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This prospective, longitudinal, multicenter study assessed the safety and efficacy of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine among children 4-11 years-old with autoimmune inflammatory rheumatologic disease (AIIRD), compared to healthy controls. The study was conducted from 11/2021-12/2022 at 4 tertiary pediatric rheumatology units in Israel. Participants received at least 2 vaccine doses. Safety analysis included adverse events and disease activity measures. Efficacy was assessed by COVID-19 infection rates. Immunogenicity was evaluated in a subset of participants using anti- receptor binding domain antibody titers. Thirty-one children with AIIRD and 45 immunocompetent controls with similar baseline characteristics were included. Safety profile was favorable, with mild or no adverse events reported. The adverse event rates were similar in the AIIRD and control groups after the first (27 (60 %) vs. 14 (45.2 %), p = 0.2977) and the second vaccine doses (22 (49.0 %) vs. 18 (58.1 %), p = 0.5799), respectively. AIIRD activity remained stable and low after vaccination. Breakthrough COVID-19 infection rates were similar between groups, with 15 (48.4 %) in the AIIRD vs. 25 (55.6 %) in the control group (p = 0.7029). All reported COVID-19 infections in the AIIRD group and 18 (72 %) in the control group were symptomatic (p = 0.033), although symptoms were generally mild, with no severe disease. The safety of the BNT162b2 COVID-19 vaccine was excellent in children ages 4-11 years with AIIRD and healthy controls. Efficacy between groups was similar., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Granulomatosis with polyangiitis (GPA) is an ANCA-associated vasculitis. The 2022 ACR/EULAR-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in paediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA., Methods: Retrospective data of paediatric patients with GPA in 20 centres from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated., Results: The study included 77 patients with GPA and 108 controls [IgA vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1) and Cogan's syndrome (n = 1)] with a median age of 17.8 and 15.2 years, respectively. Among patients with GPA, constitutional symptoms (85.7%) and ENT involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (P = 0.229 and P = 0.733, respectively)., Conclusion: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly., (© Crown copyright 2023.)

Objective: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice., Methods: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure., Results: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS., Conclusion: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

This paper aims to compare the cellular immune response to the SARS-CoV-2 BNT162b2 vaccine of pediatric patients with autoimmune inflammatory rheumatic disease (pAIIRD) and healthy controls. A prospective longitudinal study was conducted between April 2021 and December 2022 at the Tel Aviv Medical Center. Children <18 years, with pediatric-onset AIIRD and healthy controls, who have received at least two doses of the BNT162b2 vaccine, were included. Humoral response was evaluated by serum levels of anti-SARS-CoV-2 receptor-binding domain antibodies. Cellular response was evaluated by flow cytometry, measuring IFNγ and TNFα production by CD4+ T cells following stimulation with SARS-CoV-2 Spike peptide mix. The study included 20 pAIIRD patients and 11 controls. The mean age of participants was 12.6 ± 2.94 years, with 58.1% females. The cellular response to the BNT162b2 vaccine was statistically similar in both groups. However, the humoral response was statistically lower in pAIIRD compared with the healthy control group. There was no statistically significant correlation between the humoral response and cellular response. During the study period, 43.75% of AIIRD children and 72.7% of controls had a breakthrough COVID-19 infection (P = 0.48). Bivariate models examining the effect of the cellular response and presence of an AIIRD on breakthrough infections found no effect. Compared with healthy controls, pAIIRD demonstrated similar cellular responses. Patients showed reduced humoral response compared with healthy adolescents, but similar breakthrough infection rates. These findings may support the importance of the cellular response in protecting against COVID-19 infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

While most countries provide safe and effective influenza vaccines for at-risk groups, influenza vaccine coverage among children with rheumatic diseases remains uncertain. This study investigated influenza vaccination rates in children with juvenile idiopathic arthritis (JIA) during the 2019-2020 season and assessed the knowledge and attitudes of caregivers of children with JIA regarding influenza vaccination. The secondary aims were to identify barriers to vaccination and explore strategies to improve vaccination rates. A multi-centre, cross-sectional anonymous survey was conducted in 7 countries during the 2019-2020 influenza season to assess the uptake history of influenza vaccination. Among 287 participants, only 87 (30%) children with JIA received the influenza vaccine during the 2019-2020 season. Children who were more likely to be vaccinated were those with systemic juvenile idiopathic arthritis (sJIA), a history of previous vaccination and those aware of the vaccination recommendations. Conversely, children who previously experienced adverse vaccine-related events reported the lowest uptake. The primary reason for non-vaccination was lack of awareness about the necessity of influenza vaccination.  Conclusion: Despite variations among countries, the uptake of influenza vaccines remains low in children with JIA. Improving awareness among families about the importance of influenza vaccination may increase vaccination rates in children with rheumatic diseases. What is Known: • Rheumatic children are at increased risk for influenza infection due to immunosuppressive therapy and immune dysregulation. • Influenza vaccine is formally recommended to children with rheumatic diseases. What is New: • This multicentre study showed that influenza vaccine uptake rates remain suboptimal among children with Juvenile Idiopathic Arthritis despite formal recommendations. • Factors like previous experience with vaccination and information provided by medical professionals via different ways play essential roles in increasing vaccination rates and can contribute to improved health outcomes for these vulnerable children., (© 2024. The Author(s).)

Objectives: To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support., Methods: This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease., Results: Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease., Conclusion: Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: IgA vasculitis (IgAV) (formerly Henoch-Schönlein Purpura, HSP) rarely causes severe skin lesions in children. The purpose of the research was to determine whether severe skin manifestations were associated with a more severe disease course., Methods: Severe cutaneous manifestations were defined as presence of hemorrhagic vesicles, bullae, ulcerations and/or necroses. Data were collected retrospectively from 12 international tertiary university medical centers., Results: A total of 64 patients with the most severe skin changes in IgAV/HSP and median (Q 1 , Q 3 ) age of 8.08 (5.08, 11.92) years at the disease onset were compared with 596 IgAV/HSP patients without these manfiestations and median (Q 1 , Q 3 ) age of 6.33 (4.50, 8.92) years. The patients with severe cutaneous manifestations were older in comparison to other patients with IgAV/HSP (p<0.001), they developed nephritis more frequently (40.6% vs. 20.6%, p = 0.001) with worse outcome of renal disease (p = 0.001). This group of patients also had higher frequencies of severe gastrointestinal complications like hematochezia, massive bleeding and/or intussusception (29.3% vs. 14.8%, p<0.001). d-dimer concentrations were significantly higher in these patients (4.60 mg/L vs. 2.72 mg/L, p = 0.003) and they had more frequent need for treatment with systemic glucocorticoids (84.4% vs. 37.2%, p<0.001) in comparison with the control group. Further multivariate analysis showed that severe cutaneous changes were associated with higher risk of developing nephritis [OR=3.1 (95%CI 1.04-9.21), p = 0.042] and severe gastrointestinal complications [OR=3.65 (95%CI 1.08-12.37), p = 0.038]., Conclusion: Patients with IgAV/HSP and severe skin manifestations had a more severe clinical course and more frequently required glucocorticoids compared to classic IgAV/HSP patients., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, causing significant morbidity. Despite the dramatic improvement in treatment, many patients do not achieve complete remission, and biomarkers for subclinical disease, flares, and response to treatment are lacking. Neutrophils and neutrophil extracellular traps (NETs) play key roles in the pathogenesis of autoimmune and inflammatory conditions. In this study, we characterized neutrophil enzyme activity and NETs formation in oligoarticular and polyarticular JIA and explored their association with disease activity., Methods: Neutrophils from 6 healthy controls and 7 patients with oligoarticular and polyarticular JIA were freshly isolated at time of diagnosis and after glucocorticoid intra-articular injection. Enzymatic activity of neutrophil granular enzymes was monitored by colorimetry and PMA-activated NETs formation was assessed using fluorescent microscopy., Results: In this pilot and feasibility study, we revealed that NETs were significantly increased in oligoarticular JIA patients at time of diagnosis compared to healthy controls. Anti-inflammatory treatment using intra-articular steroid injection normalized NETs formation in these patients. Correlation between NETs formation and clinical Juvenile Activity Disease Activity Score-10 (cJADAS-10) was linear and significant (P = 0.007) in oligo but not in poly JIA patients., Conclusions: This is the first study exploring the link of NETs formation with oligo and poly JIA activity. We demonstrated a statistically significant linear correlation between cJADAS-10 and NETs formation in oligo but not in poly JIA patients. Hence, we suggest that NETs may reflect clinical disease activity in JIA, and may serve as a putative biomarker. Further work is needed to validate these initial results and determine the dynamics of NETs formation in JIA., (© 2023. The Author(s).)

Objective: Characterization of the stages that patients with juvenile idiopathic arthritis (JIA) pass until they are diagnosed, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel., Methods: This is a retrospective cohort study conducted in 8 pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referring physicians were collected from hospital and community medical charts., Results: Of 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients, on average, were evaluated during the diagnostic process by 3.1 different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.9%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and spondyloarthritis/enthesitis-related arthritis (SpA/ERA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis ( P < 0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time ( P < 0.05)., Conclusion: This is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness about JIA, especially for patients with SpA/ERA, is crucial in order to avoid delays in diagnosis and treatment., (Copyright © 2023 by the Journal of Rheumatology.)

Background: To explore the long-term safety and dynamics of the immune response induced by the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) compared with healthy controls., Methods: This international prospective study included adolescents with AIIRDs and controls vaccinated with two (AIIRDs n = 124; controls n = 80) or three (AIIRDs n = 64; controls n = 30) doses of the BNT162b2 vaccine, evaluated for vaccine side-effects, disease activity, COVID-19 breakthrough infection rates and severity, and anti-spike S1/S2 IgG antibody titers in a sample from both groups., Results: The vaccination safety profile was favorable, with most patients reporting mild or no side-effects. The rheumatic disease remained stable at 98% and 100% after the second and third doses, respectively. The two-dose vaccine induced comparable seropositivity rates among patients (91%) and controls (100%), ( p = 0.55), which declined within 6 months to 87% and 100%, respectively ( p = 0.3) and increased to 100% in both groups after the third vaccine dose. The overall post-vaccination COVID-19 infection rate was comparable between patients and controls, 47.6% (n = 59) and 35% (n = 28), respectively; p = 0.5278, with most infections occurring during the Omicron surge. In relation to the last vaccination, time-to-COVID-19 infection was similar between patients and controls, at a median of 5.5 vs. 5.2 months, respectively (log-rank p = 0.1555)., Conclusion: The safety profile of three doses of the BNT162b2 mRNA vaccine was excellent, with adequate humoral response and similar efficacy among patients and controls. These results support the recommendation for vaccinating adolescents with juvenile-onset AIIRDs against COVID-19.

Objective: COVID-19-associated pediatric vasculitis, other than Kawasaki disease (KD)-like vasculitis in multisystem inflammatory syndrome in children (MIS-C), is very rare. This study sought to analyze the characteristics, treatment, and outcomes in patients with COVID-19-associated pediatric vasculitis (excluding KD-like vasculitis in MIS-C)., Methods: The inclusion criteria were as follows: 1) age <18 years at vasculitis onset; 2) evidence of vasculitis; 3) evidence of SARS-CoV-2 exposure; and 4) ≤3 months between SARS-CoV-2 exposure and vasculitis onset. Patients with MIS-C were excluded. The features of the subset of patients in our cohort who had COVID-19-associated pediatric IgA vasculitis/Henoch Schönlein purpura (IgAV/HSP) were compared against a pre-pandemic cohort of pediatric IgAV/HSP patients., Results: Forty-one patients (median age 8.3 years; male to female ratio 1.3) were included from 14 centers and 6 countries. The most frequent vasculitis subtype was IgAV/HSP (n = 30). The median duration between SARS-CoV-2 exposure and vasculitis onset was 13 days. Involvement of the skin (92.7%) and of the gastrointestinal system (61%) were the most common manifestations of vasculitis. Most patients (68.3%) received glucocorticoids, and 14.6% also received additional immunosuppressive drugs. Remission was achieved in all patients. All of the patients with IgAV/HSP in our cohort had skin manifestations, while 18 (60%) had gastrointestinal involvement and 13 (43.3%) had renal involvement. When we compared the features of this subset of 30 patients to those of a pre-pandemic pediatric IgAV/HSP cohort (n = 159), the clinical characteristics of fever and renal involvement were more common in our COVID-19-associated pediatric IgAV/HSP cohort (fever, 30% versus 5%, respectively [P < 0.001]; renal involvement, 43.3% versus 17.6%, respectively [P = 0.002]). Recovery without treatment and complete recovery were each less frequent among our COVID-19-associated pediatric IgAV/HSP patients compared to the pre-pandemic pediatric IgAV/HSP cohort (recovery without treatment, 10% versus 39%, respectively [P = 0.002]; complete recovery, 86.7% versus 99.4%, respectively [P = 0.002])., Conclusion: This is the largest cohort of children with COVID-19-associated vasculitis (excluding MIS-C) studied to date. Our findings suggest that children with COVID-19-associated IgAV/HSP experience a more severe disease course compared to pediatric IgAV/HSP patients before the pandemic., (© 2022 American College of Rheumatology.)

Introduction: Several histologic classifications are used in the evaluation of IgA vasculitis nephritis (IgAVN), however, to date, no studies have determined which one has the strongest association with the severity of IgAVN and, as a consequence, its outcomes., Materials and Methods: Patients included in the study were diagnosed with IgAV and IgAVN in seven tertiary university medical centers in Croatia, Italy and Israel. The International Study of Kidney Disease in Children (ISKDC), Haas, Oxford, and Semiquantitative classification (SQC) classifications were used in the analysis and description of renal biopsy. Time from biopsy to outcome evaluation was a statistically significant factor in outcome prediction that was used to define the base model, and was a covariate in all the tested models., Results: Sixty-seven patients were included in this study. The SQC classification proved to be the best one in outcome prediction, followed by the Oxford classification. The ISKDC and Haas classifications could not predict renal outcome. The Oxford parameters for mesangial hypercellularity and tubular atrophy, as well as the SQC parameters for cellular crescents showed an independent statistically significant contribution to outcome prediction. High level of twenty-four hour protein excretion was associated with a higher grade in the Oxford, SQC and ISKDC classifications. Endocapillary proliferation was positively associated with the Pediatric Vasculitis Activity Score (PVAS) at diagnosis, while tubular atrophy was negatively associated., Conclusion: The SQC, followed by the Oxford classification were found to provide the best classifications of renal biopsy analysis in patients to predict the outcome in patients with IgAVN. Cellular crescents, mesangial hypercellularity and tubular atrophy showed significant contributions, indicating that active and chronic variables should be included in the estimation., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Objectives: The effectiveness of the BNT162b2 mRNA COVID-19 vaccine for adolescents with juvenile-onset inflammatory or immune rheumatic diseases (IRDs) is unknown. Several studies have suggested attenuated immunogenicity in patients with IRD. This study evaluated the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing COVID-19 infection in adolescents with juvenile-onset IRD compared with controls without immune rheumatic disease., Methods: We used data from Clalit Health Services, the largest health-care organization in Israel, to conduct an observational cohort study from February to December 2021, involving 12-18 year-old adolescents diagnosed with IRD. Study outcomes included documented COVID-19 infection in relation to vaccination status and immunomodulatory therapy. We estimated vaccine effectiveness as one minus the risk ratio. Adolescents aged 12-18 years without immune rheumatic disease served as controls., Results: A total of 1639 adolescents with IRD (juvenile idiopathic arthritis, SLE, or familial Mediterranean fever) were included and compared with 524 471 adolescents in the same age range without IRD. There was no difference in COVID-19 infection rates after the second dose of vaccine between those with IRD and controls (2.1% vs 2.1% respectively, P = 0.99). The estimated vaccine effectiveness for adolescents with IRD was 76.3% after the first dose, 94.8% after the second and 99.2% after the third dose., Conclusion: We found that the BNT162b2 mRNA vaccine was similarly effective against COVID-19 infection in adolescents with and without IRD. Immunomodulatory therapy did not affect its effectiveness. These results can encourage adolescents with IRD to get vaccinated against COVID-19., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

With the introduction of biological disease-modifying antirheumatic drugs (bDMARDs), the treatment of pediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) has advanced from the "Stone Age" to modern times, resulting in much better clinical outcomes. However, everything comes with a price, and use of new bDMARDs has resulted in an increased risk of infections. Therefore, preventing infections in pedAIIRD patients is one of the top priorities. The most effective preventive measure against infection is vaccination. The first study on humoral immunity after vaccination in pediatric rheumatology was published in 1974 and on safety in 1993. For many years, data about safety and immunogenicity in pedAIIRD patients were available only for non-live vaccines and the first studies on live-attenuated vaccines in pedAIIRD patients treated with immunosuppressive therapy were available only after 2007. Even today the data are limited, especially for children treated with bDMARDs. Vaccinations with non-live vaccines are nowadays recommended, although their long-term immunogenicity and efficacy in pedAIIRD patients are still under investigation. Vaccinations with live-attenuated vaccines are not universally recommended in immunosuppressed patients. However, measles-mumps-rubella booster and varicella zoster virus vaccination can be considered under specific conditions. Additional research is needed to provide more evidence on safety and immunogenicity, especially regarding live-attenuated vaccines in immunosuppressed patients with pedAIIRD. Due to the limited number of these patients, well-designed, prospective, international studies are needed. Further challenges were presented by the COVID-19 pandemic. This mini review article reviews past and present data and discusses the future of vaccinology in pediatric rheumatology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Bizjak, Heshin-Bekenstein, Jansen, Ziv, Angevare, Uziel, Wulffraat, Toplak and for the PReS Vaccination Working Party.)

Background: Following the Coronavirus Disease-19 (COVID-19) pandemic outbreaks, the hyperinflammatory condition termed Multisystem Inflammatory Syndrome in Children (MIS-C) became a healthcare issue worldwide. Since December 2020 the mRNA vaccine against SARS-CoV-2 has become available with a good safety profile. However, evidence regarding safety and vaccination strategies in children with previous MIS-C is still lacking. The aim of our study was to investigate the current approach of international centers to anti-SARS-CoV-2 and other vaccinations in children with a history of MIS-C., Methods: Physicians who care for patients with MIS-C were invited to anonymously complete a 15-question, web-based survey. The survey was open from October 6 to December 31, 2021., Results: A total of 290 replies from 236 centers in 61 countries were collected. Most respondents (86%) were pediatric rheumatologists. The anti-SARS-CoV-2 vaccine was available in 85% of the countries. Sixty-seven centers (28%) in 22 countries already vaccinated MIS-C patients without adverse reactions in most cases (89%). Six reported complications: 2 not specified, 3 mild symptoms and 1 reported a MIS-C-like reaction. Most centers (84%) favored vaccinating MIS-C patients against SARS-CoV-2, after 3-6 months (40%), 6-12 months (52%) or >12 months (8%). The survey revealed broad heterogeneity of responses among healthcare providers within the same country and within the same center. The variable with the greatest impact on the decision not to vaccinate MIS-C patients was the current lack of evidence (51%), followed by patient/parent objection (40%). The most relevant parameters in the vaccination strategy were time from MIS-C episode (78%), immunosuppressive treatment (35%), SARS-CoV-2 serologic status (32%), and MIS-C features (31%). Almost all centers favored continuing regular vaccination with non-live (99%) and live (93%) vaccines; however, with high variability in suggested timelines., Conclusion: To date, the experience of the international pediatric rheumatology community in vaccinating MIS-C patients against SARS-CoV-2 is overall reassuring. However, lack of evidence causes broad heterogeneity in vaccination strategy worldwide., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Minoia, Lucioni, Heshin-Bekenstein, Vastert, Kessel, Uziel, Lamot, Ruperto, Gattorno, Bracaglia and Toplak.)

Objectives: Adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) could be at risk for disease flare secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or to withholding anti-inflammatory therapy. While vaccination can protect against coronavirus disease 2019 (COVID-19), safety and immunogenicity data regarding anti-SARS-CoV-2 vaccines among adolescents with AIIRDs are limited. This international, prospective, multicentre study evaluated the safety and immunogenicity of the BNT162b2 anti-SARS-CoV-2 vaccine among adolescents and young adults with juvenile-onset AIIRDs, 80% of whom are on chronic immunomodulatory therapy., Methods: Vaccine side effects, disease activity and short-term efficacy were evaluated after 3 months in 91 patients. Anti-spike S1/S2 IgG antibody levels were evaluated in 37 patients and 22 controls 2-9 weeks after the second dose., Results: A total of 91 patients and 40 healthy controls were included. The safety profile was good, with 96.7% (n = 88) of patients reporting mild or no side effects and no change in disease activity. However, three patients had transient acute symptoms: two following the first vaccination (renal failure and pulmonary haemorrhage) and one following the second dose (mild lupus flare vs viral infection). The seropositivity rate was 97.3% in the AIIRD group compared with 100% among controls. However, anti-S1/S2 antibody titres were significantly lower in the AIIRD group compared with controls [242 (s.d. 136.4) vs 387.8 (57.3) BAU/ml, respectively; P &lt; 0.0001]. No cases of COVID-19 were documented during the 3 month follow-up., Conclusion: Vaccination of juvenile-onset AIIRD patients demonstrated good short-term safety and efficacy and a high seropositivity rate but lower anti-S1/S2 antibody titres compared with healthy controls. These results should encourage vaccination of adolescents with juvenile-onset AIIRDs, even while on immunomodulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Approximately 1 child in 1,000 is affected by juvenile idiopathic arthritis (JIA). Persistent, undiagnosed JIA with high disease activity interferes with daily life and carries a risk of irreversible physical and psychosocial damage. Due to its relative rarity, primary care physicians often do not recognise it. Consequently, diagnosis and referral to paediatric rheumatologists are delayed. We aimed to evaluate the knowledge of Israeli paediatricians and paediatric orthopaedic surgeons regarding the epidemiology, clinical manifestations, laboratory parameters and treatment of JIA., Methods: An 11-item, online questionnaire regarding JIA was sent to Israeli paediatricians and paediatric orthopaedic surgeons. The questionnaire was completed by 318 paediatricians and 30 paediatric orthopaedic surgeons (total response rate 22.5%)., Results: The average score was 67/100 points and the pass rate was 70.1% (set at 60 points). Several factors were associated with better overall scores: paediatric residents compared to senior physicians, exposure to rheumatology during residency, and seeing more patients with JIA in the past 5 years. No significant difference was found between paediatricians and paediatric orthopaedic surgeons. The true incidence of JIA was underestimated by 40% of participants, 30-45% were not familiar with its clinical presentation (age of onset, pain characteristics, chronic uveitis symptoms), and 60% were not familiar with up-to-date treatments., Conclusions: Paediatricians and paediatric orthopaedic surgeons in Israel have gaps in knowledge regarding JIA. This could result in delayed referral and treatment, which might affect outcomes. The results of this study highlight the need for better education and exposure to a rheumatologist, to improve knowledge and recognition of JIA.

Introduction: Since the development of COVID-19 vaccines, more than 4.8 billion people have been immunized worldwide. Soon after vaccinations were initiated, reports on cases of myocarditis following the second vaccine dose emerged. This study aimed to report our experience with adolescent and young adults who developed post-COVID-19 vaccine myocarditis and to compare these patients to a cohort of patients who acquired pediatric inflammatory multisystem syndrome (PIMS/PIMS-TS) post-COVID-19 infection., Methods: We collected reported cases of patients who developed myocarditis following COVID-19 vaccination (Pfizer mRNA BNT162b2) from all pediatric rheumatology centers in Israel and compared them to a cohort of patients with PIMS., Results: Nine patients with post-vaccination myocarditis were identified and compared to 78 patients diagnosed with PIMS. All patients with post-vaccination myocarditis were males who developed symptoms following their second dose of the vaccine. Patients with post-vaccination myocarditis had a shorter duration of stay in the hospital (mean 4.4 ± 1.9 vs. 8.7 ± 4.7 days) and less myocardial dysfunction (11.1% vs. 61.5%), and all had excellent outcomes as compared to the chronic changes among 9.2% of the patients with PIMS., Conclusion: The clinical course of vaccine-associated myocarditis appears favorable, with resolution of the symptoms in all the patients in our cohort.

Objectives: High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes., Methods: Youth <18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (>90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (<0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (>1.5mg/kg/day) starting doses of oral glucocorticoids., Results: Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes., Conclusions: Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.

Objective: Magnetic resonance imaging (MRI) is pivotal in the assessment of early sacroiliitis in children. We aimed to evaluate the agreement between local radiology reports and central imaging reviewers for active inflammation and structural damage at the sacroiliac (SI) joints., Methods: Eight hospitals each contributed up to 20 cases of consecutively imaged children and adolescents with juvenile idiopathic arthritis and suspected sacroiliitis. Studies were independently reviewed by 3 experienced musculoskeletal pediatric radiologists. Local assessments of global impression and lesions were coded from the local radiology reports by 2 study team members. Test properties of local reports were calculated using the central imaging team's majority as the reference standard., Results: For 120 evaluable subjects, the median age was 14 years, half of the cases were male, and median disease duration at the time of imaging was 0.8 years (interquartile range 0-2). Sensitivity of local reports for inflammation was high, 93.5% (95% confidence interval [95% CI] 78.6-99.2), and specificity was moderate, 69.7% (95% CI 59.0-79.0), but positive predictive value (PPV) was low, 51.8% (95% CI 38.0-65.3). Twenty-seven cases (23%) had active inflammation reported locally but rated normal at the central reading, 19 (70%) with subsequent medication changes. The sensitivity of local reports detecting structural damage was low, 45.7% (95% CI 28.8-63.4), and specificity was high, 88.2% (95% CI 79.4-94.2); PPV was low, 61.5% (95% CI 40.6-79.8)., Conclusion: Substantial variation exists in the interpretation of inflammatory and structural lesions at the SI joints in children. To reliably identify pathology, additional training in the MRI appearance of the maturing SI joint is greatly needed., (© 2020, American College of Rheumatology.)

Background: Observations among Israeli pediatric rheumatologists reveal that pediatric Juvenile Spondyloarthritis (JSpA) may present differently compared to patients from the United States (US). This study is aimed to compare the demographic and clinical variables of Israeli and US JSpA patients upon presentation., Methods: We performed a retrospective, cross-sectional, multicenter comparison of JSpA patients among 3 large Israeli pediatric rheumatology centers and a large US pediatric rheumatology center. Patients with diagnosis of Juvenile Ankylosing Spondylitis (JAS) and/or Enthesitis-related Arthritis (ERA) were included. The demographic, clinical and radiologic features were compared., Results: Overall 87 patients were included (39 Israeli, 48 US patients). Upon presentation, inflammatory back pain, sacroiliac joint tenderness and abnormal modified Schober test, were significantly more prevalent among Israeli patients (59% vs. 35.4, 48.7% vs. 16.7, and 41.2% vs. 21.5%, respectively, all p < 0.05), whereas peripheral arthritis and enthesitis were significantly more prevalent among US patients (43.6% vs. 91.7 and 7.7% vs. 39.6% in Israeli patients vs. US patients, p < 0.05). In addition, 96.7% of the Israeli patients versus 29.7% of the US patients demonstrated sacroiliitis on MRI (p < 0.001, N = 67). Less than one-third of the Israeli patients (32%) were HLA-B27 positive vs. 66.7% of US patients (p = 0.007)., Conclusion: Israeli children with JSpA presented almost exclusively with axial disease compared to US patients who were more likely to present with peripheral symptoms. HLA B27 prevalence was significantly lower in the Israeli cohort compared to the US cohort. Further studies are needed to unravel the genetic and possibly environmental factors associated with these findings.

Background: The SPARCC sacroiliac joint inflammation (SIS) and structural (SSS) scores are reliable measures to quantify abnormalities in the pediatric sacroiliac joint. We aimed to evaluate the utility of online calibration modules for the SIS and SSS and the reliability of their component change scores., Methods: Change score reliability of 6 raters was assessed by overall and pairwise intraclass correlation coefficients (ICCs) before and after the use of real-time iterative calibration (RETIC) modules for both the SIS and SSS comprised of 20 adult cases. Acceptable ICC for change scores was > 0.7 for SIS and > 0.5 for all SSS components. Sensitivity to change was assessed by the standardized response mean (SRM)., Results: In scoring exercise 1, the SIS had acceptable reliability with a change score ICC of 0.80 and sclerosis was the only SSS lesion that met the acceptability threshold with a change score ICC of 0.52. After RETIC calibration, the SIS overall (ICC = 0.83) and mean pairwise (ICC = 0.83) change scores remained reliable with a large SRM (0.90). All SSS components except sclerosis met the overall and mean pairwise change score ICC acceptability thresholds-backfill: overall = 0.54, mean pairwise = 0.50; fat metaplasia: overall = 0.65, mean pairwise = 0.57; erosion: overall = 0.60, mean pairwise = 0.58; and ankylosis: overall = 0.96, mean pairwise = 0.96. The SSS RETIC module augmented the number of SSS components surpassing the acceptability threshold from 1 to 4. Sensitivity to change, as measured by the SRM, was large for erosion (0.96), moderate for backfill (0.55) and sclerosis (0.70), and small for fat metaplasia (0.36) and ankylosis (0.28)., Conclusion: RETIC modules improved the overall reliability of SPARCC SIS and SSS change scores for previously calibrated raters. SIS recalibration was not as helpful to the most experienced raters who achieved high levels of agreement before recalibration. The SPARCC SIS and all SSS components except sclerosis are reliable measures to quantify change over time in children. A pediatric-specific RETIC tool should be developed to enhance the calibration of readers.

Purpose: To evaluate the effect of gluten-free diet (GFD) on hepatitis B surface antibody (HBsAb) concentrations among previously immunized pediatric celiac disease (CD) subjects., Methods: We retrospectively evaluated pediatric CD subjects in serological remission who were previously immunized for hepatitis B virus as infants. The temporal relationship between HBsAb concentration, the amount of time on a GFD, and age were evaluated., Results: Overall, 373 CD subjects were analyzed: 156 with HBsAb sampled prior to GFD initiation and 217 after initiation of a GFD and in serological remission. Median age at HBsAb concentration measurement for those before and after GFD initiation was 5.3 years (interquartile range [IQR], 3.1-9.2 years) and 7.6 years (IQR, 5.4-10.9 years), respectively ( p <0.001). There was no sex difference between the groups. The median time of HBsAb measurement was 2 months (IQR, 0-5.7 months) before and 12.8 months (IQR, 5.3-30.3 months) after initiation of GFD. The HBsAb concentration was low in 79 (50.6%) and 121 (55.7%) subjects before and after GFD initiation, respectively ( p =0.350). Age was inversely associated with low HBsAb concentrations. Neither being on a GFD nor sex was associated with low HBsAb concentrations., Conclusion: Adherence to a GFD does not affect HBsAb concentration in children with CD. Age is inversely associated with HBsAb concentration., Competing Interests: Conflicts of Interest: The authors have no financial conflicts of interest., (Copyright © 2020 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

Objectives: Determine whether adults with childhood-onset systemic lupus erythematosus (cSLE) are at increased risk for disease- and steroid-related damage as compared to individuals with adult-onset SLE (aSLE), and whether they continue to accumulate disease damage in adulthood., Methods: Data derive from the 2007-2015 cycles of the Lupus Outcomes Study, a longitudinal cohort of adults with confirmed SLE. The Brief Index of Lupus Damage (BILD), a validated, patient-reported measure, was used to assess SLE-associated damage. Participants with baseline BILD were included (N = 1035). Diagnosis at age < 18 years was defined as cSLE (N = 113). Outcome variables included BILD score at baseline and follow-up, clinically significant change in BILD score over follow-up period, and presence of steroid-related damage (cataracts, osteoporosis-related fracture, avascular necrosis or diabetes mellitus)., Results: Mean time between baseline and follow up BILD assessment was 6.3 ± 1.7 years. In adjusted analyses, participants with cSLE and aSLE had similar levels of disease-related damage, and accumulated damage at similar rates. Participants with cSLE were more likely to report steroid-related damage (OR 1.7, 95% CI 1.1-2.8) in the adjusted analysis as compared to those with aSLE. Likelihood of steroid-related damage increased with disease duration for both groups, but was consistently higher among cSLE participants., Conclusion: In this longitudinal cohort of adults with SLE, participants continued to accumulate damage at similar rates over time, regardless of age at onset or disease duration. Childhood-onset predicted increased risk of steroid-related damage. Aggressive use of steroid-sparing treatment strategies during childhood may be important to prevent steroid-related damage in adulthood., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: To compare final height to mid-parental target height among adults with childhood-onset systemic lupus erythematosus (cSLE) versus adult-onset SLE (aSLE), and to evaluate the impact of age at SLE onset on final height., Methods: Data derived from the Lupus Outcomes Study, a longitudinal cohort of adults with SLE, was used for this cross-sectional analysis (N = 728). Participants aged 18-63 years with complete height data were included (N = 566) and were classified as cSLE if age at diagnosis was < 18 years (N = 72). The Tanner formula was used to calculate mid-parental target height. Multivariate linear regression was used to determine mean difference between final height and target height. Multivariate logistic regression was used to compare odds of substantially reduced final height, defined as > 2 SD below target height. Separate analyses were conducted for females and males to account for differences in timing of the pubertal growth spurt for each sex., Results: Participants with cSLE were, on average, 2.4 cm shorter than their target height (95% CI -4, - 0.7). The adjusted odds ratio (OR) for substantially reduced final height was 3.9 (95% CI + 2.0, + 7.2, p < 0.001) as compared to participants with aSLE. Females diagnosed between 11 and 13 years were at greatest risk for substantially reduced final height, with adjusted OR of 11.2 (95% CI + 3.4, + 36.3) as compared to participants with aSLE (p < 0.001)., Conclusions: cSLE is associated with shorter-than-expected final height. Onset of SLE in the pubertal period, near the time of maximum linear growth, may have a particularly significant impact on final height.

Background: Familial Mediterranean fever (FMF) is a disorder characterized by recurrent attacks of fever and serosal inflammation, particularly abdominal pain. Other disease processes, including medical and surgical emergencies, may mimic FMF, especially in atypical cases., Case Presentation: We present a case of an adolescent male, referred to us with a diagnosis of colchicine resistant FMF, ultimately diagnosed with intestinal malrotation and recurrent volvulus., Conclusions: In atypical presentations of FMF with potential "red flags", a thorough patient history is extremely important and should result in prompt referral for the appropriate diagnostic tests.

Objective: Previous studies have suggested that hepatitis B virus (HBV) vaccines may be less immunogenic in individuals with celiac disease (CD). A pre-S vaccine (Sci-B-Vac) has demonstrated superior immunogenicity compared with standard HBV vaccines in several diseases. We compared the short-term immunogenicity of a pre-S vaccine with a HBV vaccine (Engerix B) for repeat vaccination of seronegative, previously immunized patients with CD., Methods: Participants were 1 to 18-year-old children with CD who despite standard HBV vaccines in infancy had nonprotective hepatitis B surface antibody (HBs-Ab) concentrations (≤10 mIU/mL). Patients were randomized to receive either Engerix B or pre-S vaccine. HBs-Ab concentrations were measured 1 month after the first dose. For those who had not responded after 1 dose, measurement was repeated after the third dose., Results: Children (n = 82) were analyzed (42 pre-S vaccine and 40 Engerix B). Baseline characteristics were similar for both groups, including gluten-free diet status. Both arms showed high response rates following the first injection: 41 (98%) versus 35 (87%) for pre-S vaccine and Engerix B recipients, respectively (P = 0.08). All other patients responded when measured after dose 3. HBs-Ab concentrations (mIU/mL) were higher in the pre-S vaccine group (median 925, interquartile range [IQR] 424-1000) than the Engerix B group (median 363, IQR 106-996, P = 0.005). Twenty (48%) of the pre-S vaccine recipients were "high responders" (>1000 mIU/mL) versus 10 (25%) in Engerix B recipients (P = 0.008)., Conclusions: Both vaccines elicited adequate booster responses in most previously vaccinated patients with CD with nonprotective HBs-Ab concentrations. Pre-S vaccine administration resulted in higher Hbs-Ab concentrations. Our data suggest that a single dose of either vaccine is sufficient to raise titers to protective levels in most patients with CD.

Objectives: Systemic lupus erythematosus (SLE) occurs more commonly in females than in males. Recent evidence suggests that genetic factors transmitted by the X-chromosome may confer increased risk for autoimmune disease in general, and for SLE in particular. It is therefore possible that X-chromosome polysomy might confer further increased risk for lupus. In addition to describing the clinical and immunologic features of a young woman with polysomy-X and SLE, we sought to review all other published cases associating female or male polysomy-X with SLE or other forms of autoimmunity., Methods: We report a case of a prepubertal girl with polysomy-X and SLE. We performed a systemic literature review for cases of polysomy-X and SLE and summarize previously published cases. In addition, we reviewed reports concerning the possible association between SLE and other connective tissue diseases and male polysomy-X., Results: An 11-year-old girl with tetrasomy-X (48 XXXX karyotype) presented with prolonged fever. Workup led to the diagnosis of SLE, and subsequent renal biopsy revealed mild diffuse mesangial proliferative glomerulonephritis. Two additional cases of SLE in women with 47 XXX and one of 48 XXXX karyotype were found in a literature review and compared to the present case. We identified studies that found X-chromosome polysomy to be over-represented in male patients with SLE and case descriptions of connective tissue diseases occurring in patients with polysomy-X., Conclusion: No consistent pattern of disease was observed in female polysomy patients with SLE. Taken together with the data concerning the frequency of polysomy-X among males with SLE, our findings provide additional support for the hypothesis that X-chromosome polysomy may confer increased susceptibility to SLE. Molecular mechanisms that might account for this phenomenon are discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gradenigo's syndrome is a rare but life threatening complication of acute otitis media (AOM), which includes a classic triad of otitis media, deep facial pain and ipsilateral abducens nerve paralysis. The incidence of Fusobacterium necrophorum infections has increased in recent years. We describe two cases of Gradenigo's syndrome caused by F. necrophorum. Additional four cases were identified in a review of the literature. Gradenigo's syndrome as well as other neurologic complications should be considered in cases of complicated acute otitis media. F. necrophorum should be empirically treated while awaiting culture results., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)