Chapter 156. Dermatomyositis

The idiopathic inflammatory myopathies (IIDMs) are a heterogeneous group of genetically determined autoimmune disorders that predominately target the skeletal musculature and/or skin and typically result in symptomatic skeletal muscle weakness and/or cutaneous inflammatory disease. Some physicians continue to refer to this group of clinical disorders by an earlier designation, idiopathic inflammatory myopathies. Among the IIDM, dermatomyositis (DM) is of special interest to the dermatologist due the universal presence of a hallmark pattern of cutaneous inflammation. DM is the only idiopathic inflammatory myopathy (IIM) that expresses a characteristic pattern of primary cutaneous inflammation.

In this chapter, the term classic DM is used to refer to DM as traditionally defined (i.e., the concurrence of myositis resulting in clinically significant proximal muscle weakness and a set of hallmark inflammatory skin lesions occurring in a specific anatomical distribution). Also of interest to the dermatologist is the subgroup of patients who express the hallmark cutaneous manifestations of DM for prolonged periods (6 months or longer) without developing clinically evident muscle weakness. This pattern of DM expression is referred to as clinically amyopathic DM (CADM); this term is synonymous with the historical designation, dermatomyositis sine myositis.

On occasion, other organ systems, such as the lungs (interstitial lung disease), joints (arthritis), and heart (cardiomyopathy, conduction defects), are targeted by inflammatory injury in IIM patients. In addition, differences exist between classic DM presenting in adults and that presenting in children. For example, juvenile-onset classic DM is associated with higher rates of vasculopathy/vasculitis resulting in the complication of dystrophic calcification, whereas adult-onset classic DM is associated with a significantly increased risk of internal malignancy and interstitial lung disease.

The diagnostic criteria for DM under the current consensus IIM classification system have not allowed for the inclusion of cutaneous-only or cutaneous-predominant subsets of DM, such as amyopathic DM and hypomyopathic DM, which together are referred to here as CADM (see eTable 156-0.1). A more inclusive disease category designation, “idiopathic inflammatory dermatomyositis,” has been proposed by one of the authors (Richard D. Sontheimer) as an alternative to the “IIM” designation because it allows for the inclusion of these cutaneous subsets of DM1–16 (eTable 156-0.2). Other rheumatologic disorders such as lupus erythematous (LE) and scleroderma are broadly recognized to include skin-only subsets (e.g., discoid LE, morphea). However, the group designation “idiopathic inflammatory dermatomyopathies” has yet to be broadly embraced.

Thus, IIDM represents a heterogeneous group of clinical disorders that can be conveniently conceptualized as a continuum of illness with subgroups of patients who share common clinical and immunologic features at distinct positions along this spectrum (Fig. 156-1).

Classic Dermatomyositis

Cutaneous involvement occurs in 30% to 40% of adults and in 95% of children with IIDM. By definition, skin disease is absent in patients with PM and present in 100% of patients with classic DM and CADM. Skin disease activity can precede muscle disease activity in classic DM by weeks to several months.

Classic DM can occur from infancy to adulthood and most frequently presents in the fifth and sixth decades (PM is extremely rare in children). The incidence of classic IIDM between 1963 and 1982 was estimated to be 5.5 cases per million. The incidence probably is higher, inasmuch as this study17 was based only on hospital inpatient-ascertained diagnoses and did not include cases of CADM. Familial concordance occurs rarely, and concordant disease expression has been reported in identical twins.

The epidemiology of juvenile-onset classic DM in the United States has been reviewed.18 For children 2–17 years of age, the estimated annual incidence rates from 1995 to 1998 in the United States ranged from 2.5 to 4.1 cases per million children, and the 4-year average annual rate was 3.2 per million children. Estimated annual incidence rates by race were 3.4 for white non-Hispanics, 3.3 for African American non-Hispanics, and 2.7 for Hispanics. Girls were affected more than boys (ratio of 2.3:1). Cutaneous ulceration occurring as a result of infarctive vasculopathy and subsequent calcification is more common in the childhood form of the disease.

Environmental factors have been implicated as disease triggers. Seasonality has been noted in both juvenile-onset and adult-onset DM, which suggests the possibility of an infectious etiology. DM- and PM-like syndromes have been reported in patients infected with coxsackievirus, parvovirus B19, Epstein–Barr virus, human immunodeficiency virus, and human T-cell leukemia virus type 1.

Clinically Amyopathic Dermatomyositis

A population-based study in Olmsted County, Minnesota identified 29 patients over a 30-year period with dermatomyositis of which 21% had the clinically amyopathic subtype. The incidence of CADM in the study was 2.08 per million persons.19–24 In Europe, a similar incidence has been observed,25 whereas in Asia, CADM appears to be relatively more common. A retrospective analysis of 28 patients with DM at the National Skin Center in Singapore between 1996 and 1998 revealed that 13 (46%) had CADM.26 In another cohort of 143 Taiwanese patients with IIDM treated in a veterans hospital system, CADM was the second most commonly encountered type of IIDM (14%) after classic adult-onset DM (64%). CADM was somewhat more common than juvenile-onset IIDM (13%) and PM (10%) in this study.27 In Asian patients, adult-onset CADM appears to be more common in males.27 One of the authors (Richard D. Sontheimer) has personally observed an unreported familial constellation of CADM in a father and his only children—two adult daughters. Indirect evidence suggests that CADM has human leukocyte antigen (HLA) associations similar to those found in patients with classic DM (i.e., HLA-DQA1).28

Drug-Induced Dermatomyositis

An increasing number of cases of DM are reported to be caused or exacerbated by systemic medications. A number of different drug classes have been implicated including statin-type cholesterol-lowering agents.31,32 The average incubation time is approximately 2 months. The majority of these cases present with both myositis and pathognomonic cutaneous findings and resolve with discontinuation of the medication. Pulmonary involvement appears to be uncommon in drug-induced DM.33 Long-term hydroxyurea therapy for chronic myelogenous leukemia can produce a DM-like cutaneous eruption that is clinically and histopathologically similar to that of idiopathic DM-specific skin disease.21 This subtype of drug-induced DM is unique in that muscle weakness and other systemic symptoms are absent. Painful leg ulcers are often seen in association, as are xerosis and cutaneous atrophy. This symptom complex usually occurs only after the patient has been treated with hydroxyurea for long periods (2–10 years). The presence of concurrent therapy with hydroxyurea has been proposed as the exclusion criterion for CADM.1

The inflammatory nature of the muscle and skin manifestations coupled with the characteristic humoral autoimmune abnormalities has led to the hypothesis that DM results from a genetically determined, aberrant autoimmune response to environmental agents. Figure 156-2 presents a summary overview of current thought in this area. Like other systemic autoimmune diseases involving autoantibody production such as systemic lupus erythematosus (SLE), DM is thought to evolve through multiple sequential phases: the susceptibility phase, the induction phase, the expansion phase, and the injury phase.

The susceptibility phase of DM is thought to result largely from a genetic predisposition. DM is one of the human autoimmune diseases that is linked to the 8.1 ancestral haplotype (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2).22 PM and DM have been specifically associated with HLA-B8, DR3, and DRw52, especially in white patients. This association is likely a result of linkage disequilibrium with HLA-DQA1*0501. The production of antisynthetase antibodies such as Jo-1 is strongly linked to HLA-DR3 and even more strongly linked to its supertypic specificity HLA-DRw52.

A single nucleotide polymorphism in the tumor necrosis factor-α promoter (TNF-α-308A), which is also a component of the 8.1 ancestral haplotype, has been associated with disease chronicity, calcinosis, and high levels of TNF-α in a cohort of white patients with juvenile-onset classic DM.23 This same TNF-α promoter polymorphism has been associated with photosensitive subacute cutaneous LE.34 This same TNF-α promoter polymorphism has been associated with photosensitive subacute cutaneous LE.24,35 Several gene polymorphisms associated with low production of mannose-binding protein, a molecule involved in the physiologic clearance of apoptotic cells, have been associated with adult DM.24 There has also been a single case report of adult-onset CADM that evolved to classic DM in a young Japanese woman who was shown to be genetically deficient in the fifth component of complement.36

The cutaneous manifestations of DM are precipitated or exacerbated by natural and artificial sources of ultraviolet (UV) light.37 Approximately 50% of patients with DM experience photosensitivity. The action spectrum appears to include both UVB and UVA light. UV radiation intensity has been shown to associate with the proportional incidence of DM compared to other IIMs and correlate with the detection of anti-Mi-2 antibodies in women.38 Environmental stimuli, including UV radiation and infection, could represent inductive factors in DM leading to loss of self-tolerance. Various types of infections have been circumstantially implicated as causative factors in DM. These include infection with RNA viruses such as coxsackievirus, echovirus, and human retroviruses (i.e., human T-cell leukemia/lymphoma virus type 1 and human immunodeficiency virus). Nonviral pathogens such as Toxoplasma gondii have also been implicated. However, repeated attempts to confirm persistent myotropic infection by viruses or other pathogens have not been successful.

The expansion phase of DM is marked by autoantibody production signaling the loss of normal immune regulation. DM is associated with the production of a number of specific autoantibodies that probably predates by some period the first evidence of clinical disease activity (Table 156-1). Whether these autoantibodies are truly pathogenetic or represent only a by-product of muscle injury is unknown. It has been suggested that CADM might be associated with a specific autoantibody profile (antibodies to 140-kDa, 155-kDa, and Se antigens).39,40

It is thought that autoantibodies, immune complexes, and/or autoreactive T cells play a major role in the tissue injury phase of DM. Cell-mediated immune activity against muscle autoantigens is thought to be primarily responsible for the muscle injury that occurs in PM. Both myocytotoxic CD3+ T-cell clones and non-HLA-restricted myocytotoxic cells of other lineages have been identified in the peripheral blood of patients with inflammatory myopathies.41 Little has been done in the past experimentally to date to probe for T-cell-mediated cytotoxic epidermal or dermal cell injury in DM skin lesions.

Predominantly humoral autoimmune mechanisms targeting the microvasculature have been implicated in the pathogenesis of muscle injury in DM. Microvascular ischemia is an early feature of DM muscle involvement. Components of the C5 to C9 membrane attack complex are regularly found in the walls of microvessels in muscle biopsy specimens from DM patients.

There is not always good agreement between the degree of muscle weakness or fatigue experienced by patients with classic DM and the degree of inflammation noted in muscle biopsy specimens and the elevation of serum muscle enzyme levels. This observation has led to the idea that inflammatory cytokines might be capable of mediating metabolic disturbances within muscle that can exacerbate muscle weakness and fatigue.42 As with other rheumatic diseases such as systemic sclerosis, maternal microchimerism has been observed in children with juvenile classic DM.43 The pathogenetic significance of the presence of alloreactive maternal lymphoid cells in the circulation, muscle, and skin of patients with juvenile DM is unknown.

The pathogenesis of cutaneous inflammation in classic DM and CADM and has received little attention, owing in part to the lack of an experimental animal model of this pattern of cutaneous inflammation. Histopathologic analysis of cutaneous DM reveals three general abnormalities: (1) a cell-poor interface dermatitis, (2) a vasculopathy of dermal microvessels, and (3) prominent dermal mucin deposition. These histopathologic elements can be precipitated or exacerbated by exposure to UV radiation.

Approach to the Patient

The approach to a new patient with cutaneous DM is presented in eFig. 156-2.1.

History

In 60% of patients with classic DM, the cutaneous lesions and muscle weakness present simultaneously. In 30% of patients, the cutaneous findings appear before the onset of muscle weakness. In 10%, muscle weakness precedes the appearance of skin lesions. The onset of cutaneous disease is typically accompanied by pruritus and/or a burning skin sensation. Sensitivity to sunlight or artificial sources of UV light is often present. Muscle weakness initially affects the shoulder and hip girdle musculature, presenting clinically as difficulty raising the arms above the head and arising from a sitting position. Weakness can be accompanied by muscle pain and tenderness.

Cutaneous Lesions

Hallmark Skin Lesions

eTable 156-1.1 presents the hallmark cutaneous manifestations of DM (to date, no recognizable differences in the clinical, histopathologic, and immunopathologic manifestations of classic DM and CADM have been reported). Some of these lesions, such as Gottron sign of DM (Fig. 156-3) and Gottron papules (see Fig. 156-4; Fig. 156-5), are pathognomonic of this disease, whereas others, such as periorbital, confluent, macular, violaceous (heliotrope) erythema/edema and grossly visible periungual telangiectasia associated with dystrophic cuticles, are highly characteristic.

The primary skin change of DM is a highly characteristic, often pruritic, symmetric, confluent, macular violaceous erythema variably affecting the skin overlying the extensor aspect of the fingers, hands, and forearms; the arms, deltoid areas, posterior shoulders, and neck (the shawl sign); the V area of the anterior neck and upper chest; and the central aspect of the face, periorbital areas, forehead, and scalp (Fig. 156-6). Central facial involvement can occasionally simulate the appearance of seborrheic dermatitis with nasolabial fold involvement. The lateral aspects of the hips and thighs (holster sign) are also frequently involved.50 Lesions such as poikiloderma atrophicans vasculare (poikilodermatomyositis) and calcinosis cutis are often present in patients with DM but may also appear in patients with cutaneous T-cell lymphoma (poikiloderma atrophicans vasculare) and scleroderma (SCL; calcinosis cutis). In addition, overlapping features of cutaneous DM and cutaneous SCL (see Chapter 155) can occur in the same individual (sclerodermatomyositis).

Several other types of skin lesions have been suggested to be characteristic of IIDM; however, there is not yet enough published experience to determine their true disease specificity or prevalence. The mechanic's hand lesion consists of a nonpruritic, hyperkeratotic eruption accompanied by scaling, fissuring, and hyperpigmentation, which give the false appearance of the callused hands of a laborer. These changes are bilaterally symmetric and distributed along the medial aspect of the thumb and lateral aspect of the index and middle fingers. These hyperkeratotic changes can extend onto the palmar surface. A strong association between this skin lesion and the presence of active myositis and antisynthetase antibodies such as Jo-1 was originally suggested. However, subsequent observations indicate that this same skin change occurs in classic DM without all the elements of the antisynthetase syndrome, as well as in CADM.51–53

Table 156-2 presents the characteristic anatomic distribution of the hallmark cutaneous manifestations of DM. There is very little published information on the prevalence of involvement in these different anatomic locations. In some series reported by dermatologists, Gottron papules have been more commonly seen than periorbital heliotrope erythema, which by many outside of dermatology is felt to be the hallmark cutaneous manifestation of DM.

The violaceous hue of the cutaneous inflammation in lightly pigmented individuals is a striking clinical finding that usually is evident from the outset of disease activity. This hue helps to distinguish cutaneous DM from cutaneous LE, in which it is a late finding when present. It has been suggested that edema associated with the DM skin disease indirectly produces the violaceous hue by displacing the hyperemic cutaneous vasculature more deeply into the dermis. One might also speculate that this could result from the deoxygenation of blood flowing through an abnormal dermal microvascular bed. In this regard, it is interesting to note that cutaneous DM often presents in the skin over joints that is frequently stretched and thus often made to become transiently ischemic under normal physiologic conditions.

A striking clinical feature that helps to distinguish cutaneous DM from cutaneous LE is pruritus, which can be so severe in DM as to be disabling, even in the absence of systemic involvement. In addition to pruritus, DM patients often described severe burning, painful sensations associated with the DM skin inflammation. Some work has suggested that severe DM skin disease can have a greater impact on quality of life than other skin diseases such as psoriasis and atopic dermatitis for which aggressive systemic immunomodulatory therapies are often used.54

A number of other skin changes can be encountered in patients with DM. Hyperkeratosis may follow the onset of the confluent, macular, violaceous erythema; however, the scale in DM skin lesions is usually less prominent than that in subacute cutaneous LE and discoid LE. Secondary skin changes in DM skin lesions include excoriation with secondary infection and ulceration. Subepidermal vesicles and/or bullae occasionally occur in areas of particularly intense cutaneous inflammation. Postinflammatory pigmentary changes, both hyperpigmentation and hypopigmentation, occur. Older lesions may have white lacy markings somewhat similar to those of Wickham's striae in lichen planus. Another similarity between cutaneous DM and lichen planus is the characteristic violaceous hue. Mucinous infiltration, a common histologic finding in the dermis of DM skin lesions, can be clinically prominent, producing an infiltrated, glistening appearance. Superficial erosions and ulcers can subsequently develop over the face and eyelids as well as in other areas affected by intense and protracted inflammation. Deep, irregular, retiform ulcers can also develop in areas of poikiloderma in both adults and children. It has been suggested that the penetrating ulcers reflecting vasculopathy can be a bad prognostic sign in both juvenile-onset and adult-onset DM.

Clinical experience suggests that, as with cutaneous LE/SLE, the activity of IIDM can be precipitated or exacerbated by emotional and physical stress, although there is scant published evidence. Strenuous physical exertion can be detrimental to patients who have active myositis.

Magnetic resonance imaging (MRI) may identify edema/inflammation in skin, subcutaneous tissue, and fascia resulting from vasculopathy and vasculitis in patients with classic juvenile DM.55 In approximately 80% of the 26 children studied, MRI abnormalities indicating skin, subcutaneous, and/or fascial edema were observed. Clinical skin disease activity scores correlated positively with MRI skin edema scores. Five children developed soft tissue calcification in areas previously found to be edematous by MRI after 4–9-month follow-up intervals. These observations suggest that the assessment of soft tissue by MRI could be of value in predicting risk for developing calcification and in monitoring treatment to prevent or minimize it.

DM can develop as a component of an overlap connective tissue disorder. Most common are overlaps with SLE (see Chapter 155) and systemic sclerosis (see Chapter 157). Raynaud phenomenon, sclerodactyly, sclerosis of the skin, and the characteristic hyperpigmentation can all be present in the latter setting. The term sclerodermatomyositis describes the disorder in patients who present with DM and who develop striking features of SCL 6 months to 3 years later. In addition, myositis occurs in approximately 5% of patients who test positive for anti-Ro/SSA autoantibody (most of whom have Sjögren's syndrome (see Chapter 161). The cutaneous manifestations of DM are not usually found in this setting.

The highly pruritic/burning scaling scalp involvement in patients with adult-onset classic DM and CADM that can be associated with nonscarring alopecia56 has also been found to occur in approximately 25% of patients with juvenile-onset DM.30 Localized scalp involvement can at times be the presenting manifestation of DM.

Other Associated Skin Lesions

Systemic Features

Table 156-3 outlines the systemic manifestations and associations of classic IIDM. Most of the extramuscular systemic features associated with classic DM have not been reported in CADM except for arthritis and interstitial lung disease.

Muscle Disease

Muscle involvement typically presents as symmetric weakness of the proximal muscles of the extremities. Lower-extremity weakness manifested as difficulty in performing routine activities of daily living, such as rising from a chair or bathtub and climbing stairs, is often the initial clinical finding. Weakness of the upper extremities soon follows, often manifested by difficulty in raising the arms above the head to perform routine activities such as combing the hair. Pain or tenderness in the affected muscle groups commonly occurs. Some patients experience a fulminant disease course that results in disabling weakness within a few weeks. Weakness involving the upper one-third of the esophagus and/or the laryngopharyngeal muscles may present as dysphagia or a hoarse voice (dysphonia), respectively.

Confirmation that proximal muscle weakness is caused by the inflammatory myositis of IIDM can be difficult, because so many other clinical disorders produce proximal muscle weakness (eTable 156-3.1). The diagnosis can be supported by demonstration of characteristic elevations in serum levels of muscle enzymes (CK, aldolase) as well as identification of diagnostic changes in electromyography (EMG) results, muscle imaging, and muscle biopsy specimens. Some patients with CADM have low-grade, subclinical muscle disease (i.e., hypomyopathic DM). However, in some patients who express the hallmark cutaneous manifestations of DM, no symptoms of muscular weakness have developed for up to 28 years (unpublished personal observation, Richard D. Sontheimer).

Inclusion-body myositis is a pathologically distinctive type of steroid-resistant myositis that more commonly affects the distal muscle groups of men in an asymmetric pattern. Cutaneous involvement is not seen with this disorder or with classic PM.

A retrospective analysis encompassing all patients with DM seen at the Mayo Clinic between 1976 and 1994 revealed that 32 (4%) of 746 patients conformed to the definition of CADM63; 27 had amyopathic DM and 5 had what can be classified as hypomyopathic DM. Follow-up information was available on 16 of the patients with amyopathic DM. Ten had no muscle weakness after 2–10 years, four had no weakness at 1 year, and two developed weakness within 5 years after diagnosis. None of the three patients classified as having hypomyopathic DM showed evidence of muscle weakness 8–17 years after diagnosis. Thus, of these 19 patients with CADM, only 2 developed clinical evidence of myositis after prolonged periods of time. Therefore, the presence of subclinical muscle abnormalities at the time of diagnosis of CADM does not necessarily portend the subsequent development of clinically significant muscle disease.

Although fatigue and/or myalgia without objective evidence of muscle inflammation have been described in a number of CADM case reports, a single case report of documented fibromyalgia occurring in amyopathic DM has now appeared.64 The symptoms of fatigue, muscle pain, and muscle tenderness associated with fibromyalgia could falsely imply the development of myositis in a patient with CADM. There continues to be debate concerning the risk that patients with juvenile-onset CADM will ultimately develop clinically significant myositis. Some groups see a relatively low risk,65 whereas others see a relatively high risk.66 For the definition of CADM to be fulfilled, clinical evidence of muscle weakness should not be present. Muscle strength testing is graded on a scale of 1–5, where 0 = no muscle action; 1 = trace contraction; 2 = visible contraction but with inability to overcome gravity; 3 = fair contraction with ability to overcome gravity; 4 = contraction with ability to offer some resistance; 5 = muscle contraction that cannot be overcome by the evaluator. The examination should focus on the proximal muscle groups that control the neck, shoulders, and hips. Manual muscle testing is reproducible; variables such as pain, contractures, voluntary effort, and motivation may influence the ability of an individual to exert maximal muscle effort.

Pulmonary Disease

Among the most feared nonmuscular systemic manifestations of IIDM is pulmonary disease. Lung function can be compromised in a number of ways in patients with classic DM: by a restrictive lung defect resulting from respiratory muscle weakness; by aspiration pneumonia secondary to gastrointestinal reflux and impaired esophageal muscle function; by opportunistic infections; or by interstitial pneumonitis related to the underlying autoimmune disease process. In addition, some systemic drugs used to treat DM can produce pulmonary complications (e.g., methotrexate hypersensitivity pneumonitis).

Interstitial pneumonitis resulting from both classic DM and CADM has been reviewed.67,68 Between 5% and 40% of patients with classic DM develop interstitial lung disease [high-resolution chest computed tomographic (CT) scan can identify lung involvement earlier than can routine chest radiography]. This complication presents clinically with symptoms of nonproductive cough and exertional dyspnea that are accompanied by bibasilar fine crackling rales. Pulmonary function test results show a restrictive pattern with reduced diffusion capacity. Several clinical patterns of interstitial lung disease have been described: usual interstitial pneumonia, nonspecific interstitial pneumonia, diffuse alveolar damage, and bronchiolitis obliterans with organizing pneumonia.

Interstitial lung disease can present clinically as an acute/subacute type or a chronic type. In the acute/subacute type, patients experience severe, rapidly progressive dyspnea and progressive hypoxemia within a month of the onset of lung involvement. In such cases, the lung disease is often resistant to treatment, and patients are at risk for death. In the chronic type, patients experience a much slower pace of progressive dyspnea. Interstitial lung disease can also be identified by chest CT and/or pulmonary function tests in the complete absence of symptoms. It has been suggested that interstitial lung disease associated with the myositis-specific autoantibodies (antisynthetases) can occasionally occur in the absence of skin and muscle disease.69 In some individuals, interstitial lung disease occurs before the clinical appearance of myositis. Patients with classic DM who have the antisynthetase syndrome (the presence of Jo-1, PL-7, PL-12, or other synthetase autoantibodies; arthritis; Raynaud phenomenon) have increased risk of developing interstitial lung disease. The antisynthetase syndrome and interstitial pneumonitis occur also in children with classic DM. Interstitial pneumonitis and air leakage were observed in one child with classic juvenile DM.70

Interstitial pneumonitis of various subtypes is increasingly being recognized as a potential complication of CADM.29,71 Published data indicate that the prevalence of interstitial pneumonitis in CADM is approximately 13%.29 A disproportionately high percentage of patients with CADM and interstitial lung disease has been reported in Japan related to the fact that interstitial pneumonitis appears to be an especially common complication of classic DM in the Japanese. Curiously, the acute/subacute pattern of disease presentation with rapidly progressive dyspnea, progressive hypoxemia, treatment resistance, and fatal outcome has been observed in CADM patients who develop interstitial pneumonitis and is less common in classic DM patients.72 A recent study from Japan demonstrated a 45% mortality rate in patients with CADM and interstitial lung disease vs. 6% in classic DM with interstitial lung disease.73 However, this difference in mortality has not yet been demonstrated in other patient populations.72

In most cases, interstitial pneumonitis has occurred in patients with CADM in the absence of antisynthetase autoantibodies such as Jo-1, which are considered to be markers for interstitial lung disease risk in patients with classic DM and the antisynthetase syndrome. However, it has been suggested that newly observed autoantibodies to 140-kDa and 155-kDa autoantigens that appear to be highly specific for classic DM and CADM might serve as a marker for interstitial lung disease in Japanese CADM patients.40

The appearance of symptoms of interstitial pneumonitis, especially the acute/subacute type, in a patient with any form of DM should be considered a medical emergency, and the assistance of a pulmonary medicine specialist should be obtained as soon as possible to ensure proper diagnosis and therapy. Aggressive multidrug systemic immunosuppressive therapy is typically required in such cases, and the patient is often admitted to a pulmonary intensive care unit.74

Arthritis

Arthritis occurs in 20% to 65% of patients with juvenile-onset classic DM.75 Typically, this is a nonerosive arthritis involving knees, wrists, elbows, and fingers. It is seen early in the course of the disease. For some patients, arthritis can be a major symptomatic problem. Arthritis also occurs in some patients with juvenile-onset CADM. In one study, three of five patients with juvenile CADM followed over an average of 4.9 years were reported to have arthritis, whereas 49 of 80 children with classic DM had arthritis.75

Relationship between Cutaneous and Systemic Manifestations

Classic Dermatomyositis

Muscle Enzymes

An elevation in the serum level of CK is the most sensitive and specific laboratory indicator of muscle disease activity in IIDM. Ninety percent of patients with classic IIDM have elevated levels of CK at some point. The elevated CK activity is caused primarily by the CK-MM isoenzyme (muscle form of CK); however, elevations caused by the CK-MB isoenzyme (muscle and brain form of CK) are also seen. Elevated levels of CK can be associated with some of the disorders listed in eTable 156-3.1 (e.g., other myopathies, hypothyroidism, and ingestion of certain drugs), as well as with strenuous physical exertion and needle trauma (intramuscular injection, EMG needle insertion). Enzymatic detection of CK activity can at times be inhibited by serum factors. Levels of CK may become elevated before the development of weakness and can normalize several weeks before the return of normal strength during treatment. Patients with IIDM who have normal CK levels may have a worse prognosis with respect to pulmonary disease and associated malignancy. Levels of CK are usually normal in patients with glucocorticoid-induced myopathy.

Serum aldolase level is a somewhat less sensitive indicator than CK for active myositis in IIDM. However, aldolase level is occasionally elevated in the presence of a normal CK level, especially in juvenile DM. Levels of transaminases (aspartate aminotransferase, alanine aminotransferase) and lactic dehydrogenase can also be elevated in active myositis, but these values are less useful clinically because of their low degree of specificity. Elevations of transaminase levels during treatment with methotrexate may reflect the activity of myositis as well as drug-induced hepatotoxicity. Urinary creatine excretion can also be used to monitor the status of myositis. However, the specificity is low because urinary creatine excretion can also be elevated in steroid myopathy. Serum myoglobin levels can also be elevated in severe IIDM.

Autoantibodies

Elevated antinuclear antibody (ANA) levels with human tumor cell substrates are found in 60% to 80% of patients with both classic DM and CADM.29 Autoantibodies of known molecular specificity in DM are now categorized into two groups: (1) myositis-specific autoantibodies and (2) myositis-associated autoantibodies.77,78 Myositis-specific autoantibodies include the antisynthetases [Jo-1, PL-7, PL-12, OJ, Mi-2, and signal-recognition particle (SRP)]. PM/Scl, Ro/SSA (Ro52, Ro60), and U1RNP represent the major myositis-associated autoantibodies. Table 156-1 lists the molecular specificities and clinical correlations of these autoantibodies. The fact that none of the myositis-specific autoantibodies occurs with a prevalence greater than one in five patients with DM makes routine testing for these autoantibodies of little clinical use.

Among the most frequently encountered myositis-specific autoantibodies are those that target the various aminoacyl-transfer RNA synthetases. Of these antisynthetase autoantibodies, autoantibodies to Jo-1 (histidyl-transfer RNA synthetase) are the most common and are found in 20% of patients with classic IIDM overall and 30% to 40% of adult patients with PM. Fever, interstitial lung disease, polyarthritis, Raynaud phenomenon, and incomplete response to therapy occur more often in patients who produce these antibodies (antisynthetase syndrome), as does the mechanic's hand skin lesion. Patients who produce Jo-1 antibodies less frequently display the classic cutaneous manifestations of DM.

SRP antibodies occur in 5% of patients with PM and are more common in those who exhibit acute-onset, severe, treatment-resistant forms of classic IIDM with cardiac involvement. Such patients rarely have any type of skin involvement. Autoantibodies to Mi-2, a nuclear protein complex containing histone deacetylase and nucleosome remodeling activities, are seen almost exclusively in patients with classic DM. Mi-2 antibody is found in 5% to 10% of patients with classic IIDM overall and in 15% to 20% of patients with classic DM. This autoantibody is associated with more treatment-responsive forms of classic DM as well as with the shawl sign and prominent cuticular changes. The clinical correlations of the myositis-specific autoantibodies found in adults (e.g., Jo-1) also occur in children with classic IIDM. IIDM autoantibodies that currently have less clinical significance are also listed in Table 156-1. An autoantibody to a 155-kDa nuclear antigen (transcriptional intermediary factor-1γ)7 has recently been reported to be highly specific for classic DM and CADM. In classic DM patients, this antibody has been suggested to be associated with an increased risk for internal malignancy.79

Other Laboratory Abnormalities

Clinically Amyopathic Dermatomyositis

Special Tests (Including Imaging Studies)

Electromyography

The EMG changes of myositis include a myopathic pattern of the motor unit action potential, a myopathic recruitment pattern, increased insertional activity, and increased spontaneous activity. EMG changes of myositis can be erratically distributed. EMG recordings from the paraspinous muscles can be abnormal when those from the limb girdle musculature are normal. As many as 10% of patients with biopsy-documented myositis have normal EMG findings.

Muscle Biopsy

Muscle fiber degeneration/regeneration, perifascicular atrophy, and capillary injury are frequently present in the muscle biopsy specimens of patients with IIDM. A perivascular infiltrate of T lymphocytes and histiocytes and, occasionally, of B lymphocytes, plasma cells, and eosinophils is also seen. Biopsy specimens from patients with DM often show CD4 T cells and B cells in the perivascular areas, whereas CD8 T cells preferentially associate with damaged muscle fibers in patients with PM. The capillary density in muscle specimens from patients with DM is decreased. Inflammation may be absent in up to 25% of biopsy specimens from patients with otherwise typical muscle disease by clinical, EMG, or biochemical criteria.

An occlusive vasculopathy is a striking aspect of the pathology of juvenile-onset classic DM. Phlebitis and arteritis leading to intimal hyperplasia, fibrinous occlusion of vessels, and infarction of the involved tissues can be seen. The muscles, gastrointestinal tract, and nerves are particularly affected. This vasculopathy in muscles is noninflammatory and occurs predominately in the capillaries. There is a spectrum of endothelial changes from swelling to obliteration to necrosis. In muscles this occlusive vasculopathy is most commonly seen in small vessels, resulting in microvascular ischemia. The local production of interferon-induced angiostatic ELR-negative CXC chemokines has been implicated as a pathogenetic factor in the vasculopathy of juvenile-onset DM.85

Muscle Imaging

Myositic inflammation can be highly focal. A number of noninvasive techniques are currently being examined for their ability to localize affected muscle groups. MRI is the method of choice for diagnostic imaging of muscle abnormalities in patients with myositis.86 However, the MRI signal associated with myositis is not specific for IIDM muscle involvement. The possibility that MRI-guided needle biopsy could obviate the need for the more costly and invasive open muscle biopsy is being explored. In addition, MRI and phosphorus-31 magnetic resonance spectroscopy are also useful in assessing the status of muscle disease activity during treatment with systemic glucocorticoids and other immunosuppressive drugs. These procedures are expensive and cannot be used in some individuals with metallic implants. Less costly approaches to monitoring muscle disease activity, such as power Doppler and grayscale ultrasonography and ultrasonography with contrast material are being examined.87

Functional metabolic changes in muscles identified by magnetic resonance spectroscopy have been especially evident on exercise in some patients with amyopathic DM (such patients would better be classified as having hypomyopathic DM). Artificial neural networks have been proposed as an effective way to analyze the multichannel functional data that result from phosphorus-31 magnetic resonance spectroscopy examination.88 A central issue in this area is whether the subtle muscular abnormalities that can be identified with these sensitive imaging systems have true prognostic value.

(Box 156-1)

In the earlier stages, cutaneous DM might be confused with contact dermatitis, seborrheic dermatitis, lichen planus, psoriasis, polymorphic light eruption, and atopic dermatitis. In the later stages, when the more typical cutaneous manifestations of DM have evolved, the greatest challenge can be to distinguish the skin involvement of DM from that of cutaneous LE, especially acute cutaneous LE and subacute cutaneous LE (Table 156-4).

Periorbital heliotrope erythema and edema can occasionally be observed in SLE, but fully formed Gottron papules are never seen as a cutaneous manifestation of LE. It has been the authors’ experience that, excluding the rare occurrence of hydroxyurea- or statin-induced DM-like skin changes, the concurrent presence of Gottron papules and grossly visible periungual nail fold telangiectasia is pathognomonic of DM skin disease. Pruritus or related dysesthetic symptoms such as burning pain are typical of DM skin inflammation, whereas the various forms of LE-specific skin disease are characteristically not pruritic.

The pattern of involvement over the hands also differs; in LE the skin over the dorsal interphalangeal and metacarpophalangeal joints is spared, and the hair-bearing skin between these joints is preferentially involved. The opposite is true for DM: the skin overlying the dorsal interphalangeal and metacarpophalangeal joints is preferentially affected (see Fig. 156-4). However, when extensive, the linear streaking of violaceous erythema that tracks over the extensor tendons of the hands and fingers can sometimes obscure this point of differential diagnosis.

Poikiloderma commonly occurs in DM patients. Various forms of “poikilodermatous” cutaneous LE have also been reported. However, it has been the authors’ personal experience that most of the patients with “poikilodermatous LE” that have been referred to them have turned out to have CADM. For most physicians outside of dermatology, the absence of clinically evident muscle weakness reflexively prevents further consideration of cutaneous DM, no matter how typical the skin features might be. This confusion is exacerbated by the fact that the majority of CADM patients test positive for ANA.

In addition, multicentric reticulohistiocytosis (see Chapter 148) has been reported to masquerade as DM. However, the “string of pearls” papules that occur in the periungual areas in multicentric reticulohistiocytosis can be clearly distinguished from the periungual inflammatory changes of DM by clinical and pathologic examination. Many conditions other than IIDM can be associated with proximal muscle weakness.89eTable 156-3.1 outlines these disorders.

As previously noted (see Section “Epidemiology”), drugs such as hydroxyurea, penicillamine, niflumic acid/diclofenac, phenytoin, tryptophan, and practolol have been reported in rare cases to produce an eruption with clinical similarities to the hallmark cutaneous features of DM. In addition, statin-type lipid-lowering drugs (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) and other classes of lipid-lowering drugs (fenofibrate, gemfibrozil) are well known to produce a drug-induced myositis and/or rhabdomyolysis that can simulate the myositis seen in DM. However, considering the high rate of usage of these drugs, confirmed reports of statins and other lipid-lowering drugs triggering the hallmark cutaneous manifestations of DM are quite rare. To prove that a case of classic DM or CADM is drug induced would require a rechallenge with the suspected drug once the cutaneous and/or muscle manifestations of DM have remitted. Few patients or physicians would be willing to do this, and the ethics of such an attempt could be questioned.

Cutaneous Ulceration

Cutaneous ulcers are more common in juvenile than in adult classic DM and appear to be quite rare in both juvenile and adult CADM. The skin can ulcerate in DM as a result of a number of different mechanisms. Superficial erosion/ulceration can develop from vesiculobullous changes occurring within intensely inflamed DM skin lesions. Retiform ulcers can result from skin breakdown in poikilodermal areas. Deep penetrating ulcers can result from cutaneous infarction secondary to vasculopathy. The skin can ulcerate as a result of pressure from underlying calcium deposits. In addition, leg ulcers are a component of the clinical constellation of hydroxyurea-induced DM skin changes. Because of their frequent association with vasculopathy, deeply penetrating cutaneous ulcers have traditionally been thought to be a poor prognostic sign. One of the authors (Melissa I. Costner) has noted that deeply penetrating ulcers may correlate with pulmonary involvement in DM.

Systemic Vasculopathy

Clinical manifestations of systemic vasculopathy are seen most often in patients with juvenile-onset classic DM. This can result in perforation of the gastrointestinal tract, ocular damage, and central nervous system damage.

Calcinosis

Extraosseous calcification is also more common in children than in adults with classic DM. As with cutaneous ulceration and systemic vasculopathy, calcinosis is seen less commonly in both children and adults with CADM. The higher rate of vasculopathy that occurs in juvenile DM is thought to be a forerunner of dystrophic calcification. Approximately 25% of children with classic DM have dystrophic calcification at the time of diagnosis, and 40% to 50% develop calcinosis sometime during the course of their illness.

DM patients experience several different patterns of calcinosis. In adults, cutaneous calcification often presents as firm dermal and/or subcutaneous papules or nodules that are often most prominent around the elbows and hands. Large subcutaneous tumoral deposits can also occur over the trunk of adults. Such lesions can be filled with a liquid suspension of calcium crystals (i.e., “milk of calcium”). Four types of calcification have been described in children with DM: (1) a superficial pattern consisting of small, firm nodules and plaques in the skin; (2) periarticular subcutaneous nodules (calcinosis circumscripta); (3) deposition along fascial planes in muscles (calcinosis universalis); and (4) a severe “exoskeleton” pattern of deposition in the subcutaneous tissue. Calcinosis cutis or calcium deposition in muscles and tendons is more common in the late phases of the disease in children. The TNF-α-308A promoter polymorphism might represent a risk factor for developing calcinosis.8 The complications of calcinosis, such as ulceration and sepsis, are a significant cause of both morbidity and mortality in patients with juvenile classic DM.

Internal Malignancy

Population-based studies document that adult-onset classic DM is associated with a higher than expected risk for internal malignancy.90–94 Relative risks for malignancy range from 2.4 in males with DM to 3.4 in females with DM. The risk for malignancies was negligible in patients with PM. During the 5-year period after the diagnosis of DM, the risk of a woman developing ovarian cancer in these studies was 16.7-fold higher than the risk for women without DM. In a more recent study, the standardized incidence ratio for malignancy in adult patients with DM was 6.5.91 In the first year after diagnosis, the relative risk for malignancy in patients with DM was 26.0. Females with DM in this study had a 32-fold higher risk of developing ovarian carcinoma. This study also found that PM was not associated with an increased risk of cancer and that the treatment of DM with cytotoxic drugs did not increase the risk of malignancy. Because of the risk of ovarian cancer in females with DM, it has been suggested that all women with DM (classic DM and CADM) undergo an initial comprehensive gynecologic examination and repeat examinations at 6–12-month intervals for at least the first 2 years after the diagnosis. Determination of serum levels of cancer antigen-125 and transvaginal ultrasonography have been recommended for females with DM who have intact ovaries. However, it is an unfortunate fact that there is no foolproof way to screen for early ovarian cancer.

Tumors other than ovarian carcinoma have been reported with DM, including melanoma, mycosis fungoides, and Kaposi sarcoma. Carcinomas are more frequent than sarcomas, and lymphoproliferative malignancies are uncommon. Except for ovarian cancer in women, no preponderance of specific types of cancer is seen in whites with IIDM. Asian males most frequently develop nasopharyngeal carcinoma.90,91

The diagnosis of cancer is most often made by history, review of systems, physical examination, and routine laboratory and radiologic testing. Debate exists about the routine use of surveillance imaging techniques, such as chest, abdominal, and pelvic CT and/or MRI in this setting. Age appears to be a factor in malignancy risk. There is not a significant risk of occult malignancy in patients with juvenile-onset classic DM,95 whereas individuals 50 years of age or older at the time of onset of classic DM appear to have a definite increased risk of malignancy (20% to 30%). The leading cause of death in patients with IIDM who have malignancy is metastatic spread of the malignancy rather than complications directly related to myositis. In patients with malignancy, the myositis and cutaneous manifestations are less responsive to systemic glucocorticoid therapy. In a few well-documented cases, definitive therapy for the malignancy resulted in resolution of the DM disease activity, and a recurrence of the cancer was associated with the reappearance of DM activity.

Older age, greater extent and severity of skin disease [i.e., intense generalized erythema (“malignancy suffusion”), blistering, ulceration], and elevated CK levels appear to enhance the risk of malignancy in adults with classic DM. It has been suggested that other systemic manifestations of DM, such as interstitial lung disease, are negatively correlated with risk for internal malignancy.27 All routine age- and sex-directed malignancy surveillance guidelines should be followed.

Malignancy Surveillance

Opportunistic Infections and Lymphoma

Early initiation of aggressive systemic immunosuppression is required for both juvenile-onset and adult-onset classic DM. Because DM frequently pursues a chronic and/or recurring course, such patients frequently are exposed to the consequences of long-term use of specific immunosuppressive regimens, including a panoply of opportunistic systemic infections (bacterial, mycobacterial, viral, fungal) and opportunistic infection-induced lymphoma (Epstein–Barr virus infection).96,97

Effects of Pregnancy

Classic Dermatomyositis

General Considerations

Reported mortality rates vary from 25% to 80%, depending on the case mix and the medical era in which the cases were collected.98,99 The 5- and 8-year survival rates for 76 patients with IIDM studied in the 1980s were 80% and 73%, respectively. Global survival rates for the IIDMs have been more reported to be 95%, 92%, and 89% for 1, 5, and 10 years, respectively. Pulmonary and cardiac complications were the most frequent causes of death. Cancer-associated myositis had the worst prognosis, whereas juvenile-onset and overlap myositis had the best. Five- and 10-year survival rates were 94.2% and 89.4% for patients with primary PM and 90.1% and 86.4% for those with primary DM.100 Individuals who receive early systemic treatment for their disease have a better prognosis. The early, aggressive use of glucocorticoids has reduced the mortality rate in children to less than 10%.

Detailed Management Considerations

Clinically Amyopathic Dermatomyositis

Data are not available to allow adequate discussion of mortality in either adult-onset or juvenile-onset CADM. Individual reports of death from occult malignancy and interstitial lung disease in adult-onset CADM have appeared.29

Insufficient long-term follow-up data are available to assess prognosis and clinical course in adults or children with CADM. All six patients in one cohort with adult-onset disease who initially had only skin disease and who were treated conservatively ultimately developed muscle disease.101 In another cohort, none of the five adults with CADM treated aggressively with high-dose systemic glucocorticoids developed clinical evidence of myositis.102 Both of these small case series could have suffered from case selection/publication bias.

A systematic review of adult-onset CADM identified 291 cases among which there was a 13% incidence of interstitial lung disease and 14% incidence of associated internal malignancy.29 However, this compilation of individual case reports and small case series is likely to have also been affected by reporter bias. Population-based studies of the epidemiology and management of CADM are greatly needed to address this and other clinical issues relating to this subtype of DM.

One study has suggested that patients with juvenile-onset DM who have only the cutaneous manifestations are usually not treated aggressively and may frequently develop pathologic calcifications.66 This report is contrary to the findings of other studies of CADM in both children65 and adults,25,63 which have indicated that this mode of presentation is usually not associated with a high rate of subsequent dystrophic calcification. One study, indicating that both rheumatologists and dermatologists tend to be conservative in treating patients with CADM,65 also reported that a high percentage of patients with juvenile-onset CADM enjoy spontaneous remission without systemic immunosuppressive treatment.

The following discussion of the clinical management of DM skin disease is the product of published anecdotal observation by others, expert opinion by others, and the personal clinical experience of the authors. The goals of treatment of DM are to arrest inflammation in the skin and muscles and obtain a clinical remission. Improvement of both the clinical and laboratory features of the disease should be objectively monitored incrementally over time during treatment. The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) appears to be a reproducible assessment tool to measure change in the cutaneous features of DM during treatment.103

The treatment of CADM patients differs from that of classic DM patients only in the absence of the need to treat symptomatic inflammatory myositis. The cutaneous manifestations of classic DM and CADM respond similarly to aggressive systemic immunosuppressive therapy; however, this therapy is difficult to justify in some cases of CADM when nonimmunosuppressive topical and systemic measures might be of benefit.

Local Treatment

Patients with either classic DM or CADM should avoid excessive sun exposure and use effective broad-spectrum sunscreens. An in-depth discussion of practical and theoretical photoprotection and local therapy for autoimmune connective tissue skin disease such as DM has been presented elsewhere.104 However, efforts should be made to insure that vitamin D deficiency does not occur.

Topical glucocorticoids (classes I and II) can dampen cutaneous inflammation and pruritus, and such agents can be used safely for prolonged periods of time when administered cyclically (2 weeks of daily treatment followed by 2 weeks off treatment). However, these agents alone usually cannot fully suppress DM skin disease activity. Daily use of a medicated shampoo followed by application of a topical class I and II glucocorticoid solution, gel, spray, or foam to the affected areas can provide relief for scalp pruritus. Xerosis is often present, especially in the elderly, and effective moisturization regimens can be of value in managing the pruritus often experienced by patients with DM. Topical antipruritic agents such as combinations of menthol/phenol/camphor, pramoxine, and doxepin can provide short-term relief.

Pulsed dye laser therapy has been advocated for the cosmetic treatment of the residual poikilodermatous skin changes that can follow in the wake of active cutaneous DM.105

Systemic Treatment

When nonimmunosuppressive systemic therapy is possible, its use should be maximized. Nonsedating or sedating antihistamines can be used during the day as appropriate. Doxepin, a tricyclic antidepressant, is a potent H1 and H2 receptor-blocking antihistamine. When given at bedtime in doses of 10–50 mg titrated to the degree of somnolence the next morning, this long-acting antihistamine can ameliorate the pruritus and excoriation that often occur during sleep. The addition of cimetidine 200–400 mg four times daily for its histamine H2 receptor-blocking ability can also be helpful. With the appropriate precautions, oral naltrexone and mirtazapine may be used to treat the intractable pruritus and burning sensations that can be seen in this setting.

Antimalarials

Hydroxychloroquine sulfate (6 mg/kg given as two divided doses per day) has been used to treat DM skin disease. Hypersensitivity reactions to hydroxychloroquine may occur at higher frequencies in DM patients than in other patient groups.106

Some DM patients will respond better to a combination of hydroxychloroquine and quinacrine, 100 mg/day, or to chloroquine (3.5 mg/kg/day) and quinacrine (100 mg/day)107 than to hydroxychloroquine alone (see Fig. 156-3). However, even combination antimalarial therapy will not adequately control the cutaneous symptoms of many DM patients. Precautions should be taken to minimize the risk of retinal toxicity with hydroxychloroquine or chloroquine and of hematologic toxicity with quinacrine. If extrapolation from the experience gained from patients with cutaneous LE is valid, patients with DM who smoke cigarettes may be less responsive to antimalarial therapy than those who do not smoke. On rare occasion, antimalarials can contribute to muscular weakness by causing a toxic vacuolar myopathy. Other nonimmunosuppressive systemic therapies may benefit in cutaneous DM include dapsone108,109 and antiestrogen therapy.110

Systemic Glucocorticoids

Systemic glucocorticoids remain the traditional first-line therapy for classic DM. Early intervention with systemic glucocorticoids is associated with a better overall prognosis. In adults, prednisone (prednisolone for those with decreased liver function) is given orally in divided doses of 1.0–1.5 mg/kg/day, whereas in children the dosage is 1–2 mg/kg/day. Significant improvement of muscle strength, normalization of muscle enzyme levels, and improvement in cutaneous inflammation are the endpoints of therapy. Most patients require 1–3 months of full-dose treatment with prednisone. When symptoms improve, the dose can be consolidated from a divided dose to a single daily dose given in the morning to reduce the risk of adrenal suppression and other glucocorticoid side effects. The glucocorticoid dosage can then be progressively decreased. Treatment should be continued for 12 to 24 consecutive months to minimize the chance for recurrence. Attention should be paid from the outset to managing the side effects of long-term systemic glucocorticoid use such as osteoporosis. Calcium loss from bones starts within the first 3 months after initiation of systemic corticosteroid therapy.

In acutely ill patients, intravenous pulse therapy with methylprednisolone can be used. This approach has become increasingly popular in the management of juvenile DM. Alternate-day glucocorticoid administration usually does not provide adequate relief during active phases of the disease. The cutaneous lesions of DM can be refractory to high-dose, long-term glucocorticoid therapy in some patients. Other patients have recrudescent disease activity only in the skin after complete suppression of muscle disease with systemic immunosuppressive therapy.

Systemic glucocorticoids and other systemic immunosuppressives can be used to treat disabling skin disease activity in patients with CADM. However, it remains to be determined whether early aggressive immunosuppressive treatment of CADM might prevent the subsequent development of clinically significant myositis in the minority of CADM patients in whom this occurs.

Approximately 25% of patients with classic DM do not respond adequately to systemic glucocorticoids within the first 2 months of treatment. Azathioprine (2–3 mg/kg/day), cyclophosphamide (1–2 mg/kg/day), methotrexate (7.5–50 mg/week), chlorambucil (2–6 mg/day), cyclosporine (3–5 mg/kg/day), and mycophenolate (1–3 g/day) have been used in this setting in patients who cannot tolerate the side effects of prolonged high-dose glucocorticoid therapy.

Methotrexate, Cyclosporine, Mycophenolate Mofetel, and Cyclophosphamide

Methotrexate (7.5–25.0 mg) given once weekly by mouth has been successful in the treatment of patients with classic DM and some patients affected primarily by the cutaneous manifestations of DM. Higher dosages can be given subcutaneously or intravenously; administration by the intramuscular route may cause spurious elevation of muscle enzyme levels. Cyclosporine and cyclophosphamide have each been reported to be of benefit in treating severe complications of interstitial lung disease in patients with CADM, especially when started before frank respiratory failure has developed.111,112 In children, oral cyclophosphamide (2–4 mg/kg/day) has traditionally been used in cases that could not be managed satisfactorily with systemic glucocorticoids. Mycophenolate mofetil has been tried with some effectiveness in recalcitrant DM.113 There are also early indications that it may be beneficial in the setting of interstitial lung disease.114 High-dose intravenous γ globulin therapy has been used in both children and adults in this setting and has the advantage of low toxicity. Plasmapheresis and leukapheresis appear to have little additional value in the management of IIDM.

Antitumor Necrosis Factor-α and Other Immunobiologic Agents

Based on experimental evidence indicating a role for TNF-α in the pathogenesis of the muscle inflammation in classic DM, anti-TNF-α therapy has been used anecdotally to treat both the muscular and cutaneous manifestations of DM. A small number of cases of severe, therapy-resistant DM have been successfully treated with etanercept (Enbrel) or infliximab (Remicade).115 More systematic study is needed to define the value of this treatment. Such therapy would have to be used with caution because of the possibility of its uncovering other patterns of systemic autoimmunity (e.g., SLE). In addition, anecdotal reports have appeared suggesting benefit from the use of rituximab, a depletor of memory B cells, in patients with therapeutically refractory DM.116,117

B cells have also been implicated in the pathophysiology of DM. Studies of therapy with rituximab (a CD20 B cell-depleting antibody) have provided encouraging results in patients whose disease responded poorly to other treatments.117,118

Additional Management

Passive range-of-motion exercise should be provided early in the disease course to prevent disabling joint contractures, especially in children. Once disease activity is suppressed medically, an active exercise program can facilitate the return of normal strength.

Surveillance for the detection of occult malignancy was discussed earlier in Section “Internal Malignancy.” In addition, changes in the clinical status of the respiratory, cardiovascular, and gastrointestinal systems should be evaluated carefully for the possibility of systemic disease activity in these target organs.

Treatment of Clinically Amyopathic Dermatomyositis

Current approaches to the treatment of adults and children with CADM are based on anecdotal observations of individual cases or a relatively small case series. One approach has been to treat patients with CADM aggressively from the outset with systemic glucocorticoids in the hope that progression to systemic involvement might be delayed or prevented.102 This approach is supported by studies of patients with both juvenile- and adult-onset classic DM, which indicate that early systemic immunosuppressive treatment can lessen long-term disability from muscle dysfunction and complications such as calcification. However, in the large majority of published reports to date, a more conservative approach has been taken to the treatment of CADM.20,29,124 This approach is validated by reports of patients with CADM who go 10 to 28 years and longer without any sign of disease activity or damage other than in the skin.1,63,64,125

Until it is confirmed that adult patients with CADM do not have a significantly increased risk of internal malignancy, they should be evaluated for this potential complication in a manner similar to for patients with classic DM. Because internal malignancy has not been reported to be associated with juvenile-onset classic DM or CADM, it can be assumed that routine evaluation for internal malignancy is not indicated in this population.