Myositis

For personal use. Only reproduce with permission from The Lancet.

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THE LANCET • Vol 362 • September 20, 2003 • www.thelancet.com 971

The inflammatory myopathies are a heterogeneous groupof subacute, chronic, or acute acquired diseases of skeletalmuscle. They have in common the presence of moderateto severe muscle weakness and inflammation in themuscle.1–6 The disorders are clinically important becausethey are potentially treatable. On the basis of well-defined clinical, demographic, histological, andimmunopathological criteria, the inflammatory myopathiesform three major and discrete groups: polymyositis,dermatomyositis, and sporadic inclusion-body myositis.1

This review describes current knowledge of the clinicalpresentation, diagnosis, pathogenesis, and treatment ofpolymyositis and dermatomyositis. Inclusion-bodymyositis, a common and important subset as recentlyreviewed,4–7 is addressed only to outline its distinguishingfeatures in the differential diagnosis of polymyositis.

Epidemiology, genetics, and general clinicalfeaturesDermatomyositis affects both children and adults, andwomen more than men. Polymyositis is seen after thesecond decade of life. Inclusion-body myositis is morecommon in men over the age of 50 than in otherpopulation groups.1–7 The frequencies of polymyositis anddermatomyositis as stand-alone disorders or in associationwith other systemic diseases are unknown. Estimates basedon old diagnostic criteria,8 which cannot distinguishpolymyositis from inclusion-body myositis,1,3 range from0·6 to 1·0 per 100 0001–10 but may not be reliable (seelater). In all age-groups, dermatomyositis is the mostcommon and polymyositis the least common; inclusion-

body myositis is the commonest myopathy above the ageof 50. In children, dermatomyositis is the most frequentinflammatory myopathy but polymyositis is very rare, asrecently confirmed.11 Genetic factors may have a role, assuggested by rare familial occurrences and association withcertain HLA genes, such as DRB1*0301 alleles forpolymyositis and inclusion-body myositis,12,13 HLA DQA10501 for juvenile dermatomyositis,14 or tumour necrosisfactor 308A polymorphism for photosensitivity indermatomyositis.15 Emerging information on the geneticbackground of various ethnic groups may allowidentification of immune-response genes that predisposecertain populations to polymyositis or dermatomyositis.16,17

Both polymyositis and dermatomyositis present with avarying degree of muscle weakness that develops slowly,over weeks to months, but acutely in rare cases.1 Patientsreport difficulty with everyday tasks, such as rising from achair, climbing steps, stepping onto a kerb, lifting objects,or combing their hair. Fine motor movements thatdepend on the strength of distal muscles, such as holdingor manipulating objects, are affected late in the course ofdermatomyositis and polymyositis, but fairly early insporadic inclusion-body myositis owing to prominentinvolvement of distal muscles, especially wrist and fingerflexors.1 Early involvement of the quadriceps muscle andankle dorsiflexors, causing buckling of the knees andfrequent falls, is common in sporadic inclusion-bodymyositis.7 Facial muscles remain normal but mild facialmuscle weakness is common in patients with sporadic

Polymyositis and dermatomyositis

Marinos C Dalakas, Reinhard Hohlfeld

The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentiallytreatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, theycan be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis.Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders.Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysisof endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via theperforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunologicalfeatures. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule,intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokinesincrease the immunopathological process. Early initiation of therapy is essential, since both polymyositis anddermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested incontrolled trials may prove promising for difficult cases.

Lancet 2003; 362: 971–82

Neuromuscular Diseases Section, National Institute of NeurologicalDisorders and Stroke, National Institutes of Health, Bethesda, MD,USA (Prof M C Dalakas MD); and Max Planck Institute ofNeurobiology and Institute for Clinical Neuroimmunology, KlinikumGrosshadern, Ludwig Maximilians University, Munich, Germany(Prof R Hohlfeld MD)

Correspondence to: Prof Marinos C Dalakas, NeuromuscularDiseases Section, NINDS, NIH, Building 10, Room 4N248,10 Center Drive MSC 1382, Bethesda, MD 20892–1382, USA(e-mail: [email protected])

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Search strategy and selection criteria

The review is based on our own experience and researchconnected with these disorders as well as a comprehensiveMEDLINE search on the topics of "polymyositis","dermatomyositis", and "inflammatory myopathies". Wefocused on peer-reviewed works published in English in majorscientific journals over the past 10 years and on reviewswritten by experts on this subject. All available articles werecritically reviewed. Papers presenting the strongest evidenceor providing important insights into the diagnosis,pathogenesis, and management of these disorders were alsoreferred to and cited.


inclusion-body myositis.7 The extraocular muscles arenever affected, in contrast to myasthenia in which they areaffected early.1 The neck extensor muscles may beinvolved, causing difficulty in holding up the head (headdrop). In advanced cases, and in rare acute cases,dysphagia with choking episodes and respiratory muscleweakness occurs. Sensation remains normal. The tendonreflexes are preserved but may be absent in severelyweakened or atrophied muscles. Contrary to widespreadbelief, myalgia is not common, occurring in less than 30%of the patients.

Specific clinical featuresDermatomyositisDermatomyositis is identified by a characteristic rashaccompanying or, more commonly, preceding muscleweakness. The skin manifestations include a heliotroperash (blue-purple discolouration) on the upper eyelids inmany cases associated with oedema, and an erythematousrash on the face, neck, and anterior chest (in manypatients in a V sign) or back and shoulders (shawl sign),knees, elbows, and malleoli; the rash can be exacerbatedafter exposure to the sun and is pruritic in some cases.Characteristic is the Gottron rash (figure 1), a raisedviolaceous rash or papules at the knuckles, prominent inmetacarpophalangeal and interphalangeal joints;18 incontrast to systemic lupus erythematosus, the rash doesnot involve the phalanges.1,9 When chronic, the rashbecomes scaly with a shiny appearance. Dilated capillaryloops at the base of the fingernails with irregular,thickened, and distorted cuticles are also characteristic.The lateral and palmar areas of the fingers may becomerough with cracked, “dirty” horizontal lines, resembling“mechanics’ hands”.

The weakness varies from mild to severe, leading toquadriparesis. At times the muscle strength appearsnormal, hence the terms dermatomyositis sine myositis oramyopathic dermatomyositis.19 When a muscle biopsy istaken from such cases, however, subclinical muscleinvolvement with perivascular and perimysialinflammation is seen.20 Although there may be cases ofamyopathic dermatomyositis limited to the skin, webelieve that amyopathic and myopathic dermatomyositisare part of the range of dermatomyositis affecting skin andmuscle to a varying degree. Rarely, when the rash is

transient or poorly recognised (eg, indark-skinned people), the termdermatomyositis sine dermatitis isappropriate. In such cases, a mistakendiagnosis of polymyositis is considered,until a muscle biopsy confirms thecorrect diagnosis. In children,dermatomyositis resembles the adultdisease, except for more frequentextramuscular manifestations (seelater). A common early abnormality inchildren is “misery”, defined as anirritable child who feels uncomfortable,has a red flush on the face, is fatigued,does not socialise, and has a varyingdegree of proximal muscle weakness.4,6

A tiptoe gait due to flexion contractureof the ankles is common.1

Dermatomyositis can be associatedwith cancer21 or may overlap withsystemic sclerosis and mixedconnective-tissue disease.1,22,23 Fasciitisand thickening of the skin, as seen inchronic dermatomyositis, can also

occur in patients with eosinophilia-myalgia syndrome,24

eosinophilic fasciitis, or macrophagic myofasciitis.25

PolymyositisPolymyositis is best defined as a subacute myopathy thatevolves over weeks to months, affects adults but rarelychildren, and presents with weakness of the proximalmuscles. Unlike dermatomyositis in which the rashsecures early recognition, the actual onset of polymyositiscannot be easily identified.1 Polymyositis mimics manyother myopathies and remains a diagnosis of exclusion(panel).26–29 It should be viewed as a syndrome of diversecauses that occurs separately or in association withsystemic autoimmune disorders or viral infections inpatients who do not have any of the exclusion criterialisted in the panel.

As a stand-alone clinical entity, polymyositis is anuncommon but frequently misdiagnosed disorder. Thecommonest myopathy misdiagnosed as polymyositis isinclusion-body myositis; this disorder is suspected inretrospect in many cases of presumed polymyositis thathave not responded to therapy.1,7 Especially in menolder than 50 years, a polymyositis-like disease isinclusion-body myositis until proved otherwise. Otherdisorders misdiagnosed as polymyositis include toxicand endocrine myopathies, dermatomyositis sinedermatitis, certain dystrophies, and some slowlyprogressive myopathies commonly starting in latechildhood (panel).

Associated clinical findings (table 1)Extramuscular manifestationsThere are many manifestations outside the muscles. Jointcontractures occur mostly in dermatomyositis. Dysphagiais due to involvement of the oropharyngeal striatedmuscles and upper oesophagus30,31 (gastrointestinalulcerations due to vasculitis and infection were commonin children with dermatomyositis before the use ofimmunosuppressants2). Cardiac disturbances includeatrioventricular conduction defects, tachyarrhythmias,myocarditis in patients with acute disease,32,33 and heartfailure commonly related to hypertension from long-termsteroid use.1 Pulmonary symptoms are due to weakness ofthe thoracic muscles or interstitial lung disease,34–36 whichis common in patients with autoantibodies to tRNA

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972 THE LANCET • Vol 362 • September 20, 2003 • www.thelancet.com

Figure 1: Rash and calcifications in dermatomyositisA: Gottron’s rash. B: Skin effects of calcification. C: Radiographic evidence of calcification.


synthetases or a mucin-like glycoprotein (KL-6).35

Subcutaneous calcifications (figure 1), occur only indermatomyositis, in some cases extruding on the skin andcausing ulcerations, infections, and pain,37 especially atsites of compression (elbows, buttocks, back). Generalsymptoms include fever, malaise, weight loss, arthralgia,and Raynaud’s phenomenon when polymyositis ordermatomyositis is associated with another connective-tissue disease.

Malignant disordersAlthough all the inflammatory myopathies can have achance association with malignant disease, especially inolder age-groups, the frequency of cancer is definitelyincreased in dermatomyositis.38 A slightly increasedfrequency reported in polymyositis39,40 must be confirmedwith use of updated diagnostic criteria. The mostcommon cancers are those of the ovaries, gastrointestinaltract, lung, and breast and non-Hodgkin lymphomas.Continuous vigilance is required for early recognition,especially in older people and during the first 3 years afterdisease onset.23,41 In patients without risk factors,expensive, radiological blind searches for occult malignantdisease is not practical or fruitful.1,41 A complete annualphysical examination with pelvic, breast (mammogram, ifindicated), rectal (with colonoscopy, according to age andfamily history) radiographs and a chest film should suffice.A report that blind search with abdominal–pelvic andthoracic CT scans increased the yield by 28%42 needsconfirmation. In Asian patients, among whomnasopharyngeal cancer is more common, carefulassessment of ears, nose, and throat is suggested.

Overlap syndromePolymyositis and dermatomyositis are seen in associationwith various autoimmune and connective tissue diseases(table 1). The term overlap syndrome is used loosely toemphasise this association but in reality it was meant toindicate that certain clinical signs are shared by bothdisorders. Accordingly, it is only dermatomyositis, andnot polymyositis, that truly overlaps and only withsystemic sclerosis and mixed connective-tissue disease.Certain signs seen in these two disorders, such as scleroticthickening of the dermis, contractures, oesophagealhypomotility, microangiopathy, and calcium deposits, arealso present in dermatomyositis but not polymyositis; bycontrast, signs of rheumatoid arthritis, lupus, or Sjögren’ssyndrome are rare in dermatomyositis (table 1).1 A reportthat dermatomyositis can overlap with lupus43 needsconfirmation.

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Characteristic Dermatomyositis Polymyositis Inclusion-body myositis

Age at onset All ages >18 years >50 years

Familial association No No In some cases

Extramuscular manifestations Yes Yes Yes

Associated disordersConnective-tissue diseases* Only with scleroderma and mixed connective-tissue disease Yes, with all Yes, in up to 20% of casesOverlap syndrome† Only with scleroderma and mixed connective-tissue disease No NoSystemic autoimmune diseases Rarely Frequently InfrequentlyMalignant disorders Yes, in up to 15% of cases No NoViruses Unproven Yes‡ Yes‡Parasites and bacteria No Yes§ NoDrug-induced myotoxicity|| Rarely Yes No

*A dermatomyositis-like disease develops in up to 12% of patients with systemic sclerosis, and polymyositis in 5–8% of lupus patients; polymyositis is less commonlyseen in patients with Sjögren’s disease or rheumatoid arthritis. †Overlap denotes that certain signs are common to both disorders; by contrast, "association" denotesthat two disorders can coexist. ‡HIV and HTLV-1. §Includes parasitic (protozoa, cestodes, and nematodes), tropical, and bacterial myositis (pyomyositis). ||Drugsinclude penicillamine (for dermatomyositis and polymyositis), zidovudine (for polymyositis), contaminated tryptophan (for a dermatomyositis-like illness), and lipid-lowering drugs rarely. Other myotoxic drugs can cause myopathy but not inflammatory myopathy.1,6,29

Table 1: Conditions and factors associated with inflammatory myopathies

Clinical characteristics of polymyositisMyopathic weaknessEvolves over weeks to months, spares facial and eyemuscles, and presents as difficulty in climbing steps, risingfrom a chair, lifting objects, combing hair.

Disease onsetAbove the age of 18 years

Features the patient DOES NOT haveRash (characteristic of dermatomyositis)Family history of neuromuscular diseasesExposure to myotoxic drugs, especially penicillamine,26

zidovudine,27 and (rarely) statins28,29

Endocrine disease (hypothyroidism, hyperthyroidism, hypoparathyroidism, hypercortisolism)

Neurogenic disease (excluded by electromyography and neurological examination)

Dystrophies and metabolic myopathies (excluded by history and muscle biopsy)

Inclusion-body myositis (excluded by clinical examination and muscle biopsy)

Possible associationsOther autoimmune or viral infections, such as:

lupus, rheumatoid arthritis, Sjögren’s syndrome, Crohn’s disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult coeliac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behçet’s syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto’s disease, granulomatous diseases, agammaglobulinaemia, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinaemic purpura, hereditary complement deficiency, HIV and HTLV-1 infection.

Reconsider polymyositisIf the diagnosis was based on Bohan and Peter’s criteria, inpatients with:Disease onset before the age of 18Slow-onset myopathy that evolved over months to years (in

such cases think of inclusion-body myositis or dystrophy)Fatigue and myalgia, without muscle weakness, even if a

transient rise in creatine kinase activity is seen (such patients may have fibromyalgia or fasciitis, and their muscle biopsy sample is normal or shows very few inflammatory cells in the endomysial septae)

No typical histological features of polymyositis


DiagnosisThe clinical diagnosis of polymyositis anddermatomyositis is confirmed by three laboratoryexaminations: serum muscle enzyme concentrations,electromyography, and muscle biopsy. In certain cases ofdermatomyositis, skin biopsy can be helpful.

The most sensitive muscle enzyme assay is creatinekinase, which is increased up to 50 times in active disease.Aspartate and alanine aminotransferases, lactatedehydrogenase, and aldolase are also increased. Althoughcreatine kinase concentration usually parallels diseaseactivity, it can be normal in some patients with activedermatomyositis; in the active phases of polymyositis, thecreatine kinase concentration is always increased.

Needle electromyography shows increased spontaneousactivity with fibrillations, complex repetitive discharges,and positive sharp waves. The voluntary motor unitsconsist of low-amplitude polyphasic units of shortduration.44,45 Although not disease specific, these findingsare useful to confirm active myopathy. Presence ofspontaneous activity can help to distinguish active diseasefrom steroid-induced myopathy, except if the two coexist.1

The muscle biopsy is the most crucial test forestablishing the diagnosis,1–6,46 but also the most commoncause of misdiagnosis due to erroneous interpretation.4 Indermatomyositis, the inflammation is predominantly

perivascular or in the interfascicular septae and aroundrather than within the fascicles.1-6 The intramuscular bloodvessels show endothelial hyperplasia with tubuloreticularprofiles, fibrin thrombi, especially in children, andobliteration of capillaries resulting in reduction of capillarydensity (figure 2).2,4,46–49 The muscle fibres undergophagocytosis and necrosis, commonly in groups(microinfarcts) involving a portion of a muscle fasciculus,or the periphery of the fascicle, resulting in perifascicularatrophy. This atrophy, characterised by two to ten layers ofatrophic fibres at the periphery of the fascicles, isdiagnostic of dermatomyositis, even in the absence ofinflammation (figure 2).1,46 The skin lesions showperivascular inflammation with CD4-positive cells in thedermis; in chronic stages there is dilatation of superficialcapillaries.2 Skin histopathology distinguishesdermatomyositis from other papulosquamous disordersbut not from cutaneous lupus.18

In polymyositis, multifocal lymphocytic infiltratessurround and invade healthy muscle fibres (figure 2).1–5,46

The inflammation is primary, a term used to indicate thatlymphocytes (CD8-positive cells) invade histologicallyhealthy muscle fibres expressing MHC class I antigens.We refer to this lesion as the CD8/MHC-I complex (seelater).50–53 In chronic stages, connective tissue is increasedand may react with alkaline phosphatase.46 When, in

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Figure 2: Histological findings in polymyositis and dermatomyositisA, B: Depletion of capillaries in dermatomyositis (A) with dilatation of the lumen of the remaining capillaries, compared with a normal muscle (B). C: Perifascular atrophy in dermatomyositis. D: Endomysial inflammation in polymyositis and inclusion-body myositis with lymphocytic cells invading healthyfibres. E: The MHC-I/CD8 complex in polymyositis and inclusion-body myositis. MHC-I (green) is upregulated on all the muscle fibres, and CD8-positive T cells (orange) that also express MHC-I, invade the fibres.


addition to primary inflammation, there are vacuolatedmuscle fibres with basophilic granular deposits aroundthe edges (rimmed vacuoles) and congophilic amyloiddeposits within or next to the vacuoles, the diagnosis ofinclusion-body myositis is likely.54,55 Errors in thehistological diagnosis of polymyositis can be avoided bythree steps. First, primary inflammation should bedemonstrated. This step has become an essentialcriterion because it distinguishes polymyositis from toxic,necrotising, or dystrophic myopathies (facioscapulo-humeral; due to deficiency of dystrophin or dysferlin) inwhich macrophages predominate.46 Second, the biopsysample should be processed for frozen sections and withenzyme histochemistry and immunohistochemistry.Paraffin embedding misdiagnoses inclusion-bodymyositis for polymyositis because it dissolves the red-rimmed granular material, and the vacuolated fibresbecome indiscernible. Also, the CD8/MHC-I complexand sarcolemmal or enzymatic proteins that excludedystrophies, metabolic myopathies, and mitochondrio-pathies are best demonstrated on frozen sections. Third,a repeat muscle biopsy may be necessary. Because theinflammation is spotty, taking a sample from a differentmuscle should be considered if a patient meets theclinical criteria (panel) but the first sample was notdiagnostic. In occasional cases, muscle MRI may beuseful to identify inflammatory sites and select the areafor biopsy.

Other inflammatory myopathies diagnosed on the basisof distinctive clinical and histological features include:infectious (parasitic, bacterial [pyomyositis]), granulo-matous, eosinophilic (polymyositis or fasciitis), andlocalised forms.1,3–5,56

Diagnostic criteriaThe subject of diagnostic criteria remains unsettledbecause the various proposed criteria3 have not beenproperly validated. The criteria of Bohan and Peter8

cannot distinguish polymyositis from inclusion-bodymyositis or from certain dystrophies. Because theimmunopathological characteristics confer specificity foreach subset, we believe that the diagnostic criteria shouldrely on histopathology and immunopathology as the bestmeans of separating polymyositis from other myopathies.1

Accordingly, we view the diagnosis of polymyositis asdefinite if a patient has an acquired, subacute myopathymeeting the inclusion and exclusion criteria (panel),raised concentrations of serum creatine kinase, andprimary inflammation in the muscle biopsy (table 2).When in such a patient, the biopsy sample showswidespread expression of MHC-I antigens57,58 but no

T cells or vacuoles, the diagnosis is probable polymyositis.Because the same histology may also be seen in somepatients who have the typical inclusion-body myositisphenotype (probable inclusion-body myositis),59 thediagnosis is aided by taking a second biopsy sample andrelating the findings to the clinical picture.

The diagnosis of dermatomyositis is definite if themyopathy is accompanied by the characteristic rash andhistopathology. If no rash is detected but the biopsysample is typical for dermatomyositis, the diagnosis isprobable dermatomyositis; conversely, if the typicaldermatomyositis rash is present but muscle weakness isnot apparent, the clinical diagnosis is amyopathicdermatomyositis.

ImmunopathogenesisThe autoimmune origin of polymyositis anddermatomyositis is supported by their association withother autoimmune disorders, autoantibodies,60 andhistocompatibility genes; the evidence of T-cell-mediatedmyocytotoxicity or complement-mediated microangi-opathy; the possible maternal microchimerism in juvenileforms;61 and their response to immunotherapies.However, no specific target antigens have been identified,and the agents initiating self-sensitisation remainunknown.

AutoantibodiesAutoantibodies against nuclear or cytoplasmic antigens,directed against ribonucleoproteins involved in proteinsynthesis (anti-synthetase) or translational transport(anti-signal-recognition particle), are found in about 20%of patients (table 3).60 These antibodies are useful clinicalmarkers because of their frequent association withinterstital lung disease. The antibody against histidyl-tRNA synthetase, anti-Jo-1, accounts for 80% of all theanti-synthetases and seems to confer specificity foridentifying a disease subset that combines myositis, non-erosive arthritis, and Raynaud’s phenomenon. Theimportance of these antibodies and their specificity in thepathogenesis of polymyositis and dermatomyositisremains unclear because they are not specific for tissue ordisease subset, they occur in less than 25% of patients,and they do occur in patients with interstitial lung diseasewithout myositis.62,63 A report that antibodies to signal-recognition particles are markers of aggressive diseasewith cardiomyopathy and poor response to therapies64 hasnot been confirmed.65 Other autoantibodies include anti-Mi-2, anti-polymyositis-Scl, found in dermatomyositiswith scleroderma, and anti-KL6 associated withinterstitial lung disease (table 3).

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Criterion Polymyositis Myopathic dermatomyositis Amyopathic dermatomyositis

Definite Probable Definite Probable Definite

Myopathic muscle weakness Yes* Yes* Yes* Yes* No†Electromyographic findings Myopathic Myopathic Myopathic Myopathic Myopathic or

non-specificMuscle enzymes High (up to 50 High (up to 50 times High (up to 50 times High High (up to 10 times

times normal) normal) normal) or normal normal) or normalMuscle-biopsy findings Primary inflammation, Ubiquitous MHC-I Perifascicular, perimysial Perifascicular, perimysial Non-specific or

with the CD8/MHC-1 expression, but no or perivascular infiltrates; or perivascular infiltrates; diagnostic for complex and no CD8-positive infiltrates perifascicular atrophy perifascicular atrophy dermatomyositis vacuoles or vacuoles‡ (subclinical myopathy)

Rash or calcinosis Absent Absent Present Not detected Present

*Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterised by a subacute onset (weeks tomonths) and rapid progression in patients who have no family history of neuromuscular disease, no exposure to myotoxic drugs or toxins, and no signs of biochemicalmuscle disease. The myopathic weakness has a pattern distinct from that seen in inclusion-body myositis (table 1). †Although strength is apparently normal, manypatients have new onset of easy fatigue, myalgia, and reduced endurance. Careful muscle testing may reveal mild muscle weakness. ‡If such a patient has theclinical phenotype of sporadic inclusion-body myositis, the diagnosis will be probable inclusion-body myositis; a repeat biopsy is indicated.

Table 2: Diagnostic criteria for inflammatory myopathies


Immunopathology of dermatomyositisThe primary antigenic target in dermatomyositis is theendothelium of the endomysial capillaries (figure 3). Thedisease begins when putative antibodies directed againstendothelial cells activate complement C3. Activated C3leads to formation of C3b, C3bNEO, and C4b fragmentsand C5b–9 membranolytic attack complex (MAC), thelytic component of the complement pathway.49,66,67 MAC,C3b, and C4b are detected early in the patients’ serum68

and are deposited on capillaries before inflammatory orstructural changes are seen in the muscle.49,66,67 Sequentially,

the complement deposits induce swollen endothelial cells,vacuolisation, capillary necrosis, perivascular inflammation,ischaemia, and destruction of muscle fibres.1,2,46,53 Thecharacteristic perifascicular atrophy (figures 2 and 3)reflects endofascicular hypoperfusion, which is prominentdistally. Finally, there is striking reduction in the number ofcapillaries per muscle fibre with compensatory dilatation ofthe lumen of the remaining capillaries.46,53 Cytokines andchemokines69–72 related to complement activation arereleased; they upregulate vascular-cell adhesion molecule(VCAM-1) and intercellular adhesion molecule (ICAM-1)on the endothelial cells and facilitate the egress of activatedT cells to the perimysial and endomysial spaces (figure 3).T cells and macrophages through their integrins (very lateactivation antigen 4 and leucocyte-function-associatedantigen 1) bind to the adhesion molecules and pass into themuscle through the endothelial cell wall. The predominantlymphocytes are B cells and CD4-positive T cells,consistent with a humorally mediated process.1,2,49–53,73 Geneexpression profiling in muscles of genetically susceptiblechildren showed interferon inducible genes implying virus-driven autoimmune dysregulation.74 However, no viruseshave been amplified.

Immunopathology of polymyositisIn polymyositis and inclusion-body myositis, CD8-positive cells invade MHC-I-antigen expressing musclefibres.50–53

Cytotoxic T cellsT-cell lines established from muscle biopsy material arecytotoxic to autologous myotubes.75 In vivo, the CD8-positive cells send spike-like processes into non-necroticmuscle fibres, traverse the basal lamina, and focally invadethe muscle cell.73 The autoinvasive cells express thememory and activation markers CD45RO and ICAM-176

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Autoantibodies associated with myositis* Antigen

Anti-aminoacyl-tRNA synthetases (in 20% of patients)Anti-Jo-1† tRNAhis synthetase‡Anti-PL-7 tRNAthr synthetaseAnti-PL-12 tRNAala synthetaseAnti-EJ tRNAgly synthetaseAnti-OJ tRNAile synthetaseAnti-KS tRNAasp synthetase

Anti-signal recognition particle <3% of patients SRP-complex

OtherAnti-Mi-2 (10–15% of dermatomyositis and Nuclear helicasepolymyositis)Anti-polymyositis-Scl (15% of dermatomyositis Nuclear complexwith scleroderma)Anti-KL6 (in patients with interstitial lung Mucin-like glycoprotein disease) (on alveoli or bronchial

epithelial cells)

SRP=signal recognition particle. *The antibodies are found mostly inpolymyositis and dermatomyositis, and occasionally in inclusion-body myositis,when the myositis is associated with another connective-tissue disorder.†Some Jo-1-positive patients with polymyositis or dermatomyositis have thetriad of non-erosive arthritis, interstitial lung disease, and Raynaud’sphenomenon; 50% of them have interstitial lung disease. ‡7% of thesepatients also have antibodies against the cognate tRNAhis.

Table 3: Various autoantibodies associated with polymyositis,dermatomyositis, and some cases of inclusion-body myositis

Figure 3: Proposed sequence of immunopathological changes in dermatomyositisVLA-4=very late activation antigen; LFA-1=leucocyte-function-associated antigen; NO=nitric oxide; TNF�=tumour necrosis factor �; TGF�=transforminggrowth factor �. Modified from reference 53.

LFA-1

VLA-4

Mac-1

B

B

CD4+

CD4+

CD4+

M� M�

M�

Molecular mimicrytumours, viruses?

ICAM-1

VCAM-1

ICAM-1

Antibody

Macrophage

C3

Complement

C3a C3b

C3bNEO

MAC MAC

Cytokines

Cytokines

Chemokines

Endothelial cell wall

NOTNF�

STAT-1,Chemokines,Cathepsin,

TGF�


and contain perforin and granzyme granules that aredirected towards the surface of the fibres.77 Thus, theperforin pathway seems to be the major cytotoxic effectormechanism. By contrast, the Fas-Fas-L-dependentapoptotic process is not functionally involved,78 despiteexpression of Fas antigen on muscle fibres and Fas-L onthe autoinvasive CD8-positive cells.79–81 The coexpressionof the anti-apoptotic molecules BCL2,79 FLICE (Fas-associated death domain-like interleukin-1-converting-enzyme inhibitory protein [FLIP]),82 and human IAP-likeprotein (hILP),83 may confer resistance of muscle to Fas-mediated apoptosis (figure 4).

In polymyositis and inclusion-body myositis but notdermatomyositis, certain CD8-positive cells of specific T-cell-receptor (TCR) families are clonally expandedboth in the circulation and in muscle.84–89 In individualpatients, the CDR3 region, the antigen-binding region ofthe TCR of the autoinvasive CD8-positive cells, hasconserved aminoacid sequences, which suggest that T-cellexpansion is driven by a common antigen, possibly anautoantigen.85–88 Remarkably, only the autoinvasive(autoaggressive) T cells are clonally expanded; the non-invasive bystander T cells are clonally diverse.85

In one case, a single clone of �/� T cells of a single clonewere the primary cytotoxic effectors.90–92 When the �/�TCR of these cells was transfected into a TCR-deficientmouse hybridoma cell line,92 the transfectants could bestimulated with an unknown autoantigen on humanmyoblasts.92 This is the first indication that in �/�-T-cellmediated polymyositis the autoaggressive T cellsrecognise muscle antigens.

MHC expressionMuscle fibres do not normally express MHC class I or IIantigens. In polymyositis and inclusion-body myositis,

however, widespread overexpression of MHC class I, andoccasionally MHC II, is seen even in areas remote fromthe inflammation.57,58,93 In human myotubes, MHCmolecules are upregulated by interferon �.94–96 Although intransgenic mice MHC-I expression was proposed to act asan inciting event triggering polymyositis with myositis-specific antibodies,97 the observed histopathology was nottypical of myositis. Furthermore, in human polymyositisupregulation of MHC-I alone does not trigger T-cellactivation or endomysial infiltration.98 Another MHCmolecule, the non-polymorphic non-classic HLA G, isupregulated in vitro by interferon � and is expressed onmuscle fibres of patients with polymyositis (and inclusion-body myositis).99 Because HLA G protects human musclecells from immune-cell-mediated lysis in vitro, it couldalso partially protect muscle fibres in vivo.100

Costimulatory moleculesIf the autoinvasive CD8-positive cells are driven byspecific antigens, as the clonally expanded TCR generearrangements indicate,84–88,101 the MHC-I molecule onthe muscle fibres should be able to present antigenicpeptides to the TCR. For primary T-cell antigenicstimulation a second signal is required and provided bythe B7 family of costimulatory molecules.102,103 Musclefibres do not express the classic costimulatory moleculesB7-1 (CD80) or B7-2 (CD86);104 instead, they express afunctional B7-related molecule defined by the monoclonalantibody BB-1.104 Indeed, the MHC-I/BB1-positivemuscle fibres make direct cell-to-cell contact with theirCD28 or CTLA-4 ligands on the autoinvasive CD8-positive cells (figure 4).104,105 The B7-related costimulatorymolecule LICOS (ligand of inducible costimulator) andthe costimulatory molecule CD40 are also upregulated onmuscle fibres.106,107

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Figure 4: Molecules, receptors, and ligands involved in transgression of T cells through endothelial cell wall and recognition ofantigens on muscle fibres in polymyositisModified from references 55 and 89.

TNF�

TNF�

IFN-�

IFN-�

IL-1,2

IL-1,2

CD8 CD8

CD8

CD8 CD8

CD8CD8 CD8

M�

MMP-9

MMP-9MMP-2

MMPs

Cytokines

Infection?

Costimulation

Antigen

IntegrinsLFA-4

VCAM-1

Systemic immunecompartment

Clonal expansion

TAP

Chemokines

CD28

BB1ICAM-1

Endoplasmic reticulum

Necrosis

CalnexinMHC-I

Perforin

TCR

MHC-1

CTLA-4 LFA-1

MHC

TCR

Antigen(virus, musclepeptide)

� �


Cytokines, cytokine signalling, chemokines, andmetalloproteinasesIn the muscles of patients with polymyositis ordermatomyositis, there is overexpression of the signaltransduction and activation of transducers type I,108

indicating cytokine upregulation. Various cytokines andtheir mRNA, including interleukins 1, 2, 6, and 10, tumournecrosis factor �, interferon �, and transforming growthfactor �, are amplified in polymyositis anddermatomyositis.69,71,72,109–111 Some of them, such asinterferon � and interleukin 1b, may have a myocytotoxiceffect112–114 whereas others, such as transforming growthfactor �, may promote chronic inflammation and fibrosis.115

Muscle-fibre necrosis occurs via the perforin granulesreleased by the autoaggressive T cells. Death of the musclefibre is mediated by a form of necrosis rather thanapoptosis, presumably because of the counterbalancingeffect or protection by the antiapoptotic molecules BCL2,hILP, and FLIP which are upregulated in polymyositis andinclusion-body myositis. Fas is also expressed, but it doesnot mediate apoptosis in the muscle. The upregulatedNCAM on degenerating muscle fibres may enhanceregeneration. After successful immunotherapy,116 there isdownregulation of cytokines with reduction ofinflammation and fibrosis.116,117 Chemokines, a class of smallcytokines,118 including interleukin 8 (CXCL8), RANTES(CCL9), MCP-1 (CCL2), Mig CXCL9), and IP-10(CXCL10) are also overexpressed in the endomysialinflammatory cells, the extracellular matrix, and the musclefibres;72,119–121 they may facilitate trafficking of activated T cells to the muscle or promote tissue fibrosis. The matrixmetalloproteinases MMP-2 and MMP-9, which promotethe migration of lymphocytes through extracellular matrix,are also overexpressed on the muscle fibres and theautoinvasive CD8-positive cells.122,123

Viral infectionsAlthough several viruses (coxsackieviruses, influenza,parvoviruses, paramyxoviruses, cytomegalovirus, Epstein-Barr virus) and bacteria (Borrelia burgdorferi, streptococci)have been indirectly associated with chronic and acutemyositis,14,124 sensitive PCR studies have not amplifiedviral genome from muscle of these patients.125,126 Aproposed molecular mimicry based on structuralhomology between coxsackieviruses and Jo-1 synthethasehas not been proved.124 The best evidence of a viralconnection is with retroviruses. At least six differentretroviruses have been associated with polymyositis andinclusion-body myositis.124,127–132 Monkeys infected withsimian immunodeficiency virus,127 and human beingsinfected with HIV and HTLV-1,128,129 developpolymyositis either as an isolated clinical entity orconcurrently with other manifestations of AIDS orHTLV-1 infection.128–133 HIV seroconversion may coincidewith myoglobulinuria and acute myalgia, suggesting thatmyotropism for HIV can be symptomatic early in theinfection. The retroviruses are found only in occasionalendomysial macrophages129–133 and do not replicate withinthe muscle fibres or cause persistent infection.131–133 InHIV-1 and HTLV-1 polymyositis, CD8-positive, non-viral-specific, cytotoxic T cells invade MHC-I-antigen-expressing non-necrotic muscle fibres in a patternidentical to retrovirus-negative polymyositis. Virus-induced cytokines, secreted also in situ by the virus-infected macrophages, could trigger T-cell activation andMHC upregulation. The relation between systemicretroviral infection and local autoimmune processes inmuscle is not precisely understood. In principle, there aretwo possibilities: either the autoimmune attack is triggered

by mimicry between retroviral and muscle antigens, or theautoimmune process is non-specifically induced viabystander stimulation.134

TreatmentThe goals of therapy are to improve the ability to carry outactivities of daily living by increasing muscle strength andto ameliorate extramuscular manifestations (rash,dysphagia, dyspnoea, arthralgia, fever). There have beenvery few controlled clinical trials, most ondermatomyositis and inclusion-body myositis.135 Overall,dermatomyositis responds better than polymyositis, andinclusion-body myositis is difficult to treat. Althoughwhen the strength improves, the serum creatine kinaseconcentration falls concurrently, the reverse is not alwaystrue because treatments (eg, plasmapheresis) can lowerthe serum creatine kinase concentration withoutimproving strength.1 This effect has been misinterpretedas “chemical improvement”, and has formed the basis forthe common habit of “chasing” or “treating” the creatinekinase concentration instead of the muscle weakness.1,6,135

The following agents are used in the treatment ofpolymyositis and dermatomyositis.

CorticosteroidsPrednisone is the first-line drug, but its applicationremains empirical. We start with 80–100 mg per day for3–4 weeks, and taper the dose over 10 weeks to alternate-day administration. Although most patients respond tosome degree and for some time, others become steroidresistant and the addition of an immunosuppressive drugbecomes necessary. The decision to initiate such therapyis based on: the need for a steroid-sparing effect, whendespite steroid responsiveness the patients developcomplications; the inability to lower the high steroid dosewithout precipitating a relapse; ineffectiveness of a 2–3-month course of high-dose prednisone; and rapidlyprogressive weakness and respiratory failure.1,6,135

Immunosuppressive drugsSelection of an immunosuppressive drug remainsempirical and depends on personal experience and therelative efficacy/safety ratio.1,6,135,136 Azathioprine (orally,2·5–3·0 mg/kg) takes 4–6 months to work. A controlledtrial in 1980 showed benefit of azathioprine.137

Methotrexate (orally, up to 25 mg weekly) acts morequickly than azathioprine. A rare side-effect ispneumonitis, which may be difficult to distinguish fromthe interstitial lung disease associated with Jo-1antibodies. Cyclosporin (orally, 100–150 mg twicedaily)138 may also benefit childhood dermatomyositis.139

Mycophenolate mofetil (2 g per day) is emerging as apromising and well tolerated drug.140 Cyclophosphamide(0·5–1·0 g/m2) intravenously has shown mixed results;141,142

it may help patients with interstitial lung disease, but theevidence remains circumstantial.143

Other treatmentsPlasmapheresis was not found to be helpful in a double-blind, placebo-controlled study.144 Total lymphoidirradiation has helped in a few patients but its long-termside-effects curtail its use.145 Intravenous immunoglobulin(2 g/kg) in uncontrolled series was promising.146 In thefirst double-blind study conducted for dermatomyositis,intravenous immunoglobulin was effective not only inimproving muscle strength but also in resolving theunderlying immunopathology, as shown by repeatedmuscle biopsies.116 The improvement can be impressive; itbegins after the first infusion but is short lived in most

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cases, and repeated infusions every 6–8 weeks areneeded.116,147–149 In polymyositis, no controlled studies havebeen completed, but intravenous immunoglobulin seemsto be effective in about 70% of patients.

Our approachThe following sequential, step-by-step, empiricalescalating approach has been successful in our patients.Step 1 is prednisone. Step 2 is azathioprine ormethotrexate (methotrexate acts faster but nocomparative trials are available;150 the choice depends onpersonal experience). In aggressive cases, steps 1 and 2may be combined from the outset. Step 3 is intravenousimmunoglobulin (this may be used as step 2). Step 4 iscyclosporin, mycophenolate mofetil, chlorambucil, orcyclophosphamide, used individually or in variouscombinations with steps 1–3,150 as dictated by diseaseseverity, coexisting disorders, or the patient’s age.Superiority of a specific combination remains unproven.150

Future immunotherapiesAlthough antigen-specific therapies are not in the offing,some rational therapeutic approaches are currently beinginvestigated with agents that: block signal transduction inT lymphocytes (such as FK506, rapamycin, CAMPATH,or monoclonal antibodies against costimulatory moleculesCD28/CTLA-4);151–153 are directed against cytokines, suchas monoclonal antibodies against tumour necrosis factor�, soluble receptors to tumour necrosis factor �, and �interferons; and interfering with integrins and theirreceptors.151–153

PrognosisAlthough the disease outcome has substantially improved,at least a third of patients are left with mild to severedisability.154-156 Older age and association with cancer arefactors associated with poor prognosis. Pulmonary fibrosis,frequent aspiration pneumonias due to oesophagealdysfunction, and calcinosis in dermatomyositis areassociated with increased morbidity.154–156 In a small cohort,the 5-year survival was 95% and the 10-year survival84%.156

ConclusionOn the basis of our own experience and that of others inmajor neuromuscular centres, the diagnosis andtreatment of dermatomyositis and polymyositis could beimproved by modification of many common practices.First, all disorders that mimic polymyositis should beexcluded, taking into account that the criteria of Bohanand Peter cannot separate polymyositis from inclusion-body myositis or other toxic, necrotising, and dystrophicmyopathies. Second, polymyositis as a stand-alone entityis rare. Although no accurate epidemiological data areavailable, polymyositis is rare in neuromuscular clinics;inclusion-body myositis is more common. Third,endomysial inflammation also occurs in non-immunemyopathies (dystrophies, toxic, metabolic). Fourth,muscle tested with needle electromyography should notbe sampled by biopsy until a month later. Fifth, inpatients presenting with fatigue and increased activities ofserum aminotransferases or lactate dehydrogenase, thecreatine kinase concentration should be also checked toexclude myogenic origin of increased “liver enzymes”and avoid misdirection towards liver disease and liverbiopsy. Sixth, patients with active polymyositis havemuscle weakness; patients presenting with myalgias butnormal strength do not have polymyositis. Seventh, ifprimary inflammation (CD8-positive/MHC-I complex) is

not demonstrable, the diagnosis of polymyositis isdoubtful. Eighth, the goal of therapy is to improvestrength; creatine kinase is a good indicator of diseaseactivity but not the target of therapy. Ninth, whentherapies for presumed polymyositis have lowered thecreatine kinase concentration but not improved strength,the patient should be reassessed, the muscle biopsysample re-examined, and a second biopsy considered toexclude inclusion-body myositis or dystrophy. Finally, when the patient’s strength has improved but is not fully restored, maintenance therapy withimmunosuppressive drugs or alternate-day prednisoneshould be continued.

Conflict of interest statementNone declared.

AcknowledgmentsWe thank the following for funding our studies for many years: IntramuralResearch Program of the National Institute of Neurological Disorders andStroke, National Institutes of Health, Bethesda, MD, USA (MCD) andMax Planck Institute of Neurobiology and Institute for ClinicalNeuroimmunology, Klinikum Grosshadern, Ludwig MaximiliansUniversity, Munich, Germany (RH).

Role of the funding sourceThe funding sources had no role in the preparation of this paper.

References1 Dalakas MC. Polymyositis, dermatomyositis and inclusion-body

myositis. N Engl J Med 1991; 325: 1487–98.2 Engel AG, Hohlfeld R, Banker BQ. The polymyositis and

dermatomyositis syndromes. In: Engel AG, Franzini-Armstrong C,eds. Myology, 2nd edn. New York: McGraw-Hill, 1994: 1335–83.

3 Mastaglia FL, Phillips BA. Idiopathic inflammatory myopathies:epidemiology, classification and diagnostic criteria. Rheum Dis Clin N Am 2002; 28: 723–41.

4 Dalakas MC, Karpati G. The inflammatory myopathies. In:Karpati G, Hilton-Jones, Griggs RC, eds. Disorders of voluntarymuscle, 7th edn. Cambridge: Cambridge University Press, 2001:636–59.

5 Hilton-Jones D. Inflammatory myopathies. Curr Opin Neurol 2001;14: 591–96.

6 Dalakas MC. Polymyositis, dermatomyositis and inclusion bodymyositis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL,Longo DL, Jameson JL, eds. Harrison’s principles of internalmedicine, 15th edn. New York: McGraw-Hill, 2001: 2524–29.

7 Sekul EA, Dalakas MC. Inclusion body myositis: new concepts.Semin Neurol 1993; 13: 256–63.

8 Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med1975; 292: 344–47, 403–07.

9 Plotz PH, Dalakas M, Leff RL, Love LA, Miller FW, Cronin ME.Current concepts in the idiopathic inflammatory myopathies:polymyositis, dermatomyositis and related disorders. Ann Intern Med1989; 111: 143–57.

10 Medsger TA, Dawson WN, Masi AT. The epidemiology ofpolymyositis. Am J Med 1979; 48: 715–23.

11 Ramanan AV, Feldman BM. Clinical features and outcomes ofjuvenile dermatomyositis and other childhood onset myositissyndromes. Rheum Dis Clin N Am 2002; 28: 833–57.

12 Shamin EA, Rider LG, Miller FW. Update on the genetics of theidiopathic inflammatory myopathies. Curr Opin Rheumatol 2000; 12:482–91.

13 Koffman BM, Sivakumar K, Simonis T, Stroncek D, Dalakas MC.HLA allele distribution distinguishes sporadic inclusion body myositisfrom hereditary inclusion body myopathies. J Neuroimmunol 1998; 84:139–42.

14 Reed AM, Ytterberg SR. Genetic and environmental risk factors foridiopathic inflammatory myopathies. Rheum Dis Clin N Am 2002; 28:891–916.

15 Werth VP, Callen JP, Ang G, Sullivan KE. Associations of tumor necrosis factor � and HLA polymorphisms with adultdermatomyositis: implications for a unique pathogenesis. J Invest Dermatol 2002; 119: 617–20.

16 Shamin EA, Rider LG, Pandey JP, et al. Differences in idiopathicinflammatory myopathy phenotypes and genotypes betweenMesoamerican Mestizos and North American Caucasians.Arthritis Rheum 2002; 46: 1885–93.

SEMINAR



17 Reed AM. Myositis in children. Curr Opin Rheumatol 2001; 13:428–33.

18 Callen JP. Dermatomyositis. Lancet 2000; 355: 53–57.19 Sontheimer RD. Dermatomyositis: an overview of recent progress

with emphasis on dermatologic aspects. Dermatol Clin 2002; 20:387–408.

20 Otero C, Illa I, Dalakas MC. Is there dermatomyositis (DM) withoutmyositis? Neurology 1992; 42: 388.

21 Callen JP. Relation between dermatomyositis and polymyositis andcancer. Lancet 2001; 357: 85–86.

22 Mimori T. Scleroderma-polymyositis overlap syndrome: clinical andserologic aspects. Int J Dermatol 1987; 26: 419–25.

23 Rosenberg NL, Carry MR, Ringel SP. Association of inflammatorymyopathies with other connective tissue disorder and malignancies.In: Dalakas MC, ed. Polymyositis and dermatomyositis. Boston:Butterworth, 1988: 37–69.

24 Hertzman PA, Blevins WL, Mayer J, Greenfield B, Ting M,Gleich GJ. Association of the eosinophilia-myalgia syndrome with theingestion of tryptophan. N Engl J Med 1990; 322: 869–73.

25 Gherardi RK, Coquet M, Chérin P, et al. Macrophagic myofasciitis:an emerging entity. Lancet 1998; 352: 347–52.

26 Doyle DR, McCurley TL, Sergent JS. Fatal polymyositis in D-penicillamine-treated rheumatoid arthritis. Ann Intern Med 1983; 98:327–30.

27 Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B,Griffin J. Mitochondrial myopathy caused by long-term zidovudinetherapy. N Engl J Med 1990; 332: 1098–105.

28 Mastaglia FL. Adverse effects of drugs on muscle. Drugs 1982; 24:304–21.

29 Dalakas MC. Diseases of muscle and the neuromuscular junction.Sci Am 1997; 11: 1–14.

30 Dietz F, Logeman JA, Sahgal V, Schmid FR. Cricopharyngeal muscledysfunction in the differential diagnosis of dysphagia in polymyositis.Arthritis Rheum 1980; 23: 491–95.

31 DeMerieux P, Verity MA, Clements PJ, Paulus HE. Esophagealabnormalities and dysphagia in polymyositis and dermatomyositis:clinical, radiographic and pathologic features. Arthritis Rheum 1983;26: 961–68.

32 Haupt HM, Hutchins GM. The heart and cardiac conduction systemin polymyositis-dermatomyositis: a clinicopathologic study of16 autopsied patients. Am J Cardiol 1982; 50: 998–1006.

33 Quartier P, Bonnet D, Fournet JC, et al. Severe cardiac involvementin children with systemic sclerosis and myositis. J Rheumatol 2002; 29:1767–73.

34 Lakhanpal S, Lie JT, Conn DL, et al. Pulmonary disease inpolymyositis/dermatomyositis: a clinicopathological analysis of65 autopsy cases. Ann Rheum Dis 1987; 46: 23–29.

35 Hirakata M, Nagai S. Interstitial lung disease in polymyositis anddermatomyositis. Curr Opin Rheumatol 2000; 12: 501–08.

36 Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositis associated interstitial lung disease.Am J Respir Crit Care Med 2001; 164: 1182–85.

37 Dalakas MC. Calcifications in dermatomyositis. N Engl J Med 1995;333: 978.

38 Sigurgeirsson B, Lindelöf B, Edhag O, Allander E. Risk of cancer inpatients with dermatomyositis or polymyositis: a population-basedstudy. N Engl J Med 1992; 326: 363–67.

39 Buchbinder R, Forbes A, Hall S, Dennett X, Giles G. Incidence ofmalignant disease in biopsy-proven inflammatory myopathy.Ann Intern Med 2001; 134: 1087–95.

40 Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancertypes in dermatomyositis and polymyositis: a population-based study.Lancet 2001; 357: 96–100.

41 Callen JP. When and how should the patient with dermatomyositis oramyopathic dermatomyositis be assessed for possible cancer?Arch Dermatol 2002; 138: 969–71.

42 Sparsa A, Liozon E, Herrmann F, et al. Routine vs extensivemalignancy search for adult dermatomyositis and polymyositis.Arch Dermatol 2002; 138: 885–90.

43 Dayal NA, Isenberg DA. SLE/myositis overlap: are the manifestations of SLE different in overlap disease? Lupus 2002;11: 293–98.

44 Barkhaus PE, Nandedkar SD, Sanders DB. Quantitative EMG ininflammatory myopathy. Muscle Nerve 1990; 13: 247–53.

45 Uncini A, Lange DJ, Hayes AP, et al. Long-duration polyphasicmotor unit potentials in myopathies: a quantitative study withpathological correlation. Muscle Nerve 1990; 13: 263–67.

46 Dalakas MC. Muscle biopsy findings in inflammatory myopathies.Rheum Dis Clin N Am 2002; 28: 779–98.

47 Banker BQ. Dermatomyositis of childhood: ultrastructural alterationsof muscle and intramuscular blood vessels. J Neuropathol Exp Neurol1975; 35: 46–75.

48 Carpenter S, Karpati G, Rothman S, Walters G. The childhood typeof dermatomyositis. Neurology 1976; 26: 952–62.

49 Emslie-Smith AM, Engel AG. Microvascular changes in early andadvanced dermatomyositis: a quantitative study. Ann Neurol 1990; 27:343–56.

50 Arahata K, Engel AG. Monoclonal antibody analysis of mononuclearcells in myopathies: V, identification and quantitation of T8+cytotoxic and T8 suppressor cells. Ann Neurol 1988; 23: 493–99.

51 Arahata K, Engel AG. Monoclonal antibody analysis of mononuclearcells in myopathies: II, phenotypes of autoinvasive cells inpolymyositis and inclusion body myositis. Ann Neurol 1984; 16:209–15.

52 Hohlfeld R, Engel AG. The immunobiology of muscle. Immunol Today 1994; 15: 269–74.

53 Dalakas MC. Immunopathogenesis of inflammatory myopathies. Ann Neurol 1995; 37 (suppl 1): S74–86.

54 Griggs RC, Askanas V, Di Mauro S, et al. Inclusion body myositisand myopathies. Ann Neurol 1995; 38: 705–13.

55 Dalakas MC. Understanding the immunopathogenesis of inclusionbody myositis: present and future prospects. Rev Neurol 2002; 158:948–58.

56 Smith AG, Urbanits S, Blaivas M, Grisold W, Russell JW. Clinicaland pathologic features of focal myositis. Muscle Nerve 2000; 23:1569–75.

57 Karpati G, Pouliot Y, Carpenter S. Expression of immunoreactivemajor histocompatibility complex products in human skeletal muscles.Ann Neurol 1988; 23: 64–72.

58 Emslie-Smith AM, Arahata K, Engel AG. Major histocompatibilitycomplex class I antigen expression, immunolocalization of interferonsubtypes and T-cellmediated cytotoxicity in myopathies. Hum Pathol1989; 20: 224–31.

59 Amato AA, Gronseth GS, Jackson CE, et al. Inclusion body myositis:clinical and pathological boundaries. Ann Neurol 1996; 40: 581–86.

60 Targoff IN. Laboratory testing in the diagnosis and management ofidiopathic inflammatory myopathies. Rheum Dis Clin N Am 2002; 28:859–90.

61 Reed AM, Picornell YJ, Harwood A, Kredich DW. Chimerism inchildren with juvenile dermatomyositis. Lancet 2000; 356: 2156–57.

62 Friedman AW, Targoff IN, Arnett FC. Interstitial lung disease withautoantibodies against aminoacyl-tRNA synthetases in the absence ofclinically apparent myositis. Semin Arthritis Rheum 1996; 26: 459–67.

63 Hengstman GJD, van Engelen BGM, Egberts WTMV,van Venrooij WJ. Myositis-specific autoantibodies: overview andrecent developments. Curr Opin Rheumatol 2001; 13: 476–82.

64 Love LA, Leff RL, Frazer DD, et al. A new approach to theclassification of idiopathic inflammatory myopathy: myositis-specificautoantibodies define useful homogeneous patient groups. Medicine1991; 70: 360–74.

65 Hengstman GJD, Brouwer R, Vree Egberts WTM, et al. Clinical andserological characteristics of 125 Dutch myositis patients. J Neurol2002; 249: 69–75.

66 Kissel JT, Halterman RK, Rammohan KW, Mendell JR. Therelationship of complement-mediated microvasculopathy to thehistologic features and clinical duration of disease in dermatomyositis.Arch Neurol 1991; 48: 26–30.

67 Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition ofcomplement membrane attack complex in dermatomyositis. N Engl J Med 1986; 314: 329–34.

68 Basta M, Dalakas MC. High-dose intravenous immunoglobulin exertsits beneficial effect in patients with dermatomyositis by blockingendomysial deposition of activated complement fragments. J Clin Invest 1994; 94: 1729–35.

69 Lundberg I, Brengman JM, Engel AG. Analysis of cytokine expressionin muscle in inflammatory myopathies, Duchennes dystrophy andnon-weak controls. J Neuroimmunol 1995; 63: 9–16.

70 Stein DP, Dalakas MC. Intercellular adhesion molecule-I expressionis upregulated in patients with dermatomyositis (DM). Ann Neurol1993; 34: 268.

71 Tews DS, Goebel HH. Cytokine expression profiles in idiopathicinflammatory myopathies. J Neuropathol Exp Neurol 1996; 55: 342–47.

72 De Bleecker JL, De Paepe B, Vanwalleghem IE, Schroder JM.Differential expression of chemokines in inflammatory myopathies.Neurology 2002; 58: 1779–85.

73 Arahata K, Engel AG. Monoclonal antibody analysis of mononuclearcells in myopathies: III, immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann Neurol 1986; 19: 112–25.

74 Tezak Z, Hoffman EP, Lutz JL, et al. Gene expression profiling inDQA1*0501+ children with untreated dermatomyositis: a novelmodel of pathogenesis. J Immunol 2002; 168: 4154–63.

75 Hohlfeld R, Engel AG. Coculture with autologous myotubes ofcytotoxic T cells isolated from muscle in inflammatory myopathies.Ann Neurol 1991; 29: 498–507.

SEMINAR



76 De Bleecker J, Engel AG. Immunocytochemical study of CD45 T cell isoforms in inflammatory myopathies. Am J Pathol 1995;146: 1178.

77 Goebels N, Michaelis D, Engelhardt M, et al. Differential expressionof perforin in muscle-infiltrating T cell in polymyositis anddermatomyositis. J Clin Invest 1996; 97: 2905.

78 Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead todeath. Nat Rev Immunol 2002; 2: 401–09.

79 Behrens L, Bender A, Johnson MA, Hohlfeld R. Cytotoxicmechanisms in inflammatory myopathies: co-expression of Fas andprotective Bcl-2 in muscle fibres and inflammatory cells. Brain 1997;120: 929.

80 Schneider C, Gold R, Dalakas MC, et al. MHC class I mediatedcytotoxicity does not induce apoptosis in muscle fibers nor ininflammatory T cells: studies in patients with polymyositis,dermatomyositis, and inclusion body myositis.J Neuropathol Exp Neurol 1996; 55: 1205–09.

81 Schneider C, Dalakas MC, Toyka KV, Said G, Hartung HP, Gold R.T cell apoptosis in inflammatory neuromuscular disorders associatedwith human immunodeficiency virus infection. Arch Neurol 1999; 56:79–83.

82 Nagaraju K, Casciola-Rosen L, Rosen A, et al. The inhibition ofapoptosis in myositis and in normal muscle cells. J Immunol 2000;164: 5459–65.

83 Li M, Dalakas MC. Expression of human IAP-like protein in skeletalmuscle: an explanation for the rare incidence of muscle fiber apoptosisin T-cell mediated inflammatory myopathies. J Neuroimmunol 2000;106: 1–5.

84 Mantegazza R, Andreetta F, Bernasconi P, et al. Analysis of T cellreceptor repertoire of muscle infiltrating T lymphocytes inpolymyositis: restricted V a/b rearrangements may indicated antigen-driven selection. J Clin Invest 1993; 91: 2880–86.

85 Bender A, Ernst N, Iglesias A, Dornmair K, Wekerle H, Hohlfeld R.T cell receptor repertoire in polymyositis: clonal expansion ofautoaggressive CD8 T cells. J Exp Med 1995; 181: 1863–68.

86 O’Hanlon TP, Dalakas MC, Plotz PH, Miller FW. PredominantT cell receptor variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies.J Immunol 1994; 152: 2569–76.

87 Nishio J, Suzuki M, Miyasaka N, Kohsaka H. Clonal biases ofperipheral CD8 T cell repertoire directly reflect local inflammation inpolymyositis. J Immunol 2001; 167: 4051–58.

88 Benveniste O, Cherin P, Maisonobe T, et al. Severe perturbations ofthe blood T cell repertoire in polymyositis, but not dermatomysitispatients. J Immunol 2001; 167: 3521–29.

89 Dalakas MC. The molecular and cellular pathology of inflammatorymuscle diseases. Curr Opin Pharmacol 2001; 1: 300–06.

90 Hohlfeld R, Engel AG, Ii K, Harper MC. Polymyositis mediated byT lymphocytes that express the �/� receptor. N Engl J Med 1991; 324:877–81.

91 Pluschke G, Ruegg D, Hohlfeld R, Engel AG. Autoaggressivemyocytotoxic T lymphocytes expressing an unusual �� T cell receptor.J Exp Med 1992; 176: 1785–89.

92 Wiendl H, Malotka J, Holzwarth B, et al. An autoreactive ��TCR derived from a polymyositis lesion. J Immunol 2002; 169:515–21.

93 Englund P, Lindroos E, Nennesmo I, Klareskog L, Lundberg IE.Skeletal muscle fibers express major histocompativility complex classII antigens independently of inflammatory infiltrates in inflammatorymyopathies. Am J Pathol 2001; 159: 1263–73.

94 Mantegazza R, Hughes SM, Mitchell D, Travis M, Blau HM,Steinman L. Modulation of MHC class II antigen expression inhuman myoblasts after treatment with IFN-gamma. Neurology 1991;41: 1128–32.

95 Michaelis D, Goebels N, Hohlfeld R. Constitutive and cytokine-induced expression of human leukocyte antigens and cell adhesion molecules by human myotubes. Am J Pathol 1993;143: 1142–49.

96 Hohlfeld R, Engel AG. Induction of HLA-DR expression on human myoblasts with interferon-gamma. Am J Pathol 1990; 136:503–08.

97 Nagaraju K, Raben N, Loeffler L, et al. Conditional up-regulation ofMHC class I in skeletal muscle leads to self-sustaining autoimmunemyositis and myositis-specific autoantibodies. Proc Natl Acad Sci USA2000; 97: 9209–14.

98 Nyberg P, Wikman AL, Nennesmo I, Lundberg I. Increasedexpression of interleukin 1� and MHC Class I in muscle tissue ofpatients with chronic, inactive polymyositis and dermatomyositis.J Rheumatol 2000; 27: 940–48.

99 Wiendl H, Behrens L, Maier S, Johnson MA, Weiss EH, Hohlfeld R.Muscle fibers in inflammatory myopathies and cultured myoblastsexpress the nonclassical major histocompatibility antigen HLA-G. AnnNeurol 2000; 48: 679–84.

100Wiendl H, Mitsdoerffer M, Hofmeister V, et al. The nonclassicalMHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and genetherapy. Brain 2003; 126: 176–85.

101Hofbauer M, Wiesener S, Babbe H, et al. Clonal tracking ofautoaggressive T cells in polymyositis by combining lasermicrodissection, single-cell PCR and CDR3 spectratype analysis. Proc Natl Acad Sci USA 2003; 100: 4090–95.

102Liang L, Sha WC. The right place at the right time: novel B7 familymembers regulate effector T cell function. Curr Opin Immunol 2002;14: 384–90.

103Krummel MF, Davis MM. Dynamics of the immunological synapse:finding, establishing and solidifying a connection. Curr Opin Immunol2002; 14: 66–74.

104Behrens L, Kerschensteiner M, Misgeld T, Goebels N, Wekerle H,Hohlfeld R. Human muscle cells express a functional costimulatorymolecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and ininflammatory lesions. J Immunol 1998; 161: 5943–51.

105Murata K, Dalakas MC. Expression of the costimulatory moleculeBB-1, the ligands CTLA-4 and CD28 and their mRNA ininflammatory myopathies. Am J Pathol 1999; 155: 453–60.

106Sugiura T, Kawaguchi Y, Harigai M, et al. Increased CD40expression on muscle cells of polymyositis and dermatomyositis: roleof CD40-CD40 ligand interaction in IL-6, IL-8, IL-15 and monocytechemoattractant protein-1 production. J Immunol 2000; 164:6593–600.

107Wiendl H, Mitsdoerffer M, Schneider D, et al. Muscle fibers andcultured muscle cells express the B7.1/2 related costimulatorymolecule ICOSL: implications for the pathogenesis of inflammatorymyopathies. Brain 2003; 126: 1026–35.

108Illa I, Gallardo E, Gimeno R, Serrano C, Ferrer I, Juarez C. Signaltransducer and activator of transcription 1 in human muscle:implications in inflammatory myopathies. Am J Pathol 1997; 151:81–88.

109Dalakas MC. Molecular immunology and genetics of inflammatorymuscle diseases. Arch Neurol 1998; 55: 1509–12.

110De Bleecker JL, Meire VI, Declercq W, Van Aken HE.Immunolocalization of tumor necrosis factor-alpha and its receptors ininflammatory myopathies. Neuromusc Disord 1999; 9: 239.

111Kuru S, Inukai A, Liang Y, Doyu M, Takano A, Sobue G. Tumornecrosis factor-� expression in muscles of polymyositis anddermatomyositis. Acta Neuropathol 2000; 99: 585–88.

112Shelton GD, Calcutt NA, Garrett RS, et al. Necrotizing myopathyinduced by overexpression of interferon-� in transgenic mice.Muscle Nerve 1999; 22: 156–65.

113Kalovidouris AE, Plotkin Z. Synergistic cytotoxic effect of interferon �and tumor necrosis factor � on cultured human muscle cells.J Rheumatol 1995; 22: 1698–703.

114Leon-Monzon M, Dalakas MC. Interleukin-1 (IL-1) is toxic tohuman muscle. Neurology 1994; 44 (suppl): 132.

115Murakami N, McLennan IS, Nonaka I, Koishi K, Baker C, Tooke-Hammond G. Transforming growth factor-�2 is elevated inskeletal muscle disorders. Muscle Nerve 1999; 22: 889–98.

116Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immunoglobulin infusions as treatment fordermatomyositis. N Engl J Med 1993; 329: 1993–2000.

117Amemiya K, Semino-Mora C, Granger RP, Dalakas MC.Downregulation of TGF-�1 mRNA and protein in the muscles ofpatients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol 2000;94: 99–104.

118Kunkel EJ, Butcher EC. Chemokines and the tissue-specific migrationof lymphocytes. Immunity 2002; 16: 1–4.

119De Rossi M, Bernasconi P, Baggi F, de Waal Maleft R,Mantegazza R. Cytokines and chemokines are both expressed byhuman myoblasts: possible relevance for the immune pathogenesis ofmuscle inflammation. Int Immunol 2000; 12: 1329–35.

120Raju R, Vasconcelos OM, Semino-Mora C, Granger RP,Dalakas MC. Expression of interferon-gamma inducible chemokinesin the muscles of patients with inclusion body myositis. Neurology2002; 58: A390.

121Confalonieri P, Bernasconi P, Megna P, Galbiati S, Cornelio F,Mantegazza R. Increased expression of beta-chemokines in muscle ofpatients with inflammatory myopathies. J Neuropathol Exp Neurol2000; 59: 164–69.

122Choi YC, Dalakas MC. Expression of matrix metalloproteinases in themuscle of patients with inflammatory myopathies. Neurology 2000; 54:65–71.

123Kieseier BC, Schneider C, Clements JM, et al. Expression of specificmatrix metalloproteinases in inflammatory myopathies. Brain 2001;124: 341–51.

124Dalakas MC. Viral related muscle disease. In: Engel AG, ed.Myology. New York: McGraw Hill (in press).

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125Leff RL, Love LA, Miller FW, et al. Viruses in the idiopathicinflammatory myopathies: absence of candidate viral genomes inmuscle. Lancet 1992; 339: 1192–95.

126Leon-Monzon M, Dalakas MC. Absence of persistent infection withenteroviruses in muscles of patients with inflammatory myopathies.Ann Neurol 1992; 32: 219–22.

127Dalakas MC, London WT, Gravell M, Sever JL. Polymyositis in animmunodeficiency disease in monkeys induced by a type D retrovirus.Neurology 1986; 36: 569–72.

128Dalakas MC, Pezeshkpour GH, Gravell M, Sever JL. Polymyositis inpatients with AIDS. JAMA 1986; 256: 2381–83.

129Morgan OStC, Rodgers-Johnson P, Mora C, Char G. HTLV-1 andpolymyositis in Jamaica. Lancet 1989; 2: 1184–87.

130Dalakas MC, Pezeshkpour GH. Neuromuscular diseases associatedwith human immunodeficiency virus infection. Ann Neurol 1988;23 (suppl): 38–48.

131Leon-Monzon M, Illa I, Dalakas MC. Polymyositis in patientsinfected with HTLV-I: The role of the virus in the cause of thedisease. Ann Neurol 1994; 36: 643–49.

132Cupler EJ, Leon-Monzon M, Miller J, Semino-Mora C,Anderson TL, Dalakas MC. Inclusion body myositis in HIV-I andHTLV-I infected patients. Brain 1996; 119: 1887–93.

133Illa I, Nath A, Dalakas MC. Immunocytochemical and virologicalcharacteristics of HIV-associated inflammatory myopathies:similarities with seronegative polymyositis. Ann Neurol 1991; 29:474–81.

134Wucherpfennig KW. Mechanisms for the induction of autoimmunityby infectious agents. J Clin Invest 2001; 108: 1097–104.

135Dalakas MC. How to diagnose and treat the inflammatorymyopathies. Semin Neurol 1994; 92: 365–69.

136Oddis CV. Idiopathic inflammatory myopathy: management andprognosis. Rheum Dis Clin N Am 2002; 28: 979–1001.

137Bunch TW, Worthington JW, Combs JJ, Ilstrup DM, Engel AG.Azathioprine and prednisone for polymyositis: a controlled clinicaltrial. Ann Intern Med 1980; 92: 365–69.

138Heckmatt J, Hasson N, Saunders C, et al. Cyclosporin in juveniledermatomyositis. Lancet 1989; 1: 1063–66.

139Grau JM, Herrero C, Casademont J, et al. Cyclosporine A as firstchoice for dermatomyositis. J Rheumatol 1994; 21: 381–82.

140Chaudhry V, Cornblath DR, Griffin JW, O’Brien R, Drachman DB.Mycophenolate mofetil: a safe and promising immunosuppressant inneuromuscular diseases. Neurology 2001; 56: 94–96.

141Cronin ME, Miller FW, Hicks JE, Dalakas M, Plotz PH. The failureof intravenous cyclophosphamide therapy in refractory idiopathicinflammatory myopathy. J Rheumatol 1989; 16: 1225–28.

142Bombardieri S, Hughes GRV, Neri R, Del Bravo P, Del Bono L.Cyclophosphamide in severe polymyositis. Lancet 1989; 1: 1138–39.

143Schnabel A, Reuter M, Gross WL. Intravenous pulsecyclophosphamide in the treatment of interstitial lung disease due tocollagen vascular disease. Arthritis Rheum 1998; 41: 1215–20.

144Miller FW, Leitman SF, Cronin ME, et al. A randomized double-blind controlled trial of plasma exchange and leukapheresis in patientswith polymyositis and dermatomyositis. N Engl J Med 1992; 326:1380–84.

145Dalakas MC, Engel WK. Total body irradiation in the treatment ofintractable polymyositis and dermatomyositis. In: Dalakas MC, ed.Polymyositis and dermatomyositis. Stoneham: Butterworth, 1988:281–91.

146Cherin P, Herson S, Wechsler B, et al. Efficacy of intravenousimmunoglobulin therapy in chronic refractory polymyositis anddermatomyositis: an open study with 20 adult patients. Am J Med1991; 91: 162–68.

147Dalakas MC. Intravenous immunoglobulin therapy for neurologicaldiseases. Ann Intern Med 1997; 126: 721–30.

148Dalakas MC. Controlled studies with high-dose intravenousimmunoglobulin in the treatment of dermatomyositis, inclusion bodymyositis and polymyositis. Neurology 1998; 51: 537–45.

149Dalakas MC. Immunotherapies in the treatment of neuromusculardiseases. In: Katirji B, Kaminski HJ, Preston DC, Ruff RL,Shapiro BE, eds. Neuromuscular disorders in clinical practice.Woburn, MA: Butterworth-Heineman, 2002: 364–83.

150Choy EHS, Isenberg DA. Treatment of dermatomyositis andpolymyositis. Rheumatology 2002; 41: 7–13.

151Dalakas MC. Progress in inflammatory myopathies: good but notgood enough. J Neurol Neurosurg Psychiatry 2001; 70: 569–73.

152Hohlfeld R. The basis of immunotherapy in neurological disease. In:Asbury AK, McKhann G, McDonald WI, Goadsby PJ, McArthur JC,eds. Diseases of the nervous system: clinical neuroscience andtherapeutic principles, 3rd edn. Cambridge: Cambridge UniversityPress, 2002: 1527–46.

153Gold R, Dalakas MC, Toyka KV. Immunotherapy in autoimmuneneuromuscular disorders. Lancet Neurology 2003; 2: 22–32.

154Maugars YM, Berthelot JM, Abbas AA, Mussini JM, Nguyen JM,Prost AM. Long-term prognosis of 69 patients with dermatomyositisor polymyositis. Clin Exp Rheumatol 1996; 14: 263–74.

155Sultan SM, Ioannou Y, Moss K, Isenberg DA. Outcome in patientswith idiopathic inflammatory myositis: morbidity and mortality.Rheumatology 2002; 41: 22–26.

156Marie I, Hachulla E, Hatron PY, et al. Polymyositis anddermatomyositis: short term and longterm outcome, and predictivefactors of prognosis. J Rheumatol 2001; 28: 2230–37.

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