Clinic Rev Allerg Immunol
DOI 10.1007/s12016-015-8513-8
The Clinical Features of Myositis-Associated
Autoantibodies: a Review
Harsha Gunawardena 1
# Springer Science+Business Media New York 2015
Abstract The idiopathic inflammatory myopathies (IIM) are
a group of autoimmune diseases traditionally defined by clin-
ical manifestations including skeletal muscle weakness, skin
rashes, elevated skeletal muscle enzymes, and neurophysio-
logical and/or histological evidence of muscle inflammation.
Patients with myositis overlap can develop other features in-
cluding parenchymal lung disease, inflammatory arthritis,
gastrointestinal manifestations and marked constitutional
symptoms. Although patients may be diagnosed as having
polymyositis (PM) or dermatomyositis (DM) under the IIM
spectrum, it is quite clear that disease course between sub-
groups of patients is different. For example, interstitial lung
disease may predominate in some, whereas cutaneous compli-
cations, cancer risk, or severe refractory myopathy may be a
significant feature in others. Therefore, tools that facilitate
diagnosis and indicate which patients require more detailed
investigation for disease complications are invaluable in clin-
ical practice. The expanding field of autoantibodies (autoAbs)
associated with connective tissue disease (CTD)-myositis
overlap has generated considerable interest over the last few
years. Using an immunological diagnostic approach, this
group of heterogeneous conditions can be separated into a
number of distinct clinical phenotypes. Rather than diagnose
a patient as simply having PM, DM or overlap CTD, we can
define syndromes to differentiate disease subsets that empha-
sise clinical outcomes and guide management. There are now
over 15 CTD-myositis overlap autoAbs found in patients with
* Harsha Gunawardena
harsha.gunawardena@nbt.nhs.uk
1
Clinical and Academic Rheumatology, North Bristol NHS Trust,
Southmead Hospital, Bristol BS10 5NB, UK
a range of clinical manifestations including interstitial pneu-
monia, cutaneous disease, cancer-associated myositis and
autoimmune-mediated necrotising myopathy. This review de-
scribes their diagnostic utility, potential role in disease moni-
toring and response to treatment. In the future, routine use of
these autoAb will allow a stratified approach to managing this
complex set of conditions.
Keywords Myopathy . Polymyositis . Dermatomyositis .
Systemic sclerosis . Interstitial lung disease . Autoantibodies
Introduction
Historically, patients presenting with symmetrical proximal
muscle weakness, elevated skeletal muscle enzymes, skin le-
sions, neurophysiological and/or histological evidence of
muscle inflammation were simply diagnosed as having poly-
myositis (PM) or dermatomyositis (DM). This was based on
hallmark clinical and pathological classification criteria de-
scribed some 40 years ago [1, 2], which we now recognise,
and does not highlight the heterogeneous nature of these com-
plex diseases. Further criteria published in 1995 did describe
additional clinical features and were the first to include the
concept of myositis autoAbs; however, the number of sero-
logical markers identified at the time was limited [3].
The diagnosis of CTD-myositis overlap remains primarily
a clinical one. Patients have shared clinical features including
muscle inflammation and weakness, skin rashes, fever and
fatigue. However, in some adult and juvenile cases, presenta-
tion and disease course is variable with different manifesta-
tions. Some have severe muscle disease at onset, whereas
some are amyopathic. Some are more at risk of lung disease
or inflammatory arthritis, in contrast to those who have more
skin disease with complications including ulceration or

calcinosis or cancer-associated myositis (CAM). Therefore,
we should no longer purely diagnose a patient with PM or
DM but concentrate on defining autoAbs syndromes. In some
cases, this may avoid the need for a muscle biopsy where
findings can be non-specific and thus lead to diagnostic delay.
Moreover, adopting this approach can determine which pa-
tients may require more detailed investigation for cancer or
lung disease, as well as potentially guide treatment. The aim of
this review is to highlight to clinicians looking these patients
that now well-defined autoAbs within this disease spectrum
should routinely be part of the diagnostic assessment and used
as prognostic tools [4, 5].
Methodology
Anti-nuclear and anti-cytoplasmic autoantibodies (ANA/
ACA) are the serological hallmark of systemic autoimmune
CTD that are used in conjunction with clinical features to
confirm an early diagnosis. However, in patients with CTD-
myositis overlap, standard ANA testing with standard extract-
able nuclear antigen (ENA) panels may be uninformative,
unless the patient is for example positive for anti-Jo-1 or
anti-U1RNP autoAbs. A ‘negative’ ANA should not deter
further serological testing in myositis patients or those with
interstitial lung disease (ILD) with other features such as
Raynaud’s or arthropathy. Therefore, identifying specific
autoAbs requires a diagnostic two-step strategy. Screening
using indirect immunofluorescence (IIF) on human epithelial
cell lines (HEp-2) remains the best means of ANA subtyping.
A key question to the clinician when approaching this disease
group should be is the ANA really negative or is it just low
titre (e.g. 1/40 or 1/80), and what is the staining pattern. In
general, a nucleolar or cytoplasmic speckle coupled alongside
specific clinical manifestations can provide insight into the
target autoantigen, for example the aminoacyl tRNA synthe-
tase group, signal recognition particle (SRP), hydroxy-3-
methylglutaryl-coenzyme A reductase (HMGCR) (all of
which are cytoplasmic autoantigens), or PM-Scl 100/75 com-
plex and U3-ribonucleoprotein (U3RNP) (the latter both nu-
cleolar autoantigens). IIF of other DM-associated autoAbs is
usually non-specific and low titre low (and may be reported as
negative), but this should not preclude further serological in-
terrogation, as it is clear that these are not seronegative condi-
tions [4, 5]. Therefore, more specific confirmatory methods
are required, such as immunoprecipitation (IPP), enzyme-
linked immunosorbent assay (ELISA) or immunoblotting.
Although IPP is an optimal research method to detect CTD-
myositis autoAbs [4, 6], in routine clinical practice, it is not
practical. There is now considerable focus to develop com-
mercially available tests and ELISAs, immunoblotting and
line or bead immunoassays that can test for the majority of
anti-synthetase group, anti-PM-Scl, anti-SRP and anti-Mi2
Clinic Rev Allerg Immunol
[6–9]. A number of research groups are now producing
ELISA and line-blot testing for some of the novel autoAb
including the rarer non-Jo1 anti-synthetases, anti-MDA5, an-
ti-TIF1g, anti-NXP2 and anti-HMGCR [6, 8, 10–18]. Cross
collaboration is required to ensure methods are reproducible
and validated in large patient cohorts, so that in the near future,
we can routinely test for all CTD-myositis overlap antibodies
in a clinical setting.
Terminology
We should move away from the concept of separating ‘myo-
sitis-specific and myositis-associated’ antibodies (MSAs /
MAAs), primarily because some patients within this spectrum
who are found to be positive for a so-called MSAs may never
actually develop myositis. It is clear that some of these
autoAbs are also found in dermato-pulmonary syndromes
and patients with overlap systemic sclerosis (SSc) [11,
19–21]. Therefore, to highlight to the clinician that these pa-
tients can present in different ways to a number of different
specialties, we should consider alternative nomenclature such
as ‘CTD-myositis overlap’ and/or ILD autoAbs.
Clinical Manifestations and AutoAbs Groups (Fig. 1)
Interstitial Lung Disease and Anti-Cytoplasmic AutoAbs
Diffuse parenchymal lung disease, in particular ILD, now
termed as interstitial pneumonia is a major clinical manifesta-
tion in CTD-myositis patients. A number of radiological and
histopathological subtypes are recognised, with non-specific
interstitial pneumonia (NSIP) the most frequently observed,
but also organising pneumonia (OP), usual interstitial pneu-
monia (UIP) and rarely acute interstitial pneumonia (AIP/dif-
fuse alveolar damage) [6, 22, 23]. Traditional risk factors in-
clude ethnicity, those with amyopathic disease, systemic fea-
tures with fever, and/or a marked acute phase response at
presentation. Moreover, it is apparent in this group of patients
that lung disease can pre-date the development of myositis and
be the predominant manifestation [23]. Sub-dividing patients
by autoAb syndrome will aid identification further with anti-
synthetase syndrome (ASS), overlap SSc-myositis syndromes
and the novel anti-MDA5 sub-group being at greatest risk.
Anti-Synthetase Syndrome
There are currently eight identified autoAb that target the
amino-acyl tRNA synthetase enzymes (ARS), anti- Jo-1,
PL12, PL7, EJ, OJ, KS, Ha and Zo, which define ASS that
was first described in 1990 [24]. Classic clinical features in-
clude myositis, non-erosive inflammatory arthritis, cutaneous
Clinic Rev Allerg Immunol
Fig. 1 CTD-myositis overlap—myositis-associated autoantigens. *Aminoacyl tRNA synthetases—Jo1, PL7, PL12, OJ, KS, EJ, Zo, Ha. ILD interstitial
lung disease, RP-ILD rapidly progressive interstitial lung disease
lesions (including mechanic’s hands), fever, Raynaud’s phe-
nomenon and interstitial pneumonia. In comparison to adult
patients, it is important to note that ASS is a relatively uncom-
mon subtype within the juvenile myositis spectrum. It is in-
creasingly evident that ASS is a spectrum disorder that not just
includes myositis. However, sub-phenotyping the syndrome is
difficult due to the relative rarity of non-Jo1 anti-ARS com-
pared to anti-Jo1, although this may be more to do with lim-
itations in diagnostic testing [25, 26]. It is possible that the
prevalence of the non-Jo1 ARS group is higher in different
cohorts such as patients labelled as ‘idiopathic’ IP, particularly
in those with UIP and AIP (DAD) subtypes [27]. Data from
several studies suggest that UIP and AIP are commonly seen
in non-Jo1 ASS, in particular anti-EJ, anti-PL7 and anti-PL12
patients, where lung disease presents early in disease course
and is the predominant manifestation [22, 27–32]. In a large
series of Japanese patients positive for anti-Jo-1, anti-EJ, anti-
PL-7, anti-PL-12, anti-KS or anti-OJ highlighted the degree of
heterogeneity within ASS in terms of distribution and onset of
myositis, lung disease and skin lesions [33]. Furthermore,
non-erosive inflammatory arthritis may be the presenting clin-
ical feature in around one third of ASS patients, with or
followed by ILD [34]. It now seems clear that as we will
evaluate the degree of myositis and dermatological findings,
we need to concentrate on different presentations of interstitial
pneumonia and arthropathy to identify patients and thus not
delay diagnosis. This is particularly important in lung disease
patients, where early intervention with immunomodulatory
therapy may well confer a better prognosis in comparison
idiopathic forms of the disease.
Anti-MDA5 AutoAb—a Distinct Cutaneous-Pulmonary
Syndrome
Recent literature has highlighted the clinical significance of
anti-MDA5 autoAb, not just in the field of myositis but also
perhaps more importantly in respiratory and dermatology
clinics. AutoAb targeting a cytoplasmic protein, first termed
CADM-140 and subsequently identified as melanoma differ-
entiation gene 5, was first described in Asian cohorts and more
recently in US and European adult and juvenile studies [11,
35–39]. Anti-MDA5 autoAb defines a specific dermato-
pulmonary syndrome, but within this, it is evident that Asian
and Caucasian patients differ implying genetic and environ-
mental factors influence the phenotype. Asian patients typi-
cally present with clinically amyopathic DM (CADM), sys-
temic features including fever and most importantly rapidly
progressive interstitial lung disease (RP-ILD), which is fre-
quently fatal [11, 35]. Markers of severe lung damage in this
group of patients include hyper-ferritinaemia, serum IL-18

concentrations and anti-MDA5 autoAb titres [40, 41]. In US
cohorts, ILD again is a predominant feature, but RP-ILD, a
less prevalent pattern with other subtypes of interstitial pneu-
monia, is also seen [36]. In addition, anti-MDA5 patients who
present with co-existent myositis, as opposed to CADM, may
also have less severe lung fibrosis, typically NSIP disease that
responds well to treatment (personal data). This group of pa-
tients has been described as having a novel dermatological
phenotype representative of severe vasculopathy, including
(muco)-cutaneous ulceration with oral mucosal pain, tender
palmar papules around the nailfolds and Gottron’s lesions
[36, 42]. Another US study has widened the ‘MDA5’ spec-
trum with phenotypic similarities to ASS, including symmet-
rical inflammatory arthritis, some with overt clinical myopa-
thy, Raynaud’s, fever and mechanic’s hands, as well as ILD
[43]. This observation is intriguing as both syndromes are
associated with cytoplasmic autoantigens with similar biolog-
ical functions, where anti-Ro52 autoAb is also often detected.
It is significant to note that anti-MDA5 is a major autoAb in
JDM, found in over one third of Japanese children and around
7 % of a UK cohort. Clinical findings are similar to adult
counterparts with characteristic cutaneous lesions including
ulcerations, arthritis, and milder muscle or amyopathic dis-
ease. Both chronic ILD and RP-ILD are prevalent especially
the latter in the Asian population, making anti-MDA5 an im-
portant serological marker in children, as parenchymal lung
disease is generally uncommon in JDM [37, 44, 45].
Systemic Sclerosis-Myositis Overlap
and Anti-Nucleolar/Anti-Nuclear AutoAb
Anti-nucleolar autoAb (AnuAb) are found in 10–15 % of SSc
patients, particularly those with overlap syndromes [21, 46].
To date, four specificities, anti-RNAPol3, anti-Th/To, anti-
P M - S c l a n d a n t i - U 3 R N P, h a v e b e e n i d e n t i f i e d .
Characterisation of AnuAb can guide the clinician and help
define specific clinical manifestations and in some cases prog-
nosis, for example anti-RNAPol3 is a strong predictor of SSc
renal crisis. In the context of CTD-myositis overlap, autoAb
against PM-Scl protein complex and U3RNP is the most rel-
evant, with a higher frequency of parenchymal or vascular
lung involvement [21, 46–48].
PM-Scl Overlap Syndrome
Antibodies directed against the PM-Scl complex in the human
exosome identify a distinct subset of patients with SSc and/or
myositis overlap [21, 46–48]. Studies highlight how anti-PM-
Scl patients tend to be younger at disease onset and have
milder cutaneous SSc features with limited skin disease and
in some inflammatory arthropathy [46–48]. Although
Raynaud’s is a common feature, peripheral vasculopathy with
Clinic Rev Allerg Immunol
digital ulceration appears less common. Skeletal muscle
weakness has been a consistent observed association but can
be subclinical with features on electromyography or MRI im-
aging. Other subcutaneous ± cutaneous features include ‘puffy
swollen fingers’, nailfold capillary distortion, calcinosis and
hyperkeratosis with fissuring of the skin on the digits, charac-
teristic of mechanic’s hands. The frequency of ILD is similar
to that seen in ASS [49], although OP and milder forms of
NSIP may predominate in anti-PM-Scl phenotype that re-
sponds well to immunomodulatory treatment (personal obser-
vation). In addition, forced vital capacity (FVC%) at presen-
tation and improvement during disease course tends to be
higher in this sub-group. This may partly explain why several
studies have shown higher progression-free survival in this
group of patients [21, 47, 48, 50, 51].
Anti-U3RNP
Antibodies against U3RNP complex, of which fibrillarin is the
autoantigenic subunit, are more commonly seen in diffuse
cutaneous SSc overlap patients of African-American race
[21, 46]. Patients may present younger and disease course
more progressive. Myositis is a consistent feature with also a
risk of other internal organ involvement including renal, car-
diac, gastro-intestinal disease and parenchymal lung disease
[21, 46, 52, 53]. A recent study has shown that ILD occurs in
around one third of anti-U3RNP patients, with a similar fre-
quency of intrinsic pulmonary hypertension (i.e. primary vas-
culopathy unrelated to lung disease), the latter being the major
poor prognostic determinant [46].
Anti-RuvBL1/Anti-RuvBL2
A novel autoantigen target RuvBL1/RuvBL2 (a nuclear/
nucleolar matrix complex) has been recently identified in
SSc patients with myositis in a combined Japanese and US
cohort. Anti-RuvBL1/anti-RuvBL2 autoAb was detected
∼2 % of SSc patients, where the frequency of ILD appears
similar to anti-PM-Scl patients (just over 50 % of patients in
both autoAb subgroups). However, anti-RuvBL1/2 patients
appear unique in that they are older at disease onset, more
likely to be male and have diffuse skin thickening [54]. It will
be interesting to see whether this finding is replicated in other
cohorts and whether pooled data can then identify specific
subtypes of lung disease, which may the determine prognosis.
Anti-Nuclear AutoAb in Cancer-Associated DM,
Skin and Subcutaneous Disease
Four specific nuclear proteins, namely transcription interme-
diary factor 1 complex (TIF1), nuclear matrix protein 2
(NXP2), small ubiquitin activating enzyme (SAE) and Mi2,
Clinic Rev Allerg Immunol
have been identified as important autoantigens in the adult and
juvenile DM spectrum [4, 5]. It is of interest that these nuclear
proteins have analogous cellular functions including gene tran-
scription, DNA synthesis and cellular repair suggesting a shared
pathogenic mechanism, despite variations in clinical presentation.
Anti-TIF1 and Anti-NXP2 AutoAb
The potential relationship between cancer and autoimmu-
nity has been interrogated for decades. The idea that anti-
tumour immune responses may attempt to regulate the
emergence of cancer, leading to the over-expression of
autoantigens, autoAb production and bystander tissue in-
jury is an intriguing theory. The increased relative risk of
malignancy and dermatomyositis compared to age- and
sex-matched controls, alongside a clear temporal relation-
ship between cancer and CTD onset, emphasises the con-
nection [55]. However, because of the previously small
number of myositis-associated autoAb described, histori-
cally cancer-associated DM was felt to be a ‘seronegative’
subset. Indeed, if one screens myositis-overlap patients by
‘routine’ standard hospital laboratory assays, autoAb-
positive patients have a lower risk of cancer compared
to those who are autoAb negative [56]. Over the last
few years, it is now evident that cancer-associated DM
is an antibody-rich rheumatic phenotype with the discov-
ery of anti-TIF1 and more recently anti-NXP2 autoAb.
Anti-TIF1 has now been described in around 15–25 %
of DM cohort studies [57–60]. The identity of the 155/
140 kDa protein was subsequently identified as the TIF1
(α, β, γ subunits) family proteins, with TIF1-γ the main
target [60]. The incidence of cancer in anti-TIF1 adult
DM patients is high in comparison to all other myositis-
associated autoAb groups. A meta-analysis of six studies
using the same methodology to detect anti-TIF1 has
shown a high negative predictive value and significant
diagnostic odds ratio of 27 for cancer-associated DM
[61]. In clinical practice, once routine testing for anti-
TIF1 autoAb becomes available, we will be able to iden-
tify those DM patients at particular risk of occult malig-
nancy and focus on early detection with imaging tech-
niques such as FDG positron emission tomography-CT
[62]. A recent US study has highlighted that adult anti-
TIF1 patients have another unique skin phenotype, which
is of significant interest because this identifies additional
risk factors for cancer-associated DM when autoAb test-
ing is not available. Patients were shown to have more
severe skin disease in terms of distribution (scalp, face,
V-sign and shawl-sign) with palmar hyperkeratotic
Gottron’s papules, ‘psoriatic’ looking lesions and
hypopigmented patches with punctate telangiectasia or er-
ythematous macules (termed by the authors as ‘red on
white lesions’). Common myositis-overlap manifestations
seen in other clinico-serological subgroups such as
Raynaud’s, arthritis and ILD were uncommon [63].
AutoAb recognising NXP2 has now been shown to be
another frequent and important group in adult DM. A
combined US cohort study detected anti-NXP2 in 17 %
and anti-TIF1 in 38 % patients, respectively, with a higher
frequency of the latter compared to older studies possibly
explained by their own higher specificity IPP assay using
cell lysates transfected with TIF1-γ [64]. Interestingly,
compared to previous work, the risk of cancer with anti-
TIF1-γ was not as strong, and the authors suggest that
this might be due to the higher specificity assay identify-
ing patients with lower positive titres combined with the
overall cohort having a low frequency of cancer (one third
of patients included had follow-up of <3 years). This
study did demonstrate a cancer risk with anti-NXP2 pos-
itivity, particularly amongst male patients (not explained
by just male-associated tumours). This observation was
previously suggested in a smaller Japanese series [65]. It
is noteworthy that Fiorentino and colleagues conclude in
DM patients under the age of 60 who are antiTIF1-γ or
anti-NXP2 negative have a very low risk of cancer [64].
Apart from cancer, both anti-TIF1 and anti-NXP2 define
their own characteristic phenotypes, highlighted by the
finding that they form the main serological groups in
JDM. Collectively, both autoAb are detected in ∼50 %
of JDM cases, which is important because previously,
these patients were classified as seronegative. In children,
anti-TIF1 positivity has been shown to be associated with
more extensive skin disease (similar to adult counter-
parts), cutaneous oedema, vasculopathy with ulcers,
lipoatrophy and limb contracture [66–68]. In contrast,
anti-NXP in JDM appears to be a clear serological marker
for calcinosis, associated with a greater degree of muscle
weakness, as well as younger age of disease onset [69,
70]. Other disease associations include muscle contrac-
tures, atrophy and worse function status [68]. Data sug-
gests that anti-NXP2 is also associated with calcinosis in
adult DM (personal observation) [71–73]. In a recent
study, 11 % had calcinosis overall, associated indepen-
dently with disease duration, fingertip ulcers, as well as
anti-NXP2 [71].
Returning to the potential link between autoimmunity and
cancer, the observation that both anti-TIF1 and antiNXP2 de-
fine similar cutaneous and subcutaneous subtypes in adult and
juvenile DM, but only cancer in adults (and in general older
adults) is tantalising. This perhaps strengthens the hypothesis
that abnormal cancer cellular responses initiate disease in this
group of patients regardless of age. A subsequent anti-cancer
immune response leads to over-expression of particular anti-
gens and then tissue damage [74]. Perhaps in children and
younger adults with a more efficient immune system, the can-
cer is abolished, whereas in some, it still emerges alongside

autoAb production (namely anti-TIF1 and NXP2) leading to
the emergence of DM.
Anti-SAE
AutoAb against small ubiquitin-like modifier activating en-
zyme (SAE) has now been described in a number of adult
DM cohorts with varying frequency of 1.5–8 % [75–79].
Patients tend to present with hallmark skin disease first
(amyopathic DM) and then progress to muscle weakness with
systemic features including in some marked gastro-intestinal
involvement with dysphagia [75, 78]. It is notable that the
frequency of anti-SAE DM patients in Japanese studies in
comparison to European cohorts is low. Although numbers
are small, certain clinical differences are described including
more ILD, which may reflect ethnic and environmental differ-
ences [79]. When combining studies, anti-SAE does not ap-
pear to be a significant clinico-serological phenotype in JDM,
seen in <1 %.
Anti-Mi-2
Anti-Mi-2 was the first specific serological marker to be de-
scribed in DM [80]. AutoAb recognising this nucleosome
helicase protein is commonly found in up to 20 % of adult
DM patients and up to 10 % of JDM. Patients present with
classic skin eruptions particularly in sun-exposed areas along-
side myositis, and it has been shown that surface ultra-violet
(UV) irradiation intensity correlates with phenotype inci-
dence, particularly in women [81, 82]. However, a recent
study suggests other factors other than UV influence the de-
velopment of anti-Mi-2 DM, where autoAb frequency was
significantly different in two Mexican cohorts, with similar
UV exposures [83]. Both adults and children with anti-Mi-2
DM tend to have mild to moderate myositis and have less
systemic disease with a low frequency of lung and joint dis-
ease [84]. In addition, patients respond well to corticosteroid
therapy and often run a monophasic disease course, with good
outcomes.
Autoimmune Necrotising Myopathy
Autoimmune necrotising myopathy (AINM) describes a sub-
group of IIM with similar clinical, biochemical and histopath-
ological features. It is clear that seropositive AIMN is a distinct
entity to what we would have previously termed classic PM.
Anti-SRP and anti-HMGCR autoAbs are found in patients who
present predominately with acute severe muscle disease, mir-
rored by CK levels, and unlike other myositis autoAb, subtypes
have few overlap features. In this context, it is noteworthy that
both target autoantigens are found in the cytoplasm and studies
have shown that SRP is required for the insertion of HMGCR
Clinic Rev Allerg Immunol
into the endoplasmic reticulum [85, 86]. Despite the relative
absence of inflammatory infiltrate, the predominance of
myofibre necrosis and in the case of anti-HMG-CoA where
discontinuation of statins does not result in clinical improve-
ment, AIMN responds to immunotherapy again highlighting
that this is an immune-mediated phenotype.
Anti-SRP AINM
Patients with anti-SRP AINM typically present with acute/
subacute onset proximal weakness, associated with high CK
levels (often over ten times the upper limit of normal) that
may progress to severe disability. In addition, dysphagia
secondary to pharyngeal muscle weakness combined with
respiratory muscle weakness increases the risk of aspiration
in these patients. A number of studies have described certain
extra-muscular manifestations including parenchymal lung
disease and cardiac involvement [87, 88], but this does not
appear to be a consistent feature [89, 90]. Subclinical myo-
carditis may explain why some patients develop palpitations,
paroxysmal arrhythmias and raised cardiac-specific Troponin
levels, regardless of cardiac MRI findings (personal obser-
vation). The key in anti-SRP patients is to intervene early,
recognise that some patients may be refractory to standard
treatments and adopt more intensive management strategies
[4, 9, 91, 92].
Anti-HMGCR Statin-Associated AINM
The classification of the statin-induced myopathy spec-
trum includes statin-induced myalgia (usually self-
limiting muscle symptoms without CK rise), statin-
induced myositis and statin-induced rhabdomyolysis
[93]. Many patients report self-limiting symptoms on
discontinuation of statin therapy, and some in the case
of statin rhabdomyolysis may have an underlying meta-
bolic myopathy. However, a small number of patients
develop progressive weakness and persistently elevated
CK. A number of studies have now shown that this
latter phenotype forms a distinct entity outside the ‘clas-
sic’ toxic stain myopathy spectrum characterised by
autoAb against the enzyme target of statins HMGCR.
Muscle biopsy changes are characteristic of an AINM
i.e. myonecrosis with little inflammation with also MHC
class 1 up-regulation and MAC deposition on non-
necrotic fibres. Expression of HMGCR is also upregu-
lated in regenerating muscle fibres [16, 94, 95]. In ad-
dition, the highest risk for anti-HMGCR statin-induced
AINM has been shown in HLA-DR11 carriers (HLA
DRB1*11:01 allele) [95, 96], in comparison to the sin-
gle nucleotide polymorphism in SLCO1B1, a genetic
risk factor seen in ‘standard’ statin toxic myositis [97].
It is notable that anti-HMGCR AINM is also seen in
Clinic Rev Allerg Immunol
patients with no prior history of statin exposure [18,
95]. Therefore, the finding of anti-HMGCR autoAb-as-
sociated myositis should signify to the clinician that
patients require treatment with steroids and at least
one other immunomodulatory agent with most showing
either partial or full response [94, 98, 99]. A number of
questions remain; are anti-HMGCR autoAb detected in
‘normal’ subjects, if they are will the introduction of a
statins the trigger AINM, and can treated patients be
rechallenged with an alternative statin.
Autoantibody Titres and Disease Activity
With the appreciation that myositis-CTD overlap autoAbs
are useful diagnostically and define clinical phenotypes,
there is a real focus to develop serological techniques that
can be used in routine clinical practice. Commercially
available ELISA kits are available for a number of
autoAb including most anti-ARS, nucleolar SSc-myositis
ANAs, anti-Mi2 and anti-SRP. In addition, a number of
research groups have developed ELISAs using highly pu-
rified recombinant proteins to detect the more novel
MAAs, namely the rarer anti-ARS, anti-MDA5, anti-
TIF1, anti-NXP2 and anti-HMGCR [9–18]. The advan-
tage of ELISA detection is higher sensitivity and efficien-
cy with rapid turnover and results. Moreover, quantitative
techniques where autoAb titres can be measured may be
useful in monitoring disease activity. A number of recent
studies have highlighted how myositis-CTD overlap
autoAb titres may be useful in this setting. Anti-Jo1,
anti-SRP and anti-HMGCR titres have all been shown to
correlate with CK levels and myositis scores [9, 99, 100].
In the case of cancer-associated DM, higher anti-TIF1
levels at baseline are associated with the presence of can-
cer [12]. In terms of lung and skin disease, the diagnostic
utility of anti-MDA5 titres has been highlighted by sever-
al studies, where levels at baseline and in response to
treatment predict outcomes of rapidly progressive ILD
and severity of skin ulceration. Importantly, high titres
despite treatment indicate refractory lung disease with in-
creased risk of mortality [101, 102].
Does Clinico-Serological Phenotype Influence
Outcome and Treatment Approaches?
Over the last few years, a number of studies have
highlighted that different treatment responses and thus
prognosis are seen depending on serological profile. For
example, non-Jo1 ASS and anti-MDA5 patients have re-
duced survival compared to other serological subtypes
[11, 29–32, 40, 41, 103, 104]. In the case of non-Jo1
ASS, this may be due to delays in diagnosis with patients
mislabelled as idiopathic pulmonary fibrosis and/or more
extensive parenchymal lung involvement with coarse
fixed fibrosis at presentation (personal observation) [26,
27]. In anti-MDA5 syndrome, we know that in specific
cohorts, the occurrence of RP-ILD influences outcome
[11, 35, 40, 41, 104], with around 50 % mortality rate
within 6 months due to respiratory failure [104]. In the
case of other subsets, progressive muscle weakness in
refractory seropositive AINM and cutaneous complica-
tions in certain DM phenotypes influences morbidity and
therefore management. However, due to heterogeneity of
CTD-myositis overlap, there are no standardised treatment
approaches. Therapeutic strategies are essentially based
on ‘best’ clinical practice and a limited number of case
series, open-label studies or randomised controlled trials
(RCTs) [105]. Alongside corticosteroids, a number of
treatment options are used in ASS and anti-MDA5 lung
disease including induction cyclophosphamide, mycophe-
nolate mofetil (MMF) and calcineurin inhibitors. Use of
the former two agents is essentially based on clinical best
practice using experience adopted in other conditions such
as systemic sclerosis, as well as retrospective observation-
al studies [106–108]. A number of studies have suggested
a potential role for calcineurin inhibitors, especially tacro-
limus as a first-line and rescue treatment in ILD-
associated ASS [109–112]. Similar regimes have been de-
scribed in amyopathic DM RP-ILD, including efficacy of
combination therapy with cyclosporine and cyclophospha-
mide [112–115]. Additional second-line treatments for
muscle, skin and subcutaneous disease in other pheno-
types include methotrexate, azathioprine and MMF, and
in refractory cases intravenous immunoglobulin. The use
of rituximab in myositis overlap syndromes has generated
considerable interest over the last few years, particularly
in those with refractory lung and muscle disease. Prior to
the RIM study (rituximab in refractory adult and juvenile
myositis), a number of retrospective series have suggested
a potential benefit [116–120]. The RIM study did not
demonstrate significant differences in primary or second-
ary end-points between treatment groups, but the majority
with refractory disease met the study definition of im-
provement [121]. Moreover, a subsequent subgroup anal-
ysis has highlighted that response to rituximab may be
influenced by serological phenotype with ASS and anti-
Mi2 patients more likely to gain benefit [122]. A thera-
peutic role for rituximab within the different clinico-
serological phenotypes has been further emphasised in a
number of series, including refractory patients with ASS-
ILD, anti-MDA5 and anti-SRP disease [117, 123–129].
Therefore, it seems that stratification based on autoAbs
can act as predictive markers of clinical response to treat-
ment, which again highlights their diagnostic utility.
Table 1 CTD-myositis overlap autoantibodies and clinical associations
ANA IIF Cytoplasmic Nucleolar Nuclear

Autoantibody An-SRP An-HMGCR An-ARSa An-MDA5 An-PM-Scl An-U3RNP An-RuvBL1/2 An-Mi2 An-SAE An-TIF1 An-NXP2

Myopathy-pulmonary spectrum
Syndrome Autoimmune Dermatomyosis
necrozing myopathy ASS Dermatopulmonary Overlap CTD-SSc-myopathy

Manifestationss
Subacute severe Subacute ILD: NSIP +/- OP or UIP or AIP (RP-ILD) ILD Classic DM CADM Adults:
myopathy myopathy
+/- Stans CADM Diffuse skin disease Less systemic Systemic Severe skin and subcutaneous disease
disease Red on white lesions
Mechanic’s hands PAH Dysphagia Palmar Goron’s lesions

Goron’s lesions Gastro-intesnal GI associated Cancer

disease
Raynaud’s phenomenon Children:

Inflammatory arthris Ulceraon

Oedema
Mucocutaneous ulcers Lipoatrophy
Contractures
Palmar papules
Calcinosis

Disease activity An-SRP tres An-HMGCR An-Jo1 tres An-MDA5 tres An-TIF1 tres
markers tres
Ferrin

IL18

Prognosis Oen refractory Related to subtype of ILD (non-an-Jo1 ASS and an-MDA5 RP-ILD) – worse Good Related to significant skin +/-
subcutaneous disease and malignancy in
Cellular NSIP and OP – beer adults

ASS anti-synthetase syndrome, MDA5 melanoma differentiation gene 5, SRP signal recognition particle, HMGCR hydroxy-3-methylglutaryl-coenzyme A reductase, SAE small-ubiquitin like modifier
activating enzyme, TIF1 transcriptional intermediary factor 1, NXP2 nuclear matrix protein 2, ILD interstitial lung disease, NSIP non-specific organising pneumonia, OP organising pneumonia, UIP usual
interstitial pneumonia, AIP acute interstitial pneumonia, RP-ILD rapidly progressive ILD, CADM clinically-amyopathic dermatomyositis
a
Anti-ARS (acetyl-tRNA synthetases): anti-Jo1, anti-PL12, anti-PL7, anti-OJ, anti-EJ, anti-KS, anti-Ha, anti-Zo
Clinic Rev Allerg Immunol
Clinic Rev Allerg Immunol
Summary
Over the last 10 years, it has become evident that CTD-
myositis overlap is an autoAb-rich condition, where serology
defines sub-syndromes within the disease spectrum. It is clear
that this approach helps diagnosis and indicates which patients
are at risk of more severe organ-based disease. In addition,
identification of specific autoAb and quantification of titres
may be useful disease activity markers, help guide treatment
strategies and indicate prognosis. The goal must now be to
make testing for this group of autoAb readily available in
clinical practice, so we can routinely adopt a clinico-
serological approach that in turn will improve management
of this difficult and diverse set of conditions (Table 1).
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