Juvenile Dermatomyositis

Etiology

Evidence suggests that the etiology of JDM is multifactorial, based on genetic predisposition and an unknown environmental trigger. Human leukocyte antigen (HLA) alleles such as B8, DRB1*0301, DQA1*0501, and DQA1*0301 are 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 (GVHD) 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 (TNF)-α promoter and variable-number tandem repeats of the interleukin (IL)-1 receptor antagonist may increase genetic susceptibility. These polymorphisms are common in the general population. A history of infection in the 3 mo before disease onset is usually 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. Short-term increases in UV index prior to onset of disease have been 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 4-10 yr. A 2nd peak of dermatomyositis onset occurs in late adulthood (45-64 yr), but adult-onset dermatomyositis appears to be a distinctly separate entity in prognosis and etiology. In the United States 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

Interferon (IFN) upregulates genes critical in immunoregulation and major histocompatibility complex (MHC) class I expression, activates natural killer (NK) cells, and supports dendritic cell (DC) maturation. Upregulation of gene products controlled by type I IFNs 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 IFN response leads to upregulation of MHC class I expression and maturation of DCs. 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 IFN 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 DCs. Neopterin, IFN-inducible protein 10, monocyte chemoattractant protein, myxovirus resistance protein, and von Willebrand factor products, as well as other markers of vascular inflammation, may be elevated in patients with JDM who have active inflammation.