Sarah L. Tansley

Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study

IntroductionThe aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile dermatomyositis (JDM).MethodsSerum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist).ResultsAnti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P = 0.03) oral ulceration (P = 0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P = 0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P = 0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease.ConclusionsAnti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed.

Calcinosis in juvenile dermatomyositis is influenced by both anti-NXP2 autoantibody status and age at disease onset

Objective. Calcinosis is a major cause of morbidity in JDM and has previously been linked to anti-NXP2 autoantibodies, younger age at disease onset and more persistent disease activity. This study aimed to investigate the clinical associations of anti-NXP2 autoantibodies in patients with JDM stratified by age at disease onset. Methods. A total of 285 patients with samples and clinical data were recruited via the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-NXP2 was determined by both immunoprecipitation and ELISA. Logistic regression analysis was performed to assess the age-dependent relationship between anti-NXP2 and the development of calcinosis and disease activity measures. Results. We identified anti-NXP2 autoantibodies in 56 patients (20%). While in all patients younger age at disease onset was associated with an increased risk of calcinosis and this relationship was nearly linear, anti-NXP2 autoantibodies substantially increased the risk of calcinosis across all ages (P = 0.025) and were detectable prior to calcinosis development. Children with anti-NXP2 autoantibodies had a greater degree of weakness (median lowest ever Childhood Myositis Assessment Score 29.6 vs 42) and were less likely to be in remission at 2 years post-diagnosis. No difference in disease activity was seen 4 years post-diagnosis. Conclusion. Children diagnosed at a young age have a high risk of calcinosis regardless of autoantibody status. However, the presence of anti-NXP2 autoantibodies substantially increases the risk of calcinosis across all ages and is associated with disease severity.

The diagnostic utility of autoantibodies in adult and juvenile myositis.

Purpose of reviewThe purpose of this study is to review recent advances in the diagnostic utility of autoantibodies in dermatomyositis. Recent findingsAlternative nonspecialist testing methods have been developed for anti-transcription intermediary factor 1 gamma, anti-MDA5 and anti-nuclear matrix protein 2, which are potentially exploitable by any hospital laboratory. Although these have yet to be validated for diagnostic use, it is likely that testing for myositis-specific antibodies will soon become readily available. SummaryThe identification of myositis-specific autoantibodies provides both diagnostic and prognostic information and offers a unique opportunity to adopt a stratified approach to treatment. Their identification, in many cases, should prevent the need for invasive diagnostic tests such as muscle biopsy.

The evolving spectrum of polymyositis and dermatomyositis--moving towards clinicoserological syndromes: a critical review.

The idiopathic inflammatory myopathies: polymyositis (PM) and dermatomyositis (DM) have been historically defined by broad clinical and pathological criteria. These conditions affect both adults and children with clinical features including muscle weakness, skin disease and internal organ involvement. Over the last few years, it has become increasingly apparent that using a clinico-serological approach, both DM and PM can be defined into more homogeneous subsets. A large number of antibodies are directed against cytoplasmic or nuclear components involved in key regulatory intra-cellular processes including protein synthesis, translocation and gene transcription within this disease spectrum. In addition, these autoantibodies are found in patients with clinical features other than myositis, in particular ‘idiopathic’ interstitial pneumonia emphasizing that these patients may in fact be a formes-frustes of autoimmune connective tissue disease. Other important findings are the identification of specific autoantibodies in both cancer-associated dermatomyositis, clinically amyopathic dermatomyositis and juvenile dermatomyositis, which previously were classically described as antibody-negative clinical subsets. Finally, work has highlighted how target autoantigens identified in the myositis-connective tissue disease overlap share common cellular mechanisms, which provides us with further insights into disease pathogenesis.

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.

Muscle biopsy in combination with myositis-specific autoantibodies aids prediction of outcomes in juvenile dermatomyositis.

Juvenile dermatomyositis (DM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. This study was carried out to investigate whether histopathologic findings and myositis‐specific autoantibodies (MSAs) have prognostic significance in juvenile DM.

Myositis Specific and Associated Autoantibodies in the Diagnosis and Management of Juvenile and Adult Idiopathic Inflammatory Myopathies

The idiopathic inflammatory myopathies are a heterogeneous group of disorders affecting both adults and children. Clinical features can include muscle weakness, skin disease and internal organ involvement. A large number of autoantibodies, directed against cytoplasmic or nuclear components, can now be identified in these patients and specific clinic-serological syndromes have been described. Laboratory testing to identify many of these autoantibodies is becoming easier, and here we discuss the clinical utility of autoantibodies in myositis both in terms of facilitating diagnosis, predicting disease course and informing management decisions.

Autoantibodies in juvenile-onset myositis: Their diagnostic value and associated clinical phenotype in a large UK cohort

Objectives Juvenile myositis is a rare and heterogeneous disease. Diagnosis is often difficult but early treatment is important in reducing the risk of associated morbidity and poor outcomes. Myositis specific autoantibodies have been described in both juvenile and adult patients with myositis and can be helpful in dividing patients into clinically homogenous groups. We aimed to explore the utility of myositis specific autoantibodies as diagnostic and prognostic biomarkers in patients with juvenile-onset disease. Methods Using radio-labelled immunoprecipitation and previously validated ELISAs we examined the presence of myositis specific autoantibodies in 380 patients with juvenile-onset myositis in addition to, 318 patients with juvenile idiopathic arthritis, 21 patients with juvenile-onset SLE, 27 patients with muscular dystrophies, and 48 healthy children. Results An autoantibody was identified in 60% of juvenile-onset myositis patients. Myositis specific autoantibodies (49% patients) were exclusively found in patients with myositis and with the exception of one case were mutually exclusive and not found in conjunction with another autoantibody. Autoantibody subtypes were associated with age at disease onset, key clinical disease features and treatment received. Conclusions In juvenile patients the identification of a myositis specific autoantibody is highly suggestive of myositis. Autoantibodies can be identified in the majority of affected children and provide useful prognostic information. There is evidence of a differential treatment approach and patients with anti-TIF1γ autoantibodies are significantly more likely to receive aggressive treatment with IV cyclophosphamide and/or biologic drugs, clear trends are also visible in other autoantibody subgroups.

Anti-HMGCR Autoantibodies in Juvenile Idiopathic Inflammatory Myopathies Identify a Rare but Clinically Important Subset of Patients

Objective. We aimed to establish the prevalence and clinical associations of anti-HMG-CoA-reductase (anti-HMGCR) in a large UK cohort with juvenile myositis. Methods. There were 381 patients investigated for anti-HMGCR using ELISA. Results. Anti-HMGCR autoantibodies were detected in 4 patients (1%). These children had no or minimal rash and significant muscle disease. Muscle biopsies were considered distinctive, with widespread variation in fiber size, necrotic fibers, and chronic inflammatory cell infiltrates; all had prolonged elevation of creatine kinase and all ultimately received biologic therapies. Conclusion. Anti-HMGCR in UK children with myositis are associated with severe disease that is poorly responsive to standard treatment.

Comparing and contrasting clinical and serological features of juvenile and adult-onset myositis: implications for pathogenesis and outcomes.

Purpose of reviewTo explore the different characteristics of the serological phenotypes identified in juvenile and adult myositis, consider how differences between the two groups might be explained and discuss how this enhances our understanding of disease pathogenesis. Recent findingsCurrent research has focussed on two main areas: first, defining the autoantibody associated disease phenotype in greater detail, particularly with regard to cutaneous disease and within specified populations such as juvenile-onset disease and different ethnic groups, and second, we have gained new insights into disease pathogenesis through studies analysing genetic associations and autoantigen expression. SummaryAlthough there are many clinically important differences between adult and juvenile-onset myositis, recent work has highlighted many of the similarities at least within autoantibody-defined subgroups. Viewing age at disease onset as a continuum with its own influence on disease phenotype strengthens the ability of autoantibodies to define homogenous disease groups, and may be important in understanding the relationship between autoantibodies and disease pathogenesis.