Chapter 20 Inflammatory myopathies

Clinical Neurophysiology of Disorders ofMuscle and Neuromuscular Junction, Including Fatigue Handbook of Clinical Neurophysiology, Vol. 2 Erik Stalberg (Ed.) © 2003 Elsevier B.V. All rights reserved

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CHAPTER 20

Inflammatory myopathies Hannah R. Briemberg and Anthony A. Amato* Department of Neurology, Neuromuscular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA

The inflammatory myopathies are a heterogeneous group of disorders characterized by muscle weakness, elevated serum creatine kinase levels, electrophysiologic abnormalities, and inflammation on muscle biopsy. The inflammatory myopathies are traditionally divided into idiopathic and secondary etiologies. The three major categories of idiopathic inflammatory myopathy are polymyositis, dermatomyositis and inclusion body myositis. The exact incidence of each is unknown as previous epidemiological studies often grouped them together. Overall, the annual incidence of the inflammatory myopathies is one in 100,000 (Medsgar et al., 1970; Dalakas, 1991). The electromyographic abnormalities associated with inflammatory myopathies do not differentiate one from the other, nor do they differentiate inflammatory muscle disease from other myopathic processes. Nonetheless, in conjunction with a thorough clinical history and exam, they can be helpful in supporting or excluding the clinical suspicion of an inflammatory myopathy. Muscle biopsy, however, remains the gold standard for diagnosis. 20.1. Idiopathic inflammatory myopathies 20.1.1. Dermatomyositis 20.1.1.1. Clinical features Dermatomyositis is a distinct disease, affecting, as its name implies, both muscle and skin. Dermatomyositis has a bimodal age distribution with peaks at 5-24 years and 45-64 years of age (Dalakas, 1991). Children are more likely to present with an insidious

* Correspondence to: Dr. Anthony A. Amato, M.D., Department of Neurology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA. E-mail address: [email protected] Tel.: 617-732-8046; fax: 617-730-2885.

onset of weakness, myalgias, fatigue and low-grade fever (Amato and Kissel, 1999). The skin manifestations are characteristic. However, patients do not necessarily exhibit all skin manifestations simultaneously. Perhaps the best known is the heliotrope rash around the eyes. This is a lilac-colored rash of the upper eyelids, often associated with periorbital edema. A macular, erythematous rash may also be seen over the face, upper trunk and limbs. Typical locations over the trunk include the anterior chest and neck, in what has been described as the V-sign, and over the posterior neck and back of the shoulders (shawl sign). The rash may also be seen on the limbs over the extensor tendon surfaces. Papular erythema of the metacarpophalangeal and interphalangeal joints with scaling of this skin (Gottron's sign) is also classic. Tiny capillary telangiectasias are often seen around the nailbeds. The rash may precede the development of muscle weakness or it may occur simultaneously with the weakness. Occasionally, one sees the typical rash in the absence of muscle weakness. This is referred to as dermatomyositis sine myositis or amyopathic dermatomyositis. Interestingly, muscle biopsy in many of these cases will demonstrate typical changes of dermatomyositis (Dalakas, 2001). Systemic complications of adult dermatomyositis include interstitial lung disease and inflammation of the pericardium and cardiac muscle. Inflammation of the skeletal and smooth muscles of the gastrointestinal tract can lead to dysphagia and delayed gastric emptying. Children are more likely to develop widespread organ involvement (Banker and Victor, 1966). Vasculopathy of the gastrointestinal tract is a serious complication that is much more common in childhood dermatomyositis. The vasculopathy can result in mucosal ulceration, perforation, and life-threatening hemorrhage.. Children are also more likely to develop subcutaneous calcification.

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This is rare in adults but is seen in 30 to 70% of children (Cohen et al., 1986; Amato and Kissel, 1999). The calcifications tend to develop over pressure points (e.g. buttocks, knees, and/or elbows) and present as painful, hard nodules. They are more likely to develop in children who have been inadequately treated. Unfortunately, once they develop, they are very difficult to treat. Despite the potential complications, the mortality rate of childhood dermatomyositis is very low (Pachman, 1995). There is an increased incidence of malignancy in adult dermatomyositis, ranging from 6 to 45% (Bohan et al., 1977; Tymms and Webb, 1985; Sigurgeirsson et aI., 1992; Callen, 1994). Unlike the adult form, there is no association between pediatric dermatomyositis and increased risk of malignancy. Detection of an underlying neoplasm can precede or follow the diagnosis of dermatomyositis; however, the majority of malignancies are identified within two years of presentation of the myositis. The risk of malignancy is similar in males and females and is greater in patients over the age of 40 years. This association is seen with malignancies in general and is not specific to one particular type. Therefore, we advocate screening with routine bloodwork (complete blood count, routine chemistries), urinalysis, CXR, and pelvic ultrasounds and mammograms in women. Further workup should be sign and symptom related. With appropriate treatment, and in the absence of malignancy or systemic complications, prognosis tends to be favorable. Five-year survival rates of adult dermatomyositis range from 70 to 93% (Hochberg et aI., 1986; Joffe et aI., 1993). 20././.2. Laboratory features Serum creatine kinase levels are typically elevated and may be increased by as much as 50 times the upper limit of normal. However, serum creatine kinase levels can be normal, particularly early in the course of the disease. Other muscle-related enzymes may also be elevated (aldolase, SGOT, SGPT and LDH). Anti-nuclear antibodies are present in 24-60% of patients (Hochberg et al., 1986; Love et aI., 1991; Targoff, 1994). Myositis specific antibodies are seen in a minority of patients with dermatomyositis and, thus, are not a sensitive screening tool. Anti-Jo-l antibodies, Mi-2 antibodies and antibodies directed against signal

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recognition protein have each been associated with dermatomyositis. Jo-l antibodies have a higher incidence in patients with myositis and associated interstitial lung disease (Hochberg et al., 1984). Signal recognition protein has been associated with a more fulminant course and poorer response to treatment (Hochberg et al., 1983).

20.1.1.3. Histopathology The characteristic histologic feature is perifascicular atrophy but this occurs in only about one-third of patients and may be even less common in adults (Kissel et al., 1991; Carpenter and Karpati, 2001). The atrophic fibers may demonstrate microvacuolation and myofibrillar disruption. Wedgeshaped microinfarcts surrounded by regenerating fibers are occasionally seen, more commonly in adult dermatomyositis (Carpenter and Karpati, 2001). Inflammatory cells are typically seen in the perimysium, especially around blood vessels, but are less common within fascicles. Unlike polymyositis and inclusion body myositis, one does not see invasion of non-necrotic fibers. Also in contrast to polymyositis and inclusion body myositis, the inflammatory infiltrate is composed primarily of Bcells, CD4+ cells and macrophages (Arahata and Engel, 1984). Dermatomyositis is a vasculopathy and the most specific histopathologic abnormalities are associated with endomysial capillaries. The earliest histological abnormality is the deposition of membrane attack complex (MAC) on capillaries and arterioles, which can be shown by immunohistochemistry stains. Other complement components (C3 and C9), IgM, and less often IgG are also deposited within the walls of intramuscular blood vessels. MAC deposition precedes the appearance of perivascular inflammation and perifascicular atrophy and is specific for dermatomyositis. The subsequent necrosis of vessels results in a reduction in the capillary density (number of capillaries per area of muscle) (Kissel et aI., 1986a; De Visser et aI., 1989; Kissel et aI., 1991). Electron microscopy (EM) reveals small intramuscular blood vessels (arterioles and capillaries) with endothelial hyperplasia, microvacuoles, and cytoplasmic inclusions; these abnormalities precede other structural abnormalities on routine light microscopy (Banker, 1975).

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20.1.1.4. Pathogenesis The immunologic studies and other histopathologic features of dermatomyositis suggest that it is a humorally mediated microangiopathy. It is believed that the microangiopathy leads to ischemic damage and subsequent infarction of muscle fibers. The perifascicular atrophy is felt to be secondary to hypoperfusion in watershed regions of muscle. However, the nature and origin of the antigen that triggers this immune attack is unknown. 20.1.1.5. Electrophysiologic findings 20.1.1.5.1. Nerve conduction studies. Assuming there is not a concomitant peripheral neuropathy, the sensory and motor nerve conduction studies are normal. Rarely, there is a reduction in the CMAP amplitude due muscle fiber loss and atrophy. 20.1.1.5.2. Needle electromyography. EMG findings in the inflammatory myopathies are neither sensitive nor specific. In patients with either mild, or treated, disease, the EMG can be normal. Because of the patchy nature of the disease, investigation of multiple muscles may be necessary to document sufficient abnormalities for diagnosis. Although characteristic EMG abnormalities have been documented, none of these abnormalities are, by themselves, specific to the inflammatory myopathies. Thus, as always, the EMG must be considered in the context of the clinical history and exam findings. If an inflammatory myopathy is suspected, muscle biopsy provides the gold standard for determining the exact etiology. Perhaps the most characteristic finding in patients with acute disease is the presence of positive sharp waves and fibrillation potentials, which have been detected in 93-100% of patients, provided an adequate search, including paraspinal muscles, is performed (Streib et al., 1979; Mitz et al., 1981). If sustained muscle membrane instability is not found in the limb muscles of a patient strongly suspected of having an acute, inflammatory myopathy, examination of the paraspinal muscles should be undertaken, particularly in the thoracic area. The thoracic paraspinal muscles are less likely to demonstrate muscle membrane instability related to degenerative spine disease than the cervical or lumbosacral

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paraspinal muscles; thus, abnormalities here are felt to be more specific for a myopathic process. In chronic myositis, the positive sharp waves and fibrillation potentials may be decreased compared to acute disease (Trojaborg, 1990). Additionally, the size of the spontaneous potentials is reduced compared to the acute stage, approximating 100 microvolts or less vs. greater than 100-200 microvolts in the acute stages. The decreased number of spontaneous potentials is likely the result of a significant degree of muscle tissue loss with replacement by connective tissue. The small size of the potentials results from long-standing failure of reinnervation with a reduction in muscle fiber size secondary to atrophy (Amato and Dumitru, 2002). Following treatment, the degree of muscle membrane instability also decreases (Sandstedt et al., 1982). This decrease can be dramatic, with essentially complete resolution of positive sharp waves and fibrillation potentials over the course of several weeks to months. However, there are occasional patients in whom it is still relatively easy to find membrane instability despite adequate treatment and symptom resolution. The presence of "myotonic" discharges in patients with idiopathic inflammatory myopathies has been reported, although we have not observed this finding. Decrescendo trains of positive sharp waves are common and it may be that these have been mistaken for myotonic potentials by some investigators. We consider these trains as "pseudomyotonic discharges" because they do not wax and wane in frequency and amplitude. Another relatively common finding in the subacute or more chronic stages of the disease process is the presence of complex repetitive discharges (Amato and Dumitru, 2002). However, as with the other abnormalities seen, this finding is not pathognomonic and is rarely seen in the acute stages of the disease. Evaluation of motor unit action potentials (MUAP) in the inflammatory myopathies is complex. Although MUAP amplitudes may be reduced. the most common abnormality is a shortening of the MUAP mean duration (Buchthal and Pinelli, 1953; Trojaborg, 1990; Jongen et aI., 1996). This is best determined quantitatively. Although the mean duration of both simple and polyphasic MUAPs in myositis patients is shorter than that of controls, the difference is accentuated if only simple as opposed to complex or polyphasic potentials are measured

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(Trojaborg, 1990). It should be emphasized that control patients also demonstrate occasional short duration and polyphasic MUAPs. Thus, in order to increase the sensitivity of diagnosis when studying patients quantitatively, one must examine at least 20, preferably simple, MUAPs. There is also an increase in the number of long duration polyphasic MUAPs compared with controls (Trojaborg, 1990). These long duration units are more commonly noted in long standing myositis and may take one of three forms (Amato and Dumitru, 2002). Highly complex potentials with abnormally long durations comprised of clearly defined phases are observed in many patients. A second type of potential consists of a major MUAP spike followed by several very low-amplitude complexes that are continuous with the major spike. A high amplifier gain may be necessary to appreciate the smaller trailing components. Lastly, true satellite potentials, with at least 5 ms of quiet baseline between the major spike and time-locked potential, can be observed. Many investigators (Mechler, 1974; Lang and Partanen, 1976; Partanen and Lang, 1982) have demonstrated an increasing frequency of these longduration MUAPs as the disease progresses from the acute to more chronic stages. These potentials are thought to result from variation in conduction velocity within a motor unit secondary to muscle fiber size variation and slowing along focal regenerating muscle segments. Long and/or immature collateral terminal nerves reinnervating segmented muscle fibers may also play a role (Amato and Dumitru, 2002). Treatment with corticosteroids generally results in a reduction in both the number of polyphasic potentials and the number of short-duration MUAPs (Mechler, 1974). The final MUAP duration in a patient who is adequately treated may not only return to normal, but may actually become longer than normal over time. A computerized decomposition program that automatically selects and analyzes recruited MUAPs for duration, amplitude and turns has been described (Dorfman and McGill, 1988). We, like others have not found this particular program to be useful, as the sensitivity of detecting idiopathic inflammatory myopathies is not increased compared with conventional EMG (Jongen et aI., 1996). However, other programs have been developed that may prove to be

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more useful (Stalberg, 2002, personal communication). The recruitment of MUAPs in myopathies, including the inflammatory myopathies, may be abnormal and is distinct from neurogenic disorders. Myopathies result in random loss of individual muscle fibers such that different motor units are affected to variable degrees. There is usually not a complete loss of motor units in myopathic disorders, at least in mild or early disease. However, the reduction in the number of muscle fibers results in the generation of less force within an individual motor unit. In mild myogenic disorders, recruitment abnormalities can unfortunately be very subtle. With mild effort, the central nervous system senses that there is a reduction of force being generated for the given number of motor units activated. The initial MUAPs fire at a normal or only mildly increased onset frequency. With modestly increased effort, additional motor units are recruited at frequencies close to the onset frequency of the first MUAP. The net result is so-called early recruitment in which multiple MUAPs are detected in excess of that anticipated for the degree of power generated by the patient. Patients often have difficulty recruiting just one or two MUAPs and instead produce a rather complete interference pattern at relatively low levels of force production. The early recruitment seen in myopathies contrasts with the decreased recruitment seen in neurogenic disorders, where one sees fewer recruitable motor units and firing rates of 15Hz or more. However, in patients with severe myositis resulting in the loss of a significant number of muscle fibers and presumably entire motor units, the recruitment pattern can be reduced similar to that seen in neurogenic disorders. 20.1.1.5.3. Single-fiber electromyography. Single muscle fiber jitter values are mildly to moderately increased in most patients with polymyositis and dermatomyositis (Foote et aI., 1978; Henriksson and Stalberg, 1978; Eisen et aI., 1983; Joy et aI., 1990). Blocking can also be observed. Fiber density is usually moderately increased in all patients. These findings suggest that there is remodeling of the motor unit through collateral sprouting of nerves most likely reinnervating segmented portions of muscle fibers. Histologic assessment of muscle confirms various degrees of fiber type grouping

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as suggested by single-fiber electromyographic studies. 20.1.2. Polymyositis 20./.2.1. Clinical features Polymyositis is the least common of the three major idiopathic inflammatory myopathies. Much of the polymyositis literature based the diagnosis on Bohan and Peter's (1975a and 1975b) criteria, which did not require a muscle biopsy. Further the biopsy criteria are not specific for polymyositis and can be seen in any form of necrotizing myopathy including inclusion body myositis and muscular dystrophies. More recent literature, using strict myopathological features for diagnosis of polymyositis, has brought into question previously reported associations. Because of this, the clinical entity of polymyositis must be said to be poorly defined at present. Polymyositis is thought to present in patients over 20 years of age with subacute onset of progressive, symmetric proximal weakness. Patients typically complain of difficulty arising from low chairs or the commode and difficulties going up and down stairs. As the arms become involved, they report difficulties with doing their hair and/or brushing their teeth. Muscle pain or tenderness, although it occurs occasionally, is rarely the chief complaint. Certainly, muscle pain without evidence of weakness should lead to consideration of other disorders, such as polymyalgia rheumatica. Neurologic exam demonstrates proximal greater than distal weakness of the extremities. Although patients rarely complain of functional difficulties related to distal weakness, mild hand, wrist and ankle weakness can often be found on exam. Mild facial weakness may also be apparent. Extra-ocular movements are spared. Muscle stretch reflexes are preserved and sensation is unaffected. At least 10% of patients with polymyositis are said to develop interstitial lung disease (Dickey and Myers, 1984) which may be associated with anti-Jo1 antibodies. However, recently Mozaff and Pestronk (2000) reviewed the myopathology of patients with myositis and Jo-l antibodies. They found that all of their patients with anti-J0-1 antibodies had histopathology consistent with a humorally-mediated disease rather than with polymyositis. This is in keeping with other studies that have demonstrated ILD and Jo-l antibodies only

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in dermatomyostis (Greenberg et aI., 2002). Similarly, signal recognition protein which was thought to be specific for polymyositis, has been associated with a humorally mediated microangiopathy in histopathological studies (Miller et aI., 2002). Most patients with polymyositis respond to treatment with immunosuppressive agents. However, some retrospective studies suggest the response to treatment is not as favorable as that seen in dermatomyositis (Joffe et aI., 1993; Amato et al., 1996). Poor prognostic features include older age, concomitant ILD or cardiac disease and delayed or inadequate treatment. Overall, most patients improve. However, up to 30% of the patients may be left with residual muscle weakness (Dalakas, 2001). The five-year survival rate for treated patients with polymyositis and dermatomyositis is close to 80% (Dalakas, 2001). 20.1.2.2. Laboratory features Serum creatine kinase (CK) is considered the most sensitive marker of muscle disease. In polymyositis, serum CK is usually, but not invariably elevated up to 50 times normal (Tymms and Webb, 1985; Hochberg et al., 1986). It should be noted that serum CK levels do not correlate with disease severity and therefore should only be used in conjunction with the clinical exam in assessing treatment response. Positive anti-nuclear antibodies have been reported in 16-40% of polymyositis patients (Tymms and Webb, 1985; Hochberg et al., 1986; Love et al., 1991). Erythrocyte sedimentation rate is typically normal. 20.1.2.3. Histopathology Characteristic findings on muscle biopsy include the presence of endomysial inflammation and the invasion of non-necrotic muscle fibers. The invading inflammatory cells consist primarily of activated CD8+ (cytotoxic), alpha/beta T-cells, and macrophages (Arahata and Engel, 1984). There is an oligoclonal pattern of gene rearrangement and restricted motif of the CDR3 within the T-cell receptor that suggests an antigen-specific immune response (Mantegazza et al., 1993). Major histocompatibility complex (MHC) class 1 antigen is present on all of the invaded fibers, as well as on many non-invaded muscle fibers (Carpenter and Karpati, 2001). This is in contrast to dermatomyositis and inclusion body myositis, where expression of

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MHC class I antigen is limited to damaged or invaded fibers, respectively (Carpenter and Karpati, 2001). It should be noted, however, that due to sampling error and the patchy involvement of the disease, these findings are not always present, and in fact, the biopsy may be normal, especially in mild disease. Electromyography (EMG) is helpful in identifying involved muscles for biopsy. Traditionally, EMG is performed on one side and the biopsy is performed on the opposite side to avoid taking tissue that may demonstrate reactive damage to the EMG needle.

20. 1.2.4. Pathogenesis The exact pathogenesis has yet to be defined. Many factors, including the prominence of T cells in the inflammatory infiltrates, the oligoclonal pattern of gene rearrangement within the T cell receptor, and the observation that the clonally expanded T cells invade muscle fibers expressing MHC class 1 antigen, suggest that the muscle fiber damage is a result of antigen-specific, cell-mediated cytotoxicity. However, no trigger for this autoimmune response has been identified.

20.1.2.5. Electrophysiological findings The electrophysiological findings in polymyositis are identical to those in dermatomyositis and are discussed in detail at the end of the following section.

20.1.3. Overlap syndromes Approximately 20% of patients with dermatomyositis and polymyositis display signs and symptoms, as well as laboratory features, suggestive of a concomitant connective tissue disorder (Amato and Dumitru, 2002). Associated disorders include scleroderma, Sjogren's syndrome, systemic lupus erythematosus, rheumatoid arthritis or mixed connective tissue disease. The clinical, electrophysiologic and histologic features of the myopathy are the same as those seen in idiopathic dermatomyositis and polymyositis. Prognosis appears to be related to the severity of the underlying connective tissue disease.

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20.1.4. Inclusion body myositis 20. 1.4.1. Clinical features Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in people over 50 years of age (Phillips et aI., 2000; Rose et aI., 2001). It presents with an insidious onset of proximal and distal weakness. Probably because of the slow progression of this disease, patients have been symptomatic for an average of approximately six years prior to diagnosis (Lotz et al., 1989; Amato et al., 1996; Felice and North, 2001). Although occasional patients are younger than 50 years at the time of symptom onset, the majority of patients come to medical attention after this age (Felice and North, 2001; Phillips et al., 2001). Men are affected more commonly than women, at a ratio of approximately 2: 1 (Felice and North, 2001; Phillips et aI., 2001). Inclusion body myositis has a characteristic pattern of weakness that is distinct from that of polymyositis or dermatomyositis. Although there is some degree of variability, the most common muscle groups affected early on in the disease are the quadriceps and tibialis anterior in the lower extremities and the deep finger flexors (flexor digitorum profundus) in the upper extremities (Lotz et aI., 1989; Amato et al., 1996; Felice and North, 200 I; Phillips et aI., 2001). Unlike polymyositis and dermatomyositis, in IBM, the deltoid muscles are relatively spared when compared with the biceps, triceps and wrist and finger flexors. Early on, the quadriceps and anterior tibial muscles are affected to the same degree as the more proximal hip girdle muscles, also unlike polymyositis and dermatomyositis where one sees a proximal greater than distal pattern of weakness. Symptoms and signs are often asymmetric (Phillips et aI., 2001). As many as half the patients with IBM complain of swallowing difficulties at presentation, although this is not the primary complaint in the majority (Lotz et al., 1989; Amato et aI., 1996; Felice and North, 2001). The dysphagia is characterized by difficulty swallowing solids. Barium swallow tests demonstrate cricopharyngeal dysfunction, prominence or spasm. Occasionally the dysphagia is so severe that patients require cricopharyngeal myotomy (Lotz et al., 1989; Amato et aI., 1996). As noted, weakness in the aforementioned muscle groups results in functional disability and eventual

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presentation to a physician. On exam, one can often also find asymptomatic, mild facial weakness. Extraocular muscles are spared. Muscle stretch reflexes are normal or slightly decreased, particularly the patellar reflexes, which are lost early on (Amato et aI., 1996). Most patients deny sensory symptoms, although evidence of sensory involvement, either clinically or electrophysiologically, can be found in up to 30% (Amato et aI., 1996). However, given the age of onset of sporadic IBM, it is possible that the sensory abnormalities are due to secondary processes. Several studies have demonstrated a slow rate of disease progression in sporadic IBM using quantitative tests of muscle strength (Lindberg et al., 1994; Peng et aI., 2000; Felice and North, 2001; Rose et aI., 2001), although occasional patients progress more rapidly. Unfortunately, there is little documentation of how this quantitative decline in muscle strength affects functional outcome. In our experience, most patients remain ambulatory, although they frequently require, or at least benefit from, a cane or a wheelchair for long distances. However, some patients become severely incapacitated and are wheelchair dependent or bedridden within 10-15 years. The older the age of onset, the more rapidly progressive the course seems to be (Peng et aI., 2000). Unlike polymyositis and dermatomyositis, IBM is not associated with myocarditis or interstitial lung disease, nor is there an increased risk of malignancy (Callen, 1994). Autoimmune disorders such as SLE, Sjogren's syndrome, scleroderma, thrombocytopenia and sarcoidosis have been reported in up to 15% of sporadic IBM patients (Danon et aI., 1986; Koffman et aI., 1998). Generally, life expectancy is not affected. 20.1.4.2. Laboratory features Unlike polymyositis and dermatomyositis, serum creatine kinase is normal or only mildly elevated (less than 10 times greater than normal) in sporadic IBM. With the exception of reports of positive antinuclear antibodies in approximately 20% of patients (Love et aI., 1991; Koffman et al., 1998), there has been no other documented association of IBM with autoantibodies. However, there is a significant incidence of the HLA DR3 phenotype in these patients (Garlepp et aI., 1994).

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Several magnetic resonance imaging (MRI) studies have demonstrated abnormalities in affected muscles (Sekul, 1997; Phillips et aI., 2001). However, MRI findings are non-specific and do not add to the clinical examination. 20.1.4.3. Histopathology As in polymyositis and dermatomyositis, pathologic involvement is patchy and muscle biopsies can be normal or show only non-specific inflammatory features due to sampling error. Typical histopathologic changes, however, include the presence of endomysial inflammation, small groups of atrophic fibers, eosinophilic cytoplasmic inclusions and single or multiple intracytoplasmic rimmed vacuoles (Lotz et aI., 1989; Griggs et aI., 1995; Amato et aI., 1996). Occasionally, amyloid deposits can be identified within fibers, using either Congo red staining or a Texas red filter (Mendell et aI., 1991). This finding is fairly specific for IBM, although it can also be seen in the myofibrillar myopathy associated with desmin accumulation (Carpenter and Karpati, 2001). There is also an increase in ragged red fibers compared with both polymyositis, dermatomyositis and age-matched controls (Rifai et aI., 1995). Electron microscopy (EM) demonstrates 15-21 nm cytoplasmic and intranuclear tubulofilaments (Lotz et al., 1989). On EM, the vacuolated fibers also contain cytoplasmic clusters of 6-10 nm amyloidlike fibrils (Griggs et aI., 1995). In addition to these pathologic changes, accumulation of various proteins, similar to those observed in the brains of patients with Alzheimer's disease. accumulate within the vacuolated fibers. As well as ~-amyloid, these include C- and N-terminal epitopes of ~-amyloid precursor protein (~-APP), prion protein, apolipoprotein E, ubiquitin, hyperphosphorylated tau protein, alpha l-antichymotrypsin, and neurofilament heavy chain (Griggs et aI., 1995; Askanas and Engel, 2001). The accumulation of these proteins and the lack of symptomatic improvement following treatment with immunomodulating therapies has fueled speculation that IBM is a primary degenerative disease and that the inflammation seen is a secondary process. However, this remains a controversial area. As in polymyositis, the inflammation in IBM is endomysial and composed of macrophages and CD8+ cytotoxic/suppressor Tdymphocytes, which

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invade non-necrotic fibers (Emslie-Smith et aI., 1989). MHC class 1 antigens are expressed on both necrotic and non-necrotic fibers. However, in contrast to polymyositis, there is an oligoclonal pattern of gene rearrangement of the T-cell receptor repertoire and heterogeneity in the CDR3 domain (O'Hanlon et aI., 1994), suggesting that the T-cell response is not directed against a muscle specific antigen. 20.1.4.4. Pathogenesis The pathogenesis of IBM is unknown. Based on the histopathologic findings, a number of theories have been proposed. The immunologic findings suggest a primary autoimmune etiology. However, the lack of a significant clinical response with various immunosuppressive therapies alone or in combination argues against this. In one study, patients treated with immunomodulating therapies demonstrated lower serum creatine kinase levels and reduced inflammation on post-treatment biopsies without any improvement in strength or function (Barohn et aI., 1995). Interestingly, the number of vacuolated muscle fibers and fibers with amyloid deposition were increased in the follow-up biopsies. As mentioned in the previous section, the abnormal accumulation of amyloid and proteins, similar to those found in Alzheimer's disease, has led to the hypothesis that sporadic IBM is primarily a degenerative disease of muscle and that the inflammatory changes are a secondary process. However, the relationship between the Alzheimer-characteristic proteins in IBM and the pathogenesis of the myopathy is not clear. The accumulation of these proteins may be an epiphenomenon rather than the primary pathogenic defect of IBM. DNA microarray studies have demonstrated similar increases in RNAs of the Alzeihmer-characteristic proteins not only in IBM but also in polymyositis and dermatomyositis (Greenberg et aI., 2002). Thus, if there is an increase in these proteins in IBM muscles compared to other inflammatory myopathies, it is likely post-transcriptionally mediated. A viral etiology has also been proposed. Early studies suggesting IBM was caused by persistent mumps infection have been rejected based on later studies which failed to demonstrate the mumps virus (Kallajoki et aI., 1991; Leff et al., 1992). Interestingly, histologic abnormalities on muscle biopsy similar to those seen in IBM have been reported in

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patients with retroviral infections (Cupler er aI., 1996). Thus, it is possible that an unidentified virus could be the trigger for the pathogenic process in sporadic IBM. 20.1.4.5. Electrophysiologic findings 20.1.4.5.1. Nerve conduction studies. In most patients with IBM, nerve conduction studies are normal. Occasionally the sensory nerve action potentials may be diminished in amplitude in a pattern suggestive of a distal symmetric mild sensory polyneuropathy (Eisen et aI., 1983; Lotz et aI., 1989; Joy et aI., 1990, Amato et aI., 1996). Mild abnormalities of motor nerve conduction, particularly in the lower limb, have also been observed (Eisen et al., 1983; Lotz et aI., 1989; Joy et aI., 1990). However, because IBM generally develops in patients over 50 years of age, these electrophysiologic findings may be age-related. 20.1.4.5.2. Needle electromyography. As in polymyositis and dermatomyositis, increased muscle membrane irritability, in the form of fibrillation potentials, positive sharp waves, complex repetitive discharges and pseudomyotonia, is common in inclusion body myositis. Although a mixed picture may be seen in routine concentric needle EMG in any of the idiopathic inflammatory myopathies, IBM has acquired a unique reputation for demonstrating both small, "myopathic" motor units and large, "neuropathic" motor units. Indeed, most investigators agree that concentric needle EMG in IBM may show an abundance of long duration, polyphasic MUAPs compared to dermatomyositis and polymyositis. This has led to the mischaracterization of IBM as a possible neurogenic disorder. Histopathologic findings, however, do not support this theory. Recent published macro-EMG studies (Luciano and Dalakas, 1997; Barkhaus et aI., 1999) consistently demonstrate a myopathic pattern (either decreased mean duration, mean amplitude:area ratio, median amplitude, or median area) at least in the muscles studied (biceps brachii and tibialis anterior). Although large units were occasionally seen on macro-EMG of distal muscles, this finding was felt to be secondary to concurrent polyneuropathy and was not seen in the absence of neuropathy (Barkhaus et aI., 1999). It should be noted that, although as a group these patients demonstrated significantly

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smaller motor unit action potentials than control subjects, the values measured were often within the normal range reinforcing the difficulty of using electrophysiology in the absence of other clinical data to make the diagnosis of IBM. Quantitative interference patterns also appear myopathic.

20.1.4.5.3. Single-fiber electromyography. A mild elevation in jitter as well as occasional blocking may be seen in patients with IBM. It is also common for fiber density to be mildly, or occasionally moderately, increased in the majority of patients examined (Eisen et al., 1983; Joy et al., 1990). 20.2. Otheridiopathic inflammatory myopathies

20.2.1. Sarcoid myopathy Many patients with sarcoidosis have granulomas in the muscle, although signs and symptoms of muscle involvement are unusual. Muscle involvement, when it occurs, can be focal, multifocal or generalized. Patients develop pain and weakness in affected muscles. Atrophy develops with chronic disease. Typically, there is clinical and laboratory evidence of systemic disease elsewhere, most commonly in the lungs. Serum creatine kinase is usually normal or only mildly elevated. Corticosteroids are effective in treating the myositis. Occasional case reports refer to the electrophysiologic findings in sarcoid myopathy; however, no detailed analysis of multiple patients has been published. In our experience, needle study may be normal or may reveal increased muscle membrane irritability and myopathic motor units in affected muscles. Nerve conduction studies may be abnormal if there is concurrent nerve involvement and neuropathic abnormalities may be seen on EMG with concurrent nerve or radicular involvement.

20.2.2. Eosinophilic polymyositis Eosinophilic polymyositis is characterized by an insidious onset of myalgias and proximal weakness (Layzer et aI., 1977). It is typically seen in conjunction with other manifestations of the hypereosinophilic syndrome including encephalopathy, peripheral neuropathy, myocarditis/pericarditis, pulmonary fibrosis, asthma, renal failure, gastrointestinal involvement and/or skin changes (petechiae, livedo reticularis, Raynaud's phenomenon).

However, occasionally myopathy is the presenting feature. Diagnosis depends on demonstrating infiltrating eosinophils in involved organs and persistent idiopathic eosinophilia. Muscle biopsy shows endomysial and perimysial inflammatory infiltrates consisting of histiocytes, eosinophils, lymphocytes and plasma cells (Layzer et aI., 1977). This is a rare entity and no detailed analysis of electrophysiological findings has been published. The prognosis is reported to be poor but it may respond to corticosteroids or to interferon-alpha.

20.2.3. Focal myositis Focal myositis presents as a solitary, painful and rapidly expanding skeletal muscle mass. It usually affects the leg but can occur anywhere. The disorder needs to be distinguished from other focal inflammatory disease, such as sarcoidosis, and particularly from soft tissue tumors. Lesions may resolve spontaneously, with corticosteroid treatment or following surgical excision. The etiology is unknown; however, unlike polymyositis, it is not felt to be the result of a cell-mediated attack on a muscle-specific antigen (Caldwell et al., 1995). No detailed analysis of electrophysiological findings has been published.

20.2.4. Granulomatous or giant-cell myositis This is an interesting variant of polymyositis that is associated with myasthenia gravis and/or thymoma (Namba et aI., 1974). The myositis, which can develop before or after the clinical presentation of myasthenia gravis or thymoma, causes proximal greater than distal weakness. A granulomatous myocarditis may also occur. Muscle biopsy demonstrates features typical of idiopathic polymyositis as well as granulomas and multinucleated giant cells. The etiology is unknown. As with the other inflammatory myopathies discussed in this section, no detailed analysis of electrophysiological findings has been published. Some patients respond to treatment with corticosteroids although the response does not seem to be as favorable as in idiopathic polymyositis, likely due to the risk of cardiac involvement as well as the concomitant myasthenia gravis and thymoma.

20.2.5. Behcet's disease Behcet's disease is a multisystem disorder which can occasionally involve skeletal and cardiac mus-

424

cleo Patients typically complain of focal myalgias with or without weakness. There is a predilection for involvement of the lower limbs, particularly the calves, although occasionally symptoms can be generalized. Muscle biopsy demonstrates granulocytic-monocytic inflammation with invasion of non-necrotic muscle fibers and deposits of complement and immunoglobulins in blood vessel walls (Worthmann et al., 1996). The myositis is responsive to immunosuppressive therapy.

20.3. Myositis associated with infections 20.3.1. Human immunodeficiency virus (HN)

An inflammatory myopathy, virtually identical to idiopathic polymyositis, can be seen in patients with HIV infection. Myositis can develop at any stage during the infection and is not related to CD4 counts. Muscle histopathologic changes are similar to those in idiopathic polymyositis except that B-cells seem to be absent and tubuloreticular structures are likely to be present in endothelium (Carpenter and Karpati, 2001). HIV has not been shown to infect skeletal muscle fibers (IlIa et al., 1991). It is important to distinguish HIV-related myositis from zidovudine (AZT) myotoxicity, which causes a reversible mitochondrial myopathy, mv wasting syndrome, which results in severe type 2 muscle fiber atrophy, and other neuromuscular disorders that can complicate HIV infection. As in the idiopathic inflammatory myopathies, concentric needle EMG may be normal or may demonstrate increased muscle membrane irritability and myopathic motor units. No detailed analysis of quantitative EMG techniques has been published, however. mv myositis can respond to immunomodulating therapy. Our first line drug of choice is intravenous immunoglobulin but, if this fails, we treat with corticosteroids. 20.3.2. Human T-cell leukemia virus type 1 (HTLV-l)

HTLV-l infection is associated with the development of adult-T-cell leukemia and tropical spastic paraparesis. However, the myositis may develop in the absence of either of these symptoms. Muscle biopsy in HTLV-l is identical to that in idiopathic

H.R. BRIEMBERGAND A.A. AMATO

polymyositis. The myositis, but not the myelopathy. may improve with corticosteroids.

20.4. Treatment of the idiopathic inflammatory myopathies In this section we outline our approach to treating patients with the idiopathic inflammatory myopathies discussed in the previous sections. Most treatment at this time is empiric, as there have only been two published prospective, double-blinded, placebo-controlled trials in the treatment of polymyositis and dermatomyositis (Bunch et al., 1980; Dalakas et al., 1993). Bunch et al. (1980) treated 16 patients with polymyositis with either prednisone and azathioprine (2 mg/kg) or prednisone and placebo, and was unable to show a significant difference between the two groups at the end of three months. However, a three-year follow up of the two groups (after unblinding at three months) demonstrated a significant difference between the groups on measures of strength testing. In addition, patients on azathioprine required lower doses of prednisone. Despite these findings, most patients on prednisone alone denied functional impairment (Bunch, 1981). Dalakas et al. (1993) demonstrated the efficacy of intravenous immunoglobulin therapy in patients with dermatomyositis who had not shown a significant improvement during prior treatment with prednisone and a second-line cytotoxic agent. Although no prospective, randomized, controlled clinical trials have studied the efficacy of corticosteroids, there is no doubt, based on clinical experience, that their use results in moderate to significant improvement in most patients with either dermatomyositis or polymyositis. Other immunomodulating agents, including azathioprine, methotrexate. cyclophosphamide, cyclosporin, mycophenylate mofetil or intravenous immunoglobulin may add additional benefit as well as provide a steroid-sparing effect in patients who do not respond adequately to steroids alone. Currently, most authorities recommend prednisone as the first-line treatment of dermatomyositis and polymyositis. Most patients demonstrate clinical improvement within 3-6 months of starting therapy. We initiate treatment with a single dose of prednisone (1.5 mg/kg up to 100 mg) every morning. After 2-4 weeks of daily prednisone. we switch to alternate-day dosing (i.e. 100 mg qod). Patients with more severe disease may need to be

425

INFLAMMATORY MYOPATHIES

slowly tapered to alternate-day dosing over 2-3 months. Once muscle strength normalizes or improvement plateaus (usually 4-6 months), we taper the prednisone by 5 mg every 2 weeks. If a patient does not significantly improve after 4-6 months of prednisone, or if there is an exacerbation during this period, we add a second-line agent (methotrexate or azathioprine). In our experience, methotrexate works faster and is more effective than azathioprine, although again there has been no prospective, double-blind trial comparing these two agents in inflammatory myopathies. In mild disease we start methotrexate at 7.5 mg orally per week and gradually increase up to 20 mg weekly. In patients with severe weakness, we may be more aggressive and initiate treatment with methotrexate 20-25 mg intramuscularly every week and increase the dose up to 50 mg weekly. Concomitantly, we start folate. Because methotrexate can cause pulmonary fibrosis, we do not use it in patients who already have the associated ILD. Further, we always check for an anti-Jo-l antibody titer in the serum because of the risk of ILD associated with these antibodies. Baseline and periodic pulmonary function tests need to be checked in patients treated with methotrexate. Complete blood counts and liver function tests need to be followed closely. We start azathioprine at a dose of 50 mg per day in adults and gradually increase over 1 month to a total dose of 2-3 mg/kg/day. Complete blood counts and liver function tests need to be closely monitored. If the white blood cell (WBC) count falls below 4,000 per mrrr', we decrease the dose. Azathioprine is held if the WBC count declines to 2,500 per mm' or the absolute neutrophil count falls to 1000 per mm'. Leukopenia can develop as early as 1 week or as late as 2 years after initiating azathioprine (Kissel et aI., 1986b). At the same time as these second agents are added, the prednisone dose is doubled and given daily (no more than 100 mg per day) for at least 2 weeks before switching back to alternate day dosing. Once a patient has regained his or her strength, we resume the prednisone taper at a slower rate. Adjustments of prednisone and other immunosuppressive agents should be based on the objective clinical examination and not the serum creatine kinase levels or the patient's subjective response. A maintenance dose of prednisone or one of the second

line agents may be required to sustain a clinical response. If patients do not respond adequately to the combination of prednisone and methotrexate or azathioprine, we give a trial of intravenous immunoglobulin (2 gmlkg body weight) monthly for three months and then spread out the dose to every 2 to 3 months. Third line agents include mycophenylate, cyclosporin or cyclophosphamide. In our experience, however, patients who fail prednisone and methotrexate, azathioprine or IVIG usually do not respond to one of these third line agents. There is currently no effective treatment for sporadic IBM. Several studies have looked at the efficacy of immunomodulating therapies in randomized placebo-controlled trials (Dalakas et aI., 1997; Walter et al., 2000; Dalakas et aI., 2001; Tawil et al., 2001). Dalakas et al. (1997, 2001) and Walter et al. (2000) studied the efficacy of intravenous immunoglobulin therapy and Tawil et al. (2001) studied the efficacy of beta-interferon. None of the studies was able to show a significant treatment difference in overall strength or function between the control and treatment groups. However, all studies suffered because of small numbers and, therefore, lack of power to show a significant difference if one existed. As well follow-up time ranged from 3 to 6 months, which, given the slowly progressive nature of IBM, may be insufficient time to demonstrate treatment effect. Although we offer a 6-month trial of highdose prednisone in patients with histologically confirmed or clinically probable IBM, we do not advocate more aggressive immuno-suppressive agents because of the associated risk and the low probability of a response.

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