Rudolph's Pediatrics, 22nd Ed.

CHAPTER 205. Juvenile Dermatomyositis

Lisa G. Rider

Juvenile dermatomyositis (JDM) is a systemic autoimmune disease characterized by chronic skeletal muscle and cutaneous inflammation of unknown cause.1,2 Symptoms generally begin before age 18. JDM is relatively responsive to immunosuppressive therapy, and rapid diagnosis, and institution of adequate therapy improves outcomes.

JDM is the most common clinical subset of a larger family of disorders known as the idiopathic inflammatory myopathies (IIM) (Table 205-1).1,3,4 Juvenile polymyositis (JPM), which constitutes 2% to 8% of childhood myositis cases, has similar features without the characteristic cutaneous manifestations, but may have more severe and distal weakness. Overlap myositis, constituting 3% to 10% of childhood IIM, occurs when JDM or JPM is associated with another autoimmune disease, such as systemic lupus erythematosus, scleroderma, juvenile idiopathic arthritis, systemic vasculitis, or type I diabetes mellitus. JDM and JPM also have been reported in combination with primary immunodeficiencies such as Wiskott-Aldrich syndrome and common variable immunodeficiency, without apparent infectious triggers. Other clinical forms of IIM have been described in children, including dermatomyositis sine myositis, and focal, orbital, cancer-associated, eosinophilic, inclusion-body, and granulomatous myositis, but these subsets occur in fewer than 1 in 1 million children and are not discussed here.

The juvenile IIM also may be classified based on the presence of certain autoantibodies that are present specifically in myositis patients (myositis-specific autoantibodies), and others that are present in myositis patients as well as patients with other autoimmune diseases (myositis-associated autoantibodies). New specificities continue to be recognized. These autoantibodies tend to aid in defining patients with similar clinical and demographic features, as well as predicting immunogenetics, responses to therapy, and prognosis (Table 205-2).3,4 They are being recognized increasingly in juvenile IIM, currently with 40% to 50% of juvenile IIM patients having a defined specificity.

Table 205-1. Clinical Classification of the Juvenile Idiopathic Inflammatory Myopathies (IIM)

EPIDEMIOLOGY

The annual incidence of juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM) ranges from 1.5 to 5 cases per 1 million children in various countries around the world, with an estimate from a national United States registry of new-onset JDM cases of 3.2 cases in 1 million children per year.1,5 JDM and JPM are 3.5- to 5-fold less common than adult DM and PM. JDM has a median age of onset at approximately 7 years, with a bimodal age distribution peaking at 3 to 7 years and during the early teenage years. Girls are affected 2 to 4 times more frequently than boys. The incidence is similar in different racial groups, with the overall racial distribution similar to that of the general population.

GENETICS AND PATHOPHYSIOLOGY

The pathogenesis of JDM appears to involve chronic immune activation in genetically susceptible individuals following exposure to specific environmental triggers. Evidence for genetic risk factors include an increased prevalence of other autoimmune diseases in relatives of IIM patients and rare families in which more than one relative develops an IIM.6,7 The major histocompatibility locus HLA B8-DRB1*0301-DQA1*0501 is the chief risk factor for JDM in Caucasian patients, with DQA1*0301 an additional risk factor for JDM.8-10

Group A beta-hemolytic streptococci has been associated as a risk factor in a case control study, while other organisms, including coxsackievirus B, influenza, parvovirus, and toxo-plasma, have been variably associated with JDM onset and inconsistently detected in affected muscle by polymerase chain reaction.15,19-21

Pathologically, affected muscle and cutaneous tissues demonstrate chronic perivascular and perimysial inflammation, with a predominance of plasmacytoid dendritic cells, CD4+ T cells and macrophages.1,23-25 Gene expression profiling studies have revealed a correlation between type I interferon inducible genes and disease activity in JDM and other inflammatory myopathies.26-28 Further supporting a role for these cytokines in the pathogenesis of inflammatory myopathies is the fact that IL1-α and IL-1β, which are the primary cytokines present in inflamed muscle of adult IIM patients, are produced by the infiltrating inflammatory cells as well as by ischemic muscle fibers and endothelial cells. TNF-α and transforming growth factor–β, as well as a number of other pro- and anti-inflammatory cytokines, are also variably produced by affected muscle.29

A number of promoters and inhibitors of angiogenesis are also overexpressed in the affected muscle tissue of inflammatory myositis, as are genes promoting endothelial differentiation and activation.24 In JDM, angiostatic chemokines are increased in expression and correlate with the degree of capillary loss.30 Upregulation of leucocyte adhesion molecules on the muscle arterioles and venules, particularly ICAM-1, results in the infiltration of B and CD4+ T lymphocytes, dendritic cells and macrophages.24 Proinflammatory cytokines result in damage and further infiltration of cells.

CLINICAL FEATURES AND COMPLICATIONS

JDM patients most often present with rash followed by muscle weakness.31,32 JDM is a systemic disease, with involvement of a number of organ systems (see eTable 205.1 ). Symptoms commonly develop over a period of weeks to months, although the disease may occasionally present acutely.

Muscle weakness is characteristically progressive and chronic, involving the proximal limb and axial muscles, although distal muscle weakness is evident in more severely affected children. The first symptom of JDM may be fatigue, decreased endurance, or muscle pain.33,34 A subtle decrease in activity and inability to keep up with peers in sports and play activities may be followed by progressive inability to perform daily life activities involving the proximal and axial muscles, such as climbing stairs, combing or shampooing the hair, bathing, and dressing, Ultimately, after weeks or months, the child may become unable to rise from a chair or bed. Many children exhibit the Gower sign, with difficulty rising from the floor due to hip extensor weakness, using the hands to climb up the legs as an aid. Weakness progresses at a variable and unpredictable pace in different children and not all patients reach the most severe stages.

Table 205-2. Myositis-specific and Myositis-associated Autoantibodies in Myositis

Characteristic rashes of JDM include the heliotrope (Fig. 205-1), a faint lilac to erythematous discoloration over the eyelids. This may be accompanied by periorbital edema and by Gottron papules, erythematous plaques on the extensor surfaces, particularly overlying the small joints of the hands (Fig. 205-2), but also frequently over the elbows, knees (eFig. 205.1 ), and ankles. One of these characteristic rashes is present in virtually all children with JDM.31,33 Periungual capillary changes, including dilatation, dropout, and tortuosity, are seen in over 90% of patients. These may reflect vasculopathy and active disease in other organs, particularly in the skin (eFig. 205.2 ).35Overgrowth of the cuticle onto the nailbed also may be seen. Malar and facial erythema, and erythematous rashes involving both sun-exposed and covered areas, are also common. Cutaneous ulceration, resulting from vasculopathy of dermal vessels, is a serious complication associated with a more severe illness course,36 but is seen in less than 30% of patients.

Dystrophic calcification of the skin, subcutaneous tissue, or muscle, often at pressure point sites, is seen in 16% to 43% of JDM patients (eFig. 205.3 ).37-39 Its development is associated with a delay in diagnosis and treatment, more severe disease, as well as cardiopulmonary involvement, and it typically becomes evident beginning 1 to 3 years after illness onset.39-40 Cellulitis, skin breakdown, joint contractures, or ulceration may develop at the sites of these deposits.40 Calcinosis may resolve over an unpredictable time frame; continued progression of calcifications, on the other hand, generally is indicative of ongoing active disease.

Involvement of the striated and smooth muscle of the gastrointestinal tract, resulting in difficulty swallowing or handling secretions, is a sign of severe disease requiring aggressive treatment. Subclinical abnormalities on modified barium swallow examination may be seen in up to 80% of JDM patients.41 Such patients are at risk for aspiration pneumonia. Vasculitis of the gastrointestinal tract, observed in less than 10% of JDM patients, may result in severe abdominal pain, gastrointestinal bleeding, or perforation.42 Abdominal pain that is persistent, progressive or severe should be carefully evaluated, and stool should be tested for occult blood. Children not at imminent risk of perforation may undergo barium examination or contrast-enhanced computed tomography, which may demonstrate dilation or thickening of the bowel wall, intra-luminal air or evidence of bowel necrosis.43 Lower gastrointestinal tract dysmotility, resulting in constipation, abdominal pain, or bloating, also may occur as a result of smooth muscle involvement.

FIGURE 205-1. Heliotrope rash, a purplish discoloration over the eyelids with associated periorbital edema, which is characteristic of dermatomyositis. This child also has a malar rash.

Palatal involvement leading to hoarseness and dysphonia is seen in up to 45% of patients.31,33 Respiratory muscle weakness with dyspnea on exertion and restrictive lung disease is common,44 but interstitial lung disease is relatively infrequent in juvenile IIM. Arthritis is present in two thirds of patients, and typically involves the knees, wrists, elbows, or interphalangeal joints.45 Contractures of large joints often accompany severe, persistent muscle weakness or may be seen in isolation. Tenosynovitis also may be present. Constitutional symptoms, including fatigue, fever, Raynaud phenomenon, and lymphadenopathy, may be noted, particularly at the onset of illness.

FIGURE 205-2. Gottron papules. Raised erythematous plaques over joint extensor surfaces, here over the finger joints, which are generally symmetric and characteristic of dermatomyositis.

Growth failure and osteoporosis are common, resulting from prolonged treatment with glucocorticoids, as well as from active disease.46 Insulin resistance and hyperlipidemia, in isolation or in conjunction with partial or total lipodystrophy (eFig. 205.4 ), increasingly has been recognized in association with longstanding, active JDM.47,48

Laboratory abnormalities include elevated serum levels of muscle enzymes, including creatine kinase, transaminases, lactate dehydrogenase, and aldolase. Creatine kinase (CK) often returns to normal early in the illness, so the other enzymes need to be followed in order to monitor disease activity later in the disease course.49 Two international collaborative study groups have standardized and validated measures of disease activity and disease damage.50

DIFFERENTIAL DIAGNOSIS

Conditions in the differential diagnosis include those with isolated weakness, those in which weakness may be associated with cutaneous and even systemic manifestations, and isolated skin conditions that are often confused with the characteristic JDM findings of Gottron papules and heliotrope rash (Table 205-3).1 Children presenting with signs of a myopathy without cutaneous involvement should have other inflammatory and noninflammatory myopathies excluded prior to establishing a diagnosis of JPM. Noninflammatory myopathies that may mimic JPM include muscular dystrophies, metabolic myopathies, mitochondrial myopathies, and endocrinopathies (see Chapter 572). Neurologic illnesses, as well as drug-induced myopathies, should also be excluded.

There are several helpful clues in the history, physical examination, and laboratory testing that may aid in discriminating the IIM from other myopathies.51 Patients with an IIM often have a family history of autoimmunity, which is not typical of patients with other myopathies. Patients with JDM and other IIM generally have symmetric, chronic proximal and axial weakness, which contrasts with other myopathies where the weakness can be related to activity or fasting, or involve different muscle groups, such as facial or scapular muscles. Patients with myositis develop muscle atrophy after chronic symptoms, whereas patients with other myopathies develop early muscle atrophy or even muscle hypertrophy. Patients with other myopathies may develop cramping, fasciculations, or an associated neuropathy, although these all rarely present in patients with IIM. Patients with IIMs often have signs of systemic connective tissue diseases, including fevers, arthritis, periungual capillary nailfold changes, and photosensitive skin rashes. In myositis patients, serum levels of the enzymes tend to be mildly to moderately elevated, but rarely are they all normal or markedly elevated, as in other myopathies. Up to 70% of juvenile IIM patients have a positive antinuclear antibody, and patients, particularly those with overlapping systemic sclerosis, often have extractable nuclear antibodies.9 Finally, children with IIM typically respond to corticosteroids and other immunosuppressive agents, whereas patients with noninflammatory myopathies respond poorly or not at all.

Table 205-3. Differential Diagnosis of Childhood Idiopathic Inflammatory Myopathies (IIM)

Benign acute childhood myositis is a self-limited illness presenting acutely following a prodromal infectious illness in which myalgias, distal lower extremity weakness, elevated serum muscle enzymes, myoglobinuria, and leukopenia are seen.52 It is associated with infectious agents such as influenza, coxsackievirus, varicella, adenovirus, herpes viruses, and mycoplasma. Pyomyositis resulting from Staphylococcus aureus and Group A Streptococcus pyogenes is a localized infection frequently involving thigh or hip muscles, associated with fever as well as muscle pain and tenderness.53Infectious myositisfrom hepatitis B, HTLV-1, and parasitic infections may present with symptoms and biopsy findings identical to those of JPM.4

Steroid myopathy should be considered in IIM patients treated for prolonged periods with high-dose glucocorticoids, particularly in patients experiencing an insidious progression of proximal muscle weakness of the pelvic girdle muscles who have normal serum muscle enzymes and other associated corticosteroid toxicities. Characteristic MRI changes may help distinguish active muscle inflammation from steroid myopathy.5

DIAGNOSIS

The diagnosis of JDM is often made using the classification criteria of Bohan and Peter,54 which require the presence of the characteristic skin findings of heliotrope rash or Gottron papules. An additional 2 of the other 4 criteria are necessary to classify a patient as having “probable” JDM, three to qualify as having “definite” JDM (Table 205-4). Other forms of myopathy must be excluded to confirm a diagnosis. Only 56% of pediatric rheumatologists surveyed internationally use EMG and only 61% use muscle biopsy in diagnosing JDM, suggesting that many patients with a diagnosis of JDM could only be called “probable” by the Bohan and Peter criteria.55 New classification criteria for myositis are under development.

A diagnosis of “probable” JPM requires the presence of three criteria, and “definite” JPM requires four criteria.54 JPM is characterized by weakness without the characteristic rashes of JDM, making differentiation from other myopathies more difficult. Thus, it is recommended that patients suspected of having JPM undergo a muscle biopsy. Further, only two thirds of affected children will have elevated creatine kinase (CK) enzyme activity levels in the serum at the time of diagnosis, so other myositis-associated enzymes, including aldolase, transaminases and lactate dehydrogenase should also be measured.31 Even with treatment, muscle enzymes may return to normal more slowly than in JDM.56

Magnetic resonance imaging of the thigh muscles is useful in confirming a diagnosis, selecting a site for a directed muscle biopsy, and assessing disease activity when the extent of myositis is unclear.57Edema in the muscles, myofascia, subcutaneous tissue, or skin may be evident on the short tau inversion recovery (STIR) or fat-suppressed T2 images during active phases of illness (eFig. 205.5A ), whereas T1-weighted images may demonstrate muscle atrophy and fatty infiltration (eFig. 205.5B ).58 Although muscle edema is nonspecific, many rheumatologists use MRI in confirming a diagnosis of IIM, particularly when the characteristic rashes are present.55

Over 70% of JDM patients have a positive antinuclear antibody, and the presence of a myositis-specific autoantibody may also aid in confirming a diagnosis in the almost 40% of childhood IIM patients who demonstrate these markers.4,59 These are autoantibodies to cellular translational proteins found only in patients meeting diagnostic criteria for an IIM. Tests for myositis-specific and myositis-associated autoantibodies using immunoprecipitation and immunodiffusion methods are reliable. Although the data in juvenile IIM are preliminary and based upon small numbers of patients, the epidemiological and clinical features as well as therapeutic responses for each of these autoantibody subsets appear to be distinct and have many similarities to those of corresponding subsets of adult IIM patients (Table 205-2).3Juvenile and adult IIM patients with antisynthetase autoantibodies, for example, have severe muscle weakness frequently in association with arthritis, fever, interstitial lung disease, Raynaud’s phenomenon, and mechanic’s hands.60 Myositis often flares in these patients when glucocorticoids are reduced, and they often require cytotoxic therapies and have a chronic illness course. Juvenile and adult PM patients with antisignal recognition particle autoantibodies have severe proximal and distal weakness and extremely elevated serum creatine kinase. They often have a chronic illness course and require multiple cytotoxic therapies, responding poorly to most treatments.60

Recently, a new myositis-associated autoantibody, anti-p155, has been detected through protein immunoprecipitation in 23% to 30% of JDM patients, 20% of adult DM patients, and in the majority of patients studied with cancer-associated DM.11,59,61 Patients with this autoantibody have typical DM features with prominent rashes. Pediatric patients tend to have more extensive cutaneous involvement, including an increased frequency of cutaneous ulcerations and subcutaneous edema.11,59

TREATMENT

A general treatment algorithm for JDM is provided in eFigure 205.6  The goals of treatment include eliminating inflammation of the muscle, skin, and other involved organs; treating and preventing acute life-threatening complications; restoring muscle strength and function; and preventing complications, such as calcinosis and osteoporosis.4,63 Therapy must be tailored to each individual patient according to disease severity, prognostic factors, as well as the likelihood for adverse events from medications. Risk factors for poor prognosis include severe disease activity, ulceration, calcification, severe dysphagia, interstitial lung disease and cardiac involvement, certain myositis-specific autoantibodies (anti-aminoacyl-tRNA-synthetases and antisignal recognition particle autoantibodies), muscle biopsy features, delay to treatment, and persistent skin disease activity.3,35,37,39,64

Table 205-4. Criteria for the Diagnosis of Dermatomyositis and Polymyositis

Definite disease: for dermatomyositis, inclusion of the rash, and presence of 3 other criteria; for polymyositis, exclusion of rash and presence of the other 4 criteria.

Probable disease: for dermatomyositis, inclusion of the rash, and presence of 2 other criteria; for polymyositis, exclusion of rash and presence of 3 other criteria.

1. Symmetric, often progressive proximal and axial weakness

2. Characteristic rashes of dermatomyositis (required)

a. Scaly, erythematous papules over the metacarpophalangeal or interphalangeal joints, elbows, knees or medial malleoli (Gottron papules), OR

b. Purplish or erythematous discoloration of the eyelids (heliotrope rash)

3. Elevation of serum levels of muscle-associated enzymes, including creatine kinase, aldolase, lactate dehydrogenase, transaminases

4. Characteristic electromyographic changes in a triad, including

a. Short duration, small, low-amplitude polyphasic potentials

b. Fibrillation potentials, positive sharp waves and insertional irritability, present even at rest

c. Bizarre high-frequency repetitive discharges

5. Evidence of chronic inflammation on the muscle biopsy, including the presence of necrosis of type I and type II muscle fibers, degeneration and regeneration of myofibers with variation in myofiber size, perivascular and interstitial infiltration of mononuclear cells, and perifascicular atrophy

These criteria require exclusion of all other forms of myopathies.

Data from Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292: 344-347. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292: 403-407.

Daily corticosteroid therapy is the foundation of treatment for JDM. It has contributed to a significantly improved prognosis, including a decrease in mortality from 40% in the pre-steroid era to the current rate of under 1%.37Prednisone is commonly started in the range of 1 to 2 mg/kg daily, often in two or three divided doses, then consolidated and slowly reduced over months as serum muscle enzymes return to normal and strength improves. It may be continued for 18 months or longer if the illness remains active; premature dose reduction or discontinuation often results in myositis flares and calcinosis.

Many pediatric rheumatologists are also using intravenous pulsed doses of methylprednisolone (10–30 mg/kg) and/or methotrexate (0.3–1 mg/kg/week) as part of the first line of therapy. Several retrospective and uncontrolled prospective studies suggest that early introduction of methotrexate reduces the frequency of calcinosis and decreases the likelihood of a chronic disease course.65,66 Patients receiving methotrexate from the start of the illness are also able to reduce corticosteroid dosages more quickly, and therefore are less likely to experience corticosteroid related side effects, including cataracts, weight gain, and impairment in height velocity.70 Treatment benefit is apparent within 4 to 8 weeks, and methotrexate may be effective for treating cutaneous disease.71 Intravenous pulse methylprednisolone is often used to obtain rapid control of symptoms and to reduce toxicity from long-term, high-dose daily oral corticosteroids.67,68 Parenteral administration also may improve bioavailability compared to oral preparations, the absorption of which can be decreased in JDM patients due to gastrointestinal vasculopathy.69 The majority of JDM patients respond at least partially to first-line therapies.

Additional first-line therapies in the management of JDM include introduction of photo-protective measures such as sunscreen and sun avoidance, use of topical steroids and hydroxychloroquine for cutaneous manifestations, and the administration of supplemental calcium and vitamin D for patients with inadequate dietary intake.2 Physical therapy is an integral part of first-line management to maintain and restore muscle strength and endurance, and improve and prevent joint contractures. During active myositis, passive range of motion exercises and pool therapy are used. Once the disease is stabilized, isometric exercises, later followed by isotonic and resistive exercises, are suggested.72 As control continues to improve and the illness approaches remission, it is often necessary to rebuild aerobic exercise capacity.73,74Graded exercise does not appear to induce disease flares.75

Second-line therapies should be considered in refractory patients, patients with unacceptable corticosteroid toxicity, in patients with more severe manifestations, or in patients with risk factors for a poor prognosis.4 Intravenous immunoglobulin (IVIG) is particularly useful in acute settings for patients who are seriously ill or at high risk for infection. IVIG may be useful as a short-term agent in JDM, particularly in treating severe cutaneous disease or in treating certain subsets of patients with infectious triggers. It has been found to be efficacious in a randomized placebo-controlled trial in adult DM at a dose of 1 gm/kg on each of two days each month.76 Cyclosporine (2.5–7.5 mg/kg/day) shows promise as a steroid-sparing agent in steroid-refractory patients, including the treatment of DM rashes.77Azathioprine (3–5 mg/kg/day), which has response rates comparable to those of methotrexate, is often reserved for more refractory patients since the onset to peak treatment effect is delayed for up to 4 months. In addition, azathioprine has a relatively high incidence of gastrointestinal intolerance and leucopenia, as well as a greater risk of secondary malignancies.4

For patients with extremely recalcitrant disease, combinations of second- and/or third-line therapies may be used. Anecdotal reports, primarily in adult patients, support the use of oral tacrolimus, mycophenolate mofetil and intravenous cyclophosphamide for patients with severe, refractory disease.78-80 Anecdotal cases and small open label trials suggest favorable responses to rituximab, a monoclonal antibody directed against B lymphocytes, in patients with severe, refractory disease.81,82 Responses to antitumor necrosis factor alpha agents have been mixed.83 Newly available biologic therapies that have been successful in the treatment of other immune-mediated diseases have not yet been tested in patients with myositis.

Amelioration of underlying myositis disease activity is important in the prevention of calcinosis.40 Colchicine has been effective in reducing the acute inflammation associated with dystrophic calcification. No controlled studies have been conducted for treating calcinosis. In severe circumstances, surgical removal may be attempted once the myositis is quiescent. On the other hand, progression of calcinosis is de facto evidence of active disease.

PROGNOSIS AND OUTCOME

Whereas data on long-term outcome are limited, prompt diagnosis and treatment have dramatically reduced mortality rates.37 Approximately 37% to 60% of JDM patients recover from the illness within two years without clinical relapse, 11% to 37% develop a relapsing-remitting (polycyclic) illness course, and 9% to 52% have continuously active disease beyond a two-year period.37,84 Calcinosis of varying severity, from minimal to severely debilitating, occurs in 16% to 43% of JDM patients in recent JDM series.37,39,84 Up to 30% of patients may have residual weakness or functional disability, and 23% to 40% have ongoing rashes, weakness and need for medications at more than 3 years follow-up.37 A large percentage of clinically inactive patients have reduced aerobic exercise tolerance.73,74 As work on disease biomarkers, genomics, and pharmacogenetics progresses, it is hoped that the outcomes of children with inflammatory myopathies will continue to improve.