Search

Background Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition. Approximately 15–20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE). Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE. This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study. Methods Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8–13 years) and adolescent (14–18 years). The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up. Results A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence. At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4–20] vs. 7(3–13] vs. 7(3–14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous ( p = 0.025), musculoskeletal ( p = 0.029), renal ( p = 0.027) and cardiorespiratory ( p = 0.001). Furthermore, adolescent JSLE patients were more frequently ANA-positive ( p = 0.034) and exhibited higher anti-dsDNA titres ( p = 0.001). Pre-pubertal individuals less frequently presented with leukopenia ( p = 0.002), thrombocytopenia ( p = 0.004) or low complement ( p = 0.002) when compared with other age groups. No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up. Conclusions Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients. Patients diagnosed during adolescence exhibit greater disease activity and “classic” autoantibody, immune cell and complement patterns when compared with younger patients. This supports the hypothesis that pathomechanisms may vary between patient age groups.

Additional file 1: Figure S1. Participant questionnaire. Supplementary Table S1. Patient reported disease features in questionnaire responders by medication status*. Supplementary Table S2. Myositis-Specific and Myositis-Associated antibody status of questionnaire responders. Supplementary Table S3. Responses to questions regarding growth and development. Supplementary Table S4. Height, weight and BMI percentiles at diagnosis and at time of questionnaire. Supplementary Table S5. Questionnaire data regarding smoking compared to UK ONS data. Supplementary Table S6. Alcohol intake of participants compared to UK ONS data. Supplementary Table S7. Numbers with ≥ 3 longitudinal values for CMAS, MMT8, modified skin DAS and Physician Global VAS.

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease.

Objectives We aimed to develop and assess the reliability of a novel MRI-based scoring system for reporting the severity of MRI findings in children with suspected JDM. Methods Nine consultant paediatric radiologists independently assessed and scored 40 axial and 30 coronal thigh MR images of children with suspected JDM on two occasions using the juvenile dermatomyositis magnetic resonance Imaging Score (JIS). JIS was calculated for both reads for each plane and each limb, with possible scores ranging from 0 (normal) to 100 (severe). Inter- and intraobserver agreement was calculated using the intraclass correlation coefficient (ICC) and two- and one-way random effects models, respectively. Bland-Altman plots of the difference in JIS against the average JIS were also produced for each rater. Results Overall, the interobserver reliability and agreement was good—for axial images, JIS ranged from 46.8 to 61.0 [ICC = 0.88 (95% CI: 0.82, 0.92)] for the left limb and 47.9–61.4 [ICC = 0.87 (95% CI: 0.81, 0.92)] for the right limb. For coronal images, JIS ranged from 56.7 to 65.1 [ICC = 0.90 (95% CI: 0.85, 0.95)] for the left limb and 55.7 to 66.8 [ICC = 0.90 (95% CI: 0.84, 0.94)] for the right limb. The intraobserver reliability and agreement was good, with ICC ranging from 0.90 to 0.94. Conclusion JIS is a semi-objective scoring system with potential to serve as a reliable biomarker of disease severity and response to therapeutic interventions in children with JDM.

Objective: The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM.Methods: Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data.Results: Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference.Conclusion: Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis.

Background: Juvenile systemic sclerosis (jSSc) is an orphan disease, associated with high morbidity and mortality. New treatment strategies are much needed. To develop an open label drug trial for the treatment of jSSc patients, it is necessary to clearly define how to evaluate outcomes in this disease,[for full text, please go to the a.m. URL], 47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.