Harrison's Neurology in Clinical Medicine, 3rd Edition

CHAPTER 49. POLYMYOSITIS, DERMATOMYOSITIS, AND INCLUSION BODY MYOSITIS

Marinos C. Dalakas

The inflammatory myopathies represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness. They are classified into three major groups: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM).

CLINICAL FEATURES

The prevalence of the inflammatory myopathies is estimated at 1 in 100,000. PM as a stand-alone entity is a rare disease. DM affects both children and adults and women more often than men. IBM is three times more frequent in men than in women, more common in whites than blacks, and is most likely to affect persons aged >50 years.

These disorders present as progressive and symmetric muscle weakness except for IBM, which can have an asymmetric pattern. Patients usually report increasing difficulty with everyday tasks requiring the use of proximal muscles, such as getting up from a chair, climbing steps, stepping onto a curb, lifting objects, or combing hair. 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 course of PM and DM, but fairly early in IBM. Falling is common in IBM because of early involvement of the quadriceps muscle, with buckling of the knees. Ocular muscles are spared, even in advanced, untreated cases; if these muscles are affected, the diagnosis of inflammatory myopathy should be questioned. Facial muscles are unaffected in PM and DM, but mild facial muscle weakness is common in patientswith IBM. In all forms of inflammatory myopathy, pharyngeal and neck-flexor muscles are often involved, causing dysphagia or difficulty in holding up the head (head drop). In advanced and rarely in acute cases, respiratory muscles may also be affected. Severe weakness, if untreated, is almost always associated with muscle wasting. Sensation remains normal. The tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles, especially in IBM, where atrophy of the quadriceps and the distal muscles is common. Myalgia and muscle tenderness may occur in a small number of patients, usually early in the disease, and particularly in DM associated with connective tissue disorders. Weakness in PM and DM progresses subacutely over a period of weeks or months and rarely acutely; by contrast, IBM progresses very slowly, over years, simulating a late-life muscular dystrophy (Chap. 48) or slowly progressive motor neuron disorder (Chap. 32).

SPECIFIC FEATURES

(Table 49-1)

TABLE 49-1

FEATURES ASSOCIATED WITH INFLAMMATORY MYOPATHIES

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Polymyositis

The actual onset of PM is often not easily determined, and patients typically delay seeking medical advice for several weeks or even months. This is in contrast to DM, in which the rash facilitates early recognition (discussed later). PM mimics many other myopathies and is a diagnosis of exclusion. It is a subacute inflammatory myopathy affecting adults, and rarely children, who do not have any of the following: rash, involvement of the extraocular and facial muscles, family history of a neuromuscular disease, history of exposure to myotoxic drugs or toxins, endocrinopathy, neurogenic disease, muscular dystrophy, biochemical muscle disorder (deficiency of a muscle enzyme), or IBM as excluded by muscle biopsy analysis (discussed later). As an isolated entity, PM is a rare (and overdiagnosed) disorder; more commonly, PM occurs in association with a systemic autoimmune or connective tissue disease, or with a known viral or bacterial infection. Drugs, especially D-penicillamine, statins, or zidovudine (AZT), may also trigger an inflammatory myopathy similar to PM.

Dermatomyositis

DM is a distinctive entity identified by a characteristic rash accompanying, or more often preceding, muscle weakness. The rash may consist of a blue-purple discoloration on the upper eyelids with edema (heliotrope rash), a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption (Gottron’s sign). The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and anterior chest (often in a V sign), or back and shoulders (shawl sign), and may worsen after sun exposure. In some patients, the rash is pruritic, especially on the scalp, chest, and back. Dilated capillary loops at the base of the fingernails are also characteristic. The cuticles may be irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling mechanic’s hands. The weakness can be mild, moderate, or severe enough to lead to quadriparesis. At times, the muscle strength appears normal, hence the term dermatomyositis sine myositis. When muscle biopsy is performed in such cases, however, significant perivascular and perimysial inflammation is often seen.

DM usually occurs alone but may overlap with scleroderma and mixed connective tissue disease. Fasciitis and thickening of the skin, similar to that seen in chronic cases of DM, have occurred in patients with the eosinophilia-myalgia syndrome associated with the ingestion of contaminated L-tryptophan.

Inclusion body myositis

In patients ≥50 years of age, IBM is the most common of the inflammatory myopathies. It is often mis-diagnosed as PM and is suspected only later when a patient with presumed PM does not respond to therapy. Weakness and atrophy of the distal muscles, especially foot extensors and deep finger flexors, occur in almost all cases of IBM and may be a clue to early diagnosis. Some patients present with falls because their knees collapse due to early quadriceps weakness. Others present with weakness in the small muscles of the hands, especially finger flexors, and complain of inability to hold objects such as golf clubs or perform tasks such as turning keys or tying knots. On occasion, the weakness and accompanying atrophy can be asymmetric and selectively involve the quadriceps, iliopsoas, triceps, biceps, and finger flexors, resembling a lower motor neuron disease. Dysphagia is common, occurring in up to 60% of IBM patients, and may lead to episodes of choking. Sensory examination is generally normal; some patients have mildly diminished vibratory sensation at the ankles that presumably is age-related. The pattern of distal weakness, which superficially resembles motor neuron or peripheral nerve disease, results from the myopathic process affecting distal muscles selectively. Disease progression is slow but steady, and most patients require an assistive device such as cane, walker, or wheelchair within several years of onset.

In at least 20% of cases, IBM is associated with systemic autoimmune or connective tissue diseases. Familial aggregation of typical IBM may occur; such cases have been designated as familial inflammatory IBM. This disorder is distinct from hereditary inclusion body myopathy (h-IBM), which describes a heterogeneous group of recessive, and less frequently dominant, inherited syndromes; the h-IBMs are noninflammatory myopathies. A subset of h-IBM that spares the quadriceps muscles has emerged as a distinct entity. This disorder, originally described in Iranian Jews and now seen in many ethnic groups, is linked to chromosome 9p1 and results from mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene.

ASSOCIATED CLINICAL FINDINGS

Extramuscular manifestations

These may be present to a varying degree in patients with PM or DM, and include:

1. Systemic symptoms, such as fever, malaise, weight loss, arthralgia, and Raynaud’s phenomenon, especially when inflammatory myopathy is associated with a connective tissue disorder.

2. Joint contractures, mostly in DM and especially in children.

3. Dysphagia and gastrointestinal symptoms, due to involvement of oropharyngeal striated muscles and upper esophagus, especially in DM and IBM.

4. Cardiac disturbances, including atrioventricular conduction defects, tachyarrhythmias, dilated cardiomyopathy, a low ejection fraction, and congestive heart failure, may rarely occur, either from the disease itself or from hypertension associated with long-term use of glucocorticoids.

5. Pulmonary dysfunction, due to weakness of the thoracic muscles, interstitial lung disease, or drug-induced pneumonitis (e.g., from methotrexate), which may cause dyspnea, nonproductive cough, and aspiration pneumonia. Interstitial lung disease may precede myopathy or occur early in the disease and develops in up to 10% of patients with PM or DM, most of whom have antibodies to t-RNA synthetases, as described later.

6. Subcutaneous calcifications, in DM, sometimes extruding on the skin and causing ulcerations and infections.

7. Arthralgias, synovitis, or deforming arthropathy with subluxation in the interphalangeal joints can occur in some patients with DM and PM who have Jo-1 antibodies (discussed later).

Association with malignancies

Although all the inflammatory myopathies can have a chance association with malignant lesions, especially in older age groups, the incidence of malignant conditions appears to be specifically increased only in patients with DM and not in those with PM or IBM. The most common tumors associated with DM are ovarian cancer, breast cancer, melanoma, colon cancer, and non-Hodgkin’s lymphoma. The extent of the search that should be conducted for an occult neoplasm in adults with DM depends on the clinical circumstances. Tumors in these patients are usually uncovered by abnormal findings in the medical history and physical examination and not through an extensive blind search. The weight of evidence argues against performing expensive, invasive, and nondirected tumor searches. A complete annual physical examination with pelvic, breast (mammogram, if indicated), and rectal examinations (with colonoscopy according to age and family history); urinalysis; complete blood count; blood chemistry tests; and a chest film should suffice in most cases. In Asians, nasopharyngeal cancer is common, and a careful examination of ears, nose, and throat is indicated. If malignancy is clinically suspected, screening with whole-body PET scan should be considered.

Overlap syndromes

These describe the association of inflammatory myopathies with connective tissue diseases. A well-characterized overlap syndrome occurs in patients with DM who also have manifestations of systemic sclerosis or mixed connective tissue disease, such as sclerotic thickening of the dermis, contractures, esophageal hypomotility, microangiopathy, and calcium deposits (Table 49-1). By contrast, signs of rheumatoid arthritis, systemic lupus erythematosus, or Sjögren’s syndrome are very rare in patients with DM. Patients with the overlap syndrome of DM and systemic sclerosis may have a specific anti-nuclear antibody, the anti-PM/Scl, directed against a nucleolar-protein complex.

PATHOGENESIS

An autoimmune etiology of the inflammatory myopathies is indirectly supported by an association with other autoimmune or connective tissue diseases; the presence of various autoantibodies; an association with specific major histocompatibility complex (MHC) genes; demonstration of T cell–mediated myocytotoxicity or complement-mediated microangiopathy; and a response to immunotherapy.

Autoantibodies and immunogenetics

Various autoantibodies against nuclear antigens (anti-nuclear antibodies) and cytoplasmic antigens are found in up to 20% of patients with inflammatory myopathies. The antibodies to cytoplasmic antigens are directed against ribonucleoproteins involved in protein synthesis (antisynthetases) or translational transport (anti-signal-recognition particles). The antibody directed against the histidyl-transfer RNA synthetase, called anti-Jo-1, accounts for 75% of all the antisynthetases and is clinically useful because up to 80% of patients with anti-Jo-1 antibodies have interstitial lung disease. Some patients with the anti-Jo-1 antibody also have Raynaud’s phenomenon, nonerosive arthritis, and the MHC molecules DR3 and DRw52. DR3 haplotypes (molecular designation DRB1*0301, DQB1*0201) occur in up to 75% of patients with PM and IBM, whereas in juvenile DM there is an increased frequency of DQA1*0501.

Immunopathologic mechanisms

In DM, humoral immune mechanisms are implicated, resulting in a microangiopathy and muscle ischemia (Fig. 49-1). Endomysial inflammatory infiltrates are composed of B cells located in proximity to CD4 T cells, plasmacytoid dendritic cells, and macrophages; there is a relative absence of lymphocytic invasion of nonnecrotic muscle fibers. Activation of the complement C5b-9 membranolytic attack complex is thought to be a critical early event that triggers release of proinflammatory cytokines and chemokines, induces expression of vascular cell adhesion molecule (VCAM) 1 and intercellular adhesion molecule (ICAM) 1 on endothelial cells, and facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces. Necrosis of the endothelial cells, reduced numbers of endomysial capillaries, ischemia, and muscle-fiber destruction resembling microinfarcts occur. The remaining capillaries often have dilated lumens in response to the ischemic process. Larger intramuscular blood vessels may also be affected in the same pattern. Residual perifascicular atrophy reflects the endofascicular hypoperfusion that is prominent in the periphery of muscle fascicles. Increased expression of type I interferon-inducible proteins is also noted in these regions.

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FIGURE 49-1

Immunopathogenesis of dermatomyositis. Activation of complement, possibly by autoantibodies (Y), against endothelial cells and formation of C3 via the classic or alternative pathway. Activated C3 leads to formation of C3b, C3bNEO, and membrane attack complexes (MAC), which are deposited in and around the endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction of capillaries, ischemia, or microinfarcts, most prominent in the periphery of the fascicles, and perifascicular atrophy. B cells, plasmacytoid dendritic cells, CD4 T cells, and macrophages traffic from the circulation to the muscle. Endothelial expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) is induced by cytokines released by the mononuclear cells. Integrins, specifically very late activation antigen (VLA)-4 and lymphocyte function–associated antigen (LFA)-1, bind VCAM and ICAM and promote T cell and macrophage infiltration of muscle through the endothelial cell wall.

By contrast, in PM and IBM a mechanism of T cell–mediated cytotoxicity is likely. CD8 T cells, along with macrophages, initially surround and eventually invade and destroy healthy, nonnecrotic muscle fibers that aberrantly express class I MHC molecules. MHC-I expression, absent from the sarcolemma of normal muscle fibers, is probably induced by cytokines secreted by activated T cells and macrophages. The CD8/MHC-I complex is characteristic of PM and IBM; its detection can aid in confirming the histologic diagnosis of PM, as discussed later. The cytotoxic CD8 T cells contain perforin and granzyme granules directed toward the surface of the muscle fibers and capable of inducing myonecrosis. Analysis of T cell receptor molecules expressed by the infiltrating CD8 cells has revealed clonal expansion and conserved sequences in the antigen-binding region, both suggesting an antigen-driven T cell response. Whether the putative antigens are endogenous (e.g., muscle) or exogenous (e.g., viral) sequences is unknown. Viruses have not been identified within the muscle fibers. Co-stimulatory molecules and their counterreceptors, which are fundamental for T cell activation and antigen recognition, are strongly upregulated in PM and IBM. Key molecules involved in T cell–mediated cytotoxicity are depicted in Fig. 49-2.

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FIGURE 49-2

Cell-mediated mechanisms of muscle damage in polymyositis (PM) and inclusion body myositis (IBM). Antigen-specific CD8 cells are expanded in the periphery, cross the endothelial barrier, and bind directly to muscle fibers via T cell receptor (TCR) molecules that recognize aberrantly expressed MHC-I. Engagement of co-stimulatory molecules (BB1 and ICOSL) with their ligands (CD28, CTLA-4, and ICOS), along with ICAM-1/LFA-1, stabilize the CD8–muscle fiber interaction. Metalloproteinases (MMPs) facilitate the migration of T cells and their attachment to the muscle surface. Muscle fiber necrosis occurs via perforin granules released by the autoaggressive T cells. A direct myocytotoxic effect exerted by the cytokines interferon (IFN) γ, interleukin (IL) 1, or tumor necrosis factor (TNF) α may also play a role. Death of the muscle fiber is mediated by necrosis. MHC class I molecules consist of a heavy chain and a light chain [β2 microglobulin (β2m)] complexed with an antigenic peptide that is transported into the endoplasmic reticulum by TAP proteins.

The role of nonimmune factors in IBM

In IBM, the presence of Congo red–positive amyloid deposits within some vacuolated muscle fibers and abnormal mitochondria with cytochrome oxidase–negative fibers suggest that, in addition to the autoimmune component, there is also a degenerative process. Similar to Alzheimer’s disease, the intracellular amyloid deposits in IBM are immunoreactive against amyloid precursor protein (APP), β-amyloid, chymotrypsin, apolipoprotein E, presenilin, ubiquitin, and phosphor-ylated tau, but it is unclear whether these deposits, which are also seen in other vacuolar myopathies, are directly pathogenic or represent secondary phenomena. The same is true for the mitochondrial abnormalities, which may also be secondary to the effects of aging or a bystander effect of upregulated cytokines. Expression of cytokines and upregulation of MHC class I by the muscle fibers may cause an endoplasmic reticulum stress response resulting in intracellular accumulation of stressor molecules or misfolded glycoproteins and activation of nuclear factor κB (NF-κB), leading to further cytokine activation.

Association with viral infections and the role of retroviruses

Several viruses, including coxsackieviruses, influenza, paramyxoviruses, mumps, cytomegalovirus, and Epstein-Barr virus, have been indirectly associated with myositis. For the coxsackieviruses, an autoimmune myositis triggered by molecular mimicry has been proposed because of structural homology between histidyl-transfer RNA synthetase that is the target of the Jo-1 antibody (discussed earlier) and genomic RNA of an animal picornavirus, the encephalomyocarditis virus. Sensitive polymerase chain reaction (PCR) studies, however, have repeatedly failed to confirm the presence of such viruses in muscle biopsies.

The best evidence of a viral connection in PM and IBM is with the retroviruses. Some individuals infected with HIV or with human T cell lymphotropic virus I (HTLV-I) develop PM or IBM; a similar disorder has been described in nonhuman primates infected with the simian immunodeficiency virus. The inflammatory myopathy may occur as the initial manifestation of a retroviral infection, or myositis may develop later in the disease course. Retroviral antigens have been detected only in occasional endomysial macrophages and not within the muscle fibers themselves, suggesting that persistent infection and viral replication within the muscle do not occur. Histologic findings are identical to retroviral-negative PM or IBM. The infiltrating T cells in the muscle are clonally driven and a number of them are retroviral-specific. This disorder should be distinguished from a toxic myopathy related to long-term therapy with AZT, characterized by fatigue, myalgia, mild muscle weakness, and mild elevation of creatine kinase (CK). AZT-induced myopathy, which generally improves when the drug is discontinued, is a mitochondrial disorder characterized histologically by “ragged-red” fibers. AZT inhibits γ-DNA polymerase, an enzyme found solely in the mitochondrial matrix.

DIFFERENTIAL DIAGNOSIS

The clinical picture of the typical skin rash and proximal or diffuse muscle weakness has few causes other than DM. However, proximal muscle weakness without skin involvement can be due to many conditions other than PM or IBM.

Subacute or chronic progressive muscle weakness

This may be due to denervating conditions such as the spinal muscular atrophies or amyotrophic lateral sclerosis (Chap. 32). In addition to the muscle weakness, upper motor neuron signs in the latter and signs of denervation detected by electromyography (EMG) aid in the diagnosis. The muscular dystrophies (Chap. 48) may be additional considerations; however, these disorders usually develop over years rather than weeks or months and rarely present after the age of 30 years. It may be difficult, even with a muscle biopsy, to distinguish chronic PM from a rapidly advancing muscular dystrophy. This is particularly true of facioscapulohumeral muscular dystrophy, dysferlin myopathy, and the dystrophinopathies where inflammatory cell infiltration is often found early in the disease. Such doubtful cases should always be given an adequate trial of glucocorticoid therapy and undergo genetic testing to exclude muscular dystrophy. Identification of the MHC/CD8 lesion by muscle biopsy is helpful to identify cases of PM. Some metabolic myopathies, including glycogen storage disease due to myophosphorylase or acid maltase deficiency, lipid storage myopathies due to carnitine deficiency, and mitochondrial diseases produce weakness that is often associated with other characteristic clinical signs; diagnosis rests upon histochemical and biochemical studies of the muscle biopsy. The endocrine myopathies such as those due to hypercorticosteroidism, hyper-and hypothyroidism, and hyper- and hypoparathyroidism require the appropriate laboratory investigations for diagnosis. Muscle wasting in patients with an underlying neoplasm may be due to disuse, cachexia, or rarely to a paraneoplastic neuromyopathy (Chap. 44).

Diseases of the neuromuscular junction, including myasthenia gravis or the Lambert-Eaton myasthenic syndrome, cause fatiguing weakness that also affects ocular and other cranial muscles (Chap. 47). Repetitive nerve stimulation and single-fiber EMG studies aid in diagnosis.

Acute muscle weakness

This may be caused by an acute neuropathy such as Guillain-Barré syndrome (Chap. 46), transverse myelitis (Chap. 35), a neurotoxin (Chap. 48), or a neuro-tropic viral infection such as poliomyelitis or West Nile virus (Chap. 40). When acute weakness is associated with very high levels of serum creatine kinase (CK) (often in the thousands), painful muscle cramps, rhabdomyolysis, and myoglobinuria, it may be due to a viral infection or a metabolic disorder such as myophosphorylase deficiency or carnitine palmitoyltransferase deficiency (Chap. 48). Several animal parasites, including protozoa (ToxoplasmaTrypanosoma), cestodes (cysticerci), and nematodes (trichinae), may produce a focal or diffuse inflammatory myopathy known as parasitic polymyositisStaphylococcus aureusYersiniaStreptococcus, or anaerobic bacteria may produce a suppurative myositis, known as tropical polymyositis, or pyomyositis. Pyomyositis, previously rare in the West, is now occasionally seen in AIDS patients. Other bacteria, such as Borrelia burgdorferi (Lyme disease) and Legionella pneumophila (Legionnaire’s disease), may infrequently cause myositis.

Patients with periodic paralysis experience recurrent episodes of acute muscle weakness without pain, always beginning in childhood. Chronic alcoholics may develop painful myopathy with myoglobinuria after a bout of heavy drinking. Acute painless muscle weakness with myoglobinuria may occur with prolonged hypokalemia, or hypophosphatemia and hypomagnesemia, usually in chronic alcoholics or in patients on nasogastric suction receiving parenteral hyperalimentation.

Myofasciitis

This distinctive inflammatory disorder affecting muscle and fascia presents as diffuse myalgias, skin induration, fatigue, and mild muscle weakness; mild elevations of serum CK are usually present. The most common form is eosinophilic myofasciitis characterized by peripheral blood eosinophilia and eosinophilic infiltrates in the endomysial tissue. In some patients, the eosinophilic myositis/fasciitis occurs in the context of parasitic infections, vasculitis, mixed connective tissue disease, hypereosinophilic syndrome, or toxic exposures (e.g., toxic oil syndrome, contaminated L-tryptophan) or with mutations in the calpain gene. A distinct subset of myofasciitis is characterized by pronounced infiltration of the connective tissue around the muscle by sheets of periodic acid–Schiff-positive macrophages and occasional CD8 T cells (macrophagic myofasciitis). Such histologic involvement is focal and limited to sites of previous vaccinations, which may have been administered months or years earlier. This disorder, which to date has not been observed outside of France, has been linked to an aluminum-containing substrate in vaccines. Most patients respond to glucocorticoid therapy, and the overall prognosis seems favorable.

Necrotizing myositis

This is an increasingly recognized entity that has distinct features, even though it is often labeled as PM. It presents often in the fall or winter as an acute or subacute onset of symmetric muscle weakness; CK is typically extremely high. The weakness can be severe. Coexisting interstitial lung disease and cardiomyopathy may be present. The disorder may develop after a viral infection or in association with cancer. Some patients have antibodies against signal recognition particle (SRP). The muscle biopsy demonstrates necrotic fibers infiltrated by macrophages but only rare, if any, T cell infiltrates. Muscle MHC-I expression is only slightly and focally upregulated. The capillaries may be swollen with hyalinization, thickening of the capillary wall, and deposition of complement. Some patients respond to immunotherapy, but others are resistant.

Hyperacute necrotizing fasciitis/myositis (flesh-eating disease)

This a fulminant infectious disease, seen most often in the tropics or in conditions with poor hygiene, characterized by widespread necrosis of the superficial fascia and muscle of a limb; if the scrotum, perineum, and abdominal wall are affected, the condition is referred to as Fournier’s gangrene. It may be caused by group A β-hemolytic streptococcus, methicillin-sensitive S. aureusPseudomonas aeruginosaVibrio vulnificus, clostridial species (gas gangrene), or polymicrobial infection with anaerobes and facultative bacteria; toxins from these bacteria may act as superantigens. The port of bacterial entry is usually a trivial cut or skin abrasion and the source is contact with carriers of the organism. Individuals with diabetes mellitus, immunodeficiency states, or systemic illnesses such as liver failure are most susceptible. Systemic varicella is a predisposing factor in children.

The disease presents with swelling, pain, and redness in the involved area followed by a rapid tissue necrosis of fascia and muscle that progresses at an estimated rate of 3 cm/h. Emergency debridement, antibiotics, as well as IVIg, or even hyperbaric oxygen have been recommended. In progressive or advanced cases, amputation of the affected limb may be necessary to avoid a fatal outcome.

Drug-induced myopathies

D-Penicillamine, procainamide, and statins may produce a true myositis resembling PM, and a DM-like illness had been associated with the contaminated preparations of L-tryptophan. As noted earlier, AZT causes a mitochondrial myopathy. Other drugs may elicit a toxic noninflammatory myopathy that is histologically different from DM, PM, or IBM. These include cholesterol-lowering agents such as clofibrate, lovastatin, simvastatin, or provastatin, especially when combined with cyclosporine, amiodarone, or gemfibrozil. Statin-induced necrotizing myopathy or asymptomatic elevations of CK usually improve after discontinuation of the drug. In rare patients, however, muscle weakness continues to progress even after the statin is withdrawn; in these cases, a diagnostic muscle biopsy is indicated, and if evidence of inflammation and MHC-I upregulation is present, immunotherapy for PM should be considered. Rhabdomyolysis and myoglobinuria have been rarely associated with amphotericin B, ε-aminocaproic acid, fenfluramine, heroin, and phencyclidine. The use of amiodarone, chloroquine, colchicine, carbimazole, emetine, etretinate, ipecac syrup, chronic laxative or licorice use resulting in hypokalemia, and glucocorticoids or growth hormone administration have also been associated with myopathic muscle weakness. Some neuromuscular blocking agents such as pancuronium, in combination with glucocorticoids, may cause an acute critical illness myopathy. A careful drug history is essential for diagnosis of these drug-induced myopathies, which do not require immunosuppressive therapy except when an autoimmune myopathy has been triggered, as noted earlier.

“Weakness” due to muscle pain and muscle tenderness

A number of conditions including polymyalgia rheumatica and arthritic disorders of adjacent joints may enter into the differential diagnosis of inflammatory myopathy, even though they do not cause myositis. The muscle biopsy is either normal or discloses type II muscle fiber atrophy. Patients with fibrositis and fibromyalgia complain of focal or diffuse muscle tenderness, fatigue, and aching, which is sometimes poorly differentiated from joint pain. Some patients, however, have muscle tenderness, painful muscles on movement, and signs suggestive of a collagen vascular disorder, such as an increased erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, or rheumatoid factor, along with modest elevation of the serum CK and aldolase. They demonstrate a “breakaway” pattern of weakness with difficulty sustaining effort but not true muscle weakness. The muscle biopsy is usually normal or nonspecific. Many such patients show some response to nonsteroidal anti-inflammatory agents or glucocorticoids, though most continue to have indolent complaints. An indolent fasciitis in the setting of an ill-defined connective tissue disorder may be present, and these patients should not be labeled as having a psychosomatic disorder. Chronic fatigue syndrome, which may follow a viral infection, can present with debilitating fatigue, fever, sore throat, painful lymphadenopathy, myalgia, arthralgia, sleep disorder, and headache (Chap. 52). These patients do not have muscle weakness, and the muscle biopsy is normal.

DIAGNOSIS

The clinically suspected diagnosis of PM, DM, or IBM is confirmed by analysis of serum muscle enzymes, EMG findings, and muscle biopsy (Table 49-2).

TABLE 49-2

CRITERIA FOR DIAGNOSIS OF INFLAMMATORY MYOPATHIES

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The most sensitive enzyme is CK, which in active disease can be elevated as much as fiftyfold. Although the CK level usually parallels disease activity, it can be normal in some patients with active IBM or DM, especially when associated with a connective tissue disease. The CK is always elevated in patients with active PM. Along with the CK, the serum glutamic-oxaloacetic and glutamate pyruvate transaminases, lactate dehydrogenase, and aldolase may be elevated.

Needle EMG shows myopathic potentials characterized by short-duration, low-amplitude polyphasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves. Mixed potentials (polyphasic units of short and long duration) indicating a chronic process and muscle fiber regeneration are often present in IBM. These EMG findings are not diagnostic of an inflammatory myopathy but are useful to identify the presence of active or chronic myopathy and to exclude neurogenic disorders.

MRI is not routinely used for the diagnosis of PM, DM, or IBM. However, it may provide information or guide the location of the muscle biopsy in certain clinical settings.

Muscle biopsy—in spite of occasional variability in demonstrating all of the typical pathologic findings—is the most sensitive and specific test for establishing the diagnosis of inflammatory myopathy and for excluding other neuromuscular diseases. Inflammation is the histologic hallmark for these diseases; however, additional features are characteristic of each subtype (Figs. 49-349-4, and 49-5).

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FIGURE 49-3

Cross-section of a muscle biopsy from a patient with polymyositis demonstrates scattered inflammatory foci with lymphocytes invading or surrounding muscle fibers. Note lack of chronic myopathic features (increased connective tissue, atrophic or hypertrophic fibers) as seen in inclusion body myositis.

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FIGURE 49-4

Cross-section of a muscle biopsy from a patient with dermatomyositis demonstrates atrophy of the fibers at the periphery of the fascicle (perifascicular atrophy).

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FIGURE 49-5

Cross-sections of a muscle biopsy from a patient with inclusion body myositis demonstrate the typical features of vacuoles with lymphocytic infiltrates surrounding non-vacuolated or necrotic fibers (A), tiny endomysial deposits of amyloid visualized with crystal violet (B), cytochrome oxidase–negative fibers, indicative of mitochondrial dysfunction (C), and ubiquitous MHC-I expression at the periphery of all fibers (D).

In PM the inflammation is primary, a term used to indicate that the inflammation is not reactive and the T cell infiltrates, located primarily within the muscle fascicles (endomysially), surround individual, healthy muscle fibers and result in phagocytosis and necrosis (Fig. 49-3). The MHC-I molecule is ubiquitously expressed on the sarcolemma, even in fibers not invaded by CD8+ cells. The CD8/MHC-I lesion is characteristic and essential to confirm or establish the diagnosis and to exclude disorders with secondary, nonspecific, inflammation, such as in some muscular dystrophies. When the disease is chronic, connective tissue is increased and may react positively with alkaline phosphatase.

In DM the endomysial inflammation is predominantly perivascular or in the interfascicular septae and around—rather than within—the muscle fascicles (Fig. 49-4). The intramuscular blood vessels show endothelial hyperplasia with tubuloreticular profiles, fibrin thrombi, and obliteration of capillaries. The muscle fibers undergo necrosis, degeneration, and phagocytosis, often in groups involving a portion of a muscle fasciculus in a wedgelike shape or at the periphery of the fascicle, due to microinfarcts within the muscle. This results in perifascicular atrophy, characterized by 2–10 layers of atrophic fibers at the periphery of the fascicles. The presence of perifascicular atrophy is diagnostic of DM, even in the absence of inflammation.

In IBM (Fig. 49-5), there is endomysial inflammation with T cells invading MHC-I-expressing nonvacuolated muscle fibers; basophilic granular deposits distributed around the edge of slitlike vacuoles (rimmed vacuoles); loss of fibers, replaced by fat and connective tissue, hypertrophic fibers, and angulated or round fibers; rare eosinophilic cytoplasmic inclusions; abnormal mitochondria characterized by the presence of ragged-red fibers or cytochrome oxidase–negative fibers; and amyloid deposits within or next to the vacuoles best visualized with crystal violet or Congo-red staining viewed with fluorescent optics. Electron microscopy demonstrates filamentous inclusions in the vicinity of the rimmed vacuoles. In at least 15% of patients with the typical clinical phenotype of IBM, no vacuoles or amyloid deposits can be identified in muscle biopsy, leading to an erroneous diagnosis of PM. Close clinicopatho-logic correlations are essential; if uncertain, a repeat muscle biopsy from another site is often helpful.


TREATMENT Therapy of Inflammatory Myopathies

The goal of therapy is to improve muscle strength, thereby improving function in activities of daily living, and ameliorate the extramuscular manifestations (rash, dysphagia, dyspnea, fever). When strength improves, the serum CK falls concurrently; however, the reverse is not always true. Unfortunately, there is a common tendency to “chase” or treat the CK level instead of the muscle weakness, a practice that has led to prolonged and unnecessary use of immunosuppressive drugs and erroneous assessment of their efficacy. It is prudent to discontinue these drugs if, after an adequate trial, there is no objective improvement in muscle strength whether or not CK levels are reduced. Agents used in the treatment of PM and DM include the following:

1. Glucocorticoids. Oral prednisone is the initial treatment of choice; the effectiveness and side effects of this therapy determine the future need for stronger immunosuppressive drugs. High-dose prednisone, at least 1 mg/kg per day, is initiated as early in the disease as possible. After 3–4 weeks, prednisone is tapered slowly over a period of 10 weeks to 1 mg/kg every other day. If there is evidence of efficacy and no serious side effects, the dosage is then further reduced by 5 or 10 mg every 3–4 weeks until the lowest possible dose that controls the disease is reached. The efficacy of prednisone is determined by an objective increase in muscle strength and activities of daily living, which almost always occurs by the third month of therapy. A feeling of increased energy or a reduction of the CK level without a concomitant increase in muscle strength is not a reliable sign of improvement. If prednisone provides no objective benefit after ~3 months of high-dose therapy, the disease is probably unresponsive to the drug and tapering should be accelerated while the next-inline immunosuppressive drug is started. Although controlled trials have not been performed, almost all patients with true PM or DM respond to glucocorticoids to some degree and for some period of time; in general, DM responds better than PM.

  The long-term use of prednisone may cause increased weakness associated with a normal or unchanged CK level; this effect is referred to as steroid myopathy. In a patient who previously responded to high doses of prednisone, the development of new weakness may be related to steroid myopathy or to disease activity that either will respond to a higher dose of glucocorticoids or has become glucocorticoid-resistant. In uncertain cases, the prednisone dosage can be steadily increased or decreased as desired: the cause of the weakness is usually evident in 2–8 weeks.

2. Other immunosuppressive drugs. Approximately 75% of patients ultimately require additional treatment. This occurs when a patient fails to respond adequately to glucocorticoids after a 3-month trial, the patient becomes glucocorticoid-resistant, glucocorticoid-related side effects appear, attempts to lower the prednisone dose repeatedly result in a new relapse, or rapidly progressive disease with evolving severe weakness and respiratory failure develops.

  The following drugs are commonly used but have never been tested in controlled studies: (1) Azathioprine is well tolerated, has few side effects, and appears to be as effective for long-term therapy as other drugs. The dose is up to 3 mg/kg daily. (2) Methotrexate has a faster onset of action than azathioprine. It is given orally starting at 7.5 mg weekly for the first 3 weeks (2.5 mg every 12 h for 3 doses), with gradual dose escalation by 2.5 mg per week to a total of 25 mg weekly. A rare side effect is methotrexate pneumonitis, which can be difficult to distinguish from the interstitial lung disease of the primary myopathy associated with Jo-1 antibodies (described earlier). (3) Mycophenolate mofetil also has a faster onset of action than azathioprine. At doses up to 2.5 or 3 g/d in two divided doses, it is well tolerated for long-term use. (4) Monoclonal anti-CD20 antibody (rituximab) has been shown in a small uncontrolled series to benefit patients with DM and PM. (5) Cyclosporine has inconsistent and mild benefit. (6) Cyclophosphamide (0.5–1 g/m2 IV monthly for 6 months) has limited success and significant toxicity. (7) Tacrolimus (formerly known as Fk506) has been effective in some difficult cases of PM.

3. Immunomodulation. In a controlled trial of patients with refractory DM, intravenous immunoglobulin (IVIg) improved not only strength and rash but also the underlying immunopathology. The benefit is often short-lived (≤8 weeks), and repeated infusions every 6–8 weeks are generally required to maintain improvement. A dose of 2 g/kg divided over 2–5 days per course is recommended. Uncontrolled observations suggest that IVIg may also be beneficial for patients with PM. Neither plasmapheresis nor leukapheresis appears to be effective in PM and DM.

The following sequential empirical approach to the treatment of PM and DM is suggested: Step 1: high-dose prednisone; Step 2: azathioprine, mycophenolate, or methotrexate for steroid-sparing effect; Step 3: IVIg; Step 4: a trial, with guarded optimism, of one of the following agents, chosen according to the patient’s age, degree of disability, tolerance, experience with the drug, and general health: rituximab, cyclosporine, cyclophosphamide, or tacrolimus. Patients with interstitial lung disease may benefit from aggressive treatment with cyclophosphamide or tacrolimus.

A patient with presumed PM who has not responded to any form of immunotherapy most likely has IBM or another disease, usually a metabolic myopathy, a muscular dystrophy, a drug-induced myopathy, or an endocrinopathy. In these cases, a repeat muscle biopsy and a renewed search for another cause of the myopathy is indicated.

Calcinosis, a manifestation of DM, is difficult to treat; however, new calcium deposits may be prevented if the primary disease responds to the available therapies. Bisphosphonates, aluminum hydroxide, probenecid, colchicine, low doses of warfarin, calcium blockers, and surgical excision have all been tried without success.

IBM is generally resistant to immunosuppressive therapies. Prednisone together with azathioprine or methotrexate is often tried for a few months in newly diagnosed patients, although results are generally disappointing. Because occasional patients may feel subjectively weaker after these drugs are discontinued, some clinicians prefer to maintain these patients on low-dose, every-other-day prednisone along with mycophenolate in an effort to slow disease progression, even though there is no objective evidence or controlled study to support this practice. In two controlled studies of IVIg in IBM, minimal benefit in up to 30% of patients was found; the strength gains, however, were not of sufficient magnitude to justify its routine use. Another trial of IVIg combined with prednisone was ineffective. Nonetheless, many experts believe that a 2- to 3-month trial with IVIg may be reasonable for selected patients with IBM who experience rapid progression of muscle weakness or choking episodes due to worsening dysphagia.

PROGNOSIS The 5-year survival rate for treated patients with PM and DM is ~95% and the 10-year survival rate is 84%; death is usually due to pulmonary, cardiac, or other systemic complications. The prognosis is worse for patients who are severely affected at presentation, when initial treatment is delayed, and in cases with severe dysphagia or respiratory difficulties. Older patients, and those with associated cancer also have a worse prognosis. DM responds more favorably to therapy than PM and thus has a better prognosis. Most patients improve with therapy, and many make a full functional recovery, which is often sustained with maintenance therapy. Up to 30% may be left with some residual muscle weakness. Relapses may occur at any time.

IBM has the least favorable prognosis of the inflammatory myopathies. Most patients will require the use of an assistive device such as a cane, walker, or wheelchair within 5–10 years of onset. In general, the older the age of onset in IBM, the more rapidly progressive is the course.