Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations

INTRODUCTION — Juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM) are rare autoimmune myopathies in childhood. JDM is primarily a capillary vasculopathy, whereas JPM involves direct T cell invasion of muscle fibers similar to that seen in adult polymyositis (PM) [1,2]. However, as the diagnostic tools become more sophisticated (eg, biopsies that demonstrate inclusion body myositis or inflammatory dystrophies, or autoantibodies that are markers of particular types of myositis such as anti-signal recognition particle [SRP] indicating necrotizing myopathy), fewer patients are diagnosed with JPM, calling into question whether JPM is a specific entity. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

The epidemiology, pathogenesis, and clinical manifestations of JDM and JPM are reviewed here. Diagnosis and treatment of these disorders are discussed elsewhere. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis" and "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis".)

EPIDEMIOLOGY — JDM is the most common idiopathic inflammatory myopathy of childhood, accounting for approximately 85 percent of cases [3,4]. In population-based studies, JDM has a reported annual incidence that ranges from two to four cases per one million children [5-9] and a prevalence of approximately 4 per 100,000 [10]. The peak incidence is from 5 to 10 years of age [8,9]. Females are affected more often than males, with a two- to fivefold greater rate [7,8,11].

JPM occurs less frequently and accounts for only 3 to 6 percent of childhood idiopathic inflammatory myopathies [3,7].

PATHOGENESIS — JDM and JPM are thought to be autoimmune disorders. JDM is associated with systemic vasculopathy. It is sometimes associated with occlusive arteriopathy and capillary necrosis; these changes eventually lead to capillary loss and tissue ischemia. Although the etiology remains unclear, it has been proposed that JDM and JPM are caused by an autoimmune reaction in genetically susceptible persons, possibly in response to infection or environmental triggers such as prenatal exposure to tobacco smoke and particulate inhalants [12]. JDM, as with adult dermatomyositis, is probably an "antibody-dependent, complement-mediated disease characterized by capillary injury that results in perifascicular muscle fiber atrophy" [13].

Genetic susceptibility — The occurrence of JPM and JDM in monozygotic twins and first-degree relatives in some families suggests a genetic predisposition to these disorders [14,15]. A genome-wide association study identified single nucleotide polymorphisms in the alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) as a genetic risk factor associated with all myositis phenotypes including JDM [16].

Non-HLA-associated genes, including genetic polymorphisms in tumor necrosis factor (TNF) alpha and interleukin (IL) 1 receptor antagonist, are known risk factors for the development of JDM and for a more severe presentation [17-19].

A significantly increased rate of autoimmune diseases, particularly systemic lupus erythematosus (SLE) and type 1 diabetes, is seen in family members of children with JDM [20]. Higher levels of interferon (IFN) alpha were seen in children with JDM who had family members with SLE, suggesting a shared predisposing factor.

Immunologic mechanisms — The following findings support the role of the immune system in the pathogenesis of JDM and JPM:

●T cell invasion of muscle fibers in patients with JPM [1].

●Epitopes that are common both to human skeletal muscle and the bacterium Streptococcus pyogenes are targets for cytotoxic T cell responses in patients with early, active JDM, indicating a possible link between an immune response to bacteria and the development of myositis [21].

●Increased mast cell numbers in the skin and mature plasmacytoid dendritic cells in both muscle and skin in patients with JDM [22].

●Antinuclear antibodies (ANAs) are present in approximately 70 percent of patients with JDM and JPM [23]. Myositis-specific autoantibodies (MSAs) are found in a significant proportion of adults with dermatomyositis and polymyositis and are associated with specific clinical subgroups. A study of 116 children registered in the UK and Ireland JDM National Registry and Repository showed a 23 percent prevalence of anti-p155/140 antibodies; children with positive antibodies had more extensive skin disease [24]. A subsequent study found specific autoantibodies in over half of the studied children; these autoantibodies correlated with histologic and clinical features [25]. (See 'Cutaneous manifestations' below and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-specific autoantibodies'.)

●Anti-melanoma differentiation-associated gene 5 antibodies are associated with the occurrence of interstitial lung disease in patients with JDM [26]. Appearance of these antibodies may precede clinical signs of interstitial lung disease. (See 'Pulmonary involvement' below.)

●Similarity of observed histologic changes between JDM and chronic graft-versus-host disease. The presence of persistent maternal cells (maternal microchimerism), which triggers an immunologic response, was proposed as a common pathogenetic pathway for the two disorders. Two studies have reported evidence of maternal microchimerism in the peripheral blood and muscle biopsies of boys with juvenile inflammatory myopathy [27,28].

●Experimental data demonstrating increased T cell reactivity of in vitro peripheral blood mononuclear cells to heat shock protein (HSP) 60 in patients compared with normal controls [29]. HSPs are proposed to have a regulatory role in chronic inflammatory diseases and may be an autoantigen for these disorders. (See "Juvenile idiopathic arthritis: Epidemiology and immunopathogenesis", section on 'Gamma-delta-T cells'.)

●An IFN-alpha-induced gene expression signature in muscle and serum, which may be stimulated by autoantibodies associated with nucleic acids, was seen in gene expression studies that used microarray-based technologies [30,31]. This gene expression is similar to the gene expression signature seen in patients with SLE. IFN gene expression and protein production are high in the muscle of untreated patients with JDM [32], and gene expression of IFN-mediated viral response genes is upregulated as well [33]. These findings suggest that a viral trigger, leading to a chronic antiviral response, is an important pathogenic mechanism.

●Perifascicular atrophy, the hallmark pathologic finding in the muscle of patients with JDM, appears to result from ischemia that is associated with marked loss of adjacent endothelial capillaries due to complement-mediated damage to the vessels. The complement-mediated damage appears to result from activation of the classical pathway, independent of immunoglobulin, and is perhaps triggered by type 1 IFN activity [34].

Infection — Several observations have suggested that JDM may develop as an unusual response to infection in a genetically susceptible host:

●There is an increased prevalence of Coxsackie B antibodies in children with JDM compared with matched controls [35].

●Case reports of viral isolation from muscle specimens in adult myositis have been described [36].

●There is an association between echovirus infection and chronic polymyositis in children with agammaglobulinemia [37].

●A seasonal variation of onset in JDM has been described, with clustering of cases in the spring and summer [38].

●Respiratory and gastrointestinal complaints and/or antibiotic use are common in the three months before diagnosis of JDM [39,40].

However, attempts at demonstrating a viral etiology of JDM have failed. As an example, a study of 79 patients with new-onset JDM found normal antibody titers to herpes simplex virus, coxsackievirus B 1 through 6, and Toxoplasma gondii [41]. Another report using the polymerase chain reaction was unable to demonstrate evidence of viral genetic material in the muscle of 20 individuals with active, untreated, recent-onset JDM [42].

CLINICAL MANIFESTATIONS — Muscle weakness is the hallmark of JDM and JPM, although approximately 5 percent of patients with JDM do not have clinically evident weakness (amyopathic or hypomyopathic JDM) [4]. In addition, patients with JDM, but not JPM, present with characteristic rashes (picture 1). Children with JDM and JPM also may have constitutional symptoms (fever, weight loss, fatigue, and headache), which may be the initial finding prior to the onset of muscle weakness and, in patients with JDM, rash.

The clinical presentation of JDM varies and is exemplified by the two following case series. In the first review from a single tertiary Canadian center of 105 patients with JDM (mean age at diagnosis 7.6 years), the most common symptoms/findings and their frequency noted at disease onset were [4]:

●Gottron's rash – 91 percent

●Heliotrope rash – 83 percent

●Malar/facial rash – 42 percent

●Nailfold capillary change – 80 percent

●Myalgia/arthralgia – 25 percent

●Dysphonia or dysphagia – 24 percent

●Anorexia – 18 percent

●Fever – 16 percent

The second case series is from the JDM Research Registry and included 166 newly diagnosed children living in the continental United States from 1994 to 1999 [11]. The mean age of diagnosis was 7.5±3.8 years, and the median duration of symptoms prior to diagnosis was four months. There was no difference in the age of diagnosis or duration of untreated disease based upon sex or ethnicity. The initial symptoms/findings on presentation were:

●Rashes – 65 percent

●Weakness alone – 29 percent

●Both rash and weakness – 6 percent

Thus, although nearly all patients with JDM develop muscle weakness, the classic rashes are the more common initial finding on presentation. The severity of the weakness increased with the duration of symptoms prior to diagnosis.

Additional findings included:

●Lower height and weight compared with normative data from the National Health and Nutrition Examination Study (NHANES) III survey

●Nailfold capillary dilation

●Arthritis

●Difficulty swallowing

●Abdominal pain

●Fever

The cutaneous manifestations of JDM may appear in the absence of clinically apparent muscle disease in a small number of children. This presentation is termed amyopathic (or hypomyopathic) JDM. All such children require evaluation by an experienced pediatric rheumatologist, physiotherapist, or pediatric neurologist to assure that they are not, in fact, weak. Children with this presentation may never develop muscle weakness. However, in others, amyopathic JDM may reflect an early phase in the disease course before muscle weakness has developed.

There are fewer data available on the clinical manifestations of JPM since it is a rare disease. In one series of 39 patients diagnosed with JPM, the most common clinical features included [43]:

●Proximal muscle weakness – 100 percent

●Fatigue – 82 percent

●Arthritis or arthralgias – 69 percent

●Myalgias – 64 percent

●Falling – 60 percent

●Weight loss – 54 percent

●Fever – 47 percent

●Muscle atrophy – 46 percent

●Distal muscle weakness – 44 percent

●Dysphagia – 41 percent

●Abdominal pain – 31 percent

●Periungual capillary changes – 31 percent

●Raynaud phenomenon – 28 percent

●Dysphonia – 24 percent

●Palpitations – 23 percent

Patients with periungual capillary changes, Raynaud phenomenon, and gastrointestinal manifestations most likely have overlap syndrome (JPM with features of scleroderma).

Muscle weakness — The inflammatory myopathies are characterized by symmetric muscle weakness that is more apparent proximally than distally (but often presents distally as well). This may present with functional limitations, such as difficulty getting up from the floor, getting into and out of motor vehicles, or climbing stairs. Washing or grooming hair may pose a challenge, and severely affected children may not be able to feed themselves. In very young children, frequent falls may be an important symptom. A Gower's sign (pushing with the hands on the legs, from the knees to hips, to attain an upright position) is frequently present.

Weakness of the palate and cricopharyngeal muscle may result in problems swallowing, a nasal voice, tracheal aspiration, and reflux of food into the nasopharynx. Involvement of the upper esophagus can lead to dysphagia for solids and liquids [44].

Testing of muscle strength is reviewed separately. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis", section on 'Muscle strength testing'.)

Cutaneous manifestations — Cutaneous manifestations are common in children with JDM and include a characteristic heliotrope rash, Gottron's papules, nailfold capillary changes, and skin ulcerations (picture 2). The rashes may occur simultaneously with muscle involvement or appear prior to obvious muscular weakness. Rash is an important distinguishing feature between JDM and JPM as it is not present in the latter condition. Skin disease may be exacerbated by exposure to sunlight [45]. Skin disease appears to last longer and be more resistant to treatment than muscle disease [46,47]. Calcinosis, a well-recognized complication, is discussed in detail separately. (See "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis", section on 'Calcinosis'.)

Heliotrope rash — Heliotrope dermatitis is a reddish-purple rash on the upper eyelids, often accompanied by swelling of the eyelid (picture 1). Malar and facial erythema may also be present. Heliotrope rash is one of the most common findings in patients with JDM, with a reported rate of 83 percent in the previously mentioned Canadian study and a 94 percent rate in 44 patients from Hungary [4,48]. Periorbital edema, upper lid edema, or telangiectasia of the eyelid capillaries can be seen in 50 to 90 percent of children [49,50].

Gottron's papules — Gottron's papules are an erythematous, papulosquamous eruption over the dorsal surfaces of the knuckles (picture 1). The term "Gottron's sign" is often used if the lesions are not papular. Similar lesions can occur over the extensor aspects of the elbows, knees, and medial malleoli, at times mimicking psoriasis. Gottron's papules are a common feature in patients with JDM, with a reported rate of 91 percent of Canadian and 77 percent of Hungarian patients from the previously mentioned studies [4,48].

Nailfold capillary changes — Nailfold capillary changes, including capillary dilatation, tortuosity, and dropout (loss of capillary loops), as shown in panel C (picture 2), are a frequent sign and are probably present in all patients with JDM at early stages of the disease [51]. The changes may be seen grossly but usually are only apparent under magnification. Nailfold capillaroscopy is reviewed in detail separately. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis", section on 'Nailfold capillaroscopy'.)

Skin ulcerations — Ulcerative skin disease, as shown in panel E (picture 2), is a serious and potentially life-threatening manifestation of JDM. Ulcers presumably reflect significant vasculopathy in the skin (with tissue hypoxia and necrosis) and may signal vasculopathy in other organs (especially the lungs and gut). Patients with ulcerative lesions have more severe disease and a worse prognosis. (See "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis", section on 'Prognosis'.)

Arthritis — Nonerosive arthralgia and arthritis may be present at the time of diagnosis or during the disease course [3,4,52]. Contractures are sometimes seen but are usually related to muscle inflammation rather than arthritis.

Lipodystrophy — Acquired lipodystrophy, as shown in panel F (picture 2), and associated metabolic abnormalities such as insulin resistance, acanthosis nigricans, and type 2 diabetes are increasingly recognized in patients with JDM [53]:

●In a study of 20 patients with JDM, four were found to have lipodystrophy accompanied by either insulin resistance or type 2 diabetes, while an additional eight had glucose and lipid abnormalities without evidence of lipodystrophy [54].

●In another study of 20 patients, 13 patients had lipoatrophy based upon subcutaneous fat quantification by skinfold caliper, including eight patients with physical findings of lipodystrophy [55]. Oral glucose tests were normal in all patients, but 12 of 18 patients tested were found to have hypertriglyceridemia.

●In a retrospective review, JDM alone or in association with another autoimmune disease (eg, juvenile idiopathic arthritis) was the underlying disease in 18 of 23 children with acquired lipodystrophy. Other findings included acanthosis nigricans (n = 5 patients), hyperpigmentation (n = 5), elevated liver enzymes (n = 5), and hypertension (n =3) [56].

●A study, published from the National Institutes of Health (NIH) Childhood Myositis Heterogeneity Collaborative Study, showed that lipoatrophy is associated with a more severe and chronic disease course, with a higher frequency of muscle atrophy, joint contractures, calcinosis, metabolic abnormalities, and rashes [53].

Pulmonary involvement — Pulmonary manifestations are much less common in children with JDM or JPM than adults, but interstitial lung disease may occur [43,57]. High serum levels of Krebs von den Lungen 6 (KL-6), anti-melanoma differentiation-associated gene 5 (MDA5) antibodies, and interleukin (IL) 18 are associated with rapidly progressive interstitial lung disease [58]. (See 'Immunologic mechanisms' above.)

Gastrointestinal vasculopathy — Gastrointestinal tract involvement is relatively rare in patients with JDM and in patients with JPM and scleroderma features (overlap syndrome) but can be life threatening. Affected patients may present with abdominal pain, pneumatosis intestinalis, gastrointestinal bleeding, or perforation [2,59]. Acute gastrointestinal vasculitis and chronic abdominal endarteropathy have been described in patients with JDM, indicating that the underlying pathology leading to ulceration and perforation of the intestines is complex [60]. (See "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis", section on 'Intestinal perforation'.)

Any patient with JDM experiencing abdominal pain that persists or progresses warrants careful investigation because gastrointestinal vasculopathy may occur late in the disease course or in a patient with only mild myositis. Of note, abdominal radiographs and stool testing for occult blood may be normal in patients with gastrointestinal involvement. The need for further investigation, such as abdominal ultrasonography or computed tomography (CT), must be guided by clinical suspicion for significant gastrointestinal involvement.

Anasarca — Anasarca is an uncommon finding seen in patient with JDM. The presence of anasarca at presentation is a potential poor prognostic sign indicating severe disease that may respond slowly to treatment and may not respond to glucocorticoids alone. The generalized edema may be the result of a diffuse capillary leak resulting from vascular endothelial damage [61]. Subcutaneous edema, conversely, is probably common, although it may fail to be appreciated clinically. It is associated with fascial inflammation, and its presence may predict the development of calcinosis [62].

LABORATORY FINDINGS — Elevated levels of serum muscle enzymes (creatine kinase, lactate dehydrogenase, aldolase, alanine aminotransferase, aspartate aminotransferase) indicate muscle damage and are often found in JDM or JPM. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis", section on 'Measurement of muscle enzymes'.)

Although other blood tests are often performed in patients suspected of having childhood inflammatory myopathy, these studies are often not directly useful in establishing the diagnosis. They include the following:

●Complete blood count – Leukocytosis and anemia are uncommon findings at disease onset, with the possible exception of a low hematocrit in a child with significant gastrointestinal bleeding. Lymphopenia may be present in children with JDM and usually resolves after glucocorticoid therapy [63].

●Inflammatory markers – Both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may be elevated in patients with JDM and JPM [64]. However, these often do not correlate with the degree of inflammation detected clinically and are not useful in making the diagnosis or monitoring disease activity in patients with JDM or JPM.

●von Willebrand factor (vWF) – Although several studies have shown that children with active JDM have increased plasma vWF levels [65,66], increased vWF levels are not more specific for active disease than serum muscle enzyme measurements. Blood vessel injury is thought to cause the release of vWF from platelets and endothelial cells, resulting in elevated plasma levels of vWF.

●Autoantibodies – Although antinuclear antibodies (ANAs) are present in 70 percent of patients with JDM and JPM, a positive ANA is nonspecific and has limited diagnostic value. Testing for myositis-specific antibodies (MSAs) is routinely performed at many centers, and commercially available assays are becoming more common and more easily available. (See 'Immunologic mechanisms' above and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis", section on 'Antibody testing'.)

HISTOLOGY — The hallmark biopsy finding in JDM is perifascicular atrophy (see 'Immunologic mechanisms' above). Other common findings on light microscopy include centralization of nuclei, degeneration, regeneration, and a scant inflammatory infiltrate. Tubular reticular inclusions are often seen on electron microscopy.

Muscle biopsy specimens from patients with JDM often contain an inflammatory infiltrate. The inflammatory cells are located perivascularly. These scattered inflammatory infiltrates are composed predominantly of monocytes and T cells, but other cells types such as B cells, mast cells, and, rarely, eosinophils are also present [67].

Normal muscle cells do not express class I major histocompatibility complex (MHC) antigens, but these antigens are strongly expressed on muscle fibers in patients with JDM [68]. MHC class I overexpression is an early event in JDM and may occur in the absence of lymphocytic infiltration and muscle damage.

In one study, the degree of inflammation on biopsy (as measured using a standardized scoring method) predicted the development of calcinosis [69].

SUMMARY

●Epidemiology – Juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM) are rare autoimmune myopathies affecting children. JDM is the most common of these disorders, accounting for 85 percent of cases, with a reported incidence that ranges from two to four cases per million children. (See 'Epidemiology' above.)

●Pathogenesis – Although the etiology of JDM and JPM remains unclear, it is suspected that these disorders are caused by an autoimmune reaction within the small blood vessels and/or the muscle tissue of genetically susceptible individuals, in whom the innate immune system is activated, possibly in response to infection or environmental triggers. (See 'Pathogenesis' above.)

●Clinical manifestations – Symmetrical proximal muscle weakness is the most striking clinical feature of these two disorders. In addition, heliotrope rash (reddish-purple rash on the upper eyelids, often accompanied by swelling of the eyelid) (picture 1) and Gottron's papules (erythematous, papulosquamous eruption over the dorsal surfaces of the knuckles) (picture 1) are characteristic rashes of JDM. Children with JDM and JPM may also have constitutional symptoms (fever, weight loss, fatigue, and headache), which may appear prior to the onset of muscle weakness and rash (in patients with JDM). (See 'Clinical manifestations' above.)

Other clinical manifestations of JDM include nailfold capillary changes, skin ulcerations, calcinosis (soft tissue calcification), nonerosive arthralgia and arthritis, lipodystrophy, and insulin resistance (picture 2). Interstitial lung disease, when it occurs, may be severe. Gastrointestinal vasculopathy is a relative rare but life-threatening manifestation that may present as abdominal pain, pneumatosis intestinalis, gastrointestinal bleeding, or perforation.