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Childhood-onset systemic lupus erythematosus (cSLE) is a multisystem autoimmune disease characterized by immune dysregulation affecting patients less than 18 years old. One-fifth of SLE cases are diagnosed during childhood. cSLE presents differently from adults and has a more severe and aggressive course. We describe the clinical and antibody profiles in our cSLE Singapore cohort. All cSLE patients who satisfied the 1997 American College of Rheumatology diagnostic criteria were captured in our lupus registry from January 2009 to January 2014. Data including demographic, cumulative clinical, serologic data, and damage indices were collected. Adjusted mean SLEDAI-2K (AMS) was used to summarize disease activity over multiple visits. Cluster analysis using non-hierarchical K-means procedure was performed on eight selected antibodies. The 64 patients (female:male ratio 5:1; Chinese 45.3%, Malay 28.1%, Indian 9.4%, and other races 17.2%) had a mean onset age of 11.5 years (range 2.1–16.7) and mean age at diagnosis was 11.9 years (range 2.6–18.0). Our study demonstrated differences in clinical manifestations for which hematologic involvement was the most common manifestation with less renal disease and uncommon neurologic manifestation as compared to other cSLE cohorts reported in our region. Antibody clusters were identified in our cohort but their clinical association/discrimination and outcome prediction required further validation study. Outcomes of our cohort in regard to disease activity after therapy and organ damages were comparable if not better to other cSLE cohorts elsewhere. Steroid-related damage, including symptomatic multifocal avascular necrosis and cataract, were not uncommon locally. Infection remains the major cause of death for the continent. Nevertheless, the five year survival rate of our cohort (98.4%) was high. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG. METHODS: Eligible patients had been diagnosed by site rheumatologists (termed the 'MD diagnosis') since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients. RESULTS: MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6). CONCLUSION: The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers. [ABSTRACT FROM AUTHOR]

A 2-year-old girl presented with a one-day history of acute-onset bilateral painful, swollen eyes and a two‑month history of loose stools. Physical examination revealed a right eyelid swelling with proptosis. Magnetic resonance imaging revealed a right orbital pseudotumour. The patient responded well to treatment with intravenous antibiotics and nonsteroidal anti-inflammatory drugs. However, three weeks later, she was readmitted with a vasculitic lesion over her left upper chest, with mucous-bloody diarrhoea. Histopathology confirmed the diagnosis of ulcerative colitis. The patient was treated with intravenous pulse methylprednisolone and sulphasalazine. Two weeks after discharge, she was readmitted for cutaneous vasculitis and worsening diarrhoea. The patient's bowel and extraintestinal diseases resolved upon addition of infliximab to her treatment regimen. Her inflammatory markers also normalised. Azathioprine was subsequently added. Infliximab was discontinued after four doses and prednisolone was tapered off. The patient remained well without any flare-up after 24 months of follow-up. [ABSTRACT FROM AUTHOR]

Objective: To develop a set of quality indicators (QIs) tailored to improve the care provided to children with juvenile idiopathic arthritis (JIA) in countries across the Asia-Pacific region., Methods: An adaptation of the Research and Development Corporation (RAND)/University of California, Los Angeles (UCLA) Appropriateness Method (RAM) was used. An initial set of 32 QIs was developed after a systematic search of the literature. These were presented to members of a Delphi panel composed of pediatric rheumatologists and other relevant stakeholders from the Asia Pacific League of Associations for Rheumatology Pediatric Special Interest Group (APLAR-Pediatric SIG). After each round, the mean scores for validity and reliability, level of disagreement, and median absolute deviation from the mean were calculated., Results: The panelists were presented with 32 QIs in two rounds of voting, resulting in the formulation of a final set of 22 QIs for JIA. These QIs are categorized within six domains of care, including access to care, clinical assessment, medications and medication monitoring, screening for comorbidities, counseling, and self-efficacy and satisfaction with care., Conclusion: These QIs have been developed to evaluate and improve the quality of care provided to children with JIA, aiming to enhance health outcomes and ensure that healthcare services are tailored to the unique needs of this patient population., Competing Interests: CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

Objectives: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome., Study Design: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified., Results: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes., Conclusions: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Classification criteria for systemic lupus erythematosus (SLE) include American College of Rheumatology (ACR) 1997, Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) 2012 and European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria. Their performance in an Asian childhood-onset SLE (cSLE) population remains unclear as the clinical manifestations differ. We aim to evaluate the diagnostic performance in a cSLE cohort in Singapore., Method: Cases were physician-diagnosed cSLE, while controls were children with mixed and undifferentiated connective tissue disease that posed an initial diagnostic challenge. Data were retrospec-tively reviewed to establish the 3 criteria fulfilled at diagnosis and over time., Results: The study population included 120 cSLE cases and 36 controls. At diagnosis, 102 (85%) patients fulfilled all criteria. SLICC-2012 had the highest sensitivity (97.5%, 95% confidence interval [CI] 92.3-99.5), while ACR-1997 had the highest specificity (91.7%, 95% CI 77.5-98.3). All criteria had diagnostic accuracies at more than 85%. Over time, 113 (94%) fulfilled all criteria. SLICC-2012 remained the criteria with the highest sensitivity (99.2%, 95% CI 95.4-99.9), while ACR-1997 had the highest specificity (75.0%, 95% CI 57.8-87.9). Only SLICC-2012 and ACR-1997 had more than 85% diagnostic accuracy over time. Using a cutoff score of ≥ 13 for EULAR/ACR-2019 criteria resulted in improved diagnostic performance., Conclusion: SLICC-2012 criteria had the highest sensitivity early in the disease course in this first study evaluating the SLE classification criteria performance in a Southeast Asian cSLE cohort, while the ACR-1997 criteria had the highest specificity. Using a cutoff score of ≥ 13 for EULAR/ACR-2019 improved the diagnostic performance., Competing Interests: The authors have declared no conflicts of interest.

Background: To compare outcomes of a short and long weaning strategy of anti-tumor necrosis factor (aTNF) in our prospective juvenile idiopathic arthritis (JIA) cohort., Research Design and Methods: JIA patients on subcutaneous adalimumab with at least 6 months of follow-up were recruited (May 2010-Jan 2022). Once clinical remission on medication (CRM) was achieved, adalimumab was weaned according to two protocols-short (every 4-weekly for 6 months and stopped) and long (extending dosing interval by 2 weeks for three cycles until 12-weekly intervals and thereafter stopped) protocols. Outcomes assessed were flare rates, time to flare, and predictors., Results: Of 110 JIA patients, 77 (83% male, 78% Chinese; 82% enthesitis-related arthritis) underwent aTNF weaning with 53% on short and 47% on long weaning protocol. The total flare rate during and after stopping aTNF was not different between the two groups. The time to flare after stopping aTNF was not different (p = 0.639). Positive anti-nuclear antibody increased flare risk during weaning in long weaning group (OR 7.0, 95%CI: 1.2-40.8). Positive HLA-B27 (OR 6.5, 95%CI: 1.1-30.4) increased flare risks after stopping aTNF., Conclusion: Duration of weaning aTNF may not minimize flare rate or delay time to flare after stopping treatment in JIA patients. Recapture rates for inactive disease at 6 months remained high for patients who flared after weaning or discontinuing medication., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Early-onset systemic lupus erythematosus presents with a more severe disease and is associated with a greater genetic burden, especially in patients from Black, Asian or Hispanic ancestries. Next-generation sequencing techniques, notably whole exome sequencing, have been extensively used in genomic interrogation studies to identify causal disease variants that are increasingly implicated in the development of autoimmunity. This Review discusses the known casual variants of polygenic and monogenic systemic lupus erythematosus and its implications under certain genetic disparities while suggesting an age-based sequencing strategy to aid in clinical diagnostics and patient management for improved patient care., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yeo, Lim, Yaung, Khoo, Arkachaisri, Albani and Yeo.)

We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination., Methods: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses., Results: Two clusters were identified in the test (C1 vs. C2), validation (C1' vs. C2') and combined (C1″ vs. C2″) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2' and C2″) was smaller compared to the first. SLE patients in the second cluster (C2 and C2') were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2″) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1-1.9, p = 0.014) after vaccination. A higher proportion of patients in C2″ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1″ (6.6% vs. 0.2%) ( p < 0.001)., Conclusion: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.

Objectives: To evaluate the humoral immunogenicity for 6 months after the two-dose coronavirus disease 2019 (COVID-19) mRNA vaccination in adolescents and young adults (AYAs) with childhood-onset rheumatic diseases (cRDs)., Methods: This monocentric observational study was conducted between August 2020 and March 2022. Humoral immunogenicity was assessed at 2-3 weeks after first vaccine dose and 1, 3 and 6 months after the second dose by the cPass™ severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization antibody (nAb) assay. An inhibition signal of ≥30% defined the seroconversion threshold and the readings were calibrated against the World Health Organization International Standard for SARS-CoV-2 antibodies., Results. One Hundred and Sixty-Nine: AYAs with cRDs were recruited [median age 16.8 years (interquartile range, IQR 14.7-19.5), 52% female, 72% Chinese]. JIA (58%) and SLE (18%) comprised the major diagnoses. After second vaccine dose, 99% seroconverted with a median nAb titre of 1779.8 IU/ml (IQR 882.8-2541.9), declining to 935.6 IU/ml (IQR 261.0-1514.9) and 683.2 IU/ml (IQR 163.5-1400.5) at the 3- and 6-month timepoints, respectively. The diagnosis of JIA [odds ratio (OR) 10.1, 95% CI 1.8-58.4, P = 0.010] and treatment with anti-TNF-α (aTNF) (OR 10.1, 95% CI 1.5-70.0, P = 0.019) were independently associated with a >50% drop of nAb titres at 6 months. Withholding MTX or MMF did not affect the vaccine response or decay rate. The COVID-19 breakthrough infection was estimated at 18.2 cases/1000 patient-months with no clinical risk factors identified., Conclusion: Over half of AYAs with cRDs had a significant drop in SARS-CoV-2 nAb at 6-month despite an initial robust humoral response. JIA and aTNF usage are predictors of a faster decay rate., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: This review aims to provide evidence-based recommendations for an enhanced primary series (third dose) coronavirus disease 2019 (COVID-19) vaccination in people with rheumatic diseases (PRDs) in the local and regional context., Methods: Literature reviews were performed regarding the necessity, efficacy, safety and strategies for enhanced primary series COVID-19 vaccination in PRDs. Recommendations were developed based on evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Evidence was synthesised by eight working group members, and the consensus was achieved by a Delphi method with nine members of an expert task force panel., Results: Two graded recommendations and one ungraded position statement were developed. PRDs have impaired immunogenicity from the COVID-19 vaccine and are at an increased risk of postvaccine breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and poor clinical outcomes, compared to the general population. We strongly recommend that PRDs on immunomodulatory drugs be offered a third dose of the messenger RNA (mRNA) vaccine as part of an enhanced primary series, after the standard two-dose regimen. We conditionally recommend that the third dose of mRNA vaccine against SARS-CoV-2 be given at least 4 weeks after the second dose or as soon as possible thereafter. There is insufficient data to inform whether the third mRNA vaccine should be homologous or heterologous in PRDs., Conclusion: These recommendations that were developed through evidence synthesis and formal consensus process provide guidance for an enhanced primary series COVID-19 vaccination in PRDs., Competing Interests: None

Competing Interests: None

Systemic lupus erythematosus is a complex, systemic autoimmune disease characterised by immune dysregulation. Pathogenesis is multifactorial, contributing to clinical heterogeneity and posing challenges for diagnosis and treatment. Although strides in treatment options have been made in the past 15 years, with the US Food and Drug Administration approval of belimumab in 2011, there are still many patients who have inadequate responses to therapy. A better understanding of underlying disease mechanisms with a holistic and multiparametric approach is required to improve clinical assessment and treatment. This Review discusses the evolution of genomics, epigenomics, transcriptomics, and proteomics in the study of systemic lupus erythematosus and ways to amalgamate these silos of data with a systems-based approach while also discussing ways to strengthen the overall process. These mechanistic insights will facilitate the discovery of functionally relevant biomarkers to guide rational therapeutic selection to improve patient outcomes., Competing Interests: Declaration of interests AR reports consulting fees from AbbVie, Galapagos, Novartis, and Pfizer, and honoraria for lectures from AbbVie, Alexion, Angelini, Novartis, Reckitt-Benckiser, Pfizer, and Sobi. AM reports consulting fees from AbbVie, Eli Lilly, EMD Serono, Idorsia, Janssen, Novartis, and Pfizer, and has participated on a data safety advisory or monitoring board for EMD Serono and Pfizer. DSP has served on advisory boards for Immunovant and Bristol Myers Squibb, and a data safety advisory board for Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Studies of flares of autoimmune inflammatory rheumatic diseases (AIIRD) after COVID-19 mRNA vaccination are limited by small sample size, short follow up or at risk of selection bias., Methods: A national retrospective cohort study of consecutive AIIRD patients ≥12 years old, across 8 hospitals who received at least one dose of a COVID-19 mRNA vaccine. Patients were included from the date of 1st vaccine dose and censored at the time of flare or on the date of the clinic visit at least 3 months from cohort entry, whichever came first. Predictors of flare were determined by Cox proportional hazards analysis., Findings: 4627 patients (73% Chinese, 71% female) of median (IQR) age 61 (48, 70) years were included; 42% Rheumatoid arthritis, 14% Systemic lupus erythematosus and 11% Psoriatic arthritis. 47% were in remission, 41% low disease activity, 10% moderate disease activity and 1% in high disease activity. 18% patients flared, of which 11.7% were within the 3-month period of interest. 11.8% patients improved. Median (IQR) time-to-flare was 60 (30, 114) days. 25% flares were self-limiting, 61% mild-moderate and 14% severe. Older patients (53-65 years and >66 years) had a lower risk of flare [HR 0.6 (95% CI 0.5-0.8) and 0.7 (0.6-0.8) respectively]. Patients with inflammatory arthritis and with active disease had a higher risk of flare [HR 1.5 (1.2-2.0) and 1.4 (1.2-1.6), respectively]. Treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), immunosuppression and prednisolone was also associated with an increased risk of flare [HR 1.5 (1.1-2), 1.2 (1.1-1.4) and 1.5 (1.2-1.8) for prednisolone ≤7.5 mg respectively]., Interpretation: There was a moderately high rate of AIIRD flares after mRNA vaccination but also improvement in several patients. Severe flares and hospitalisation were rare. Thus, vaccination remains safe and highly recommended., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Immunogenicity to the SARS-CoV-2 mRNA vaccines in adolescents and young adults (AYA) with childhood-onset rheumatic diseases (cRD) is unknown. We aimed to evaluate the humoral immunogenicity and safety of the vaccines in our AYA with cRD., Methods: A monocentric observational study with 159 AYA (50.3% female and 70.4% Chinese). Humoral immunogenicity was assessed at 2-3 and 4-6 weeks following first and second vaccination by cPass™ SARS-CoV-2 Neutralization Antibody Assay. Inhibition signal of ≥30% defined the cut-off for positive detection of the SARS-CoV-2 neutralizing antibodies. Vaccine safety and disease activity were assessed within 6 weeks after second vaccination., Results: A total of 64.9% and 99.1% of 159 patients (median age: 16.9, IQR: 14.7-19.5) mounted positive SARS-CoV-2 neutralizing responses after first and second vaccination, respectively. Most patients (89.8%) had ≥90% inhibition signal after second vaccination. Methotrexate and mycophenolate mofetil increased the risk associated with negative cPass neutralization responses following the first vaccination. Holding both medications after each vaccination did not affect immunogenicity. There was no symptomatic COVID-19 infection. Local reaction remained the most common (23.3-25.2%) adverse event, without serious complication. Two and seven patients flared following the first and second vaccination, respectively. Subgroup analyses of the 12-18-year-old cohort did not show any differences in vaccine efficacy, predictors of poor response and general safety, but higher proportion of disease flares., Conclusions: SARS-CoV-2 mRNA vaccines were efficacious after the two-dose regimen in almost all AYA with cRD without serious adverse event. The rate of disease flare observed is 4.4% after the second mRNA vaccine dose., (© 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.)

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a rare inflammatory syndrome with multisystem involvement affecting children exposed to COVID-19. This condition is rarely reported in East Asia and was not detected in Singapore until 2021. We present 12 cases of MIS-C diagnosed in KK Women's and Children's Hospital (KKH) from October 2021 to December 2021., Method: We conducted an observational study on cases fulfilling the Singapore Ministry of Health criteria for MIS-C from January 2020 to December 2021 in KKH. Medical records were reviewed to obtain information on clinical presentation, disease course, treatment received and outcomes., Results: In the 12 cases detected, the median age was 7.50 years (interquartile range 4.00-9.25); 8 were male. All patients had mucocutaneous symptoms similar to Kawasaki disease. Other commonly involved systems were: haematological (coagulopathy 100%, lymphopaenia 91.70% and thrombocytopaenia 75.00%), gastrointestinal (75.00%) and cardiovascular (83.30%). Six patients (50.00%) had shock and were admitted to the intensive care unit. The majority of patients received treatment within 2 days of hospitalisation with intravenous immunoglobulin (IVIg) and steroids. All survived; the majority had normal echocardiograms and no long-term organ sequelae at 6 months post-discharge., Conclusion: MIS-C emerged in Singapore as the incidence of COVID-19 in the community increased in 2021. The clinical presentation of our patients is similar to earlier reports, with some significant differences from Kawasaki disease. Multidisciplinary management, timely diagnosis, and early initiation of treatment with IVIg and steroids likely contributed to comparatively good outcomes. Our cases highlight the need for continued awareness of MIS-C among physicians, and surveillance of its incidence, short- and long-term outcomes.

Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×10 11 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis., (© 2022. The Author(s).)

Objectives: To assess short- and long-term outcomes of ERA in a large monocentric cohort in Singapore., Methods: Children diagnosed with ERA according to ILAR criteria from 2002 to 2021 were recruited. Nonparametric statistics were used to describe the data. Outcomes were defined according to modified Wallace criteria, and probabilities and predictors were determined using Kaplan-Meier survival and logistic regression analyses., Results: One hundred fifty-one ERA patients (male 86%; Chinese 81%) were included. The median age at onset was 11.9 years (IQR: 9.4-13.9), and disease duration was 5.3 years (IQR: 2.9-8.4). At diagnosis, 39% of the patients had sacroiliitis. HLA-B27 was positive in 83%, and biologics were used in 72% of the patients. Clinical inactive disease (CID) was achieved in 92% of the patients, of which 27% achieved within 6 months. Sacroiliitis at diagnosis is an unfavorable predictor of early CID at 6 months. Medication was discontinued in one-third of the patients. Favorable predictor of medication withdrawal includes male gender, while unfavorable predictors include positive HLA-B27 and ANA. Two-thirds of the patients with CID had at least one disease flare. Sacroiliitis at diagnosis is a protective predictor of flare after stopping medication., Conclusion: Despite a high proportion of ERA patients achieving CID, only one-third could stop medication with high rates of disease flare. Unfavorable predictors include older age at onset, HLA-B27, and ANA positivity. While sacroiliitis at diagnosis is a negative predictor of CID at 6 months, it is associated with less disease flare after discontinuing medication., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Little is known about the impact of delayed initiation of anti-tumor necrosis factor (TNF) therapy in patients with enthesitis-related arthritis (ERA). Here, we compared the impact of delayed treatment on disease outcomes of ERA patients in Southeast Asia., Research Design and Methods: This retrospective study enrolled 149 ERA patients from Thailand and Singapore. Early (e-aTNF) and late (l-aTNF) treatment groups received anti-TNF therapy starting at ≤6 months and >6 months, respectively, after diagnosis. Outcomes included mean differences in disease activity parameters, Juvenile Spondyloarthritis Disease Activity (JSpADA) score, Juvenile Arthritis Diseases Activity (JADAS)-10 score, and American College of Rheumatology Pediatric (ACR Pedi) criteria, and the frequency of clinically inactive disease and first flare event., Results: The mean changes in JSpADA (p = 0.002) and JADAS-10 (p < 0.001) scores over time were significantly higher in the e-aTNF group than in the l-aTNF group. A significantly higher proportion of patients in the e-aTNF group than l-aTNF group satisfied ACR Pedi 100 criteria at 2 years (p = 0.042). All other long-term outcomes were not significantly different between the groups., Conclusions: Although early anti-TNF treatment improved disease activity parameters somewhat better than delayed anti-TNF therapy, there was no significant difference in long-term outcomes.

Epileptogenic triggers are multifactorial and not well understood. Here we aimed to address the hypothesis that inappropriate pro-inflammatory mechanisms contribute to the pathogenesis of refractory epilepsy (non-responsiveness to antiepileptic drugs) in human patients. We used single-cell cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to reveal the immunotranscriptome of surgically resected epileptic lesion tissues. Our approach uncovered a pro-inflammatory microenvironment, including extensive activation of microglia and infiltration of other pro-inflammatory immune cells. These findings were supported by ligand-receptor (LR) interactome analysis, which demonstrated potential mechanisms of infiltration and evidence of direct physical interactions between microglia and T cells. Together, these data provide insight into the immune microenvironment in epileptic tissue, which may aid the development of new therapeutics., (© 2022. The Author(s).)

Chronic heart failure (HF) is a syndrome of heterogeneous etiology associated with multiple co-morbidities. Inflammation is increasingly recognized as a key contributor to the pathophysiology of HF. Heterogeneity and lack of data on the immune mechanism(s) contributing to HF may partially underlie the failure of clinical trials targeting inflammatory mediators. We studied the Immunome in HF cohort using mass cytometry and used data-driven systems immunology approach to discover and characterize modulated immune cell subsets from peripheral blood. We showed cytotoxic and inflammatory innate lymphoid and myeloid cells were expanded in HF patients compared to healthy controls. Network analysis showed highly modular and centralized immune cell architecture in healthy control immune cell network. In contrast, the HF immune cell network showed greater inter-cellular communication and less modular structure. Furthermore, we found, as an immune mechanism specific to HF with preserved ejection fraction (HFpEF), an increase in inflammatory MAIT and CD4 T cell subsets., 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., (Copyright © 2022 Kumar, Lim, Poh, Hazirah, Chua, Sutamam, Arkachaisri, Yeo, Kofidis, Sorokin, Lam, Richards and Albani.)

Background: Transition from pediatric to adult care is a challenging time for adolescents and young adults (AYA) with rheumatic diseases. Validated tools have been developed to assess transition readiness., Aim: To evaluate transition readiness among AYA with rheumatic diseases and to identify factors associated with transition readiness., Methods: Patients ≥15 years old were enrolled into our transition program and administered a Transition Readiness Assessment Tool (TRAT) from July 2017. The TRAT consists of 3 components: (a) patient's perception on importance of transition and confidence toward transition on a Likert scale 0-10; (b) assessment of knowledge on medical and healthcare usage using a set of 23 questions; (c) transition readiness using the Transition Readiness Assessment Questionnaire (TRAQ). Differences between groups were compared to identify factors associated with transition readiness., Results: Transition readiness assessment was performed in 152 patients. The median score for perception on transition importance was 7.0 (5.0-8.8) and the median score for confidence in transition was 7.0 (5.0-9.0). Majority of the patients (>50%) lack knowledge in health insurance, carrying health information, healthcare privacy changes and making own healthcare decision. Patients <20 years old were also deficient in knowledge in navigating healthcare systems. TRAQ scores were lowest in areas pertaining to healthcare insurance and obtaining financial help., Conclusion: Healthcare insurance literacy and self-management skills were lacking in the assessment of transition readiness in AYA with rheumatic diseases. Targeted intervention in these areas will improve transition readiness and promote successful transition processes., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology., Methods: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%., Results: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6)., Conclusion: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials., (© 2021, American College of Rheumatology.)

Introduction: Severe Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. However, delaying BCG vaccination can be detrimental to the population in tuberculosis-endemic regions. Early diagnosis of SCID through newborn screening followed by pre-emptive treatment with anti-mycobacterial therapy may be an alternative strategy to delaying routine BCG vaccination. We report the results of the first year of newborn SCID screening in Singapore while continuing routine BCG vaccination at birth., Method: Newborn screening using a T-cell receptor excision circle (TREC) assay was performed in dried blood spots received between 10 October 2019 to 9 October 2020 using the Enlite Neonatal TREC kit. Patients with low TREC had lymphocyte subset analysis and full blood count performed to determine the severity of lymphopenia and likelihood of SCID to guide further management., Results: Of the 35888 newborns screened in 1 year, no SCID cases were detected, while 13 cases of non-SCID T-cell lymphopenia (TCL) were picked up. Using a threshold for normal TREC to be >18 copies/μL, the retest rate was 0.1% and referral rate to immunologist was 0.04%. Initial low TREC correlated with low absolute lymphocyte counts (ALC), and subsequent normal ALC corresponded with increases in TREC, thus patients with normal first CD3+ T cell counts were considered to have transient idiopathic TCL instead of false positive results. 7/13 (54%) had secondary TCL (from sepsis, Trisomy 21 with hydrops and stoma losses or chylothorax, extreme prematurity, or partial DiGeorge Syndrome) and 6/13 (46%) had idiopathic TCL. No cases of SCID were diagnosed clinically in Singapore during this period and for 10 months after, indicating that no cases were missed by the screening program. 8/9 (89%) of term infants with abnormal TREC results received BCG vaccination within the first 6 days of life when TREC and ALC were low. No patients developed BCG complications after a median follow-up of 17 months., Conclusion: Newborn screening for SCID can be implemented while continuing routine BCG vaccination at birth. Patients with transient TCL and no underlying primary immunodeficiency are able to tolerate BCG vaccination., 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., (Copyright © 2021 Chan, Zhong, Lim, Poh, Teh, Soh, Chong, Thoon, Seng, Tan, Arkachaisri and Liew.)

Objective: To build a prediction model for uveitis in children with JIA for use in current clinical practice., Methods: Data from the international observational Pharmachild registry were used. Adjusted risk factors as well as predictors for JIA-associated uveitis (JIA-U) were determined using multivariable logistic regression models. The prediction model was selected based on the Akaike information criterion. Bootstrap resampling was used to adjust the final prediction model for optimism., Results: JIA-U occurred in 1102 of 5529 JIA patients (19.9%). The majority of patients that developed JIA-U were female (74.1%), ANA positive (66.0%) and had oligoarthritis (59.9%). JIA-U was rarely seen in patients with systemic arthritis (0.5%) and RF positive polyarthritis (0.2%). Independent risk factors for JIA-U were ANA positivity [odds ratio (OR): 1.88 (95% CI: 1.54, 2.30)] and HLA-B27 positivity [OR: 1.48 (95% CI: 1.12, 1.95)] while older age at JIA onset was an independent protective factor [OR: 0.84 (9%% CI: 0.81, 0.87)]. On multivariable analysis, the combination of age at JIA onset [OR: 0.84 (95% CI: 0.82, 0.86)], JIA category and ANA positivity [OR: 2.02 (95% CI: 1.73, 2.36)] had the highest discriminative power among the prediction models considered (optimism-adjusted area under the receiver operating characteristic curve = 0.75)., Conclusion: We developed an easy to read model for individual patients with JIA to inform patients/parents on the probability of developing uveitis., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To assess short- and long-term outcomes and predictors of juvenile idiopathic arthritis (JIA) children treated with contemporary therapy and compare those with reports elsewhere., Methods: Children with JIA were recruited from our web-based REgistry for Childhood Onset Rheumatic Diseases (RECORD) from 1997 to 2015. Disease status was defined using modified Wallace criteria. Nonparametric statistics described the data. Kaplan-Meier survival and logistic regression analyses were used to estimate probabilities and to determine predictors of outcomes., Results: A total of 251 children with JIA (62% males, 71% Chinese) were included. Median follow-up duration was 2.9 years (range 0.1-17.5). Short-term clinical inactive disease (CID) was attained in 37% with 62% systemic JIA (sJIA) and 47% persistent oligoarthritis (oJIA). Methotrexate (OR 0.34) decreased but sJIA (OR 3.25) increased chance of attaining CID at 6 months. Overall, 79% of patients achieved CID within 2 years (sJIA 92%, the highest, and RF+ polyarthritis 50%, the lowest probability). Biologics were associated with CID attainment (OR 2.73). One-half of patients flare after CID, median 1.2 years (IQR 0.71-1.97). Late CID achievement predicted flare (OR 2.15). Only 15% had clinical remission off medication (none RF+ polyarthritis and 7% ERA). Only 13% of patients had active arthritis as young adults and 22% had active arthritis at last visit., Conclusion: Despite high proportion of JIA patients attaining CID, only one-fourth could stop all medications for at least 1 year. Persistent oJIA patients were less likely to achieve clinical remission on medication and ERA patients had the least chance stopping medications. One-tenth of patients had active arthritis as young adults. Key Points • Majority of Asian children with JIA attained inactive disease within 2 years after diagnosis. • Outcome predictors were different from reports from the West. • Despite high inactive disease numbers, only one-in-four JIA patients discontinued treatment within 5 years.

Aim: People with rheumatic diseases (PRD) remain vulnerable in the era of the COVID-19 pandemic. We formulated recommendations to meet the urgent need for a consensus for vaccination against SARS-CoV-2 in PRD., Methods: Systematic literature reviews were performed to evaluate: (a) outcomes in PRD with COVID-19; (b) efficacy, immunogenicity and safety of COVID-19 vaccination; and (c) published guidelines/recommendations for non-live, non-COVID-19 vaccinations in PRD. Recommendations were formulated based on the evidence and expert opinion according to the Grading of Recommendations Assessment, Development and Evaluation methodology., Results: The consensus comprises 2 overarching principles and 7 recommendations. Vaccination against SARS-CoV-2 in PRD should be aligned with prevailing national policy and should be individualized through shared decision between the healthcare provider and patient. We strongly recommend that eligible PRD and household contacts be vaccinated against SARS-CoV-2. We conditionally recommended that the COVID-19 vaccine be administered during quiescent disease if possible. Immunomodulatory drugs, other than rituximab, can be continued alongside vaccination. We conditionally recommend that the COVID-19 vaccine be administered prior to commencing rituximab if possible. For patients on rituximab, the vaccine should be administered a minimum of 6 months after the last dose and/or 4 weeks prior to the next dose of rituximab. Post-vaccination antibody titers against SARS-CoV-2 need not be measured. Any of the approved COVID-19 vaccines may be used, with no particular preference., Conclusion: These recommendations provide guidance for COVID-19 vaccination in PRD. Most recommendations in this consensus are conditional, reflecting a lack of evidence or low-level evidence., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

An accurate depiction of the convalescent COVID-19 immunome will help delineate the immunological milieu crucial for disease resolution and protection. Using mass cytometry, we characterized the immune architecture in patients recovering from mild COVID-19. We identified a virus-specific immune rheostat composed of an effector T (T eff ) cell recall response that is balanced by the enrichment of a highly specialized regulatory T (T reg ) cell subset. Both components were reactive against a peptide pool covering the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. We also observed expansion of IFNγ + memory CD4 + T cells and virus-specific follicular helper T (T FH ) cells. Overall, these findings pinpoint critical immune effector and regulatory mechanisms essential for a potent, yet harmless resolution of COVID-19 infection., 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., (Copyright © 2021 Yeo, Leong, Tay, Nadua, Anderson, Lim, Ng, Poh, Guo, Yaung, Kumar, Wasser, Hazirah, Sutamam, Chua, Qui, Foo, Gamage, Yeo, Ramakrishna, Arkachaisri, Young, Lye, Wang, Chong, Tan, Li, Kam, Ginhoux, Thoon, Chan, Yung and Albani.)

Juvenile spondyloarthritis (JSpA) refers to a diverse spectrum of immune-mediated inflammatory arthritides whose onset occurs in late childhood and adolescence. Like its adult counterpart, JSpA is typified by a strong association with human leukocyte antigen-B27 (HLA-B27) and potential axial involvement, while lacking rheumatoid factor (RF) and distinguishing autoantibodies. A characteristic manifestation of JSpA is enthesitis (inflammation of insertion sites of tendons, ligaments, joint capsules or fascia to bone), which is commonly accompanied by bone resorption and new bone formation at affected sites. In this Review, advances in the role of HLA-B27, enthesitis and its associated osteoproliferation in JSpA pathophysiology and treatment options will be discussed. A deeper appreciation of how these elements contribute to the JSpA disease mechanism will better inform diagnosis, prognosis and therapy, which in turn translates to an improved quality of life for patients., 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., (Copyright © 2021 Tay, Yeo, Leong, Albani and Arkachaisri.)

The transition from pediatric to adult health care is a challenging yet important process in rheumatology as most childhood-onset rheumatic diseases persist into adulthood. Numerous reports on unmet needs as well as evidence of negative impact from poor transition have led to increased efforts to improve transition care, including international guidelines and recommendations. In line with these recommendations, transition programs along with transition readiness assessment tools have been established. Despite these efforts, there are still a lot of work to be done for transition care in rheumatology. This review article focuses on how transition care in rheumatology has developed in recent years and highlights the gaps in current practices.

Objective . To describe the clinical characteristics, predictors and treatment of children with Enthesitis Related Arthritis (ERA) in a Singapore longitudinal cohort over 11 years. Methods . ERA patients were recruited from our registry (2009-2019). Nonparametric descriptive statistics including median (interquartile range, IQR) were used to describe data. Kaplan-Meier survival and logistic/Cox regression analyses were used to estimate the probabilities and determine predictors of clinical variables, respectively. The significance level was set at <0.05. Results . One hundred and forty-six ERA patients (87% male, 82% Chinese) were included. Median onset age was 11.9 years (IQR 9.4-14.0) and median disease duration was 4.9 years (IQR 2.6-8.3). Family history of Human Leukocyte Antigen (HLA)-B27 associated diseases was positive in 7.5%. Acute uveitis occurred in 3.4%. Oligoarthritis was present in 89.7%. Hip, knee and ankle joints were among the most common joints involved. One-fourth had enthesitis at diagnosis (Achilles tendon entheses, 82.9%). Sacroiliitis occurred in 61%. Probabilities of sacroiliitis development were 0.364, 0.448 and 0.578 at 1, 2 and 5 years after onset, respectively. Negative HLA-B27, female, older age at onset and hip arthritis at diagnosis were associated with shorter time for sacroiliitis development ( p = 0.001-0.049). Methotrexate (MTX) remained the most common disease modifying anti-rheumatic drug (DMARD) used (77.4%). However, 77.9% required anti-TNF (aTNF) therapy secondary to MTX failure. Among MTX-treated sacroiliitis patients, 85.3% failed, requiring aTNF, as compared to 63.2%patients without axial disease. Longer duration to diagnosis ( p = 0.038) and MTX use ( p = 0.007) predicted aTNF therapy. None had joint deformity. Conclusions . This study underscores differences in ERA clinical characteristics, predictors and treatment responses. Our ERA population had many unique findings but good functional outcomes.

Childhood onset systemic lupus erythematosus is a rare disease that is more common amongst Southeast Asian children compared to the West. It is typified by a peripubertal onset and a female preponderance, which increases with advancing age. Organs commonly involved at diagnosis include haematological, renal, and mucocutaneous. Fever, malar rash, and cutaneous vasculitis are common. Lupus nephritis is typically proliferative especially Class IV and contributes to both disease activity and damage. Antinuclear antibody and anti-dsDNA positivity are both prevalent in this region. Disease activity is higher than Western cohorts at onset but responds to therapy reducing to low disease activity by six months. However, organ damage occurs early and continues to accumulate over the time, a consequence of both active disease (neurological and renal systems) and steroid-related complications especially in the eye (cataract and glaucoma) and musculoskeletal systems (avascular necrosis). Infections remain the leading cause of death and mortality in this region is highly variable contributed by the heterogeneity in social economic status, healthcare access, and availability of paediatric rheumatology expertise in the region.