Polymyositis

The pathogenesis of polymyositis points toward a T-cell–mediated cytotoxic process directed against unidentified muscle antigens. Supporting this conclusion is the involvement of CD8 T cells, which, along with macrophages, initially surround healthy nonnecrotic muscle fibers and eventually invade and destroy them.[8]  (See the image below.)

Polymyositis. Close view of muscle biopsy, showing chronic inflammatory infiltrate consisting of T lymphocytes, especially CD8+ T lymphocytes.

The factors triggering a T-cell–mediated process in polymyositis are unclear. Viruses have been implicated; so far, however, the only viruses that have been etiologically connected with the disease are the human retroviruses human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus type I (HTLV-I), the simian retroviruses, and coxsackievirus B. Those viruses may directly invade the muscle tissue, damaging the vascular endothelium and releasing cytokines, which then induce abnormal expression of the major histocompatibility complex (MHC) and render the muscle susceptible to destruction.

An autoimmune response to nuclear and cytoplasmic autoantigens is detected in about 60-80% of patients with polymyositis and dermatomyositis. Some serum autoantibodies are shared with other autoimmune diseases (ie, myositis-associated antibodies [MAAs]), and some are unique to myositis (ie, myositis-specific antibodies [MSAs]). MSAs are found in approximately 40% of patients with polymyositis or dermatomyositis, whereas MAAs are found in 20-50% of these patients.

Myositis-specific antibodies

The identified MSA targets include the following 3 distinct groups of proteins:

• Aminoacyl–transfer ribonucleic acid (tRNA) synthetases (anti–Jo-1)
• Nuclear Mi-2 protein
• Components of the signal-recognition particle (SRP)

Most of the anti-tRNA synthetase antibodies are directed toward functional and highly conserved domains of the enzyme. As many as 6 of 20 aminoacyl-tRNA synthetases have been described, but anti-histidyl-tRNA synthetase (Jo-1) is most common (20-30%). Autoantibodies directed toward the other synthetases specific for alanine (anti-PL12), glycine (anti-EJ), isoleucine (anti-OJ), threonine (anti-PL7), and asparagine (anti-KS) have been reported in only about 1% of patients.

Anti–Jo-1 autoantibodies were originally described as precipitating autoantibodies in sera of patients with polymyositis. Subsequently, the anti-Jo-1 antibodies were recognized to be specific for patients with polymyositis. The target for the anti-Jo-1 antibodies was the aminoacyl-tRNA synthetases, a family of distinct cellular enzymes.

The Jo-1 antigen is histidyl-tRNA synthetase. This enzyme is partially responsible for attaching tRNA to its cognate ribosomal RNA (rRNA). The Jo-1 antigen migrates as a 53-kd protein on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE).

The presence of autoantibodies against the Jo-1 antigen has been reported in 15-30% of polymyositis patients by immunodiffusion. Anti–Jo-1 antibodies are almost completely specific for myositis and are more common in polymyositis than in dermatomyositis; they are rare in children. The presence of anti–Jo-1 antibodies defines a distinct group of polymyositis patients with interstitial lung disease, arthritis, and fevers. The anti–Jo-1 response appears to be self-antigen driven, having a broad spectrotype over time and undergoing isotype switching. Anti–Jo-1 antibodies also inhibit the function of histidyl-tRNA synthetase in humans more than they do in other species.

Anti–Mi-2 antibodies recognize a major protein of a nuclear complex formed by at least 7 proteins that is involved in the transcription process. Autoantibodies recognizing Mi-2 are considered specific serologic markers of dermatomyositis. They are detected in about 10% of patients with myositis and are associated with relatively acute onset, a good prognosis, and a good response to therapy.

Anti-SRP antibodies are directed toward an RNA-protein complex that consists of 6 proteins and a 300-nucleotide RNA molecule (7SL RNA) and present in 5% of myositis patients[9] . Patients with anti-SRP antibodies have acute polymyositis with cardiac involvement, a poor prognosis, and a poor response to therapy.

Myositis-associated antibodies

The MAA are found in the sera of 20-50% of patients and are commonly encountered in other connective tissue diseases. The most important antigenic targets of the MAA are the following:

• PM/Scl nucleolar antigen
• Nuclear Ku antigen
• Small nuclear ribonucleoproteins (snRNP)
• Cytoplasmic ribonucleoproteins (RoRNP)

Anti-PM/Scl autoantibodies are generally found in patients affected by polymyositis overlapping with scleroderma. Anti-Ku antibodies are found in patients with myositis overlapping with other connective tissue diseases.

Antibodies directed against snRNP are frequently found in patients with myositis and in patients with connective tissue–disease overlap syndrome, whereas antibodies toward Ro/SSA 60 kD, Ro/SSA 52 kD, and La/SSB protein components of the RoRNP complex are almost exclusively found in patients with Sjögren syndrome and systemic lupus erythematosus (SLE).

Polymyositis is an immune-mediated syndrome secondary to defective cellular immunity that is most commonly associated with other systemic autoimmune diseases. It may be due to diverse causes that occur alone or in association with viral infections, malignancies, or connective-tissue disorders.

Risk factors

An increased association of myositis has been found with human leukocyte antigen (HLA) haplotypes A1, B8, and DR3, which also increase the risk for autoimmune diseases. Environmental triggers, especially infectious agents, have been suggested as etiologic agents. These include the following:

• Coxsackievirus B1
• HIV
• HTLV-1
• Hepatitis B virus
• Influenza
• Echovirus
• Adenovirus

Many drugs are known to cause myopathy. Most of those drugs, such as hydroxychloroquine and colchicine, cause a toxic or metabolic myopathy. However, several drugs may rarely induce an immune-mediated myopathy or myositis; in these cases, muscle biopsy shows chronic inflammatory changes consistent with polymyositis. Drugs such as D-penicillamine, hydralazine, procainamide, phenytoin, and angiotensin-converting enzyme (ACE) inhibitors have been associated with this type of inflammatory myopathy. Statins can cause severe muscle inflammation and rhabdomyolysis.

Frequency

Idiopathic inflammatory myopathies are relatively rare diseases, with an incidence in the United States that ranges from 0.5-8.4 cases per million population. Polymyositis is more common in the United States within the Black population, with the estimated Black-to-White incidences for polymyositis and dermatomyositis being 5:1 and 3:1, respectively. Internationally, polymyositis is less common among the Japanese. 

Sex- and age-related demographics

Polymyositis and dermatomyositis are more common in women than in men (2:1 ratio), while inclusion body myositis is twice as common in men.

Polymyositis usually affects adults older than 20 years, especially those aged 45-60 years. Polymyositis rarely affects children. The age of onset of polymyositis with another collagen vascular disease is related to the associated condition.

Although dermatomyositis is primarily a disease of adults, it can be seen in children, usually those aged 5-14 years. Eighty percent of patients with inclusion body myositis are older than 50 years at onset.

In most patients, polymyositis responds well to treatment, although residual weakness occurs in approximately 30% of patients. Osteoporosis, a common complication of long-term corticosteroid therapy, may cause significant morbidity. A study from Taiwan determined that the risk of osteoporosis was 2.99 times higher in patients with polymyositis, and that the risk was independent of corticosteroid and immunosuppressant treatment.[10]

Poor prognostic factors include the following:

• Advanced age
• Female sex
• African-American race
• Interstitial lung disease
• Presence of anti-Jo-1 (lung disease) and anti-SRP antibodies (severe muscle disease, cardiac involvement)
• Associated malignancy
• Delayed or inadequate treatment
• Dysphagia, dysphonia
• Cardiac and pulmonary involvement

Watanabe et al reported that negative assays for myositis-specific autoantibodies and the absence of severe muscle weakness requiring assistance at diagnosis are independent predictive factors for sustained remission in adult patients with polymyositis/dermatomyositis.[11]

Complications

Complications of polymyositis may include the following:

• Interstitial lung disease (ILD)
• Aspiration pneumonia
• Heart block
• Arrhythmias
• Congestive heart failure
• Pericarditis
• Dysphagia
• Malabsorption
• Pneumonia
• Infection ^[12]
• Myocardial infarction ^[13]
• Carcinoma - Especially in the breast and lung ^[14]
• Steroid myopathy or other complications of steroid therapy

Carruthers et al reported that patients with polymyositis are at increased risk for venous thromboembolism (VTE), with hazard ratios of 7.0 for VTE, 6.16 for deep venous thrombosis, and 7.23 for pulmonary embolism. Overall, the highest calculated incidence rate ratios were observed in the first year after diagnosis of polymyositis.[15]

A meta-analysis estimated that worldwide, the prevalence of ILD in patients with polymyositis and dermatomyositis is 41%, with the highest prevalence among Asians (50%). ILD was more frequently associated with anti-Jo-1 and anti-melanoma differentiation–associated gene 5 antibodies than other myositis-specific autoantibodies.[16]

The incidence of lung, bladder, and non-Hodgkin lymphoma may be increased in patients with polymyositis, especially in the first year after diagnosis. Nicoletis et al reported that a high pretreatment neutrophil-to-lymphocyte ratio (≥5.5) is associated with an increased risk of cancer in patients with polymyositis/dermatomyositis. These authors concluded that in patients age 60 years and older, a high neutrophil-to-lymphocyte ratio should prompt investigation for cancer, both at diagnosis of polymyositis and during follow-up.[17]

Polymyositis shares pathologic characteristics and immunologic features with amyotrophic lateral sclerosis (ALS), and a nationwide cohort study from Taiwan found that a diagnosis of polymyositis increased the likelihood of a subsequent diagnosis of ALS (P < 0.001). The association was independent of sex, age, and concomitant autoimmune diseases.[18]

Five-year survival rates in polymyositis have been estimated at more than 80%. Mortality is most often related to associated malignancy or pulmonary complications; however, elderly patients with cardiac involvement or dysphagia also have a higher mortality rate.[19]

Patients with polymyositis should be educated early about the disease, its complications, and treatment options and should be provided with realistic expectations about outcomes. Most patients show significant improvement with treatment. Stress the need for close follow-up care, continued physical therapy, and long-term therapy with monitoring of several parameters including medication toxicity and screening for malignancy. 

For patient education information, see Polymyositis. In addition, patients may visit The Myositis Association Web site.

Symptoms of polymyositis gradually develop over a period of 3-6 months. Diagnosis is usually delayed, because, unlike in dermatomyositis, no associated rash occurs before the onset of muscle disease. Family history and medication history are important in excluding other causes of myopathy.

The history of patients with polymyositis or dermatomyositis typically includes the following:

• Symmetrical, proximal muscle weakness with insidious onset
• Pain is not a predominant symptom (Myalgias occur in fewer than 30% of patients.)
• Dysphagia (30%) and aspiration, if pharyngeal and esophageal muscles are involved
• Arthralgias may be associated
• Difficulty kneeling, climbing or descending stairs, stepping onto a curb, raising arms, lifting objects, combing hair, and arising from a seated position
• Weak neck extensors cause difficulty holding the head up
• Involvement of pelvic girdle usually greater than upper body weakness
• Cardiac involvement may cause symptoms of pericarditis or cardiomyopathy
• Characteristic rash on face, trunk, and hands seen in dermatomyositis only

Muscular symptoms

Patients with polymyositis usually present with symmetrical, proximal muscle weakness in the upper and lower extremities. Weakness of neck flexors also occurs. Patients with polymyositis may occasionally report muscle pain and tenderness, which may be confused with symptoms of polymyalgia rheumatica. The disease may exist for several months before the patient seeks medical advice, and all of the muscles of the thighs, trunk, shoulders, hips, and upper arms are usually involved. Muscle weakness may fluctuate on different days and at different times. 

Fine motor movements that depend on the strength of distal muscles, such as buttoning a shirt, sewing, knitting, or writing, are affected only late in the disease.

Dysphagia secondary to oropharyngeal and esophageal involvement occurs in about one third of patients with polymyositis and is a poor prognostic sign. Dysphonia is also a poor prognostic sign but is much less common.

Ocular muscles are never involved in generalized polymyositis. However, isolated orbital myositis, an inflammatory disorder involving the extraocular muscles, is well described. Facial and bulbar muscle weakness is extremely rare in individuals with polymyositis.

A family history of neuromuscular disease, endocrinopathy, or exposure to myotoxic drugs or toxins is absent.

Constitutional symptoms and signs

Polymyositis is a systemic disease. Symptoms and signs may include the following:

• Morning stiffness
• Fatigue
• Anorexia
• Fever (associated with antisynthetase antibodies such as anti–Jo-1)
• Weight loss

Pulmonary manifestations

Pharyngeal and esophageal weakness may lead to aspiration pneumonia. Patients with polymyositis may experience exertional dyspnea secondary to weakness of chest wall muscles and diaphragmatic muscles. Patients receiving immunosuppressants are at an increased risk of infection.

Interstitial lung disease occurs in 5-30% of patients with idiopathic inflammatory myopathy (associated with antisynthetase antibodies, especially anti–Jo-1). Patients may be asymptomatic or present with exertional dyspnea, cough, and fever.[20]

Interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary capillaritis have been described in conjunction with polymyositis.

Cardiac manifestations

Cardiac involvement is unusual and, if present, portends a bad prognosis. Rhythm disturbances, conduction defects, congestive heart failure, pericarditis, pulmonary hypertension, and myocarditis can occur.

Joint involvement

Patients can present with arthralgias or arthritis. Arthritis is usually symmetrical and involves the knees, wrists, and hands (associated with antisynthetase antibodies). A severe, deforming arthropathy without erosions has been reported; erosive changes are very rare.

Overlap syndromes

Polymyositis has been associated with other connective-tissue diseases, including the following:

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Mixed connective-tissue disease
• Sjögren syndrome
• Scleroderma

About 25% of patients with scleroderma have myositis; this phenomenon has been associated with anti-PM/Scl (anti–PM-1) antibody. In Japan, anti-Ku antibody has been described with this condition.

Gastrointestinal manifestations

Symptoms may include the following:

• Dysphagia
• Odynophagia
• Nasal regurgitation
• Reflux esophagitis
• Abdominal bloating
• Constipation

Renal manifestations

Intrinsic kidney disease is rare in patients with polymyositis. Occasionally, severe rhabdomyolysis with myoglobinuria can result in acute tubular necrosis.

Cutaneous manifestations

Unlike in dermatomyositis, rash is absent in polymyositis. However, "mechanic's hands" (associated with antisynthetase antibodies), ie, hyperkeratotic eruptions over the finger pads and lateral aspects of the fingers can be seen.

Raynaud phenomenon has been described in patients with antisynthetase antibodies. Rarely, periorbital edema may occur (best described in dermatomyositis). Calcinosis occurs in approximately 5% of patients with polymyositis (in association with scleroderma-like illness). Telangiectasias are uncommon.

Amyopathic dermatomyositis is a condition in which patients have cutaneous findings of dermatomyositis without muscle weakness.

Inclusion body myositis

This condition is a slowly progressive, idiopathic, inflammatory myopathy that mostly affects men older than age 50 years. Muscle involvement predominantly includes proximal muscles but may also include distal muscles (50%), and involvement may be asymmetrical. Dysphagia occurs in most patients (60%).

Muscle weakness in polymyositis is symmetric and proximal. It is not painful, although a minority of patients report aches or cramps. On occasion, the muscle may be sore to palpation and may have a nodular and grainy feel.

Sensory examination findings are normal. Ocular and facial muscles remain normal even in advanced, untreated cases. However, ocular involvement can result in significant retinal inflammation associated with hemorrhage with possible detachment resulting in vision loss.[21]  

The pharyngeal and neck flexor muscles are often involved, causing dysphagia and difficulty in holding up the head. When the patient is first seen, many of the muscles of the trunk, shoulders, hips, upper arms, and thighs are usually involved. In restricted forms of the disease, only the neck or paraspinal muscles (camptocormia) are affected.[22]

In advanced cases and rarely in acute cases, respiratory muscles are affected. Severe weakness is almost always associated with muscular wasting. Dysphonia with nasal speech may be noted. Lung examination findings may include evidence of interstitial lung disease, such as dry inspiratory crackles ("Velcro") in the lung bases.

The tendon reflexes are preserved, but they may be absent in severely weakened or atrophied muscles.

Primary cardiac abnormalities due to myocarditis may be present in a few patients. These abnormalities mainly manifest as atrioventricular conduction defects, tachyarrhythmias, low ejection fraction, dilated cardiomyopathy, or congestive heart failure.

General systemic disturbances, such as fever, malaise, weight loss, arthralgia, and Raynaud phenomenon, may occur when polymyositis is associated with another connective-tissue disorder.

Inclusion body myositis

Inclusion body myositis manifests as severe, proximal muscle weakness with atrophy, often with distal muscle weakness. The weakness may be asymmetrical. Deep tendon reflexes may be impaired or absent if weakness is severe.

Complications include the following:

• Pulmonary (eg, aspiration pneumonia, interstitial lung disease, hypoventilation ^[23] )
• Increased incidence of malignancy in dermatomyositis as well as polymyositis ^[24]
• Dysphagia, weight loss, and malnutrition
• Ambulatory dysfunction
• Adverse effects of immunosuppressive therapy

The following laboratory findings may be present in polymyositis:

• Complete blood count (CBC) - May show leukocytosis or thrombocytosis; leukocytosis is present in more than 50% of patients
• Erythrocyte sedimentation rate or C-reactive protein level - Elevated in 50% of patients with polymyositis
• Elevated muscle enzyme levels - creatinine phosphokinase (CPK), aldolase
• Myoglobinuria
• Autoantibodies
• Positive rheumatoid factor  - Found in more than 50% of patients

Perform age-appropriate evaluation for malignancy. Testing for associated malignancy is based on age and sex and can be performed using imaging techniques such as the following[25] :

• Chest radiography
• Computed tomography (CT)
• Mammography
• Pelvic ultrasonography
• Upper and lower gastrointestinal endoscopy
• Magnetic resonance imaging (MRI)

Depending on the clinical presentation, other studies that may be appropriate include the following:

• Pulmonary function tests and diffusion capacity for evaluation of interstitial lung disease
• Electrocardiogram/echocardiogram
• Swallowing study

Muscle enzyme levels

Serum creatine kinase (CK) levels are usually elevated in persons with polymyositis, ranging from 5-50 times the reference range. A level greater than 100 times the reference level is rare.

Serum CK levels, along with careful physical examination, may be used to monitor myositis activity. However, serum CK levels may be within reference ranges despite increased disease activity (eg, in cases of chronic and late-stage polymyositis). CK levels are usually minimally elevated or within the reference range in patients with inclusion body myositis. CK levels are within the reference range in patients with corticosteroid-induced myopathy.

Other muscle enzyme levels that may be elevated include the following:

• Lactate dehydrogenase
• Aspartate aminotransferase
• Alanine aminotransferase
• Aldolase

Antibody findings

Antinuclear antibody assays are positive in one third of patients with polymyositis and in only 15% of patients with inclusion body myositis. In patients with overlap syndromes, other disease-specific antibodies may be present, such as those of Sjögren syndrome, systemic lupus erythematosus, or systemic sclerosis (eg, SSA, SSB, dsDNA, anti Sm/RNP, Scl ). 

Myositis-specific antibodies include the following[26] :

• Antisynthetase antibodies (such as anti-Jo-1 antibodies) - Associated with certain clinical features; antisynthetase syndrome may manifest as idiopathic inflammatory myopathy, interstitial lung disease, arthritis, Raynaud phenomenon, fever, and/or mechanic's hands

• Signal-recognition particle (SRP) antibodies - Approximately 5% of patients with polymyositis have antibodies to signal recognition particles (SRPs), which are associated with acute onset of severe weakness, increased incidence of cardiac involvement, and higher mortality rates.

• Anti-HMGCR autoantibodies in statin-induced auto immune myopathy[27]

• Other myositis-specific autoantibodies (MSA) include Mi-2 ,TIF1-γ, anti-p155/p140, anti-CADM-140, NXP2, and SAE, among others[28]

Muscle-imaging techniques such as magnetic resonance imaging (MRI) and ultrasonography may be useful to document and localize the extent of muscle involvement. MRI scans show signal intensity abnormalities of muscle due to inflammation, edema, or scarring (see the image below) .Whole-body MRI can also identify associated extramuscular diseases, such as interstitial lung disease and systemic malignancy.[29]

Polymyositis. MRI of thighs showing increased signal in the quadriceps muscles bilaterally consistent with inflammatory myositis.

MRI scans may also be used to guide muscle biopsy and to monitor disease activity.[30] However, many clinicians choose the biopsy site on the basis of findings at electromyography and clinical examination and believe that MRI is not required. Barium swallow studies are helpful for evaluation of dysphagia or dysphonia.

Chest radiography and high-resolution CT scanning of the chest are helpful for the evaluation of interstitial lung disease. CT scanning of the chest, abdomen, and pelvis is considered for screening of associated malignancy. Chest radiography may also reveal evidence of associated malignancy.

Other studies to consider in screening for associated malignancy are as follows:

• Mammography 
• Pelvic ultrasonography
• Upper and lower gastrointestinal endoscopy

Electromyographic findings are abnormal in almost all patients (90%) with polymyositis. Various abnormalities consistent with polymyositis may be found, depending on the stage of disease. In patients with inclusion body myositis, the following myopathic and neuropathic changes may be present:

• Evidence of membrane irritability, increased insertional activity, fibrillation potentials, positive sharp waves at rest

• Myopathic changes of motor unit action potential; decreased amplitude and duration; increased polyphasic potentials; bizarre, high-frequency, repetitive discharges

• Chronic changes, evidence of denervation-reinnervation

Muscle biopsy (eg, deltoid or quadriceps femoris) is crucial in helping to diagnose polymyositis and in excluding other rare muscle diseases.[31] MRI and EMG can be used to guide the site of biopsy. Avoid biopsy of sites recently studied with EMG by using the contralateral side.

Inflammatory changes are seen on muscle biopsy. Findings occasionally may be normal because of patchy involvement. (See the images below.)

Polymyositis. Hematoxylin and eosin frozen section shows polymyositis. Endomysial chronic inflammation is present among intact myofibers, which are remarkable only for increased variability of fiber size. Image courtesy of Roberta J. Seidman, MD.

Polymyositis. Hematoxylin and eosin paraffin section shows polymyositis. Patient had dense endomysial inflammation that contains an abundance of plasma cells, which can be observed in patients with chronic polymyositis. Two necrotic myofibers, characterized by dense eosinophilic staining, are observed. Focal fatty infiltration of the muscle is present in the lower left quadrant of the photomicrograph. Image courtesy of Roberta J. Seidman, MD.

Polymyositis. Hematoxylin and eosin paraffin section shows polymyositis. Photomicrograph illustrates attack on a nonnecrotic myofiber by autoaggressive T lymphocytes. On the left, the central myofiber is intact. On the right, it is obliterated by a segmental inflammatory attack. If immunohistochemistry were performed, expected findings would include an admixture of CD8 T lymphocytes and macrophages in the inflammatory process. Image courtesy of Roberta J. Seidman, MD.

Polymyositis. Hematoxylin and eosin paraffin section shows polymyositis. Longitudinal section shows a dense, chronic, endomysial inflammatory infiltrate. Image courtesy of Roberta J. Seidman, MD.

Macrophage-predominant myocyte destruction, with few to no lymphocytes, is the histopathologic hallmark of necrotizing autoimmune myopathy (NAM), a recently recognized entity within the spectrum of idiopathic inflammatory myopathies. Patients typically have a history of malignancy or statin use and present with proximal muscle weakness and markedly elevated creatine kinase levels.

Muscle biopsy shows muscle fibers in varying stages of inflammation, necrosis, and regeneration. Findings include focal endomysial infiltration by mononuclear cells (consisting of mostly CD8+ T lymphocytes and macrophages), capillary obliteration, endothelial cell damage, and increased amounts of connective tissue. Later in the course of polymyositis, muscle-cell degeneration, fibrosis, and regeneration may be observed. (See the images below.)

Polymyositis. Histopathology slide shows endomysial mononuclear inflammatory infiltrate and muscle fiber necrosis.

Polymyositis. Close view of muscle biopsy, showing chronic inflammatory infiltrate consisting of T lymphocytes, especially CD8+ T lymphocytes.

Because the inflammatory infiltrates can be small and multifocal, they can be missed in a small muscle-biopsy specimen. Perifascicular atrophy or prominent perivascular infiltrates are not present, and the blood vessels are normal. When the disease becomes chronic, the connective tissue increases. The diagnosis of polymyositis is definite when a patient has subacute elevated levels of serum CK and findings on muscle biopsy consistent with the histologic features of polymyositis.

Inclusion body myositis is histologically similar to polymyositis, with the additional presence of intracytoplasmic inclusion bodies observed on electron microscopy. Dermatomyositis shows inflammatory changes, predominantly in the perimysial and perivascular regions with CD4+ T and B lymphocytes (see the image below). Corticosteroid-induced myopathy causes no inflammatory changes. Type II fiber atrophy is the characteristic feature.

Polymyositis. Hematoxylin and eosin paraffin shows dermatomyositis. In dermatomyositis, inflammation is characteristically perivascular and perimysial. Vessel oriented approximately vertically in the center has a mild perivascular chronic inflammatory infiltrate. The endothelium is plump. The wall is not necrotic. A few lymphocytes in the wall of the vessel are probably in transit from the lumen to the external aspect of the vessel. Some observers may interpret this finding as vasculitis, but it is certainly neither necrotizing vasculitis nor arteritis. Image courtesy of Roberta J. Seidman, MD.

Treatment of polymyositis (PM) is empirical because of the rarity of the disease and the paucity of randomized, controlled trials. Established options include corticosteroids and immunosuppressants; limited data support the use of other agents.

Corticosteroids

Prednisone is the first-line treatment of choice for polymyositis. Typically, the dose is 1 mg/kg/day, either as a single dose or in divided doses. This high dose is usually continued for 4-8 weeks, until the creatine kinase (CK) level returns to reference ranges. Taper prednisone by 5-10 mg on a monthly basis until the lowest dose that controls the disease is reached.

Monitor response to therapy based on improvement in muscle strength and muscle endurance and decrease in CK levels. Closely monitor patients with polymyositis for disease activity and adverse effects of corticosteroids, such as weight gain, hypertension, diabetes mellitus, osteopenia, and steroid myopathy.

Corticosteroid myopathy can occur during the course of treatment and must be distinguished from reactivation of muscle disease. The CK level is usually within reference ranges in patients with steroid myopathy. No improvement is observed with raised doses of steroids; rather, the condition worsens if the dose is increased.

Immunosuppressants

Immunosuppressive agents are indicated in patients who do not improve with steroids within a reasonable period (ie, 4 wk) or in whom adverse effects from corticosteroids develop. Patients with poor prognostic indicators, such as dysphagia or dysphonia, are likely to require immunosuppressive agents. Under these circumstances, methotrexate is the second-line agent. Azathioprine, cyclophosphamide, and cyclosporine have been used with varying success as second-line agents for polymyositis. Patients with inclusion body myositis usually respond poorly to corticosteroids and immunosuppressive agents.

Obtain the following baseline tests before initiating immunosuppressive therapy:

• Complete blood cell count (CBC)
• Liver function tests
• Muscle enzymes
• Pulmonary function studies
• Chest x-ray
• Tuberculosis testing
• Hepatitis B and C serology

Other agents

Intravenous immunoglobulin (IVIG) has been used for the short-term treatment of steroid-resistant cases of polymyositis.[32, 33]

The role of newer agents, such as tumor necrosis factor (TNF) inhibitors, remains unclear. Case reports describe successful use of the TNF inhibitor infliximab in refractory cases, but small clinical trials have yielded mixed results, with clinical flares occurring in some patients.[34, 35, 36, 37, 38]  In a randomized controlled trial with crossover, 4 of 12 patients with refractory dermatomyositis and polymyositis responded to infliximab at a dose of 5 or 7.5 mg/kg; infliximab was well tolerated.[39]  

A small trial of the TNF inhibitor etanercept provided encouraging results.[40]

The anti-CD20 monoclonal antibody rituximab may be an approach to therapy for refractory cases. The benefit of rituximab was demonstrated in the Rituximab in Myositis (RIM) study, the largest randomized trial ever completed in myositis. RIM included 200 patients with polymyositis, dermatomyositis, or juvenile dermatomyositis not controlled by corticosteroids and other immunosuppressive agents.[41]

The study had a placebo phase design in which half the patients received two rituximab infusions at baseline, whereas the other half received rituximab 8 weeks later. At a median of approximately 20 weeks, 83% of study subjects receiving rituximab met the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement. Whether rituximab was received early or late made no significant difference in the time to achieve the definition of improvement.[41]

The calcineurin inhibitor tacrolimus appears to be effective, safe, and well tolerated in patients with polymyositis that is refractory to other treatments.[42] In a systematic review, CK levels patients decreased in all patients treated with tacrolimus, the average glucocorticoid dosage was reduced from 33.8 to 11.5 mg/day, and the majority of patients showed improvement in muscle strength and physical function status. However, randomized, controlled trials of tacrolimus in poymyositis have yet to be conducted.[43]

Mycophenolate mofetil has been reported in case reports to be effective.[44]

ACTH gel has shown some promise in case series with improvement in muscle as well as skin disease. Further randomized trials are required.[45]  

Diet and Activity

Patients with polymyositis may benefit from a high-protein diet. Monitor patients to avoid excessive weight gain due to corticosteroid use.

Encourage patients with polymyositis to start a supervised exercise program early in the disease course.[46] During the acute stage of polymyositis, patients may benefit from heat therapy, passive range-of-motion exercises, and splints to avoid contractures.

Once acute inflammation is under control, the rehabilitation program should include active range-of-motion exercises and isometric contractions of the muscle groups. With improvement in muscle strength, patients should perform isotonic exercises with light resistance. Encourage patients to do 15-30 minute sessions of aerobic exercise when the disease is inactive.

Consultations

A neurologist or rheumatologist is the primary consultant. Consultation may also be required with the following specialists:

• Pulmonary specialists
• Cardiologists
• Physical therapists
• Speech therapists (for swallowing evaluation)

Treatment of extramuscular manifestations of polymyositis includes the following:

• Constitutional symptoms, such as fever and fatigue - Usually respond to corticosteroids

• Articular symptoms - Usually resolve with treatment of the myositis; some patients develop a rheumatoid-like arthropathy, which may require immunosuppressive treatment such as methotrexate

• Interstitial lung disease - These patients may benefit from high-dose steroids and immunosuppressive treatment, especially cyclophosphamide. In a study of 30 patients and a historical comparison group of 21 patients, Shimojima et al reported improved outcomes when corticosteroids were combined with cyclosporine, administered orally or by continuous intravenous (IV) infusion for more severe cases; IV cyclophosphamide pulse therapy was added for exacerbations.[47]  In a study of 14 patients with dermatomyositis and acute interstitial pneumonia treated with infliximab, Chen et al reported satisfactory relief in the 10 patients given early treatment but treatment failure and death in those treated late.[48] Results of a study by Takada et al in 26 patients suggest that initial treatment with tacrolimus and corticosteroids may improve short-term mortality of patients with interstitial pneumonia.[49]

• Cardiac abnormalities - May respond to corticosteroids; symptomatic arrhythmias require antiarrhythmic therapy, and symptomatic heart block is treated with placement of a pacemaker

Dysphagia secondary to cricopharyngeal involvement in polymyositis/dermatomyositis is a rare manifestation and usually reflects poor prognosis. Dysphagia responds either slowly or poorly to immunosuppressive therapies or high-dose corticosteroids. A large case series indicated that treatment with IVIG can be effective in patients with steroid-resistant esophageal manifestations of polymyositis/dermatomyositis.[50]

Dysphagia may be severe enough to require enteral feeding through a gastrostomy tube or parenteral nutrition.

Inpatient care

Patients with polymyositis should be closely monitored in the hospital while they are taking high-dose corticosteroids. Ideally, testing for tuberculosis should be performed before initiation of corticosteroid treatment.

Serial creatine kinase (CK) levels should be monitored to assess improvement. Severe pulmonary or cardiac involvement may require management in an intensive care setting. In patients treated with immunosuppressive agents, regularly monitor CBC, liver function test and renal function. Patients with polymyositis usually need aggressive inpatient physical therapy.

Outpatient care

Patients with polymyositis should be seen every 2-3 weeks initially; if they are stable, they should be seen at monthly intervals thereafter.

Frequently check laboratory tests, including CK, and document muscle strength evaluation results. Check the patient's weight at each visit. Routine age-appropriate cancer screening is recommended. Arrange outpatient physical therapy.

The following precautions can aid against the following complications associated with polymyositis or its treatment:

• Raynaud phenomenon - Patients with polymyositis should avoid cold exposure if Raynaud phenomenon is a significant problem

• Esophageal involvement - Patients with esophageal involvement can elevate the head of the bed and avoid eating before bedtime to minimize reflux and risk of aspiration; histamine-2 receptor antagonists, proton pump inhibitors, and/or prokinetic agents may be useful in patients with esophageal reflux and dysmotility.

• Osteoporosis - Check a baseline bone density scan. Prescribe calcium with vitamin D supplementation and oral bisphosphonates for osteoporosis prophylaxis or other agents for osteoporosis treatment.

Therapy for polymyositis is based on immune suppression, starting with corticosteroids. Prednisone is the first-line treatment of choice. Immunosuppressive agents are indicated in patients who do not improve with steroids within a reasonable period (ie, 4 weeks) or who experience adverse effects from corticosteroids. Newer agents such as rituximab are showing promise.[36]

Class Summary

These agents inhibit the inflammatory process via multiple mechanisms, including the inhibition of proinflammatory cytokine production, monocyte/macrophage function, and angiogenesis.

Prednisone

Prednisone is an anti-inflammatory and immunosuppressive agent used in the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing neutrophilic activity. Prednisone also stabilizes the lysosomal membrane and suppresses lymphocytes, reducing cytokine and antibody production.

Corticotropin (Acthar Gel, HP Acthar Gel)

Porcine ACTH, stimulates adrenocortical hormone production

Class Summary

These agents may be of benefit in patients whose condition has not responded to steroids or in patients unable to tolerate prednisone.

Methotrexate (Rheumatrex, Trexall)

Methotrexate has an unknown mechanism of action in the treatment of chronic inflammatory diseases. It may affect immune function, including through inhibition of the production of proinflammatory cytokines. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response.

Azathioprine (Imuran, Azasan)

Azathioprine is a purine analog that inhibits the synthesis of deoxyribonucleic acid (DNA), RNA, and proteins. It may decrease the proliferation of immune cells, resulting in lower immunologic activity.

IV Immunoglobulin (Privigen, Hizentra, Octogam, Gammagard)

IVIG neutralizes circulating myelin antibodies through anti-idiotypic antibodies. It down-regulates proinflammatory cytokines, including interferon gamma; blocks Fc receptors on macrophages; suppresses helper T and B lymphocytes; and augments suppressor T lymphocytes. IVIG's exact mechanism of action in the treatment of polymyositis is unknown.

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal cells such as lymphocytes and neoplastic cells.

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclosporine is a cyclic polypeptide that suppresses cell-mediated immune reactions such as delayed hypersensitivity and, to a lesser extent, humoral immunity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. Cyclosporine selectively inhibits the transcription of interleukin 2, predominantly in helper lymphocytes.

Mycophenolate (CellCept, MMF, Myfortic)

Inhibits T- and B-cell proliferation, as well as antibody production

Tacrolimus (Astagraf XL, Envarsus XR, Hecoria)

Tacrolimus is a calcineurin inhibitor and inhibits the phosphatase activity of calcineurin which leads to inhibition of T cell response to antigens.

Class Summary

These agents may be used in refractory cases of polymyositis that have failed to respond to conventional therapy with steroids.

Etanercept (Enbrel)

Etanercept binds specifically to TNF and blocks its interaction with cell-surface TNF receptors, rendering TNF biologically inactive.

Infliximab (Remicade)

Infliximab binds to soluble and transmembranous forms of TNF-alpha, rendering TNF biologically inactive.

Class Summary

Clinical trials with rituximab have shown encouraging results in patients who are refractory to first-line treatment.

Rituximab (Rituxan)

(Off-label) Rituximab is a humanized monoclonal antibody that binds to CD20 antigen, thereby inducing complement- or antibody-mediated cytolysis. Clinical trials in refractory polymyositis have shown improvement in patients who have failed corticosteroids and other immunosuppressive agents.