COVID-19 mRNA vaccine immunogenicity decay and breakthrough illness in adolescents and young adults with childhood-onset rheumatic diseases.

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.

Robust neutralizing antibody response to SARS-CoV-2 mRNA vaccination in adolescents and young adults with childhood-onset rheumatic diseases.

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.

Diagnostic performance of classification criteria for systemic lupus erythematosus: A validation study from Singapore.

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.

Anti-tumor necrosis factor (aTNF) weaning strategy in juvenile idiopathic arthritis (JIA): does duration matter?

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.

Sacroiliitis at diagnosis as a protective predictor against disease flare after stopping medication: outcomes of a Southeast Asian enthesitis-related arthritis (ERA) longitudinal cohort.

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.

Comparison of the outcomes between early and late anti-tumor necrosis factor therapy in patients with enthesitis-related subcategory of juvenile idiopathic arthritis: a multi-center study in Southeast Asia.

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.

Transition readiness assessment in adolescents and young adults with rheumatic diseases: The Singapore experience.

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.

Enthesitis Related Arthritis in a Longitudinal Southeast Asian Registry: High Prevalence of HLA-B27, Different Sacroiliitis Risk Factors and Less Common Drug-Free Remission.

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.

Urinalysis monitoring in children with Henoch-Schönlein purpura: Is it time to revise?

OBJECTIVES: To describe the natural history and risk factors of renal involvement in our Henoch-Schönlein purpura (HSP) inception cohort. METHODS: HSP patients followed at our center for at least 6 months between 1/2009-4/2017 were included. A 2-year urinalysis (UA) monitoring protocol was adopted (6 monthly and another 6 of 3 monthly UA). Renal involvement included minimal renal involvement defined as isolated hematuria (urine red blood cells >5/high-power field or 10/µL) and/or proteinuria (urine protein >1+), and renal impairment defined as nephritic, nephrotic symptoms, or renal insufficiency. Recurrent HSP were excluded. Kaplan-Meier estimates and log-rank test were used to analyze the duration to onset and resolution of abnormal UA. Relationships between demographic and clinical features and renal involvement were studied using logistic regression analyses. RESULTS: Two hundred and thirty-eight patients (52.9% male) were analyzed. Median duration of follow up was 20.6 (interquartile range 11.3-24.4) months. Eighty-nine children (37.4%) developed abnormal UA either at diagnosis (n = 43), or during follow up (n = 46), mostly (91.0%) within 6 months. Seventeen patients (7.1%) developed renal impairment. Among patients without renal impairment, an earlier subsidence (P = 0.008) was noted in those with normal UA at diagnosis and most abnormal UA resolved by 18 months in this subgroup. Older age at diagnosis was a risk factor of renal involvement (P < 0.001). Prednisolone therapy for non-renal indications did not affect the onset or duration of renal involvement. CONCLUSIONS: Normal UA at diagnosis indicated a shorter duration of renal involvement. We propose a curtailed duration of follow up for those with normal and abnormal UA at diagnosis.