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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||
*A dermatomyositis-like disease develops in up to 12% of patients with systemic sclerosis, and polymyositis in 58% of lupus patients; polymyositis is less commonly
seen in patients with Sjgrens 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
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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,16,46 but also the most common
cause of misdiagnosis due to erroneous interpretation.4 In
dermatomyositis, the inflammation is predominantly
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Criterion
Polymyositis
Definite
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.
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
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 Raynauds 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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Antigen
SRP-complex
Other
Anti-Mi-2 (1015% 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)
Immunopathology of polymyositis
In polymyositis and inclusion-body myositis, CD8positive cells invade MHC-I-antigen expressing muscle
fibres.5053
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 C5b9 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
M Macrophage
Complement
B
C3
C3bNEO
Molecular mimicry
tumours, viruses?
C3a
C3b
MAC
MAC
Cytokines
CD4+ LFA-1
ICAM-1
CD4+ VLA-4
VCAM-1
ICAM-1
Cytokines
CD4+
Mac-1
STAT-1,
Chemokines,
Cathepsin,
TGF
M
NO
TNF
Chemokines
976
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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.
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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 80100 mg per day for
34 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
23-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,
2530 mg/kg) takes 46 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, 100150 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
(0510 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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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.154156 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
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).
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