Cytokine xxx (2014) xxx–xxx

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Cytokine
journal homepage: www.journals.elsevier.com/cytokine

The role of type I interferons and other cytokines in dermatomyositis

Ashish Arshanapalli a,1, Mihir Shah b,1, Vindhya Veerula a, Ally-Khan Somani a,⇑
a
Department of Dermatology, Indiana University School of Medicine, 545 Barnhill Dr., Indianapolis, IN 46202, USA
b
Northeast Ohio Medical University, 4209 SR 44, Rootstown, OH 44272, USA

a r t i c l e i n f o a b s t r a c t

Article history: Much work has been done to unveil the mechanisms behind the pathogenesis of dermatomyositis (DM) –
Received 31 August 2014 mainly those involving certain pathogenic cytokines, termed ‘‘pathokines’’ as the principal cytokines
Received in revised form 20 November 2014 involved. Recently, it has become clear that a group of cytokines known as type I interferons (IFN-Is) play
Accepted 21 November 2014
a significant role in the development of DM. We review the literature published between 1946 and 2014
Available online xxxx
using an Ovid Medline database search to provide an update on the role of IFN-Is and other cytokines in
the pathogenesis of DM. We provide information about the genes and proteins induced by IFN-Is and
Keywords:
potential mechanisms by which these downstream products relate to clinical disease activity. We also
Type I interferons
Dermatomyositis
explore findings of other autoimmune phenomena that may contribute to disease onset and activity
Pathogenesis including T-helper 17 (Th17) cells and associated interleukins, as well as autoantibodies. Finally, we
Cytokines provide a brief update on current treatment options for DM as well as some new immunomodulatory
Inflammatory myopathy treatment modalities in development.
Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction phenomenon, ulceration, and livedo reticularis [1]. A thorough

Dermatomyositis (DM) is an autoimmune inflammatory myop-
athy with characteristic cutaneous findings, distinguishing it from
other autoimmune myopathies such as polymyositis (PM).
Clinically, the myopathy of DM presents symmetrically and
involves the proximal extremities. Cutaneous involvement classi-
cally includes photodistributed pink to violaceous skin eruptions
with accentuation over extensor surfaces. The classic ‘‘shawl sign’’
is a photodistributed poikiloderma (features of hyperpigmentation,
hypopigmentation, telangiectasias and epidermal atrophy) or
macular erythema involving the chest, back and upper shoulders,
classically in a ‘‘V’’ shaped distribution [1]. Other characteristic
signs include Gottron’s papules (lichenoid papules overlying the
knuckles), Gottron’s sign (violaceous discoloration of the knuckles,
elbows, and/or knees), cuticular dystrophy (Fig. 1), nail fold telan-
giectasias, heliotrope sign (periorbital violaceous discoloration),
eyelid edema (Fig. 2), and facial or malar erythema [1]. Nonsun-
exposed areas are often involved, including the scalp and lateral
thighs (Holster sign) [2]. Extracutaneous manifestations include
arthritis/arthralgias, dysphagia, and dyspnea with the
development of interstitial lung disease, cardiac complications,
renal disease, gastrointestinal disease, neuropathy, Raynaud’s
⇑ Corresponding author at: 545 Barnhill Dr., EH 139, Indianapolis, IN 46202, USA.
E-mail address: somania@iu.edu (A.-K. Somani).
1
Both authors contributed equally.
review of systems and physical examination is thus required to
diagnose DM.
Histopathologic findings of DM include epidermal atrophy,
basement membrane degeneration, vacuolar alteration of basal
keratinocytes, and dermal changes consisting of interstitial mucin
deposition and a sparse lymphocytic infiltrate [1]. Muscle biopsies
demonstrate characteristic changes of type II muscle fiber atrophy,
necrosis, regeneration, and hypertrophy with centralized sarco-
lemmal nuclei. Lymphocytic inflammation in a perifascicular and
perivascular distribution is characteristic [3].
There are several subtypes of DM – the current classification
separates it into adult-onset and juvenile-onset. Further subtypes
within adult-onset DM include classic DM, classic DM with malig-
nancy (especially ovarian cancer or breast cancer in females and
lung cancer in males), classic DM associated with other connective
tissue disorders, and clinically amyopathic DM (including amyo-
pathic or dermatomyositis sine myositis and hypomyopathic DM)
[1,4]. Juvenile-onset subtypes include classic DM and clinically
amyopathic DM [1]. Calcinosis cutis (calcium deposition in the skin
especially prone to sites of trauma) and ulceration are commonly
associated with juvenile DM [1]. Malignancy risk is increased in
adult-onset subtypes, with the current prevalence ranging from
7% to 30% [4]. Therefore, it is prudent to rule out an underlying
malignancy and undergo routine surveillance with age-appropriate
malignancy screening in all patients with confirmed DM.

http://dx.doi.org/10.1016/j.cyto.2014.11.026
1043-4666/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Arshanapalli A et al. The role of type I interferons and other cytokines in dermatomyositis. Cytokine (2014), http://
dx.doi.org/10.1016/j.cyto.2014.11.026
2 A. Arshanapalli et al. / Cytokine xxx (2014) xxx–xxx
Fig. 1. Cutaneous features of dermatomyositis. See lichenoid papules (Gottron’s
papules) overlying metacarpophalangeal (MCP), proximal interphalangeal (PIP),
and distal interphalangeal (DIP) joints. Also observe violaceous discoloration
(Gottron’s sign) and cuticular dystrophy present.
The differential diagnosis of dermatomyositis includes cutane-
ous lupus, psoriasis, phototoxic or photodrug eruption, and an
airborne or allergic contact dermatitis [1]. There can also be over-
lap with other mixed connective tissue diseases. Laboratory testing
can often aid in the diagnosis of DM. Laboratory markers of muscle
injury include elevations in blood levels of creatine kinase (CK),
aldolase, aspartate aminotransferase (AST), alanine aminotransfer-
ase (ALT), and lactate dehydrogenase (LDH) [5–7]. Antinuclear
antibody (ANA), most commonly in the speckled or nucleolar pat-
tern, is often positive but nonspecific, and DM-specific autoanti-
bodies (such as MDA5) may help differentiate between
dermatomyositis and other connective tissue diseases [8]. Muscle
and skin biopsies are also helpful to aid in definitive diagnosis,
however a skin biopsy often demonstrates subtle findings in DM,
and cannot definitively distinguish DM from cutaneous lupus
[9,10]. Nail fold capillaroscopy using dermatoscopy or other mag-
nifying instruments is useful for diagnosis and can help differenti-
ate DM from other connective tissue diseases [11]. Classically,
dilated capillaries in the proximal nail fold along with alternated
vessel drop-off is appreciated [12]. Treatment is multifaceted and
depends on the clinical severity, but includes a combination of cor-
ticosteroids and steroid-sparing immunosuppressive agents such
as hydroxychloroquine, mycophenolate mofetil, methotrexate,
and azathioprine [13]. Hydroxychloroquine is especially useful in
controlling photosensitivity. IVIG may also be an effective addi-
tional therapy for patients with dermatomyositis who fail to
respond to conventional therapy or who experience unacceptable
side effects [14].
1.1. Role of interferons
It has become widely understood that cytokines, secreted cell-
signaling proteins, play a significant role in regulating immune
responses in inflammatory and autoimmune diseases. Particular
attention has been drawn to a class of cytokines known as type I
interferons (IFN-Is) and their involvement in the pathogenesis of
DM [15]. We review the current literature using the Ovid Medline
database to search for articles published between 1946 and 2014
in order to update the current understanding of the role of type I
interferons and other cytokines in the pathogenesis of DM. Key
words utilized in searches included ‘dermatomyositis’ and
‘interferon type I’ and ‘pathogenesis’. Previously published review
articles and corresponding primary sources were reviewed as well
Please cite this article in press as: Arshanapalli A et al. The role of type I interferons and other cytokines in dermatomyositis. Cytokine (2014), http://
dx.doi.org/10.1016/j.cyto.2014.11.026
Fig. 2. Periorbital features of dermatomyositis. Notice violaceous discoloration
(heliotrope sign) and marked eyelid edema.
as newly published data to evaluate the gaps and uncertainties in
our current understanding of this disease and to discuss other
possible treatments.
2. Cytokines in the pathophysiology of DM
2.1. IFN-Is and their sources
Interferons (IFNs) are a group of glycoproteins first described for
their involvement in viral proliferation [16]. Since their discovery,
they have been found to contribute to a variety of immune pro-
cesses beyond their anti-viral role including autoimmune diseases
[17,18]. Within the IFN family, three specific classes (type I, type
II, and type III) of IFNs have emerged based on the receptor through
which these cytokines signal. Of particular interest in autoinflam-
matory diseases are IFN-Is, consisting of IFNa and IFNb, along with
less studied subtypes including -x, -j, and -e [19,20]. IFN-Is act at
the IFNa receptor, present on most human cells, to induce a signal-
ing cascade causing activation of IFN stimulated gene factor 3
(ISGF-3), a transcription factor. ISGF-3 translocates to the nucleus
and binds to IFN stimulated response elements (ISREs) causing
transcription of multiple genes and immunomodulation (Fig. 3)
[21–23].
IFN-Is can be produced by almost all nucleated cells [16,24,25],
but pathologic levels of IFN-Is may be associated with plasmacy-
toid dendritic cells (pDCs). Several disease states characterized
by lichenoid skin reactions (skin manifestations and pathology that
resemble lichen planus), histologically demonstrate increased infil-
tration of pDCs [26–29]. These lichenoid reaction patterns are
linked to IFN-I exposure and increased levels of IFN-I gene tran-
scripts [26,30]. pDCs are cells that produce high levels of IFN-Is;
they have been shown to be increased in DM muscle and skin
[27–29,31,32]. pDCs are frequently mistaken for other classes of
immune cells, due to a wide variety of cell surface markers
expressed [31,33,34]. DM muscle is characterized by the presence
of perivascular inflammation, consisting of primarily B cells, but
also a small number of CD4+ cells, long thought to be T-helper cells
[35]. It was later discovered that pDCs express CD4 cell markers,
mistaking them with T helper cells [5]. In addition, they commonly
express cell markers, CXCR3 and CD63, mistaking them for
lymphocytes and macrophages, respectively [33,34].
pDCs are activated by toll-like receptor 7 (TLR7) and toll-like
receptor 9 (TLR9) agonists [36]. Corresponding TLR9 levels are
increased in patients with DM and PM when compared to healthy
controls [37]. The exact mechanism of TLR induction has yet to be
determined, but it is currently thought to be a result of tissue
damage [38]. In patients with systemic lupus erythematosus, TLR
stimulation has been seen by the presence of IgG-apoptotic cell
or antibody-DNA complexes [39,40]. Signaling through the TLR9
leads to increased production of IFN-Is by the pDCs [41]. Through
an auto-stimulatory mechanism, the IFN-Is bind to their receptor
on pDCs, with subsequent production of IFN-Is (Fig. 3) [36].
 A. Arshanapalli et al. / Cytokine xxx (2014) xxx–xxx 3

Fig. 3. Type I interferon pathway. Mechanistic pathway showing production of IFN-Is, signaling pathway induced by IFNa and -b, and downstream effects including
stimulation of genes, production of proteins, and resulting inflammation. IFNAR, IFNa receptor; JAK, Janus Kinase; Tyk2, Tyrosine Kinase 2; STAT, Signal Transducer and
Activator of Transcription; ISGF3, Interferon Stimulated Gene Factor 3; IRF, Interferon Regulatory Factor; ISRE, Interferon Stimulated Response Element; ISGs, Interferon
Stimulated Genes; ss, single-stranded; ds, double-stranded; LPS, Lipopolysaccharides; TLR, Toll-like receptor; NF-Kb, nuclear factor kappa-light-chain-enhancer of activated B
cells; TBK1, TANK-binding kinase 1. Activation and positive feedback pathways of the type I IFN receptor are shown with dotted arrows.

2.2. IFN-I inducible genes
IFN-Is promote transcription of particular genes through the
activity of ISGF-3 (Fig. 3). In recent years, studies have found DM
muscle to express large amounts of type I interferon-inducible
genes, supporting the role of IFN-Is in DM and prompting further
investigations [42]. When compared with other forms of myositis,
the overproduction of IFN-I inducible transcripts and proteins in
muscle tissue is a unique feature of DM [31,43–45]. A 2002 study
identified genes associated with IFN-I to be upregulated in patients
with juvenile DM, with certain genes amplified to a level up to one
hundred fold higher than those found in healthy patients [46]. The
upregulation of IFN-I induced genes has since been demonstrated
in adult DM by a variety of studies, including a microarray study
in 2005 that found upregulation of interferon stimulated gene 15
(ISG15), an IFN-I inducible gene, in DM muscle samples with peri-
fascicular atrophy [31]. Beyond ISG15, of the 14 most highly
expressed genes in patients with DM, 12 were genes induced by
IFN-Is [31]. This study also demonstrated that the genes induced
by IFN-Is were more likely to be upregulated in patients with
DM compared with other inflammatory myopathies studied,
including inclusion body myositis, PM, and others [31]. Further-
more, elevated levels of pDCs were identified in the DM patient
population [31], serving as a presumable source of elevated levels
of IFN-Is and subsequent changes in gene expression.
Another microarray gene expression study in 2010 further sup-
ported these findings. It showed muscle biopsies of patients with
DM had a significant elevation of IFN-I inducible transcripts, such
as ISG15 transcript, in comparison to other inflammatory myopa-
thies [43]. These findings were specifically seen in DM patients
with perifascicular atrophy [43]. The authors discovered that
human peripheral blood mononuclear cells stimulated with IFN-I
in vitro, demonstrated upregulation of genes that closely mimicked
those which were upregulated in patients with DM. In addition,
these genes were only upregulated when the peripheral blood
mononuclear cells were stimulated with IFN-Is but not by other
cytokines [43]. A similar set of genes as those upregulated in
patients with DM were also found when normal human skeletal
muscle cells were stimulated with IFN-Is [43]. Studies by Chen
et al. provided evidence that the relationship between IFN-I
inducible genes and DM is more than temporal as no significant
difference in levels of IFN-I inducible gene transcripts could be
identified between two cohorts of juvenile DM patients, one with
disease activity for greater than two months and one less than
two months [47].
The compilation of previously mentioned studies and multiple
others have led to the identification of a cluster of IFN-I inducible
genes, referred to as the IFN signature, that are upregulated in
the peripheral blood and muscle of patients with DM [31,43,48–
50]. This IFN signature has also been exhibited in lymphoid cells

Please cite this article in press as: Arshanapalli A et al. The role of type I interferons and other cytokines in dermatomyositis. Cytokine (2014), http://
dx.doi.org/10.1016/j.cyto.2014.11.026
4 A. Arshanapalli et al. / Cytokine xxx (2014) xxx–xxx
in the peripheral blood and the kidneys of patients with systemic
lupus erythematosus [18]. These studies also identified a positive
correlation between the quantity of IFN-I inducible transcripts
and clinical disease activity in adult DM, but no association was
identified with other hematologic markers of inflammation includ-
ing erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP) [48,50]. These findings taken together with prior findings
of a lack of a relationship between IFN-I induced transcripts and
disease duration [47], may suggest that the level of IFN-Is and sub-
sequent gene expression dictates disease severity.
While the IFN signature has also been found upregulated in the
blood (but not muscle) of patients with PM, it is not elevated to the
same extent as in DM [44,51]. In DM, there is upregulation of the
IFN signature in both diseased muscle and blood, with significantly
higher augmentation in diseased muscle [44]. In order to further
understand the induction of the IFN signature, Liao et al. explored
the ability of IFNa, IFNb, and IFNx (all IFN-Is) to stimulate IFN sig-
nature expression. They found that IFNb, but not IFNa or IFNx, was
associated with an upregulated IFN signature. They also identified
that serum of DM patients was more associated with IFNb than the
other IFN-Is [52]. The role of IFNb in DM has also been demon-
strated by a case of severe DM triggered by the treatment of multi-
ple sclerosis with IFNb therapy [15]. The induction of autoimmune
disease by IFNb has also been shown with subacute cutaneous
lupus, another disease strongly linked with the IFN signature [53].
2.3. IFN-I induced proteins
The characteristic expression of the IFN signature in DM leads
to the production of a unique milieu of proteins that has recently
begun to be classified (Fig. 3). Myxovirus resistance protein A
(MxA) is an example of an IFN-I induced protein that normally
serves an antiviral role [54]. MxA is specific to DM and has been
detected in elevated levels in the muscle [31] and skin [55] of
patients with DM but not patients with other inflammatory muscle
conditions including PM. MxA is detected mainly in the perifasci-
cular region of muscle in patients with DM, and specifically found
to be elevated in those muscles undergoing active inflammation
and atrophy [43]. Furthermore, MxA has also been detected in ele-
vated levels in the epidermis and inflammatory infiltrates of skin
biopsies from patients with DM [43]. In addition to MxA’s presence
at active disease areas, MxA RNA in peripheral blood mononuclear
cells in patients with juvenile DM have been positively correlated
with muscle but not skin disease activity [56].
Other IFN-I induced proteins associated with DM include ISG15
protein [43], interferon regulatory factor 7 (IRF7) [43], radical S-
adenosyl methionine domain-containing 2 (RSAD2; viperin) [57],
and retinoic acid-inducible gene 1 (RIG-I) [57]. ISG15 protein is
an ubiquitin-like modifier which attaches to various proteins in
DM muscle and may contribute to disease activity (Fig. 3) [43].
Detection of ISG15 protein by immunofluorescence in the regions
of DM pathologic activity, such as perifascicular myofibers and
capillaries of DM muscle, supports this idea [43]. Interestingly,
RIG-I, one of the most prominent proteins expressed in perifascicu-
lar DM muscle [43], also has the ability to cause the production of
IFN-Is [58]. RIG-I is a cytosolic receptor that is activated by short
double-stranded RNA and single-stranded RNA in virus-infected
cells [59,60]. RIG-I stimulation in human myotubes has been dem-
onstrated to cause production of IFNb but not IFNa [57]. The IFNb
produced by muscle cells stimulates further production of IFN-I
inducible proteins, including RIG-I, which results in a positive feed-
back loop. This positive feedback loop may allow for the sustained
autoimmune inflammation that is present in DM, as postulated by
Greenberg [61]. This association of INFb via autocrine stimulation
may indicate a key role for this interferon in the pathogenesis of
DM because of the previously mentioned unique correlation of
Please cite this article in press as: Arshanapalli A et al. The role of type I interferons and other cytokines in dermatomyositis. Cytokine (2014), http://
dx.doi.org/10.1016/j.cyto.2014.11.026
IFNb with the IFN signature and clinical case of IFNb induced DM
[15,52].
Furthermore, melanoma differentiation-associated gene 5
(MDA5) is in the same family as RIG-I and may similarly play a role
in the positive feedback loop involved in DM [62,63]. MDA5, an
IFN-induced protein, also functions as a cytosolic receptor for viral
double-stranded RNA that when activated, stimulates an innate
immune response including production of IFN-Is [60,62,64]. Both
MDA5 and RIG-I have been demonstrated to cause IFN-I produc-
tion in virally-infected cells [65], and the association of a positive
feedback loop (Fig. 3) of IFN-I production and viral infection raises
the question of a viral insult as the inciting event in DM and other
autoimmune phenomena.
While no strong associations have been drawn between IFN
inducible proteins and DM disease activity, the specificity of these
proteins for DM, compared to other inflammatory myopathies,
along with their predilection for areas of active disease and poten-
tial contribution to IFN-I dysregulation provide compelling evi-
dence for the role of IFN-Is in the pathogenesis of DM.
2.4. IFN-I related cytokines
IFN-Is stimulate the production of other cytokines influencing
cell migration, maturation, and injury, which may contribute to
the pathogenesis of DM. IFN-Is have been reported to induce pro-
duction of multiple chemokines as well as cause recruitment of
lymphocytes to sites of inflammation. Chemokines (including
MIG/CXCL9, IP10/CXCL10, and I-TAC/CXCL11) that serve as CXCR-
3 ligands as well as lymphocytes with the CXCR-3 receptor have
been detected in increased concentration in affected areas of skin
[28,66] and muscle [32,67] in DM. IFNa has also been demon-
strated to cause production of CXCL10 in keratinocytes, in vitro,
supporting the role of IFN-Is in immunomodulation [55]. Numer-
ous studies have reported elevated levels of other IFN-I inducible
cytokines in DM, including monocyte chemo attractant protein-1
(MCP-1/CCL2) and macrophage inflammatory protein-1 (MIP-1a/
CCL3 and MIP-1b/CCL4) [68–71]. These cytokines are not specific
to DM and are present in other inflammatory myopathies, but
are found to localize to areas of myopathic inflammation suggest-
ing a generalized role in the pathogenesis of myopathic conditions
[69]. In patients with DM, MIP-1b was also demonstrated in capil-
laries near muscle not undergoing active inflammation, which may
suggest a role of this cytokine in the preclinical stages of disease
[68]. Staining for MCP-1 has demonstrated a predilection for endo-
thelial cells near areas of active inflammation with DM [70]. This
endothelial localization suggests that MCP-1 may play a role in
complement deposition in the microvasculature of affected mus-
cles [72]. DM muscle biopsies express the C5b-9 membrane attack
complex (MAC) on endothelial cells which may play a role in cap-
illary damage [73,74]. The depletion and damage of capillaries may
result in hypoxia and subsequent damage to myofibers seen in DM
[75]. This abnormal capillary morphology and capillary loss is an
early manifestation of DM, often seen prior to inflammatory infil-
trates [76,77].
In all inflammatory myopathies, expression of receptors for
MCP-1 (CCR2A and CCR2B) is also upregulated on endothelial cells
and inflammatory cells [67]. The contribution of MCP-1, is not be
exclusively attributable to IFN-Is; in vitro studies have demon-
strated stimulation of MCP-1 by type II IFNs as well [78]. IFN-I
inducible cytokines have been demonstrated to have a positive
correlation with clinical disease activity in both juvenile DM and
adult DM [48]. The cytokines produced in response to IFN-I may
contribute to the pathogenesis of DM by damaging endothelial
cells, keratinocytes, and myocytes by the upregulation of MHC
class I and recruitment of T cells leading to inflammation (Fig. 3)
[79]. Cellular damage can also occur simply from long-term
 A. Arshanapalli et al. / Cytokine xxx (2014) xxx–xxx
production and accumulation of IFN-I inducible proteins, which
exhibit antiproliferative effects [80].
2.5. Emerging role of T-helper 17 (Th17) cells and interleukins (IL)
The role of Th17 lymphocytes and IL-17 in the pathogenesis of
DM is also a subject of recent interest and may be associated with
IFN-Is [48]. Th17 cells are a subset of CD4+ T cells that are distinct
from the Th1 and Th2 cell lines. They secrete the pro-inflammatory
cytokine IL-17, among others, and are believed to play a role in
multiple autoimmune conditions including DM [81]. Muscle biop-
sies of patients with DM have demonstrated the presence of extra-
cellular IL-17 and within inflammatory infiltrates [82]. IL-17 also
appears to be more highly expressed in the blood and plasma of
DM patients in comparison to controls [83,84], and patients with
DM have been found to have a higher frequency of Th17 cells
[85]. Studies examining IL-17 in inflammatory myopathies have
detected that this cytokine acts with TLR3 agonists to cause IL-6
production in myoblasts in addition to yielding alterations in myo-
blast differentiation and migration [86,87]. The production of IL-6
and alteration in myoblast behavior may provide further insights
into the pathogenesis of DM. IL-6, an acute phase reactant produc-
ing inflammation, has been demonstrated to influence muscle
damage in mouse models with inflammatory myositis [88]. The
roles of IL-6 in DM are supported by findings that levels of this
cytokine are elevated in DM, and IL-6 has been correlated with
IFN signature expression, other IFN-I induced cytokine levels
(previously discussed), and clinical disease activity [48]. While no
precise model is known, the production of IFN inducible
chemokines in DM may cause increased migration and activation
of Th17 cells leading to increased IL-17 and IL-6. These cytokines
can then produce chronic inflammation and damage leading to
muscle tissue injury.
3. Autoantibodies in DM
An association between DM and a variety of autoantibodies has
been identified, but the specific role of autoantibodies in the path-
ogenesis of DM and use as clinical markers of disease is not well
defined. Two main classes of autoantibodies have been detected
in DM, myositis specific antibodies (MSAs) and myositis associated
antibodies (MAAs). MSAs are correlated with specific clinical sub-
types and manifestations of DM.
Anti-aminoacyl tRNA synthetase antibodies (most commonly
anti-Jo-1) are associated with anti-synthetase syndrome [89],
which is a syndrome that can present with a constellation of signs
and symptoms including anti-tRNA synthetase antibodies, intersti-
tial lung disease, inflammatory myopathy, polyarthropathy, and
other minor features. Anti-aminoacyl tRNA synthetase antibodies
may be pathogenic in DM due to the ability to induce IFNa produc-
tion in the presence of RNA [90].
The autoantigen CADM-140 is identical to two previously iden-
tified gene products, interferon induced with helicase C domain
(IFIH1) and melanoma differentiation-associated gene 5 (MDA5)
[62]. Anti-CADM-140 antibodies are associated with progressive
interstitial lung disease and a poor prognosis, especially in Japa-
nese patients [63]. A study by Labrador-Horillo et al., examined
Mediterranean patients with anti-MDA5 antibodies and demon-
strated three cohorts with specific clinical findings; the first with
progressive interstitial lung disease and poor prognosis (similar
to the Japanese patients), the second with primarily cutaneous
findings including palmar pustules, increased skin ulcerations,
and panniculitis, and lastly, the third with less progressive intersti-
tial lung disease and symptoms similar to antisynthetase syn-
drome [91]. Fiorentino et al. identified that some of unique
Please cite this article in press as: Arshanapalli A et al. The role of type I interferons and other cytokines in dermatomyositis. Cytokine (2014), http://
dx.doi.org/10.1016/j.cyto.2014.11.026
5
cutaneous phenotypes in patients with anti-MDA5 antibodies,
especially palmar papules and mucocutaneous ulcers may, be
linked with an increased risk of severe cutaneous vasculopathy
associated with these autoantibodies [92]. Anti-MDA5 antibodies
have also been associated with clinically amyopathic DM [63].
The clinical manifestations of these autoantibodies are of particular
interest due to the role of MDA5 in IFN-I-mediated production.
Anti-Mi-2 antibodies are often detected in DM patients with
classic cutaneous lesions [89]. Anti-small ubiquitin-like modifier
activating enzyme antibodies are often present in DM with sys-
temic features [89]. Anti-p155/140 antibodies are often found in
subsets of DM with cutaneous features and are associated with a
greater risk of internal malignancy [93].
MAAs are present in association with multiple autoimmune
conditions including DM. MAAs to RNA containing antigens such
as anti-Ro, anti-La, anti-Sm, and anti-RNP are associated with ele-
vated serum IFNa in juvenile DM, and serum with these autoanti-
bodies have demonstrated the ability to induce IFNa production
in vitro [94]. Further studies are indicated to better understand
the role of MAAs and MSAs in DM as well as clarify any potential
link between autoantibodies and type I interferons.
4. Novel treatment modalities
Standard therapy for DM currently includes highly active
immunosuppressants, but use is often limited by side effects. Fur-
thermore, disease activity is often refractory to therapy. Many
exciting new targeted therapies are being tested and are showing
promise as treatment modalities for DM, and they have been
recently reviewed by Venalis and Lundberg [95]. Some notable
experimental treatments include sifalimumab, a monoclonal anti-
body against IFNa [96], and IL-6 receptor antagonists including
tocilizumab [97,98]. Increased understanding of the pathogenesis
of DM can allow for more targeted immunotherapy to improve
the debilitating sequelae and comorbidities associated with DM,
with minimized side effects and improved quality of life.
5. Conclusion
The pathogenesis of DM involves complex immunologic inter-
actions of both the innate and adaptive systems, and the precise
mechanism of disease is yet to be fully elucidated. The majority
of the current evidence suggests that the dysregulation of pDCs,
and other sources of IFN-Is, allows for pathologic levels of IFNa
and -b, which plays a key role in the initiation and maintenance
of the disease process. The original cause of this dysregulation is
yet to be discovered; current hypotheses include genetic and/or
viral-mediated causes. However, it is likely a combination of both
environmental and genetic factors. Regardless of the cause, ele-
vated levels of IFN-Is leads to a signaling cascade that results in
the upregulation of specific genes and production of a unique
group of proteins. These proteins include enzymes and pathokines
that may either contribute directly to the pathogenesis or induce
and exacerbate inflammatory responses resulting in cellular
damage.
Other autoimmune phenomena such as MSAs, MAAs, and
increased levels of Th17-associated cytokines have also been impli-
cated in the pathogenesis of DM. However, the link between these
processes and IFN-Is is not well understood, and further studies are
indicated to allow for a better understanding of the immunologic
interactions occurring with disease activity. Further elucidation
of these interactions along with more information about the spe-
cific contributions of IFN-I inducible proteins may prove pivotal
in creating a clear disease-model for DM. With this knowledge,
more effective immunotherapies can be developed to replace the
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