The Evolving Spectrum of Polymyositisand Dermatomyositis—Moving Towards ClinicoserologicalSyndromes: A Critical Review

Sarah Tansley & Harsha Gunawardena

# Springer Science+Business Media New York 2013

Abstract The idiopathic inflammatory myopathies: poly-myositis (PM) and dermatomyositis (DM) have been histori-cally defined by broad clinical and pathological criteria. Theseconditions affect both adults and children with clinical fea-tures including muscle weakness, skin disease and internalorgan involvement. Over the last few years, it has becomeincreasingly apparent that using a clinico-serological ap-proach, both DM and PM can be defined into more homoge-neous subsets. A large number of antibodies are directedagainst cytoplasmic or nuclear components involved in keyregulatory intra-cellular processes including protein synthesis,translocation and gene transcription within this disease spec-trum. In addition, these autoantibodies are found in patientswith clinical features other than myositis, in particular ‘idio-pathic’ interstitial pneumonia emphasizing that these patientsmay in fact be a formes-frustes of autoimmune connectivetissue disease. Other important findings are the identificationof specific autoantibodies in both cancer-associated dermato-myositis, clinically amyopathic dermatomyositis and juveniledermatomyositis, which previously were classically describedas antibody-negative clinical subsets. Finally, work hashighlighted how target autoantigens identified in themyositis-connective tissue disease overlap share common cel-lular mechanisms, which provides us with further insights intodisease pathogenesis.

Keywords Polymyositis . Dermatomyositis . Clinicalsyndromes . Autoantibodies . Autoantigens

Introduction

Polymyositis (PM) and dermatomyositis (DM) are a group ofrare autoimmune connective tissue diseases that are tradition-ally classified by proximal muscle weakness, biochemical,neurophysiological and/or histological evidence of muscleinflammation, and characteristic skin lesions [1]. By defini-tion, the terms PM and DM (poly—many, dermato—skin,myositis—muscle inflammation) perhaps do not highlight theheterogeneous nature of these complex diseases. These con-ditions affect both children and adults, but presentation anddisease course are variable with different systemic overlapmanifestations. In adults, morbidity outcomes relate to well-known complications, e.g. cancer-associated myositis andinterstitial pneumonia. In contrast, morbidity in children isassociatedwith vasculopathic organ involvement, in particularsoft tissue calcinosis and skin ulceration. Subsequent classifi-cation criteria have recognized other important features in-cluding the presence of specific autoantibodies [2]. It is nowincreasingly apparent that this concept needs to be expandedand further defined in the connective tissue disease (CTD)myositis overlap spectrum [3]. To the clinician, these autoan-tibodies are excellent tools and highlight how we should nowdefine patients in to clinicoserological phenotypes [3, 4]. Theyare of significant clinical utility and potentially can be used asprognostic and therapeutic markers.

Should We Use the Term Myositis-Specific Antibodies?

Autoantibodies target nuclear or cytoplasmic intra-cellularcomponents, and specific patterns are associated with clinicalphenotypes within the CTD disease spectrum. Over the lastfew years, this has become increasingly apparent in myositis,and the concept of myositis-specific autoantibodies (MSAs)andmyositis-associated autoantibodies (MAAs) has beenwell

S. TansleyRoyal National Hospital for Rheumatic Diseases NHS FoundationTrust, Bath BA1 1RL, UK

H. Gunawardena (*)Clinical and Academic Rheumatology, North Bristol NHS Trust,Southmead Hospital, Bristol BS10 5NB, UKe-mail: harsha.gunawardena@nbt.nhs.uk

Clinic Rev Allerg ImmunolDOI 10.1007/s12016-013-8387-6

described [3, 4]. Corresponding target autoantigens are in-volved in gene transcription, protein translocation and innateimmunity. Moreover, it is apparent that those proteins withanalogous cellular functions are associated with similar clin-ical phenotypes. Although MSAs by definition is a relativelynew and well-recognized terminology, one might argue thatthis is an incorrect classification. For example, in some casesof anti-synthetase autoantibody syndrome or some of thenewer serological phenotypes (which we currently term asMSAs), either never develop myositis or myositis is not thepredominant clinical manifestation [5, 6]. Perhaps the bestexample of so-called MSAs in this context is the non-Jo-1anti-synthetase subgroup in patients with purely interstitialpneumonia [5, 6], as described below. From a clinical per-spective, this is an important point because the term ‘myositis-specific’ may not highlight the importance of these autoanti-bodies in patients who present with primarily respiratory and/or dermatological disease. In comparison, the MAAs, such asanti-PM-Scl and anti-U3RNP (fibrillarin), are traditionallydescribed in overlap CTD syndromes such as systemic scle-rosis (SSc) or mixed connective tissue disease [7]. Therefore,it may be more appropriate that all established and novelautoantibodies in this spectrum are considered as MAAsrather considered separately as myositis specific or associated.

Clinical Utility of Standard ANATesting and OtherMethodology

Standard techniques include immunofluorescence on human-epithelial cell lines (HEp-2 cells), generic or antigen-specificELISA tests, immunodiffusion and counter-immuno-electrophoresis. More specific techniques including immuno-blotting and in particular protein radioimmunoprecipitation(IPP) have the advantage of being able to identify novelautoantigen targets [4]. Around 70 % of adult patients and60% of juvenile patients now have well-defined autoantibodyspecificities when tested by IPP (Betteridge—personal com-munication, on behalf of Euro-MyoNet Study Group). How-ever, IPP is not readily available, has low throughput and thusis not particularly practical in clinical practice. Therefore, inpatients with CTD-myositis overlap, detailed ANA specificityon HEp-2 cells or similar substrates in terms of titre andstaining patterns can provide insight into the targetautoantigen (Fig. 1). For example, a homogeneous nucleolarstaining pattern in a patient with overlap myositis, Raynaud’s,limited sclerodermatous skin changes and lung infiltrates mayindicate autoantibodies against the PM-Scl complex [8]. Incontrast, different cytoplasmic patterns in an otherwise nega-tive ANA (i.e. anti-cytoplasmic autoantibodies) with similar

Fig. 1 Immunofluorescence ofHEp-2 cells showing stainingpatterns compatible withmyositis-associatedautoantibodies

Clinic Rev Allerg Immunol

clinical manifestations to anti-PM-Scl positive patients aresuggestive of anti-synthetase syndrome [5, 6, 8]. Furthermore,a nucleocytoplasmic or low titre homogenousANA in patientswith hallmarkDM skin lesions, who are otherwise negative onstandard ANA/ENA testing, may indicate one of the novelspecificities in the DM clinical spectrum, as described below.In the future, the development of specific ELISAs and elec-trophoretically labelled line blots will help identify the fullrange of CTD-myositis overlap autoantibodies in routine clin-ical practice [9].

So-called MSAs and MAAs in this spectrum are typicallymutually exclusive but have been identified in conjunctionwith less specific connective tissue disease associated autoan-tibodies such as anti-Ro52 [10–12]. Whilst a negative ANAand/or a standard ENA panel does not preclude the presenceof autoantibodies in CTD-myositis overlap patients, it is sim-ilarly important to appreciate that the identification of lessspecific autoantibodies does not preclude the presence of anundetected myositis-associated antibody.

Adopting a ClinicoserologicalClassification—Autoantibody Syndromes (Table 1)

Anti-Synthetase and Anti-PM-Scl Syndrome

From a clinical perspective, patients with anti-synthetase syn-drome (ASS) and ‘anti-PM-Scl’ syndrome (PM-Scl) share anumber of common manifestations. PM-Scl patients overlapwith myositis and SSc, but from a personal perspective appearto form a distinct phenotype within this spectrum, whichincludes Raynaud’s phenomenon, inflammatory joint disease,puffy swollen fingers with limited cutaneous SSc and in somecase mechanic’s hands (typically described in ASS) [8, 13]. Inaddition to myositis, inflammatory lung disease in the form ofnon-specific interstitial pneumonia (NSIP) or organizingpneumonia (OP; or in combination) can predominate andinfluence treatment strategies [8, 13].

Anti-synthetase autoantibodies collectively form the larg-est subgroup in the CTD-myositis overlap spectrum [4]. Jo-1is the most frequently targeted autoantigen in comparison tothe non-Jo1 group put together (PL12, PL7, OJ, EJ, KS, Zo,Ha), and in general are mutually exclusive. ASS has been welldescribed, and classic clinical features include myositis, inter-stitial pneumonia, Raynaud’s, mechanic’s hands, Gottron’slesions, non-erosive inflammatory arthritis and a characteristicswinging pyrexia. Interstitial pneumonia is a major manifes-tation; with NSIP+/−OP the most frequent radiological andhistopathological patterns. Interstitial pneumonia is reportedin 50–95 %, but it is clear from clinical practice and variousstudies that even within the ASS spectrum, Jo1 differs fromnon-Jo1 ASS patients [4, 5, 8, 13–17]. In particular, the non-Jo1 ASS clinical phenotype may be present with lung disease

first, and patients may never develop myositis, have subclin-ical myopathy or milder muscle disease. This group of pa-tients may have usual interstitial pneumonia (UIP), the radio-logical and histological pattern synonymous with idiopathicpulmonary fibrosis (IPF) [13] (Gunawardena—personalunpublished data). In some cases, IPF may actually representa ‘formes frustes ’ of autoimmune connective tissue disease,especially in patients with non-Jo-1 anti-synthetase autoanti-bodies [6, 17], which may not be tested for in routine clinicalpractice. In a recent study of 198 patients with a diagnosis ofIPF, 6.6 % were retrospectively found to have an anti-synthetase antibody. Crucially of these patients subsequentlyfound to have an anti-synthetase antibody just under 50% hadno extra-pulmonary features [18]. The detection of anti-synthetase autoantibodies in patients with a diagnosis of IPFmight influence therapy and thus prognosis, particularly in thenon-Jo1 group with worse survival compared to Jo-1 patients[19]. Non-Jo1 patients have a greater delay in diagnosis,presumably related to differences in disease presentation andthe availability of testing for ‘non-standard’ autoantibodiesusing a limited ENA screen compared to Jo-1 patients [19].It seems likely that this is at least partially responsible for theprognostic differences, although the incidence and respon-siveness to therapy of interstitial pneumonia will undoubtedlyalso have a role. The most common cause of death in thisgroup was found to be pulmonary fibrosis [19]. Anti-synthetases autoantibodies have previously been shown tofrequently co-exist with anti-Ro52, which can be identifiedin up to 56 % of those with anti-Jo-1 autoantibodies [12, 20,21]. This finding is not due to autoantibody cross-reactivity[20]. Anti-Ro autoantibodies consist of two subtypes directedto Ro52 and Ro60, respectively. They can be identified in avariety of connective tissue diseases including myositis, butthe clinical significance of anti-Ro52 remains controversial;indeed, some laboratories choose not to report this. It has beenreported that while frequency of anti-Ro52 in comparison toanti-Ro60 is similar in other connective tissue diseases, thisdoes not appear to be the case in myositis, where anti-Ro60was not identified [22]. This finding is important as in additionto potentially masking the presence of a cytoplasmic anti-synthetase pattern; the additional presence of anti-Ro52 hasbeen associated with more severe interstitial pneumonia[23, 24]. Furthermore, a recent study comparing anti-Jo1autoantibody positive patients with and without anti-Ro52autoantibodies found that overall outcome was poorer inthose anti-Ro52, with reduced survival. This sub-groupwas more likely to have acute onset interstitial pneumonia,more severe myositis, joint impairment and an increasedoccurrence of malignancy [25].

We note with interest that anti-Ro52 has also been fre-quently identified in conjunction with anti-MDA5 autoanti-bodies in myositis, which are also associated with lung disease(as described below) [10, 11] and has been associated in

Clinic Rev Allerg Immunol

Tab

le1

Clin

icoserologicalsyndromes

Clinicoserological

syndrome

Anti-synthetase

syndrome

Necrotisingmyositis

Cancerassociated

Other

Autoantibody

Anti-synthetases

Anti-Pm

Scl

Anti-MDA5

Anti-SR

PAnti-HMG-coA

Anti-TIF1

Anti-NXP2

Anti-SA

EAnti-Mi2

Musculoskeletal

Myositis

may

beabsent

particularly

fornon-Jo-1

ASS

.Arthritiscommon.

Often

amyopathic

ormild

myositis

ArthritisinUScohorts

Necrotisingmyositis.

With

high

CK.

Arthritisreported

Necrotisingmyositis.

With

high

CK.

Myositis

Myositis

May

beam

yopathic

initially

buttypically

developlater

Myositis

Cutaneous

Associatedwith

mechanics

handsandRaynaud’s

phenom

enon.

May

have

additio

nal

DM

lesions

Mucocutaneous

ulceratio

n,palm

arpapulesand

Raynaud’sreported

inUScohorts.

Often

absent

Often

absent

Severe

skin

disease

particularly

inchild

renwith

ulceration,

oedema,

lipoatrophy

and

contractures.

Severe

skin

disease

particularly

inchild

renwith

calcinosis.P

ossible

associationwith

calcinosisin

adults.

May

presentw

ithDM

rash

alone

‘Classic’

DM

rash

Gastrointestin

alDysphagia

DysphagiaandGI

diseaseassociated

Respiratory

ILDcommon

andmay

bepresentin

gfeature.

Mostcom

monly

NSIP

butU

IPalso

reported.

Associatedwith

ILD.

InEastA

sian

populatio

nsassociated

with

RP-ILD

Lesstypical

Cardiac

Cardiac

involvem

ent

reported

Malignancy

Strong

association

inadults.N

olin

kdemonstratedin

juvenile-onset

disease.

Possibleassociation

inadults.

Noapparent

increasedrisk

Prognosis

Related

prim

arily

toILD.N

on-Jo-1

ASS

worse

prognosis.

RP-ILDassociated

with

poor

response

totreatm

entand

poor

prognosis

Chronicprogressive

course

associated

with

worse

prognosis

Poor

inadultsdue

toassociationwith

malignancy

Associatedwith

worse

functio

nal

status

inchildren.

Good

Clinic Rev Allerg Immunol

patients with systemic sclerosis lung fibrosis [26]. Furtherwork is needed to establish how the additional presence ofanti-Ro52 may modify clinically the phenotype in CTD-myositis overlap patients.

Autoimmune Necrotizing Myopathy Syndromes

Autoimmune necrotizing myopathy (ANM) is a relativelynewly recognized subgroup of idiopathic inflammatory myop-athies that are defined by common clinical and histopatholog-ical features. Patients present with subacute proximal weaknesswith high creatinine kinase levels. On muscle biopsy, charac-teristic features include myofibre necrosis, minimal endomysialand perivascular inflammatory infiltrate, and in some casesfocal endomysial fibrosis [27]. Despite little or no muscleinflammation, ANM usually responds to immunomodulatorytherapy highlighting that this is an immune-mediated pheno-type associated with two specific autoantibodies.

Anti-SRPANM

Anti-SRP patients (signal recognition particle, a cytoplasmicribonucleoprotein) usually present with severe high CK my-opathy, systemic features including dysphagia, cardiac muscleinvolvement and arthritis. Contrary to previous reports, in theclinic, parenchymal lung disease appears rare. This group ofpatients may be refractory to standard treatments andrequire more intensive management [4, 28]. Anti-SRPANM can be difficult to treat; some patients have chronicprogressive disease leading to worse clinical outcomes andsevere residual deficits compared to those with a subacutepresentation [29].

Anti-HMG-CoA AMN

Recent studies have described a new subset of AMN associat-ed with prior statin exposure who also present with significantweakness and high CK levels (mean maximum levels above10,000 IU/l) [30]. It is noteworthy that the target autoantigenhas been identified as 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMG-CoA), the enzyme involved in cholesterolbiosynthesis, which is upregulated by statins in regeneratingmuscle. This finding provides further clues in our un-derstanding of the pathogenesis of myositis and poten-tial triggers [31]. To date, the anti-HMG-CoA antibodyhas not been identified in patients with statin intoleranceassociated with myalgias or mild elevations of creatininekinase and appears to be specific for those with AMN[31].

Dermatomyositis Syndromes

DM is characterised by hallmark skin lesions, interstitialpneumonia, a risk of malignancy in adults and other systemicmanifestations. Certain features are more common in juveniledermatomyositis (JDM) in particular vasculopathy complica-tions including gastro-intestinal disease, skin ulceration andcalcinosis. Some patients present DM skin changes only withno clinical evidence of myopathy, termed clinically amyopathicDM (CADM). In recent years, a number of novel autoanti-bodies have expanded the clinicoserological spectrum and areassociated with specific DM manifestations.

Anti-Mi2

Anti-Mi2 is typically associated with classic DM [32]; prox-imal myopathy, hallmark cutaneous lesions, a low frequencyof cancer-associated myositis (CAM), and perhaps less inter-nal organ involvement. In general, from a clinical perspectiveanti-Mi2 patients tend to run a monocyclic course and respondwell to therapy.

Anti-TIF1 Cancer-Associated Myositis

Autoantibodies directed against the transcriptional intermedi-ary factor 1 family proteins (TIF1) are the first specific auto-antibody to be described DM and CAM [33, 34]. Anti-TIF1α,β and γ autoantibodies have all been described, the mostcommon antigenic target being TIF1γ [34]. In the majorityof cases, anti-TIF1γ and α co-exist and can be detected as a155/140-kDa doublet by IPP [34]. This autoantibody complexis found in 15–25 % of adult DM and 15–20 % JDM. In adultDM, over 50 % of anti-TIF1 patients have CAM with pooleddata showing a high negative predictive value and odds ratiofor malignancy [35]. Furthermore, the frequency of malignan-cy appears higher in those with anti-TIF1γ/α autoantibodiesthan anti-TIF1γ alone [34]. TIF1β is the least common anti-genic target in this group and has been identified in a smallproportion of those with anti-TIF1γ/α and very rarely alone[34, 36]. Interestingly, the TIF1 family of proteins all haveimportant roles in cell growth and potentially oncogenesis.For example, TIF1γ acts within the cell nucleus throughSMAD family member 4, a protein involved in cell signallingto play an important role in TGFβmodulation and subsequentsuppression of cell growth [37, 38]. In view of these observa-tions, it has been postulated that anti-TIF1 autoantibodies maybe produced as part of a misdirected anti-tumour immuneresponse, leading to bystander skin and muscle injury, whichmanifests as DM.

While a high associated risk of malignancy in adults withanti-TIF1 autoantibodies is of major clinical interest, it is notthe only distinctive feature of patients with this autoantibody.Anti-TIF1 adults appear to have more systemic features and

Clinic Rev Allerg Immunol

severe DM lesions. Curiously, although amajor autoantigen inJDM, studies to date have not shown any association withmalignancy but suggest a specific clinical phenotype withmore severe disease including skin ulceration, lipoatrophyand contractures [39, 40].

Anti-SAE

Anti-small ubiquitin-like modifier enzyme (SAE) has beendescribed in UK, European and Japanese cohorts [41–44].The clinical phenotype has yet to be fully determined, butthe initial UK study highlighted that the majority of patientspresent with CADM with classic skin disease first, and maytherefore present in the Dermatology clinic first. Detection ofanti-SAE in this subtype of CADM is important because themajority of patients appear to go onto develop myositis with ahigher frequency of systemic involvement includingdysphagia and gastrointestinal disease [44]. Based onthe limited number of studies to date, anti-SAE doesnot appear to carry a significant risk for interstitialpneumonia or CAM.

Anti-MDA5

Melanoma differentiation associated protein 5 (MDA5) is acytoplasmic RNA helicase autoantigen and autoantibodieshave been described in different ethnic cohorts [10, 45]. ThisDM syndrome was first reported in patients with CADMwitha high frequency of rapidly progressive interstitial pneumonia;acute interstitial pneumonia subtype (AIP) with diffuse alve-olar damage [45]. The risk of severe AIP appears to be uniqueto anti-MDA5 East Asian patients, although lung inflamma-tion was a feature in a recent US study [10]. This latter studyhas also highlighted that anti-MDA5 positivity is associatedwith a distinct skin and mucocutaneous phenotypecharacterised by skin ulceration, palmar papules, oral mucosalpain/ulceration and arthritis with little myositis [10]. Subse-quent work investigating ethnically similar rheumatologyrather than dermatology-based patient cohort identified simi-lar cutaneous features. Interestingly, many patients with anti-MDA5 autoantibodies in this study presented with inflamma-tory joint pain and were initially investigated for rheumatoidarthritis or labelled as having an “overlap” syndrome due tothe presence of marked synovitis on clinical examination. Theauthors also commented that disease phenotype in this patientgroup appeared clinically similar to the anti-synthetase syn-drome; with the identification of other features such asRaynaud’s phenomenon, mechanics hands and interstitialpneumonia but in the absence of anti-synthetase antibodies[11]. Interestingly, anti-Ro52 autoantibodies were a commonadditional finding.

To date, there is very little data describing the anti-MDA5clinical phenotype in JDM. In Japanese studies, anti-MDA5

has been identified in approximately 31–38 % of juvenilepatients, where it has been associated with a similar phenotypeto East Asian adults with a high frequency of lung involve-ment, which included AIP and therefore a poorer prognosis[46, 47]. The frequency and clinical features in other ethnicgroups have yet to be established, but preliminary work fromthe Juvenile Dermatomyositis Cohort Biomarker Study andRepository (UK and Ireland) has identified anti-MDA5 auto-antibodies in 7.4 % of 285 UK juvenile myositis patients.Interestingly, this group has a clinical phenotype similar tothat described in predominantly Caucasian adult cohorts withmucocutaneous ulceration, arthritis and minimal myosi-tis. A higher than expected proportion had interstitialpneumonia on chest imaging but none had AIP, and thefrequency is much lower than has been reported inJapanese populations [47, 48].

Anti-NXP2 (Anti-MJ)

Autoantibodies to nuclear matrix protein 2 have been primar-ily described in JDM with to date a much lower frequencydetected in adult patient cohorts. In JDM, similar to anti-TIF1positive children, anti-NXP2 appears to be associated withmore severe clinical manifestations including calcinosis, mus-cle atrophy and contractures [49, 50]. The anti-NXP2 subsetin adult DM is yet to be fully defined. Recent work hassuggested a possible association with CAM, but this appearsnot to be as strong as anti-TIF1 autoantibodies [51]. A possi-ble association with calcinosis has also been described inadults, although this failed to reach statistical significance[52]. This potential association has also been noted in theadult UK MYONET cohort (Tansley, Betteridge—personalcommunication).

Clinicoserological Classification: InfluencingManagement

Adopting a clinicoserological classification in adult and juve-nile patients with CTD-myositis overlap can provide impor-tant prognostic information on disease outcome and the like-lihood of specific complications (Fig. 2). In an otherwiseheterogeneous patient population, this information is invalu-able in facilitating decisions on appropriate investigationswhere complications such as malignancy or interstitial pneu-monia are a major concern. The identification of a ‘specific’autoantibody can also provide confidence in confirming diag-nosis where the clinical presentation is otherwise unusual. Forexample, patients with amyopathic disease, in the context of asubtle or atypical rash or in patients presentingwith significantinflammatory polyarthritis as has been described with anti-MDA5 autoantibodies [11]. The effects of a firmly establisheddiagnosis in these situations should not be underestimated.

Clinic Rev Allerg Immunol

Uncertainty may lead to further, otherwise unnecessary inves-tigations and/or delayed escalation of treatment in a patientresponding poorly.

At present, there is little evidence base for treatments cur-rently used in myositis overlap, and current treatment ap-proaches are based on clinical experience and expert consensus[53]. It seems crucial to now include clinicoserological classi-fication of patients in future clinical trials as heterogeneitybetween autoantibody-defined subgroups has the potential tointroduce bias if not accounted for. The move towards strati-fying patients by autoantibody profile and thus identifyingmore homogenous subgroups will facilitate good quality clin-ical trials and generate clearer evidence-based guidelines onappropriate treatment strategies. Moreover, in the future clas-sifying patients in this way might well determine the treatmentapproach and influence choice of immunomodulatory agents.There is emerging evidence to suggest a differential responseto some treatments dependent on autoantibody subgroup, forexample, as was seen on subgroup analysis of the Rituximab inMyositis study with a significantly better response to B celldepletion seen in patients with anti-Jo1 or anti-Mi2 autoanti-bodies [54].

Clinicoserological Classification: Understanding DiseasePathogenesis

Idiopathic inflammatory myopathies are believed to occurfollowing an as yet undefined environmental trigger in a ge-netically predisposed individual (Fig. 3). The pathogenesisremains poorly understood, but there is some evidence for arole of autoantibodies, and it is hoped that a greater under-standing of the mechanisms and cellular pathways involvedwill provide insight into potentially novel therapeutic strate-gies.While the autoantigens known thus far are all intracellularand therefore can only be accessed by the immune systemindirectly, via MHC class I presentation, there is developingevidence that they are involved in disease pathogenesis and aremore than simply a ‘bystander or epiphenomena’. In the nowseminal study undertaken by Casciola-Rosen et al., Mi2 ex-pression was found to be upregulated in regenerating in musclecells taken from DM patients, in contrast to the low levelsidentified in control muscle [55]. The authors subsequentlyhypothesised that regenerating muscle may provide an on-going source of antigen supply in patients with myositis,leading to a self-sustaining autoimmune response [55]. The

Fig. 2 Clinicoserological syndromes in the myositis spectrum

Clinic Rev Allerg Immunol

subcellular localisation of more recently identified autoanti-bodies has yet to be established in both control and diseasemuscle, and further work in this area is needed.

It has been noted with interest that autoantibodies directedagainst antigenic targets with similar cellular roles are associ-atedwith similar clinical phenotypes and the tRNA synthetasesprovide an excellent example of this. Furthermore, the role ofantigenic targets can be linked directly with potential environ-mental triggers, such as in the case of AMN associated withstatin use where antibodies frequently target HMG-co-A re-ductase, an enzyme upregulated by statins in regeneratingmuscle. Malignancy is likely to be another such trigger inselected cases, and the antigenic targets of both anti-TIF and anti-NXP2, which have been linked to CAM,intriguingly have important roles to play in cell growthand DNA repair [37, 56].

Other potential triggers previously postulated include in-fection (i.e. innate viral responses) and ultra-violet (UV) lightexposure as a result of identified seasonal associations andspatial clustering in the onset of inflammatory myopathies.Here, differences in seasonal onset have been found betweenautoantibody subgroups with a clustering of myositis associ-ated with anti-Jo1 positivity in spring and anti-SRP in autumn[57, 58]. Recently, it has been shown that there is a potentialrelationship between short-term UV exposure in the monthbefore symptom onset and the clinical phenotype in JDM.Interestingly, greater UV exposure was associated with in-creasing odds of anti-TIF and reduced odds of anti-NXP2autoantibodies [57–59].

Summary

Over the last few years, the number of autoantibodies identi-fied in the CTD myositis overlap spectrum has increasedsignificantly. Furthermore, our understanding of the functionand relationship between target autoantigens has started tounravel key questions that may provide insight into certainpathogenic mechanisms. It is now increasingly clear that theautoantibodies detailed in this review are helpful both diagnos-tically and prognostically. Their clinical utility should empha-sise to clinicians that we should now approach this complexgroup of overlap diseases as clinicoserological syndromesrather than simply diagnose patients are purely PM or DM.

Acknowledgments We would like to thank Juliet Dunphy (Bath Insti-tute for Rheumatic Diseases, Bath, UK) for providing the images forFig. 1 (ANA immunofluorescence patterns). We also thank and acknowl-edge Dr. Zoe Betteridge and Professor Neil McHugh for their continuedsupport.

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