Idiopathic inflammatory myopathies, which include polymyositis and dermatomyositis, primarily affect skeletal muscle. The common features of these diseases are weakness of and inflammatory changes in skeletal muscle. In general, the idio-pathic inflammatory myopathies are serious disorders that respond variably to therapy. Polymyositis and dermatomyositis may be linked with other rheumatic diseases, notably sclero-derma, and with malignancies. Prognosis varies according to the specific syndrome that is expressed.
Classification
Classification of these heterogeneous muscle disorders into subtypes is useful for determining diagnostic and therapeutic approaches.1,2 Categories are defined on the basis of clinical and histologic features rather than on laboratory or radiologic tests [see Table 1].
Dermatomyositis
Patients with dermatomyositis usually show symmetrical proximal muscle weakness in all extremities, accompanied by a characteristic skin rash. Neck and back muscles may also be weak. Areas of skin most commonly affected by the rash include extensor surfaces of the hands and knees. Subtypes of dermatomyositis include the juvenile form [see Juvenile Myosi-tis, below]. Another recognized subtype is amyopathic dermatomyositis.3-5 Patients with this disorder have the characteristic rash but do not have demonstrable muscle abnormalities. One study of such patients has shown that sensitive magnetic resonance imaging techniques can reveal changes after exercise that indicate a metabolic abnormality.6
Polymyositis
Patients with polymyositis have symmetrical proximal muscle weakness similar to that experienced in dermatomyositis, but the rash is absent. Onset of polymyositis may be more difficult to determine, in part because no rash is available as an indicator of possible inflammation. Muscle weakness and atrophy may be more profound than that usually seen in patients with dermatomyositis. However, no formal studies of long-term outcome have been carried out that prove this assertion.
Juvenile myositis
Children ranging in age from younger than 5 years through the teen years may be affected by juvenile myositis. Most children have a skin rash, and vasculitis and soft tissue calcifications are much more common in children than in adults.7 Although residual dermatologic changes, muscle fibrosis, and calcification may occur, the long-term outlook is generally favorable.8
Myositis with malignancy
Most, but not all, cases of malignancy-associated myositis are accompanied by the typical rash of dermatomyositis. A recent study showed that patients with dermatomyositis had a relative risk of malignancy of 6.2. For patients with polymyosi-tis or inclusion body myositis, the risk was lower but still sig-nificant.9-11 The incidence of underlying malignancy increases with age12 and decreases with increasing time from diagnosis.9 Onset of the myositis may precede or follow discovery of the malignancy. Adults with dermatomyositis should be screened for occult malignancies in the first 2 years after onset of disease.
Myositis with other rheumatic diseases
Inflammatory myositis may occur with another established rheumatic disease, most commonly scleroderma. Other conditions that can occur with myositis include rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjogren syndrome. Recent reports have linked scleromyxedema to dermatomyositis13 and have linked inclusion body myositis to subacute cutaneous lupus.14,15 Many patients with these overlap conditions have a relatively mild form of muscle inflammation that responds well to treatment. However, a small subset of patients, especially those with coexistent scleroderma, may have a severe and very debilitating muscle weakness that is resistant to therapy.16
Inclusion body myositis
The pattern and severity of muscle weakness in inclusion body myositis (IBM) differs from the pattern of severity seen in the other idiopathic inflammatory myopathies. In addition to the presence of proximal weakness, distal muscles may be involved; and in some cases, muscle abnormalities are asymmetrical. Unlike most of the other muscle disorders discussed in this subsection, IBM afflicts more men than women, with approximately two thirds of affected persons being men. Response to treatment is generally poor.
Epidemiology
Prevalence and incidence
The estimated prevalence of idiopathic inflammatory my-opathies is approximately one case per 100,000 individuals.
Table 1 Classification of Myositis Syndromes
|
Clinicopathologic Category |
Characteristics |
|
Dermatomyositis |
Proximal weakness, skin rash; amyo-pathic variant with rash only |
|
Polymyositis |
Proximal weakness without rash |
|
Juvenile myositis |
Myositis in childhood, usually with a rash |
|
Myositis with malignancy |
Myositis with associated underlying neo-plastic disease |
|
Myositis with another connective tissue disease |
Coexistent syndrome, usually scleroder-ma, rheumatoid arthritis, or systemic lupus erythematosus |
|
Inclusion body myositis |
Severe weakness with characteristic inclusions on muscle biopsy |
This prevalence makes these disorders about 1,000 times less common than rheumatoid arthritis. The rarer syndromes, such as IBM, may constitute 20% or less of all cases. In one study, the annual incidence of idiopathic inflammatory myopathies was 5.5 cases per million population.17 Incidence rates, however, may be increasing, possibly because of improved methods of detection.
Ethnic, racial, and gender group differences
No ethnic clustering of the idiopathic inflammatory my-opathies has been reported. It has been suggested that incidence rates in North America are increasing faster in African Americans than in whites.17 In adults, polymyositis is more common than dermatomyositis, whereas in children and young adults, dermatomyositis is the predominant form. It has been suggested that incidence rates are higher in regions that have greater amounts of sun exposure.18 Polymyositis and der-matomyositis show a female-to-male ratio of approximately 2:1. Risk of underlying malignancy increases significantly after 40 years of age.12 Malignancies in children are rare but have been reported. The diagnosis of inclusion body myositis is rarely made in persons younger than 50 years.
Etiology and Pathogenesis
The etiology of inflammatory muscle disease remains unknown. The most widely accepted hypotheses suggest multiple factors. One possible scenario is that an initial insult—for example, a virus or another infectious agent or an environmental toxin—leads to muscle damage in a genetically susceptible host. This process in turn triggers an immune response, subsequently causing chronic muscle inflammation.19
Infectious agents
A role for viruses in the etiology of idiopathic inflammatory myopathies has been suggested by seasonal and geographic clustering of new cases. Furthermore, infection with HIV or hepatitis C virus has been associated with the development of my-opathy.20 Most studies looking for evidence of viral genomic material in muscle tissue have failed to find such evidence.21 Immunoreactivity for hepatitis C in involved muscle tissues has been reported in a single case.20 Viruses may mediate tissue damage, which may in turn lead to immunologic responses that target or damage muscle tissues.22 The relative rarity of the myositis syndromes would suggest that if a common infectious agent were involved, coexistent factors would also be required. These factors could include host-specific genetic loci that control the immune response or other noninfectious factors such as drugs or environmental toxins.18
Noninfectious factors
Lipid-lowering agents such as clofibrate and the statin group of drugs have been associated with elevated levels of serum muscle enzymes and with muscle weakness in a small number of patients. However, most patients are asymptomatic. The list of drugs reported to be associated with development of myopathy is very long. For this reason, concomitant medications should be examined closely in any patient with unexplained muscle weakness.23 Both HIV infection and drugs used in its treatment, such as zidovudine (AZT), have been implicated in the development of myopathy. It is possible that as yet undefined environmental toxins play a role.
Genetic factors
Familial clustering of inflammatory myositis syndromes occurs, but the great majority of cases are sporadic. Sporadic cases have been linked to HLA-DRB1*0301, whereas familial cases have shown increased prevalence of HLA-DQA1 (DQA1*0501). A form of hereditary IBM has been described in several ethnic groups. Chromosomal links with this disorder have been identified, but candidate genes are as yet undefined.24 Many of the reported studies of genetic links in inflammatory myopathies have grouped several types of syndromes together. It is probable that future studies that perform separate analyses of the various distinct clinical syndromes will show stronger associations with genetic markers.
Autoimmune factors
The presence of cellular infiltrates in muscle tissues is a defining feature of inflammatory muscle diseases [see Figure 1]. Light microscopic examination of these infiltrates reveals different patterns of infiltration. In tissues from patients with der-matomyositis, the lymphocytes are generally located around blood vessels and at the periphery of the muscle bundles. Invasion of muscle fibers by mononuclear cells is rarely observed, and there is a relative paucity of necrotic muscle fibers. Complement-mediated capillary damage is also more commonly observed in biopsy samples from dermatomyositis patients, especially those patients with an underlying malignancy. Some studies suggest that dermatomyositis patients with capillary damage who do not have a malignancy have a more acute syndrome that responds better to immunosuppressive treatment. In polymyositis, muscle fibers may be invaded by the mononuclear infiltrates, and focal areas of muscle destruction are seen. Tissues from patients with IBM usually show some degree of inflammation accompanied by intracellular rimmed vacuoles.25
Two groups have identified chimeric cells of maternal origin in the peripheral blood and inflammatory lesions of children with myositis. These findings support the hypothesis that childhood myositis is a manifestation of a graft-versus-host reaction.
Figure 1 Extensive pathologic changes can be seen in involved muscle in myositis. These changes include a decrease in the number of striated muscle fibers and a loss of cross-striations in the remaining fibers. Some fibers demonstrate increased numbers of rounded nuclei and basophilic staining (arrows), which suggests attempted regeneration. There is also intense infiltration of the muscle by mononuclear inflammatory cells, predominantly lymphocytes and plasma cells.
Differences between polymyositis and dermatomyositis are revealed by immunophenotyping of the cellular infiltrates.28 Mononuclear cell infiltrates in polymyositis and probably in IBM tissues are predominantly of the CD8+ cytotoxic T cell phenotype. The CD8+ T cells in polymyositis show evidence of clonal expansion, which is most likely driven by muscle-specific antigens.29 Activated CD8+ T cells probably mediate cytotox-ic, immune-mediated, and antigen-specific muscle cell destruction. In dermatomyositis, T cells, predominantly of the CD4+ helper-inducer phenotype, are present along with B cells; restricted clonality is not seen.29 These differences in histology support the hypothesis that polymyositis and dermatomyositis are distinct disorders with different etiologies.
Diagnosis
Major diagnostic criteria that were proposed by Bohan and Peter in 19751,2 remain useful for defining most of the myositis syndromes. However, IBM, which was not recognized at the time these criteria were written, differs somewhat from polymyositis and dermatomyositis. Although sophisticated diagnostic tests, including autoantibody profiles and imaging techniques, are now available, findings obtained through a careful history and physical examination remain indispensable for both making the initial diagnosis and evaluating responses to treatment.
Clinical features
Muscle Weakness
In polymyositis and dermatomyositis, the weakness is predominantly proximal. Distal strength is usually preserved. In IBM, the weakness may be asymmetrical, and diminished distal strength is commonly seen. Muscle strength can be tested in the office or at the bedside and estimated on a semiquantitative scale from 1 to 5. Devices for quantitative assessment of muscle strength, some of which can be used at the bedside, are also available.
Characteristic Skin Rash
The rash of dermatomyositis is a deep-red erythematous eruption, with or without mild scaling and atrophy. It occurs on the face, neck, upper chest, and extensor surfaces of joints such as elbows and those of the hands. Periorbital edema may appear, as may heliotrope erythema, which is characterized by a violet or lilac color, especially of the eyelids. Occasionally, the rash is more widespread or takes different forms [see Figure 2]. Erythema and telangiectasia also occur in periungual areas. In adults, vasculitis is usually confined to the skin and takes the form of urticaria, subcutaneous nodules, periungual infarcts, or digital ulcerations. Cutaneous vasculitis has been associated with underlying malignant disease.
Pulmonary Involvement
Pulmonary involvement occurs in nearly 50% of patients who have myositis, with pneumonia being the most common pulmonary abnormality. Aspiration pneumonia, which is often recurrent, is prevalent in patients who have pharyngeal muscle weakness. Ineffective coughing caused by ventilatory muscle weakness also occurs but is far less common than swallowing problems. In general, the patient with recurrent aspiration pneumonia has a poor prognosis; it indicates marked dysfunction of many muscle groups. Bacterial pneumonia caused by aspiration is a major cause of death in elderly patients.12 Opportunistic infections may occur in patients undergoing immunosuppressive drug therapy. In addition, some of these drugs, most notably methotrexate, can be associated with the development of pneu-monitis, which is usually reversible but is potentially fatal.
Figure 2 Skin eruption in a patient with dermatomyositis consists of a deep-red, erythematous, papular rash over the nasal and forehead areas and a lilac-colored, or heliotrope, erythema of the upper eyelid and orbital area.
Interstitial lung disease (ILD) occurs in up to 30% of myositis patients and in approximately 60% of patients who have antibodies directed against aminoacyl-transfer RNA (tRNA) syn-thetases. The advent and application of newer, sensitive diagnostic techniques such as high-resolution computed tomography may lead to an increase in the detection of pulmonary abnormalities. The most common presentation is with progressive shortness of breath, which may be accompanied by a nonproductive cough. On physical examination, basilar crepitant rales are usually detected. Progression may be slow, and symptoms may occur in patients with established disease; or onset may be rapid and may occur at the same time as the muscle weakness.30 Hypoxemia and respiratory alkalosis may be present. In some patients, these abnormalities are detected only after exercise. High-resolution CT scanning is useful for detection of interstitial fibrosis that might not be appreciated on routine chest radiography. Pulmonary function tests may reveal reduced lung volume and diminished diffusion capacity. One of three forms of histology of ILD is usually found: interstitial pneumonia, diffuse alveolar damage, or bronchiolitis obliter-ans with or without organizing pneumonia. ILD occurs with or without skin involvement. There is no correlation between the development of ILD and the severity of muscle involvement, and ILD may precede or follow the onset of muscle weakness. ILD is associated with a high mortality. Treatment with cy-clophosphamide or azathioprine has been reported to be beneficial in some patients.30 A small number of patients with acute pneumonitis may respond to corticosteroid treatment alone.
