Idiopathic Inflammatory Myopathies

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[edit] Idiopathic Inflammatory Myopathies

Steven R. Ytterberg

Idiopathic inflammatory myopathies (IMs) are acquired inflammatory disorders of skeletal muscle of unknown etiology.They are characterized clinically by muscle weakness that is classically symmetric, involving proximal muscles of the limbs, but may include neck and pharyngeal muscles.The chief conditions in this group are polymyositis (PM) and, when accompanied by cutaneous manifestations, dermatomyositis (DM).Several clinically defined subgroups of PM and DM have been described (Box 131-1).DM or PM may be associated with another connective tissue disease or malignancy.Inclusion body myositis (IBM) is a distinctive member of the IM group, with more frequent distal weakness and unique inclusions seen on muscle biopsy.^[1] Several other less often diagnosed disorders have features of inflammatory myositis (Box 131-2).^[2] Although the IMs have many similarities, they can be distinguished on clinical and histologic grounds.In addition to these IMs, a number of infectious agents and toxins can cause inflammatory myositis (see Differential Diagnosis).

[edit] EPIDEMIOLOGY

The IMs are rare disorders, with a combined annual incidence of approximately 5 to 10 per million.^[3] In adult patients with IM, isolated PM and DM are each found in approximately one third of patients.PM or DM is associated with connective tissue disease in about 20% of patients and with malignancy in approximately 15%.IBM has been reported in up to 25% of adult patients with inflammatory myositis, although this estimate may be high in coming from a referral center.PM and DM have a female/male ratio of approximately 2:1.There is a greater female predominance among younger patients and among those patients who have another connective tissue disease, whereas the gender ratio is equal in patients with associated malignancy.In contrast, IBM occurs most often in middle-aged to older men.PM and DM have two peaks of incidence: during childhood and during the fifth to sixth decades.Patients with IM associated with malignancy have a mean age over 60.PM and DM are three to four times more common in blacks than whites.Seasonal variation in the onset of PM and DM has been reported, suggesting a role for environmental agents in the etiology.

The relationship between IMs and malignancy is controversial.Early observations suggested an increased frequency of malignancy in patients with PM and DM.A review of several large clinical series found malignancy in 20% of adult patients with DM, 13% with PM, and 15% overall.^[4] Several case-controlled and population-based studies port the association of DM and PM with malignancy, demonstrating that patients with DM are at greater risk than those with PM.Data suggest that the relationship between IMs and malignancy is indirect, not causal.Of patients with IMs associated with malignancy, some develop malignancy first and others myositis first; no particular type of malignancy has been associated with IMs.Malignancy is more frequent in patients diagnosed with myositis after age 45.Malignancy has been reported in only a small number of patients with IBM, but experience with this condition is less extensive than with PM and DM.

[edit] PATHOPHYSIOLOGY

The etiology of the IMs is unknown.Microorganisms have long been considered as potential etiologic agents, including Toxoplasma gondii and several different groups of viruses, but direct evidence implicating microorganisms has been difficult to obtain.Group B coxsackieviruses and encephalomyocarditis virus, members of the Picornaviridae family, can cause inflammatory myositis in mice with similarities to human PM.Various viruses have been isolated in select patients with PM and DM, and elevated titers of antibodies to group B coxsackieviruses have been found in some children with recent onset DM.Coxsackievirus ribonucleic acid (RNA) may persist in some patients with PM and DM.No studies have shown a clear relationship of infection with IM in large groups of patients.The characteristic muscle fiber inclusions in patients with IBM resemble viral inclusions, but no virus has been linked clearly with IBM.PM and DM may be associated with retroviral infection, including human immunodeficiency virus (HIV) and human T-cell lymphotropic virus type I (HTLV-I).These viruses do not invade muscle directly.

Each of the disorders classified as IMs is characterized by clinical weakness and histologic muscle inflammation, but they have different pathophysiologic mechanisms.^[3][5] Cell-mediated immunologic mechanisms are involved in the pathogenesis of PM and IBM.T cells, especially CD8 cytotoxic T cells, predominate in inflammatory infiltrates, typically in the endomysium, in PM and IBM.Activated CD8 T cells can be found invading viable muscle fibers.Humoralimmune mechanisms play a greater role in DM.More CD4 T cells and a higher proportion of B cells are found, with a perivascular and perifascicular distribution.Mononuclear cells do not invade muscle fibers directly in DM, as they do in PM and IBM.In juvenile DM, vascular damage is apparent.Endothelial cell hyperplasia and vascular infarction are present, with atrophy of muscle fibers at the periphery of the fascicles (perifascicular atrophy).Immunoglobulin and the membrane attack complex of complement are found in areas of muscle necrosis, underscoring the role of humoral mechanisms in disease pathogenesis.

A variety of autoantibodies can be found in patients with IMs (Table 131-1).^[6][7][8] They are infrequently found in patients with IBM.Several myositis-specific autoantibodies have been identified in patients with IMs.Most of these antibodies are directed against cytoplasmic ribonucleoproteins involved in protein synthesis.The antigens for one group of these myositis-specific antibodies are the aminoacyl tRNA synthetases, enzymes that charge the appropriate amino acid onto its corresponding tRNA.It is unclear if myositis specific antibodies inhibit cellular function in vivo; they may be markers, rather than causes, of disease.

Table 131-1 Autoantibodies in Patients With Idiopathic Inflammatory Myopathies (IMs)

Muscle inflammation results in weakness and muscle tenderness.Muscle fibers demonstrate necrosis, degeneration, regeneration, and phagocytosis.The cause of weakness appears to be multifactorial.In addition to loss of muscle fibers and muscle bulk, functional abnormalities of muscle may be involved.Fibrosis and muscle atrophy may be present in later stages, also contributing to muscle weakness.Genetic factors play a role in disease, presumably through control of immunologic responsiveness.^[6][7] Approximately half of white patients with PM and DM have the HLA-DR3 phenotype, usually linked with HLA-B8.In African-American patients with PM and DM, HLA-DR3 is only slightly increased, but linkage with B8 is increased over the frequency in control populations.These markers are most common in patients with anti-Jo-1 antibodies, regardless of race.In patients with IBM, HLA-DR1 is increased threefold compared with control populations.Familial cases of IBM have been described.

[edit] PATIENT EVALUATION

[edit] History

Muscle weakness is the most frequent presenting complaint in patients with IMs.Weakness is usually insidious in onset and slowly progressive, although its onset may be more abrupt, with rapid progression.Acute onset is often associated with more severe disease.Weakness is characteristically symmetric and unrelated to exercise, affecting the legs before the arms.In PM and DM, proximal limb weakness is typical; distal weakness suggests IBM.Neck, pharyngeal, and respiratory muscles may be involved.It is helpful to identify specific activities affected by weakness, such as rising from a low chair or toilet seat, getting out of a car, climbing stairs, or combing hair.Involvement of pharyngeal or esophageal muscle may result in dysphonia, dysphagia, or aspiration.Muscle tenderness and aching occur in about 50% of patients.Muscle atrophy may occur with later disease.

When a patient complains of weakness, it is important to differentiate true loss of muscle strength from fatigue or pain.Fatigue may be present in the IMs, but it is a nonspecific complaint and is seen in a variety of inflammatory diseases, as well as some noninflammatory disorders that may be confused with IMs, such as polymyalgia rheumatica and fibromyalgia.Limitation of activity by pain from articular or periarticular sources in patients with arthritis may be identified as weakness by some patients.A thorough history and muscle strength testing with elicitation of maximal effort can eliminate these possibilities and identify muscle as the source of weakness.

Skin rash may be the presenting complaint of patients with DM.Arthralgia and Raynaud's phenomenon are present in approximately 25% of patients.Systemic features can include fatigue, morning stiffness, and weight loss.In patients who have myositis associated with another connective tissue disease, features of the associated condition may be apparent.The most common associated connective tissue or autoimmune disorder is systemic lupus erythematosus (SLE); others include Hashimoto's thyroiditis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, insulin-dependent diabetes mellitus, and Graves' disease.Thus arthritis, sclerodactyly, or cutaneous symptoms of SLE may be present.Occasionally, cardiac or pulmonary symptoms lead the patient to seek attention.Pulmonary involvement may lead to diminished chest wall motion or interstitial fibrosis, resulting in complaints of dyspnea or cough.Cardiac involvement may produce conduction disturbances or myocarditis with symptoms from dysrhythmia, congestive heart failure, or ischemia.Symptoms of associated malignancy may be found in some patients.

[edit] Physical Examination

Examination should exclude other causes of muscle weakness, especially neuropathic causes; identify systemic features of myositis; recognize an associated connective disease; and detect an associated malignancy.A thorough general physical examination is required, with special attention given to the neurologic examination.Muscle strength is important in a suspected IM patient.Although strength can be measured using a dynamometer, manual muscle strength testing is usually employed (Box 131-3).Manual testing has crude sensitivity but can monitor response to therapy.

Dermatomyositis is present when cutaneous manifestations accompany inflammatory myositis.A variety of skin lesions may be found in patients with DM.Two characteristic lesions are the heliotrope rash and Gottron's papules.A heliotrope rash is a faint, lilac-colored eruption on the upper eyelids. Gottron's papules are raised, red or violaceous, sometimes scaly lesions overlying the metacarpophalangeal and proximal interphalangeal joints, sparing the phalanges (Fig.131-1).Gottron's papules may be found over the elbows or knees as well.Other nonspecific lesions, including an erythematous macular rash on the face, neck, upper chest, or shawl distribution, might be present.Vasculitic lesions may be seen at the base of the nails.Some patients have “machinist's hands.” Subcutaneous calcification may be found, most often in childhood DM.

Figure 131-1 Dermatomyositis (Gottron's papules), with erythematous papules over joints and periungual telangiectasias.

[edit] LABORATORY STUDIES AND DIAGNOSTIC PROCEDURES

Serum creatine kinase (CK) and other muscle-associated enzymes are typically elevated in patients with IMs and can be useful as indicators of response to therapy.CK levels may be modestly or markedly elevated in PM and DM; in IBM they are typically only mildly elevated.Elevation of the MB isoenzyme of CK may occur in patients with IM in the absence of myocardial involvement.A variety of pathologic and nonpathologic conditions can elevate serum CK values.Men have higher values than women, reflecting increased muscle mass.CK levels in blacks are higher than those in whites; healthy African-American subjects frequently have values that are above normal, as defined by most laboratories.^[8] Elevated serum CK values can follow muscle trauma, jogging, or use of certain medications.In some patients with IMs, the CK level may be normal, whereas levels of other muscle-associated enzymes, including aldolase, lactate dehydrogenase (LDH), alanine transaminase (ALT), or aspartate transaminase (AST), are elevated.^[9] Myoglobin and creatine levels may be elevated; myoglobinuria occurs in rare patients.To evaluate patients who have muscle weakness, tests for electrolytes, renal function, thyroid function, calcium, magnesium, and phosphorus are needed to exclude other causes of weakness; these tests are usually normal in patients with IM.

Autoantibodies are found in most patients with PM and DM (see Table 131-1).^[6][7] Some are unique to patients with myositis, but many are seen in other connective tissue disorders as well.Serologic testing for autoantibodies can help categorize patients into subgroups and diagnose a specific connective tissue disorder.^[6] Positive antinuclear antibodies (ANAs) are found in 50% to 90% of patients with IMs.The other non-muscle-specific antibodies may be seen in patients with myositis alone but occur most often in patients who have an overlap syndrome of another connective tissue disorder.Myositis-specific antibodies are found in approximately 50% of patients with PM or DM and occur infrequently in patients with IBM.The most common myositis-specific antibodies are the antisynthetase antibodies, most often anti-Jo-1 (antihistidyl tRNA synthetase).Anti-Jo-1 antibodies are found in approximately 10% of adult patients with DM and 30% to 40% with PM; they are rare inchildhood disease.Anti-Jo-1 antibodies are highly specific for IMs and have a strong association with interstitial lung disease.Patients with any of the antisynthetases have a higher incidence of interstitial lung involvement and arthritis.Patients with antibodies to signal recognition particle (SRP) have the worst prognosis, often with acute onset, severe disease, and myocardial involvement.^[6] To evaluate a patient with suspected IM, the primary care physician generally finds ANA, anti-Jo-1 antibody, and anti-Sci-70 antibody determinations most helpful.

Electromyography (EMG) helps differentiate myopathic from neuropathic causes of weakness and active from inactive myositis.^[9][2] The myopathic pattern seen in patients with IMs is not diagnostic and is seen in other forms of active myopathy.Findings include irritability and increased insertional and spontaneous activity manifested by fibrillations, complex repetitive discharges, and positive sharp waves.With voluntary muscle activity, short-duration, low-amplitude polyphasic motor unit action potentials are observed.Patients with IBM may show neuropathic EMG changes as well.Normal EMGs are obtained in approximately 5% of patients with active IM.

Muscle biopsy is critical to establish the diagnoses of PM, DM, and IBM and to exclude other neuromuscular disorders.^[3][7] Biopsy can be performed by needle technique, although many pathologists prefer open biopsies.Normal biopsies are found in approximately 7% of patients.Despite a possible false-negative result, biopsy is important before initiating therapy with significant potential for morbidity.The muscle for biopsy should be carefully selected, neither the most nor the least affected muscle.A muscle studied previously by EMG should not be biopsied because the needle may have caused pathologic changes.Magnetic resonance imaging (MRI) can help identify inflamed muscles for biopsy and can be useful in following disease progress.^[5]

The key findings on muscle biopsy in patients with IMs are prominent inflammatory cells and muscle fiber changes, including degeneration, variation in cross-sectional diameter, necrosis, regeneration, and phagocytosis.^[9] Biopsies are usually diffusely abnormal, but approximately 25% show only focal changes.Capillary damage and increased amounts of connective tissue and fat may be noted.In DM, inflammation tends to be perivascular and around muscle fascicles, with fiber atrophy in perifascicular areas.Perifascicular atrophy is not a characteristic finding in PM or IBM.In PM the inflammation is primarily endomysial, within muscle fascicles.Necrotic fibers are not grouped as in DM and may not be near areas of inflammation.The characteristic histologic finding in IBM is nuclear and cytoplasmic inclusions, with rimmed vacuoles.^[1] These inclusions show masses of filamentous material on electron microscopy.Although inflammatory cells on biopsy are characteristic of IMs, their presence alone does not make the diagnosis.Muscle inflammation can be seen in other necrotizing conditions, including Duchenne's dystrophy and myasthenia gravis.

Other workup should be directed by specific complaints or physical findings.A chest radiograph is helpful in identifying interstitial fibrosis or associated pulmonary malignancy.If interstitial fibrosis is present, the lung diffusion capacity is often diminished.Because of the cost and potential hazards of performing tests and procedures to identify an occult malignancy, an exhaustive search for malignancy in all patients with a new diagnosis of IM is unreasonable.^[1] A patient should undergo a thorough history and physical examination, chemistry panel, blood count, stool guaiac examination, and chest radiograph.Appropriate cancer screening for colon, cervical, breast, and prostate cancers is appropriate if not done recently.

[edit] Course and Prognosis

Survival rates for patients with PM and DM are approximately 80% 5 years after diagnosis and 73% after 8 years.Several clinical features correlate with poor prognosis: older age at diagnosis; cardiac involvement, dysphagia, or malignancy; long delay between symptom onset and initiation of therapy; and poor initial response to corticosteroids.Patients with antibodies to SRP or to any of the aminoacyl-tRNA synthetases have more severe disease than those without these antibodies.^[6] Of patients with PM or DM, approximately half have complete or near-complete recovery.In contrast, patients with IBM often do not respond to therapy and usually follow a gradually deteriorating course.

[edit] Differential Diagnosis

The diagnosis of PM, DM, or IBM is based on muscle inflammation in a patient with muscle weakness, but the physician must consider other diseases that can cause weakness and inflammatory myositis (Fig.131-2).Criteria for diagnosing PM and DM are widely used; preliminary criteria for diagnosing IBM are also available (Boxes 131-4 and 131-5).These criteria were established to facilitate classification of patients for study purposes rather than to be specific diagnostic criteria for individuals, but they can be useful when considering the diagnosis of IM in an individual.Before these criteria are used, other causes of weakness must be excluded.Muscle weakness can result from different disease processes (Box 131-6).^[2][8] Many can be excluded by the history and physical examination, but laboratory and biopsy data may be required.

Figure 131-2 Treatment of patient with diffuse muscle pain and stiffness. PMR, Polymyalgia rheumatica;GCA, giant cell arteritis. (From Maricic MJ: Diffuse muscle pain and stiffness: polymyalgia rheumatica and giant cell arteritis.In Greene HL, Johnson WP, Maricic MJ, editors:Decision making in medicine, ed 2, St Louis, 1998, Mosby, p 445.)

Neurologic disorders are primary differential diagnoses of patients with weakness.The presence of other neurologic abnormalities on examination strongly suggests a neuropathic rather than a myopathic etiology.IBM may have neuropathic features, however, including diminished deep tendon reflexes.Asymmetric or early distal muscle involvement or muscle hypertrophy may be clues to a diagnosis other than IM.The presence of facial or ocular complaints and unique EMG findings help identify myasthenia gravis or Eaton-Lambert syndrome.A familial history of weakness and younger age at onset may suggest a muscular dystrophy, which may increase the serum CK (e.g., Duchenne's).

Electrolyte abnormalities and metabolic disorders must be excluded.Elevation or lowering of serum sodium, potassium, or calcium levels, as well as hypophosphatemia and hypomagnesemia, should be sought.Hypothyroidism can cause weakness and marked CK elevations.Hyperthyroidism, hyperparathyroidism, Cushing's disease, and Addison's disease are other easily excluded endocrine causes of muscle weakness.

Some drugs can cause weakness, with or without CK elevation.The list of implicated agents is long, but several merit specific mention.Ethanol is probably the most common drug that produces myopathy; it can cause acute muscle swelling and pain after binge drinking or chronic progressive proximal myopathy with long-term alcohol use.Corticosteroidscan cause proximal muscle weakness, which can be confusing in patients with IM treated with steroids, but CK levels are typically normal.Clofibrate, colchicine,d-penicillamine, chloroquine, hydroxychloroquine, ɛ-amino caproic acid, and vincristine can cause weakness with CK elevation.Zidovudine (AZT) has been associated with myalgia and muscle weakness, which may produce diagnostic difficulty because HIV infection itself has been associated with PM.In primary care patients, among the most common medications to cause myopathy are the lipid-lowering HMG-coenzyme reductase inhibitors such as lovastatin, especially when combined with gemfibrozil, clofibrate, niacin, erythromycin, or cyclosporine.Cocaine may cause an elevated CK and even rhabdomyolysis.

Chronic myositis can result from parasitic infections, including toxoplasmosis, trichinosis, and schistosomiasis, and with certain viral infections, most notably coxsackieviruses and influenza virus.HIV and HTLV-I infections have been associated with PM, but these agents do not infect muscle directly.Bacterial infection of muscle usually causes acute symptoms that are usually not confused with IMs.

Metabolic myopathies can cause muscle weakness and may be confused with the IMs.Several glycogen storage diseases, including McArdle's disease (myophosphorylase deficiency), can cause elevation of the CK and muscle weak ness.Symptoms exacerbated by exercise, muscle cramps, or myoglobinuria may suggest these diagnoses.Disorders of fat metabolism (e.g., carnitine deficiency, carnitine palmitoyltransferase deficiency) and purine metabolism (e.g., myoadenylate deaminase deficiency) can present with proximal weakness and CK elevation as well.Ischemic forearm muscle exercise testing can help identify some of these patients.In normal subjects, venous lactate and ammonia levels rise afterischemic exercise.In patients with glycogen storage disorders, ammonia, but not lactate, rises after such exercise, whereas in myoadenylate deaminase deficiency, lactate levels but not ammonia levels rise.Histochemical studies of muscle biopsy specimens are key to making the diagnosis of a storage disease.

Myositis and muscle weakness may occur with connective tissue disorders that include rheumatoid arthritis, SLE, and scleroderma.Among the more common disorders considered in the differential diagnosis of the IMs are polymyalgia rheumatica and fibromyalgia.Key features in the workup can eliminate these disorders (Table 131-2).Most notable is the presence of pain with normal muscle strength in the latter two conditions.The patient must be urged to maximal effort during the examination to demonstrate normal strength.

Table 131-2 Findings in Idiopathic Inflammatory Myopathies (IMs) and Differential Diagnoses

✢Characteristic features may be seen in these biopsies (see text).

[edit] MANAGEMENT

Given the complexity of the differential diagnosis in patients suspected of having an IM, the need to assess the overlap with other connective tissue diseases, and the potential for complications of therapy, confirmation of diagnosis and management plans should be made in consultation with a rheumatologist.Corticosteroids are the mainstay of treatment, although their use has not been tested in controlled studies.^{[9][3][10][7]} Treatment should be started at approximately 1 to 2 mg/kg/day, given in two to three divided doses.Patients with a more acute onset and more severe disease should be treated at the more aggressive end of this range.Clinical and laboratory parameters should be monitored to assess the response to therapy.Muscle enzymes may respond before improvement in muscle strength, but evaluation of functional improvement is most important.Patience is required; unlike many other inflammatory autoimmune disorders, the IMs often respond slowly.In patients who respond to steroids, strength usually improves in 1 to 2 months but may require 3 months.As the patient responds, the dosing frequency must be consolidated, ultimately to a single daily dose.High-dose steroids should be continued for 4 to 6 weeks after strength has improved, before tapering is slowly begun.The lowest possible dosage that controls the disease should be used.Attaining a stable condition on the minimal dosage often requires 1 to 2 years.Alternate-day steroids may be effective but should be reserved for patients with mild disease.

Some patients respond initially but then have a decrease in strength while tapering steroid dosage.Coincident elevation of CK values suggests exacerbation of myositis, but if the serum CK remains normal, steroid myopathy should be considered.The EMG in steroid myopathy may show a myopathic pattern, but the fibrillations seen in IMs are not present.Muscle biopsy can help in showing type II fiber atrophy without inflammation in the patient with steroid myopathy, but this is not absolute, given the focal nature of inflammation that may occur in IMs.At times the steroid dosage may need to be raised or lowered, awaiting signs of improvement or worsening.Since high dosages are usually given over long periods, measures to prevent potential complications of corticosteroid therapy should be instituted.Prophylaxis of steroid-induced osteoporosis with calcium (1 to 2 gm/day) and vitamin D should be undertaken.In postmenopausal women, hormone replacement therapy should be considered.Bone mineral density screening can help guide measures directed at preventing or treating osteoporosis.

For patients who do not respond to corticosteroids, accuracy of the diagnosis should be questioned, with consideration of IBM or an associated malignancy, because both typically respond less well to treatment.Immunosuppressive agents may be required for patients who do not respond to steroids, who flare while the dose is being lowered, or who develop intolerable side effects from steroids.Some authors advocate early use of immunosuppressives in an attempt to minimize the potential side effects of corticosteroids.The most frequently used immunosuppressive agents are azathioprine and methotrexate; 6-mercaptopurine, cyclophosphamide, chlorambucil, and cy closporin A are also reported to be effective.^[3][10][7] Methotrexate can be administered intravenously, intramuscularly, or orally; the oral route is preferred to avoid elevation of CK values from the injections.A potential problem of methotrexate therapy is interstitial pulmonary fibrosis, which is also a potential extramuscular site of pathology in IMs.

For patients unresponsive to standard immunosuppressants, other immunosuppressive modalities have been at tempted.Intravenous immunoglobulin (IVIg) appears to be the most promising, with biochemical and clinical response shown in patients with severe disease.Combinations of immunosuppressives may be needed in some patients.Patients with IBM are considered to be unresponsive to therapy with steroids, although some may respond with improvement or at least stabilization of strength and function.Thus an attempt to treat patients with IBM is warranted.For patients with IM associated with malignancy, the first step is to deal with the malignancy.If the malignancy responds to treatment, the IM may as well, but this is highly variable.

Physical therapy and other modalities are important adjuncts to the therapy of patients with IMs.During periods of active muscle inflammation, patients should be kept on bed rest.An exercise program should include daily stretching done passively or with therapist assistance to maintain range of motion and prevent contractures.With response to medical therapy, active exercise should be encouraged, avoiding over work that can damage muscle.Adaptive aids can improve function.A raised toilet seat and grip bars can be helpful.Inspiratory muscle training can help patients with respiratory muscle weakness.

[edit] REFERENCES