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Polymyositis (PM) is one of the inflammatory myopathies, disorders characterized pathologically by the presence of inflammatory infiltrates in striated muscle. The principal clinical manifestation of PM is proximal muscle weakness. The cause of PM is unknown, but current evidence suggests that it is an autoimmune disorder. PM can affect people of any age, but most commonly presents between the ages of 50 to 70. PM is rarely seen in people younger than 18 years of age, and is twice as common among females than males. PM is more common in blacks than in whites. The overall prevalence of PM is 1 per 100,000. Muscle weakness may develop suddenly or more insidiously over a period of weeks to months. The classic symptom of PM is proximal weakness, which may manifest as difficulty holding the arms over the head, climbing stairs, or rising from a chair. Weakness of the striated muscle of the upper esophagus may result in dysphagia, dysphonia, and aspiration. The chest wall muscles may be affected, leading to ventilatory compromises. Involvement of cardiac muscle may lead to arrhythmias and congestive heart failure. Dermatomyositis (DM) is closely related to PM, and both are distinguished primarily by the occurrence of characteristic skin abnormalities in the former. PM and DM may be associated with a variety of malignancies. PM may also occur as part of the spectrum of other rheumatic diseases like systemic lupus erythematosus and mixed connective tissue disease. Moreover, inflammatory myopathy may be caused by some drugs (procainamide, D-penicillamine), and viruses, most notably the retroviruses. Corticosteroids and immunosuppressive agents are the mainstays of therapy for PM. The principal goals of therapy are to improve strength and improve physical functioning. Many patients require treatment for several years. The 5-year survival rate for treated patients is in the order of 95%. Up to one-third of PM patients may be left with some degree of residual muscle weakness.
DM and PM are classified as idiopathic inflammatory myopathies. They are clinically characterized by proximal muscle weakness, elevations of serum muscle enzymes and additionally in DM by skin abnormalities. Immune mechanisms are involved to various degrees in the physiopathogenesis of PM and DM. Both disorders, as defined clinically, have prevalence rates estimated at approximately 1 per 100,000 in the general population. There is a female to male predominance of about 2:1. The peak incidence in adults is between the ages of 40 and 50, but any age group may be affected. PM often occurs more common in blacks than in whites.[1,2] Typical histopathological findings in the muscle tissue are inflammatory infiltrates, mainly composed of T-lymphocytes and macrophages. DM is distinguished from PM by skin abnormalities, usually manifested by a red, scaly and plaque-like rash, over the knuckles, wrists, elbows, knees and ankle malleoli. In addition, there are often violaceous lesions in the peri-orbital and trunk areas. Typically there will be electromyographic (EMG) abnormalities, including polyphasic potentials, spontaneous fibrillations, and spontaneous high frequency discharges. The characteristic findings on muscle biopsy are those of a necrotizing, inflammatory process. A proposed classification for the idiopathic inflammatory myopathies is the following:
PM affects striated skeletal muscles, but not smooth muscles. Although the inciting event of PM is unknown, it has been postulated that some microvascular injury may lead to the release of muscle autoantigens, which are then presented to T-lymphocytes by macrophages in the muscle. T-lymphocytes that have been activated then proliferate and release cytokines such as interferon gamma and interleukin. Interferon gamma promotes further macrophage activation and release of mediators of inflammation such as IL-1 and tumor necrosis factor-alpha.[5–7]
The first symptoms are usually painless weakness of the pelvic and proximal lower extremity muscles, which can result in difficulty walking and climbing stairs or in getting up after sitting in a chair. Often the next muscles affected are those of the neck and shoulder girdle. The degree of weakness may vary from mild to near paralysis. Weakness usually develops slowly over weeks to months, although in rare cases weakness may progress more rapidly.
Other PM symptoms include:
The predominant symptom of PM is muscle weakness. Weakness is symmetric, affecting the proximal muscles of the extremities as well as the neck flexors. Weakness of the distal muscles is rare, and when present should warrant consideration of another type of myopathy, such as inclusion body myositis. PM patients may occasionally experience pain and tenderness in the muscles, which can mimic the symptoms of polymyalgia rheumatica.[2,3] Involvement of the striated muscles of the oropharynx and upper esophagus occurs in 10-15% of patients, is a poor prognostic indicator, and may lead to dysphagia, regurgitation, and aspiration pneumonia. Interstitial lung disease occurs in 5-10% of patients. In addition, there may be ventilatory dysfunction due to involvement of the diaphragm and intercostal muscles. Cardiac involvement is most often asymptomatic, but may result in conduction disturbances, myocarditis, or congestive heart failure. Raynaud's phenomenon, non-erosive arthritis, and systemic symptoms of morning stiffness, fatigue, weight loss, and fever all may be present during the course of PM.[3,8]
Symmetric weakness of the proximal muscles is the most constant physical finding in PM. Muscle tenderness may occasionally be present, but deep tendon reflexes are preserved. The sensory examination is usually normal. Muscle wasting or atrophy may be present in advanced cases. Examination of the lungs may reveal dry inspiratory crackles. Dysphonia with a nasal speech quality may be noted. Detailed manual muscle strength testing is critically important to perform. The Medical Research Council's grading system for muscle strength assessment is widely used. Strength is graded according to the following scale:
Grade 0=No discernible muscle contraction.
Grade 1=Muscle contraction visible but no limb movement possible.
Grade 2=Movement of limb possible with gravity eliminated.
Grade 3=Movement against gravity only without additional resistance.
Grade 4=Movement against some resistance.
Grade 5=Normal strength against resistance.
Muscle Enzymes: Laboratory markers of muscle injury include elevations in the blood levels of CK, aldolase, AST, ALT, and LDH. CK elevations occur at some point in most PM patients, and CK is probably the most reliable enzyme to measure. CK levels may sometimes be normal in late disease, or may remain above normal even after muscle strength has improved with treatment.[1,3,4,7–9]
A variety of autoantibodies may be present in the serum of patients with PM. Some of these, such as anti-nuclear antibodies (ANA) and antibodies to ribonucleoprotein (RNP), have low specificity for PM. Antibodies to RNA synthetases (Jo-1, PL-7, and PL-12) have greater specificity, and may identify a subgroup of patients with the so-called anti-synthetase syndrome. The anti-synthetase syndrome is characterized by clinical features of Raynaud′s, inflammatory arthritis, and interstitial lung disease. Anti-signal recognition antibodies are associated with more aggressive PM having a worse overall prognosis.[5,8,9]
As MRI has become more sensitive, it has become more useful in the diagnosis of PM. The high sensitivity MRI enables the detection of subtle muscle inflammation early in the disease. The ability to image large areas of muscle in an extremity may be helpful in localizing the most abnormal areas for subsequent muscle biopsy.[10,11]
In evaluating a patient with PM, EMG and nerve conduction studies may aid in diagnosis. The findings of spontaneous fibrillations at rest or with needle insertion, spontaneous high-frequency discharges and positive sharp waves are the characteristic abnormalities. EMG tests are usually performed unilaterally. Muscle biopsy may then be performed on the contralateral side so as to avoid the risk of needle artifact in the biopsy specimen.
Muscle biopsy is the definitive procedure to establish a diagnosis of PM. MRI and/or EMG may help to identify the areas of potentially highest yield for biopsy. The muscle biopsy demonstrates muscle fibers in various stages of inflammation, necrosis and regeneration. Other pathologic findings include endomysial infiltration by mononuclear cells, capillary obliteration, endothelial cell damage, and increased amounts of connective tissue.[4,9,12]
The goals of therapy are twofold:
The presence of vital organ extra-muscular disease is associated with worse outcomes.
In general, the more severe the disease, the less responsive it is to treatment. The mainstays of therapy are corticosteroids and other immunosuppressive drugs. Adjunctive, non-pharmacologic therapies are also important. These include exercise regimens appropriate to strength, measures to prevent aspiration, and general supportive care.[3,4,9]
Corticosteroids like prednisone are the first line of therapy for PM. The usual starting dose is 1 mg/kg/day of prednisone or its equivalent. This dose is usually maintained for the first 6-8 weeks. The response to therapy should be assessed every 2-4 weeks by monitoring the proximal muscle strength, muscle enzyme levels, and patient functionality. Muscle strength and functional measures are better indicators of improvement than muscle enzyme levels.
After the initial 6-8 weeks, a slow taper of steroids should begin. The goal is to taper steroids off or to the lowest possible effective dose over a period of 9-12 months. A significant proportion of patients cannot be managed with steroids alone, either because of side effects, poor disease control, or both. Many rheumatologists start a steroid-sparing immunosuppressive agent at the time steroids are initiated, while others prefer to reserve these agents for patients who have clearly failed corticosteroid monotherapy.[12,13]
In a steroid responsive patient, the goal is to attain the lowest dose of steroids that will adequately manage the disease. In order to achieve this goal, steroid-sparing agents are necessary in most PM patients. The process of selecting steroid-sparing drugs is empirical, although the most commonly used are azathioprine (AZA) and methotrexate (MTX).
AZA is usually administered orally at a dose of 1.5- 3 mg/kg/day. The drug may not be fully effective for up to 4 months. Nausea, bone marrow suppression, and hepatotoxicity are the major adverse effects. Regular laboratory monitoring of complete blood counts and liver function studies is required.[8,9,13]
MTX may be administered orally, subcutaneously, or intramuscularly. MTX is given once a week at doses ranging from 10-40 mg. Doses above 20 mg weekly are best tolerated when given parenterally. The peak effect of MTX is seen within 2 months. Bone marrow suppression and hepatotoxicity are the major adverse effects, and the dose must be adjusted downward in the face of renal insufficiency. Regular laboratory monitoring of complete blood counts, liver function tests, and serum creatinine is required.[9,13]
Some patients, after an initial response to conventional therapies, may develop recurrent disease activity. Other patients may not respond optimally to conventional therapies. Although efficacy data are limited, there are several treatment options for patients in the aforementioned categories.
Mycophenolate mofetil is administered orally in doses up to 3 g/day. The drug may not be maximally effective for 3 months. It is generally well tolerated. Gastrointestinal symptoms and leukopenia are the most commonly encountered adverse effects.
Cyclosporine A and tacrolimus have both shown some efficacy in the treatment of refractory PM. Cyclosporine A is administered orally in doses up to 150 mg twice a day. Hypertension and nephrotoxicity are the major adverse effects. The optimal dose of tacrolimus is not clear. One study utilized doses of 0.075 mg/kg/day in 2 divided doses, with normalization of strength in 5 of 8 patients.[4,9,15]
In patients who are corticosteroid resistant, especially where there is rapidly progressive or life-threatening progression, intravenous immunoglobulin (IVIG) may be helpful. The recommended initial dose is 2 g/kg. Improvement in strength may be evident within days of the first infusion. Repeated infusions at 5-8 week intervals may be necessary to maintain response.
Rituximab (RTX) is a monoclonal antibody against CD 20 positive B-cells, which causes depletion of these cells for 6 months or longer. The optimal dose of RTX in PM is unknown. One protocol is to use 375 mg/m2, infused intravenously once a week for 4 weeks. Another dosing regimen is to administer 2 biweekly infusion of 1 g (2 g total dose) intravenously. A multicenter, placebo-controlled trial of RTX in patients with PM is currently ongoing. RTX is generally well tolerated. Infusion reactions can usually be managed with corticosteroids or antihistamines. There is also some increase in the risk of infections in RTX treated patients.
Cyclophosphamide (CTX) is an alkylating agent that is toxic to lymphopoietic cells. Both T-cells and antibody producing B-cells are affected. CTX has considerable hematologic and bladder toxicity, and is a potent immunosuppressive. CTX should therefore be reserved for those PM patients who had multiple failures with other second line agents. This drug may be most useful in patients who have PM with interstitial lung disease. The drug may be given intravenously at 0.8-1 g/m2/month for several months. CTX may also be administered orally at 1.5-2 mg/kg/day.[15,18]
PM is an idiopathic inflammatory disorder of striated muscle. The disease occurs most commonly in women between the ages of 50 and 70. The predominant clinical manifestation is proximal muscle weakness. There may be extra muscular involvement such as inflammatory arthritis, Raynaud's phenomenon, myocarditis, and interstitial lung disease. Serum muscle enzymes are usually elevated during periods of active disease. A variety of autoantibodies are often found in the serum of PM patients. Characteristic abnormalities are often seen on EMG and muscle MRI. Definitive diagnosis is established by muscle biopsy. Corticosteroids are the mainstay of therapy, but a number of other immunomodulatory agents are used in the management of this disease. The majority of patients respond to therapy, although some degree of long-term muscle damage is not uncommon.
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