Search

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.

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.

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.

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

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

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.

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.

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.

Background/aimsThere is a paucity of high-level evidence to support the management of childhood uveitis, particularly for those children without juvenile idiopathic arthritis uveitis (JIA). We undertook a modified Delphi consensus exercise to identify agreement in the management of chronic anterior uveitis (CAU), the most common manifestation of childhood disease.MethodsA four-round, two-panel process was undertaken between June and December 2017. Paediatric uveitis specialists identified through multiple sources, including a multicentre network (the Paediatric Ocular Inflammation Group), were invited to participate. They were asked whether they agreed with items derived from existing guidelines on the management of JIA-U when extrapolated to the population of all children with CAU. Consensus was defined as agreement greater than or equal to 75% of respondents.Results26 of the 38 (68%) invited specialists participated with the exercise, and response rates were 100% for rounds one to three, and 92% for round four. Consensus was reached on 23 of the 44 items. Items for which consensus was not reached included management at presentation, use of systemic and periocular steroids for children with severe disease and the role of conventional steroid sparing immunosuppressants beyond methotrexate.ConclusionThe areas of management uncertainty at the level of the group, as indicated by absence of consensus, reflect the areas where the evidence base is particularly poor. Our findings identify the key areas for the future research needed to ensure better outcomes for this blinding childhood ocular inflammatory disorders.

Objectives SS with childhood onset is a rare autoimmune disease characterized by heterogeneous presentation. The lack of validated classification criteria makes it challenging to diagnose. Evidence-based guidelines for treatment of juvenile SS are not available due to the rarity of disease and the paucity of research in this patient population. This systematic review aims to summarize and appraise the current literature focused on pharmacological strategies for management of SS with childhood onset. Methods PubMed and MEDLINE/Scopus databases up to December 2020 were screened for suitable reports highlighting pharmacological treatment of SS with childhood onset using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 reporting checklist. Animal studies were excluded. Results A total of 43 studies (34 case reports, 8 mini case series and 1 pilot study) were eligible for analysis. The studies retrieved included girls in 88% (120/137) of cases and had very low confidence levels. HCQ was prescribed for parotid swelling, as well as in association with MTX and NSAIDs in patients with arthritis and arthralgia. Corticosteroids such as long courses of oral prednisone and i.v. methylprednisolone were commonly prescribed for children with severe disease presentations. Rituximab was mainly indicated for mucosa-associated lymphoid tissue lymphoma and renal and nervous system complications. Other conventional DMARDs were prescribed in selected cases with extraglandular manifestations. Conclusion Various therapies are used for the management of juvenile SS and are prescribed based on expert clinician’s opinion. There are currently no good-quality studies that allow clinical recommendations for treatment of SS with childhood onset.

Objectives JIA is the most common paediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanism and ultimately benefit patients. This review aimed to collate and synthesize the current evidence of environmental factors associated with JIA. Methods Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to January 2020. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesized in narrative form. Results This review includes 66 environmental factors from 39 studies (11 cohort and 28 case-control studies) over 45 years. Study sample sizes ranged from 41 to 1.9 million participants. Eight environmental factors from ten studies were meta-analysed. Caesarean section delivery was associated with increased JIA risk [pooled odds ratio (OR) 1.11, 95% CI: 1.01, 1.22]. Conversely, presence (vs absence) of siblings (pooled OR 0.60, 95% CI: 0.44, 0.81) and maternal prenatal smoking (pooled OR 0.70, 95% CI: 0.58, 0.84) were associated with decreased JIA risk. Conclusion This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research undertaken over five decades. We also highlight the challenges of combining data collected over this period due to limited between study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies.

BackgroundThe efficacy and safety of baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC) in hospitalised adults with COVID-19 is unknown.MethodsIn this phase 3, global, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America (ClinicalTrials.govNCT04421027). Hospitalised adults with COVID-19 receiving SOC were randomly assigned (1:1) to once-daily baricitinib 4-mg or placebo for up to 14 days. SOC included systemic corticosteroids in 79·3% of participants (dexamethasone ∼90%). The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. All-cause mortality by days 28 and 60 were key secondary and exploratory endpoints, respectively. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.FindingsBetween June 11, 2020 and January 15, 2021, 1525 participants were randomly assigned to baricitinib 4-mg (n=764) or matched placebo (n=761). Overall, 27·8% of participants receiving baricitinib vs 30·5% receiving placebo progressed (primary endpoint, odds ratio 0·85, 95% CI 0·67-1·08; p=0·18). The 28-day all-cause mortality was 8·1% (n=62) for baricitinib and 13·1% (n=100) for placebo, corresponding to a 38·2% reduction in mortality (hazard ratio [HR] 0·57, 95% CI 0·41-0·78; nominal p=0·0018). The 60-day all-cause mortality was 10·3% (n=79) for baricitinib and 15·2% (n=116) for placebo (HR 0·62, 95% CI 0·47-0·83; p=0·0050). Frequency of serious adverse events (14·7% [n=110] vs 18·0% [n=135]), serious infections (8·5% [n=64] vs 9·8% [n=74]), and venous thromboembolic events (2·7% [n=20] vs 2·5% [n=19]) was similar between baricitinib and placebo, respectively.InterpretationWhile reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (including dexamethasone) significantly reduced mortality, with a similar safety profile to SOC, in hospitalised COVID-19 participants.FundingEli Lilly and Company.Research in contextEvidence before this studyWe searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib” and “JAK inhibitor” for articles in English published up to April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib, before undertaking this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and limited phase 3 randomised placebo-controlled studies had been completed. Limited phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir/ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. 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 for targeting host proteins for its antiviral mechanism. Additionally, early case series evaluating the efficacy and safety of baricitinib in the hospitalised patient population supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While COV-BARRIER was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir was completed showing that baricitinib added to remdesivir improved time to recovery and other outcomes.Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC) and included antivirals, anticoagulants, and corticosteroids. After the earliest publication of the RECOVERY study in June 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as SOC. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit/risk of baricitinib when added to the most current SOC (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high flow oxygen, invasive mechanical ventilation, or death for baricitinib plus SOC (including dexamethasone) compared to placebo plus SOC did not reach statistical significance. However, in a pre-specified key secondary endpoint, treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared to placebo (HR 0·57, 95% CI 0·41-0·78; nominal p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained by day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.Implications of all the available evidenceIn this phase 3 trial, baricitinib given in addition to SOC (which predominantly included dexamethasone) did not reduce a composite endpoint of disease progression, but showed a strong effect on reducing mortality by 28 days, an effect which was maintained by 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.

Funder: LUPUS UK, Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease. Patients diagnosed with juvenile-onset SLE (jSLE), when compared to individuals with adult-onset SLE, develop more severe organ involvement, increased disease activity and greater tissue and organ damage. In adult-onset SLE, clinical characteristics, pathomechanisms, disease progression and outcomes do not only vary between individuals and age groups, but also ethnicities. However, in children and young people, the influence of ethnicity on disease onset, phenotype and outcome has not been investigated in detail. In this study, we investigated clinical and laboratory characteristics in pediatric SLE patients from different ethnic backgrounds (White Caucasian, Asian, Black African/Caribbean) accessing data from a national cohort of jSLE patients (the UK JSLE Cohort Study). Among jSLE patients in the UK, ethnicity affects both the disease's clinical course and outcomes. At diagnosis, Black African/Caribbean jSLE patients show more "classical" laboratory and clinical features when compared to White Caucasian or Asian patients. Black African/Caribbean jSLE patients exhibit more renal involvement and more frequently receive cyclophosphamide and rituximab. Studies targeting ethnicity-specific contributors to disease expression and phenotypes are necessary to improve our pathophysiological understanding, diagnosis and treatment of jSLE.

ObjectiveTo ascertain the role of platelet glycoprotein Ib α‐chain (GPIbα) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by platelet count.MethodsWe performed a two‐sample Mendelian randomization (MR) study, using both a cis‐acting protein quantitative trait locus (cis‐pQTL) and trans‐pQTL near the GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two‐step MR study. Putative associations (GPIbα/platelet count/disease) detected by MR analyses were subsequently assessed using multiple‐trait colocalization analyses.ResultsAfter correction for multiple testing (Bonferroni‐corrected threshold P ≤ 2 × 10−3), GPIbα, instrumented by either cis‐pQTL or trans‐pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)–negative polyarticular juvenile idiopathic arthritis (JIA). These effects of GPIbα appeared to be mediated by platelet count and were supported by strong evidence of colocalization (probability of all 3 traits sharing a common causal variant ≥0.80). GPIbα instrumented by cis‐pQTL did not appear to affect cardiovascular risk, although the GPIbα trans‐pQTL was associated with an increased risk of cardiovascular diseases and autoimmune diseases but a decreased risk of autoinflammatory diseases, suggesting that this trans‐acting instrument operates through other pathways.ConclusionThe role of platelets in thrombosis is well‐established; however, our findings provide some novel genetic evidence that platelets may be causally implicated in the development of oligoarticular and RF‐negative polyarticular JIA, and indicate that GPIbα may serve as a putative therapeutic target for these JIA subtypes.

Sjögren’s syndrome (SS) is very rare in teenagers and there are only anecdotal reports world-wide of its occurrence in prepubertal children. Paediatric cohort studies have demonstrated that approximately half of patients with Sjögren’s syndrome (SS) have primary disease. As with adults, secondary SS is most commonly associated with systemic lupus erythematosus, although cases have also been reported in patients with juvenile idiopathic arthritis, mixed connective tissue disease, and other autoimmune conditions. The condition is almost certainly underdiagnosed. Children and young adults rarely complain of dryness and usually present with parotid gland swelling and systemic disease. Clinical manifestations, diagnosis, and management are all discussed in this chapter.

Background: Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV-2 (PIMS-TS), first identified in April 2020, shares features of both Kawasaki disease (KD) and toxic shock syndrome (TSS). The surveillance describes the epidemiology and clinical characteristics of PIMS-TS in the United Kingdom and Ireland. Methods: Public Health England initiated prospective national surveillance of PIMS-TS through the British Paediatric Surveillance Unit. Paediatricians were contacted monthly to report PIMS-TS, KD and TSS cases electronically and complete a detailed clinical questionnaire. Cases with symptom onset between 01 March and 15 June 2020 were included. Findings: there were 216 cases with features of PIMS-TS alone, 13 with features of both PIMS-TS and KD, 28 with features of PIMS-TS and TSS and 11 with features of PIMS-TS, KD and TSS, with differences in age, ethnicity, clinical presentation and disease severity between the phenotypic groups. There was a strong geographical and temporal association between SARS-CoV-2 infection rates and PIMS-TS cases. Of those tested, 14.8% (39/264) children had a positive SARS-CoV-2 RT-PCR, and 63.6% (75/118) were positive for SARS-CoV-2 serology. In total 44·0% (118/268) required intensive care, which was more common in cases with a TSS phenotype. Three of five children with cardiac arrest had TSS phenotype. Three children (1·1%) died. Interpretation: the strong association between SARS-CoV-2 infection and PIMS-TS emphasises the importance of maintaining low community infection rates to reduce the risk of this rare but severe complication in children and adolescents. Close follow-up will be important to monitor long-term complications in children with PIMS-TS. Funding: PHE

COVID-19 has been occasionally linked to histologically confirmed cutaneous vasculitis and a Kawasaki-like vasculitis, with these entities generally having minimal or no lung involvement and a good prognosis. Unlike these vasculitis types, patients with severe COVID-19 pneumonia can develop cutaneous vasculitis-like lesions and systemic arterial and venous thromboemboli, including cryptogenic strokes and other vasculopathy features. Proposed underlying mechanisms for these severe manifestations have encompassed immune dysregulation, including an anti-phospholipid syndrome-like state, complement activation, viral dissemination with direct systemic endothelial infection, viral RNAaemia with immunothrombosis, clotting pathway activation mediated by hypoxaemia, and immobility. In this Viewpoint, we highlight how imaging and post-mortem findings from patients with COVID-19 indicate a novel thrombosis in the pulmonary venous territory distal to the alveolar capillary bed, a territory that normally acts as a clot filtration system, which might represent an unappreciated nidus for systemic microembolism. Additionally, we suggest that this mechanism represents a novel vasculitis mimic related to COVID-19 that might lead to cryptogenic strokes across multivessel territories, acute kidney injury with haematuria, a skin vasculitis mimic, intestinal ischaemia, and other organ ischaemic manifestations. This finding is supported by pathological reports of extensive pulmonary venular thrombosis and peripheral organ thrombosis with pauci-immune cellular infiltrates. Therefore, severe COVID-19 pneumonia with extensive pulmonary intravascular coagulopathy might help to explain the numerous systemic complications of COVID-19, in which the demonstration of direct organ infection has not adequately explained the pathology.

Introduction Children usually present with minimal or no symptoms of COVID-19 infection. Antibody responses to SARS-CoV-2 in children from low- and middle-income countries (LMIC) have not been well described. We describe the prevalence of anti-SARS-CoV-2 antibodies and clinical phenotype of seropositive children admitted to a tertiary children’s hospital in South India. Methods To determine the seropositivity and describe the clinical characteristics of COVID-19 infection amongst hospitalised children, we performed a prospective clinical data collection and blood sampling of children admitted to Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India over 4 months of the COVID-19 pandemic. In seropositive children, we compared antibody titres between children with and without PIMS-TS. Results Of 463 children, 91 (19.6%) were seropositive. The median (range) age of seropositive children was 5 years (1 month–17 years). Clinical presentation was consistent with Paediatric inflammatory multisystem syndrome associated or related with SARS-CoV-2 infection (PIMS-TS) in 48% (44/91) of seropositive children. The median (range) antibody titre was 54.8 (11.1–170.9) AU/ml among all seropositive children. The median antibody titre among the children with PIMS-TS (60.3 AU/mL) was significantly (p = 0.01) higher when compared to the children without PIMS-TS (54.8 AU/mL). Conclusion We describe the antibody responses to SARS-CoV-2 amongst hospitalised children in a LMIC tertiary children’s hospital. Almost half of the seropositive children had PIMS-TS. Antibody levels may be helpful in the diagnosis and disease stratification of PIMS-TS. LAY SUMMARY Children usually present with minimal or no symptoms of COVID-19 infection. However, Multisystem Inflammatory Syndrome in Children (MIS-C) or Paediatric inflammatory multisystem syndrome associated or related with SARS-CoV-2 infection (PIMS-TS) has emerged as a distinctive paediatric illness related to SARS-CoV-2. Recently, antibody testing for SARS-CoV-2 is being used increasingly as a diagnostic test for PIMS-TS. However, data on the antibody responses to SARS-CoV-2 in children are sparse. We, therefore, attempted to identify the seropositivity and describe the clinical spectrum of COVID-19 infection amongst infants and children getting hospitalised in a children’s hospital in south India. Nearly one-fifth of the hospitalised children tested serology positive over 4 months. Antibody levels in children with PIMS-TS were significantly higher in comparison to the other two groups (acute COVID-19 infection and children without PIMS-TS). Results from our study suggest that all children are at risk of COVID-19 infection though they may present with mild illness or no symptoms. We also observed that antibody testing may have a possible role in diagnosis of PIMS-TS.

A hyperinflammatory ‘cytokine storm’ state termed macrophage activation syndrome (MAS), culminating from a complex interplay of genetics, immunodeficiency, infectious triggers and dominant innate immune effector responses, can develop across disparate entities including systemic juvenile idiopathic arthritis (sJIA) and its counterpart adult-onset Still disease (AOSD), connective tissue diseases, sepsis, infection, cancers and cancer immunotherapy. Classifying MAS using the immunological disease continuum model, with strict boundaries that define the limits of innate and adaptive immunity, at one boundary is MAS with loss of immune function, as occurs in the ‘perforinopathies’ and some cases of sJIA–AOSD. Conversely, at the other boundary, immune hypersensitivity with gain of immune function in MHC class II-associated sJIA–AOSD and with chimeric antigen receptor (CAR) T cell therapy also triggers MAS. This provides a benchmark for evaluating severe inflammation in some patients with COVID-19 pneumonia, which cripples primary type I interferon immunity and usually culminates in a lung-centric ‘second wave’ cytokine-driven alveolitis with associated immunothrombosis; this phenomenon is generally distinct from MAS but can share features with the proposed ‘loss of immune function’ MAS variant. This loss and gain of function MAS model offers immune cartography for a novel mechanistic classification of MAS with therapeutic implications., In this Review, the authors discuss macrophage activation syndrome (MAS) in relation to other cytokine storm scenarios, and provide a framework for understanding MAS within the spectrum of innate and adaptive immunity in the context of gain or loss of immune function., Key points Dysregulated production of IFNγ and other pivotal cytokines including IL-1, IL-6 and IL-18 can arise from either loss or gain of function in the immune response, with different implications for therapy and prognosis.Although macrophage activation syndrome (MAS) is often termed autoinflammatory in both loss and gain of function phenotypes, adaptive lineage cells, especially T cells, are clearly important in both settings.The distinct MAS phenotype that arises with hypercytokinaemia can be explained by activation of macrophages that are closely juxtaposed to sinusoids that permit direct phagocytic access to haematopoietic lineage cells.Recognizing MAS variants and the important anatomical considerations around macrophage perivascular topography in the marrow, liver and spleen allows for a novel evaluation of other states associated with hypercytokinaemia.Considering the boundaries of immunodeficiency and immune hypersensitivity in MAS related to systemic juvenile idiopathic arthritis and adult-onset Still disease, and the role of lymphoid cells, severe COVID-19 is generally a distinctive lung-specific immunopathology.The proposed model for MAS immune heterogeneity and cellular topography can be applied to understanding other hyper-inflammatory conditions.

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a novel condition that was first reported in April, 2020. We aimed to develop a national consensus management pathway for the UK to provide guidance for clinicians caring for children with PIMS-TS. A three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management, and research priorities from multidisciplinary clinicians caring for children with PIMS-TS. We used 140 consensus statements to derive a consensus management pathway that describes the initial investigation of children with suspected PIMS-TS, including blood markers to help determine the severity of disease, an echocardiogram, and a viral and septic screen to exclude other infectious causes of illness. The importance of a multidisciplinary team in decision making for children with PIMS-TS is highlighted throughout the guidance, along with the recommended treatment options, including supportive care, intravenous immunoglobulin, methylprednisolone, and biological therapies. These include IL-1 antagonists (eg, anakinra), IL-6 receptor blockers (eg, tocilizumab), and anti-TNF agents (eg, infliximab) for children with Kawasaki disease-like phenotype and non-specific presentations. Use of a rapid online Delphi process has made it possible to generate a national consensus pathway in a timely and cost-efficient manner in the middle of a global pandemic. The consensus statements represent the views of UK clinicians and are applicable to children in the UK suspected of having PIMS-TS. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS. This process has directly informed new PIMS-TS specific treatment groups as part of the adaptive UK RECOVERY trial protocol, which is the first formal randomised controlled trial of therapies for PIMS-TS globally.

Background: Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), first identified in April 2020, shares features of both Kawasaki disease (KD) and toxic shock syndrome (TSS). Methods: Public Health England initiated prospective national surveillance of PIMS-TS through the British Paediatric Surveillance Unit. Paediatricians were contacted monthly to report PIMS-TS, KD and TSS cases electronically and complete a detailed clinical questionnaire. Cases with symptom onset between 01 March and 15 June 2020 were included. Findings: There were 216 cases with features of PIMS-TS alone, 13 with features of both PIMS-TS and KD, 28 with features of PIMS-TS and TSS and 11 with features of PIMS-TS, KD and TSS, with differences in age, ethnicity, clinical presentation and disease severity between the three phenotypic groups. There was a strong geographical and temporal association between SARS-CoV-2 infection rates and PIMS-TS cases. Of those tested, 14·8% (39/264) children had a positive SARS-CoV-2 RT-PCR, and 63·6% (75/118) were positive for SARS-CoV-2 serology. In total 118 children (44·0%) required intensive care, which was more common in cases with a TSS phenotype: 89/216 (41·2%) with PIMS-TS only vs. 19/28 (67·9%) with PIMS-TS/TSS and 6/11 (54·5%) with PIMS-TS/KD/TSS. Three of five children with cardiac arrest had PIMS-TS/TSS phenotype. Three children (1·1%) died. Interpretation: The strong association between SARS-CoV-2 infection and PIMS-TS emphasises the importance of maintaining low community infection rates to reduce the risk of this rare but severe complication in children and adolescents. Close follow-up will be important to monitor long-term complications in children with PIMS-TS. Funding: PHE Declaration of Interests: None to declare. Ethics Approval Statement: PHE has legal permission under Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002, to conduct national surveillance of communicable diseases in England and, as such, individual patient consent is not required. Public Health Wales, through the established order legislation, is required to conduct surveillance of communicable diseases in Wales and, as such, individual patient consent is not required. The surveillance protocol was approved by the Public Benefit and Privacy Panel for Health and Social Care in Scotland (Ref: 2021-0041, 19th May 2020).

This work was funded by European League Against Rheumatism (CLI122). PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). JDI is a NIHR Senior Investigator and his work is supported by the NIHR Newcastle Biomedical Research Centre in Ageing and Long- Term Conditions, and the Research Into Inflammatory Arthritis Centre versus Arthritis. AVR is a member of the paediatric steering committee of RECOVERY, the steering committee of COVINTOC study and the steering committee of baricitinib in COVID-19., Alunno, A., Najm, A., MacHado, P.M., Bertheussen, H., Burmester, G.R., Carubbi, F., De Marco, G., Giacomelli, R., Hermine, O., Isaacs, J.D., Koné-Paut, I., Magro-Checa, C., McInnes, I., Meroni, P.L., Quartuccio, L., Ramanan, A.V., Ramos-Casals, M., Carrio, J.R., Schulze-Koops, H., Stamm, T.A., Tas, S.W., Terrier, B., McGonagle, D.G., Mariette, X.

Summary Background Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course. Methods In this multicentre prospective longitudinal study, we included children and young people recruited before Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in active joint count, physician's global assessment, and patient or parental global evaluation, we used latent profile analysis at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following 3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony. Finding Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS, 239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions of children and young people had high patient or parent global scores despite low or improving joint counts and physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitis-related JIA and lower socioeconomic status, compared with those in other groups. Interpretation Almost one in four children and young people with JIA in our study reported persistent, high patient or parent global scores despite having low or improving active joint counts and physician's global scores. Distinct patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise health-care services and treatment plans for individuals with JIA. Funding Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and National Institute for Health Research.

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.

ObjectiveTo develop a consensus management pathway for children with Paediatric Inflammatory Multisystem Syndrome - Temporally associated with SARS-CoV-2 (PIMS-TS).DesignA three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management and research priorities from 98 multidisciplinary participants caring for children with PIMS-TS. 46 participants (47%) completed all three phases. Participants were grouped into three panels and scored each statement from 1 (disagree) to 9 (strongly agree). In phase two participants were shown their panel’s scores, and in phase three all panels’ scores.Consensus agreement was defined as ≥70% of participants in each panel scoring the statement 7-9, and Results255 statements were assessed, with ‘consensus agreement’ achieved for 111 (44%), ‘consensus disagreement’ for 29 (11%), and no consensus for 115 (45%). The 140 consensus statements were used to derive the consensus management pathway.ConclusionsA national consensus pathway has been developed for children suspected of having the novel syndrome PIMS-TS in a timely, cost-efficient manner, in the midst of a global pandemic. Use of a rapid online Delphi process has made this consensus process possible. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS.

The pandemic of COVID-19 initially appeared to cause only a mild illness in children. However, it is now apparent that a small percentage of children can develop a hyperinflammatory syndrome labeled as Pediatric inflammatory multisystem syndrome — temporally associated with SARS-CoV-2 (PIMS-TS). Features of this newly recognized condition may include persistent fever, evidence of inflammation, and single or multi-organ dysfunction in the absence of other known infections. Some of these children may share features of Kawasaki disease, toxic shock syndrome or cytokine storm syndrome. They can deteriorate rapidly and may need intensive care support as well. The PCR test is more often negative; although, most of the children have antibodies to SARS-CoV-2. Although the pathogenesis is not clearly known, immune-mediated injury has been implicated. We herein provide current information on this condition, in order to raise awareness amongst pediatricians.

[No abstract]

Background To initiate the development of a machine learning algorithm capable of comparing segments of pre and post pamidronate whole body MRI scans to assess treatment response and to compare the results of this algorithm with the analysis of a panel of paediatric radiologists. Methods Whole body MRI of patients under the age of 16 diagnosed with CNO and treated with pamidronate at a tertiary referral paediatric hospital in United Kingdom between 2005 and 2017 were reviewed. Pre and post pamidronate images of the commonest sites of involvement (distal femur and proximal tibia) were manually selected (n = 45). A machine learning algorithm was developed and tested to assess treatment effectiveness by comparing pre and post pamidronate scans. The results of this algorithm were compared with the results of a panel of radiologists (ground truth). Results When tested initially the machine algorithm predicted 4/7 (57.1%) examples correctly in the multi class model, and 5/7 (71.4%) correctly in the binary group. However when compared to the ground truth, the machine model was able to classify only 33.3% of the samples correctly but had a sensitivity of 100% in detecting improvement or worsening of disease. Conclusion The machine learning could detect new lesions or resolution of a lesion with good sensitivity but failed to classify stable disease accurately. However, further validation on larger datasets are required to improve the specificity and accuracy of the machine model.

Background STING-associated vasculopathy with onset in infancy (SAVI) is a type 1 interferonopathy manifesting as a pulmonary and vascular syndrome resulting from gain-of-function mutations in TMEM173, the gene encoding STING. Familial reports in the literature are sparse. Case presentation We report a case series of SAVI in a three generation kindred, with a phenotype of interstitial lung disease (ILD) and rheumatoid factor positive polyarticular juvenile idiopathic arthritis (JIA). Current and historical medical records were reviewed for clinical and laboratory information. Whole blood from cases 1 and 2, plus stored appendicectomy tissue from case 3, underwent DNA sequencing of the TMEM173 gene. Peripheral blood RNA was obtained from cases 1 and 2 for functional assessment of the TMEM173 mutation. DNA sequencing identified the same heterozygous TMEM173 mutation (c.463G > A; p.Val155Met) in all three cases, consistent with a diagnosis of the autosomal dominant condition SAVI. Functional assessment of this mutation identified a prominent interferon signature which was confirmed on repeat testing. Conclusions SAVI presented in this family as ILD with early onset juvenile rheumatoid arthritis. This condition should be considered in all rheumatoid arthritis patients with early-onset ILD and in all JIA patients with ILD.

Background: Uveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors.Methods: This multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2-18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23).Findings: 22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25-57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab.Interpretation: The primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options.Funding: Versus Arthritis and the National Institute for Health Research Clinical Research Network: Children.