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More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Leche Humana , Adulto , Lactancia Materna/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Lactante , LactanciaRESUMEN
To compare the incidence of respiratory symptoms and short-term consequences between children with Down syndrome and children from the general population, we conducted a prospective parent-reported observational study. Children with Down syndrome (≤ 18 years) were included between March 2012 and June 2014. Caregivers received a baseline questionnaire with follow-up 1-2 years after inclusion. Caregivers received a weekly questionnaire about respiratory symptoms, fever, antibiotic prescriptions, doctor's visits, and consequences for school and work attendance. Children with Down syndrome were compared to a cohort of the general population ("Kind en Ziek" study) with similar weekly questionnaires. A total of 9,011 childweeks were reported for 116 participants with Down syndrome (75% response rate). The frequency of respiratory symptoms was higher in children with Down syndrome than in children from the general population (30% vs 15.2%). In addition, symptoms subsided later (around 8 vs 5 years of age). The seasonal influence was limited, both in children with Down syndrome and children from the general population. Consequences of respiratory disease were significant in children with Down syndrome compared to children from the general population, with a higher rate of doctor's visits (21.3% vs 11.8%), antibiotic prescriptions (47.8% vs 26.3%), and absenteeism from school (55.5% vs 25.4%) and work (parents, 9.4% vs 8.1%). Conclusion: Children with Down syndrome have a higher frequency of respiratory symptoms and symptoms last until a later age, confirming the impression of professionals and caregivers. Individualized treatment plans might prevent unfavorable consequences of chronic recurrent respiratory disease in children with Down syndrome. What is Known: ⢠Children with Down syndrome have an altered immune system and are prone to a more severe course of respiratory tract infections. ⢠The overall conception is that patients with Down syndrome suffer from respiratory tract infections more often. What is New: ⢠Children with Down syndrome suffer from respiratory symptoms more frequently than children from the general population. ⢠The respiratory symptoms in children with Down syndrome subside at a later age compared to children from the general population.
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Síndrome de Down , Infecciones del Sistema Respiratorio , Niño , Humanos , Estudios Prospectivos , Síndrome de Down/complicaciones , Síndrome de Down/epidemiología , Padres , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/epidemiología , Antibacterianos/uso terapéutico , InternetRESUMEN
OBJECTIVES: The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. METHODS: A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. RESULTS: A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. CONCLUSIONS: ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.
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Neutropenia Febril , Vancomicina , Antibacterianos , Niño , Neutropenia Febril/tratamiento farmacológico , Tasa de Filtración Glomerular , Humanos , Lactante , Método de MontecarloRESUMEN
Down syndrome fits an immunophenotype of combined immunodeficiency with immunodysregulation, manifesting with increased susceptibility to infections, autoimmunity, autoinflammatory diseases, and hematologic malignancies. Qualitative and quantitative alterations in innate and adaptive immunity are found in most individuals with Down syndrome. However, there is substantial heterogeneity and no correlation between immunophenotype and clinical presentation. Previously, it was thought that the immunological changes in Down syndrome were caused by precocious aging. We emphasize in this review that the immune system in Down syndrome is intrinsically different from the very beginning. The overexpression of specific genes located on chromosome 21 contributes to immunodeficiency and immunodysregulation, but gene expression differs between genes located on chromosome 21 and depends on tissue and cell type. In addition, trisomy 21 results in gene dysregulation of the whole genome, reflecting the complex nature of this syndrome in comparison to well-known inborn errors of immunity that result from monogenic germline mutations. In this review, we provide an updated overview focusing on inborn errors of adaptive immunity in Down syndrome.
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Inmunidad Adaptativa/genética , Síndrome de Down/genética , Síndrome de Down/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Animales , Autoinmunidad/genética , Biomarcadores , Relación CD4-CD8 , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunidad Innata/genética , Mediadores de Inflamación/metabolismo , Interferones/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Modelos Biológicos , Receptores de Antígenos de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timo/embriología , Timo/inmunología , Timo/metabolismoRESUMEN
OBJECTIVES: Before a clinician decides whether treatment with TNF inhibition in children with JIA has failed, one should ensure adequate systemic exposure has been achieved. Therapeutic drug monitoring might allow for improved treatment outcome with lower treatment-associated costs. However, this requires understanding of the pharmacokinetic (PK) characteristics, and the pharmacokinetic/pharmacodynamic (PK/PD) relationship for children with JIA. We performed a scoping review to summarize the available literature and identify areas for future research. METHODS: A systematic search was conducted of the Medline, EMBASE, Web of Science and Cochrane databases as well as the clinicaltrials.gov registry. In total, 3959 records were screened and 130 publications were selected for full text assessment. RESULTS: Twenty publications were included and divided into three categories: PK (n = 9), PK/PD (n = 3) and anti-drug antibodies (n = 13). Industry involvement was significant in 14 publications. Although data are limited, systemic exposure to TNF inhibitors is generally lower in younger children but meta-analysis is not possible. The PK/PD relationship has had limited study but there is partial evidence for infliximab. Anti-drug antibodies are common, and are related to impaired clinical outcome with adalimumab and infliximab therapy. CONCLUSION: The current knowledge about the PK and PK/PD of TNF inhibitors in the treatment of children with JIA is limited, which prevents the introduction of TDM. Re-analysis of available data from previous trials, incorporation of pharmacologic assessments into existing biorepository studies as well as new prospective PK and PK/PD trials are required to obtain this knowledge.
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Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Monitoreo de Drogas , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Antirreumáticos/efectos adversos , Niño , Humanos , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
Children with Down syndrome have changes in their innate and adaptive immunity, which contribute to increased rates of infections, autoimmune diseases, and haematological malignancies. While improved care for congenital heart disease has decreased mortality and morbidity, complications related to immune-mediated diseases continue to limit the life expectancy in Down syndrome. Infectious diseases are common and have a significant effect on development, behaviour and quality of life. Infection frequency and severity are influenced by various anatomical and physiological alterations in addition to immunological changes in Down syndrome. Thus, prevention of respiratory tract infections requires a multifactorial approach. This could include additional active and/or passive immunizations, prophylactic antibiotics, immunoglobulin replacement and ear, nose and throat surgical interventions. Autoimmune conditions like coeliac disease, type I diabetes mellitus and thyroid disease are classically mentioned in the context of Down syndrome. However, autoinflammatory conditions are more prevalent as well. Screening for autoimmune diseases is required and immunosuppression has to be used with caution. Future studies should address optimal screening programmes for immune-mediated diseases in individuals with Down syndrome, as well as the effect of immune modulation, to further decrease morbidity and mortality, and improve the quality of life of individuals with Down syndrome.
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Síndrome de Down/inmunología , Enfermedades del Sistema Inmune/inmunología , Inflamación/inmunología , Leucemia/inmunología , Infecciones del Sistema Respiratorio/inmunología , Niño , Preescolar , Síndrome de Down/complicaciones , Humanos , Enfermedades del Sistema Inmune/etiología , Enfermedades del Sistema Inmune/prevención & control , Inmunomodulación , Inflamación/etiología , Inflamación/prevención & control , Leucemia/etiología , Leucemia/prevención & control , Calidad de Vida , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/prevención & controlRESUMEN
Although most medications can be taken safely during breastfeeding, potential risks of infant toxicity do exist because all medications will be excreted into the breast milk to some extent. The amount of medication excreted in the milk depends mainly on (i) within-drug variation, such as dosing; (ii) between-drug variation including chemical characteristics of the medication; and (iii) host factors, such as maternal pharmacokinetics (PK), including variations of pregnancy-associated changes and their post-partum recovery. Neonatal drug exposure is usually assessed by calculating an expected total infant daily dose through breast milk and comparing it to the normal therapeutic dose. However, clinical PK studies in this population are challenging to conduct. Recently, research methods using population PK analyses and physiologically-based PK modeling and simulation techniques have been recognized as a complementary approach to the conventional PK studies in this field. These efforts are important for rational risk assessment balancing the toxicity risk against the benefits of human milk. Health benefits of lactation for both mother and child are significant and a decision to withhold from this should not be taken lightly. In case limited information is present, additional expertise from pharmacists or clinical pharmacologist with expertise in this area should be sought.
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Lactancia Materna , Lactancia , Leche Humana/metabolismo , Medicamentos bajo Prescripción/farmacocinética , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Medición de RiesgoRESUMEN
BACKGROUND: Patients with Down syndrome carry immunologic defects, as evidenced by the increased risks for autoimmune diseases, hematologic malignancies, and respiratory tract infections. Moreover, the low numbers of circulating B cells suggest impaired humoral immunity. OBJECTIVE: We sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment. METHODS: We studied blood B-cell subset composition, replication history, somatic hypermutation status, and class-switch recombination in 17 children with Down syndrome. Germinal centers and plasma cells were studied in tonsils from 4 additional children with Down syndrome. RESULTS: Blood transitional B-cell numbers were normal, but naive mature and memory B-cell numbers were reduced despite slightly increased serum B cell-activating factor levels. Germinal centers and plasma cells in tonsils appeared normal, as were serum immunoglobulin levels. CD27(+)IgD(+)IgM(+) "natural effector" B cells showed reduced proliferation and somatic hypermutation levels, whereas these were normal in CD27(+)IgD(-) memory B cells. Furthermore, IgM(+) and IgA(+), but not IgG(+), memory B cells showed impaired molecular signs for antigen selection. The B-cell pattern was highly similar to that of patients with common variable immunodeficiency and a defect in B-cell activation and proliferation. CONCLUSION: Children with Down syndrome seem capable of normal germinal center and plasma cell formation. Still, blood memory B-cell numbers were reduced and showed impaired molecular maturation of IgA and IgM, which are important for mucosal immunity. The observed molecular defects in circulating IgA and IgM B-cell memory could reflect impaired local responses, which underlie the increased susceptibility to respiratory tract infections of patients with Down syndrome.
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Linfocitos B/inmunología , Síndrome de Down/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Memoria Inmunológica , Adolescente , Subgrupos de Linfocitos B/inmunología , Diferenciación Celular , Niño , Preescolar , Inmunodeficiencia Variable Común/inmunología , Femenino , Centro Germinal , Humanos , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/inmunología , Recuento de Linfocitos , Masculino , Tonsila Palatina/citología , Tonsila Palatina/inmunología , Células Plasmáticas/citologíaRESUMEN
BACKGROUND: Children with Down syndrome suffer from recurrent respiratory tract and ear-nose-throat complaints that influence daily life. Little is known about the frequency of these complaints, as well as their relation to co-morbidity and ageing. METHODS/DESIGN: A prospective web-based parent-reported observational study was designed for parents having a child with Down syndrome (age 0 to 18 years). Upon registration, parents receive an email containing a link to a weekly questionnaire regarding respiratory symptoms during two consecutive years. Additionally, at the beginning, after one year and at the end of the study they receive an extended questionnaire concerning baseline data, daily activities and medical history. The data will be compared to the ongoing "child-is-ill" study, which collects weekly data in an identical fashion in children that are considered to be "normal as to being ill" by their parents. DISCUSSION: This study will provide important data on the epidemiology of respiratory symptoms in children with Down syndrome, which will be useful for further studies on treatment options. Also, this study will gain insight in healthcare usage and work absence due to the child's illnesses.
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Síndrome de Down/epidemiología , Enfermedades Otorrinolaringológicas/epidemiología , Enfermedades Respiratorias/epidemiología , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Países Bajos/epidemiología , Padres , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
Drug reaction with eosinophilia and systemic symptoms (DReSS) is known to cause mortality and long-term sequelae in the pediatric population, however there are no established clinical practice guidelines for the management of pediatric DReSS. We conducted a scoping review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to summarize the currently available data on treatment, mortality, and long-term sequelae of DReSS in children (aged 0-18 years). Data from 644 individuals revealed that various treatment strategies are being used in the management of pediatric DReSS, and strategies were often used in combination. The diversity in treatment approaches cannot be solely attributed to age or disease severity and reflects the lack of evidence-based management guidelines for DReSS. Children are also at risk of developing autoimmune sequelae following DReSS, most commonly thyroid disease and type 1 diabetes mellitus. We found that the eventual development of autoimmune disease was more often associated with DReSS caused by antibiotics, especially minocycline and sulfamethoxazole, in comparison with individuals who did not develop sequelae. In this study, we identify strengths and weaknesses in the currently available literature and highlight that future prospective studies with structured and long-term follow-up of children with DReSS are needed to better understand potential risk factors for mortality and development of sequelae after DReSS.
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Síndrome de Hipersensibilidad a Medicamentos , Humanos , Síndrome de Hipersensibilidad a Medicamentos/etiología , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/terapia , Niño , Adolescente , Preescolar , Lactante , Factores de Riesgo , Antibacterianos/efectos adversos , Resultado del Tratamiento , Enfermedades Autoinmunes/inducido químicamente , Índice de Severidad de la EnfermedadRESUMEN
Effective treatment of drug reactions with eosinophilia and systemic symptoms (DReSS) requires early diagnosis and close monitoring. Diagnosing DReSS is especially challenging in children due to a low incidence rate, heterogeneous clinical presentation, and a lack of (pediatric) diagnostic criteria and clinical practice guidelines. We performed a scoping review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to summarize the clinical presentation and diagnostic process of DReSS in children (aged 0-18 years). Data from 644 individuals showed that DReSS manifests differently in children compared to adults. Children have a higher number of organs involved, including higher rates of cardiac and respiratory involvement compared to adults. Children < 6 years of age appear more prone to develop neurologic symptoms. Conversely, eosinophilia, edema, and kidney involvement are less frequently observed in children. Anti-seizure medications are by far the most common causative drug class, but the range of implicated drugs increases as children get older. This study highlights that children with DReSS not only differ from adults but also that differences exist between children of different ages. As such, there is a need to establish pediatric-specific diagnostic criteria. These efforts will promote earlier diagnosis of DReSS and likely lead to improved clinical care offered to children and their families.
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Síndrome de Hipersensibilidad a Medicamentos , Humanos , Niño , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/etiología , Adolescente , Preescolar , Lactante , Recién Nacido , Factores de EdadRESUMEN
BACKGROUND: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs. RESULTS: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10-35 and P = 1.1 × 10-24, respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes.
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Core clinical pharmacology principles must be considered when designing and executing neonatal clinical trials. In this review, the authors discuss important aspects of drug dose selection, pharmacokinetics, pharmacogenetics and pharmacodynamics that stakeholders may consider when undertaking a neonatal or infant clinical trial.
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OBJECTIVE: To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). METHODS: Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long-term follow-up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass. RESULTS: Participants treated with adalimumab (n = 328) and etanercept (n = 437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66-1.04] and 0.83 mg/kg body weight [IQR 0.75-0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations. CONCLUSION: This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.
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Antirreumáticos , Artritis Juvenil , Reumatología , Niño , Humanos , Adalimumab/uso terapéutico , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Etanercept/efectos adversos , Antirreumáticos/uso terapéutico , Metotrexato/uso terapéutico , Reumatología/métodos , Factor de Necrosis Tumoral alfa , Resultado del Tratamiento , Sistema de RegistrosRESUMEN
Down syndrome (DS) resembles immunodeficiency with increased infections, auto-immune diseases, and hematological malignancies. Until now, immunological studies in DS mainly focused on T-lymphocytes. We recently described a profound B-lymphocytopenia in children with DS. This could be caused by increased apoptosis. Therefore, we determined expression of flowcytometric markers for apoptosis [Annexin-V (AV) and propidium iodide (PI)] on peripheral lymphocytes in 72 children with DS and 32 age-matched controls (AMC). Within the total lymphocyte compartment, apoptosis was more pronounced in DS; it increased with age. Moreover, apoptosis was highest within the B-lymphocyte compartment which may be a contributing factor to the B-lymphocytopenia found in DS. Pediatr Blood Cancer 2012; 59: 1310-1312. © 2012 Wiley Periodicals, Inc.
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Apoptosis , Síndrome de Down/inmunología , Linfocitos/fisiología , Anexina A5 , Niño , Colorantes , Citometría de Flujo , Fluoresceína-5-Isotiocianato , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Subgrupos Linfocitarios , PropidioRESUMEN
Hemophagocytic disorders are severe and life-threatening conditions that can be genetic in origin [i.e., primary hemophagocytic lymphohistiocytosis (HLH)] or result from infections (i.e., secondary hemophagocytic lymphohistiocytosis), rheumatologic disease [i.e., macrophage activation syndrome (MAS)], and less frequently immunodeficiency or metabolic disease. Although rare, drug-induced hemophagocytosis needs to be considered in the work-up as it requires specific management strategies. Most drug-induced hemophagocytic disorders are related to Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). We present the case of a 7-year-old girl who initially presented with fever, maculopapular rash, and unilateral lymphadenopathy, who went on to develop hemophagocytosis secondary to DRESS caused by prolonged combination treatment with amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole. This case illustrates the importance of considering adverse drug reactions in the evaluations of patients with a hemophagocytic process.
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OBJECTIVE: To describe high-dose biologic use when treating juvenile idiopathic arthritis (JIA). METHODS: Patients with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry and treated with a biologic after enrollment were eligible. We described the frequency of high-dose biologic use and characteristics of patients receiving high-dose biologics. We used regression modeling to compare 6-month outcomes (using disease activity measures) between those who increased their biologic from standard to high dose (high-dose group) to those who initiated and remained on standard dosing (no-change group), and to those who switched biologic agents (biologic-switch group). We also compared serious adverse events (SAEs) between groups. RESULTS: A total of 5,352 patients with JIA were treated with biologics following enrollment; 1,080 (20%) had ever received a high-dose biologic. There were no significant differences in outcomes between the high-dose group and the biologic-switch group; both improved disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score 10 (-3.53 and -3.95, respectively; P = 0.68). Although the SAE rates in the high-dose group and the biologic-switch group were numerically higher than the no-change group, the event rates were similar, and neither rate was significantly higher than in the no-change group (unadjusted incident rate ratio 2.5 [95% confidence interval (95% CI) 0.7-8.5] and 1.8 [95% CI 0.7-4.6], respectively). CONCLUSION: Dosing escalation appears to be a reasonable choice to improve disease control, but large, prospective, randomized studies evaluating specific biologic agents are needed.