Seminar www.thelancet.com Vol 371 June 28, 2008 2201 Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood Brian M Feldman, Lisa G Rider, Ann M Reed, Lauren M Pachman Juvenile dermatomyositis, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterised by weakness in proximal muscles and pathognomonic skin rashes. The length of time before the initiation of treatment affects presenting symptoms, laboratory measures, and pathophysiology. It also affects disease outcomes, including the development of pathological calcifications, which are associated with increased morbidity. Both genetic and environmental risk factors seem to have a role in the cause of juvenile dermatomyositis; HLA B8–DRB1*0301 ancestral haplotype is a strong immunogenetic risk factor, and antecedent infections and birth seasonality suggest that environmental stimuli might increase risk. Activation of dendritic cells with upregulation of genes induced by type-1 interferon (α) in muscle and peripheral blood seems to be central to disease pathogenesis. Treatment often includes combinations of corticosteroids, methotrexate, and other immunosuppressive agents. Disease outcome, if treatment is initiated early, is generally good. Randomised controlled trials are needed to define the most effective treatments. Introduction Juvenile dermatomyositis is a rare, often chronic, auto- immune disease with onset during childhood. It is a sys- temic vasculopathy characterised by symmetrical proximal muscle weakness, raised serum concentrations of muscle enzymes, and pathognomonic skin rashes that include the heliotrope rash over the eyelids and Gottron’s papules over the extensor joint surfaces (figure 1). This disease is classi- fied as one of the idiopathic inflammatory myopathies (table 1); the adult forms are more common. 1–4 In this Seminar, we will focus on juvenile dermatomyositis, but refer to other idiopathic inflammatory myopathies with juvenile onset where relevant. We review some important advances in the understanding of the causes, epidemiology, pathophysiology, clinical features, and treatment of idio- pathic inflammatory myopathies in childhood. Causes and epidemiology The incidence of juvenile dermatomyositis in the USA is 3·2 per million children per year, 5 which is similar to that in the UK. 6 The average age at onset is 7 years, but 25% of patients are younger than 4 years at onset. 7 In the USA, the ratio of girls to boys is 2·3 to 1, 7 compared with 5 to 1 in the UK. 6 Rash is the first symptom to be recognised in half the children and weakness is the first symptom in a quarter. 8 Childhood idiopathic inflammatory myopathies, like other autoimmune diseases, could result from environ- mental triggers in the setting of an underlying genetic susceptibility. 9 Specific HLA alleles, such as B8, 10 DRB1*0301, 11,12 DQA1*0501, 11 and DQA1*0301, 12 are more common in juvenile dermatomysitis. Cytokine poly- morphisms, including a tumour necrosis factor (TNFα)–308A promoter polymorphism, 13 and intronic poly- morphisms of the interleukin-1 receptor antagonist, 14 are also risk factors in white patients. Geographical or seasonal clustering with the onset of disease suggests an environ- mental trigger for juvenile dermatomyositis—eg, an increased temporal incidence was identified in the midwestern states of the USA. 15 However, this clustering was not confirmed in a national study a decade later. 7 Subgroups of patients with juvenile dermatomyositis, including Hispanic patients, those with the HLA-DRB1*0301 risk-factor allele, 12 and those with a specific autoantibody (anti-p155), have seasonal birth distributions which differ from patients without these features. This birth seasonality in these subgroups suggests a potential role for perinatal exposures or exposures in early life to onset of illness. 16 Additional evidence suggests the presence of an infectious trigger. In two studies, most children with juvenile dermatomyositis had antecedent illnesses, which were mostly upper respiratory and gastrointestinal, in the 3 months before onset of symptoms. 7,17 A history of contact with sick animals was frequently seen. 7 Consequently, several microbes have been implicated, especially group A β haemolytic streptococci (GABHS), in a case–control study. 18 Such patients have an increased cellular response to GABHS antigens that might result from molecular mimicry between GABHS and myosin heavy chain. 19 Several other agents have also been inconsistently associated with disease onset, including coxsackievirus B, 20 toxoplasma, 21 enterovirus, 17 and parvovirus. 22 In case– control studies, however, antibody titres or detection of virus by PCR-based methods in blood or muscle did not differ between patients and matched controls. 22,23 Lancet 2008; 371: 2201–12 Departments of Pediatrics, Health Policy Management and Evaluation, and Public Health Sciences, University of Toronto, Division of Rheumatology, Hospital for Sick Children, Toronto, ON, Canada (Prof B M Feldman MD); Environmental Autoimmunity Group, Office of Clinical Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA (Prof L G Rider MD); Departments of Medicine and Pediatrics, Division of Rheumatology, Mayo College of Medicine, Mayo Clinic, Rochester, MN, USA (Prof A M Reed MD); Department of Pediatrics, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Children’s Memorial Hospital, Chicago, IL, USA (Prof L M Pachman MD); and Molecular and Cellular Pathobiology Program, Children’s Memorial Research Center, Chicago, IL, USA (L M Pachman) Correspondence to: Prof Brian M Feldman, Division of Rheumatology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada brian.feldman@sickkids.ca Search strategy and selection criteria We searched five databases: Medline (1950 to April week 4, 2007); Embase (1980 to week 18, 2007); Cinahl (1982 to May week 1, 2007); Evidence-Based Medicine Reviews (including the Cochrane Library); and Allied and Complementary Medicine (1985 to April, 2007). Any article on myositis in children was eligible for inclusion, with no restrictions on language or year of publication. The main search terms were “dermatomyositis”, “myositis”, “polymyositis”, “orbital myositis”, “overlap myositis”, “focal myositis”, “eosinophilic myositis”, “granulomatous myositis”, “inclusion body myositis”, “cancer-associated myositis”, “interferon 1 and rheumatic diseases”, and “interferon 1 and systemic lupus erythematosus”. We identified 2757 unique publications, many of which were related mainly to adult disease.