Inflammatory Myopathies: Narrowing the Differential Diagnosis

REVIEW

KAREN RENDT, MD Department of Rheumatic and Immunologic Diseases, Cleveland Clinic

Inflammatory myopathies: Narrowing the differential diagnosis

■ ABSTRACT HEN A PATIENT PRESENTS with weak- W ness, the first step is to distinguish Muscle weakness is a feature of numerous conditions, but true muscular weakness from the perception the muscle weakness of inflammatory myopathies, of “weakness” due to other problems, such especially polymyositis and dermatomyositis, is easy to as arthritis, anemia, congestive heart fail- differentiate by specific clinical, laboratory, ure, neuropathy, or deconditioning. Once electromyographic, and histological features. muscular weakness is confirmed via manual resistive testing, the next step is to consider inflammatory myopathy—polymyositis, der- ■ KEY POINTS matomyositis, and inclusion body myositis—and drug-induced and metabolic Diagnostic criteria currently include proximal muscle myopathy. weakness, increased creatine kinase, abnormal (myopathic) This article addresses how to differentiate electromyogram, typical histologic appearance on muscle inflammatory myopathy from other causes of biopsy, and cutaneous abnormalities typical of muscle weakness by observation of clinical, dermatomyositis. laboratory, and histologic features. The focus is mainly on polymyositis and dermatomyositis, A muscle biopsy specimen demonstrating typical histologic the most common types of inflammatory features in the absence of metabolic myopathy, infection, or myopathy. drug effect establishes the diagnosis of polymyositis. ■ CLASSIFICATION

Numerous prescription and over-the-counter drugs, notably The original classification of inflammatory the statins, are associated with myopathy. Prudent practice myopathies by Bohan and colleagues1 included is to check the creatine kinase levels of patients taking five types of myositis: statins. • Adult polymyositis • Adult dermatomyositis Although there is an association between inflammatory • Juvenile polymyositis and dermatomyo- myopathy and malignancy, there is no consensus for sitis screening for cancer in patients with myositis. • Myositis associated with cancer • Myositis associated with another connec- tive tissue disease, also called “overlap syndrome.” This classification has since been modified to include: • Amyopathic dermatomyositis, an uncom- mon condition affecting only the skin • Inclusion body myositis, an inflammatory myopathy with different clinical and pathologic features and course.

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■ Polymyositis and dermatomyositis less symmetrical proximal muscle weakness, vs inclusion body myositis with symptoms dating back to 3 to 6 months by the time of the first physician visit. Polymyositis and dermatomyositis are fre- Upper-extremity muscle weakness mani- quently considered together because they have fests as difficulty in performing activities that similar clinical, laboratory, and pathologic fea- require holding the arms up, such as hair wash- tures and because they progress at the same ing, shaving, or reaching into overhead cup- tempo. While inclusion body myositis shares boards. Neck muscle weakness may lead to dif- some features with polymyositis and dermato- ficulty raising the head from a pillow or even myositis, it generally follows a more indolent holding it up while standing. Involvement of course and is more refractory to therapy. Other pharyngeal muscles may result in hoarseness, distinguishing features are discussed below. dysphonia, dysphagia, and nasal regurgitation after swallowing. ■ PREVALENCE Lower-extremity proximal muscle weakness manifests as difficulty climbing stairs and Polymyositis and dermatomyositis are uncom- rising from a seated or squatting position. mon, with an annual incidence ranging from 2 Patients seek chairs with armrests to push off to 10 new cases per million persons.2 By com- from or grab the sink or towel bar to rise from parison, scleroderma is twice as common, and the toilet. systemic lupus erythematosus is about four times as common. The mean age of onset of Other clinical features polymyositis is 45 years, whereas a bimodal age Weakness is the major complaint, but proxi- distribution is observed with dermatomyositis, mal myalgias and constitutional symptoms with peaks at around 10 and 40 years of age. such as fever, fatigue, and weight loss may Among adults, women are affected twice as occur. often as men, while among children both sexes are affected equally. In the case of over- Cutaneous features of dermatomyositis lap syndrome, the peak age of onset and male- In dermatomyositis, patients may have an Muscle female ratios reflect the underlying connec- erythematous, often pruritic rash over the weakness is tive tissue disease.2 face, including the cheeks, nasolabial folds, Inclusion body myositis is considerably chin, and forehead. Heliotrope (purplish) gradual, more common in men than in women and is discoloration over the upper eyelids with progressive, more prevalent in patients over 50 years old.3 periorbital edema is characteristic, as is the “shawl sign,” an erythematous rash in a V- painless ■ KEY DIAGNOSTIC CRITERIA distribution on the chest and across the shoulders posteriorly. The criteria used by Bohan et al1 to establish Gottron papules—flat-topped raised non- the diagnosis of polymyositis and dermato- pruritic lesions found over the dorsum of the myositis include: metacarpophalangeal, proximal interpha- • Symmetrical proximal muscle weakness langeal, and distal interphalangeal joints—are • Increased serum enzyme levels, especially virtually pathognomonic for dermatomyositis creatine kinase (FIGURE 1).4,5 Often pinkish to violaceous, • Electromyographic signs of myopathy sometimes with a slight scale, they are distin- • Muscle biopsy abnormalities guished from cutaneous lupus in that lupus has •Typical cutaneous abnormalities (of der- a predilection for the dorsum of the fingers matomyositis). between the joints. Calcinosis cutis. Children with dermato- ■ CLINICAL FEATURES myositis are also particularly prone to calcinosis cutis, the development of dystrophic cal- Symmetrical proximal muscle weakness cification in the soft tissues and muscles, The chief clinical feature of polymyositis and which may lead to skin ulceration, secondary dermatomyositis is gradual, progressive, pain- infection, and joint contracture. Calcinosis

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serum creatine kinase, often in the range of 1,000 to 10,000 mg/dL, though early in the disease process milder elevations may be seen. In inclusion body myositis, creatine kinase elevations tend to be less striking, often rising only to the 600 to 800 mg/dL range; 20% to 30% of patients with inclusion body myositis may have a normal creatine kinase at presentation. With initiation of effective treatment, creatine kinase levels fall rapidly, and peri- odic measurements are used to follow disease activity over the course of long-term follow- up. Caution is advised when interpreting creatine kinase elevations, as levels may remain FIGURE 1. Gottron papules—the flat-topped raised nonpruritic mildly elevated chronically in the face of clin- lesions found over the dorsum of the metacarpophalangeal, ically quiescent disease. In addition, the degree proximal interphalangeal, and distal interphalangeal joints— of elevation does not correlate well with the are pathognomonic for dermatomyositis. In contrast, degree of muscle weakness. Significant eleva- cutaneous lupus erythematosus has a predilection for the tions accompany a disease flare in most dorsum of the fingers between the joints. instances, exceptions being patients with severe muscle atrophy.2 cutis occurs in up to 40% of children with dermatomyositis and less commonly in adults; Usefulness of creatine kinase MB levels there is no proven therapy to prevent this and other studies complication.4 Anecdotal use of calcium- Skeletal muscle regeneration and myocardial Serum creatine channel blockers,6 probenecid,7 aluminum involvement may cause an elevation of the kinase hydroxide,8 and warfarin9 has been described serum creatine kinase myocardial band (MB) in established calcinosis cutis. enzyme (normal range 0-4 ng/mL). Elevated elevation is serum levels of aldolase, lactate dehydroge- often Features specific nase (LDH), aspartate aminotransferase to inclusion body myositis (AST), and alanine aminotransferase (ALT) dramatic Inclusion body myositis tends to present with are less sensitive and specific for active a more gradual onset of weakness, which may myositis.2 Measurements of acute-phase date back several years by the time of diagno- reactants (eg, via the sedimentation rate) sis. While the muscle weakness is proximal, may show moderate elevations. distal muscle groups may also be affected, and asymmetry of involvement is characteristic. ■ AUTOANTIBODIES IN POLYMYOSITIS Atrophy of the deltoids and quadriceps is AND DERMATOMYOSITIS often present, and weakness of forearm muscles (especially finger flexors) and ankle dorsi- Autoantibodies may be present in polymyosi- flexors is typical. Peripheral neuropathy with tis and dermatomyositis, but they are general- loss of deep tendon reflexes may be present in ly absent in inclusion body myositis. some patients.10 Autoantibodies present in polymyositis and dermatomyositis include the myositis- ■ INCREASED SERUM ENZYME LEVELS specific autoantibodies anti-Jo-1, seen in 20% of patients, and the less commonly Creatine kinase serum levels encountered anti-PL-7, anti-PL-12, anti-OJ, The laboratory hallmark of polymyositis and and anti-EJ. These antibodies recognize dermatomyositis, although not specific to cytoplasmic transfer RNA synthetases (for either of these, is a dramatic elevation of the instance, anti-Jo-1 recognizes histidyl trans-

510 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 6 JUNE 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. fer RNA synthetase), and they are markers leaving the contralateral side (typically the of the subset of polymyositis and dermato- deltoid or quadriceps) for muscle biopsy myositis patients described as having anti- should the physical exam and typical elec- synthetase syndrome, which is characterized tromyographic abnormalities indicate active by fever, inflammatory arthritis, Raynaud involvement. phenomenon, and interstitial lung disease and is associated with a reduction in survival ■ MUSCLE BIOPSY ABNORMALITIES compared with uncomplicated polymyositis and dermatomyositis.11 A muscle biopsy specimen demonstrating typical histologic features (described below) in Anti-signal recognition particle the absence of markers of metabolic myopa- Anti-signal recognition particle is a myositis- thy, infection, or drug effect establishes the specific autoantibody that identifies a sub- diagnosis of polymyositis. Muscle biopsy may group of polymyositis patients with particular- not be necessary in a patient presenting with ly aggressive and refractory disease (5-year sur- proximal muscle weakness, creatine kinase vival 30%). It is associated with a tendency for elevation, and the classic cutaneous manifes- myocardial involvement.11 tations of dermatomyositis. When biopsy is performed, however, care Other autoantibodies must be taken not to select a muscle that is so Other autoantibodies that may be present weak or atrophic that the biopsy reveals end- “nonspecifically” in patients with poly- stage disease. myositis and dermatomyositis include anti- nuclear antibody (ANA), Sjögren syn- Magnetic resonance imaging drome-A (SSA) antibodies, and antibodies as a guide to biopsy site selection to ribonucleoprotein (RNP). Such autoanti- In recent years magnetic resonance imaging bodies may be seen in 80% of patients with (MRI) has been explored as a means to assess myositis, but their lack of specificity make the presence and activity of myositis noninva- them of little clinical utility to the general sively. Enhancement of muscle tissue on T2- A myopathic internist. weighted images (but not T1-weighted images) abnormality indicates edema consistent with active inflam- ■ ELECTROMYOGRAPHIC FEATURES mation. In contrast, enhancement of both T1- on the weighted and T2-weighted images indicates fat electromyogram A key criterion in the diagnosis of infiltration (lipomatosis), which may be seen polymyositis is an abnormal (myopathic) later in the course of the illness. MRI with is a key to the electromyogram. The evaluation of the short tau inversion recovery (STIR) images diagnosis patient with suspected myositis should can identify edema distinct from fatty infiltra- include electromyography and nerve con- tion, which makes it a useful tool in detecting duction studies. recurrent disease activity in patients with In addition to helping to exclude many long-standing inflammatory myositis, sec- neuropathic etiologies, electromyography also ondary muscle atrophy, and lipomatosis.12 helps to identify the most inflamed muscle To date, MRI does not replace the need groups. for biopsy for initial evaluation and diagnosis. Typical electromyographic findings in However, it is useful in identifying the biopsy inflammatory myopathy include: site with the most actively inflamed muscle, or • Spontaneous fibrillations at rest or with in helping to distinguish steroid myopathy needle insertion from flaring myositis in the patient developing • Short-duration, small-amplitude polypha- recurrent weakness during treatment with cor- sic motor unit potentials with muscle con- ticosteroids. traction • Spontaneous bizarre high-frequency dis- Pathophysiologic features charges.1 The common pathophysiologic features of Usually, one arm and one leg are studied, polymyositis, dermatomyositis, and inclusion

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body myositis are chronic inflammation, an cle peptides have been proposed as the trig- attempt at healing by fibrosis, and a net loss of gering stimulus, but thus far data demon- myofibrils. strating viral peptides on polymerase chain The inflammatory infiltrate is composed reaction analyses are lacking. mainly of lymphocytes. In polymyositis and Inclusion body myositis is immunohisto- inclusion body myositis, the lymphocytes are logically similar to polymyositis in that in found predominantly within the fascicles; in both conditions cytotoxic CD8+ T cells dermatomyositis they are found predominant- invade muscle tissue exhibiting class I HLA ly in the perivascular and perifascicular antigens. Data suggesting clonality of the T regions.13 Perifascicular atrophy is diagnostic cells are less compelling thus far, with some of dermatomyositis regardless of the presence but not all studies demonstrating clonality of of inflammatory cells.13 Myophagocytosis by the TCR gene.15 On routine histochemical macrophages occurs with myocyte necrosis analysis, myocytes exhibit a variety of abnor- and degradation. Centralization of the mal inclusions, including eosinophilic cyto- myofibril nuclei is also seen. Inflammation plasmic inclusions, vacuoles rimmed with may be patchy and skip areas may occur. An basophilic granules, and foci that stain posi- adequate biopsy sample improves diagnostic tively with Congo red, consistent with amy- yield.14 loid deposits. On electron microscopy, inclusion body myositis is characterized by the pres- Histochemical analysis ence of cytoplasmic helical filaments (tubo- Histochemical analysis of biopsy tissue is used filaments) which contain beta-amyloid pro- to identify a metabolic cause of myopathy, tein.16 such as the glycogen storage diseases, and neu- Immunohistochemical studies suggest ropathic injuries. that dermatomyositis is quite different patho- The pattern of myocyte atrophy, as physiologically from polymyositis and inclu- determined by histochemical staining, hints sion body myositis. The predominant infiltrat- at the underlying mechanism of injury: dener- ing lymphocytes are B cells and CD4+ T cells, Consider any vation (ie, muscle injury from damage to the suggesting a humorally mediated process. condition that nerve supplying it) results in fiber type group- Furthermore, molecules of the terminal com- ing, in which the atrophic fibers are of the plement membrane attack complex can be causes myalgia, same type (type I or slow-twitch oxidative vs demonstrated early in the disease process weakness, or type II or fast-twitch glycolytic), whereas in within the walls of muscle capillaries. polymyositis and dermatomyositis, both Capillary injury results in marked capillary high serum groups are affected. Steroid-induced myopa- depletion and possibly ischemic injury to creatine kinase thy is associated with selective type II fiber myocytes.13 atrophy.14 Immunophenotypical differences have ■ DIFFERENTIAL DIAGNOSIS been noted between polymyositis and dermatomyositis. Polymyositis is characterized The differential diagnosis of inflammatory by the predominance of CD8+ T cells and by myopathy is broad and includes conditions the presence of major histocompatibility that present with myalgia, weakness, or serum complex (MHC) class I markers on myofib- creatine kinase elevation or any combination rils. Analysis of the T-cell receptor genes has of these features, and may or may not be asso- shown that the invading T cells are clonally ciated with an infiltrate of inflammatory cells restricted, consistent with an antigen-driven on muscle biopsy. response. It is notable that healthy resting For example, though many drugs and tox- myocytes do not express class I HLA anti- ins can induce a metabolic myopathy with gens on their surface; the stimulus that trig- weakness, serum creatine kinase elevation, gers expression of the class I HLA and the and myalgia, only penicillamine and zidovu- antigen or antigens being presented to the dine are associated with inflammatory infil- cytotoxic T cells are not known.13,15 Both trates. Infection, endocrinopathy, neurologi- viral peptide antigens and endogenous mus- cal illness, metabolic myopathy, fibromyalgia,

512 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 6 JUNE 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. polymyalgia rheumatica, sarcoid, and paraneo- T ABLE 1 plastic phenomena require consideration Differential diagnosis (TABLE 1).14 If the characteristic rashes of dermato- of inflammatory myopathy myositis are absent, no single marker of Drug or toxin (see also TABLE 2) inflammatory myopathy is diagnostic, and the clinical and laboratory findings must be Infection considered carefully to exclude other diag- Bacterial (staphylococcal, streptococcal, pneumococcal, noses. Salmonella) Treponemal (syphilis) In the case of drug or toxin ingestion, Mycobacterial (Mycobacterium tuberculosis, M leprae) discontinuation of the offending drug usually Viral (cytomegalovirus, Epstein-Barr virus, HIV, herpes simplex results in rapid resolution of the myositis. virus, adenoviruses, others) Fungal (cryptococcosis, mucormycosis) Viral causes Parasitic (trichinosis, toxoplasmosis) Viral myositis can cause dramatic elevations Metabolic myopathy in serum creatine kinase levels with corre- Glycogen storage diseases sponding weakness. A rapid progression of dis- Carnitine deficiency ease in the setting of an antecedent viral syn- Carnitine palmityltransferase deficiency drome hints at the diagnosis. Often, such as in adenovirus or influenza infection, the clinical Endocrinopathy picture spontaneously improves in the time it Hypothyroidism Hyperthyroidism* takes to obtain an electromyogram and other Hyperparathyroidism* diagnostic tests. Cushing syndrome Human immunodeficiency virus (HIV) Vitamin D deficiency and the antiretroviral agent zidovudine may cause myositis with inflammatory infiltrates. Polymyalgia rheumatica* Ragged red fibers, indicative of abnormal Fibromyalgia* mitochondria, are seen in myositis secondary Sarcoidosis to zidovudine, but not HIV-induced myositis.13 Neuromuscular disorders Amyotrophic lateral sclerosis Parasitic causes Muscular dystrophy Parasitic infections such as trichinosis and Myasthenia gravis* toxoplasmosis can cause myositis with inflammatory infiltrates. The diagnosis requires a *Because presentations vary, generalizations about the presence and heightened index of suspicion and directed magnitude of serum creatine kinase elevation in these disorders are difficult; however, entities marked with an asterisk are associated with questioning about potential exposure: inges- normal creatine kinase levels, and elevation of creatine kinase in a tion of undercooked pork for trichinosis, and patient with these disorders should prompt further evaluation. handling or ingesting cat feces or undercooked ADAPTED FROM BUNCH TW. POLYMYOSITIS: A CASE HISTORY APPROACH TO THE pork, lamb, or beef for toxoplasmosis. DIFFERENTIAL DIAGNOSIS AND TREATMENT. MAYO CLIN PROC 1990; 65:1480–1497.

Polymyalgia rheumatica Distinguishing between polymyalgia rheumatica and polymyositis is usually not difficult if improvement in symptoms as the day pro- one keeps in mind that polymyalgia rheumat- gresses, while the patient with polymyositis ica causes aching pain and stiffness in the has the same degree of weakness throughout proximal muscle groups, but not true weakness the day. on manual resistive testing. While the sedimentation rate is typically elevated in Drug interactions: Lipid-lowering drugs polymyalgia rheumatica, the serum creatine Numerous prescription and over-the-counter kinase level is normal. Furthermore, the medicines are associated with myopathy that patient with polymyalgia rheumatica describes can mimic polymyositis. A partial list of

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T ABLE 2 concordant with another study of 265 patients Drugs associated on a combination of gemfibrozil and prava- with myopathy* statin or simvastatin, in which no patient developed myopathy.17 Amiodarone Cytochrome P450 3A4 inhibition Chloroquine increases the risk. Use of drugs that signifi- Cimetidine Clofibrate cantly inhibit cytochrome P450 3A4 Cocaine (cyclosporine A, nefazodone, itraconazole, Colchicine ketoconazole, erythromycin, clarithromycin, Corticosteroids and protease inhibitors) is associated with an Danazol increased risk of myopathy in patients taking Emetine simvastatin, which is metabolized by Ethanol cytochrome P450 3A4. Lovastatin and ator- Gemfibrozil Heroin vastatin are also metabolized by cytochrome HMG-CoA reductase inhibitors (statins) P450 3A4. Pravastatin is not significantly Hydralazine metabolized through this pathway, yet patients Ipecac who take both pravastatin and cyclosporine Ketoconazole concomitantly tend to have higher plasma lev- Levodopa els of pravastatin and a greater risk of myopa- Nicotinic acid thy than do patients taking pravastatin Penicillamine Phenytoin alone.This suggests that cyclosporine may alter Procainamide statin metabolism by mechanisms other than Rifampin cytochrome inhibition.18 Sulfonamides When to stop the statin. Sinzinger et al19 Vincristine described the occurrence of exertional myal- Zidovudine gias with normal creatine kinase levels in patients taking an HMG-CoA reductase Check CK *Only myopathy caused by penicillamine and inhibitor (statin), which resolved upon dis- zidovudine is associated with inflammatory continuation of the offending drug. Notably, levels infiltrates.13 all patients were able to switch to a different periodically HMG-CoA reductase inhibitor for long-term in patients use without development of myalgias, though potentially offending drugs is found in TABLE 2. the myalgias returned if the original agent was taking statin Several lipid-lowering agents have been reintroduced. This suggests that this side drugs associated with myalgia, myopathy, or rhab- effect was not a class effect, but dependent on domyolysis. Originally described in patients individual drug characteristics. being treated with the combination of gemfi- Prudent practice is to check creatine brozil and lovastatin,17 myositis has also been kinase levels periodically in patients taking reported to occur in patients treated with a statin drug, and to discontinue the drug if gemfibrozil and the other statins (simvastatin, the creatine kinase level rises above the pravastatin, fluvastatin, atorvastatin).17 upper limit of normal. New onset of myal- Combination lipid-lowering therapy is gias or exertional cramping or weakness attractive in a large subset of patients with should also prompt alteration of therapy. hyperlipidemia—ie, those with both hyper- Elevated creatine kinase levels generally cholesterolemia and hypertriglyceridemia. In return to normal within a few weeks after one series of 252 patients treated with combi- the drug is stopped. nation therapy, 6 patients (3%) stopped the If a patient is doing well on statin therapy treatment regimen because of myalgias in the but requires a limited course of therapy with setting of normal serum creatine kinase levels, another agent known to be a strong inhibitor and 1 (0.4%) stopped the treatment because of cytochrome P450 3A4, statin therapy of presumed myositis (myalgias with 12-fold should be stopped for the short time that elevation of creatine kinase).17 This result was treatment with the other drug is in effect.18

514 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 6 JUNE 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. ■ TREATMENT OF ate and azathioprine, or using agents such as INFLAMMATORY MYOPATHY cyclosporine or chlorambucil. Intravenous immunoglobulin infusion on a monthly basis Polymyositis and dermatomyositis may be helpful in some patients with refracto- The mainstay of therapy for polymyositis and ry dermatomyositis.21,22 dermatomyositis is oral prednisone given ini- tially at a dose of 1 mg/kg in the morning. Inclusion body myositis Tapering the dose may be attempted after 4 to Inclusion body myositis was once believed to 6 weeks, with very gradual tapering after- be refractory to any medical therapy, but a few wards2: as a guide, the tapered dose of pred- small series have been published reporting sta- nisone should be roughly half the starting dose bilization and even improvement in some after 6 months of treatment.4 patients treated with prednisone alone or in If the diagnosis and treatment occur soon combination with azathioprine3,10,23 or after disease onset, the response to treatment methotrexate.10 is generally rapid, both in terms of laboratory abnormalities and strength. However, sympto- ■ POTENTIAL COMPLICATIONS OF matic improvement is slower when the diag- UNTREATED INFLAMMATORY MYOPATHY nosis is delayed.20 The dose of prednisone should not be Pulmonary complications tapered quickly even if a prompt normaliza- Involvement of the respiratory system may tion of creatine kinase occurs. Patients should occur as a result of several different processes: expect to be on prednisone for at least 1 year. •Weakness of the diaphragm and inter- Adverse effects of high-dose steroid ther- costal muscles may lead to dyspnea, ventilato- apy are common, and active prophylaxis for ry insufficiency, and atelectasis steroid-induced osteoporosis should be con- • Pharyngeal muscle weakness increases the sidered in patients of both sexes. Steroid- risk of aspiration induced myopathy is a common problem that • Interstitial pneumonitis occurs in approx- may occur within the first several months of imately 10% of patients with polymyositis, If untreated, therapy, leading to confusion about whether usually developing gradually over the course patients risk new weakness represents a flare of the under- of the illness, leading to interstitial lung dis- lying disease or an adverse effect of therapy. ease and restrictive physiology, or occasional- pulmonary, There is no specific test to distinguish ly remaining asymptomatic.13,14,24 myocardial between these possibilities; even muscle biopsy does not reliably settle the issue. Type II Myocardial complications complications fiber atrophy, while associated with steroid Myocardial involvement in polymyositis and use, may also be seen in postinflammatory dermatomyositis is well described. Autopsy states and in disuse atrophy. studies have shown the presence of active MRI with STIR images may offer another myositis, contraction band necrosis, and tool for distinguishing patients with muscle myocardial fibrosis.25,26 edema consistent with inflammation from The reported frequency of congestive those with lipomatosis.12 heart failure (with or without cardiomegaly) In patients whose disease responds only ranges from fewer than 5% of patients27 to partially to corticosteroids, or who require an 45%.26 unacceptably high dose to maintain disease Electrocardiographic abnormalities are control, other agents such as methotrexate or more common, with left anterior fascicular azathioprine are alternatives. Use of either block and right bundle branch block represent- agent requires an understanding of its toxicity ing the most frequent conduction defects.27 profile and careful monitoring for adverse Elevations in creatine kinase MB do not effects; this is most appropriately handled by correlate with the presence or the extent of the consulting rheumatologist. Other options myocardial disease, as regenerating skeletal for the treatment of polymyositis and der- muscle fibers release this isoform of the matomyositis include combining methotrex- enzyme.2,27

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Associated malignancy cancer was over-represented in women with An association between inflammatory myopa- dermatomyositis, and both groups of thy and malignancy was first reported in the patients displayed a greater-than- expected late 1800s, and despite much attention to this occurrence of non-Hodgkin lymphoma.29 topic in the literature the actual incidence There is still no consensus as to the extent and types of malignancies in patients with of screening for malignancy in patients with polymyositis and dermatomyositis are still the myositis.13,30 The minimum approach is a subject of controversy. thorough history and physical exam, with While some experts have said that the standard laboratory tests and health mainte- relative risk of malignancy is higher in nance screening exams (Papanicolaou smear, patients with dermatomyositis compared pelvic exam, mammography, prostate-specific with the normal population, and that the antigen testing, chest radiography), pursuing relative risk in patients with polymyositis is any abnormalities discovered.13 not substantially increased,4,28 we have data However, some experts, mindful of the to refute this belief. A recent report review- increased frequency of ovarian cancer and ing 618 cases of dermatomyositis and 914 non-Hodgkin lymphoma, suggest pursuing a cases of polymyositis29 addressed the stan- more rigorous workup with computed tomo- dardized incidence ratio (SIR) of specific graphic scanning of the chest, abdomen, and malignancies and the time they were discov- pelvis.29 ered relative to the diagnosis of the myosi- We must also bear in mind that malig- tis.29 (The SIR is the number of cancer cases nancy may not be diagnosed until 1 or more that arose among dermatomyositis or years after the onset of inflammatory myopa- polymyositis patients divided by the expect- thy. Hill et al29 concluded that dermatomyosi- ed number of cancer cases according to tis is strongly associated with a wide range of national age-specific, sex-specific, and peri- cancers for the 5 years following diagnosis of od-specific cancer rates.) Of note, both the myositis, and that polymyositis is associat- polymyositis and dermatomyositis were asso- ed with a modest increase in the overall risk of Be alert to ciated with an increased risk of malignancy, cancer. signs of cancer with a threefold risk demonstrated in Therefore, even if an initial evaluation for patients with dermatomyositis and a 1.4-fold malignancy at the time of presentation of in first risk for patients with polymyositis. The types myositis is unrevealing, the clinician should be few years of malignancy generally reflected those alert to signs and symptoms of new malignan- expected for age and sex, though ovarian cy in the first several years of follow-up. of follow-up

■ REFERENCES Calcinosis universalis complicating juvenile dermatomyositis: resolution during probenecid therapy. J Clin 1. Bohan A, Peter JB, Bowman RL, Pearson CM. A com- Endocrinol Metab 1997; 82:3536–3542. puter-assisted analysis of 153 patients with polymyosi- 8. Wang W, Lo W, Wong C. Calcinosis cutis in juvenile tis and dermatomyositis. Medicine 1977; 56:255–286. dermatomyositis: remarkable response to aluminum 2. Medsger TA, Oddis CV. Clinical features of inflamma- hydroxide therapy [letter]. Arch Dermatol 1988; tory muscle disease. In: Klippel JH, Dieppe PA, editors: 124:1721–1722. Practical rheumatology. London; Mosby, 1995. 9. Matsuoka Y, Miyajima S, Okada N. A case of calcinosis 3. Cohen MR, Sulaiman AR, Garancis JC, Wortmann RL. universalis successfully treated with low-dose warfarin. Clinical heterogeneity and treatment response in J Dermatol 1998; 25:716–720. inclusion body myositis. Arthritis Rheum 1989; 10. Leff RL, Miller FW, Hicks J, Fraser DD, Plotz PH. The 32:734–740. treatment of inclusion body myositis: a retrospective 4. Callen JP. Dermatomyositis. Lancet 2000; 355:53–57. review and a randomized, prospective trial of 5. Krajnc I. Dermatomyositis: diagnosis and evaluation of immunosuppressive therapy. Medicine 1993; dermatomyositis, polymyositis, and inclusion-body 72:225–235. myositis. In: Mallia C, Uitto J, editors. Rheumaderm: 11. Love LA, Leff RL, Fraser DD, et al. A new approach to current issues in rheumatology and dermatology. New the classification of idiopathic inflammatory myopa- York: Plenum Publishers, 1999. thy: myositis-specific autoantibodies define useful 6. Oliveri MB, Palermo R, Mautalen C, Hubscher O. homogeneous patient groups. Medicine 1991; Regression of calcinosis during diltiazem treatment in 70:360–374. juvenile dermatomyositis. J Rheumatol 1996; 12. Reimers CD, Schedel H, Fleckenstein JL, et al. 23:2152–2155. Magnetic resonance imaging of skeletal muscles in 7. Eddy MC, Leelawattana R, McAlister WH, Whyte MP. idiopathic inflammatory myopathies of adults. J

518 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 6 JUNE 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Neurol 1994; 241:306–314. 13. Dalakas MC. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 1991; 325:1487–1498. 14. Bunch TW. Polymyositis: a case history approach to the differential diagnosis and treatment. Mayo Clin Proc 1990; 65:1480–1497. 15. Dalakas MC. Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol 1998; 55:1509–1512. 16. Askanas V, Engel WK, Alvarez RB. Light and electron microscopic localization of β-amyloid protein in muscle biopsies of patients with inclusion-body myositis. Am J Pathol 1992; 141:31–36. 17. Murdock DK, Murdock AK, Murdock RW, et al. Long- term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999; 138:151–155. 18. Gruer PJK, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999; 84:811–815. 19. Sinzinger J, Schmid P, O’Grady J. Two different types of exercise-induced muscle pain without myopathy and CK-elevation during HMG-Co-enzyme A reductase inhibitor treatment. Atherosclerosis 1999; 143:459–460. 20. Fafalak RG, Peterson MGE, Kagen LJ. Strength in polymyositis and dermatomyositis: best outcome in patients treated early. J Rheumatol 1994; 21:643–648. 21. Cherin P, Herson S, Wechsler B, et al. Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients. Am J Med 1991; 91:162–168. 22. Lang BA, Laxer RM, Murphy G, Silverman ED, Roifman CM. Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med 1991; 91:169–172. 23. Lane RJM, Fulthorpe JJ, Hudgson P. Inclusion body myositis: a case with associated collagen vascular disease responding to treatment. J Neurol Neurosurg Psychiatry 1985; 48:270–273. 24. Salmeron G, Greenberg SD, Lidsky MD. Polymyositis and diffuse interstitial lung disease. Arch Intern Med 1981; 141:1005–1010. 25. Haupt HM, Hutchins GM. The heart and cardiac conduction system in polymyositis-dermatomyositis: a clinicopathologic study of 16 autopsied patients. Am J Cardiol 1982; 50:998–1006. 26. Denbow CE, Lie JT, Tancredi RG, Bunch TW. Cardiac involvement in polymyositis: a clinicopathologic study of 20 autopsied patients. Arthritis Rheum 1979; 22:1088–1092. 27. Stern R, Godbold JH, Chess Q, Kagen LJ. ECG abnormalities in polymyositis. Arch Intern Med 1984; 144:2185–2189. 28. Callen JP. Dermatomyositis and malignancy. Clin Rheum Dis 1982; 8:369–381. 29. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357:96–100. 30. Cox NH, Lawrence CM, Langtry JAA, Ive FA. Dermatomyositis: disease associations and an evaluation of screening investigations for malignancy. Arch Dermatol 1990; 126:61–65.

ADDRESS: Karen Rendt, MD, Department of Rheumatic and Immunologic Diseases, A50, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected].

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