Reliability assessment of the OMERACT whole-body magnetic resonance imaging scoring system for juvenile idiopathic arthritis.

Inter-reader reliability of a new scoring system for evaluating joint inflammation and enthesitis in whole body MRI (WBMRI) in juvenile idiopathic arthritis was tested. The scoring system grades 732 item-region combinations of bone marrow and soft tissue changes for commonly involved joints and entheseal sites. Five radiologists rated 17 WBMRI scans through an online rating platform. Item-wise reliability was calculated for 117 items with non-zero scores in >10 % of readings. Interquartile ranges of the five-reader Kappa reliability coefficients were 0.58-0.73 (range: 0.36-0.88) for the joints, 0.65-0.81 (range: 0.39-0.95) for the entheses, and 0.62-0.75 (range: 0.60-0.76) for chronic nonbacterial osteomyelitis-like lesions.

Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis.

OBJECTIVES: CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with JIA, categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA) or PsA. METHODS: Participants with eoJIA (2-17 years old), ERA or PsA (each 12-17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA ACR 30/50/70/90/100 criteria and ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis DAS (JADAS) ≤1. RESULTS: Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 [n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 (78%) on active treatment]; 84 (66%) completed 120 months' follow-up [32 (25%) on active treatment]. One malignancy (Hodgkin's disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates (events per 100 patient-years) of TEAEs (excluding infections/ISRs) decreased from 193 (173.81) in Year 1 to 9 (27.15) in Year 10; TE infections and serious infections also decreased. Over 45% of participants (n = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 34 (27%) participants achieved JADAS and ACR clinical remission, respectively. CONCLUSIONS: Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit-risk assessment of etanercept in these JIA categories remains favourable. TRIAL REGISTRATION: ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069).

Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis.

OBJECTIVE: Prospective comparative effectiveness research (CER) in chronic nonbacterial osteomyelitis (CNO) is lacking. Our objectives were to (1) determine the use and safety of each consensus treatment plan (CTP) regimen for CNO, (2) assess the feasibility of using the Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) data for CER, and (3) develop and validate a CNO clinical disease activity score (CDAS) using CHOIR. METHODS: Consenting children or young adults with CNO were enrolled into CHOIR. Demographic, clinical, and imaging data were prospectively collected. The CNO CDAS was developed through a Delphi survey and nominal group technique. External validation surveys were administered to CHOIR participants. RESULTS: One hundred forty (78.2%) CHOIR participants enrolled between August 2018 and September 2020 received at least 1 CTP regimen. Baseline characteristics from different CTP groups were well matched. Patient pain, patient global assessment, and clinical CNO lesion count were key variables included in the CNO CDAS. The CDAS showed a strong correlation with patient/parent report of difficulty using a limb, back, or jaw and patient/parent report of disease severity, but a weak correlation with patient/parent report of fatigue, sadness, and worry. The change in CDAS was significant in patients reporting disease worsening or improvement (P < 0.001). The CDAS significantly decreased after initiating second-line treatments from median 12.0 (IQR 8.0-15.5) to 5.0 (IQR 3.0-12.0; P = 0.002). Although second-line treatments were well tolerated, psoriasis was the most common adverse event. CONCLUSION: The CNO CDAS was developed and validated for disease monitoring and assessment of treatment effectiveness. CHOIR provided a comprehensive framework for future CER.

Determination of Relative Weightings for Sacroiliac Joint Pathologies in the OMERACT Juvenile Arthritis Magnetic Resonance Imaging Sacroiliac Joint Score.

This study aims to determine the relative weights (point value) of items of the juvenile idiopathic arthritis magnetic resonance imaging-sacroiliac joint scoring system (JAMRIS-SIJ). An adaptive multicriteria decision analysis was performed using the 1000Minds web application to determine the relative weights of the items in the JAMRIS-SIJ inflammation and damage domains. Experts in imaging and rheumatology independently completed a conjoint analysis survey (CAS) to determine the point value of the measurement items of the JAMRIS-SIJ. Each CAS survey question asked the expert to compare two hypothetical patient profiles, which were otherwise similar but different at two items at a time, and to select which item showed a more severe stage of inflammation or osteochondral damage. In addition, experts ranked 14 JAMRIS-SIJ grade only or image + grade patient vignettes while blinded to the CAS-derived weights. The validity of the weighted JAMRIS-SIJ was tested by comparing the expert CAS-weighted score and the image + grade ranking method. Seventeen experts completed the CAS (11 radiologists and 6 rheumatologists). Considering the point value for inflammation domain items, osteitis (24.7%) and bone marrow edema (24.3%) had higher group-averaged percentage weights compared to inflammation in erosion cavity (16.9%), joint space enhancement (13.1%), joint space fluid (9.1%), capsulitis (7.3%), and enthesitis (4.6%). Similarly, concerning the damage domain, ankylosis (41.3%) and erosion (25.1%) showed higher group-averaged weights compared to backfill (13.9%), sclerosis (10.7%), and fat metaplasia lesion (9.1%). The Spearman correlation coefficients of the CAS-weighted vignette order and unweighted JAMRIS-SIJ grade only order vignettes for all experts were 0.79 for inflammation and 0.80 for damage. The correlations of image vignettes among imaging experts to CAS were 0.75 for inflammation and 0.90 for damage. The multicriteria decision analysis identified differences in relative weights among the JAMRIS-SIJ measurement items. The determination of the relative weights provided expert-driven score scaling and face validity for the JAMRIS-SIJ, enabling the future evaluation of its longitudinal construct validity.

Patterns and rates of confirmed transfer of care of patients with juvenile idiopathic arthritis at a tertiary paediatric rheumatology centre.

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 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 and 2019 were identified. A chart review was undertaken to collect relevant data. RESULTS: One hundred and seventy-seven patients were identified. In all, 64% (114/177) were referred for adult care. The commonest JIA subtypes referred were seronegative polyarticular (35/114; 30.7%) and oligoarticular JIA (22/114; 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.

Consensus-driven conceptual development of a standardized whole body-MRI scoring system for assessment of disease activity in juvenile idiopathic arthritis: MRI in JIA OMERACT working group.

OBJECTIVES: Whole body-MRI is helpful in directing diagnostic and treatment approaches, and as a research outcome measure. We describe our initial consensus-driven phase towards developing a whole body-MRI scoring system for juvenile idiopathic arthritis. METHODS: An iterative approach using three rounds of anonymous Delphi surveys followed by a consensus meeting was used to draft the structure of the whole body-MRI scoring system, including the relevant anatomic joints and entheses for assessment, diagnostic item selection, definition and grading, and selection of appropriate MRI planes and sequences. The surveys were completed independently by an international expert group consisting of pediatric radiologists and rheumatologists. RESULTS: Twenty-two experts participated in at least one of three rounds of Delphi surveys and a concluding consensus meeting. A first iteration scoring system was developed which ultimately included the assessment of 100 peripheral, 23 chest, and 76 axial joints, and 64 entheses, with 2-4 diagnostic items graded in each of the items, using binary (presence/absence) and 2-3-level ordinal scores. Recommendations on anatomic MRI planes and sequences were specified as the minimally necessary imaging protocol for the scoring system. CONCLUSION: A novel whole body-MRI scoring system for juvenile idiopathic arthritis was developed by consensus among members of MRI in JIA OMERACT working group. Further iterative refinements, reliability testing, and responsiveness are warranted in upcoming studies.

Establishing core domain sets for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO): A report from the OMERACT 2020 special interest group.

OBJECTIVE: A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1. METHODS: A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework. RESULTS: Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%). CONCLUSION: Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.

Toward Developing a Semiquantitative Whole Body-MRI Scoring for Juvenile Idiopathic Arthritis: Critical Appraisal of the State of the Art, Challenges, and Opportunities.

With powerful new therapies available for management of juvenile idiopathic arthritis (JIA), early diagnosis leading to appropriate treatment may prevent long-term structural joint damage. Although magnetic resonance imaging (MRI) is typically used to assess individual body parts, indications for whole body (WB) MRI are increasing. Its utility as a diagnostic and monitoring tool has already been widely investigated in adult rheumatology patients, but less so in pediatric rheumatologic patients. This paper is a comprehensive review of scoring systems and a proposal for the conceptual development of a WB-MRI scoring system for the evaluation of JIA. In this review we identify, summarize, and critically appraise the available literature on the use of WB-MRI in inflammatory arthritis, addressing relevant considerations on components of a classification system that can lead to the development of a future pediatric WB-MRI scoring system for use in children with JIA. We also discuss advantages and challenges of developing such a WB-MRI scoring system for assessment of JIA and outline next steps toward the conceptual development of this scoring system.

Functional Ability and Health-Related Quality of Life in Randomized Controlled Trials of Tocilizumab in Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: To evaluate changes in health-related quality of life (HRQoL) and disability in children with systemic juvenile idiopathic arthritis (JIA) or polyarticular JIA treated with tocilizumab. METHODS: Secondary analyses of two double-blind, placebo-controlled trials of intravenous tocilizumab in children with active systemic JIA or polyarticular JIA were conducted. Patient-reported outcomes of disability (Childhood Health Assessment Questionnaire [C-HAQ]), HRQoL (Child Health Questionnaire Parent Form 50 [CHQ-P50], health concepts, physical summary score [CHQ-P50-PhS], psychosocial summary score [CHQ-P50-PsS]), pain, and well-being (100-mm visual analog scale [VAS]) were measured at weeks 0 and 12 for systemic JIA, weeks 16 and 40 for polyarticular JIA, and week 104 for both JIA subgroups. RESULTS: The trial included 112 patients with systemic JIA and 188 patients with polyarticular JIA. In patients with polyarticular JIA, the mean ± SD C-HAQ score decreased from 1.39 ± 0.74 at baseline to 0.67 ± 0.65 at week 16 (P < 0.001). In patients with systemic JIA, the mean ± SD CHQ-P50-PhS improved more with tocilizumab therapy than with placebo at week 12 (7.3 ± 10.2 versus 2.4 ± 10.6) (P < 0.05). Almost all mean CHQ-P50 health concept scores, CHQ-P50-PsS, and CHQ-P50-PhS improved (P ≤ 0.002) by week 104 for patients with systemic JIA. Patients with polyarticular JIA and patients with systemic JIA showed significant reductions in disability (mean ± SD C-HAQ scores of -1.09 ± 0.71 and -1.17 ± 0.80, respectively), improvements in well-being (mean ± SD well-being VAS scores of -43.76 ± 26.61 and -51.53 ± 23.57, respectively), and decreases in pain (mean ± SD pain VAS scores of -41.56 ± 31.06 and -51.26 ± 26.79, respectively) (P < 0.001); in patients with polyarticular JIA and patients with systemic JIA who were treated with tocilizumab, 92.9% of polyarticular JIA patients and 96.8% of systemic JIA patients reported no more than minimal pain (a score of ≤35 mm on the VAS) at week 104. CONCLUSION: Tocilizumab treatment was associated with significantly reduced disability and pain and improved HRQoL in patients with systemic JIA and polyarticular JIA.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.

Vaccinations Do Not Increase Arthritis Flares in Juvenile Idiopathic Arthritis: A Study of the Relationship between Routine Childhood Vaccinations on the Australian Immunisation Schedule and Arthritis Activity in Children with Juvenile Idiopathic Arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a collective term for a group of inflammatory conditions of uncertain origin, which causes chronic arthritis in one or more joints. The clinical course of JIA is characterised by episodes of increased activity, termed flares. Vaccinations have previously been proposed as a "trigger" for some flares, although evidence supporting this is scant. OBJECTIVE: To explore whether routine childhood vaccinations are associated with an increased risk of flares of arthritis activity in children with JIA. METHODS: Patients aged below 6 years with a diagnosis of JIA were recruited from the Rheumatology Clinical Database at the Royal Children's Hospital, Melbourne, Australia, from 1 January 2010 to 30 April 2016. Patient immunisation status was cross-checked with the Australian Childhood Immunisation Register (ACIR). The self-controlled case series methodology (Rowhani-Rahbar et al., 2012) was applied to determine whether the risk of arthritis flares in the three months following immunisation was greater than the baseline risk for each patient. RESULTS: 138 patients were included in the study. 32 arthritis flares occurred in the 90 days following immunisation. The risk of arthritis flares during the 90 days following immunisation was reduced compared with patients' baseline risk (RR 0.59 (95% CI 0.39-0.89, p = 0.012)). CONCLUSION: Routine childhood immunisations were not associated with arthritis flare onset in patients with JIA. The risk of arthritis flares in the 90 days following vaccination was lower than the baseline risk. In the context of COVID19, vaccination will not increase interaction with the healthcare system beyond the immunisation encounter.

Live attenuated MMR/V booster vaccines in children with rheumatic diseases on immunosuppressive therapy are safe: Multicenter, retrospective data collection.

PURPOSE: To collect retrospective data of patients with Juvenile Idiopathic Arthritis (JIA) and other rheumatic diseases who received live attenuated booster measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMR/V) during treatment with immunosuppressive therapy. RESULTS: Data from 13 pediatric rheumatology centers in 10 countries, including 234 patients, were collected. Mean age at diagnosis was 5 ± 2.7 years, 67% were girls. Among them, 211 (90.2%) had JIA and 110 (47%) were in remission on medication. Disease activity was low in 37%, high in 8%, and moderate in 8%. One hundred-twenty-four received MMR/V booster while on methotrexate (MTX); 3 reported local mild adverse events (AE). Among 62 on MTX + biologics and 9 patients who received a combination of 2 disease modifying antirheumatic drugs (DMARDs), 9 reported mild AE. Among 39 on biologics, 1 reported fever one day after booster vaccination. No vaccine-related infection of measles, rubella, mumps or varicella was reported, none of the patients developed disease flare, including those with high disease activity. CONCLUSIONS: In this retrospective study, live-attenuated MMR/V booster vaccines were safe for children with rheumatic diseases, on immunosuppressive therapies. This strengthens the Paediatric Rheumatology European Society (PReS) recommendation that vaccination with live attenuated vaccines in patients on immunosuppressive therapies can be considered individually, weighing the benefit of vaccination against the risk of inducing infection through vaccination. These data provide the basis for a prospective data collection study, planned by the PReS vaccination study group.

Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a complex group of systemic vasculitides that are characterized by primary small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are challenging conditions associated with high cumulative disease and treatment related morbidity and mortality. Given its rarity and the resulting paucity of pediatric-specific clinical trial evidence, pediatric rheumatologists have had to often extrapolate from adult literature for management and therapeutic decisions. The aim of this review is to provide a comprehensive overview of the important findings and overall conclusions of critical landmark clinical trials in the induction and maintenance treatments in adult AAV for the pediatric rheumatologist. This review also highlights the outcomes of recent pediatric AAV observational studies and discusses the future research priorities in pediatric AAV management.

Association of Increased Sun Exposure Over the Life-course with a Reduced Risk of Juvenile Idiopathic Arthritis.

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.

Juvenile idiopathic arthritis managed in the new millennium: one year outcomes of an inception cohort of Australian children.

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.

Treating juvenile idiopathic arthritis to target: recommendations of an international task force.

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA.

Treatment Options for Resistant Kawasaki Disease.

"Resistant" Kawasaki disease is defined by the American Heart Association as failure to respond within 36 h following the first dose of intravenous immunoglobulin. The optimal management of resistant Kawasaki disease remains uncertain, the outcomes are potentially serious, and the cost of some treatments is considerable. We review the current evidence to guide treatment of resistant Kawasaki disease. Given the relative rarity, there are few trial data, and studies tend to be small and methodologically heterogeneous, making interpretation difficult and limiting generalisability. The literature on resistant Kawasaki disease should be interpreted with reference to current expert consensus guidelines.

The DNA methylation landscape of CD4+ T cells in oligoarticular juvenile idiopathic arthritis.

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<0.01) at genes of known/potential relevance to disease. At VPS53, we demonstrated a regional shift towards higher methylation in oJIA (all-inclusive) compared to controls. At REEP3, where polymorphism has been previously associated with JIA, we demonstrated higher DNA methylation in male oJIA compared to male controls. This is the most comprehensive JIA case-control analysis of DNA methylation to date. While we have generated some evidence of altered methylation in oJIA, substantial differences are not apparent in CD4+ T cells. This may indicate a lesser relevance of DNA methylation levels in childhood, compared to adult, rheumatic disease.