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

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

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

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

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

The 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)

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features

AIM: Juvenile idiopathic inflammatory myopathies (IIM) have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically-defined juvenile IIM from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review, and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2, and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101), and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes. This article is protected by copyright. All rights reserved

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

OBJECTIVE: Juvenile dermatomyositis (JDM) is a rare and severe autoimmune condition characterized by rash and proximal muscle weakness. While some patients respond to standard treatment, others do not. We investigated whether histopathology and myositis-specific autoantibodies (MSA) have prognostic significance. // METHODS: Muscle biopsy samples (n=101) from the UK JDM Cohort and Biomarker Study were stained, analyzed and scored. Autoantibodies were measured (n=90) and longitudinal clinical data were collected (median follow-up 4.9 years). Long-term treatment status was modelled using generalized estimating equations. // RESULTS: Muscle biopsy scores differed according to MSA. When effects of MSA were accounted for, increased severity of muscle pathology predicted increased risk of remaining on treatment over time: 1.48-fold higher odds (1.12-1.96, p=0.0058) for the global pathology score (hVAS) and 1.10-fold higher odds (1.01-1.21, p=0.038) for the total biopsy score for the standardized score tool. A protective effect was identified in patients with anti-Mi2 autoantibodies, who had 7.06-fold lower odds (1.41-35.36, p=0.018) of remaining on treatment, despite displaying more severe muscle pathology at biopsy. For patients with anti-NXP-2, anti-TIF1γ autoantibodies or no-detectable autoantibody, increased severity of muscle pathology alone could predict the risk of remaining on treatment, without adjustment for MSA: 1.61-fold higher odds (1.16-2.22, p=0.0040) for hVAS and 1.13-fold higher odds (1.03-1.24, p=0.013) for total biopsy score. // CONCLUSION: Muscle pathology, in combination with MSA, predicts the risk of remaining on treatment in JDM and may be useful for discussing probable treatment length with parents and patients. Understanding these associations may identify patients at greater risk of severe disease

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Down syndrome, caused by an extra copy of chromosome 21, is associated with a greatly increased risk of early onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP), an Alzheimer risk factor, although the possession of extra copies of other chromosome 21 genes may also play a role. Further study of the mechanisms underlying the development of Alzheimer disease in Down syndrome could provide insights into the mechanisms that cause dementia in the general population