The red face: Dermatomyositis

The Red Face: Derma tomyositis MARCUS R. STONECIPHER, MD JEFFREY I?. CALLEN, MD JOSEPH L. JORIZZO, MD

ermatomyositis (DM)is a disease that manifests as an inflammatory myopathy typically producing a symmetric proximal muscle weakness and a characteristic cutaneous eruption. lb3 This disorder is closely related to polymyositis (PM), which has all the clinical features of DM without the presence of skin disease. Both of these disorders are of unknown etiology, but pathogenetic mechanisms are believed to involve immunologically mediated muscle damage.4 Both DM and PM may occur in the presence of other collagen vascular diseases such as lupus erythematosus, scleroderma, Sjiigren’s syndrome, rheumatoid arthritis, and various vasculitides. Dermatomyositis seems to be characterized by an increased frequency of internal malignancy, whereas malignancy association in patients with PM is less clearly established. Recent data suggest that PM, as well as DM, occurs in children. Both DM and PM are associated with morbidity and mortality and, therefore, prompt and aggressive therapy is necessary. In this review we emphasize practical clinical aspects of DM.

D

Definition and Classification Bohan and Peter suggested the use of five criteria to define the entities of DM and PM in 1975.’ Signs and symptoms of muscle disease and the presence of typical cutaneous disease were the main aspects. The criteria include (1) proximal symmetric muscle weakness that progresses over a period of weeks to months, (2) elevated serum levels of muscle enzymes, (3) an abnormal electromyogram, (4) an abnormal muscle biopsy that is consistent From the Department ofDermatology, Bowman Gray School ofMedicine, Wake Forest University, Winston-Salem, North Carolina. Address correspondence to: Marcus R Stonecipher, MD, Department of Dermatology, Bowman Gray School of Medicine, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157.

0 1993 by Elsevier Science Publishing Co., Inc.

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with myositis, and (5) the presence of cutaneous disease compatible with dermatomyositis. The use of the criteria in a systematic fashion helps to exclude other disease processes in the differential diagnosis. These criteria are useful for the evaluation of a given patient or for critical evaluation of reports in the literature. In clinical practice, however, the criteria should not be used in a dogmatic fashion.

Etiology and Pathogenesis The etiology and pathogenesis of DM are still not well understood.2,5*6 Multiple types of insults through common pathways lead to muscle damage and, thus, to the clinical manifestations of myositis. The muscle disease is somewhat better understood than the pathogenetic mechanisms involved in the skin disease. Multiple associations have been recognized to occur with the onset of dermatomyositis or polymyositis, including infections, postvaccination effects, neoplasms, drug-induced disease, stress, and trauma. Linkage of dermatomyositis and polymyositis to preexistent infection is supported by epidemiologic studies,’ serologic studies, and, recently, the demonstration of these agents within muscle biopsy specimens. In particular, viral agents and parasitic agents have been linked to typical patients with dermatomyositis or polymyositis.6 The link of malignancy to DM is a topic that will be discussed at length. Reports have suggested that the malignancies occur concurrently and that the course of the myositis may parallel that of the malignancy.9 Earlier studies had suggested that there may be allergic phenomena that occur to antigens seen on malignant tumors that could induce myositis; however, the exact mechanisms of this linkage await further investigation. Several authors have linked DM with induction by penicillamine therapy used for rheumatoid arthritis or

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Wilson’s disease.1° Several other drugs have been linked to the development of dermatomyositis-like syndromes, including alcohol, clofibrate, ipecac, and, most recently, cimetidine. Patients with disease induced by these drugs develop disease that may be indistinguishable from the usual cases of polymyositis on a clinical, histopathologic, and electrical basis; however, when the drugs are withdrawn, the disease process may spontaneously remit. Dermatomyositis and polymyositis have been pathogenetically linked to various immunologic abnormalities.6,1*J2 Three types of hypersensitivity phenomena have been postulated to occur. Immune complex disease (a type III hypersensitivity reaction in the Gel and Coombs’ schema) has been suspected in multiple patients with childhood dermatomyositis. Abnormal cell-mediated immune phenomenon (delayed hypersensitivity type IV reaction) has been linked to dermatomyositis and polymyositis in adults. In addition, there is some support for antibody-dependent cellular cytotoxicity (ADCC) as a potential factor in adult patients. Immune complex disease has been reported in children with DM and patients with associated collagen vascular diseases and on occasion in adult patients with PM or DM. It appears that there is a genetic predisposition, in particular to childhood dermatomyositis.13 Several reports have linked the human leukocyte antigens (HLA) B8 and DR3 to PM and DM. This linkage has been most strongly demonstrated in childhood DM.13 Other studies have shown a high association with null alleles of C4 genes in juvenile DM. l4 Several authors have suggested that in adults, HLA Cw7 was significantly increased in patients with myositis. Thus, it seems that there may be a predisposition in certain patients in the right circumstances for the development of DM. Further immunogenetic data may allow us to determine which patients are at risk for future development of these conditions. Thus, in appropriate circumstances an immunogenetitally predisposed individual may, after an infection, a drug, trauma, or neoplasm, be able to develop an inflammatory reaction within the muscle and the skin. Through a complex set of reactions involving both humoral and cellular immunologic phenomena, both muscle damage and cutaneous involvement may occur.

Clinical Manifestations Cutaneous Disease The characteristic, and possibly pathognomonic, cutaneous features of DM are the heliotrope eruption and Gottron’s sign. Several other cutaneous changes occur in patients who have DM, and their presence allows us to confirm a diagnosis of DM despite their not being path-

Figure

1.

Typical heliotrope

eruption in dermatomyositis.

ognomonic signs. These include malar erythema, poikiloderma in a photo distribution, and periungual and cuticular changes. These signs can also occur in other connective tissue diseases and, thus, are not pathognomanic for DM. They remain important in differentiating DM from PM. There are several cutaneous lesions that occur in other connective tissue diseases but may also occur in patients with inflammatory myositis that do not allow for the diagnosis of DM. These include discoid lupus erythematosus lesions, sclerodermatous changes, urticaria-like lesions, leukocytoclastic vasculitis, and Raynaud’s phenomenon. Several other cutaneous manifestations occur in patients with myositis that may or may not be related to the disease process. These include deposition of mutinous material within the skin and the development of waxy, papular lesions on the lateral surface of the digits. The heliotrope eruption consists of a lilac discoloration or a violaceous to dusky erythema with or without edema in a symmetric distribution involving the periorbital skin (Fig 1). There is generally greater involvement of the upper eyelids and at times only the upper lid may be affected. This sign may be quite subtle and may appear as only a mild discoloration along the eyelid margin. The heliotrope sign can follow the course of myositis or it can wax and wane in discordance with the disease activity. Reactivation of this eruption in a patient otherwise considered to be in remission has generally signified a relapse of the myositis. Gottron’s papules/plaques (Gottron’s sign) occur over bony prominences, particularly over the metacarpal phalangeal joints and the proximal interphalangeal or the distal interphalangeal joints (Fig 2). They may also be found over other bony prominences such as the elbows, knees, and ankles (Fig 3). Lesions consist of slightly ele-

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Figure 2. Eythematous papules and plaques over joints representing Gottron’s sign.

Figure 3. Gottron’s lesions may be seen over other bony prominences as illustrated here on the elbow.

vated, violaceous, or dusky erythematous papules and plaques. Within the lesions, there are often telangiectasias and there may be hyper- or hypopigmentation. These changes, consisting of dyspigmentation, telangiectasias, and atrophy, are known as poikiloderma, and these lesions can develop an atrophic appearance with time. Usually the activity of the muscle disease is not reflected by this skin change. These lesions can be confused with lesions of lupus erythematosus or, at times, with papulosquamous disorders such as psoriasis and lichen planus. Psoriasis can also occur over bony prominences, particularly over the elbows and knees. Biopsy for routine histopathology may be helpful in confirming the diagnosis of DM.15 Nailfold changes consist of periungual telangiectasias and a characteristic cuticular change with hypertrophy of the cuticle and small hemorrhagic infarcts within this hypertrophic area (Fig 4). l6 The periungual telangiectasias seen clinically in this disease may be extremely prominent or may be appreciable only by capillary microscopy.” Clinically, the periungual telangiectasias may be indistinguishable from those that are seen in other connective tissue diseases such as scleroderma and lupus erythematosus. The cuticular overgrowth that occurs may be similar to that seen in scleroderma. Nailfold microscopy may be helpful in evaluation of confusing patients with dermatomyositis.*8

Poikiloderma can occur within Gottron’s papule s or can occur alone on sun-exposed skin. These charages occur in about one third to one half of the patients 1with DM but do not occur in patients with PM. The pati ents often do not notice the photosensitivity, which is cha ratteristic of DM. The poikilodermatous eruption can iIhen

Figure

4.

Periungual telangectasia.

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become generalized and, in this case, is known as a “malignant suffusion,” because it has been suggested that there is a higher incidence of underlying malignant disease. The poikiloderma of DM must be clinically differentiated from that seen in patients with lupus erythematosus, radiodermatitis, chronic sun exposure, and cutaneous T-cell lymphoma (CTCL). Biopsy of the poikiloderma in DM is not specific and thus may not differentiate it from the poikilodermatous eruption seen in lupus erythematosus but should differentiate DM from the poikiloderma of CTCL. The presence of skin lesions usually seen with other connective tissue diseases is important to recognize because patients with these signs may be classified in the overlap category. It is possible that patients in the overlap category have a lower frequency of internal malignancy, and therefore it is reasonable to assume that this subclassification is important. l9 Also several internal manifestations of DM and PM occur more frequently in patients with overlap syndromes; in particular, gastrointestinal involvement and pulmonary involvement may be more prominent. *OThe most common feature seen is a sclerodermatous skin change usually affecting the acral areas with thickened, tight, and bound-down skin, which may restrict the mobility of the joints. In addition, patients with typical discoid lesions of lupus erythematosus, patients with rheumatoid nodules, and patients with vasculitic lesions have been described in association with inflammatory myopathy. Patients may develop mucin deposition within the skin. Often, this is not clinically appreciated but may be seen on biopsy examination. Another nonspecific association is cutaneous vasculitis.21 This may take the form of palpable purpura, urticaria-like lesions, or livedo reticularis. Callen and Dubin have described a patient in whom urticaria-like lesions developed preceding flares of PM on several occasions2* Workers at the National Institutes of Health have described a unique type of skin change that consists of papular lesions along the lateral aspects of the fingers in patients with inflammatory myopathy.23 They also describe these lesions in patients with other connective tissue disease; therefore, this may not be specific for DM. Patients who have the heliotrope eruption, Gottron’s sign, poikiloderma, photosensitivity, and nailfold changes are classified as having DM. Patients with other skin disorders that are less specific for inflammatory myositis but occur in conjunction with it are not classified as having DM; rather they are classified as having PM or DM with these skin changes. This becomes important when dealing with the potential differences between DM and PM for the presence of internal malignant disease.

There are a group of patients who are said to have dermatomyositis sine myositis,24 denoted by some authors as amyopathic dermatomyositis.25 These patients have cutaneous disease typical of DM but in the absence of demonstrable inflammatory myopathy. These patients form a rare subset of disease and may, if followed long enough or if examined closely enough, have an inflammatory myopathy evolve or be detected.

MuscleDisease Clinical and laboratory abnormalities suggestive of muscle disease are characteristic features of DM and PM. Even in those patients who initially have only skin disease (dermatomyositis sine myositis), myositis often follows the appearance of the skin lesions. The myositis occurring in DM is indistinguishable from that occurring in PM by clinical, histopathologic, or laboratory features. Also, when considered alone, the individual features of myositis are not diagnostic of DM or PM; rather, the diagnosis is one of exclusion. Clinically the myopathy of DM or PM tends to affect mainly proximal muscle groups of the shoulder and pelvic girdle. In severe progressive disease, all muscles may become involved. The disease is usually symmetric. Initial complaints of patients may include weakness, fatigue, and diminished ability to climb stairs, to raise their arms for actions such as grooming of hair and shaving, and to rise from a squatting, sitting, or lying position, or a combination of these features. The progression of the disease is variable but usually occurs over a period of weeks to months. Muscle aching is a common complaint, but frank tenderness on palpation is variable. Inability to swallow and symptoms of aspiration may reflect the involvement of striated muscle of the pharynx or upper esophagus. Dysphagia often signifies a rapidly progressive course and may be associated with a poor prognosis. The laboratory abnormalities can be enzymatic, electrical, or histopathologic. Sarcoplasmic membrane-derived enzymes (muscle enzymes) are frequently elevated in patients with inflammatory myopathy. The enzymes most commonly elevated are creatine kinase (CK), which was formerly known as creatine phosphokinase; aldolase; lactic dehydrogenase (LDH); and serum glutamic oxalate transaminase (SGOT). With the exception of aldolase, the other enzymes can be elevated in other disease states. CK is made up of three isoenzymes: the CK-MM band from muscle, the CK-MB band from myocardial muscle, and the CK-BB band from brain and nervous tissue. The principal elevation in PM or DM occurs in the CK-MM band; however, several patients without cardiac

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involvement have had significant elevations of the CKMB band. It has been suggested that elevation of the CK-MB band is due to regeneration of muscle with the development of a phylogenetically earlier enzyme, which is less well differentiated than the CK-MM band.26 Patients with DM or PM may have normal muscle enzymes.*’ In these instances, creatine, a breakdown product of muscle, can be measured in the urine and may be reflective of muscle disease. Several studies have suggested that creatine measurement in the urine is more sensitive and occurs earlier in patients with myositis. This test is cumbersome, however, because a 24-hour urine collection must be obtained. In addition, the test may be confused with creatinine, and the wrong test is often performed. Electromyography (EMG) characteristically shows a triad of findings including sharp or positive waves, insertional irritability and fibrillation, and short polyphasic motor units. Innervation remains intact, and there is an absence of neuropathic changes. Proximal muscles are more affected than distal muscles. There is debate as to whether experienced electromyographers can recognize a typical pattern of myositis. EMG may lack specificity, as typical myopathic changes may be seen in other connective tissue diseases that are indistinguishable electrically from dermatomyositis or polymyositis. The use of EMG for directing muscle biopsy is controversial. Some identify an abnormal muscle with EMG and then ask the surgeon to biopsy this site. Identifying the muscle on a clinical basis for biopsy and sparing it from EMG may be preferable because insertion of needles has been shown to lead to changes including inflammation and necrosis of muscle. Muscle biopsy specimens show typical features, including type II fiber atrophy, necrosis, regeneration with hypertrophic fibers, a centralization of the sarcolemmal nuclei, and a lymphocytic infiltrate in a perifascicular and perivascular region. 28 Vasculopathy is seen in children but is uncommon in adults. The vasculopathy may be characterized by endothelial cell damage and, occasionally, an inflammatory infiltrate in the perivascular location. Muscle biopsy may be performed by needle biopsy or by an open technique. A probable higher sensitivity is seen with an open biopsy. The biopsy specimens are not always abnormal in patients with DM or PM, which is possibly attributable to the variable nature of the disease process. In addition, abnormalities seen on biopsy are not necessarily indicative of active muscle disease. The muscle biopsy is also useful in ruling out infiltrative and infectious processes. With advances in imaging techniques a variety of additional modes of investigation may prove useful in evaluation of muscle disease, including, but not

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limited to, magnetic resonance imaging, technetium-99, thallium-201, and ultrasound.

Systemic Manifestations of Dermatomyositis DM and PM are multisystem disorders, reflected by the high frequency of other clinical features in patients with these diseases.29-32 Patients with overlapping features of other connective tissue diseases may demonstrate an even greater frequency of these complaints.

Articular Disease Arthralgias and arthritis may be present in 20 to 25% of patients with DM or PM. 33 In patients with overlap syndromes, this percentage may rise but averages approximately 50%. The usual clinical picture is one of generalized arthralgias accompanied by morning stiffness. The joints affected appear to be the small joints of the hands, wrists, and ankles, but larger joints, such as the knees, may also be affected. Arthritis, when present, is symmetric. Spondylitis and disease of the lumbosacral spine are not features of polymyositis or dermatomyositis. There may be a lower frequency of malignancy in patients who have arthritis.

Esophageal

Disease

Dysphagia occurs in approximately 15 to 50% of patients with inflammatory myopathy.29 The dysphagia can be of several types. Proximal dysphagia is caused by involvement of the pharyngeal, cricopharyngeal, or striated muscle of the esophagus. This involvement results in aspiration when the patient attempts to swallow, and patients often describe food sticking in the high esophagus. This type of involvement is related to the disease effects on striated muscle and seems to be corticosteroid responsive. Distal dysphagia is related to esophageal involvement of nonstriated muscle and appears to be more frequent in patients with overlap syndromes. These patients state that food becomes lodged in the midchest to upper abdominal area. They may also have symptoms of reflux esophagitis. This type of involvement is similar to that seen in systemic sclerosis and seems to not be corticosteroid responsive. Dysphagia portends a poor prognosis, is often associated with pulmonary involvement, and is occasionally associated with progressive myositis.34

Lung Disease Pulmonary disease occurs in DM and PM in approximately 15 to 30% of patients.30*35*36It can be characterized by a primary, diffuse interstitial fibrosis (DIF) manifested

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radiologically or by abnormalities seen on gas exchange by pulmonary function testing. The DIF is similar in its nature to the lung disease that may occur in rheumatoid arthritis or scleroderma but is probably of a different pathogenetic mechanism. Salmeron and associates reported that 9% of patients with DM have pulmonary disease35; Dickey and Meyers have reported approximately a 31% incidence of lung involvement in patients with DM and I’M.30 Chest radiographs may be totally normal, although pulmonary function studies may show a decrease in gas exchange, suggestive of a diffuse interstitial fibrosis. Tazelaar et al describe three major groups of lung disease based on open lung biopsy of 14 patients: bronchiolitis obliterans organizing pneumonia (BOOP), usual interstitial pneumonia (UP), and diffuse alveolar damage (DAD). 36 Patients with BOOP had the most favorable prognosis, whereas patients with DAD uniformly did poorly. The cause and pathogenesis of DAD process in patients with myositis is not known. Lung disease may occur as a complication of the disease or its treatment. Severe weakness may result in hypoventilation. Dysphagia or involvement of pharyngeal muscles may result in an aspiration pneumonitis. Opportunistic infections may develop as a result of drug therapy and several of the drugs used in therapy may cause a hypersensitivity pneumonitis. Pulmonary complications have been related to a poorer prognosis; however, in some studies, prognosis does not seem to be altered by the presence of pulmonary disease alone. It has been suggested that patients with the Jo-l antibody are at greater risk for pulmonary involvement with l?M.37

Cardiac Disease The heart muscle may be affected in PM by myocarditis or the patient may have pericarditis.38 Pericarditis appears to be more common in patients with overlap features of other connective tissue diseases. Myocarditis can result in conduction defects, dysrhythmias, or, when severe, congestive heart failure. Patients with congestive heart failure have a poor prognosis. The prognosis for patients with dysrhythmias or conduction defects may not vary from that in uncomplicated cases. It seems that cardiac disease may be more frequent in patients with PM and is less frequent in those with malignancy or in children. Bohan and associates reported a 30% incidence of cardiac abnormality, most often a nonspecific ST-T wave change demonstrated on electrocardiography (ECG).19 Gottdeiner and associates reported that 52% of their patients with PM had evidence of cardiac disease.39 Their studies, which included echocardiography, showed evidence of mitral valve prolapse, decreased ejection fractions, and ECG revealed frequent conduction

defects and several dysrhythmias. Holter monitor analysis may be more sensitive in defining dysrhythmias and may be considered in some patients.40*41 Elevation of the CK-MB band should warrant the investigation of a cardiac source; however, the presence of a CK-MB band alone does not prove cardiac involvement.

Calcinosis Calcinosis of the skin or muscle is very unusual in adults but may occur in up to 40% of children with DM.42-44 Calcinosis cutis manifests as firm, yellow or flesh-colored nodules often on the hands or arms. Occasionally, these nodules can extrude through the surface of the skin, in which case secondary infection may occur. Muscular calcinosis is often asymptomatic and is seen only on radiologic examination. Four types of dystrophic calcification are recognized: (1) small hard plaques or nodules, located superficially; (2) nodular subcutaneous deposits, which occur frequently near joints (calcinosis circumscripta); (3) deposits in fascial planes within muscles (calcinosis universalis); and (4) an exoskeleton pattern with extensive subcutaneous deposition, which may be associated with vasculitis and more severe disease. In severe cases, the calcinosis can cause loss of function and even formation of osteoma in extremely rare individuals. Early therapy may decrease the incidence and severity of disease.

Nephropafhy

and Myosifis

Renal disease has rarely been reported in patients with DM or PM. Dyck et al studied five patients in whom abnormalities of urinary sediment or proteinuria led to a renal biopsy. 31 In all patients there was no evidence of another collagen vascular disease and none had a cutaneous eruption of DM. In our combined 150 patients with DM, we have not detected any with renal disease to date.

Serologic Tesfing in the Myosifis Patient Antinuclear antibodies (ANA) have been reported in 15% to 80% of patients with DM -PM depending on the substrate used and the subgroup selected.27*45 Patients with overlapping features of another collagen vascular disease probably have a higher frequency of autoantibodies than other subsets. Recently, several autoantibodies have been described that might be more specific for DM-PM. Interest in some of these antibodies has been rekindled because the Jo-l antigen, which is histidyl-tRNA synthetase, is also a known viral antigen.46 Multiple autoantibodies have been identified in DMPM patients. Some of these antibodies are associated with other connective tissue diseases, whereas others are

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Table 1. Myositis-Specific Antibodies Association*

Antibody Antisynthetases: Jo-l, OJ, EJ, PL-7, PL-12

Antitranslation: KJ Anti-Mi-2 Anti-Mas l

PM -

DM, ILD, arthritis, Raynaud’s phenomenon PM, ILD, Raynaud’s DM Rhadomyolysis

PM, polymyositis; DM. dennatomyositis; ILD, interstitial lung disease.

known as myositis-specific autoantibodies (MSA) (Table 1). Reichlin and Mattioli first detected an antibody to calf thymus extract (CTE) in a DM patient and designated it Mi-1. Mi-1 was found in 2 of 19 DM patients but in none of the controls nor in PM patients, although it has been found in 5% of systemic lupus erythematosus (SLE) patients. A second antibody in this same patient’s serum is known as Mi-2; it is the most specific antibody for DM, occurring in about 20% of adult DM patients, and is less strongly associated with PM.*’ Mi-2 reacts with an unidentified nuclear antigen. Some of these antibodies have been identified in myositis - scleroderma overlaps. The antibody PM-SCL (formerly PM-l) occurs in one half to two thirds of sclerodermatomyositis patients. The PM-Scl antigen is nucleolar and possibly a nuclear protein complex.** Recently, another antinuclear antibody, which reacts with a 56-kd protein of ribonucleoprotein particles from Syrian hamster cell nuclei, has been described and was found in 45 of 52 patients with DM/PM. 49 The Ku antibody (anti-Ku) is also found in overlap patients. This antibody is chemically distinct from the PM-Scl antibody and is located in the nucleolus as a complex of proteins that bind to DNA. Anti-U1 RNP (antibody against ribonucleoproteins containing Ul RNP), can occur in DM - PM patients, but it is detected more frequently in overlap syndromes. Anti-U2 RNP is very rare and may be found in DM-PM/ scleroderma overlap. Probably the most important autoantibody found in DM-PM has been the Jo-l antibody. This antibody is one of a group of antibodies that react with cytoplasmic antigens involved in protein synthesis. This antibody has been found much more frequently in PM patients than DM patients. so Anti-Jo-l is also linked to the occurrence of interstitial lung disease (pulmonary fibrosis) in the PM patient.31*5* Anti-Jo-l is the most common antibody in the antisynthetase group and is known to react with histidylThe histidyl-tRNA synthetase setRNA synthetase. quences have been shown to closely match proteins present in skeletal muscle, thereby giving anti-Jo-l an appropriate target. Anti-Jo-l has also been associated with a subluxing arthropathy.sl Antibodies to other synthetases have been recognized although these are much less common than anti-Jo-l.

Other such antibodies to synthetases are described for threonine, alanine,s2*53 glycine,54 and isoleucine. Other anticytoplasmic antibodies described include antibody to signal recognition particle (anti-SRI’), peptide transcription factors (anti-KJ), unidentified small RNA (anti-Mas), and elongation factor la (anti-Fer).

Myositis and Malignancy Significant controversy exists relating to the problem of DM and PM and their relationship to malignancy. The incidence of malignancies varies between 6 and 60% in various series of patients with myositis.55-59 This has occurred both in studies prior to the establishment of the criteria by Bohan and Peter and in studies subsequent to the use of these criteria. Several studies have failed to differentiate between DM and PM. In addition, some reports did not document which cutaneous findings were considered to differentiate DM from PM. Overall, it appears that roughly 20% of the reported patients with DM have an associated malignancy, whereas only 15% of those with PM have a malignancy. These data, however, cannot be compared in a meaningful statistical fashion because of differences from study to study. In a recent study with a population-based cohort of 788 patients, Sigurgeirsson et al found an increased risk of malignancy in patients with polymyositis or dermatomyositis and noted a higher rate of mortality from cancer in patients with dermatomyositis.60 A wide variety of malignancies have been reported with DM and PM; however, the list and relative frequencies of these malignancies reported in the literature may not be reflective of a practice type of experience. Barnes had suggested that gynecologic malignancy, in particular ovarian carcinoma, was overrepresented in reports in the literature.61 This has been supported by a study at the Mayo Clinic by Verducci et al, in which there was a disproportionately large number of patients with ovarian carcinoma.62 Another tumor that may be overrepresented in the Oriental population is carcinoma occurring in the nasopharynx 63; however, because any organ system can be involved with cancer in patients with DM and PM, the significance of these reports awaits confirmation. Another controversy is whether or not age is a factor in

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the frequency of malignancy in patients with myositis. It has traditionally been suggested that adults over the age of 50 years were at greater risk; however, several young adults in their thirties had malignancy in Callen’s studies. In addition, several children have been reported with malignancies. Lakhanpal et al found four malignancies in 65 patients aged 15 to 29 years and 10 malignancies in their 94 patients who were in their thirties.” Although the frequency of malignancy increased with age, this may be reflective of an increasing frequency of malignancy in the general population. Malignancies in younger patients may be different in their site or type from those in older patients, Although they are less common, there appears to be some risk, and these patients possibly should have the same careful approach that older adults have. Patients with overlap myositis rarely, if ever, have internal malignancy. There have been recent reports in which neoplasia has been present in patients in the overlap myositis group. 2o Patients who are treated with immunosuppressive drugs may be at greater risk for the development of subsequent malignancies.65,66 Approximately seven patients have been reported who have had malignancy following the use of an immunosuppressive agent for the treatment of inflammatory myopathy. The malignancies developing in these patients have rarely been in the lymphoreticular system, and, thus, the exact risk of neoplastic change in these patients is not known. At the current time it appears that the risk of subsequent neoplasia is greatly outweighed by the benefits of a potentially successful therapy. Perhaps the most emotional controversy is how to evaluate the patient with DM or PM for malignancy. Bohan and Peter first questioned the value of workup in 1975.’ Subsequently, Moss and Hanelin, in a radiologic study, were unable to detect any benefit of performing multiple roentgenographic examinations in patients with myositis. 67 Callen et al suggested that these procedures were of no value68 and, in a careful analysis of the literature in 1982, came to the conclusion that tests that were not directed by signs of symptoms were of little value.69 This has been subsequently supported by the work of Hoffman et a170and Lakhanpal et al.” Patients who have myositis should have a thorough history and physical examination and health maintenance update based on age and sex; however, other testing should not be ordered unless there is a symptom or sign that is unexplained or as indicated following initial evaluation. Patients with DM sine myositis (cutaneous disease without detectable myositis) may best be managed in the same manner.

Evaluation

of the Patient

The diagnosis of DM or PM is one of exclusion. A complete history should be conducted with particular atten-

Table 2. Evaluation of a Patient with Myositis Thorough history Previous malignancy Complete review of systems History of toxins, infection, travel, medicines Complete physical examination, including pelvic, breast, and rectal examinations Evaluation of muscle disease Strength testing EMG Creatine kinase aldolase Muscle biopsy Other laboratory tests Complete blood count Urinalysis Serum multiphasic analysis ECG Pap smear Mammogram Additional testing to be directed to any abnormalities in above tests

tion to drugs or toxins that may be involved (Table 2). A history should include previous malignancies, previous travel, changes in diet, and any symptoms of associated phenomena such as dysphagia, dyspnea, and arthritis. A thorough review of systems is necessary, which will aid in the evaluation of patients with malignancies. A complete history and physical examination should be conducted by the treating physician or a consultant. The examination should include careful breast and pelvic examinations in women and a rectal and prostate examinations in men. These should not be deferred. If the examiner does not feel confident in these areas it is necessary to obtain appropriate consultation. Routine laboratory determinations include a complete blood count (CBC) and serum multiphasic analysis, urinalysis, chest roentgenogram, stool for hematest, thyroid function tests, ECG, and, in women, mammography and Pap smear. Pulmonary function tests (PFT) may be performed, including diffusion studies, regardless of whether there are symptoms or abnormalities on chest radiographs. An esophageal study is necessary to evaluate the possibility of dysmotility if that is suspected. Optional studies include a Holter monitor and echocardiography and serologic tests. Tests for ANA, although they may be positive in pure cases of DM or PM, have not been shown to influence or predict the course of the disease or its therapy. Newer serologic studies, such as the Jo-l and Mi antibodies, may provide insight into pathogenesis4’,‘l but, at present, are perhaps useful for investigators. The correlation of Jo-l with pulmonary disease has been reported, but pulmonary function testing should be considered regardless of the results of anti-Jo-l testing. Immunogenetic testing has been of no practical value. Subsequent evaluation is necessary following the initiation of therapy. Repeat testing of abnormal results is

Clinics in Dermatology 2993;21:261-273 advised. Clinical examination and enzyme determination are typically used to follow patients clinically. Repeat muscle biopsy or EMG is reserved for unusual circumstances. The use of biomechanical assessment to quantitate muscle strength may be of benefit in following the patient’s course. Careful questioning for new symptoms should occur on each follow-up visit, and if a symptom develops, careful evaluation is necessary. On at least a yearly basis, a repeat chest radiograph; urinalysis; CBC; serum multiphasic analysis; stool guaiac; rectal, pelvic, and breast examinations; mammography; and Pap smear should be conducted. In patients age 50 or older colorectal screening should perhaps also be performed on an annual basis.

Course and Therapy Several general measures are helpful in patients with DM and PM. Bedrest is often valuable in the individual with progressive weakness; however, this must be combined with aggressive but reasonably passive range-of-motion exercises to prevent contract-rues. Nutrition is important because of a negative nitrogen balance that exists in inflammatory myositis. 72 Patients who have evidence of dysphagia should have the head of their bed elevated and should avoid eating meals before retiring. The mainstay of therapy for DM is the use of systemic corticosteroids.” Debate over low-dose therapy versus high-dose therapy and alternate-day therapy recently occurred.6,74,75 Traditionally, prednisone given orally in a dose of 40 to 60 mg daily is recommended as the initial therapy. Hoffman et al, 7o have recently shown lower doses given on an every-other-day basis were able to induce and maintain remission; however, we generally have continued to approach patients with corticosteroids administered every day, often in divided daily doses. The treatment should continue for at least 1 month after the myositis has become clinically and enzymatically inactive. At that point, the dose is slowly lowered, generally over a period lasting approximately one and one half to two times as long as the induction therapy.76 Up to one third of patients with DM and PM will not respond adequately to systemic corticosteroids or will develop significant corticosteroid-related side effects.77 In these patients, immunosuppressive agents may be an effective means of inducing a remission or maintaining a remission. Azathioprine and methotrexate have been the best-studied agents 7s*78,79;however, cyclophosphamide and chlorambucil have also been used. Bohan and associates were not able to demonstrate an advantage of one agent over another.19 Roughly one half to three fourths of the patients treated with an immunosuppressive agent will respond with an increase in muscle strength, a decrease in enzyme

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levels, or a reduction in corticosteroid dosage. Although these agents are effective, they must be used with caution, because multiple side effects can occur. Authors from Scandinavia have found a similar incidence of side effects in patients who were treated with immunosuppressive agents and corticosteroids.80 Methotrexate can be used on a weekly basis, given either by mouth or intravenously.81 We rarely use it intramuscularly, because methotrexate is well dissolved orally and because intramuscular injections have been linked to increases in the serum levels of muscle enzymes. Thus, it is possible to confound the ability of the examiner to follow enzyme determinations as a measure of improvement or worsening when repeated intramuscular injections are used. In the adult, methotrexate is administered in an empiric dose which is usually below 25 mg per week. A drug effect is seen within 4 to 8 weeks, and therefore this approach is not recommended for rapid control of a fulminant disease process. Methotrexate has been demonstrated to be corticosteroid-sparing by Metzger et al, who examined 22 patients and found that 17 of them achieved significant reductions in corticosteroid dosage. 82From the authors’ personal experience and that seen in the literature, it appears that methotrexate is effective in approximately 75% of the patients. Azathioprine has recently been well studied by Bunch and associates from the Mayo Clinic.77.78 In their initial report, they prospectively analyzed 16 patients who were treated with prednisone and azathioprine versus prednisone and placebo. In the short-term analysis at 3 months, there were no differences between these two groups. In the open follow-up study examined at 3 years, however, there were significant differences between the groups, favoring those treated with azathiorpine. Azathiorpine is administered orally in a dose of 2 mg/kg per day. Cyclophosphamide has been reported to be useful for treating dermatomyositis in children and in adults.83*” Cyclophosphamide is a potent cytotoxic and immunosuppressive agent that is given orally in a single morning dosage of 2 to 4 mg/kg. Hydration is extremely important in the prevention of hemorrhagic cystitis. The use of immunosuppressive agents is to be undertaken with caution. The usual follow-up measures are necessary for these patients. Complete evaluation, prior to initiation of immunosuppressive therapy is also necessary. The need for a liver biopsy in patients treated with methotrexate is somewhat controversial, but certainly if chronic therapy is used, liver biopsy should accompany this therapy. Some patients still will fail to respond to these agents. In these patients, various “heroic” measures have been suggested, including plasmapheresis,85 pulse methylprednisolone therapy,86 combination immunosuppressive therapy, cyclosporin A,87,88 total body irradiatione9,

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and plasma exchange and leukapheresis.90 At the current time, most of these methods have all been shown to work in anecdotal reports only. They are all associated with multiple side effects and should be reserved for the most severe and nonresponsive patients. Recent studies on the use of intravenous gamma globulin have demonstrated that this mode of therapy may be an alternative to cytotoxic therapy and allow corticosteroid sparinggl Therapy of cutaneous disease in patients with DM is often difficult because even though the myositis may respond well to the treatment with corticosteroids or immunosuppressives, the cutaneous lesions often persist. Although the cutaneous disease may be of minor importance in patients with serious fulminant myositis, in multiple patients, cutaneous disease becomes a most important aspect of the care. To this end, antimalarials have been used in recent years in the treatment of these cutaneous lesions.92,93 Hydroxychloroquine in dosages of 200 to 400 mg per day is effective in approximately 80% of the patients treated. The therapy does not provide total control of disease in most patients; rather, there is a partial control of disease with inability to lower corticosteroid dosage in approximately 80% of the responding patients. Patients who do not respond well or fully to hydroxychloroquine can be switched to choroquin therapy, 250 to 500 mg. The usual precautions regarding antimalarial therapy should be undertaken, including careful ophthalmologic examination and follow-up. Treatment of pulmonary fibrosis complicating myositis involves the use of corticosteroids and immunosuppressive agents. Several authors have suggested that corticosteroids in full therapeutic dosages are helpful in improving pulmonary function in patients with pulmonary fibrosis. Treatment for esophageal involvement, Raynaud’s phenomenon, or complicating vasculitis is no different from treatment of these disorders in patients without myositis. The prognosis of DM and PM varies greatly depending on the series of patients studied.94-97 Factors that affect prognosis include the patient’s age, the type and severity of myositis, the presence of dysphagia, the presence of malignant disease, and the response to corticosteroid therapy. Severe muscle weakness on initial examination is a poor prognostic sign regardless of response to therapy. Studies by Carpenter et a198 and Bohan et all9 revealed dysphagia and pulmonary disease associated with a poorer prognosis. In contrast, Benbassat et al failed to demonstrate that pulmonary fibrosis was associated with an altered prognosis but agreed that the presence of dysphagia was a poor sign3’ Clearly, an ominous prognostic factor is the presence of an associated malignant disease.58 Most studies have

reported between 50 and 90% mortality in patients with an associated malignancy. In contrast, Benbassat et al have failed to show that malignancy was a poor prognostic finding. 34 Death in most patients with malignant disease complicating myositis is usually related to the malignant disease, although continued progressive myositis has appeared as a cause of death in an occasional patient. That therapy alters prognosis seems to be well established by retrospective reports on the benefits of corticosteroids and immunosuppressives.

Drug Names azathioprine chlorambucil chloroquine hydrochloride cyclophosphamide cyclosporine hydroxychloroquine sulfate methotrexate methylprednisolone prednisone

Imuran Leukeran Aralen Cytoxan Sandimmune Plaquenil Methotrexate Depo Medrol Prednisone

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