Choosing Wisely: The Canadian Rheumatology Association Pediatric Committee's List of Items Physicians and Patients Should Question.

OBJECTIVE: To develop a list of tests or treatments frequently used in pediatric rheumatology practice that may be unnecessary based on existing evidence. METHODS: A Choosing Wisely (CW) working group composed of 16 pediatric rheumatologists, 1 allied health professional, 1 parent, and 1 patient used the Delphi method to generate, rank, and refine a list of tests and treatments that may be unnecessary or harmful. The items with the highest content agreement and perceived impact were presented in a survey to all Canadian Rheumatology Association (CRA) physicians who practice pediatric rheumatology. Respondents were asked to rate their agreement and impact, and to rank the items. Five items with the highest composite scores and 2 additional items selected by the CW working group were put forward for literature review. RESULTS: The initial Delphi procedure generated 80 items. After 3 rounds, the list was narrowed to 13 items. The survey was completed by 41/81 (51%) CRA pediatric members across Canada. Respondent characteristics were similar to those of the CRA pediatric membership for self-reported gender, geographical location, and career stage. The highest composite score items were antinuclear antibody testing, drug toxicity monitoring, HLA-B27 testing, rheumatoid factor/anticyclic citrullinated peptide testing, and Lyme serology testing. Two additional items (numerous or repeated intraarticular corticosteroid injections, and autoinflammatory diseases genetic testing) were also selected. Literature review was performed for these 7 highest priority items. CONCLUSION: We have identified areas for quality improvement in the evaluation and treatment of rheumatic diseases in Canadian children.

Parent-Reported Medication Side Effects and Their Impact on Health-Related Quality of Life in Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To describe the frequency and severity of parent-reported medication side effects (SEs) in children with juvenile idiopathic arthritis (JIA) relative to physician-reported actionable adverse events (AEs), and to assess their impact on health-related quality of life (HRQoL). METHODS: Newly diagnosed JIA patients recruited between 2017 and 2019 to the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry were included. Parents reported presence and severity (0 = no problem, 10 = very severe) of medication SEs at every clinic visit. Physicians were asked to report any actionable AE. HRQoL was assessed using the Quality of My Life (QoML) questionnaire (0 = the worst, 10 = the best) and parent's global assessment (0 = very well, 10 = very poor). Analyses included proportion of visits with SEs or actionable AEs, cumulative incidence by Kaplan-Meier methods, and HRQoL impact measured with longitudinal mixed-effects models. RESULTS: SEs were reported at 371 of 884 (42%) visits (95% confidence interval [95% CI] 39, 45%) in 249 patients, with a median of 2 SEs per visit (interquartile range [IQR] 1-3), and median severity of 3 (IQR 1.5-5). Most SEs were gastrointestinal (32.5% of visits) or behavioral/psychiatric (22.4%). SE frequency was lowest with nonsteroidal antiinflammatory drugs alone (34.7%) and highest with prednisone and methotrexate combinations (66%). SE cumulative incidence was 67% (95% CI 59, 75) within 1 year of diagnosis, and 36% (95% CI 28, 44) for actionable AEs. Parent global and QoML scores were worse with SEs present; the impact persisted after adjusting for pain and number of active joints. CONCLUSION: Parents report that two-thirds of children with JIA experience SEs impacting their HRQoL within 1 year of diagnosis. SE mitigation strategies are needed in managing JIA.

Predictive value of 3D imaging to guide implant selection in immediate breast reconstruction.

BACKGROUND: Pre-operative estimation of breast mound volume for immediate breast reconstruction is necessary for operative planning, especially in direct-to-implant reconstruction. Our purpose was to investigate the relationship between pre-operative predictions of breast mound weight from 3D imaging and actual mastectomy weight and implant size. METHODS: A retrospective chart review of all patients who had previously undergone nipple-sparing mastectomy (NSM) by a single surgeon was performed. Pre-operative 3D images were reviewed and calculations of breast mound weight were performed by three independent reviewers. Intra-operative mastectomy weight and final implant weight were collected from patient charts. A regression analysis between calculated and actual values was performed. RESULTS: There were 59 reconstructed breasts included. Pre-operative 3D imaging-guided breast weight calculations were similar across reviewers (R=0.96). Pre-operative calculations of breast weight were 49.4g (SD=134.0) smaller than actual mastectomy specimens. Mastectomy specimens were 41.0g (SD=130.2) smaller than final implant sizes. Thereby, the relationship was as follows: Pre-operative calculated breast weight < actual Mastectomy weight < implant weight. Mastectomy weight and final implant size had linear relationships with pre-operative calculations of breast weight. Formulas for predicting mastectomy weight [mastectomy weight = 63.2 + 0.95 (pre-operative calculated weight)] and implant size [Implant weight = 209.7+ 0.56 (pre-operative calculated weight)] from pre-operative calculations of breast weight were generated. CONCLUSIONS: Three-dimensional scanning technologies may be a useful tool to predict implant sizes for direct-to-implant breast reconstruction. Final implant size was heavier than intra-operative mastectomy weight and pre-operative calculated breast mound weight.

A Canadian evaluation framework for quality improvement in childhood arthritis: key performance indicators of the process of care.

BACKGROUND: The evaluation of quality of care in juvenile idiopathic arthritis (JIA) is critical for advancing patient outcomes but is not currently part of routine care across all centers in Canada. The study objective is to review the current landscape of JIA quality measures and use expert panel consensus to define key performance indicators (KPIs) that are important and feasible to collect for routine monitoring in JIA care in Canada. METHODS: Thirty-seven candidate KPIs identified from a systematic review were reviewed for inclusion by a working group including 3 pediatric rheumatologists. A shortlist of 14 KPIs was then assessed using a 3-round modified Delphi panel based on the RAND/UCLA Appropriateness Method. Ten panelists across Canada participated based on their expertise in JIA, quality measurement, or lived experience as a parent of a child with JIA. During rounds 1 and 3, panelists rated each KPI on a 1-9 Likert scale on themes of importance, feasibility, and priority. In round 2, panelists participated in a moderated in-person discussion that resulted in minor modifications to some KPIs. KPIs with median scores of ≥ 7 on all 3 questions without disagreement were included in the framework. RESULTS: Ten KPIs met the criteria for inclusion after round 3. Five KPIs addressed patient assessments: pain, joint count, functional status, global assessment of disease activity, and the clinical Juvenile Arthritis Disease Activity Score (cJADAS). Three KPIs examined access to care: wait times for consultation, access to pediatric rheumatologists within 1 year of diagnosis, and frequency of clinical follow-up. Safety was addressed through KPIs on tuberculous screening and laboratory monitoring. KPIs examining functional status using the Childhood Health Assessment Questionnaire (CHAQ), quality of life, uveitis, and patient satisfaction were excluded due to concerns about feasibility of measurement. CONCLUSIONS: The proposed KPIs build upon existing KPIs and address important processes of care that should be measured to improve the quality of JIA care. The feasibility of capturing these measures will be tested in various data sources including the Understanding Childhood Arthritis Network (UCAN) studies. Subsequent work should focus on development of meaningful outcome KPIs to drive JIA quality improvement in Canada and beyond.

A new Canadian inception cohort for juvenile idiopathic arthritis: The Canadian Alliance of Pediatric Rheumatology Investigators Registry.

OBJECTIVES: The aim was to describe the design, methods and initial findings of a new Canadian inception cohort of children with JIA, The Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) JIA Registry. METHODS: The CAPRI JIA Registry was started in 2017 to collect information prospectively on children enrolled within 3 months of JIA diagnosis across Canada. The registry has a non-traditional modular design, with no artificially set times for registry visits to occur, streamlined multi-method data collection that requires 2-4 min per visit, and reports cumulative incidence of treatments, outcomes and adverse events calculated by Kaplan-Meier survival methods. RESULTS: A total of 166 patients, enrolled a median of 6 weeks after JIA diagnosis at 10 centres, were included. The median age at diagnosis was 9 years [interquartile range (IQR) 3, 13], 61% were female and 51% had oligoarticular JIA. The median three-variable clinical Juvenile Arthritis Disease Activity Score was 6.5 (IQR 4, 10) at enrolment, and the median time to first attainment of clinically inactive disease (CID) was 24 weeks (by 1 year, 81%). Within 1 year of diagnosis, 70% of patients had started a DMARD and 35% a biologic agent. The rates of adverse events and serious adverse events were 60 and 5.8 per 100 patient-years, respectively. CONCLUSION: This streamlined and flexible registry minimizes the burden of data collection and interference with clinic operations. Initial findings suggest that treatments for newly diagnosed patients with JIA in Canada have intensified, and now 81% of patients attain CID within 1 year of diagnosis.

Approach to recurrent fever in childhood.

OBJECTIVE: To provide an approach to recurrent fever in childhood, explain when infections, malignancies, and immunodeficiencies can be excluded, and describe the features of periodic fever and other autoinflammatory syndromes. SOURCES OF INFORMATION: PubMed was searched for relevant articles regarding the pathogenesis, clinical findings, diagnosis, prognosis, and treatment of periodic fever and autoinflammatory syndromes. MAIN MESSAGE: Fever is a common sign of illness in children and is most frequently due to infection. However, when acute and chronic infections have been excluded and when the fever pattern becomes recurrent or periodic, the expanding spectrum of autoinflammatory diseases, including periodic fever syndromes, should be considered. Familial Mediterranean fever is the most common inherited monogenic autoinflammatory syndrome, and early recognition and treatment can prevent its life-threatening complication, systemic amyloidosis. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome is the most common periodic fever syndrome in childhood; however, its underlying genetic basis remains unknown. CONCLUSION: Periodic fever syndromes and other autoinflammatory diseases are increasingly recognized in children and adults, especially as causes of recurrent fevers. Individually they are rare, but a thorough history and physical examination can lead to their early recognition, diagnosis, and appropriate treatment.

Approche à la fièvre récurrente de l'enfant.

OBJECTIF: Fournir une approche à la fièvre récurrente de l'enfant, expliquer quand les infections, les affections malignes et les immunodéficiences peuvent être exclues, et décrire les caractéristiques de la fièvre périodique et des autres syndromes auto-inflammatoires. SOURCES DE L'INFORMATION: Une recherche d'articles pertinents sur la pathogenèse, les observations cliniques, le diagnostic, le pronostic et le traitement de la fièvre périodique et des syndromes auto-inflammatoires a été effectuée sur PubMed. MESSAGE PRINCIPAL: La fièvre est un signe courant de maladie chez les enfants, et elle est le plus souvent causée par une infection. Mais lorsque les infections aiguës et chroniques ont été exclues et que la fièvre devient récurrente ou périodique, le spectre croissant des maladies auto-inflammatoires, y compris les syndromes de fièvre périodique, doit être envisagé. La fièvre méditerranéenne familiale est le syndrome auto-inflammatoire monogénique héréditaire le plus fréquent, et sa reconnaissance et son traitement précoces peuvent prévenir l'amylose systémique, sa complication menaçant le pronostic vital. Le syndrome de fièvre périodique accompagnée d'une stomatite aphteuse, d'une pharyngite et d'une adénite cervicale est le syndrome de fièvre périodique le plus souvent observé chez l'enfant, mais son fondement génétique sous-jacent est toujours inconnu. CONCLUSION: Les syndromes de fièvre périodique et autres maladies auto-inflammatoires sont de plus en plus dépistés chez les enfants et les adultes, surtout comme causes de la fièvre récurrente. Sur le plan individuel, ils sont rares, mais une anamnèse et un examen physique détaillés peuvent mener au dépistage précoce, au diagnostic et au traitement approprié.

Recurrence and outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.

OBJECTIVES: To report clinical course, etiology, management, and long-term outcomes of children suffering from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). METHODS: We conducted a study of all pediatric patients with SJS or TEN admitted between 2000 and 2007 to the Hospital for Sick Children and Children's Hospital Boston, and particular attention was paid to clinical manifestations, etiology, mortality, and long-term outcomes. RESULTS: We identified 55 cases of SJS (n = 47), TEN (n = 5), or SJS/TEN overlap syndrome (n = 3). Drugs were identified as the most likely etiologic agent in 29 children (53%); antiepileptic drugs were the most common agents (n = 16), followed by sulfonamide antibiotics (n = 7) and chemotherapy drugs (n = 2). Acute Mycoplasma pneumoniae infection was confirmed in 12 children (22%), and herpes simplex virus was confirmed in 5 children (9%). Treatment regimens differed significantly between participating sites and included systemic antimicrobial agents (67%), systemic corticosteroids (40%), and antiviral drugs (31%). Intravenous immunoglobulin was administered to 21 children (38%), of whom 8 received concomitant systemic corticosteroids. Ten children (18%) had recurrence of SJS up to 7 years after the index episode, and 3 experienced multiple recurrences. Twenty-six children (47%) suffered long-term sequelae that mostly involved the skin and eyes. CONCLUSIONS: Mortality rate in children was lower than that reported in adults, but half of affected children suffered long-term complications. The recurrence rate of SJS was high (1 in 5), which suggests vulnerability and potential genetic predisposition. In the absence of standardized management guidelines for these conditions, treatment regimens differed significantly between participating institutions.

Community-based case-control study of childhood chronic abdominal pain: role of selected laboratory investigations.

OBJECTIVE: To compare laboratory investigation results in children with chronic abdominal pain and in healthy control children. Our hypothesis was that parasitic infection was not a causal factor for chronic abdominal pain and that there would be no difference in leukocyte count, hemoglobin level, or erythrocyte sedimentation rate (ESR) between the 2 groups. PATIENTS AND METHODS: Children with chronic abdominal pain and healthy control children (5-15 years) were recruited from the practices of 6 primary care pediatricians in Toronto, Canada. Stool samples were analyzed for ova and parasites, and serum samples were used to estimate leukocyte count, hemoglobin, and ESR. A standardized questionnaire was used to gather social, demographic, and clinical information. RESULTS: A total of 157/200 children (79%) provided samples. Children with chronic abdominal pain were more likely to be female than were control children. Stool samples were positive for parasitic infection in 15 children, with no difference in prevalence between children with chronic abdominal pain (6/87; 7%) and healthy control children (9/70; 13%); P = 0.28). The mean (standard deviation) leukocyte count in children with chronic abdominal pain was 7.4 x 10(9)/L (2.03), compared with 8.3 x 10(9)/L (1.82) in healthy control children. No child had a leukocyte count above 20 x 10(9)/L. The mean (SD) hemoglobin in children with chronic abdominal pain was 131 g/L (8.4), compared with 130 g/L (9.2) in healthy control children. Last, the median ESR in children with chronic abdominal pain was 5 mm/hour, compared with 3 mm/hour in control children. CONCLUSIONS: The study findings suggest that in the absence of alarming symptoms and signs, parasitic infection is not a causal factor for chronic abdominal pain and that routine screening tests (leukocyte count, hemoglobin, ESR) are not useful.

Amino-terminal determinants of U-type inactivation of voltage-gated K+ channels.

The T1 domain is a cytosolic NH2-terminal domain present in all Kv (voltage-dependent potassium) channels, and is highly conserved between Kv channel subfamilies. Our characterization of a truncated form of Kv1.5 (Kv1.5deltaN209) expressed in myocardium demonstrated that deletion of the NH2 terminus of Kv1.5 imparts a U-shaped inactivation-voltage relationship to the channel, and prompted us to investigate the NH2 terminus as a regulatory site for slow inactivation of Kv channels. We examined the macroscopic inactivation properties of several NH2-terminal deletion mutants of Kv1.5 expressed in HEK 293 cells, demonstrating that deletion of residues up to the T1 boundary (Kv1.5deltaN19, Kv1.5deltaN91, and Kv1.5deltaN119) did not alter Kv1.5 inactivation, however, deletion mutants that disrupted the T1 structure consistently exhibited inactivation phenotypes resembling Kv1.5deltaN209. Chimeric constructs between Kv1.5 and the NH2 termini of Kv1.1 and Kv1.3 preserved the inactivation kinetics observed in full-length Kv1.5, again suggesting that the Kv1 T1 domain influences slow inactivation. Furthermore, disruption of intersubunit T1 contacts by mutation of residues Glu(131) and Thr(132) to alanines resulted in channels exhibiting a U-shaped inactivation-voltage relationship. Fusion of the NH2 terminus of Kv2.1 to the transmembrane segments of Kv1.5 imparted a U-shaped inactivation-voltage relationship to Kv1.5, whereas fusion of the NH2 terminus of Kv1.5 to the transmembrane core of Kv2.1 decelerated Kv2.1 inactivation and abolished the U-shaped voltage dependence of inactivation normally observed in Kv2.1. These data suggest that intersubunit T1 domain interactions influence U-type inactivation in Kv1 channels, and suggest a generalized influence of the T1 domain on U-type inactivation between Kv channel subfamilies.