.73 The rash precedes or
occurs at the same time as the weakness. Inter-
stitial lung disease can be a facet of the multi-
system inflammatory disease that causes DM.
Older age at diagnosis, fever, heliotrope rash,
and arthritis increase the risk of interstitial
lung disease,74 which results in increased
morbidity and mortality.75 Juvenile DM
frequently follows a febrile episode and rash.
It often has multisystem involvement and
much more frequent subcutaneous calcinosis
compared with adult DM.76 Severe juvenile
DM can also affect the gastrointestinal tract,
leading to severe abdominal pain, ulceration,
or perforation.77 Dermatomyositis is associated
with an increased risk of malignant disease
compared with age- and sex-matched controls,
especially in males and in patients older than 45
years.78 The risk of cancer is higher in the 5
years surrounding the diagnosis of DM (2 years
before and 3 years after) and also over the life-
time following the diagnosis of DM. The most
frequent malignant disorders affect the breast,
lung, pancreas, and colon. Patients with cancer
seem less likely to have interstitial lung disease.
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IMMUNE-MEDIATED MYOPATHIES

A form of amyopathic DM manifests with the
hallmark skin findings and no clinical or labora-
tory evidence of myositis but preserved suscepti-
bility to the development of interstitial lung
disease.79 In regard to the risk of malignancy in
amyopathic DM, there is conflicting information.
Therefore, cancer screening is advised in patients
with amyopathic DM.79,80
Diagnosis
The diagnosis of DM relies on clinical mani-
festations and muscle pathologic findings.
The hallmark pathologic feature of DM is
the perifascicular muscle fiber atrophy, often
accompanied by one or more of the following
perifascicular structural abnormalities: inter-
nalized nuclei, muscle fiber necrosis, regener-
ation, focal basophilia, vacuolar changes,
increased oxidative enzyme reactivity, and
endomysial fibrosis (Figure 4, Table 1). The
perifascicular atrophy is invariably associated
with capillary depletion, often accompanied
by membrane attack complex deposition on
the muscle microvasculature.81 The inflam-
mation is predominantly perimysial and peri-
vascular and consists of CD4þ T cells and
plasmacytoid dendritic cells. Autoaggressive
inflammatory CD8þ T cells invading nonne-
crotic muscle fibers are not a feature of DM.
associated with DM without lung involvement.
Anti-Mi2 antibodyepositive patients respond
well to corticosteroids and rituximab.8
Antiemelanoma differentiationeassociated
gene 5 antibodies predict rapidly progressive
interstitial lung disease.74 They are associated
with minimal or no perifascicular atrophy,
despite the MHC-1 up-regulation in perifa-
scicular regions, and their titer correlates with
disease activity.8,86
Anti-Jo1 (or antiehistidyl-tRNA synthetase)
antibodies have long been known to predict
interstitial lung disease with an incidence as
high as 90%. The combination of inflammatory
myopathy, interstitial lung disease, arthritis, Rey-
naud phenomenon, and mechanic’s hand and
antisynthetase antibodies characterize the anti-
synthetase syndrome.8 In addition to anti-Jo1
antibodies, there are other less common antisyn-
thetase antibodies, such as anti-PL-7, PL-12, OJ,
KS, EJ, Zo, and Ha antibodies. Severe skin
involvement and systemic features have also
been linked to the antiesmall ubiquitinlike
modifier activating enzyme.87

Serologic Markers
In DM, CK values are often but not always
elevated. Therefore, CK measurement may
not be helpful in measuring disease activity.
Various antibodies can be associated with
DM (Table 2).
The presence of antietranscriptional inter-
mediary factor 1-g antibodies in adult patients
with DM has a particularly high risk of cancer
(48%-75%),82-84 which, according to the most
recent study, is detected within a year of the
diagnosis of myopathy.84 Dysphagia may also
be more frequent in patients with DM who
have antietranscriptional intermediary factor
1-g antibodies.72
Antibodies directed against the nuclear FIGURE 4. Muscle biopsy specimens from a patient with dermatomyositis.
matrix protein NXP2 also carry an increased A and B, Note perifascicular muscle atrophy (arrows), a hallmark of der-
risk of cancer.83 In addition, anti-NXP2 matomyositis (A, hematoxylin-eosin; B, ATPase stain, pH 4.3). C, The
inflammatory exudate concentrates in the perimysium at perivascular sites
antibodies predict the presence of calcinosis,
(arrow) (hematoxylin-eosin). D, Additional structural abnormalities are
especially in juvenile DM.85
present in perifascicular regions: internalized nuclei (blue arrow), necrotic
Antibodies directed against Mi2, a compo- (asterisk) and regenerating (arrowheads) muscle fibers, vacuolar changes
nent of the nucleosome remodelingedeacetylase (black arrow) (hematoxylin-eosin).
chromatin remodeling complex, have been

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Pathogenesis
The pathogenesis of DM is still poorly
understood. Several studies have focused on
dissecting the mechanism leading to the myo-
pathologic hallmark of perifascicular muscle
atrophy. Results have been controversial,
spanning from ischemia secondary to micro-
vascular insult to increased expression of
type 1 interferoneinduced gene transcripts
and proteins in the perifascicular muscle fibers
and capillaries.88,89 The mechanism driving
the overproduction of type 1 interferon and
how this process results in capillary damage
remains to be elucidated. A recent study
confirmed that the perifascicular muscle atro-
phy is associated with focal microvascular
depletion and that ischemia contributes to
the perifascicular atrophy.81 The same study
found that the observed microvascular mem-
brane attack complex deposits in DM result
from activation of the classic complement
pathway, triggered by direct binding of C1q
to injured endothelial cells. However, these
observations did not explain the primary cause
of the microangiopathy. An inflammatory vas-
culopathy has also been recognized as cause of
the gastrointestinal ulceration and perforation
in severe juvenile DM.77
Treatment
Corticosteroids at various dosages are the first-
line treatment.90,91 Higher dosages of predni-
sone may provide more immunosuppression
but carry a risk of corticosteroid-induced
myopathy. The greatest improvement in
strength seems to occur in the first 6 to 12
months after treatment initiation.90 Various
immunotherapeutic agents (methotrexate,
azathioprine, IVIG, cyclosporine, mycopheno-
late mofetil) can be used as second-line agents
or first-line agents combined with corticoste-
roids, but none is superior to others.90,91 A
retrospective study found that methotrexate
combined with corticosteroids is superior to
prednisolone alone.92 However, methotrexate
carries the risk of pulmonary fibrosis. There-
fore, methotrexate should be avoided in
patients with interstitial lung disease or anti-
bodies predicting interstitial lung disease. Rit-
uximab has been used successfully in adult
and pediatric patients with refractory
myositis.93 Other drugs, such as tacrolimus
n n
834 Mayo Clin Proc.
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MAYO CLINIC PROCEEDINGS
or etanercept, and plasmapheresis have also
been utilized for management of refractory
DM.91,94 It is important to treat infections,
which are partially due to immuno-
suppression, because of the associated 5%
mortality rate.90
Consensus-based recommendations were
recently published for treatment of juvenile
DM.95 Recommended therapy includes com-
bined use of corticosteroids and methotrexate.
Intravenous immunoglobulin, mycophenolate
mofetil, cyclophosphamide, rituximab, inflixi-
mab, and cyclosporine should be used only to
treat more severe DM or a disease partially
responsive to corticosteroids and metho-
trexate. Skin disease requires aggressive
therapy because of the associated high
morbidity. Calcinosis may respond to
bisphosphonates. It has been suggested that
discontinuation of the methotrexate or other
disease-modifying drug be considered once
the patient is in remission and has not taken
corticosteroids for at least 1 year.
ADDITIONAL INVESTIGATIONS
Needle electromyography is useful in con-
firming the myopathic nature of the weak-
ness in IMMs but does not differentiate the
various subtypes. Motor unit potentials have
myopathic features (reduced amplitude and
duration) in most autoimmune myopathies
but in sporadic IBM exhibit mixed myopathic
and neurogenic changes. Abnormal sponta-
neous muscle activity includes fibrillation
potentials, sharp waves, and complex repeti-
tive discharges. Myotonic discharges are
often recorded in statin-associated NAM.11
The lack of abnormal spontaneous muscle
activity in a patient with IMM who has
worsening weakness while taking corticoste-
roids often suggests a corticosteroid-induced
myopathy.
T2-weighted muscle MRI may reveal
signal abnormality in muscle and fascia due
to inflammation, edema, or muscle replace-
ment by connective tissue. In addition, MRI
can be a useful tool to monitor disease
activity.77
CHALLENGES AND PITFALLS
Diagnostic criteria and classification of IMMs
remain challenging. Some diagnostic criteria
are based on clinical and muscle pathologic
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IMMUNE-MEDIATED MYOPATHIES
criteria, while others are more clinically and
serologically oriented. Additional correlation
between pathologic findings, specific anti-
bodies, and extramuscular features would be
valuable in better characterizing these diseases.
The lack of universally accepted diagnostic
criteria continues to be an obstacle to clinical
trials, which are already hampered by the
rarity of these myopathies. The variability of
diagnostic criteria may lead to the enrollment
of patients with different IMMs into a clinical
trial and the exclusion of others. The crucial
role of physical therapy and occupational ther-
apy is not emphasized enough in clinical prac-
tice and should be part of the treatment plan.
UNSOLVED CLINICAL QUESTIONS
The role of myositis-associated antibodies
remains poorly understood and requires further
investigations. Their pathogenicity has not been
proved. The correlation between the presence
of a specific antibody and muscle pathologic
findings should be better defined and validated.
The value of anti-cN1A autoantibodies as a
diagnostic and prognostic tool in IBM requires
further investigation. Similarly, the role played
by statins as a trigger for the anti-HMGCR
antibody formation and development of NAM
warrants further elucidation, especially in light
of the presence of anti-HMGCR antibodies in
statin-naive (or presumably naive) patients.
Understanding what leads to microangiopathy
in DM or whether IBM is a primary inflamma-
tory or degenerative muscle disease would be
fundamental to opening avenues to treatment.
There is a need for randomized clinical trials
to standardize and optimize evidence-based pa-
tient care. Longitudinal studies to learn more
about the disease progression and markers of
disease activity would enhance our understand-
ing of these myopathies and would provide
more solid guidance for timing of immuno-
therapy withdrawal.
CONCLUSION
Immune-mediated myopathies are clinically,
serologically, and pathologically heteroge-
neous. The lack of inflammation on muscle bi-
opsy does not exclude an IMM. The presence
of certain antibodies may predict specific com-
plications and a higher risk of cancer.
Mayo Clin Proc. n May 2017;92(5):826-837 n http://dx.doi.org/10.1016/j.mayocp.2016.12.025
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ACKNOWLEDGMENTS
Special thanks to my patients who agreed to
have photographs taken and reproduced to
enhance our understanding of immune-medi-
ated myopathy.
Abbreviations and Acronyms: CK = creatine kinase; cN1A
= cytosolic 50 -nucleotidase 1A; DM = dermatomyositis;
HMGCR = 3-hydroxy-3-methylglutaryl coenzyme A reduc-
tase; IBM = inclusion body myositis; IIM = idiopathic in-
flammatory myopathy; IMM = immune-mediated myopathy;
IVIG = intravenous immunoglobulin; MHC = major histo-
compatibility complex; MRI = magnetic resonance imaging;
NAM = necrotizing autoimmune myopathy; PM = poly-
myositis; SRP = signal recognition particle
Potential Competing Interests: Dr Milone received fund-
ing from the Center for Individualized Medicine and Depart-
ment of Neurology, Mayo Clinic.
Correspondence: Address to Margherita Milone, MD, PhD,
Neuromuscular Medicine Division, Department of
Neurology, Mayo Clinic, 200 First St SW, Rochester, MN
55905 (Milone.margherita@mayo.edu). Individual reprints
of this article and a bound reprint of the entire Symposium
on Neurosciences will be available for purchase from our
website www.mayoclinicproceedings.org.
The Symposium on Neurosciences will continue in an
upcoming issue.
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