Dermatoniyositis and polymyositis

DEFtMATOMYOSITIS POLYMYOSITIS

AND

ABSTRACT .-Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory myopathies. The major manifestation of the myositis is proximal muscle weakness. Thirty percent to 40% of adults and 95% of children have cutaneous manifestations (DM) that include: (1) Got&on’s papules; (2) the heliotrope suffusion around the eyes, associated with periorbital edema; (3) poikiloderma, often photosensitive; and (4) nailfold changes including erythema, telangiectasia, and depletion or abnormality of the nailfold capillaries, visible with magnification. In juvenile DM, calcinosis is often seen in skin, subcutaneous tissue, or muscle. DM and PM are systemic diseases, and manifestations outside the skin and muscle may occur. Fever, weight loss, arthritis, and Raynaud’s phenomenon are seen in some cases. Interstitial lung disease may develop, as well as lung involvement from ventilatory failure or aspiration. Cardiac involvement may include arrhythmias, heart block, and congestive heart failure. Dysphagia may result from myositis of the pharyngeal muscles or from decreased lower esophageal motility. In about 20% to 25% of adults with DM, and less commonly with PM, there is an associated malignancy. The nature of the association is not known, and the increased frequency of malignancy in PM/DM has not been statistically established. The relative frequency of different tumors is similar to that in the general population, but ovarian tumors may be more frequent. In some cases, there may be a relationship of activity of the myositis to that of the malignancy. In adults with PMDM, a careful baseline screening is important, and any abnormalities should be pursued. Risk of malignancy is higher in older patients with DM, but without connective tissue overlap, who have a poor response to treatment or have a previous malignancy. Diagnostic criteria include proximal muscle weakness, elevated muscle enzymes, typical findings on electromyography and muscle biopsy, and characteristic cutaneous lesions. Measurement of creatine kinase is commonly used to assist in monitoring disease activity, as well as to support the diagnosis. Electromyography can document the presence of a myopathy and help to exclude neuropathies. Muscle biopsy can provide the strongest evidence for establishing a diagnosis. Mononuclear cell infiltration, necrosis, degeneration, and regeneration are seen. Perimysial inflammation with perifascicular atrophy is characteristic of DM, while endomysial infiltration is more common in PM. Vasculopathy with endothelial cell damage and capillary loss is characteristic of DM. Cutaneous histopathology can show compatible 134

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changes but cannot establish the diagnosis. Vacuolar changes in the basal layer, basement membrane thickening, epidermal atrophy, dermal edema with increased mucin, and a mononuclear cell infiltrate at the dermal-epidermal junction are seen. Immunofluorescence does not show specific findings. Other conditions that may cause a clinically similar myopathy must be excluded, including infections (with human hnmunodeficiency virus [HIV], human T-cell leukemia virus type I [HTLV-11, To,xopZasma, and other agents), inclusion body myositis, congenital or metabolic myopathies, drug effects, endocrine disorders, and others. Autoimmunity is clearly involved in the pathogenesis of PM and DM, but the factors leading to the autoimmune response have not been identified. Genetic influences are important, as demonstrated by an increased frequency of HLA-DR3. Viruses are most commonly suspected as possible triggering factors, especially picornaviruses and retroviruses. Other possibilities include Toxoplasma, drugs or toxins, and malignancy. Recent studies of the phenotypes of mononuclear cells infiltrating muscle biopsies have revealed that T-cell cytotoxicity against muscle fibers appears to be an important mechanism of muscle injury in PM but not DM. Vasculopathy associated with deposition of activated complement in the muscle vessels appears to be important in DM. Autoantibodies to nuclear and cytoplasmic antigens are common in PMDM. A group of myositis-specific antibodies are directed at aminoacyl-tRNA synthetases, of which the most common is anti-histidyltRNA synthetase (anti-Jo-l), found in 20% of PMDM patients. Antisynthetases are associated with a high frequency of interstitial lung disease, arthritis, and Raynaud’s phenomenon. Anti-Mi-2, another myositisspecific antibody, is directed at an unidentified nuclear antigen. When present, it is strongly associated with cutaneous involvement. Ninetyfive percent of patients with anti-Mi-2 have DM, while 15% to 20% with DM have anti-Mi-2. Several autoantibodies, including anti-PMScl, anti-Ku, anti-UlRNP, and anti-U2RNP, have been associated with myositis-scleroderma overlap syndrome. The myositis-specific antibodies may be helpful in diagnosis and in identifying significant patient subgroups and have implications for etiology and pathogenesis. The treatment of the myositis is generally initiated with corticosteroids, in adults usually prednisone, 60 to 80 mg/d. Immunosuppressive agents, most often azathioprine or methotrexate, are used in up to 25% of patients, usually for steroid resistance or severe steroid side effects. Case reports have described success with cyclosporin in resistant cases. The skin disease may persist despite control of the myositis, and hydroxychloroquine has been useful in such cases. With current treatment, the prognosis of PMDM has improved and morbidity is decreased, with an 80% 5-ydar survival rate. Malignancy, interstitial lung disease, and cardiac disease contribute to mortality. Those with a long delay before initiation of treatment have less chance of recovering full strength.

IN BRIEF Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory myopathies, distinguished from each other by the presence of the cutaneous lesions. The most common classification recognizes five types: adult Curr

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PM, adult DM, PM/DM with malignancy, juvenile DM, and PM/DM as part of overlap syndromes. PM/DM is quite uncommon, with an annual incidence of about 5 per million. It is more common in blacks and in females. Thirty percent to 40% of adult patients have DM skin lesions, while 95% of children have DM. The cutaneous changes are usually found at the time of presentation and often precede the muscle weakness by 1 to 3 months, but this can be prolonged. Characteristic lesions include: (1) Gottron’s papules, erythematous or violaceous plaques or papules appearing over the knuckles, with similar lesions over the large joints; (2) the heliotrope, a red or purplish suffusion around the eyes, often with periorbital edema; (3) poikiloderma, especially in a characteristic “V” and “shawl” distribution over the upper torso, neck, and shoulders; and (4) nailfold changes that include periungual telangiectasia, erythema, and cuticular changes. The poikiloderma and facial rash are often photosensitive. Capillary abnormalities and capillary loss may be visible in the nailfold with magnification, similar to those seen in scleroderma, and reflecting the underlying vasculopathy. More severe vasculitis with ulceration may be seen in juvenile DM. Also important in juvenile DM is calcinosis, which may become a serious clinical problem resulting in large tumorous nodules over joints, and deposits along fascial planes in muscle, interfering with function. “Mechanic’s hands,” hyperkeratosis with fissuring and hyperpigmentation giving the appearance of dirty horizontal lines on the lateral aspects of the fingers, has been increasingly recognized. The myositis is characterized by proximal muscle weakness, resulting in difficulty with rising from a chair, climbing stairs, or reaching overhead. Involvement of the distal muscles is uncommon, and that of the face is quite unusual. Extraocular muscle involvement is rare. Myalgia may occur in half the patients, but it tends to be mild and usually not the main feature. Systemic features including fever and weight loss may be seen. Arthritis and Raynaud’s phenomenon may occur, especially in patients with overlap syndromes and in patients with antisynthetases. Patients may satisfy criteria for other connective tissue diseases as well as those for PM/DM. Overlap is most commonly seen with scleroderma but is also seen with systemic lupus erythematosus, Sjogren’s syndrome, or rheumatoid arthritis. PM and DM are systemic diseases and may affect other systems. Lung involvement may occur in up to 45% of patients. In addition to complications of muscle weakness that may manifest in the lungs, such as ventilatory failure or aspiration, and complications of treatment, such as opportunistic infection or hypersensitivity pneumonitis, patients with PM/DM may develop interstitial pneumonitis and pulmonary fibrosis. This may occur in all forms of PM/DM, and while it is often asymptomatic, in others it may be the predominant clinical problem. It is strongly associated with the antisynthetase autoantibodies, but may also occur in other patients. Cardiac involvement may take the form of arrhythmias, heart block, or myocarditis with resulting congestive heart failure. Gastrointestinal involvement with dysphagia is common. This may be due to weakness of the pharyngeal muscles and upper esophagus, as with other skeletal muscles; to involvement of the lower esophagus, with decreased motility and reflux, sometimes affecting other portions of the intestinal tract; or to cricopharyngeal muscle dysfunction. An association of some cases of PM/DM with malignancies has long been recognized, although it has been hard to demonstrate this association statistically. Although the relative frequency of different tumors is similar to that in the general population, with lung and breast most common, there may be an increase in ovarian tumors. A relationship of the activity of the myositis to that of the malignancy may be seen, but not in all cases. A careful baseline evaluation including history, physical examination, screening 136

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laboratory tests, occult blood testing, chest radiograph, mammogram, and pelvic examination are important, and any abnormalities pursued. However, when these are normal, extensive expensive screening tests are usually not recommended. Patients at greater risk include those with DM rather than PM who are over 45 years of age, without connective tissue disease overlap or autoantibodies, with poor response to treatment, or with a previous malignancy. The diagnosis is established using the criteria of Bohan and Peter, which include: (1) proximal muscle weakness, (2) elevated muscle enzymes, (3) typical findings on electromyography, (4) typical muscle biopsy changes, and (5) the characteristic cutaneous lesions. The presence of four criteria indicates definite PM/DM. Creatine kinase (CK) is the muscle factor most commonly used for disease monitoring because it is elevated in most patients with active myositis, has relative muscle specificity, is generally correlated with disease activity, and is readily available. Before attributing elevations to myositis, other conditions that raise the CK level, such as hypothyroidism, drugs, muscle trauma, and other myopathies, should be excluded. The CK level may occasionally fail to rise during active disease, sometimes due to a CK inhibitor. When the CK level is normal, aldolase, myoglobin, or urinary creatine may sometimes be used to monitor disease activity. Elevation of the CK-MB is sometimes seen, even in the absence of cardiac involvement. Electromyography can document the presence of a myopathy, help to exclude neuropathies, and show a typical picture of myositis, but it is not specific. Myopathic potentials, early full recruitment, increased insertional activity, fibrillations and positive sharp waves, and complex repetitive discharges are typically seen. There is recent interest in the use of magnetic resonance imaging to demonstrate muscle inflammation and help direct the biopsy. Muscle biopsy can provide the strongest evidence for establishing a diagnosis and can exclude certain conditions that may be confused with PM/ DM. Although open biopsy gives the best sample, needle biopsy often gives adequate information with lower morbidity. Inflammation with mononuclear cell infiltration is the hallmark. In DM, infiltration tends to be predominantly perimysial, and perifascicular atrophy is often seen. In PM, infiltration is more often endomysial, usually without perifascicular atrophy. Necrosis, degeneration, and regeneration are also typically seen. In DM, particularly in the juvenile form, evidence of vasculopathy may be seen, marked by endothelial cell damage, including tubuloreticular inclusions, and capillary loss. Skin biopsy is less helpful in establishing a diagnosis. There are no pathognomonic histologic features, and the findings may closely resemble those of cutaneous lupus. The poikilodermatous lesions are most commonly biopsied and show vacuolar changes of the basal layer, periodic acid- Schiff (PAS)-positive basement membrane thickening, flattening and atrophy of the epidermis, dermal edema with increased mucin, vascular dilation, and a sparse mononuclear cell infiltrate at the dermal-epidermal junction. Immunofluorescence does not show specific findings. Lupus band formation does not occur in nonlesional skin and is very uncommon (5~) in lesional skin. For a diagnosis to be established, not only must the criteria be fulfilled, but other conditions that may cause a clinically similar form of myopathy must be excluded. These include other neurologic conditions such as motor neuron disease and myasthenia gravis; other myopathies such as metabolic myopathies and congenital myopathies; other forms of myositis, especially inclusion body myositis and infectious myositis as with viruses or Tox&wma; drug-induced myopathy, as with o-penicillamine, colchicine, lovastatin, or zidovudine (AZTI; or endocrine disorders, such as hypothyCurr

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roidism or steroid myopathy. It is important to exclude human immunodeficiency virus (HIV) and human T-cell leukemia virus type 1 (HTLV-1) infections, which put the patient at increased risk from immunosuppressive treatment. Autoimmunity is clearly involved in the pathogenesis of PM and DM, but the factors leading to the autoimmune response have not been identified. Picornaviruses, such as coxsackievirus or echovirus, are most commonly suspected as possible triggering factors. A strain of coxsackievirus can induce a PM-like myositis in mice that is mediated by cellular immunity. Titers to coxsackie but not other viruses are elevated more frequently in juvenile DM than in healthy control children. In situ hybridization with coxsackie probes was positive in muscle from almost half of PM/DM patients in one study. Another study found no coxsackievirus, but a murine picornavirus probe may have identified a related unidentified viral RNA in muscle macrophages in half of adult DM patients. Retroviruses have also been suggested as possible triggering factors, supported by the association of HTLV-1 and HIV with PM-like myositis. Other viruses, such as hepatitis B, have been associated with myositis in case reports. Other factors have been suggested. Patients with PM/DM have an increased frequency of positive Toxoplasma titers, including IgM, suggesting that To)toplasma may play a role in some apparently idiopathic cases. Drugs or unidentified toxins may be important in some cases. D-Penicillamine, for example, can induce autoimmune myositis. Malignancy has been suggested as a possible factor in initiating myositis in those patients in whom it is present, but the nature of the relationship of PM/DM and malignancy is not kTlOWll.

Genetic factors are of importance in conferring susceptibility to myositis, but other factors are needed. An increase in HLA-B8 and -DR3 has been found in both adult PM/DM and juvenile DM. Deletion of the C4A gene, which is linked to the B8-DR3 haplotype, has also been associated with juvenile DM, but the primary factor in conferring susceptibility may be DC&l. HLA-DR genes have also been associated with production of myositisspecific antibodies. HLA-DR3 is associated with production of anti-Jo-l in white patients, but DRw52 is associated with production of antisynthetases in all patients. DR3 is also associated with anti-PM&l. Whether other genetic influences are important is not known. Recent studies of the phenotypes of mononuclear cells infiltrating muscle biopsies have been very revealing regarding pathogenetic mechanisms. Nonnecrotic muscle fibers surrounded and invaded by lymphocytes are abundant in PM but are rare in DM. The lymphocytes involved are predominantly cytotoxic T lymphocytes, suggesting that T-cell-mediated cytotoxicity is an important pathogenetic mechanism in PM. In DM, more B cells are seen, and deposition of the membrane attack complex of complement has been demonstrated in the muscle blood vessels, most commonly in juvenile DM but also in many adult DM patients. This indicates local complement activation, consistent with evidence of the importance of vasculopathy. The endothelial cell damage and capillary dropout associated with the vasculopathy are very early changes, suggesting that they are primary, leading to ischemit muscle damage. Autoantibodies to nuclear and cytoplasmic antigens are common in both PM and DM. Some are found almost exclusively in myositis, while others are primarily associated with other connective tissue diseases. The most common myositis-specific antibodies are directed at the aminoacyl-tRNA synthetases. The most common of these is anti-histidyl-tRNA synthetase (antiJo-l), found in 20% of PMDM patients. Antibodies to four other synthetases have been, identified in myositis. Antisynthetases are associated with a high 138

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frequency of interstitial lung disease, arthritis, and Raynaud’s phenomenon. Anti-Jo-l is more common in PM but can be seen in adult DM. Adult DM is more common with other antisynthetases than with anti-Jo-l. Anti-Mi-2, another myositis-specific antibody, is directed at an unidentified nuclear antigen. It is strongly associated with cutaneous involvement. Of patients with the antibody, 95% have DM, and it is found in 15% to 20% of patients, including 10% of those with juvenile DM. Several autoantibodies, including anti-PM-W, anti-Ku, anti-UlRNP, and anti-UZRNP, have been associated with myositis-scleroderma overlap syndrome. The myositis-specific antibodies may be helpful in diagnosis and in identifying significant patient subgroups, and risk of certain clinical features, such as interstitial lung disease. Anti-Jo-l has a general correlation with disease activity, which could be useful in some situations. More important are their implications for etiology and pathogenesis of the disease. The treatment of the myositis is generally initiated with corticosteroids. In most adults, treatment is initiated with high-dose daily oral prednisone in the range of 60 to 80 mgd. It is usually continued for 1 to 3 months, until the CK level has normalized and strength has improved. The dose is then slowly tapered by 10% to 25% per month, to a maintenance of about 5 to 10 mgd, or 10 to 20 mg on alternate days. Steroid myopathy may occur and can be confused with exacerbation of disease activity. Initial therapy with alternate-day steroids is advocated by some for milder disease. Very high dose intravenous pulse methylprednisolone is sometimes used in severe disease or in juvenile DM. Steroid resistance or severe steroid side effects may necessitate the use of immunosuppressive agents in up to 25% of patients. Azathioprine and methotrexate are most often used, and both appear to be effective. Several case reports have described success with cyclosporin in resistant cases. Although successes with cyclophosphamide have been reported, it is often ineffective and carries a high risk of toxicities. Combination chemotherapy, plasmapheresis, high-dose intravenous gamma globulin, and total body irradiation have been tried in refractory disease. The skin disease may persist despite control of the myositis or may be present without myositis. Topical steroids may be tried but are often ineffective. Hydroxychloroquine has been useful in such cases. In addition, protection from the sun is an important aspect of treatment. There is no proven effective therapy for established calcinosis. It is best prevented to the extent possible by early and aggressive treatment in juvenile DM. The prognosis of PMDM has improved with current treatment, and morbidity is decreased. Data from the 1970s indicate an 80% 5-year survival rate. Older age and dysphagia are associated with poorer prognosis. Malignancy, interstitial lung disease, and cardiac disease contribute to mortality. Those with a long delay before initiation of treatment have less chance of recovering full strength. Patients with DM may respond better than those with PM, and patients with antisynthetase antibodies respond less well than those without these antibodies.

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Zra N. Targofl M.D., is Associate Professor of Medicine at the University of Oklahoma Health Sciences Center (OUHSC) in the Rheumatology, Immunology, and Allergy Section, and an Assistant Member at the Oklahoma Medical Research Foundation. He is also a StaffPhysician at the Veterans Afsairs Medical Center in Oklahoma City. He graduated from the Albert Einstein College of Medicine in 197.5, did residency training at the State University of New York at Bufsalo, did a fellowship in rheumatology at OUHSC, and is board certij?ed in rheumatology. He did further training in research as an Associate Investigator and Research Associate of the Veterans Administration. His major research interest is in polymyositis and dermatomyositis, particularly with regard to the myositis-specific autoantibodies. 140

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DEFtMATOlWYOSITIS POLYMYOSITIS

Dermatomyositis (DM) and the related polymyositis (PM) are among the group of acquired muscle disorders known as idiopathic inflammatory myopathies, which also include inclusion body myositis and several rare forms of myositis. Muscle weakness is the predominant symptom in most patients with idiopathic inflammatory myopathies. DM is distinctive in the presence of the characteristic cutaneous findings, which by definition separate it from PM. Despite increasing evidence of significant differences in the myositis of PM and DM, they are clearly related disorders, and both will be discussed and compared in this review.

CLASSIFICATION

OF MYOSITIS

Heterogeneous clinical pictures are seen among patients with idiopathic inflammatory myopathies, and several classification systems have been proposed to categorize patients into more homogeneous groups on clinical grounds. Most recent studies have used the system of Bohan and Peter,l who distinguished five types of PM and DM (Table 1). The system has been very helpful, and it is usually easy to assign a patient to a particular category. PM and DM are considered together in the classes of myositis with malignancy and connective tissue overlap, although some would separate PM and DM in those classes also.’ The classification will continue to evolve as knowledge of etiology and pathogenesis increases. For example, specific autoantibody testing can help to further classify patients, identifying subgroups of patients Curr

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AND

who share significant clinical, prognostic, and immunogenetic features,3 while muscle histology can identity different patterns of involvement.’

EPIDEMIOLOGY Most estimates of the annual incidence of PM and DM together fall within the range of two to nine cases per million population per year.4 Most of the studies on which these estimates are based identified hospitalized patients only and may therefore produce underestimates. The incidence rate is lower in children, at 0.6 to 3.2/million/year.4 While PM and DM may begin at almost any age, there is a bimodal distribution, with the first peak in children and the larger peak in adults between 40 and 60 years of age? The prevalence ranges from five to ten per 100,000 population4” The incidence rate increases over time in long-range studies. For example, in a recent study from Pittsburgh,7 the overall rate over 20 years was 5.5/million/year, but the rate for the second decade was 8.9/million/year. Although there may be a true increase, this finding may reflect better detection and recognition of disease. Some differences in risk have been noted. The rate is higher in black than white patients by about 4:lSJ7 and higher in females than males by 2: 1, rising to 5 : 1 during the childbearing years.7 Black women therefore have the highest incidence, reaching a peak of 32.2 cases/million/year during the last quarter of the Pittsburgh study. The female:male ratio is lower in patients with malig141

TABLE 1.

TABLE 2.

Classification of Polymyositis Bohan and Peter Type

and Dermatomyositis”

Primary idiopathic polymyositis Primary idiopathic dermatomyositis Dermatomyositis (or polymyositis) with malignancy Juvenile dermatomyositis (or polymyositis) Overlap of polymyositis or dermatomyositis with another connective tissue disease *Adapted from Bohan and Peter.’

Estimated

Frequency,

Major %

30-40 20-30 10-1.5

10

20

nancy but is higher (9: 1) with an associated connect&e tissue disease.’ The higher rate in black and female patients is also seen in children. PM is more common than DM among adults, by less than 2 : 1 in most studies.” ’ DM is much more common than PM in children by 20 : 1. DM may be less common in men. Adult PM (type I, Table 1) is the most common type of myositis, usually accounting for about one third of patients, while about one quarter have adult DM (type IU7’ ’ and one fifth have connective tissue disease overlap syndromes. Patients with PM/DM show no significant family clustering, although rare familial cases have been reported. A family history of myopathy should make one question the diagnosis. PM/DM has been encountered in all parts of the world. Most studies of adults have found no correlation of incidence rate and time of year, although one recent study from Greece found a higher rate from March through May.” In juvenile DM IJDM), one study found a higher rate of onset in the latter part of the year,l* consistent with a relationship with coxsackievirus infection, but others have not found this.4 The rate may vary with the time of year among certain autoantibody-defined subgroups, since the onset of weakness in patients with antiJo-l is more often early in the year, but with anti-signal recognition particle, late in the year.*’ CLINICAL CUTANEOUS

PICTURE A4ANlFESTATIONS

Cutaneous changes are present in 30% to 40% of adult patients with PM/DM and 95% of children 142

Cutaneous

Manifestations

of Dermatomyositis

Gottron’s papules or Gottron’s sign (erythema alone) Over finger joints Over other joints Heliotrope Erythematous eruption, especially over the upper chest, often showing photosensitivity and poikiloderma Nailfold changes Erythema, telangiectasis Abnormal capillaries and capillary loss Cuticular overgrowth Calcinosis* Skin Subcutaneous Muscle Cutaneous vasculitis Periungual and digital Ulcers* Mechanic’s handst Mucin deposition Features of other, overlapping connective tissue diseasest Scleroderma Lupus erythematosus *More tAls0

common in juvenile seen in polymyositis.

dermatomyositis.

(Table 2). The onset of skin and muscle disease is usually within 2 to 3 months of each other, but it is common for the rash to precede the weakness, and the rash is usually seen at presentation. Bohan et al.’ found compatible cutaneous features in 93% of adult DM patients (type II) at the time of presentation, but found weakness in only 53%. Hochberg et al.l3 noted skin findings at the time of diagnosis in 100% of adult DM patients. The subsequent activity of the skin disease will often parallel that of the myositis, but it may persist after the myositis resolves.14 When the skin is involved first, muscle weakness usually develops within 1 to 3 months, but this can be more prolonged.15 Rockerbie et al.l6 found that cutaneous changes of DM preceded the myositis by more than 1 year in six of 50 patients, while the myositis preceded the rash by more than 1 year in only one of 50. Patients may have the typical skin findings of DM but never develop any sign of myositis. It may be difficult to detect the skin lesions in some cases, especially the heliotrope, particularly in black patients,l’ or it may be subtle or transient, and patients may be incorrectly classified as PM on this basis. Also, in patients with lupus overlap syndromes, cutaneous changes resulting from DM may be attributed to the lupus, especially when a photosensitive facial rash is presenLg The most characteristic and common cutaneous lesions of DM are Gottron’s Cur-r Probl

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FIG 2. The skin overlying the knee of this patient shows an erythematous eruption similar to that over the finger joints, characteristic of dermatomyositis. (Photograph courtesy of Department of Dermatology, University of Oklahoma Health Sciences Center.)

erythema over the fingers along tendon sheaths may occur.17 The distribution over the joints is in contrast to the erythematous lesions sometimes seen on the fingers in systemic lupus erythematosus (SLE), which typically occur over the middle part of the proximal phalanges between the joints. Similar red or violaceous lesions may also involve the extensor surfaces of the knees (Fig 21, elbows, and wrists and the medial malleoli, and occasionally other parts of the extremities.

FIG 1. Gottron’s papules. The skin overlying metacarpophalangeal joints shows the papules with a small amount of scale. is also evident. (Photograph courtesy lecular Immunology Laboratory, US tion)

the second through fifth characteristic erythematous Periungual erythema distally of F.W. Miller, MD, PhD, MoFood and Drug Administra-

papules, seen in 70% to 80% of patients, and the heliotrope rash, identified in 30% to 60%. Tymms and Webb’ found Gottron’s papules in all 36 of their DM patients, but the heliotrope in only one third. Gottron’s Papules Gottron’s papules are erythematous or violaceous raised papules or plaques that occur over bony prominences, most characteristically over the metacarpophalangeal, and proximal and sometimes distal interphalangeal, joints of the hands (Fig 1). They are sometimes scaly, they can show telangiectasia, and atrophy may develop. In the early phases, findings may be limited to erythema over these joints, referred to as Gottron’s sign? When severe, involvement may extend over the dorsum of the hand and wrist. Streaking of Cur-r Probl

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Heliotrope The heliotrope rash is a red to purplish, lilaccolored suffusion seen around the eyes (Fig 31, particularly on the upper eyelid, sometimes along the edge of the upper lid (Fig 4). It is commonly accompanied by periorbital edema. It may reflect disease activity, but not in all cases. This sign is often described as pathognomonic for DM, but it is not absolutely specificl’ A similar change has been seen in trichinosis, in sarcoidosis, and as an allergic manifestation. It has been seen in Togoplasmosis-associated DM.l’ Periorbital edema with erythema can occur in SLE.” A red or violaceous rash may occur over other parts of the face, including the forehead, malar areas, and chin (Fig 3). It may be photosensitive, but usually not as strikingly as in SLE. The nasolabial folds may be invo1ved.l’ Poikiloderma In addition to involving the skin overlying the joints, the rash may be more widespread and extensive. A characteristic pattern of involvement in143

FIG 3.

FIG 5.

An extensive, photosensitive facial rash in a patient with dermatomyositis. The area around the eyes shows the typical heliotrope suffusion, accompanied by periorbital edema, that has become confluent with the surrounding erythematous facial eruption. (Photograph courtesy of Department of Dermatology, University of Okiahoma Health Sciences Center.)

Poikiloderma involving most of the torso in a patient with dermatomyositis. Although this is unusually extensive, the change is similar to that more commonly seen limited to upper chest and back regions (Photograph courtesy of Department of Dermatology. University of Oklahoma Health Sciences Center.)

Nailfold eludes the base of the neck and upper chest (“V”) and the upper back, back of neck, and shoulders (“shawl”), suggestive of photosensitivity. Callenzl estimates that photosensitivity is seen in 75% to 80% of cases, induced by ultraviolet-B light. These changes and those over the joints can develop into poikiloderma with varied hyperpigmentation and hypopigmentation, atrophy, telangiectasia, and erythema (Fig 5). Poikiloderma may be seen in other situations, but suggests DM in a patient with myositis.‘* Epidermal atrophy can be severe, with superficial erosions.”

FIG 4. The skin at the lower edge of the upper lid shows the violaceous change typical of the heliotrope. (Photograph courtesy of F.W. Miller, MD, PhD, Molecular Immunology Laboratory, Food and Drug Administration.) 144

Changes and Vasculitis

Nailfold and cuticular changes are significant, but not specific for DM. Periungual erythema and telangiectasia are frequent. By examining the nailfold capillaries with magnification, capillary changes similar to those found in scleroderma may be seen, including thrombosis, hemorrhage, “bushy capillaries,” giant capillary loops, and capillary loss. Such changes are prominent in JDM but may also be seen in adult DM and a smaller proportion of adult PM cases.23 They are associated with severe disease and followed clinical activity in some studies.Z4 Vasculitic changes may be observed in the nailfold or periungual area. Cutaneous vasculitis may also be seen elsewhere, including ulcers, especially in JDM. Extensive cutaneous vasculopathy in JDM has been associated with severe muscle involvement resistant to treatment, with a nonremitting course.” In two recent studies of adults, all myositis patients with signs of cutaneous vasculitis had other cutaneous features of DM.“, 27 It is not necessarily associated with vasculitis of the muscle. Cutaneous vasculitis or necrosis may be associated with malignancy.26S ” Capillary thrombosis may also be seen in the eyelids. The cuticles may be thickened, roughened, and irregular, with hyperkeratosis, resembling changes seen in repeated trauma.” These changes are also similar to those seen in scleroderma.

Mechanic’s

Hands

An interesting lesion of the fingers with DM has been termed “mechanic’s Cum

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cause of its resemblance to the calloused hands of manual laborers. Hyperkeratosis with scaling, fissuring, and hyperpigmentation give the appearance of dirty horizontal lines, seen in a symmetrical distribution over the ulnar aspect of the thumb and the radial aspect of the fingers, extending onto the palmar aspect3’ Other features of DM may or may not be present, and it is not in itself enough to classify a patient as DM rather than PM. It has been associated with connective tissue disease features, especially Raynaud’s phenomenon, and may be more frequent in patients with antisynthetase autoantibodies (see below).

MYOSITIS

The clinical features of the myopathy of PM and DM are similar, although it is often recognized earlier in DM and may tend to develop more acutely. Muscle weakness is the major manifestation and occurs in almost all patients. It usually develops insidiously over a period of weeks to months, but more acute and more slowly progressive presentations may be seen. Typically, weakness affecting the large proximal muscles around the shoulders, hips and thighs develops in a symmetrical fashion. The muscles of the trunk and neck are also prominently affected. Involvement of the lower extremities, which more Calcinosis often occurs first,” can lead to an abnormal gait Soft-tissue calcification is found in 40% to 74% of and difficulties with such activities as rising from a children with DM,17 developing an average of 2 to chair, getting out of a car, or climbing stairs. In2.5 years after onset. The deposits can become volvement of the upper extremities leads to diffipainful and inflamed, can interfere with function culty combing the hair or reaching or working of adjacent joints or muscles, can form abscesses, overhead. Weakness of muscles of the torso and and can lead to ulceration of the overlying skin neck can lead to difficulties getting out of bed or with extrusion of calcific material. Bowyer et a131 raising the head off the pillow. Distal weakness is described four types of dystrophic calcification: (1) uncommon, and involvement of the face is una superficial pattern of small, hard plaques or nodusual, but patients may note impairment of chewules in the skin; (2) nodular subcutaneous deposits ing, and dysphagia is common. Involvement of the that may become large, often near joints (calcinoextraocular muscles is rare, in contrast to myassis circumscripta); (3) deposition in fascial planes thenia and some other myopathies. Within regions within the muscles, often with limitation of motion of weakness, there is usually diffuse involvement, of the muscle (calcinosis universalis); and (4) a seunlike some myopathies in which weakness and vere “exoskeleton” pattern with extensive deposiatrophy may be highly selective for specific mustion in the subcutaneous tissue, associated with cles . vasculitis, erythroderma, and skin ulceration, which Myalgia and muscle tenderness occur in about was felt to require particularly aggressive treathalf of patients with PMDM, manifested mainly as ment. Calcification is related to severity and duraaching or soreness but tend to be mild and are tion of disease activity, and early and aggressive usually not the predominant features. However, therapy may decrease the incidence or extenL31’ 32 when PM/DM develops acutely and progresses rapCalcinosis is rare in adults but can occur. Disidly, pain and tenderness may be more severe,35 tal soft-tissue deposits have been seen with the and edema over the muscles may occur. In the deforming arthritis associated with anti-Jo-l antiearly stages, there is little atrophy despite the bodies. weakness, but atrophy may be seen in the later stages. Contractures may occur with chronic disOther Manifestations ease of long duration, particularly in children. Panniculitis may occur in PM/DM, that is usually Demonstration of decreased muscle strength is subclinical and associated with inflamed muscle.33 needed in initial patient assessment, and a quantiRare clinical cases have been reported, including tative evaluation of muscle strength is important in one that presented as localized lipoatrophy.34 assessing patient progress. Bedside maneuvers Other cutaneous findings have been reported in that are helpful in demonstration of proximal patients with DM, but they are generally rare, not muscle weakness include observaton of the paDM specific, and do not help to confer a diagnosis tient rising from a low chair without the help of of DM.” The skin disease has been severe enough the arms, or rising from the supine position on the at times to lead to generalized erythroderma.27 examining table. The gait should also be observed. Changes in the skin may also result from overlap Measuring the time required for rising from a chair with other connective tissue diseases (sclero10 times36 has been suggested for rapid assessment of patient progress. Direct testing of muscle derma, lupus erythematosus, etc.). groups is also performed, concentrating on proxiCurr

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145

mal muscles such as deltoid, iliopsoas, and quadriceps. There is also increasing interest in the use of mechanical measures of muscle strength, to standardize testing and increase objectivity and sensitivity.37 Myalgia or arthritis or other sources of pain may interfere with all types of muscle strength testing, and fatigue may also impair a patient’s effort.

OTHER

SYMPTOMS

Fever and weight loss may be impressive in some patients. Tymms and Webb’ reported fever in 30% of their patients, and in 50% with DM. It is usually mild but may be marked. Weight loss was seen in 42%. Fatigue and malaise are also common. It is sometimes difficult to distinguish a complaint of fatigue from a complaint of muscle weakness. Raynaud’s phenomenon is usually found in 20% to 30% of patients.‘, l3 It is more common in patients with overlap syndromes with scleroderma or SLE (50%), occurs in about 10% with DM, and is uncommon in myositis with malignancy. It may be the initial manifestation of disease. In most series, arthralgias or arthritis are found in 20% to 40% of patients. Frank arthritis is most commonly found in overlap syndromes and is generally uncommon in other patients, although it was found in half of patients without overlap in one study.’ It tends to be mild, nonerosive, usually nondeforming, and quickly responsive to treatment directed at the myositis, but a deforming arthritis of the hands may be seen,38J 3s often with instability of the interphalangeal joint of the thumb. Arthritis and Raynaud’s phenomenon have been associated with antisynthetases, as discussed below.

COMPLICATIONS Lung

IN OTHEA

SYSTEMS

Disease

Pulmonary complications occur in as many as 45% of patients with PM/DM and are an important cause of morbidity and mortality. Complications may derive from (1) muscle weakness (ventilatory failure, aspiration pneumonia); (2) treatment topportunistic infection, hypersensitivity pneumonitis); or (3) disease involvement (interstitial lung disease [XLDJ)40 (Table 3). Significant respiratory muscle weakness occurs in about 5% of patients,6’40 but measurable decreases in respiratory muscle strength are more common. The diaphragm, accessory muscles, in146

TABLE 3. Involvement

of Other

Systems

Systemic Fever Weight loss Arthritis Mild, nondeforming Deforming (antisynthetase positive) Pulmonary Ventilatory failure Aspiration Interstitial lung disease Cardiac Arrhythmias Block Myocarditis Gastrointestinal Dysphagia due to myositis or pharyngeal Dysmotility of esophagus, stomach Vasculitis* Other Raynaud’s phenomenon Retinopathy” Vasculitis Associated diseases *Usually

associated

with

juvenile

muscles

dermatomyositis.

tercostals, and abdominal muscles may be affected, with reduction in total lung capacity and vital capacity. Severe weakness may lead to hypercapnia and ventilatory failure requiring intubation and assisted ventilation. It usually responds to or is prevented by treatment but may develop rapidly. Most such patients also have involvement of the pharyngeal and tongue muscles, with dysphagia and impaired speech. PM/DM may predispose to aspiration because of dysphagia, impaired cough, and difficulty turning or sitting up in bed. It occurs in 10% to 15%, and is usually preceded by dysphagia.40 Respiratory muscle weakness can also predispose to pulmonary infection due to atelectasis and difficulty with clearing secretions. Recent series have reported ILD in 10% to 30% of PM/DM patients.13, 4o The frequency of apparent ILD by pulmonary function testing may be higher than the frequency that can be documented on chest radiograph, although respiratory muscle weakness can complicate interpretation of these tests. Asymptomatic involvement, evident only in abnormalities of chest radiograph or pulmonary function tests, is probably most common. In other cases, gradually developing dyspnea develops, while a small proportion of patients have a fulminant course, with fever, cough, and rapidly developing dyspnea. ILD in PM and DM is similar to idiopathic ILD, with a reticulonodular pattern on Curr

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chest radiograph, more prominent in the bases, and a restrictive pattern on pulmonary function testing. Decreased carbon monoxide diffusing capacity and hypoxemia with exercise are early signs. Lung history shows an interstitial mononuclear cell inflammatory infiltrate, with a variable amount of fibrosis. Histologic patterns include bronchiolitis obliterans with organizing pneumonia, interstitial pneumonitis, and diffuse alveolar damage, which has the worst prognosis41 Direct immunofluorescence is usually negative for immunoglobulin and complement deposition in the lung. ILD may occur in any form of PM/DM, including DM with malignancy4’ and JDM.43 The severity of the ILD is not correlated with the severity of the myositis, and the ILD may precede the myositis or be the dominant feature of disease. The myositis component may be missed, either because it is mild or because it is masked by inactivity imposed by the ILD. In one case, a patient with cutaneous DM developed rapidly fatal fibrosing alveolitis without developing myositis.44 Two patients with typical cutaneous findings of DM associated with ILD subsequently developed myositis.15 In addition to the skin lesions, other clues to underlying PM/DM would be elevated creatine kinase (CK) levels or autoantibodies. ILD is strongly associated with the presence of myositis-specific autoantibodies. ILD must be differentiated from opportunistic pulmonary infections that may develop because of immunosuppressive treatment, and in some cases from methotrexate-induced hypersensitivity pneumonitis. The latter may present as an acute illness with fever, cough, dyspnea, bilateral interstitial infiltrates on chest radiograph, and lymphocytic infiltrates on biopsy. It usually responds to withdrawal of the drug, although corticosteroids are sometimes required. The ILD of PMDM may respond better to treatment than other forms of ILD, particularly if treatment is begun early, when active inflammation is seen on biopsy as opposed to interstitial fibrosis. Treatment is usually begun with prednisone in high doses, but cyvtotoxic agents are often needed.45 Cardiac Disease Cardiac manifestations occur in as many as 70% of PM/DM patients46 but are commonly asymptomatic. The major manifestations include conduction disturbances, arrhythmias, and myocarditis (Table 3). Electrocardiographic abnormalities may be found in one third to one half of patients. Fascicular or bundle branch block is most comCurr

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mon, but advanced heart block requiring a pacemaker may occur. Arrhythmias, particularly tachyarrhythmias and extrasystoles, may occur. Electrocardiographic (ECG) changes have been associated with inflammation and fibrosis of the conduction system. There is no correlation of ECG abnormalities or their progression with activity of the myositis, and they do not respond to treatment in adults. In children, half of whom may have ECG abnormalities, the abnormalities may resolve with decreased disease activity?7 Holter monitor evaluation may be advisable, particularly in patients with ECG abnormalities. Myocarditis may occur, with resulting congestive heart failure, but is uncommon, found in only 3.3% by Bohan et al,’ although higher rates have been reported.13 Autopsy studies show myocarditis in about one quarter of patients, but cardiac disease may be overrepresented in such studies. Histology may reveal an interstitial and perivascular mononuclear cell infiltrate as in skeletal muscle, replacement fibrosis, and smooth muscle hyperplasia of small vessels?’ Pericarditis is rare in the absence of overlap syndromes. Gastrointestinal Disease Dysphagia is the most common symptom of gastrointestinal involvement. It increases the risk of aspiration and has been associated with a poor prognosis. It may be found in 30% of patients or more at some point in their course” ‘,I3 Dysphagia may result from weakness of the pharyngeal muscles and the striated muscles of the upper part of the esophagus, resulting from inflammation similar to that in other skeletal muscle. Patients often have regurgitation of liquids into the nose with attempted swallowing, hoarseness or nasal speech, or difficulty swallowing when recumbent .4s It usually responds to treatment of the myositis . Dysphagia may also result from abnormalities of the lower esophagus, with decreased motility reported in up to three quarters of patients.50 Heartburn reflux, and stricture may be seen. Gastric emptying may also be delayed. Rarely, other portions of the bowel are affected. Involvement is similar to that in scleroderma, and inflammation is generally not observed. Lower esophageal involvement will generally not respond to treatment, but measures similar to those used in esophageal reflux may be helpful. Cricopharyngeal muscle dysfunction has also been reported in patients with PM/DM, attributed to inflammation and fibrosis of the cricopharyngeus muscle. The patient has a “blocking” sensation and may cough when swallowing. This dis147

tinctive dysphagia will not respond to treatment of the myositis and may require surgical myotomy.4g In children, vasculitis affecting any part of the intestinal tract may occur, leading to ulcerations, bleeding, and perforation?1 This is an important cause of mortality. It appears to be very rare in adults. Other Diseases Retinopathy may occur in tion of vasculopathy in the with cotton wool spots, disk pigmentary changes. Visual

JDM5’ as a manifestaoptic disk and retina, swelling, and macular recovery is variable.

MYOSITIS AND MXLIGNANCY Reports of the association of DM with malignancy are frequent, and there is generally believed to be an association in some patients. Patients with malignancy are considered separately in most classification systems because of the possibility of an etiologic relationship, although the relationship between the DM and the malignancy is not known. There is not believed to be an association of JDM with malignancy. A review of recent reports found malignancy in 20.4% of DM patients and 13.2% of PM patients, with a rate of 14.9% overall in adults.53 Most individual studies also find a higher rate in DM than in PM, with DM found in about two thirds of patients with myositis and malignancy.54 The most common cancers in the general population, lung and breast, are also the most common in patients with PM/DM. However, there are some indications of an increased frequency of ovarian tumors and possibly stomach tumors. Nasopharyngeal carcinoma is more common in Asia, but it is also more common in the general population.55 Malignancy may be antecedent, concurrent, or subsequent to the onset of DM. The activity of the myositis or the skin lesions does not necessarily follow that of the malignancy, but such a relationship is sometimes seen. Failure of the DM to respond to treatment may increase suspicion of occult malignancy, but response of DM to treatment does not exclude malignancy, and the DM should be treated even if an associated malignancy cannot be removed. Cases in which the skin lesions and/or myositis have responded to tumor removal have occurred, but this is often not seen.55, 56. Exacerbation of DM may occur with tumor recurrence. Feldman et alz6 found an association between cutaneous vasculitis (periungual lesions, digital infarcts) and an increased frequency of malignancy. 148

Basset-Seguin et al?’ found an association in adult DM between malignancy and cutaneous necrosis, i.e., eroded or ulcerated lesions on erythematous or violaceous indurated plaques. An association of malignancy with vasculitis was not seen by Ramirez et alz7 or others. In addition, “malignant erythema,” a fiery red, more extensive erythema that has been associated with malignancy and might indicate the need for a more extensive evaluation, is rarely seen.54 Malignancy is less common in connective tissue overlap syndromes; none of 32 patients of Bohan et al. with overlap syndromes had malignancy.’ Patients who have antisynthetase autoantibodies such as anti-Jo-l also have a low frequency of malignancy. Malignancy occurs in about 10% of patients with anti-Mi-2 antibodies; the higher rate compared to anti-Jo-l may relate to the strong association of anti-Mi-2 with DM. Details of some individual cases of concurrent malignancy and myositis may be very suggestive of an association, and the consistent trend toward a higher rate in DM than PM is also supportive. However, the association has not been firmly established by controlled studies. Most of the studies of malignancy in PM/DM have not compared the frequency to that in control patients. Although prospective studies are not available, at least two studies have looked for statistical confirmation using a case-control method. Surprisingly, Lakhanpal et al.57 were unable to document a statistical assocation. Their comparison of adult PM/DM patients to age- and sex-matched controls did show a higher frequency of malignancy in the PM/DM patients (25.2% vs. 17.4%), but this difference was not significant, nor were individual differences in antecedent, concurrent, or subsequent malignancies. Retrospective analysis did reveal an increase during the first 3 years subsequent to myositis onset, but its statistical validity was not establishedY3 Manchul et a15’ compared 71 adult PM/DM patients to a group with other rheumatic diseases and a second group with noninflammatory rheumatic disease. PM/DM patients had more total antecedent and concurrent malignancies (21.1% ) than either inflammatory (5.6%) or noninflammatory (1.4%) disease controls, with the greatest difference in concurrent malignancies. However, no difference was seen in subsequent malignancies occurring later than 6 months after the onset of myositis. The PM/DM patients had more testing for malignancy than the controls, which may have affected the results. Similar methods applied to more homogeneous subpopulations of patients might identify more convincing associations with malignancy. Studies of adult DM patients without Curr

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1991

PM or overlap patients usually show a higher frequency of malignancy.28J 56J5g Extensive testing to discover an occult ma@ nancy in patients with a new diagnosis of PM/DM has often been performed, particularly in older adult patients with DM. However, given current estimates of excess malignancies, many have questioned this practice. Several studies have found a low yield with screening for malignancy with expensive and/or invasive testing in patients with no abnormalities on routine studies. A good baseline evaluation in all patients is important, including a complete and careful history and physical examination. A careful review of systems, stool occult blood testing, breast examination with screening mammography, and pelvic examination with Papanicolaou smear in women and testicular examination in men should be performed. In some reported cases, associated ovarian tumors were small and were missed on routine examination, so particular attention is needed.5s All patients should have baseline laboratory testing including complete blood counts, blood chemistries, urinalysis, and chest radiograph. Any abnormalties should be pursued. In the absence of abnormalities, further testing should be selective and should be reserved for those expected to be at higher risk.55 The features that have been associated with increased risk of malignancy are listed in Table 4, with the highest risk in those over 4.5 years of age with DM rather than PM and without connective tissue disease overlap or autoantibodies, particularly if response to therapy is less than expected?3 CONNECTIVE TISSUE OVERLAP SYNDROMES

DISEASE

Patients with SLE, scleroderma, drome can have an inflammatory

or Sj6gren’s synmyopathy that is

Associated

With Malignancy

Age over 45 years Resistance to treatment Absence of signs of connective tissue disease, including absence of autoantibodies* Previous malignancy Cutaneous involvement (dermatomyositis as opposed to polymyositisi Malignant erythema eUtaneOUS vasculitis in adultst Cutaneous necrosis in adults* *Presence of autoantibodies or connective tissue disease does not exclude

malignancy,

TFeldman et aIF6 *Basset-Seguin et aIT CUIT

Probl

Dermatol,

DIAGNOSIS Diagnosis in patients with DM is considerably easier than in patients with PM because of the skin findings and particularly the combination of skin and muscle disease. PM may be more heterogeneous. The diagnostic criteria of Bohan and Peter,’ listed in Table 5, have been widely used in clinical studies and practice. Physical examination, CK level, electromyography IEMG), and muscle biopsy are used to establish the presence of a compatible myositis. In patients with DM, the characteristic rash is also a criterion. Conditions that can be confused with PM/DM must be excluded. While not a criterion, myositis-specific antibodies can greatly aid in diagnosis. ZABORATOAY Creatine

TABLE 4. Features

indistinguishable from PM or DM, fulfilling diagnostic criteria for both PM/DM and the other connective tissue diseases. Overlap with scleroderma is probably most common.8 This frequent overlap, along with other similarities of the two conditions such as their lung and gastrointestinal tract involvement, may relate to the finding that microvascular change and capillary loss are a major pathogenetic mechanism in both conditions,25 exemplified by the identical nailfold capillary changes in the two conditions. Some patients with PM/DM, particularly those with antisynthetase antibodies, have connective tissue disease features such as Raynaud’s phenomenon, arthritis, or systemic signs, without necessarily having overlap syndromes. Overlap with SLE may be more common in PM/DM patients with anti-UlRNP, and a series of antibodies have been associated with overlap with scleroderma.

1991

Kinase

CK is the most widely used laboratory monitoring parameter since it has high sensitivity and relative muscle specificity, has a general correlation with disease activity, and is readily available. Most patients with PM/DM will have an elevation TABLE 5. Diagnostic

Criteria

for Polymyositis/Dermatomyositis*

Symmetrical proximal muscle weakness Characteristic findings on muscle biopsy Elevated muscle enzyme levels Characteristic findings on electromyography Characteristic cutaneous features ‘Based

September/October

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on Bohan

and

Peter.’

149

of the CK level at the time of the presentation of the myositis, and over 95% will have an elevation at some time during their course.8’13 Some studies have found a lower frequency, 60% to 65% elevation at presentation, possibly related to patient selection. Patients who come to medical attention because of their skin disease tend to have a lower frequency because some will not yet have developed myositis.60 CK is measured enzymatically, and serum inhibitors of CK enzyme activity have been described, apparently released with muscle damage,6l which may account for some cases of active disease with normal enzymes. One study of 7 patients with active PM/DM but a normal CK found that the prognosis was worse than other patients, and that ILD and malignancy were more common than expected.62 Other reasons for elevation of the CK level should be considered when evaluating its significance in a patient with skin changes suggestive of DM63 (Table 6). Strenuous physical exertion can raise the CK level in normal persons. The average CK is higher in men than in women and higher in black patients than white patients. The CK level can rise with strenuous physical exercise or muscle trauma such as that caused by intramuscular injections, electromyography needles, etc. CK may be elevated in a wide variety of conditions other than PM/DM (Table 61, including other myopathies, hypothyroidism, amyotrophic lateral sclerosis, diabetic nephrotic syndrome, and others. Various drugs can raise CK,64’ 65 either by having a direct toxic effect on muscle (alcohol, lovastatin, colchicine, etc.), by inducing an inflammatory myositis (D-pencillamine), or by interfering with excretion of CK (morphine, barbiturates). The CK level is usually not increased in conditions causing simple atrophy, such as disuse, denervation, steroid myopathy, or hyvperthyroidism. The mean initial CK elevation is about ten times normal,‘j greater than that of other enzymes measured. The CK level correlates with biomechanical measurement of muscle strength in individual patients over time.37 The CK frequently rises before or during exacerbations, as a potential warning sign, and falls during remissions. While it usually indicates improvement, a fall in CK can precede recovery of strength by weeks or can occur in response to steroid therapy without remission of the disease. Persistent elevation of the CK usually means that the disease has not gone into remission. CK may be normal in active disease when there is extensive atrophy. Although most of the CK elevation in PM/DM is CK-MM, elevation of the CK-MB fraction may be seen. Normal skeletal muscle contains less than 150

TABLE 6. Differential

Diagnosis

of Polymyositis

and Dermatomyositis

Inflammatory myopathies Infections Retroviruses (human immunodeficiency virus, human T-cell leukemia virus type I) Picornaviruses (coxsackievirus, echovirus in agammaglobulinemia) Other viruses (influenza, adenovirus, hepatitis B, Epstein-Barr virus, etc.) Parasitic (toxoplasmosis, trichinosis, etc.) Idiopathic Inclusion body myositis Other connective tissue diseases Vasculitis Rare forms modular, granulomatous, eosinophilic) Other myopathies Dystrophies Congenital myopathies Metabolic myopathies Neurologic conditions (especially with pure motor manifestations) Myasthenia gravis Amyotrophic lateral sclerosis, spinal muscular atrophy Guillain-Barr6 syndrome Endocrine conditions Hypothyroidism Hyperthyroidism (usually without creatine kinase elevation) Cushing’s syndrome Parathyroid disease Diabetic neuropathy Hypokalemia Drugs Alcohol Anesthetics (malignant hyperthermiai Antimalarials (vacuolar myopathy) Colchicine (neuromyopathy with increased creatine kinasel Corticosteroids Cyclosporin Drugs of abuse (cocaine, heroin, etc.) Lipid-lowering agents (especially lovastatin combined with cyclosporin, gemfibrozil, clofibrate, or niacin) o-Penicillamine (autoimmune polymyositis/dermatomyositisl Zidovudine (mitochondrial myopathy, may contribute to myositis)

4% CK-MB, while cardiac muscle is 20 to 30% CKMB. The CK-MB fraction may increase in chronically stressed or regenerating skeletal muscle, and the CK-MB elevation in PM/DM is generally felt to arise from this source. While myocarditis can occur in PM/DM, large studies have found no correlation of CK-MB and cardiac involvement,1z’13 and Curr

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1991

CK-MB elevations have been found of cardiac involvement.

in the absence

Other Enzymes Aldolase, lactic dehydrogenase, and transaminases are commonly elevated in PM/DM, but usually not by as much as CK. Occasionally, the aldolase or one of the other enzymes will be elevated as a result of PM/DM without elevation of the CK and will therefore be helpful in disease monitoring. Almost all patients with active myositis will have elevation of at least one enzyme at some point in their course.8’ l3 Lactic dehydrogenase and transaminases are widely distributed, and elevations are of less diagnostic significance than that of CK. Other Muscle Factors Creatine UV-[aminoiminomethyl]-N-methylglytine) is produced in the liver, pancreas, and kidney and is taken up by the muscle from the circulation. Creatine excretion rises with muscle disease, due to defects in uptake and retention, and measurement of 24-hour urinary creatine or the creatine : (creatinine + creatine) ratio has been used to detect muscle disease and monitor activity. Urinary creatine is even less disease specific than CK, since all diseases that reduce muscle mass cause elevated creatine excretion, even if they are not primary myopathies. However, it is elevated in most cases of PM/DM and was more sensitive than CK in some studies”, 6G It can be used for monitoring disease activity in patients without CK or other enzyme elevation, although fixed elevations may occur due to atrophy. Myoglobin is detectable in the serum of most patients with active PM and DM, including some with a normal CK.67 Like the CK, it tends to rise with exacerbations and fall with remissions. It also can be used to follow disease activity. It should be measured at a standard time during the day because of diurnal variation. It is unusual for myoglobin to be released in such large amounts as to lead to acute renal failure, as in rhabdomyolysis, but it can occur. Autoantibodies The presence of autoantibodies can be helpful in diagnosis, favoring PM/DM over other myopathies or neuropathies. The absence of autoantibodies does not exclude the diagnosis. Serum autoantibodies as determined by indirect immunofluorescence on HEp-2 cell substrate are positive in 60% to 80% of patients with PM/DM6’ (Fig 6). Some patients will have anti-Jo-l or other specific antibodies despite negative indirect immunofluorescence. A high proportion of JDM patients have Curr

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FIG 6. A. Indirect immunofluorescence on HEp-2 cells with anti-Jo-fpositive serum, showing the typical cytoplasmic fluorescence pattern seen with many, but not all, anti-Jo-l sera. (Original magnification, x 400.) B. Indirect immunofluorescence on HEp-2 cells with anti-Mi-2-positive serum, showing the nuclear pattern sparing the nucleoli that is typically seen with all anti-ML2 sera. (Original magnification, x 100.)

antinuclear antibodies by indirect immunofluorescence when tested early in the course. Autoantibodies are somewhat less common in myositis with malignancy. The presence of myositis-specific antibodies is strongly supportive of a diagnosis of PM or DM and can be valuable in patient classification and in identifying risks of associated complications, such as ILD. Other Tests In patients with JDM, levels of factor VIII-related antigen (van Willebrand factor) have been used as a measure of vasculitis. They are elevated in a wide variety of conditions and are not useful for diagnosis, but may be helpful in monitoring disease activity, especially when CK is normal. They were found to correlate with active skin vasculitis better than does CKGs and were not corre151

lated with sedimentation rate, C-reactive protein, or CK. Neopterin levels also correlated with disease activity in JDM and are felt to represent macrophage activation.32 In patients with PM/DM without associated conditions, most routine laboratory studies are usually normal. The sedimentation rate is elevated in about half the cases, but there is a poor correlation with disease activity or response to treatment. The rheumatoid factor is positive in about 20%,~ most commonly in the overlap group. Circulating immune complexes have been reported,70 but their significance is unclear and their clinical usefulness is doubtful. Due to myoglobinuria, the urine may show a positive dipstick test for blood with no cells on microscopy.

than expected, indicating that more muscle fibers than normal are required to achieve a given force. In addition to these expected signs of myopathy, three quarters of patients may also show increased insertional activity and spontaneous activity with the muscle at rest8 Fibrillations and positive sharp waves are common. These can signify denervation, but in myositis they have been attributed to damage to intramuscular nerves or motor end plates by inflammation, or to segmental muscle fiber necrosis, denervating the fiber beyond it.73 One third to one half of patients show complex repetitive discharges (bizarre high-frequency discharges) that have been attributed to inflammatory damage to the sarcolemma. The spontaneous activity can subside with treatment.

ELE CTROMYOGRAPHY

The EMG is abnormal in approximately 90% of active PM/DM cases. EMG cannot establish the diagnosis with certainty, but the expected constellation of findings can support it. EMG and nerve conduction studies can also help to exclude many neuropathies and certain myopathies that may be confused with PM and DM. Although a muscle subjected to EMG testing should not be used for biopsy because of needle trauma, it can help to direct a biopsy to areas of disease activity by demonstrating involvement of the contralateral side. In a patient with cutaneous findings of DM and an elevated CK level without weakness, EMG may help reveal subtle muscle involvement. The distribution of abnormalities demonstrated by EMG should follow the typical pattern of symmetrical proximal muscle involvement. Involvement of the paraspinal muscles is particularly common, and occasionally, the EMG may be normal in the extremities but abnormal in the paraspinal muscles.’ The full picture of inflammatory myopathies includes (1) myopathic abnormalities of the motor unit action potential; (2) a myopathic recruitment pattern; (3) increased insertional activity; and (4) increased spontaneous activity. Nerve conduction and repetitive stimulation tests should be normal. Most patients with active myositis have lowamplitude, short-duration motor unit action potentials, characteristic of muscle disease.71’ 72 An increase is seen in polyphasic potentials and complex potentials with increased turns, attributed to asynchronous firing of individual fibers. In chronic disease, long-duration, high-amplitude polyphasic potentials may appear. As in other myopathies, EMG shows early recruitment and a full interference pattern with less voluntary force 152

IMAGING Magnetic resonance imaging (MRI) of muscles can reveal areas of inflammation in PM/DM. T,weighted images are most sensitive and may show abnormalities when T,-weighted images are normal. Variation in intensity can be seen between different muscles and within muscles, reflecting the patchy nature of the disease. In MRI of the thigh in four patients with DM, Park et al.74 found the most activity in the vastus lateralis. There was no visible activity in the rectus femoris and biceps femoris, but mild involvement of these muscles could be detected quantitatively. Follow-up studies have indicated that the findings may return to normal with remission and that continued abnormalities may be an indication of disease activity.75 Localization of abnormal areas by MRI imaging may help direct the biopsy to areas of more severe involvement. 31P magnetic resonance spectroscopy can measure various phosphate metabolites in the muscle and is used in myopathies to assess energy utilization and reserve. The ratio of inorganic phosphate to phosphocreatine (Pi/p01 rises in most myopathies. The P,/PCr rises in PM/DM and is correlated with disease activity.76 Park et al.74 found that the P,/PCr was elevated at rest in four DM patients, attributed to a drop in PCr, and that PCr decreased further with exercise, with delayed recovery to baseline. Adenosine triphosphate (ATPI was also decreased at rest and fell with exercise in the severely affected patients. These abnormalities may be more evident in PM than in DM.76 Muscle pH was elevated in PM, but one patient with acute DM had markedly decreased pH. While these abnormalities would not be helpful in diagnosis, 31P spectroscopy may have value in monitoring disCm-r

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ease activity and may have potential research applications. The usefulness of MRI imaging and 31P spectroscopy is limited because of their high cost, but there are situations in which additional information concerning disease activity could influence treatment decisions. Technetium 99 uptake is increased in muscles affected by active myositis but must be differentiated from uptake in bone. Gallium 67 scanning has been used to detect focal processes such as Lyme myositis. Anti-myosin labeled with indium 111 will bind to exposed myosin in necrotic muscle and has been used for imaging cardiac muscle in myocardial infarction or myocarditis, and it is positive in DM in the extremities.77 Plain radiographs can detect the calcifications described above, commonly found in JDM in the soft tissues. An unusual type of calcium deposition, calcium-laden fluid (“milk of calcium”) in the subcutaneous and intermuscular areas,78 may not be visible on radiography, but can be demonstrated on ultrasound, which can also guide aspiration of the fluid. PATHOLOGY CuLmeous There are no pathognomonic histologic features of the cutaneous lesions of DM, and while it can support the clinical impression, biopsy generally cannot establish the diagnosis. Skin overlying the muscle biopsy, if not clinically involved, is usually normal, and the biopsy should be taken from lesional skin. Skin biopsies from patients with DM are usually taken from the lesions on the upper torso or extremities, the erythematous eruption that may develop into poikiloderma. These lesions show vacualar degeneration of the basal cell layer, periodic acid- Schiff (PAS)-positive basement membrane thickening, and hyperkeratosis.33 There is flattening of the epidermis with atrophy. Upper dermal edema may be seen, often with increased dermal mucin, predominantly hyaluronic acid,7s that may become clinically evident. A sparse mononuclear cell infiltrate, usually diffuse but sometimes perivascular, may be seen in the upper dermis and along the dermal-epidermal junction.33 In the poikilodermatous stages, vascular dilation and telangiectasia are prominent, pigment incontinence may be seen, and there is more epidermal atrophy. The histologic changes in Gottron’s papules are similar to those in other areas, including liquefaction degeneration of the basal layer, PAS-positive basement membrane thickening, dermal mucin deposition, and a sparse mononuclear cell infilCur-r Probl

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trate. However, they differ in that acanthosis and mild papillomatosis, usually absent in other areas, are commonly seen, and epidermal atrophy is less common.80 As with the poikilodermatous lesions, the biopsy is sometimes helpful in diagnosis but is not specific. The histologic findings in DM may closely resemble the findings in SLE, making it difficult to distinguish these conditions. The infiltrate is usually less extensive in DM, although the amount of infiltrate in DM is variable.‘* Dermal mucinosis is more consistent and more prominent in DM than in SLE, and epidermal change tends to be less in SLE. By electron microscopy, the endothelial cells in DM lesions may show tubuloreticular inclusions” similar to those in the muscle endothelial cells,83 particularly in JDM, but also in some cases of adult DM. Neither these nor other ultrastructural changes in the skin are pathognomonic. Deposition of immunoglobulin in the skin, as detected by immunofluorescence, is inconsistent, without specific findings, and much less prominent than in SLE.84 In patients without SLE overlap, lupus band formation in nonlesional skin does not occur. In biopsies from lesional skin, focal granular deposition of immunoglobulins and C3 at the dermal-epidermal junction may sometimes be seen, usually of low intensity and not specific.85 This may be more common in skin taken from a band nailfold lesionss6 In a small proportion, may develop,818 84, 85,87 occurring in 5% in one study? Nonspecific immunofluorescence was seen more commonly, detected in the dermal connective tissue, dermal nuclei epidermal cytoplasm, or subepidermal cytoid bodies in 44% of lesional biopsies. Muscle Biopsy.- For idiopathic inflammatory myopathies in general, muscle biopsy can provide the most convincing evidence supporting the diagnosis, and can definitively exclude certain other conditions that can be the source of diagnostic confusion. Most adults in whom the diagnosis of DM is considered should have a muscle biopsy. Confidence in the diagnosis is important when patients will be treated with long-term high-dose steroids, and possibly immunosuppressive agents. This is more controversial in children; some authorities would not require muscle biopsy in typical cases, although others feel there is important information to be gained that could influence treatment, even when the likely diagnosis is evident3’ Muscle biopsy can be done as an open proce153

dure through a 4- to S-cm incision or as a needle biopsy. With the large sample obtained with open biopsy, there is less artifact and less chance of sampling error and a better picture of the muscle architecture. Complications such as bleeding, infection, and nerve damage are rare, but a significant scar may result.88 Needle biopsy can give adequate information in most cases, while resulting in substantially less morbidity, with three minor complications in 800 needle biopsies in one study.” Multiple specimens may be taken at the same site to minimize sampling error and provide samples for special studies. The lower morbidity allows repeat biopsy to help clarify a confusing clinical situation. The needle biopsy is not adequate for sampling of medium-size arteries, as when polyarteritis nodosa is considered.” It is important to coordinate the procedure with the pathologist for optimal processing and evaluation of specimens. The quadriceps, biceps, and deltoid are often used, with the best information obtained from a muscle with active disease but without end-stage fibrosis and atrophy. Electron microscopy is usually not necessary but can be helpful in excluding other conditions (inclusion body myositis, mitochondrial myopathy, etc.) and should be performed when indications of these conditions are seen on light microscopy. Enzyme histochemistry may be helpful to test for enzyme deficiencies. A4uscZe HistopathoZogy.-In both PM and DM, mononuclear inflammatory cell infiltration may be seen, predominantly with lymphocytes, but also with macrophages, plasma cells, and in some cases, smaller numbers of eosinophils, basophils, and neutrophils. The amount of inflammation varies in different cases. In some cases, no inflammation is seen, which is usually attributed to sampling error. Patients with PM more often show a predominance of endomysial inflammatory infiltration (around the muscle fibers, within the fascicle), typically without perifascicular atrophy, while patients with DM show a predominance of inflammation in perimysial areas (around the fascicle) that may extend into the endomysial areas0 (Fig 7). The inflammation may be prominent around small blood vessels, more often venules than arterioles. The DM pattern is often associated with perifascicular atrophy, areas of central myofibrillar loss, and microvascular changes. Although the predominance of the patterns in DM or PM has been supported by quantitative studies,‘l there is considerable overlap of patterns, and they do not strictly separate according to DM or PM. 154

FIG 7. Muscle specimen from perimysial inflammation.

a patient (Original

with dermatomyositis, magnification, x 400.)

showing

The pattern of perifascicular atrophy, decreased size of the fibers along the periphery of the fascicle, has long been recognized as characteristic of idiopathic inflammatory myopathy, although it is not specific (Fig 8). This pattern of atrophy is frequently attributed to microvascular damage and capillary loss and may relate to the more intense infiltrate in the perimysial area. Perifascicular atrophy is seen most commonly in JDM (90%) and frequently occurs in adult DM (50%), but it is uncommon in PM. Necrosis of individual muscle fibers may be observed in the muscle, particularly in PM. They may

FIG 8. Muscle specimen from a patient with dermatomyositis, showing a cross-section of fibers at the edges of adjacent fascicles. Considerable atrophy is seen in the fibers bordering the edges of the fascicles (perifascicular atrophy). Less atrophy is seen among those fibers further in. This pattern is very common in biopsy specimens from patients with juvenile dermatomyositis and is also seen in adult dermatomyositis but is less common in polymyositis. (Original magnification, x 400.) Curr

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be affected in all or part of their length and appear swollen, with homogeneous contents rather than the normal striations of the contractile proteins. They may be invaded by mononuclear cells, and phagocytosis may occur. In childhood DM, necrotic fibers distributed through the muscle are uncommon, but necrosis may be seen in the periphery of the fascicle and in grouped clusters suggesting infarcts. Regeneration is also usually seen, with fibers showing sarcoplasmic basophilia, large vesicular internalized nuclei, and prominent nucleoli. With chronic disease, variation of fiber size, increased interstitial connective tissue and fibrosis, increased fat, and type II fiber atrophy may occur. Type II atrophy is common after corticosteroid treatment. The vasculopathy, with endothelial cell damage and capillary loss, is most evident in childhood ~~,83, 9.2 but vascular changes may also occur in adult DMT3 By electron microscopy, endothelial cells may show swelling and hyperplasia, with vacuolization as well as necrosis, degeneration, and regenerations4’ s5 Capillary thrombosis and obliteration are evident. Decreased capillary density and decreased capillaries per muscle fiber are seen in quantitative studies in JDM and adult DM but not in PM.93, g6 Frank necrotizing vasculitis is not usually seen, particularly in adults, although invasion of the vessel wall may occur. The endothelial cells may contain characteristic tubuloreticular inclusions (“undulating tubules”) ,8% 83, 95 These occur as aggregates of 25- to 2%nm tubular structures, arranged in an intermeshed network, often surrounded by endoplasmic reticulum. They had been thought to be viral structures but are now believed to be a degenerative change reflecting endothelial cell damage that can be induced by interferon alfa. Ring-shaped cylindric confronting cisternae have been described in severe casess2 Inclusions may be found in endothelial cells of other tissues affected by DM, including the skin, lungs, and synovium, and may be found in lymphocytes, macrophages, and other cells. These structures are prominent in JDM and also occur in adult DM. They are generally not found in PM but may be seen in lupus-associated myositis. Their presence outside muscle is less specific and may be found in other autoimmune diseases, viral infection, lymphoproliferative disorders, and acquired immune deficiency syndrome (AIDS) .” Other than endothelial cell changes, electron microscopic changes in the muscle fibers in DM are generally nonspecific. Reduplication of the basal lamina around muscle capillaries may be prominent9’ Cur-r Probl

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DIFFERENTIAL

DZAGNOSZS

Before the diagnosis of PM or DM can be established using the criteria of Bohan and Peter,l other conditions that may resemble PM/DM must be excluded. Conditions to consider include other forms of myositis, other myopathies, certain forms of neuropathy, drug-induced conditions, and endocrine disorders (Table 6). The presence of connective tissue disease features or autoantibodies can help to support the impression of PMDM rather than other neuropathies or myopathies. Other Neurologic Conditions Of the neuropathies, disorders that present with exclusively motor disease in a diffuse pattern are most likely to be confused with PM/DM. Distal involvement may suggest a neuropathy or inclusion body myositis. Involvement of the extraocular or facial muscles and a picture of decreasing strength with repeated effort may be clues to myasthenia gravis. Fasciculations and atrophy may suggest motor neuron diseases. EMG can be helpful in excluding neuropathies. Myopathies A family history of myopathy is an important clue in detecting genetic diseases, including dystrophies or metabolic myopathies such as glycogen storage diseases. An episodic pattern of weakness, or prominent cramping, may be a clue to metabolic myopathies. However, the crucial test in distinguishing PMDM from these conditions is muscle biopsy. Biopsy can usually detect abnormal structures in congenital myopathies (nemaline rod myopathy, central core disease, and others), and ragged-red fibers in mitochondrial myopathy, which can be confirmed with electron microscopy. Metabolic myopathies such as enzyme deficiency diseases (myoadenylate deaminase, myophosphorylase, phosphofructokinase, acid maltase, etc.) can also be detected by biopsy, using special stains, such as PAS stain to reveal glycogen, lipid stains to reveal lipid accumulation in lipid storage disease, or histochemical stains for specific enzyme activities. If these conditions are a significant consideration, it is important that the appropriate stain be applied to the muscle specimen. Patients with unrecognized myophosphorylase deficiency who have received inappropriate treatment for PM for years have been described.s7 A forearm ischemit exercise test can sometimes be helpful in excluding these conditions.” Biopsy can also be helpful in distinguishing dystrophies, but certain dystrophies such as fascioscapulohumeral dystro155

phy may show some degree can cause confusion.

of inflammation

that

Other Forms of Myositis Infectious A4yositis.- Infectious myositis is of particular interest because some infections may be associated with cutaneous features that can be confused with DM. Several viruses have been associated with myositis. Most important of these are human immunodeficiency virus (HIV1 and human T-cell leukemia virus type I (HTLV-1) (see below). Inflammatory myopathy indistinguishable from PM or DM may be the presenting manifestation of HIV infection.” Weakness, elevated CK, myopathic EMG findings, and inflammation with lymphocytic infiltration and necrosis on biopsy are seen.“’ loo At least two cases with typical DM cutaneous findings have been reported,101’102 with heliotrope, Gottron’s papules, and malar erythema that showed vacuolization of the basal cell layer on biopsy. In some cases, PM or DM was the first manifestation of disease or PM developed prior to treatment. In other cases, an inflammatory myopathy was associated with zidovudine (AZT), possibly resulting from effects on mitochondria.lo3 Some patients have been treated successfully with corticosteroids, while others who developed disease while taking zidovudine responded to its discontinuation. HIV has also been associated with a nemaline rod myopathy that may not be inflammatory.100 Any patients with risk factors for HIV infection should be tested. HTLV-1 has been associated with myositis in several case reports, including one patient who had infection with both HTLV-1 and HIV and developed PM.lo4 Analysis of the muscle showed HTLV-l-associated proteins, but not HIV, in the muscle fiber. Of great interest has been a report suggesting that HTLV-1 infection may be a major cause of PM in areas where it is endemic. Morgan et a1105 studied tropical spastic paraparesis, known to result from HTLV-1 infection, in Jamaica. They noted that among their 100 controls, all seven with PM had HTLV-1 antibodies, while only seven of the other 93 were positive. Study of six additional PM patients showed that four were positive. The PM was clinically similar to idiopathic PM, and none of the patients had other HTLV-l- associated conditions. Although the association with PM was striking, more direct evidence for an etiologic role was not provided. The prevalence of HTLV-1 in PM in other areas appears to be much lower, but HTLV-1 infection should be considered when myositis develops in patients at risk. A syndrome of slowly developing myositis, skin 156

manifestations, and encephalitis has been described in patients with X-linked agammaglobulinemia, apparently caused by chronic echovirus infectionlo An erythematous or violaceous rash may be found on the limbs that is usually transient, but lesions suggestive of Gottron’s have occurred.lo7 The virus can usually be grown from the spinal fluid even when encephalitis has not yet developed. Although the patients are usually already on maintenance immunoglobulin treatment, some have responded to intravenous gamma globulin or specific antibody to echovirus,lo6 but these treatments have not been uniformly successful.108 Hepatitis B has been associated with PMDM-like myositis, including one case with a typical heliotrope and facial rash.l’” Myositis has been associated with infection with other viruses, but these are not typical of PM/DM.ll’ Postinfluenza myositis, for example, usually is manifested by calf myalgias and tends to be self-limited. Coxsackievirus may affect the chest muscles and diaphragm, leading to a self-limited pleurodynia. The role of these viruses in apparently idiopathic PM/DM is the subject of current research. Several cases have been reported in which apparent PM/DM has been associated with evidence of toxoplasmosis, including cases with typical cutaneous features of DM.l” “’ Although recovery with treatment for toxoplasmosis alone has been described,” prednisone has been given in many cases?’ Positive To)toplasma seroloa has been found in a significant proportion of apparently idiopathic PM/DM patients (see below).l13 The possibility of toxoplasmosis should be considered in evaluation of patients for myositis. Trichinosis can cause a myopathy with myalgia and weakness, often with facial swelling and periorbital edema. Extraocular muscle involvement is common, unlike in PM/DM, and there may be a history of ingestion of improperly cooked meat.“’ Bacterial infection can also cause myositis, but it is seldom confused with PM/DM. A focal myositis may occur in Lyme disease.l14 Tropical pyomyositis is an interesting condition in which abscesses, usually due to staphylococci, develop spontaneously in the muscle.115 It is increasingly encountered in nontropical areas, particularly in patients with AIDS. Muscle symptoms are usually local, except in occasional cases with multiple abscesses.l16 Other forms of opportunistic infections may lead to myositis in AIDS patients. Inclusion Body Myositis (ZBM).- IBM is a distinct clinicopathologic entity that is the most common form of idiopathic inflammatory myopathy other than PM and DM,l17 found in 15% to 28% of Curr

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myositis patients. Cutaneous manifestations are not part of the picture of IBM, but it can be difficult to distinguish from PM. It is twice as common in males and typically occurs after age 50 years. The onset of IBM is insidious, and progression is slow. This, plus difficulty in diagnosis, leads to a long period between onset and diagnosis (3 to 6 years). Most IBM patients have proximal muscle weakness, but distal weakness may also occur in half of patients, sometimes greater than proximaly.‘17 The reflexes tend to be depressed, and a small proportion have an associated polyneuropathy. The CK level is usually elevated but less than 10 times normal. The EMG picture is similar to that of PM. Biopsy is required to make the diagnosis.118’11s Light microscopy shows vacuoles rimmed by basophilic material and small eosinophilic cytoplasmic and nuclear inclusions. By electron microscopy, distinctive filaments can be identified in the inclusions. The inclusions are not absolutely specific, but they are not found in other inflammatory myopathies. Other typical findings include gro’uped atrophic fibers and endomysial inflammatory infiltrates of variable severity. Criteria for the diagnosis have been proposed.l17, *18 Although a small number of patients have overlap,12o connective tissue disease features and autoantibodies are uncommon, and myositis-specific antibodies are not seen. IBM is similar to PM in the apparent importance of T-cell-mediated cytotoxicity in pathogenesislzl (see below). It is important to identify patients with IBM because they are much less responsive to treatment, and overtreatment is common if this is not recognized and goals are not adjusted.l” Other Connective Tissue Diseases.-As noted, myositis indistinguishable from PM or DM may occur as part of an overlap syndrome in association with other connective tissue diseases. The myositis is generally treated like PM or DM alone. Other forms of myositis or myopathy have been described with some connective tissue diseases, differing from PM or DM. In scleroderma, in addition to a typical PM overlap syndrome, a “simple myopathy” has been describedlz3 that may occur in a relatively high proportion of patients. It is unrelated to the severity or extent of the scleroderma. There may be mild abnormalities of strength, enzymes, or EMG, and in some cases, low-level aldolase elevations with normal CK. A biopsy may show fibrosis but generally not inflammation. In SLE, in addition to clear overlap syndromes, a PM-like myositis may occur in association with flares of disease activity. Some patients with SLE have prominent myalgias that may represent reCut-r Probl

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ferred joint pain. A vacuolar myopathy has been reported in SLE. In some cases, this has been attributed to antimalarials or steroid therapy, but it has occurred in the absence of such therapy.lz4 Steroid myopathy may also occur. A myositis has been associated with rheumatoid arthritis, characterized by muscle fiber necrosis and interstitial mononuclear cell infiltrates.125 These patients may have prominent systemic features (weight loss, anorexia, fatigue), marked sedimentation rate elevation, but relatively mild synovitis, and often respond to low-dose prednisone (< 12.5 mgi. A small percentage of patients with Sjdgren’s synd?ome have associated PM or DM, although myalgias are more common. Inflammation around small or medium-size blood vessels may be seen, with microvascular injury leading to muscle damage. lz6 Anti-RoSSA and anti-LaSSB are usually present. The CK elevations are often milder than expected. The stiffness and myalgia of polymyalgia rheumatica may at times resemble PM, but there is no muscle weakness, and enzymes, EMG, and biopsy are normal. Rarely, polyarteritis nodosa may be predominantly expressed in muscles, with calf myalgias as the main symptom. A variety of other connective tissue diseases have been reported in association with PM and DM, including Grave’s disease or Hashimoto’s disease, inflammatory bowel disease, celiac disease, dermatitis herpetiformis,‘27 Behcet’s disease,128 etc. Rare Forms of Idiopathic A4yositis.-Other forms of idiopathic inflammatory myopathy have been described, but are very rare.l” A syndrome resembling PM may be associated with noncaseating granulomata in the muscles. Asymptomatic granulomata may be present in the muscle in sarcoidosis, and occasionally, muscle nodules or granulomatous myopathy may occur.13o Eosinophilic myositis may occur either as part of the hypereosinophilic syndrome or as an isolated condition. Several nodular forms of myositis may occur. Of particular interest is localized nodular myositis, which may be associated with features of vasculitis and may go on to become a diffuse PM.131 Drug-Induced Myopathy A medication history is very important because of the long list of drugs that can cause muscle toxicity, myopathy, myositis, or elevated CK leve1.64J65 o-Penicillamine is particularly interesting because it appears to induce an inflammatory myopathy indistinguishable from PM/DM.13’ About one third of patients have skin findings suggestive of DM. The mechanism is unknown, and it is not related to dose or duration of treatment. It usually re157

sponds to discontinuation of the drug, although steroids are often necessary. Cardiac involvement and deaths have occurred.133 It may be more common in Japanese or Asian Indian patients than in white patients (1.2% to 1.4% vs. 0.2% to 0.4%)~~~ Asian Indians had increased DR2 and DQl, while Australian patients had increased DR4, as expected in a population with RA.1328134 Zidovudine plays a role in some cases of HIVassociated myositis. Myositis may be seen with or without zidovudine, but those taking zidovudine show evidence of mitochondrial myopathy in addition to the myositisFo3 Zidovudine has also been associated with myopathy without evident inflammation. In individual cases, it may be difficult to sort out the contribution of the drug to the myopathy. Also of note is colchicine, which causes a neuromyopathy that is often misdiagnosed as PM.135 This usually occurs when usual maintenance doses are used in patients with renal insufficiency. Chloroquine may cause a myopathy marked by vacuolation and curvilinear bodies. Muscle toxicity may occur with lovastatin, particularly when taken in combination with cyclosporin, as after heart transplants, in which muscle toxicity may occur in up to 30% of cases, or with clofibrate, gemfibrozil, or niacin. It may be severe, with rhabdomyolysis. Cyclosporin and the other lipid-lowering agents have themselves been associated with myopathy. Several drugs of abuse, including alcohol, cocaine, and others, may lead to myopathy, CK elevation, or rhabdomyolysis.65 Severe myalgias were a constant finding in eosinophilia-myalgia syndrome associated with L-tryptophan ingestion,136 and significant proximal myopathy was seen in two thirds of cases. The aldolase was elevated in some cases, but the CK generally was not. Mononuclear and eosinophilic interstitial infiltrates were seen, sometimes surrounding blood vessels, but fiber necrosis was rare. There were similarities to the toxic oil syndrome that occurred in Spain.

Endocrine Disorders Hypothyroidism commonly causes elevated CK levels, with or without weakness, and thyroid function should be tested in all patients in whom myositis is considered. Hyperthyroidism may cause a myopathy, but elevation of the CK level is generally not seen. Several other endocrine abnormalities have been associated with myopathy, such as hypercortisolism, hyperparathyroidism, or Other metabolic derangehypoparathyroidism. ments such as hypokalemia or uremia may also cause weakness. 158

Steroid Myopathy Use of corticosteroids, especially in high doses for extended periods, may lead to proximal muscle weakness. This appears to be the result of accentuated type II muscle fiber atrophy. In PM/DM, this poses a special problem because it can be confused with exacerbation of the underlying disease. Elevation of the CK level would suggest reactivation of disease, since it is usually normal in steroid myopathy, but the CK can be normal in active disease. The urinary creatine rises in both PM/DM and steroid myopathy.137 The increased spontaneous activity usually seen on EMG in active PM/DM is usually absent in steroid myopathy. This is sometimes helpful, but again is not reliable. Repeat biopsy, usually a needle biopsy, can show inflammation indicating active disease, but a negative biopsy may result from sampling error. Ultimately, a trial of decreasing the dose is often necessary (assuming there is no life-threatening situation), which should lead to improvement in steroid myopathy. Steroid myopathy may develop while disease activity is still present, indicating the likely need for the addition of a steroid-sparing medication. Presentation Without Muscle Involvement As noted, the cutaneous features often precede the muscle disease, and patients may present prior to muscle involvement. It is difficult to confirm a diagnosis of DM without muscle involvement, and the Bohan and Peter criteria1 cannot be met. We have identified one such patient who had the DM-specific anti-Mi-2 autoantibody, which helped to establish the diagnosis, but this is unusual. A patient with apparent cutaneous DM with no sign or history of myositis requires careful follow-up, including serial CK measurements and strength testing, so that treatment directed at the myositis can be initiated early if necessary. It is important to exclude other causes. Lupus is most often a consideration. Psoriasis may be considered for the lesions over the extremities. Other causes of poikiloderma, such as other connective tissue diseases or mycosis fungoides might also be considered. In some patients, ILD or arthritis may be the first manifestation of disease, and may occasionally develop years before the myositis. Elevated CK levels may be an early sign of muscle involvement.

ETIOLOGY

AND PATHOGENESIS

Several lines of evidence implicate autoimmunity in the pathogenesis of PM and DM. SuggesCurr

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tions of autoimmunity include the inflammatory pathologic picture; the presence of features typically associated with other connective tissue diseases such as Raynaud’s phenomenon or arthritis, as well as the presence of overlap with other connective tissue diseases; and the responsiveness to corticosteroid and immunosuppressive treatment. The findings of humoral and cellular immunologic abnormalities, including disease-specific autoantibodies, have strongly supported this concept. The etiologic factors leading to this autoimmune response remain unknown, but genetic predisposition seems to be important. A likely scenario is that one or more etiologic agents act in a genetically susceptible host to initiate an autoimmune response that becomes directed at muscle fibers, endothelial cells, fibroblasts, or other targets. A number of potential triggering factors have been suggested: infections, toxins, malignancy, and muscle injury. POTENTIAL

ETIOLOGIC

FACTORS

Infections Recent interest has centered around the possibility that viral infection might incite the immune response. Persistent infection might be necessary to perpetuate the autoimmune response, or a virus might initiate an immune response that becomes self-perpetuating even after the virus is eliminated. Various mechanisms have been proposed that could lead to viral-induced autoimmunity.1”8 Examples include: molecular mimicry, in which an immune response to a virus cross-reacts with muscle cell protein; exposure of normally hidden antigens or abnormal presentation of proteins; chronic infection with expression of viral antigens on muscle fibers, capillary endothelial cells, or other cells; disruption of immune regulation, eitber through induction of the production of interferon or other cytokines or through effects on key cells or functions, as with HIV infection. Two classes of viruses are currently receiving the most attention as possible etiologic agents: picornaviruses and retroviruses. Picornaviruse.s.Picornaviruses are small RNA viruses that include the enteroviruses (coxsackievirus CCVI, poliovirus, echovirus, etc.) and other human and murine viruses (encephalomyocarditis virus, Theiler’s murine encephafomyelitis virus, etc.). CV and several other picornaviruses have muscle tropism, a tendency to infect muscle. CV or echovirus infection can lead to rhabdomyolysis, epidemic pleurodynia, or acute viral myocarditis as expressions of this tropism,l” and is a suspected Curr

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cause of chronic myocarditis. Chronic echovirus DM that occurs in agammaglobulinemia, discussed above, indicates the capacity of such viruses to lead to PM/DM-like disease. A chronic myopathy appeared to result from CV-A9 infection,13’ and other case reports have associated CV with myositis. Thus, CV and other picornaviruses can cause acute and chronic muscle infection and myositis. Mouse models demonstrate the capability of CV and encephalomyocarditis viruses to lead to a PMlike inflammatory myositis.140, I41 The development of myositis in these models requires particular strains of virus and genetic susceptibility of the mouse, including at the major histocompatibility complex. The models demonstrate further that the myositis can progress after the virus can no longer be recovered from the muscle or detected in muscle by conventional methods,14z although recent studies suggest that viral nucleic acid, detected by in situ hybridization, may remain for at least part of the time. CV-induced myositis requires cellular immunity, since mice that were genetically deficient in cellular immunity did not develop myositis,143 but would develop myositis if first given spleen cells from uninfected immunocompetent mice. CV can also induce chronic myocarditis in animal models. These models remain a major avenue for study of the viral hypothesis. For these reasons, efforts have been made to determine whether picornaviruses were responsible for idiopathic PM and DM. There was a suggestion of this from studies of viral antibody titers.*” Christensen et al? found that ten (8%) of 12 JDM patients tested within 4 months of onset of disease had antibody to coxsackie B virus, while antibody was found in only 25% of juvenile rheumatoid arthritis or normal children. Titers to other viruses were not significantly different among the groups. More direct evidence of viral infection of muscle has been difficult to obtain. Early studies reported that picornaviruslike structures could be identified in muscle from patients with PM by electron microscopy, but later studies questioned whether these structures were viral in origin. Efforts to grow CV from muscle of patients with typical PM or DM, or to demonstrate the presence of CV or other picornatiruses or viral proteins in the muscle in a direct manner, had been unsuccessful. However, a series of recent studies looking for the presence of viral nucleic acid in the muscle by hybridization with complementary DNA probes have been more encouraging. This method has advantages in that it can detect evidence of virus that is present in incomplete form and is unable to grow or produce protein, and the probes can cross-re159

act with related viruses that may not react with antiviral antibodies. The increased sensitivity was demonstrated in the encephalomyocarditis mouse model, in which virus could be detected by in situ hybridization at a point when it was not evident by conventional means despite continued worsening of myositis.14’ Similar results were recently obtained in the CV-B mouse model. Bowles et al:& found evidence of CV RNA by blot hybridization with extracts of muscle biopsies from five of nine PM/DM patients, but none of ten controls. Four of seven JDM patients were positive, including three of four tested within 5 months of disease onset. Two recent studies examined this question with in situ hybridization, which can localize viral genetic material in the muscle. Yousef et al.,145 using an enterovirus probe derived from CV-B3, demonstrated hybridization within muscle fibers in biopsies from six of 11 PM patients but not in two DM biopsies or 13 control biopsies. Viral protein was not found immunologically in the positive biopsies. There was no clinical difference between patients with hybridization-positive or -negative biopsies. Different results were reported by Rosenberg et al,,146 who studied biopsies from 19 PM/DM patients and 14 patients with other diagnoses. They found no positives with a CV-B3 enterovirus probe or with a poliovirus probe. Surprisingly, however, a probe for Theiler’s murine encephalomyelitis virus, designed to be a control because it recognized mouse virus RNA, did show hybridization with three of the 33 biopsies, all three of which were from the five adult DM patients tested. This raised the possibility that a new picornavirus related to Theiler’s murine encephalomyelitis virus might be important in adult DM. Most of the hybridization was with macrophages, which may have implications for pathogenesis. The limitation of positives to adult DM cases, a high proportion of which were positive, supported the specificity of the finding. However, the reactive material in the muscle has not been further characterized, and confirmation and additional studies are needed. The possible role of picornaviruses in idiopathic PM or DM remains a subject of active investigation. Retrotiruses.-As noted above, human retroviruses such as HIV and HTLV-1 have been associated with conditions closely resembling PM or DM, including cases that appeared to be idiopathic PM.*05 HIV itself has not been identified in intact muscle fibers, although it may be found in cells infiltrating muscle or necrotic muscle. It is not yet clear whether HIV causes myositis directly or whether it potentiates the development of idio160

pathic myositis by allowing a second infection or by disturbing immune regulation. In view of the major role of CD8+ lymphocytes in PM, the increased ratio of CD8-t to CD4-t lymphocytes in HIV infeciton and AIDS is of interest. Infection of monkeys with the simian retrovirus SRV-1, which can cause an immunodeficiency similar to AIDS, is associated with a PM-like myositis in up to half of cases.147 This retrovirus can infect muscle cells in culture, suggesting that the retrovirus may be playing a primary role. The association of HIV, HTLV-1, and SRV-1 with inflammatory myopathies similar to PM also raises the possibility that idiopathic PM and DM may be caused by an as-yet-unidentified retrovirus, possibly one related to the new retrovirus recently implicated in some cases of Sjogren’s syndrome. Of possible relevance is the finding that a short amino acid sequence of a murine retroviral protein is shared by the 70-kD protein of LJlRNP, a target for autoantibodies in myositis overlap syndromes and SLE, and antibodies may cross-react with these proteins.14’ This suggests that molecular mimicry with a retrovirus may be involved in anti-LJlRNP production. Understanding the mechanism for the association of HIV with PM may provide insight into the etiology and pathogenesis of idiopathic PM. Other Viruses.-As noted above, influenza can affect muscles and cause a transient myositis. In at least one case, influenza B was shown to be responsible for an acute inflammatory myositis in an adult, with demonstration of the virus in the muscle .14’ A possible site of molecular mimicry with the 70-kD protein of LJlRNP and an influenza B virus protein has also been identified. However, involvement in typical PM or DM has not been shown. Adenovirus has been isolated from muscle in a case of IBM,lSo but further evidence implicating adenovirus in IBM has not emerged. Other viruses have been associated with myositis, as noted above (such as hepatitis B, Epstein-Barr, etc.), but their role in the development of the myositis is not hOWlI.

A role for mumps virus in IBM has been suggested based on the resemblance of the IBM inclusions to paramyxovirus inclusions. Reports of reaction of the inclusions with mumps virus antisera have supported this possibility,11s but others have not been able to confirm these results.151 T~~opZasmosis.-Toxoplasma gondii infection has been documented in patients with a clinical picture resembling that of PM or even typical DM, but active Toxoplasma infection cannot be found in the muscle in most typical cases of PM or DM. Phillips et a1.l” suggested that it might be involved Curr

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in some cases in which it is not evident, finding antibodies to Toxoplasma in a higher proportion of patients with PM or DM than in controls, including complement-fixing antibody, suggesting recent infection. Magid and Kagen113 supported this association, finding IgM antibodies to To,xoplasma in half of those PM/DM patients with IgG anti-To)topZasma, also suggesting recent or active infection. This was found more frequently in PM and DM and less frequently in SLE-overlap ,syndromes. A role for To)topZasma in the etiology or pathogenesis of PM/DM in these patients has not been established, and the findings may represent reactivation of infection due to immunosuppressive treatment or muscle damage.ll’ However, some cases of apparently idiopathic PM or DM may result from unrecognized To)topZasma infection.

Other Factors As noted above, o-penicillamine, which can induce myasthenia gravis, pemphigus, and other autoimmune conditions, can induce what appears to be typical PM or DM. The observed association with HLA13’, 134 suggests that this involves an exogenous factor interacting with a genetic predisposition. Other drugs, such as cimetidine and possibly zidovudine, have been associated with inflammatory myopathies, rather than a toxic myopathy, suggesting that exogenous chemicals or other agents might be involved in PM/DM. Assuming a relationship between a malignancy and DM or PM exists in some cases, various mechanisms are possible. The tumor could lead to the development of the myositis by initiation of a specific autoimmune response against muscle, by elaboration of cytokines or other factors causing nonspecific immune enhancement, by disrupting immune regulation, or by immune complex mechanisms. Alternatively, the tumor and the myositis may have a common etiologic agent, such as a virus or toxin, or may have a common predisposition, such as a genetic factor or immunologic abnormality. In a recent large survey looking for possible risk factors, recent heavy exertion was positively correlated with risk of PM/DM.153 Although this may have ,related to a perception of increased effort because of early, unrecognized weakness, a case of classic DM developing 6 weeks after severe rhabdomyolysis suggests the possibility that muscle damage may be involved in some patients.154 The survey found no association with immunization, which had been suggested as a possible risk factor based on case reports, particularly in JDM. Cm-r

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GENETIC FACTORS The genetic background of the patient appears to be important in conferring susceptibility to PM/ DM. PM/DM may develop as an abnormal response to a common environmental trigger in a genetically susceptible host. Injluence of Major Histocompatibility CompZe;u The most consistent genetic association with PM has been an increase in the frequency of HLA-B8 and -DR3. Hirsch et al.,155 comparing PM patients with controls, found a statistically significant increase in the frequency of HLA-B8 (54% vs. 21%) and -DR3 (67% vs. 24%). However, this study did not find an association of these HLA markers with DM. Plotz et al?’ found that DR3 and B8 were associated with both PM and DM in white patients and to a lesser degree in black patients. The association of PM with B8 was also confirmed by other groups. inPachman et al.156 also found a significant crease in B8 and DR3 in JDM versus controls (53% vs. 23% for DR3; relative risk = 3.8 for white children). The genes for complement component C4 are within the major histocompatibility complex, and a deletion of the C4A gene (C4A null) is in linkage disequilibrium with the BS-DR3 haplotype. One recent study of JDM157 found that the C4A null gene was more closely associated with JDM (16 of 20 patients) than BS or DR3, suggesting that the C4 gene was the primary susceptibility factor. Theoretically, a partial complement component deficiency could impair removal of immune complexes or could cause problems with handling viral infection. However, Reed et a1.l” found no independent association with C4 genes when JDM patients were compared to a control group matched for DR3 frequency, and C4 genes do not appear to have a primary association in adults. Reed et al. did find a significant association of JDM with a HLA-DQAl allele 4.0 that was independent of DR3 and may be the primary susceptibility factor. Strong associations have also been noted between specific autoantibodies and HLA. The frequency of HLA-DR3 is higher among patients with anti-Jo-l than among PM/DM patients without anti-Jo-l (64% vs. 22% ).15’ Using restriction fragment length polymorphisms to determine HLA type,160 the association of anti-Jo-l with DR3 was confirmed among white patients but not black patients. However, the supertypic marker HLADRw52, which is seen in association with the DR antigens DR3, DR5, DRw6, and DRw8, was found in all patients who had anti-Jo-l or any other anti161

synthetase autoantibody. This implied that a portion of the DRPl chain was crucial for the production of antisynthetases. A strong genetic influence on the production of anti-PM-SC1 has also been demonstrated. Genth et al. in GermanyZ61 found that the frequency of HLADR3 was significantly higher in patients with antiPM-Scl than in controls, finding DR3 in all 12 antiPM-Scl patients (100% vs. 23.5%; P < .OOl). This contrasted with patients with anti-Scl-70 (antitopoisomerase Ii and anticentromere, other autoantibodies associated with scleroderma, who did not have an increase in DR3. When the DR3 was found in association with DR4 in anti-PM-SC1 patients, a higher frequency of arthritis was found (83% vs. 17%). Patients with antisynthetases or anti-PM&l may account for a significant part of the increased frequency of DR3 in PM/DM, but other myositis-specific antibodies have been associated with other DR antigens (anti-signal recognition particle with DR5 and anti-Mi-2 with DRT and DRw53).

Canine DM Also of interest with regard to possible genetic factors contributing to myositis is a condition resembling DM that occurs in juvenile collies and Shetland sheep dogs and has autosomal dominant inheritance with variable expressivity.162 Myositis can be demonstrated by EMG and muscle histology, but it differs from human DM in that the distal muscles are primarily affected and the muscle enzymes are not increased. The periorbital areas, face, distal extremities, tip of the tail, and ears may develop erythema, scaling, alopecia, ulceration, and hyperpigmentation or hypopigmentation. Vesiculation also occurs in some dogs, and the condition is felt to resemble or be identical to canine epidermolysis bullosa. It can resolve after 3 months or go on for an extended period. The myositis usually begins after the dermatitis and is proportional in severity. The temporalis muscle may be affected first, and atrophy is prominent. The muscle shows inflammation, sometimes with vasculitis, necrosis, regeneration, and atrophy. Lymphadenopathy and elevated IgG and circulating immune complexes have been reported, but serologic tests are usually negative, and deposition of IgG in the skin is usually not seen. While it has significant differences from human disease, it most closely resembles JDM and may serve as an animal model. The mechanism by which genetic factors contribute to development of this condition is not known but may have implications for human myositis. 162

PATHOGENESIS There is increasing information regarding the immunologic mechanisms of muscle damage in PM and DM. Both humoral and cellular autoimmune responses are seen. The contribution of cellular immunity to muscle fiber damage in PM and in IBM is becoming increasingly clear. In DM, humoral mechanisms may be more important, and vasculopathy is prominent. This is most consistently observed in JDM, but is also important in adults. Autoantibodies are common in both PM and DM, including some that are specific for PM/ DM, suggesting important links to fundamental etiologic factors. However, the role of autoantibodies in tissue damage is unclear. Cellular Immunity The importance of cellular immunity in the pathogenesis of PM has been suspected for many years. Evidence has included animal models of cell-mediated immune muscle damage, sensitization of circulating lymphocytes to muscle, cytotoxicity of peripheral lymphocytes against muscle cells, studies of phenotypes of lymphocytes infiltrating muscle, and peripheral lymphocyte subset abnormalities. The potential for cellular immunity to induce myositis was demonstrated in experimental autoimmune myositis, in which a myositis was induced in animals by immunization with muscle homogenates .163 The myositis, which responded to antilymphocyte serum and was transferred with lymphocytes but not serum, was clearly mediated by cellular immunity. Recent studies demonstrating the crucial role of cellular immunity in virally induced mouse myositis were noted above. Early attempts to show the role of cellular immunity in human PM/DM focused on peripheral blood lymphocytes, looking at the responses of lymphocytes to muscle tissue and the effect of lymphocytes on muscle cells?38 Some of the studies did find increased proliferation of lymphocytes from patients with myositis in response to muscle homogenates but not other tissues.164 Proliferation was greater for clinically active and untreated patients, but it was generally of a low level, it was seen in other conditions, and it was not seen in all studies7’ More recently, Kalovidouris et al.165 found significant proliferation in response to autologous or allogeneic muscle extract with lymphocytes from 16 of 21 patients with active DM or PM, but only one of eight who had been treated, three of 10 with other myopathies, and no controls . Early reports found that peripheral blood lymCur-r ProbZ

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phocytes from PM/DM patients showed cytotoxicity for muscle cells in culture, as assessed by microscopic examination and release of muscle factors.164, 166 The lymphocytes could be observed to selectively attach to muscle cells and to invade and destroy them.‘“” When lymphocytes from PM/DM patients were cultured with autologous muscle tissue, the supernatants were cytotoxic for fetal muscle cultures,167 indicating release of a cytokine. However, the studies were not consistent, and cytotoxicity was not completely specific for PM/DM. Concerns were also raised that the lymphocyte cytotoxicity did not require major histocompatibility complex compatibility, and that the effects might result from natural killer cells or other nonspecific mechanisms.70, 163 Other properties of peripheral blood mononuclear cells in PM/DM have also been studied. Camfrom some bridge et al.16’ found that lymphocytes adults with PM had a decreased proliferative response to mitogens compared with unaffected controls. Lymphocytes from patients with JDM did not show a decreased proliferative response, but did show increased spontaneous IgM production, which appeared to be due to increased activated B and T cells. Miller et al.16’ studied the surface markers of peripheral mononuclear cells and found that patients with active myositis had more T cells expressing activation markers than unaffected controls and that this decreased with treatment. Those with DM showed a lower proportion of T cells and of activated T cells and a higher proportion of B cells than those with PM or IBM. These studies are consistent with other evidence suggesting the importance of humorally mediated muscle damage in DM and cell-mediated muscle damage in PM and IBM. Evidence of increased lymphocyte activation is interesting in view of a recent finding of increased serum levels of interleukin (IL)-2 receptor and IL-la in active PM that fall with treatment.170 Recent studies characterizing the lymphocytes in the inflammatory infiltrates in muscle using monoclonal antibodies to multiple cell surface markers have been very revealing. T cells are prominent in areas of severe inflammation, many of which are activated.171 While CD4+ T cells are most abundant in biopsies from untreated adults with acute disease, the proportion of T cells in the infiltrates decreased with treatment.17’ The proportion of CD4+ to CD8+ T cells and the proportion of activated T cells were both higher in myositis than in noninflammatory myopathies. Arahata and Engel found that in moving from the perivascular to the endomysial area, the proportion of T cells and of the CD8+ suppressor/cytotoxic subset Curr

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increased, while the proportion of B cells and of the CD4+ helper T cell subset decreased.173 In both adult DM and JDM biopsies, the proportion of B cells was higher and the proportion of CD8+ T suppressor/cytotoxic cells was lower than in PM or IBM. Engel and Arahata”’ focused particularly on fibers that were surrounded and invaded by mononuclear cells but were not necrotic, since necrotic fibers are often nonspecifically infiltrated secondarily. This picture suggested that the cells were directly involved in damage to the muscle fiber. Such surrounded and invaded fibers were common in PM and IBM, but were much less common in DM. Among T cells surrounding the fibers, CD8+ cells outnumbered CD4+ cells by 2 : 1, while among invading cells, this ratio was 10: 1. Almost twice as many of the invading CD8+ cells were activated (expressed the DR antigen) as compared to surrounding CD8+ cells. Among CD8+ surrounding and invading cells in PM and IBM, cytotoxic cells outnumbered suppressor cells 4:1, with the ratio increasing with longer duration of disease.174 Killer or natural killer cells did not seem to be making a significant contribution to muscle damage. The overall picture seen with nonnecrotic fibers was very different from the picture seen with necrotic fibers, where over 80% of cells were macrophages.lzl Ultrastructural studies17’ showed that cytotoxic T cells and macrophages adhered to nonnecrotic muscle fibers and sent “spikelike” processes into them. Fibers became focally compressed by increasing numbers of invading cells. The spikelike processes proliferated into a “honeycomb” pattern. The surface membrane of the fiber remained intact. The exact mechanism by which necrosis developed. was unclear and possibly involved humoral mechanisms. These studies suggest that the predominant mechanism for immunologically mediated muscle damage in PM and in IBM is T-cell cytotoxicity directed at an as yet unidentified antigen, presumably on the surface of the muscle fiber. Activated, cytotoxic T cells surround and invade the muscle fiber, lzl, 174,175 and other mechanisms may participate in the final destruction of the muscle fiber. Antigen-directed T-cell cytotoxicity would be expected to require the expression of MHC class I antigens on the target tissue. While major histocompatibility complex class I antigens are not normally expressed on muscle fibers, in muscle biopsies from PM/DM patients many fibers strongly express class I antigens on their surface.1’6 All fibers that were invaded by CD8+ lymphocytes were among those expressing class I antigens. Class I ex163

pression in this setting may be mediated by interferon. Some have postulated that interferon produced in response to viral infection might lead to increased expression of class I antigens, which would leave the fiber vulnerable to T cell-mediated cytotoxicity. Isenberg et al.177 found interferon deposition in areas of class I expression, consistent with this hypothesis, although others could not confirm this.17’ Class I antigen expression might be a nonspecific response to injury. It is seen in DM,17’ particularly in perifascicular regions,176 but fibers invaded by T cells are rare. While cell-mediated attack on muscle fibers is rare in DM, cell-mediated cytotoxicity against fibroblasts has been described in vitro.17’ Mononuclear cells from patients with DM, but not PM or other conditions, adhere to normal human cultured fibroblasts with subsequent cytotoxicity. Eighty percent to 90% of adherent cells are T lymphocytes, two thirds of which are CDS+ and expressing DR markers, indicating activation.180 The effect is not restricted by the major histocompati’ bility complex. Such a mechanism could be significant in DM, since much of the inflammatory infiltrate is in the interstitial fibrous tissue. Muscle cell dysfunction without necrosis may result from factors released by infiltrating mononuclear cells and may contribute to weakness. A high-molecular-weight mediator may interfere with calcium binding to the sarcoplasmic reticulum, while a low-molecular-weight (2&D) factor can directly suppress contractility of normal muscle .lsl As the factors leading to muscle weakness become better defined, they may become the focus of new treatments. Humoral Immunity Despite their abundance in PM, nonnecrotic surrounded and invaded muscle fibers are rare in DM, indicating that T-cell cytotoxicity against muscle fibers is not an important pathogenetic mechanism in DM.173 The intense B-cell and CD4+ T-cell infiltrate in the perivascular area in DM suggests that a local humoral response might be occurring in the muscle itself. Vascular Injury.-As discussed above, vasculopathy is observed in JDM and classic adult DM involving the small vessels and capillaries and is felt to be an important mechanism of muscle injury in DM.',83, %93 Endarteropathy with endothelial cell damage, necrosis and thrombosis of capillaries, capillary obliteration, and resultant ischemic damage are seen. A recent study analyzed muscle biopsies taken from patients with clinical DM that showed minimal or no structural change by rou164

tine microscopy.s4 They were thus felt to represent the earliest stages of DM. All showed definite microvascular changes by electron microscopy not seen in control normal biopsies, including endothelial cell injury and microtubular inclusions, but capillary necrosis, which was extensive in advanced DM, was rare. Quantitative immunofluorescence studiess3 revealed that nine of ten early DM biopsies had significantly decreased capillary density compared to normal biopsies (P < .OOl), while the capillary density of advanced DM was even lower (P < ,011. In PM and IBM, capillaries showed increased regional variation but the mean capillary density was not decreased. This implies that the capillaries are affected very early in the process, preceding the typical DM abnormalties of inflammatory infiltrates and muscle fiber damage, suggesting a primary role for microvascular damage in DM. Deposition of Zmmunoglobulin and Complement.Other evidence suggests that this vascular damage is humorally mediated. Many studies have looked for deposition of immunoglobulin and complement in muscle in PM and DM, but the data are inconsistent.182,183 Such deposition is not seen in biopsies from healthy controls, but has been found in some cases of PM and DM in some studies, although it is not specific for these conditionsl” It does not correlate with areas of inflammation. Staining has been found in the muscle blood vessels, in the periphery of the fiber where the sarcolemma and basement membrane are found, and in the fiber itself. It is found more commonly in JDM than in adult PM/DM,8Z,183 more commonly in DM than in PM,83 and more commonly in PM/DM with connective tissue disease than in other forms?82 Whitaker and EngelXs3 found deposition of IgG and C3 in intramuscular blood vessel walls in nine of 11 patients with JDM, but less often in adults (three of 12 with DM, two of seven with PM). Crowe et alF3 found deposition of IgM in vessel walls in JDM, but no IgG was seen, and there was no deposition in adult disease. No dense deposits to suggest immune complex deposition were found. The significance of the observed immunoglobulin deposition with regard to muscle injury is not known. Recent studies using immunofluorescent techniques have demonstrated deposition of the membrane attack complex of complement (MAC) in muscle microvasculature, suggesting local activation of complement. Kissel et alla found MAC deposition in intramuscular arterioles and capillaries in 83% of JDM biopsies and 26% of those from patients with adult PM, but none in biopsies Curr

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from patients with PM. Emslie-Smith and Engels found deposition of MAC in a higher proportion of adult DM cases, including nine of ten early DM biopsies prior to typical histologic change, as well as the advanced DM biopsies. In one patient, unusually extensive MAC deposition in a biopsy prior to the onset of weakness was followed by a fulminant and fatal course. The early deposition of MAC supports a role for local activation of complement in the pathogenesis of muscle capillary endothelial cell damage and subsequent ischemic muscle damage. The factors leading to complement activation are not known.

AUTOANTIBODIES The most clear-cut evidence of abnormal humoral autoimmune responses in PM and DM is the high rate of autoantibodies. Autoantibodies to nuclear and cytoplasmic cellular antigens have

been detected by either indirect immunofluorescence on HEp-2 cells or Ouchterlony immunodiffusion against calf thymus extract in up to 89% of patient#’ (Fig 6). The specificities of these antibodies have been studied in detail63 (Table 7). They are heterogeneous, with no single specificity being characteristic of the whole group. About half of patients have autoantibodies of recognized specificity. These can be divided into two groups: (1) “myositis-specific autoantibodies” (MSA) that are primarily or exclusively associated with PM/ DM, and (2) autoantibodies that are primarily associated with other connective tissue diseases, often found in patients with myositis overlap syndromes. In addition to disease specificity, most MSA are associated with characteristic clinical subgroups, which may not necessarily fall within subgroups defined by the Bohan and Peter classification.’ It is very uncommon for patients to have more than one MSA, but patients with MSA may also have antibodies associated with other connec-

TABLE 7. Autoantibodies

Associated

With Polymyositis/Dermatomyositis

Antibody

Antigen

Myositis-specific Antisynthetase Anti-Jo-l

Frequency,

Histidyl-tRNA

synthetase

18-20

Threonyl-tRNA synthetase Alanyl-tRNA synthetase Isoleucyl-tRNA synthetase Glycyl-tRNA synthetase Signal recognition particle, 54-kD protein, sometimes others

3 3 <2 <2 4

Antitranslation Anti-K.J

Translation

factor

1

Anti-Fer Anti-Mas

Elongation Unidentified

factor lo small RNA

1 1

Anti-Mi-2 Anti-58 kD Antibodies associated Anti-PM-SC1 Anti-U2RNP Anti-Ku

with

myositis

Anti-LJlRNP

Nuclear protein complex 56-kD nuclear protein overlap syndromes Nucleolar protein complex LJZ small nuclear RNP 70- and 80&D DNA binding proteins Ul small nuclear RNP

Anti-RoSSA (with or Ribonucleoprotein complex without anti-LafSSBI PM = polymyositis; DM = dermatomyositis; ILD = interstitial lung disease; erythematosus. Probl

Dermatol,

Clinical

Association

antibodies antibodies

Anti-PL-7 Anti-PL-12 Anti-OJ Anti-EJ Anti-SRP

CUT

%

September/October

19%

8 85-90 8

1 <3

12 10 RNP

= ribonucleoprotein;

PM/DM, ILD, Raynaud’s phenomenon, arthritis Same as Jo-l Same as Jo-l Same as Jo-l Same as Jo-l, more DM PM

PM, ILD, Raynaud’s phenomenon PM Alcoholic rhabdomyolysis DM All myositis Myositis-scleroderma Myositis-scleroderma Myositis-scleroderma SLE, sclerodermamyositis SLE, Sjogren’s-myositis SLE = systemic lupus

165

tive tissue diseases. These features and others suggest that the antibodies are related to fundamental disease mechanisms and are likely to be of significance in understanding PM/DM, but their role in pathogenesis remains unclear?

Antisynthetases One group of MSA, present in about 30% of PM/DM patients, is directed at cytoplasmic antigens involved in protein synthesis (“translation related”). Most of these are directed at aminoacyltRNA synthetases, a group of enzymes each of which attaches one specific amino acid to its cognate tRNAs. An individual patient’s serum contains antibody that reacts specifically with one single synthetase enzyme,185 but antibodies to five synthetases have been identified thus far in sera from PM/DM patients. The most common is anti-Jo-l, which reacts with histidyl-tRNA synthetase.186 It is present in 20% of PM/DM patients, about three to four times as common as the other antisynthetases combined. Immunogenetic associations with these antibodies were discussed above. The antisynthetases have been associated with characteristic clinical features and may define a distinct subgroup of patients. Anti-Jo-l is most common in adult PM patients (seen in 30% to 40%)ls7 but is also found in patients with overlap syndromes, and in 5% to 10% of adult DM patients. It is not found in JDM and is rare in myositis with malignancy. Fifty percent to 75% of patients with antiJo-l have ILD, compared to less than 10% of patients without anti-Jo-l or related antibodies.188’ la9 The ILD is similar to that of other patients with PM/DM. In addition, inflammatory polyarthritis has been found in two thirds of patients with antiJo-l .38 It is usually mild and responsive to treatment, but one third with arthritis may have deformity, especially in the fingers, usually nonerosive. Calcinosis in the fingers has occasionally been associated.38 Arthritis had previously been associated with ILD, probably due to its association with antisynthetase antibodies. Raynaud’s phenomenon is also more common with anti-Jo-l and is found in about two thirds of patients3,18’ Other features that have been associated with this group include fevers, mechanic’s bands, and less complete responses to treatment, with more frequent relapses. Antibodies to synthetases for threonine, alanine lso, lg* glycine,ls5 and isoleucine have also been described. Although fewer patients have been observed, those antibodies have also been associated with a similar clinical picture to that of anti-Jo-l, inILD, arthritis, and Raynaud’s cluding myositis, 166

phenomenon. This set of clinical features has been referred to as the “antisynthetase syndrome.” The skin manifestations of DM are seen in a higher proportion of patients with other antisynthetases than with anti-Jo-l, including five of six of our patients with anti-glycyl-tRNA synthetase (anti-EJ). Most antisynthetase antibodies react with the enzyme protein rather than the tRNA, but the tRNAs have high affinity for the respective enzymes and are found associated with the antigens. This is similar to the case for most other nucleoprotein antigens such as UlRNP, Sm, and RoSSA, in which the antigenicity is primarily carried on the protein. Antibody to alanyl-tRNA synthetase (anti-PL-12) differs, however, in that antibody that reacts directly with tRNAala is . also present in most sera with the antibody to the enzyme.lgO, lsl This difference is significant, and raises the possibility that the antitRNAaia is an anti-idiotype to the antienzyme in these sera. All sera with anti-PL-12 react with the same site on tRNAda, which could have implications in understanding the original mechanism that led to production of the antibodies. Almost every serum tested with all five antisynthetases has inhibited the enzymatic activity of the antigenic synthetase.la7’ lgol lgl This property of functional inhibition of the antigen has been observed with most other autoantibodies that have been studied. This may relate to reaction with active sites of the antigens, which tend to be conserved regions. Autoantibodies to synthetases appear to react with different epitopes than do animal antisera against the antigens.l” Multiple epitopes are recognizedlg3 and they tend to be conformational rather than linear epit0pes.l” In one interesting case, serial serum samples were followed beginning prior to onset of myositis. AntiJo-l first appeared in the serum several months prior to the development of weakness. The response was marked by switching from IgM to IgG and by affinity maturation,l” properties typical of a natural immune response after immunization. This and other evidence strongly support the concept that continuing production of antisynthetase autoantibodies is in response to the synthetase antigens themselves, although the autoimmune response may have been originally initiated in response to other factors such as molecular mimicry.

Other Anticytoplasmic

Antibodies

Antibodies to the (anti-SRP) may occur tein particle is involved from the cytoplasm to

signal recognition particle in PM. This ribonucleoproin translocation of proteins the endoplasmic reticulum.

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The antibodies recognize one or more protein components rather than the RNA. The antibody is seen almost exclusively in adult PM without skin disease and usually without other features of the antisynthetase syndrome.*s4 Some patients with anti- signal recognition particle have had an acute, fulminant course that was resistant to treatment. Antibodies to peptide translation factors have been identified in rare patients with PM or DM. One such antibody, anti-KJ, was associated with myositis, ILD, and Raynaud’s phenomenon, similar to the antisynthetase syndrome.1s5 In addition, antibody to a small RNA (“Mas”) was found in rare patients with myositis that appeared to follow an alcohol-induced myopathy.3 There appears to be a general relationship between myositis and antibodies to cytoplasmic antigens, particularly those directed at tRNA-related antigens, which are rare in other conditions.

Antinuclear

Antibodies

Anti-Mi-2, which reacts with an unidentified nuclear antigen (Fig 6B1, is highly specific for PM/DM patients, and very strongly associated with DM rather than PM. It is found in 5% to 10% of PM/DM overall, and 15% to 20% of DM patients.ls6 Thirtyseven (95%) of 39 patients with anti-Mi-2 had DM in one recent study, while another patient had cutaneous findings resembling those of DM without myositis.ls7 The skin disease is often florid and easily recognized. No increase in ILD or Raynaud’s phenomenon has been found. Some patients have had arthritis, but it does not appear to be increased in frequency compared to other PM/DM patients. Unlike anti-Jo-l, anti-MY-2 has been found in JDM in 10% of patients. It has also been found in myositis with malignancy. The Mi-2 antigen appears to be a complex of proteins, of which the 220-M, protein is the most prominent. No associated nucleic acid has yet been found. The role of the antigen in the cell is unknown. The Mi serum that defined anti-Mi-2 also served as prototype for anti-Mi-1,1g8 but anti-Mi-1 has not been found to be specific for PM/DM. The Mi-1 antigen is related to bovine immunoglobulin. The myositis-scleroderma overlap syndrome (PM-SSc) is serologically heterogeneous, associated with a number of autoantibodies. The antibody most clearly associated with PM-SSc is anti-PM-Scl, which is found in 5% to 10% of PM/DM patients, and less than 5% of scleroderma patients.“’ Patients with anti-PM-SC1 may have PM or DM or scleroderma alone, without overlap. They may have scleroderma with signs of myositis, such as elevated CK levels, without definite overlap or with Curr

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transient myositis that responds to treatment. The scleroderma is often diffuse but may be limited. The PM-Scl antigen is a protein complex of unknown function found in the nucleolus and possibly the nucleus, containing more than 11 polypeptides.“’ Ninety percent to 95% of patients react with a lOO- to 110&D component, while one third of patients also react with a second, 7.5~kD component. Anti-Ku may be found in PM-SSc but is also seen in SLE. It occurs in less than 3% of PMDM patients in the United States overall, but in about 10% of patients with PM-SSc. It is more common in PMSSc in Japan (38%), while anti-PM-SC1 is rare.zo1 This antibody reacts with a complex of proteins of 70 and 80 kD that bind to DNA. Antibody to proteins that are specific for the LJ2 small nuclear ribonucleoprotein (anti-U2RNP), always found in association with anti-UlRNP, is very rare, but is usually found in association with PM-SSc.2” Anti-Jo-l, anticentromere, and other antibodies associated with PM or DM or scleroderma alone have also been found in patients with PM-SSC.“~ Anti-UlRNP antibodies are commonly associated with myositis overlap syndromes, including PMSSc, PM-SLE, and mixed connective tissue disease and may be seen in SLE, PM/DM, or other conditions alone. Raynaud’s phenomenon seems to be more common in patients with anti-UlRNP. Some studies have found that among patients with antiLJlRNP, those who have PM-SLE overlap syndromes are more likely to react with the 68- to 70-kD protein of UlRNP than patients with SLE alone, and that the antibody to this protein is associated with myositis,Z03 although this has not been universally found. An interesting antibody has been identified that reacts with a 56-kD protein of ribonucleoprotein particles from Syrian hamster cell nuclei. It was found in a high proportion of PM/DM patients of all subgroups 145 of 52 patients), but it was slightly more common in DM than in PM.‘04 It was rare and weak in other connective tissue diseases (10% 1 and not seen in healthy controls or those with other muscle diseases. The antibody level varied with disease activity. There was no observed relationship to other autoantibodies. The lack of clinical subgroup association is an important difference from the other MSA discussed, and it may have a different significance for the disease.

Antimuscle

Antibodies

The MSA react with antigens present in all cells, and the reason they are specific for PM/DM is unknown. Autoantibodies to muscle-specific proteins 167

have also been studied in PM/DM, witb conflicting results.138 Most studies have found such antibodies to be absent or not different in frequency from control patients, but some have found antibodies to myosinzo5 and myoglobinzo6 more frequently and in higher titer in PM/DM than in controls. However, they are not specific for PM/DM, raising the possibility that they occur secondary to muscle damage .” Their role in PM/DM is unclear.

Significance

for Pathogenesis

The MSA appear to be related to fundamental disease mechanisms. The disease and subgroup specificity and the selectivity for specific antigens suggest that they are not simply a consequence of muscle damage. However, their significance for the disease is unclear. The finding of antibodies to multiple members of an enzyme family that are related by function but are antigenically independent, with an individual patient having antibodies to only one, is an interesting and unique situation., If the antibodies are related to fundamental disease mechanisms, understanding the mechanisms of their formation will be important in understanding etiology and pathogenesis. These mechanisms are unknown, and no animal model for their production exists. Genetic predisposition is known to be important to formation of the MSA, as discussed above, but production appears to be triggered by other factors, perhaps viral infection. Once antibody production is initiated, it appears to be driven by the antigens that we recognize, as discussed above.1” Further support comes from the finding of antibodies to multiple components of the same complex, as with anti-SRP and antiPM-&l, or the finding of reaction with multiple epitopes of anti-Jo-l. As with other autoantibodies, there is a tendency to react with conformational epitopes and with conserved epitopes that are different from the epitopes recognized by animals immunized with these antigens.*” There are some indications that different patients with anti-Jo-l share a major epitope demonstrated in Western blot?” The universal findings among anti-Jo-l sera of inhibition of the antigenic enzyme and immunoprecipitation of the associated tRNAs indicate a similarity in the response and epitopes among patients. The responses to anti-Mi-2 may also have similarities: all react exclusively with conformational epitopes and recognize a recently cloned 40-kD fragment of the 220&D antigenic protein. These features are compatible with hypotheses of autoantibody formation based on molecular mimicfl or on immunization with complexes formed between virus and host proteins or nucleic acids.13’, ls6, Is5 168

It is not yet known if autoantibodies play a direct role in pathogenesis. In support of this possibility are the findings of antibody production prior to disease onset and a general correlation of antibody titer with disease activity,“” 19’, ‘07 although other explanations of this are possible. Increases in titer have in some cases indicated exacerbation, and disappearance of the antibody is usually associated with remission, although most patients continue to produce antibody. Antisynthetases have been shown to inhibit the function of their antigens, which could lead to cell damage if this occurred in v&o. However, they are not believed to have access to those antigens in living cells, and the tissue localization of disease would not be explained. They may participate in muscle damage by other mechanisms, such as by formation of immune complexes or possibly by expression of the antigens on cell surfaces.

Clinical Significance The disease specificity of the antibodies means that the presence of an MSA is strongly supportive of a diagnosis of PM or DM, although they have low sensitivity. The association of antisynthetases with ILD can reveal an increased risk for ILD in a patient with myositis or the likelihood of PM in a patient with apparently idiopathic ILD. The presence of an MSA might support a diagnosis of DM in a patient with involvement of the skin but not the muscle. The general correlation of anti-Jo-l titer with disease activity noted above could be helpful clinically in some situations, if serial quantitative measurements were available.

TREATMENT

AND PROGNOSIS

CORTZCOSTEROZDS Corticosteroids are the mainstay of treatment for DM and PM (Table 8). Most patients with PM and DM respond initially, at least partially, to treatment with corticosteroids. The efficacy of corticosteroids has not been demonstrated by prospective randomized controlled trials, and there have been some studies that have suggested that the frequency of remission may not be improved by steroid treatment. However, even these studies may find lower morbidity and faster onset of remission, and most analyses and clinical experience indicate that steroids are valuable therapeutic agents. Steroids are established and accepted therapy. Responsiveness of the majority of patients has been reported in many large series. Cum Probl

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TABLE 8. Outline

of Suggested

Treatment

of Adult

Polymyositis/Dermatomyositis*

Initial treatment Daily oral corticosteroids, 1 mg/kg/d, usually 60-80 mg/d in 3 or 4 divided doses, may increase to 100 mg/d. Some recommend alternate-day steroids for mild cases but this is less reliable. For severe cases, some add azathioprine or try pulse methylprednisolone. Steroid responsive Taper after creatine kinase normal and strength improved. Decrease daily dose by 10%-Z% per month. Consider switch to alternate day steroids, especially if steroid side effects occur. Maintenance at 5-10 mg/d or lo-20 mgalt d for extended period. Immunosuppressive agents Indications Severe steroid side effects Very severe disease Resistant to steroids Repeated flare on steroid taper Methotrexate Intravenous: begin at lo-15 mgwk; increase to 0.5-0.8 mg/kgwk (30-50 mghuk). Oral: begin at 7.5 mgwk; increase as needed up to 20 mgwk. \ Azathioprine 1.5-3.0 mg/kg/d (100-200 mg/dl Experimental therapies Cyclosporin Combination therapy Plasmapheresis Intravenous gamma globulin Total body irradiation Resistant cutaneous disease Hydroxychloroquine, ZOO-400 mg/d Sun protection *Adapted from Oddis and MedsgerFo9

Initial

Treatment

Once the diagnosis of PM/DM is established, treatment is usually initiated as soon as possible if significant weakness is present. Significant delays in initiation of therapy may lead to incomplete recovery of strength. Factors that would indicate more urgency and possible need for hospital admission would be respiratory insufficiency, cardiac involvement, rapid onset of severe weakness, dysphagia with risk of aspiration, or systemic signs, and in children, vasculitis or cutaneous ulceration. Uncomplicated cases can be managed outside the hospital. Most adult patients are treated initially with high-dose daily oral corticosteroids. Prednisone is commonly begun at approximately 1 mg/ kg/d, usually 60 to 80 rngd.2” Daily doses of 1.5 m#kg/d or higher have been used for initial therapy. In adults, the added value of such high doses is unclear. Dalakas”’ recommends prednisone 100 mg/d for initial therapy and feels that there is additional benefit without additional side effects. In children, higher doses up to 2 mg/kg are used. In Curr

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severely ill patients, especially with vasculitis and gastrointestinal involvement, steroids may be administered intravenously at first.32 The daily dose is often given as 3 or 4 divided doses initially, particularly in more severe cases. Some have advocated beginning therapy with alternate-day steroids’ll because of the lower incidence of side effects. Retrospective comparisons have found fewer side effects with good efficacy, particularly in less severe disease?l’ However, beginning therapy with alternate-day steroids is usually considered less reliable and is not recommended for severe or complicated cases. Very high dose intravenous “pulse” methylprednisolone has also been used in PM/DM. A dosage of 1 g/d for 3 days is often used in adults, and 30 mgkg or other modified regimens are used in children. Pulse methylprednisolone is often used to achieve an immediate effect in severely ill patients or those with rapidly advancing weakness, to obtain a more rapid onset of maximum effect. It has also been used to help control patients who are 169

not responding to conventional doses of steroids or to allow reduction of steroid maintenance doses. There has been increasing use of pulse steroids in early treatment of JDMs3’ This was studied in seven patients with JDM with good results, including some patients that did not require daily maintenance steroids, thus avoiding side effects,‘13 although relapses have been seen with pulse steroids alone, and maintenance therapy is commonly used.

or dosage reduction schedules must be adapted and modified to the situation of the patient. Conversion to an alternate-day regimen is sometimes recommended after the initial month or more of a high-dose daily regimen.21o’ ‘I4 While it may be less reliable in maintaining remission, it may be advantageous in patients who have developed or are at high risk for significant steroid side effects. Dalakas’l’ recommends routine conversion to an alternate-day regimen by weekly reduction of the alternate-day dose until full alternate-day therapy is achieved, usually at 16 weeks. Further taperMaintenance and Dosage Reduction ing in this regimen is then very slow. After the acute period, the dosage is often conHoffman et al?12 found that among 27 patients solidated to a single daily dose and continued at in a rural facility providing primary care, many pathe initial level until the CK has returned to nortients could be managed with less aggressive thermal and the patient’s strength has substantially apy. Eight of 11 achieved good results with alternate-day treatment and did not need other treatimproved or normalized, usually 4 to 12 weeks. Responses are sometimes dramatic, but the response ment, and 41% could discontinue all treatment without recurrence during follow-up. Tymms and may be slower than that seen in SLE or rheumatoid arthritis,” and it may take months to achieve Webb9 found that 11% could be treated with lower doses of steroids i< 40 mg/d prednisolone), and the full effect. Tymms and Webb9 found the mean 12% received no treatment, either because they interval from start of high-dose steroids to full rehad no weakness or because they were spontanecovery strength to be 3.3 months. The importance of high initial doses of prednisone for an adequate ously improving. Careful follow-up is needed period (60 mg/d or more in adults for at least 1 when such regimens are used. It is important to monitor patients closely durmonth) has been stressed repeatedly.6’ ‘lo, 214,215 High initial doses have been correlated with reing treatment and tapering for signs of improvement or complications. Disease activity is assessed sponsiveness. When the initial goals are reached, the dosage is by both strength and CK level, as discussed above. gradually reduced over a period of 6 to 8 months The cutaneous lesions may respond also, but they until a low maintenance dose is achieved. Exacermay remain active, and the dose of steroid therapy is usually adjusted based on the myositis. Persisbations of disease may occur during dosage retent elevation of the CK usually means that the duction and are more likely if it is reduced rapidly. Qddis and Medsger recommend dosage disease has not been controlled. An increase in the CK during tapering of treatment after control has reduction be accomplished through decreasing been achieved frequently heralds an exacerbation. the existing dosage by 25% per month,“’ while Oddis and Medsge? found that elevation of the Bunch recommends 10% per month,‘16 and others use similar regimens. Several authors have CK from the low-normal to the high-normal range predicted frank elevations of the CK in 13 of 16 recommended continuing a low maintenance doscases and, often, exacerbations of weakness. Howage for an extended period of 1 to 2 years or predever, when evaluating the significance of a rise in more. 6,20%210,214>217,218 The maintenance CK level after it has fallen, other causes for CK elenisone dose should be high enough to help prevation should be considered, particularly when no vent recurrences but low enough to minimize side other signs of exacerbation are present. CK elevaeffects, usually 5 to 10 mg/d or 10 to 20 mg on tion may be a less reliable predictor of exacerbaalternate days. tion with advanced disease, particularly in JDM. If Oddis and Medsge? found that treatment signs of exacerbation occur as the dosage of predcourses were much more likely to result in prolonged suppression of disease (more than 1 year) if nisone is reduced, tapering should be suspended, they followed certain guidelines, which included: and increases in the dosage may be required, usu(1) continuation of the initial treatment at 60 mg/d ally to levels above the one that last maintained or more of prednisone for at least 1 month; (2) control of the disease, but less than full dose. continuation of initial treatment until or after the CK becomes normal; and 13) reduction of steroid Side Efiects dose slowly, so that the average reduction is 10 The side effects of corticosteroids encountered in patients with PM/DM are similar to those in mg/month or less. Guidelines for initial treatment 110

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other situations. Steroid myopathy can present more of a problem in this setting because it can be confused with exacerbation of the underlying disease, as discussed above. In addition, hypokalemia, which can lead to weakness, should be avoided. Since it is anticipated that prolonged treatment will be required in most cases, osteoporosis is a long-term problem, and adequate calcium and vitamin D intake is needed, especially in women. Aseptic necrosis may occur in patients with PM/DM receiving high doses of steroids. This was found in seven (8.6%) of 81 patients of Tymms and Webb’ given such treatment. Prophylaxis against peptic ulcers as with an HZ-blocker is commonly used with the high doses of steroids used in PM/DM .‘l” Due to the increased risk of steroids and immunosuppressives in patients with HIV infection (increased risk of opportunistic infections and possibly progression of HIV infection), it is important to identify patients with HIV-associated myositis prior to treatment. In some cases, zidovudine plays a role in development of the myopathy, and withdrawal or reduction of dosage may lead to improvement .lo3 If it does not, daily or alternate-day prednisone has been used cautiously when necessary, despite the risk.

IMMUNOSUPPRESSIVES Most patients can be treated with prednisone alone, but additional therapy is needed in up to 25% of cases.2og Indications for addition of an immunosuppressive agent include (1) lack of response of the CK or strength after 2 to 3 months of high-dose steroids; (2) persistent disease activity after prolonged therapy, even if initial improvement occurred; (3) repeated recurrence of disease with attempted taper or prednisone; or (4) severe steroid side effects. Immunosuppressives are sometimes added earlier when disease is particularly severe or rapidly progressive. When steroid resistance is encountered, the basis for the diagnosis should be reviewed to determine if further diagnostic evaluation is needed, as discussed above, to exclude infections, metabolic myopathies, endocrinologic disorders, inclusion body myositis, or other conditions. It is also important to consider possible confounding factors such as steroid myopathy. Patients who had a long delay before treatment was begun, especially more than 12 to 18 months, may not recover full strength even with complete suppression of disease activity. 9,214 The most experience in PMDM is with methCur-r Probl

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otrexate (MTX) and azathioprine QUA). Either may be used in patients who do not respond adequately to prednisone alone. Prospective randomized studies comparing the two are not available. Some retrospective analyses,‘, ‘16 have suggested that steroid-resistant patients may have a higher response rate with MTX, and MTX may have a more rapid onset of effect. However, AZA may have less toxicity and is easier to use, particularly compared to intravenous MTX, and is the only agent whose efficacy has been documented in at least one prospective controlled trialzl’ Some clinicians begin therapy with both prednisone and AzA in severe disease.‘lg Immunosuppressive agents are typically used in conjunction with steroid therapy, at least at the outset. The immunosuppressive may have a steroid-sparing effect, allowing the steroids to be tapered first.

Methotrexate MTX may be used intravenously or orally, but intramuscular administration may lead to CK elevations, which can complicate disease monitoring. A commonly used regimen for intravenous MTX begins with 10 to 15 mg/wk and gradually increases to 0.5 to 0.8 mg/kg/wk (30 to 50 mg/wk).220 Metzger et alzzo found that 17 (77%) of 22 patients improved with this regimen, including 15 with good or excellent responses or remissions. Two of the nonresponders had a malignancy, and one stopped the drug after 2 weeks. Normalization of the CK level was generally seen by the tenth week, with significant improvement in strength occurring after an average of 13 weeks, but this is variable over a wide range.“* The cutaneous lesions tend to improve about the same time as the muscle enzyme normalization. A steroid-sparing effect was seen, with the average prednisone dose decreasing from 47 mg/d to 19 mg/d at 6 months. Responses have been seen as early as 3 weeks and as late as 44 wkszzl After an adequate response has been obtained, the MTX may be tapered by extending the dosing interval to 2, 3, and 4 weeks or by decreasing the administered dose. The effectiveness of the higher-dose intravenous regimens is better documented in PM/DM than are the oral regimens, but there is increasing recent use of low-dose oral weekly MTX in PM/DM, and many patients appear to get adequate benefit from the lower doses.lZ~ZOg Parenteral therapy may be required when higher doses are needed for severe disease or when there is gastrointestinal intolerance. Weekly oral doses are usually begun at 7.5 mg/wk and increased at 2.5mg/wk intervals to a maximum of 20 to 25 mg/wk. The dose may be 171

split into three doses given 12 hours apart as in psoriasis, but daily oral MTX should not be used. Toxicity is usually mild, but severe toxicities have occurred. Stomatitis was the most common side effect”’ and could usually be managed by dosage reduction. Severe hepatotoxicity and MTXinduced hypersensitivity pneumonitis (see above), including a fatality, have been reported.2z1 The contraindications in PM/DM are similar to those in psoriasis or rheumatoid arthritis. The medication is usually avoided in patients with renal insufficiency (creatinine clearance < 75 ml/min) or preexisting hepatic damage, and alcohol should not be used. A liver biopsy is usually not performed at the start of therapy unless previous hepatic damage is suspected; the use of routine liver biopsy to detect MTX-induced cirrhosis is controversial and has not been specifically studied in PM/DM. Preexisting ILD, with decreased pulmonary reserve, confers increased risk should MTX-pneumonitis develop. When MTX is clinically indicated, preexisting lung disease does not necessarily preclude its cautious use. It should also be used with caution in patients with antisyvnthetases, even if ILD is not evident, because of the difficulty in distinguishing MTX-pneumonitis from ILD should it develop. Other side effects of MTX and monitoring of treatment are as with its other uses (opportunistic infections, bone marrow suppression, abortifacient and teratogenic activity, drug interactions, gastrointestinal bleeding, etc.). Azathioprine AZA was shown to have activity in PM/DM in the prospective controlled trial of Bunch,“” in which use of AZA in addition to prednisone as part of initial therapy resulted in better long-term outcome, with less disability and lower prednisone requirements. The trial was small, with eight patients in each group, and benefit was shown only in the l- and 3-year follow-up, not short-term at 3 months. A steroid-sparing effect can be seen in half the patients given AZA, and improvement in disability is seen in a third.8 AZA is used orally at 1.5 to 3.0 mg/kg/d, usually 100 to 200 mg/d. Side effects are similar to other situations (bone marrow suppression, opportunistic infections, possible increased frequency of hematologic malignancy, drug-interaction with allopurinol, nausea and vomiting, and hepatic or pulmonary reactions), and careful laboratory and clinical follow-up are important. Cyclophosphamide Several additional immunosuppressive agents have been used in PM/DM. Daily oral cyclophos172

phamide has been used at 1 to 2 mg/kg/d. Fries et aFz2 saw a poor response in all five patients treated, but several successes have been reported. There is a high risk of serious side effects, including hemorrhagic cystitis, malignancy, bone marrow suppression, and infertility. In one study, monthly intravenous pulse cyclophosphamide, beginning at 0.75 g/m’, was associated with poor efficacy and high toxicity.ZZ3 Of 11 patients, six completed the planned seven cycles, one improved significantly in strength and function, and three improved partially in strength but not function. Others have had more success, including Kono et al.,224 who found good responses with low toxicity in three patients with PM-SLE overlap syndromes given monthly intravenous cyclophosphamide pulses. A recent study found benefit of cyclophosphamide in three patients with PM/DM-related ILD, orally in one and monthly intravenous pulses in two.45 Cyclosporin There have been several reports describing beneficial effects of cyclosporin A in PM/DM,225,226 including JDM,227 and it is the subject of continuing trials. It was able to reverse severe disease resistant to steroids and cytotoxic agents. Although it is not always effective and carries the risk of nephrotoxicity and other problems, it is very promising.

EXPERIMENTAL Several treatments have been used in patients with severe and resistant disease. Pulse methylprednisolone may be useful for disease flares, as noted above. Combinations of immunosuppressives are sometimes successful, particularly MTX md

~.36,228

Plasmapheresis has been successful in resistant cases. The largest study was that of Dauz2’ who found improvement in 32 (91%) of 35 patients treated with plasmapheresis, although all patients also received cyclophosphamide or chlorambucil. The cytotoxic agents were felt to prevent synthesis of new antibodies, but the independent contribution of the plasmapheresis was unclear. Patients with active, rapidly progressive disease did best. Herpes zoster was frequent (20%). Recent controlled trials should help clarify the value of this treatment. High-dose intravenous gamma globulin was of benefit in a patient with severe, chronic, unresponsive JDMZ3’ and in other cases. In a recent series of 15 adults, 13 improved clinically, and nine decreased their steroid requirementF31 One paCurr

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tient, who was “picornavirus positive,” responded to intravenous gamma globulin without other treatment. This suggests that some of the effects of this treatment might result from effects on myositis-inducing viruses, but the therapy also has effects in other autoimmune diseases, and the mechanism is unclear. One report described a patient with adult DM, digital infarcts, and ocular ischemia with amaurosis fugax, unresponsive to steroids and immunosuppressives, whose DM and ischemia improved with addition of three antiplatelet drugs.232 As a last resort, total body irradiation has been used in a small number of cases of intractable PM/DM, with severe, life-threatening activity. Dramatic, prolonged responses have occurred,Z33 but at least one patient died, and others have not responded.35

PHYSICAL

THERAPY

Active exercise should be avoided in the acute period when muscle inflammation is present, since it may increase CK levels, probably reflecting increased muscle damage. Passive range-of-motion exercises should be begun early to help prevent contractures. After the initial stages, when inflammation has been controlled and CK levels are normalized, active exercise may be of benefit, to help recover lost strength from disease, immobility, and steroid-related atrophy?34 It should be cautiously introduced and slowly advanced. During the period of severe disability, assistance with activities of daily living and assistive devices may be required, and if permanent disability develops, vocational rehabilitation may be helpful.

CUTANEOUS

DISEASE

The skin lesions of DM may respond to treatment of the myositis with systemic steroids or immunosuppressive agents, but they often do not respond. Potent topical steroids may be helpful, often reducing erythema, but commonly do not lead to resolution of the lesions. Persistent cutaneous lesions requiring further therapy may respond to hydroxychloroquine. Woo et al.235 treated seven patients with DM whose cutaneous lesions were not responding to prednisone and in some cases immunosuppresive agents, with addition of hydroxychloroquine, 200 to 400 mg/d. All seven improved with hydroxychloroquine, and a steroidsparing effect was seen in some patients. The similarity of the clinical and histologic appearance to Curr

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that of cutaneous lupus suggested the likelihood of success with hydroxychloroquine. Its effectiveness may be related to the frequently observed photosensitivity of DM. Other antimalarials such as chloroquine have been used. Hydroxychloroquine would not be expected to benefit the myositis, and Woo et al. found no benefit in adults, with one patient having a flare of myositis activity. However, Olson and Lindslep6 found that in nine patients with JDM responding inadequately to prednisone, adding hydroxychloroquine, 2 to 5 mg/ kg/d, not only led to improvement in the skin lesions but also led to a significant improvement in muscle strength. Due to the risk of retinopathy, ophthalmologic monitoring at least every 6 months is needed. As noted above, antimalarials may cause a vacuolar myopathy, which must be considered when muscle disease flares or develops in patients with only skin lesions. An important component of treatment of the skin lesions is sun protection, and sunscreens and physical measures should be instituted. Several treatments for calcinosis have been attempted without consistent or proven benefit. If a deposit is inhibiting function or causing significant discomfort or other problems, surgical excision can be helpful if the deposit is accessible. An inflammatory component may result from response to hydroxyapatite and has been reported to respond to colchicine.237 Adequate treatment of the myositis seems to be effective at preventing the development of calcinosis in adults, and aggressive early treatment of JDM also appears to decrease the incidence of calcinosis.31

PROGNOSIS

The current survival rate for PM/DM has improved compared to that prior to the use of corticosteroids. Among 76 patients with PM or DM studied by Hochberg et al. between 1970 and 1981,13 survival at 5 years was 80.4% and at 8 years was 72.8%. This was improved compared to the rates found by Medsger et al. in Tennessee between 1947 and 1968 of 65% at 5 years and 53% at 7 years.z38 This may be indicating that survival has improved over time and has continued to improve after the introduction of steroids. This improvement may be related to better general medical care, improved use of steroids, recognition of milder disease, or other factors. The overall mortality among 118 patients followed for varying periods by Devere and Bradley was 28% (fourfold higher than expected),6 while that among the 153 patients of Bohan et al. was 14% .’ 173

The mortality of PM/DM increases with increasing age of onset of disease. Dysphagia has been associated with increased mortality in some studies, probably because it is present in the more severely affected cases.13 ILD and cardiac involvement also increase mortality. Cutaneous signs other than severe vasculitis have not generally been predictive, although a recent study by Basset-Seguin et al?’ found that extensive erythematous plaques on the trunk, sometimes with infiltrated papules, were associated with a poor prognosis and were significantly more frequent in patients who died. The most common causes of mortality in PM/DM are malignancy, infection, cardiac involvement, and lung involvement. Association with malignancy would be expected to worsen the prognosis, and several studies have found this to be the case.28 Bohan et al. found that survival for myositis with malignancy was 46% but was 87% to 91% for other PM/DM groups.8 However, Hochberg et al.13 such and Medsger et al.238 could not demonstrate an effect overall. A poorer prognosis may also be associated with more severe or rapid onset, resistance to treatment, or long delay before treatment is initiated.6 Patients with a chronic progressive course, and those whose treatment was delayed, are less likely to achieve full recovery of strength.6’ ‘, ‘I4 Tymms and Webb’ found that if treatment was delayed by more than 4 months, only 21% improved versus 72% of those treated earlier. Older patients may also respond less well and may require a longer duration of treatment?14 Patients with adult DM are more likely than patients with adult PM to have a complete response to treatment. Prognosis may also be altered in certain autoantibodydefined subgroups.3 Patients with antisynthetases are significantly less likely to have a complete clinical response to treatment than those without these antibodies, although they usually partially respond initially. Patients with anti- signal recognition particle tend to have acute onset and severe disease that may be resistant to treatment. The prognosis in JDM also seems to have improved with current treatments. Bowyer et al?l found that early treatment with high doses of steroids for an adequate period led to good functional outcome in 78%, compared to 33% with low-dose treatment. Calcinosis was seen in less than 20% with high-dose treatment. Severe vasculitis was associated with a poor outcome. Early studies indicated mortality of up to one third, but a recent retrospective review found mortality in and poor initial 12.8% .23s Pharyngeal involvement response to steroids were poor prognostic signs.

174

REFERENCES* 1.

2. 3.

4. 5. 6. 7.

8. 3. 10. 11.

12.

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