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Seminar

Polymyositis and dermatomyositis


Marinos C Dalakas, Reinhard Hohlfeld The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they can 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 lysis of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological features. 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 cytokines increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in controlled trials may prove promising for difficult cases. The inflammatory myopathies are a heterogeneous group of subacute, chronic, or acute acquired diseases of skeletal muscle. They have in common the presence of moderate to severe muscle weakness and inflammation in the muscle.16 The disorders are clinically important because they are potentially treatable. On the basis of welldefined clinical, demographic, histological, and immunopathological criteria, the inflammatory myopathies form three major and discrete groups: polymyositis, dermatomyositis, and sporadic inclusion-body myositis.1 This review describes current knowledge of the clinical presentation, diagnosis, pathogenesis, and treatment of polymyositis and dermatomyositis. Inclusion-body myositis, a common and important subset as recently reviewed,47 is addressed only to outline its distinguishing features in the differential diagnosis of polymyositis. body myositis is the commonest myopathy above the age of 50. In children, dermatomyositis is the most frequent inflammatory myopathy but polymyositis is very rare, as recently confirmed.11 Genetic factors may have a role, as suggested by rare familial occurrences and association with certain HLA genes, such as DRB1*0301 alleles for polymyositis and inclusion-body myositis,12,13 HLA DQA1 0501 for juvenile dermatomyositis,14 or tumour necrosis factor 308A polymorphism for photosensitivity in dermatomyositis.15 Emerging information on the genetic background of various ethnic groups may allow identification of immune-response genes that predispose certain populations to polymyositis or dermatomyositis.16,17 Both polymyositis and dermatomyositis present with a varying degree of muscle weakness that develops slowly, over weeks to months, but acutely in rare cases.1 Patients report difficulty with everyday tasks, such as rising from a chair, climbing steps, stepping onto a kerb, lifting objects, or combing their hair. Fine motor movements that depend on the strength of distal muscles, such as holding or manipulating objects, are affected late in the course of dermatomyositis and polymyositis, but fairly early in sporadic inclusion-body myositis owing to prominent involvement of distal muscles, especially wrist and finger flexors.1 Early involvement of the quadriceps muscle and ankle dorsiflexors, causing buckling of the knees and frequent falls, is common in sporadic inclusion-body myositis.7 Facial muscles remain normal but mild facial muscle weakness is common in patients with sporadic

Epidemiology, genetics, and general clinical features


Dermatomyositis affects both children and adults, and women more than men. Polymyositis is seen after the second decade of life. Inclusion-body myositis is more common in men over the age of 50 than in other population groups.17 The frequencies of polymyositis and dermatomyositis as stand-alone disorders or in association with other systemic diseases are unknown. Estimates based on old diagnostic criteria,8 which cannot distinguish polymyositis from inclusion-body myositis,1,3 range from 06 to 10 per 100 000110 but may not be reliable (see later). In all age-groups, dermatomyositis is the most common and polymyositis the least common; inclusionLancet 2003; 362: 97182
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA (Prof M C Dalakas MD); and Max Planck Institute of Neurobiology and Institute for Clinical Neuroimmunology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany (Prof R Hohlfeld MD) Correspondence to: Prof Marinos C Dalakas, Neuromuscular Diseases Section, NINDS, NIH, Building 10, Room 4N248, 10 Center Drive MSC 1382, Bethesda, MD 208921382, USA (e-mail: dalakasm@ninds.nih.gov)

Search strategy and selection criteria


The review is based on our own experience and research connected with these disorders as well as a comprehensive MEDLINE search on the topics of "polymyositis", "dermatomyositis", and "inflammatory myopathies". We focused on peer-reviewed works published in English in major scientific journals over the past 10 years and on reviews written by experts on this subject. All available articles were critically reviewed. Papers presenting the strongest evidence or providing important insights into the diagnosis, pathogenesis, and management of these disorders were also referred to and cited.

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transient or poorly recognised (eg, in dark-skinned people), the term dermatomyositis sine dermatitis is appropriate. In such cases, a mistaken diagnosis of polymyositis is considered, until a muscle biopsy confirms the correct diagnosis. In children, dermatomyositis resembles the adult disease, except for more frequent extramuscular manifestations (see later). A common early abnormality in children is misery, defined as an irritable child who feels uncomfortable, has a red flush on the face, is fatigued, does not socialise, and has a varying degree of proximal muscle weakness.4,6 A tiptoe gait due to flexion contracture of the ankles is common.1 Dermatomyositis can be associated with cancer21 or may overlap with systemic sclerosis and mixed connective-tissue disease.1,22,23 Fasciitis Figure 1: Rash and calcifications in dermatomyositis A: Gottrons rash. B: Skin effects of calcification. C: Radiographic evidence of calcification. and thickening of the skin, as seen in chronic dermatomyositis, can also occur in patients with eosinophilia-myalgia syndrome,24 inclusion-body myositis.7 The extraocular muscles are never affected, in contrast to myasthenia in which they are eosinophilic fasciitis, or macrophagic myofasciitis.25 affected early.1 The neck extensor muscles may be involved, causing difficulty in holding up the head (head Polymyositis drop). In advanced cases, and in rare acute cases, Polymyositis is best defined as a subacute myopathy that dysphagia with choking episodes and respiratory muscle evolves over weeks to months, affects adults but rarely weakness occurs. Sensation remains normal. The tendon children, and presents with weakness of the proximal reflexes are preserved but may be absent in severely muscles. Unlike dermatomyositis in which the rash weakened or atrophied muscles. Contrary to widespread secures early recognition, the actual onset of polymyositis belief, myalgia is not common, occurring in less than 30% cannot be easily identified.1 Polymyositis mimics many of the patients. other myopathies and remains a diagnosis of exclusion (panel).2629 It should be viewed as a syndrome of diverse causes that occurs separately or in association with Specific clinical features systemic autoimmune disorders or viral infections in Dermatomyositis patients who do not have any of the exclusion criteria Dermatomyositis is identified by a characteristic rash listed in the panel. accompanying or, more commonly, preceding muscle As a stand-alone clinical entity, polymyositis is an weakness. The skin manifestations include a heliotrope uncommon but frequently misdiagnosed disorder. The rash (blue-purple discolouration) on the upper eyelids in commonest myopathy misdiagnosed as polymyositis is many cases associated with oedema, and an erythematous inclusion-body myositis; this disorder is suspected in rash on the face, neck, and anterior chest (in many retrospect in many cases of presumed polymyositis that patients in a V sign) or back and shoulders (shawl sign), have not responded to therapy.1,7 Especially in men knees, elbows, and malleoli; the rash can be exacerbated after exposure to the sun and is pruritic in some cases. older than 50 years, a polymyositis-like disease is Characteristic is the Gottron rash (figure 1), a raised inclusion-body myositis until proved otherwise. Other violaceous rash or papules at the knuckles, prominent in disorders misdiagnosed as polymyositis include toxic metacarpophalangeal and interphalangeal joints;18 in and endocrine myopathies, dermatomyositis sine dermatitis, certain dystrophies, and some slowly contrast to systemic lupus erythematosus, the rash does progressive myopathies commonly starting in late not involve the phalanges.1,9 When chronic, the rash childhood (panel). becomes scaly with a shiny appearance. Dilated capillary loops at the base of the fingernails with irregular, thickened, and distorted cuticles are also characteristic. Associated clinical findings (table 1) The lateral and palmar areas of the fingers may become Extramuscular manifestations rough with cracked, dirty horizontal lines, resembling There are many manifestations outside the muscles. Joint mechanics hands. contractures occur mostly in dermatomyositis. Dysphagia The weakness varies from mild to severe, leading to is due to involvement of the oropharyngeal striated quadriparesis. At times the muscle strength appears muscles and upper oesophagus30,31 (gastrointestinal normal, hence the terms dermatomyositis sine myositis or ulcerations due to vasculitis and infection were common amyopathic dermatomyositis.19 When a muscle biopsy is in children with dermatomyositis before the use of immunosuppressants2). Cardiac disturbances include taken from such cases, however, subclinical muscle involvement with perivascular and perimysial atrioventricular conduction defects, tachyarrhythmias, inflammation is seen.20 Although there may be cases of myocarditis in patients with acute disease,32,33 and heart amyopathic dermatomyositis limited to the skin, we failure commonly related to hypertension from long-term believe that amyopathic and myopathic dermatomyositis steroid use.1 Pulmonary symptoms are due to weakness of are part of the range of dermatomyositis affecting skin and the thoracic muscles or interstitial lung disease,3436 which muscle to a varying degree. Rarely, when the rash is is common in patients with autoantibodies to tRNA

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synthetases or a mucin-like glycoprotein (KL-6).35 Subcutaneous calcifications (figure 1), occur only in dermatomyositis, in some cases extruding on the skin and causing ulcerations, infections, and pain,37 especially at sites of compression (elbows, buttocks, back). General symptoms include fever, malaise, weight loss, arthralgia, and Raynauds phenomenon when polymyositis or dermatomyositis is associated with another connectivetissue disease. Malignant disorders Although all the inflammatory myopathies can have a chance association with malignant disease, especially in older age-groups, the frequency of cancer is definitely increased in dermatomyositis.38 A slightly increased frequency reported in polymyositis39,40 must be confirmed with use of updated diagnostic criteria. The most common cancers are those of the ovaries, gastrointestinal tract, lung, and breast and non-Hodgkin lymphomas. Continuous vigilance is required for early recognition, especially in older people and during the first 3 years after disease onset.23,41 In patients without risk factors, expensive, radiological blind searches for occult malignant disease is not practical or fruitful.1,41 A complete annual physical examination with pelvic, breast (mammogram, if indicated), rectal (with colonoscopy, according to age and family history) radiographs and a chest film should suffice. A report that blind search with abdominalpelvic and thoracic CT scans increased the yield by 28%42 needs confirmation. In Asian patients, among whom nasopharyngeal cancer is more common, careful assessment of ears, nose, and throat is suggested. Overlap syndrome Polymyositis and dermatomyositis are seen in association with various autoimmune and connective tissue diseases (table 1). The term overlap syndrome is used loosely to emphasise this association but in reality it was meant to indicate that certain clinical signs are shared by both disorders. Accordingly, it is only dermatomyositis, and not polymyositis, that truly overlaps and only with systemic sclerosis and mixed connective-tissue disease. Certain signs seen in these two disorders, such as sclerotic thickening of the dermis, contractures, oesophageal hypomotility, microangiopathy, and calcium deposits, are also present in dermatomyositis but not polymyositis; by contrast, signs of rheumatoid arthritis, lupus, or Sjgrens syndrome are rare in dermatomyositis (table 1).1 A report that dermatomyositis can overlap with lupus43 needs confirmation.

Clinical characteristics of polymyositis


Myopathic weakness Evolves over weeks to months, spares facial and eye muscles, and presents as difficulty in climbing steps, rising from a chair, lifting objects, combing hair. Disease onset Above the age of 18 years Features the patient DOES NOT have Rash (characteristic of dermatomyositis) Family history of neuromuscular diseases Exposure 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 associations Other autoimmune or viral infections, such as: lupus, rheumatoid arthritis, Sjgrens syndrome, Crohns disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult coeliac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behets syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimotos disease, granulomatous diseases, agammaglobulinaemia, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinaemic purpura, hereditary complement deficiency, HIV and HTLV-1 infection. Reconsider polymyositis If the diagnosis was based on Bohan and Peters criteria, in patients with: Disease onset before the age of 18 Slow-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

Characteristic Age at onset Familial association Extramuscular manifestations Associated disorders Connective-tissue diseases* Overlap syndrome Systemic autoimmune diseases Malignant disorders Viruses Parasites and bacteria Drug-induced myotoxicity||

Dermatomyositis All ages No Yes Only with scleroderma and mixed connective-tissue disease Only with scleroderma and mixed connective-tissue disease Rarely Yes, in up to 15% of cases Unproven No Rarely

Polymyositis >18 years No Yes Yes, with all No Frequently No Yes Yes Yes

Inclusion-body myositis >50 years In some cases Yes Yes, in up to 20% of cases No Infrequently No Yes No No

*A dermatomyositis-like disease develops in up to 12% of patients with systemic sclerosis, and polymyositis in 58% of lupus patients; polymyositis is less commonly seen in patients with Sjgrens disease or rheumatoid arthritis. Overlap denotes that certain signs are common to both disorders; by contrast, "association" denotes that two disorders can coexist. HIV and HTLV-1. Includes parasitic (protozoa, cestodes, and nematodes), tropical, and bacterial myositis (pyomyositis). ||Drugs include penicillamine (for dermatomyositis and polymyositis), zidovudine (for polymyositis), contaminated tryptophan (for a dermatomyositis-like illness), and lipidlowering drugs rarely. Other myotoxic drugs can cause myopathy but not inflammatory myopathy.1,6,29

Table 1: Conditions and factors associated with inflammatory myopathies

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Diagnosis
The clinical diagnosis of polymyositis and dermatomyositis is confirmed by three laboratory examinations: serum muscle enzyme concentrations, electromyography, and muscle biopsy. In certain cases of dermatomyositis, skin biopsy can be helpful. The most sensitive muscle enzyme assay is creatine kinase, which is increased up to 50 times in active disease. Aspartate and alanine aminotransferases, lactate dehydrogenase, and aldolase are also increased. Although creatine kinase concentration usually parallels disease activity, it can be normal in some patients with active dermatomyositis; in the active phases of polymyositis, the creatine kinase concentration is always increased. Needle electromyography shows increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves. The voluntary motor units consist of low-amplitude polyphasic units of short duration.44,45 Although not disease specific, these findings are useful to confirm active myopathy. Presence of spontaneous activity can help to distinguish active disease from steroid-induced myopathy, except if the two coexist.1 The muscle biopsy is the most crucial test for establishing the diagnosis,16,46 but also the most common cause of misdiagnosis due to erroneous interpretation.4 In dermatomyositis, the inflammation is predominantly

perivascular or in the interfascicular septae and around rather than within the fascicles.1-6 The intramuscular blood vessels show endothelial hyperplasia with tubuloreticular profiles, fibrin thrombi, especially in children, and obliteration of capillaries resulting in reduction of capillary density (figure 2).2,4,4649 The muscle fibres undergo phagocytosis and necrosis, commonly in groups (microinfarcts) involving a portion of a muscle fasciculus, or the periphery of the fascicle, resulting in perifascicular atrophy. This atrophy, characterised by two to ten layers of atrophic fibres at the periphery of the fascicles, is diagnostic of dermatomyositis, even in the absence of inflammation (figure 2).1,46 The skin lesions show perivascular inflammation with CD4-positive cells in the dermis; in chronic stages there is dilatation of superficial capillaries.2 Skin histopathology distinguishes dermatomyositis from other papulosquamous disorders but not from cutaneous lupus.18 In polymyositis, multifocal lymphocytic infiltrates surround and invade healthy muscle fibres (figure 2).15,46 The inflammation is primary, a term used to indicate that lymphocytes (CD8-positive cells) invade histologically healthy muscle fibres expressing MHC class I antigens. We refer to this lesion as the CD8/MHC-I complex (see later).5053 In chronic stages, connective tissue is increased and may react with alkaline phosphatase.46 When, in

Figure 2: Histological findings in polymyositis and dermatomyositis


A, 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 healthy fibres. 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.

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Criterion

Polymyositis Definite Probable Yes* Myopathic

Myopathic dermatomyositis Definite Yes* Myopathic Probable Yes* Myopathic

Amyopathic dermatomyositis Definite

Myopathic muscle weakness Yes* Electromyographic findings Myopathic Muscle enzymes Muscle-biopsy findings

Rash or calcinosis

No Myopathic or non-specific 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 normal 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) 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 to months) and rapid progression in patients who have no family history of neuromuscular disease, no exposure to myotoxic drugs or toxins, and no signs of biochemical muscle disease. The myopathic weakness has a pattern distinct from that seen in inclusion-body myositis (table 1). Although strength is apparently normal, many patients have new onset of easy fatigue, myalgia, and reduced endurance. Careful muscle testing may reveal mild muscle weakness. If such a patient has the clinical 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

addition to primary inflammation, there are vacuolated muscle fibres with basophilic granular deposits around the edges (rimmed vacuoles) and congophilic amyloid deposits within or next to the vacuoles, the diagnosis of inclusion-body myositis is likely.54,55 Errors in the histological diagnosis of polymyositis can be avoided by three steps. First, primary inflammation should be demonstrated. This step has become an essential criterion because it distinguishes polymyositis from toxic, necrotising, or dystrophic myopathies (facioscapulohumeral; due to deficiency of dystrophin or dysferlin) in which macrophages predominate.46 Second, the biopsy sample should be processed for frozen sections and with enzyme histochemistry and immunohistochemistry. Paraffin embedding misdiagnoses inclusion-body myositis for polymyositis because it dissolves the redrimmed granular material, and the vacuolated fibres become indiscernible. Also, the CD8/MHC-I complex and sarcolemmal or enzymatic proteins that exclude dystrophies, metabolic myopathies, and mitochondriopathies are best demonstrated on frozen sections. Third, a repeat muscle biopsy may be necessary. Because the inflammation is spotty, taking a sample from a different muscle should be considered if a patient meets the clinical criteria (panel) but the first sample was not diagnostic. In occasional cases, muscle MRI may be useful to identify inflammatory sites and select the area for biopsy. Other inflammatory myopathies diagnosed on the basis of distinctive clinical and histological features include: infectious (parasitic, bacterial [pyomyositis]), granulomatous, eosinophilic (polymyositis or fasciitis), and localised forms.1,35,56

T cells or vacuoles, the diagnosis is probable polymyositis. Because the same histology may also be seen in some patients who have the typical inclusion-body myositis phenotype (probable inclusion-body myositis),59 the diagnosis is aided by taking a second biopsy sample and relating the findings to the clinical picture. The diagnosis of dermatomyositis is definite if the myopathy is accompanied by the characteristic rash and histopathology. If no rash is detected but the biopsy sample is typical for dermatomyositis, the diagnosis is probable dermatomyositis; conversely, if the typical dermatomyositis rash is present but muscle weakness is not apparent, the clinical diagnosis is amyopathic dermatomyositis.

Immunopathogenesis
The autoimmune origin of polymyositis and dermatomyositis is supported by their association with other autoimmune disorders, autoantibodies,60 and histocompatibility genes; the evidence of T-cell-mediated myocytotoxicity or complement-mediated microangiopathy; the possible maternal microchimerism in juvenile forms;61 and their response to immunotherapies. However, no specific target antigens have been identified, and the agents initiating self-sensitisation remain unknown. Autoantibodies Autoantibodies against nuclear or cytoplasmic antigens, directed against ribonucleoproteins involved in protein synthesis (anti-synthetase) or translational transport (anti-signal-recognition particle), are found in about 20% of patients (table 3).60 These antibodies are useful clinical markers because of their frequent association with interstital lung disease. The antibody against histidyltRNA synthetase, anti-Jo-1, accounts for 80% of all the anti-synthetases and seems to confer specificity for identifying a disease subset that combines myositis, nonerosive arthritis, and Raynauds phenomenon. The importance of these antibodies and their specificity in the pathogenesis of polymyositis and dermatomyositis remains unclear because they are not specific for tissue or disease subset, they occur in less than 25% of patients, and they do occur in patients with interstitial lung disease without myositis.62,63 A report that antibodies to signalrecognition particles are markers of aggressive disease with cardiomyopathy and poor response to therapies64 has not been confirmed.65 Other autoantibodies include antiMi-2, anti-polymyositis-Scl, found in dermatomyositis with scleroderma, and anti-KL6 associated with interstitial lung disease (table 3).

Diagnostic criteria
The subject of diagnostic criteria remains unsettled because the various proposed criteria3 have not been properly validated. The criteria of Bohan and Peter8 cannot distinguish polymyositis from inclusion-body myositis or from certain dystrophies. Because the immunopathological characteristics confer specificity for each subset, we believe that the diagnostic criteria should rely on histopathology and immunopathology as the best means of separating polymyositis from other myopathies.1 Accordingly, we view the diagnosis of polymyositis as definite if a patient has an acquired, subacute myopathy meeting the inclusion and exclusion criteria (panel), raised concentrations of serum creatine kinase, and primary inflammation in the muscle biopsy (table 2). When in such a patient, the biopsy sample shows widespread expression of MHC-I antigens57,58 but no

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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 synthetase Anti-PL-12 tRNAala synthetase Anti-EJ tRNAgly synthetase Anti-OJ tRNAile synthetase Anti-KS tRNAasp synthetase Anti-signal recognition particle <3% of patients Other Anti-Mi-2 (1015% of dermatomyositis and polymyositis) Anti-polymyositis-Scl (15% of dermatomyositis with scleroderma) Anti-KL6 (in patients with interstitial lung disease) SRP-complex Nuclear helicase Nuclear complex Mucin-like glycoprotein (on alveoli or bronchial epithelial cells)

SRP=signal recognition particle. *The antibodies are found mostly in polymyositis 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 the triad of non-erosive arthritis, interstitial lung disease, and Raynauds phenomenon; 50% of them have interstitial lung disease. 7% of these patients also have antibodies against the cognate tRNAhis.

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

the complement deposits induce swollen endothelial cells, vacuolisation, capillary necrosis, perivascular inflammation, ischaemia, and destruction of muscle fibres.1,2,46,53 The characteristic perifascicular atrophy (figures 2 and 3) reflects endofascicular hypoperfusion, which is prominent distally. Finally, there is striking reduction in the number of capillaries per muscle fibre with compensatory dilatation of the lumen of the remaining capillaries.46,53 Cytokines and chemokines6972 related to complement activation are released; they upregulate vascular-cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) on the endothelial cells and facilitate the egress of activated T cells to the perimysial and endomysial spaces (figure 3). T cells and macrophages through their integrins (very late activation antigen 4 and leucocyte-function-associated antigen 1) bind to the adhesion molecules and pass into the muscle through the endothelial cell wall. The predominant lymphocytes are B cells and CD4-positive T cells, consistent with a humorally mediated process.1,2,4953,73 Gene expression profiling in muscles of genetically susceptible children showed interferon inducible genes implying virusdriven autoimmune dysregulation.74 However, no viruses have been amplified. Immunopathology of polymyositis In polymyositis and inclusion-body myositis, CD8positive cells invade MHC-I-antigen expressing muscle fibres.5053 Cytotoxic T cells T-cell lines established from muscle biopsy material are cytotoxic to autologous myotubes.75 In vivo, the CD8positive cells send spike-like processes into non-necrotic muscle fibres, traverse the basal lamina, and focally invade the muscle cell.73 The autoinvasive cells express the memory and activation markers CD45RO and ICAM-176

Immunopathology of dermatomyositis The primary antigenic target in dermatomyositis is the endothelium of the endomysial capillaries (figure 3). The disease begins when putative antibodies directed against endothelial cells activate complement C3. Activated C3 leads to formation of C3b, C3bNEO, and C4b fragments and C5b9 membranolytic attack complex (MAC), the lytic 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 or structural changes are seen in the muscle.49,66,67 Sequentially,

Antibody M Macrophage Complement B C3 Molecular mimicry tumours, viruses? C3a C3b MAC

Endothelial cell wall B

C3bNEO

MAC

Cytokines CD4+ LFA-1


ICAM-1

Cytokines CD4+

STAT-1, Chemokines, Cathepsin, TGF

CD4+ VLA-4

VCAM-1

Mac-1

ICAM-1

M NO TNF

Chemokines

Figure 3: Proposed sequence of immunopathological changes in dermatomyositis


VLA-4=very late activation antigen; LFA-1=leucocyte-function-associated antigen; NO=nitric oxide; TNF =tumour necrosis factor ; TGF =transforming growth factor . Modified from reference 53.

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Antigen Infection? M MHC Costimulation TCR CD8 Integrins LFA-4 CD8 CD8 CD8

Systemic immune compartment

Clonal expansion

CD8

CD8

Chemokines

VCAM-1 MMPs CD8 IFNCD8 Cytokines IL-1,2 TNF IFNTNF


Perfor in

CTLA-4
CD28
TCR
BB1

LFA-1 MMP-9
ICAM-1
MMP-9 MMP-2

Antigen (virus, muscle peptide)

-1 MHC

Endoplasmic reticulum Calnexin MHC-I

IL-1,2

Necrosis
TAP Figure 4: Molecules, receptors, and ligands involved in transgression of T cells through endothelial cell wall and recognition of antigens on muscle fibres in polymyositis
Modified from references 55 and 89.

and contain perforin and granzyme granules that are directed towards the surface of the fibres.77 Thus, the perforin pathway seems to be the major cytotoxic effector mechanism. By contrast, the Fas-Fas-L-dependent apoptotic process is not functionally involved,78 despite expression of Fas antigen on muscle fibres and Fas-L on the autoinvasive CD8-positive cells.7981 The coexpression of the anti-apoptotic molecules BCL2,79 FLICE (Fasassociated death domain-like interleukin-1-convertingenzyme inhibitory protein [FLIP]),82 and human IAP-like protein (hILP),83 may confer resistance of muscle to Fasmediated apoptosis (figure 4). In polymyositis and inclusion-body myositis but not dermatomyositis, certain CD8-positive cells of specific T-cell-receptor (TCR) families are clonally expanded both in the circulation and in muscle.8489 In individual patients, the CDR3 region, the antigen-binding region of the TCR of the autoinvasive CD8-positive cells, has conserved aminoacid sequences, which suggest that T-cell expansion is driven by a common antigen, possibly an autoantigen.8588 Remarkably, only the autoinvasive (autoaggressive) T cells are clonally expanded; the noninvasive bystander T cells are clonally diverse.85 In one case, a single clone of / T cells of a single clone were the primary cytotoxic effectors.9092 When the / TCR of these cells was transfected into a TCR-deficient mouse hybridoma cell line,92 the transfectants could be stimulated with an unknown autoantigen on human myoblasts.92 This is the first indication that in / -T-cell mediated polymyositis the autoaggressive T cells recognise muscle antigens. MHC expression Muscle fibres do not normally express MHC class I or II antigens. In polymyositis and inclusion-body myositis,

however, widespread overexpression of MHC class I, and occasionally MHC II, is seen even in areas remote from the inflammation.57,58,93 In human myotubes, MHC molecules are upregulated by interferon .9496 Although in transgenic mice MHC-I expression was proposed to act as an inciting event triggering polymyositis with myositisspecific antibodies,97 the observed histopathology was not typical of myositis. Furthermore, in human polymyositis upregulation of MHC-I alone does not trigger T-cell activation or endomysial infiltration.98 Another MHC molecule, the non-polymorphic non-classic HLA G, is upregulated in vitro by interferon and is expressed on muscle fibres of patients with polymyositis (and inclusionbody myositis).99 Because HLA G protects human muscle cells from immune-cell-mediated lysis in vitro, it could also partially protect muscle fibres in vivo.100 Costimulatory molecules If the autoinvasive CD8-positive cells are driven by specific antigens, as the clonally expanded TCR gene rearrangements indicate,8488,101 the MHC-I molecule on the muscle fibres should be able to present antigenic peptides to the TCR. For primary T-cell antigenic stimulation a second signal is required and provided by the B7 family of costimulatory molecules.102,103 Muscle fibres do not express the classic costimulatory molecules B7-1 (CD80) or B7-2 (CD86);104 instead, they express a functional B7-related molecule defined by the monoclonal antibody BB-1.104 Indeed, the MHC-I/BB1-positive muscle fibres make direct cell-to-cell contact with their CD28 or CTLA-4 ligands on the autoinvasive CD8positive cells (figure 4).104,105 The B7-related costimulatory molecule LICOS (ligand of inducible costimulator) and the costimulatory molecule CD40 are also upregulated on muscle fibres.106,107

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Cytokines, cytokine signalling, chemokines, and metalloproteinases In the muscles of patients with polymyositis or dermatomyositis, there is overexpression of the signal transduction and activation of transducers type I,108 indicating cytokine upregulation. Various cytokines and their mRNA, including interleukins 1, 2, 6, and 10, tumour necrosis factor , interferon , and transforming growth factor , are amplified in polymyositis and dermatomyositis.69,71,72,109111 Some of them, such as interferon and interleukin 1b, may have a myocytotoxic effect112114 whereas others, such as transforming growth factor , may promote chronic inflammation and fibrosis.115 Muscle-fibre necrosis occurs via the perforin granules released by the autoaggressive T cells. Death of the muscle fibre is mediated by a form of necrosis rather than apoptosis, presumably because of the counterbalancing effect or protection by the antiapoptotic molecules BCL2, hILP, and FLIP which are upregulated in polymyositis and inclusion-body myositis. Fas is also expressed, but it does not mediate apoptosis in the muscle. The upregulated NCAM on degenerating muscle fibres may enhance regeneration. After successful immunotherapy,116 there is downregulation of cytokines with reduction of inflammation and fibrosis.116,117 Chemokines, a class of small cytokines,118 including interleukin 8 (CXCL8), RANTES (CCL9), MCP-1 (CCL2), Mig CXCL9), and IP-10 (CXCL10) are also overexpressed in the endomysial inflammatory cells, the extracellular matrix, and the muscle fibres;72,119121 they may facilitate trafficking of activated T cells to the muscle or promote tissue fibrosis. The matrix metalloproteinases MMP-2 and MMP-9, which promote the migration of lymphocytes through extracellular matrix, are also overexpressed on the muscle fibres and the autoinvasive CD8-positive cells.122,123 Viral infections Although several viruses (coxsackieviruses, influenza, parvoviruses, paramyxoviruses, cytomegalovirus, EpsteinBarr virus) and bacteria (Borrelia burgdorferi, streptococci) have been indirectly associated with chronic and acute myositis,14,124 sensitive PCR studies have not amplified viral genome from muscle of these patients.125,126 A proposed molecular mimicry based on structural homology between coxsackieviruses and Jo-1 synthethase has not been proved.124 The best evidence of a viral connection is with retroviruses. At least six different retroviruses have been associated with polymyositis and inclusion-body myositis.124,127132 Monkeys infected with simian immunodeficiency virus,127 and human beings infected with HIV and HTLV-1,128,129 develop polymyositis either as an isolated clinical entity or concurrently with other manifestations of AIDS or HTLV-1 infection.128133 HIV seroconversion may coincide with myoglobulinuria and acute myalgia, suggesting that myotropism for HIV can be symptomatic early in the infection. The retroviruses are found only in occasional endomysial macrophages129133 and do not replicate within the muscle fibres or cause persistent infection.131133 In HIV-1 and HTLV-1 polymyositis, CD8-positive, nonviral-specific, cytotoxic T cells invade MHC-I-antigenexpressing non-necrotic muscle fibres in a pattern identical to retrovirus-negative polymyositis. Virusinduced cytokines, secreted also in situ by the virusinfected macrophages, could trigger T-cell activation and MHC upregulation. The relation between systemic retroviral infection and local autoimmune processes in muscle is not precisely understood. In principle, there are two possibilities: either the autoimmune attack is triggered

by mimicry between retroviral and muscle antigens, or the autoimmune process is non-specifically induced via bystander stimulation.134

Treatment
The goals of therapy are to improve the ability to carry out activities of daily living by increasing muscle strength and to ameliorate extramuscular manifestations (rash, dysphagia, dyspnoea, arthralgia, fever). There have been very few controlled clinical trials, most on dermatomyositis and inclusion-body myositis.135 Overall, dermatomyositis responds better than polymyositis, and inclusion-body myositis is difficult to treat. Although when the strength improves, the serum creatine kinase concentration falls concurrently, the reverse is not always true because treatments (eg, plasmapheresis) can lower the serum creatine kinase concentration without improving strength.1 This effect has been misinterpreted as chemical improvement, and has formed the basis for the common habit of chasing or treating the creatine kinase concentration instead of the muscle weakness.1,6,135 The following agents are used in the treatment of polymyositis and dermatomyositis. Corticosteroids Prednisone is the first-line drug, but its application remains empirical. We start with 80100 mg per day for 34 weeks, and taper the dose over 10 weeks to alternateday administration. Although most patients respond to some degree and for some time, others become steroid resistant and the addition of an immunosuppressive drug becomes necessary. The decision to initiate such therapy is based on: the need for a steroid-sparing effect, when despite steroid responsiveness the patients develop complications; the inability to lower the high steroid dose without precipitating a relapse; ineffectiveness of a 23-month course of high-dose prednisone; and rapidly progressive weakness and respiratory failure.1,6,135 Immunosuppressive drugs Selection of an immunosuppressive drug remains empirical and depends on personal experience and the relative efficacy/safety ratio.1,6,135,136 Azathioprine (orally, 2530 mg/kg) takes 46 months to work. A controlled trial in 1980 showed benefit of azathioprine.137 Methotrexate (orally, up to 25 mg weekly) acts more quickly than azathioprine. A rare side-effect is pneumonitis, which may be difficult to distinguish from the interstitial lung disease associated with Jo-1 antibodies. Cyclosporin (orally, 100150 mg twice daily)138 may also benefit childhood dermatomyositis.139 Mycophenolate mofetil (2 g per day) is emerging as a promising and well tolerated drug.140 Cyclophosphamide (0510 g/m2) intravenously has shown mixed results;141,142 it may help patients with interstitial lung disease, but the evidence remains circumstantial.143 Other treatments Plasmapheresis was not found to be helpful in a doubleblind, placebo-controlled study.144 Total lymphoid irradiation has helped in a few patients but its long-term side-effects curtail its use.145 Intravenous immunoglobulin (2 g/kg) in uncontrolled series was promising.146 In the first double-blind study conducted for dermatomyositis, intravenous immunoglobulin was effective not only in improving muscle strength but also in resolving the underlying immunopathology, as shown by repeated muscle biopsies.116 The improvement can be impressive; it begins after the first infusion but is short lived in most

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cases, and repeated infusions every 68 weeks are needed.116,147149 In polymyositis, no controlled studies have been completed, but intravenous immunoglobulin seems to be effective in about 70% of patients. Our approach The following sequential, step-by-step, empirical escalating approach has been successful in our patients. Step 1 is prednisone. Step 2 is azathioprine or methotrexate (methotrexate acts faster but no comparative trials are available;150 the choice depends on personal experience). In aggressive cases, steps 1 and 2 may be combined from the outset. Step 3 is intravenous immunoglobulin (this may be used as step 2). Step 4 is cyclosporin, mycophenolate mofetil, chlorambucil, or cyclophosphamide, used individually or in various combinations with steps 13,150 as dictated by disease severity, coexisting disorders, or the patients age. Superiority of a specific combination remains unproven.150 Future immunotherapies Although antigen-specific therapies are not in the offing, some rational therapeutic approaches are currently being investigated with agents that: block signal transduction in T lymphocytes (such as FK506, rapamycin, CAMPATH, or monoclonal antibodies against costimulatory molecules CD28/CTLA-4);151153 are directed against cytokines, such as monoclonal antibodies against tumour necrosis factor , soluble receptors to tumour necrosis factor , and interferons; and interfering with integrins and their receptors.151153

not demonstrable, the diagnosis of polymyositis is doubtful. Eighth, the goal of therapy is to improve strength; creatine kinase is a good indicator of disease activity but not the target of therapy. Ninth, when therapies for presumed polymyositis have lowered the creatine kinase concentration but not improved strength, the patient should be reassessed, the muscle biopsy sample re-examined, and a second biopsy considered to exclude inclusion-body myositis or dystrophy. Finally, when the patients strength has improved but is not fully restored, maintenance therapy with immunosuppressive drugs or alternate-day prednisone should be continued.
Conflict of interest statement
None declared.

Acknowledgments
We thank the following for funding our studies for many years: Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA (MCD) and Max Planck Institute of Neurobiology and Institute for Clinical Neuroimmunology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany (RH).

Role of the funding source


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

References
1 2 Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 1991; 325: 148798. 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: 133583. Mastaglia FL, Phillips BA. Idiopathic inflammatory myopathies: epidemiology, classification and diagnostic criteria. Rheum Dis Clin N Am 2002; 28: 72341. Dalakas MC, Karpati G. The inflammatory myopathies. In: Karpati G, Hilton-Jones, Griggs RC, eds. Disorders of voluntary muscle, 7th edn. Cambridge: Cambridge University Press, 2001: 63659. Hilton-Jones D. Inflammatory myopathies. Curr Opin Neurol 2001; 14: 59196. Dalakas MC. Polymyositis, dermatomyositis and inclusion body myositis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrisons principles of internal medicine, 15th edn. New York: McGraw-Hill, 2001: 252429. Sekul EA, Dalakas MC. Inclusion body myositis: new concepts. Semin Neurol 1993; 13: 25663. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med 1975; 292: 34447, 40307. 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 Med 1989; 111: 14357. Medsger TA, Dawson WN, Masi AT. The epidemiology of polymyositis. Am J Med 1979; 48: 71523. Ramanan AV, Feldman BM. Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin N Am 2002; 28: 83357. Shamin EA, Rider LG, Miller FW. Update on the genetics of the idiopathic inflammatory myopathies. Curr Opin Rheumatol 2000; 12: 48291. Koffman BM, Sivakumar K, Simonis T, Stroncek D, Dalakas MC. HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies. J Neuroimmunol 1998; 84: 13942. Reed AM, Ytterberg SR. Genetic and environmental risk factors for idiopathic inflammatory myopathies. Rheum Dis Clin N Am 2002; 28: 891916. Werth VP, Callen JP, Ang G, Sullivan KE. Associations of tumor necrosis factor and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis. J Invest Dermatol 2002; 119: 61720. Shamin EA, Rider LG, Pandey JP, et al. Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians. Arthritis Rheum 2002; 46: 188593.

Prognosis
Although the disease outcome has substantially improved, at least a third of patients are left with mild to severe disability.154-156 Older age and association with cancer are factors associated with poor prognosis. Pulmonary fibrosis, frequent aspiration pneumonias due to oesophageal dysfunction, and calcinosis in dermatomyositis are associated with increased morbidity.154156 In a small cohort, the 5-year survival was 95% and the 10-year survival 84%.156

5 6

Conclusion
On the basis of our own experience and that of others in major neuromuscular centres, the diagnosis and treatment of dermatomyositis and polymyositis could be improved by modification of many common practices. First, all disorders that mimic polymyositis should be excluded, taking into account that the criteria of Bohan and Peter cannot separate polymyositis from inclusionbody myositis or other toxic, necrotising, and dystrophic myopathies. Second, polymyositis as a stand-alone entity is rare. Although no accurate epidemiological data are available, polymyositis is rare in neuromuscular clinics; inclusion-body myositis is more common. Third, endomysial inflammation also occurs in non-immune myopathies (dystrophies, toxic, metabolic). Fourth, muscle tested with needle electromyography should not be sampled by biopsy until a month later. Fifth, in patients presenting with fatigue and increased activities of serum aminotransferases or lactate dehydrogenase, the creatine kinase concentration should be also checked to exclude myogenic origin of increased liver enzymes and avoid misdirection towards liver disease and liver biopsy. Sixth, patients with active polymyositis have muscle weakness; patients presenting with myalgias but normal strength do not have polymyositis. Seventh, if primary inflammation (CD8-positive/MHC-I complex) is

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