Etiology
The precise cause of these diseases is unknown, but interplay between host genetic factors, viral infection of muscle, and autoimmune mechanisms is probably contributory. Familial occurrence of these diseases, and the increased frequency of HLA-DR3 and -DRw52 antigens in patients, suggest an underlying genetic and immunologic predisposition.
Experimental viral myositis can be induced in animals by coxsackievirus. A mild inflammatory myopathy can occur with influenza and coxsackieviruses in humans. However, the several electron-microscopic observations of virus-like particles in muscle fibers in dermatomyositis or polymyositis have not been confirmed by virus isolation or demonstration of rising viral antibody titers, and the disease has not been passed into animals by injection of extracts of skeletal muscles.
Nevertheless, the presence of serum antibodies to several cytoplasmic ribonucleoproteins involved in translation [especially histidyl tRNA synthetase or Jo-1 and signal recognition particle (SRP)] may result from an immune response to an altered virus that serves as an immunogen in polymyositis. These antibodies probably represent a cross-reactive phenomenon.
A lymphocyte-mediated disease resembling polymyositis has been reported in laboratory animals injected with muscle antigens together with Freund's adjuvant (experimental allergic myositis).
Immunohistochemical and muscle co-culture studies indicate that muscle fiber necrosis in polymyositis and inclusion body myositis probably derive from activation of CD8+ T lymphocytes, accompanied by CD4+ T lymphocytes and macrophages present in the inflammatory infiltrates. In dermatomyositis, deposition of immunoglobulins and the C5b-9 complement membrane attack complex has been demonstrated on intramuscular blood vessels even in unaffected or minimally involved regions of muscle, suggesting that humorally mediated blood vessel damage initiates the angiopathy that precedes muscle destruction. The final pathway for muscle fiber damage in dermatomyositis may be T cell-dependent stimulation of B cells, with resultant antibody-mediated cytotoxicity. In inclusion body myositis, the accumulation of amyloid, paired helical filaments, and several other proteins typically seen at autopsy in brain specimens of patients with Alzheimer's disease suggest some overlap of pathogenic mechanisms in these disorders.
Classification
A widely used classification of the dermatomyositis-polymyositis group. Other diseases uncommonly associated with polymyositis are sarcoidosis, giant cell myositis with thymoma, and myositis in systemic infections due to viruses, toxoplasma, or parasites. A focal infective myositis due to streptococcal or staphylococcal infection is mostly seen in the tropics. Focal nodular myositis is a variant of polymyositis in which focal areas of myositis cause hot, often painful, multifocal muscle masses. Table 315-1
Classification Of Polymyositis-Dermatomyositis
Group I = Primary idiopathic polymyositis
Group II = Primary idiopathic dermatomyositis
Group III = Dermatomyositis (or polymyositis) associated with neoplasia
Group IV = Childhood dermatomyositis (or polymyositis) associated with vasculitis
Group V = Polymyositis (or dermatomyositis) with associated collagen vascular disease
Incidence
Current estimates of the annual incidence of the inflammatory myopathies are approximately five cases per million population. These estimates are probably low, however; the true incidence may be as high as two to three per hundred thousand.
Clinical Manifestations
Group I: Primary Idiopathic Polymyositis
This group comprises about one-third of all cases of inflammatory myopathy. It is usually insidiously progressive over weeks, months, or even years.
Rarely the disease is acute, producing severe muscle weakness in a matter of days or even rhabdomyolysis. The disease may develop at any age. Affected females outnumber males 2:1.
Patients first become aware of weakness of the proximal limb muscles, especially the hips and thighs, and find difficulty in arising from the squatting or kneeling position and in climbing or descending stairs. When shoulder girdle muscles are involved, placing an object on a high shelf or combing the hair becomes difficult. Occasionally the disease is more restricted, affecting only the neck, the shoulder, or the quadriceps muscles. Aching pain in the buttocks, thighs, and calves is experienced in about 10 percent of the cases, and tenderness on palpation in another 20 percent. In the majority of patients the disorder is painless.
Early symptoms of dysphagia and weakness of flexor muscles of the neck in a patient with a chronic myopathy suggest the diagnosis of polymyositis.
When the patient is first seen, there may be weakness of the muscles of the trunk, the pectoral and pelvic girdles, the upper arms and thighs, the neck, and the pharynx. Ocular muscles are almost never affected except in a rare association with myasthenia gravis. The distal muscles are spared in about 75 percent of cases. Muscle atrophy, contractures, and diminished tendon reflexes are rare in early myositis and never as pronounced as in muscular dystrophies and denervating conditions.
When the reflexes are disproportionately reduced, carcinoma with polymyositis and polyneuropathy or the Lambert-Eaton syndrome should be considered.
Occasionally, the reflexes may be paradoxically brisk in dermatomyositis-polymyositis, perhaps due to irritation of muscle spindle receptors by the inflammation.
At presentation about 25 percent of patients have dysphagia, about 5 percent have significant respiratory impairment, and 5 percent are unable to walk. Dysphagia is due to involvement of striated muscles of the pharynx and upper esophagus. At some time in the course of the disease, cardiac abnormalities are observed in about 30 percent of cases; these include electrocardiogram (ECG) changes, arrhythmias, and heart failure secondary to myocarditis. About half of the fatal cases have pathologic evidence of cardiac disease with necrosis of myocardial fibers, usually with only modest inflammatory reaction. The frequency of myocardial infarction may be increased in those treated for long periods with glucocorticoids. In a few cases there is dyspnea due to lymphocytic pneumonitis, obliterating bronchiolitis, pulmonary edema, or pulmonary fibrosis. Arthralgia, Raynaud's phenomenon, and, rarely, low-grade fever may also be present.
Group II: Primary Idiopathic Dermatomyositis
This group comprises just over one-third of all cases of myositis. The skin changes may precede or follow the muscle syndrome and include a localized or diffuse erythema, maculopapular eruption, scaling eczematoid dermatitis, or, rarely, an exfoliative dermatitis. The classic lilac-colored (heliotrope) rash is on the eyelids, bridge of the nose, cheeks (butterfly distribution), forehead, chest, elbows, knees and knuckles, and around the nail beds. Itching may be troublesome in some cases. The skin lesions may be subtle and easily overlooked.
Periorbital edema is frequent, particularly in acute cases. The skin lesions may occasionally ulcerate.
Subcutaneous calcification may occur, especially in children.
The typical rash and myositis allow a diagnosis of dermatomyositis, and such cases may be placed in this category if idiopathic and into groups III, IV, and V if there are other features, namely malignancy, vasculitis in children, and an established collagen vascular disease. There should be concern about an underlying malignancy in patients over the age of 40 with dermatomyositis.
Group III: Polymyositis Or Dermatomyositis With Neoplasia
This syndrome, which comprises about 8 percent of all cases of myositis, is categorized separately, although muscle and skin changes are indistinguishable from those in the other groups.
Malignancy, however, is uncommon in myositis seen in children and in association with a connective tissue disorder. The malignancy may antedate or postdate the onset of the myositis by up to 2 years.
The incidence of neoplasia is higher in patients over the age of 40 and is particularly high in patients over age 60; therefore, in such patients a thorough history and clinical examination (including breast, gynecologic, and rectal) should be supplemented by complete blood count, biochemical profile, serum protein electrophoresis and immunofixation, screening for carcinoembryonic antigen, urine analysis for blood and cytology, stool samples for occult blood, chest x-ray, sputum for cytology, and bone scan seeking clues for an underlying malignancy. This relatively inexpensive search uncovers most malignancies; undirected radiologic screening procedures are costly and unhelpful in improving the yield. The most common malignancies are lung, ovary, breast, gastrointestinal tract, and lymphoproliferative disorders. The myositis is a paraneoplastic syndrome, the cause of which may lie in an altered immune status, cross-reactive antigens between tumor and muscle, or an occult viral infection of the muscle.
Group IV: Childhood Polymyositis And Dermatomyositis Associated With Vasculitis
This group comprises about 8 to 20 percent of all cases of myositis in various series. Inflammatory myopathy in childhood is frequently associated with skin involvement and clinical or histologic evidence of vasculitis in skin, muscles, gastrointestinal tract, and other organs. Degeneration and loss of capillaries in a perifascicular distribution occur in the skeletal muscles; often necrotizing lesions of the skin, and ischemic infarction of kidneys, gastrointestinal tract, and rarely brain may be seen.
Consequently, some authors have reported mortality rates of up to one-third in childhood dermatomyositis, though most have found that the prognosis is better than in adult dermatomyositis-polymyositis. Based upon current data, it is unclear whether or not all cases of childhood myositis should be included in group IV.
Subcutaneous calcification is frequently present in childhood dermatomyositis.
Group V: Polymyositis Or Dermatomyositis With An Associated Connective Tissue Disorder
This "overlap group" of myositis comprises about one-fifth of all cases that occur in association with several connective tissue diseases. Progressive systemic sclerosis, rheumatoid arthritis, mixed connective tissue disease (the rheumatologic overlap disorder), and lupus erythematosus are the most common associated conditions; polyarteritis nodosa and rheumatic fever are more rarely associated. Criteria for placement in the "overlap group" combine the demonstration of the appropriate clinical and laboratory abnormalities required for the diagnosis of the connective tissue disorder together with clinical and laboratory evidence of myositis. The diagnosis of myositis is often difficult in patients with a connective tissue disorder producing arthritis with secondary (disuse) muscle weakness with type II fiber atrophy.
Moreover, perivascular inflammatory foci are common in muscle in connective tissue disorders.
Demonstration of increased serum creatine kinase (CK), electromyography (EMG), and muscle biopsy are often required to make this diagnosis. Though patients in this overlap group usually respond to glucocorticoid therapy, the prognosis for recovery of function is poorer than in pure dermatomyositis-polymyositis. Dysphagia in group V patients with progressive systemic sclerosis is often due to involvement of the smooth muscle of the distal third of the esophagus.
Laboratory Findings
In all forms of polymyositis there may be elevated serum levels of the enzymes present in skeletal muscle, such as, aldolase, serum glutamic oxaloacetic transaminase, lactic acid dehydrogenase, and serum glutamic pyruvate transaminase. The degree of elevation decreases from the first to the last in this series of enzymes, and the pattern is the reverse of that seen in liver disease. The erythrocyte sedimentation rate is elevated in about two-thirds of cases. Tests for circulating rheumatoid factor are positive in less than one-half and for antinuclear antibodies in about three-quarters of the cases. Most other hematologic indexes are normal. Several autoantibodies seem to be associated with clinically distinct groups of patients. Anti-Jo-1 antibodies are more common in polymyositis, especially in patients with interstitial lung disease, and anti-nRNP antibodies are often associated with polymyositis seen in lupus erythematosus. Other antibodies seen in patients with dermatomyositis and polymyositis in association with connective tissue diseases include anti-Scl-70 (progressive systemic sclerosis), anti-Sm (lupus erythematosus), anti-Ro and anti-La (Sjögren's syndrome and lupus erythematosus), and anti-ENA (mixed connective tissue disease).
Myoglobin can be found in the urine when muscle destruction is acute and extensive; rarely, acute polymyositis causes the full syndrome of rhabdomyolysis and myoglobinuria. In about 40 percent of cases EMG reveals a markedly increased insertional activity (muscle irritability), together with the typical myopathic triad of motor unit action potentials, which are of low amplitude, are polyphasic, and have an abnormally early recruitment. In a further 40 percent of the patients only myopathic changes are present. The ECG is abnormal in about 5 to 10 percent of the cases at presentation. Since the pathologic process in myositis is patchy, greater diagnostic yield is accomplished by obtaining a biopsy from two clinically affected muscles and by skip serial sectioning of all specimens. Magnetic resonance imaging may serve to identify sites of muscle involvement. Muscles recently used for EMG or intramuscular injection must be avoided as these procedures can produce inflammatory changes and muscle fiber damage, leading to false-positive results. In about two-thirds of cases, the biopsies will demonstrate the typical pathologic changes of myositis, but despite following the above recommendations, about 10 percent of cases have normal muscle biopsy.
Skeletal Muscle Pathology
The principal changes in muscle consist of infiltrates of inflammatory cells (lymphocytes, macrophages, plasma cells, and rare eosinophils and neutrophils) and destruction of muscle fibers with a phagocytic reaction. Perivascular (usually perivenular) inflammatory cell infiltration is the hallmark of polymyositis. Interstitial inflammatory cell infiltration is also a prominent feature of the disease, but lesser degrees of it may be seen in other conditions as a secondary reaction (e.g., in facioscapulohumeral and Becker's muscular dystrophy). Evidence of muscle fiber degeneration and regeneration is almost invariably present. Many of the residual muscle fibers are small, with increased numbers of sarcolemmal nuclei. Either the degeneration of muscle fibers or the infiltration of inflammatory cells may predominate in any given biopsy specimen. Blood vessel changes and perifascicular atrophy are more prominent in childhood dermatomyositis than in adult dermatomyositis and polymyositis. Capillary loss due to endothelial cell necrosis occurs particularly in the periphery of fascicles and may explain the perifascicular atrophy. Other features include reduplication of capillary basement membrane and the presence of tubular inclusions within endothelial cells. Type II muscle fiber atrophy and muscle infarcts also may be found. Vasculitis is also seen in polymyositis or dermatomyositis associated with connective tissue disorders.
Diagnosis
Patients with dermatomyositis who have the characteristic skin rash, muscle weakness, EMG changes, and elevation of serum CK may not require a muscle biopsy to confirm the diagnosis. In the case of idiopathic polymyositis, however, a firm diagnosis must be based on the presence of a typical clinical picture, a typical EMG, elevation of serum CK, and a diagnostic muscle biopsy. All four of these criteria are required to be certain of the diagnosis, since inflammatory changes may occasionally occur in other myopathies (e.g., facioscapulohumeral muscular dystrophy) and in other connective tissue disorders without clear muscle weakness. However, in fewer than one-third of cases of polymyositis are ALL these criteria satisfied. It may be particularly difficult to obtain a diagnostic muscle biopsy because of the patchy nature of the disease. Thus, a therapeutic trial of glucocorticoids should be given when full investigation of a patient with significant disability leaves a diagnosis of "possible polymyositis," usually because of a nondiagnostic muscle biopsy.
Treatment
Glucocorticoids in high dosage is the accepted treatment for severe dermatomyositis-polymyositis, though there is no controlled trial to prove its effectiveness. Prednisone is generally started at a dose of 1 to 2 mg/kg body weight per day (60 to 100 mg/d for adults). Improvement may begin within 1 to 4 weeks, though in some patients treatment may need to be continued for 3 months before improvement occurs. When improvement is noted, the daily dose may be reduced by 5 mg every 4 weeks. Repeated manual muscle testing and serum CK determinations should be performed to ensure that the myositis does not relapse. At about 40 mg/d, the schedule is changed gradually to 80 mg every other day in order to reduce the incidence of glucocorticoid side effects. There is some evidence that the use of alternate-day glucocorticoids from the outset may be effective, particularly in patients with milder disease. Adults with acute to subacute dermatomyositis-polymyositis tend to improve more rapidly than those with chronic polymyositis; children also respond in most cases. If the dose is reduced too rapidly, or to too low a level, relapse will occur, necessitating return to high dosage.
Prednisone therapy may have to be continued for several years, but an attempt should be made every year to withdraw the therapy from patients who are clinically stable in order to determine if the disease is still active.
Cytotoxic drugs should be tried when the response to glucocorticoids is inadequate after 1 to 3 months or when relapses are frequent. The combined use of glucocorticoids and a cytotoxic drug usually allows a lower dose of glucocorticoids to be used.
Azathioprine (2.5 to 3.5 mg/kg body weight per day in divided doses) is the most commonly used cytotoxic drug in this disease; preliminary studies have shown a benefit of azathioprine as adjunctive therapy in glucocorticoid-treated patients. The aim of therapy with azathioprine is to lower the total lymphocyte count to about 750/mcL, while maintaining the hemoglobin level above 12 g/dL, the total white cell count above 3000/mcL, and the platelet count about 125,000/mcL. Periodic blood counts are required to monitor the cytotoxic drug therapy. Uncontrolled studies have shown some benefit with methotrexate, cyclophosphamide, and cyclosporine. Methotrexate is effective at doses that do not produce lymphopenia (usual dose about 0.5 mg/kg body weight per week achieved by slowly increasing from a starting dose of 10 mg). In a small controlled study, high-dose intravenous immunoglobulin (IVIg) therapy (0.4 g/kg daily for 5 consecutive days) produced improvement in patients with steroid-resistant dermatomyositis and probably should be used in severe or refractory cases.
Anecdotal reports have suggested that IVIg may also be effective in polymyositis resistant to other forms of therapy. Total-body irradiation has been successfully used in some patients with disease refractory to glucocorticoids and immunosuppressants, but long-term follow-up and controlled studies are lacking for this potentially dangerous therapy. A controlled trial of plasma exchange and leukapheresis in a small number of patients with dermatomyositis-polymyositis resistant to glucocorticoids showed no benefit over sham pheresis. Bed rest has been recommended in the acute phase of the disease but is harmful in the long term. Physiotherapy and rehabilitative devices are important in the long-term treatment of patients with dermatomyositis-polymyositis.
Patients older than age 40, particularly those with dermatomyositis, should be followed closely for the possibility of malignant disease. If a malignant lesion is found, it should be treated, since the muscle weakness may disappear if the neoplasm is eradicated. However, a response to glucocorticoids can usually be obtained even in patients with dermatomyositis-polymyositis associated with a malignancy.
Monitoring serum CK levels during reduction of immunosuppressive therapy is useful, since a rise in level generally indicates an incipient clinical relapse. CK levels are not used to monitor initial response to prednisone, because prednisone reduces CK levels independent of any effects on the disease process.
Side effects of high-dose daily glucocorticoid therapy are relatively common in patients treated for polymyositis and may limit therapy. However, these can be minimized by appropriate use of alternate-day therapy and judicious use of calcium supplements, vitamin D, and H2-receptor blockers.
When patients who have been stable on a static dose of prednisone develop increasing muscle weakness, this may be due to either a relapse of the myositis or to glucocorticoid myopathy. An EMG, serum CK measurement, and, rarely, muscle biopsy may help in differentiating these two conditions if the changes of myositis are present.
Often, however, the only way to distinguish between these two conditions is to reduce the dose of prednisone slowly; if glucocorticoid myopathy is the cause of the weakness, it will improve as the dose is reduced; if a relapse of the myositis is responsible, the weakness will increase with reduction in the dose.
Side effects of cytotoxic drugs include marrow suppression, alopecia, gastrointestinal tract disorders, damage to the testes and ovaries, infections, and potential for malignancy.
