Etiology

Evidence suggests that the etiology of JDM is multifactorial, based on genetic predisposition and an unknown environmental trigger. HLA alleles such as B8, DRB1*0301, DQA1*0501, and DQA1*0301 have been associated with increased susceptibility to JDM in selected populations. Maternal microchimerism may play a part in the etiology of JDM by causing graft versus host disease or autoimmune phenomena. Persistent maternal cells have been found in blood and tissue samples of children with JDM. An increased number of these maternal cells are positive for HLA-DQA1*0501, which may assist with transfer or persistence of chimeric cells. Specific cytokine polymorphisms in tumor necrosis factor-α (TNF-α) promoter and variable number tandem repeats of the interleukin-1 receptor antagonist (IL-1Ra) also may increase genetic susceptibility. These polymorphisms are common in the general population. A history of infection in the 3 mo prior to disease onset is commonly reported; multiple studies have failed to produce a causative organism. Constitutional signs and upper respiratory symptoms predominate, but one third of patients report preceding gastrointestinal (GI) symptoms. Group A streptococcus, upper respiratory infections, GI infections, coxsackievirus B, toxoplasma, enteroviruses, parvovirus B19, and multiple other organisms have been postulated as possible pathogens in the etiology of JDM. Despite these concerns, results of serum antibody testing and polymerase chain reaction amplification of the blood and muscle tissue for multiple infectious diseases have not been revealing. Environmental factors may also play a contributing role, with geographic and seasonal clustering reported; however, no clear theory of etiology has emerged.

Epidemiology

The incidence of JDM is approximately 3 cases/1 million children/yr without racial predilection. Peak age of onset is between 4 and 10 yr. There is a second peak of dermatomyositis onset in late adulthood (45-64 yr), but adult-onset dermatomyositis appears to be a distinctly separate entity in prognosis and etiology. In the USA, the ratio of girls to boys with JDM is 2 : 1. Multiple cases of myositis in a single family are rare, but familial autoimmune disease may be increased in families with children who have JDM than in families of healthy children. Reports of seasonal association have not been confirmed, although clusters of cases may occur.

Pathogenesis

Type I interferons may be important in the pathogenesis of juvenile dermatomyositis. Interferon upregulates genes critical in immunoregulation and major histocompatibility class (MHC) class I expression, activates natural killer (NK) cells, and supports dendritic cell maturation. Upregulation of gene products controlled by type I interferons occurs in patients with dermatomyositis, potentially correlating with disease activity and holding promise as clinical biomarkers.

It appears that children with genetic susceptibility to JDM (HLA-DQA1*0501, HLA-DRB*0301) may have prolonged exposure to maternal chimeric cells and/or an unknown environmental trigger. Once triggered, an inflammatory cascade with type I interferon response leads to upregulation of MHC class I expression and maturation of dendritic cells. Overexpression of MHC class I upregulates adhesion molecules, which influence migration of lymphocytes, leading to inflammatory infiltration of muscle. In an autoregulatory feedback loop, muscle inflammation increases the type I interferon response, regenerating the cycle of inflammation. Cells involved in the inflammatory cascade include NK cells (CD56), T-cell subsets (CD4, CD8, Th17), monocytes/macrophages (CD14), and plasmacytoid dendritic cells. Neopterin, interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein (MCP), myxovirus resistance protein (MxA), and von Willebrand factor products as well as other markers of vascular inflammation may be elevated in patients with JDM who have active inflammation.

Clinical Manifestations

Children with JDM present with either rash, insidious onset of weakness, or both. Fevers, dysphagia or dysphonia, arthritis, muscle tenderness, and fatigue are also commonly reported at diagnosis.

Rash develops as the first symptom in 50% of cases and appears concomitant with weakness only 25% of the time. Children often exhibit extreme photosensitivity to ultraviolet light exposure with generalized erythema in sun-exposed areas. If seen over the chest and neck, this erythema is known as the “shawl sign.” Erythema is also commonly seen over the knees and elbows. The characteristic heliotrope rash (Fig. 153-1) is a blue-violet discoloration of the eyelids that may be associated with periorbital edema. Facial erythema crossing the nasolabial folds is also common, in contrast to the malar rash without nasolabial involvement typical of systemic lupus erythematosus. Classic Gottron papules (Fig. 153-2) are bright pink or pale, shiny, thickened or atrophic plaques over the proximal interphalangeal joints and distal interphalangeal joints and occasionally on the knees, elbows, small joints of the toes, and ankle malleoli. The rash of JDM is sometimes mistaken for eczema or psoriasis. Rarely, a thickened erythematous and scaly rash develops in children over the palms (known as mechanic’s hands) and soles along the flexor tendons, which is associated with anti-Jo-1 antibodies.

Figure 153-1 The facial rash of juvenile dermatomyositis. There is erythema over the bridge of the nose and malar areas with violaceous (heliotropic) discolorations of the upper eyelids.

Figure 153-2 The rash of juvenile dermatomyositis. The skin over the metacarpal and proximal interphalangeal joints may be hypertrophic and pale red (Gottron papules).

Evidence of small vessel inflammation is often visible in the nail folds and gums as individual capillary loops that are thickened, tortuous, or absent (Fig. 153-3). Telangiectasias may be visible to the naked eye but are more easily visualized under capillaroscopy or with use a magnifier such as an ophthalmoscope. Severe vascular inflammation causes cutaneous ulcers on toes, fingers, axillae, or epicanthal folds.

Figure 153-3 Nail-fold capillary pattern in rheumatic disease. A, Normal nail-fold capillary pattern in a healthy child with a homogeneous distribution and uniform appearance of capillary loops. B, The nail-fold capillary pattern in a child with juvenile dermatomyositis shows dropout of capillary end loops, resulting in a wide band of avascularity. Dilated, tortuous capillaries can also be seen. C, Severe periungual telangiectasias may be seen without microscopy.

Weakness associated with JDM is often insidious and difficult to differentiate from fatigue at onset. It is typically symmetric, affecting proximal muscles such as the neck flexors, shoulder girdle, and hip flexors. Parents may report difficulty climbing stairs, combing hair, and getting out of bed. Examination reveals inability to perform a sit-up, head lag in a child after infancy, and Gower sign (use of hands on thighs to stand from a sitting position). Patients with JDM may roll to the side rather than sit straight up from lying to compensate for truncal weakness. Approximately half of children exhibit muscle tenderness as a result of muscle inflammation.

Esophageal and respiratory muscles are also affected, resulting in aspiration or respiratory failure. It is essential to assess for dysphonia or nasal speech, palatal elevation with gag, dysphagia, and gastroesophageal reflux by means of history, physical exam, and swallow study, if symptoms are present. Respiratory muscle weakness can be a medical emergency and lead to respiratory failure. Children with respiratory muscle weakness do not manifest typical symptoms of impending respiratory failure with increased work of breathing, instead demonstrating hypercarbia rather than hypoxemia.

Lipodystrophy and calcinosis (Fig. 153-4) are thought to be associated with longstanding or undertreated disease. Dystrophic deposition of calcium phosphate, hydroxyapatite, or fluoroapatite crystals occurs in subcutaneous plaques or nodules, resulting in painful ulceration of the skin with extrusion of crystals or calcific liquid. Calcinosis is reported in up to 40% of children with JDM, but the prevalence is thought to be lower in children who are treated early and aggressively. In rare instances, an “exoskeleton” of calcium deposition forms, greatly limiting mobility. Lipodystrophy results in progressive loss of subcutaneous and visceral fat, typically over the face and upper body, and may be associated with a metabolic syndrome similar to polycystic ovarian syndrome with insulin resistance, hirsutism, acanthosis, hypertriglyceridemia, and abnormal glucose tolerance. Lipodystrophy may be generalized or localized.

Figure 153-4 Rash and calcifications in dermatomyositis. A, Skin effects of calcification. B, Radiographic evidence of calcification.

Rarely, vasculitis of the GI tract develops in children with severe JDM, with crampy abdominal pain, pancreatitis, GI bleeding, and potential for intestinal perforation or infarction. Involvement of the cardiac muscle with pericarditis, myocarditis, and conduction defects has been reported. An association with malignancy at disease onset is observed in adults with dermatomyositis but very rarely in children.

Diagnosis

Diagnosis of dermatomyositis requires the presence of characteristic rash as well as at least three signs of muscle inflammation and weakness (Table 153-1). Diagnostic criteria developed in 1975 predate the use of MRI and have not been validated in children. Diagnosis is often delayed because of the insidious nature of disease onset.

Table 153-1 DIAGNOSTIC CRITERIA FOR JUVENILE DERMATOMYOSITIS

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

Electromyography shows signs of myopathy and denervation (increased insertional activity, fibrillations, and sharp waves) as well as muscle fiber necrosis (decreased action potential amplitude and duration). Nerve conduction studies are typically normal unless severe muscle necrosis and atrophy are present. It is important that electromyography (EMG) be performed in a center with experience in pediatric EMG and its interpretation. Muscle biopsy is typically indicated when diagnosis is in doubt or for grading disease severity. Biopsy of involved muscle reveals focal necrosis and phagocytosis of muscle fibers, fiber regeneration, endomysial proliferation, inflammatory cell infiltrates and vasculitis, and tubuloreticular inclusion bodies within endothelial cells. Findings of lymphoid structures and vasculopathy may portend more severe disease.

Some children present with classic rash but no apparent muscle weakness or inflammation; this variation is called amyopathic JDM. It is unclear whether these children have isolated skin disease or mild undetected muscle inflammation, risking progression to more severe muscle involvement with long-term sequelae such as calcinosis and lipodystrophy if untreated.

Differential diagnosis depends on the presenting symptoms. If the presenting complaint is solely weakness without rash or atypical disease, other causes of myopathy should be considered, including polymyositis, infection-related myositis (influenza A and B, coxsackievirus B, and other viral illnesses), muscular dystrophies (Duchenne and Becker as well as others), myasthenia gravis, Guillain-Barré syndrome, endocrinopathies (hyperthyroidism, hypothyroidism, Cushing syndrome, Addison disease, parathyroid disorders), mitochondrial myopathies, and metabolic disorders (glycogen and lipid storage diseases). Infections associated with prominent muscular symptoms include trichinosis, Bartonella infection, toxoplasmosis, and staphylococcal pyomyositis. Blunt trauma and crush injuries may lead to transient rhabdomyolysis with myoglobinuria. Myositis in children may also be associated with vaccinations, drugs, growth hormone, and graft versus host disease. The rash of JDM may be confused with eczema, dyshidrosis, psoriasis, malar rash from systemic lupus erythematosus, capillary telangiectasias from Raynaud phenomenon, and other rheumatic diseases. Muscle inflammation is also seen in children with systemic lupus erythematosus, juvenile idiopathic arthritis, mixed connective tissue disease, inflammatory bowel disease, and anti-neutrophil cytoplasmic antibody (ANCA)–positive vasculitides.

Laboratory Findings

Elevated serum levels of muscle-derived enzymes (creatine kinase [CK], aldolase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) reflect muscle inflammation. Not all enzyme levels rise with inflammation in a specific individual; alanine aminotransferase is most commonly elevated on initial presentation, whereas the CK level may be normal. The erythrocyte sedimentation rate is often normal, and the rheumatoid factor test result is typically negative. There may be anemia consistent with chronic disease. Antinuclear antibody (ANA) is present in >80% of children with JDM. Results of tests for antibodies to SSA, SSB, Sm, ribonucleoprotein (RNP), and double-stranded DNA are generally negative. Antibodies to Pm/Scl identify a small, distinct subgroup of myopathies with a protracted disease course, often complicated by pulmonary interstitial fibrosis and/or cardiac involvement. Unlike in adults with JDM, presence of myositis-specific autoantibodies (MSAs) is rare in children; positive test results for anti-Jo-1, anti-Mi-2, and other MSAs may portend more significant disease.

Radiographic studies aid both diagnosis and medical management. MRI using T2-weighted images and fat suppression (Fig. 153-5) identifies active sites of disease, reducing sampling error and increasing the sensitivity of muscle biopsy and electromyography, results of which are nondiagnostic in 20% of instances if the procedures are not directed by MRI. Extensive rash and abnormal MRI findings may be found despite normal serum levels of muscle-derived enzymes. Muscle biopsy often demonstrates evidence of disease activity and chronicity that is not suspected from the levels of the serum enzymes alone.

Figure 153-5 MRI using T2-weighting and fat suppression of the proximal muscle of the lower extremities of a child with juvenile dermatomyositis with normal muscle enzyme levels. There is focal inflammatory myopathy. The bright areas reflect the inflammatory response in involved muscle. The darker areas are more normal. Identification of involved areas by MRI directs the location of the muscle biopsy or electromyography.

A contrast swallow study may document palatal dysfunction and risk of aspiration. Pulmonary function testing detects a restrictive defect consistent with respiratory weakness and reduced diffusion capacity of carbon monoxide (DLCO) from alveolar fibrosis associated with other connective tissue diseases. Serial measurement of vital capacity or negative inspiratory force can document changes in respiratory weakness, especially in an inpatient setting. Calcinosis is seen easily on radiographs, along the fascial planes and within muscles.

Treatment

The aid of an experienced pediatric rheumatologist is invaluable in outlining an appropriate course of treatment for a child with JDM. Prior to the advent of corticosteroids, one third of patients spontaneously improved, one third had a chronic, lingering course, and one third died from the disease. Corticosteroids have altered the course of disease, lowering morbidity and mortality. Methotrexate decreases the length of treatment with corticosteroids, thereby reducing morbidity from steroid toxicity. Intravenous gammaglobulin is frequently used as an adjunct for treatment of severe disease. No evidence-based guidelines for optimal treatment of JDM currently exist.

Corticosteroids are still the mainstay of treatment. In a clinically stable child without debilitating weakness, oral prednisone at 2 mg/kg/day is usually started. Children with GI involvement have decreased absorption of oral steroids and require intravenous administration. In more severe cases with respiratory or oropharyngeal weakness, high-dose pulse methylprednisolone is used (30 mg/kg/day for 3 days, maximum dose 1 g/day) with ongoing weekly or monthly IV dosing along with daily oral corticosteroids as needed. Corticosteroid dosage is slowly tapered over a period of 12-24 mo, after indicators of inflammation (muscle enzymes) normalize and strength improves.

Weekly oral, intravenous, or subcutaneous methotrexate (0.5-1 mg/kg or 15-20 mg/m², max 25 mg) is commonly used as a steroid-sparing agent in JDM. The concomitant use of methotrexate halves the cumulative dosage of steroids needed for disease control. Risks of methotrexate include immunosuppression, blood count dyscrasias, chemical hepatitis, pulmonary toxicity, nausea/vomiting, and teratogenicity. Folic acid is typically given with methotrexate starting at a dose of 1 mg daily to reduce toxicity and side effects of folate inhibition (oral ulcers, nausea, and anemia). Children who are taking immunosuppressive medications such as methotrexate should avoid live-virus vaccination, although inactivated influenza vaccination is recommended yearly.

Hydroxychloroquine has little toxicity risk and is used as a secondary disease-modifying agent to reduce rash and maintain remission. Typically, it is administered at doses between 4 and 6 mg/kg/day orally in either tablet or liquid form. Ophthalmologic follow-up 1 to 2 times per year to monitor for rare retinal toxicity due is recommended. Other side effects include hemolysis in patients with glucose-6-phosphate deficiency, GI intolerance, and skin/hair discoloration.

Other medications for severe unresponsive disease include intravenous immunoglobulin, mycophenolate mofetil, cyclosporine, and cyclophosphamide. Children with pharyngeal weakness may need nasogastric or gastrostomy feedings to avoid aspiration, whereas those with GI vasculitis require full bowel rest. Rarely, children with severe respiratory weakness require ventilator therapy and even tracheostomy until the respiratory weakness improves.

Physical therapy and occupational therapy are integral parts of the treatment program, initially for passive stretching early in the disease course and then for direct reconditioning of muscles to regain strength and range of motion once active inflammation has resolved. Bed rest is not indicated, because weight bearing improves bone density and prevents contractures. Social work and psychology services may facilitate adjustment to the frustration of physical impairment in a previously active child.

All children with JDM should avoid sun exposure and apply high–sun protection factor (SPF) sunscreen daily, even in winter and on cloudy days. Vitamin D and calcium supplements are indicated for all children undergoing long-term corticosteroid therapy, in an attempt to reduce osteopenia and osteoporosis from medication.

Complications

Most complications from JDM are related to prolonged and severe weakness, including muscle atrophy, to cutaneous calcifications and scarring or atrophy, and to lipodystrophy. Secondary complications from medical treatments are also common. Children with acute and severe weakness are at risk for aspiration pneumonia and respiratory failure and occasionally require nasogastric feeding and mechanical ventilation until weakness improves. Crampy abdominal pain and occult GI bleeding may indicate bowel wall vasculitis and lead to ischemia, GI bleeding, and perforation if not treated with complete bowel rest and aggressive treatment for the underlying inflammation. Surgery should be avoided if possible, because the GI vasculitis is diffuse and not easily amenable to surgical intervention. Contrast-enhanced CT may show dilation or thickening of the bowel wall, intraluminal air, or evidence of bowel necrosis. Cardiac involvement by JDM is rare but includes arrhythmias.

Pathologic calcifications may be related to severity of disease and prolonged delay to treatment and potentially to genetic polymorphisms of TNF-α-308. Calcium deposits tend to form in subcutaneous tissue and along muscle. Some ulcerate through the skin and drain a soft calcific liquid, and others manifest as hard nodules along extensor surfaces or embedded along muscle. Draining lesions serve as a nidus for cellulitis or osteomyelitis. Nodules cause skin inflammation that may mimic cellulitis. Spontaneous regression of calcium deposits may occur, but there is no evidence-based recommendation for treatment of calcinosis.

Lipodystrophy manifests in 10-40% of patients with JDM and can be difficult to recognize. Fat atrophy may be generalized, partial, or local. Lipodystrophy has been associated with insulin resistance, acanthosis nigricans, dyslipidemia, hypertension, and menstrual irregularity, similar to features seen in polycystic ovarian disease or metabolic syndrome X.

Children receiving prolonged corticosteroid therapy are prone to complications such as cessation of linear growth, weight gain, hirsutism, adrenal suppression, immunosuppression, striae, cushingoid fat deposition, mood changes, osteoporosis, cataracts, avascular necrosis, and steroid myopathy. Families should be counseled on the effects of corticosteroids and advised to use medical alert identification and to consult a nutritionist regarding a low-salt, low-fat diet with adequate vitamin D and calcium supplementation.

Prognosis

The mortality rate in JDM has decreased since the advent of corticosteroids, from 33% to currently about 1%; little is known about the long-term consequences of persistent vascular inflammation. The period of active symptoms has decreased from about 3.5 years to <1.5 years with more aggressive immunosuppressive therapy; the vascular, skin, and muscle symptoms of children with JDM generally respond well to therapy. At 7 years of follow-up, 75% of patients have little to no residual disability, but 25% continue to have chronic weakness and 40% have chronic rash. Up to one third may need long-term medications to control their disease. Children with JDM appear able to repair inflammatory damage to vasculature and muscle.