Review Article

Inflammatory
Address correspondence to
Dr Anthony A. Amato,
Department of Neurology,
Brigham and Womens

Myopathies Hospital and Harvard Medical

School, 75 Francis Street,
Boston, MA 02115,
aamato@partners.org.
Anthony A. Amato, MD, FAAN; Steven A. Greenberg, MD
Relationship Disclosure:
Dr Amato has served on the
medical advisory board of
ABSTRACT Biogen Idec, as a consultant
for MedImmune, LLC, and
Purpose of Review: To discuss the clinical, laboratory, and histopathologic provided expert testimony for
features and presumed pathogenic mechanisms of the four major categories of litigation on a neuropathy
idiopathic inflammatory myopathy, namely dermatomyositis, polymyositis, immune- case. Dr Amato serves as an
associate editor of Neurology.
mediated necrotizing myopathy, and inclusion body myositis. Dr Greenberg has served as a
Recent Findings: Dermatomyositis, polymyositis, necrotizing myopathy, and consultant for aTyr Pharma, as
inclusion body myositis are clinically, histologically, and pathogenically distinct. an expert witness in litigation
pertaining to copper deficiency,
Polymyositis is a T cellYmediated disorder directed against muscle fibers. The patho- and is supported by a
genesis of dermatomyositis, necrotizing myopathy, and inclusion body myositis are grant from the Muscular
unknown. Dermatomyositis, polymyositis, and necrotizing myopathy are generally, but Dystrophy Association.
Unlabeled Use of
not always, responsive to immunosuppressive therapy, in contrast to inclusion body Products/Investigational
myositis, which is generally refractory to therapy. Use Disclosure: Drs Amato
Summary: The pattern of muscle weakness, other clinical features (eg, rash, concurrent and Greenberg discuss
therapies for the treatment
interstitial lung disease), laboratory features (creatine kinase, autoantibodies), and muscle of myositis, all of which
biopsies are useful in distinguishing subtypes of inflammatory myopathy and in guiding are unlabeled.
treatment. More research is necessary to unravel the exact pathogenic bases of these * 2013, American Academy
myopathies and identify better treatments. of Neurology.

Continuum (Minneap Minn) 2013;19(6):16151633.

INTRODUCTION legs more than the arms. Difficulties

Idiopathic inflammatory myopathy
can be broken into four major catego-
ries: dermatomyositis, polymyositis,
immune-mediated necrotizing myopa-
thy, and inclusion body myositis,
which are clinically, histologically, and
pathogenically distinct (Table 5-11).2Y10
These disorders may occur in isolation
or in association with cancer or with
various connective tissue diseases (over-
lap syndromes).
DERMATOMYOSITIS
Clinical Features
The incidence of dermatomyositis is
higher in women compared to men
and can present at any age. Weakness
can develop rather acutely (over sev-
eral weeks) or insidiously (over
months) and tends to affect the prox-
imal greater than distal muscles in the
swallowing, chewing, and speaking
occur in up to a third of patients
secondary to masticatory, oropharyn-
geal, and esophageal muscle involve-
ment. A characteristic rash typically
accompanies or precedes the onset of
muscle weakness. However, the rash
can develop years after the onset of
weakness, which could lead to an
erroneous diagnosis of polymyositis.
Additionally, some patients have a
characteristic rash but never develop
weakness (so-called amyopathic der-
matomyositis or dermatomyositis sine
myositis). Most patients with derma-
tomyositis have both skin and muscle
involvement (Case 5-1), but on either end
of the spectrum are rare patients who
have only muscle or skin involvement.
The classical skin manifestations
include a purplish discoloration of

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 Inflammatory Myopathies

a
TABLE 5-1 Idiopathic Inflammatory Myopathies: Clinical and Laboratory Features

Inclusion Body Necrotizing

Dermatomyositis Polymyositis Myositis Myopathy
Sex Female 9 male Female 9 male Male 9 female Male = female
Age of Onset Childhood and Adult Elderly (950 y) Adult and
adult elderly
Rash Yes No No No
Pattern of Proximal 9 distal Proximal 9 distal Proximal and distal Proximal 9
Weakness Predilection for distal
finger/wrist flexors
and knee extensors
Serum Creatine Normal or increased Increased (up to Normal or mildly Elevated
Kinase (up to 50 normal) 50 normal) increased (G10 normal) (910normal)
Muscle Biopsy Perimysial and Endomysial Endomysial inflammation, Necrotic muscle
perivascular inflammation, inflammation rimmed vacuoles, fibers, absent
interferon-1 regulated amyloid deposits inflammatory
proteins, membrane Electron microscopy: infiltrate
attack complex, 15Y18 nm
immunoglobulin, tubulofilaments
complement deposition
on vessels
Cellular Infiltrate CD4+ dendritic cells, CD8+ T cells, CD8+ T cells, None
B cells, macrophages macrophages, macrophages,
plasma cells plasma cells
Response to Yes Yes None or minimal Yes
Immunosuppressive
Therapy
Common Associated Myocarditis, Myocarditis, Monoclonal gammopathy Malignancy,
Conditions interstitial lung disease, interstitial lung of unclear significance connective
malignancy, vasculitis, disease, other (MGUS), perhaps tissue diseases
and other connective connective sarcoidosis, Sjogren Possibly
tissue diseases tissue diseases syndrome (also known as triggered by
sicca syndrome) statin use
a
Modified from Amato AA, Barohn RJ, Neurol Clin.1 B 1997, with permission from Elsevier. www.neurologic.theclinics.com/article/
S0733-8619(05)70337-6/fulltext.

KEY POINT the eyelids (heliotrope rash), and papular, tions may appear over pressure points
h Idiopathic inflammatory erythematous lesions over the knuckles (buttocks, knees, elbows), which can
myopathy can be (Gottron papules) (Figure 5-1). In be complicated by ulceration of the
broken into four
addition, an erythematous, macular, overlying skin. Calcifications are more
major categories:
sun-sensitive rash may appear on the common in juvenile dermatomyositis,
dermatomyositis,
polymyositis,
face, neck, and anterior chest (V-sign); but some do develop in adult-onset cases.
immune-mediated on the shoulders and upper back Interstitial lung disease is a compli-
necrotizing myopathy, (shawl sign); and on the extensor cation occurring in approximately 10%
and inclusion body surfaces of the elbows, knuckles, hips, to 20% of patients with dermatomyosi-
myositis, which are knees, and malleoli (Gottron sign). tis and manifests as dyspnea and non-
clinically, histologically, The nail beds often have dilated capil- productive cough. Pulmonary function
and pathogenically lary loops, occasionally with thrombi or tests reveal reduced forced vital ca-
distinct. hemorrhage. Subcutaneous calcifica- pacity (FVC) and decreased diffusing

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 KEY POINTS

Case 5-1 h Most patients with

dermatomyositis have
A 74-year-old woman began to notice a rash on her shins 3 months ago
both skin and muscle
that gradually spread to cover the extensor surfaces of her upper limbs,
involvement, but on
then onto her face and trunk and the back of her neck. About 2 months
either end of the
ago, she started to notice weakness in her legs. She initially reported
spectrum are rare
difficulty raising herself up off the toilet or chairs and walking up stairs.
patients who have
The weakness more recently spread to her arms. She denied shortness of
only muscle or skin
breath at rest but had some dyspnea upon exertion. She had no myalgia,
involvement.
arthralgia, fever, chills, weight loss, or bowel or bladder problems.
Her medical history was remarkable for type 2 diabetes mellitus, for h Interstitial lung disease
which she took glyburide. Family history was unrevealing. is a complication
Clinical examination was remarkable for a moderate-severe erythema occurring in
on the patients face and scalp, neck and trunk (front and back), arms, approximately 10% to
knuckles (Gottron sign and papules), and periungual telangiectasia. She 20% of patients with
had mild alopecia as well. dermatomyositis and
Manual muscle testing revealed the following Medical Research Council manifests as dyspnea
scores: neck flexion 4j, neck extension 4+, shoulder abduction 4j, and nonproductive
elbow extension and flexion 4, wrist flexion and extension 4+, hip cough.
flexion/abduction/extension 3, knee extension 5, knee flexion 4, ankle h Incidence of cancer is
dorsiflexion 4+, and plantar flexion 5/5. increased, ranging from
Her creatine kinase (CK) level was normal at 52 U/L. Her EMG revealed 6% to 45%, in adult
fibrillation potentials in proximal muscles as well as many small-amplitude, dermatomyositis (usually
short-duration, polyphasic motor unit action potentials (MUAPs) that over the age of 40
recruited very early. A biceps muscle biopsy was performed and years), with most cases
revealed perivascular, perimysial inflammatory cell infiltration along occurring within the first
with perifascicular atrophy. Jo-1 antibodies were not evident in her 2 years of diagnosis of
serum. Pulmonary function tests and ECG were normal. A malignancy dermatomyositis.
workup was unrevealing. Dual-energy x-ray absorptiometry (DEXA)
revealed osteoporosis.
Comment. This patient had classic clinical and histopathologic features
of dermatomyositis, in which normal muscle enzymes (eg, CK) can be seen.
She was started on prednisone 60 mg/d. Because of her diabetes and
osteoporosis, she was also started on methotrexate 7.5 mg weekly at
the same time. She gradually improved, and the treating physicians were
able to slowly taper her off prednisone and maintain her on methotrexate
7.5 mg weekly.

capacity of lungs for carbon monoxide
(DLCO). Antibodies directed against
T-histidyl transfer RNA synthetaseV
so-called antiYJo-1 antibodiesVare
present in at least 50% of interstitial
lung disease cases associated with
inflammatory myopathies. Cardiomy-
opathy manifesting as arrhythmias or
congestive heart failure is a less fre-
quent complication but one of which
clinicians need to be aware. Involve-
ment of the skeletal and smooth mus-
cles of the gastrointestinal tract can
lead to dysphagia, aspiration, and de-
layed gastric emptying. Vasculopathy
of the gut can result in gastrointestinal
hemorrhage; this appears to be more
common in juvenile dermatomyositis.
Incidence of cancer is increased,
ranging from 6% to 45%, in adult der-
matomyositis (usually over the age of
40 years), with most cases occurring
within the first 2 years of diagnosis of
dermatomyositis. Risk of cancer is not
increased in juvenile dermatomyositis,
and no correlation has been shown

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 Inflammatory Myopathies
FIGURE 5-1 Dermatomyositis. Macular erythematous rash
is seen over the extensor surface of the
fingers along with cracked skin (mechanic
hands) and nail bed changes.
KEY POINT between the severity of weakness,
h Serum creatine kinase rash, or creatine kinase levels and
levels do not correlate malignancy in adult dermatomyositis.
with the severity of
Because of the increased risk of can-
weakness and can be
cer, a comprehensive history and annual
normal even in
markedly weak
physical examinations are recommended
individuals, particularly with breast and pelvic examinations for
in childhood women and testicular and prostate
dermatomyositis examinations for men to search for an
patients and in those underlying malignancy. In addition,
with slow, insidious laboratory studies should be obtained,
disease. including a complete blood count
(CBC), routine blood chemistries, serum
immunofixation/immunoelectrophoresis,
serum free light chains, urinalysis, and
stool specimens for occult blood.
Chest, abdominal, and pelvic CT scans
are recommended as well as pelvic
ultrasound and mammogram for wom-
en. Colonoscopy should be done on all
patients over the age of 50 years or in
those who have attributable gastroin-
testinal symptoms (eg, abdominal
pain, constipation, blood in the stool).
Laboratory Features
Blood work. Necrosis of muscle fibers
usually leads to increases in serum
creatine kinase (CK), aldolase, myo-
globin, lactate dehydrogenase, aspar-
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tate aminotransferase (AST), and
alanine aminotransferase (ALT) levels.
Serum CK is elevated in approximately
70% of dermatomyositis patients.
However, serum CK levels do not
correlate with the severity of weakness
and can be normal even in markedly
weak individuals, particularly in child-
hood dermatomyositis patients and in
those with slow, insidious disease. In
approximately 10% of cases, an aldol-
ase level is elevated while the serum
CK is still within normal limits. Eryth-
rocyte sedimentation rate (ESR) is
usually normal or only mildly elevated
and is not a reliable indicator of
disease severity.
Antinuclear antibodies (ANAs) have
been detected in 24% to 60% of
patients with dermatomyositis and
are much more common in patients
with overlap syndromes. Some pa-
tients have so-called myositis-specific
antibodies, which may be useful in
predicting response to therapy and
prognosis but have never been stud-
ied prospectively regarding their pre-
dictive value. These antibodies have
not been demonstrated to be patho-
genic and may just represent an epi-
phenomenon. Nevertheless, they may
be helpful in categorizing syndromes.
For example, the antisynthetases such
as antiYJo-1 antibodies are associated
with interstitial lung disease and
Raynaud phenomena. AntiYMi-2 anti-
bodies have been reported in patients
with acute onset, severe rash, and a
good response to therapy. Antibo-
dies directed against melanoma
differentiation-associated 5 (anti-
MDA5), also known as antiYCADM-140
antibodies, are associated with aggres-
sive interstitial lung disease in Asians.
Autoantibodies to p155/140 targeting
transcriptional intermediary factor 1-+
(TIF1-+) are found in adult cancer-
associated dermatomyositis with an
89% specificity and 70% sensitivity.
December 2013

Imaging. MRI may demonstrate sig-
nal abnormalities in affected muscles
secondary to inflammation, replace-
ment by fibrotic tissue, or atrophy.
Although MRI has been advocated as
a tool to indicate which muscle to
biopsy, the authors have found that it
adds little to a good clinical examina-
tion and EMG in defining the pattern
of muscle involvement and determin-
ing which muscle to biopsy.
EMG. In patients with myositis, the
characteristic EMG features observed
include (1) increased insertional and
spontaneous activity with fibrillation
potentials, positive sharp waves, and
occasionally pseudomyotonic or com-
plex repetitive discharges; (2) short-
duration, low-amplitude, polyphasic
motor unit action potentials (MUAPs);
and (3) early recruitment. Decreased
recruitment (fast-firing MUAPs) may
occur in the presence of marked loss
of muscle fibers from advanced
disease. Decreased insertional activity
may be seen in long-standing cases if
fibrofatty replacement of muscles has
occurred. In addition, large-duration,
polyphasic MUAPs may also be evident
later in long-standing disease due to
muscle fiber splitting and regeneration
rather than a superimposed neurogenic
process.
The authors have found EMG help-
ful in determining which muscle to
biopsy in patients with only mild
weakness. Furthermore, EMG may
also be useful in the assessment of
previously responsive myositis pa-
tients who become weaker, by differ-
entiating an increase in disease activity
from weakness secondary to type 2
muscle fiber atrophy from disuse or
chronic steroid administration. In ac-
tive myositis, abnormal insertional and
spontaneous activity is expected,
while isolated type 2 muscle fiber
atrophy is not associated with such
abnormal activity on EMG. However,
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KEY POINTS
EMG may remain abnormal, reflecting h MRI in patients with
previous muscle damage. In such dermatomyositis may
cases, skeletal muscle MRI may be of demonstrate signal
use because increased signal abnor- abnormalities in affected
malities reflective of active inflamma- muscles secondary
tion would be expected in a relapse to inflammation,
but not in cases of type 2 muscle fiber replacement by fibrotic
atrophy. tissue, or atrophy.
h In dermatomyositis,
Histopathology decreased recruitment
The classic histology of dermatomyosi- (fast-firing motor unit
tis is perifascicular atrophy (Figure 5-2), action potentials) may
although this is typically a late finding occur in the presence of
and, in the authors experience, is marked loss of muscle
fibers from advanced
found in less than 50% of patients. In-
disease.
flammatory cells are located around
blood vessels (perivascular) in the h The classic histology
perimysium and composed primarily of dermatomyositis is
perifascicular atrophy,
of macrophages, B cells, and CD4+
although this is typically
plasmacytoid dendritic cells. Unlike
a late finding and in the
that seen in polymyositis and inclusion authors experience is
body myositis (discussed later), inva- found in less than 50%
sion of non-necrotic muscle fibers is not of patients.
prominent in dermatomyositis.
Electron microscopy (EM) reveals
small intramuscular blood vessels (ar-
terioles and capillaries) with endothe-
lial hyperplasia, microvacuoles, and
tubuloreticular cytoplasmic inclusions;
these abnormalities precede other
FIGURE 5-2 Dermatomyositis. Muscle biopsy
demonstrates classic perifascicular atrophy of
muscle fibers (hematoxylin and eosin stain).
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 Inflammatory Myopathies
KEY POINT
h For definitive
histopathologic
diagnosis of
polymyositis, many
myopathologists want
to see mononuclear
inflammatory cells
(CD8+ T cells) invading
non-necrotic muscle
fibers that express
major histocompatibility
1 antigen.
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structural abnormalities on EM. DNA
microarray and immunohistochemis-
try studies of biopsied muscle tissue
demonstrate an increased expression
of genes induced by type 1 inter-
ferons.11 These interferons are synthe-
sized by plasmacytoid dendritic cells in
response to a serum factor or factors
containing immune complexes of anti-
body, double-stranded DNA, or RNA
viruses. Abundant plasmacytoid den-
dritic cells are evident in the dermato-
myositis muscle biopsies. Increased
expression of type 1 interferon-
inducible proteins, such as myxovirus
resistance 1 (MxA), are evident on
blood vessels and muscle fibers (with
a predilection for the perifascicular
fibers). Interestingly, one postulated
function of MxA is to form tubulo-
reticular inclusions around RNA viruses.
These inclusions have the same mor-
phology as the tubuloreticular inclu-
sions seen on EM in blood vessels in
dermatomyositis. Using immuno-
electron microscopy, MxA was demon-
strated within inclusions in vessels in
dermatomyositis muscle biopsies.
Pathogenesis
Although capillary injury and peri-
fascicular myofiber injury are key
features of dermatomyositis muscle
pathology, the central pathogenic dis-
ease question is how these two fea-
tures relateVie, whether the former
causes the latter or some other mech-
anism causes them both. In this
regard, the skin involvement of der-
matomyositis has never been modeled
as a result of ischemia. Dermatomyo-
sitis skin pathology is generally that of
a cell-poor interface dermatitis in
which loss of the basal layer of
keratinocytes occurs in the absence
or paucity of cellular inflammation.
The topology of this cell loss is es-
sentially the same as the perifascicular
atrophy seen in muscle.
What dermatomyositis skin and mus-
cle do have in common is the presence
of molecular biomarkers of type 1
interferon (interferon-!, interferon-",
and others) exposure. The marked
overproduction of type 1 interferon-
inducible transcripts and proteins in
muscle is remarkably unique to derma-
tomyositis in comparison to all other
muscle diseases studied.11 Exposure of
human skeletal muscle cell cultures to
type 1 interferons produces a similar
picture to that present in human der-
matomyositis samples.
POLYMYOSITIS
Polymyositis is a heterogeneous group
of disorders rather than a distinct
entity. A major problem is the lack of
universally accepted criteria for diagnos-
ing polymyositis. The most commonly
employed criteria were developed by
Bohan and Peters in 1975,6,7 but these
do not take into account advancements
in our understanding of the immuno-
pathogenesis of the various inflamma-
tory myopathies or even the existence
of inclusion body myositis and
immune-mediated necrotizing myopa-
thy. Several revised criteria for the
various idiopathic inflammatory myopa-
thies have been proposed. For defini-
tive histopathologic diagnosis of
polymyositis, many myopathologists
want to see mononuclear inflammatory
cells (CD8+ T cells) invading non-
necrotic muscle fibers that express
major histocompatibility 1 (MHC-1)
antigen. However, this biopsy feature
is also seen in inclusion body myositis
and rarely in dystrophies. Further,
mononuclear cell invasion of non-
necrotic muscle fibers is uncommon in
suspected cases of polymyositis, and
some argue that it is not necessary for
diagnosis of polymyositis. More fre-
quently seen on biopsy are perivascular,
perimysial inflammatory cell infiltrates,
or endomysial inflammatory cells but
December 2013

no actual invasion of non-necrotic mus-
cle fibers. Whether these cases repre-
sent polymyositis (with the absence of
CD8+ T cells invading non-necrotic
muscle fibers being due to sampling
error), the same disorder as polymyosi-
tis, or a distinct type of inflammatory
myopathy is unclear. Such perivascular,
perimysial inflammation is common,
particularly in patients with overlap
myositis, but can be seen in dermato-
myositis, inclusion body myositis, and
occasionally in dystrophies.
For the various reasons listed above,
it is impossible to derive from the
literature the true incidence of poly-
myositis or its subtypes (eg, associated
laboratory abnormalities or medical
conditionsVsuch as connective tissue
disorders, interstitial lung disease, myo-
carditis, and cancerVthat may accom-
pany it) and prognosis. Prospective
studies using more consensus-driven
histopathologic criteria for polymyositis
are needed to address these issues.
Nevertheless, what is reported in the
literature regarding polymyositis is sum-
marized below.
Clinical Features
Polymyositis generally presents in pa-
tients over the age of 20 years and is
more common in women. As with
dermatomyositis, patients with poly-
myositis present with symmetric proxi-
mal arm and leg weakness that typically
develops over several weeks or months.
Approximately one-third of patients
report swallowing difficulties. The car-
diac and pulmonary complications of
polymyositis are reportedly similar to
those described in the dermatomyositis
section. Myositis with secondary con-
gestive heart failure or conduction
abnormalities occurs in up to 1/3 of
patients, but again, histopathologic con-
firmation of definite polymyositis using
more up-to-date criteria is lacking in
most of these studies.
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KEY POINTS
Polyarthritis has been reported in h As with dermatomyositis,
as many as 45% of patients with patients with
polymyositis at the time of diagnosis. polymyositis present
The risk of malignancy with polymyo- with symmetric proximal
sitis has been reported to be higher arm and leg weakness
than the age-matched population but that typically develops
lower than that seen in dermatomyo- over several weeks or
sitis. However, it is likely that these months.
epidemiologic studies included inclu- h Performance of a
sion body myositis and dystrophy malignancy workup
patients with inflammation, which are in patients with
not associated with an increased risk polymyositis is
of malignancy, so the true risk in poly- recommended.
myositis is probably higher than h Serum creatine kinase
reported. Therefore, performance of a can be useful in
malignancy workup in patients with monitoring response
polymyositis is recommended, as dis- to therapy in
cussed in the dermatomyositis section. dermatomyositis,
polymyositis, and
Laboratory Features immune-mediated
necrotizing myopathy,
Blood work. Serum CK level is usually but only in conjunction
elevated fivefold or more in polymyo- with the physical
sitis cases. Unlike dermatomyositis examination, as the
and inclusion body myositis, in which creatine kinase level
the CK can be normal, the serum CK does not necessarily
should never be normal in active correlate with the
polymyositis. Serum CK can be useful degree of weakness.
in monitoring response to therapy,
but only in conjunction with the
physical examination, as the CK level
does not necessarily correlate with the
degree of weakness.
Positive ANAs are reportedly present
in 16% to 40% of patients with poly-
myositis. Again, however, the exact
relationship of ANAs and connective
tissue disorders in patients with histo-
logically defined polymyositis is unclear.
The questionable relationships of
myositis-specific antibodies to poly-
myositis were previously addressed.
Imaging
MRI may demonstrate signal abnormal-
ities in affected muscles secondary to
inflammation and edema or replace-
ment by fibrotic tissue (Figure 5-3).
EMG is usually abnormal in poly-
myositis, with increased insertional
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 Inflammatory Myopathies

size, scattered necrotic and regenera-

FIGURE 5-3
KEY POINT
h The predominant
histologic features
in polymyositis are
variability in fiber size,
scattered necrotic and
regenerating fibers,
and an inflammatory
cell infiltrate.
Skeletal muscle MRI scan. MRI (T2 with fat
saturation) of thighs in a patient with
polymyositis reveals increased signal in
quadriceps (arrow) and, to a lesser extent,
in the hamstrings.
and spontaneous activity, small poly-
phasic MUAPs, and early recruitment.
These abnormal features do not dis-
tinguish polymyositis from other in-
flammatory myopathies or myopathies
with muscle membrane instability.
Histopathology
The predominant histologic features
in polymyositis are variability in fiber
ting fibers, and an inflammatory cell
infiltrate (Figure 5-4). However, as
mentioned previously, the specific
characteristics of this inflammatory
cell infiltrate have been a subject of
recent debate. Small studies of poly-
myositis demonstrated that muscle
biopsies demonstrate CD8+ T cells
and macrophages invading non-
necrotic muscle fibers expressing
MHC-1 antigen. Subsequently, some
authorities have argued that this his-
topathologic feature is required for
the diagnosis of definite polymyositis.
Other authorities feel that invasion of
non-necrotic muscle fibers is not nec-
essary and perivascular, perimysial, or
endomysial inflammation without ac-
tual invasion of non-necrotic muscle
fibers can suffice for diagnosis of
polymyositis in the proper clinical
context. In the authors opinion, how-
ever, demonstrating invasion of non-
necrotic endomysial muscle fibers by
T cells is required to make a definite
diagnosis of polymyositis on histo-
pathologic grounds, as perivascular,
perimysial, and even endomysial in-
flammatory cell infiltrates can be seen

FIGURE 5-4 Polymyositis. Muscle biopsy demonstrates

endomysial mononuclear inflammatory
cell infiltrate surrounding and invading
non-necrotic muscle fibers (modified Gomori
one-step trichrome stain).

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in inclusion body myositis, dermato-
myositis, and dystrophies.
The endomysial inflammatory cells
consist primarily of activated CD8+
(cytotoxic) alpha-beta T cells and mac-
rophages. Although B cells are rare,
plasma cells are common in the en-
domysium and likely account for the
increased expression of immunoglobu-
lin genes on microarray experiments.
Pathogenesis
Polymyositis is likely caused by a
human leukocyte antigenYrestricted,
antigen-specific, cell-mediated immune
response directed against muscle fibers.
The trigger of this autoimmune attack is
not known, but viral infections have
been speculated. However, no conclu-
sive evidence supports this hypothesis.
OVERLAP SYNDROMES
The term overlap syndrome is ap-
plied when dermatomyositis or poly-
myositis is associated with another
well-defined connective tissue disorder
such as scleroderma, mixed connective
tissue disease, Sjogren syndrome, sys-
temic lupus erythematosus, and rheu-
matoid arthritis. Retrospective series of
patients suggest that the myositis asso-
ciated with overlap syndromes is more
responsive to immunosuppressive
treatment than isolated dermatomyosi-
tis and polymyositis, but again, prospec-
tive studies are lacking.
INCLUSION BODY MYOSITIS
Clinical Features
Inclusion body myositis is character-
ized by slowly progressive proximal
and distal weakness in the arms and
legs that usually develops after the age
of 50 years (see Table 5-11). Many
experts consider it to be the most com-
mon myopathy (apart from sarcopenia
of aging) in patients over the age of
50 years. The slow, progressive nature
of the myopathy probably accounts in
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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
part for the delay in diagnosis that h Demonstrating invasion
averages 6 to 7 years after the onset of of non-necrotic
symptoms. Unlike dermatomyositis and endomysial muscle
polymyositis, inclusion body myositis is fibers by T cells is
more common in men than in women. required to make a
The clinical hallmark of inclusion definite diagnosis of
body myositis is early weakness and polymyositis on
atrophy of the quadriceps, flexor fore- histopathologic
arm muscles (ie, wrist and finger grounds, as
flexors), and the ankle dorsiflexors, that perivascular, perimysial,
and even endomysial
is often asymmetric. Many patients
inflammatory cell
develop dysphagia than can be severe
infiltrates can be seen in
enough to require esophageal dilation inclusion body myositis,
or cricopharyngeal myotomy. Facial dermatomyositis, and
weakness can also be demonstrated. dystrophies.
No association with myocarditis, lung
h The endomysial
disease, or malignancy is evident. The inflammatory cells
course of the disease is a slow progres- consist primarily of
sion, and it does not typically respond activated CD8+
to immunotherapies. (cytotoxic) alpha-beta
T cells and
Laboratory Features macrophages.
Blood work. Serum CK is normal or h Inclusion body myositis
only mildly elevated (usually less than is characterized by
10-fold above normal). Some clini- slowly progressive
cians have reported positive ANAs in proximal and distal
approximately 20% of their patients weakness in the arms
with inclusion body myositis. Anti- and legs that usually
bodies directed against cytosolic 5- develops after the age
nucleotidase 1A (cN1A) have been of 50 years.
detected in as many as two-thirds of h The clinical hallmark
inclusion body myositis patients, where- of inclusion body
as their prevalence in dermatomyositis, myositis is early
polymyositis, and other neuromuscular weakness and atrophy
of the quadriceps,
disorders is much lower.12,13
flexor forearm muscles
Imaging. Skeletal muscle MRI scans
(ie, wrist and finger
demonstrate atrophy and signal ab- flexors), and the ankle
normalities in affected muscle groups. dorsiflexors that is often
In the thighs, there appears to be a asymmetric.
predilection for the vastus lateralis and
medialis with sparing of the rectus
femoris (Figure 5-5).
EMG. Nerve conduction studies re-
veal evidence of a mild axonal sensory
neuropathy in up to 30% of patients.
EMG demonstrates increased sponta-
neous and insertional activity, small
polyphasic MUAPs, and early recruit-
ment. In addition, large polyphasic
www.ContinuumJournal.com 1623
 Inflammatory Myopathies

phies), which probably reflects the

chronicity of the disease process rather
than a neurogenic etiology.

Histopathology
Muscle biopsy characteristically reveals
endomysial inflammation, small groups
of atrophic fibers, eosinophilic cytoplas-
mic inclusions, and muscle fibers with
one or more rimmed vacuoles lined
with granular material (Figure 5-6).
Endomysial inflammatory cells (macro-
phages and CD8+ lymphocytes)
appear to surround and invade non-
necrotic fibers. MHC-1 antigens are
expressed on necrotic and non-
necrotic muscle fibers. The T-cell recep-
FIGURE 5-5 Inclusion body myositis. Skeletal muscle MRI scan tor repertoire of the inflammatory cells
of thighs reveals atrophy of muscles and fibrofatty
replacement, particularly affecting the vastus lateralis (VL) have an oligoclonal pattern of gene
and vastus medialis (VM) muscles (arrows) with relative sparing of the rearrangement, although there is het-
rectus femoris muscle in between.
erogeneity in the CDR3 domain. These
findings suggest that the T-cell re-
KEY POINTS MUAPs can also be demonstrated in sponse is not directed against a
h Antibodies directed one-third of patients. This finding may muscle-specific antigen, although a
against cytosolic lead to the misinterpretation of a neu- superantigen could trigger the re-
5-nucleotidase 1A have sponse. Oligoclonal plasma cells are
rogenic process and misdiagnosis in
been detected in as
some patients as having ALS. However, also quite prominent in the endo-
many as two-thirds of
large polyphasic MUAPs can also be mysium, but their pathogenic role is
patients with inclusion
body myositis, whereas seen in myopathies (ie, polymyositis, unclear. Amyloid deposition in vacuo-
their prevalence in dermatomyositis, muscular dystro- lated muscle fibers and, to a lesser
dermatomyositis,
polymyositis, and
other neuromuscular
disorders is much lower.
h Muscle biopsy in
patients with inclusion
body myositis
characteristically
reveals endomysial
inflammation, small
groups of atrophic
fibers, eosinophilic
cytoplasmic inclusions,
and muscle fibers with
one or more rimmed
vacuoles lined with
granular material. FIGURE 5-6 Inclusion body myositis. Muscle biopsy reveals
muscle fiber with rimmed vacuole and
cytoplasmic body inclusions (modified
Gomori one-step trichrome stain).

1624 www.ContinuumJournal.com December 2013

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extent, within nuclei can be demon-
strated on Congo red staining using
polarized light or fluorescence tech-
niques. The numbers of ragged red fibers
and cyclooxygenase (COX)Ynegative fi-
bers are also increased. On EM, 15-nm to
21-nm cytoplasmic and intranuclear
tubulofilaments are found in vacuolated
muscle fibers, although they can be
difficult to see. Not all of the features of
inclusion body myositis are evident on
any given muscle biopsy, which probably
accounts for many cases of inclusion
body myositis being misdiagnosed as
polymyositis (Case 5-2).
KEY POINT
Pathogenesis
h Not all of the features of
Inclusion body myositis is a poorly inclusion body myositis
understood disease. Although various are evident on any given
pathophysiologic aspects have been muscle biopsy, which
reported, understanding of any un- probably accounts for
derlying unifying mechanism is lack- many cases of inclusion
ing. This topic has been recently body myositis being
reviewed,14 and that review is para- misdiagnosed as
phrased here. Two aspects that have polymyositis.
been studied are myonuclear degener-
ation and autoimmunity.
Degeneration of myonuclei and their
association with rimmed vacuoles
were noted in histochemical studies.
Most rimmed vacuoles contain nuclear

Case 5-2
A 71-year-old right-handed man was incidentally noted to have slightly
elevated serum creatine kinase (CK) levels for the past 10 years during his
routine cardiology checkups, in the 400 U/L to 600 U/L range. Over the past
6 years, he had noticed increasing difficulty with walking, particularly
involving climbing stairs. He also noted difficulty grasping with his hands
and mild difficulty swallowing.
He was seen by an outside provider, who performed a biceps muscle
biopsy that was interpreted as polymyositis. He was treated with high-dose
prednisone, and then methotrexate was added. His serum CK decreased
to the normal range, but he did not feel his strength or function had
improved. Therefore, the prednisone and methotrexate were
discontinued, and the patient was referred for a second opinion.
His medical history was remarkable for hypertension and coronary
artery disease. He took hydrochlorothiazide and aspirin. Family history was
unremarkable.
Physical examination was remarkable for moderate atrophy of his
thighs and forearms bilaterally. Manual muscle testing revealed the
following Medical Research Council scores: neck flexors 4, neck extension
5, shoulder abduction 5, elbow flexion and extension 4, wrist extension
4+, wrist flexion 4j, finger extension 4 on the right and 4j on the left,
deep finger flexors 4j, flexor pollicis longus 4j, hip flexion/abduction/
extension 4, knee extension 3j, knee flexion 4j, foot dorsiflexion 0, and
ankle plantar flexion 5. He had a steppage gate that was stable with a
cane. The patient was unable to get out of a chair without using his arms.
Deep tendon reflexes were 3 at the biceps, triceps, brachioradialis, and
knees, and 2 at the ankles. Plantar responses were flexor bilaterally.
His outside muscle biopsy slides revealed moderate variation in
myofiber size, with many atrophic fibers (some in small groups) and rare
slightly hypertrophic fibers measuring up to 120 6m. Mononuclear

Continued on page 1626

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 Inflammatory Myopathies

Continued from page 1625

inflammatory cell infiltrates were present in the endomysium and
perimysium, with inflammatory cells surrounding and invading
non-necrotic muscle fibers. Scattered muscle fibers contained rimmed
vacuoles and eosinophilic inclusions.
Comment. This patient had a classic clinical pattern of weakness seen in
inclusion body myositis. His muscle biopsy also had typical features, but
these were missed by the outside pathologist. At any rate, as many as 30%
of muscle biopsies in such patients do not show all of the typical features
(eg, rimmed vacuoles or inclusions), which is why it is imperative to do a
good clinical examination. Not recognizing that he had a typical pattern of
weakness seen in inclusion body myositis led to a misdiagnosis of
polymyositis and treatment with prednisone and methotrexate, which
were not effective. He was referred for physical, occupational, and speech
therapy and given ankle-foot orthoses, adaptive equipment, and home
exercises, which improved his function and quality of life.

proteins and are derived from nuclei.
Immunohistochemical evidence shows
that rimmed vacuoles are lined with
the nuclear membrane proteins lamin
A/C and emerin as well as other nuclear
proteins (histone H1, histone 2AX,
DNA-PK, Hu70, and Hu80). An accu-
mulation of mislocalized nucleic
acidYbinding proteins (including TDP-
43, a predominantly nuclear heteroge-
neous nuclear ribonucleoprotein
[hnRNP] that undergoes nucleo-
cytoplasmic shuttling and associates
with translation machinery in the cyto-
plasm) was identified in inclusion body
myositis nonnuclear sarcoplasm.
Of the four largest categories of
inflammatory myopathy, inclusion
body myositis muscle has the greatest
degree of adaptive immune response.
Highly refined T-cell and B-cell re-
sponses are present in inclusion body
myositis muscle, and the disease has
commonly been categorized as having
prominent cytotoxic T-cell destruction
of myofibers. Extensive research on
inclusion body myositis muscle T cells
has failed to define their autoantigen,
but recent studies have demonstrated
a prominent B-cell response against a
43-kDa muscle protein identified as
1626 www.ContinuumJournal.com
cN1A (also known as NT5C1A).12,13
The detection of serum and plasma
antibodies against this muscle protein
is highly sensitive and specific for
inclusion body myositis among muscle
diseases. Furthermore, the immuno-
histochemical localization of cN1A
protein in areas of rimmed vacuole
formation suggest that inclusion body
myositis myonuclear degeneration
and autoimmunity are mechanistically
linked, but does not indicate that
these anti-cN1A antibodies are them-
selves pathogenic.
IMMUNE-MEDIATED
NECROTIZING MYOPATHY
Clinical Features
This category of idiopathic myopathy
has only been recently identified as a
probable distinct autoimmune myosi-
tis. In the authors experience, nearly
20% of inflammatory myopathy pa-
tients have immune-mediated necro-
tizing myopathy. Patients present with
proximal weakness and often myalgia
that may begin acutely or more insid-
iously. Patients may have an underly-
ing connective tissue disease (usually
scleroderma or mixed connective tis-
sue disease) or cancer (paraneoplastic
December 2013

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS
necrotizing myopathy) or be idiopathic. corticosteroids plus another immuno- h In most patients who
The most common associated malig- suppressive agent and occasionally IV have immune-mediated
nancies are gastrointestinal tract ade- immunoglobulin (IVIg) or rituximab necrotizing myopathy,
nocarcinomas and small cell and (Case 5-3). the disease was likely
nonYsmall cell carcinomas of the lung. triggered by statin use.
Again, as in polymyositis and dermato- Laboratory Features
h Most patients with
myositis, a malignancy workup should Blood work. Serum CK is usually immune-mediated
be performed on all patients. In the markedly elevated. Antinuclear anti- necrotizing myopathy
authors experience, most patients have bodies suggestive of an underlying require corticosteroids
immune-mediated necrotizing myopa- connective tissue disorder may be plus another
thy that was likely triggered by statin found. Patients with immune-mediated immunosuppressive
use (discussed in greater detail in Toxic necrotizing myopathy may have agent and occasionally
Myopathies, by Dr Andrew L. Mammen antiYsignal recognition particle (SRP) IV immunoglobulin or
in this issue of ). Pa- antibody, which is associated with an rituximab.
tients generally improve with immu- acute-onset necrotizing myopathy that h Patients with
nosuppressive and immunomodulating may be associated with a dilated cardio- immune-mediated
therapies but, in the authors experi- myopathy and often is poorly respon- necrotizing myopathy
ence, are more difficult to treat sive to standard immunosuppression. may have antiYsignal
recognition particle
than those with dermatomyositis or Recent studies have demonstrated
antibody, which is
polymyositis. Most patients require that patients with statin-associated
associated with an
acute-onset necrotizing
myopathy that may be
Case 5-3 associated with a
A 61-year-old woman with a history of diabetes and hyperlipidemia dilated cardiomyopathy
presented with a 3-month history of soreness and weakness in her arms and often is poorly
and legs. Six months earlier she was noted to have creatine kinase (CK) responsive to standard
levels over 3400 U/L. She had been on simvastatin at that time but had no immunosuppression.
muscle weakness. The statin was stopped, but the CK continued to rise,
and she had become weak. Her medical history was otherwise
unremarkable.
Physical examination was remarkable for the absence of any rash.
Manual muscle testing revealed the following Medical Research Council
scores: neck flexion 4j, neck extension 4+, shoulder abduction 4, elbow
flexion/extension 4+, wrist extension/flexion 5, finger extension/finger
flexion 5, hip flexion/extension/abduction 4j, knee flexion 4+, knee
extension 5, ankle dorsiflexion 4+, and ankle plantar flexion 5.
Her serum CK was over 10,000 U/L. An EMG was not done as it was
obvious that with a CK of that magnitude she had a myopathy. A biceps
muscle biopsy revealed many scattered regenerating and necrotic fibers
undergoing myophagocytosis. Aside from the inflammatory cells invading
necrotic muscle fibers, inflammation was minimal. AntiYsignal recognition
particle (SRP) antibodies were tested for but absent. A malignancy workup
was negative.
Comment. The presumptive diagnosis was immune-mediated necrotizing
myopathy that was most likely triggered by statin use. She was started on
both prednisone and methotrexate because this disorder can be difficult to
treat and because she also had diabetes. She slowly improved but flared
when prednisone was tapered below 20 mg/d. Therefore, IV immunoglobulin
(IVIg) was added, and the treating physicians subsequently were able to
taper her off prednisone.

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 Inflammatory Myopathies
KEY POINTS
h Patients with
statin-associated
immune-mediated
necrotizing myopathy,
particularly if over
50 years of age, often
have autoantibodies
directed, interestingly
enough, against
hydroxymethylglutaryl
coenzyme A reductase.
h The most
prominent feature of
immune-moderated
necrotizing myopathy
on muscle biopsy is
scattered necrotic
muscle fibers.
h Corticosteroids are
considered the first-line
treatment of choice
for dermatomyositis,
polymyositis, and
necrotizing myopathy.
FIGURE 5-7
polymyositis, there is scant, if any, inflammatory cell infiltrate,
except in fibers undergoing phagocytosis (hematoxylin and
eosin stain).
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immune-mediated necrotizing myopa-
thy, particularly if over 50 years of age,
often have autoantibodies directed,
interestingly enough, against hydro-
xymethylglutaryl coenzyme A (HMG-
CoA) reductase.15,16 These antibodies
are not typically found in patients who
take statins but have no symptoms or
in those who have myopathic symptoms/
signs that reverse upon discontinuation
of statins.
Imaging. MRI may demonstrate
signal abnormalities in affected mus-
cles secondary to inflammation and
edema. EMG demonstrates increased
insertional and spontaneous activity,
myopathic MUAPs, and early recruit-
ment similar to the other described
inflammatory myopathies.
Histopathology
The most prominent feature on mus-
cle biopsy is scattered necrotic muscle
fibers (Figure 5-7). By Bohan and
Peters criteria,6,7 patients with these
necrotizing myopathies might be
misdiagnosed as polymyositis. Inflam-
matory cell infiltration is sparse and
Necrotizing myositis. Muscle biopsy reveals
scattered necrotic fibers, some in the process
of undergoing phagocytosis. Unlike
confined mainly to necrotic muscle
fibers. The sarcolemma of non-
necrotic muscle fibers usually express
MHC-1, and membrane attack com-
plex deposition may occur as well.
Thickened, pipestem capillaries may
be evident on routine histochemistry
and EM.
Pathogenesis
The pathogenesis of this necrotizing
myopathy is unknown; however, the
deposition of membrane attack complex
on small arterioles and capillaries with
thickened endothelial walls suggests a
humorally mediated microangiopathy.
TREATMENT OF INFLAMMATORY
MYOPATHIES
Dermatomyositis, polymyositis, and
necrotizing myopathy typically re-
spond to immunotherapy, while inclu-
sion body myositis usually does not.
Although class 1 evidence of any
specific therapy is lacking, the authors
have used several standard treatments
based on experience. There is no one
correct way to treat myositis, and the
authors refer readers to several re-
views.2,5 That said, the standard of
care is high-dose corticosteroids. Equi-
poise exists regarding when to start
second-line agents (see below). Con-
currently, the authors recommend
physical, occupational, and speech/
swallowing therapy as warranted.
Corticosteroids. Corticosteroids are
considered the first-line treatment of
choice for dermatomyositis, polymyosi-
tis, and necrotizing myopathy. Ap-
proaches to dosing steroids vary; the
most common regimen is to start pa-
tients on high-dose daily prednisone (eg,
60 mg/d or 0.75 mg/kg/d to 1.5 mg/kg/d).
In patients with severe weakness, a short
course of IV methylprednisolone (1 g/d
for 3 days) may be given, continuing
with high-dose prednisone until mus-
cle strength normalizes, improvement
December 2013
 KEY POINTS
in strength has reached a plateau, or at While an increasing serum CK may h In patients with severe
least normalization of the serum CK precede a relapse, the authors would weakness, a short
occurs (this typically takes 3 to 6 not increase dosages unless it were course of IV
months). Thereafter, the authors de- accompanied by increased weakness; methylprednisolone
crease the prednisone by 10 mg/d in such cases, it is advisable to hold (1 g/d for 3 days) may
every 4 weeks until the patient is on the dosages and follow the patient be given, continuing
20 mg/d; at this dose, prednisone is more closely. with high-dose
decreased by 5 mg/d every 4 weeks Concurrent Management. In pa- prednisone until muscle
until the patient is on 10 mg/d, then tients who have interstitial lung dis- strength normalizes,
decreased by 2.5 mg/d every 4 weeks. ease or are on prednisone plus improvement in
strength has reached
Although most patients improve, the another immunosuppressive agent,
a plateau, or at least
response may not be complete, and the authors start a prophylactic antibi-
normalization of the
most will require at least a small dose of otic for pneumocystis (eg, sulfameth- serum creatine kinase
prednisone or a second-line agent to oxazole and trimethoprim). Because occurs (this typically
have a sustained remission. In those of the potential for osteoporosis with takes 3 to 6 months).
patients who do not respond at all to chronic steroid administration, the
h The authors usually
high-dose prednisone, the clinician authors obtain a baseline dual-energy start a second-line
needs to consider alternative disorders x-ray absorptiometry (DEXA) and fol- agent along with
(eg, inclusion body myositis or an low yearly while the patient is on corticosteroids in
inflammatory muscular dystrophy). corticosteroids. The authors also start patients with severe
As noted above, equipoise also calcium supplementation (1 g/d) and weakness or other
exists regarding when to start vitamin D (800 IU/d). Depending on organ system
second-line agents (eg, methotrexate, results of the DEXA and other risk involvement
azathioprine, mycophenolate, or im- factors (eg, postmenopausal status), (eg, myocarditis,
munoglobulin). The clinician must the authors may also treat patients with interstitial lung disease),
review with the patient the increased a bisphosphonate. In addition, patients those with increased
risk of steroid
risks of immunosuppression versus are counseled on a low-sodium, low-
complications
possible benefits (eg, faster improve- carbohydrate, high-protein diet, and
(eg, diabetics, patients
ment, steroid-sparing effect). The au- treating physicians should monitor with osteoporosis,
thors usually start a second-line agent fasting blood glucose and serum or postmenopausal
along with corticosteroids in patients potassium levels, blood pressure, and women), and those
with severe weakness or other organ eyes (for cataracts) while patients are known to have
system involvement (eg, myocarditis, on high doses of prednisone. difficult-to-treat myositis
interstitial lung disease), those with (eg, immune-mediated
increased risk of steroid complications Second-Line Therapies necrotizing myopathy).
(eg, diabetics, patients with osteopo- Methotrexate. Methotrexate is often h The authors follow
rosis, or postmenopausal women), regarded as the second-line treatment the serum creatine
and those known to have difficult-to- of choice in dermatomyositis, poly- kinase levels when
treat myositis (eg, immune-mediated myositis, and immune-mediated nec- treating the
necrotizing myopathy). A second-line rotizing myopathy. The authors inflammatory
agent should also be strongly consid- usually initiate methotrexate orally at myopathies;
ered in patients who fail to signifi- 7.5 mg/wk, gradually increased by however, adjustments
of immunotherapies
cantly improve after 2 to 4 months of 2.5 mg each week or two up to
are primarily based
treatment or who experience an exac- 25 mg/wk as appropriate and toler-
on the objective clinical
erbation during treatment with pred- ated. The dosage needs to be adjusted examination.
nisone. The authors follow the serum in patients with renal insufficiency. All
CK levels; however, adjustments of patients are concomitantly given folate
immunotherapies are primarily based or folinic acid. Methotrexate has many
on the objective clinical examination. potential side effects (Table 5-21).
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 Inflammatory Myopathies
TABLE 5-2 Immunosuppressive/Immunomodulating Therapy for Inflammatory Myopathies
Therapy Route Dose
Prednisone Oral 0.75Y1.5 mg/kg/d
Methylprednisolone IV 1 g in 100 mL normal
saline over 1Y2 h, daily
or every other d for
3Y6 doses
Azathioprine Oral 2Y3 mg/kg/d, divided
into two daily doses
Methotrexate Oral 7.5Y20 mg weekly,
single or divided doses;
one d/wk dosing
IV/IM 20Y50 mg weekly;
one d/wk dosing
Cyclophosphamide Oral 1.5Y2 mg/kg/d, single
AM dose
IV 0.5Y1 g/m2/mo
for 6Y12 mo
Cyclosporine Oral 4Y6 mg/kg/d split into
two daily doses
Tacrolimus Oral 0.1Y0.2 mg/kg/d in
two divided doses
Mycophenolate Oral Adults: (1Y1.5 g twice
mofetil daily) Note: no more
than 1 g/d in patients
with renal failure
Children: 600 mg/m2/
dose twice daily (not
to exceed 2 g/d)
1630 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
a
Side Effects Monitor
Hypertension, fluid and Weight, blood pressure,
weight gain, hyperglycemia, serum glucose/
hypokalemia, cataracts, potassium, cataract
glaucoma, gastric irritation, formation
osteoporosis, infection, aseptic
femoral necrosis, steroid
myopathy, mood alteration,
psychosis
Arrhythmia, flushing, Heart rate, blood
dysgeusia, anxiety, insomnia, pressure, serum
fluid and weight gain, glucose/potassium
hyperglycemia, hypokalemia,
infection
Flulike illness, hepatotoxicity, Blood count, liver
pancreatitis, leukopenia, enzymes
macrocytosis, neoplasia,
infection, teratogenicity
Hepatotoxicity, pulmonary Liver enzymes, blood
fibrosis, infection, neoplasia, count, creatinine/blood
infertility, leukopenia, urea nitrogen
thrombocytopenia, alopecia,
gastric irritation, stomatitis,
teratogenicity
Same as oral route Same as oral route
Bone marrow suppression, Blood count, urinalysis
infertility, hemorrhagic
cystitis, alopecia, infections,
neoplasia, teratogenicity
Nephrotoxicity, hypertension, Blood pressure,
infection, hepatotoxicity, creatinine/blood urea
hirsutism, tremor, gum nitrogen, liver enzymes,
hyperplasia, teratogenicity cyclosporine levels
Nephrotoxicity, hypertension, Blood pressure,
infection, hepatotoxicity, creatinine/blood urea
hirsutism, tremor, gum nitrogen, liver enzymes,
hyperplasia, headache, tacrolimus levels
insomnia, paresthesias,
teratogenicity
Bone marrow suppression, Blood count
hypertension, tremor,
diarrhea, nausea, vomiting,
headache, sinusitis, confusion,
amblyopia, cough,
teratogenicity, infection,
neoplasia
Continued on next page
December 2013
 a
TABLE 5-2 Immunosuppressive/Immunomodulating Therapy for Inflammatory Myopathies
(continued )

Therapy Route Dose Side Effects Monitor

IVIg IV 2 g/kg total dose over
2Y5 d, then 1 g/kg
every 4Y8 wk as
needed
Rituximab IV 750 mg/m2 once (up to
1 g) and repeated in
2 wk; course is then
repeated every 6Y18 mo
a
Modified from Amato AA, Barohn RJ, Neurol Clin.1 B 1997, with permission from Elsevier. www.neurologic.theclinics.com/article/
S0733-8619(05)70337-6/fulltext.
Hypotension, arrhythmia,
diaphoresis, flushing,
nephrotoxicity, headache,
flu-like symptoms, aseptic
meningitis, anaphylaxis, stroke
Infusion reactions (as per
IVIg), infection, progressive
multifocal leukoencephalopathy
Heart rate, blood
pressure, creatinine/
blood urea nitrogen
Some physicians check
B-cell count before
subsequent courses, but
this may not be warranted

Because one rare side effect of meth-
otrexate is pulmonary fibrosis, the
authors typically avoid using it in
patients with interstitial lung disease
or Jo-1 antibodies. In patients treated
with methotrexate, pulmonary func-
tion tests (FVC and DLCO) should be
periodically repeated. The authors
monitor the pulmonary function tests
(FVC and DLCO), CBC, renal and liver
function tests (ALT, AST, bilirubin),
and gamma-glutamyl transpeptidase
(GGT). GGT is the most reliable
indicator of hepatic dysfunction, be-
cause AST and ALT can be elevated
from muscle involvement alone.
Azathioprine. Azathioprine is an-
other frequently used second-line
agent, but the authors prescribe it less
often than methotrexate, as it tends to
take a little longer to work. The
authors usually screen patients for
thiopurine methyltransferase (TPMT)
deficiency; the authors avoid using
azathioprine in those who are homo-
zygous for TPMT mutations because of
an increased risk for severe bone
marrow toxicity. The authors begin
azathioprine at 50 mg twice daily and
then increase 50 mg every 2 weeks up
to 2 mg/kg/d to 3 mg/kg/d. Approxi-
mately 12% of patients do not tolerate
azathioprine and develop fever, ab-
dominal pain, nausea, vomiting, and KEY POINTS
anorexia. Azathioprine has several other h Gamma-glutamyl
potential side effects (see Table 5-21). transpeptidase is the
most reliable indicator
Allopurinol should be avoided, because
of hepatic dysfunction,
combination with azathioprine in-
because aspartate
creases the risk of bone marrow and aminotransferase and
liver toxicity. alanine aminotransferase
Mycophenolate mofetil. The au- can be elevated from
thors use mycophenolate mofetil in muscle involvement
patients who do not tolerate metho- alone.
trexate or azathioprine or in whom h A large, prospective,
those treatments are contraindicated. double-blind NIH trial
The authors initiate treatment at 1.0 g of rituximab found no
twice daily; it can be increased to 3 g/d benefit, but the study
in divided doses as needed. In patients design had significant
with renal insufficiency, the dosage is flaws. In the authors
limited to 500 mg twice daily. experience, rituximab
IV immunoglobulin. The authors may be beneficial in
typically reserve treatment with IVIg in patients with refractory
dermatomyositis,
polymyositis, dermatomyositis, and
polymyositis, and
immune-mediated necrotizing myopa-
immune-mediated
thy patients who are refractory to necrotizing myopathy.
prednisone and one of the other
above second-line agents. However,
in patients with severe myositis, the
authors may start treatment with a
triple cocktail (eg, prednisone, meth-
otrexate, and IVIg). The authors give
IVIg (2 g/kg total dose) over 2 to 5
days and repeat infusions performed
at monthly intervals for at least 3
months, then decrease the dosage to
1 g/kg/month.

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 Inflammatory Myopathies
KEY POINTS
h Physical and
occupational therapy
are important and may
help improve function
and reduce type 2
fiber muscle atrophy
associated with chronic
steroids and inactivity.
h Dysphagia is very
common in patients
with inclusion body
myositis and often
requires esophageal
dilatation or
cricopharyngeal
myotomy.
1632 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Rituximab. Rituximab is a mono-
clonal antibody that targets B cells.
Studies involving small series of pa-
tients have suggested that rituximab
may be an effective therapy in derma-
tomyositis and polymyositis. A large,
prospective, double-blind NIH trial
found no benefit, but the study de-
sign had significant flaws. In the
authors experience, rituximab may
be beneficial in patients with refrac-
tory dermatomyositis, polymyositis,
and immune-mediated necrotizing
myopathy. The authors use it in
patients who are refractory to predni-
sone and at least one of the other
second-line agents discussed above, at
a dosage of 750 mg/m2 (up to 1 g) IV,
with the infusion repeated in 2 weeks.
A course of rituximab, as above, is
usually repeated every 6 to 18 months.
There is a risk of progressive mul-
tifocal leukoencephalopathy (PML),
which, although low, should be dis-
cussed with patients before prescrib-
ing rituximab.
Cyclosporine and tacrolimus. Cy-
closporine and tacrolimus may be
beneficial, but their cost and potential
side effects (see Table 5-21) have
limited their use. Cyclosporine is
started at a dose of 3.0 mg/kg/d to
4.0 mg/kg/d in two divided doses and
gradually increased to 6.0 mg/kg/d as
necessary to achieve a trough serum
cyclosporine level of 50 ng/mL to 200
ng/mL. The authors start tacrolimus at
a dose of 0.1 mg/kg and increase it up
to 0.2 mg/kg (in two divided doses
daily) as needed to achieve a trough
level of 5 ng/mL to 15 ng/mL. Blood
pressure, electrolytes, renal function,
CBC, and liver function tests are
monitored closely, and the doses are
adjusted if renal insufficiency de-
velops.
Cyclophosphamide. Cyclophos-
phamide is rarely used because of its
potential side effects, and the authors
reserve it for patients refractory to
other treatments discussed above.
Typically, the authors treat patients
with IV cyclophosphamide at 0.5 g/m2/mo
to 1 g/m2/mo for 6 to 12 months.
Cyclophosphamide can also be given
orally (1.0 mg/kg/d to 2.0 mg/kg/d),
although oral administration may
present a greater risk of hemorrhagic
cystitis. Before IV cyclophosphamide
treatment, patients should be hydrated
with IV fluids to help avoid hemorrhagic
cystitis. Urinalysis and CBC should be
monitored closely.
Tumor necrosis factor-! (TNF-!)
blockers. The results of these agents
in the myositides have been mixed,
and therefore the authors tend to
avoid them.
Other Therapies. Physical and oc-
cupational therapy are important and
may help improve function and re-
duce type 2 fiber muscle atrophy
associated with chronic steroids and
inactivity. Speech/swallowing therapy
is beneficial in patients with dyspha-
gia, which is very common in inclu-
sion body myositis patients and often
requires esophageal dilatation or
cricopharyngeal myotomy. Some pa-
tients need a feeding tube to prevent
recurrent aspiration.
SUMMARY
Dermatomyositis, polymyositis, necro-
tizing myopathy, and inclusion body
myositis are clinically, histologically,
and pathogenically distinct. In particu-
lar, the pattern of muscle involvement,
other organ system involvement, the
presence of certain autoantibodies, and
muscle biopsy findings are useful in
distinguishing these different types of
inflammatory myopathy. Polymyositis
is a T cellYmediated disorder directed
against muscle fibers. The pathogene-
sis of dermatomyositis, necrotizing
myopathy, and inclusion body myo-
sitis are unknown. Dermatomyositis,
December 2013
polymyositis, and necrotizing myopa-
thy are generally, but not always,
responsive to immunosuppressive
therapy, in contrast to inclusion body
myositis, which is generally refractory
to therapy.
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