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Childhood-onset Takayasu arteritis (TA) is a rare, heterogeneous disease with limited diagnostic markers. Our objective was to identify and classify all candidates for biomarkers of TA diagnosis in children reported in the literature. A systematic literature review (PRISMA) of MEDLINE, EMBASE, Wiley Cochrane Library, ClinicalTrias.gov, and WHO ICTRP for articles related to TA in the pediatric age group between January 2000 and August 2023 was performed. Data on demographics, clinical features, laboratory measurements, diagnostic imaging, and genetic analysis were extracted. We identified 2026 potential articles, of which 52 studies (81% case series) met inclusion criteria. A total of 1067 TA patients were included with a peak onset between 10 and 15 years. Childhood-onset TA predominantly presented with cardiovascular, constitutional, and neurological symptoms. Laboratory parameters exhibited a low sensitivity and specificity. Imaging predominantly revealed involvement of the abdominal aorta and renal arteries, with magnetic resonance angiography (MRA) being the preferred imaging modality. Our review confirms the heterogeneous presentation of childhood-onset TA, posing significant challenges to recognition and timely diagnosis. Collaborative, multinational efforts are essential to better understand the natural course of childhood-onset TA and to identify accurate biomarkers to enhance diagnosis and disease management, ultimately improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Juvenile idiopathic arthritis (JIA) is a chronic illness with a high risk of developing long-term disability. Disease activity is currently being monitored and quantified by ACR core set. Here, joint inflammation is determined; however joint function is the crucial component for developing disability. The aim of this study was to quantify and compare dynamic joint function in healthy and arthritic knee joints and to evaluate response to improvement. Methods: A single center cohort study of consecutive children presenting to the rheumatology outpatient clinic was performed to measure dynamic knee joint function. Serial measures were performed if possible. Splint fixed electrogoniometers were used to measure dynamic knee joint function including ROM and flexion and extension torque. Results: A total of 54 children were tested including 44 with JIA, of whom eight had to be excluded for non-JIA-related knee problems. The study included 36 JIA patients of whom eight had strictly unilateral knee arthritis, and nine controls. Dynamic joint function ROM and torque depended on age and bodyweight, as demonstrated in healthy joints. ROM and torques were significant lower in arthritic compared to unaffected knee joints in children with unilateral arthritis and across the cohort. Importantly, extension torque was the most sensitive marker of impaired joint function. Follow up measurements detected responsiveness to change in disease activity. Conclusions: Measuring dynamic joint function with electrogoniometers is feasible and objective. Active ROM and torque during flexion and extension of arthritic knee joints were significant lower compared to unaffected. In dynamic joint measurement extension torque is a sensitive marker for disease activity. [ABSTRACT FROM AUTHOR]

Inflammatory brain diseases (IBrainDs) are a leading cause of devastating neurological deficits or neuropsychiatric syndromes in previously healthy children. The spectrum is expanding rapidly and new disease entities have been discovered in the last decade. IBrainD can occur as a primary disease or may occur secondary to an underlying cause. This review focuses on the clinical presentation, diagnostic features, pathology and histology characteristics and treatment of the primary childhood IBrainDs. [ABSTRACT FROM PUBLISHER]

Children and adults who present with severe, newly acquired neurological or psychiatric deficits should be evaluated for an underlying inflammatory brain disease--the inflammation could be reversible, if diagnosed and treated rapidly. In our experience, primary angiitis of the central nervous system (PACNS) is the most common inflammatory brain disease and is increasingly recognized across patients of all ages. Distinct disease subtypes have been reported with characteristic disease courses, neuroimaging features and histopathological findings. In this Review, we provide a comprehensive comparison of childhood and adult PACNS, revealing distinct gender distributions, characteristic presenting clinical phenotypes and tailored differential diagnosis evaluations in the different subtypes of PACNS. Novel and traditional laboratory markers can help to define disease subtype and activity, whilst MRI and angiography can aid diagnosis in both children and adults. Characteristic patterns of parenchymal lesions and vessel involvement have been identified in PACNS and differ markedly between subtypes. Brain histopathology has also revealed distinct inflammatory pathways at different ages. Immunosuppressive treatment protocols have been shown to be effective and safe across the age spectrum; overall, in the past few years, the mortality of PACNS has decreased dramatically. [ABSTRACT FROM AUTHOR]

Objectives: Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children. It can cause joint pain and permanent physical damage, which affects mobility and daily activities. The EQ-5D-Y-3L self-report version has been validated in JIA, but the validity of EQ-5D-Y-5L remains unknown. We examined the psychometric properties of the EQ-5D-Y-5L parent-proxy version among children with JIA. Methods: We used data from the Understanding Childhood Arthritis Network Canadian-Dutch collaboration study cohort, including patients with new-onset JIA, and those starting or stopping biologics. Clinical data and the parent-proxy version of the childhood health assessment questionnaire (CHAQ) and EQ-5D-Y-5L were collected. We evaluated the ceiling and floor effect; convergent and divergent validity using Spearman's rank correlation; known-group validity using one-way ANOVA (Analysis of Variance) and effect size; and informativity using Shannon's evenness index. Results: 467 patient visits representing 407 patients were analyzed. The EQ-5D-Y-5L had no ceiling/floor effect. The EQ-5D-Y-5L showed good convergent (e.g., EQ-5D-Y-5L pain/discomfort dimension vs. CHAQ pain index (Spearman's r = 0.74, 95% confidence interval (C.I.): 0.69–0.79)), divergent (e.g., EQ-5D-Y-5L pain/discomfort dimension vs. CHAQ eating dimension (Spearman's r = 0.19, 95% C.I.: 0.09–0.29)) and known-group validity (e.g., mean EQ-5D-Y-5L level summary score for patients with inactive versus active disease status, 6.34 vs. 10.52 (p < 0.001, effect size = 1.20 (95% C.I.: 0.95–1.45)). Shannon's evenness index ranged from 0.52 to 0.88, suggesting most dimensions had relatively even distributions. Conclusions: In this patient sample, EQ-5D-Y-5L parent-proxy version exhibited construct validity and informativity, suggesting the EQ-5D-Y-5L can be used to measure the quality of life of children with JIA. Plain English summary: Juvenile idiopathic arthritis is the most common type of arthritis affecting children. It can cause pain and permanent physical damage to joints and affects mobility and daily activities. While there is no cure yet, new therapies like biologics are effective. However, biologics are expensive and can have side effects. To decide when is the best time to use these biologics, we need to understand their cost and impact on patients. EQ-5D-Y-5L is a common tool to measure how the disease affects a patient's life. It is unclear whether EQ-5D-Y-5L works well for patients with juvenile idiopathic arthritis. In this study, we compared the EQ-5D-Y-5L to another tool that measures how the illness impacts functional ability. We looked to see if the EQ-5D-Y-5L could tell the difference between children who were more or less sick. We also assessed whether the EQ-5D-Y-5L has the ability to describe patients with different severity in health status. This study indicates that the EQ-5D-Y-5L is a good tool to measure the health of patients with juvenile idiopathic arthritis. Findings from this study support the use of the EQ-5D-Y-5L among this patient population in future clinical trials and research studies. [ABSTRACT FROM AUTHOR]

Objective To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNF-α inhibitors (TNFi) in JIA patients. Methods This was a retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were 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, hospitalization) 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 €9165/patient on active treatment (pre-withdrawal) and decreased significantly to €5063/patient (−44.8%) and €6569/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, €1180/patient, and €1320/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 were 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 withdrawal decisions, future research should assess the full long-term societal cost impacts, and include all biologics. [ABSTRACT FROM AUTHOR]

Objective To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing 2005–2010 and 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 good health-related quality of life (≥9/10). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Childhood primary angiitis of the central nervous system: identifying disease trajectories and early risk factors for persistently higher disease activity," in the May 2012 issue.

The article offers views on central nervous system (CNS) vasculitis in children. According to the authors, CNS vasculitis is a treatable and reversible inflammation of the blood vessels when treated with immunosuppresants. They believe diagnosis of CNS vasculitis remains a challenge because of a dearth of specific, clinical, laboratory and neuroimaging markers. They add that children with large-to-medium CNS vasculitis have a better neurological outcome when treated with immunosuppressants.

Background: Intracranial arteriopathies are frequent causes of pediatric stroke and important risk factors for stroke recurrence. Without tissue diagnosis, vascular imaging is relied upon to identify the underlying etiology and prognosis. We hypothesized that children with unilateral intracranial arteriopathy with lenticulostriate collaterals would demonstrate distinct vascular outcomes compared with children without collaterals.Methods: We retrospectively identified children with unilateral intracranial arteriopathy from two institutions. Two blinded raters from each institution reviewed magnetic resonance or digital subtraction angiography at baseline and ≥12 months. Patients were grouped according to presence or absence of lenticulostriate collaterals. Clinical features and vascular imaging outcomes were compared using univariate analysis and multivariate logistic regression.Results: Forty-four children were included: 22 males, median age 8.2 years (range two to 16.9 years), and further stratified into the collateral group (n = 20) and non-collateral group (n = 24), with median follow-up of 25.5 months and 23 months, respectively. Both groups demonstrated similar rates of progression on vascular imaging at ≥12 months, 50% in the collateral group versus 37.5% in the non-collateral group (P > 0.05). The collateral group was associated with asymptomatic clinical presentation, normal brain MRI, border zone infarcts, and either vascular stabilization or new contralateral disease. The non-collateral group demonstrated either vascular improvement or discordant progression (combination of improved and progressive lesions). Using a multivariate model, collaterals continued to be an independent predictor of vascular outcome.Conclusions: This study suggests that lenticulostriate collaterals in children with unilateral intracranial arteriopathy may serve as a useful neuroimaging biomarker that helps to stratify patients with distinct clinical features and patterns of vascular evolution. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Treatment preferences in juvenile idiopathic arthritis: A comparative analysis in two health care systems," by Boris Hugle and Susanne M. Benseler is presented.

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. [ABSTRACT FROM AUTHOR]

Background: Arterial vessel wall dissection is a rare, life-threatening and rarely described complication in childhood Takayasu Arteritis (cTA). Prevalence and risk factors for arterial dissection in cTA are unknown. We sought to study the prevalence and analyse risk factors for arterial dissection in cTA. Findings: A single center retrospective review of all children with cTA was performed. Patients with arterial dissection at cTA diagnosis were reported in detail and compared to the remaining single center retrospective cohort of children without dissection. Disease activity was assessed by the Pediatric Vasculitis Disease Activity Score (PVAS). A total of 27 cTA patients (74% girls) were included. Three children (11%) presented with dissection at diagnosis of cTA. They had higher PVAS (median 21 versus 10, p = 0.26), increased neutrophils (p < 0.0001) and lower albumin levels (p = 0.05). Arterial hypertension was common in both groups: in 67% of children with dissection and 54% of those without. Conclusions: Arterial dissection was more frequent in our cTA cohort than previously reported. Careful vascular imaging assessment is crucial to document this complication. High disease activity and markers of inflammation especially in combination with arterial hypertension, may be associated with the risk for vessel wall dissection in children with cTA. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to develop consensus‐based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile infection‐related epilepsy syndrome (FIRES) based on best evidence and experience. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article. Significance: This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research. [ABSTRACT FROM AUTHOR]

Objective: To develop consensus‐based recommendations for the management of adult and pediatric patients with new‐onset refractory status epilepticus (NORSE)/febrile infection‐related epilepsy syndrome (FIRES) based on best available evidence and expert opinion. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated that were then voted on using a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was greater than or equal to 7, and inappropriate if the median score was less than or equal to 3. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the post‐acute phase; and (5) research, registries, and future directions in NORSE/FIRES. These are summarized in this article along with two practical clinical flowsheets: one for diagnosis and evaluation and one for acute treatment. A corresponding evidence‐based analysis of all 85 recommendations alongside responses by the Delphi panel is presented in a companion article. Significance: The recommendations generated by this consensus can be used as a guide for the diagnosis; evaluation; and management of patients with NORSE/FIRES; and for planning of future research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood, with many children requiring immunomodulatory therapies for many years following diagnosis. A considerable proportion of children experience therapeutic inefficacy or substantial adverse effects, or both, but a lack of reliable clinical indicators and biomarkers to predict treatment response prevents optimization of existing therapies. The identification of valid candidate gene variants involved in the pathways of methotrexate and etanercept, the most commonly used medications in JIA, has seen little success to date. The limited success of these studies is possibly due to the presence of confounding variables in the study populations, the heterogeneity of outcome parameters used to determine treatment response and the small number of candidate gene variants analysed. The first genome-wide pharmacogenetic study in JIA has identified gene regions of particular biological interest, but these findings require validation. Moreover, epigenetic mechanisms as well as ontogeny processes might be additional factors influencing drug responses. Access to large, well-documented JIA cohorts and the rapid development of advanced genome analytics is ushering in a personalized approach to treatment. The discovery of new pharmacogenomic biomarkers and systems pathways can provide new drug targets and predictive tools for improved drug response and fewer adverse drug reactions in JIA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Variations in the treatment of juvenile idiopathic arthritis (JIA) may impact on quality of care. The objective of this study was to identify and compare treatment approaches for JIA in two health care systems. Methods: Paediatric rheumatologists in Canada (n=58) and Germany/Austria (n=172) were surveyed by email, using case-based vignettes for oligoarticular and seronegative polyarticular JIA. Data were analysed using descriptive statistics; responses were compared using univariate analysis. Results: Total response rate was 63%. Physicians were comparable by age, level of training and duration of practice, with more Canadians based in academic centres. For initial treatment of oligoarthritis, only approximately half of physicians in both groups used intra-articular steroids. German physicians were more likely to institute DMARD treatment in oligoarthritis refractory to NSAID (p<0.001). Canadian physicians were more likely to switch to a different DMARD rather than a biologic agent in polyarthritis refractory to initial DMARD therapy. For oligoarthritis and polyarthritis, respectively, 86% and 90% of German physicians preferred regular physiotherapy over home exercise, compared to 14% and 15% in Canada. Except for a Canadian preference for naproxen in oligoarthritis, no significant differences were found for NSAID, intra-articular steroid preparations, initial DMARD and initial biologic treatment. Conclusions: Treatment of oligo- and polyarticular JIA with DMARD is mostly uniform, with availability and funding obviously influencing physician choice. Usage of intra-articular steroids is variable within physician groups. Physiotherapy has a fundamentally different role in the two health care systems. [ABSTRACT FROM AUTHOR]

Central nervous system vasculitis is an increasingly recognized inflammatory brain disease causing devastating neurological deficits and psychiatric manifestations in previously healthy children. Primary central nervous system vasculitis represents an isolated inflammatory attack targeting the cerebral vessels. In contrast, in children with secondary central nervous system vasculitis, an underlying condition can be identified. The spectrum of childhood primary and secondary central nervous system vasculitis is rapidly expanding, as is the differential diagnosis including nonvasculitic inflammatory brain diseases and noninflammatory vasculopathies. Early recognition, rapid diagnostic evaluation, and initiation of treatment have led to improved morbidity and mortality. This review focuses on clinical, laboratory, and neuroimaging characteristics of the distinct subtypes of primary childhood central nervous system vasculitis, reports the etiology of secondary central nervous system vasculitis, provides an overview of the differential diagnosis, and reviews the current approaches in treatment. [ABSTRACT FROM AUTHOR]

Objectives. To determine and compare the prevalence of disturbed sleep in JIA and JDM and the relationship of sleep disturbance to pain, function, disease activity and medications.Methods. One hundred fifty-five patients (115 JIA, 40 JDM) were randomly sampled and were mailed questionnaires. Sleep disturbance was assessed by the sleep self-report (SSR) and the children's sleep habits questionnaire (CSHQ). Fatigue, pain and function were assessed by the paediatric quality of life inventory (PedsQL) and disease activity by visual analogue scales (VASs). Joint counts were self-reported.Results. Eighty-one per cent responded, of whom 44% reported disturbed sleep (CSHQ > 41); there were no differences between disease groups. Poor reported sleep (SSR) was highly correlated with PedsQL fatigue (r = 0.56, P < 0.0001). Fatigue was highly negatively correlated with quality of life (r = −0.77, P < 0.0001). The worst pain intensity in the last week was correlated to sleep disturbance (r = 0.32, P = 0.0005). Fatigue was associated with prednisone and DMARD use.Conclusions. Sleep disturbance and fatigue are prevalent among children with different rheumatic diseases. Sleep disturbance and fatigue are strongly associated with increased pain and decreased quality of life. Strategies aimed at improving sleep and reducing fatigue should be studied as possible ways of improving quality of life for children with rheumatic illness. [ABSTRACT FROM PUBLISHER]

We sought to determine whether differences exist in the factors associated with transient coronary artery (CA) dilation only compared to CA aneurysms after Kawasaki disease (KD). We reviewed all patients with KD assessed and treated at a single tertiary institution from January 1990 to April 2007. Of 1,374 patients (63% men) with KD, 1,108 (81%) had no CA abnormalities; 180 (13%) had CA dilation only, and 86 (6%) had CA aneurysms. The factors associated with any CA abnormality included male gender (odds ratio [OR] 1.8, p <0.001), lower albumin (OR per 1 g/dl, 1.07; p < 0.001), lower hemoglobin (OR per 10 g/dl; 1.02, p = 0.008), diagnosed outside of the 1 to 9-year-age range (OR for <1 year old, 1.5; p = 0.04; OR for >9 years old, 1.9, p = 0.03), longer duration of fever before treatment (OR per day, 1.05, p = 0.002), greater platelet count (OR per 10 × 109/L, 1.14, p = 0.008), and nonresponse to initial intravenous immunoglobulin treatment (OR 2.4, p <0.001). Only age at diagnosis, duration of fever before treatment, greater platelet count, and nonresponse to initial intravenous immunoglobulin discriminated between CA dilation only versus CA aneurysms (c-statistic, 0.80, p <0.001). In conclusion, CA dilation only and CA aneurysms differ only in the total duration of inflammation, as measured by the number of days from fever onset to defervescence. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) patterns in children with juvenile idiopathic arthritis (JIA) over time are not well described. The aim of this study was to describe associations of physical activity (PA) with disease activity, function, pain, and psychosocial stress in the 2 years following diagnosis in an inception cohort of children with juvenile idiopathic arthritis (JIA). Methods: In 82 children with newly diagnosed JIA, PA levels, prospectively determined at enrollment, 12 and 24 months using the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) raw scores, were evaluated in relation to disease activity as reflected by arthritis activity (Juvenile Arthritis Disease Activity Score (JADAS-71)), function, pain, and psychosocial stresses using a linear mixed model approach. Results in the JIA cohort were compared to normative Pediatric Bone Mineral Accrual Study data derived from healthy children using z-scores. Results: At enrollment, PA z-score levels of study participants were lower than those in the normative population (median z-score − 0.356; p = 0.005). At enrollment, PA raw scores were negatively associated with the psychosocial domain of the Juvenile Arthritis Quality of Life Questionnaire (r = − 0.251; p = 0.023). There was a significant decline in PAQ-C/A raw scores from baseline (median and IQR: 2.6, 1.4–3.1) to 24 months (median and IQR: 2.1, 1.4–2.7; p = 0.003). The linear mixed-effect model showed that PAQ-C/A raw scores in children with JIA decreased as age, disease duration, and ESR increased. The PAQ-C/A raw scores of the participants was also negatively influenced by an increase in disease activity as measured by the JADAS-71 (p < 0.001). Conclusion: Canadian children with newly diagnosed JIA have lower PA levels than healthy children. The decline in PA levels over time was associated with disease activity and higher disease-specific psychosocial stress. [ABSTRACT FROM AUTHOR]

Background: Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies. Methods: The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice. Results: The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS. Conclusions: The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical features, efficacy and safety of treatment regimens, and outcomes of childhood‐ and adult‐onset Takayasu arteritis (TAK). Methods: The study was designed as a retrospective cohort study comparing patients with childhood‐onset TAK (from 1986 onward) to patients with adult‐onset TAK (from 1988 onward) who were followed up until 2014 or 2015 at 4 centers in Ontario, Canada. Demographic, clinical, laboratory, and angiographic features, treatment regimens, and outcomes were recorded throughout the course of the disease. Disease activity and damage scores were completed retrospectively. Results: Twenty‐nine children and 48 adults (median age at diagnosis 12.1 years and 31.2 years, respectively) were included. A lower predominance of females was observed among the childhood‐onset TAK cohort (76% versus 100% of patients with adult‐onset TAK; P < 0.01), and children had a shorter delay to diagnosis (median 6.0 months versus 12.2 months for adults; P = 0.03). The distribution of vascular involvement was also different, with children having significantly more aortic and renal artery involvement and a higher frequency of arterial hypertension. Relapses in the first year after diagnosis were common both in children (39%) and in adults (28%). Two children, but no adults, died. Conclusion: Childhood‐onset TAK has a lower female predominance and a higher frequency of aortic and renal involvement compared to adult‐onset TAK. Relapses and disease burden were high in both groups, corroborating the need for careful monitoring of disease activity and aggressive therapeutic management. [ABSTRACT FROM AUTHOR]

Objective To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. Results In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Conclusion Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding. [ABSTRACT FROM AUTHOR]

Objective. Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases char-acterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. Methods. A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. Results. A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). Conclusion. Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS. [ABSTRACT FROM AUTHOR]

Background: Muckle-Wells-syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. Methods: A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. Results: A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5-4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. Conclusions: Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response. [ABSTRACT FROM AUTHOR]

Anti–glutamic acid decarboxylase directed antibodies are a rare cause of autoimmune limbic encephalitis that is relatively resistant to immunotherapy. Here we report a 15-year-old boy with nonparaneoplastic, anti–glutamic acid decarboxylase limbic encephalitis presenting with subacute headache, memory disturbance, psychiatric symptoms, and seizures. At onset, his memory disturbance manifested as transient global amnesia-like episodes. Clinical remission was achieved with rituximab, intravenous immunoglobulin, and corticosteroids. [ABSTRACT FROM PUBLISHER]

Objective To identify distinct clusters of children with inflammatory brain diseases based on clinical, laboratory, and imaging features at presentation, to assess which features contribute strongly to the development of clusters, and to compare additional features between the identified clusters. Methods A single-center cohort study was performed with children who had been diagnosed as having an inflammatory brain disease between June 1, 1989 and December 31, 2010. Demographic, clinical, laboratory, neuroimaging, and histologic data at diagnosis were collected. K-means cluster analysis was performed to identify clusters of patients based on their presenting features. Associations between the clusters and patient variables, such as diagnoses, were determined. Results A total of 147 children (50% female; median age 8.8 years) were identified: 105 with primary central nervous system (CNS) vasculitis, 11 with secondary CNS vasculitis, 8 with neuronal antibody syndromes, 6 with postinfectious syndromes, and 17 with other inflammatory brain diseases. Three distinct clusters were identified. Paresis and speech deficits were the most common presenting features in cluster 1. Children in cluster 2 were likely to present with behavior changes, cognitive dysfunction, and seizures, while those in cluster 3 experienced ataxia, vision abnormalities, and seizures. Lesions seen on T2/fluid-attenuated inversion recovery sequences of magnetic resonance imaging were common in all clusters, but unilateral ischemic lesions were more prominent in cluster 1. The clusters were associated with specific diagnoses and diagnostic test results. Conclusion Children with inflammatory brain diseases presented with distinct phenotypical patterns that are associated with specific diagnoses. This information may inform the development of a diagnostic classification of childhood inflammatory brain diseases and suggest that specific pathways of diagnostic evaluation are warranted. [ABSTRACT FROM AUTHOR]

Objective Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin-1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes. Methods A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype-specific risk of progression of hearing loss was determined. Results A total of 33 patients ages 3-75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss. Conclusion Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions. [ABSTRACT FROM AUTHOR]

Summary: Background: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome. Methods: In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution. Results: We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months, range 4–186): 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0–2) than those who did not (odds ratio [OR] 2·69, CI 1·24–5·80; p=0·012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0–2; median 6 months, IQR 2–12) and 30 died. At 24 months’ follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0·62, 0·50–0·76; p<0·0001) and no admission to an intensive care unit (0·12, 0·06–0·22; p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46 (67%) of 69 relapses were less severe than initial episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort. Interpretation: Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. Funding: The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundació la Marató de TV3. [Copyright &y& Elsevier]

Objective. The main objective was to develop a trajectory for von Willebrand factor (vWF) antigen in childhood primary CNS vasculitis (cPACNS) after treatment and compare this with disease activity and other inflammatory markers.Methods. A single-centre cohort study of consecutive children diagnosed with cPACNS was performed. Demographic, clinical, laboratory, imaging and histological data were collected at diagnosis and during standardized clinic visits. Outcome measures included disease activity measured by physician global assessment and serial measures of vWF antigen. Analysis included descriptive statistics and parametric methods.Results. The study cohort consisted of 39 children diagnosed with cPACNS: 25 with angiography-negative cPACNS and 14 with angiography-positive disease. Twenty-one patients were female, median age at diagnosis was 9.8 years, and median follow-up was 18 months. All patients presented with neurological deficits. Disease activity and neurological outcome improved significantly during follow-up. vWF antigen levels were increased at diagnosis in 65% of children with cPACNS and were decreased significantly after treatment. In contrast, levels of CRP and ESR fluctuated over time. Higher vWF antigen levels at diagnosis were associated with lower measures of disease activity at 12 months.Conclusion. In our study, all children with cPACNS improved over time. Changes in CRP and ESR, other laboratory tests, and MRI did not consistently reflect altered disease activity. However, vWF antigen may help clinicians to identify changes in disease activity during follow-up and predict treatment response. Controlled studies are necessary to evaluate the sensitivity and specificity of vWF antigen as a biomarker of disease activity. [ABSTRACT FROM PUBLISHER]

Children and adults who present with severe, newly acquired neurological or psychiatric deficits should be evaluated for an underlying inflammatory brain disease-the inflammation could be reversible, if diagnosed and treated rapidly. In our experience, primary angiitis of the central nervous system (PACNS) is the most common inflammatory brain disease and is increasingly recognized across patients of all ages. Distinct disease subtypes have been reported with characteristic disease courses, neuroimaging features and histopathological findings. In this Review, we provide a comprehensive comparison of childhood and adult PACNS, revealing distinct gender distributions, characteristic presenting clinical phenotypes and tailored differential diagnosis evaluations in the different subtypes of PACNS. Novel and traditional laboratory markers can help to define disease subtype and activity, whilst MRI and angiography can aid diagnosis in both children and adults. Characteristic patterns of parenchymal lesions and vessel involvement have been identified in PACNS and differ markedly between subtypes. Brain histopathology has also revealed distinct inflammatory pathways at different ages. Immunosuppressive treatment protocols have been shown to be effective and safe across the age spectrum; overall, in the past few years, the mortality of PACNS has decreased dramatically. [ABSTRACT FROM AUTHOR]

Objective Anti- N-methyl- D-aspartate receptor (anti-NMDAR) encephalitis is a newly recognized antineuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurologic deficits in previously healthy children. The present study was undertaken to describe characteristic clinical features and outcomes in children diagnosed as having anti-NMDAR encephalitis. Methods Consecutive children presenting over a 12-month period with newly acquired psychiatric and/or neurologic deficits consistent with anti-NMDAR encephalitis and evidence of central nervous system (CNS) inflammation were screened. Children were included in the study if they had confirmatory evidence of anti-NMDAR antibodies in the serum and/or cerebrospinal fluid. Features at clinical presentation and results of investigations were recorded. Type and duration of treatment and outcomes at last followup were documented. Results Seven children were screened, and 3 children with anti-NMDAR encephalitis were identified. All patients presented with neurologic and/or psychiatric abnormalities, seizures, speech disorder, sleep disturbance, and fluctuating level of consciousness. The 2 older patients had more prominent psychiatric features, while the younger child had significant autonomic instability and prominent involuntary movement disorder. None had an underlying tumor. Immunosuppressive therapy resulted in near or complete recovery; however, 2 of the patients had early relapse necessitating re-treatment. Conclusion Anti-NMDAR encephalitis is an important cause of neuropsychiatric deficits in children, which must be included in the differential diagnosis of CNS vasculitis and other inflammatory brain diseases. Early diagnosis and treatment are essential for neurologic recovery. [ABSTRACT FROM AUTHOR]

The article presents information on a study which determined the clinical and laboratory features of Muckle-Wells syndrome (MWS), an inherited autoinflammatory disease, contrasted genetically defined subcohorts, and identified risk factors for severe MWS. A review of the related literature is presented. Variables examined included MWS Disease Activity Score (MWS-DAS), inflammation markers and cytokine levels. It discusses the findings of the study. It observes that women patients with hearing loss are more susceptible at manifesting severe MWS.

Objective:: Primary angiitis of the central nervous system in childhood (cPACNS) is an immune-mediated inflammatory process directed toward blood vessels in the central nervous system. It has been associated with variable clinical and radiological presentations, and devastating consequences without treatment. Brain biopsy is required for definitive diagnosis. The objective of this study was to characterize the clinical and histopathological features of brain biopsies in small-vessel cPACNS (SVcPACNS). Methods:: A single-center prospective cohort study of children diagnosed with cPACNS from 1998 to 2008 was performed. All patients with negative cerebral angiography and brain biopsy were included. Patient data were reviewed for clinical, laboratory, and radiological characteristics at presentation. Standardized brain biopsy review protocols were established, with independent analysis by 2 neuropathologists. Histopathology was correlated with collected clinical data. Results:: A total of 13 SVcPACNS patients were included. Ages ranged from 5 to 17 years. Presenting features included seizures (85%), headache (62%), and cognitive decline (54%). Brain biopsy confirmed SVcPACNS in 11 patients with intramural lymphocytic infiltrate. Two had nonspecific perivascular inflammation only. All 6 nonlesional biopsies yielded a diagnosis of SVcPACNS. Lack of specific histological features correlated with prolonged time to biopsy, prior steroid treatment, and inadequate specimen sampling. Interpretation:: In children presenting with new onset severe headaches, seizures, or cognitive decline, SVcPACNS and brain biopsy should be considered. Lesional biopsies are preferred; however, nonlesional biopsies may succeed in yielding the diagnosis. Steroid treatment prior to biopsy and inadequate biopsy sampling may obscure the diagnosis in true cases of SVcPACNS. ANN NEUROL 2010;68:602-610 [ABSTRACT FROM AUTHOR]