Adult and juvenile dermatomyositis: are the distinct clinical features explained by our current understanding of serological subgroups and pathogenic mechanisms?

Adult and juvenile dermatomyositis share the hallmark features of pathognomic skin rash and muscle inflammation, but are heterogeneous disorders with a range of additional disease features and complications. The frequency of important clinical features such as calcinosis, interstitial lung disease and malignancy varies markedly between adult and juvenile disease. These differences may reflect different disease triggers between children and adults, but whilst various viral and other environmental triggers have been implicated, results are so far conflicting. Myositis-specific autoantibodies can be detected in both adults and children with idiopathic inflammatory myopathies. They are associated with specific disease phenotypes and complications, and divide patients into clinically homogenous subgroups. Interestingly, whilst the same autoantibodies are found in both adults and children, the disease features remain different within autoantibody subgroups, particularly with regard to life-threatening disease associations, such as malignancy and rapidly progressive interstitial lung disease. Our understanding of the mechanisms that underlie these differences is limited by a lack of studies directly comparing adults and children. Dermatomyositis is an autoimmune disease, which is believed to develop as a result of an environmental trigger in a genetically predisposed individual. Age-specific host immune responses and muscle physiology may be additional complicating factors that have significant impact on disease presentation. Further study into this area may produce new insights into disease pathogenesis.

Both JDM and adult DM are heterogeneous disorders, and clinical outcome is highly variable. In children early studies described three groups: those with monocyclic (permanent remission within 2 years), polycyclic (periods of remission followed by relapse) and chronic continuous disease. Although modern treatment has improved outcomes, recent long-term outcome studies still show signifi cant numbers of patients with ongoing disease or damage [5,6]. Inadequate or delayed treatment has been shown to be an important factor in predicting a chronic course and poor outcome, while several studies suggest that aggressive early treatment results in lower morbidity and improved outcome [7][8][9].
Laboratory tests such as creatinine kinase are less likely to be elevated in JDM than adult DM and therefore other myositis-associated enzyme levels (such as aldolase, lactate dehydrogenase and transaminases) are also tested [10]. Amyopathic myositis is rare in children; more often patients have mild muscle disease or progressive muscle disease that was not detected on earlier assessment [1, 11,12]. Studies of disease outcome in juvenile and adult myositis are diffi cult to compare due to the lack of standardised outcomes. Overall, however, whilst JDM may have a rapid onset and is associated with considerable morbidity, and even mortality, it appears to have a better prognosis than adult disease if treated appropriately in terms of recovery of both muscle power and function.

Malignancy
In adults there is a clearly established association between DM and the development of malignancy. In all patients with idiopathic infl ammatory myopathy the incidence of cancer is 7 to 30% [2, 13,14]. Th e increased risk is higher in patients with DM than polymyositis, and overall there is a threefold increase in risk of malignant disease for all cancer types after diagnosis of DM [4,15].
Whilst no specifi c cancer subtype is associated with DM, and an increased risk of all cancer histological subtypes is seen, approximately 80% of associated malignancies are adenocarcinomas [5, 6,15]. Th e risk of malignancy is highest in the fi rst year after diagnosis and reduces thereafter [7][8][9]15]. Malignancy can also predate the diagnosis of myositis, and the clustering of cancer cases before diagnosis of myositis suggests that the association is not merely the result of increased cancer surveillance in patients with known myositis [10,14,15]. Two studies showed that the risk of cancer remained increased up to 5 years after the diagnosis of myositis [15,16].
It has been suggested that DM in adults should be considered a paraneoplastic syndrome. Certainly DM has been noted to improve with treatment of an associated cancer, and muscle weakness to recur at relapse of malignant disease, further suggesting a paraneoplastic origin [15]. Th is appears to apply to a subgroup of patients, however, and given that the average age of onset in adults is 50 to 60 years, the longer patients survive the more likely they are to develop non-myositis-associated cancers.
In contrast, to date, JDM has not been clearly associated with malignancy and cases of malignancy in children with JDM are limited to case reports [17]. Routine malignancy screening is not therefore generally performed in children unless unusual features are present, for example, splenomegaly. Interestingly, amongst adult DM patients, younger patients have a lower risk of associated malignant disease than those aged over 45 years [15]. Th is may refl ect the general increased risk of malignant disease with increasing age, and diff erent triggers for myositis according to age. In the UK JDM Cohort Study, now comprising >390 children, the majority with JDM, there have been no reported malignancies (LW, unpublished observations). However, longterm follow-up is needed to ascertain the malignancy risk of these individuals in adult life.

Lung disease
Lung disease in myositis includes aspiration pneumonia, respiratory muscle weakness and ILD. ILD is a signifi cant cause of mortality in adults with DM and is associated with a poorer prognosis [18,19]. ILD aff ects 20 to 65% of adults with idiopathic infl ammatory myopathy [20]. However, prevalence varies with the means of detection and the wide range of reported prevalence is likely to refl ect the lack of a standard screening approach in newly diagnosed patients. Increased awareness of ILD as a presenting symptom, and improved diagnostic techniques have led to increasing rates of ILD in myositis patient cohorts; 19% of idiopathic infl ammatory myositis patients present with ILD prior to muscle weakness [21]. ILD in adult myositis can run a rapidly progressive course or a chronic course. In a study of 36 adult patients with ILD, 58% had a chronic course, 25% were asymptomatic and 17% presented with acute respiratory failure [21]. In a retrospective study of Korean myositis patients, ILD was observed in 40.3%, and was associated with reduced survival. Poor prognostic markers were a Hamman-Richlike (acute interstitial pneumonitis) presentation, amyopathic dermatomyositis and an initial forced vital capacity <60% [19]. Prospective studies suggest a 40% increase in mortality associated with ILD in adult patients with idiopathic infl ammatory myositis [22].
Rapidly progressive ILD is frequently associated with amyopathic DM (patients with the characteristic skin rashes but without muscle weakness or raised muscle enzymes). Th is phenotype is more commonly seen in Eastern Asia [23]. Th ese patients are often resistant to intensive therapy with high dose corticosteroids and immunosuppressive treatments, leading to respiratory failure and death. Associated mortality is high.
Several pathologic patterns of ILD are found in myositis, and as with other causes of ILD, the pathologic appearance impacts on prognosis regardless of the underlying aetiology: non-specifi c interstitial pneumonia (NSIP) is associated with a better prognosis than other subtypes. Connective tissue disease-associated ILD, includ ing histopathologic subtypes, has been recently reviewed [24]. Diagnosis on CT chest patterns in patients with anti-Jo1 antibodies and anti-synthetase syndrome showed a preponderance of NSIP aff ecting 50% and usual interstitial pneumonia (UIP) aff ecting 30%. Surgical biopsy patterns were diff erent, however, with diff use alveolar damage in 55% and UIP in 45% and NSIP in 15% [25]. Th is may refl ect a selection bias for performing biopsies in patients presenting with acute interstitial pneumonia or those who are not responding well to treatment. Another study looking at similar patients with anti-PL12 antibodies showed a similar incidence on biopsy or CT consistent with UIP in 45% of patients, 16% NSIP and 16% cryptogenic organising pneumonia [26]. Th is is in contrast to an earlier study of 17 adult idiopathic infl ammatory myositis patients all of whom underwent biopsy. NSIP was seen in 11 cases (65%) and UIP in 4 cases [22].
Although data on pulmonary involvement in JDM are limited, reported rates of lung disease in JDM are far less common than in adult DM [27]. Asymptomatic impairment in pulmonary function has been reported to be common, with 40% of aff ected children having ab normal pulmonary function tests [28]. Radiographically proven ILD is rare, however. Kobayashi [29] reported fi ve cases of JDM-associated ILD: lung disease progressed despite treatment and was refractory to methyl pred nisolone in all cases. One patient died of respiratory failure. No patient underwent lung biopsy but radio logical diagnoses were interstitial pneumonia in three cases and bronchiolitis obliterans organising pneumonia in two cases. Th e apparent incidence of JDM-associated ILD in this study was 50%, much higher than reported elsewhere, which may refl ect referral bias to a specialist hospital [29]. Genetic and environmental factors may also have a role to play. It has been speculated that abnormal pulmonary function tests and asympto matic high-resolution computed tomography (HRCT) abnormalities seen in JDM may represent a background of subclinical ILD that responds well to conventional immunosuppressive treatment, and therefore needs no further action [29]. A small study looking at the pulmo nary outcome in JDM found that, on follow-up, JDM patients had smaller lung volumes than controls, and that 75% had impaired diff usion, restriction or an HRCT abnormality [30].
Given that HRCT abnormalities correlated with cumulative organ damage and poorer patient-reported health status, the authors speculated that lung symptoms may have been masked by damage to diff erent organ systems, which in turn limit exercise capacity. Th us, some degree of pulmonary involvement in JDM may be higher than previously recognised. However, a recent outcome study comparing adults with children found only 3.5% of children with JDM, compared to 49% of adults with DM (P < 0.001), to have pulmonary damage at long-term follow-up [6].

Calcinosis
Calcinosis is a relatively common disease manifestation in JDM and occurs in up to 30% of cases; it is a cause of considerable morbidity, and can lead to skin ulceration, pain from nerve entrapment and joint contractures [4, 6,31]. It typically occurs 1 to 3 years after JDM diagnosis, but may develop at the onset of illness or up to 20 years later [32]. Calcinosis most frequently aff ects pressure areas such as the elbows, knees, buttocks and digits. It is associated with delayed diagnosis, a chronic disease course and inadequately treated disease [7,10]. Increased local production of the proinfl ammatory cytokine TNFα has been associated with the development of calcinosis and therefore the intensity of infl ammation may contribute [33]. Th e UK JDRG cohort study found the frequency of calcinosis to be 12% of children [4]. Th e lower frequency than in other studies may refl ect earlier diagnosis and more aggressive treatment in the UK JDRG cohort, or relatively short follow-up in some patients at the time of analysis. Calcinosis is less common in adult patients and when present appears to occur later in the disease course [34].
Whilst the associated clinical features of ILD, malignancy and calcinosis contribute to the morbidity and mortality observed in DM, the diff erences between adult and childhood disease extend beyond these key well studied complications. Other important disease associations include skin ulceration, and major organ vasculopathy (in particular gut, cardiac, and central nervous system), which are known to be much more common in JDM than in adult disease [35].

Pathogenesis
Comparisons of the pathogenesis of adult DM and JDM are hampered by the fact that few studies have directly compared the two groups. Studies in this area tend to be limited to modelling adult or juvenile disease, or because of the rarity of the conditions, have included both adults and children and combined the results. Th e pathological fi ndings in muscle in adult and juvenile myositis have recently been comprehensively reviewed [27].

Age of onset
Not only are there diff erences in the clinical phenotype of adult DM and JDM, but also within each subgroup age of onset appears to infl uence disease features and outcome. A recent study comparing children whose JDM starts before the fi fth birthday with those who have onset after 5 years, suggests that young age of onset is associated with more ulceration and generalised oedema, both considered to be poor prognostic features [36]. Interestingly, adapting a major histocompatibility complex (MHC) class I heavy chain overexpressioninduced mouse model of DM, so that MHC class I protein was expressed from a younger age, resulted in a more severe disease phenotype with rapid onset of weakness and even early death [37]. Histological analysis did not suggest a diff erent infl ammatory process but rather more rapid kinetics. Younger more rapidly growing muscle tissue may be more sensitive to disturbances in the balance of myoblasts to myofi bres, and changes in these pathways could induce more rapid overall muscle damage [37]. Th ese studies suggest that diff erences in physiology at varying ages impact on the pathophysiology of myositis disease, with young muscle perhaps being more sensitive to stressful stimuli. However, considerable data also suggest that, in model systems, young muscle is more able to recover from injury than old muscle, perhaps due to a diff erence in satellite cell activity [38].

Myositis-specifi c autoantibodies
Myositis-specifi c autoantibodies (MSAs) can now be identifi ed in 80% of adults [39] and >60% of children with myositis (NM and ST, personal data). Th ese serological markers help defi ne distinct clinical subsets and can predict the likelihood of developing complications [39,40] (Table 1). In DM the same autoantibodies are seen in both adult and juvenile forms, and specifi c associations between HLA risk alleles and serology are common across the age range, suggesting similarities in the underlying pathogenesis. Th e frequency of MSA subgroups varies between adult and juvenile disease and the population studied. Th e specifi c disease phenotype for autoantibody subgroups also varies depending on the population studied and between adults, children and even young adults. It remains unclear whether these autoantibodies themselves contribute to pathology and, if so, how age and ethnic background/environmental eff ects are mediated.
Anti-Jo1 and other anti-synthetase autoantibodies, including anti-PL-7, PL12, EJ, OJ, KS, Ha and Zo, are the most common and well described MSAs found in adult myositis Caucasian populations, and can be identifi ed in approximately 40% of those with idiopathic infl ammatory myopathies. tRNA-synthetases are cytoplasmic enzymes that catalyse the binding of amino acids to their cognate tRNAs. Autoantibodies are found in patients with a distinct clinical phenotype known as the anti-synthetase syndrome, comprising myositis, ILD, arthritis, fever, Raynaud's phenomenon and mechanic's hands. Patients can also have DM skin lesions, including Gottron's papules [41]. Th e risk of ILD is signifi cantly higher in this patient subgroup. Th e prevalence of ILD in anti-Jo1positive patient cohorts has been found to be 86% [25] and 90 to 100% in patients with anti-PL12 [26,42]. ILD is a major cause of morbidity and mortality in the antisynthe tase syndrome [22]. Although this group of autoantibodies is common in adult myositis, it is rare in JDM. Where anti-Jo1 autoantibodies have been identifi ed in JDM, however, aff ected children may have clinical features similar to anti-synthetase syndrome in adults [43,44].
Anti-Mi2 is the 'classic' DM autoantibody discovered in 20% of adult patients and 4 to 10% of those with JDM. It is associated with hallmark cutaneous features and milder muscle disease. It carries a good prognosis in adults and children [43][44][45][46]. Anti-p155 (anti-TIF1γ) is found in 13 to 21% of adults with DM, usually in association with anti-TIF1α (anti-p155/140) and occasionally anti-TIF1β [47]. It is strongly associated with the develop ment of malignancy, and more so when found in combination with anti-TIF1α [47][48][49].
More than 50% of adults with this autoantibody will develop an associated malignancy within 3 years of diagnosis. Anti-p155/140 is also the most common autoantibody found in JDM (23%) where no associated malignancy is seen [50]. Interestingly, like children, young adults with anti-p155 do not appear predisposed to malignancy [47]. Both adults and children with this MSA have worse cutaneous involvement, and in children there is also a trend towards worse muscle weakness [48,50]. An association between anti-p155 and generalised lipodystrophy has also been reported in JDM [51].
Anti-NXP2 (also known as p140 or MJ) is another common JDM MSA, found in 11 to 23% of aff ected children [52,53]. In JDM, anti-NXP2 antibody is associated with a more severe disease course, with worse functional status and more persistent disease activity [52], and positivity for this autoantibody is strongly associated with the development of calcinosis [53]. Anti-NXP-2 autoantibody is uncommon in adults (1.6% of patients) [54]. Disease associations in adults have yet to be fi rmly established but a small study has recently demonstrated a possible association with malignancy, with three of the eight anti-NXP2 antibody-positive study patients developing malignancy within 3 years of presentation, and a fourth patient 42 months prior to DM presentation [54]. Th is fi nding was not replicated in a recent study of adult myositis Italian patients where, surprisingly, anti-NXP2 was the most common auto antibody identifi ed, and was present in 30% of DM patients [55]. Th is study found no association with malignancy but a trend towards increased calcinosis. Th e discrepancy between this study and those previously published may refl ect the younger age of this cohort; only two out of ten anti-NXP2-positive patients were over the age of 50 years.
Anti-MDA5 was initially identifi ed in Japanese DM patients with clinically amyopathic myositis and ILD; a phenotype more commonly seen in Eastern Asia [56]. Studies based in Japan have identifi ed anti-MDA5 in 19 to 35% of DM patients [56,57]. Th is MSA has since been identifi ed in Caucasian cohorts but at a lower frequency [58]. In adults it is associated with clinically amyopathic myositis (81%) and rapidly progressive ILD (74%) [59]. Th ese patients also typically have characteristic patterns of skin ulceration and painful palmar papules [58]. Because of the association with rapidly progressive ILD, which often responds poorly to immunosuppressive treat ment, mortality is high (33%) and often occurs within 6 months of diagnosis [59,60]. Anti-MDA5 has been shown to be a poor prognostic marker associated with signifi cantly higher mortality at 6 months and 5 years [60].
Of interest, a recent study of 25 newly diagnosed patients with DM-ILD showed signifi cantly diff erent HRCT patterns between anti-MDA5-positive and anti-MDA5-negative groups [61]. Whilst 69.2% of anti-MDA5-negative patients had a HRCT pattern suggestive of NSIP, fi ndings in the anti-MDA5-positive group were distinct and more suggestive of organising pneumonia or diff use alveolar damage. Th e mortality in the patients with this pattern was high (50%), suggesting a high prevalence of diff use alveolar damage. No patients underwent comparative biopsy.

Autoimmunity
Th e presence of MSAs provides strong evidence for the importance of autoimmune mechanisms in DM. MSAs frequently target nuclear or cytoplasmic cellular components that are involved in gene transcription, protein translocation and antiviral responses. Whilst auto antigens with comparable cellular functions are associated with similar disease phenotypes, there are important diff erences in clinical features depending on whether these autoantibodies are found in children or adults. It is not yet clear whether these clinical diff erences relate to diff erences in the underlying disease trigger and pathogenesis, or are a refl ection of diff erences in cellular processes and immune function in diff erent age groups.
As discussed above, MSA may play a role in the pathogenesis of myositis. An important study by Cascioloa-Rosen [67] looked at myositis-specifi c autoantigen Mi2 expression in muscle cells. Enhanced autoantigen expression was seen in regenerating muscle cells in DM, with very low levels of expression in control muscle. Th e authors hypothesised that regenerating muscle may be the ongoing source of antigen supply in myositis, leading to a forward feed-back system and selfsustaining autoimmune response [67]. MSA expression is increased in several cancer cells, but not their associated normal tissues and in cases associated with malignancy, this may provide the initial immune stimulus for autoantibody generation [67]. Interestingly, the antigenic targets of MSAs that have been linked to the development of malignancy both have important roles to play in cell growth and DNA repair: TIF1γ is a nuclear factor that, via SMAD4, plays an important role in transforming growth factor-β signalling and suppression of cell growth [68]. NXP2 is essential for regulating the activation and subcellular localisation of tumour suppressor gene p53 [69]. TIF1 and NXP2 proteins have a signifi cant role in oncogenesis and autoantibodies may be produced during misdirected anti-tumour immunity. MSAs have not been identifi ed in patients with malignancy but without DM, thereby implying that the generation of MSAs is crucially linked to the development of DM. Further work is needed to examine the subcellular localisation of more recently identifi ed MSAs in both control and disease muscle, and evaluate any diff erences between JDM and adult DM muscle.

Environmental factors
DM is believed to be the result of an autoimmune process that develops in a genetically susceptible individual in response to an environmental trigger. Whilst one such trigger may be malignancy this is not present in all cases and is exceptionally rare in JDM. Similarly, common triggers may exist for malignancy and DM amyopathic myositis in adults, which are not pertinent in childhood.
Several reports have found seasonal associations and spatial clustering in the onset of infl ammatory myopathies, and various infectious triggers have therefore been postulated [70][71][72][73][74][75]. Elevated titers of antibodies to certain viruses in some juvenile and adult patients with myositis, as well as the presence of viral RNA in muscle biopsy specimens, have been reported, but not all studies support these fi ndings [72]. Th e trigger may vary with the MSAs generated as diff erences in seasonal onset have been found between autoantibody subgroups with a clustering of myositis associated with anti-Jo positivity in spring and anti-SRP in autumn [74,75].
An association between anti-Mi2-positive DM and surface ultraviolet radiation exposure has also been demonstrated [76]. In JDM diff erent birth patterns have been observed for patients with and without anti-TIF1γ antibodies, suggesting perinatal or early life exposures may play a role [77].
Th e increased prevalence of anti-MDA5-positive DM in Eastern Asia may refl ect diff erences in signifi cant environmental exposures or racial genetic background. A recent study confi rmed the observed increasing frequency of anti-MDA5-positive patients amongst DM patients in central Japan, and established regional diff erences suggesting that environmental factors may contribute [78]. Melanoma associated diff erentiation gene 5, the antigenic target of anti-MDA5 autoantibodies, is involved in the innate immune system and host defence against picornaviruses [79]. It may play a wider role in infection, however, and increased MDA5 mRNA expression has been found in gastric mucosal cells infected with Helicobacter pylori [80].

Genetic factors
In contrast to the multiple diff erences in clinical features between adult and juvenile DM, genetic evidence to date has been remarkably overlapping for the two groups. It is well established that the MHC, also known as the human leukocyte antigen (HLA) system, confers susceptibility to a variety of autoimmune diseases, including DM in both adults and children. Th us, in predominantly Caucasian popu la tions the HLA 8.1 ancestral haplotype (HLA-B*08/DRB1*03/DQA1*05/DQB1*02) has been linked to increased risk of many autoimmune diseases, including adult DM and JDM [44]. In similar JDM populations there is also evidence that the TNF-308A allele, a single nucleotide polymorphism, may be a risk factor for calcinosis and prolonged disease course, although this is also in strong linkage disequilibrium with the HLA 8.1 ancestral haplotype. Th e association between the HLA 8.1 haplotype has been shown to be stronger in certain autoantibody subgroups, namely anti-Jo1 and anti-PmScl [81]. Th ese data show that genetic background modifi es clinical presentation; results from a recently completed, genome-wide association study of adult DM and JDM may shed light on other important loci implicated in pathogenesis [33]. In JDM, familial aggregation of specifi c autoimmune diseases has been seen, including type 1 diabetes mellitus and systemic lupus erythe matosus, suggesting shared pathogenic factors and possibly rare causal genes with large eff ects [82]. Given the potentially diff erent aetiologies of malignancy-associated and non-malignancy-associated DM, it would be interesting to compare the genetic background of these two groups.

Conclusion
Whilst adult DM and JDM share the hallmark disease characteristics of classical rash and muscle weakness, the frequency of other disease features varies with age of onset. Important clinical features such as ILD and malignancy are less common in younger adults and rarely seen in children. Conversely, cutaneous features such as calcinosis are more of a disease burden in younger patients. Th ese diff erences may refl ect diff erent disease triggers between children and adults, either external environmental factors or internal factors such as the development of malignancy. Clinical diff erences between adults and children within autoantibody subgroups are likely to refl ect modifi cation of the disease response by more rapidly growing muscle in children, and age-related diff er ences in cellular processing and the immune response.
Our understanding of the mechanisms that underlie these diff erences is limited by a lack of studies directly comparing adults and children both clinically and histologically. Further work in this area may greatly increase our understanding of the disease process in DM and the modifying factors aff ecting the development of signifi cant clinical complications.

Competing interests
The authors declare that they have no competing interests.