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Context: Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions.Objectives: To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares.Design, Setting, and Patients: Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.Intervention: Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission.Main Outcome Measures: Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed.Results: Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90).Conclusions: In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.Trial Registration: isrctn.org Identifier: ISRCTN18186313. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140-kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland. METHODS: Clinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140-kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation/immunodepletion, using commercial monoclonal antibodies to NXP-2, reference anti-p140, and anti-p155/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects. RESULTS: Sera from 37 (23%) of 162 patients with juvenile myositis were positive for anti-p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM-overlap syndrome or control subjects. No anti-p140 antibody-positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP-2 (the previously identified MJ autoantigen). In children with anti-p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0-16.1). The clinical features of patients with anti-p140 autoantibodies were different from those of children with anti-p155/140 autoantibodies. The presence of HLA-DRB1*08 was a possible risk factor for anti-p140 autoantibody positivity. CONCLUSION: This study has established that anti-p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the juvenile myositis spectrum that includes an association with calcinosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The spondylarthritides (SpA) are strongly associated with possession of HLA-B27. We hypothesized that the expression of abnormal forms of HLA-B27 in SpA may have a pathogenic role through interaction with cells bearing natural killer (NK) receptors, in particular, killer immunoglobulin-like receptor (KIR) KIR3DL2, a receptor for HLA-B27 homodimer (B27(2)). We therefore undertook the present study to determine the number and function of NK and T cells bearing KIR3DL2 in SpA. METHODS: Expression of KIR3DL2 on NK and T cells was quantified in peripheral blood (PB) from 35 patients with SpA and 5 patients with juvenile enthesitis-related arthritis (juvenile ERA); samples were compared with samples from healthy and rheumatoid arthritis (RA) controls. Paired synovial fluid (SF) was studied where available. Expression of other KIRs as well as activation, memory, and homing markers on KIR3DL2+ NK and T cells was quantified. NK cell survival was assessed using the apoptotic markers annexin V and 7-aminoactinomycin D, and cytotoxicity by (51)Cr release assay. RESULTS: In SpA, an increased number of PB and SF NK and CD4+ T cells expressed the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells had an activated phenotype, and were protected from apoptosis by culture with a cell line expressing B27(2). SpA PB mononuclear NK cells from SpA patients showed greater cytotoxicity than those from controls. CONCLUSION: KIR3DL2 expression on NK cells and CD4 lymphocytes is increased in SpA and ERA. These cells are activated and may have a pathogenic role. [ABSTRACT FROM AUTHOR]

We have demonstrated a stable expansion of CD8+ T cells in the peripheral blood of a child with chronic arthritis. The expanded TCRBV family (TCRBV14) was enriched for CD57hicd28- T cells. Sequencing of the TCRBV14 amplification products showed a TCR sequence which contributed 32% of the total TCR in the CD8+TCRBV14 population. Using the modified heteroduplex technique, the CD8+TCRBV14 cells showed a clonal pattern and these bands were restricted to the CD28- population. This method also detected multiple other clones within the CD8+ population but few in the CD4+ cells. The dominant TCRBV14+ clone was not detectable in synovial fluid T cells from two inflamed joints by CDR3 length analysis or heteroduplex probing, suggesting that this long-lived clone is excluded from inflammatory sites. Synovial fluid T cells showed an unexpected discordance of the CD28 and CD57 phenotype compared to peripheral blood mononuclear cells. T cells from both inflamed joints both showed marked oligoclonality in all TCR families and had almost identical heteroduplex patterns. Taken together these data suggest that some clones are actively excluded from inflamed sites in juvenile chronic arthritis, yet the pattern of restricted T cell expansion is shared between sites of inflammation. [ABSTRACT FROM PUBLISHER]

Cellular phenotype and function are altered in different microenvironments. For targeted therapies it is important to understand site-specific cellular adaptations. Juvenile Idiopathic Arthritis (JIA) is characterised by autoimmune joint inflammation, with frequent inadequate treatment responses. To comprehensively assess the inflammatory immune landscape, we designed a 37-parameter spectral flow cytometry panel delineating mononuclear cells from JIA synovial fluid (SF) of autoimmune inflamed joints, compared to JIA and healthy control blood. Synovial monocytes and NK cells (CD56bright) lack Fc-receptor CD16, suggesting antibody-mediated targeting may be ineffective. B cells and DCs, both in small frequencies in SF, undergo maturation with high 4-1BB, CD71, CD39 expression, supporting T cell activation. SF effector and regulatory T cells were highly active with newly described co-receptor combinations that may alter function, and suggestion of metabolic reprogramming via CD71, TNFR2 and PD-1. Most SF effector phenotypes, as well as an identified CD4-Foxp3+ T cell population, were restricted to the inflamed joint, yet specific SF-predominant CD4+Foxp3+ Treg subpopulations were increased in blood of active but not inactive JIA, suggesting possible recirculation and loss of immunoregulation at distal sites. This first comprehensive dataset of the site-specific inflammatory landscape at protein level will inform functional studies and the development of targeted therapeutics to restore immunoregulatory balance and achieve remission in JIA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Objectives: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM., Methods: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash)., Results: In total 1054 patients were included (DM, n = 405; ASyS, n = 649). In the ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P < 0.001), whereas higher frequency of any of four DM-type rashes-heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V-sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%)-differentiated DM from ASyS-DMskin (all P < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both P < 0.001)., Conclusion: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD., Competing Interests: Declaration of interests Dr. Wallace receives research funding from GSK and MSD and is a part-time employee of GSK. Neither company had any influence on this work or its publication. Dr. Radstake is an employee of Abbvie and may hold stock. Abbvie had no influence on the content of this work or its publication. Dr. Chinoy has received fees as a speaker for GSK and UCB; consulting for PTC Therapeutics; advisory board member for Astra Zeneca, Pfizer, Argenx, and Galapagos; and as a data and science monitoring board chair for Horizon Therapeutics. Dr. Maurer has grants from Novartis, consulting fees from Novartis, Boehringer Ingelheim, Jannsen-Cilag, and GSK; speaker fees from Boehringer-Ingelheim, GSK, Novartis, Otsuka, and MSD; congress support from Medtalk, Pfizer, Roche, Actelion, Mepha, and MSD; and has a patent mir-29 for the treatment of SSc (US8247389, EP2331143). Dr. Wedderburn has received speaker and consultancy fees from Pfizer paid to UCL, unrelated to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Juvenile idiopathic arthritis (JIA)-associated uveitis (JIAU) is a serious JIA comorbidity that can result in vision impairment. This study aimed to identify genetic risk factors, within the major histocompatibility complex , for JIAU and evaluate their contribution for improving risk classification when combined with clinical risk factors., Methods: Data on single nucleotide polymorphisms, amino acids and classical human leukocyte antigen (HLA) alleles were available for 2,497 JIA patients without uveitis and 579 JIAU patients (female=2060, male=1015). Analysis was restricted to patients with inferred European ancestry. Forward conditional logistic regression identified genetic markers exceeding a Bonferroni corrected significance (6x10 -6 ). Multivariable logistic regression estimated the effects of clinical and genetic risk factors and a likelihood ratio test calculated the improvement in model fit when adding genetic factors. Uveitis risk classification performance of a model integrating genetic and clinical risk factors was estimated using area under the receiver operator characteristic curve and compared to a model of clinical risk factors alone., Results: Three genetic risk factors were identified mapping to HLA-DRB1, HLA-DPB1 and HLA-A. These markers were statistically independent from clinical risk factors and significantly improved the fit of a model when included with clinical risk factors (P = 3.3x10 -23 ). The addition of genetic markers improved the classification of JIAU compared to a model of clinical risk factors alone (AUC 0.75 vs. 0.71)., Conclusions: Integration of a genetic and clinical risk prediction model outperforms a model based solely on clinical risk factors. Future JIAU risk prediction models should include genetic risk factors., (This article is protected by copyright. All rights reserved.)

Objective: The goal was to assess the degree of overlap between existing International League of Associations for Rheumatology (ILAR) and preliminary Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria for juvenile idiopathic arthritis (JIA)., Methods: Participants from the Childhood Arthritis Prospective Study, a multicenter UK JIA inception cohort, were classified using the PRINTO and ILAR classification criteria into distinct categories. Systemic JIA was excluded because several classification items were not collected in this cohort. Adaptations to PRINTO criteria were required to apply to a UK health care setting, including limiting the number of blood biomarker tests required. The overlap between categories under the two systems was determined, and any differences in characteristics between groups were described., Results: A total of 1,223 children and young people with a physician's diagnosis of JIA were included. Using PRINTO criteria, the majority of the patients had "other JIA" (69.5%). There was a high degree of overlap (91%) between the PRINTO enthesitis/spondylitis- and ILAR enthesitis-related JIA categories. The PRINTO rheumatoid factor (RF)-positive category was composed of 48% ILAR RF-positive polyarthritis and 52% undifferentiated JIA. The early-onset antinuclear antibodies-positive PRINTO category was largely composed of ILAR oligoarthritis (50%), RF-negative polyarthritis (24%), and undifferentiated JIA (23%). A few patients were unclassified under PRINTO (n = 3) and would previously have been classified as enthesitis-related JIA (n = 1) and undifferentiated JIA (n = 2) under ILAR., Conclusion: Under the preliminary PRINTO classification criteria for childhood arthritis, most children are not yet classified into a named category. These data can help support further delineation of the PRINTO criteria to ensure homogenous groups of children can be identified., (© 2024 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Juvenile PsA (JPsA) has varied clinical features that are distinctive from other JIA categories. This study investigates whether such features impact patient-reported and clinical outcomes., Methods: Children and young people (CYP) were selected if recruited to the Childhood Arthritis Prospective Study, a UK multicentre JIA inception cohort, between January 2001 and March 2018. At diagnosis, patient/parent-reported outcomes (as age-appropriate) included the parental global assessment (10 cm visual analogue scale), functional ability (Childhood Health Assessment Questionnaire (CHAQ)), pain (10 cm visual analogue scale), health-related quality of life (Child Health Questionnaire PF50 psychosocial score), mood/depressive symptoms (Moods and Feelings Questionnaire) and parent psychosocial health (General Health Questionnaire 30). Three-year outcome trajectories have previously been defined using active joint counts, physician and parent global assessments (PGA and PaGA, respectively). Patient-reported outcomes and outcome trajectories were compared in (i) CYP with JPsA vs other JIA categories and (ii) CYP within JPsA, with and without psoriasis via multivariable linear regression., Results: There were no significant differences in patient-reported outcomes at diagnosis between CYP with JPsA and non-JPsA. Within JPsA, those with psoriasis had more depressive symptoms (coefficient = 9.8; 95% CI: 0.5, 19.0) than those without psoriasis at diagnosis. CYP with JPsA had 2.3 times the odds of persistent high PaGA than other ILAR categories, despite improving joint counts and PGA (95% CI: 1.2, 4.6)., Conclusion: CYP with psoriasis at JPsA diagnosis report worse mood, supporting a greater disease impact in those with both skin and joint involvement. Multidisciplinary care with added focus to support wellbeing in children with JPsA plus psoriasis may help improve these outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Pediatric rheumatology is a term that encompasses over 80 conditions affecting different organs and systems. Children and young people with rheumatological chronic conditions are known to have high levels of mental health problems and therefore are at risk of poor health outcomes. Clinical psychologists can help children and young people manage the daily difficulties of living with one of these conditions; however, there are insufficient pediatric psychologists in the United Kingdom. We urgently need to consider other ways of providing early, essential support to improve their current well-being. One way of doing this is to empower parents and caregivers to have more of the answers that their children and young people need to support them further between their hospital appointments., Objective: The objective of this co-designed proof-of-concept study is to design, develop, and test a chatbot intervention to support parents and caregivers of children and young people with rheumatological conditions., Methods: This study will explore the needs and views of children and young people with rheumatological conditions, their siblings, parents, and caregivers, as well as health care professionals working in pediatric rheumatology. We will ask approximately 100 participants in focus groups where they think the gaps are in current clinical care and what ideas they have for improving upon them. Creative experience-based co-design workshops will then decide upon top priorities to develop further while informing the appearance, functionality, and practical delivery of a chatbot intervention. Upon completion of a minimum viable product, approximately 100 parents and caregivers will user-test the chatbot intervention in an iterative sprint methodology to determine its worth as a mechanism for support for parents., Results: A total of 73 children, young people, parents, caregivers, and health care professionals have so far been enrolled in the study, which began in November 2023. The anticipated completion date of the study is April 2026. The data analysis is expected to be completed in January 2026, with the results being published in April 2026., Conclusions: This study will provide evidence on the accessibility, acceptability, and usability of a chatbot intervention for parents and caregivers of children and young people with rheumatological conditions. If proven useful, it could lead to a future efficacy trial of one of the first chatbot interventions to provide targeted and user-suggested support for parents and caregivers of children with chronic health conditions in health care services. This study is unique in that it will detail the needs and wants of children, young people, siblings, parents, and caregivers to improve the current support given to families living with pediatric rheumatological conditions. It will be conducted across the whole of the United Kingdom for all pediatric rheumatological conditions at all stages of the disease trajectory., International Registered Report Identifier (irrid): DERR1-10.2196/57238., (©Polly Livermore, Klaudia Kupiec, Lucy R Wedderburn, Andrea Knight, Ameenat L Solebo, Roz Shafran, Glenn Robert, N J Sebire, Faith Gibson, IMPACT Steering Group. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 03.04.2024.)

Objective: To explore the cost-effectiveness of a web-based support tool for parents of children with Juvenile Idiopathic Arthritis., Methods: A multi-centred randomised controlled trial was conducted in paediatric rheumatology centres in England. The WebParC intervention consisted of online information about JIA and its treatment and a toolkit using cognitive-behavioural therapy principles to support parents manage their child's JIA. An economic evaluation was performed alongside the trial involving 220 parents. The primary outcome was the self-report Pediatric Inventory for Parents measure of illness-related parenting stress, with two dimensions; difficulty and frequency. These measures along with costs were assessed post intervention at 4 months and 12 months. Costs were calculated for healthcare usage using a UK NHS economic perspective. Data was collected and analysed on the impact of caring costs on families. Uncertainty around cost effectiveness was explored using bootstrapping and cost-effectiveness acceptability curves., Results: The intervention arm showed improved average Pediatric Inventory for Parents scores for the dimensions of frequency and difficulty, of 1.5 and 3.6 respectively at 4 months and. 0.35 and 0.39 at 12 months, representing improved PIP scores for the intervention arm. At both 4 and 12 month follow up the average total cost per case was higher in the control group when compared with the intervention arm with mean differences of £360 (95% CI £29.6 to £691) at 4 months and £203 (95% CI £16 to £390) at 12 months. The probability of the intervention being cost effective ranged between 49% and 54%., Conclusion: The WebParC intervention led to reductions in primary and secondary healthcare resource use and costs at 4 and 12 months. The intervention demonstrated particular savings for rheumatology services at both follow ups. Future economies of scale could be realised by health providers with increased opportunities for cost effectiveness over time., Trial Registration: ISRCTN, ISRCTN13159730., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)