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OBJECTIVES: Observational studies report mixed findings regarding the association between vitamin D and JIA incidence or activity, however such studies are susceptible to considerable bias. Since low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation we examined the causal effect of the major circulating form of vitamin D, 25-(OH)D, on JIA incidence using Mendelian randomization (MR).METHODS: In this two sample MR analysis we used summary level data from the largest and most recent genome wide association study (GWAS) of 25-(OH)D levels (sample size 443,734), alongside summary data from two JIA GWASs (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy we employed multiple MR methods and sensitivity analyses.RESULTS: We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (OR 1.00, 95% CI 0.76-1.33 per standard deviation increase in standardised natural-log transformed 25-(OH)D levels). This estimate was consistent across all methods tested. Additonally there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 standard deviation change in standardised natural-log transformed 25-(OH)D levels per doubling odds in genetically predicted JIA, 95% CI -0.006-0.002).CONCLUSION: Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.

Objectives Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation, and neural-crest tumour (ROHHAD(NET)) is a rare syndrome presenting in early childhood associated with high morbidity and mortality. There is no specific diagnostic biomarker and diagnosis is based on clinical features. An autoimmune origin has been postulated. Case presentation Management is largely supportive. We report a case of a five-year old female who presented in respiratory arrest after 6-months of rapid weight gain. She had central hypoventilation, central diabetes insipidus, growth hormone deficiency and hyperprolactinaemia. She displayed elevated interleukin-6 levels on cytokine serology which normalised after rituximab treatment. After rituximab treatment, her weight reduced significantly from greatly above the 99.6th to the 50th centile in 12 months. Conclusions This response possibly reflects an underlying, immune-inflammatory pathology driving excess adiposity in this condition. Potentially, other aspects of ROHHAD(NET) may be mediated through autoimmune dysregulation in which case rituximab may provide benefits for prognosis and survival.

Introduction Juvenile-onset systemic lupus erythematosus (JSLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Neuropsychiatric (NP) involvement is a severe complication, encompassing a heterogeneous range of neurological and psychiatric manifestations. Methods Demographic, clinical, and laboratory features of NP-SLE were assessed in participants of the UK JSLE Cohort Study, and compared to patients in the same cohort without NP manifestations. Results A total of 428 JSLE patients were included in this study, 25% of which exhibited NP features, half of them at first visit. Most common neurological symptoms among NP-JSLE patients included headaches (78.5%), mood disorders (48.6%), cognitive impairment (42%), anxiety (23.3%), seizures (19.6%), movement disorders (17.7%), and cerebrovascular disease (14.9%). Peripheral nervous system involvement was recorded in 7% of NP-SLE patients. NP-JSLE patients more frequently exhibited thrombocytopenia (9/L) ( p = 0.04), higher C-reactive protein levels ( p = 0.01), higher global pBILAG score at first visit ( p < 0.001), and higher SLICC damage index score at first ( p = 0.02) and last ( p < 0.001) visit when compared to JSLE patients without NP involvement. Conclusions A significant proportion of JSLE patients experience NP involvement (25%). Juvenile-onset NP-SLE most commonly affects the CNS and is associated with increased overall disease activity and damage.

Background There is growing concern about the long-term cardiovascular health of patients with juvenile idiopathic arthritis (JIA). In this study we assessed the association between JIA polygenic risk and cardiovascular phenotypes (cardiovascular risk factors, early atherosclerosis/arteriosclerosis markers, and cardiac structure and function measures) early in life. Methods JIA polygenic risk scores (PRSs) were constructed for 2,815 participants from the Avon Longitudinal Study of Parents and Children, using the single nucleotide polymorphism (SNP) weights from the most recent JIA genome wide association study. The association between JIA PRSs and cardiovascular phenotypes at age 24 years was assessed using linear and logistic regression. For outcomes with strong evidence of association, further analysis was undertaken to examine how early in life (from age seven onwards) these associations manifest. Results The JIA PRS was associated with diastolic blood pressure (β 0.062, 95% CI 0.026 to 0.099, P = 0.001), insulin (β 0.050, 95% CI 0.011 to 0.090, P = 0.013), insulin resistance index (HOMA2_IR, β 0.054, 95% CI 0.014 to 0.095, P = 0.009), log hsCRP (β 0.053, 95% CI 0.011 to 0.095, P = 0.014), waist circumference (β 0.041, 95% CI 0.007 to 0.075, P = 0.017), fat mass index (β 0.049, 95% CI 0.016 to 0.083, P = 0.004) and body mass index (β 0.046, 95% CI 0.011 to 0.081, P = 0.010). For anthropometric measures and diastolic blood pressure, there was suggestive evidence of association with JIA PRS from age seven years. The findings were consistent across multiple sensitivity analyses. Conclusions Genetic liability to JIA is associated with multiple cardiovascular risk factors, supporting the hypothesis of increased cardiovascular risk in JIA. Our findings suggest that cardiovascular risk is a core feature of JIA, rather than secondary to the disease activity/treatment, and that cardiovascular risk counselling should form part of patient care.

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.

Machine learning (ML) is a branch of artificial intelligence (AI) that enables computers to learn without being explicitly programmed, through a combination of statistics and computer science. It encompasses a variety of techniques used to analyse and interpret extremely large amounts of data, which can then be applied to create predictive models. Such applications of this technology are now ubiquitous in our day-to-day lives: predictive text, spam filtering, and recommendation systems in social media, streaming video and e-commerce to name a few examples. It is only more recently that ML has started to be implemented against the vast amount of data generated in healthcare. The emerging role of AI in refining healthcare delivery was recently highlighted in the ‘National Health Service Long Term Plan 2019’. In paediatrics, workforce challenges, rising healthcare attendance and increased patient complexity and comorbidity mean that demands on paediatric services are also growing. As healthcare moves into this digital age, this review considers the potential impact ML can have across all aspects of paediatric care from improving workforce efficiency and aiding clinical decision-making to precision medicine and drug development.

The outcome for children with rheumatic diseases has been dramatically altered by the use of biological therapies. Increasing use of these agents will need careful monitoring for long term safety, particularly in children. Current data on safety of these drugs stem exclusively from Western literature. There is clear need for a registry of all children with rheumatic diseases who are commenced on biological agents to ensure appropriate pharmacovigilance. In this perspective we discuss the need for and the role of a biologics registry for children with rheumatic diseases in India.

BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.

Summary Treatment for juvenile idiopathic arthritis has undergone substantial changes in recent decades. These changes are partly due to the availability of new treatments, mainly biological agents, as well as developments in treatment strategies, including a focus on concepts such as treat-to-target. In addition, the creation of large paediatric research networks has improved patient access to, and design of, clinical trials for rare paediatric diseases. Although these advances have resulted in improvements in care for most patients with juvenile idiopathic arthritis, certain subgroups of patients continue to have a poor prognosis. Further research aims to identify patients in these subgroups early, to personalise their care, improve functional outcomes, and minimise long-term damage and harm. Optimising the duration of therapy for those individuals who require systemic immunosuppression is also of importance. Incorporation of novel biomarkers in combination with validated clinical measures in an effort to predict outcomes and target therapy accordingly is an exciting development.

The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol [1]. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Objectives To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). Methods In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or Results Study participants were 51 sJIA patients and 52 pJIA patients aged 1–17 years who received s.c.-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. Conclusion s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279

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.

Background/Aims The evidence base underlying the management of children and young people (CYP) with paediatric rheumatic diseases (PRDs) is inadequate, with many critical outstanding questions warranting investigation. The aim of this study was to elicit multidisciplinary PRDs research priorities, through consultation with patients, carers and healthcare professionals. Methods This study was led by the UK NIHR CRN Children/Versus Arthritis Paediatric Rheumatology CSG (referred to as ‘the CSG’) and its Topic Specific Groups (TSGs). The CSG is a multidisciplinary group with strong patient/parent representation, supporting the development of clinical studies in the UK. Research priority ideas were sought from paediatric rheumatologists, trainees, allied healthcare professional (AHP), nurses, patients, parents and charities, through online surveys and face-to-face meetings. Research ideas were categorised as disease-specific or broad/general. They were grouped into sub-themes, duplicates/questions that had already been answered were removed, and similar submissions combined. A modified Delphi process was undertaken, including online research priority ranking, and an online consensus workshop to derive top PRD research priorities. Results The initial consultation yielded 304 research priority ideas; 25% from patients/parents, 22% from the CSG, 18% from TSGs, 13% from AHPs, 11% from trainees, 11% from Nurses. 55 disease-specific and 37 broad/general research priorities were voted upon in the first online survey, yielding a top 11 general broad research priorities. The top 10 disease specific priorities were discussed at the online Delphi priority setting workshop, and two online surveys were held during the workshop to determine their final ranking. Two of the disease-specific priorities were combined, leading to a top 9 (see Table). Disease specific proprieties related to clinical trials in JIA (n = 3) / Juvenile Dermatomyositis (n = 1) / Chronic Recurrent Multifocal Osteomyelitis (n = 1) / Juvenile Systemic Lupus Erythematosus (n = 1) Scleroderma (n = 1), management of JIA in adulthood (n = 1) and chronic pain (n = 1). Conclusion UK consensus-based PRD research priorities have been derived, underpinned by collaboration with patients/carers and healthcare professionals, helping to guide funding bodies to improve the evidence base in PRD’s. Disclosure E.M.D. Smith: None. N. Egbivwie: None. K. Cowan: None. A.V. Ramanan: None. C.E. Pain: None.

Objective To summarize evidence regarding efficacy of anti-TNFα in childhood chronic uveitis, refractory to common DMARDs. Methods An updated systematic search was conducted between November 2012 and January 2020. Studies investigating the efficacy of anti-TNFα therapy, in children of ages Results We identified 1677 articles of which 37 articles were eligible. Three were randomized controlled trials, one on ETA and two on ADA, and were excluded from pooled analysis. From the observational studies, a total of 487 children were identified: 226 received ADA, 213 INF and 48 ETA. The proportion of responding children was 86% (95% CI: 76%, 95%) for ADA, 68% (95% CI: 50%, 85%) for INF and 36% (95% CI: 9%, 67%) for ETA. Pooled analysis showed clear differences (χ2 = 32.2, P Conclusion This meta-analysis, consistent with recent randomized controlled trial data, suggests the efficacy of ADA and INF in childhood chronic uveitis treatment. However, ADA results were superior to those of INF in this clinical setting.

Background We describe the demographic, clinical and laboratory findings along with the treatment and outcomes among children meeting the case definition of Pediatric Inflammatory Multisystem Syndrome — Temporally associated with SARS-CoV-2 (PIMS-TS). Methods We analyzed the clinical and laboratory findings of children who presented with PIMS-TS during an 8-week period from May 4, 2020 to July 8, 2020. Results We report 19 children with a median age of 6 year (IQR: 13 months-16 years), who met the case definition of PIMS-TS. All of them presented with fever. Multi organ involvement (79%), mucocutaneous involvement (74%), cardiovascular symptoms (63%) and gastrointestinal symptoms (42%) were the other features. Elevated levels of C-reactive protein was found in all of them and the majority of them had evidence of coagulopathy; intensive care admissions were needed in 12 (63%) and vasoactive medications were given to 6 (31.5%) children. There were no deaths. Conclusion Children with PIMS-TS present with a wide range of signs and symptoms. Fewer children in this series had coronary artery abnormalities, and there was a low incidence of RT-PCR positivity with high presence of SARS-CoV-2 antibodies.

Purpose of review To give an overview of recently published articles covering risk factors, novel biomarkers and treatment for noninfectious uveitis in children. Recent findings In the last few years, several genetic markers, serum biomarkers, aqueous humor markers, tear biomarkers and clinical factors have been identified, which are associated with childhood noninfectious uveitis. We describe the most important reports in this field that may help to tailor the screening and monitoring of this population in the future and might become the target of novel therapies. The advances in the biologic therapy of paediatric uveitis, thanks to evidence provided by the SYCAMORE, ADJUVITE and APTITUDE trials, offer new possibilities for the treatment of patients who fail methotrexate with adalimumab and tocilizumab. We discuss the importance of comprehensive outcome measures as proposed by the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC). Summary Paediatric noninfectious uveitis is a sight-threatening condition and the identification of risk factors and novel biomarkers is critical for tailored management. Biologic therapies are revolutionizing the outcomes of patients resistant to conventional therapy. Increasing our knowledge of disease pathogenesis is crucial to improve targeting of screening to those at highest risk and stratification of treatments.

Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory disorder affecting the skeleton of children and adolescents. Whole-body MRI (WBMRI) is key in the diagnosis and follow-up of CRMO. Imaging protocols should include sagittal short Tau inversion recovery of the spine, imaging of the hands and feet, and T1 images for distinguishing normal bone marrow. CRMO lesions can be metaphyseal, epiphyseal and physeal—potentially causing growth disturbance and deformity. Spinal lesions are common, important and can cause vertebral collapse. Lesion patterns include multifocal tibial and pauci-focal patterns that follow a predictable presentation and course of disease. Common pitfalls of WBMRI include haematopoietic marrow signal, metaphyseal signal early on in bisphosphonate therapy and normal high T2 signal in the hands and feet. Pictorial reporting assists in recording lesions and follow-up over time. The purpose of this paper is to review the different WBMRI protocols, imaging findings, lesion patterns and common pitfalls in children with CRMO

Background:\ud In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary.\ud \ud Aim:\ud To explore ‘real world’ treatment utilising longitudinal UK JSLE Cohort Study data.\ud \ud Methods:\ud Data collected between 07/2009–05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice.\ud \ud Result:\ud 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65–2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator.\ud \ud Conclusions:\ud Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly.

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 0.05). Attainment of all targets reduced the hazards of new damage (P 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.

Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is characterised by episodes of fever lasting a few days that classically exhibit clockwork periodicity. Since the initial description of PFAPA syndrome by Gary Marshall in 1987, it has been recognised that stomatitis, pharyngitis and adenitis are variably present.1 Its phenotype is consistent with an autoinflammatory condition of unknown genetic aetiology possibly involving an infectious/environmental trigger, given that a family history is present in approximately 27% of cases.2 The natural history is onset before 6 years old, followed by spontaneous resolution by 15 years. Treatment with colchicine can reduce the frequency of episodes and tonsillectomy is usually curative.3 The diagnosis of PFAPA syndrome is clinical but can be challenging because it predominantly affects young children who typically experience frequent febrile viral infections. We hypothesised that reduced transmission of viruses due to COVID-19 public health control measures …

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.

Background The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. Methods This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. Findings Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31–0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33–0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. Interpretation In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. Funding Eli Lilly and Company.

BackgroundThe oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).MethodsCOV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection (ClinicalTrials.govNCT04421027). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.FindingsSOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39·2% vs 58·0%; hazard ratio [HR]=0·54 [95%CI 0·31–0·96]; p=0·030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45·1% vs 62·0%; HR=0·56 [95%CI 0·33–0·97]; p=0·027).Baricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23·7 vs 26·1 days, p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms.InterpretationIn critically ill patients with COVID-19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0·56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV-BARRIER study population.FundingEli Lilly and Company.Research in contextEvidence before this studyWe evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “critical illness”, “invasive mechanical ventilation”, “baricitinib”, and “JAK inhibitor” for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID-19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV-BARRIER study was designed, there was only one open-label study of dexamethasone showing mortality benefit in hospitalised patients with COVID-19 requiring IMV. Small studies of interleukin-6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin-6 inhibitors, except in a clinical trial. Overall, there were no reported double-blind, placebo-controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID-OS 7 population. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT-2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larger proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID-OS score of 7) at baseline. We designed COV-BARRIER, a phase 3, global, double-blind, randomised, placebo-controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID-19 who did not require mechanical ventilation (i.e., NIAID-OS 4-6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0·57, corresponding to a 43% relative reduction, p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. In the more severely ill NIAID-OS 6 subgroup, one additional death was prevented per nine baricitinib-treated participants (HR 0·52, corresponding to a 48% relative reduction, p=0·0065). We therefore implemented an addendum to the COV-BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID-OS 7 population and considered the sample size of 100 participants sufficient for this trial.Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double-blind, placebo-controlled trial in regions with high COVID-19 hospitalisation rates. Treatment with baricitinib reduced 28-day all-cause mortality compared to placebo (HR 0·54, 95% CI 0·31–0·96; nominal p=0·030), corresponding to a 46% relative reduction, and significantly reduced 60-day all-cause mortality (HR 0·56, 95% CI 0·33–0·97; p=0·027); overall, one additional death was prevented per six baricitinib-treated participants. Numerical improvements in endpoints such as number of ventilator-free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.The COV-BARRIER study overall trial results plus these COV-BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29·3% following treatment with dexamethasone compared to 41·4% for usual care (rate ratio of 0·64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0.93, corresponding to a 7% relative reduction). The ACTT-2 study reported 28-day mortality of 23·1% and 22·6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population; however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality.Implications of all the available evidenceIn this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV-BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID-19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.

Background Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and the most common systemic disorder associated with uveitis in childhood. Uveitis is more common in JIA patients who are antinuclear antibody (ANA)-positive, have an early-onset disease, and have oligoarticular arthritis. JIA-associated uveitis (JIA-uveitis) is typically anterior, chronic, bilateral, nongranulomatous, and asymptomatic. Visual outcomes in JIA-uveitis have improved with current screening and treatment options; however, many patients fail to respond or do not achieve long-lasting remission. Baricitinib, an oral selective Janus kinase (JAK)1 and 2 inhibitor, may impact key cytokines implicated in the pathogenesis of JIA-uveitis or ANA-positive uveitis, representing a potential novel treatment option for disease management. Methods The multicenter, phase 3 trial will be conducted using an open-label Bayesian design. The study will enroll at least 20 and up to 40 patients aged 2 to Discussion This is the first pediatric clinical trial to assess the clinical effectiveness and safety of a JAK inhibitor in JIA-uveitis or chronic ANA-positive uveitis. A novel Bayesian design is used to assess the efficacy of baricitinib, including an adalimumab reference arm, in this small patient population with unmet medical need. Trial registration EudraCT 2019-000119-10. Registered on January 4, 2019; NCT04088409. Registered on September 12, 2019

ObjectivesTo update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19.MethodsAccording to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting.ResultsWe updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapyConclusionsGrowing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

In childhood arthritis, collectively known as Juvenile idiopathic arthritis (JIA), the rapid rise of available licensed biological and targeted small molecule treatments in recent years has led to improved outcomes. However, real-world data from multiple countries and registries show that despite a large number of available drugs, many children and young people continue to suffer flares and experience significant periods of time with active disease for many years. More than 50% of young people with JIA require ongoing immune suppression well into adult life, and they may have to try multiple different treatments in that time. There are currently no validated tools with which to select specific treatments, nor biomarkers of response to assist in such choices, therefore, current management uses essentially a trial-and-error approach. A further consequence of recent progress is a reducing pool of available children or young people who are eligible for new trials. In this review we consider how progress towards a molecular based approach to defining treatment targets and informing trial design in JIA, combined with novel approaches to clinical trials, could provide strategies to maximise discovery and progress, in order to move towards precision medicine for children with arthritis.

Summary Background Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov , NCT04421027 . Findings Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. Funding Eli Lilly and Company. Translations For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.