Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

Objective: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations. Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST. Conclusion: We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

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.

Von Willebrand factor antigen as a marker of disease activity in childhood-onset antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Von Willebrand Factor (VWF) antigen plays a role in vascular inflammation and thrombosis, both important in the pathogenesis of Antineutrophil Cytoplasmic Antibody-associated vasculitis (AAV). Previous work found that VWF correlates with disease activity in childhood-onset primary CNS vasculitis. We sought to determine the relationship between VWF and disease activity over time in children with AAV. METHODS: AAV patients with more than one VWF level measured were included in this retrospective stuy, and the relationship between active vasculitis, VWF and other disease measures were analyzed. Generalized estimating equations (GEE) analysis was used to account for repeated VWF measurements within a patient. Repeated measures correlation was used to determine associations of paired laboratory observations. Diagnostic performance was evaluated using receiver operating curve (ROC) analysis. RESULTS: 732 total VWF measurements were collected in 33 AAV patients. VWF antigen levels were higher during active disease (median = 2.03 IU/ml, IQR = [1.35, 2.55]) compared with inactive disease (median = 1.18 IU/ml, IQR = [0.94, 1.53). VWF antigen was the only variable that was significantly associated with active disease (OR 3.01, p< 0.001, 95CI [2.3, 3.93]). The effect of VWF did not show a substantial difference between the disease subtypes. There was a moderate positive correlation between VWF antigen and disease activity, with an acceptable sensitivity and specificity rates. CONCLUSION: Increased VWF antigen levels correlate with active vasculitis in this paediatric-onset AAV cohort and may be used as an additional biomarker in childhood AAV.

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.

What's in a Name? That Which We Call JIA, by Any Other Name, Would It Still Be the Same Childhood Arthritis?

Disease classification remains one of the great debates in rheumatology. The age-old question of being a lumper or a splitter is now complicated by the principles underlying precision health, where the aim is for a solution tailored to each individual, technically making every person unique and their own subgroup. Continuing debate swirls over classification and nomenclature in childhood arthritis. This article will provide an unapologetically Canadian lens to the debate and highlight discussions from the recent Dunlop-Dottridge Lectureship at the 2023 Canadian Rheumatology Association Annual Scientific Meeting.

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.

Mercury increases IL-1ß and IL-18 secretion and intensifies coronary arteritis in an animal model of Kawasaki disease.

Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in young children. Epidemiological data suggest both environmental and genetic factors contribute to the susceptibility and severity of the disease. Mercury (Hg) is a known environmental pollutant and a Ca2+ signaling modulator. Ca2+ signaling regulates the activation of NLRP3 inflammasome. Using the Lactobacillus casei cell wall extract (LCWE) induced coronary arteritis mouse model of KD; we studied the effect of mercury on inflammasome activation and its impact on the immunopathogenesis of KD. Mercury enhances the expression of inflammasome activation resulting in caspase-1 mediated secretion of IL-1ß and IL-18 cytokines. In vivo, the administration of mercury together with disease inducing LCWE exacerbates disease resulting in increased incidence and severity of coronary arteritis compared to LCWE alone. Mercury can act as a novel danger signal modulating Ca2+ signaling to increase IL-1ß and IL-18 secretion and intensifies coronary arteritis in an animal model of KD.

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.

Differentiation of COVID-19-Associated Multisystem Inflammatory Syndrome From Kawasaki Disease With the Use of Cardiac Biomarkers.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) after COVID-19 shares clinical similarities to Kawasaki disease (KD). We sought to determine whether cardiac biomarker levels differentiate MIS-C from KD and their association with cardiac involvement. METHODS: Subjects included 38 MIS-C patients with confirmed prior COVID-19 and 32 prepandemic and 38 contemporaneous KD patients with no evidence of COVID-19. Patient, clinical, echocardiographic, electrocardiographic, and laboratory data timed within 72 hours of cardiac biomarker assessment were abstracted. Groups were compared, and regression analyses were used to determine associations between biomarker levels, diagnosis and cardiac involvement, adjusting for clinical factors. RESULTS: MIS-C patients had fewer KD clinical features, with more frequent shock, intensive care unit admission, inotrope requirement, and ventricular dysfunction, with no difference regarding coronary artery involvement. Multivariable regression analysis showed that both higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (TnI) were associated with MIS-C vs KD, after adjusting for significant covariates. Receiver operating characteristic curves for diagnosis showed that any detectable TnI greater than 10 ng/L was predictive of MIS-C vs KD with 91% sensitivity and 76% specificity. NT-proBNP > 2000 ng/L predicted MIS-C vs KD with 82% sensitivity and 82% specificity. Higher TnI but not NT-proBNP was associated with lower LV ejection fraction. Neither biomarker was associated with coronary artery involvement. CONCLUSIONS: Positive TnI and higher NT-proBNP may differentiate MIS-C from KD, which may become more relevant as evidence of prior COVID-19 becomes more challenging to determine. Cardiac biomarkers may have limited associations with cardiac involvement in this setting.

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.

Evaluating the time-varying risk of hypertension, cardiac events, and mortality following Kawasaki disease diagnosis.

BACKGROUND: This study evaluated the risk of hypertension, major adverse cardiac events (MACE), and all-cause mortality in Kawasaki disease (KD) patients up to young adulthood. METHODS: An inception cohort of 1169 KD patients between 1991 and 2008 from a tertiary-level hospital in Ontario, Canada was linked with health administrative data to ascertain outcomes up to 28 years of follow-up. Their risk was compared with 11,690 matched population comparators. The primary outcome was hypertension and secondary outcomes were MACE and death. RESULTS: After a median follow-up of 20 years [IQR: 8.3], the cumulative incidence of hypertension and MACE in the KD group was 3.8% (95% CI: 2.5-5.5) and 1.2% (95% CI: 0.6-2.4%), respectively. The overall survival probability in the KD group was 98.6% (95% CI: 97.2-99.3%). Relative to comparators, KD patients were at an increased risk for hypertension [aHR: 2.2 (95% CI: 1.5-3.4)], death [aHR: 2.5 (95% CI: 1.3-5.0)], and MACE [aHR: 10.7 (95% CI: 6.4-17.9)]. For hypertension and MACE, the aHR was the highest following diagnosis and then the excess risk diminished after 16 and 13 years of follow-up, respectively. MACE occurred largely in KD patients with coronary aneurysms [cumulative incidence: 12.8%]. CONCLUSIONS: KD patients demonstrated a reassuring cardiac prognosis up to young adulthood with low events and excellent survival. KD patients were at increased risk for hypertension, but this excess risk occurred early and declined with time. IMPACT: With the current standard of care, KD patients demonstrated favorable cardiac prognosis, with low events of hypertension, MACE, and excellent survival. Hypertension and MACE risk appear to be highest around the time of KD diagnosis. MACE occurred primarily in KD patients with coronary aneurysms. Our findings are reassuring to KD patients, families, and their providers. Our study demonstrated an association between KD exposure and hypertension. This association is relatively novel. Previous studies have remained conflicting if KD contributes to long-term atherosclerotic risk.

Disease Recapture Rates After Medication Discontinuation and Flare in Juvenile Idiopathic Arthritis: An Observational Study Within the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: Children with well-controlled juvenile idiopathic arthritis (JIA) frequently experience flares after medication discontinuation, but the outcomes of these flares have not been well described. The objective of this study was to characterize the rates and predictors of disease recapture among children with JIA who restarted medication to treat disease flare. METHODS: Children with JIA who discontinued conventional synthetic or biologic disease-modifying antirheumatic drugs for well-controlled disease but subsequently experienced a flare and restarted medication were identified from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. The primary outcome was inactive disease (ID) (physician global assessment <1 and active joint count = 0) 6 months after flare. RESULTS: A total of 333 patients had complete data for ID at 6 months after flare. The recapture rate for the cohort was 55%, ranging from 47% (persistent oligoarthritis) to 69% (systemic arthritis) (P = 0.4). Approximately 67% of children achieved ID by 12 months. In the multivariable model, history and reinitiation of biologic drugs were associated with increased odds of successful recapture (odds ratio [OR] 4.79 [95% confidence interval (95% CI) 1.22-18.78] and OR 2.74 [95% CI 1.62-4.63], respectively). Number of joints with limited range of motion was associated with decreased odds (OR 0.83 per 1 joint increase [95% CI 0.72-0.95]). CONCLUSION: Approximately half of JIA flares post-discontinuation were recaptured within 6 months, but rates of recapture varied across JIA categories. These findings inform shared decision-making for patients, families, and clinicians regarding the risks and benefits of medication discontinuation. Better understanding of biologic predictors of successful recapture in JIA are needed.

Resource use and disease severity of children hospitalized for COVID-19 versus multisystem inflammatory syndrome in children (MIS-C) in Canada.

Background: Direct comparisons of paediatric hospitalizations for acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. We describe the absolute and relative hospital burden of acute paediatric COVID-19 and MIS-C in Canada. Methods: This national prospective study was conducted via the Canadian Paediatric Surveillance Program from March 2020-May 2021. Children younger than 18 years old and hospitalized for acute COVID-19 or MIS-C were included in the analysis. Outcomes included supplemental oxygen (low-flow oxygen or high-flow nasal cannula), ventilation (non-invasive or conventional mechanical), vasopressors, paediatric intensive care unit (PICU) admission, or death. Adjusted risk differences (aRD) and 95% confidence intervals (CI) were calculated to identify factors associated with each diagnosis. Results: Overall, we identified 330 children hospitalized for acute COVID-19 (including five deaths) and 208 hospitalized for MIS-C (including zero deaths); PICU admission was required for 49.5% of MIS-C hospitalizations versus 18.2% of acute COVID-19 hospitalizations (aRD 20.3; 95% CI, 9.9-30.8). Resource use differed by age, with children younger than one year hospitalized more often for acute COVID-19 (aRD 43.4% versus MIS-C; 95% CI, 37.7-49.1) and more children 5-11 years hospitalized for MIS-C (aRD 38.9% vs. acute COVID-19; 95% CI, 31.0-46.9). Conclusion: While there were more hospitalizations and deaths from acute paediatric COVID-19, MIS-C cases were more severe, requiring more intensive care and vasopressor support. Our findings suggest that both acute COVID-19 and MIS-C should be considered when assessing the overall burden of severe acute respiratory syndrome coronavirus 2 in hospitalized children.

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.

An Update on Childhood-Onset Takayasu Arteritis.

Takayasu Arteritis (TAK) is a rare large vessel vasculitis affecting the aorta and its major branches. The heterogeneous and often severe clinical manifestations result from systemic and local inflammation as well as end-organ ischemia. Disease flares are common and contribute to accrued damage over time with significant morbidity and mortality. Newer understanding of the pathogenesis in TAK has paved the way for the use of pathway targeting agents such as tumor necrosis factor (TNF)α- or interleuking (IL)-6-inhibitors with improved disease control. Nevertheless, long-term data are lacking, particularly in children; prognosis often remains guarded and the disease burden high. This article aims at providing a comprehensive review of childhood-onset TAK with a focus on recent publications.

Gene Expression Profiles of Treatment Response and Non-Response in Children With Juvenile Dermatomyositis.

OBJECTIVE: The study objective was to identify differences in gene expression between treatment responders (TRs) and treatment non-responders (TNRs) diagnosed with juvenile dermatomyositis (JDM). METHODS: Gene expression analyses were performed using whole blood messenger RNA sequencing in patients with JDM (n = 17) and healthy controls (HCs; n = 10). Four analyses were performed (A1-4) comparing differential gene expression and pathways analysis exploiting the timing of sample acquisition and the treatments received to perform these comparative analyses. Analyses were done at diagnosis and follow-up, which averaged 7 months later in the cohort. RESULTS: At diagnosis, the expression of 10 genes differed between TRs and TNRs. Hallmark and canonical pathway analysis revealed 11 and 60 pathways enriched in TRs and 3 and 21 pathways enriched in TNRs, respectively. Pathway enrichment at diagnosis in TRs was strongest in pathways involved in metabolism, complement activation, and cell signaling as mediated by IL-8, p38/microtubule associated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK), Phosphatidylinositol 3 Kinase Gamma (PI3Kγ), and the B cell receptor. Follow-up hallmark and canonical pathway analysis showed that 2 and 14 pathways were enriched in TRs, whereas 24 and 123 pathways were enriched in treatment TNRs, respectively. Prior treatment with glucocorticoids significantly altered expression of 13 genes in the analysis of subjects at diagnosis with JDM as compared with HCs. CONCLUSION: Numerous genes and pathways differ between TRs and TNRs at diagnosis and follow-up. Prior treatment with glucocorticoids prior to specimen acquisition had a small effect on the performed analyses.