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BACKGROUND Disease activity in Juvenile Idiopathic Arthritis (JIA) commonly persists into adulthood. Transfer of JIA patients to adult healthcare services can be challenging, with prior studies showing poor rates of success. AIMS This audit sought to examine characteristics of patients undergoing transfer of care within the rheumatology unit at the Royal Children's Hospital (RCH) in Melbourne, with the aim of identifying areas for improvement. Specifically, we sought to determine the rate at which confirmation of established care with an adult service (confirmed transfer of care) was documented in the patient chart. METHODS Patients with a diagnosis of JIA who turned 18 years of age between 2012-2019 were identified. A chart review was undertaken to collect relevant data. RESULTS 177 patients were identified. 64% (114/177) were referred for adult care. The commonest JIA subtypes referred were seronegative polyarticular (35/114 or 30.7%) and oligoarticular JIA (22/114 or 19.3%). Documentation of confirmed transfer of care occurred in 62.3% (71/114), with correspondence received from adult services in 49.1% (56/114). There was no difference in rate of return correspondence from public versus private providers (45% vs. 53.8%, p=0.38). The use of 'backstop appointments' was more likely in those with confirmed transfer of care (66% vs. 30%, p=0.0002). CONCLUSIONS Lack of confirmed transfer of care for JIA patients is common and carries a risk of suboptimal outcomes. Strategies to improve communication with adult services, the routine use of 'backstop' appointments and vigilance regarding potential loss to follow-up at the time of transfer would minimise this risk. This article is protected by copyright. All rights reserved.

Background The advent of new treatments for Juvenile Idiopathic Arthritis (JIA) has prompted interest in systematically studying the outcomes of patients treated in the ‘modern era’. Such data provide both benchmarks for assessing local outcomes and important information for use in counselling families of newly diagnosed patients. While data are available for cohorts in Europe and North America, no such data exist for Australian patients. The aim was to examine the demographics, treatment and outcomes at 12 months of an inception cohort of newly diagnosed patients with JIA at a single tertiary referral paediatric rheumatology centre in Australia. Methods Retrospective review of prospectively collected data from patients newly diagnosed with JIA between 2010 and 2014 at the Royal Children’s Hospital in Melbourne. Results One hundred thirty four patients were included (62% female). Oligoarthritis was the single largest category of JIA (36%) and rheumatoid factor positive polyarthritis the least common (2%). Undifferentiated JIA accounted for 13% of patients and was the third largest category. Across the cohort 94% received NSAIDs, 53% oral steroids, 62% methotrexate and 15% a biologic DMARD. Intra-articular steroids were used in 62%, most commonly in the oligoarticular subtype (94%). 95% of patients achieved a joint count of zero at a median of 4.1 months, however flares occurred in 42%. At 12 months 65% had no active joint disease, though more than half remained on medication. Conclusion Australian children with JIA managed in the modern era have similar characteristics and achieve short term outcomes comparable to cohorts in Europe and North America, with high rates of joint remission in the first 12 months of follow-up but with a significant relapse rate and requirement for ongoing medication.

Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA. Here, we performed a genome-scale case-control analysis of CD4+ T cell DNA methylation from 56 oligoarticular JIA (oJIA) cases and 57 age and sex matched controls using Illumina HumanMethylation450 arrays. DNA methylation at each array probe was tested for association with oJIA using RUV (Remove Unwanted Variation) together with a moderated t-test. Further to this 'all-inclusive' analysis, we stratified by age at diagnosis (≤6yrs, >6yrs) and by sex as potential sources of heterogeneity. Following False Discovery Rate (FDR) adjustment, no probes were associated with oJIA in the all-inclusive, >6yrs-diagnosed, or sex-stratified analyses, and only one probe was associated with oJIA in the ≤6yrs-diagnosed analysis. We attempted technical validation and replication of 14 probes (punadj

Aim Cryopyrin-associated periodic syndromes (CAPS) encapsulate three auto-inflammatory conditions, ranging in severity from mild (familial cold auto-inflammatory syndrome: FCAS), moderate (Muckle-Wells syndrome: MWS) and severe (neonatal onset multi-inflammatory disorder: NOMID). We aimed to describe the epidemiology, clinical features and outcomes of Australian children and adults with CAPS. Methods Patients were identified and clinical data collected through a questionnaire sent during 2012–2013 to clinicians reporting to the Australian Paediatric Surveillance Unit and subscribing to the Australasian Societies for Allergy/Immunology, Rheumatology and Dermatology. Results Eighteen cases of CAPS were identified (8 NOMID; 8 MWS, 2 FCAS); 12 in children

Cutaneous sun exposure is an important determinant of circulating vitamin D. Both sun exposure and vitamin D have been inversely associated with risk of autoimmune disease. In juvenile idiopathic arthritis (JIA), low circulating vitamin D appears common, but disease‐related behavioral changes may have influenced sun exposure. We therefore aimed to determine whether predisease sun exposure is associated with JIA. Using validated questionnaires, we retrospectively measured sun exposure for 202 Caucasian JIA case–control pairs born in Victoria Australia, matched for birth year and time of recruitment. Measures included maternal sun exposure at 12 weeks of pregnancy and child sun exposure across the life‐course prediagnosis. We converted exposure to UVR dose and looked for case–control differences using logistic regression, adjusting for potential confounders. Higher cumulative prediagnosis UVR exposure was associated with reduced risk of JIA, with a clear dose–response relationship (trend P = 0.04). UVR exposure at 12 weeks of pregnancy was similarly inversely associated with JIA (trend P = 0.011). Associations were robust to sensitivity analyses for prediagnosis behavioral changes, disease duration and knowledge of the hypothesis. Our data indicate that lower UVR exposure may increase JIA risk. This may be through decreased circulating vitamin D, but prospective studies are required to confirm this.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

Objective Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail. Methods We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case–hospital control sample (302 cases and 676 controls) from Victoria, Australia. Results We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28–0.74) (P = 0.001). The protective association appeared to increase with increasing number of siblings (e.g., for ≥3 siblings, adjusted OR 0.25 [95% CI 0.13–0.48], P

Objective To investigate the impact of tocilizumab treatment on growth and growth-related laboratory parameters in patients with systemic juvenile idiopathic arthritis (JIA) enrolled in a phase III clinical trial. Methods Patients with systemic JIA ages 2–17 years (n = 112) received tocilizumab in a 12-week, randomized, placebo-controlled period and a long-term open-label extension. Height velocity and standard deviation (SD) score; levels of insulin-like growth factor 1 (IGF-1), osteocalcin (OC), and C-telopeptide of type I collagen (CTX-I); and Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) were measured in a post hoc analysis of 83 patients who never received growth hormone and did not reach Tanner stage 5 by the end of the first year of treatment. Results Patients had stunted growth at baseline (mean height SD score −2.2). During tocilizumab treatment, males (73%) and females (83%) experienced above-normal mean height velocities of 6.6 cm/year (P < 0.0001 versus World Health Organization norms). Mean height SD score increases during year 1 (0.29) and year 2 (0.31) were significant (both P < 0.0001). The mean SD score for IGF-1 levels increased significantly (−0.2 for year 1 and −0.1 for year 2 versus −1.0 at baseline; both P < 0.0001). Mean OC and CTX-I levels (both P < 0.0001) and the OC:CTX-I ratio (P = 0.014) significantly increased from baseline to year 2. In multiple regression analysis, first-year height velocity had a significant inverse relationship to JADAS-71 at year 1, age, mean glucocorticoid dosage during the year, and height SD score at baseline. Conclusion Our findings indicate that during treatment with tocilizumab, patients with systemic JIA experience significant catch-up growth, normalization of IGF-1 levels, and bone balance improvement favoring bone formation.

Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA. Here, we performed a genome-scale case-control analysis of CD4

This standards document outlines accepted standards of management for children, adolescents and young adults with juvenile idiopathic arthritis (JIA) in Australia. This document acknowledges that the chronic inflammatory arthritis conditions (JIA) in childhood are different diseases from inflammatory arthritis in adults and that specific expertise is required in the care of children with arthritis.

Objective To describe the clinical features and course of a cohort of patients with juvenile dermatomyositis (JDM) at a tertiary referral pediatric centre in Australia and examine changes in diagnostic and therapeutic approach over time. Methods Retrospective review of patients diagnosed with JDM at the Royal Children's Hospital, Melbourne, between 1989 and 2010. Results Fifty-seven patients were identified. The female : male ratio was 2 : 1 and median age at diagnosis was 7.1 years (2.2–15.3). At diagnosis, 95% had weakness, all had typical rash and 68% had nailfold capillary changes. Calcinosis was not present in any patients at diagnosis and occurred in 18% over time. Creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and aldolase levels were abnormal in 65%, 92%, 88%, 58% and 100%, respectively. Magnetic resonance imaging (MRI) was abnormal in 97% of patients, electomyograph (EMG) in 83% and muscle biopsy in all four patients in whom it was performed. MRI was used in 86% (24/28) of patients diagnosed after 2000. Muscle biopsy was used in four and EMG in no patients over the same period. Treatment used throughout the disease course included oral steroids (93%), high-dose pulse intravenous steroids (82%), methotrexate (63%), intravenous immunoglobulin (32%) and cyclosporin (18%). The disease was monophasic in 46.7% (21/45), polyphasic in 17.7% (8/45) and chronic in 35.5% (16/45). Conclusions Australian patients with JDM have similar characteristics to previously described cohorts. In practice, MRI has replaced the invasive diagnostic tests included in the Bohan and Peter criteria for the diagnosis of JDM. The early use of disease-modifying anti-rheumatic drugs has become the most common treatment approach.

Background: Despite a move towards the provision of specialist training in Australia in settings that extend beyond the public hospital system, formal comparisons of case mix between public and private specialty clinics have rarely been performed. It is therefore unclear for many specialties how well training in one setting prepares trainees for practice in the other. Aims: This study aims to compare the case mix of paediatric rheumatology patients seen in public and private settings and the referral sources of patients in each. Methods: An audit of all new patients seen in the public and private paediatric rheumatology clinics on campus at Royal Children's Hospital between June 2009 and January 2011. Data related to demographics, primary diagnosis, referral source and location seen were abstracted and compared. Results: Eight hundred and seventy-six new patients were seen during the period of interest. Of these, 429 patients (48.9%) were seen in private clinics. The commonest diagnostic categories for both type of clinics were non-inflammatory musculoskeletal pain/orthopaedic conditions (public 39.4%, private 33.6%) followed by juvenile idiopathic arthritis (public 16.6%, %, private 18.6%), other skin/soft tissue disorders (public 8.7%, private 9.6%) and pain syndromes (public 4.9%, private 11.4%). Patients with haematological and vasculitic disorders were predominantly seen in public clinics. The commonest source of referrals to both clinics was general practitioners (public 40.6%, private 53.1%). Conclusion: The case mix in private paediatric rheumatology clinics closely mirrors that of public clinics at our centre. Training in either setting would provide sufficient case-mix exposure to prepare trainees for practice in the other.

This article aims to review the various aspects of paediatric rheumatology that might be looked on as having a more global emphasis, the advances achieved through new technology and communication, the importance of education for both the medical community as well as the patient population, the epidemiologic variation of diseases and how population migration has brought potential changes as well as canvassing some of the considerable new challenges that still need to be addressed.

Objective To test the safety and efficacy of biphosphonates in chronic recurrent multifocal osteomyelitis (CRMO). Study design Five patients with CRMO, all of whom had ongoing pain and loss of function despite conventional treatment with non-steroidal anti-inflammatory agents, were treated with pamidronate (1 mg/kg/dose with a dosing frequency of 2 to 4 monthly for a total treatment duration of 12 to 42 months). Results Pain decreased after the first infusion for 4 of 5 patients, with symptomatic improvement maintained with time. Significant improvement was seen in radiological lesions for these 4 patients. Conclusion Bisphosphonates appear to be a useful and safe adjunctive treatment in CRMO when simple therapies such as anti-inflammatory agents fail to control symptoms or cases in which lesion expansion continues.

Objective: To determine the clinical outcomes of children with chronic recurrent multifocal osteomyelitis (CRMO). Study design: Inception cohorts of children with CRMO were established at two tertiary pediatric centers. Outcome data were obtained through review of hospital charts, interview and examination of patients, and completion of questionnaires by patients. Results: Of 45 eligible subjects, 23 (51%) were assessed. Median time since diagnosis was 13 years (range, 6-25). At evaluation, 6 (26%) had active disease; 18 (78%) had Health Assessment Questionnaire scores of 0 (no/minimal physical disability), and 5 had scores >0. Some impairment was seen in all domains of measurement of quality-of-life test, especially those concerning nonphysical aspects of health. Six (26%) subjects continued to have pain as a result of CRMO. Associated medical problems included arthritis in 6, sacroiliitis in 3, psoriasis in 5, recurrent pustular rashes in 2, and inflammatory bowel disease in 3. Conclusions: Long-term clinical outcomes for children with CRMO appear to be generally good, with most subjects having no evidence of disease activity or sequelae. However, a number of subjects had persistent disease and, therefore, remain at risk of physical and psychologic complications. Further research is required to identify patients at risk for persistent disease, and to determine therapies that may prevent morbidity. (J Pediatr 2002;141:198-203)

Reducing the impact of rheumatic diseases in childhood is the fundamental objective of every member of the multi-disciplinary team involved in the care of affected children and families. The means by which this objective may be achieved are broad and include the implementation of a range of non-pharmacological therapies to address the effects of rheumatic diseases on the physical development of the child. In addition, the treating team must be aware of the psychosocial impact that these diseases may have and the ways in which this may be minimized. This chapter is devoted to an examination of some of the non-pharmacological issues that arise in the management of the commonest rheumatic disease found in children, juvenile idiopathic arthritis (JIA). Aspects of physical rehabilitation, schooling, medication compliance, pain management and family dynamics are discussed, as are interventions to reduce the impact of this disease and its sequelae, utilizing, where possible, evidence-based principles from the literature. Although specific issues applicable to children with arthritis will be discussed, the broad principles of much of what follows applies to all of the rheumatic diseases in childhood.

Chronic recurrent multifocal osteomyelitis (CRMO) is a childhood, bone disorder causing bone pain, swelling, malaise, and fever. A study of 22 children with CRMO, treated at the Royal Children's Hospital, Melbourne, was reported previously. This present study reviews 8 of these, together with 4 additional patients. The patients were interviewed and examined by the first two authors, who had not been involved in their management. The patients were 9 females and 3 males, with a mean age of 22 years (16-31 years). Age at onset of symptoms was between 4 and 11 years and duration 2.5-20 years. Only 1 patient experienced difficulties in school and in maintaining a job. However, only 2 patients experienced complete resolution of symptoms. The number of affected sites was 2-9, most commonly ankle, knee, and clavicle. Seven patients have noticeable deformity. Five had leg-length inequality of at least 1.5 cm, one of whom, with shortening of 5.5 cm, has undergone a lengthening procedure. CRMO is not a benign condition and if not followed to maturity can have disabling sequelae.

Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail.We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case-hospital control sample (302 cases and 676 controls) from Victoria, Australia.We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28-0.74) (P = 0.001). The protective association appeared to increase with increasing number of siblings (e.g., for ≥3 siblings, adjusted OR 0.25 [95% CI 0.13-0.48], P 0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g., for ≥3 years of exposure versus no exposure, adjusted OR 0.49 [95% CI 0.30-0.79], P = 0.003). We also compared cases to a second control sample (n = 341) collected from the community and weighted to represent the child population of Victoria. Data remained supportive of an association between sibling exposure and protection against JIA, particularly for exposure to younger siblings.Increased exposure to siblings is associated with a reduced risk of disease in our sample. This suggests that increased microbial exposure in childhood may confer protection against the development of JIA.

Background Our understanding of the genetic factors underlying juvenile idiopathic arthritis (JIA) is growing, but remains incomplete. Recently, a number of novel genetic loci were reported to be associated with JIA at (or near) genome-wide significance in a large case–control discovery sample using the Immunochip genotyping array. However, independent replication of findings has yet to be performed. We therefore attempted to replicate these newly identified loci in the Australian CLARITY JIA case–control sample. Findings Genotyping was successfully performed on a total of 404 JIA cases (mean age 6.4 years, 68% female) and 676 healthy child controls (mean age 7.1 years, 42% female) across 19 SNPs previously associated with JIA. We replicated a significant association (p

Intra-articular steroid (IAS) injections are a safe and effective therapy in the management of Juvenile Idiopathic Arthritis (JIA). Timely access to joint injections, including appropriate anaesthesia, is now considered standard of care in the treatment of JIA. Despite this, little is known about the resource burden created by IAS provision. Published data is also lacking to inform families of the likely role that IAS will play in the management of their child’s disease.

Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene–gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC , VDR , CYP24A1 , CYP2R1 , and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene–gene combinations ( e.g. , GC rs1155563 and PTPN2 rs2542151, OR int = 0.45, p = 0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2 , CYP2R1 and VDR , and VDR and PTPN2 , similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene–gene combinations identified in the discovery sample ( p -values ranging from 5.6 × 10 −9 to 7.5 × 10 −7 ). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.

The causes of autoimmune diseases, including juvenile idiopathic arthritis (JIA) are presumed to involve the interplay of genes and environment. Vitamin D interacts with genes via vitamin D response elements (vdres). The gene PTPN2, associated with various autoimmune diseases including JIA, carries a VDRE and is regulated by vitamin D. Recently, an interaction between PTPN2 and VDR (vitamin D receptor gene) was reported for type 1 diabetes, such that disease association with VDR differed by PTPN2 genotype.

Aim—To describe the epidemiology, management, and rate of cardiac sequelae of Kawasaki disease in Australia. Design—Cases were notified to the Australian Paediatric Surveillance Unit, an active national surveillance scheme, from May 1993 to June 1995. Results—139 cases of Kawasaki disease were confirmed. In 1994, the annual incidence was 3.7/100 000 children < 5 years old. Sixteen children were not admitted to hospital. Coronary artery abnormalities were reported in 35 (25%) children. Two patients were diagnosed at postmortem examination. Sixty six per cent of patients were diagnosed within 10 days of onset and 81% of these received intravenous gammaglobulin within 10 days.Fortyfive of the notified children did not fulfil the study criteria because of streptococcal infection or insuYcient clinical criteria. One child with streptococcal infection had coronary artery dilatation. Conclusion—Diagnosis of Kawasaki disease was delayed beyond 10 days in one third of patients, and almost 20% of children who could have received gammaglobulin within 10 days did not. The distinction between Kawasaki disease, streptococcal infection, and other possible diagnoses is problematic in some children. (Arch Dis Child 1998;78:33‐39)

This standards document outlines accepted standards of management for children, adolescents and young adults with juvenile idiopathic arthritis (JIA) in Australia. This document acknowledges that the chronic inflammatory arthritis conditions (JIA) in childhood are different diseases from inflammatory arthritis in adults and that specific expertise is required in the care of children with arthritis.

Background Traditional funding models for public paediatric rheumatology care are typically based on providing medical services for a defined number of clinics per week. Anecdotally there is significant demand by patients and families for out-of-clinic communication with care providers and services provided under traditional funding models may not meet this need. Our aim was to determine the extent and nature of this ‘hidden’ demand in a tertiary paediatric rheumatology centre. Methods Communication data and diagnoses were extracted from the Rheumatology service database at our centre for the period 1/1/2009 to 31/12/2011. Clinical activity data over the same time were obtained from hospital clinic databases. Results There were 5672 instances of communication with 749 patients/families over 3 years, (mean 7.3/weekday). This increased over time in parallel with clinical activity. 41% of clinic patients sought communication with the team out of clinic hours. 58% were telephone calls, 36% emails and 6% letters. The communication topics were for advice, results or general updates (28%), medication queries (24%), appointment/admission coordination (20%), disease flare or other disease events (14%), psychosocial, school or transition issues (6%) and miscellaneous queries (8%). Of the most frequent communicators, those with juvenile idiopathic arthritis were the majority (85%). The remainder had other chronic inflammatory conditions. Conclusions The communication and support needs of patients with chronic rheumatic diseases and their families extend beyond that which can be provided in the clinic environment. It is essential that funding for paediatric rheumatology services allows for staffing sufficient to meet this need.

Background Juvenile idiopathic arthritis (JIA) is a paediatric autoimmune disease (AD) with a female preponderance, though this differs by subtype. Whether this sex bias is reflective of differing disease pathogenesis between the sexes is unknown. Gene expression signatures can be biologically and clinically informative, but few expression studies have been performed in JIA. Though gene expression is recognised as sexually dimorphic in many states, its role in JIA sex bias has not been considered. In response to infection females produce more antibodies than males, which could increase natural autoantibody production and the risk of developing AD. Gene expression differences between the sexes may reflect this. The reduced heterogeneity afforded by sex-stratified transcriptome-wide analysis may provide insight into how sex influences disease pathogenesis in JIA. Objectives We aimed to identify sex-specific differences in patients with oligoarticular JIA versus healthy controls through RNA-seq analysis on CD4+ T cells. Methods Six male and six female oligoarticular JIA cases, with no prior exposure to disease-modifying anti-rheumatic drugs, were age and sex-matched to healthy controls. CD4+ T cells were selected as existing data links T cell gene networks to JIA. RNA was extracted from CD4+ T cells using the Qiagen miRNeasy extraction kit. Sequencing library preparation was performed using the Illumina TruSeq Stranded Total RNA LT kit. One female sample did not pass quality control and was not sequenced. Sequencing was performed using 75bp paired-end reads to a depth of ∼20 million reads on the Illumina NextSeq. Quality trimmed reads were mapped to the genome using the STAR aligner. Read counts across exons and genes were summarised using featureCounts. Normalised read counts were used for differential gene expression analysis with edgeR. GOseq was used for gene ontology analysis. Males and females were analysed separately. Results No sex-specific differentially expressed (DE) genes reached FDR adjusted p Conclusions We have identified sex-specific differences in CD4+ T cell gene expression between healthy controls and oligoarticular JIA cases predominantly in males, despite the female preponderance. Our data may reflect that some of the pathogenesis for JIA differs between the sexes, and that gene expression differences play a particularly important role in male JIA, perhaps by a more “female” immune response occurring in male cases. Given the small sample size, replication is necessary and is underway. Disclosure of Interest None declared

Background Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune rheumatic disease of largely unknown cause. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune disease. However, nothing is currently known about the potential role of aberrant DNA methylation in JIA. As a first step to addressing this knowledge gap, we have profiled DNA methylation in purified CD4+ T cells from JIA subjects and controls. Genomic DNA was isolated from peripheral blood CD4+ T cells from 14 oligoarticular and polyarticular JIA cases with active disease, and healthy age- and sex-matched controls. Genome-scale methylation analysis was carried out using the Illumina Infinium HumanMethylation27 BeadChip. Methylation data at >25,000 CpGs was compared in a case-control study design. Results Methylation levels were significantly different (FDR adjusted p Conclusions Our data suggests that differential T cell DNA methylation may be a feature of JIA, and that reduced methylation at IL32 is associated with this disease. Further work in larger prospective and longitudinal sample collections is required to confirm these findings, assess whether the identified differences are causal or consequential of disease, and further investigate the epigenetic modifying properties of therapeutic regimens.

OBJECTIVE: To understand aggrecan degradation in juvenile idiopathic arthritis (JIA), the pattern and abundance of aggrecan fragments in synovial fluid aspirates from JIA patients were analysed and compared with aggrecan fragments in synovial fluids from patients with other arthritides, juvenile knee injury and a knee-healthy reference group. METHODS: The concentration of sulphated glycosaminoglycans in synovial fluid was measured by the Alcian blue precipitation assay. Aggrecan fragments were purified by dissociative CsCl density gradient centrifugation, deglycosylated and analysed by Western blot using antibodies specific for either aggrecanase-derived ARGS, SELE and KEEE neoepitopes, or the aggrecan G3-domain. RESULTS: The concentration of sulphated glycosaminoglycans in JIA synovial fluids was significantly lower compared with the levels in fluids from OA (P

Despite a move towards the provision of specialist training in Australia in settings that extend beyond the public hospital system, formal comparisons of case mix between public and private specialty clinics have rarely been performed. It is therefore unclear for many specialties how well training in one setting prepares trainees for practice in the other.This study aims to compare the case mix of paediatric rheumatology patients seen in public and private settings and the referral sources of patients in each.An audit of all new patients seen in the public and private paediatric rheumatology clinics on campus at Royal Children's Hospital between June 2009 and January 2011. Data related to demographics, primary diagnosis, referral source and location seen were abstracted and compared.Eight hundred and seventy-six new patients were seen during the period of interest. Of these, 429 patients (48.9%) were seen in private clinics. The commonest diagnostic categories for both type of clinics were non-inflammatory musculoskeletal pain/orthopaedic conditions (public 39.4%, private 33.6%) followed by juvenile idiopathic arthritis (public 16.6%, %, private 18.6%), other skin/soft tissue disorders (public 8.7%, private 9.6%) and pain syndromes (public 4.9%, private 11.4%). Patients with haematological and vasculitic disorders were predominantly seen in public clinics. The commonest source of referrals to both clinics was general practitioners (public 40.6%, private 53.1%).The case mix in private paediatric rheumatology clinics closely mirrors that of public clinics at our centre. Training in either setting would provide sufficient case-mix exposure to prepare trainees for practice in the other.

Methods Data from TB screening by tuberculin skin test (TST) and interferon gamma release assay (Quantiferon TB Gold In tube, (IGRA)) involving at-risk children with rheumatic disease was reviewed. Exposed patients were considered to be at moderate risk of LTBI if they were under 5 years of age, or receiving conventional DMARDs or corticosteroids > 0.5 mg/kg/day, and at high risk if they were receiving biologic DMARDS. High risk patients also had chest X-rays.

This study assessed the safety and preliminary efficacy of the interleukin-1 receptor antagonist anakinra in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). Eighty-six patients entered a 12-week open-label run-in phase (1 mg/kg anakinra daily,or =100 mg/day). Fifty responders were randomized to anakinra or placebo in a 16-week blinded phase, followed by a 12-month open-label extension (N = 44). Due to low enrollment, the primary endpoint was changed from efficacy to safety. The incidence and nature of adverse events were similar across all study phases, with the exception of injection site reactions, which were mild to moderate and decreased with time. Anakinra produced a nonsignificant (P = 0.11) reduction in disease flares compared with placebo. When normalized to 1 mg/kg dose, anakinra plasma concentrations were similar to values in adult patients with rheumatoid arthritis. These results indicate that anakinra 1 mg/kg once daily (or =100 mg/day) is safe and well tolerated in patients with JRA.

Systemic juvenile idiopathic arthritis (sJIA) shares clinical features with classic monogenic autoinflammatory diseases, characterised by fevers, arthritis and evanescent rashes. Disease exacerbations are associated with elevated serum cytokine levels including 1L-1β, IL-6, and IL-18; and clinical response to anakinra, canakinumab and tocilizumab suggests that cytokine dysregulation is a key pathophysiological mechanism. Macrophage activation syndrome (MAS) may complicate sJIA, rendering individuals clinically indistinguishable from their familial haemophagocytic lymphohistiocytosis (fHLH) counterparts; with NK and CD8+ cell dysfunction leading to sustained immune cell activation and cytokine storm. Whilst there have been HLA associations and polymorphisms noted on sJIA genome-wide association studies, in rare cases mutations have been found in genes encoding key components of the inflammatory response, which may contribute to disease pathogenesis.

Background A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. Objectives We sought to determine whether PTPN22 rs2476601 exhibits a female-specific association with JIA. Methods The discovery sample was drawn from the Australian CLARITY JIA biobank. rs2476601 was genotyped in 413 cases (67% female, mean age 9.1 years) and 690 healthy controls (42% female, mean age 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype x sex interaction analysis. Sensitivity analyses were performed by restricting to individuals of European descent, subtypes of oligoarticular and polyarticular RF negative disease course, and exclusion of systemic JIA. We sought to replicate the sex-specific associations in an independent JIA case-control sample collected from the USA and Norway and held at the Children9s Hospital of Philadelphia. Analyses were performed using Stata or PLINK. Results The outcomes of analyses are shown in the Table. rs2476601 was associated with all JIA in both the discovery and replication samples, and the association remained when adjusted for sex. When stratified by sex, a strong association was observed for females, but not for males. There was evidence for genotype-by-sex interaction (p=0.0087). Similar patterns were observed in all sensitivity analyses. In the replication sample, we also observed association of rs2476601 with JIA in females, but not in males. Conclusions We have demonstrated, in both a discovery and replication sample, that the association between PTPN22 rs2476601 and JIA appears restricted to females, helping to explain the greater number of females that develop this disease. Disclosure of Interest None declared

Background The aetiology of juvenile idiopathic arthritis (JIA) is largely unknown. We have established a JIA biobank in Melbourne, Australia called CLARITY – ChiLdhood Arthritis Risk factor Identification sTudY, with the broad aim of identifying genomic and environmental disease risk factors. We present here study protocols, and a comparison of socio-demographic, pregnancy, birth and early life characteristics of cases and controls collected over the first 3 years of the study. Methods Cases are children aged ≤18 years with a diagnosis of JIA by 16 years. Controls are healthy children aged ≤18 years, born in the state of Victoria, undergoing a minor elective surgical procedure. Participant families provide clinical, epidemiological and environmental data via questionnaire, and a blood sample is collected. Results Clinical characteristics of cases (n = 262) are similar to those previously reported. Demographically, cases were from families of higher socio-economic status. After taking this into account, the residual pregnancy and perinatal profiles of cases were similar to control children. No case-control differences in breastfeeding commencement or duration were detected, nor was there evidence of increased case exposure to tobacco smoke in utero. At interview, cases were less likely to be exposed to active parental smoking, but disease-related changes to parent behaviour may partly underlie this. Conclusions We show that, after taking into account socio-economic status, CLARITY cases and controls are well matched on basic epidemiological characteristics. CLARITY represents a new study platform with which to generate new knowledge as to the environmental and biological risk factors for JIA.

Background Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disorder likely to be determined by multiple genetic and environmental factors. Mounting evidence shows that epigenetic variation influences autoimmune disease risk. The most well-studied epigenetic mark is DNA methylation; increased methylation of CpG dinucleotides can reduce gene expression. Nothing is currently known about the role of methylation in JIA. In 2008, we established CLARITY, a JIA Biobank that is collecting biospecimens and extensive information about environment from cases presenting to the Royal Children’s Hospital (RCH), Melbourne, Australia. A control sample of healthy children attending the RCH Day Surgery Unit has also been collected. Aims To identify key differences in methylation patterns across the genome associated with the most common subtypes of JIA. Methods

Background Juvenile idiopathic arthritis (JIA) is a complex disease determined by both genetic and environmental factors. Whilst prior research has provided preliminary evidence for some factors, most studies have been hindered by small sample sizes and low statistical power. It is clear that to successfully identify causal factors for complex diseases, large sample sizes and comprehensive approaches will be required. To this end, we have established the Victorian JIA Biobank (VJIAB), a collaborative effort between the Royal Children's Hospital (RCH) and the Murdoch Childrens Research Institute in Melbourne Australia. Our aim is to collect biospecimens and extensive clinical and environmental information on 1000 cases (incident and prevalent, attending RCH Paediatric Rheumatology Clinic) and 1000 controls (healthy children, matched to cases by age and sex, attending RCH for elective surgery).

Skin hypersensitivity to a gliadin subfraction (Fraction 3) was tested in patients with coeliac disease, patients with inflammatory bowel disease, and controls. Those with coeliac disease showed substantially greater hypersensitivity than controls, but there was no significant difference between the frequency of hypersensitivity in patients with coeliac disease and in those with inflammatory bowel disease. Fraction 3 did not provide a sufficiently specific skin reaction to be of use in the diagnosis of coeliac disease.

• Five ambulatory children with various types of chronic arthritis developed renal papillary necrosis (RPN), as documented by intravenous pyelography. Each child was being treated with nonsteroidal anti-inflammatory drugs (NSAIDs) at the time of diagnosis of RPN and had had episodes of gross or microscopic hematuria for several months prior to diagnosis. In each child hematuria was associated with more than one NSAID, and three of the five children also had ingested acetaminophen intermittently. Glomerular function has remained normal and hypertension has not developed, but management of these children has necessitated reduction or elimination of NSAIDs. As evidenced by these five cases, microscopic or gross hematuria in a child with chronic arthritis treated with anti-inflammatory drugs should raise the possibility of RPN. ( AJDC 1986;140:20-22)

Sixty children were diagnosed with JIA at RCH in 2009, 77% of these families who had undertaken JIA education were invited to complete the questionnaire used previously in the AMQuiP project. Completed questionnaires were received from 63% of families. There was a substantial improvement of between 22-48% in parental satisfaction in all education related domains. The greatest improvements were in the disease (38%) and treatment (42%) domains. The areas with the least improvement were related to self management (22%) and support services (26%). Conclusion The inclusion of a nurse-led education program has substantially improved parental satisfaction regarding their knowledge of issues integral to caring for children with JIA.

Background Over the last five years, there have been numerous reports of association of juvenile idiopathic arthritis with single nucleotide polymorphisms (SNPs) at various loci outside the major histocompatibility complex (MHC) region. However, the majority of these association findings have been generated using a limited number of international cohorts, and thus there is benefit in further independent replication. To address this, we examined a total of 56 SNPs in 42 non-MHC gene regions previously reported to be associated with JIA, in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls. Findings Genotyping was performed on a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female). We demonstrated clear evidence for replication of association of JIA with SNPs in or around c12orf30, c3orf1, PTPN22, STAT4, and TRAF1-C5, confirming the involvement of these loci in disease risk. Further, we generated evidence supportive of replication of association of JIA with loci containing AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). These results were robust to sensitivity analyses for ethnicity. Conclusion We have provided valuable independent data as to the underlying genetic architecture of this understudied pediatric autoimmune disease, further confirming five loci outside the MHC, and supporting a role for a further five loci in determining disease risk.