The Vasculopathy of Juvenile Dermatomyositis

Juvenile dermatomyositis (JDM) is a rare autoimmune disease mainly characterized by muscle and skin involvement. Vasculopathy is considered central to the pathogenesis of the disease. The exact nature of vasculopathy is not yet understood but it is a complex process with both an inflammatory and a non-inflammatory, occlusive component. Impaired function of JDM vasculature includes immune complex deposition, altered expression of cell adhesion molecules predominantly inducing Th17 cell infiltration, and endothelial cell dysfunction. Development of vasculopathy is associated with the severe extra-muscular manifestations of JDM, such as gastrointestinal and cardiac manifestations, interstitial lung disease, ulcerative skin disease or development of calcinosis, and portends a poor prognosis. Correlation of histopathological findings, autoantibodies, and extensive diagnostic workup represent key elements to the early detection of vasculopathic features and early aggressive treatment. Monitoring of vasculopathy remains challenging due to the lack of non-invasive biomarkers. Current treatment approaches provide variable benefit, but better understanding of the essential pathogenic mechanisms should help lead to improved outcomes. Whilst acknowledging that evidence is limited, this review aims to describe the vasculopathy of JDM in the context of pathophysiology, clinical features, and treatment of disease

Mapping the current psychology provision for children and young people with juvenile dermatomyositis

Objectives: Juvenile Dermatomyositis (JDM) is a rare, chronic autoimmune condition of childhood, with known psychosocial implications. In this study, we sought to establish current psychological support for children and young people across the UK with rheumatic conditions, with a specific focus on those with JDM. Methods: Electronic surveys were distributed to the 15 centres that belong to the JDM Research Group in the UK, collecting responses from health-care professionals in the fields of medicine, nursing and psychology. Results: One hundred per cent of professionals from medicine and nursing replied from all 15 centres. Of these, 7 (47%) did not have a named psychologist as part of their rheumatology team, despite the majority [13 (87%)] having >200 paediatric rheumatology patients. Of the remaining centres, hospital psychology provision varied considerably. When rating their service, only 3 (8%) of 40 professionals scored their service as five (where one is poor and five is excellent); there were wide discrepancies in these scores. Many challenges were discussed, including limited psychology provision, lack of time and difficulties in offering support across large geographical areas. Conclusion: Many of the challenges discussed are applicable to other centres worldwide. Suggestions have been proposed that might help to improve the situation for children and young people with rheumatic conditions, including JDM. Based on these findings, we suggest that rheumatology teams maximize use of these data to advocate and work toward more comprehensive psychology provision and support in their individual centres

Juvenile dermatomyositis: Latest advances

Registries and biobanks for juvenile dermatomyositis (JDM) have generated statistical power to help understand pathogenesis and determine treatment and long-term outcomes in this rare and heterogeneous disease. Genotype, autoantibodies, muscle histology and early clinical features may predict prognosis and guide personalised treatment. While corticosteroids and disease-modifying anti-rheumatic drugs improve outcomes, there remain children who experience refractory disease. Ongoing research into the aberrant immune response and novel biological targets is necessary. Best practice guidelines promote prompt stepwise treatment, and there is growing appreciation of the role of exercise in improving prognosis. Validated tools standardise assessment of disease activity and damage in musculoskeletal, mucocutaneous, pulmonary, cardiac, gastrointestinal and endocrine systems. Recently, an internationally agreed dataset for JDM has been defined for clinical practice and incorporation into registries. In the future, with bigger datasets, statistical models may guide stratification for personalised medicine and discern the most relevant outcome markers for research

Identification and prediction of novel classes of long-term disease trajectories for patients with juvenile dermatomyositis using growth mixture models

OBJECTIVES: Uncertainty around clinical heterogeneity and outcomes for patients with JDM represents a major burden of disease and a challenge for clinical management. We sought to identify novel classes of patients having similar temporal patterns in disease activity and relate them to baseline clinical features. METHODS: Data were obtained for n = 519 patients, including baseline demographic and clinical features, baseline and follow-up records of physician's global assessment of disease (PGA), and skin disease activity (modified DAS). Growth mixture models (GMMs) were fitted to identify classes of patients with similar trajectories of these variables. Baseline predictors of class membership were identified using Lasso regression. RESULTS: GMM analysis of PGA identified two classes of patients. Patients in class 1 (89%) tended to improve, while patients in class 2 (11%) had more persistent disease. Lasso regression identified abnormal respiration, lipodystrophy and time since diagnosis as baseline predictors of class 2 membership, with estimated odds ratios, controlling for the other two variables, of 1.91 for presence of abnormal respiration, 1.92 for lipodystrophy and 1.32 for time since diagnosis. GMM analysis of modified DAS identified three classes of patients. Patients in classes 1 (16%) and 2 (12%) had higher levels of modified DAS at diagnosis that improved or remained high, respectively. Patients in class 3 (72%) began with lower DAS levels that improved more quickly. Higher proportions of patients in PGA class 2 were in DAS class 2 (19%, compared with 16 and 10%). CONCLUSION: GMM analysis identified novel JDM phenotypes based on longitudinal PGA and modified DAS

Developing a provisional, international Minimal Dataset for Juvenile Dermatomyositis: for use in clinical practice to inform research.

Juvenile dermatomyositis (JDM) is a rare but severe autoimmune inflammatory myositis of childhood. International collaboration is essential in order to undertake clinical trials, understand the disease and improve long-term outcome. The aim of this study was to propose from existing collaborative initiatives a preliminary minimal dataset for JDM. This will form the basis of the future development of an international consensus-approved minimum core dataset to be used both in clinical care and inform research, allowing integration of data between centres

A randomised, open label, active comparator trial assessing the effects of 26 weeks of liraglutide or sitagliptin on cardiovascular function in young obese adults with type 2 diabetes

Aim To compare the effects of a glucagon‐like peptide‐1 receptor agonist and a dipeptidyl peptidase‐4 inhibitor on magnetic resonance imaging‐derived measures of cardiovascular function. Materials and methods In a prospective, randomized, open‐label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non‐insulin treated young (aged 18‐50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight. Results Seventy‐six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m−2), of whom 65% had ≥1 cardiovascular risk factor. Sixty‐one participants had primary outcome data available. There were no statistically significant between‐group differences (intention‐to‐treat; mean [95% confidence interval]) in PEDSR change (−0.01 [−0.07, +0.06] s−1), left ventricular ejection fraction (−1.98 [−4.90, +0.94]%), left ventricular mass (+1.14 [−5.23, +7.50] g) or aortic distensibility (−0.35 [−0.98, +0.28] mmHg−1 × 10−3) after 26 weeks. Reductions in HbA1c (−4.57 [−9.10, −0.37] mmol mol−1) and body weight (−3.88 [−5.74, −2.01] kg) were greater with liraglutide. Conclusion There were no differences in cardiovascular structure or function after short‐term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin‐based therapies

An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.This work was supported by NIHR Exeter Clinical Research Facility through funding for SE and ATH and general infrastructure. The authors thank Michael Day, Annet Damhuis and Richard Gilbert for technical assistance. We thank Karen Knapp for providing the data for the DEXA calculations. SE, ATH, SO are supported by Wellcome Weedon et al. Page 6 Nat Genet. Author manuscript; available in PMC 2014 February 01. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Trust Senior Investigator awards. DS and RKS (098498/Z/12/Z) are supported by Wellcome Trust Senior Research Fellowships in Clinical Science. MNW is supported by the Wellcome Trust as part of the WT Biomedical Informatics Hub funding. RO is supported by Diabetes UK. DS, RKS and SO are supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. KJG is supported by the Agency for Science, Technology and Research, Singapore (A*STAR). LAL and MJP are supported by grants NCI-61-6845 and 62-4860