Optimized Treatment of Interleukin (IL-1)-Mediated Autoinflammatory Diseases: Impact of Disease Activity-Based Treatment Adjustments.

Background: Effective control of disease activity in Interleukin-1 autoinflammatory diseases (IL-1 AID) is crucial to prevent damage. The aim was to longitudinally analyze the impact of protocolized disease activity-based treatment adjustments in a real-life cohort. Methods: A single-center study of consecutive children with IL-1 AID followed between January 2016 and December 2019 was performed. Demographics, phenotypes, genotypes, inflammatory markers, physician (PGA), and patient/parent (PPGA) global assessment were captured. Disease activity and treatment changes were assessed. The impact of distinct parameters on disease activity trajectories was analyzed. Results: A total of 56 children were included, median follow-up was 2.1 years reflecting 361 visits. Familial Mediterranean Fever was the most common IL-1 AID. At the first visit, 68% of the patients had moderate/severe disease activity. Disease activity-based treatment adjustments were required in 28/56 children (50%). At last follow-up, 79% had a well-controlled disease. Both PGA and PPGA decreased significantly over time (p < 0.001; p < 0.017, respectively), however, both differed statistically at last visit (p < 0.001). Only PGA showed a significant estimated mean decrease across all IL-1 AID over time. Conclusions: Disease activity-based treatment adjustments can effectively refine treat-to-target strategies, enable personalized precision health approaches, and improve outcomes in children with IL-1 AID.

Quantifying hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing tumour necrosis factor-alfa inhibitors in juvenile idiopathic arthritis.

OBJECTIVE: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNFi in JIA patients. METHODS: Retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were either immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalisation) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal). RESULTS: Fifty-six patients were included of whom 26 immediately discontinued TNFi, 30 spaced and zero tapered. Mean annual costs were €9,165/patient on active treatment (pre-withdrawal) and decreased significantly to €5,063/patient (-44.8%) and €6,569/patient (-28.3%) in the first and second year post-withdrawal, respectively (p< 0.05). Of these total annual costs, travel costs plus productivity losses were €834/patient, €1,180/patient, and €1,320/patient, in the three periods respectively. Medication comprised 80.7%, 61.5% and 72.4% of total annual costs in the pre-withdrawal, first, and second year post-withdrawal period, respectively. CONCLUSION: In the first two years after initiating withdrawal, the total annual costs are decreased compared with the pre-withdrawal period. However, cost reductions were lower in the second year compared with the first year post-withdrawal, primarily due to restarting or intensifying biologics. To support biologic withdraw decisions, future research should assess the full long-term societal cost impacts, and include all biologics.

A decade of progress in juvenile idiopathic athritis treatments and outcomes in Canada: results from ReACCh-Out and the CAPRI registry.

OBJECTIVE: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.

Neuroimaging Scoring Tools to Differentiate Inflammatory Central Nervous System Small-Vessel Vasculitis: A Need for Artificial Intelligence/Machine Learning?-A Scoping Review.

Neuroimaging has a key role in identifying small-vessel vasculitis from common diseases it mimics, such as multiple sclerosis. Oftentimes, a multitude of these conditions present similarly, and thus diagnosis is difficult. To date, there is no standardized method to differentiate between these diseases. This review identifies and presents existing scoring tools that could serve as a starting point for integrating artificial intelligence/machine learning (AI/ML) into the clinical decision-making process for these rare diseases. A scoping literature review of EMBASE and MEDLINE included 114 articles to evaluate what criteria exist to diagnose small-vessel vasculitis and common mimics. This paper presents the existing criteria of small-vessel vasculitis conditions and mimics them to guide the future integration of AI/ML algorithms to aid in diagnosing these conditions, which present similarly and non-specifically.

Withdrawing biologics in non-systemic JIA: what matters to pediatric rheumatologists?

OBJECTIVE: Approximately one third of children with JIA receive biologic therapy, but evidence on biologic therapy withdrawal is lacking. This study aims to increase our understanding of whether and when pediatric rheumatologists postpone a decision to withdraw biologic therapy in children with clinically inactive non-systemic JIA. METHODS: A survey containing questions about background characteristics, treatment patterns, minimum treatment time with biologic therapy, and 16 different patient vignettes, was distributed among 83 pediatric rheumatologists in Canada and the Netherlands. For each vignette, respondents were asked whether they would withdraw biologic therapy at their minimum treatment time, and if not, how long they would continue biologic therapy. Statistical analysis included descriptive statistics, logistic and interval regression analysis. RESULTS: Thirty-three pediatric rheumatologists completed the survey (40% response rate). Pediatric rheumatologists are most likely to postpone the decision to withdraw biologic therapy when the child and/or parents express a preference for continuation (OR 6.3; p < 0.001), in case of a flare in the current treatment period (OR 3.9; p = 0.001), and in case of uveitis in the current treatment period (OR 3.9; p < 0.001). On average, biologic therapy withdrawal is initiated 6.7 months later when the child or parent prefer to continue treatment. CONCLUSION: Patient's and parents' preferences were the strongest driver of a decision to postpone biologic therapy withdrawal in children with clinically inactive non-systemic JIA and prolongs treatment duration. These findings highlight the potential benefit of a tool to support pediatric rheumatologists, patients and parents in decision making, and can help inform its design.

Paediatric inflammatory multisystem syndrome in Canada: population-based surveillance and role of SARS-CoV-2 linkage.

BACKGROUND: Paediatric inflammatory multisystem syndrome (PIMS) is a rare condition temporally associated with SARS-CoV-2 infection. Using national surveillance data, we compare presenting features and outcomes among children hospitalized with PIMS by SARS-CoV-2 linkage, and identify risk factors for intensive care (ICU). METHODS: Cases were reported to the Canadian Paediatric Surveillance Program by a network of >2800 pediatricians between March 2020 and May 2021. Patients with positive versus negative SARS-CoV-2 linkages were compared, with positive linkage defined as any positive molecular or serologic test or close contact with confirmed COVID-19. ICU risk factors were identified with multivariable modified Poisson regression. RESULTS: We identified 406 children hospitalized with PIMS, including 49.8% with positive SARS-CoV-2 linkages, 26.1% with negative linkages, and 24.1% with unknown linkages. The median age was 5.4 years (IQR 2.5-9.8), 60% were male, and 83% had no comorbidities. Compared to cases with negative linkages, children with positive linkages experienced more cardiac involvement (58.8% vs. 37.4%; p < 0.001), gastrointestinal symptoms (88.6% vs. 63.2%; p < 0.001), and shock (60.9% vs. 16.0%; p < 0.001). Children aged ≥6 years and those with positive linkages were more likely to require ICU. CONCLUSIONS: Although rare, 30% of PIMS hospitalizations required ICU or respiratory/hemodynamic support, particularly those with positive SARS-CoV-2 linkages. IMPACT: We describe 406 children hospitalized with paediatric inflammatory multisystem syndrome (PIMS) using nationwide surveillance data, the largest study of PIMS in Canada to date. Our surveillance case definition of PIMS did not require a history of SARS-CoV-2 exposure, and we therefore describe associations of SARS-CoV-2 linkages on clinical features and outcomes of children with PIMS. Children with positive SARS-CoV-2 linkages were older, had more gastrointestinal and cardiac involvement, and hyperinflammatory laboratory picture. Although PIMS is rare, one-third required admission to intensive care, with the greatest risk amongst those aged ≥6 years and those with a SARS-CoV-2 linkage.

What matters most to pediatric rheumatologists in deciding whether to discontinue biologics in a child with juvenile idiopathic arthritis? A best-worst scaling survey.

OBJECTIVES: Care for JIA patients has been transformed in the biologics era; however, biologics carry important (although rare) risks and are costly. Flares after biological withdrawal are seen frequently, yet there is little clinical guidance to identify which patients in clinical remission can safely have their biologic discontinued (by stopping or tapering). We examined what characteristics of the child or their context are important to pediatric rheumatologists when making the decision to discuss withdrawal of biologics. METHODS: We conducted a survey including a best-worst scaling (BWS) exercise in pediatric rheumatologists who are part of the UCAN CAN-DU network to assess the relative importance of 14 previously identified characteristics. A balanced incomplete block design was used to generate choice tasks. Respondents evaluated 14 choice sets of 5 characteristics of a child with JIA and identified for each set which was the most and least important in the decision to offer withdrawal. Results were analyzed using conditional logit regression. RESULTS: Fifty-one (out of 79) pediatric rheumatologists participated (response rate 65%). The three most important characteristics were how challenging it was to achieve remission, history of established joint damage, and time spent in remission. The three least important characteristics were history of temporomandibular joint involvement, accessibility of biologics, and the patient's age. CONCLUSIONS: These findings give quantitative insight about factors important to pediatric rheumatologists' decision-making about biologic withdrawal. In addition to high quality clinical evidence, further research is needed to understand the perspective of patients and families to inform shared decision-making about biologic withdrawal for JIA patients with clinically inactive disease. Key Points ● What is already known on this topic-there is limited clinical guidance for pediatric rheumatologists in making decisions about biologic withdrawal for patients with juvenile idiopathic arthritis who are in clinical remission. ● What this study adds-this study quantitatively examined what characteristic of the child in clinical remission, or of their context, are most important to pediatric rheumatologists in deciding whether to offer withdrawal of biologics. ● How this study might affect research, practice or policy-understanding of these characteristics can provide useful information to other pediatric rheumatologists in making their decisions, and may guide areas to focus on for future research.

Developing a Framework of Cost Elements of Socioeconomic Burden of Rare Disease: A Scoping Review.

BACKGROUND AND OBJECTIVE: Rare diseases place a significant burden on patients, families, the healthcare system, and society. Evidence on the socioeconomic burden of rare disease is limited and mostly reflects diseases where treatments are available. We developed a framework encompassing recommended cost elements for studies of the socioeconomic burden of rare diseases. METHODS: A scoping review, conducted in five databases (Cochrane Library, EconLit, Embase, MEDLINE, and APA PsycINFO), identified English language publications from 2000 to 2021 presenting frameworks developed for determining, measuring or valuing costs for rare or chronic diseases. Cost elements were extracted and used to develop a literature-informed framework. Structured feedback was gathered from experts in rare diseases, health economics/health services, and policy research to revise the framework. RESULTS: Of 2990 records identified, eight papers were included and informed our preliminary framework; three focused on rare disease and five on chronic disease. Following expert input, we developed a framework consisting of nine cost categories (inpatient, outpatient, community, healthcare products/goods, productivity/education, travel/accommodation, government benefits, family impacts, and other), with several cost elements within each category. Our framework includes unique costs, added from the expert feedback, including genetic testing to inform treatment, use of private laboratories or out-of-country testing, family involvement in foundations and organizations, and advocacy costs for special access programs. CONCLUSIONS: Our work is the first to identify a comprehensive list of cost elements for rare disease for use by researchers and policy makers to fully capture socioeconomic burden. Use of the framework will increase the quality and comparability of future studies. Future work should focus on measuring and valuing these costs through onset, diagnosis, and post-diagnosis.

Association Between HLA-DPB1 and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Children.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients. METHODS: We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population-matched controls). RESULTS: We identified a significant genetic association between pediatric AAV and the HLA-DPB1*04:01 allele (P = 1.5 × 10-8 , odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3-ANCA positivity than in children with myeloperoxidase-ANCA positivity. Among the HLA alleles, the HLA-DPB1*04:01 allele was the most highly associated with AAV, although not significantly, in a follow-up adult AAV cohort (P = 2.6 × 10-4 , OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort. CONCLUSION: The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.

Pharmacological treatment patterns in patients with juvenile idiopathic arthritis in the Netherlands: a real-world data analysis.

OBJECTIVE: To investigate medication prescription patterns among children with JIA, including duration, sequence and reasons for medication discontinuation. METHODS: This study is a single-centre, retrospective analysis of prospective data from the electronic medical records of JIA patients receiving systemic therapy aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype) and medication prescriptions were extracted and analysed using descriptive statistics, Sankey diagrams and Kaplan-Meier survival methods. RESULTS: Over a median of 4.2 years follow-up, the 20 different medicines analysed were prescribed as monotherapy (n = 15) or combination therapy (n = 48 unique combinations) among 236 patients. In non-systemic JIA, synthetic DMARDs were prescribed to almost all patients (99.5%), and always included MTX. In contrast, 43.9% of non-systemic JIA patients received a biologic DMARD (mostly adalimumab or etanercept), ranging from 30.9% for oligoarticular persistent ANA-positive JIA, to 90.9% for polyarticular RF-positive JIA. Among systemic JIA, 91.7% received a biologic DMARD (always including anakinra). When analysing medication prescriptions according to their class, 32.6% involved combination therapy. In 56.8% of patients, subsequent treatment lines were initiated after unsuccessful first-line treatment, resulting in 68 unique sequences. Remission was the most common reason for DMARD discontinuation (44.7%), followed by adverse events (28.9%) and ineffectiveness (22.1%). CONCLUSION: This paper reveals the complexity of pharmacological treatment in JIA, as indicated by: the variety of mono- and combination therapies prescribed, substantial variation in medication prescriptions between subtypes, most patients receiving two or more treatment lines, and the large number of unique treatment sequences.

Tapering of biological treatment in autoinflammatory diseases: a scoping review.

BACKGROUND: Biological treatment and treat-to-target approaches guide the achievement of inactive disease and clinical remission in Autoinflammatory Diseases (AID). However, there is limited evidence addressing optimal tapering strategies and/or discontinuation of biological treatment in AID. This study evaluates available evidence of tapering biological treatment and explores key factors for successful tapering. METHODS: A systematic literature search was conducted in Embase, MEDLINE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials using the OVID platform (1990-08/2020). Bibliographic search of relevant reviews was also performed. Studies/case series (n ≥ 5) in AID patients aged ≤ 18 years with biological treatment providing information on tapering/treatment discontinuation were included. After quality assessment aggregated data were extracted and synthesized. Tapering strategies were explored. RESULTS: A total of 6035 records were identified. Four papers were deemed high quality, all focused on systemic juvenile idiopathic arthritis (sJIA) (1 open-label randomized trial, 2 prospective, 1 retrospective observational study). Biological treatment included anakinra (n = 2), canakinumab (n = 1) and tocilizumab (n = 1). Strategies in anakinra tapering included alternate-day regimen. Canakinumab tapering was performed randomized for dose reduction or interval prolongation, whereas tocilizumab was tapered by interval prolongation. Key factors identified included early start of biological treatment and sustained inactive disease. CONCLUSION: Tapering of biological treatment after sustained inactive disease should be considered. Guidance for optimal strategies is limited. Future studies may leverage therapeutic drug monitoring in combination with pharmacometric modelling to further enhance personalized "taper-to-target" strategies respecting individual patients and diseases aspects.

Factors associated with care- and health-related quality of life of caregivers of children with juvenile idiopathic arthritis.

OBJECTIVE: This study investigates the relationship of child, caregiver, and caring context measurements with the care-related quality of life (CRQoL) and health-related quality of life (HRQoL) of caregivers of children with juvenile idiopathic arthritis (JIA). METHODS: We performed a cross-sectional analysis of baseline data on caregivers of children with JIA from Canada and the Netherlands collected for the "Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases" study from June 2019 to September 2021. We used the CRQoL questionnaire (CarerQoL), adult EQ-5D-5L, and proxy-reported Youth 5-Level version of EuroQoL (EQ-5D-5L-Y) to assess caregiver CRQoL, caregiver HRQoL, and child HRQoL, respectively. We used a multivariate analysis to assess the relationship between both caregiver CRQoL and HRQoL and patient, caregiver, and caring context measurements. RESULTS: A total of 250 caregivers were included in this study. Most of the caregivers were from the Netherlands (n = 178, 71%) and 77% were females (n = 193). The mean CarerQoL scores was 82.7 (standard deviation (SD) 11.4) and the mean EQ-5D-5L utility score was 0.87 (SD 0.16). Child HRQoL and employment had a positive relationship with both caregiver CarerQoL and EQ-5D-5L utility scores (p < 0.05), while receiving paid or unpaid help had a negative relationship with both scores (p < 0.05). CONCLUSION: Our findings indicated that to understand the impact of JIA on families, we need to consider socio-economic factors, such as employment and support to carry caregiving tasks, in addition to child HRQoL.

Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study.

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

Real-world data reveals the complexity of disease modifying anti-rheumatic drug treatment patterns in juvenile idiopathic arthritis: an observational study.

OBJECTIVE: Pharmacological treatment is a cornerstone of care for children with juvenile idiopathic arthritis (JIA). The objective of this study is to evaluate prescription patterns of conventional and biologic disease modifying anti-rheumatic drugs (c-DMARDs and b-DMARDs) for patients with JIA. METHODS: We conducted a retrospective cohort study of children diagnosed with JIA at a rheumatology pediatric clinic. Eligibility criteria were defined as children and youth newly diagnosed with enthesis-related arthritis, polyarticular, or oligoarticular JIA between 2011 and 2019, with at least one year of observation. Data on c-DMARDs and b-DMARDs prescriptions were obtained from electronic medical charts. We used descriptive statistics, Kaplan-Meier survival methods, and Sankey diagrams to describe treatment prescription patterns. RESULTS: A total of 325 patients with JIA were included, with a median observation time of 3.7 years. The most frequently prescribed c-DMARD and b-DMARD were methotrexate and etanercept, respectively. Within the first year of rheumatology care, 62% and 21% of patients had a c-DMARD and a b-DMARD prescribed, respectively. These proportions varied greatly by JIA subtype. Among the 147 (147/325, 45%) patients that had at least one b-DMARD prescribed, 24% were prescribed a second, and 7% a third-line of b-DMARD. A total of 112 unique treatment sequences were observed, with c-DMARD monotherapy followed by the addition of either a b-DMARD (56%) or another c-DMARD (30%) being the two most prevalent patterns in this cohort. CONCLUSION: We observed a variety of treatment trajectories, with many patients experiencing multiple treatment lines, illustrating the complexity of the overall JIA treatment path.

Perspectives of Pediatric Rheumatologists on Initiating and Tapering Biologics in Patients with Juvenile Idiopathic Arthritis: A Formative Qualitative Study.

BACKGROUND: Few studies have examined pediatric rheumatologists' approaches to treatment decision making for biologic therapy for patients with juvenile idiopathic arthritis (JIA). This study presents the qualitative research undertaken to support the development of a Best-Worst Scaling (BWS) survey for tapering in JIA. The study objectives were to (1) describe the treatment decision-making process of pediatric rheumatologists to initiate and taper biologics; and (2) select attributes for a BWS survey. METHODS: Pediatric rheumatologists across Canada were recruited to participate in interviews using purposeful sampling. Interviews were conducted until saturation was achieved. Interview recordings were transcribed verbatim and transcripts were analyzed using deductive thematic analysis. Initial codes were organized into themes and subthemes using an iterative process. Attributes for the BWS survey were developed from these themes and a literature review was conducted in parallel to inform survey development. Further refinement of the attributes was done through consultation with the research team. RESULTS: Five pediatric rheumatologists participated in the interviews. Shared decision making was part of the approach to initiating and tapering biologics in their practice. Tapering approaches differed; some pediatric rheumatologists preferred to stop biologics immediately, while others tapered by reducing dose and/or increasing the dose interval over time. A total of 14 attributes were developed for the BWS. Thirteen attributes were selected from the themes that emerged from the qualitative interviews and one attribute was included after review with the research team. Attributes related to patient characteristics included JIA subtype, time in remission, history or presence of joint damage or erosive disease, how challenging it was to achieve remission, and history of flares. Contextual attributes included accessibility of biologics and willingness to taper biologics. CONCLUSION: This study contributes to the limited literature on pediatric rheumatologists' approaches to treatment decision making for biologics in JIA and identifies attributes that affect the decision to both initiate and taper. Further research is planned to implement the BWS survey to understand the importance of the attributes identified. Additional investigation is required to determine if these characteristics align with patient and parent preferences.

Costs of Hospital-Associated Care for Patients With Juvenile Idiopathic Arthritis in the Dutch Health Care System.

OBJECTIVE: The aim of this study was to quantify costs of hospital-associated care for juvenile idiopathic arthritis (JIA), provide insights in patient-level variation in costs, and investigate costs over time from the moment of JIA diagnosis. Results were reported for all JIA patients in general and by subtype. METHODS: This study was a single-center, retrospective analysis of prospective data from electronic medical records of children with JIA, ages 0-18 years, between April 1, 2011 and March 31, 2019. Patient characteristics (age, sex, JIA subtype) and hospital-based resource use (consultations, medication, radiology procedures, laboratory testing, surgeries, emergency department [ED] visits, hospital stays) were extracted and analyzed. Unit prices were obtained from Dutch reimbursement lists and pharmaceutical and hospital list prices. RESULTS: The analysis included 691 patients. The mean total cost of hospital care was €3,784/patient/year, of which €2,103 (55.6%) was attributable to medication. Other costs involved pediatric rheumatologist visits (€633/patient/year [16.7%]), hospital stays (€439/patient/year [11.6%]), other within-hospital specialist visits (€324/patient/year [8.6%]), radiology procedures (€119/patient/year [3.1%]), laboratory tests (€114/patient/year [3.0%]), surgeries (€46/patient/year [1.2%]), and ED visits (€6/patient/year [0.2%]). Mean annual total costs varied between JIA subtypes and between individuals and were the highest for systemic JIA (€7,772/patient/year). Over the treatment course, costs were the highest in the first month after JIA diagnosis. CONCLUSION: Hospital care costs of JIA vary substantially between individuals, between subtypes, and over the treatment course. The highest annual costs were for systemic JIA, primarily attributable to medication (i.e., biologics). Costs of other hospital-associated care were comparable regardless of subtype.

Colchicine Effectiveness and Safety in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis.

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common fever syndrome in childhood. High disease activity (DA) dramatically impacts the health-related quality of life. Thus, effective and safe treatment is crucial. Colchicine might be effective, but data are still lacking. Study aimed to assess colchicine safety and effectiveness in PFAPA. Methods: This single center study was conducted between 03/2012 and 05/2021 in PFAPA patients without variants in genetic panel testing aged ≤ 18 years fulfilling Marshall criteria and classification criteria of Gattorno et al. Exclusion criteria were elevated liver enzymes, impaired kidney function, celiac disease, lactose intolerance, previous/ongoing biologics, known colchicine-intolerance. Demographics, clinical characteristics, treatment, DA, colchicine effectiveness and safety were recorded at baseline, first and last visit. Colchicine was started at 0.5-1.0 mg/day. DA was captured by physician (PGA) and patient/parent (PPGA) global assessment on a 10 cm visual analog scale, categorized as mild (<2), moderate (2-4), and high (≥5). Adverse event (AE) monitoring included gastrointestinal symptoms, liver enzyme/creatinine elevation, leukopenia, neutropenia. Primary outcome included response (R; composite of PPGA + PGA decrease ≥2) at last follow-up. Secondary outcomes were partial response (PR; PGA decrease = 1 + PPGA decrease ≥1), no response (NR; unchanged/worsened PGA/PPGA), colchicine safety, flare characteristics. Results: Twenty-seven PFAPA patients were included, 52% were female, median age was 5.8 years (1-10.75), median follow-up time was 13 months. At baseline, median PPGA was high; median PGA moderate. All patients had febrile flares. Median flare frequency was every 4-5 weeks; median duration 5-6 days. Nine patients were pre-treated with corticosteroids, increasing flare frequency in 8/9. Primary Outcome: 17 patients (63%) were responders. Secondary outcomes: PR was achieved in 15%; NR in 22% at last follow-up. DA decreased significantly (p <0.0001). At last follow-up, 52% reported no flares, median flare duration decreased to 1-2 days. At first follow-up, 22% reported mild abdominal pain/diarrhea. Moderate abdominal pain/diarrhea occurred with ≥1 mg/day. Mild asymptomatic liver enzyme elevation or leucopenia were rare; no severe AE or colchicine discontinuation were observed. Conclusion: Colchicine seems to be safe, well-tolerated, and effective in PFAPA patients. It can be considered in children with moderate/high DA even those without corticosteroid-benefit.

Colchicine - an effective treatment for children with a clinical diagnosis of autoinflammatory diseases without pathogenic gene variants.

BACKGROUND: Autoinflammatory diseases (AID) are rare chronic conditions with high disease burden, affecting children and adults. Clinically and genetically confirmed, AID can be effectively treated with targeted cytokine inhibition. In contrast, for patients with clinical AID symptoms without pathogenic gene variants, no treatment recommendations are available. Colchicine is approved and established as effective, safe and low-cost first-line therapy in Familial Mediterranean Fever. Up to now, efficacy data for colchicine in children with a clinical AID diagnosis without pathogenic gene variants are rare. This pilot study was performed to evaluate the effectiveness of colchicine in children with a clinical diagnosis of AID without pathogenic gene variants. METHODS: A pilot cohort study of consecutive children with active clinical AID without pathogenic gene variants treated with colchicine monotherapy was performed between 01/2009 and 12/2018. Demographics, clinical and laboratory characteristics were determined serially. Colchicine dosing and safety were documented. Physician estimate of disease activity was captured on visual analogue scales (VAS). PRIMARY OUTCOME: Complete response (PGA ≤2 plus CRP ≤0.5 mg/dL and/or SAA ≤10 mg/L) at last follow-up. SECONDARY OUTCOMES: partial/no response, flare characteristics and requirement for rescue therapies. ANALYSIS: Nonparametric comparison of disease activity measures. RESULTS: A total of 33 children were included; 39% were female. Median age at colchicine start was 3.8 years, median follow-up was 14.1 months. Clinical AID diagnoses included CAPS (24%), FMF (27%), PFAPA (43%) and unclassified AID (6%). At baseline, overall disease activity was moderate (PGA 4), inflammatory markers were elevated (CRP 12.1 mg/dL; SAA 289.2 mg/L), and 97% reported febrile flares. OUTCOME: 55% achieved complete response, 35% showed partial response and 58% had no febrile flares at last follow-up. Inflammatory markers (SAA: p < 0.0001, CRP: p < 0.005) and disease activity (p < 0.0001) decreased significantly. Overall, 93% of children experienced improvement of flare characteristics. CONCLUSION: Colchicine was found to be effective and safe in children with a clinical AID diagnosis in the absence of pathogenic gene variants. Colchicine is a low-cost treatment option for non-organ threatening AID.

Evaluation of Real-World Healthcare Resource Utilization and Associated Costs in Children with Juvenile Idiopathic Arthritis: A Canadian Retrospective Cohort Study.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease, whose multifaceted care path can lead to significant expenditure for the healthcare system. We aim to assess the real-world healthcare resource use (HCRU) and associated cost for children with JIA in a single center in Canada. METHODS: A single-center consecutive cohort of newly diagnosed patients with JIA attending the pediatric rheumatology clinic from 2011 to 2019 was identified using an administrative data algorithm and electronic medical charts. HCRU was estimated from six administrative health databases that included hospital admissions, emergency, outpatient care, practitioners' visits, medication, and laboratory and imaging tests. Costs were assigned using appropriate sources. We reported the yearly overall and JIA-associated HCRU and costs 5 years prior to and 6 years after the first visit to the pediatric rheumatologist. The Zhao and Tian estimator was used to calculate cumulative mean costs over a 6-year timeframe. Results were stratified by disease subtype. RESULTS: A total of 389 patients were identified. The yearly total overall mean costs per patient ranged between $804 and $4460 during the 5 years prior to the first visit to the pediatric rheumatologist and $8529 and $10,651 for the 6 years after. Medication cost, driven by use of biologic therapies, and outpatient visits were the greatest contributor to the total cost. The overall cumulative mean cost for 6 years of care was $48,649 per patient, while the JIA-associated cumulative mean cost was $26,820 per patient. During the first year of rheumatology care, systemic onset JIA had the highest cumulative mean overall cost, while oligoarticular JIA had the lowest cumulative mean cost. CONCLUSION: The care pathway for children with JIA can be expensive, and complex-and varies by JIA subtype. Although the yearly total mean cost per patient was constant, the distribution of costs changes over time with the introduction of biologic therapies later in the care pathway. This study provides a better understanding of the JIA costs profile and can help inform future economic studies.

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis.

OBJECTIVE: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE). METHODS: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement). RESULTS: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided. CONCLUSION: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.