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Background: Awareness of paediatric-specific predictors of damage in Childhood-lupus is needed to inform mitigation measures., Objectives: To ascertain how clinical and demographic variables correlate with damage accrual and identify predictors of damage., Methods: Analysis included UK JSLE Cohort Study participants. Univariable and multivariable Prentice-Williams-Peterson models investigated how demographic and clinical factors influenced hazards of new damage. Analyses were performed across the entire cohort, in patients with minimal disease activity marked by a time-adjusted average SLEDAI-2K score (AMS)≤2, low activity (AMS ≤ 4), moderate-high activity (AMS > 4) and those with no corticosteroids., Results: Within the entire cohort (n = 430), factors associated with damage included: any methylprednisolone (Hazard Ratio, HR 2.20, [CI 1.33-3.62]), time-adjusted mean Physicians Global Assessment (PGA) (HR 2.87, [CI 1.48-5.56]) and AMS score (HR 1.13, [CI 1.03-1.24], all p< 0.05). Within the low activity subgroup, any methylprednisolone (HR 2.61, [CI 1.04-6.53]) and time-adjusted mean PGA (HR 3.41, [CI 1.52-7.76]) were associated with damage (both p< 0.05). Within the moderate-high activity subgroup, any methylprednisolone (HR 2.29, [CI 1.31-4.00]), time-adjusted mean PGA (HR 2.66, [CI 1.20-5.87]) and AMS score (HR 1.15, [CI 1.03-1.29]), were predictive of damage (all p< 0.05). Baseline organ damage was predictive of subsequent damage accrual in the minimal activity (HR 1.33, CI [1.78-8.08]) and no corticosteroids subgroups (HR 3.64, CI [1.83-7.24], both p< 0.005)., Conclusion: Disease activity levels (AMS/PGA) and proxy indicators (methylprednisolone exposure, baseline damage) were found to be key predictors of damage accrual. This highlights the importance of practical strategies, to reduce disease activity and long-term treatment toxicity, such as treat-to-target., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Clinicians concerned about long-term safety of biologics in JIA may consider tapering or stopping treatment once remission is achieved despite uncertainty in maintaining drug-free remission. This analysis aims to (i) calculate how many patients with JIA stop biologics for remission, (ii) calculate how many later re-start therapy and after how long, and (iii) identify factors associated with re-starting biologics., Methods: Patients starting biologics between 1 January 2010 and 7 September 2021 in the UK JIA Biologics Register were included. Patients stopping biologics for physician-reported remission, those re-starting biologics and factors associated with re-starting, were identified. Multiple imputation accounted for missing data., Results: Of 1451 patients with median follow-up of 2.7 years (IQR 1.4, 4.0), 269 (19%) stopped biologics for remission after a median of 2.2 years (IQR 1.7, 3.0). Of those with follow-up data (N = 220), 118 (54%) later re-started therapy after a median of 4.7 months, with 84% re-starting the same biologic. Patients on any-line tocilizumab (prior to stopping) were less likely to re-start biologics (vs etanercept; odds ratio [OR] 0.3; 95% CI: 0.2, 0.7), while those with a longer disease duration prior to biologics (OR 1.1 per year increase; 95% CI: 1.0, 1.2) or prior uveitis were more likely to re-start biologics (OR 2.5; 95% CI: 1.3, 4.9)., Conclusions: This analysis identified factors associated with successful cessation of biologics for remission in JIA as absence of uveitis, prior treatment with tocilizumab and starting biologics earlier in the disease course. Further research is needed to guide clinical recommendations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients., Methods: Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets., Results: Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit., Conclusion: Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: The primary objective was to define the incidence of JSLE in children <16 years of age in the UK and Republic of Ireland (ROI). The secondary objective was to describe presenting features, classification criteria, initial management and disease damage in newly presenting JSLE patients., Methods: A prospective JSLE epidemiological study was undertaken between September 2017 and September 2019 with support of the British Paediatric Surveillance Unit and other professional groups involved in diagnosis and management of JSLE patients. Treating consultants reported all cases of JSLE seen. A follow-up study at 1 year examined management and progression of disease and treatment., Results: There were 124 incident cases included in the final analysis. Incidence was estimated using ACR-1997 classification criteria (0.36/100 000), SLICC-2012 classification criteria (0.41/100 000) and clinician expert opinion (0.46/100 000). A high disease burden was seen, with 71.0% of patients requiring ongoing systemic CS treatment at 1 year; 98.2% receiving immunomodulatory treatment; and 20.4% accruing damage in the year following diagnosis (predominantly neuropsychiatric-related), with substantial involvement from multiple speciality teams., Conclusions: The minimum UK and ROI incidence of JSLE is between 0.36 and 0.46/100 000, depending on the case definition used. Challenges in classification of patients with JSLE are highlighted, but overall this study supports the use of SLICC-2012 classification criteria. The high levels of disease damage and ongoing CS use 1 year after diagnosis is concerning, highlighting the need for further interventions to improve outcomes in JSLE., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood-onset SLE (cSLE)., Methods: Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen gap recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage., Results: LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (P < 0.001). As cumulative time in each target increased, hazard of severe flare progressively reduced. LLDAS attainment reduced the hazard of severe flare more than LA or Toronto-LDA (P < 0.001). Attainment of LLDAS and all remission definitions led to a statistically comparable reduction in the hazards of severe flare (P > 0.05). Attainment of all targets reduced the hazards of new damage (P < 0.05)., Conclusions: This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical remission., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: We sought to explore patient and parental views on treatment targets, outcome measures and study designs being considered for a future JSLE treat-to-target (T2T) study., Methods: We conducted topic-guided, semistructured interviews with JSLE patients and parents and analysed the audio recorded interviews using thematic approaches., Results: Patients and parents differed regarding symptoms they felt would be tolerable, representing 'low disease activity'. Patients often classed symptoms that they had previously experienced, were 'invisible' or had minimal disruption on their life as signs of low disease activity. Parents were more accepting of visible signs but were concerned about potential organ involvement and symptom severity. Overall, patients and parents preferred that children were entirely asymptomatic, with no ongoing treatment side effects. They regarded fatigue as particularly challenging, requiring proper monitoring using a fatigue patient-reported outcome measure. Most families felt that reducing corticosteroids would also be a good treatment target. Overall, families liked the concept of T2T, commenting that it could help to improve disease control, help structure treatment and improve communication with clinicians and treatment compliance. They were concerned that T2T might increase the frequency of hospital visits, thus impacting upon schooling, parental employment and finances. Families made suggestions on how to modify the future trial design to mitigate such effects., Conclusion: This study provides guidance from patients and parents on T2T targets and study designs. Complementary quantitative studies assessing the achievability and impact of different targets (e.g. lupus low disease activity state or remission) are now warranted to inform an international consensus process to develop treatment targets., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE., Methods: Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria., Results: At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%)., Conclusion: In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To define the incidence and prevalence of Behçet's syndrome (BS) in children and young people (CYP) up to the age of 16 years in the United Kingdom (UK) and Republic of Ireland (ROI)., Methods: A prospective epidemiological study was undertaken with the support of the British Paediatric Surveillance Unit (BPSU) and the British Society of Paediatric Dermatologists (BSPD). Consultants reported anonymised cases of BS seen. A follow-up study at one year examined progression of disease and treatment., Results: Over a two-year period, 56 cases met the International Criteria for Behçet's Disease. For children under 16 years of age, the two-year period prevalence estimate was 4.2 per million (95% CI: 3.2, 5.4) and the incidence was 0.96 per million person years (95% CI: 0.66, 1.41). Mucocutaneous disease was the most common phenotype (56/100%), with ocular (10/56; 17.9%), neurological (2/56; 3.6%) and vascular involvement (3/56; 5.4%) being less common. Median age at onset was 6.34 years and at diagnosis was 11.72 years. There were slightly more female than male children reported (32/56; 55.6%). The majority of cases (85.7%) were white Caucasian. Apart from genital ulcers, which were more common in females, there were no significant differences in frequency of manifestations between male or females, nor between ethnicities. Over 83% of cases had three or more non-primary care healthcare professionals involved in their care., Conclusion: BS is extremely rare in CYP in the UK and ROI and most have mucocutaneous disease. Healthcare needs are complex, and coordinated care is key., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: ∼30% of patients with SLE develop LN. Presence and/or severity of LN are currently assessed by renal biopsy, but biomarkers in serum or urine samples may provide an avenue for non-invasive routine testing. We aimed to validate a urinary protein panel for its ability to predict active renal involvement in SLE., Methods: A total of 197 SLE patients and 48 healthy controls were recruited, and urine samples collected. Seventy-five of the SLE patients had active LN and 104 had no or inactive renal disease. Concentrations of lipocalin-like prostaglandin D synthase (LPGDS), transferrin, alpha-1-acid glycoprotein (AGP-1), ceruloplasmin, monocyte chemoattractant protein 1 (MCP-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were quantified by MILLIPLEX® Assays using the MAGPIX Luminex platform. Binary logistic regression was conducted to examine whether proteins levels associate with active renal involvement and/or response to rituximab treatment., Results: Urine levels of transferrin (P <0.005), AGP-1 (P <0.0001), MCP-1 (P <0.001) and sVCAM-1 (P <0.005) were significantly higher in SLE patients when compared with healthy controls. Furthermore, levels of transferrin, AGP-1, ceruloplasmin, MCP-1 and sVCAM-1 (all P <0.0001) were higher in SLE patients with active LN when compared with patients without active LN. A combination of five urine proteins, namely LPGDS, transferrin, ceruloplasmin, MCP-1 and sVCAM-1 was a good predictor of active LN (AUC 0.898). A combined model of LPGDS, transferrin, AGP-1, ceruloplasmin, MCP-1 and sVCAM-1 predicted response to rituximab treatment at 12 months (AUC 0.818)., Conclusions: Findings support the use of a urinary protein panel to identify active LN and potentially predict response to treatment with rituximab in adult SLE patients. Prospective studies are required to confirm findings., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To describe and compare the occurrence of newly diagnosed uveitis in children with JIA receiving MTX, etanercept, adalimumab and infliximab., Methods: This on-drug analysis included patients within UK JIA registries (British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study and Biologics for Children with Rheumatic Diseases) with non-systemic disease, registered at MTX or biologic start with no history of uveitis. Follow-up began from date of first treatment, continuing until first uveitis, discontinuation of registered drug, most recent follow-up up or death, whichever came first. Hazard ratios comparing risk of uveitis between drugs were calculated using propensity-adjusted Cox regression., Results: A total of 2294 patients were included (943 MTX, 304 adalimumab/infliximab, 1047 etanercept). There were 44 reported cases of uveitis (27 MTX, 16 etanercept, 1 adalimumab). Unadjusted hazard ratio showed a reduced risk of uveitis in biologic cohorts compared with MTX. After adjusting for propensity deciles, there was no significant difference in the risk of uveitis between patients receiving etanercept or MTX [hazard ratio 0.5 (0.2-1.1)]. Fully adjusted comparisons were not possible for adalimumab/infliximab as there were too few events., Conclusions: In this first paper to compare the rate of new onset uveitis across the three main anti-TNF therapies used in JIA, a new diagnosis of uveitis is less common among patients starting biologics compared with MTX, although this did not reach statistical significance. The suggested protective effect of etanercept is likely explained by confounding, whereby patients in the MTX cohort are younger and earlier in disease, and therefore at greater risk of developing uveitis compared with etanercept patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: IgA vasculitis (IgAV, formerly known as Henoch-Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV., Methods: Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed., Results: In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy., Conclusion: The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To provide an overview of the paediatric rheumatology (PR) services in Europe, describe current delivery of care and training, set standards for care, identify unmet needs and inform future specialist service provision., Methods: An online survey was developed and presented to national coordinating centres of the Paediatric Rheumatology International Trials Organisation (PRINTO) (country survey) and to individual PR centres (centre and disease surveys) as a part of the European Union (EU) Single Hub and Access point for paediatric Rheumatology in Europe project. The survey contained components covering the organization of PR care, composition of teams, education, health care and research facilities and assessment of needs., Results: Response rates were 29/35 (83%) for country surveys and 164/288 (57%) for centre surveys. Across the EU, approximately one paediatric rheumatologist is available per million population. In all EU member states there is good access to specialist care and medications, although biologic drug availability is worse in Eastern European countries. PR education is widely available for physicians but is insufficient for allied health professionals. The ability to participate in clinical trials is generally high. Important gaps were identified, including lack of standardized clinical guidelines/recommendations and insufficient adolescent transition management planning., Conclusion: This study provides a comprehensive description of current specialist PR service provision across Europe and did not reveal any major differences between EU member states. Rarity, chronicity and complexity of diseases are major challenges to PR care. Future work should facilitate the development, dissemination and implementation of standards of care, treatment and service recommendations to further improve patient-centred health care across Europe., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The European Single Hub and Access point for paediatric Rheumatology in Europe initiative aimed to optimize care for children with rheumatic diseases. Kawasaki disease (KD) is the most common cause of acquired heart disease in children and an important cause of long-term cardiac disease into adulthood. Prompt diagnosis and treatment of KD is difficult due to the heterogeneity of the disease but is crucial for improving outcome. To date, there are no European internationally agreed, evidence-based guidelines concerning the diagnosis and treatment of KD in children. Accordingly, treatment regimens differ widely. The aim of this study is to provide consensus-based, European-wide evidence-informed recommendations for diagnosis and treatment of children with KD., Methods: Recommendations were developed using the EULAR's standard operating procedures. An extensive systematic literature search was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of international experts via online surveys and subsequently discussed in three consensus meetings, using nominal group technique. Recommendations were accepted when ⩾80% agreed., Results: In total, 17 recommendations for diagnosis and 14 for treatment of KD in children were accepted. Diagnostic recommendations included laboratory and imaging workup for complete as well as incomplete KD. Treatment recommendations included the importance of early treatment in both complete and incomplete KD, use of intravenous immunoglobulin, aspirin, corticosteroids for high-risk cases, and other treatment options for those with resistant disease., Conclusion: The Single Hub and Access point for paediatric Rheumatology in Europe initiative provides international evidence-based recommendations for diagnosing and treating KD in children, facilitating improvement and uniformity of care., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis., Methods: Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed., Results: Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided., Conclusion: These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This analysis aims to calculate MTX monotherapy persistence and describe the occurrence of and factors associated with the occurrence of adverse drug reactions (ADRs) with MTX., Methods: Patients with JIA starting MTX monotherapy from two UK studies were included. Patient characteristics, treatment details and ADR occurrence were collected at treatment start, 6 months, 1 year and annually. The following groups of ADRs were included: gastrointestinal, elevated liver enzymes, leukopenia, drug hypersensitivity, rash, needle phobia and any events leading to permanent MTX discontinuation. Treatment exposure was calculated from MTX start until MTX monotherapy cessation, last follow-up or 31 December 2017 (cut-off), whichever came first. Survival analysis assessed the time on MTX monotherapy and the time to the first ADR on MTX monotherapy within 2 years. Multivariable logistic regression assessed characteristics associated with any ADR and gastrointestinal ADRs., Results: A total of 577 patients started MTX. At 2 years, 310 (54%) were no longer on MTX monotherapy. Reasons included ineffectiveness (60%; 161/185 started a biologic), adverse event (25%), remission (8%) and patient/family decision (3%). Over this time, 212 (37%) patients experienced one or more ADR; commonly gastrointestinal (68%) or elevated liver enzymes (26%). Lower physician global assessment and older age predicted any ADR and gastrointestinal ADR, respectively. Patients with polyarticular RF and JIA had reduced odds of both any ADR and a gastrointestinal ADR., Conclusion: After 2 years, more than half the patients were no longer on MTX monotherapy, while more than one-third experienced one or more ADR, most commonly gastrointestinal. Research focusing on identifying which children will respond and/or experience ADRs is crucial to inform treatment decisions and management planning., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction or Background: Stratified medicine is an important area of research across all clinical specialties, with far reaching impact in many spheres. Despite recently formulated global policy and research programmes, major challenges for delivering stratified medicine studies persist. Across the globe, clinical research infrastructures have been setup to facilitate high quality clinical research., Sources of Data: This article reviews the literature and summarizes views collated from a workshop held by the UK Pharmacogenetics and Stratified Medicine Network and the NIHR Clinical Research Network in November 2016., Areas of Agreement: Stratified medicine is an important area of clinical research and health policy, benefitting from substantial international, cross-sector investment and has the potential to transform patient care. However there are significant challenges to the delivery of stratified medicine studies., Areas of Controversy: Complex methodology and lack of consistency of definition and agreement on key approaches to the design, regulation and delivery of research contribute to these challenges and would benefit from greater focus., Growing Points: Effective partnership and development of consistent approaches to the key factors relating to stratified medicine research is required to help overcome these challenges., Areas Timely for Developing Research: This paper examines the critical contribution clinical research networks can make to the delivery of national (and international) initiatives in the field of stratified medicine. Importantly, it examines the position of clinical research in stratified medicine at a time when pressures on the clinical and social services are mounting., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Rituximab (RTX) may be a treatment option for children and young people with JIA, although it is not licensed for this indication. The aim of this study was to describe RTX use and outcomes among children with JIA., Methods: This analysis included all JIA patients within the UK Biologics for Children with Rheumatic Diseases study starting RTX. Disease activity was assessed at RTX start and at follow-up. The total number of courses each patient received was assessed. Serious infections and infusion reactions occurring following RTX were reported., Results: Forty-one JIA patients starting RTX were included, the majority with polyarthritis: polyarthritis RF negative [n = 14 (35%)], polyarthritis RF positive [n = 13 (33%)] and extended oligoarthritis [n = 9 (23%)]. Most were female (80%) with a median age of 15 years [interquartile range (IQR) 12-16] and a median disease duration of 9 years (IQR 5-11). The median improvement in the clinical Juvenile Arthritis Disease Activity Score (cJADAS; three-variable 71-joint JADAS) from RTX start was 9 units (n = 7; IQR -14-2). More than half reported more than one course of RTX. The median time between each course was 219 days (IQR 198-315). During follow-up, 17 (41%) patients reported switching to another biologic, including tocilizumab (n = 8), abatacept (n = 6) and TNF inhibitor (n = 3). Three patients (7%) reported a serious infection on RTX (rate of first serious infection 6.2/100 person-years). Four patients (10%) reported an infusion reaction., Conclusions: This real-world cohort of children with JIA, the majority with polyarticular or extended oligoarticular JIA, showed RTX may be an effective treatment option for children who do not respond to TNF inhibitor, with a low rate of serious infections on treatment.

Objectives: To investigate real-world short-term outcomes among patients with systemic JIA starting tocilizumab or anakinra., Methods: This analysis included all systemic JIA patients within the UK Biologics for Children with Rheumatic Diseases study starting tocilizumab or anakinra between 2010 and 2016. Disease activity was assessed at baseline and one year. At one year the following outcomes were assessed: minimal disease activity, clinically inactive disease, 90% ACR Paediatric response (ACRPedi90). Univariable logistic regression was used to identify baseline characteristics associated with these outcomes. Multiple imputation was used to account for missing data., Results: Seventy-six systemic JIA patients were included (54 tocilizumab; 22 anakinra). More patients starting anakinra as their first biologic compared with tocilizumab (86% vs 63%; P = 0.04), with shorter disease duration (1 vs 2 years; P = 0.003) and higher frequency of prior macrophage activation syndrome (37% vs 8%; P = 0.004). Overall, at one year, 42% achieved ACRPedi90, 51% minimal disease activity, and 39% clinically inactive disease, with similar responses seen between the two drugs. Response was not associated with baseline disease characteristics. Fifteen (20%) patients stopped biologic treatment by one year. Treatment survival was better with tocilizumab (89% at one year vs 59% anakinra; P = 0.002), with three stopping for anakinra injection-related problems., Conclusion: In this real-world cohort of patients with systemic JIA receiving tocilizumab or anakinra, approximately half achieved a minimal disease state by one year. Treatment responses appeared similar between the two therapies albeit with better persistence observed with tocilizumab.

Objective: JIA is an autoimmune, inflammatory disease with involvement of innate and adaptive immune responses. However, the role of neutrophils in JIA pathogenesis remains unclear. This study aimed to identify and validate neutrophil gene expression signatures in JIA using public microarray datasets and new clinical samples., Methods: Three suitable datasets were analysed by significance analysis of microarray and Ingenuity. Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from a new cohort of JIA patients and healthy paediatric controls (HCs). Gene expression was validated using quantitative PCR. Serum concentrations of proteins were measured using ELISA. Low-density granulocytes (LDGs) in JIA and HC PBMCs were quantified by flow cytometry using forward/side-scatter properties., Results: Ingenuity identified transcriptional regulation (false discovery rate < 0.05) by G-CSF, GM-CSF and IL-8 along with expression of neutrophil granule protein genes including ELANE, MPO, MMP8 and MMP9 in datasets from JIA PBMCs. LDG counts were elevated in JIA compared with HCs (2.5% vs 1.4%; P = 0.007). Transcripts for MMP8 (P = 0.005), MPO (P = 0.0124) and Fcγ Receptor 1B (FCγR1B) (P = 0.0417) were significantly higher in JIA compared with HC neutrophils. MMP9 protein levels were lower in systemic JIA patient sera [355.95 ng/ml (s.d. 250.03)] compared with HCs [675.41 ng/ml (s.d. 181.17); P = 0.007], but levels of elastase, MPO and MMP8 were not significantly different., Conclusion: LDGs are elevated in JIA and contribute to the transcriptomic profile of JIA PBMCs. JIA neutrophils express higher levels of MMP8 and FCGR1B, which may be implicated in disease pathology through the release of proteases and reactive oxygen metabolites, causing systemic inflammation and damage to joints., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: There is uncertainty about the optimal teicoplanin regimens for neonates. The study aim was to determine the population pharmacokinetics (PK) of teicoplanin in neonates, evaluate currently recommended regimens and explore the exposure-effect relationships., Methods: An open-label PK study was conducted. Neonates from 26 to 44 weeks post-menstrual age were recruited (n = 18). The teicoplanin regimen was a 16 mg/kg loading dose, followed by 8 mg/kg once daily. Therapeutic drug monitoring and dose adjustment were not conducted. A standard two-compartment PK model was developed, followed by models that incorporated weight. A PK/pharmacodynamic (PD) model with C-reactive protein serial measurements as the PD input was fitted to the data. Monte Carlo simulations (n = 5000) were performed using Pmetrics. The AUCs at steady state and the proportion of patients achieving the recommended drug exposures (i.e. C min >15 mg/L) were determined. The study was registered in the European Clinical Trials Database Registry (EudraCT: 2012-005738-12)., Results: The PK allometric model best accounted for the observed data. The PK parameters medians were: clearance = 0.435 × (weight/70) 0.75 (L/h); volume = 0.765 (L); K cp  = 1.3 (h -1 ); and K pc  = 0.629 (h -1 ). The individual time-course of C-reactive protein was well described using the Bayesian posterior estimates for each patient. The simulated median AUC 96-120 was 302.3 mg·h/L and the median C min at 120 h was 12.9 mg/L; 38.8% of patients attained a C min >15 mg/L by 120 h., Conclusions: Teicoplanin population PK is highly variable in neonates, weight being the best descriptor of PK variability. A low percentage of neonates were able to achieve C min >15 mg/L. The routine use of therapeutic drug monitoring and improved knowledge on the PD of teicoplanin is required., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objectives of this study were to describe patients starting first-line biologics for JIA, to describe characteristics over time among patients starting etanercept, and to describe patterns of second biologic prescribing., Methods: The British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study, and the Biologics for Children with Rheumatic Diseases study are ongoing prospective observational cohorts, collecting data on patients starting biologic therapy for JIA. Patients registered from 1 January 2010 starting their first biologic were compared between therapies. Patients starting etanercept before 2010 were included to analyse changes in etanercept prescribing. The pathway of patients starting a second biologic was recorded in all patients., Results: To 26 August 2014, 931 patients were recruited starting a first-line biologic (142 Biologics for Children with Rheumatic Diseases; 789 British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study). From 2010, patients with systemic JIA (sJIA) were almost exclusively prescribed anakinra or tocilizumab. Choice between anti-TNF therapies was largely driven by history of chronic anterior uveitis (CAU). When investigating trends in patients starting etanercept over time, disease duration at etanercept start, patients with sJIA, a history of CAU, and those who received concomitant oral corticosteroids decreased over time. Patients who started a second biologic from 1 January 2010 showed a similar stratification., Conclusion: Although etanercept remains the most common biologic prescribed for JIA, there has been a clear shift towards the use of alternative biologics, largely driven by disease subtype and history of CAU. This channelling of children towards specific therapies should be considered carefully in future studies and in clinical guidelines and ongoing research., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To determine whether mucocutaneous manifestations are associated with major organ involvement in a UK national cohort of juvenile-onset SLE (JSLE) patients., Methods: JSLE patients (n = 241) from 15 different centres whose diagnosis fulfilled four or more of the ACR criteria were divided into two groups: those with at least one ACR mucocutaneous criterion (ACR skin feature positive) and those without (ACR skin feature negative) at diagnosis. The relative frequency of skin involvement was described by the paediatric adaptation of the 2004 British Isles Lupus Assessment Group (pBILAG-2004) index., Results: One hundred and seventy-nine patients (74%) had ACR-defined skin involvement with no significant demographic differences compared with those without. ACR skin feature negative patients showed greater haematological (84% vs 67%), renal (43% vs 26%) (P < 0.05) and neurological (16% vs 4%) involvement (P = 0.001). Forty-two per cent of ACR skin feature negative patients had skin involvement using pBILAG-2004, which included maculopapular rash (17%), non-scaring alopecia (15%), cutaneous vasculitis (12%) and RP (12%). ACR skin feature negative patients with moderate to severe skin involvement by pBILAG-2004 showed greater renal and haematological involvement at diagnosis and over the follow-up period (P < 0.05). Higher immunosuppressive drug use in the skin feature negative group was demonstrated., Conclusion: Patients who fulfil the ACR criteria but without any of the mucocutaneous criteria at diagnosis have an increased risk of major organ involvement. The pBILAG-2004 index has shown that other skin lesions may go undetected using the ACR criteria alone, and these lesions show a strong correlation with disease severity and major organ involvement., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The objective of this study was to investigate factors that may influence the interval between symptom onset and JSLE diagnosis., Methods: Data from all patients recruited to the UK JSLE Cohort Study between 2006 and 2011 and meeting ACR criteria for lupus were analysed. Variables associated with time between symptom onset and diagnosis were identified using correlation tests. Linear regression was used to identify independent predictors of access to care., Results: Two hundred and fifty-seven children with JSLE were included in the analysis (216 females, 41 males, ratio 5.3:1). The median time from symptom onset to diagnosis was 0.4 years (range 0.0-14.1 years, interquartile range 0.2-1.4). A linear regression model identified being of African or Caribbean origin (P = 0.006), Asian (P = 0.045), referred by a paediatrician (P = 0.047) or having nephritis (P = 0.045) at presentation as independent predictors of shorter time to diagnosis. Being of Caribbean or Asian origin, compared with white, was associated with a 56% and 37% reduction in geometric mean time to diagnosis, respectively. Similarly, being referred to paediatric rheumatology by a paediatrician or having nephritis at presentation was also associated with a 32% and 36% reduction in geometric mean time to diagnosis, respectively., Conclusion: Within this national UK cohort, ethnic origin, initial source of referral and having lupus nephritis at presentation were strong predictors of the interval to establishing a diagnosis of JSLE.

There has been a concerted and important international effort to develop and validate disease activity and outcome instruments specific to JIA in recent years. This review aims to describe the disease assessment indices important to routine clinical care and integral to the design of outcome studies and clinical trials in JIA. In view of the increasing number of JIA clinical studies and clinical trials, together with a number of national and international paediatric biologic registers, it is important that knowledge of these new outcome measures is widespread, such that results can be placed in a meaningful context.

Novel therapies including biologic agents offer paediatric rheumatologists significant opportunity to improve long-term prognosis for children with rheumatic disease. However, comorbidities related to the diseases themselves and their treatments pose specific challenges to be overcome. Prompt recognition and appropriate management will improve quality of life, effectiveness of treatment and overall prognosis. In this review, we discuss key areas of comorbidity frequently encountered in paediatric rheumatology including cardiovascular, renal, genito-urinary and visual comorbidity, bone health, drug-related issues and the influence of rheumatic disease on growth and puberty.

Objectives: Toll-like receptors (TLRs) essential in the functioning of the immune system have been implicated in the development of autoimmunity. TLR3, 7, 8 and 9 are capable of recognizing nucleic autoantigens typical of SLE. Their expression correlates positively with disease activity in adult-onset SLE. This study aimed to determine the role of TLRs in JSLE and whether apoptotic neutrophils are a source of nuclear autoantigen being detected through TLR3, 7, 8 and 9, leading to an inflammatory response., Methods: TLR3, 7, 8 and 9 mRNA and protein expression were measured in peripheral blood mononuclear cells (PBMCs) in JSLE patients compared with JIA and non-inflammatory controls. Activation of the TLRs by JSLE serum-induced apoptotic neutrophils was detected by measuring IFN-α mRNA and protein expression, and confirmed using myeloid differentiation factor 88 (MyD88) and TIR domain-containing adapter-inducing IFN-β (TRIF) inhibitors., Results: JSLE patients have increased TLR3, 8 and 9 mRNA and protein expression compared with controls (P < 0.05). Incubation of PBMCs with apoptotic neutrophils demonstrated a dose-response relationship for IFN-α mRNA expression. Inhibition of TLR signalling by blocking MyD88 and TRIF signalling decreased IFN-α mRNA expression in PBMCs incubated with apoptotic neutrophils (P < 0.05)., Conclusions: This study demonstrated significantly increased TLR expression in JSLE compared with controls. Our data indicate that apoptotic neutrophils trigger TLR activation through their presentation of autoantigens. The role of TLRs in this inflammatory response was demonstrated by a dose-response relationship to apoptotic neutrophil concentration and confirmed by a decrease in IFN-α production after inhibition of TLR signalling.

Objective: Joint hypermobility, common in childhood, can be associated with severe pain and significant morbidity. Physiotherapy, the mainstay of treatment, lacks a robust evidence base. This study is aimed at determining the best physiotherapy intervention in managing childhood hypermobility., Methods: A prospective randomized comparative trial (RCT) compared a 6-week generalized programme, improving muscular strength and fitness, with a targeted programme aimed at correcting motion control of symptomatic joints. Patients were assessed on symptom scores (pain/global-impact), function, muscle strength and fitness., Results: Fifty-seven children, aged 7-16 years with symptomatic hypermobility, were randomly assign to receive a targeted (T; n = 30) or generalized (G; n = 27) programme. Statistically significant improvements were demonstrated in both the children's and parental pain scores across both the randomized groups between baseline and follow-up assessments (P < 0.05). However, the difference in improvement between the groups was not statistically significant. Child's assessment of change in pain score: mean difference (95% CI) T - G, 3.97 (-15.59, 20.85) at the end of treatment and 9.41 at 3-month follow-up (-17.42, 36.24). At the end of treatment, parental assessment of change in pain score, T - G was: -0.27 (-15.05, 14.50) and at 3-month follow-up it was: -9.48 (-26.40, 7.43). Change in parental global assessment was statistically significant, in favour of targeted physiotherapy at final assessment: -21.29 (-40.03, -2.55)., Conclusion: This is the first physiotherapy RCT for treating hypermobility. It demonstrated significant and sustained reduction in pain when both groups were combined, but did not detect any difference between the groups. This study provides normative and methodological data for future studies of hypermobility., Trial Registration: Current Controlled Trials, www.controlled-trials.com, ISRCTN58523390.

Objectives: There are few data on the treatment patterns and associated cost of treating children with inflammatory arthritis including juvenile idiopathic arthritis (JIA), in the short or long term. The aim of this study was to obtain patient-based costs for treating children with JIA in the UK, in the first year from diagnosis and from the secondary health care payer perspective., Methods: The Childhood Arthritis Prospective Study (CAPS) is an ongoing longitudinal study recruiting children with inflammatory arthritis from four UK hospital centres. Included children are newly diagnosed,

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.

Background: SAPHO syndrome is increasingly recognized within the paediatric population. Conventional therapeutic approaches have often not been effective. Pamidronate is a second-generation bisphosphonate that affects bone turnover and demonstrates anti-inflammatory properties. In small case series it has given symptomatic relief to adults with this condition., Objectives: To report the clinical experience with pamidronate in childhood SAPHO syndrome., Methods: A retrospective observational study of all children with SAPHO syndrome treated with pamidronate between 1996 and 2003 at a tertiary rheumatology centre. The standard dosing regime for pamidronate was 1 mg/kg to a maximum of 30 mg, administered daily for three consecutive days, repeated 3-monthly as required. Response to treatment was determined by clinical observation, patient subjective response and reduction in other treatments, Results: Seven girls were treated, with a median (range) age at diagnosis of 11 yr (9-15 yr). All patients demonstrated a beneficial clinical response, with relief of pain, increased activity and improved well-being. Subsequent courses of pamidronate were used in all patients. Other medications including corticosteroids and methotrexate could subsequently be stopped. Transient symptoms were associated with the initial course of pamidronate in some patients. No serious adverse events were reported., Conclusions: Pamidronate was associated with a marked improvement in function and well-being, and a reduction of pain and use of other medications in all patients, with no significant adverse effects. This study represents preliminary clinical data. A prospective multicentre study is necessary to assess the role and long-term safety of pamidronate in the management of childhood SAPHO syndrome