Abstract Background Hyperinflammation ranges from monophasic to rapidly progressive, life-threatening courses. Early biomarkers to identify high-risk children are needed. Methods This single-center cohort included consecutive children with hyperinflammation between 01/2021 and 01/2024. Demographic, clinical, laboratory, cardiac imaging, and treatment data were analysed. Results Of 80 patients, 56 (70%) had a recalcitrant course. Fever was universal. Rash, mucosal involvement, and conjunctivitis were more common in the monophasic group, while abdominal pain, neurological signs, pleural effusion, lymphopenia, thrombocytopenia, hypoalbuminemia, and elevated ferritin characterised the recalcitrant group (p < 0.01). Myocarditis and reduced ejection fraction occurred only in the recalcitrant cohort; coronary artery changes were more frequent in monophasic cases (21% vs. 5%). All survived. All received IVIG; steroids and anakinra were used only in recalcitrant cases, who also had longer hospital stays, ICU admissions (21% vs. 0%, p < 0.01), and required inotropes/ventilation. Baseline SAA, IL-2R, and NT-proBNP were significantly higher in the recalcitrant cohort. In ROC analyses, NT-proBNP showed the highest diagnostic accuracy (AUC 0.912), followed by IL-2R (AUC 0.873) and SAA (AUC 0.793) (all p < 0.001). Conclusions NT-proBNP, IL-2R, and SAA were strongly associated with a recalcitrant hyperinflammatory course and may aid early prognostication and monitoring.

OBJECTIVE:Inflammatory arthritis (IA) can impair physical function, health-related quality of life (HRQoL) and productivity. Associations among these domains are recognized; however, evidence quantifying them across clearly defined disability levels remains limited. This study aimed to evaluate HRQoL and productivity across functional disability levels in IA using standardized patient-reported outcome measures (PROMs). METHODS:This cross-sectional analysis included consecutive IA patients attending rheumatology clinics in Calgary/Canada, enrolled in the Rheum4U Precision Health Registry (2018-2026). The Health Assessment Questionnaire Disability Index (HAQ-DI = 0-3) assessed functional disability, categorized as no 0, mild-to-moderate (>0-1), moderate-to-severe (1-2) or severe-to-very-severe disability (2-3). EuroQol 5-Dimension 5-Level (EQ-5D-5L; utility = -0.148 to 0.948; Visual Analogue Scale [VAS] = 0-100) measured HRQoL. The Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) evaluated productivity. Differences across disability levels were analysed using Kruskal-Wallis tests with Dunn's post hoc comparisons and effect sizes. Minimum important difference (MID) thresholds supported the interpretation (EQ-5D-5L utility = 0.20; VAS = 9.3; productivity = 20%). RESULTS:One thousand one hundred seventy-seven (1177) IA patients were included. Worsening functional disability was associated with progressively lower HRQoL and productivity (P < 0.001). Deterioration was evident starting at mild-to-moderate disability, with the moderate-to-severe disability representing a critical threshold for impairment compared with no disability (difference utility = 0.223; VAS = 25; productivity = 40%). CONCLUSION:In this robust real-world study using standardized PROMs, functional decline was associated with progressively worse HRQoL and productivity, with differences statistically significant and clinically meaningful. Moderate-to-severe disability appeared to mark a critical threshold. These findings underscore the importance of early identification and management of disability to prevent clinically meaningful impairments in quality of life and productivity.

OBJECTIVE:Still disease (SD) is an autoinflammatory syndrome characterized by innate immune dysregulation. While complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD. METHODS:Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n=15), non-systemic juvenile idiopathic arthritis (JIA, n=8), and SD patients at onset (n=19), remission (n=18), and macrophage activation syndrome (n=2). Whole-blood NanoString analysis of complement and interferon-related gene expression was conducted in SD (active n=41, inactive n=33) and JIA patients (n>600). Complement products and inflammatory mediators were measured by Luminex and ELISA. Functional complement activity was evaluated in SD (active n=30, inactive n=67) and JIA sera (n=12). In vitro assays examined monocytic C1q induction and complement-mediated CD8+ T cell activation. RESULTS:Transcriptomic analysis of monocytes from SD patients at onset revealed enrichment of the complement cascade compared to patients in remission (Padj=3.7×10-36), ranking among the top ten upregulated pathways. Classical complement genes (C1QB/C1QC) were markedly upregulated in onset SD compared to remission SD and JIA patients. Active SD patients showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole-blood C1QB/C1QC expression correlated with interferon-related markers, including IL-18, CXCL9 and CXCL10. Recombinant IFN-γ induced monocytic C1q, while C1q enhanced IFN-γ production by CD8+ T cells, supporting a feed-forward loop. CONCLUSION:SD is characterized by complement activation with marked upregulation of C1q, which is closely linked to IFN-γ/type-II signaling.

BACKGROUND:Valid and reliable health-related quality of life (HRQoL) instruments are needed in clinical practice to quantify the burden of juvenile idiopathic arthritis (JIA) and capture changes in health over time. We examined the responsiveness of the parent-proxy EuroQol 5-Dimension Youth 5-Level (EQ-5D-Y-5L) instrument in children with JIA. METHODS:This multicenter international cohort study included consecutive children with JIA who were enrolled in the Understanding Childhood Arthritis Network Canadian-Dutch (UCAN CAN-DU) eHealth platform. Demographics, Clinical Juvenile Arthritis Disease Activity Score-10 (cJADAS10) disease activity, Childhood Health Assessment Questionnaire (CHAQ) disability index, and health status were assessed at baseline and at follow-up visits 3-12 months later. Patients were categorized as improved, stable, or deteriorated using cJADAS10 and CHAQ. Responsiveness was evaluated at both the dimension level (distributional change) and continuous score level (EQ-5D-Y-5L level summary score [LSS] and EuroQol Visual Analogue Scale [EQ VAS]) using effect size and standardized response mean (SRM). RESULTS:A total of 246 patients were included (median age 12 years [interquartile range: 8-15]; 54% female). At the dimension level, children classified as improved showed clear shifts toward lower problem levels across all five EQ-5D-Y-5L dimensions, particularly in physical dimensions, while stable patients showed minimal distributional change. At the continuous score level, improvements were mostly associated with large effect size and SRM for both LSS and EQ VAS (0.8-1.6), whereas changes in stable groups were negligible to small. CONCLUSIONS:The parent-proxy EQ-5D-Y-5L demonstrates responsiveness to clinically defined changes in children with JIA. Its ability to detect improvement while remaining stable in the absence of change supports its use in longitudinal clinical studies and economic evaluations.

OBJECTIVE:To estimate the effect of time from symptom onset to start of biologic treatment on achieving inactive arthritis within six months in a cohort of patients with juvenile idiopathic arthritis (JIA). METHODS:The international UCAN CAN-DU study prospectively enrolled patients with JIA across Canada and the Netherlands. A nested cohort study was performed and biologic-naive patients with nonsystemic JIA were included at the start of biologic therapy. The primary outcome was inactive arthritis at six months. Demographics, disease-related parameters, and treatment response were compared using (non)parametric tests among early (time symptom onset to biologic start: 0-6 months), intermediate (7-12 months), and late (13-24 months) treatment groups. A logistic regression model analyzed the effect of time to biologic start on the response at six months, adjusting for active joint count and physician global assessment. A graphical representation of the model was created. RESULTS:One hundred and thirty children with JIA were included (early: n = 35; intermediate: n = 46; late: n = 49), 66% were female, and the median age at symptom onset was 11.0 years. The proportion of patients that reach inactive arthritis in the early starters (83%) was significantly higher than in late starters (57%). For each month of delay to the start of biologic treatment, the adjusted odds of having active arthritis after six months of therapy was 1.09 (interquartile range: 1.02-1.17, P = 0.009). CONCLUSION:Early start of biologic therapies in patients with JIA was associated with a higher proportion of patients reaching inactive arthritis within six months, suggesting a window of opportunity to control disease activity.

OBJECTIVE:To identify modifiable risk factors associated with progression of hearing impairment from a longitudinal cohort of anti-IL-1-treated children and adults with Cryopyrin-Associated Periodic Syndromes (CAPS) and explore real-life barriers to optimal long-term management. METHODS:A single-centre, longitudinal study included consecutive paediatric and adult anti-IL-1-treated CAPS patients with sensorineural hearing loss between 2006 and 2024. Data collected encompassed demographics, disease characteristics, genotype, treatment regimens and hearing assessments using 4PTA, HF-PTA. Primary outcome was WHO grade of hearing impairment at last follow-up. Factors associated with hearing impairment and real-life barriers mandating therapy escalation were identified. RESULTS:The study included 36 patients; 20 males, 16 females, median age at CAPS disease onset and hearing loss diagnosis was 11.8 and 40 years, respectively. Most patients (83%) exhibited moderate CAPS phenotype, carrying pathogenic or likely pathogenic NLRP3 variants (78%). Hearing loss was present in 83% at baseline and 88% at last follow-up with HF-PTA-sensitivity of 100%. Patients diagnosed in adulthood, those with a late treatment start, and/or with pathogenic or likely pathogenic variants demonstrated higher WHO grades of hearing impairment. Ten patients required therapy escalation due to progressive hearing loss, eight of whom carried pathogenic mutations. Early progression was primarily driven by disease activity, while late progression was predominantly influenced by non-compliance. Over time, 86% maintained stable hearing, 8% showed improvement and 6% experienced worsening. CONCLUSION:Early diagnosis, timely intervention and a refined Treat-to-Target approach are vital for hearing in lifelong CAPS management. Precision care and continuous monitoring are key to improving long-term outcomes.

Objective Health recommender systems (HRSs) are increasingly used to complement existing clinical decision-making processes, but their use for chronic diseases remains underexplored. Recognizing the importance of collaborative decision making (CDM) and patient engagement in chronic disease treatment, this review explored how HRSs support patients in managing their illness. Methods A scoping review was conducted using the framework proposed by Arksey and O’Malley, advanced by Levac et al., in line with the PRISMA-ScR checklist. Quantitative (descriptive numerical summary) and qualitative (inductive content analysis) methods wered used to synthesize the data. Results Forty-five articles were included in the final review, most commonly covering diabetes (9/45, 20%), mental health (9/45, 20.0%), and tobacco dependence (7/45, 15.6%). Behavior change theories (10/45, 22.2%) and authoritative sources (10/45, 22.2%) were the most commonly referenced sources for design and development work. From the thematic analysis, we conclude: (a) the main goal of HRSs is to induce behavior change, but limited research investigates their effectiveness in achieving this aim; (b) studies acknowledge that theories, models, frameworks, and/or guidelines help design HRSs to elicit specific behavior change, but they do not implement them; (c) connections between CDM and HRS purpose should be more explicit; and (d) HRSs can often offer other self-management services, such as progress tracking and chatbots. Conclusions We recommend a greater emphasis on evaluation outcomes beyond algorithmic performance to determine HRS effectiveness and the creation of an evidence-driven, methodological approach to creating HRSs to optimize their use in enhancing patient care. Lay summary Our work aims to provide a summary of the current landscape of health recommender system (HRS) use for chronic disease management. HRSs are digital tools designed to help people manage their health by providing personalized recommendations based on their health history, behaviors, and preferences, enabling them to make more informed health decisions. Given the increased use of these tools for personalized care, and especially with advancements in generative artificial intelligence, understanding the current methods and evaluation processes used is integral to optimizing their effectiveness. Our findings show that HRSs are most used for diabetes, mental health, and tobacco dependence, but only a small percentage of publications directly reference and/or use relevant frameworks to help guide their design and evaluation processes. Furthermore, the goal for most of these HRSs is to induce behavior change, but there is limited research investigating how effective they are in accomplishing this. Given these findings, we recommend that evaluations shift their focus from algorithms to more holistic approaches and to be more intentional about the processes used when designing the tool to support an evidence-driven approach and ultimately create more effective and useful HRSs for chronic disease management.

Introduction. Limited evidence guides pediatric rheumatologists on when to withdraw biologic therapy in children with juvenile idiopathic arthritis, resulting in wide variation in clinical practice. This study aimed to develop and evaluate a decision support tool (DST) based on expert opinion to support pediatric rheumatologists in making withdrawal decisions. Methods. A literature review, focus groups, interviews, and prior research informed the design of the prototype DST. Evaluation of the DST’s face validity, content validity, acceptance, and feasibility was conducted through user testing interviews and a survey among pediatric rheumatologists from the Netherlands and Canada. Findings were summarized using descriptive and qualitative content analyses. Results. The prototype DST requires input on relevant patient, disease, and treatment characteristics. Its primary output is the predicted likelihood of biologic therapy withdrawal. Pediatric rheumatologists can adjust the importance of characteristics and observe the resulting impact on withdrawal likelihood. Eleven pediatric rheumatologists participated in testing. Key themes identified included the need for 1) clear terminology to ensure consistent interpretation of model inputs, 2) concise instructions on how and when to adjust the relative importance of characteristics, and 3) practice rounds to build trust among pediatric rheumatologists in the DST’s output. Participants found the DST feasible for clinical use, with its main value in explaining decisions to patients and engaging them in the decision-making process. Suggested future improvements include tracking the outcomes of withdrawal decisions and integrating predictive models based on clinical data. Conclusions. The DST developed in this study was well-received. Its main value lies in helping pediatric rheumatologists explain their decisions to patients and parents. The top priority for further development is integrating scientific evidence on successful withdrawal decisions. Highlights Decision support tools that provide structure to decisions based on expert opinion can increase transparency and consistency in medical decision making in the absence of clinical evidence. Data from clinical vignette studies that use an experimental design to elicit treatment preferences can be used to predict treatment decision making. A decision support tool to support biologic therapy withdrawal decisions has the most value in explaining the decision to children with nonsystemic juvenile idiopathic arthritis and their parents.

OBJECTIVE:We aimed to study the disease course, outcomes, and predictors of outcome in pediatric-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affecting the kidneys. METHODS:Patients eligible for this study had a diagnosis of granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or ANCA-positive pauci-immune glomerulonephritis, were 18 years or younger at diagnosis, had renal disease defined by biopsy or dialysis dependence, and had clinical data at diagnosis and at either 12 or 24 months. Ambispective data from A Registry for Children with Vasculitis/Pediatric Vasculitis Initiative Registry was used. The primary outcome was inactive renal disease (pediatric vasculitis activity score = 0 or 1) at 12 months. Secondary outcomes included rates of improved renal function and damage within 24 months. Renal function, defined by estimated glomerular filtration rate, was categorized into Kidney Disease Improving Global Outcomes (KDIGO) stages at diagnosis and tested as a predictor of outcome using a proportional-odds logistic regression model. RESULTS:A total of 145 patients were included: 68% were female, and 78% had GPA. At 12 months, 83% of patients achieved inactive renal disease; however, 42% had evidence of permanent renal damage. Compared with patients with normal renal function at diagnosis, patients with moderate to severely reduced renal function, or kidney failure at diagnosis, had an odds ratio of 8.62 (P = 0.002; 95% confidence interval [CI] 2.31-32.1) and 26.3 (P < 0.001; 95% CI 6.32-109), respectively, for being in a non-normal KDIGO category at 12 months. CONCLUSION:The majority of patients with pediatric AAV achieve inactive renal disease by 12 months; however, almost half have evidence of damage. Renal function at diagnosis is a strong predictor of renal function at 12 months.

To describe the care-related quality of life of caregivers of children with juvenile idiopathic arthritis (JIA). The Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases (UCAN CAN-DU) and CURE study captures consecutive caregiver reported data including the standardized instrument CarerQoL questionnaire. The cohort includes all subtypes of JIA, and patients across the disease trajectory from new diagnosis to starting or stopping biologics. The analytic sample included all patients with a completed CarerQOL measure at baseline. Data collected included demographics, and a standardized measure of caregiving impact, the CarerQol instrument, and questions about paid/unpaid caregiving help. The CarerQol has 6 domains (problems with physical health, mental health, daily activities, relational, financial, and caregiving fulfillment and caregiving support) and can be summarized with a utility score from 0-100 with higher numbers indicating higher impact. Descriptive analyses were performed using RStudio. Among 498 participants, 282 (56.5%) were from the Netherlands, and 418 (83.9%) were mothers with median age of 42 years [IQR 36.0-46.0]. Most caregivers (n=427, 85.7%) lived with a spouse/partner, and 430 (86.3%) had either university or technical/college education. In terms of employment, 200 (40.8%) worked full-time, and 195 (39.8%) part-time, while 350 (70.4%) of spouses/partners worked full-time. Physical health conditions were reported by 349 (51%) caregivers, and 110 (16%) had mental health conditions. For spouses, 211 (36%) had physical health conditions, and 48 (8%) had mental health conditions. The mean CarerQoL utility score was 81.5 (SD: 11.1), with a median of 84.2 [IQR 77.1-88.2]. In terms of domains, physical health problems were the most common (43.8%), followed by mental health problems (41.8%) and daily activity problems (41.3%). Financial problems (13.2%) and relational problems (16.9%) were less commonly reported. Conversely, 92.4% felt some or a lot of fulfillment, and 80.3% felt they had caregiving support. Other questions examined unpaid and paid help. There, 20.1% of caregivers reported receiving unpaid help from family, friends, or neighbors in the last 3 months (median 15 hours, [IQR 5-26.2]), 3.8% received paid help with childcare (median 16 hours, [IQR 5-38.5), and 17 (3.4%) received paid help with household tasks (median 12 hours, [IQR 4-20]. The study highlights the caregiving impact experienced by caregivers of children with JIA. Despite high levels of fulfillment and support, a substantial proportion reported unmet needs. These findings underscore the importance of targeted interventions to support caregivers.

Children living with rare diseases often face significant psychosocial challenges; recognizing and addressing these effectively is crucial. However, there is a paucity of comprehensive screening tools. This study aimed to assess the feasibility and acceptance of the comprehensive KIDSCREEN-52 tool in identifying unmet needs of children with rare inflammatory diseases and their caregivers and identifying factors associated with low health-related quality of life (HRQoL). A prospective single-center study of consecutive pediatric patients aged 8–18 with inflammatory diseases and their caregivers was performed to assess HRQoL utilizing the multidimensional KIDSCREEN-52 self-report and proxy tool. The validated KIDSCREEN-52 tool is available in 13 languages with corresponding Norm Data. It captures HRQoL across 10 domains including 52 inquiries. HRQoL of children with rare inflammatory diseases was described utilizing the multidimensional KIDSCREEN-52 self-report and proxy tool. The feasibility and acceptability of KIDSCREEN-52 was determined using a simple, dichotomous three item acceptance tool. Factors associated with low self-reported HRQoL were explored. A total of 104 participants, comprising 51 pediatric patients and their 53 caregivers, were included. The patients were 35 females and 16 males, with a median age of 16 years (range: 9–18). Among them, 25 (49

OBJECTIVES:To determine the effect of paternal and maternal anti-IL-1 treatment exposures on pregnancies and neonatal outcomes in CAPS. METHODS:A single-centre study consecutive adult CAPS patients and their partners was performed between January 2012 and July 2024. All were screened for pregnancies and anti-IL-1 exposure before conception and/or during pregnancy; teratogenic co-therapies resulted in exclusion. Data included patient characteristics, disease activity, anti-IL-1 treatment, pregnancy complications, neonatal outcomes and child health trajectories. RESULTS:Among 112 patients 11 pregnancies were recorded including eight maternal and three paternal anti-IL-1 exposures. All patients had moderate CAPS, 43% had hearing loss. At conception, all patients received canakinumab. Among the eight maternal exposures, six switched to anakinra, one refused the switch and continued canakinumab, and one had to be switched back to canakinumab due to significant local injection reactions. Pregnancy complications included one miscarriage and one preterm birth, both associated with disease activity. Neonatal outcomes were favorable, with a mean gestational age of 37 + 6 weeks and an average birth weight of 3028 g. No congenital malformations were observed. Neonatal complications included one presumed sepsis (culture negative) requiring IV antibiotics and one mild respiratory syncytial virus infection. CAPS was diagnosed in 5 of 11 offspring, all of whom achieved effective disease control early, with no cases of hearing loss or amyloidosis. CONCLUSION:In summary, the benefit risk ratio of maternal and paternal anti-IL-1 exposure during conception and pregnancy in our CAPS patients was favourable. CAPS disease activity may have a significant impact on development of pregnancy complications.

Objective: To characterize debilitating fatigue in children and adults across inactive auto-inflammatory diseases (AID), identifying distinct disease-specific fatigue phenotypes and modifiable risk factors is necessary for optimal care. Methods: A single-center cohort of consecutive patients with inactive AID between 2007 and 2024 was performed. Demographics, clinical and laboratory features, and treatment were captured. Fatigue was characterized and quantified using the PedsQL-MFS and VAS; the CES-D/CESD-R was applied to assess depression risk. Comparisons were made using non-parametric methods, multivariable regression identified risk factors of fatigue in inactive disease. Results: 66 patients were included: 39 (59%) were children; the median age at symptom onset was 4 years, at treatment start was 8 years, and study follow-up was 7 years. All patients had inactive disease at the last visit. Patients with cryopyrin-associated periodic syndromes (CAPS) had the highest Cognitive Fatigue scores (p = 0.04). Univariate analyses identified higher fatigue scores (1) in adults across all domains except Sleep/Rest (all p ≤ 0.002), (2) in patients with pathogenic/likely pathogenic variants, and (3) for disease duration ≥10 years except Sleep/Rest (all p ≤ 0.01). Depression was the single most important factor associated with fatigue in all domains (p < 0.001). In multivariable analysis, depression remained the strongest predictor of fatigue even when accounting for age, gene variant, disease duration, and treatment delay. Conclusions: Fatigue remains the major burden in AID despite the availability of effective anti-inflammatory therapies. Depression was identified as the strongest determinant of debilitating fatigue in inactive AID. Systematic screening and integrated approaches addressing both psychological and inflammatory domains are essential for optimal care.

OBJECTIVES:Cryopyrin-associated periodic syndromes (CAPS) encompasses a spectrum of IL-1 driven systemic diseases with dramatic individual and societal burden. The study aimed to identify parameters and instruments to refine real-life treat-to-target (T2T) strategies and control CAPS disease activity. METHODS:A single-centre, longitudinal study of consecutive children and adults diagnosed with CAPS and treated with anti-IL-1 therapy was performed. Demographics, clinical phenotype and NLRP3 gene variants in addition to serial inflammatory markers and physician and patient/parent global assessments (PGA/PPGA) were captured. Effectiveness of anti-IL-1 T2T strategies and factors associated with therapy escalation were determined. RESULTS:A total of 54 CAPS patients with 759 follow-up visits were included; 31/54 (57%) were children; the median follow-up was 108 months (12-620). The moderate CAPS phenotype was present in 89%; overall 59% had pathogenic/likely pathogenic NLRP3 variants. Therapy adjustments were documented in 50/759 visits including 35 therapy escalations and 15 reductions; 74% of the therapy escalation visits were for children. At time of visit, 63% showed moderate, 37% severe clinical disease activity. Inflammatory markers remained largely normal. Significant improvement was observed in both PGA/PPGA throughout the study (P < 0.01). At the last follow-up, 96% of patients achieved remission. CONCLUSION:Guidance for refining real-life T2T strategies in CAPS cohorts can be drawn from serial assessments of PGA and PPGA, reliably reflecting changes in disease activity. Individual parameters including age and NLRP3 gene variants are important predictors, while the sensitivity of inflammatory markers is limited due to the confounding anti-IL-1 therapy.

Objective: To characterize debilitating fatigue in children and adults across inactive autoinflammatory diseases (AID), identify distinct disease-specific fatigue phenotypes, and modifiable risk factors for optimal care. Methods: A single-centre cohort of consecutive patients with inactive AID between 2007 and 2024 was performed. Demographics, clinical and laboratory features and treatment were captured. Fatigue was characterized and quantified using the PedsQL-MFS and VAS; the CES-D/CESD-R was applied to assess depression risk. Comparisons were made using non-parametric methods, multivariable regression identified risk factors of fatigue in inactive disease. Results: Sixty-six patients were included; 39 (59%) were children; median age at symptom onset was 4 years, at treatment start 8 years, and study follow-up was 7 years. All patients had inactive disease at last the visit. Patients with cryopyrin associated periodic syndromes (CAPS) had the highest cognitive fatigues scores (p=0.04). Univariate analyses identified higher fatigue scores 1) in adults across all domains except sleep/rest (all p≤0.002), 2) in patients with pathogenic/likely pathogenic variants and 3) for disease duration ≥10 years except sleep/rest (all p≤0.01). Depression was the single most important factor associated with fatigue in all domains (p< 0.001). In multivariable analysis, depression remained the strongest predictor of fatigue even when accounted for age, gene variant, disease duration and treatment delay. Conclusion: Fatigue remains the major burden in AID despite availability of effective anti-inflammatory therapies. Depression was identified as the strongest determinant of debilitating fatigue in inactive AID. Systematic screening and integrated approaches addressing both psychological and inflammatory domains are essential for optimal care.

BACKGROUND: Sharing health data within and across jurisdictions is important for research and improving healthcare quality; however, researchers, governments and funders must balance the benefits of data sharing with data privacy. Though frameworks exist to guide data sharing it can be difficult to translate these into practice. Therefore, our aim was to create a practical example of data sharing for researchers in pediatric rheumatology. METHODS: We utilized expert consultation with leaders in child health, genomics, rheumatology, bioethics, privacy and records, bioinformatics, and legal counsel to better understand barriers and enablers for sharing of health data. We used these barriers to frame the learnings of UCAN CAN-DU (Understanding Childhood Arthritis Network Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases) which is a collaboration that collects and shares phenotypic, genomic, health economic and patient reported data across centers in Canada and the Netherlands in order to provide a real-life, practical example of data sharing across borders in pediatric rheumatology. RESULTS: Barriers to data sharing include lack of standardized consent, ethics review processes for multi-site projects, developing data governance frameworks aligned with institutional and regulatory requirements, differing data standards and a lack of interoperability, and managing data access. UCAN CAN-DU provides lessons for navigating these barriers through standardized consent forms, centralized ethics review and reciprocity agreements; building a network to support data interoperability and harmonization of procedures; documentation to support data sharing, including legal agreements, utilization of a secure healthcare data storage compute facility, and a data access advisory committee with clear policies for secondary data use. CONCLUSION: We have shared how UCAN CAN-DU navigated barriers to data sharing, providing an example of data sharing for researchers in pediatric rheumatology. This work highlights the importance of research networks in establishing interoperability including minimal data sets, standard operating procedures, and institutional legal/contracts partnerships that ultimately support data sharing. The barriers and enablers presented are broadly applicable across countries and provide direction on areas for future research and initiatives to foster data sharing.

BACKGROUND:As many jurisdictions move towards seasonal COVID-19 vaccines, there remains insufficient data on optimal vaccination strategies for children with immune-mediated inflammatory diseases (IMID) treated with immunomodulatory therapies. METHODS:A prospective observational cohort study was performed, with clinical data and biosamples longitudinally collected to determine the effect of immunomodulatory therapies on the antibody response to four COVID-19 vaccine doses. Antibodies against the SARS-CoV-2 spike, receptor-binding domain, and nucleocapsid proteins were measured. RESULTS:Following doses two and three, antibody responses were lowest in participants treated with biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs), of which TNF inhibitors were the most common. Rates of antibody decay were similar between treatment groups, but weaker initial responses in the b/tsDMARD group led to antibody levels dipping to low values within four months of vaccination. The fourth vaccine dose significantly boosted antibody levels in the b/tsDMARD group, resulting in a sustained response. Among additional samples collected from children with hybrid immunity (i.e., vaccinated and prior SARS-CoV-2 infection), no differences in antibody levels were found between participants who were or were not treated with b/tsDMARDs. CONCLUSIONS:These data support providers in counselling families regarding the importance of annual COVID-19 booster vaccines in children with IMID. IMPACT:There is conflicting evidence on the effect of immunosuppressive treatments on the antibody response to vaccination in paediatric populations. Long-term follow-up of children treated with various immunosuppressive therapies as they received booster COVID-19 vaccines demonstrated that antibody responses to the second and third vaccine dose were impaired in children treated with biologics (mainly TNF inhibitors). Deficits in the antibody response were largely corrected by a fourth vaccine dose or infection with SARS-CoV-2. Children treated with biologic therapies require a full suite of COVID-19 vaccines and should be strongly encouraged to receive seasonal COVID-19 vaccine boosters.

Silent lupus nephritis (sLN) describes the histopathological presence of nephritis in systemic lupus erythematosus (SLE) without evident clinical or biochemical kidney manifestations. Kidney biopsy practises in suspected sLN vary widely among centers. We report three cases of sLN from our center and review existing literature on sLN prevalence and the role of baseline kidney biopsies. Characteristics of three patients with childhood-onset (cSLE) sLN from our center, including clinical and laboratory features as well as kidney biopsy findings, are reported. A systematic literature review was performed to evaluate the prevalence of proliferative LN among patients with sLN. Relevant studies were identified using a predefined search strategy on Ovid, MEDLINE, EMBASE, CINAHL Plus, Scopus, and Web of Science. Publications meeting inclusion criteria and reporting baseline kidney biopsy results with histopathological classification were included. Three cSLE patients with sLN from our center who underwent baseline kidney biopsies revealing class III LN in two and class II LN in one. The systematic review identified 4153 potential articles, of which 37 studies met inclusion criteria describing 639 patients with sLN; patients were aged 2–70 years. Among them, 30

Objectives:Fatigue in cryopyrin-associated periodic syndromes (CAPS) often persists despite controlling inflammation. This study explores fatigue burden, its link to disease activity, and factors tied to chronic fatigue in autoinflammatory conditions. Methods:A single-centre study (2007-2024) of children and adults with CAPS analysed demographics, clinical data, inflammation, treatment, disease activity, and fatigue scores. Relationships between these factors and predictors of chronic fatigue were assessed. Results:A total of 108 patients with CAPS were included; 53 were female (49%). Median age at diagnosis was 11 years (range, 0-73); median follow-up duration 7 years (range, 1-18). Muckle-Wells syndrome was the most common phenotype (86%). At the time of diagnosis, hearing loss was present in 30%, aseptic meningitis in 6%. At enrolment, fatigue was the most common symptom, affecting 100 patients (93%), with a median fatigue score of 7 (0-10, visual analogue scale); high disease activity was present in 67%. At the last visit, fatigue remained prevalent, reported in 83 (77%), with a median score of 3 (range, 0-10). Importantly, only 4% of patients had high disease activity, whereas 83% had inactive disease. Factors influencing chronic fatigue in CAPS included age at diagnosis (P < .001, Cohen's d = -0.776, β = -2.15), NLRP3 mutation status (P = .009, Cohen's d = -0.516, β = -1.48), disease activity (P < .001), familial CAPS (62% vs 38%, P = .132, Cohen's d = -0.298, β = -0.87), and the COVID-19 pandemic (P < .001). Conclusions:Fatigue persists in autoinflammatory diseases despite effective disease control. Further research is needed to identify mechanisms and interventions.

Background: In recent years, advances have been made in the treatment of severe autoimmune and inflammatory diseases in pediatric patients. However, some patients still experience persistent or recurrent disease activity. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is used as a therapeutic approach in such cases since more than two decades. However, there is limited data specifically from pediatric patients. Objectives: The primary objective is efficacy as measured by treatment response, PFS (Progression Free Survival) and OS (Overall survival). The secondary objectives are safety; infectious and non-infectious adverse events within 2 years after AHSCT and disease status at long-term follow-up. Methods: This retrospective, non-interventional study presents outcome data from 7 consecutive pediatric patients (2 systemic sclerosis, 1 pan-sclerosis, 2 systemic juvenile idiopathic arthritis, 1 dermatomyositis, 1 eosinophilic fasciitis) who underwent AHSCT for treatment-resistant autoimmune diseases at the Tübingen Center for Pediatric Rheumatology and Autoinflammatory Diseases between 1999 and 2021. Results: The median age of patients at the time of AHSCT was 10 years (IQR 8-17). The median follow-up duration was 17 years (IQR 14-21 years). Median PFS was 3 years (95% CI: 0.43-5.5). Median OS was 17 years (95% CI: 11.8-22.1). At 1 and 2 years after AHSCT, PFS rates were 100% and 77% (95% CI: 54-88), respectively, and overall survival rate was 100%. No serious infectious complications were observed except for one patient with an infection leading to SIRS and requiring intensive care therapy. 3 patients developed secondary autoimmune diseases (1 MAS, 1 Graves' disease, 1 autoimmune hemolytic anemia), 1 patient had fibroadenoma on routine screening during follow-up, 1 patient experienced deterioration in renal parameters and pericardial effusion thought to be due to cyclophosphamide but resolved spontaneously after discontinuation of treatment. One patient developed amenorrhea after transplantation. Today, all patients are still alive and 4/7 are in clinical remission on medication, 3/7 in clinical remission off medication. Conclusion: AHSCT is effective in the treatment of severe auto-immune syndromes in children and may be considered as a treatment option. Data on the pediatric patient population are limited, so more data are needed on the long-term efficacy and safety of transplantation. The indication and timing of transplantation requires a multidisciplinary approach. REFERENCES: [1] Alexander, T., et al., [Autologous hematopoietic stem cell transplantation for autoimmune diseases: Current indications and mode of action, a review on behalf of the EBMT Autoimmune Diseases Working Party (ADWP)]. Z Rheumatol, 2020. 79(5): p. 419-428. [2] Tyndall, A. and A. Gratwohl, Haemopoietic stem and progenitor cells in the treatment of severe autoimmune diseases. Ann Rheum Dis, 1996. 55(3): p. 149-51. [3] Tsukamoto, H., et al., A phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease. Ann Rheum Dis, 2006. 65(4): p. 508-14. [4] Alexander, T., R. Greco, and J.A. Snowden, Hematopoietic Stem Cell Transplantation for Autoimmune Disease. Annu Rev Med, 2021. 72: p. 215-228. Acknowledgements: NIL. Disclosure of Interests: None declared.