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. 2012 Feb;4(1):41–50. doi: 10.1177/1759720X11424460

Juvenile dermatomyositis: new insights and new treatment strategies

Neil Martin, Charles K Li, Lucy R Wedderburn ✉
PMCID: PMC3383527  PMID: 22870494

Abstract

Juvenile dermatomyositis (JDM) is a rare but complex and potentially life-threatening autoimmune disease of childhood, primarily affecting proximal muscles and skin. Although the cause of JDM remains unknown it is clear that genetic and environmental influences play a role in the aetiology. In contrast to adults with dermatomyositis, children with JDM are more likely to have complications that are thought to indicate a vasculopathic process, such as severe skin disease, with ulceration or calcinosis, gut vasculopathy or central nervous system disease. New treatments are much needed and are becoming available and being tested through international multicentre trials. This review will focus on recent insights into pathogenesis, the assessment of the disease in children and the modern approach to its treatment.

Keywords: dermatomyositis, idiopathic inflammatory muscle disease, juvenile, myopathy

Introduction

Juvenile dermatomyositis (JDM) is a rare but serious systemic autoimmune condition of childhood primarily affecting proximal muscles and skin. Polymyositis and inclusion body myositis are rare in children. Although historically many clinical studies concentrated on muscular features, the cutaneous manifestations of JDM can be serious and difficult to treat and may progress to ulcerative disease and or subcutaneous calcification, impacting seriously on quality of life in the long term.

JDM has an incidence of approximately 3.2 per million children per year in the UK with differences between ethnic groups, and is at least three times more common in girls than boys [Feldman et al. 2008; Symmons et al. 1995]. The mean age of onset is 7 years [Martin et al. 2011a], although about 25% of patients with JDM present under the age of 5 years.

Unlike the adult idiopathic inflammatory myopathies (IIM), JDM is generally thought not to be a paraneoplastic phenomenon. In the UK JDM Cohort study (currently n = 336 patients) there have been no neoplasms reported in association with childhood myositis in a 12-year data collection period, although long-term follow up of these patients will be important to validate this finding. A recent literature review including studies from the past 15 years [Morris and Dare, 2010] described a handful of patients in whom unusual physical findings such as splenomegaly or lymphadenopathy were noted on diagnosis, and in whom a primary malignancy was found within 12 months of diagnosis.

Assessment of suspected cases of juvenile inflammatory myositis

Children with suspected inflammatory myositis are ideally cared for in specialist centres where there is easy access to an experienced multidisciplinary team, including paediatric rheumatologists and neurologists, specialist nurses, physiotherapists, speech therapists, dermatologists, muscle histopathologists and also access to imaging and other investigations. The increasingly common model of providing care through networks of specialists who share expertise and knowledge should improve the care of these complex patients, although delay in access to specialist care remains an issue [Martin et al. 2011a].

Although the criteria for diagnosis still used for many studies are still those of Bohan and Peter [Bohan and Peter, 1975a, 1975b] these criteria have been shown to be no longer reflective of modern day paediatric practice, since many paediatricians do not choose to perform electromyography on children, and some centres no longer routinely perform muscle biopsy [Brown et al. 2006]. Clinical examination should include formal assessment of muscle strength using a validated tool, such as the Childhood Myositis Assessment Scale (CMAS) or manual muscle testing of the standardized eight groups of muscles (MMT8) [Huber, 2010; Huber et al. 2004; Lovell et al. 1999]. In addition, careful assessment of the skin is mandatory, and this should include nail fold capillary examination. Two skin score systems for the assessment of skin involvement in JDM have been proposed. The Disease Activity Score (DAS) for JDM includes assessment of skin and muscle involvement and distribution of rash. It has good reliability and scores correlate with periungual nailfold capillary changes [Bode et al. 2003; Smith et al. 2004]. The Cutaneous Assessment Tool (CAT) assesses skin disease in myositis by considering activity in 10 lesions, damage in four lesions and a combination of activity and damage in seven lesions. The tool has been partially validated in a large JDM population and demonstrated good reliability, content and construct validity, and responsiveness [Huber and Feldman, 2005; Huber et al. 2008a, 2008b]. Assessment of other organ systems, including respiratory, gastrointestinal, speech and language is also critical.

The investigation of a child suspected of having an inflammatory myopathy should include magnetic resonance imaging (MRI) of muscles in a specialist centre with experience of interpretation of such images. The degree of muscle change on MRI can be quantified on T2 STIR images and has been shown to correlate with disease activity [Maillard et al. 2004]. While classical proximal muscle weakness is typical, it is also important the child undergoes thorough investigation for other organ involvement, such as of the gastrointestinal tract, including a speech and swallowing assessment [McCann et al. 2007] or respiratory system (typically a high-resolution computed tomography scan). In addition to MRI, some centres still perform biopsy, most usually from quadriceps or biceps muscle; a proposed muscle score tool assessing pathological severity in four domains (inflammation, vasculopathic change, muscle fibre and connective tissue) has been shown to have good interobserver reliability and to correlate with clinical severity [Wedderburn et al. 2007, 2010, 2011].

Two international groups of investigators, the Paediatric Rheumatology International Trials Organization (PRINTO) and the International Myositis Assessment and Clinical Studies Group (IMACS) have proposed a core set of tools for the assessment of disease activity and damage in JDM [Miller et al. 2001; Ruperto et al. 2003, 2008]. Such core outcome variables include an overall physician assessment and a parent/patient assessment by visual analogue or Likert scale, a measure of functional ability typically using the Child Health Assessment Questionnaire (CHAQ), assessment of muscle strength using CMAS or MMT8, laboratory variables (creatine kinase, lactate dehydrogenase, erythrocyte sedimentation rate) and assessment of disease activity that captures extramuscular disease (the DAS or the Myositis Disease Activity Assessment Tool, MDAAT) [Wedderburn and Rider, 2009]. The Myositis Damage Index is another potentially useful tool which has recently been validated in both adult and paediatric populations for the assessment of disease-related damage in patients with dermatomyositis [Isenberg, 2004; Rider et al. 2011]. As the collection of such data items becomes more routine in specialist centres and beyond, the comparison of outcomes between different treatment protocols and regimes, as well as in clinical trials, will become possible.

Aetiology and pathogenesis of juvenile dermatomyositis

Genetics

As for many autoimmune rheumatic diseases, JDM is thought to arise from a complex interplay of immunological dysfunction resulting from environmental stimuli in genetically susceptible patients. The inflammatory myopathies are complex polygenic disorders, and the identification of specific genetic loci has been hampered by the rarity of these diseases. With the establishment of multicentre collaborations and registries we are not only beginning to understand the intricacies of both protective and susceptible alleles within the highly polymorphic human leukocyte region (HLA) region, but have identified other regions of interest, including proinflammatory cytokine genes, lymphocyte signalling genes [Chinoy et al. 2008] among others. Within the HLA region, one of the most highly polymorphic regions of the human genome, there are allelic variants associated with increased risk for many autoimmune diseases, including JDM. Thus HLA-B*08, DRB1*0301, and DQA1*0501 are part of a haplotype that confers risk of myositis in both children and adults, in white people [Chinoy et al. 2009a; Mamyrova et al. 2006; Reed et al. 1991; Wedderburn et al. 2007].

Recent work has shown that HLA-DPB1*0101 also confers independent risk of myositis in particular serological subgroups [Chinoy et al. 2009b] and that the DQA1*0301 allele is an additional risk factor for JDM. Interestingly there are strong associations between specific risk alleles and the serological phenotype [Chinoy et al. 2006], suggesting that T-cell help of specific autoreactive B cells may play a key role in early pathological events.

Genetic factors have been associated with specific manifestations, disease susceptibility and severity in both adult onset myositis syndromes and JDM. The tumour necrosis factor α variant, TNFα-308A, carries a higher risk of prolonged disease course, calcinosis and ulcerative skin disease, although there is controversy about whether this may be in part due to linkage disequilibrium with the HLA-B locus [Chinoy et al. 2007]. The presence of the TNFα-308A allele in conjunction with an osteopontin promoter polymorphism (rs28357094G) has been found to be associated with high serum interferon-γ activity in the serum from untreated patients with JDM of European ancestry [Niewold et al. 2010] in a subset of patients who exhibit a more severe disease phenotype and are more likely to develop skin calcinosis. The TNFα-308A allele itself has previously been shown to be associated with vascular occlusion [Lutz et al. 2002] and increased TNFα production [Pachman et al. 2001]; however, an interleukin (IL)-1 polymorphism [Mamyrova et al. 2008] also seems to confer additional risk of calcinosis [Lutz et al. 2002].

The strong associations with HLA allelic differences and a genetic association with the T-cell signalling molecular PTPN22 [Chinoy et al. 2008] all suggest a key role for T cells in the pathogenesis of JDM. Certainly, immune dysregulation in innate, humoral and cellular responses have all been described in JDM [Elst et al. 2008; O’Connor et al. 2006; Wedderburn et al. 2007]. Recent studies have also implicated nonimmune mechanisms that may involve molecules typically identified with an immunological role, for example major histocompatibility complex (MHC) class I [Li et al. 2009; Nagaraju et al. 2005] in the pathogenesis of adult IIM and JDM. The interplay between these systems may offer novel therapeutic targets.

Humoral and cellular immunity

Historically, myositis-specific and myositis-associated autoantibodies were thought to be rare in JDM. However, when full testing methodology is employed serological analysis from large cohorts achieved through national and international collaborations seem to contradict this view, identifying up to 70% of patients who show specific autoantibody responses [Wedderburn et al. 2007]. As in adults, the majority of antigenic targets of the specific autoantibodies associated with JDM are cytoplasmic or nuclear proteins involved either in protein synthesis (e.g. the tRNA synthetase enzymes), or gene regulation.

Certain myositis-specific antibodies and their associated clinical phenotype hold true across age groups, when children with JDM mirror manifestations in adult patients with IIM; for example, anti-PM-Scl with scleroderma overlap features, anti-Mi-2 with classic skin rash of dermatomyositis, and antihistidyl RNA synthetase (Jo-1) with interstitial lung disease [Wedderburn et al. 2007]. Other associations diverge. A novel anti-p155/140 represents autoantibodies to a 155-kDa and a 140-kDa protein found in 23–29% of patients with JDM, which are associated with an increased risk of cutaneous disease and a prolonged course in JDM [Gunawardena et al. 2008]. Furthermore, the same group has found a different autoantibody anti-p140 associated with the development of calcinosis in children with JDM [Gunawardena et al. 2009]. Whether these particular antibodies predate the specific features with which they associate and therefore could be used as prognostic biomarkers remains to be defined. This remains an area of active research, with ultimately the identification of these autoantibodies possibly offering more than mere prognostication in the condition but specifically targeted therapy.

Some autoantibodies are thought to confer a role in the pathogenesis of myositis, although the paradox of how such antibodies lead to muscle damage, given that the antigens which are in general ubiquitously expressed is yet unresolved. Several elegant studies have demonstrated specific upregulation of the autoantigens in regenerating myoblasts [Casciola-Rosen et al. 2005] or the ability of these autoantibodies to promote proinflammatory type l interferon activation [Eloranta et al. 2007] or chemotaxis [Howard et al. 2002].

A recent study has suggested a specific link between T-cell and B-cell immunity in JDM, by showing that T-follicular helper cells (which are CXCR5 positive) are over represented in the blood of patients with JDM, are heavily skewed towards IL-17 production, and that these T cells can provide a potent role in driving antibody production by B cells [Morita et al. 2011].

Endoplasmic reticulum (ER) stress

Since the identification of MHC class I over-expression on muscle cells in IIM over 25 years ago [Isenberg et al. 1985], this abnormality has remained an important and sensitive, although not specific, feature for diagnosis of IIM on biopsy features, including for JDM [Li et al. 2004; Wedderburn et al. 2007]. This observation prompted the generation of a transgenic murine model in which expression of self-MHC class l in muscle tissue leads to myositis [Nagaraju et al. 2000]. When this model was adapted, by induction of the disease in very young mice, to reflect JDM, results suggested an increased susceptibility of very young muscle to the effects of overexpression of MHC. The high levels of MHC class l protein lead to activation of the endoplasmic reticulum stress response, itself highly proinflammatory, and consequent muscle damage [Li et al. 2009].

Innate immunity

Endothelial dysfunction is another important aspect in JDM and lies behind some of the most devastating and life-threatening complications. Capillary loss is a feature of early biopsy changes and is thought to be associated with poor prognosis [Christen-Zaech et al. 2008; Emslie-Smith and Engel, 1990; Smith et al. 2004]. Antibody deposition and complement activation on small vessels both in muscle and other tissues is implicated when various cytokines and chemokines (IL-1, intercellular adhesion molecule-1, vascular cell adhesion molecule, CXCL10) [Fall et al. 2005; Lundberg et al. 1997; Sallum et al. 2004] have been identified in inflamed muscle tissues, which may propagate the disease process.

Heterogeneous populations of dendritic cells (DCs) may also play a pivotal role in the pathogenesis of IIM. Not only have mature DCs been identified in inflamed muscles [López de Padilla et al. 2007], but in addition, a recent study showed mature dendritic cells and mast cells present in involved and uninvolved skin from patients with JDM [Shrestha et al. 2010]. Both cell types are capable of driving the type I interferon response; the propensity of the former is also associated with more severe clinical disease [López De Padilla et al. 2009].

Current treatments and new developments in therapy for juvenile dermatomyositis

Initial therapy

Over the past five decades steroid-based treatment strategies have transformed the prognosis for children with JDM. Before 1960, one-third of patients with JDM would die and one-third developed severe disability [Bitnum et al. 1964; Huber and Feldman, 2005] while the current estimated mortality for JDM is less than 2% [Huber et al. 2000]. Steroids remain the basis of initial therapy for patients with JDM and early aggressive therapy has been associated with improved outcome; however, uncertainty remains over the optimum therapeutic strategy and to what extent severity of disease at presentation should guide treatment. Vasculopathic involvement of the proximal intestine in JDM has been shown to reduce absorption and bioavailability of enteral corticosteroids [Rouster-Stevens et al. 2008]. As a result, it has been suggested that aggressive initial treatment with intravenous methylprednisolone may be superior to traditional steroid regimens based on oral prednisolone [Fisler et al. 2002]. To date, there have been no prospective clinical trials to confirm this. One retrospective nonrandomized comparative study found no difference in a number of important outcome measures between patients treated with aggressive therapy using either intravenous methylprednisolone or high-dose oral prednisolone (5–30 mg/kg/day) versus treatment with standard-dose oral prednisolone (1–2 mg/kg/day) [Seshadri et al. 2008]. Two further retrospective case series reported that the use of intravenous methylprednisolone was associated with significant reductions in duration of active disease, disease-related costs and other complications, including calcinosis [Fisler et al. 2002; Klein-Gitelman et al. 2000]. A single-centre retrospective study from North America reported 49 patients with JDM treated with a standardized protocol. This involved patients with moderate or severe weakness receiving three initial doses of intravenous methylprednisolone followed by methotrexate, oral prednisolone and weekly intravenous methylprednisolone until muscle enzymes and strength normalized. Patients treated by this aggressive protocol had improved outcomes and reduced disease-related complications compared with historical controls, including drug-free remission in 57% of patients with a median time to inactive disease of 38 months and persistent calcinosis in 4% of patients [Kim et al. 2009].

A recent, large survey of paediatric rheumatologists throughout North America and Canada found that most respondents would treat moderate or severe JDM with parenteral steroids initially and the majority would treat mild JDM with oral steroids initially [Stringer et al. 2010]. This pragmatic approach in the absence of prospective evidence appears to reflect an underlying belief that patients with apparently mild skin and muscle disease are less likely to have significant intestinal vasculopathy. The same survey found that most patients were treated with a combination of steroids and methotrexate regardless of severity and that methotrexate was usually given by the subcutaneous route. These results are similar to data from a survey of paediatric rheumatology centres throughout the UK [Martin et al. 2011b], which also found that most centres would use a combination of methotrexate and steroids as initial therapy for JDM irrespective of severity. A retrospective study comparing patients treated at the same centre before and after instigating a policy of treating with methotrexate showed that children treated with methotrexate received significantly less steroids with a median duration of steroid treatment of 10 months versus 27 months in the group treated without methotrexate [Ramanan et al. 2005]. Perhaps unsurprisingly, the group who received methotrexate developed less steroid-related side effects. Although steroids and methotrexate clearly form the basis for current therapy in North America and the UK, firm evidence to support this is lacking and treatment strategies vary in other parts of the world. Results should soon be available from a large, prospective multicentre randomized controlled trial (RCT) run by PRINTO comparing corticosteroids versus corticosteroids with methotrexate versus corticosteroids with cyclosporine (www.printo.it). Other treatments given as initial therapy by some centres include intravenous immunoglobulin (IvIg) and hydroxychloroquine [Stringer et al. 2010].

Cyclophosphamide

A retrospective case series of 12 patients treated with intravenous cyclophosphamide for severe JDM showed a good response in all survivors [Riley et al. 2004]. Two patients died who already required ventilation for severe disease prior to receiving treatment and there was no evidence of serious cyclophosphamide related toxicity in the short term. Data from the recent UK and North American surveys suggest that the use of cyclophosphamide is reserved as a treatment for severe disease, pulmonary involvement, ulcerative skin disease or wider systemic involvement. In the UK it is often used as initial therapy for these patients whereas in North America it is usually reserved for patients whose condition fails to respond to standard therapy.

Treatment of refractory disease

IvIg was associated with both clinical and histological improvement in a prospective crossover double-blind RCT of patients with refractory adult myositis [Dalakas et al. 1993; Al-Mayouf et al. 2000]. Data from both the UK and North America [Martin et al. 2011b; Stringer et al. 2010] suggest that most paediatric rheumatologists reserve IvIg for patients with an inadequate response to first-line therapy.

Raised levels of TNFα have been associated with a chronic disease course and calcinosis in JDM [Pachman et al. 2001]. A case series of five patients successfully treated with infliximab for calcinosis and JDM refractory to standard therapy has been described [Riley et al. 2008]. Our recent survey suggests that anti-TNFα therapy has become the most commonly considered second- or third-line therapy for patients with refractory JDM in the UK [Martin et al. 2011b].

In addition to blockade of TNFα, other biological therapies have also been tried in severe and refractory cases of JDM. Given the increasing information regarding the importance of novel autoantibodies in the pathogenesis of JDM, it has been hoped that B-cell depletion with agents such as rituximab may prove to be effective. An initial case series of patients with JDM treated with rituximab showed clinical improvement in three out of four patients [Cooper et al. 2007]. Results from a prospective RCT with a crossover design including patients with both adult and juvenile dermatomyositis are likely to be available soon.

Mycophenolate mofetil (MMF) has been shown to be an efficacious treatment in renal and extra renal lupus [Posalski et al. 2009] and profiling of blood from patients with JDM has shown some important similarities to systemic lupus erythematosus, particularly with regard to type 1 interferon-induced gene expression. One retrospective case series of 50 patients with JDM treated with MMF after suboptimal response to aggressive initial therapy with parenteral steroids and methotrexate showed improvement in both skin and muscle disease activity and a steroid-sparing effect [Dagher et al. 2010]. In a small series of patients with refractory JDM treated with tacrolimus, skin disease, global disease activity and physical function were reported to improve. Patients were able to reduce corticosteroid therapy, and the medication was well tolerated [Hassan et al. 2008].

Finally, for extremely severe disease resistant to multiple immunosuppressive therapies, autologous stem-cell transplant has been reported in two children with sustained remission occurring in both patients. However, it is likely that this approach has to be embarked upon before irreversible damage has been acquired to be beneficial [Holzer et al. 2010].

Nondrug aspects of management

In addition to drug therapy, other key aspects of management of patients with JDM that involve the whole multidisciplinary team are pivotal. Intensive physiotherapy can assist in maintaining and restoring muscle strength and there is evidence that physiotherapy is a safe therapy for muscles in JDM [Maillard et al. 2005]. Use of photo protection for skin, at all times, must be emphasized. Other interventions, such as nasogastric intubation with dysphagia or speech and language therapy with dysphonia, and specialist skin care, may be needed.

Treatment algorithms developed by consensus

Despite the variety of new treatment approaches available for children with JDM, their remains a paucity of prospective RCTs to provide solid evidence on which to base treatment decisions. The rarity of JDM means that for any trial to provide useful information, multicentre collaboration is required. Such trials are vital but also costly and time consuming. An additional method of collecting and comparing therapeutic regimens has been suggested by Huber and colleagues [Huber et al. 2010]. Three separate algorithms for the initial treatment of moderately severe JDM were developed using international expert opinion and guided by information from the survey of North American practice published by Stringer and colleagues [Stringer et al. 2010]. This approach would allow the standardized prospective collection of data comparing treatment approaches, such as the use of IvIg and the route of corticosteroid administration, without requiring a significant change in clinical practice for the majority of paediatric rheumatologists in the UK and North America [Martin et al. 2011b; Stringer et al. 2010].

Conclusions

The prognosis of JDM and the related childhood IIM has improved dramatically in recent years. Despite this, these conditions remain serious and still potentially life threatening, and since they are so rare, an evidence base for treatment is difficult to build. The long-term comorbidities in children treated in the modern era are as yet unknown, but several reports suggest that these children may be at increased risk of cardiovascular disease in adult life [Schwartz et al. 2011]. Central to our ability to compare data and long-term outcomes reliably is the development of an internationally agreed set of core data. Collaborative work towards this, in order to harmonize data collection from centres throughout Europe and America, and then share information on clinical features, biomarkers and response to medication in large numbers of children, remains ongoing.

Acknowledgments

We are very grateful to the families and patients who make our work on JDM possible as well as to all the contributors and researchers of the UK and Ireland JDM Cohort and Biomarker study, who contribute to the study. Neil Martin and Charles K. Li contributed equally to this work.

Footnotes

The JDM Cohort Study has been supported by generous grants from the Cathal Hayes Research Trust, the Wellcome Trust UK (085860), Action Medical Research UK, (SP4252), The Henry Smith Charity, Arthritis Research UK (14518 and 18796) (formerly the ARC), Raynaud’s and Scleroderma Association and the UK Myositis Support Group. The study has been adopted onto the Comprehensive Research Network through the Medicines for Children Research Network (MCRN, www.mcrn.org.uk). LW is supported in part by the Great Ormond Street Hospital Children’s Charity.

The authors declare no conflicts of interest in preparing this article.

References

  1. Al-Mayouf S.M., Laxer R.M., Schneider R., Silverman E.D., Feldman B.M. (2000) Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol 27(10): 2498–2503 [PubMed] [Google Scholar]
  2. Bitnum S., Daeschner C.W., Jr, Travis L.B., Dodge W.F., Hopps H.C. (1964) Dermatomyositis. J Pediatr 64: 101–131 [DOI] [PubMed] [Google Scholar]
  3. Bode R.K., Klein-Gitelman M.S., Miller M.L., Lechman T.S., Pachman L.M. (2003) Disease activity score for children with juvenile dermatomyositis: reliability and validity evidence. Arthritis Rheum 49(1): 7–15 [DOI] [PubMed] [Google Scholar]
  4. Bohan A., Peter J.B. (1975a) Polymyositis and dermatomyositis (first of two parts). N Engl J Med 292(7): 344–347 [DOI] [PubMed] [Google Scholar]
  5. Bohan A., Peter J.B. (1975b) Polymyositis and dermatomyositis (second of two parts). N Engl JMed 292(8): 403–407 [DOI] [PubMed] [Google Scholar]
  6. Brown V.E., Pilkington C.A., Feldman B.M., Davidson J.E. (2006) An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology 45(8): 990–993 [DOI] [PubMed] [Google Scholar]
  7. Casciola-Rosen L., Nagaraju K., Plotz P., Wang K., Levine S., Gabrielson E., et al. (2005) Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med 201(4): 591–601 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chinoy H., Lamb J.A., Ollier W.E.R., Cooper R.G. (2009a) An update on the immunogenetics of idiopathic inflammatory myopathies: major histocompatibility complex and beyond. Curr Opin Rheumatol 21(6): 588–593 [DOI] [PubMed] [Google Scholar]
  9. Chinoy H., Payne D., Poulton K.V., Fertig N., Betteridge Z., Gunawardena H., et al. (2009b) HLA-DPB1 associations differ between DRB1*03 positive anti-Jo-1 and anti-PM-Scl antibody positive idiopathic inflammatory myopathy. Rheumatology 48(10): 1213–1217 [DOI] [PubMed] [Google Scholar]
  10. Chinoy H., Platt H., Lamb J.A, Betteridge Z., Gunawardena H., Fertig N., et al. (2008) The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients. Arthritis Rheum 58(10): 3247–3254 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chinoy H., Salway F., Fertig N., Shephard N., Tait B.D., Thomson W., et al. (2006) In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype. Arthritis Res Ther 8(1): R13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chinoy H., Salway F., John S., Fertig N., Tait B.D., Oddis C.V., et al. (2007) Tumour necrosis factor-alpha single nucleotide polymorphisms are not independent of HLA class I in UK Caucasians with adult onset idiopathic inflammatory myopathies. Rheumatology 46(9): 1411–1416 [DOI] [PubMed] [Google Scholar]
  13. Christen-Zaech S., Seshadri R., Sundberg J., Paller A.S., Pachman L.M. (2008) Persistent association of nailfold capillaroscopy changes and skin involvement over thirty-six months with duration of untreated disease in patients with juvenile dermatomyositis. Arthritis Rheum 58(2): 571–576 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cooper M.A., Willingham D.L., Brown D.E., French A.R., Shih F.F., White A.J. (2007) Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients. Arthritis Rheum 56(9): 3107–3111 [DOI] [PubMed] [Google Scholar]
  15. Dagher R., Desjonquères M., Duquesne A., Quartier P., Bader-Meunier B., Fischbach M., et al. (2010) Mycophenolate mofetil in juvenile dermatomyositis: a case series. Rheumatol Int 9 December [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  16. Dalakas M.C., Illa I., Dambrosia J.M., Shawke A.S., Stein P.D., Otero C., et al. (1993) A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 329(27): 1993–2000 [DOI] [PubMed] [Google Scholar]
  17. Eloranta M-L., Barbasso Helmers S., Ulfgren A.K., Ronnblom L, Alm G.V., Lundberg I.E. (2007) A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies. Arthritis Rheum 56(9): 3112–3124 [DOI] [PubMed] [Google Scholar]
  18. Elst E.F., Klein M., de Jager W., Kamphuis S., Wedderburn L.R., van der Zee R., et al. (2008) Hsp60 in inflamed muscle tissue is the target of regulatory autoreactive T cells in patients with juvenile dermatomyositis. Arthritis Rheum 58(2): 547–555 [DOI] [PubMed] [Google Scholar]
  19. Emslie-Smith A.M., Engel A.G. (1990) Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 27(4): 343–356 [DOI] [PubMed] [Google Scholar]
  20. Fall N., Bove K.E., Stringer K., Lovell D.J., Brunner H.I., Weiss J., et al. (2005) Association between lack of angiogenic response in muscle tissue and high expression of angiostatic ELR-negative CXC chemokines in patients with juvenile dermatomyositis: possible link to vasculopathy. Arthritis Rheum 52(10): 3175–3180 [DOI] [PubMed] [Google Scholar]
  21. Feldman Brian M., Rider L.G., Reed A.M., Pachman L.M. (2008) Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet 371(9631): 2201–2212 [DOI] [PubMed] [Google Scholar]
  22. Fisler R.E., Liang M.G., Fuhlbrigge R.C., Yalcindag A., Sundel R.P. (2002) Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol 47(4): 505–511 [DOI] [PubMed] [Google Scholar]
  23. Gunawardena H., Wedderburn L.R., Chinoy H., Betteridge Z.E., North J., Ollier W.E., et al. (2009) Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum 60(6): 1807–1814 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gunawardena H., Wedderburn L.R., North J., Betteridge Z., Dunphy J., Chinoy H., et al. (2008) Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatology 47(3): 324–328 [DOI] [PubMed] [Google Scholar]
  25. Hassan J., van der Net J.J., van Royen-Kerkhof A. (2008) Treatment of refractory juvenile dermatomyositis with tacrolimus. Clin Rheumatol 27(11): 1469–1471 [DOI] [PubMed] [Google Scholar]
  26. Holzer U., van Royen-Kerkhof A., van der Torre P., Kuemmerle-Deschner J., Well C., Handgretinger R., et al. (2010) Successful autologous stem cell transplantation in two patients with juvenile dermatomyositis. Scand J Rheumatol 39(1): 88–92 [DOI] [PubMed] [Google Scholar]
  27. Howard O.M.Z., Dong H.F., Yang D., Raben N., Nagaraju K., Rosen A., et al. (2002) Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med 196(6): 781–791 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Huber A.M. (2010) Update on the assessment of children with juvenile idiopathic inflammatory myopathy. Curr Rheumatol Rep 12(3): 204–212 [DOI] [PubMed] [Google Scholar]
  29. Huber A.M., Dugan E.M., Lachenbruch P.A., Feldman B.M., Perez M.D., Zemel L.S., et al. (2008a) Preliminary validation and clinical meaning of the cutaneous assessment tool in juvenile dermatomyositis. Arthritis Rheum 59(2): 214–221 [DOI] [PubMed] [Google Scholar]
  30. Huber A.M., Feldman B.M. (2005) Long-term outcomes in juvenile dermatomyositis: how did we get here and where are we going? Curr Rheumatol Rep 7(6): 441–446 [DOI] [PubMed] [Google Scholar]
  31. Huber A.M., Feldman B.M., Rennebohm R.M., Hicks J.E., Lindsley C.B., Perez M.D., et al. (2004) Validation and clinical significance of the Childhood Myositis Assessment Scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies. Arthritis Rheum 50(5): 1595–1603 [DOI] [PubMed] [Google Scholar]
  32. Huber A.M., Giannini E.H., Bowyer S.L., Kim S., Lang B., Lindsley C.B., et al. (2010) Protocols for the initial treatment of moderately severe Juvenile dermatomyositis: results of a children’s Arthritis and Rheumatology Research Alliance consensus conference. Arthritis Care Res (Hoboken) 62: 219–225 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Huber A.M., Lachenbruch P.A., Dugan E.M., Miller F.W., Rider L.G. (2008) Alternative scoring of the Cutaneous Assessment Tool in juvenile dermatomyositis: results using abbreviated formats. Arthritis Rheum 59(3): 352–356 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Huber A.M., Lang B., LeBlanc C.M., Birdi N., Bolaria R.K., Malleson P., et al. (2000) Medium- and long-term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis. Arthritis Rheum 43(3): 541–549 [DOI] [PubMed] [Google Scholar]
  35. Isenberg D.A., Allen E., Farewell V., Ehrenstein M.R., Hanna M.G., Lundberg I.E., et al. (2004) International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology 43(1): 49–54 [DOI] [PubMed] [Google Scholar]
  36. Isenberg D.A., Rowe D., Beverley P.C. (1985) HLA antigen expression in myositis. Lancet 1(8430): 703. [DOI] [PubMed] [Google Scholar]
  37. Kim S., Moussa D., Fatma D., Zurakowski D., Fuhlbrigge R.C., Sundel R.P. (2009) Complete and sustained drug free remission of juvenile dermatomyositis resulting from aggressive treatment. Arthritis Rheum 60(6): 1825–1830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Klein-Gitelman M.S., Waters T., Pachman L.M. (2000) The economic impact of intermittent high-dose intravenous versus oral corticosteroid treatment of juvenile dermatomyositis. Arthritis Care Res 13(6): 360–368 [DOI] [PubMed] [Google Scholar]
  39. Li C.K., Knopp P., Moncrieffe H., Singh B., Shah S., Nagaraju K., et al. (2009) Overexpression of MHC class I heavy chain protein in young skeletal muscle leads to severe myositis: implications for juvenile myositis. Am J Pathol 175(3): 1030–1040 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Li C.K., Varsani H., Holton J.L., Gao B., Woo P., Wedderburn L.R., et al. (2004) MHC class I overexpression on muscles in early juvenile dermatomyositis. J Rheumatol 31(3): 605–609 [PubMed] [Google Scholar]
  41. López De Padilla C.M., Vallejo A.N., Lacomis D., McNallan K., Reed A.M. (2009) Extranodal lymphoid microstructures in inflamed muscle and disease severity of new-onset juvenile dermatomyositis. Arthritis Rheum 60(4): 1160–1172 [DOI] [PubMed] [Google Scholar]
  42. López de Padilla C.M., Vallejo A.N., McNallan K.T., et al. (2007) Plasmacytoid dendritic cells in inflamed muscle of patients with juvenile dermatomyositis. Arthritis Rheum 56(5): 1658–1668 [DOI] [PubMed] [Google Scholar]
  43. Lovell D.J., Lindsley C.B., Rennebohm R.M., Ballinger S.H., Bowyer S.L., Giannini E.H., et al. (1999) Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies. II. The Childhood Myositis Assessment Scale (CMAS): a quantitative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Arthritis Rheum 42(10): 2213–2219 [DOI] [PubMed] [Google Scholar]
  44. Lundberg I., Ulfgren A.K., Nyberg P., Andersson U., Klareskog L. (1997) Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum 40(5): 865–874 [DOI] [PubMed] [Google Scholar]
  45. Lutz J., Huwiler K.G., Fedczyna T., Lechman T.S., Crawford S., Kinsella T.R., et al. (2002) Increased plasma thrombospondin-1 (TSP-1) levels are associated with the TNF alpha-308A allele in children with juvenile dermatomyositis. Clin Immunol 103(3 Pt 1): 260–263 [DOI] [PubMed] [Google Scholar]
  46. Maillard S.M., Jones R., Owens C., Pilkington C., Woo P., Wedderburn L.R., et al. (2004) Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis. Rheumatology 43(5): 603–608 [DOI] [PubMed] [Google Scholar]
  47. Maillard S.M., Jones R., Owens C., Pilkington C., Woo P., Wedderburn L.R., et al. (2005) Quantitative assessment of the effects of a single exercise session on muscles in juvenile dermatomyositis. Arthritis Rheum 53(4): 558–564 [DOI] [PubMed] [Google Scholar]
  48. Mamyrova G., O’Hanlon T.P., Monroe J.B., Carrick D.M., Malley J.D., Adams S., et al. (2006) Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians. Arthritis Rheum 54(12): 3979–3987 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Mamyrova G., O’Hanlon T.P., Sillers L., Malley K., James-Newton L., Parks C.G., et al. (2008) Cytokine gene polymorphisms as risk and severity factors for juvenile dermatomyositis. Arthritis Rheum 58(12): 3941–3950 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Martin N., Krol P., Smith S., Murray K., Pilkington C.A., Davidson J.E., et al. (2011a) A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years’ experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies. Rheumatology 50(1): 137–145 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Martin N., Wedderburn L.R., Pilkington C.A., Davidson J.E. (2011b) A survey of current practice in the management of Juvenile Dermatomyositis in the UK and Ireland. Abstract from the 17th Paediatric Rheumatology European Society Congress. Clin Exp Rheumatol 29(Suppl.): 372 [Google Scholar]
  52. McCann L.J., Garay S.M., Ryan M.M., Harris R., Riley P., Pilkington C.A. (2007) Oropharyngeal dysphagia in juvenile dermatomyositis (JDM): an evaluation of videofluoroscopy swallow study (VFSS) changes in relation to clinical symptoms and objective muscle scores. Rheumatology 46(8): 1363–1366 [DOI] [PubMed] [Google Scholar]
  53. Miller F.W., Rider L.G., Chung Y.L., Cooper R., Danko K., Farewell V., et al. (2001) Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology 40(11): 1262–1273 [DOI] [PubMed] [Google Scholar]
  54. Morita R., Schmitt N., Bentebibel S-E., Ranganathan R., Bourdery L., Zurawski G., et al. (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34(1): 108–121 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Morris P., Dare J. (2010) Juvenile dermatomyositis as a paraneoplastic phenomenon: an update. J Pediatr Hematol Oncol 32(3): 189–191 [DOI] [PubMed] [Google Scholar]
  56. Nagaraju K., Casciola-Rosen L., Lundberg I., Ranganathan R., Bourdery L., Zurawski G., et al. (2005) Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 52(6): 1824–1835 [DOI] [PubMed] [Google Scholar]
  57. Nagaraju K., Raben N., Loeffler L., Parker T., Rochon P.J., Lee E., et al. (2000) Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci U S A 97(16): 9209–9214 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Niewold T.B., Kariuki S.N., Morgan G.A., Shrestha S., Pachman L.M. (2010) Gene–gene–sex interaction in cytokine gene polymorphisms revealed by serum interferon alpha phenotype in juvenile dermatomyositis. J Pediatr 157(4): 653–657 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. O’Connor K.A., Abbott K.A., Sabin B., Kuroda M., Pachman L.M. (2006) MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: association with muscle involvement. Clin Immunol 120(3): 319–325 [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Pachman L.M., Fedczyna T.O., Lechman T.S., Lutz J. (2001) Juvenile dermatomyositis: the association of the TNF alpha-308A allele and disease chronicity. Curr Rheumatol Rep 3(5): 379–386 [DOI] [PubMed] [Google Scholar]
  61. Posalski J.D., Ishimori M.I., Wallace D.J., Weisman M.H. (2009) Does mycophenolate mofetil prevent extra-renal flares in systemic lupus erythematosus? Results from an observational study of patients in a single practice treated for up to 5 years. Lupus 18(6): 516–521 [DOI] [PubMed] [Google Scholar]
  62. Ramanan A.V., Campbell-Webster N., Ota S., Parker S., Tran D., Tyrell P.N., et al. (2005) The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis Rheum 52(11): 3570–3578 [DOI] [PubMed] [Google Scholar]
  63. Reed A.M., Pachman L., Ober C. (1991) Molecular genetic studies of major histocompatibility complex genes in children with juvenile dermatomyositis: increased risk associated with HLA-DQA1 *0501. Hum Immunol 32(4): 235–240 [DOI] [PubMed] [Google Scholar]
  64. Rider L., Lachenbruch P.A., Monroe J.B., Ravelli A., Cabalar I., Feldman B.M., et al. (2011) Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the Myositis Damage Index. Arthritis Rheum 60(11): 3425–3435 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Riley P., Maillard S.M., Wedderburn L.R., Woo P., Murray K.J., Pilkington C.A. (2004) Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Rheumatology 43(4): 491–496 [DOI] [PubMed] [Google Scholar]
  66. Riley P., McCann L.J., Maillard S.M., Woo P., Murray K.J., Pilkington C.A. (2008) Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology 47(6): 877–880 [DOI] [PubMed] [Google Scholar]
  67. Rouster-Stevens K.A., Gursahaney A., Ngai K-L., Daru J.A., Pachman L.M. (2008) Pharmacokinetic study of oral prednisolone compared with intravenous methylprednisolone in patients with juvenile dermatomyositis. Arthritis Rheum 59(2): 222–226 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Ruperto N., Ravelli A., Murray K.J., Lovell D.J., Andersson-Gare B., Feldman B.M., et al. (2003) Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis. Rheumatology 42(12): 1452–1459 [DOI] [PubMed] [Google Scholar]
  69. Ruperto N., Ravelli A., Pistorio A., Ferriani V., Calvo I., Ganser G., et al. (2008) The provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology/European League Against Rheumatism Disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: a prospective validation study. Arthritis Rheum 59(1): 4–13 [DOI] [PubMed] [Google Scholar]
  70. Sallum A.M.E., Marie S.K.N., Wakamatsu A., Sachetti S., Vianna M.A., Silva C.A., et al. (2004) Immunohistochemical analysis of adhesion molecule expression on muscle biopsy specimens from patients with juvenile dermatomyositis. J Rheumatol 31(4): 801–807 [PubMed] [Google Scholar]
  71. Schwartz T., Sanner H., Husebye T., Flatø B., Sjaastad I. (2011) Extended report: cardiac dysfunction in juvenile dermatomyositis: a case-control study. Ann Rheum Dis 70(5): 766–771 [DOI] [PubMed] [Google Scholar]
  72. Seshadri R., Feldman B.M., Ilowite N., Cawkwell G., Pachman L.M. (2008) The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: a propensity score analysis. Arthritis Rheum 59(7): 989–995 [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Shrestha S., Wershil B., Sarwark J.F., Niewold T.B., Philipp T., Pachman L.M. (2010) Lesional and nonlesional skin from patients with untreated juvenile dermatomyositis displays increased numbers of mast cells and mature plasmacytoid dendritic cells. Arthritis Rheum 62(9): 2813–2822 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Smith R.L., Sundberg J., Shamiyah E., Dyer A., Pachman L.M. (2004) Skin involvement in juvenile dermatomyositis is associated with loss of end row nailfold capillary loops. J Rheumatol 31(8): 1644–1649 [PubMed] [Google Scholar]
  75. Stringer E., Bohnsack J., Bowyer S.L., Griffin T.A., Huber A.M., Lang B., et al. (2010) Treatment approaches to juvenile dermatomyositis (JDM) across North America: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Treatment Survey. J Rheumatol 37(9): 1953–1961 [DOI] [PubMed] [Google Scholar]
  76. Symmons D.P., Sills J.A., Davis S.M. (1995) The incidence of juvenile dermatomyositis: results from a nation-wide study. Br J Rheumatol 34(8): 732–736 [DOI] [PubMed] [Google Scholar]
  77. Wedderburn L.R., McHugh N.J., Chinoy H., Cooper R.G., Salway F., Ollier W.E., et al. (2007) HLA class II haplotype and autoantibody associations in children with juvenile dermatomyositis and juvenile dermatomyositis-scleroderma overlap. Rheumatology 46(12): 1786–1791 [DOI] [PubMed] [Google Scholar]
  78. Wedderburn L.R., Rider L.G. (2009) Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pract Res Clin Rheumatol 23(5): 665–678 [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Wedderburn L.R., Varsani H., Charman S.C., Amato A.A. (2010) Validation of a histopathological score tool for the measurement of severity in muscle biopsies from patients with juvenile dermatomyositis. Rheumatology 49(Suppl. 1): i116 [Google Scholar]
  80. Wedderburnm L.R., Varsani H., Charman S.C., Marie S.K.N., Amato A.A. (2011) Validation and clinical testing of a standardised assessment of juvenile dermatomyositis muscle biopsy. Neuropathol Appl Neurobiol 37(Suppl. 1): 13 [Google Scholar]
  81. Wedderburn L.R., Varsani H., Li C.K.C., Newton K.R., Amato A.A., Banwell B., et al. (2007) International consensus on a proposed score system for muscle biopsy evaluation in patients with juvenile dermatomyositis: A tool for potential use in clinical trials. Arthritis Rheum 57(7): 1192–1201 [DOI] [PubMed] [Google Scholar]

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