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Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

Competing Interests: CC is funded by a grant from the National Institute of Health Research. KB is supported by the Czech Ministry of Health (DRO FNOl, 00098892). The other authors declare no competing interests.

Background: The safety and efficacy of mycophenolate mofetil (MMF) for lupus nephritis (LN) treatment is established in adults and in some children. MMF is rapidly converted to the biologically active metabolite mycophenolic acid (MPA) whose pharmacokinetics (PK) is characterized by large inter- and intra-individual variability., Methods/design: This randomized, double-blind, active comparator, controlled clinical trial of pediatric subjects with proliferative LN compares pharmacokinetically-guided precision-dosing of MMF (MMF PK , i.e. the dose is adjusted to the target area under the concentration-time curve (AUC 0-12h ) of MPA ≥ 60-70 mg*h/L) and MMF dosed per body surface area (MMF BSA , i.e. MMF dosed 600 mg/m 2 body surface area), with MMF dosage taken about 12 hours apart. At baseline, subjects are randomized 1:1 to receive blinded treatment with MMF PK or MMF BSA for up to 53 weeks. The primary outcome is partial clinical remission of LN (partial renal response, PRR) at week 26, and the major secondary outcome is complete renal response (CRR) at week 26. Subjects in the MMF BSA arm with PRR at week 26 will receive MMF PK from week 26 onwards, while subjects with CRR will continue MMF BSA or MMF PK treatment until week 53. Subjects who achieve PRR at week 26 are discontinued from study intervention., Discussion: The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) study will provide a thorough evaluation of the PK of MMF in pediatric LN patients, yielding a head-to-head comparison of MMF BSA and MMF PK for both safety and efficacy. This study has the potential to change current treatment recommendations for pediatric LN, thereby significantly impacting childhood-onset SLE (cSLE) disease prognosis and current clinical practice.

Background: Given the impact of psychological factors on rheumatic disease, pediatric psychologists serve a vital role in promoting quality of life and managing common problems among youth with rheumatic disease. The aim of this project was to increase access to psychological services among youth with rheumatic disease at a children's hospital., Methods: A quality improvement (QI) team identified key drivers and interventions aimed to increase access to psychological services for youth with rheumatic disease. Data was collected for a 6-month baseline period and 4-year intervention period. We applied the Plan-Do-Study Act method of QI and the American Society for Quality criteria to adjust the center line and control limits., Results: There were two statistically significant center line shifts in the number of patients seen by psychology and one statistically significant shift in referrals to psychology over time with applied stepwise interventions. Patients seen by a psychologist increased by 3,173% from a baseline average of 1.8 to 59.9 patients seen per month (p < 0.03). Psychology referrals increased by 48% from a baseline average of 9.85 to 14.58 referrals per month over the intervention period (p < .01)., Conclusions: Youth with rheumatic disease received increased access to mental health treatment when psychological services were imbedded within rheumatology care. Psychology referrals also increased significantly, suggesting that psychology integration within a medical clinic can increase identification of needs. Results suggest that psychology integration into rheumatology care may increase access to mental health treatment and identification of psychological needs in this at-risk population., (© 2023. The Author(s).)

This article offers a summary, synthesis, and highlights of processes, surveys, summits, and discussions among members of the Society for the Study of School Psychology exploring current and historical perspectives as to a potential definition of school psychology research. After multiple revisions, the final definition is as follows: School psychology research is the systematic investigation of phenomena concerning the educational, emotional, behavioral, and social outcomes, as well as the school, family, and societal systems in which these outcomes are imbedded. It is principally concerned with socially responsive implementation and translating research into equitable practices that can lead to improved functioning of students, families, schools, and community systems that support educational and psychological services. It includes basic and applied research and theory development that focuses on a wide array of topics including, for example, prevention, intervention, assessment, diagnosis, diversity, equity and inclusion, measurement, methodology, statistics, and professional issues. This wide range of topics is informed by diverse theories arising from a broad array of disciplines and investigated by researchers from a variety of educational and scientific backgrounds. Common to all of the areas of research inquiry is a focus on enhancing student, family, and community outcomes-particularly educational and social outcomes of all students-and in building the capacity of systems (schools, communities, and other systems) to support those outcomes with a commitment to incorporating social responsiveness in the research process. The aim of this definition is to embrace the breadth of scholarship informing and advancing the science, practice, and policy relevant to the field of school psychology., (Copyright © 2022. Published by Elsevier Ltd.)

In this chapter, the authors synthesize ideas presented by authors in this issue and provide considerations of social class in leadership development. Recommendations and guidance for deepening the influence educators have on leadership learning practices regarding social class are included., (© 2021 Wiley Periodicals, LLC.)

In this chapter, the authors offer constructs for understanding the broad nature of social class and how social class identity can, and does, influence leadership identity, capacity, and efficacy. Utilizing the social class worldview model in combination with cultural mismatch theory, the authors position culturally relevant leadership learning as essential to reduce classism and advance class equity in leadership learning, development, and practice., (© 2021 Wiley Periodicals, LLC.)

Hydroxychloroquine (HCQ) has become the rheumatologists's "Swiss army knife" when it comes to managing the rheumatologic manifestations of SLE and other auto-immune disorders. By contrast, nephrologists are much less comfortable in managing the multifaceted effect of HCQ. As a result, nephrologists are inclined to abdicate their responsibility for HCQ management, if this therapy was initiated by a rheumatologist. This report describes such a situation, which had devastating consequences for the patient. On this basis we suggest that this report is a story worth telling, and should encourage the nephrologist to be more involved in their patients' HCQ management.

Objective: Systemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship between complement and CVD in cSLE., Methods: Gene copy numbers (GCNs) for total C4 , C4A and C4B were measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student's t-test and χ 2 analyses. Effects of total C4 , C4A and C4B GCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses., Results: At baseline, C4 protein levels strongly correlated with GCNs of total C4 (p=1.8×10 -6 ). Each copy of C4 gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10 -25 ; C3: P=5.84×10 -20 ). Individuals with ≥2 C4B genes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those with C4B deficiency. At the study end, subjects with ≥2 C4B and atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018)., Conclusions: cSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN of C4B ; cSLE with ≥2 C4B genes would benefit from statins therapy to prevent atherosclerosis., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Objective: To determine the efficacy in improving pain and health-related quality of life (HRQOL) of an online self-management program for adolescents with juvenile idiopathic arthritis (JIA)., Methods: Youth ages 12-18 years with JIA were recruited from 10 rheumatology clinics across the United States and randomized to complete an online self-management program (n = 144) or an online disease education program (n = 145). Participants in the self-management group worked through multimedia-based modules comprising psychoeducation, training in cognitive-behavioral coping skills and stress management, and other self-management topics over a 12-week period. Participants in the control group viewed a series of preselected quality educational websites about JIA over the same interval. Online content for both groups was made available in English and Spanish to facilitate inclusion of Hispanic participants. Blinded assessment of main outcomes (pain intensity, pain interference, and HRQOL) and process outcomes (disease knowledge, self-efficacy, pain coping, and emotional adjustment) occurred at baseline, posttreatment, and at 6- and 12-month postrandomization follow-up visits., Results: Participants on average demonstrated significant improvements over the study period in the main outcomes, with no significant group differences in the degree of improvement. Effect sizes for these improvements were small. The amount of improvement in self-efficacy, emotional avoidance coping, disease knowledge, and emotional functioning in part predicted improvement in pain and HRQOL outcomes., Conclusions: Primarily self-directed online self-management training and online disease education comparably and modestly improve pain and HRQOL in youth with JIA., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High-mobility group box 1 (HMGB1) is a chromatin-associated protein that, in response to stress or injury, translocates from the nucleus to the extracellular milieu, where it functions as an alarmin. HMGB1's function is in part determined by the complexes (HMGB1c) it forms with other molecules. However, structural modifications in the HMGB1 polypeptide that may regulate HMGB1c formation have not been previously described. In this report, we observed high-molecular weight, denaturing-resistant HMGB1c in the plasma and peripheral blood mononuclear cells of individuals with systemic lupus erythematosus (SLE) and, to a much lesser extent, in healthy subjects. Differential HMGB1c levels were also detected in mouse tissues and cultured cells, in which these complexes were induced by endotoxin or the immunological adjuvant alum. Of note, we found that HMGB1c formation is catalyzed by the protein-cross-linking enzyme transglutaminase-2 (TG2). Cross-link site mapping and MS analysis revealed that HMGB1 can be cross-linked to TG2 as well as a number of additional proteins, including human autoantigens. These findings have significant functional implications for studies of cellular stress responses and innate immunity in SLE and other autoimmune disease., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Daily moderate exercise (DME) and stress management are underemphasized in the care of patients with lupus nephritis (LN) due to a poor comprehensive understanding of their potential roles in controlling the inflammatory response. To investigate these effects on murine LN, disease progression was monitored with either DME or social disruption stress (SDR) induction in NZM2410/J mice, which spontaneously develop severe, early-onset LN. SDR of previously established social hierarchies was performed daily for 6 days and DME consisted of treadmill walking (8.5 m/min for 45 min/day). SDR significantly enhanced kidney disease when compared to age-matched, randomly selected control counterparts, as measured by histopathological analysis of H&E staining and immunohistochemistry for complement component 3 (C3) and IgG complex deposition. Conversely, while 88% of non-exercised mice displayed significant renal damage by 43 weeks of age, this was reduced to 45% with exercise. DME also reduced histopathology in kidney tissue and significantly decreased deposits of C3 and IgG complexes. Further examination of renal infiltrates revealed a macrophage-mediated inflammatory response that was significantly induced with SDR and suppressed with DME, which also correlated with expression of inflammatory mediators. Specifically, SDR induced IL-6, TNF-α, IL-1β, and MCP-1, while DME suppressed IL-6, TNF-α, IL-10, CXCL1, and anti-dsDNA autoantibodies. These data demonstrate that psychological stressors and DME have significant, but opposing effects on the chronic inflammation associated with LN; thus identifying and characterizing stress reduction and a daily regimen of physical activity as potential adjunct therapies to complement pharmacological intervention in the management of autoimmune disorders, including LN.

Recent studies implicate innate immunity to systemic lupus erythematosus (SLE) pathogenesis. Toll-like receptor (TLR)8 is estrogen-regulated and binds viral ssRNA to stimulate innate immune responses, but recent work indicates that microRNA (miR)-21 within extracellular vesicles (EVs) can also trigger this receptor. Our objective was to examine TLR8 expression/activation to better understand sex-biased responses involving TLR8 in SLE. Our data identify an estrogen response element that promotes STAT1 expression and demonstrate STAT1-dependent transcriptional activation of TLR8 with estrogen stimulation. In lieu of viral ssRNA activation, we explored EV-encapsulated miR-21 as an endogenous ligand and observed induction of both TLR8 and cytokine expression in vitro. Moreover, extracellular miR detection was found predominantly within EVs. Thus, just as a cytokine or chemokine, EV-encapsulated miR-21 can act as an inflammatory signaling molecule, or miRokine, by virtue of being an endogenous ligand of TLR8. Collectively, our data elucidates a novel innate inflammatory pathway in SLE., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: RhEumAtic Disease activitY (READY) is a mobile health (mHealth) application that aims to create a shared platform integrating data from both patients and physicians, with a particular emphasis on arthritis disease activity., Methods: We made READY available on an iPad and pilot implemented it at a rheumatology outpatient clinic. We conducted 1) a usability evaluation study to explore patients' and physicians' interactions with READY, and 2) a time motion study (TMS) to observe the clinical workflow before and after the implementation., Results: A total of 33 patients and 15 physicians participated in the usability evaluation. We found usability problems in navigation, data entry, pain assessment, documentation, and instructions along with error messages. Despite these issues, 25 (75,76%) patients reported they liked READY. Physicians provided mixed feedback because they were concerned about the impact of READY on clinical workflow. Six physicians participated in the TMS. We observed 47 patient visits (44.72 hours) in the pre-implementation phase, and 42 patient visits (37.82 hours) in the post-implementation phase. We found that patients spent more time on READY than paper (4.39mins vs. 2.26mins), but overall, READY did not delay the workflow (pre = 52.08 mins vs. post = 45.46 mins). This time difference may be compensated with READY eliminating a workflow step for the staff., Conclusion: Patients preferred READY to paper documents. Many found it easier to input information because of the larger font size and the ease of 'tapping' rather than writing-out or circling answers. Even though patients spent more time on READY than using paper documents, the longer usage of READY was mainly due to when troubleshooting was needed. Most patients did not have problems after receiving initial support from the staff. This study not only enabled improvements to the software but also serves as good reference for other researchers or institutional decision makers who are interested in implementing such a technology.

Introduction: Romiplostim is a thrombopeitin-receptor agonist approved for raising platelet counts in patients with immune thrombocytopenia (ITP). Several hematologic adverse effects have been reported including acute myeloid leukemia, myelofibrosis, and thrombosis., Methods: We report two cases, one pediatric and one adult patient, who had antiphospholipid antibodies and received romiplostim for ITP. Additionally, we conducted medline, Food and Drug Administration (FDA) Adverse Events reports website, and manufacturer's adverse events database., Results: Both patients developed thrombosis with evidence for catastrophic antiphospholipid syndrome (CAPS) after treatment with romiplostim. No reports or events were found from literature and database searches in regards to thrombosis associated with romiplostim in patients with antiphospholipid syndrome., Conclusion: These cases illustrate the potential for thrombosis with the administration of romiplostim. The administration of this drug to patients with a history of an autoimmune disease, especially those with positive antiphospholipid antibodies, should be done with caution., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To assess North American pediatric rheumatology providers' perspectives on practices, barriers, and opportunities concerning the transition from pediatric-centered to adult-centered care., Methods: Childhood Arthritis and Rheumatology Research Alliance (CARRA) members completed a 25-item survey assessing current transition practices, transition policy awareness, and transitional care barriers and needs. Results were compared to the American Academy of Pediatrics (AAP) 2008 survey on transitional care., Results: Over half (158/288, 55%) of CARRA members completed the survey. Fewer than 10% are very familiar with AAP guidelines about transition care for youth with special healthcare needs. Eight percent have a formal written transition policy, but 42% use an informal approach. Patient request (75%) most frequently initiates transfer to adult care. Two major barriers to transition are fragmented adult medical care and lack of sufficient time to provide services. Compared with AAP survey participants, pediatric rheumatology providers are significantly more likely to help youth find an adult specialist (63% vs 45%) and discuss confidentiality and consent before age 18 (45% vs 33%), but are less likely to help with medical summary creation (16% vs 27%) or find a primary care provider (25% vs 47%). Outcomes ranked as "very important" in defining a successful transition are survival (76%), seeing an adult rheumatologist within 6 months of final pediatric rheumatology visit (66%), and maintaining insurance coverage (57%)., Conclusion: This comprehensive survey of North American pediatric rheumatology providers regarding transitional care practices demonstrates deficiencies in education, resources, and a formalized process. Respondents support development of standardized rheumatology-specific transition practices.

Rheumatoid arthritis (RA) is a systemic, inflammatory disease with female preponderance, characterized by severe articular and extraarticular manifestations. Cardiovascular (CV) disease in RA usually occurs a decade earlier than age- and sex-matched controls and patients with RA are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD events and traditional CV risk factors. It has been shown that atherosclerotic CV disease in RA shares similarities with CV disease in diabetes mellitus (DM) in terms of clinical presentation and preclinical atherosclerosis. In addition to atherosclerosis, RA also increases risk of non-ischemic heart failure, valvular disease and myopericardial disease. Therefore, RA is considered at least a cardiovascular equivalent to diabetes mellitus. Cardiovascular magnetic resonance (CMR), a non-invasive, nonradiating technique, and due to its capability to perform tissue characterisation, can effectively identify CVdisease acuity and etiology during the course of RA. CMR, by using a combination of function evaluation, oedema-fibrosis detection and stress perfusion-fibrosis imaging can unveil myocarditis, cardiomyopathy, diffuse subendocardial vasculitis, coronary and peripheral artery disease in RA patients, who usually are oligo-asymptomatic. Additionally, CMR is the ideal technique for operator independent, reproducible diagnostic and follow up assessment. However, lack of availability, expertise and high cost still remain serious drawbacks of CMR.

Objective: Published criteria on the degree of proteinuria increase that defines a proteinuric flare in systemic lupus erythematosus (SLE) with glomerulonephritis (GN) vary widely, likely because they are not evidence based, but are largely based on expert opinion. Ideally, the threshold for proteinuric flare should be set sufficiently high that spontaneous variation in proteinuria does not likely explain the increase, but not so high that the patient needlessly experiences prolonged severe proteinuria before a flare is declared and therapy is increased. The present study was undertaken to develop an evidence-based approach to setting the threshold for proteinuric flare, based on quantifying the spontaneous variation in the urine protein:creatinine ratio in SLE GN patients who are not experiencing SLE flare., Methods: SLE GN patients (n = 71) in the Ohio SLE Study were tested at prespecified bimonthly intervals within windows of ±1 week. The median duration of followup was >44 months, and the rate of visit compliance was >90%. To assess spontaneous variation in the protein:creatinine ratio under no-flare conditions, we excluded protein:creatinine ratios measured within 4 months before or after renal flare., Results: Our findings showed that in the group of SLE GN patients with a mean no-flare protein:creatinine ratio of ≤0.5, the published flare thresholds are set well above the 99% confidence interval of the no-flare protein:creatinine ratio. The opposite was seen in the group with a mean no-flare protein:creatinine ratio of ≥1.0., Conclusion: Current thresholds for defining proteinuric flare appear to be set either too high or too low. A randomized trial would be needed to test whether resetting the thresholds would result in faster remission, reduction in therapy, and decrease in the frequency of chronic kidney disease., (Copyright © 2011 by the American College of Rheumatology.)

Patients presenting to an Emergency Department with an altered mental state, whether from a psychiatric, medical or surgical condition or a combination of psychiatric and medical or surgical conditions, require more than the usual amount of diagnostic acumen. General medical conditions often appear in the guise of dysfunctional emotions and/or behaviors. Acute and chronic psychosis may mask underlying acute and chronic medical and surgical conditions. As the case of Esmin Green of Brooklyn, New York, illustrates, the failure to identify underlying medical and surgical conditions in delirious, demented, or psychotic patients can prove fatal to the patient and economically costly to the medical center and its employees.