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Classification of myositis
Ingrid E. Lundberg1,2*, Marianne de Visser3 and Victoria P. Werth4
Abstract | The idiopathic inflammatory myopathies (IIMs; also known as myositis) are
a heterogeneous group of disorders in which a common feature is chronic inflammation of
skeletal muscle, leading to muscle weakness. Other organs are frequently affected in IIMs, such as
the skin, joints, lungs, gastrointestinal tract and heart, contributing to morbidity and mortality.
Currently, IIMs are most often subclassified into polymyositis, dermatomyositis and inclusion
body myositis, but this subclassification has limitations as these subgroups often have
overlapping clinical and histopathological features, and outcomes vary within the subgroups;
additionally, subgroups without considerable myopathy are not included. A new way of
subgrouping patients could be on the basis of the presence of myositis-specific autoantibodies.
These autoantibodies are associated with distinct clinical features and, moreover, can help to
identify subsets of IIMs in which extramuscular symptoms, such as skin manifestations, arthritis or
interstitial lung disease, might be the presenting or predominant feature when muscle symptoms
are mild or absent. The recognition that subphenotypes with single-organ involvement other
than muscles exist is important for identifying patients with early disease, for clinical care
demanding team management and in designing clinical studies to improve our understanding of
this heterogeneous disease to develop new therapies.

1
Division of Rheumatology,
Department of Medicine,
Solna, Karolinska Institutet,
and Karolinska University
Hospital, Stockholm, Sweden.
2
Center for Molecular
Medicine, Karolinska
Institutet, Stockholm, Sweden.
3
Department of Neurology,
Academic Medical Center,
Amsterdam, Netherlands.
4
Department of Dermatology,
Perelman School of Medicine,
University of Pennsylvania,
Philadelphia, PA, USA.
*email: Ingrid.Lundberg@ki.se
doi:10.1038/nrrheum.2018.41
Published online 12 Apr 2018
The idiopathic inflammatory myopathies (IIMs), known
collectively as myositis, constitute a large spectrum of
clinical phenotypes. As indicated by the name, the
classical clinical manifestations of IIMs, such as mus-
cle weakness, relate to chronic inflammation in skele-
tal muscle. This inflammation frequently affects other
organs, including the skin, joints, lungs, gastrointestinal
tract and heart, indicating the systemic nature of this
disease. On the basis of muscle symptoms, skin rash
and histopathological features, different subgroups
have been identified in IIM, including dermato­myositis,
poly­myositis, inclusion body myositis (IBM) and, in
the past 15 years, immune-mediated necrotizing myo­
pathy (IMNM)1,2. These subgroups have dominated the
classification criteria of IIMs to date. A limitation with
this subgrouping is that the histopathological features
might overlap between the subgroups, and some isolated
features (for example, the presence of inflammation or
rimmed vacuoles) are not specific for IIMs and can
also be found in other myopathies. Moreover, in some
patients with IIM, the histopathological features might
be nonspecific, discrete or nearly normal, emphasizing
the need to combine histopathological features with
clinical and serological data in the classification of IIMs.
Furthermore, treatment response and prognosis vary
within the subgroups, indicating that the pathogenesis
differs both between and within these subgroups.
To increase our understanding of disease mecha-
nisms and to develop new therapies, new classification
criteria are needed for the IIM disease spectrum that
not only identify and distinguish patients with IIM
from patients with other myopathies but also capture
patients with mild or no overt clinical muscle weakness
in whom extramuscular manifestations are the predom-
inant clinical features, such as in amyopathic dermato­
myositis and antisynthetase syndrome (ASS)3,4. There
are several challenges in developing classification crite-
ria for IIMs as these are rare disorders, and the clinical
and muscle tissue variables have rarely been defined or
validated. Previously published criteria have been dis-
cussed in detail elsewhere5. Most available criteria until
now have been based on expert opinion, of which some
criteria mainly included clinical variables whereas others
focused on histopathology. The strong need for new clas-
sification criteria led to the development of the EULAR–
ACR classification criteria for adult and juvenile IIMs
and their major subgroups6,7. These criteria are the result
of an international, multidisciplinary collaboration, are
data driven and include definitions of variables.
In this Review, we discuss the new EULAR–ACR
classification criteria, and in this context, we also dis-
cuss the emerging importance of identifying individuals
from the broad clinical spectrum of IIMs who do not
have notable muscle abnormalities, such as patients with

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Key points autoantibodies (MSAs) — the anti-histidyl-transfer

• The clinical spectrum of idiopathic inflammatory myopathies (IIMs) has evolved from
diseases in which muscle weakness was the main manifestation to systemic
inflammatory diseases with multiple organ involvement.
• The EULAR–ACR classification criteria for adult and juvenile IIMs and their major
subgroups capture patients with the typical skin rash of dermatomyositis without
muscle weakness (amyopathic dermatomyositis).
• The myositis-specific autoantibodies (MSAs) are helpful in supporting the diagnosis,
classification and subclassification of IIMs, but muscle biopsies with histopathological
and immunohistochemical evaluation are still important in many cases to rule out
other myopathies.
• Inclusion body myositis is suggested to be classified on the basis of three features:
finger flexor or quadriceps weakness, endomysial inflammation, and invasion of
non-necrotic muscle fibres or the presence of rimmed vacuoles.
• Immune-mediated necrotizing myopathy is characterized by the presence of necrotic
muscle fibres, often with scarce or no inflammatory cell infiltrates, typically together
with the presence of specific MSAs.
• Antisynthetase syndrome is characterized by the presence of myositis, interstitial
lung disease, mechanic’s hand, arthritis and Raynaud phenomenon (albeit some of
these features might predominate) together with an antisynthetase antibody.
amyopathic dermatomyositis and patients with ASS,
which needs to be further defined in future versions of
IIM classification criteria.
Clinically defined IIM
The first set of modern criteria for IIM were developed
in the 1970s by Medsger et al.8 and DeVere and Bradley 9,
and in 1975 the criteria proposed by Bohan and Peter 10,11
were published and became for more than 40 years the
most widely used criteria (FIG. 1). The Bohan and Peter
criteria were put forward as diagnostic criteria as well as
classification criteria and were developed on the basis of
expert opinion and data from a single institute. Bohan
and Peter proposed several subgroups: polymyositis,
dermatomyositis, juvenile dermatomyositis, overlap
myositis (which was defined as the presence of myo­sitis
and another distinct rheumatological diagnosis) and
myositis associated with cancer. These criteria had sev-
eral limitations, including the lack of IBM as a subgroup.
The criteria included both muscle and skin manifesta-
tions, and, by definition, signs of a myopathy needed
to be present for a classification of probable or definite
polymyositis or dermatomyositis. The Bohan and Peter
criteria also included the need to exclude other condi-
tions, such as muscular dystrophies, that might be asso-
ciated with prominent inflammation. Bohan and Peter
later provided detailed descriptions of clinical data from
153 patients who they thought fit into the spectrum of
polymyositis and dermatomyositis12. Interestingly, inter-
stitial lung disease (ILD) was not mentioned among the
cardiopulmonary manifestations.
In 1995, Tanimoto et al.13 developed classification cri-
teria for polymyositis and dermatomyositis that, similar
to the Bohan and Peter criteria, had a strong emphasis on
muscle manifestations. The Tanimoto criteria included
the five items of the Bohan and Peter criteria but also
had additional items: myalgia, non-erosive arthritis,
fever and, for the first time, one of the myositis-specific
RNA synthetase (Jo1) autoantibodies13. Targoff and
colleagues14 also further developed the Bohan and Peter
criteria, adding as an item the presence of any of the then
known MSAs (specified as antibodies that recognize
aminoacyl transfer RNA synthetases (ARSs), signal rec-
ognition particle (SRP) or Mi2 autoantigens) and modi-
fying the criteria so that MRI-determined inflammation
of skeletal muscle could substitute for clinical muscle
weakness or elevated muscle enzyme activities in sera. In
2015, Troyanov and colleagues15 proposed another clas-
sification system that was based on clinical–­serological
definitions, in which a new clinical subgroup was intro-
duced, termed clinicoserological overlap myositis, which
was defined by the presence of myositis and at least one
clinical overlap feature and/or an overlap autoantibody,
including the anti-ARS autoantibodies (commonly
referred to as antisynthetase antibodies), anti-SRP anti-
bodies, systemic sclerosis-associated antibodies (includ-
ing antibodies to centromeres, topoisomerase I, Th/To
autoantigens, RNA polymerase I or III, Pm/Scl, U1
ribonucleoprotein or Ku protein), as well as antibodies
against nucleoporins. This classification system had a
broader inclusion than previous criteria but still required
signs of an inflammatory myopathy for a patient to be
classified as having IIM.
Over the past 10 years, we have seen the IIM disease
spectrum undergo evolution from a disease character-
ized mainly by muscle weakness and partly by skin rash
to include patients with a complex, and sometimes fatal,
disease with multi-organ involvement. One distinct sub-
set of patients that has become more apparent in recent
years is a group of patients who present with ILD that
might be severe and even fatal16. Another ‘novel’ subset
includes patients presenting in early arthritis clinics with
symptoms resembling rheumatoid arthritis but being
negative for rheumatoid factor and anti-­citrullinated
protein antibodies and positive for anti-ARS antibodies
(most commonly, anti‑Jo1 autoantibodies), representing
a phenotype named ASS4,17. Identification of these sub-
groups within the IIM disease spectrum has been made
possible owing to the discovery of MSAs4,18. The MSAs
are associated not only with distinct clinical phenotypes
but also with different HLA-DR alleles, as discussed by
McHugh and Tansley in this Issue of Nature Reviews
Rheumatology19, and with different histopathologies,
as discussed in this Review. Another observation is
that patients who have previously been diagnosed with
poly­myositis on the basis of histopathological findings
in muscle biopsy samples, such as the presence of T cells
surrounding and/or invading normal-appearing muscle
fibres without the presence of rimmed vacuoles, can now
be considered to have IBM on the basis of having typi-
cal clinical features of IBM, emphasizing the importance
of both clinical and histopathological features in the
classification of IIM subgroups20.
Dermatomyositis subsets
Over the past decade, new subsets of dermatomyositis
have become increasingly recognized. Patients with
dermatomyositis can be subclassified on the basis of the

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The first set of modern Targoff et al.

diagnostic criteria for classification
myositis (Medsger criteria)8 criteria for IIMs14

Love et al. put forward a new

approach for the classification
of IIMs, on the basis of MSAs4
ENMC proposes two new entities
Dalakas proposes classification within the PM spectrum: IMNM ENMC diagnostic
criteria for PM, DM and IBM65 and nonspecific myositis2 criteria for IBM48

1970 1975 1991 1995 1997 2003 2004 2005 2011 2013 2017

Bohan and Peter criteria
for the diagnosis of PM
and DM10,11
DeVere and Bradley
criteria for PM9
Dalakas and Hohlfeld put Pestronk proposes
forward distinguishing classification criteria
unique histological features for IIM on the basis
of DM, PM and IBM1 of histopathological
features66
Griggs et al. diagnostic
criteria for IBM45 Troyanov et al. propose a EULAR–ACR classification
classification system on the basis criteria for adult and
Tanimoto et al. of clinical–serological definitions, juvenile IIMs and their
classification criteria introducing the subgroup major subgroups6,7
for PM and DM13 clinicoserologic overlap myositis15

IIM criteria Specific criteria for IBM

Figure 1 | Development of classification and diagnostic criteria for inclusion body myositis (IBM; indicated in blue). DM, dermatomyositis;
idiopathic inflammatory myopathies over time. Since the 1970s, multiple ENMC, European NeuromuscularNature Centre;Reviews
IMNM,| Rheumatology
immune-mediated
sets of criteria have been published for the classification and/or diagnosis necrotizing myopathy; MSAs, myositis-specific autoantibodies; PM,
of idiopathic inflammatory myopathies (IIMs), including specific criteria for polymyositis.

Heliotrope
A pink, red or purplish colouring
around the eyes and eyelids,
with or without oedema.
Gottron sign
A symmetrical, occasionally
scaly, erythematous eruption
over the extensor surfaces of
the metacarpophalangeal and
interphalangeal joints of the
fingers, knees and elbows.
Gottron papules
Red, and often scaly, papules
overlying the extensor surfaces
of the metacarpophalangeal
and interphalangeal joints of
the fingers.
Poikiloderma
Areas of hypopigmentation,
hyperpigmentation,
telangiectasias and atrophy of
the skin.
Telangiectasias
Dilated capillaries that can be
seen in areas of poikiloderma
or at the proximal nailfold.
presence or absence of clinical or laboratory muscle fea-
tures or, via another emerging method, on the basis of
the presence of certain MSAs.
Clinically amyopathic dermatomyositis subsets.
Clinically amyopathic dermatomyositis (CADM)
defines a subgroup of patients with dermatomyositis
and skin-predominant clinical features and includes
both patients with amyopathic dermatomyositis and
patients with hypomyopathic dermatomyositis. The
amyopathic dermatomyositis subset is typically char-
acterized by the presence of biopsy-confirmed hallmark
cutaneous manifestations of dermatomyositis that occur
for 6 months or longer with no clinical evidence of prox-
imal muscle weakness and no abnormalities in serum
levels of muscle enzymes21,22. If additional strength, lab-
oratory and/or imaging tests of the muscle are carried
out, the results should indicate normal muscle function.
Patients with amyopathic dermatomyositis have cuta-
neous manifestations identical to those seen in patients
with classic dermatomyositis (FIG. 2), which frequently
include heliotrope erythema (FIG. 2d), erythema over joints
(Gottron sign) and papules over joints (Gottron papules).
Gottron sign (FIG. 2a–c) and Gottron papules (FIG. 2f) can
be seen over areas that experience stretching, including
the metacarpophalangeal, proximal interphalangeal
and distal interphalangeal joints, knees and elbows. As
active skin lesions of dermatomyositis resolve, patients
are frequently left with pokiloderma (FIG. 2e), defined as
areas of hypopigmentation and hyperpigmentation,
as well as telangiectasias and atrophy of the epidermis3.
Patients with hypomyopathic dermatomyositis have the
same clinical findings in the skin as patients with amyo­
pathic dermatomyositis but demonstrate some muscle
abnormalities on laboratory testing that are clinically
imperceptible23.
When possible, a skin biopsy should be performed
to confirm a diagnosis of dermatomyositis, in which
case a positive sample will normally show interface
dermatitis, frequently with mucin accumulation and
perivascular inflammation (FIG. 2g), which is identical
to that sometimes seen in cutaneous lupus erythemato-
sus. A skin biopsy is also needed to rule out conditions
that mimic various clinical features of dermato­
myositis, including psoriasis, eczema and multicentric
reticulohistiocytosis (MRH)24.
Deposits of the membrane attack complex, or C5b–
C9, in vessel walls can also be observed in muscle biopsy
samples of patients with dermatomyositis.
Skin findings and myositis-specific autoantibodies.
Some of the MSAs are associated with distinct clini-
cal skin manifestations in dermatomyositis25–27. The
anti‑Mi2 antibody was the first reported MSA asso-
ciated with skin rash. In dermatomyositis, anti‑Mi2‑­
positive patients frequently have classic skin eruptions
in sun-exposed areas27, whereas patients positive for
anti-melanoma differentiation-associated protein 5
(MDA5) antibodies frequently develop ulcerations over
the interphalangeal joints, palmar erythematous macules
and papules over the interphalangeal joint creases and
palmar and fingertip mottled erythema25,26. Anti‑MDA5
antibodies are also associated with CADM and a very
high incidence of ILD, with one study reporting that

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93% of anti‑MDA5‑positive Japanese patients, 77% of Patients with anti-ARS antibodies typically have
who had CADM, also had ILD25. Overall, the mortality mechanic’s hand 4, which is also frequently seen in
of patients with CADM due to rapidly progressive ILD patients with characteristic features of dermato­myositis
is high compared with patients with dermatomyositis with or without anti-ARS antibodies27,29. Mechanic’s
and ILD, emphasizing the need for early recognition of hand is defined as symmetrical, nonpruritic, hyper­
this subset of IIM28. keratotic, scaly or fissured patches, linear papules or
Dermatomyositis
a d

Eczema

Interface dermatitis
Dermatitis in which the primary
pathology involves the
dermo-epidermal junction,
with basal cell vacuolization,
apoptotic keratinocytes and a
band-like infiltrate of
inflammatory cells at the
dermo-epidermal junction;
other characteristics in
dermatomyositis include
lymphocytic perivascular
infiltrates and interstitial mucin
deposition.
Figure 2 | Clinical and histological features of the skin in dermatomyositis and conditions that mimic
dermatomyositis. Cutaneous clinical manifestations of dermatomyositis include Gottron sign, presenting as erythema
over areas that experience stretching, including the elbows (part a), the metacarpophalangeal,
Natureproximal
Reviewsinterphalangeal
| Rheumatology
and distal interphalangeal joints (part b) and the knees (part c); the presence of heliotrope erythema on the eyelids
(part d); poikiloderma, including hyperpigmentation distributed on the upper back, referred to as a ‘shawl sign’ (indicated
by arrows; part e); and Gottron papules, presenting as erythematous papules over joints on the hands (indicated by
arrows; part f). One histological feature of dermatomyositis is interface dermatitis of the skin, which presents as lichenoid
inflammation at the dermal–epidermal junction, vacuolar changes in the epidermis and perivascular inflammation (part g).
Various skin conditions can mimic dermatomyositis, including eczema, in which patients present with erythema over
joints on hands that show spongiotic changes consistent with hand dermatitis but not dermatomyositis.

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Mechanic’s hand
The presence of scaling,
fissuring, hyperpigmentation
and hyperkeratosis, distributed
in a characteristic fashion on
the lateral fingers and
sometimes the palmar
surfaces, fingertips and distal
skin, as well on the feet.
Palmar hyperkeratotic
papules
Describes scaly verrucous
papules on the palm.
plaques on the lateral aspects of the digits. These fea-
tures are most prominent on the ulnar surface of the
thumb and the radial surface of the index and middle
fingers and can extend to the palmar surfaces and the
fingertips. Similarly, other skin findings of dermatomy-
ositis can be observed in patients who have anti-ARS
antibodies; therefore, it is important to recognize the
frequent overlap between subgroups of IIMs in terms
of skin findings29.
Patients with dermatomyositis and anti-transcription
intermediary factor 1γ (TIF1γ; also known as TRIM33)
antibodies frequently have more extensive skin involve-
ment than those patients without anti‑TIF1γ antibodies,
and the presence of these antibodies in dermatomy-
ositis is associated with palmar hyperkeratotic papules,
psoriasis-­like lesions, hypo­pigmented and telangiec-
tatic (‘red on white’) patches and a reduction in calcino-
sis25,30. In addition, the presence of anti‑TIF1γ antibodies
is associated with cancer 31. The presence of antibodies
against nuclear matrix protein 2 (NXP2; also known as
MORC3) is also associated with cancer, in addition to
peripheral oedema, calcinosis, milder skin lesions (rela-
tive to dermatomyositis associated with other autoanti­
bodies) and a decreased frequency of Gottron sign,
in adult patients with dermato­myositis32. Anti-small
ubiquitin-like modifier activating enzyme (SAE) anti-
bodies are often associated with an initial presentation
of amyopathic dermatomyositis, sometimes with quite
severe rash, and subsequent progression to IIM with a
high incidence of severe dysphagia33. Another impor-
tant characteristic of dermatomyositis is the presence of
nearly ubiquitous severe pruritus, although this feature
is not clearly associated with a specific autoantibody.
Overall, the different skin features associated with the
different MSAs might indicate different molecular path-
ways involved in the subsets of dermatomyositis with
different autoantibody profiles.
Evaluation of skin severity. The skin is a prominent and
responsive feature of dermatomyositis, and thus, the
ability to measure disease activity and damage in the skin
is important for clinical and investigative studies. The
Cutaneous Dermatomyositis Disease Area and Severity
Index (CDASI), a one-page instrument that measures
key features of disease activity (erythema, scale, ero-
sion and/or ulcerations and nailfold telangiectasias)
and damage (poikiloderma, calcinosis and scarring),
has excellent inter-rater and intra-rater reliability, as
well as responsiveness34–38,. A second modified version
of CDASI, which combines the separate evaluations of
excoriation and ulceration in the disease activity meas-
urements into one and has had other minor modifica-
tions, has also been validated, showing similar reliability
to the initial version39,40. Data from a 2017 study indicate
that CDASI scores highly correlate with the expression
of genetic biomarkers of the type I interferon pathway
(referred to as the type I interferon signature)41. Version 2
of the CDASI is being used in international trials, and
published data suggest that the CDASI score can dis-
tinguish between placebo and treatment arms and
correlates with improvement in quality of life38,42.
Muscle biopsy findings
Another way of classifying and subclassifying patients
with inflammatory myopathies is on the basis of clin-
ical manifestations, with a strong weight given for
muscle biopsy findings. In the 1980s and 1990s, ele-
gant immunohistochemistry studies demonstrated that
biopsy-obtained muscle samples from patients with
dermato­myositis contained deposits of C5b–C9 primar-
ily in the skeletal muscle microvasculature, whereas in
patients with either polymyositis or IBM, non-necrotic
muscle fibres were surrounded by CD8+ T cells, suggesting
an immune attack on the muscle fibres43,44.
Evolving definition of inclusion body myositis.
According to criteria established by Griggs and col-
leagues45, a diagnosis of IBM required the presence of
rimmed vacuoles and other histopathological features.
However, the sensitivity of these criteria for classifying
definite IBM was very low. In addition, investigators
have reported the common occurrence of endomysial
infiltration by CD8+ T cells in non-necrotic muscle fibres
without the presence of rimmed vacuoles in patients
showing a clinically characteristic IBM phenotype, even
in repeat muscle biopsies46. Over the past 5 years, stud-
ies have convincingly demonstrated that the disease
course or response to treatment does not differ between
patients with IBM who fulfil all histopathological cri-
teria and patients who fulfil clinical but not all histo-
pathological criteria47. At a workshop of the European
Neuromuscular Centre (ENMC), experts agreed upon a
set of ‘clinically defined’ criteria for IBM in patients with
a ‘typical’ pattern of weakness (that is, knee extension
weakness greater than or equal to hip flexion weakness
and finger flexion weakness greater than or equal to
shoulder abduction weakness)48. However, these criteria
seemed of fairly low sensitivity, particularly as a substan-
tial number of patients failed to meet ‘weakness of knee
extension greater than weakness of hip flexion’ (REF. 49).
On the basis of patient data and deep machine learning,
a fairly simple and clinically useful set of criteria for IBM
has subsequently been proposed that has 90% sensitivity
and 96% specificity 49. These criteria consist of the pres-
ence of finger flexor or quadriceps weakness, endomysial
inflammation and either the invasion of CD8+ T cells in
non-necrotic muscle fibres or the presence of rimmed
vacuoles. Thus, if the histopathological picture is dom-
inated by endomysial inflammation, an active search
for additional histological features (for example, mito-
chondrial changes and subtle p62 deposits), and for
clinical features pointing to a diagnosis of IBM, includ-
ing asymmetrical weakness of distal muscles (such as
of the deep finger flexors or anterior tibial muscles), is
recommended.
Evolving definition of polymyositis. The concept of histo­
pathologically defining polymyositis by the presence of
endomysial infiltrates composed of CD8+ T cells has been
questioned, given that a similar histopathological finding
can also be present in patients with IBM, as discussed
in the previous section. At an ENMC workshop held in
2004, two new entities within the polymyositis spectrum

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were proposed: IMNM and so‑called nonspecific myosi-
tis (NSM)2. The former disorder is characterized by the
predominance of necrotic muscle fibres (FIG. 3a), often
with scarce or no inflammatory infiltrates and some-
times with prominent endomysial fibrosis50. Patients
with IMNM usually have markedly high levels of cre-
atine kinase activity in their serum. A workshop organ-
ized by ENMC in 2016 was dedicated to this novel entity
among IIMs and included treatment recommendations51.
IMNM can be subdivided into three subgroups: anti‑­
3‑hydroxy‑3‑methylglutaryl-coA reductase (HMGCR)-
positive IMNM (with or without prior statin exposure),
which is associated with an increased risk of cancer
in adults; anti-SRP positive IMNM; and sero­negative
IMNM. The first two subgroups are also found in chil-
dren51. NSM is a term proposed for patients character-
ized histopathologically by the presence of infiltrates,
composed mainly of macrophages, around perimysially
located blood vessels, similar to that observed in dermato-
myositis but without the occurrence of skin rash52. In
contrast to dermatomyositis, the occurrence of perifas-
cicular atrophy has not been observed in patients with
NSM. NSM is associated with connective tissue disor-
ders (CTDs) or CTD-like features (occurring in 20–40%
of patients52), which is similar to the overlap myositis
subgroup suggested by Troyanov; however, Troyanov
et al.15 did not include histopathological analyses when
conducting their study.
Histopathology and myositis-specific autoantibodies.
In the past 5 years, there have been reports of different
histo­pathological features in muscle tissue associated
with different MSA profiles50,53,54. Patients with anti‑Mi2‑­
associated dermatomyositis typically show signs of
‘vasculopathy’ (that is, a loss of capillaries, deposits of
C5b–C9 on the capillaries and the presence of endothelial
microtubular inclusions) in the muscles54. In addition,
muscle biopsy samples from these patients show signs of
perifascicular atrophy with intense MHC class I staining
(albeit usually as a late phenomenon), necrotic myo­fibres
undergoing myophagocytosis and foci of peri­vascular
infiltrates of lymphocytes, as well as macrophages, in
the perimysium53,54. By contrast, anti‑MDA5‑positive
patients often lack these characteristic morphological
features of anti‑Mi2‑positive dermatomyositis54. Muscle
biopsy findings of anti-NXP2-positive patients resem-
ble those of anti‑TIF1γ‑positive patients — including
perifascicular atrophy, MHC class I upregulation in
the perifascicular atrophic myofibres and perivascu-
lar inflammation — but show little evidence of pri-
mary inflammation (that is, invasion of non-­necrotic
fibres by mononuclear cells)53,54. ARS antibodies are
associated with some dermatomyositis-related features
(such as abnormalities of the microvasculature) but
are additionally associated with features distinct from
dermato­myositis, such as necrosis of muscle fibres in the
perifascicular areas instead of atrophy (FIG. 3b), perimys-
ial fragmentation and increased perimysial histochem-
ical activity of alkaline phosphatase55–60. All of these
features are seen in the most common ARS-positive
subgroup — anti‑Jo1‑positive patients.
In IMNM, anti-HMGCR and anti-SRP antibodies are
associated with the frequent presence of necrotic fibres
and often sparse inflammation of the muscle fibres50,61.
Notably, in a proportion of patients with dermato­
myositis, the histopathological picture can resemble that
of IMNM, including the presence of myofibre degen-
eration, necrosis and myophagocytosis, but without
perivascular inflammation, perifascicular atrophy and
endothelial microtubular inclusions51,62.
A muscle biopsy is still recommended in most of
the patients with presumed IIM in the absence of skin
findings of dermatomyositis as MSAs are found in only
half of patients with IIM18; the associations between
auto­antibody profiles and muscle morphology are not
fully understood, and muscle biopsy can be particularly

a IMNM b Antisynthetase syndrome

Figure 3 | Muscle biopsy findings of patients with two different idiopathic inflammatory myopathies. a | Muscle
biopsy sample (haematoxylin and eosin stain) from a patient with immune-mediated necrotizing
Naturemyopathy
Reviews | (IMNM)
Rheumatology
showing scattered necrotic muscle fibres with some undergoing myophagocytosis (arrow). b | Muscle biopsy sample
(haematoxylin and eosin stain) from a patient with antisynthetase syndrome showing necrotic muscle fibres undergoing
myophagocytosis in the perifascicular area (arrow) and perimysial fragmentation of connective tissue (asterisk). Both
images courtesy of E. Aronica, Department of Pathology, Academic Medical Center, Amsterdam, Netherlands.

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useful as some muscular dystrophies, such as dysfer-
linopathies, might mimic an inflammatory myopathy54.
However, the interpretation of specific histopatho­logical
patterns is cumbersome, even for experts. Therefore,
consensus on a proposed scoring system for muscle
biopsy tissue sample evaluation should be achieved, as
has been done for juvenile dermatomyositis63.
New EULAR–ACR classification criteria
Several classification criteria have been developed for
IIMs since 1970, all with different emphases and based
mainly on clinical or muscle biopsy features (FIG. 1).
Over the past 15 years, we have seen an increasing
number of criteria being proposed; however, most of
these criteria have limitations, such as capturing only
patients with some but not all of the phenotypes of IIMs
and not being data driven. Thus, in 2004, the impetus
began to develop new classification criteria for IIMs.
This undertaking included the involvement of inter-
national experts in adult and paediatric rheumatology,
neurology, dermatology, epidemiology and biostatistics
and resulted in the development of the EULAR–ACR
classification criteria for adult and juvenile IIMs and
their major subgroups6,7.
Development of the new criteria. Candidate criterion
items were selected on the basis of existing criteria for
IIMs and expert opinion6,7. Large organizations repre-
senting experts who manage patients with IIMs (includ-
ing EULAR, the ACR and the International Myositis
Assessment and Clinical Studies Group (IMACS)) pro-
vided support for this project, which was an important
aim from the beginning. and endorsed the final version
of the criteria.
Of the several models tested in the development of the
new criteria, a novel probability-score model performed
the best in distinguishing patients with IIMs from com-
parators. In this model, 16 variables were identified, and
each variable was given a score on the basis of its predic-
tive ability (BOX 1). The sum of the points corresponds to
a probability of having an IIM. A probability cut-off of
≥55% was defined as the minimum probability needed
to classify a patient as having an IIM. A probability of
55–75% (with muscle biopsy data), which corresponds
to an aggregated score of ≥6.7 and ≤7.6, and a probabil-
ity of 55–60% without muscle biopsy data, which cor-
responds to an aggregated score of ≥5.5 and ≤5.7, had
the best balance between sensitivity and specificity 6,7.
A classification tree approach was the best method for
identifying subgroups of IIMs in patients who first ful-
filled the classification criteria for IIMs. Through this
tree, patients with juvenile or adult dermatomyositis,
amyopathic dermatomyositis, IBM or polymyositis
could be subclassified.
These criteria have several novelties compared with
previous criteria (BOX 2). The practical implication of the
probability model and the different weights each varia-
ble contributes mean that one needs to test only enough
variables to reach a predefined probability (correspond-
ing to an aggregated score), lending flexibility to the
classification criteria. Notably, the presence of anti‑Jo1
autoantibodies gives the highest score among the varia-
bles in the new criteria, supporting a high level of spec-
ificity for this single criterion. In this model, two sets of
scores were developed: one for when muscle biopsy data
are available and one for when muscle biopsy data are
unavailable, the latter of which can be applied to patients
with a skin rash typical of dermatomyositis. Importantly,
a muscle biopsy is required in patients without a typi-
cal skin rash. With the new EULAR–ACR classification
criteria, patients with dermatomyositis without clinical
muscle weakness (amyopathic dermatomyositis) can be
classified as having IIM. In these patients, a skin biopsy
should be performed to exclude other causes of the
skin rash.
Skin variables assessed in the EULAR–ACR clas-
sification criteria. In the project leading up to the
EULAR–ACR IIM criteria, skin variables were col-
lected retrospectively and could have been present at
any time during the disease course. The data collected
from patients with dermatomyositis for the derivation
of the criteria included 236 patients with adult dermato­
myositis, 251 patients with juvenile dermatomyositis and
56 patients with CADM (44 with amyopathic dermato-
myositis and 12 with hypomyopathic dermatomyositis).
The patients with CADM chosen for evaluation all had
skin biopsies confirming the presence of typical changes
in the skin, including interface dermatitis and perivascu-
lar and periadnexal inflammation. Identical skin biopsy
changes can be seen in cutaneous lupus erythematosus;
thus, identifying which clinical variables, including skin
variables, correlate with which pathologies is of great
importance. A skin biopsy is also needed to rule out con-
ditions mimicking dermatomyositis, such as psoriasis,
eczema (FIG. 2) or even MRH, and to confirm changes
consistent with a diagnosis of dermatomyositis.
The new EULAR–ACR criteria include three skin
variables: heliotrope erythema, Gottron papules and
Gottron macules. The presence of two of these three
variables in a given patient allows for a diagnosis of
CADM in the absence of muscle findings, preferably
after a confirmatory skin biopsy. In the validation sam-
ples derived from the Euromyositis Registry, there were
only four samples from patients with CADM, thus mak-
ing it difficult to confirm the skin criteria for patients
with CADM. A subsequent analysis using a prospective
dermatomyositis database has determined that the new
classification criteria capture nearly 75% of patients with
amyopathic dermatomyositis; therefore, the new classifi-
cation criteria are clearly better at detecting CADM than
previous IIM classification criteria64.
Criteria limitations. For the development of the EULAR–
ACR classification criteria, patients with and without
IIMs were recruited from 47 centres in Europe, North
and South America and Asia, representing adult patients
from rheumatology, neurology and dermatology cen-
tres and juvenile patients from paediatric rheumato­logy
centres. In total, 976 patients with an IIM (74.5% adults;
25.5% children) and 624 patients with conditions mim-
icking IIMs (81.6% adults; 18.4% children), of different

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Box 1 | The EULAR–ACR classification criteria for adult and juvenile IIMs and their major subgroups6,7
Muscle biopsy available
• Probable idiopathic inflammatory myopathies (IIMs): aggregated score (probability ≥55% and <90%) ≥6.7 and <8.7
• Definite IIMs: aggregated score (probability ≥90%) ≥8.7
Muscle biopsy not available
• Probable IIMs: aggregated score (probability ≥55% and <90%) ≥5.5 and <7.5
• Definite IIMs: aggregated score (≥90% probability) ≥7

Variable Score
Without With muscle
muscle biopsy biopsy
Age of onset of first symptom assumed to be related to the disease ≥18 years 1.3 1.5
and <40 years
Age of onset of first symptom assumed to be related to the disease ≥40 years 2.1 2.2
Muscle weakness
Objective symmetrical weakness, usually progressive, of the proximal upper 0.7 0.7
extremities
Objective symmetrical weakness, usually progressive, of the proximal lower 0.8 0.5
extremities
Neck flexors are relatively weaker than neck extensors 1.9 1.6
In the legs, proximal muscles are relatively weaker than distal muscles 0.9 1.2
Skin manifestations
Heliotrope rash 3.1 3.2
Gottron papules 2.1 2.7
Gottron sign 3.3 3.7
Other clinical manifestations
Dysphagia or oesophageal dysmotility 0.7 0.6
Laboratory measurements
Anti-histidyl-transfer RNA synthetase (Jo1) autoantibody present 3.9 3.8
Elevated serum levels of one of the following enzymes : creatine kinase, lactate
a
1.3 1.4
dehydrogenase, aspartate aminotransferase or alanine aminotransferase
Muscle biopsy features — presence of
Endomysial infiltration of mononuclear cells surrounding, but not invading, – 1.7
myofibres
Perimysial and/or perivascular infiltration of mononuclear cells – 1.2
Perifascicular atrophy – 1.9
Rimmed vacuoles – 3.1
Table adapted from Lundberg, I. E. et al. 2017 European League Against Rheumatism/American College of Rheumatology
classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann. Rheum. Dis. 76,
1955–1964 (2017) (REF. 6) and with permission from REF. 7, Wiley. aSerum levels above the upper limit of normal.

ethnicities, were recruited6,7. To ensure the feasibility of
applying the new criteria in future trials, it was important
that the variables included in the new criteria were acces-
sible in many centres worldwide. Therefore, some vari-
ables were not included in the new criteria, such as MRI
findings, which were available for less than 38% of the
patients in our study cohort. This reasoning also applied
to most MSAs, as when the project started there were
few commercially available tests for MSAs and some of
the MSAs had not yet been identified (for example, anti-
HMGCR antibodies that are associated with IMNM).
A limitation of the EULAR–ACR classification
criteria is that too few patients with clinical features
of IMNM were included as this condition had only
just been identified when this project started in 2004
(REFS 2,6,7). Hence, the polymyositis subgroup likely
contains patients with IMNM. The same limitation
applies to patients with ASS, who were not specifically
identified among the included patients. Another limita-
tion relates to the patients classified as having IBM, as at
the time of data collection most experts relied on histo-
pathological variables, such as the presence of rimmed
vacuoles and endomysial T cell infiltrates, to define
IBM whereas suggestive clinical criteria for IBM have
since been proposed48. Finally, some patients might also
have been misclassified as having an IIM when they
actually had muscular dystrophies with inflammatory
infiltrates similar to IIMs.

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Box 2 | Advantages of the new EULAR–ACR classification criteria for IIMs and their major subgroups6,7

• The criteria are data driven.

• The probability-score model enables flexibility in the number of variables needed to be tested and enables further
development after testing new cohorts.
• Two models were developed, one with muscle biopsy data and one without muscle biopsy data, to be applied for
patients with typical dermatomyositis skin rash when no biopsy is available.
• Each variable contributes with different weights to an aggregated score.
• Patients classified as having an idiopathic inflammatory myopathy (IIM) can be subclassified using a classification tree.
• Patients with dermatomyositis without clinical muscle weakness (so-called amyopathic dermatomyositis) can be
classified as having an IIM using the new criteria.
• A web-based calculator was developed to facilitate the calculation of the probability score and subclassification
of IIMs.

The EULAR–ACR criteria for IIMs were validated Conclusions

in external cohorts of patients with IIMs and demon-
strated an excellent performance (as measured by sensi-
tivity) in classifying both IIMs and subgroups of IIMs6,7.
Importantly, these external cohorts did not include
patients without IIMs. Therefore, further validation
of the EULAR–ACR classification criteria for IIMs is
needed with an external cohort that includes all new
subgroups of patients with IIMs, including patients with
IMNM, patients without myopathy such as amyopathic
dermatomyositis and ASS, patients with IBM diagnosed
mainly on the basis of clinical features and not requir-
ing the presence of rimmed vacuoles and patients with
various MSAs, as well as patients without IIMs as com-
parators. Assays for MSAs also need to be validated. An
advantage of using the probability model is that it enables
further development of these criteria, enabling the inclu-
sion of new variables or the modification of the weights
of different variables after new data have been collected
and tested in patients with IIMs and patients with dis-
eases mimicking IIMs. Multidisciplinary, international
collaborations should strive to undertake these validation
processes and to develop these criteria, considering the
emerging new scientific information in the field of IIMs.
In conclusion, over the past decade, with the detection
of an increasing number of MSAs researchers have
recognized that IIM encompasses a broad spectrum
of conditions that includes patients with multi-organ
involvement, including sometimes critically ill indi-
viduals, and patients in whom muscle symptoms might
be absent. This spectrum needs to be fully captured in
classification criteria for future clinical trials. The new
EULAR–ACR classification criteria for adult and juve-
nile IIMs and their major subgroups are an improvement
in this direction as these criteria capture subgroups with-
out clinically manifest muscle symptoms, such as amyo-
pathic dermatomyositis, but the criteria might still leave
out some patient categories (for example, those with only
ILD and an MSA). Therefore, the new classification cri-
teria need to be continually developed and validated in
cohorts of patients that include patients and comparators
that have been tested for MSAs using validated assays.
This continued development needs to be performed in
multidisciplinary, international collaborations and can
be accomplished with the probability model, which ena-
bles modifications of the criteria when new data become
available.

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Acknowledgements
The authors thank A. Tjärnlund for being the research coor-
dinator of the International Myositis Classification Criteria
Project (IMCCP) and for the critical reading of this manu-
script. The authors also thank the IMCCP consortium. The
authors thank V. Leclair for her help with Fig. 1. V.P.W. was
involved in the development of the Cutaneous
Dermatomyositis Disease Area and Severity Index (CDASI);
the copyright for this instrument is owned by the University
of Pennsylvania. This work was supported by the US NIH
(R21 AR066286 and K24‑AR 02207) as well as a US
Veterans Affairs Merit Review grant (I01BX000706) (V.P.W.).
I.E.L. has received grant support from the Swedish Research
Council and the Regional Agreement on Medical Training and
Clinical Research between the Stockholm County Council
and Karolinska Institutet.
Author contributions
All authors researched the data for the article, provided sub-
stantial contributions to discussions of its content, wrote the
article and reviewed and/or edited the manuscript before
submission.
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Referee accreditation statement
Nature Reviews Rheumatology thanks W. Stenzel and the
other anonymous reviewer(s), for their contribution to the
peer review of this work.
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