Juvenile Dermatomyositis

Updated: Sep 21, 2016
  • Author: Ann M Reed, MD; Chief Editor: Lawrence K Jung, MD  more...
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Overview

Background

Juvenile dermatomyositis (JDM) is a systemic, autoimmune inflammatory muscle disorder and vasculopathy that affects children younger than 18 years. JDM primarily affects the skin and the skeletal muscles. Characteristic findings include Gottron papules, a heliotrope rash, calcinosis cutis, and symmetrical, proximal muscle weakness (see the images below).

A characteristic, violaceous rash is present over A characteristic, violaceous rash is present over the eyelids with periorbital edema in a child with juvenile dermatomyositis.
Gottron papules are present over the metacarpophal Gottron papules are present over the metacarpophalangeal joints and proximal interphalangeal joints in a child with juvenile dermatomyositis.
An erythematous "V-neck" rash is present on the up An erythematous "V-neck" rash is present on the upper chest of a child with juvenile dermatomyositis.
An erythematous, violaceous, scaly rash is present An erythematous, violaceous, scaly rash is present over extensor surfaces in a child with juvenile dermatomyositis.
Calcinosis cutis over the left elbow in a patient Calcinosis cutis over the left elbow in a patient with juvenile dermatomyositis for 16 years.

Although similar in many respects to adult dermatomyositis with characteristic skin findings and muscle weakness, JDM is often associated with calcinosis cutis, cutaneous ulcerations, and vasculopathy characterized by intimal proliferation of small blood vessels and infarctions. [1, 2]

Traditionally, diagnosis of JDM has been based on the following 5 criteria, specified by Bohan and Peter in 1975 [3, 4] :

  • Characteristic skin rash
  • Proximal muscle weakness
  • Elevated muscle enzymes
  • Myopathic changes on electromyography
  • Abnormal muscle biopsy findings

Typical skin findings in combination with 3 other criteria are necessary to make the diagnosis; patients with the characteristic rash who fulfill only 2 criteria have probable JDM.

On the basis of a 2006 international consensus survey, expanded criteria have been proposed. [5] These in part reflect the development of noninvasive techniques since the 1975 criteria were formulated and include the following:

  • Typical findings on muscle MRI and ultrasonography
  • Nailfold capillaroscopy abnormalities
  • Calcinosis
  • Dysphonia

Several clinical course variations in JDM have been identified, including the following [1, 6] :

  • Monocyclic (remission within 2-3 y)
  • Polycyclic (periods of remission followed by relapse)
  • Chronic
  • Ulcerative

Extramuscular manifestations include arthritis and cardiac manifestations (eg, conduction defects, myocarditis, dilated cardiomyopathy. [7] The vasculopathy may affect the GI tract.

Juvenile-onset amyopathic dermatomyositis refers to characteristic skin changes without muscle weakness or elevated muscle enzymes for longer than 6 months. One quarter of patients may progress to clinically significant myositis. [8]

Unlike adults, juvenile polymyositis is less common than JDM, and inclusion body myositis is rare in children. [2]

Overlap myositis occurs in conjunction with other connective tissue diseases such as scleroderma, systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, vasculitis, Kawasaki disease, and psoriasis. [1] Overlap myositis generally demonstrates a milder muscle disease with favorable treatment response.

In contrast to adult dermatomyositis, cancer-associated myositis and interstitial lung disease is uncommon in children. [1, 9, 2] Cancers described have included lymphoma and leukemia. [1]

A multidisciplinary approach to treatment is required to prevent and reduce long-term morbidity in JDM. Various therapies are used to treat skin manifestations of JDM. For active muscle disease, oral corticosteroids are the mainstay of treatment. Second-line agents are routinely added for steroid-sparing effects and for recalcitrant or refractory disease. (See Treatment.)

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Pathophysiology

The current model of the pathogenesis of JDM involves both humoral and cell-mediated mechanisms that cause vascular and muscle damage. Autoantibodies directed against an unknown endothelial antigen may cause vascular injury, resulting in ischemia and subsequent muscle damage with increased expression of major histocompatibility complex (MHC) class I and II. [10, 11, 12, 13, 14, 15]

CD4+ T cells, B cells, plasmacytoid dendritic cells (pDCs), and macrophages are arranged in a perivascular and perifascicular distribution, with capillary thrombosis and deposition of membrane attack complex and complement. [10, 11, 12, 14, 16] Immune complex deposition mediates vascular injury, resulting in activation of complement and muscle inflammation. [17, 18, 13, 15]

T cells, as well as B cells, play a dominant role in disease pathogenesis. TH 17 cells are a subset of CD4 cells that have been found with neutrophils in inflammatory infiltrates and are producers of interleukin (IL)–17 found in inflamed tissues of JDM patients. [19] IL-17 induces MHC class I and IL-6 (a proinflammatory cytokine) expression in myoblasts in concert with IL-1 (a proinflammatory cytokine). [19, 20, 21] B cells have been found in the primary follicles of lymph nodes and lymphoid tissues forming germinal centers and are also found in perivascular infiltrates in patients newly diagnosed with JDM. [22]

Emerging research suggests that type I interferon-alpha/beta inducible genes of the innate immune system play a central role in the pathogenesis of dermatomyositis. [15] These genes mediate upregulation of MHC class I, induction of proinflammatory cytokines and chemokines, and dendritic cell maturation. [23, 24]

Plasmacytoid dendritic cells are involved in the innate immune system and produce large amounts of interferon-alpha (α) and beta (β) in vivo after viral stimulation. [25, 26] They have been found in the muscle, peripheral blood, and epidermis of skin lesions in patients with dermatomyositis. [16, 27] Overproduction of interferon alpha/beta proteins may lead to endothelial and myofiber damage. [26]

In a study that assessed family histories from 304 families of children with JDM, Niewold et al found that 51% of these families reported at least one additional member affected by an autoimmune disease. [28] Higher serum interferon-alpha values were found in untreated subjects with JDM who had a family history of SLE, suggesting that interferon-alpha may be a pathogenic factor shared by these autoimmune diseases.

Juvenile polymyositis is mediated by cytotoxic CD8+ T cells, activated macrophages, and expression of MHC-I. [11, 10, 18]

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Etiology

The etiology of JDM is incompletely understood. Evidence suggests a complex interplay of the innate and adaptive immune systems with environmental triggers in a genetically susceptible host.

Seasonal clustering of JDM in the months of April and May suggests the role of environmental triggers in the onset or exacerbation of the disease. [29] Infectious agents include viruses, parasites, and bacterial antigens that may produce a break in self-tolerance. Infectious agents implicated include the following [30, 31, 32, 33, 34] :

  • Coxsackie B virus
  • Parvovirus B19
  • Enteroviruses
  • Streptococcus species

Several mechanisms for infection-triggered autoimmunity have been proposed, including molecular mimicry, induction of anti-idiotypic antibodies, and modification of self-antigens through microbial proteins. [35, 36]

Type I interferon-alpha/beta genes are overexpressed in dermatomyositis. [37, 26, 38] Gene expression profiles of untreated patients may provide indirect evidence of an activated immune response, with an upregulation of interferon alpha/beta genes associated with viral and microbial antigens. [23, 37] Type I interferons can up-regulate MHC class I expression, promote T-cell survival, induce proinflammatory cytokine elaboration and dendritic cell maturation. [39]

levels of type I interferon gene expression in peripheral blood mononuclear cells therefore may be a marker for increased disease activity. [37, 38] Downregulation of type I interferon genes is correlated with clinical improvement in dermatomyositis. [38]

Noninfectious agents implicated in the onset of JDM include D-penicillamine, vaccinations, and bone marrow transplants. [40, 41, 42]

Certain factors that have been associated with adult-onset myositis have not been described in children. These include the following [2] :

  • Agents related to occupational exposures
  • Silica
  • Silicone implants
  • Lipid-lowering medicines

Patients with human leukocyte antigen DQA1*0501 (HLA-DQA1*0501) have an increased susceptibility to JDM, in a strong linkage disequilibrium to HLA-DR3, compared with age-matched controls in white, black, and Hispanic children. [43, 44] The HLA-DQA1*0301 and HLA-DRB*0301 alleles confer an increased risk in whites compared with race-matched controls. [45]

Maternally derived chimeric cells have been identified in patients with JDM, suggesting a role in pathogenesis. Chimeric cells from mothers with HLA-DQA1*0501 may interact with hosts’ immune responses. [46] Microchimerism has been found in 70-100% of muscle tissue and peripheral blood mononuclear cells in patients with JDM. [47, 48]

Cytokine polymorphisms (eg, the substitution of A to G in the promoter region of tumor necrosis factor [TNF]–alpha-308 allele) is associated with a prolonged, refractory course. The course may be related to an increased production of TNF-alpha in peripheral blood mononuclear cells and muscle fibers of untreated patients with JDM. [49, 50] Polymorphisms in the variable number tandem repeat (VNTR) of the interleukin (IL)-1 receptor antagonist have also been implicated as a risk factor in JDM. [51]

A study that investigated the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of juvenile idiopathic inflammatory myopathies (IIM) found that short-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Further research examining the mechanisms of action of UVR in the pathogenesis of juvenile IIM is needed. [52, 53]

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Epidemiology

In the United States, the annual incidence of JDM ranges from 2.5-4.1 cases per million population. [54] In the United Kingdom, the incidence is lower at 1.9 cases per million children younger than 16 years. [29]

Racial, sexual, and age-related differences in incidence

Racial differences are observed in the incidence of JDM in the United States. The estimated annual incidence in whites is 3.4 cases per million children; the annual incidence in blacks is 3.3 cases per million children; and the incidence in Hispanics is 2.7 cases per million children. [54]

JDM affects females more often than males, with a ratio of 2.3:1 in the United States. [54] In the United Kingdom, the ratio is even higher at 5:1. [29]

The median age of onset of JDM is 6.8 years in girls and 7.3 years in boys, with a median delay to diagnosis of 3-4 months. [29, 30, 55] One fourth of patients are aged 4 years or younger at diagnosis. [55]

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Prognosis

Prior to the widespread use of corticosteroids, the prognosis was poor. One third of patients died from JDM and another third suffered from significant long-term disability. [56, 57] Mortality has been related to complications from the vasculopathy, chronic infections, and septicemia. [57] Mortality has now declined to 2-3% with improvement in functional outcomes. [57, 58, 59, 60]

The average disease duration has varied widely, from 1.5 years to throughout the life span. In general, children with JDM are able to lead normal lives with full recovery, compared with adults. [61, 6] Delayed or inadequate treatment with corticosteroids is a predictor of poor outcome and a prolonged disease course. [30, 62]

Calcinosis cutis develops in one third of patients and is a major cause of morbidity. [58, 62] Calcinosis cutis leads to pain, cosmetic disfigurement, and decreased physical function and quality of life. It may lead to skin atrophy, contractures, nerve entrapment, and ulceration with secondary skin infections. [58, 63, 64] Calcinosis has been associated with a delay in diagnosis, lack of aggressive treatment, and cardiac involvement; progression may occur with inadequately treated disease. [30, 65] Over one half of patients with JDM develop a chronic disease 24 months after diagnosis; the disease manifests as rash, muscle weakness, or both. [58] In severe disease, impairments in physical function may lead to limb contractures.

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