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Review

Inflammatory myopathy:
diagnosis and clinical course,
specific clinical scenarios and
new complementary tools
Expert Rev. Clin. Immunol. 11(6), 737747 (2015)

Albert
Selva-OCallaghan*1,
Ernesto
Trallero-Araguas,
Maria Angeles
Martnez2, Moises
Labrador-Horrillo1,
Iago Pinal-Fernandez1,
Josep Maria
Grau-Junyent3 and
Candido Juarez2
1
Internal Medicine Department,
Vall dHebron General Hospital,
Universitat Autonoma de Barcelona,
Barcelona, Spain
2
Immunology Department, Hospital
De La Santa Creu I Sant Pau, Universitat
Autonoma De Barcelona, Barcelona,
Spain
3
Internal Medicine Department, Hospital
Clinic, Universitat De Barcelona,
Barcelona, Spain and CIBERER
*Author for correspondence:
aselva@vhebron.net

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Idiopathic inflammatory myopathies are a heterogeneous group of rare autoimmune diseases

characterized by symmetric proximal muscle weakness and inflammatory infiltrates on muscle
biopsy. A meticulously collected combination of clinical, serological, and pathological data is
essential to correctly diagnose and classify myositis patients, often a considerable challenge
for clinicians. This article provides a comprehensive overview of the most useful tools for the
diagnosis and follow-up of patients with myositis. Capillaroscopy, serological biomarkers
(particularly the autoantibody profile) and imaging techniques, such as muscle magnetic
resonance and chest ultrasound, are of great aid in diagnosing, classifying and managing
these patients. Relevant clinical scenarios, such as interstitial lung disease, associated cancer
and pregnancy are also addressed in this review. Myositis registries, identification of new
autoantibodies, and genetic studies will enhance our understanding of the pathogenesis of
these conditions and help to define new diagnostic and therapeutic approaches.
KEYWORDS: autoantibodies . classification . dermatomyositis . diagnosis . idiopathic inflammatory myopathies
.

myositis

polymyositis

Diagnosis & classification of idiopathic

inflammatory myopathy

Idiopathic inflammatory myopathy (IIM), also

known as myositis, refers to a group of rare
diseases with a global incidence of 510 new
cases per million population per year [1,2]. It is
partly because of this limited number of
affected patients that advances in our knowledge of these diseases are slow to materialize.
This brings us to the first difficulty related to
myositis: properly diagnosing and classifying
these disorders. Since the seminal description
of the different forms of myositis published in
1975 by Bohan and Peter [3], several classifications have been proposed, based on histopathological findings [4], the autoantibody
profile [5] or a mixed set of criteria, including
clinical manifestations, muscle biopsy, and
serological tests, among others [68]. Nevertheless, the criteria of Bohan and Peter are often
used in the related literature, only challenged
by the European Neuromuscular Centre classification [9] and the recently communicated,
10.1586/1744666X.2015.1035258

but not yet published, American College of

Rheumatology and European League Against
Rheumatism (ACR/EULAR) classification [10].
The proposed classification systems have
dealt with the high clinical variability of IIM
by segregating patients into clinical subgroups.
Bohan and Peter [3] differentiated dermatomyositis (DM) from polymyositis (PM) according
to the skin involvement, recognized cancerassociated myositis and described a juvenile
form (childhood DM) with vasculitis as a
prominent feature, but did not consider amyopathic DM or inclusion body myositis (IBM)
as different entities. Dalakas [4] took a step forward, excluding from the PM group patients
with IBM, probably the least inflammatory of
these myopathies, usually refractory to treatment and showing characteristic rimmed
vacuoles on muscle biopsy. Nonetheless,
immune-mediated
necrotizing
myopathy
(IMNM) and again, amyopathic DM, were
not recognized as separate entities. In the
1990s, L.A. Love, from the NIH, in Bethesda,
Maryland, established a novel classification

2015 Informa UK Ltd

ISSN 1744-666X

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Selva-OCallaghan, Trallero-Aragua

Table 1. Comparison of the different idiopathic inflammatory myopathies classifications.

IMCCP [ACR/EULAR]
(2015) [10]

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Model 1 (%)

Bohan & Peter

(1975) [3,10] (%)

Dalakas
(1991)
[4,17] (%)

Tanimoto
(1995)
[2,10] (%)

Targoff
(1997)
[7,10] (%)

Dalakas
(2003)
[10,50] (%)

ENMC
(2004)
[9,10] (%)

Model (2) (%)

Sensitivity

87

88

98

89

96

93

51

Specificity

88

89

55

47

31

88

99

96

Correctly
classified

87

88

86

66

79

91

45

70

Model 1: Without muscle biopsy. Model 2: With muscle biopsy.

ENMC: European Neuromuscular Centre; IMCCP (ACR/EULAR): International Myositis Classification Criteria Project (American College of Rheumatology and European
League Against Rheumatism).

based on what was called myositis-specific and myositisassociated autoantibodies [5]. For the first time, different clinical subsets of myositis patients were associated with different
autoantibodies, a valuable help for recognizing the individual
forms. Manifestations of interstitial lung disease (ILD), arthritis
and mechanics hands were highly associated with the presence
of antisynthetase autoantibodies, in either DM or PM. Patients
with DM and widespread pathognomonic skin manifestations
(Gottrons papules, heliotrope rash, cuticular overgrowth, V
sign, shawl sign) often tested positive for anti-Mi2 autoantibodies, and a sudden severe onset of PM with cardiac involvement in black females was found to be associated with antisignal recognition particle autoantibodies, although later studies
expanded this clinical spectrum [1114]. This was a very creative
approach, but it had one major drawback: myositis-specific
autoantibodies were highly specific but lacked sensitivity. Thus,
at that time, around half the patients with other features of
myositis did not have any autoantibodies to aid in the diagnosis or classification [15].
Considering these results, some authors have attempted to
combine clinical, histological and serological information to
identify different patient groups, although the Bohan and Peter
classification still prevails in the current literature, even being
used in the largest clinical trial to date on IIM treatment [16].
The European Neuromuscular Centre classification went further by differentiating between all the main clinical subgroups,
including amyopathic DM, IBM and IMNM.
An analysis comparing different myositis classifications established that the 2003 Dalakas criteria (different from the abovementioned 1991 criteria and including amyopathic DM) and
the European Neuromuscular Centre classification had the
highest specificity and sensitivity and were the most reproducible [17]. Recently, following the EULAR/ACR recommendations, a multidisciplinary, collaborative international project
developed and validated new classification criteria for adult and
juvenile IIM [10]. Nearly 1000 patients with different types of
myositis and more than 600 comparators were classified
accordingly in 47 clinics devoted to the study of myositis
worldwide, with external validation showing good performance.
Using this classification, the diagnoses can be reached without
the need for muscle biopsy, and it includes anti-Jo1, one of the
738

most relevant myositis-specific autoantibodies. Although these

classification criteria are supported by most of the related international scientific societies, some minor issues remain to be
solved before their publication (TABLE 1 summarizes the main
myositis classifications).
All in all, the EULAR/ACR classification seems to be the
most useful in terms of specificity/sensitivity, but it does not
include certain new autoantibodies, such as anti-MDA5 or
anti-TIF1-g, which are considered specific to DM patients [18],
or the new anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCT) autoantibodies, highly associated with an
IMNM often related to statin exposure [19]. In sum, myositis
classification should be viewed as an ever-changing topic that
must be updated periodically to adapt to the pace of emerging
scientific data.
How to succeed in the diagnosis of myositis: the
parable of the six blind men & the elephant

Diagnosing myositis is a challenge, as the boundaries between

the different clinical subgroups are not always clear-cut [20]. It
is of paramount importance to establish an accurate diagnosis,
as implementation of immunosuppressive therapy to treat autoimmune myositis is not without potential side effects. Limb
girdle muscle dystrophies, especially dysferlinopathies, are common mimics of PM, and differentiation between these conditions can be difficult [2124]. Several methods are available,
some invasive and some not, to achieve the highest probability
of an accurate diagnosis. Among the noninvasive tests, autoantibody analysis has a central role. Myositis-specific and -associated autoantibodies are rare in limb-girdle muscle dystrophies
and other non-inflammatory muscle diseases [2527]; hence, their
presence supports the diagnosis of an inflammatory myopathy.
The last few years have witnessed the revolutionary discovery
of several new autoantibodies in myositis patients, and this has
lowered the percentage of IIM patients testing negative to all
the known autoantibodies from 50 to 20%. Now, most IIM
patients have at least one myositis-specific or -associated antibody to support the diagnosis. Moreover, some of these new
autoantibodies identify specific subsets of patients. For example,
positive testing for anti-TIF1-g (formerly known as anti-p155)
in an adult with cancer, periungual erythema and a moderately
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Inflammatory myopathy

high plasma creatine phosphokinase concentration suffices for

the DM diagnosis, even in the absence of muscle biopsy information or other clinical manifestations, as this autoantibody is
highly specific for DM [28,29]. Likewise, the presence of antiMDA5 antibodies in a young adult with rapidly progressive
ILD and a slight heliotrope rash suggests the diagnosis of
amyopathic DM and prompts initiation of aggressive immunosuppressive therapy [18,30,31].
Muscle biopsy, a relatively invasive diagnostic test, can be
avoided in childhood forms of myositis, but is still important
in adult patients, particularly if it shows characteristic findings,
such as perifascicular atrophy, considered pathognomonic for
DM even in the absence of the typical skin rash [9]. However,
muscle biopsy findings can be very heterogeneous and the diagnostic yield may vary depending on factors such as prior
immunosuppressive treatment and the location of the biopsy.
Furthermore, other non-inflammatory muscle diseases, such as
the dysferlinopathies, sometimes show an inflammatory infiltrate on muscle biopsy. Consequently, non-specific inflammatory muscle biopsy findings should be interpreted with caution,
and alternative diagnoses should be considered in the proper
clinical context. In addition, some biopsy findings formerly
considered to be associated with specific myositis subgroups
now seem inadequate to establish the diagnosis. In addition,
some biopsy findings such as upregulation of major histocompatibility class I antigen in non-necrotic muscle fibers, commonly used to identify patients with IMNM, or the finding of
an infiltrate of CD8-positive cells in the absence of a partial
invasion phenomenon, in patients with PM, formerly considered to be associated with specific myositis sub-groups now
seem inadequate to establish the diagnosis [20].
In summary, an accurate diagnosis of myositis is achieved
through a combination of clinical, serological and pathological
information. An example would be a patient treated with statins experiencing myalgia and showing high creatine kinase values. The presence of antibodies against anti-HMGCR and
IMNM on muscle biopsy will enable the clinician to establish
the diagnosis of statin-associated autoimmune myopathy [19].
Myositis is like the elephant in the parable of the six blind
men from Indostan. Each person touched only a part of the
huge elephant and therefore, each one wrongly interpreted the
nature of the animal they were examining [32]. Myositis can be
interpreted from the perspective of the autoantibody profile,
the muscle disease or the clinical manifestations, but to reach
an accurate diagnosis, all these findings have to be integrated.
As the conclusion of the story states: Only by sharing what
each of you knows can you possibly reach true understanding .
Clinical course & organ involvement

The clinical course of patients with myositis is quite variable.

Classically, patients have been categorized into different groups
to assess the development of the disease along time [15]. Thus, a
monocyclic course is defined as full recovery within 2 years
without a subsequent relapse, chronic polycyclic disease is
described as prolonged disease with one or more relapses
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Review

Box 1. Myositis assessment instruments

recommended by the International Myositis
Assessment and Clinical Studies group [39].
Disease activity core set measures (last 4 weeks)
.

.
.
.

Physician global activity (PGA) (visual analogue scale/Likert

scale)
Patient/parent global activity (visual analogue scale/Likert
scale)
Manual muscle testing (MMT8)
Health assessment questionnaire (HAQ)
Myositis disease activity assessment tool (MDAAT), which
includes
Myositis disease activity assessment visual analog scales
(MYOACT), myositis intention to treat activity index
(MITAX)

Disease damage core set measures (persistent pathological,

and functional changes present for at least 6 months)
.
.

Myositis damage index (MDI)

Physician global damage (PGD) (visual analogue scale/Likert
scale)

occurring between periods of inactive disease, a chronic continuous course corresponds to persistently active disease for more
than 2 years despite drug therapy, and finally, an illness of less
than 2 years duration is classified as an undefined clinical
course. It should be mentioned that even patients who achieve
complete remission do not usually regain their former health
status before development of the disease, and a certain degree
of exhaustion remains in some cases.
According to our personal experience and that of other groups,
it seems that approximately one-third of patients show each of
these courses (monocyclic, polycyclic or chronic continuous)
[15,33,34]. In most relapsing patients, the clinical relapse occurs
during the first 2 years of disease onset and after an initially
favorable response. Nonetheless, the frequency of relapses and
the influence of factors, such as the initial disease severity, delays
in treatment and seasonality on the risk of relapse are topics of
debate [3538]. Standardized, practical definitions of relapse,
recovery, and disease activity are vitally needed to answer these
and other questions in properly designed clinical studies. The
International Myositis Assessment Clinical Studies group has
made huge efforts in this direction by developing and validating
scales to estimate disease activity and damage that are being
increasingly used in research and clinical practice (BOX 1) [39].
Cancer-associated myositis, the so-called paraneoplastic myositis, which affects one-third of patients with DM, can be a
particularly complex situation. Usually the relationship between
cancer and myositis is quite clear that is, when cancer is controlled, myositis activity decreases but this is not always the
rule. Cancer can trigger IIM and, as happens in other autoimmune disorders, after the disease is activated, it can progress
with full autonomy, indifferent to the cancer course. Furthermore, some cancer drugs act as strong immunosuppressive
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agents, and clinicians cannot know whether the clinical

improvement in myositis symptoms is the result of cancer
improvement or the effect of therapy [40].
During the follow-up of patients with myositis, clinicians
should reconsider their diagnosis when the clinical course is not
as expected, especially in patients with PM, which is increasingly considered a diagnosis of exclusion [23]. In a recent study,
re-evaluation of 10 patients with isolated PM 15 years after the
diagnosis showed that only one patient continued with the PM
diagnosis at that time [24]. Clinicians should be aware that
patients considered to have refractory myositis may be affected
with muscle disorders, such as IBM or limb-girdle muscle dystrophies, and act accordingly.
At the onset and during the clinical course of IIM, organs
other than muscle may be affected. A meticulous history taking
and exhaustive examination are the best initial approaches to
determine what body structures are involved. Clinical findings,
such as auscultation of dry crackles in lung fields or the presence of mechanics hands, may point to ILD and prompt a
more refined evaluation. This could imply pulmonary function
testing (PFT), chest computed tomography imaging and determination of an appropriate autoantibody profile, possibly
including different antisynthetase autoantibodies, anti-PM/Scl
antibodies or the recently described anti-MDA5 autoantibody.
Some clinical manifestations run in parallel with the skeletal
muscle involvement, improving when the general condition
does. This is the case of diaphragm muscle weakness with an
impact on pulmonary ventilation, and cricopharyngeal muscle
involvement, affecting deglutition. Occasionally, diaphragm
and cricopharyngeal involvement are severe and life-threatening,
requiring aggressive immunosuppressive therapy or even nonpharmacologic therapies. These may include nasal or tracheal
intermittent positive pressure ventilation for diaphragm involvement in myositis patients, or cricopharyngeal myotomy, endoscopic balloon dilatation or even local Clostridium botulinum
toxin injection for cricopharyngeal muscle involvement [41,42].
Regular performance of PFT, including maximum inspiratory
pressure and maximum expiratory pressure measurement, may
help in the evaluation of diaphragm weakness, with lower maximum inspiratory pressure values indicating greater diaphragm
involvement. Alternatively, a hypertonic upper esophageal
sphincter (cricopharyngeal bar), the main culprit of severe oropharyngeal dysphagia in myositis patients, should be diagnosed
by videofluoroscopy, the reference standard for detecting this
clinical situation. To date, no specific autoantibodies have been
identified in association with diaphragm or cricopharyngeal
involvement.
Venous thromboembolism is a serious condition that may
have a fatal outcome. Several articles have reported an association between IIM and venous thromboembolism, with a risk
up to seven-times higher in IIM patients than in the general
population [43,44] Plausible mechanisms to explain this relationship include vascular inflammation, especially in DM
patients [45], the association of IIM with occult neoplasm,
immobility due to the muscle weakness characteristic of the
740

disease and some therapies, such as intravenous immunoglobulins. Consequently, clinicians should have a high index of suspicion for venous thromboembolism in myositis patients.
Mandatory prophylaxis may be needed in certain cases and in
specific clinical scenarios that remain to be determined.
Complementary tools for the follow-up of myositis
patients
Capillaroscopy

Nailfold capillary microscopy is a noninvasive technique that

enables study of the microcirculation at bedside. Its main application is to differentiate between patients with idiopathic or
primary Raynaud phenomenon, which usually has no clinical
relevance, and those with secondary Raynaud, due to systemic
autoimmune diseases, specifically systemic sclerosis. The role of
this test in IIM is still being defined [46]. Several features such
as enlarged capillaries, giant capillaries and microhemorrhages
seem to be more prominent in patients with DM than in
PM [47,48] and may be of help to support the diagnosis.
A deranged capillary pattern in DM patients has been proposed
as a surrogate marker of occult malignancy [47]. Capillaroscopic
changes have been reported to predict the evolution of systemic
sclerosis over time [48]. If this were also true for IIM, periodic
nailfold capillaroscopy could be useful to assess the patients
microcirculatory status; however, to our knowledge, there are
no available studies investigating this possibility.
Serological biomarkers & autoantibody profile

Serum concentrations of the muscle enzymes creatine kinase,

aspartate, alanine aminotransferase, lactate dehydrogenase and
aldolase are usually increased in myositis patients. Creatine
kinase is the most sensitive parameter, showing an increase up
to 50-fold in active disease [49]. When creatine kinase values are
initially high, subsequent reductions are a useful surrogate
marker of clinical improvement. Clinicians should be aware of
some relevant drawbacks regarding these simple serological biomarkers. First, high transaminase values in the absence of creatine kinase analysis may lead to an erroneous diagnosis of
hepatitis in patients with mild muscle disease. Second, not all
the patients with active myositis have a high creatine kinase
level; occasionally the tests are normal, even in active disease.
Third, the presence of high aldolase values in the absence of
elevated creatine kinase is not unusual and points to muscle
disease, especially directed against early regenerative muscle
cells, which are often found near the perimysium. This may
explain why aldolase is a good marker of perimyositis in
patients with eosinophilic fasciitis [5052].
It is now well recognized that myositis-specific and -associated autoantibodies are of great value for the diagnosis and
identification of different subgroups of patients with
myositis (TABLES 2 & 3) [26,27,53], but their value in follow-up
remains controversial. Some studies have investigated the use of
autoantibodies as prognostic factors [54] (e.g., higher anti-Jo1
plasma levels associated with disease severity), to define uncommon clinical manifestations [55] (e.g., pericardial effusion due to
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Inflammatory myopathy

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anti-PL7 in antisynthetase syndrome),

Table 2. Myositis specific antibodies [26,53].
and as surrogate markers of disease activClinical
Autoantibodies Target autoantigen
Protein
ity [56] (e.g., anti-signal recognition partiphenotype
molecular
cle as a marker of activity). The
weight kD (~)
development of simple tests that can be
Anti-ARS
tRNA syntethase
ASS
performed in standard laboratories, such
as in-house or commercial ELISAs conAnti-Jo1
Histidyl
50
firmed by blotting, has facilitated autoanAnti-PL-7
Threonyl
80
tibody analysis, enabling accurate
Anti-PL-12
Alanyl
110
measurement of these markers over time
and determination of their association
Anti-OJ
Isoleucyl
160
with different clinical manifestations.
Anti-EJ
Glycyl
75
Analysis of anti-MDA5 antibody levels
Anti-KS
Asparaginyl
65
by ELISA in patients with rapidly progressive ILD associated with clinically
Anti-Zo
Phenylalanyl
60,70
amyopathic DM seems to have considerAnti-Ha
Tyrosyl
able value. Accumulating evidence has
(previously YRS)
shown that the levels of these autoantiNecrotizing
54
Anti-SRP
SRP54
bodies correlate well with the patients
myopathy
68
SRP68
clinical course [57,58]. In addition, ferritin
72
SRP72
levels can be used as a surrogate of disease
activity in these patients [59]. Preliminary
Anti-Mi-2
DNA helicase family protein
220 (a)/218(b)
DM, Juvenil DM
(NuRD): Mi2-a, Mi2-b
results suggest that anti-TIF1-g levels in
cancer-associated myositis may decrease
Anti-TIF-1g
TIF-1g
155
CAM, DM, Juvenil
after cancer treatment [60]. Research is in
Anti- TIF1a
TIF-1a
140
DM
progress to confirm these results, to furAnti-MJ
NXP-2
107
DM, Juvenil DM
ther investigate the relationship between
MDA5
117
DM, CADM, RP-IP
serum anti-TIF1-g levels and cancer, and Anti-MDA5
to delineate the value of longitudinal antiAnti-SAE
SUMO-1 Activating Enzyme
72 (2)/38 (1)
DM, CADM
TIF1-g measurement to predict the devel1, 2
opment of new malignancies. Other autoAnti-HMGCR
HMG-CoA reductase
200, 100
Necrotizing
antibodies, such as anti-NXP2, have been
myopathy
related to the presence of calcinosis in
ASS: Antisynthetase syndrome; CADM: Clinically amyopathic DM; CAM: Cancer-associated myositis;
children and adults [61] and to cancer, but DM: Dermatomyositis; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; MDA5: Melanoma differentiationassociated gene 5; NuRD: Nucleosome remodeling-histone deacetylase; RP-IP: Rapidly progressive interstitial
only in adult myositis, not in juvenile
pneumonia; SRP: Signal recognition particle; SUMO-1: Small ubiquitin-like modifier-1; TIF1: Transcriptional
DM [62]. This dual behavior of autoantiintermediary factor 1.
bodies regarding the risk of cancer in
Chest ultrasound, an imaging technique that does not use
adults and juvenile DM patients also occurs with anti-p155,
which is clearly related to cancer in adults, but not in children. ionizing radiation, can be considered a useful alternative to
Interestingly, anti-p155 is directed against TIF1-g in adults, but computed tomography for patients with arthritis, myositis, ILD
and positive testing for any of the known antisynthetase
it is not clear whether this is the same antigen in children.
antibodies (TABLE 2), a combination of features known as the
antisynthetase syndrome. In these patients, a good correlation
MRI & ultrasound
Whole-body muscle MRI, a noninvasive technique, is a useful has been found between B-lines (lung comets) on chest ultraimaging method for myositis patients [63]. Certain muscle dis- sound and the ground glass appearance on chest CT scaneases included in the differential diagnosis of these patients ning [65]. Although prospective and longitudinal studies are
(e.g., muscular dystrophy) have characteristic patterns of muscle lacking, if these results are confirmed, chest ultrasound perinvolvement that can be recognized using MRI. This technique formed at bedside or in outpatient clinics may prove to be a
is also useful to quantify muscle inflammation and damage valuable means for monitoring ILD in these patients.
(e.g., edema vs fatty atrophy) and has been proposed for guiding muscle biopsies to achieve a higher diagnostic yield [64]. Specific clinical scenarios
The magnitude of muscle signal changes has been shown to Cancer-associated myositis
correlate with loss of muscle strength and disease severity; thus, Up to one-third of IIM cases, especially DM, are associated
MRI may be also useful for monitoring the course of the with cancer. Although most of these cases show the pattern of
a paraneoplastic disease (close temporal relationship with
disease.
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New onset
dermatomyositis
or polymyositis

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Conventional
cancer screening
or
FDG-PET/CT

CAM
Polymyositis

Dermatomyositis

Interstitial lung disease

Anti-TIF1
+

Annual cancer screening

(conventional or FDG-PET/CT
during 35 years)

Future cancer
assessment according to
age and risk factors

Figure 1. Algorithm for cancer screening in patients with

idiopathic inflammatory myopathy.

If available.
CAM: Cancer-associated myositis; FDG-PET/CT: [18F] fluorodeoxyglucose PET/computed tomography.

cancer), myositis patients in general seem to have an increased

risk of cancer [40,66]. Therefore, clinicians should actively rule
out occult cancer in all patients with myositis, particularly at
the time of the diagnosis. In addition to a careful history taking and physical examination, other tests should be ordered,
especially if there is any clue that might point to a specific
type (e.g., bloody sputum in a heavy smoker obviously
requires a chest CT scan). Whole-body PET/CT scanning
using [18F] fluorodeoxyglucose and TIF1-g antibody determination may be helpful to rule out cancer in myositis
patients [28,29,67]. PET/CT scanning seems to have similar sensitivity and specificity to exclude an occult cancer as classical
cancer screening, including thoracoabdominal computed
tomography and tumor marker analysis or mammography and
gynecological examination with transvaginal ultrasonography
for women. The predictive value for both screenings (PET/
computed tomography and classical cancer screening) is
92.7%. Alternatively, a meta-analysis reported that anti-p155
autoantibodies (anti-TIF1-g in adults) have a sensitivity of
78%, specificity of 89% and area under the curve of 0.91 to
detect cancer, indicating that it is a very good test for diagnosing cancer-associated DM. The presence of anti-TIF1-g
742

antibodies in a patient with DM denotes a 27-fold increase in

the probability of developing cancer compared to anti-TIF1-gnegative patients [28]. Anti-TIF1-g determination by ELISA or
blotting facilitates implementation of this analysis in standard
laboratories and favors the applicability of this marker in clinical practice. One of the drawbacks is that it appears to be useful only in DM patients. To our knowledge, there are no
reports of anti-TIF1-g autoantibody detection in PM patients.
A proposed algorithm for cancer screening in myositis patients
is described in FIGURE 1.
Several questions currently remain unanswered regarding
cancer screening in myositis. How often should it be performed? How reliable is a negative screening result? What is
the role of anti-TIF1-g along time, and can it really predict the
development of cancer in DM patients who do not have cancer
at the diagnosis? Why is the association between cancer and
DM different in juvenile and adult DM cases?

ILD is common in DM and PM patients. Up to 80% of

patients who are asymptomatic at the onset of the disease are
estimated to experience this complication [6870]. Chest x-ray,
high-resolution CT scanning and PFT, including the diffusing
capacity of the lung for carbon monoxide, forced vital capacity
(FVC), maximum inspiratory pressure, and maximum expiratory pressure are the main resources for evaluating ILD in
myositis patients. Chest ultrasound may also be useful in
selected patients with antisynthetase syndrome if the results of
the abovementioned study [65] are confirmed. In IIM patients,
initial evaluation of the lung parenchyma using high-resolution
computed tomography is recommended, but does not have to
be repeated periodically unless there is a medical indication for
doing so, such as a suspected lung infection or cancer, or worsening of the ILD.
The clinical course of ILD can be divided into three groups
(the third rule), one-third of patients improve, a third
remain stable and the remaining patients worsen over time in
terms of PFT results [71,72]. Nowadays, FVC is probably the
most reproducible parameter related to ILD involvement; a
significant reduction by more than 10% of the baseline value
prompts a change of therapy to control ILD activity.
Although diffusing capacity of the lung for carbon monoxide
seems to be equally or even slightly more sensitive than FVC,
it seems to be a less reproducible parameter. As was mentioned above, in anti-MDA5 patients with rapidly progressive
ILD associated with clinically amyopathic DM, autoantibody
levels and ferritin seem to run in parallel with the lung disease
activity [57,58].
Several serum biomarkers are reported to be useful for assessing inflammatory activity in patients with myositis-associated
ILD. For example, high values of KL-6, a glycoprotein secreted
by Type II alveolar pneumocytes and bronchiolar epithelial
cells, have proven to inversely correlate with FVC and diffusing
capacity of the lung for carbon monoxide. Nevertheless, these
biomarkers are rarely used in clinical practice [73,74].
Expert Rev. Clin. Immunol. 11(6), (2015)

Inflammatory myopathy

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Pregnancy

Idiopathic inflammatory myopathies are autoimmune diseases

that predominantly affect women and often occur during the
childbearing years. Thus, women with IIM may be worried
about the risk of pregnancy related to the activity of their disease. It has been suggested that pregnancy can act as a trigger
for a disease flare, but recent research has indicated that pregnancy does not seem to carry a poorer prognosis or act as a
myositis trigger, and may have a protective role, at least during
the entire period of pregnancy and puerperium [75,76]. In our
experience, patients often show a clinical improvement during
pregnancy, although a relapse is not rare afterward. Development of a severe myositis flare in a pregnant patient may be a
potentially serious situation, conferring a risk for the mother
and fetus due to expected difficulties during labor and delivery
because of pelvic muscle weakness. Reproductive counseling in
which a period of low disease activity is selected for pregnancy
is key to a favorable outcome. When a pregnant myositis
patient requires treatment, glucocorticoids and intravenous
immunoglobulins are effective and safe during gestation.
The recommended tests for IIM patients at disease onset
and during follow-up are summarized in TABLE 4.

Table 3. Myositis associated antibodies

informahealthcare.com

[26,27,53].

Autoantibodies Target
autoantigen

Molecular
Mass kDa

Clinical
phenotype

Anti-PM/Scl

PM/Scl-75
PM/Scl-100

75
100

Polymyositis
scleroderma
overlap
syndrome

Anti-Ro/SS-A

Ro52
Ro60

52
60

Anti-La/SS-B

La

48

Anti-U1RNP

U1-A
U1-C
U1-70

34
22
70

Anti-Cortactin

Cortactin

66

Anti-Ku

Ku70
Ku80

70
80

Anti-PMS

PMS1, PMS2

n.d.

Anti-KJ
Anti-56K

PM

30/34
Nuclear RNP
Sec

56

Anti-Mas

Serine-tRNA protein complex

48

Anti-Wa

nd

48

Anti-Fer

eEF1

Expert commentary & five-year view

Myositis is an ever-changing topic, so it is likely that new issues

will have to be faced in the next 5 years. New specific and
associated autoantibodies have been described recently, and
additional ones will likely appear. Eight antisynthetase autoantibodies have been described to date, each formed by a tRNA
molecule with its cognate amino acid. Considering that our
organism contains 20 amino acids, one wonders whether at
least 12 antisynthetase antibodies remain to be described, and
perhaps this will occur during the next years. Protein and RNA
immunoprecipitation techniques enable identification of new
antigens recognized by autoantibodies in these patients, and if
they prove to be useful, simpler methods for their detection,
such as ELISA and blotting, will be made commercially available. These advances in myositis immunology will facilitate
identification of some hitherto unknown associations, enable
recognition of these highly heterogeneous syndromes and estimation of their prognosis, and will certainly help to achieve
better comprehension and management of our patients.
Some of the questions related to anti-TIF1-g antibodies will
likely be answered in the near future. International consortiums
devoted to the study of myositis are addressing these relevant
issues. The antigen first known as anti-p155 antibody because
it was directed against a 155-kD protein has now been identified as TIF1-g in adult patients, although it is not clear
whether the culprit antigen is the same in juvenile DM. Antip155 antibodies are the most common autoantibodies in juvenile DM, but the antigen against which these antibodies are
directed is uncertain and likely not anti-TIF1-g, at least in
most cases. Other antigens with a similar apparent molecular
weight in SDS-polyacrilamide gel, such as NXP2 or antiTIF1-a may be the targets of anti-p155/140 in juvenile DM.

Review

eEF1: Eukaryotic elongation factor 1; n.d: Not determined; PMS: Postmeiotic segregation; PM/Scl: Polymyositis, scleroderma overlap; RNP: Ribonucleoprotein.

It is important to clarify this point because it may contribute

to explaining the differing association of this antibody with
cancer in adults and children. Longitudinal studies are in progress to determine whether positive testing for anti-TIF1-g in
adult DM patients predicts the development of cancer over the
next months or years, and to clarify the patterns of this autoantibody in relation to cancer and its therapy.
Myositis registries including cohorts of patients from different centers and countries will be a valuable means for obtaining
robust data to better define the different myositis subgroups
and understand the various manifestations of the disease [77].
It is well recognized that studies with a small number of
patients have a higher probability of being biased, finding false
clinical associations, or losing relevant relationships. In rare diseases, like myositis, the only way to solve this limitation and
undertake powered clinical trials and significant epidemiological
projects is through the collaboration of various centers worldwide or within a certain geographic area. This is also true for
genetic studies. In fact, the first genome-wide association study
in patients with inflammatory myopathy [78] was completed
thanks to a genetic biorepository shared by different centers
and countries. This project will certainly enhance our understanding of the pathogenesis of myositis and will probably help
to define new diagnostic and therapeutic approaches for these
patients.
743

Review

s, Martnez et al.
Selva-OCallaghan, Trallero-Aragua

Table 4. Recommended tests at disease onset and during follow-up in patients with idiopathic
inflammatory myopathy.
At disease onset (idiopathic inflammatory myopathy diagnosis)

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During follow-up

Electrophysiology (electromyography) and muscle biopsy

General laboratory and serological markers

Every 36 months

Autoantibody profile (MSA/MAA)

Every 36 months
(selectively anti-MDA5 or anti-TIF1-g)

Nailfold capillary microscopy

Every 6 months

Cancer screening (see algorithm)

Muscle magnetic resonance imaging
(may help in the diagnosis and to identify the best site for muscle biopsy)

When lung or diaphragm involvement is suspected

PFT (including FVC, FEV, DLCO and MIP/MEP)

Every 6 months (If lung or diaphragm involvement

confirmed)

Chest HRCT scan

Occasionally#

Bronchoalveolar lavage and cytology#

Occasionally#

Chest ultrasound exam

Every 6 months

Polysomnography
Echocardiography

Perform if needed

When dysphagia is a relevant manifestation

Videofluoroscopy (when cricopharyngeal involvement is suspected)
High-resolution manometry

Perform if needed

Skin biopsy, usually unnecessary in clinical practice.

At the discretion of the clinician.
Only for research purposes.

Optional if available, and for research purposes.

#
Only if infection or cancer is suspected.
DLCO: Diffusing capacity of the lung for carbon monoxide; FVC: Forced vital capacity; FEV: Forced expiratory volume; HRCT: High-resolution computed tomography;
MIP: Maximum inspiratory pressure; MEP: Maximum expiratory pressure; MSA/MAA: Myositis-specific and -associated antibodies (TABLE 2); PFT: Pulmonary function tests.

Regarding therapy for these conditions, we urgently need

new randomized clinical trials to guide immunosuppressive
treatment from the perspective of evidence-based medicine. In
a typical myositis patient, we can achieve satisfactory clinical
improvement with the standard armamentarium of glucocorticoids, immunosuppressive drugs and intravenous immunoglobulins, but in patients with myositis refractory to these
treatments, neither biologic therapy nor other off-label therapies
has demonstrated significant efficacy. Therefore, a new paradigm is needed in addition to the immunosuppressive approach
to improve therapy response in refractory cases. Possible
options include specific physical therapy and exercise programs
for myositis patients [79] and lung transplantation in severe
myositis-associated ILD, yielding a good postoperative course
and survival rates similar to those of ILD unrelated to
myositis [80].

744

Idiopathic inflammatory myopathies are systemic diseases

that require the collaboration of several medical specialties for
their management [81]. Physicians treating these patients should
be committed to sharing their knowledge and experience to
unveil the secrets of these complex diseases and improve the
care of affected patients, thus avoiding the perplexing situation
encountered by the six blind men and the elephant.
Financial & competing interests disclosure

The authors were supported by a grant from the Spanish Ministry of

Health and Consumer Affairs (PI12-01320). The authors have no other
relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
Ms Celine Cavallo, an English language consultant reviewed the
article.

Expert Rev. Clin. Immunol. 11(6), (2015)

Inflammatory myopathy

Review

Key issues
.

Although several classifications and diagnostic criteria have been reported for idiopathic inflammatory myopathies, the diagnosis of
these conditions mainly relies on accurate interpretation of combined clinical, serological and pathological data.

The clinical course of patients with myositis varies considerably. Even so, patients can be categorized into three main groups in the first
2 years after disease onset monocyclic, chronic polycyclic and chronic continuous depending on the disease activity and frequency
of relapse.

Cancer-associated myositis occurs more often in patients with dermatomyositis. The relationship between myositis and cancer is
paraneoplastic in nature (close temporal relationship), but the two conditions do not always follow the rule of presenting in parallel

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along time.
.

The use of imaging techniques (PET/computed tomography) and new serological determinations (anti-TIF1-g antibodies) will likely help
in screening for occult cancer in dermatomyositis patients, although prospective studies addressing this topic are lacking.

Complementary tools, such as capillaroscopy, whole-body muscle MRI and chest ultrasound study and serological markers, including
new autoantibodies such as anti-MDA5, may be useful in the follow-up of myositis patients.

Pulmonary function testing plays a central role in the control and follow-up of ILD in myositis patients.

Many questions remain unsolved regarding anti-TIF1-g autoantibodies, which seem to be relevant in the relationship between cancer
and dermatomyositis. Progress in answering these questions is expected in the near future.

analysis of 100 French Canadian patients.

Medicine (Baltimore) 2005;84:231-49

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