REVIEWS

Pathogenesis, classification and treatment

of inflammatory myopathies
Mei Zong and Ingrid E. Lundberg
Abstract | The inflammatory myopathies—collectively, myositis—are a heterogeneous group of chronic
muscle disorders that differ in response to immunosuppressive treatment. Insufficient knowledge of the
molecular pathways that drive pathogenesis (and underlie the clinical differences between subtypes) has
hindered accurate classification, which in turn has been detrimental for clinical research. Nevertheless, new
insights into pathogenesis are paving the way for improvements in diagnosis, classification and treatment.
Accumulating data suggest that both immune and nonimmune mechanisms cause muscle weakness.
Phenotyping of the T cells that accumulate in muscle tissue has identified proinflammatory, apoptosis
resistant and cytotoxic CD4+ and CD8+ CD28null populations. Several myositis-specific autoantibodies
have been identified, associated with distinct clinical phenotypes. Thus, adaptive immunity is involved
in pathogenesis, and both T and B cells are interesting targets for therapy. Furthermore, genotyping has
revealed activation of the type I interferon pathway in patients with dermatomyositis or with expression of
particular autoantibodies. Decreased release of Ca2+ from the sarcoplasmic reticulum, as a consequence
of release of proinflammatory cytokines and high mobility group protein B1, might contribute to muscle
weakness, and nonimmune mechanisms potentially include a role for endoplasmic reticulum stress,
autophagy and hypoxia. Deeper understanding, careful phenotyping of patients—and new classification
criteria—will expedite clinical research.
Zong, M. & Lundberg, I. E. Nat. Rev. Rheumatol. 7, 297–306 (2011); published online 5 April 2011; doi:10.1038/nrrheum.2011.39

Introduction
The idiopathic inflammatory myopathies (IIM), col­
lectively named myositis, are characterized clinically
by weakness and low endurance of skeletal muscle, and
histo­pathologically by the presence of inflammatory cells
in muscle tissue. On the basis of differences in clinical and
histopathological findings, separate IIM subtypes have
been identified, most often classified into poly­myositis,
dermatomyositis and sporadic inclusion body myo­
sitis (sIBM).1–3 Organs other than muscle are frequently
involved in polymyositis and dermatomyositis, but less
often in sIBM, including skin in dermato­myositis, and
lungs in both polymyositis and dermatomyositis, suggest­
ing that these ‘myopathies’ are actually systemic connective
tissue diseases.
Autoantibodies are frequently present in IIM, particu­
larly in polymyositis and dermatomyositis, and a number
of autoantibodies specific to myositis have recently been
detected, most of them in association with distinct clinical
phenotypes. These findings have raised a need for novel
classification criteria that take account of the newly dis­
covered autoantibodies. Indeed, increasing the mol­ecular
detail used in classification of patient subsets is likely to
improve our understanding of important pathogenic
pathways in IIM, as we discuss in this article.
Competing interests
The authors declare no competing interests.
Pathogenesis
Muscle is the target organ of inflammation in myositis,
and the distinct histopathological features that occur in
muscle tissue indicate that different disease mechanisms
predominate in each IIM subtype. Thus, inflammatory
infiltrates surrounding vessels are preferentially found in
patients with dermatomyositis, and might indicate an auto­
immune reaction directed against blood vessels, whereas
cell infiltrates predominately surround muscle fibers
in patients with polymyositis and sIBM, and, similarly,
might indicate an autoimmune reaction directed against
muscle fibers in these myositis subsets. Histopathological
features are not always distinct, how­ever, and a substantial
proportion of patients have mild or no histopathological
changes despite pronounced symptoms. This observation
has led to the proposal that both immune and nonimmune
mechanisms are involved in causing muscle weakness.4,5
Furthermore, the molecular pathogenesis of sIBM is the
subject of debate, and is suggested to comprise a primary
degenerative disease process accompanied by a secondary Rheumatology Unit,
immune reaction, based on the typical findings of accumu­ Department of
lations of degenerative proteins in muscle tissue in sIBM.6,7 Medicine, Karolinska
University Hospital,
Another histo­pathological feature of some myopathies is Solna, Karolinska
muscle fiber necrosis with few or no inflammatory infil­ Institutet, SE-171 76
Stockholm, Sweden
trates; this disease subset is often named necrotizing myo­ (M. Zong,
pathy, yet involvement of the immune system is suggested I. E. Lundberg)
by the recently detected presence of autoantibodies.8,9
Correspondence to:
Thus, the pathogenic mechanisms that are involved in I. E. Lundberg
clinical myositis are complex. In this Review we discuss ingrid.lundberg@ki.se

NATURE REVIEWS | RHEUMATOLOGY VOLUME 7  |  MAY 2011  |  297

© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ Myositis is a heterogeneous group of chronic inflammatory muscle disorders, the
origins of which are not yet clear and for which efficient treatment is largely lacking
■■ Recent findings suggest that both immune and nonimmune mechanisms are
involved in the pathogenesis of myositis, and that different molecular pathways
might predominate in different subsets of myositis
■■ The immune mechanisms involve immune cells—T cells, B cells, dendritic cells
and macrophages—and their products, such as cytokines and antibodies
■■ Myositis-specific autoantibodies are helpful in the diagnosis of myositis, they
identify different clinical subsets of myositis, and they might be important for
differentiating pathogenic mechanisms between patients with myositis
■■ Among nonimmune pathogenic mechanisms, there seem to be roles for
endoplasmic reticulum stress, hypoxia and autophagy, contributing to the cause
of muscle weakness
■■ New classification criteria are needed to identify more homogenous subsets
of patients, and subsets that are likely to share molecular pathways
■■ Studying the outcomes of targeted therapies will facilitate understanding
of disease mechanisms
the potential roles of both immune and nonimmune
mechanisms in myositis, with a focus on the subtypes that
are most widely accepted to be immune-mediated, poly­
myositis and dermatomyositis. We also discuss the insights
into pathogenesis that might be offered by studying the
clinical and molecular effects of targeted therapies.
Immune mechanisms
The various histopathological patterns of inflamma­
tion that occur in myositis are associated with different
immune cell phenotypes. Thus, endomysial infiltrates—
found predominantly in polymyositis and sIBM—are
mainly composed of CD8+ T cells, CD4+ T cells, dendritic
cells (DCs) and macrophages, whereas the peri­vascular
infiltrates that predominate in dermatomyositis are mainly
composed of CD4+ T cells, DCs, and macro­phages, with
occasional B cells (Figure 1).10–12
T cells in myositis
The precise role of T cells in IIM pathogenesis is still
not clear, but their involvement is supported by genetic
associa­tion in myositis; for example, HLA-DRB1*0301 is
a risk factor for both polymyositis and dermato­myositis,
and an important role of HLA-DR molecules is to present
antigens to CD4+ T cells.13 Similarly, CD8+ T cells are
plentiful in muscle tissue of patients with poly­myositis
and sIBM. These cells express perforin‑1 and granzyme B,
suggesting that they have a myocytotoxic effect, but the
co-stimulatory factors required for such an effect have
not been convincingly demonstrated in myositis muscle
fibers.14 Previous studies have identified clonally restricted
T-cell populations that might be indicative of a patho­
genic process driven or perpetuated by antigens.15 In this
context, the observation that many muscle-­infiltrating
CD4+ and CD8+ T cells in patients with IIM are so-called
CD28null T cells, which lack the activation molecule CD28,
is interesting.16,17 CD28null T cells represent chronically
stimulated, clonally-restricted effector cells that bypass the
co-stimulation by T‑lymphocyte activation antigen CD86
and are instead co-stimulated by other means.18 CD28null
298  |  MAY 2011  |  VOLUME 7  www.nature.com/nrrheum
© 2011 Macmillan Publishers Limited. All rights reserved
T cells have cytotoxic effects similar to natural killer cells;
they are proinflammatory and apoptosis resistant, and
might contribute to the chronicity and treatment resis­
tance seen in myositis. However, whether these cells have
myocytotoxic effects remains to be demonstrated.
Other T-cell subtypes have been found in IIM cell infil­
trates. Type 17 T helper cells, which have a role in the
pathogenesis of several autoimmune diseases, have been
identified in inflamed muscle tissue of patients with poly­
myositis or dermatomyositis.19,20 These cells are a major
source of IL‑17, a proinflammatory cytokine that plays
an important part in rheumatoid arthritis (RA). IL‑17
in combination with IL‑1, another important cytokine in
IIM, can induce expression of MHC class I molecules
and IL‑6 in cultured myoblasts, and might have a role in
disease mechanisms of IIM.21
Another T‑cell subset, FOXP3+ regulatory T (TREG) cells,
has been detected in dermatomyositis, polymyositis and
sIBM, with localization close to other mononuclear cells
surrounding or invading muscle fibers.22 TREG cells are
important regulators of the immune system, and low
numbers or dysfunction of these cells are associated
with several autoimmune disorders. TREG cell numbers in
peripheral blood correlate inversely with the severity of
disease activity in patients with polymyositis or dermato­
myositis.23 On the basis of these observations, therapies
that block T cells seem to be an interesting prospect, but
such blockade will probably require targeting of specific
T‑cell subsets.
B cells in myositis
B cells are present in IIM less often than T cells, and are
preferentially found in perivascular infiltrates in dermato­
myositis, but plasma cells have been detected in all three
subtypes of IIM.24 B cells and plasma cells occasionally
form germinal centers in muscle tissue of patients with
IIM.25 The observation that these intramuscular B cells
and plasma cells have undergone clonal expansion, class-
switch recombination and somatic hypermutation indi­
cates that an antigen-driven B-cell response has occurred,
but the nature of the antigen is not yet clear.26 A role for
B cells in the pathogenesis of polymyositis and dermato­
myositis is supported by favorable responses to the B‑cell-
blocking therapy rituximab, as reported in case studies.27–31
Furthermore, involvement of B cells in the pathogenesis of
all IIM subtypes is indicated by the frequent occurrence
of autoantibodies, as we discuss in the next section.
Dendritic cells and macrophages in myositis
Both immature and mature DCs are present in lympho­
cytic infiltrates of muscle tissue of patients with poly­
myositis or dermatomyositis, where they might serve as
anti­gen presenting cells.32 In addition, plasmacytoid DCs
(pDCs), a main source of type I interferon (IFN), are also
present in muscle tissue of patients with poly­myositis
or dermatomyositis, as well as in the skin of patients
with dermatomyosit­is.33–35 pDCs have occasionally been
observed in muscle tissue of patients with sIBM.33
Infiltrating macrophages are often detected in muscle
tissue from patients with IIM, of all subtypes. They may
 REVIEWS

a b c di
ei
Susceptibility Lymph nodes Circulation
genes
Muscle
fiber

Polymyositis
dii
eii

Environmental Muscle
factors fiber

Dermatomyositis

CD4+ T cell pDC Virus Vessel Perforin and granzyme

CD8+ T cell mDC Bacteria Type I IFN

B cell Macrophage Autoantibody Cytokines

Figure 1 | Potential immune mechanisms in myositis pathogenesis. a | Immune activators, for example, respiratory
infection, trigger disease in myositis susceptibility gene carriers. Other environmental factors might contribute. b | Innate
and adaptive responses are activated in lymph nodes; macrophages secrete cytokines; mDCs present antigens to T cells;
activated T cells assist B-cell activation and proliferation; some B cells differentiate into autoantibody-secreting plasma
cells. c | Activated immune cells enter general circulation. Upon encountering specific antigens, immune cells penetrate
endothelia, into local muscle. di | In polymyositis (and perhaps sIBM), CD8+ T cells expressing perforin-1 and granzyme
invade non-necrotic muscle fibers expressing MHC class I molecules (continuous MHC expression might be induced by
pDC-derived type I IFN); mDCs activate T cells, and macrophage-derived cytokines control T-cell homeostasis, activation
and proliferation. dii | In dermatomyositis, infiltrates—composed of CD4+ T cells, B cells, DCs and macrophages—usually
invade perivascular and perimysial muscle tissue, and might organize into structures resembling lymph node germinal
centers. ei | Immunohistochemistry of muscle tissue from a patient with polymyositis, showing CD8 + T cells localized to
endomysium. eii | Perivascular localization of CD4+ T cells in muscle tissue of a patient with dermatomyositis, revealed by
immunohistochemistry. Abbreviations: IFN, interferon; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; sIBM,
sporadic inclusion body myositis.

act by presenting antigens to T cells, by invading and
clearing up necrotic muscle fibers, and/or most impor­
tantly, they can be a source of a multitude of cytokines
and chemokines.36–39
Autoantibodies in myositis
Myositis-specific autoantibodies (MSAs) are strongly
associated with distinct clinical profiles. The most fre­
quent MSAs are the anti-Jo‑1 autoantibodies, which are
directed against histidyl-tRNA synthetase and are present
in 20–25% of patients with polymyositis or dermato­
myositis. Their levels correlate with disease activity, and
they are associated with a distinct clinical phenotype,
antisynthetase syndrome (Box 1).40,41 Altogether, eight
types of antisynthetase autoantibodies have been iden­
tified (Table 1),42–46 and MSAs directed against other
autoantigens also occur. For example, antibodies to Mi‑2
autoantigens (also known as chromodomain-helicase-
DNA-binding proteins) are preferentially present in
patients with dermatomyositis, and are usually associated
with a good response to treatment. The Mi‑2 auto­antigen
is expressed in regenerating muscle fibers, and might
have a modulatory role during myofiber regeneration.47
Anti-signal recognition particle (SRP) autoantibodies are
associat­ed with necrotizing myopathy (Table 1).
Other MSAs have been identified recently (Table 1).
These include anti‑155/140, which is associated with
juvenile dermatomyositis, and with cancer in adult
dermatomyositis.48 The antigen is not yet known, but
has been suggested to be transcriptional intermedi­
ary factor γ (TIF1γ; also known as E3 ubiquitin-protein
ligase TRIM33).49 The only reliable detection method for
anti‑155/140 is radioactive immunoprecipitation, which
is unsuitable for routine analyses.
Another MSA, anti-CADM‑140, is associated with
a subset of patients with dermatomyositis who have
cutaneous lesions in the absence of muscle weakness, a
presentation known as clinically amyopathic dermato­
myositis (CADM). These autoantibodies have so far only
been reported in Asian patients.50 Patients with anti-
CADM‑140 sometimes develop life-threatening acute
progressive interstitial lung disease (ILD).50 The antigen
has been identified as an RNA helicase called melanoma
differentiation-associated protein 5 (MDA‑5; also known
as interferon-induced helicase C domain-containing
protein 1), and encoded by IFIH1. Finally, a novel auto­
antibody, recognizing 200 kD and 100 kD proteins, has
been detected in patients with necrotizing myopathy who
were previously considered to be auto­antibody negative.8
The MSAs can be helpful in the diagnosis of IIM. The
specific clinical phenotypes associated with the various
MSAs might also indicate that MSAs and/or their anti­
gen targets have a role in the pathogenesis of myo­sitis.
Although histidyl-tRNA synthetase is ubiquitously

NATURE REVIEWS | RHEUMATOLOGY VOLUME 7  |  MAY 2011  |  299

© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 1 | Clinical features of antisynthetase syndrome
Myositis
Polymyositis or dermatomyositis
Polyarthritis
Non-destructive polyarthritis of finger joints, wrists,
elbows or knees
Fever
Present in 80% of patients
Mechanic’s hands
Thick cracked skin over the tips and sides of the fingers
Interstitial lung disease
Present in over 70% of patients
Raynaud phenomenon
Present in 60% of patients
expressed in cells, its expression is highest in organs tar­
geted by antisynthetase syndrome, and in regenerating
muscle fibers.51
A pathogenic role for histidyl-tRNA synthetase is sup­
ported by its effect in C57BL/6 and NOD congenic mice.52
Immunization with the autoantibody is able to induce
myositis, ILD and anti-Jo‑1 antibodies, all features of
human antisynthetase syndrome, in the mice.52 Notably,
the muscle inflammation is independent of T or B cells,
as the NOD congenic mice lack these cell types. This
observed independence suggests that histidyl-tRNA
synthetase can trigger both innate and adaptive immune
responses, and lead to muscle inflammation.53 Further
support for involvement of the anti-Jo‑1 anti­bodies in the
disease mechanisms is provided by the finding that sera
containing anti-Jo‑1 autoantibodies together with nucleic
acid can activate the type I IFN system,33 similar to reports
of the effect of antibodies to the SSA auto­antigen and U1
ribonucleoprotein complex in systemic lupus erythemato­
sus (SLE).54 Sera from patients with myositis positive for
anti-Jo‑1 antibodies have also been shown to induce
increased expression of intercellular adhesion molecule 1
in human lung endothelial cells, in comparison with other
sera, further supporting a potential role for MSAs in the
disease mechanisms of myositis.55
Cytokines in myositis
Cytokines are generated by immune cells, endo­thelial cells
and muscle cells, and can contribute to a pro­inflammatory
environment in the muscle tissue of patients with myo­
sitis. IL‑1, tumor necrosis factor (TNF) and IFNs are the
most frequently found cyto­kines in muscle tissue. Roles
for other cytokines, such as IL‑6, IL‑15 and the alarmin
high mobility group protein B1 (HMGB1), have however,
also been proposed, as we discuss in this section.
Overexpression of IL‑1α and IL‑1β has been demon­
strated in muscle tissue from patients with polymyositis,
dermatomyositis or sIBM.56,57 Similarly, IL‑1 receptors
(IL-1R) have been observed in muscle fibers from patients
with polymyositis or dermatomyositis, and co-localization
between IL‑1R and their respective ligands was noted.56,57
These findings suggest a role for IL‑1 in the pathogenesis
300  |  MAY 2011  |  VOLUME 7  www.nature.com/nrrheum
© 2011 Macmillan Publishers Limited. All rights reserved
of myositis, which is further supported by the beneficial
therapeutic effects of anakinra (a recombinant IL‑1R
antagonist) in patients with myositis, as discussed in
further detail in the section on treatment.
TNF can have a direct impact on muscle function,
although its importance in IIM is not well defined.58 TNF
expression is low in muscle tissue of patients with IIM, and
TNF-blocking therapy has generated inconsistent results
(further discussed in the section on treatment).59 Some
evidence exists of a role for B‑cell-activating factor (BAFF;
also known as TNF ligand superfamily member 13B),
which enhances the survival of immature and mature
B cells, and is involved in autoantibody production as
well as in T‑cell activation and differen­t iation. High
serum levels of BAFF were found in patients with IIM,
particular­ly in patients with anti-Jo‑1 autoantibodies.60
Accumulating evidence suggests a role for type I IFN
in IIM, on the basis of IFN-inducible gene expression in
muscle tissue and peripheral blood, which is particularly
striking in dermatomyositis.34,61 Complexes containing
RNA and anti-Jo‑1, or autoantibodies to the SSA sub­
units Ro52 and Ro60, can act as inducers of endogenous
type I IFN, and activate IFN production in pDCs, similar
to mechanisms reported in SLE.33,54 Thus, patients with
anti-Jo‑1 or anti-Ro52 autoantibodies might share activa­
tion of the type I IFN pathway regardless of whether they
are diag­nosed with polymyositis or dermatomyositis.
IFNs are major inducers of expression of MHC class I and
class II antigens, elevated levels of which are present in
muscle fibers of patients with IIM (Figure 2). Expression of
MHC class I molecules has been observed to correlate with
the presence of pDCs positive for BDCA‑2 (blood den­
dritic cell antigen 2, also known as C‑type lectin domain
family 4 member C) in IIM muscle tissue.33
IL‑6 is a proinflammatory cytokine that is critically
involved in immune responses. Occasional IL‑6+ cells have
been reported in muscle tissue from patients with poly­
myositis or dermatomyositis,57 and cultured muscle fibers
were found to release IL‑6.62 Furthermore, in a myositis
mouse model, clinical outcome was improved by reducing
levels of IL‑6.63
Elevated serum levels of IL‑15, as well as expression of
IL‑15 in muscle tissue, have been reported in patients with
polymyositis or dermatomyositis.64,65 IL‑15 is an important
activator of T cells, and it can downregulate the expres­
sion of CD28 on T-cell membranes, producing CD28null
T cells—identified as a dominant T‑cell pheno­type in
muscle tissue of patients with myositis.16,17,66 These obser­
vations have raised an interest in the pathogenic role of
IL‑15 in IIM. Importantly, IL‑15 is also involved in muscle
fiber regeneration, in a mechanism yet to be elucidated.67
HMGB1 is a DNA binding protein that is regarded
as an alarmin, as it is released into the extranuclear and
extra­cellular spaces when cells are subjected to various
types of stress, such as hypoxia. Implicated in the patho­
genesis of rheumatic diseases,68 HMGB1 expression has
been identified in synovial tissue of patients with RA,
and in joints of arthritis mouse models, where HMGB1-
neutralizing therapy can attenuate joint inflammation and
damage.69,70 Expression of HMGB1 has also been observed
 REVIEWS

Table 1 | Myositis-specific autoantibodies

Autoantibody name Antigen Clinical association Frequency in IIM
Antibodies to aminoacyl-tRNA synthetases
Anti-Jo‑1 Histidyl-tRNA synthetase Antisynthetase syndrome 20–25%
Anti-PL‑7 Threonyl-tRNA synthetase Antisynthetase syndrome 5–10%
Anti-PL‑12 Alanyl-tRNA synthetase Antisynthetase syndrome <5%
Anti-Ej Glycyl-tRNA synthetase Antisynthetase syndrome 5–10%
Anti-OJ Isoleucyl-tRNA synthetase Antisynthetase syndrome <5%
Anti-KS Asparaginyl-tRNA synthetase Antisynthetase syndrome Rare
Anti-Ha Tyrosyl-tRNA synthetase Antisynthetase syndrome One patient
Anti-Zo Phenylalanyl-tRNA synthetase Antisynthetase syndrome One patient
Other myositis-specific autoantibodies
Anti‑P155/140 TIF1γ (putative) Juvenile dermatomyositis, 13–30%
cancer in adult dermatomyositis
Anti-CADM‑140 MDA‑5 CADM 50% of CADM
Anti-Mi‑2 Mi‑2α and Mi‑2β Dermatomyositis 8% of IIM generally, 15–20% of
dermatomyositis
Anti-SRP SRP Necrotizing myopathy 4–6% of IIM
Anti‑200/100 200 kD and 100 kD proteins Necrotizing myopathy 60% of necrotizing myopathy
Abbreviations: CADM, clinically amyopathic dermatomyositis; IIM, idiopathic inflammatory myopathies; Mi‑2, Mi‑2 autoantigens; MDA‑5, melanoma
differentiation-associated protein 5; SRP, signal recognition particle; TIF1γ, transcriptional intermediary factor γ.

in inflammatory infiltrating cells, endothelial cells and

muscle fibers of patients with polymyositis or dermato­
myositis.71 Furthermore, HMGB1 can induce reversible
upregulation of MHC class I molecules in differentiated,
healthy muscle fibers, and an irreversible decrease in Ca2+
release from the sarcoplasmic reticulum during induction
*
of fatigue in intact single fibers.72 These data indicate that
HMGB1 might be involved in the mechanisms of muscle
weakness in IIM. Moreover, HMGB1 might be impor­
tant in the initiation phase of myositis, as its extranuclear * *
expression occurs in endothelial cells and muscle fibers
of patients with early myositis without detectable inflam­
matory infiltrates in muscle.71 Further work is required,
however, to determine the role of HMGB1 in IIM, as well
as to understand its effects on calcium homeostasis in
skeletal muscle.
Figure 2 | Localization of MHC class I antigens in muscle
Nonimmune mechanisms tissue of a patient with myositis. Note the MHC class I
expression (brown staining) both on the membrane (arrow)
The potential involvement of nonimmune mechanisms
and in the cytoplasm (stars) of muscle fibers, as revealed by
in the pathogenesis of myositis is increasingly recognized. immunohistochemistry. Inset in upper right corner shows a
Such mechanisms include hypoxia, endoplasmic reticulum negative control stain using an isotype control from the same
(ER) stress and autophagy, all of which we discuss here. species as the antibody to MHC class I, in the same patient.
Although we consider these three aspects separately, they
are actually closely interlinked (Figure 3); for example, All of these findings have suggested a role for hypoxia in
hypoxia might induce ER stress, as discussed below. the pathogenesis of myositis. Further support is provided
by the low percentage of type I, oxygen-dependent, muscle
Hypoxia fibers in patients with chronic polymyositis or dermato­
Why consider hypoxia in myositis? The question was raised myositis, together with improved muscle endurance and
by several observations: firstly, substantial muscle weak­ an increased percentage of type I fibers after a 12‑week
ness can occur despite little or no apparent muscle inflam­ submaximal home exercise program.78 Moreover, after a
mation;73 secondly, capillaries are lost in IIM tissues;74–75 7‑week intensive resistance training program, the levels of
and finally, overexpression of hypoxia-inducible factor 1‑α 265 gene transcripts were substantially modified in muscle
(HIF‑1-α) and its downstream gene products, vascular tissue of patients with myositis, and seven of them showed
endothelial growth factor and erythro­poietin, and their a shift towards altered expression of enzymes involved
receptors, are all detectable in muscle tissues in IIM.76,77 with oxidative metabolism.79

NATURE REVIEWS | RHEUMATOLOGY VOLUME 7  |  MAY 2011  |  301

© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Myositis
HMGB1 or other MHC-1 Muscle fatigue
proinflammatory cytokines
Hypoxia ER stress Muscle apoptosis
and/or impaired autophagy
Disturbed microcirculation, Continuous expression Accumulation of
trauma, infections, aging of cytokines abnormal proteins
and/or proteins
Figure 3 | Potential nonimmune mechanisms in myositis pathogenesis. It is
thought that nonimmune mechanisms might affect the performance of muscle
fibers and weaken muscle in the absence of inflammatory cell infiltrates. Hypoxia,
potentially induced by capillary loss, can induce expression and extracellular
release of HMGB1 in endothelial cells and muscle fibers. HMGB1 might induce
expression of MHC class I molecules, which in turn might cause ER stress, which
can lead to expression of NFκB and perpetuation of inflammation. MHC class I
molecules might also reduce Ca2+ release from the sarcoplasmic reticulum,
inducing muscle fatigue. Substantial accumulation of abnormal proteins in
muscle fibers might induce ER stress and/or autophagy. If these unwanted
proteins cannot be cleared in an appropriate period then muscle apoptosis or
autophagic cell death will occur, contributing to muscle fatigue. Abbreviations:
ER, endoplasmic reticulum; HMGB1, high mobility group protein B1; NFκB,
nuclear factor κB.
Hypoxia might induce muscle weakness by a number
of pathways. It can cause metabolic alterations in muscle,
such as reduced levels of ATP and phosphocreatine, both
of which have been reported in muscle tissue of patients
with polymyositis or dermatomyositis.80 It might also
induce production of proinflammatory cytokines and
adhesion molecules, such as IL‑1α, IL‑1β and transform­
ing growth factor β, in muscle tissue. Colocalization of
HMGB1 and hypoxia can be observed in the lesions
of mice with collagen-induced arthritis, and hypoxia-
induced extracellular release of HMGB1 occurs in vitro.81
As HMGB1 can induce muscle fatigue, and is expressed
in muscle fibers of patients with myositis without muscle
inflammation,71,72 hypoxia might induce translocation of
HMGB1 from nuclei to cytoplasm of muscle fibers, and
thereby affect the fiber contractility; this hypothesis is
worth investigating further.
ER stress
ER stress is generated when unfolded or misfolded pro­
teins accumulate within the organelle. Such accumula­
tion elicits the unfolded protein response (UPR) and
the ER overload response (nuclear factor κB [NFκB]
pathway). The UPR has two primary functions: halting
protein translation through the PERK (pancreatic eIF2‑α
kinase, also known as eukaryotic translation initiation
factor 2‑α kinase 3) pathway, and activating signaling
pathways that lead to the production of molecular chap­
erones involved in protein folding (through the serine/
threonine-protein kinase/endoribonuclease IRE1 and
302  |  MAY 2011  |  VOLUME 7  www.nature.com/nrrheum
© 2011 Macmillan Publishers Limited. All rights reserved
cyclic AMP-dependent transcription factor ATF6α
pathways). 82,83 Failure of these mechanisms leads to
cell apoptosis.
In skeletal muscle, several proteins that bind and/or
regulate calcium exist in the sarcoplasmic reticulum (SR),
a specialized form of ER. These proteins have central roles
in muscle calcium homeostasis, and improper modifica­
tions of these proteins resulting from stress will definitely
disrupt muscle functions. Thus, skeletal muscle is more
sensitive to, and more easily affected by, ER stress than
other tissue types. Upregulation of the UPR and NFκB
pathways has been observed in muscle tissue from
patients with IIM.5 Expression of E3 ubiquitin-protein
ligase RNF5, an ER-associated protein involved in the
recognition and processing of misfolded proteins, was
elevated in patients with sIBM.84
A potential inducer of ER stress in myositis is the
upregula­tion of MHC class I that occurs in muscle fibers.4,5
Normally, MHC class I expression is down­regulated when
muscle fibers undergo differentiation from myoblasts to
myotubes, and its level should remain low in differen­tiated
myofibers, but it is overexpressed in myofibers of 75% of
patients with myositis.85 Furthermore, the UPR and NFκB
pathways are upregulated in a transgenic mouse model
of myositis, with upregulation of MHC class I molecules
in the muscle fibers occurring to a similar degree to that
observed in patients with myositis. 86 Other possible
in­ducers of ER stress in myositis include viral infection and
hypoxia. ER stress can result in NFκB activation, which
promotes transcription of cytokine genes and induces a
self-sustaining inflammatory response—this process can
further contribute to muscle damage.5 Finally, ER stress
might contribute to muscle dysfunction by inducing
muscle fiber apoptosis or autophagic cell death.87
Autophagy
Autophagy removes unwanted or damaged proteins from
cells; during this process, autophagosomes form to carry
proteins destined for degradation to the lysosomes. If this
autophagosomal–lysosomal system cannot work nor­
mally, autophagic cell death will take place.88 Involvement
of autophagy in myositis was proposed after the obser­
vation that muscle fiber death happens despite over­
expression of anti-apoptotic molecules in patients with
myositis.89 Autophagy seems to be particularly rele­vant for
sIBM, as abnormal intracellular accumulation of multi­
protein inclusions in muscle fibers is a typical feature of
sIBM muscle. The origin and formation of these protein
inclusions are not well understood, but if they cannot be
cleared within a proper period, they might become a detri­
mental factor and influence normal muscle function. In
support of this hypothesis is the finding that accumula­
tion of amyloid causes a reduction in muscular peak force
and lower calcium peak amplitude in mouse models of
sIBM.90 Moreover, autophagy-related protein LC3 B was
found in muscle fibers of patients with sIBM, but not in
muscle biopsy samples of patients with polymyositis.91
Disturbance of the autophagosomal–lysosomal system
in sIBM was further supported by the observation of
decreased lysosomal proteolytic activity in muscle tissue

of patients with the disease. Interestingly, ER stress might
induce lysosomal dysfunction in sIBM.92
Classification
Currently, the most used classification criteria for IIM
(known as the Bohan and Peter 93 and Tanimoto94 crit­eria)
are based on clinical, histopathological and neuro­physio­
logical findings, in combination with elevated serum levels
of muscle enzymes, but they do not incorpo­rate more
recent mechanistic data that might help to distin­guish
subsets of patients with myositis in a clinically meaning­
ful fashion.93,94 In a more recent set of criteria, published
in 2004,95 MSAs and MRI of muscle tissues were included.
Each of these criteria sets has limitations, how­ever; for
example, in the Bohan and Peter criteria the muscle
biopsy criterion is not specified in detail, and does not
exclude other forms of myopathy such as muscular dys­
trophy. Furthermore, the Bohan and Peter criteria, which,
with a publication date of 1975,93 are the oldest, might
also misclassify patients with sIBM as having polymyo­
sitis, because sIBM had not been described when these
criteria were devised. Indeed, several discoveries that have
occurred since the 1980s could affect the methods used to
subtype myo­sitis, including assays for the MSAs discussed
above and listed in Table 1, immunohistochemical charac­
terization of muscle biopsies—including expression of
MHC class I molecules in muscle fibers—and sub­typing
of invading inflammatory cells.1,96,97 Similarly, MRI can
be used to visualize muscle inflammation and might be
helpful in the classification of IIM. To solve the unmet
need for updated and validated classification cri­teria,
an inter­national, multidisciplinary, data-driven project
is ongoing, within the framework of the International
Myositis Assessment and Clinical Research (IMACS)
program,98 within the National Institute of Environmental
Health Sciences of the USA.
Treatment
Current practice
As we lack thorough understanding of the disease mecha­
nisms that underlie myositis, traditional therapies are
largely nonspecific, and are associated with the risks of
generalized immunosuppression. There have only been
a few controlled trials in polymyositis and dermato­
myositis, and treatment recommendations are therefore
based mostly on clinical experience and open-label trials,
as has been recently summarized.99 The introduction of
glucocorticoids in the 1950s had a major impact on mor­
bidity and mortality, and these drugs still form the basis of
treatment. High doses of glucocorticoids, 0.75–1.00 mg/kg
per day, are often required for several weeks. Many
patients respond with improved function, but few recover
their former physical performance, and side effects are
common. Many experts therefore recom­mend combina­
tion therapy with another immuno­suppressive agent to
improve response and reduce the need for steroids. The
most frequently used first-line agents are methotrexate
at 15–25 mg/week or azathioprine at 2 mg/kg per day. If
these drugs are not tolerated, or have insufficient effect,
the most frequently recommended second-line agents
NATURE REVIEWS | RHEUMATOLOGY VOLUME 7  |  MAY 2011  |  303
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
are cyclosporin A, which has been found to be as effec­
tive as methotrexate,100 or mycophenylate mofetil, use of
which is supported by case reports.101–103 One of the few
placebo-controlled trials to report beneficial outcomes
in treatment-resistant dermatomyositis used high-dose
intravenous immunoglobulin in combination with con­
ventional immunosuppressive agents for 3 months.104
How­ever, an open-label study that included treatment-
resistant dermato­myositis, polymyositis and sIBM
could not confirm this effect in any of the three myositis
subsets, in terms either of clinical outcome measures or of
in­flammatory changes in muscle tissue.
A particular therapeutic challenge is presented by
patients with myositis and ILD, who have high morbidity
and mortality. In this patient subset there are even fewer
evidence-based treatment recommendations than for
myositis generally. Several case reports suggest a bene­
ficial effect of cyclophosphamide or tacrolimus on ILD.
An effect of tacrolimus on both pulmonary and muscular
function was suggested from an open-label retrospective
study of patients with antisynthetase syndrome,106 but this
observation needs to be followed up by a controlled trial.
Future prospects
The new biologic agents that are in use or under develop­
ment for the treatment of rheumatic diseases permit
targeted therapy, and are thereby helpful for elucidating
key molecular pathways, as has been the case for TNF
bloc­kade in RA. Nevertheless, extensive experience of
treatment with targeted therapies using biologic agents is
lacking in myositis.
The B‑cell-targeting agent rituximab is the biologic
therapy for which most beneficial reports exist, provid­
ing support for a role for B cells in at least a subset of
patients with polymyositis or dermatomyositis.28–31,107 An
international multicenter trial of rituximab in myositis
has recently concluded, but no data have been reported
to date.
Beneficial effects of IL‑1 blockade with another bio­
logic agent, anakinra, were reported in one patient with
myo­sitis with anti-Jo‑1 autoantibodies.108 Further­more,
in a pilot study that included 15 patients with refractory
myositis treated with anakinra, clinical outcome was
improved in half of the patients,109 but these observations
need to be confirmed in a controlled trial. The results of
TNF bloc­kade in myositis are conflicting. In one open-
label study of infliximab treatment, some patients experi­
enced disease flares, and induction of type I IFN activity
was recorded. These data argue against a key role for
TNF in chronic, treatment-resistant cases.110 In sIBM, the
effects of pharmacological treatment have been limited,
and to date there is no evidence to suggest any benefit of
im­munosuppressive treatment in sIBM.
Thus, there is a clear need for new therapies, not only
for sIBM but also for polymyositis and dermatomyositis.
Successful development of such therapies will be depen­
dent on improved knowledge of the molecular pathways
that operate in these diseases. Current therapies are
directed against immune-mediated muscle dysfunction,
but newer therapies will need to incorporate advances
REVIEWS

in understanding of nonimmune mechanisms (such as
ER stress and dysfunctional autophagy). In this context,
recent data on the beneficial effects of adding physical
exercise to conventional immunosuppressive treatment
are encouraging.111–113 In a pilot study, resistance exercise
led to improved clinical performance, and the expres­
sion of genes involved in inflammation and fibrosis was
reduced in muscle tissue.79 This observation might indi­
cate that exercise in established polymyositis or dermato­
myositis has a beneficial effect on molecular expression in
the target organ of myositis, but it requires replication
in larger studies.
Conclusion
In summary, recent advances suggest that different
molecu­lar pathways predominate in different subsets of
myositis, and that targeted therapies consequently vary
in efficacy among patients with IIM. Our knowledge of
disease mechanisms needs to improve, which will allow
us to develop validated classification criteria and reliable
prognostic biomarkers. One promising way to subtype
patients with IIM is autoantibody profiling, but this
approach needs to be tested in future trials. Studying the
outcomes of targeted therapies will facilitate understand­
ing of disease mechanisms and improvement in classifi­
cation criteria, which will, in turn, increase our ability to
provide patients with properly targeted therapy.
Review criteria
This Review was predominately based on articles
published in the past 3–5 years, and found in PubMed
using the search terms “myositis AND (pathogenesis OR
classification OR treatment)”, “myositis AND immune
cells”, “myositis AND (T cell OR B cell OR macrophage OR
dendritic cell)”, “myositis AND autoantibody”, “myositis
AND (cytokines OR chemokines)”, “myositis AND (HMGB1
OR IL‑6 OR IL‑15 OR BAFF)”, “myositis AND hypoxia”,
“myositis AND (ER OR endoplasmic reticulum)”, “myositis
AND autophagy”. Older publications found using “myositis
AND (pathogenesis OR classification OR treatment)” were
included. Some additional papers were selected from
reference lists of papers identified in PubMed.

1. Dalakas, M. C. Polymyositis, dermatomyositis
and inclusion-body myositis. N. Engl. J. Med. 325,
1487–1498 (1991).
2. Dalakas, M. C. & Hohlfeld, R. Polymyositis and
dermatomyositis. Lancet 362, 971–982 (2003).
3. Plotz, P. H. et al. Current concepts in the
idiopathic inflammatory myopathies:
polymyositis, dermatomyositis, and related
disorders. Ann. Intern. Med. 111, 143–157
(1989).
4. Li, C. K. et al. Overexpression of MHC class I
heavy chain protein in young skeletal muscle
leads to severe myositis: implications for
juvenile myositis. Am. J. Pathol. 175, 1030–1040
(2009).
5. Nagaraju, K. et al. Activation of the endoplasmic
reticulum stress response in autoimmune
myositis: potential role in muscle fiber damage
and dysfunction. Arthritis Rheum. 52,
1824–1835 (2005).
6. Askanas, V. & Engel, W. K. Inclusion-body
myositis: a myodegenerative conformational
disorder associated with Aβ, protein misfolding,
and proteasome inhibition. Neurology 66,
S39–S48 (2006).
7. Greenberg, S. A. How citation distortions create
unfounded authority: analysis of a citation
network. BMJ 339, b2680 (2009).
8. Christopher-Stine, L. et al. A novel autoantibody
recognizing 200‑kd and 100‑kd proteins is
associated with an immune-mediated necrotizing
myopathy. Arthritis Rheum. 62, 2757–2766
(2010).
9. Hengstman, G. J. et al. Anti-signal recognition
particle autoantibodies: marker of a necrotising
myopathy. Ann. Rheum. Dis. 65, 1635–1638
(2006).
10. de Padilla, C. M. & Reed, A. M. Dendritic cells
and the immunopathogenesis of idiopathic
inflammatory myopathies. Curr. Opin. Rheumatol.
20, 669–674 (2008).
11. Reed, A. M. & Ernste, F. The inflammatory milieu
in idiopathic inflammatory myositis. Curr.
Rheumatol. Rep. 11, 295–301 (2009).
12. Szodoray, P. et al. Idiopathic inflammatory
myopathies, signified by distinctive peripheral
cytokines, chemokines and the TNF family
members B‑cell activating factor and a
proliferation inducing ligand. Rheumatology
(Oxford) 49, 1867–1877 (2010).
13. Englund, P., Lindroos, E., Nennesmo, I.,
Klareskog, L. & Lundberg, I. E. Skeletal muscle
fibers express major histocompatibility complex
class II antigens independently of inflammatory
infiltrates in inflammatory myopathies. Am. J.
Pathol. 159, 1263–1273 (2001).
14. Behrens, L. et al. Human muscle cells express a
functional costimulatory molecule distinct from
B7.1 (CD80) and B7.2 (CD86) in vitro and in
inflammatory lesions. J. Immunol. 161,
5943–5951 (1998).
15. Hofbauer, M. et al. Clonal tracking of
autoaggressive T cells in polymyositis by
combining laser microdissection, single-cell PCR,
and CDR3-spectratype analysis. Proc. Natl Acad.
Sci. USA 100, 4090–4095 (2003).
16. Fasth, A. E. et al. T cell infiltrates in the muscles
of patients with dermatomyositis and
polymyositis are dominated by CD28null T cells.
J. Immunol. 183, 4792–4799 (2009).
17. Pandya, J. M. et al. Expanded TCR-Vβ restricted
T cells from sporadic inclusion body myositis
patients are proinflammatory and cytotoxic
CD28(null) T cells. Arthritis Rheum. 62,
3457–3466 (2010).
18. Fasth, A. E., Bjorkstrom, N. K., Anthoni, M.,
Malmberg, K. J. & Malmstrom, V. Activating
NK‑cell receptors co-stimulate CD4(+)CD28(–)
T cells in patients with rheumatoid arthritis. Eur.
J. Immunol. 40, 378–387 (2010).
19. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K.
Induction and effector functions of T(H)17 cells.
Nature 453, 1051–1057 (2008).
20. Page, G. et al. Plasma cell-like morphology of
Th1‑cytokine‑producing cells associated with the
loss of CD3 expression. Am. J. Pathol. 164,
409–417 (2004).
21. Chevrel, G. et al. Interleukin‑17 increases the
effects of IL‑1β on muscle cells: arguments for
the role of T cells in the pathogenesis of
myositis. J. Neuroimmunol. 137, 125–133
(2003).
22. Waschbisch, A., Schwab, N., Ruck, T.,
Stenner, M. P. & Wiendl, H. FOXP3+ T regulatory
cells in idiopathic inflammatory myopathies.
J. Neuroimmunol. 225, 137–142 (2010).
23. Banica, L. et al. Quantification and molecular
characterization of regulatory T cells in
connective tissue diseases. Autoimmunity 42,
41–49 (2009).
24. Greenberg, S. A. et al. Plasma cells in muscle in
inclusion body myositis and polymyositis.
Neurology 65, 1782–1787 (2005).
25. De Bleecker, J. L., Engel, A. G. & Butcher, E. C.
Peripheral lymphoid tissue-like adhesion
molecule expression in nodular infiltrates in
inflammatory myopathies. Neuromuscul. Disord.
6, 255–260 (1996).
26. Bradshaw, E. M. et al. A local antigen-driven
humoral response is present in the inflammatory
myopathies. J. Immunol. 178, 547–556 (2007).
27. Levine, T. D. Rituximab in the treatment of
dermatomyositis: an open-label pilot study.
Arthritis Rheum. 52, 601–607 (2005).
28. Majmudar, S., Hall, H. A. & Zimmermann, B.
Treatment of adult inflammatory myositis with
rituximab: an emerging therapy for refractory
patients. J. Clin. Rheumatol. 15, 338–340
(2009).
29. Rios Fernandez, R., Callejas Rubio, J. L.,
Sanchez Cano, D., Saez Moreno, J. A. &
Ortego Centeno, N. Rituximab in the treatment
of dermatomyositis and other inflammatory
myopathies. A report of 4 cases and review of
the literature. Clin. Exp. Rheumatol. 27,
1009–1016 (2009).
30. Tournadre, A. et al. Polymyositis and pemphigus
vulgaris in a patient: successful treatment with
rituximab. Joint Bone Spine 75, 728–729
(2008).
31. Vandenbroucke, E. et al. Rituximab in life
threatening antisynthetase syndrome.
Rheumatol. Int. 29, 1499–1502 (2009).
32. Page, G., Chevrel, G. & Miossec, P. Anatomic
localization of immature and mature dendritic
cell subsets in dermatomyositis and
polymyositis: interaction with chemokines and
Th1 cytokine-producing cells. Arthritis Rheum.
50, 199–208 (2004).
33. Eloranta, M. L. et al. A possible mechanism for
endogenous activation of the type I interferon
system in myositis patients with anti‑Jo‑1 or
anti-Ro 52/anti-Ro 60 autoantibodies. Arthritis
Rheum. 56, 3112–3124 (2007).

304  |  MAY 2011  |  VOLUME 7  www.nature.com/nrrheum

© 2011 Macmillan Publishers Limited. All rights reserved

34. Greenberg, S. A. et al. Interferon α/β-mediated
innate immune mechanisms in dermatomyositis.
Ann. Neurol. 57, 664–678 (2005).
35. McNiff, J. M. & Kaplan, D. H. Plasmacytoid
dendritic cells are present in cutaneous
dermatomyositis lesions in a pattern distinct
from lupus erythematosus. J. Cutan. Pathol. 35,
452–456 (2008).
36. Civatte, M. et al. Expression of the β chemokines
CCL3, CCL4, CCL5 and their receptors in
idiopathic inflammatory myopathies.
Neuropathol. Appl. Neurobiol. 31, 70–79 (2005).
37. Confalonieri, P. et al. Increased expression of
β-chemokines in muscle of patients with
inflammatory myopathies. J. Neuropathol. Exp.
Neurol. 59, 164–169 (2000).
38. De Paepe, B. & De Bleecker, J. L. β-Chemokine
receptor expression in idiopathic inflammatory
myopathies. Muscle Nerve 31, 621–627 (2005).
39. Rostasy, K. M. et al. Monocyte/macrophage
differentiation in dermatomyositis and
polymyositis. Muscle Nerve 30, 225–230 (2004).
40. Stone, K. B. et al. Anti‑Jo‑1 antibody levels
correlate with disease activity in idiopathic
inflammatory myopathy. Arthritis Rheum. 56,
3125–3131 (2007).
41. Brouwer, R. et al. Autoantibody profiles in the
sera of European patients with myositis. Ann.
Rheum. Dis. 60, 116–123 (2001).
42. Mahouachi, R. et al. Antisynthetase syndrome
[French]. Tunis Med. 86, 195–196 (2008).
43. Jordan Greco, A. S., Métrailler, J. C. & Dayer, E.
The antisynthetase syndrome: a cause of
rapidly progressive interstitial lung disease.
Rev. Med. Suisse 3, 2675–2676, 2679–2681
(2007).
44. Gomard-Mennesson, E. et al. Clinical
significance of anti‑histidyl‑tRNA synthetase
(Jo1) autoantibodies. Ann. NY Acad. Sci. 1109,
414–420 (2007).
45. Genth, E. Inflammatory muscle diseases:
dermatomyositis, polymyositis, and inclusion
body myositis [German]. Internist (Berl.) 46,
1218–1232 (2005).
46. Legout, L. et al. The antisynthetase syndrome:
a subgroup of inflammatory myopathies not to
be unrecognized [French]. Rev. Med. Interne 23,
273–282 (2002).
47. Mammen, A. L. et al. Expression of the
dermatomyositis autoantigen Mi‑2 in
regenerating muscle. Arthritis Rheum. 60,
3784–3793 (2009).
48. Kaji, K. et al. Identification of a novel autoantibody
reactive with 155 and 140 kDa nuclear proteins in
patients with dermatomyositis: an association
with malignancy. Rheumatology (Oxford) 46,
25–28 (2007).
49. Targoff, I. N. et al. A novel autoantibody to a
155‑kd protein is associated with
dermatomyositis. Arthritis Rheum. 54,
3682–3689 (2006).
50. Sato, S. et al. RNA helicase encoded by
melanoma differentiation-associated gene 5 is
a major autoantigen in patients with clinically
amyopathic dermatomyositis: association with
rapidly progressive interstitial lung disease.
Arthritis Rheum. 60, 2193–2200 (2009).
51. Levine, S. M. et al. Novel conformation of
histidyl-transfer RNA synthetase in the lung:
the target tissue in Jo‑1 autoantibody-associated
myositis. Arthritis Rheum. 56, 2729–2739
(2007).
52. Soejima, M. et al. Role of innate immunity in a
model of histidyl-tRNA synthetase (Jo‑1)-
mediated myositis. Arthritis Rheum. (2010).
53. Katsumata, Y. et al. Species-specific immune
responses generated by histidyl-tRNA
synthetase immunization are associated with
NATURE REVIEWS | RHEUMATOLOGY VOLUME 7  |  MAY 2011  |  305
muscle and lung inflammation. J. Autoimmun.
29, 174–186 (2007).
54. Lovgren, T. et al. Induction of interferon-α by
immune complexes or liposomes containing
systemic lupus erythematosus autoantigen- and
Sjögren’s syndrome autoantigen-associated
RNA. Arthritis Rheum. 54, 1917–1927 (2006).
55. Barbasso Helmers, S. et al. Sera from anti‑Jo‑1-
positive patients with polymyositis and
interstitial lung disease induce expression of
intercellular adhesion molecule 1 in human lung
endothelial cells. Arthritis Rheum. 60,
2524–2530 (2009).
56. Grundtman, C. et al. Immunolocalization of
interleukin‑1 receptors in the sarcolemma and
nuclei of skeletal muscle in patients with
idiopathic inflammatory myopathies. Arthritis
Rheum. 56, 674–687 (2007).
57. Lundberg, I., Ulfgren, A. K., Nyberg, P.,
Andersson, U. & Klareskog, L. Cytokine
production in muscle tissue of patients with
idiopathic inflammatory myopathies. Arthritis
Rheum. 40, 865–874 (1997).
58. St. Pierre, B. A., Kasper, C. E. & Lindsey, A. M.
Fatigue mechanisms in patients with cancer:
effects of tumor necrosis factor and exercise on
skeletal muscle. Oncol. Nurs. Forum 19,
419–425 (1992).
59. Tateyama, M. et al. Expression of tumor necrosis
factor-α in muscles of polymyositis. J. Neurol. Sci.
146, 45–51 (1997).
60. Krystufkova, O. et al. Increased serum levels of
B cell activating factor (BAFF) in subsets of
patients with idiopathic inflammatory
myopathies. Ann. Rheum. Dis. 68, 836–843
(2009).
61. Walsh, R. J. et al. Type I interferon-inducible gene
expression in blood is present and reflects
disease activity in dermatomyositis and
polymyositis. Arthritis Rheum. 56, 3784–3792
(2007).
62. Serrano, A. L., Baeza-Raja, B., Perdiguero, E.,
Jardi, M. & Munoz-Canoves, P. Interleukin‑6 is an
essential regulator of satellite cell-mediated
skeletal muscle hypertrophy. Cell. Metab. 7,
33–44 (2008).
63. Scuderi, F., Mannella, F., Marino, M.,
Provenzano, C. & Bartoccioni, E. IL‑6‑deficient
mice show impaired inflammatory response in a
model of myosin-induced experimental myositis.
J. Neuroimmunol 176, 9–15 (2006).
64. Sugiura, T. et al. Increased IL‑15 production of
muscle cells in polymyositis and
dermatomyositis. Int. Immunol. 14, 917–924
(2002).
65. Suzuki, J. et al. Serum levels of interleukin 15 in
patients with rheumatic diseases. J. Rheumatol.
28, 2389–2391 (2001).
66. Chiu, W. K., Fann, M. & Weng, N. P. Generation
and growth of CD28nullCD8+ memory T cells
mediated by IL‑15 and its induced cytokines.
J. Immunol. 177, 7802–7810 (2006).
67. Furmanczyk, P. S. & Quinn, L. S. Interleukin‑15
increases myosin accretion in human skeletal
myogenic cultures. Cell Biol. Int. 27, 845–851
(2003).
68. Andersson, U. & Harris, H. E. The role of HMGB1
in the pathogenesis of rheumatic disease.
Biochim. Biophys. Acta 1799, 141–148 (2010).
69. Kokkola, R. et al. Successful treatment of
collagen-induced arthritis in mice and rats by
targeting extracellular high mobility group box
chromosomal protein 1 activity. Arthritis Rheum.
48, 2052–2058 (2003).
70. Jiang, W. & Pisetsky, D. S. Mechanisms of
disease: the role of high-mobility group protein 1
in the pathogenesis of inflammatory arthritis.
Nat. Clin. Pract. Rheumatol. 3, 52–58 (2007).
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
71. Ulfgren, A. K. et al. Down-regulation of the
aberrant expression of the inflammation
mediator high mobility group box chromosomal
protein 1 in muscle tissue of patients with
polymyositis and dermatomyositis treated with
corticosteroids. Arthritis Rheum. 50,
1586–1594 (2004).
72. Grundtman, C. et al. Effects of HMGB1 on in vitro
responses of isolated muscle fibers and
functional aspects in skeletal muscles of
idiopathic inflammatory myopathies. FASEB J.
24, 570–578 (2010).
73. Alexanderson, H. et al. Patients with idiopathic
inflammatory myopathies have low muscle
endurance rather than low muscle strength
[abstract 823]. Arthritis Rheum. 60 (Suppl.),
S307 (2009).
74. Emslie-Smith, A. M. & Engel, A. G. Microvascular
changes in early and advanced dermatomyositis:
a quantitative study. Ann. Neurol. 27, 343–356
(1990).
75. Estruch, R. et al. Microvascular changes in
skeletal muscle in idiopathic inflammatory
myopathy. Hum. Pathol. 23, 888–895 (1992).
76. Grundtman, C., Tham, E., Ulfgren, A. K. &
Lundberg, I. E. Vascular endothelial growth
factor is highly expressed in muscle tissue of
patients with polymyositis and patients with
dermatomyositis. Arthritis Rheum. 58,
3224–3238 (2008).
77. Probst-Cousin, S., Neundorfer, B. & Heuss, D.
Microvasculopathic neuromuscular diseases:
lessons from hypoxia-inducible factors.
Neuromuscul. Disord. 20, 192–197 (2010).
78. Dastmalchi, M. et al. Effect of physical training
on the proportion of slow-twitch type I muscle
fibers, a novel nonimmune-mediated mechanism
for muscle impairment in polymyositis or
dermatomyositis. Arthritis Rheum. 57,
1303–1310 (2007).
79. Nader, G. A. et al. A longitudinal, integrated,
clinical, histological and mRNA profiling study of
resistance exercise in myositis. Mol. Med. 16,
455–464 (2010).
80. Park, J. H. et al. Use of magnetic resonance
imaging and P‑31 magnetic resonance
spectroscopy to detect and quantify muscle
dysfunction in the amyopathic and myopathic
variants of dermatomyositis. Arthritis Rheum.
38, 68–77 (1995).
81. Hamada, T. et al. Extracellular high mobility group
box chromosomal protein 1 is a coupling factor
for hypoxia and inflammation in arthritis. Arthritis
Rheum. 58, 2675–2685 (2008).
82. Kim, I., Xu, W. & Reed, J. C. Cell death and
endoplasmic reticulum stress: disease
relevance and therapeutic opportunities. Nat.
Rev. Drug Discov. 7, 1013–1030 (2008).
83. Hosoi, T. & Ozawa, K. Endoplasmic reticulum
stress in disease: mechanisms and therapeutic
opportunities. Clin. Sci. (Lond.) 118, 19–29
(2010).
84. Delaunay, A. et al. The ER‑bound RING finger
protein 5 (RNF5/RMA1) causes degenerative
myopathy in transgenic mice and is deregulated
in inclusion body myositis. PLoS ONE 3, e1609
(2008).
85. van der Pas, J., Hengstman, G. J., ter Laak, H. J.,
Borm, G. F. & van Engelen, B. G. Diagnostic
value of MHC class I staining in idiopathic
inflammatory myopathies. J. Neurol. Neurosurg.
Psychiatry 75, 136–139 (2004).
86. Salomonsson, S. et al. Upregulation of MHC
class I in transgenic mice results in reduced
force-generating capacity in slow-twitch muscle.
Muscle Nerve 39, 674–682 (2009).
87. Henriques-Pons, A. & Nagaraju, K. Nonimmune
mechanisms of muscle damage in myositis:
REVIEWS
role of the endoplasmic reticulum stress
response and autophagy in the disease
pathogenesis. Curr. Opin. Rheumatol. 21,
581–587 (2009).
88. Askanas, V., Engel, W. K. & Nogalska, A.
Inclusion body myositis: a degenerative muscle
disease associated with intra-muscle fiber multi-
protein aggregates, proteasome inhibition,
endoplasmic reticulum stress and decreased
lysosomal degradation. Brain Pathol. 19,
493–506 (2009).
89. Nagaraju, K. et al. The inhibition of apoptosis in
myositis and in normal muscle cells. J. Immunol.
164, 5459–5465 (2000).
90. Shtifman, A. et al. Amyloid-β protein impairs
Ca(2+) release and contractility in skeletal
muscle. Neurobiol. Aging 31, 2080–2090
(2010).
91. Temiz, P., Weihl, C. C. & Pestronk, A.
Inflammatory myopathies with mitochondrial
pathology and protein aggregates. J. Neurol. Sci.
278, 25–29 (2009).
92. Nogalska, A., D’Agostino, C., Terracciano, C.,
Engel, W. K. & Askanas, V. Impaired autophagy in
sporadic inclusion-body myositis and in
endoplasmic reticulum stress-provoked cultured
human muscle fibers. Am. J. Pathol. 177,
1377–1387 (2010).
93. Bohan, A. & Peter, J. B. Polymyositis and
dermatomyositis (first of two parts). N. Engl. J.
Med. 292, 344–347 (1975).
94. Tanimoto, K. et al. Classification criteria for
polymyositis and dermatomyositis. J. Rheumatol.
22, 668–674 (1995).
95. Hoogendijk, J. E. et al. 119th ENMC international
workshop: trial design in adult idiopathic
inflammatory myopathies, with the exception of
inclusion body myositis, 10–12 October 2003,
Naarden, The Netherlands. Neuromuscul. Disord.
14, 337–345 (2004).
96. Engel, A. G. & Arahata, K. Mononuclear cells
in myopathies: quantitation of functionally
distinct subsets, recognition of antigen-specific
306  |  MAY 2011  |  VOLUME 7  www.nature.com/nrrheum
cell-mediated cytotoxicity in some diseases, and
implications for the pathogenesis of the different
inflammatory myopathies. Hum. Pathol. 17,
704–721 (1986).
97. Arahata, K. & Engel, A. G. Monoclonal antibody
analysis of mononuclear cells in myopathies.
III: Immunoelectron microscopy aspects of cell-
mediated muscle fiber injury. Ann. Neurol. 19,
112–125 (1986).
98 National Institue of Environmental Health
Sciences. International Myositis Assessment and
Clinical Research (IMACS) [online], http://
www.niehs.nih.gov/news/events/pastmtg/
imacs/index.cfm (2011).
99. Dalakas, M. C. Immunotherapy of myositis:
issues, concerns and future prospects. Nat. Rev.
Rheumatol. 6, 129–137 (2010).
100. Vencovsky, J. et al. Cyclosporine A versus
methotrexate in the treatment of polymyositis
and dermatomyositis. Scand. J. Rheumatol. 29,
95–102 (2000).
101. Caramaschi, P., Volpe, A., Carletto, A.,
Bambara, L. M. & Biasi, D. Long-standing
refractory polymyositis responding to
mycophenolate mofetil: a case report and review
of the literature. Clin. Rheumatol. 26,
1795–1796 (2007).
102. Gelber, A. C., Nousari, H. C. & Wigley, F. M.
Mycophenolate mofetil in the treatment of severe
skin manifestations of dermatomyositis: a series
of 4 cases. J. Rheumatol 27, 1542–1545 (2000).
103. López de la Osa, A., Sánchez Tapia, C.,
Arias Díaz, M. & Terrancle de Juan, I.
Antisynthetase syndrome with good response to
mycophenolate mofetil [Spanish]. Rev. Clin. Esp.
207, 269–270 (2007).
104. Dalakas, M. C. et al. A controlled trial of high-
dose intravenous immune globulin infusions as
treatment for dermatomyositis. N. Engl. J. Med.
329, 1993–2000 (1993).
105. Barbasso Helmers, S. et al. Limited effects of
high-dose intravenous immunoglobulin (IVIG)
treatment on molecular expression in muscle
© 2011 Macmillan Publishers Limited. All rights reserved
tissue of patients with inflammatory myopathies.
Ann. Rheum. Dis. 66, 1276–1283 (2007).
106. Wilkes, M. R., Sereika, S. M., Fertig, N.,
Lucas, M. R. & Oddis, C. V. Treatment of
antisynthetase-associated interstitial lung
disease with tacrolimus. Arthritis Rheum. 52,
2439–2446 (2005).
107. Haroon, M. & Devlin, J. Rituximab as a first-line
agent for the treatment of dermatomyositis.
Rheumatol. Int. doi:10.1007/S00296-010-
1458-6.
108. Furlan, A., Botsios, C., Ruffatti, A., Todesco, S. &
Punzi, L. Antisynthetase syndrome with
refractory polyarthritis and fever successfully
treated with the IL‑1 receptor antagonist,
anakinra: A case report. Joint Bone Spine 75,
366–367 (2008).
109. Dorph, C. et al. Anakinra in patients with
refractory idiopathic inflammatory myopathies
[abstract 589]. Arthritis Rheum. 60 (Suppl.)
S218 (2009).
110. Dastmalchi, M. et al. A high incidence of disease
flares in an open pilot study of infliximab in
patients with refractory inflammatory
myopathies. Ann. Rheum. Dis. 67, 1670–1677
(2008).
111. Alexanderson, H. Exercise effects in patients
with adult idiopathic inflammatory myopathies.
Curr. Opin. Rheumatol. 21, 158–163 (2009).
112. Alexanderson, H., Dastmalchi, M., Esbjornsson-
Liljedahl, M., Opava, C. H. & Lundberg, I. E.
Benefits of intensive resistance training in
patients with chronic polymyositis or
dermatomyositis. Arthritis Rheum. 57, 768–777
(2007).
113. de Salles Painelli, V. et al. The possible role of
physical exercise on the treatment of idiopathic
inflammatory myopathies. Autoimmun. Rev. 8,
355–359 (2009).
Author contributions
M. Zong and I. E. Lundberg contributed equally to all
aspects of the preparation of this manuscript.