Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis

664 | NOVEMBER 2011 | VOLUME 7 www.nature.com/nrrheum

Department of Pediatrics, Case Western Reserve University Hospital, 11100 Euclid Avenue, Cleveland, OH 44106, USA (A. B. Robinson). Department of Pediatrics and Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA (A. M. Reed).

Correspondence to: A. M. Reed [email protected]

Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis Angela B. Robinson and Ann M. Reed

Abstract | Juvenile and adult dermatomyositis (DM) have multiple commonalities, yet display differing prevalence of features, outcomes and comorbidities. In general, compared with the disease in adults, children with DM have more vasculopathy and a greater likelihood of calcinosis, periungual and gingival telangiectasias, and ulceration, but have a better long-term prognosis with improved survival. Adults with DM are more likely to have myositis-specific antibodies, develop interstitial lung disease, have amyopathic disease, and have a marked association with malignancy and other comorbidities. Both diseases have similar features on muscle biopsy and interferon gene signature, although subtle differences can exist in pathogenesis and pathology, such as more capillary loss and a greater degree of C5b–9 complement deposition in affected muscle of juvenile patients. Initiatives are underway to improve classification, markers of disease activity and ability to predict outcome of juvenile and adult DM. The purpose of this Review is to compare and contrast the unique features between juvenile and adult disease and to outline new initiatives in the field.

Robinson, A. B. & Reed, A. M. Nat. Rev. Rheumatol. 7, 664–675 (2011); published online 27 September 2011; doi:10.1038/nrrheum.2011.139

IntroductionIdiopathic inflammatory myopathies (IIM) are a group of inflammatory muscle conditions with varying additional organ involvement. In adults, dermatomyositis (DM) and polymyositis (PM) are both common IIM conditions; in children, juvenile DM is the most prevalent IIM.1 Adult and juvenile DM are autoimmune myopathies characterized clinically by proximal muscle weakness, muscle inflammation, characteristic rash and, frequently, the presence of autoantibodies.2 Although some overlap between disease characteristics exist, adult and juvenile DM are separate entities with variable features. Prior to corticosteroid treatment, mortality for juvenile DM approached 33%. Currently, juvenile DM has a 5year survival of >95%, while the 5year survival in adult DM is 75–90%.3–5 Incidence is 3.2 cases per million children per year in juvenile DM, but 5–8.9 cases per million population per year in adult DM.6–8 All forms of IIM are more common in females.9 The average age of onset is 7yearsold in juvenile DM and the 4th to 6th decades in adult DM.6,10–13 In this Review, we will concentrate on clinical aspects of both adult and juvenile diseases, as well as the latest advances in pathogenesis and treatment, highlighting the differences between the two disease entities.

Clinical aspectsAdults and children with DM manifest with rash, proximal weakness, or both, on presentation.2 Diagnosis of definite DM requires the presence of characteristic rash as well as at least three of the four signs of muscle inflammation and weakness—symmetric proximal weakness, elevated levels

of muscle enzymes (creatine kinase, aspartate aminotransferase, lactate dehydrogenase and aldolase), electromyographical changes consistent with irritable myopathy, or necrosis and inflammation on muscle biopsy.14 Two positive signs are considered consistent with a diagnosis of probable DM. MRI using T2weighted imaging and fat suppression can localize active sites of disease for biopsy and improve diagnostic yield;15 however, the diagnostic criteria date back to 1975 and do not include the use of MRI for either guiding electromyography or biopsy, or for diagnosis.14 Muscle biopsy often demonstrates evidence of disease activity and chronicity that is not suspected from the levels of the serum enzymes alone; findings might be useful in grading the extent of disease and predicting disease severity or refractory disease.16

Characteristic rashTypical rashes in DM include a generalized photo sensitive erythema, Gottron papules over extensor surfaces and a periorbital heliotrope rash. Multiple rashes have been described in adult and juvenile DM, but heliotrope rash and Gottron papules are pathognomonic for DM.14 Adults can develop a thickened, erythematous, and scaly rash over the tips and lateral aspects of the fingers (known as ‘mechanic’s hands’); this rash occurs less often in children. Evidence of smallvessel inflammation can be seen in the nail folds, eyelids, and gums as telangiectasias of the capillary loops.17 The number of endrow nailfold loops can be quantified, and normal numbers of endrow loops in juvenile DM has been correlated with earlier diagnosis and lesssevere skin disease (Table 1).17 Persistent capillary abnormalities and Gottron papules at 6 months may be associated with longer time to remission in children

Competing interestsThe authors declare no competing interests.

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with DM.18 Severe vascular inflammation can cause cutaneous ulcerations and might be an indicator of increased severity and poor prognosis; adults (4%) are less likely than children (24%) to develop ulceration.19

Proximal muscle weaknessIn our experience, weakness is often insidious and difficult to recognize at onset. Typically, the weakness is symmetric and affects proximal muscles. Adults may be better able to quantify and describe symptoms of early weakness; however, their weakness is described more as decreases in endurance, especially in repetitive movements such as walking uphill. Patients report fatigue and difficulty climbing stairs, combing hair, or getting out of bed. Young children may want to be carried more frequently or not want to get down or up off the floor. On examination, clinical weakness can manifest as difficulty performing situps, development of head lag in a child after infancy, Gower sign (use of hands on thighs to stand from a sitting position), or difficulty raising the arms straight above the head. In severe cases, weakness affects esophageal and respiratory muscles.20,21 Children with DM can demonstrate symptoms of choking with drinking liquids or voice changes. Respiratory weakness might lead to acute respiratory failure with hypercarbia rather than hypoxemia.21

Systemic manifestationsLipodystrophy and calcinosis are thought to be associ ated with longstanding or undertreated disease in juvenile DM and are uncommon in adults (Table 1). Calcinosis is reported in up to 30% of patients with juvenile DM, but has been reported rarely in adult literature. The prevalence of calcinosis is thought to be decreased in chil dren who are treated early and aggressively.22 Rarely, immobiliza tion resulting from an ‘exoskeleton’ of calcium has been reported.23,24 Descriptions of the calcified masses are closest to that of enamel, whilst clearly differing from bone and with a decrease in small proteins as compared with bone.25 Calcium and phosphate, normally present in affected tissues, are hypothesized to precipitate as carbonate apatite owing to local loss of mineralization inhibitors.25 Lipodystrophy, reported in 10% of children with juvenile DM, clinically results in a progressive loss of subcutaneous and visceral fat, and might be associated with a metabolic syndrome similar to polycystic ovarian syndrome with insulin resistance, acanthosis, hypertriglyceridemia and abnormal glucose tolerance.26 Only a few cases of adults with myositis and lipodystrophy are reported in the literature (Table 1).27 Fevers, dysphagia or dysphonia, arthritis, muscle tenderness and fatigue are also commonly reported at diagnosis. Rarely, patients develop vasculitis of the gastrointestinal tract with crampy abdominal pain, pancreatitis, gastro intestinal bleeding, and potential for intestinal perforation or infarction, which is more often seen in juvenile DM.22

Lung involvementPatients with juvenile DM have rarely been described to develop fatal pulmonary complications, but up to 16% of

Key points

■ Despite multiple commonalities between the two diseases, differences between adult and juvenile dermatomyositis (DM) do exist

■ Adults with DM are at an increased risk of malignancy and are more likely to develop interstitial lung disease

■ Juvenile DM is associated with increased vasculopathy, but children and adolescents with DM have improved long-term prognosis and survival

■ Consensus-driven treatment suggestions have been developed to understand best treatments for moderate juvenile DM, but the same consensus-driven treatment is lacking in adults

adults with DM have severe lung disease.28 Interstitial lung disease (ILD) has been described in 7–19% of children with DM and as high as 46% of adults with DM (Table 1).29 In a case–control study, patients with juvenile DM had lower total lung capacity and diffusing capacity for carbon monoxide on pulmonary function tests than healthy controls. Abnormalities were found in 37% of the children and included ILD, chest wall calcinosis, and airway disease; most results were subclinical and owing to weakness and not parenchymal disease.29 In adults, ILD is a major contributor to morbidity and mortality in myositis. 35–46% of adults with DM develop ILD during the course of their disease, which is associated with anti synthetase antibodies such as antiJo1.30 Rapidly progressive ILD has also been associated with clinically amyopathic dermatomyositis (CADM) and antiCADM140 autoantibodies in Japanese adults, and is rarely seen in children;31 although data for patients of other ethnic origins has not yet been reported. Pulmonary function tests will show a restrictive pattern with decreased diffusing capacity for carbon monoxide; highresolution chest CT should be used for confirmation, as pulmonary function test abnormalities can result from respiratory weakness alone. Imaging abnormalities

Table 1 | Clinical characteristics and mortality associated with juvenile and adult DM

Disease features Juvenile DM Adult DM

Peak age of onset 7 years6,10–12 30–50 years13

Proportion of IMM cases

80–95%,19,127,128 35–50%129

Proximal weakness 85–95%10,12 88%130

Characteristic rash Gotton papule: 73–91%7,131 Heliotrope rash: 62–83%7,131 Malar rash: 42–57%7,131 Abnormal nailfold capillaries: 80%131

Gottron papule: 54%130 Heliotrope rash: 74%130 Malar rash: data not available Abnormal nailfold capillaries: 43%132

Calcinosis or ulceration 26–40%19,131,133 2–16%19,133

Refractory or chronic disease

59–63%12,134 63%133

Malignancy 1%12,133 15–24%41,133

Myositis-specific antibodies

2–40%19,59 48–70%38,59

Interstitial lung disease 7–19%29 35–40%30

Gastrointestinal disease 2–3%4,19 1%19

Raynaud disease 10%135 11%136

Mortality <5%12,13,133 21%133

Abbreviations: DM, dermatomyositis; IMM, inflammatory myopathic myositis.

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include nodules, linear opacities, ir regularity, groundglass opacities, and fibrosis.30

Cardiac involvementPatients with DM have been reported to develop involvement of the cardiac muscle with pericarditis, myo carditis, conduction defects or heart block. Cardiovascular complications in juvenile DM are rare (Table 1). In a case–control study, patients with juvenile DM had evidence of diastolic dysfunction, pericarditis, and hyper tension compared with healthy controls, although disease was largely subclinical.32 In adults, cardiac involvement causes death in 10–20% of patients with myositis, with a reported 16 times increased risk of myocardial infarction.33 Congestive heart failure has been reported in 3–45% of adults with myositis, with diastolic dysfunction in 12–42%, and pericarditis has been reported in about 10%.33 Subclinical electrocardiogram abnormalities are observed in 33–72% of patients with adult DM, particularly conduction blocks.33 In general, longstanding nonspecific inflammation can be associated with atherosclerosis and cardiovascular disease; some cardiac effects are secondary to direct inflammation of the heart muscle, whereas other effects are secondary to longstanding systemic inflammation.33,34

Clinically amyotrophic dermatomyositisIn our experience, some patients present with classic DM rash, but no sign of muscle weakness or inflammation, which has been described in CADM.35 In children, controversy exists as to whether these patients have mild undiagnosed muscle inflammation or what is termed hypomyopathic DM, or will progress to moresevere muscle involvement and/or longterm sequelae (such as calcinosis and lipodystrophy) if untreated. Case report findings have associated CADM with aggressive ILD in Japanese children, with possible overlap of disease features with scleroderma.36–38 In adults, CADM progresses to muscle weakness in 20% of cases, is associated with risk of ILD, and carries similar risk of malignancy to DM (Table 1).39

MalignancyAn association with malignancy at disease onset is observed in adults with DM, but rarely in children with atypical features of disease (Table 1).40 As many as 15–24% of adult patients can be diagnosed with malignancy, either at the time of diagnosis with DM or shortly thereafter.41 Most commonly, these patients are diagnosed with adenocarcinomas of cervix, lung, ovaries, pancreas, bladder or stomach, and the tumors are similar in distribution to types of cancers found in control populations.41,42 Malignancy in adults with DM can be resistant to treatment. Risk factors for malignancy include moresevere skin and muscle disease, ILD, or the presence of antip155/140 antibodies.31

Laboratory resultsDisease markersElevated serum levels of musclederived enzymes (crea tine kinase, aldolase, aspartate aminotransferase and lactate dehydrogenase) reflect muscle inflammation or damage.14

In juvenile DM, elevation of creatine kinase becomes less sensitive as a marker with chronic disease.43 Evidence of antinuclear antibodies are seen in 20–30% of adult DM and >70% of juvenile DM.44,45 However, myositisspecific antibodies (MSAs) are more prevalent in adults with DM than in juvenile DM, and are therefore more indicative of different disease subsets in these patients; in our experience, children who are positive for MSAs are less likely to have a specific disease course and MSA levels are less prognostic than in adults. In the past 5 years, reports of new auto antibodies in juvenile DM have enabled the prediction of disease subsets in these patients (discussed below).

Neopterin and products of von Willebrand factor have been reported to be elevated in a subset of patients with active inflammation from juvenile DM or vasculitis, but are not specific for juvenile DM.46,47 Because of the low sensitivity of the available laboratory testing, further gene expression, cytokine, and chemokine markers are under investigation. Type I interferon (IFN)regulated genes, cytokines (IL6 and IL1) and chemokines (such as CXCchemokine ligand [CXCL] 10, also known as IP10; CCchemokine ligand [CCL] 2, also known as monocyte chemoattract protein or MCP1; and CCL8, also known as MCP2) are overexpressed in peripheral blood of adult and juvenile patients with DM, which seem to be sensitive markers of disease activity and differ between adult and juvenile DM.48 The IFN–chemokine score correlated with disease activity (global visual analog scale) in both adult and juvenile DM cohorts, whereas the IFN gene signature correlation with disease activity was statistically significant only in adult DM.48

Autoantibody profilesMyositis-associated antibodiesMyositisassociated antibodies (MAAs) and antinuclear antibodies (ANAs) are commonly present in juvenile (>70%) and adult DM (30%); however, tests for anti bodies to SSA, SSB, Sm, RNP, and DNA are less often used in juvenile DM unless overlap connective tissue features such as scleroderma are present (<20%).45.49 MAAs (especially antiSSA) are more commonly found in the adult population clinically thought to have DM (24–35%) (Table 2).50 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 as well as sclero dactyly.50,51 This subset in juvenile DM has many presenting features shared with scleroderma, such as severe Raynaud disease. In adults, PMScl is associated with scleroderma myo pathy and with cardiac involvement.51,52

Myositis-specific antibodiesMSAs are divided into three main groups: anti synthetase antibodies, antisignal recognition particle (SRP) autoantibodies, and antiMi2 autoantibodies, each with unique clinical features and outcomes.53 Antisynthetase anti bodies (antiARS, antiJo1, antiPL12, antiPL7, antiEJ, antiOJ, antiKS, antiHA, and antiZA) have been associated with antisynthetase syndrome, consisting of mechanic’s hands, Raynaud syndrome, ILD, arthritis,

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and fever.54 In 2008, antip155/140 and antip140 autoantibodies have been described in 20–30% of children with juvenile DM, but their clinical significance is not fully established.55 Antip140 antibodies might be associated with increased odds of calcinosis (odds ratio 7.0, range 3.0–16.1).56 In adults, antip155/140 and antip155 autoantibodies have been associated with malignancy.57 Another autoantibody, labeled antiMJ antibody, recognizes a 140 kDa protein and was associated with severe disease with contractures and atrophy in Argentinian children.58 Furthermore, an antiCADM140 auto antibody has been reported in Japanese patients with CADM who developed rapidly progressive ILD.31 Whether these autoantibodies target similar proteins or are epitopically distinct is unclear. AntiSRP antibodies have been described

in DM, but are more commonly described with severe acquired necrotizing myopathies. Presence of MSAs is rare in children compared with adults; positive tests for antiJo1, antiMi2 and other MSAs may portend marked disease (Table 2). With increasing knowledge of new autoantibodies, currently as many as 40% of children and 70% of adults could have MSAs or MAAs present.59 These numbers may change as our knowledge increases.

Pathogenesis of juvenile and adult DMAlthough early IIM classification schemes suggested differences in DM presenting in adults and children, few direct investigations support these differences and current clinical and pathological data support both sides of the argument.

Table 2 | Autoantibodies in juvenile and adult DM

Antibody Autoantigen target Frequency in white patients with juvenile DM (%)

Frequency in white adults with DM (%)

Frequency in non-white adults with DM (%)

References

MSAs

Anti-ARS Aminoacyl-tRNA synthetases 1–5 30 Koreans: 12 African Americans: 29

Kang et al. (2010)137; O’Hanlon et al. (2006)138

Anti-Jo1 Histidyl-tRNA synthetase 2–5 25–30 African Americans: 13 Wedderburn et al. (2009)53; O’Hanlon et al. (2006)138

Anti-PL12 Alanyl-tRNA synthetase 1–3 <5 African Americans: O’Hanlon et al. (2006)138

Anti-PL7 Theonyl-tRNA synthetase <1 <5 Japanese: 17 African Americans: 1.6

O’Hanlon et al. (2006)138; Yamasaki et al. (2006)139

Anti-EJAnti-OJ

Glycyl-tRNA synthestaseIsoleucyl-tRNA synthetase

<1 <5 African Americans: 1.6 O’Hanlon et al. (2006)138

Anti-KSAnti-HAAnti-ZA

Asparagynyl-tRNA synthetaseTyrosyl-tRNA synthetasePhenylalanyl-tRNA synthetase

NA <1 NA Wedderburn et al. (2009)53

Other MSAs

Anti-Mi2 DNA Helicase 5 20–30 Koreans: 60 African Americans: 18

Kang et al. (2010)137; O’Hanlon et al. (2006)138; Brouwer et al. (2001)140; Okada et al. (2003)141

Anti-SRP Signal recognition particle 1–3 4–5 Korean: 2 African Americans: 3

Kang et al. (2010)137; O’Hanlon et al. (2006)138

New myositis autoantibodies

Anti-p155/140 Transcriptional intermediary factor 1-gamma protein

23–29 13–21 Koreans: 63 Japanese: 13–20

Kang et al. (2010)137; Hoshino et al. (2010)142; Kaji et al. (2007)143

Anti-p140 (Mj) Nuclear matrix protein NXP2 13–23 NA Koreans: 18 Argentineans: 22

Gunawardena et al. (2009)56; Espada et al. (2009)58; Kang et al. (2010)137

Anti-CADM140 – NA 10 Japanese: 10 Gunawardena et al. (2009)56; Nakashime et al. (2010)144

MAAs

Anti-U1-RNP U1 ribonucleoprotien (snRNP) 6 2–3 African Americans: 10 O’Hanlon et al. (2006)138

Anti-U3-RNP U3 ribonucleoprotein (fibrillarin) 1 NA NA Wedderburn et al. (2009)53

Anti-PM-SclAnti-Ro

Anti-La

Nucleolar multi-protein complex52 or 60Kd ribonucleoproteins (hYRNA) Ribonucleoprotein

5–72

1

212

8

African Americans: 1.6African Americans: 8

African Americans: 1.6

O’Hanlon et al. (2006)138

Anti-Ku P70/p80neterodimer, DNA-associated proteins

<1 0–9 African Americans: 1.6 O’Hanlon et al. (2006)138; Hausmanowa-Petrisewiscz et al. (1997)145

Anti-Topo DNA topoisomerase I 1 NA NA Wedderburn et al. (2009)53

Abbreviation: DM, dermatomyositis; MAA, myositis-associated antibody; MSA, myositis-specific antibody; NA, not available.

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Genetic susceptibilityGenetic background is thought to predispose individuals to DM, with HLA class an important factor (Figure 1). The major immunogenetic risk factor for adult and juvenile DM in white individuals is the HLA 8.1 ancestral haplotype (HLAB*08; DRB1*03; DQA1*05; DQB1*02) (Table 3).60–62 The presence of the HLADQA1*0501 allele is not only increased in white individuals, but also in other populations and clinical disease subsets in children.45,62,63 Protective alleles have been described in large genetic association studies in both adult and juvenile DM. Gene variation has been seen within an interferon regulatory factor 5 (IRF5) gene sequence, which might be associated with increased IFNregulated gene expression in individuals with juvenile DM.64 Polymorphisms in the tumor necrosis factor gene (TNFA –308A allele) have been implicated in increased disease severity or protection in patients with juvenile DM.65 The TNFA –308A allele may be increased in both adult and juvenile DM; however, disease significance is lost in DM when adjusting for HLAB, but not HLADB.66 IL1α polymorphisms might also convey protection for or risk of juvenile DM for white individuals.67 A weak association between an R620W variant of the PTPN22 gene in juvenile IIMs has been observed.68

Pathological findings in muscleIn our opinion, muscle biopsy is indicated for an atypical presentation or when diagnosis is in doubt. The presentation of clinical and muscle findings can be discordant, and evidence suggests that a muscle biopsy is useful for grading the extent of disease and staging potential longterm severity in juvenile DM.16,45,69 Adult and juvenile DM are characterized pathologically by varying degrees of peri fascicular atrophy, vasculopathy, and peri vascular inflammation (composed predominantly of plasmacytoid dendritic cells [pDCs], B cells, CD4+ T cells and macrophages), focal necrosis and phagocytosis of muscle fibers, fiber regeneration, inflammatory cell infiltrates and

vasculitis, and tubuloreticular inclusion bodies within endothelial cells (Table 3).70,71,100 Evidence of vasculopathy includes muscle capillary thrombosis and deposition of complement and the membrane attack complex on muscle capillaries, and reduction in number of, and enlargement of, remaining endomysial capil laries (capillary dropout).59,70,71 Capillary dropout has been found more prominently in areas of peri fascicular atrophy, although capillary remnants can still be found in areas of endothelial cell loss.70 Intermediatesized vessels are also be affected in juvenile DM, with a greater degree of C5b–9 complement membrane attack complex.71 A Chinese study compared muscle biopsies from adult and pediatric patients with DM and found increased evidence of vasculopathy in pediatric biopsies compared with adults; the findings were consistent with the descriptions from Bohan and Peter in 1975 and 1977.14,72,73 Formation of neolymphoid structures in juvenile DM muscle, where immature and mature CD4+ T cells are seen with B cells and pDCs, suggest local maturation of T cells.16,74 Similar structures were reported in adult DM with CD4+ T cells surrounded by B cells.75 One of the earliest findings in adult and juvenile DM muscle tissue is the upregulation of major histocompatibility complex (MHC) class I, which is almost universal in juvenile DM and to a lesser extent in DM.71,76,77 Whether the upregulation of MHC class I molecules is one of the precipitating events in myo sitis is unclear; however, animal models suggest a role in the unfolded protein response, which correlates with up regulation of IFNβ.78

In both juvenile and adult DM, the predominance of CD4+ cells are not only CD3+ (traditional CD4+ cells); a subset are positive for CD123 and CD83 (markers for mature pDCs), and positive for IL17, suggestive of T helper (TH)17 cells.79–82 Further phenotyping in adult DM shows increased numbers of cells expressing CD68 plus CD163, leukocyte function–associated antigen 1α (LFA1α), and CD11b compared with controls (P <0.05). Increased numbers of capillaries expressed IL1α and intercellular adhesion molecule 1 (ICAM1) in DM,83 with limited data in juvenile DM. Further studies in adult DM suggest that steroid treatment and improvement of muscle function coincide with disappearance of in flammatory cells, including CD3+ T cells.84,85

Type 1 IFNs (IFNα and IFNβ) are important in the pathogenesis of juvenile and adult DM (Figure 2). IFNs upregulate genes critical in immunoregulation and MHC class I expression, activate natural killer cells, support dendritic cell maturation, and promote the activation and survival of T cells. Muscle and skin biopsies in DM have shown increased pDCs and upregulation of IFN signaling.86 It is thought that MHC class I upregulation by IFNα in myofibers might cause activation of the endoplasmic reticulum stress response in DM, which could lead to muscle tissue injury and resulting myositis.87 Damage could also be caused by the cytokines upregulated by type 1 IFNs, including CXC chemokines (CXCL10; CXCL9, also known as MIG; and CXCL11, also known as ITAC).71 Tubuloreticular inclusion bodies are seen in adult and juvenile DM, but rarely

Multifactorial genetic inheritance■ HLA class maternal microchimerism■ Cytokine polymorphisms

Unknown enviromental trigger■ No known infectious etiology■ Birth seasonality

In�ammatory cascade■ Maturation of dendritic cells type 1 IFN response■ Cycle of in�ammation, damaged muscle and vascular endothelium■ B cells, CD4

+ T cells■ Overexpression of MHC class 1

Figure 1 | Genetics and environmental factors predisposing to juvenile and adult DM. The combination of both the genetic background and environmental stimuli are proposed to result in the initiation of the inflammatory cascade in DM. Abbreviations: DM, dermatomyositis; IFN, interferon; MHC, major histocompatibility complex.

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seen in other forms of myositis; they have been reported in circulating blood cells of other patients treated with IFNα and in cultured endothelial cells in response to

treatment with type I IFNs.88–90 Presence of these inclusion bodies may represent viral infection or increased IFN signaling.

Table 3 | Immunological and pathological findings in juvenile and adult DM

Features Juvenile DM Adult DM Controls References

Peripheral blood

Total peripheral blood lymphocytes 64% total peripheral count

50–75% 50–75% O’Gorman et al. (2000)96; Viguier et al. (2003)97; Iannone et al. (1996)146

CD3+CD4+ (as a % of total peripheral blood mononuclear cells)

40 38–60 43 Ishii et al. (2008)94; Viguier et al. (2003)97

CD3+CD8+ peripheral blood (% of total mononuclear cells)

21 14–18 20–26 Ishii et al. (2008)94;O’Gorman et al. (2000)96;

Iannone et al. (1996)146

CD20+ or CD19+ (% total peripheral blood mononuclear cells)

30 5–24 13–19 Ishii et al. (2008)94; Eisenstein et al. (1997)95; O’Gorman et al. (2000)96 ; Viguier et al. (2003)97

CD3+CD16+CD56+ (% total peripheral blood mononuclear cells)

0–17 0–4 4 Ostrowski et al. (2010)17; Ishii et al. (2008)94

O’Gorman et al. (2000)96

CD3-CD16+CD56+ (% total peripheral blood mononuclear cells)

0–15 0–15 17 Ishii et al. (2008)94

O’Gorman et al. (2000)96

Pathological features (muscle and skin)

MHC class I upregulation (% of samples)

97–100 67–100 0 Emslie-Smith et al. (1990)71; Sallum et al. (2006)84; Jain et al. (2007)147

Perivascular Inflammation (predictor of disease)

0.77 CI0.66 CI

NA70 CI

NANA

Wedderburn et al. (2007)148

CD4+CD3+ muscle (as a % of total mononuclear cells)

20–80 30–60 0 Mizuno et al. (2004)149; Choi et al. (2009)150

CD4+CD3+ skin (as a % of total mononuclear cells)

NA 30 0 Wenzel et al. (2006)151

B cells (as a% of the total muscle tissue mononuclear cells)

20–80 13 24 Mizuno et al. (2004)149

pDCs (% total muscle mononuclear cells)

45 42 19 Lopez de Padilla et al. (2007)74; Greenberg et al. (2005)79; Page et al. (2004)81

TREG cells in muscle 0–12 10 30–37 Khanna & Reed (2010)59; Waschbisch et al. (2010)152

TREG cells in skin NA 9 20–21 Antiga et al. (2010)153

CD4+CD25+ (total peripheral blood mononuclear cells)

NA 0.9 1.4 Antiga et al. (2010)153

Muscle capillary thrombosis (predictor of disease)

0.04–0.36 (95% CI 50)

NA 0 Wedderburn et al. (2007)148; Crowe et al. (1982)154

MAC (samples) 55–83 26–81 0 Pestronk et al. (2010)70; Kissel et al. (1986)155; Jain et al. (2011)156

MxA (samples) 85 55–93 0 Greenberg et al. (2005)79; Shrestha et al. (2010)86

IL-1 (samples) NA 100 50 Grundtman et al. (2007)157

TNF (samples) 1.25–13 mean 5.2 mean 2.9 Fedczyna et al. (2001)158; Hassan et al. (2006)159

Genetics

HLA DRB1*0301 46 44 28 Chinoy et al. (2009)160

DQA1*0501 58–85 40 39 Mamyrova et al. (2006)61; Reed & Stirling (1995)62; Reed et al. (1991)63; Wedderburn et al. (2007)148; O’Hanlon et al. (2005)161

DQB1*02 52 30 30–40 Chinoy et al. (2006)162

DPB1*0101 22.5 20.5 12.7 Chinoy et al. (2009)160

TNF-308A 50 26–56 14–44 Chinoy et al. (2007)66; Pachman et al. (2001)163; Werth et al. (2002)164

Pathological features in juvenile and adult DM noted as a % unless otherwise noted. Abbreviations: DM, dermatomyositis; IL, interleukin; MAC, membrane attack complex; NA, not available; pDC, plasmacytoid dendritic cell; TREG cell, regulatory T cell.

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Other immune pathways are involved in both adult and juvenile DM, including IFNγ, IL1 and TNF. High levels of TNF are reported in both adult and juvenile DM and proposed to be directly toxic to myofibers, while preventing muscle regeneration.75,91,92 TNF levels do not correlate directly with amount of inflammatory cells and suggest roles for TNF in DM other than the classic proinflammatory effects. IL1α and IL1β are consistently expressed in adult DM muscle tissue and are directly related to TNF expression in muscle.92,93 Blockade of IL1 in a small openlabeled study was effective in improving disease.92 Little is known about the role of IL1 in juvenile DM.

Furthermore, the proinflammatory cytokine IFNγ, important in the TH1 inflammatory pathway, is involved in both adult and juvenile DM. Tournadre and colleagues82 demonstrated that, in adult DM, muscle biopsies tended to have more TH1driven inflammation and IFNγ expression versus TH17stained cells, suggesting either differences in the disease or disease state.

Peripheral blood phenotypingLymphopenia is reported in both adult and juvenile DM. Lymphocyte enumeration studies are variable and difficult to compare.75,78,94–96 However, phenotyping of the peripheral immune blood cells, while not diagnostic, show dysregulated phenotype subsets proposed to be reflective of active disease.75,78,94–96 In adult DM, reports of a decrease in total lymphocyte (CD3+) numbers as well as the number of cell subsets (CD19+, CD4+, CD8+) are seen before the onset of treatment, which recovers shortly after treatment.76 Studies also suggest that CD19+ and specifically CD19+CD23+ T cells are increased in adult DM, while CD4+CD45RO+ T cells are decreased in the peripheral blood.73 In children less than 10 years of age, an increase in CD19+ B cells and decreases in the number of CD3–CD16+ and/or CD56+ natural killer cells and CD3+CD8+ T suppressor or cytotoxic cells are reported (Table 3).94–97 Studies on recovery of these cells are overall lacking and little data exists to suggest usefulness in

monitoring of disease activity, with the exception of a marked increase in adult total lymphocyte counts.76

Maternal michrochimerismJuvenile DM has been postulated to resemble chronic graft versus host disease, and maternally derived chimeric cells have been found more often in children with juvenile DM than in either siblings or healthy controls.98–100 These chimeric cells can be present in lymphoid aggregates in muscle tissue of affected children with juvenile DM, and chimeric stem cells can be seen in peripheral blood.16 Studies in adult DM are lacking; however, PM was seen in 8% of individuals who underwent hematopoietic stem cell transplantation whereby 33–64% of patients develop chronic graft versus host disease.101

Infectious and environmental triggersMany children will report symptoms consistent with infect ion before the development of juvenile DM; however, viral illness is common in this age group and retrospective analyses of infectious history before develop ment of juvenile DM is prone to recall bias.103 Multiple retrospective studies have been performed indicating high frequency of infectious symptoms within a few months before onset of juvenile disease.102,103 Searches for infectious agents in tissue or serum have been negative.104 Some association of birth seasonality, especially in Hispanic individuals, has been observed with risk of juvenile DM, but this result was not reproduced in other ethnic groups within the same cohort.105 Adult and juvenile DM also share a number of suspected environ mental triggers that have been temporally associated with the onset of myositis (Figure 1), including exposure to excessive ultraviolet light, certain drugs (such as d penicillamine), and infectious agents. A retrospective multicenter crosssectional study in 2009 found that ultraviolet radiation intensity was associated with increased odds of DM compared with other inflammatory myo pathies (odds ratio, 2.3; 95% CI 0.9–5.8), and increased odds of antiMi2 antibodies (odds ratio, 6.0; 95% CI 1.1–34.1), and this effect was stronger in women.106

Treatment of juvenile and adult DMTraditional therapiesNo prospective case–control doubleblinded studies of immunosuppressive therapy in adult or juvenile DM have been performed (Table 4). After the inception of cortico steroid treatment of juvenile DM, the mortality rate reduced markedly compared with historical controls. Pro longed corticosteroid treatment is associated with substantial morbidity including decreased height velocity in children, weight gain, osteoporosis, immuno suppres sion, avascular necrosis, adrenal suppression, cataracts, diabetes, among others.53 With the concomitant use of methotrexate in juvenile DM, the mean time of corticosteroid use was reduced to 10 months compared with historical controls, which required a mean time of 27 months.107 Surveys of North American pediatric rheumatolo gists indicate that most practitioners will treat typical juvenile DM with corticosteroids and metho trexate although

iDC pDC

Enviromental trigger (infection,UV light, D-penicillamine)

and endoplasmic reticulum stress

Type 1 IFNresponse

■ IL-1■ CCL2 and CCL8■ CXCL10■ MxA■ CXCL11■ IL-15

EndothelialCD4

+ T cell

Figure 2 | Early pathological changes in juvenile and adult DM. Proposed early events in the innate immune system response in DM, with the maturation of dendritic cells after an environmental trigger, which could include the endoplasmic reticulum stress response. This activation results in a type 1 IFN response and, ultimately, the inflammatory environment seen with active disease. Abbreviations: CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand; DM, dermatomyositis; iDC, immate dendritic cells; IFN, interferon; pDC, plasmacytoid dendritic cells; UV, ultraviolet.

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there is great discrepancy between dosing regimens.108 Adjunct medications and medications for refractory disease vary, but include hydroxy chloroquine, intravenous immuno globulin (IVIG), rituximab, cyclophosphamide, ciclosporin, azathioprine, tacrolimus and mycophenolate mofetil.108 In a large cohort of European and South American individuals with juvenile DM, European patients were more likely to receive cyclophosphamide, ciclosporin, and azathioprine as treatment than South American patients, suggesting some cultural or national variations in prescribing practices.5

In adults, corticosteroids and multiple immunosuppressive agents have been used for treatment of DM. In retrospective studies, methotrexate has been postulated to be effective as a steroidsparing agent, but comparisons with other immunosuppressive agents have shown no superiority.53,127 Prospective clinical trials of methotrexate versus placebo have not been conducted in adults or children. A randomized trial of azathioprine versus methotrexate showed no marked difference in effect between the two agents.109 Similarly, in a randomized controlled trial of ciclosporin versus metho trexate showed no difference in efficacy or toxicity.110 Methotrexate and azathioprine have also been tried in combination, with no marked difference between the combination therapy and methotrexate alone, although the study was limited by a lack of power.111 No evidence exists that methotrexate is associated with ILD in adult DM, which might explain the rationale for the increased use of azathioprine in adults compared with children.

Therapy for refractory diseaseIn openlabel studies, intravenous IVIG has been helpful for patients with refractory disease and may help decrease steroid toxicity and improve skin and muscle disease, but placebocontrolled trials of this therapy are not available

in children.1 In adults with DM, a doubleblind placebocontrolled trial showed improvement in skin and muscle disease, with improvement in biopsy results after IVIG treatment.112 IVIG can help with severe dysphagia and esophageal weakness in adults.113 Adverse reactions in juvenile patients with DM have been associated with the IgA content in IVIG infusions. In a retrospective review of 38 patients with juvenile DM receiving 1,056 IVIG infusions (between 1986 and 2005), 9% of infusions were associated with adverse reactions (fever, lethargy, or vomiting), more frequently in those receiving IVIG preparations with IgA concentrations >15 μg/ml.114 In retrospective studies, mycophenolate mofetil has been used as a steroid sparing agent and could benefit patients with refractory skin and muscle disease.115,116 Similarly, ciclosporin has been reported to have beneficial results on juvenile DM in small case series.117,118 Randomized controlled trials of these agents in adult myositis are also lacking.

In juvenile DM, no specific evidence supports treatment of calcinosis although multiple case reports of various treatments have been reported.119–122 AntiTNF agents, bisphosphonates, and calciumchannel blockers have been used for this purpose.116–119 In our experience, surgical excision may be indicated in areas of recurrent infection, chronic pain, or impedance of function from calcinosis. Treatment of resistant skin disease is controversial—topical corticosteroids and pimecrolimus can help with symptomatic itching or redness, but expert opinion suggests that resistant skin disease reflects ongoing systemic disease and should be treated with increasing immunosuppression.

Biologic therapies are beginning to emerge for the treatment of myositis, and given the findings of increased serum CD19+ B cells and lymphoid follicles in muscle biopsies of affected patients, rituximab has been proposed as a possible therapy.123 Initial case series noted clinical

Table 4 | Treatment of juvenile and adult DM

Therapy Juvenile DM Adult DM

First line therapy

Corticosteroids (2 mg/kg oral therapy or pulse intravenous 30 mg/kg therapy for more-severe disease) Methotrexate (oral or subcutaneous 1 mg/kg or 15 mg/m2 weekly, maximum dose 40 mg) Intravenous immunoglobulin (2 g/kg, maximum dose 70 g) monthly may be used in refractory or severe disease

Corticosteroids (0.75–1 mg/kg or 60–80 mg daily)Methotrexate (oral or subcutaneous 20–30 mg weekly)Azathioprine (oral 2 mg/kg per day)

Second-line therapy

Intravenous immunoglobulin Rituximab (750 mg/m2, maximum dose 1,000 mg per two doses 2 weeks apart) Ciclosporin Azathioprine Tacrolimus Mycophenolate mofetil

Intravenous immunoglobulin Rituximab (750 mg/m2, maximum dose 1,000 mg per two doses 2 weeks apart) Ciclosporin Tacrolimus Mycophenolate mofetil

Third-line therapy

Bone marrow or stem cell transplant Cyclophosphamide Other biologics (anti-TNF therapy, anakinra, alemtuzumab)

Bone marrow or stem cell transplant Cyclophosphamide (can be first-line therapy in patients with ILD) Other biologic agents (anti-TNF therapy, anakinra, alemtuzumab)

Adjunct therapy

Sunscreen and sun avoidance Hydroxychloroquine (5-7 mg/kg per day) Calcium and vitamin D for osteoporosis prevention

Sunscreen and sun avoidance Hydroxychloroquine (200–400 mg per day) Calcium and vitamin D for osteoporosis prevention and treatment

Abbreviations: DM, dermatomyositis; ILD, interstitial lung disease.

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improvements in skin and muscle in patients with DM that paralleled Bcell depletion.123 A large randomized controlled crossover trial of rituximab in refractory juvenile DM and adult DM or PM (the Rituximab in Myositis Study) was conducted.124 Patients refractory to corticosteroids and at least one other immunosuppressive agent were given rituximab or placebo on weeks 0 and 1, and weeks 8 and 9. All study participants received rituximab, and the outcome was time to response. The study found 83% of refractory adult and juvenile patients with myositis met the definition of improvement, but no difference in time to improvement was observed between the study groups.124 Early findings suggest that the juvenile cohort had improved response to rituximab within this study.125

Consensus protocolsThe Childhood Arthritis and Rheumatology Research Alliance (CARRA) has developed consensus protocols for therapy of patients with moderately severe juvenile DM, which include combinations of oral cortico steroids, pulse intravenous corticosteroids, methotrexate and IVIG.125 Within the CARRAnet cohort, almost all patients have been treated with corticosteroids and about half have been exposed to pulse corticosteroids or IVIG.126 Use of consensus protocols over time will hopefully lead to a more evidencebased rationale for treatment in the future.

ConclusionsAlthough the causes of juvenile and adult DM are still elusive, the latest developments point to the involvement

of IFN and lymphoid follicles in the pathogenesis of DM (Figures 1 and 2). International and national collaborators are working on developing standard protocols for assessment and treatment of juvenile DM. An initially aggressive approach with corticosteroids and DMARDs (such as methotrexate) could result in improved longterm outcomes and reduced calcinosis and steroid toxicity. In children, prognosis is generally favorable, although work needs to be done in minimizing treatment toxicity and longterm morbidities of disease (calcinosis, lipodystrophy, cardiac and pulmonary complications). In adults, cardiovascular complications, ILD, and malignancy associated with DM are leading causes of mor tality; routine screening and evidencebased treatment for these manifestations are necessary to improve outcomes in adult DM. Work using IFN signaling as a biomarker and using findings in pathogenesis as a rational basis for treatment and therapy will be a challenge for DM researchers in the future.

Review criteria

We searched for original articles focusing on dermatomyositis in PubMed published between 1975 and 2011. The search terms we used were “dermatomyositis”, “juvenile”, and “adult”, alone or in combination. All papers identified were English-language full-text papers. We also searched the reference lists of identified articles for further relevant papers, and abstracts from the 2010 American College of Rheumatology Annual Meeting.

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AcknowledgmentsThe authors would like to acknowledge the support of the State of Minnesota Partnership and the National Institute of Arthritis and Musculoskeletal and Skin Diseases for grant support.

Author contributionsBoth authors contributed equally to researching, discussing, writing, reviewing and editing the manuscript.

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Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis