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SEMINAR
Seminar
Polymyositis and dermatomyositis
Marinos C Dalakas, Reinhard Hohlfeld
The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially
treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they
can be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis.
Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders.
Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysis
of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the
perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological
features. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule,
intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokines
increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and
dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in
controlled trials may prove promising for difficult cases.
The inflammatory myopathies are a heterogeneous group
of subacute, chronic, or acute acquired diseases of skeletal
muscle. They have in common the presence of moderate
to severe muscle weakness and inflammation in the
muscle.1–6 The disorders are clinically important because
they are potentially treatable. On the basis of welldefined
clinical,
demographic,
histological,
and
immunopathological criteria, the inflammatory myopathies
form three major and discrete groups: polymyositis,
dermatomyositis, and sporadic inclusion-body myositis.1
This review describes current knowledge of the clinical
presentation, diagnosis, pathogenesis, and treatment of
polymyositis and dermatomyositis. Inclusion-body
myositis, a common and important subset as recently
reviewed,4–7 is addressed only to outline its distinguishing
features in the differential diagnosis of polymyositis.
Epidemiology, genetics, and general clinical
features
Dermatomyositis affects both children and adults, and
women more than men. Polymyositis is seen after the
second decade of life. Inclusion-body myositis is more
common in men over the age of 50 than in other
population groups.1–7 The frequencies of polymyositis and
dermatomyositis as stand-alone disorders or in association
with other systemic diseases are unknown. Estimates based
on old diagnostic criteria,8 which cannot distinguish
polymyositis from inclusion-body myositis,1,3 range from
0·6 to 1·0 per 100 0001–10 but may not be reliable (see
later). In all age-groups, dermatomyositis is the most
common and polymyositis the least common; inclusionLancet 2003; 362: 971–82
Neuromuscular Diseases Section, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, MD,
USA (Prof M C Dalakas MD); and Max Planck Institute of
Neurobiology and Institute for Clinical Neuroimmunology, Klinikum
Grosshadern, Ludwig Maximilians University, Munich, Germany
(Prof R Hohlfeld MD)
Correspondence to: Prof Marinos C Dalakas, Neuromuscular
Diseases Section, NINDS, NIH, Building 10, Room 4N248,
10 Center Drive MSC 1382, Bethesda, MD 20892–1382, USA
(e-mail: dalakasm@ninds.nih.gov)
body myositis is the commonest myopathy above the age
of 50. In children, dermatomyositis is the most frequent
inflammatory myopathy but polymyositis is very rare, as
recently confirmed.11 Genetic factors may have a role, as
suggested by rare familial occurrences and association with
certain HLA genes, such as DRB1*0301 alleles for
polymyositis and inclusion-body myositis,12,13 HLA DQA1
0501 for juvenile dermatomyositis,14 or tumour necrosis
factor 308A polymorphism for photosensitivity in
dermatomyositis.15 Emerging information on the genetic
background of various ethnic groups may allow
identification of immune-response genes that predispose
certain populations to polymyositis or dermatomyositis.16,17
Both polymyositis and dermatomyositis present with a
varying degree of muscle weakness that develops slowly,
over weeks to months, but acutely in rare cases.1 Patients
report difficulty with everyday tasks, such as rising from a
chair, climbing steps, stepping onto a kerb, lifting objects,
or combing their hair. Fine motor movements that
depend on the strength of distal muscles, such as holding
or manipulating objects, are affected late in the course of
dermatomyositis and polymyositis, but fairly early in
sporadic inclusion-body myositis owing to prominent
involvement of distal muscles, especially wrist and finger
flexors.1 Early involvement of the quadriceps muscle and
ankle dorsiflexors, causing buckling of the knees and
frequent falls, is common in sporadic inclusion-body
myositis.7 Facial muscles remain normal but mild facial
muscle weakness is common in patients with sporadic
Search strategy and selection criteria
The review is based on our own experience and research
connected with these disorders as well as a comprehensive
MEDLINE search on the topics of "polymyositis",
"dermatomyositis", and "inflammatory myopathies". We
focused on peer-reviewed works published in English in major
scientific journals over the past 10 years and on reviews
written by experts on this subject. All available articles were
critically reviewed. Papers presenting the strongest evidence
or providing important insights into the diagnosis,
pathogenesis, and management of these disorders were also
referred to and cited.
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971
SEMINAR
transient or poorly recognised (eg, in
dark-skinned people), the term
dermatomyositis sine dermatitis is
appropriate. In such cases, a mistaken
diagnosis of polymyositis is considered,
until a muscle biopsy confirms the
correct
diagnosis.
In
children,
dermatomyositis resembles the adult
disease, except for more frequent
extramuscular manifestations (see
later). A common early abnormality in
children is “misery”, defined as an
irritable child who feels uncomfortable,
has a red flush on the face, is fatigued,
does not socialise, and has a varying
degree of proximal muscle weakness.4,6
A tiptoe gait due to flexion contracture
of the ankles is common.1
Dermatomyositis can be associated
with cancer21 or may overlap with
systemic
sclerosis
and
mixed
connective-tissue disease.1,22,23 Fasciitis
Figure 1: Rash and calcifications in dermatomyositis
A: Gottron’s rash. B: Skin effects of calcification. C: Radiographic evidence of calcification.
and thickening of the skin, as seen in
chronic dermatomyositis, can also
occur in patients with eosinophilia-myalgia syndrome,24
inclusion-body myositis.7 The extraocular muscles are
never affected, in contrast to myasthenia in which they are
eosinophilic fasciitis, or macrophagic myofasciitis.25
affected early.1 The neck extensor muscles may be
involved, causing difficulty in holding up the head (head
Polymyositis
drop). In advanced cases, and in rare acute cases,
Polymyositis is best defined as a subacute myopathy that
dysphagia with choking episodes and respiratory muscle
evolves over weeks to months, affects adults but rarely
weakness occurs. Sensation remains normal. The tendon
children, and presents with weakness of the proximal
reflexes are preserved but may be absent in severely
muscles. Unlike dermatomyositis in which the rash
weakened or atrophied muscles. Contrary to widespread
secures early recognition, the actual onset of polymyositis
belief, myalgia is not common, occurring in less than 30%
cannot be easily identified.1 Polymyositis mimics many
of the patients.
other myopathies and remains a diagnosis of exclusion
(panel).26–29 It should be viewed as a syndrome of diverse
causes
that occurs separately or in association with
Specific clinical features
systemic autoimmune disorders or viral infections in
Dermatomyositis
patients who do not have any of the exclusion criteria
Dermatomyositis is identified by a characteristic rash
listed in the panel.
accompanying or, more commonly, preceding muscle
As a stand-alone clinical entity, polymyositis is an
weakness. The skin manifestations include a heliotrope
uncommon but frequently misdiagnosed disorder. The
rash (blue-purple discolouration) on the upper eyelids in
commonest myopathy misdiagnosed as polymyositis is
many cases associated with oedema, and an erythematous
inclusion-body myositis; this disorder is suspected in
rash on the face, neck, and anterior chest (in many
retrospect in many cases of presumed polymyositis that
patients in a V sign) or back and shoulders (shawl sign),
have not responded to therapy.1,7 Especially in men
knees, elbows, and malleoli; the rash can be exacerbated
after exposure to the sun and is pruritic in some cases.
older than 50 years, a polymyositis-like disease is
Characteristic is the Gottron rash (figure 1), a raised
inclusion-body myositis until proved otherwise. Other
violaceous rash or papules at the knuckles, prominent in
disorders misdiagnosed as polymyositis include toxic
metacarpophalangeal and interphalangeal joints;18 in
and endocrine myopathies, dermatomyositis sine
dermatitis, certain dystrophies, and some slowly
contrast to systemic lupus erythematosus, the rash does
progressive myopathies commonly starting in late
not involve the phalanges.1,9 When chronic, the rash
childhood (panel).
becomes scaly with a shiny appearance. Dilated capillary
loops at the base of the fingernails with irregular,
thickened, and distorted cuticles are also characteristic.
Associated clinical findings (table 1)
The lateral and palmar areas of the fingers may become
Extramuscular manifestations
rough with cracked, “dirty” horizontal lines, resembling
There are many manifestations outside the muscles. Joint
“mechanics’ hands”.
contractures occur mostly in dermatomyositis. Dysphagia
The weakness varies from mild to severe, leading to
is due to involvement of the oropharyngeal striated
quadriparesis. At times the muscle strength appears
muscles and upper oesophagus30,31 (gastrointestinal
normal, hence the terms dermatomyositis sine myositis or
ulcerations due to vasculitis and infection were common
amyopathic dermatomyositis.19 When a muscle biopsy is
in children with dermatomyositis before the use of
immunosuppressants2). Cardiac disturbances include
taken from such cases, however, subclinical muscle
involvement
with
perivascular
and
perimysial
atrioventricular conduction defects, tachyarrhythmias,
inflammation is seen.20 Although there may be cases of
myocarditis in patients with acute disease,32,33 and heart
amyopathic dermatomyositis limited to the skin, we
failure commonly related to hypertension from long-term
believe that amyopathic and myopathic dermatomyositis
steroid use.1 Pulmonary symptoms are due to weakness of
are part of the range of dermatomyositis affecting skin and
the thoracic muscles or interstitial lung disease,34–36 which
muscle to a varying degree. Rarely, when the rash is
is common in patients with autoantibodies to tRNA
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SEMINAR
synthetases or a mucin-like glycoprotein (KL-6).35
Subcutaneous calcifications (figure 1), occur only in
dermatomyositis, in some cases extruding on the skin and
causing ulcerations, infections, and pain,37 especially at
sites of compression (elbows, buttocks, back). General
symptoms include fever, malaise, weight loss, arthralgia,
and Raynaud’s phenomenon when polymyositis or
dermatomyositis is associated with another connectivetissue disease.
Malignant disorders
Although all the inflammatory myopathies can have a
chance association with malignant disease, especially in
older age-groups, the frequency of cancer is definitely
increased in dermatomyositis.38 A slightly increased
frequency reported in polymyositis39,40 must be confirmed
with use of updated diagnostic criteria. The most
common cancers are those of the ovaries, gastrointestinal
tract, lung, and breast and non-Hodgkin lymphomas.
Continuous vigilance is required for early recognition,
especially in older people and during the first 3 years after
disease onset.23,41 In patients without risk factors,
expensive, radiological blind searches for occult malignant
disease is not practical or fruitful.1,41 A complete annual
physical examination with pelvic, breast (mammogram, if
indicated), rectal (with colonoscopy, according to age and
family history) radiographs and a chest film should suffice.
A report that blind search with abdominal–pelvic and
thoracic CT scans increased the yield by 28%42 needs
confirmation. In Asian patients, among whom
nasopharyngeal cancer is more common, careful
assessment of ears, nose, and throat is suggested.
Overlap syndrome
Polymyositis and dermatomyositis are seen in association
with various autoimmune and connective tissue diseases
(table 1). The term overlap syndrome is used loosely to
emphasise this association but in reality it was meant to
indicate that certain clinical signs are shared by both
disorders. Accordingly, it is only dermatomyositis, and
not polymyositis, that truly overlaps and only with
systemic sclerosis and mixed connective-tissue disease.
Certain signs seen in these two disorders, such as sclerotic
thickening of the dermis, contractures, oesophageal
hypomotility, microangiopathy, and calcium deposits, are
also present in dermatomyositis but not polymyositis; by
contrast, signs of rheumatoid arthritis, lupus, or Sjögren’s
syndrome are rare in dermatomyositis (table 1).1 A report
that dermatomyositis can overlap with lupus43 needs
confirmation.
Clinical characteristics of polymyositis
Myopathic weakness
Evolves over weeks to months, spares facial and eye
muscles, and presents as difficulty in climbing steps, rising
from a chair, lifting objects, combing hair.
Disease onset
Above the age of 18 years
Features the patient DOES NOT have
Rash (characteristic of dermatomyositis)
Family history of neuromuscular diseases
Exposure to myotoxic drugs, especially penicillamine,26
zidovudine,27 and (rarely) statins28,29
Endocrine disease (hypothyroidism, hyperthyroidism,
hypoparathyroidism, hypercortisolism)
Neurogenic disease (excluded by electromyography and
neurological examination)
Dystrophies and metabolic myopathies (excluded by history
and muscle biopsy)
Inclusion-body myositis (excluded by clinical examination and
muscle biopsy)
Possible associations
Other autoimmune or viral infections, such as:
lupus, rheumatoid arthritis, Sjögren’s syndrome, Crohn’s
disease, vasculitis, sarcoidosis, primary biliary cirrhosis,
adult coeliac disease, chronic graft-versus-host disease,
discoid lupus, ankylosing spondylitis, Behçet’s syndrome,
myasthenia gravis, acne fulminans, dermatitis
herpetiformis, psoriasis, Hashimoto’s disease,
granulomatous diseases, agammaglobulinaemia,
hypereosinophilic syndrome, Lyme disease, Kawasaki
disease, autoimmune thrombocytopenia,
hypergammaglobulinaemic purpura, hereditary
complement deficiency, HIV and HTLV-1 infection.
Reconsider polymyositis
If the diagnosis was based on Bohan and Peter’s criteria, in
patients with:
Disease onset before the age of 18
Slow-onset myopathy that evolved over months to years (in
such cases think of inclusion-body myositis or dystrophy)
Fatigue and myalgia, without muscle weakness, even if a
transient rise in creatine kinase activity is seen (such
patients may have fibromyalgia or fasciitis, and their
muscle biopsy sample is normal or shows very few
inflammatory cells in the endomysial septae)
No typical histological features of polymyositis
Characteristic
Dermatomyositis
Polymyositis
Inclusion-body myositis
Age at onset
All ages
>18 years
>50 years
Familial association
No
No
In some cases
Extramuscular manifestations
Yes
Yes
Yes
Associated disorders
Connective-tissue diseases*
Overlap syndrome†
Systemic autoimmune diseases
Malignant disorders
Viruses
Parasites and bacteria
Drug-induced myotoxicity||
Only with scleroderma and mixed connective-tissue disease
Only with scleroderma and mixed connective-tissue disease
Rarely
Yes, in up to 15% of cases
Unproven
No
Rarely
Yes, with all
No
Frequently
No
Yes‡
Yes§
Yes
Yes, in up to 20% of cases
No
Infrequently
No
Yes‡
No
No
*A dermatomyositis-like disease develops in up to 12% of patients with systemic sclerosis, and polymyositis in 5–8% of lupus patients; polymyositis is less commonly
seen in patients with Sjögren’s disease or rheumatoid arthritis. †Overlap denotes that certain signs are common to both disorders; by contrast, "association" denotes
that two disorders can coexist. ‡HIV and HTLV-1. §Includes parasitic (protozoa, cestodes, and nematodes), tropical, and bacterial myositis (pyomyositis). ||Drugs
include penicillamine (for dermatomyositis and polymyositis), zidovudine (for polymyositis), contaminated tryptophan (for a dermatomyositis-like illness), and lipidlowering drugs rarely. Other myotoxic drugs can cause myopathy but not inflammatory myopathy.1,6,29
Table 1: Conditions and factors associated with inflammatory myopathies
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Diagnosis
The
clinical
diagnosis
of
polymyositis
and
dermatomyositis is confirmed by three laboratory
examinations: serum muscle enzyme concentrations,
electromyography, and muscle biopsy. In certain cases of
dermatomyositis, skin biopsy can be helpful.
The most sensitive muscle enzyme assay is creatine
kinase, which is increased up to 50 times in active disease.
Aspartate and alanine aminotransferases, lactate
dehydrogenase, and aldolase are also increased. Although
creatine kinase concentration usually parallels disease
activity, it can be normal in some patients with active
dermatomyositis; in the active phases of polymyositis, the
creatine kinase concentration is always increased.
Needle electromyography shows increased spontaneous
activity with fibrillations, complex repetitive discharges,
and positive sharp waves. The voluntary motor units
consist of low-amplitude polyphasic units of short
duration.44,45 Although not disease specific, these findings
are useful to confirm active myopathy. Presence of
spontaneous activity can help to distinguish active disease
from steroid-induced myopathy, except if the two coexist.1
The muscle biopsy is the most crucial test for
establishing the diagnosis,1–6,46 but also the most common
cause of misdiagnosis due to erroneous interpretation.4 In
dermatomyositis, the inflammation is predominantly
perivascular or in the interfascicular septae and around
rather than within the fascicles.1-6 The intramuscular blood
vessels show endothelial hyperplasia with tubuloreticular
profiles, fibrin thrombi, especially in children, and
obliteration of capillaries resulting in reduction of capillary
density (figure 2).2,4,46–49 The muscle fibres undergo
phagocytosis and necrosis, commonly in groups
(microinfarcts) involving a portion of a muscle fasciculus,
or the periphery of the fascicle, resulting in perifascicular
atrophy. This atrophy, characterised by two to ten layers of
atrophic fibres at the periphery of the fascicles, is
diagnostic of dermatomyositis, even in the absence of
inflammation (figure 2).1,46 The skin lesions show
perivascular inflammation with CD4-positive cells in the
dermis; in chronic stages there is dilatation of superficial
capillaries.2
Skin
histopathology
distinguishes
dermatomyositis from other papulosquamous disorders
but not from cutaneous lupus.18
In polymyositis, multifocal lymphocytic infiltrates
surround and invade healthy muscle fibres (figure 2).1–5,46
The inflammation is primary, a term used to indicate that
lymphocytes (CD8-positive cells) invade histologically
healthy muscle fibres expressing MHC class I antigens.
We refer to this lesion as the CD8/MHC-I complex (see
later).50–53 In chronic stages, connective tissue is increased
and may react with alkaline phosphatase.46 When, in
Figure 2: Histological findings in polymyositis and dermatomyositis
A, B: Depletion of capillaries in dermatomyositis (A) with dilatation of the lumen of the remaining capillaries, compared with a normal muscle (B).
C: Perifascular atrophy in dermatomyositis. D: Endomysial inflammation in polymyositis and inclusion-body myositis with lymphocytic cells invading healthy
fibres. E: The MHC-I/CD8 complex in polymyositis and inclusion-body myositis. MHC-I (green) is upregulated on all the muscle fibres, and CD8-positive
T cells (orange) that also express MHC-I, invade the fibres.
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SEMINAR
Criterion
Polymyositis
Definite
Myopathic muscle weakness Yes*
Electromyographic findings
Myopathic
Muscle enzymes
Muscle-biopsy findings
Rash or calcinosis
Myopathic dermatomyositis
Amyopathic
dermatomyositis
Probable
Definite
Probable
Definite
Yes*
Myopathic
Yes*
Myopathic
Yes*
Myopathic
No†
Myopathic or
non-specific
High (up to 50
High (up to 50 times
High (up to 50 times
High
High (up to 10 times
times normal)
normal)
normal) or normal
normal) or normal
Primary inflammation, Ubiquitous MHC-I
Perifascicular, perimysial Perifascicular, perimysial Non-specific or
with the CD8/MHC-1 expression, but no
or perivascular infiltrates; or perivascular infiltrates; diagnostic for
complex and no
CD8-positive infiltrates perifascicular atrophy
perifascicular atrophy
dermatomyositis
vacuoles
or vacuoles‡
(subclinical myopathy)
Absent
Absent
Present
Not detected
Present
*Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterised by a subacute onset (weeks to
months) and rapid progression in patients who have no family history of neuromuscular disease, no exposure to myotoxic drugs or toxins, and no signs of biochemical
muscle disease. The myopathic weakness has a pattern distinct from that seen in inclusion-body myositis (table 1). †Although strength is apparently normal, many
patients have new onset of easy fatigue, myalgia, and reduced endurance. Careful muscle testing may reveal mild muscle weakness. ‡If such a patient has the
clinical phenotype of sporadic inclusion-body myositis, the diagnosis will be probable inclusion-body myositis; a repeat biopsy is indicated.
Table 2: Diagnostic criteria for inflammatory myopathies
addition to primary inflammation, there are vacuolated
muscle fibres with basophilic granular deposits around
the edges (rimmed vacuoles) and congophilic amyloid
deposits within or next to the vacuoles, the diagnosis of
inclusion-body myositis is likely.54,55 Errors in the
histological diagnosis of polymyositis can be avoided by
three steps. First, primary inflammation should be
demonstrated. This step has become an essential
criterion because it distinguishes polymyositis from toxic,
necrotising, or dystrophic myopathies (facioscapulohumeral; due to deficiency of dystrophin or dysferlin) in
which macrophages predominate.46 Second, the biopsy
sample should be processed for frozen sections and with
enzyme histochemistry and immunohistochemistry.
Paraffin
embedding
misdiagnoses
inclusion-body
myositis for polymyositis because it dissolves the redrimmed granular material, and the vacuolated fibres
become indiscernible. Also, the CD8/MHC-I complex
and sarcolemmal or enzymatic proteins that exclude
dystrophies, metabolic myopathies, and mitochondriopathies are best demonstrated on frozen sections. Third,
a repeat muscle biopsy may be necessary. Because the
inflammation is spotty, taking a sample from a different
muscle should be considered if a patient meets the
clinical criteria (panel) but the first sample was not
diagnostic. In occasional cases, muscle MRI may be
useful to identify inflammatory sites and select the area
for biopsy.
Other inflammatory myopathies diagnosed on the basis
of distinctive clinical and histological features include:
infectious (parasitic, bacterial [pyomyositis]), granulomatous, eosinophilic (polymyositis or fasciitis), and
localised forms.1,3–5,56
Diagnostic criteria
The subject of diagnostic criteria remains unsettled
because the various proposed criteria3 have not been
properly validated. The criteria of Bohan and Peter8
cannot distinguish polymyositis from inclusion-body
myositis or from certain dystrophies. Because the
immunopathological characteristics confer specificity for
each subset, we believe that the diagnostic criteria should
rely on histopathology and immunopathology as the best
means of separating polymyositis from other myopathies.1
Accordingly, we view the diagnosis of polymyositis as
definite if a patient has an acquired, subacute myopathy
meeting the inclusion and exclusion criteria (panel),
raised concentrations of serum creatine kinase, and
primary inflammation in the muscle biopsy (table 2).
When in such a patient, the biopsy sample shows
widespread expression of MHC-I antigens57,58 but no
T cells or vacuoles, the diagnosis is probable polymyositis.
Because the same histology may also be seen in some
patients who have the typical inclusion-body myositis
phenotype (probable inclusion-body myositis),59 the
diagnosis is aided by taking a second biopsy sample and
relating the findings to the clinical picture.
The diagnosis of dermatomyositis is definite if the
myopathy is accompanied by the characteristic rash and
histopathology. If no rash is detected but the biopsy
sample is typical for dermatomyositis, the diagnosis is
probable dermatomyositis; conversely, if the typical
dermatomyositis rash is present but muscle weakness is
not apparent, the clinical diagnosis is amyopathic
dermatomyositis.
Immunopathogenesis
The autoimmune origin of polymyositis and
dermatomyositis is supported by their association with
other autoimmune disorders, autoantibodies,60 and
histocompatibility genes; the evidence of T-cell-mediated
myocytotoxicity or complement-mediated microangiopathy; the possible maternal microchimerism in juvenile
forms;61 and their response to immunotherapies.
However, no specific target antigens have been identified,
and the agents initiating self-sensitisation remain
unknown.
Autoantibodies
Autoantibodies against nuclear or cytoplasmic antigens,
directed against ribonucleoproteins involved in protein
synthesis (anti-synthetase) or translational transport
(anti-signal-recognition particle), are found in about 20%
of patients (table 3).60 These antibodies are useful clinical
markers because of their frequent association with
interstital lung disease. The antibody against histidyltRNA synthetase, anti-Jo-1, accounts for 80% of all the
anti-synthetases and seems to confer specificity for
identifying a disease subset that combines myositis, nonerosive arthritis, and Raynaud’s phenomenon. The
importance of these antibodies and their specificity in the
pathogenesis of polymyositis and dermatomyositis
remains unclear because they are not specific for tissue or
disease subset, they occur in less than 25% of patients,
and they do occur in patients with interstitial lung disease
without myositis.62,63 A report that antibodies to signalrecognition particles are markers of aggressive disease
with cardiomyopathy and poor response to therapies64 has
not been confirmed.65 Other autoantibodies include antiMi-2, anti-polymyositis-Scl, found in dermatomyositis
with scleroderma, and anti-KL6 associated with
interstitial lung disease (table 3).
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Autoantibodies associated with myositis*
the complement deposits induce swollen endothelial cells,
vacuolisation, capillary necrosis, perivascular inflammation,
ischaemia, and destruction of muscle fibres.1,2,46,53 The
characteristic perifascicular atrophy (figures 2 and 3)
reflects endofascicular hypoperfusion, which is prominent
distally. Finally, there is striking reduction in the number of
capillaries per muscle fibre with compensatory dilatation of
the lumen of the remaining capillaries.46,53 Cytokines and
chemokines69–72 related to complement activation are
released; they upregulate vascular-cell adhesion molecule
(VCAM-1) and intercellular adhesion molecule (ICAM-1)
on the endothelial cells and facilitate the egress of activated
T cells to the perimysial and endomysial spaces (figure 3).
T cells and macrophages through their integrins (very late
activation antigen 4 and leucocyte-function-associated
antigen 1) bind to the adhesion molecules and pass into the
muscle through the endothelial cell wall. The predominant
lymphocytes are B cells and CD4-positive T cells,
consistent with a humorally mediated process.1,2,49–53,73 Gene
expression profiling in muscles of genetically susceptible
children showed interferon inducible genes implying virusdriven autoimmune dysregulation.74 However, no viruses
have been amplified.
Antigen
Anti-aminoacyl-tRNA synthetases (in 20% of patients)
Anti-Jo-1†
tRNAhis synthetase‡
Anti-PL-7
tRNAthr synthetase
Anti-PL-12
tRNAala synthetase
Anti-EJ
tRNAgly synthetase
Anti-OJ
tRNAile synthetase
Anti-KS
tRNAasp synthetase
Anti-signal recognition particle
<3% of patients
SRP-complex
Other
Anti-Mi-2 (10–15% of dermatomyositis and
polymyositis)
Anti-polymyositis-Scl (15% of dermatomyositis
with scleroderma)
Anti-KL6 (in patients with interstitial lung
disease)
Nuclear helicase
Nuclear complex
Mucin-like glycoprotein
(on alveoli or bronchial
epithelial cells)
SRP=signal recognition particle. *The antibodies are found mostly in
polymyositis and dermatomyositis, and occasionally in inclusion-body myositis,
when the myositis is associated with another connective-tissue disorder.
†Some Jo-1-positive patients with polymyositis or dermatomyositis have the
triad of non-erosive arthritis, interstitial lung disease, and Raynaud’s
phenomenon; 50% of them have interstitial lung disease. ‡7% of these
patients also have antibodies against the cognate tRNAhis.
Table 3: Various autoantibodies associated with polymyositis,
dermatomyositis, and some cases of inclusion-body myositis
Immunopathology of polymyositis
In polymyositis and inclusion-body myositis, CD8positive cells invade MHC-I-antigen expressing muscle
fibres.50–53
Immunopathology of dermatomyositis
The primary antigenic target in dermatomyositis is the
endothelium of the endomysial capillaries (figure 3). The
disease begins when putative antibodies directed against
endothelial cells activate complement C3. Activated C3
leads to formation of C3b, C3bNEO, and C4b fragments
and C5b–9 membranolytic attack complex (MAC), the
lytic component of the complement pathway.49,66,67 MAC,
C3b, and C4b are detected early in the patients’ serum68
and are deposited on capillaries before inflammatory or
structural changes are seen in the muscle.49,66,67 Sequentially,
Antibody
Cytotoxic T cells
T-cell lines established from muscle biopsy material are
cytotoxic to autologous myotubes.75 In vivo, the CD8positive cells send spike-like processes into non-necrotic
muscle fibres, traverse the basal lamina, and focally invade
the muscle cell.73 The autoinvasive cells express the
memory and activation markers CD45RO and ICAM-176
Endothelial cell wall
M␾ Macrophage
B
Complement
B
C3
C3bNEO
Molecular mimicry
tumours, viruses?
C3a
C3b
MAC
MAC
Cytokines
CD4+ LFA-1
ICAM-1
CD4+ VLA-4
VCAM-1
M␾
ICAM-1
Cytokines
CD4+
Mac-1
STAT-1,
Chemokines,
Cathepsin,
TGF␤
M␾
NO
TNF␣
Chemokines
Figure 3: Proposed sequence of immunopathological changes in dermatomyositis
VLA-4=very late activation antigen; LFA-1=leucocyte-function-associated antigen; NO=nitric oxide; TNF␣=tumour necrosis factor ␣; TGF␤=transforming
growth factor ␤. Modified from reference 53.
976
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SEMINAR
Systemic immune
compartment
Antigen
Infection?
M␾
MHC
Costimulation
CD8
TCR
CD8
Integrins
LFA-4
CD8
Clonal expansion
CD8
CD8
CD8
VCAM-1
Chemokines
MMPs
CD8
CD8
Cytokines
IFN-␥ IL-1,2 TNF␣
␣␤
LFA-1 MMP-9
CTLA-4
IFN-␥
CD28
TCR
Antigen
(virus, muscle
peptide)
BB1
-1
MHC
ICAM-1
MMP-9
MMP-2
TNF␣
Perfor
IL-1,2
in
Endoplasmic reticulum
Calnexin
MHC-I
Necrosis
TAP
Figure 4: Molecules, receptors, and ligands involved in transgression of T cells through endothelial cell wall and recognition of
antigens on muscle fibres in polymyositis
Modified from references 55 and 89.
and contain perforin and granzyme granules that are
directed towards the surface of the fibres.77 Thus, the
perforin pathway seems to be the major cytotoxic effector
mechanism. By contrast, the Fas-Fas-L-dependent
apoptotic process is not functionally involved,78 despite
expression of Fas antigen on muscle fibres and Fas-L on
the autoinvasive CD8-positive cells.79–81 The coexpression
of the anti-apoptotic molecules BCL2,79 FLICE (Fasassociated death domain-like interleukin-1-convertingenzyme inhibitory protein [FLIP]),82 and human IAP-like
protein (hILP),83 may confer resistance of muscle to Fasmediated apoptosis (figure 4).
In polymyositis and inclusion-body myositis but not
dermatomyositis, certain CD8-positive cells of specific
T-cell-receptor (TCR) families are clonally expanded
both in the circulation and in muscle.84–89 In individual
patients, the CDR3 region, the antigen-binding region of
the TCR of the autoinvasive CD8-positive cells, has
conserved aminoacid sequences, which suggest that T-cell
expansion is driven by a common antigen, possibly an
autoantigen.85–88 Remarkably, only the autoinvasive
(autoaggressive) T cells are clonally expanded; the noninvasive bystander T cells are clonally diverse.85
In one case, a single clone of ␥/␦ T cells of a single clone
were the primary cytotoxic effectors.90–92 When the ␥/␦
TCR of these cells was transfected into a TCR-deficient
mouse hybridoma cell line,92 the transfectants could be
stimulated with an unknown autoantigen on human
myoblasts.92 This is the first indication that in ␥/␦-T-cell
mediated polymyositis the autoaggressive T cells
recognise muscle antigens.
MHC expression
Muscle fibres do not normally express MHC class I or II
antigens. In polymyositis and inclusion-body myositis,
however, widespread overexpression of MHC class I, and
occasionally MHC II, is seen even in areas remote from
the inflammation.57,58,93 In human myotubes, MHC
molecules are upregulated by interferon ␥.94–96 Although in
transgenic mice MHC-I expression was proposed to act as
an inciting event triggering polymyositis with myositisspecific antibodies,97 the observed histopathology was not
typical of myositis. Furthermore, in human polymyositis
upregulation of MHC-I alone does not trigger T-cell
activation or endomysial infiltration.98 Another MHC
molecule, the non-polymorphic non-classic HLA G, is
upregulated in vitro by interferon ␥ and is expressed on
muscle fibres of patients with polymyositis (and inclusionbody myositis).99 Because HLA G protects human muscle
cells from immune-cell-mediated lysis in vitro, it could
also partially protect muscle fibres in vivo.100
Costimulatory molecules
If the autoinvasive CD8-positive cells are driven by
specific antigens, as the clonally expanded TCR gene
rearrangements indicate,84–88,101 the MHC-I molecule on
the muscle fibres should be able to present antigenic
peptides to the TCR. For primary T-cell antigenic
stimulation a second signal is required and provided by
the B7 family of costimulatory molecules.102,103 Muscle
fibres do not express the classic costimulatory molecules
B7-1 (CD80) or B7-2 (CD86);104 instead, they express a
functional B7-related molecule defined by the monoclonal
antibody BB-1.104 Indeed, the MHC-I/BB1-positive
muscle fibres make direct cell-to-cell contact with their
CD28 or CTLA-4 ligands on the autoinvasive CD8positive cells (figure 4).104,105 The B7-related costimulatory
molecule LICOS (ligand of inducible costimulator) and
the costimulatory molecule CD40 are also upregulated on
muscle fibres.106,107
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977
SEMINAR
Cytokines, cytokine signalling, chemokines, and
metalloproteinases
In the muscles of patients with polymyositis or
dermatomyositis, there is overexpression of the signal
transduction and activation of transducers type I,108
indicating cytokine upregulation. Various cytokines and
their mRNA, including interleukins 1, 2, 6, and 10, tumour
necrosis factor ␣, interferon ␥, and transforming growth
factor
␤,
are
amplified in polymyositis
and
dermatomyositis.69,71,72,109–111 Some of them, such as
interferon ␥ and interleukin 1b, may have a myocytotoxic
effect112–114 whereas others, such as transforming growth
factor ␤, may promote chronic inflammation and fibrosis.115
Muscle-fibre necrosis occurs via the perforin granules
released by the autoaggressive T cells. Death of the muscle
fibre is mediated by a form of necrosis rather than
apoptosis, presumably because of the counterbalancing
effect or protection by the antiapoptotic molecules BCL2,
hILP, and FLIP which are upregulated in polymyositis and
inclusion-body myositis. Fas is also expressed, but it does
not mediate apoptosis in the muscle. The upregulated
NCAM on degenerating muscle fibres may enhance
regeneration. After successful immunotherapy,116 there is
downregulation of cytokines with reduction of
inflammation and fibrosis.116,117 Chemokines, a class of small
cytokines,118 including interleukin 8 (CXCL8), RANTES
(CCL9), MCP-1 (CCL2), Mig CXCL9), and IP-10
(CXCL10) are also overexpressed in the endomysial
inflammatory cells, the extracellular matrix, and the muscle
fibres;72,119–121 they may facilitate trafficking of activated
T cells to the muscle or promote tissue fibrosis. The matrix
metalloproteinases MMP-2 and MMP-9, which promote
the migration of lymphocytes through extracellular matrix,
are also overexpressed on the muscle fibres and the
autoinvasive CD8-positive cells.122,123
Viral infections
Although several viruses (coxsackieviruses, influenza,
parvoviruses, paramyxoviruses, cytomegalovirus, EpsteinBarr virus) and bacteria (Borrelia burgdorferi, streptococci)
have been indirectly associated with chronic and acute
myositis,14,124 sensitive PCR studies have not amplified
viral genome from muscle of these patients.125,126 A
proposed molecular mimicry based on structural
homology between coxsackieviruses and Jo-1 synthethase
has not been proved.124 The best evidence of a viral
connection is with retroviruses. At least six different
retroviruses have been associated with polymyositis and
inclusion-body myositis.124,127–132 Monkeys infected with
simian immunodeficiency virus,127 and human beings
infected with HIV and HTLV-1,128,129 develop
polymyositis either as an isolated clinical entity or
concurrently with other manifestations of AIDS or
HTLV-1 infection.128–133 HIV seroconversion may coincide
with myoglobulinuria and acute myalgia, suggesting that
myotropism for HIV can be symptomatic early in the
infection. The retroviruses are found only in occasional
endomysial macrophages129–133 and do not replicate within
the muscle fibres or cause persistent infection.131–133 In
HIV-1 and HTLV-1 polymyositis, CD8-positive, nonviral-specific, cytotoxic T cells invade MHC-I-antigenexpressing non-necrotic muscle fibres in a pattern
identical to retrovirus-negative polymyositis. Virusinduced cytokines, secreted also in situ by the virusinfected macrophages, could trigger T-cell activation and
MHC upregulation. The relation between systemic
retroviral infection and local autoimmune processes in
muscle is not precisely understood. In principle, there are
two possibilities: either the autoimmune attack is triggered
978
by mimicry between retroviral and muscle antigens, or the
autoimmune process is non-specifically induced via
bystander stimulation.134
Treatment
The goals of therapy are to improve the ability to carry out
activities of daily living by increasing muscle strength and
to ameliorate extramuscular manifestations (rash,
dysphagia, dyspnoea, arthralgia, fever). There have been
very few controlled clinical trials, most on
dermatomyositis and inclusion-body myositis.135 Overall,
dermatomyositis responds better than polymyositis, and
inclusion-body myositis is difficult to treat. Although
when the strength improves, the serum creatine kinase
concentration falls concurrently, the reverse is not always
true because treatments (eg, plasmapheresis) can lower
the serum creatine kinase concentration without
improving strength.1 This effect has been misinterpreted
as “chemical improvement”, and has formed the basis for
the common habit of “chasing” or “treating” the creatine
kinase concentration instead of the muscle weakness.1,6,135
The following agents are used in the treatment of
polymyositis and dermatomyositis.
Corticosteroids
Prednisone is the first-line drug, but its application
remains empirical. We start with 80–100 mg per day for
3–4 weeks, and taper the dose over 10 weeks to alternateday administration. Although most patients respond to
some degree and for some time, others become steroid
resistant and the addition of an immunosuppressive drug
becomes necessary. The decision to initiate such therapy
is based on: the need for a steroid-sparing effect, when
despite steroid responsiveness the patients develop
complications; the inability to lower the high steroid dose
without precipitating a relapse; ineffectiveness of a
2–3-month course of high-dose prednisone; and rapidly
progressive weakness and respiratory failure.1,6,135
Immunosuppressive drugs
Selection of an immunosuppressive drug remains
empirical and depends on personal experience and the
relative efficacy/safety ratio.1,6,135,136 Azathioprine (orally,
2·5–3·0 mg/kg) takes 4–6 months to work. A controlled
trial in 1980 showed benefit of azathioprine.137
Methotrexate (orally, up to 25 mg weekly) acts more
quickly than azathioprine. A rare side-effect is
pneumonitis, which may be difficult to distinguish from
the interstitial lung disease associated with Jo-1
antibodies. Cyclosporin (orally, 100–150 mg twice
daily)138 may also benefit childhood dermatomyositis.139
Mycophenolate mofetil (2 g per day) is emerging as a
promising and well tolerated drug.140 Cyclophosphamide
(0·5–1·0 g/m2) intravenously has shown mixed results;141,142
it may help patients with interstitial lung disease, but the
evidence remains circumstantial.143
Other treatments
Plasmapheresis was not found to be helpful in a doubleblind, placebo-controlled study.144 Total lymphoid
irradiation has helped in a few patients but its long-term
side-effects curtail its use.145 Intravenous immunoglobulin
(2 g/kg) in uncontrolled series was promising.146 In the
first double-blind study conducted for dermatomyositis,
intravenous immunoglobulin was effective not only in
improving muscle strength but also in resolving the
underlying immunopathology, as shown by repeated
muscle biopsies.116 The improvement can be impressive; it
begins after the first infusion but is short lived in most
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SEMINAR
cases, and repeated infusions every 6–8 weeks are
needed.116,147–149 In polymyositis, no controlled studies have
been completed, but intravenous immunoglobulin seems
to be effective in about 70% of patients.
Our approach
The following sequential, step-by-step, empirical
escalating approach has been successful in our patients.
Step 1 is prednisone. Step 2 is azathioprine or
methotrexate (methotrexate acts faster but no
comparative trials are available;150 the choice depends on
personal experience). In aggressive cases, steps 1 and 2
may be combined from the outset. Step 3 is intravenous
immunoglobulin (this may be used as step 2). Step 4 is
cyclosporin, mycophenolate mofetil, chlorambucil, or
cyclophosphamide, used individually or in various
combinations with steps 1–3,150 as dictated by disease
severity, coexisting disorders, or the patient’s age.
Superiority of a specific combination remains unproven.150
Future immunotherapies
Although antigen-specific therapies are not in the offing,
some rational therapeutic approaches are currently being
investigated with agents that: block signal transduction in
T lymphocytes (such as FK506, rapamycin, CAMPATH,
or monoclonal antibodies against costimulatory molecules
CD28/CTLA-4);151–153 are directed against cytokines, such
as monoclonal antibodies against tumour necrosis factor
␣, soluble receptors to tumour necrosis factor ␣, and ␤
interferons; and interfering with integrins and their
receptors.151–153
Prognosis
Although the disease outcome has substantially improved,
at least a third of patients are left with mild to severe
disability.154-156 Older age and association with cancer are
factors associated with poor prognosis. Pulmonary fibrosis,
frequent aspiration pneumonias due to oesophageal
dysfunction, and calcinosis in dermatomyositis are
associated with increased morbidity.154–156 In a small cohort,
the 5-year survival was 95% and the 10-year survival
84%.156
Conclusion
On the basis of our own experience and that of others in
major neuromuscular centres, the diagnosis and
treatment of dermatomyositis and polymyositis could be
improved by modification of many common practices.
First, all disorders that mimic polymyositis should be
excluded, taking into account that the criteria of Bohan
and Peter cannot separate polymyositis from inclusionbody myositis or other toxic, necrotising, and dystrophic
myopathies. Second, polymyositis as a stand-alone entity
is rare. Although no accurate epidemiological data are
available, polymyositis is rare in neuromuscular clinics;
inclusion-body myositis is more common. Third,
endomysial inflammation also occurs in non-immune
myopathies (dystrophies, toxic, metabolic). Fourth,
muscle tested with needle electromyography should not
be sampled by biopsy until a month later. Fifth, in
patients presenting with fatigue and increased activities of
serum aminotransferases or lactate dehydrogenase, the
creatine kinase concentration should be also checked to
exclude myogenic origin of increased “liver enzymes”
and avoid misdirection towards liver disease and liver
biopsy. Sixth, patients with active polymyositis have
muscle weakness; patients presenting with myalgias but
normal strength do not have polymyositis. Seventh, if
primary inflammation (CD8-positive/MHC-I complex) is
not demonstrable, the diagnosis of polymyositis is
doubtful. Eighth, the goal of therapy is to improve
strength; creatine kinase is a good indicator of disease
activity but not the target of therapy. Ninth, when
therapies for presumed polymyositis have lowered the
creatine kinase concentration but not improved strength,
the patient should be reassessed, the muscle biopsy
sample re-examined, and a second biopsy considered to
exclude
inclusion-body
myositis
or
dystrophy.
Finally, when the patient’s strength has improved
but is not fully restored, maintenance therapy with
immunosuppressive drugs or alternate-day prednisone
should be continued.
Conflict of interest statement
None declared.
Acknowledgments
We thank the following for funding our studies for many years: Intramural
Research Program of the National Institute of Neurological Disorders and
Stroke, National Institutes of Health, Bethesda, MD, USA (MCD) and
Max Planck Institute of Neurobiology and Institute for Clinical
Neuroimmunology, Klinikum Grosshadern, Ludwig Maximilians
University, Munich, Germany (RH).
Role of the funding source
The funding sources had no role in the preparation of this paper.
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