Self-Reported Health Outcomes of Children and Youth with 10 Chronic Diseases.

OBJECTIVES: To identify pediatric patient-reported outcomes (PROs) that are associated with chronic conditions and to evaluate the effects of chronic disease activity on PROs. STUDY DESIGN: Participants (8-24 years old) and their parents were enrolled into 14 studies that evaluated Patient-Reported Outcome Measurement Information System PROs across 10 chronic conditions-asthma, atopic dermatitis, cancer, cancer survivors, chronic kidney disease, Crohn's disease, juvenile idiopathic arthritis, lupus, sickle cell disease, and type 1 diabetes mellitus. PRO scores were contrasted with the US general population of children using nationally representative percentiles. PRO-specific coefficients of variation were computed to illustrate the degree of variation in scores within vs between conditions. Condition-specific measures of disease severity and Cohen d effect sizes were used to examine PRO scores by disease activity. RESULTS: Participants included 2975 child respondents and 2392 parent respondents who provided data for 3409 unique children: 52% were 5-12 years old, 52% female, 25% African American/Black, and 14% Hispanic. Across all 10 chronic conditions, children reported more anxiety, fatigue, pain, and mobility restrictions than the general pediatric population. Variation in PRO scores within chronic disease cohorts was equivalent to variation within the general population, exceeding between-cohort variation by factors of 1.9 (mobility) to 5.7 (anxiety). Disease activity was consistently associated with poorer self-reported health, and these effects were weakest for peer relationships. CONCLUSIONS: Chronic conditions are associated with symptoms and functional status in children and adolescents across 10 different disorders. These findings highlight the need to complement conventional clinical evaluations with those obtained directly from patients themselves using PROs.

Multisite Randomized Clinical Trial Evaluating an Online Self-Management Program for Adolescents With Juvenile Idiopathic Arthritis.

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.

Bayesian comparative effectiveness study of four consensus treatment plans for initial management of systemic juvenile idiopathic arthritis: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST).

BACKGROUND: Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely. PURPOSE: To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA). METHODS: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential confounding. With 200 patients in a 2:1 ratio of biologic to non-biologic, there is a >90% probability of finding biologic consensus treatment plans more effective if the rate of clinically inactive disease is 30% higher than for non-biologic therapy. Additional outcomes include Patient-Reported Outcomes Measurement Information System measures and other parent-/patient-reported outcomes reported in real time using smartphone technology. Routine operation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry will allow assessment of outcomes over at least 10 years. RESULTS: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) began enrollment in November 2016. LIMITATIONS: The observational design may not provide balance in measured and unmeasured confounders. Use of consensus treatment plan (CTP) strategies at frequencies more unbalanced than predicted could reduce the chance of finding differences in efficacy. CONCLUSION: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) will provide the first prospective comparison of Childhood Arthritis and Rheumatology Research Alliance's (CARRA's) consensus-derived non-biologic versus biologic management strategies in systemic juvenile idiopathic arthritis, performed in a real-world setting wherein each patient receives standard-of-care treatment selected by the treating physician. Outcomes include clinician- and patient-/family-reported outcomes, empowering both physician and patient decision making in new-onset systemic juvenile idiopathic arthritis.

Atherosclerosis Progression in the APPLE Trial Can Be Predicted in Young People With Juvenile-Onset Systemic Lupus Erythematosus Using a Novel Lipid Metabolomic Signature.

OBJECTIVE: Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the largest investigator-led randomized control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as the primary outcome. METHODS: Unsupervised clustering of baseline CIMT and CIMT progression over 36 months was used to stratify patients with JSLE. Disease characteristics, cardiovascular risk scores, and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify and validate a serum metabolomic signature of CIMT progression. RESULTS: Baseline CIMT stratified patients with JSLE (N = 151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease risk based on recommended assessment criteria. In the placebo group (n = 60), patients with high versus low CIMT progression had higher total (P = 0.001) and low-density lipoprotein (LDL) (P = 0.002) cholesterol levels, although within the reference range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT progression was identified in the placebo arm (area under the curve, 80.7%). Patients treated with atorvastatin (n = 61) had reduced LDL cholesterol levels after 36 months, as expected; however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting nonlipid drivers of atherosclerosis in JSLE with management implications for this subset of patients. CONCLUSION: Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some patients with JSLE with relevance for clinical trial stratification.

Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis.

OBJECTIVE: To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months. METHODS: Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months. RESULTS: By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ(2) = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 (P = 0.053). There were no significant interarm differences in adverse events. CONCLUSION: Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms.

Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response.

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure-response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure-response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults.

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.

Construct validity of Patient-Reported Outcomes Measurement Information System Paediatric measures in juvenile idiopathic arthritis and systemic lupus erythematosus: cross-sectional evaluation.

OBJECTIVES: Evaluate construct validity of Patient-Reported Outcomes Measurement Information System (PROMIS) Paediatric measures of symptoms and functioning against measures of disease activity among youth with juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE). DESIGN: Cross-sectional associations among PROMIS measures and clinical metrics of disease activity were estimated. SETTING: Seven clinical sites of the Childhood Arthritis and Rheumatology Alliance (CARRA) in the USA. PARTICIPANTS: Youth aged 8-17 years enrolled in the CARRA Registry. INTERVENTION: PROMIS measures were collected and associations with clinical measures of disease activity estimated, by condition, in bivariate and multivariable analyses with adjustment for sociodemographics, insurance status, medications and disease duration. MAIN OUTCOME MEASURES: PROMIS Paediatric measures of mobility, physical activity, fatigue, pain interference, family relationships, peer relationships, depressive symptoms, psychological stress, anxiety, and meaning and purpose, and clinical metrics of disease. RESULTS: Among 451 youth (average age 13.8 years, 71% female), most (n=393, 87%) had a JIA diagnosis and the remainder (n=58, 13%) had SLE. Among participants with JIA, those with moderate/high compared with low/inactive disease had, on average, worse mobility (multivariable regression coefficient and 95% CIs) (-7.40; -9.30 to -5.50), fatigue (3.22; 1.02 to 5.42), pain interference (4.76; 3.04 to 6.48), peer relationships (-2.58; -4.52 to -1.64), depressive symptoms (3.00; 0.96 to 5.04), anxiety (2.48; 0.40 to 4.56) and psychological stress (2.52; 0.68 to 4.36). For SLE, youth with active versus inactive disease had on average worse mobility (-5.07; -10.15 to 0.01) but PROMIS Paediatric measures did not discriminate participants with active and inactive disease in adjusted analyses. CONCLUSIONS: Seven PROMIS Paediatric measures discriminated between active and inactive disease in youth with JIA. Results advance the usefulness of PROMIS for understanding well-being and improving interventions for youth with JIA, but larger studies are needed to determine utility in SLE cohorts. TRIAL REGISTRATION NUMBER: National Institute of Arthritis and Musculoskeletal and Skin Diseases (U19AR069522).

Therapeutic Development in Polyarticular Course Juvenile Idiopathic Arthritis: Extrapolation, Dose Selection, and Clinical Trial Design.

OBJECTIVE: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders. METHODS: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions. RESULTS: The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families. CONCLUSION: This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long-term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long-term follow-up.

Emotion regulation predicts pain and functioning in children with juvenile idiopathic arthritis: an electronic diary study.

OBJECTIVES: This study utilized e-diaries to evaluate whether components of emotion regulation predict daily pain and function in children with juvenile idiopathic arthritis (JIA). METHODS: 43 children ages 8-17 years and their caregivers provided baseline reports of child emotion regulation. Children then completed thrice daily e-diary assessments of emotion, pain, and activity involvement for 28 days. E-diary ratings of negative and positive emotions were used to calculate emotion variability and to infer adaptive emotion modulation following periods of high or low emotion intensity. Hierarchical linear models were used to evaluate how emotion regulation related to pain and function. RESULTS: The attenuation of negative emotion following a period of high negative emotion predicted reduced pain; greater variability of negative emotion predicted higher pain and increased activity limitation. Indices of positive emotion regulation also significantly predicted pain. CONCLUSIONS: Components of emotion regulation as captured by e-diaries predict important health outcomes in children with JIA.

Cardiovascular Health in Pediatric Rheumatologic Diseases.

Cardiovascular disease risk is evident during childhood for patients with juvenile systemic lupus erythematosus, juvenile dermatomyositis, and juvenile idiopathic arthritis. The American Heart Association defines cardiovascular health as a positive health construct reflecting the sum of protective factors against cardiovascular disease. Disease-related factors such as chronic inflammation and endothelial dysfunction increase cardiovascular disease risk directly and through bidirectional relationships with poor cardiovascular health factors. Pharmacologic and nonpharmacologic interventions to improve cardiovascular health and long-term cardiovascular outcomes in children with rheumatic disease are needed.

Pediatric rheumatologists' perspectives on diagnosis, treatment, and outcomes of Sjögren disease in children and adolescents.

BACKGROUND: Sjögren disease in children and adolescents (pedSD) presents differently than adult disease. Diagnosis and classification are controversial, optimal treatment is unknown and outcomes are poorly understood. Here, we describe the current perspectives of pediatric rheumatologists on diagnosis, treatment, and outcomes of pedSD. METHODS: A voluntary, 17-question survey was distributed to providers in the Childhood Arthritis and Rheumatology Research Alliance and/or the American College of Rheumatology Childhood Sjögren's Study Group at the 2020 Convergence Virtual Conference. Findings are reported using descriptive statistics and chi-square testing. RESULTS: Of 465 eligible providers, 157 (34%) responded with 135 (29%) completing the survey. The majority (85%) saw five or fewer patients with pedSD in the past year. Parotitis, dry eye and/or dry mouth, and constitutional symptoms were among the most specific and common clinical features. Most providers (77%) used clinical judgment guided by adult criteria for diagnosis. The vast majority (86-99%) of survey participants indicated routine use of serologic testing, while salivary gland ultrasound, minor salivary gland biopsy and other diagnostic tests were less often used. The most commonly prescribed systemic immunomodulators were hydroxychloroquine, corticosteroids, methotrexate, rituximab, and mycophenolate. Seven providers reported malignancy in a patient with pedSD, including one death. CONCLUSIONS: Pediatric rheumatologists diagnose and treat pedSD; however, most only see a few patients per year and rely on clinical judgment and laboratory testing for diagnosis. Treatment frequently includes systemic immunomodulators and malignancies are reported. More studies are needed to better understand natural history, risk factors, and the impact of interventions on outcomes.

Feasibility and Efficacy of Online Strategies to Recruit Parents of Children With Rheumatic Diseases for Research.

OBJECTIVE: We aimed to determine the feasibility and efficacy of online strategies to recruit parents of children with pediatric rheumatic diseases (PRDs) for research and to evaluate the degree to which known features of various rheumatic disease groups were present in the online cohort. METHODS: We studied two cohorts; the first was composed of respondents from a cross-sectional parental survey of children with PRDs contacted through patient support groups and social media platforms, and the second cohort was composed of participants from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) legacy clinical registry. RESULTS: In the social media cohort, 712 complete surveys were analyzed. Most (65.9%) were referred from Facebook. The most common rheumatic disease was juvenile idiopathic arthritis (JIA) (27.1%), followed by juvenile dermatomyositis (22.1%). In the CARRA registry cohort, 7985 records were included. JIA was the largest disease group (70.3%), followed by systemic lupus erythematosus (12.0%). The age at disease onset for most PRDs was similar between those in the social media and CARRA registry cohorts (mean difference = 1.3 years). CONCLUSION: Recruitment through Facebook was the most fruitful. The clinical characteristics of the social media cohort were similar to those of patients recruited through a clinical registry, suggesting the utility of online recruitment for engaging disease-relevant cohorts. Parents of children with rare PRDs were overrepresented in the social media cohort, perhaps reflecting the increased need of those parents to find online information and receive emotional support. Social media recruitment for research studies may help expand the number and diversity of participants in clinical research, especially by including those with rare diseases.

First-line options for systemic juvenile idiopathic arthritis treatment: an observational study of Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans.

BACKGROUND: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) to compare treatment initiation strategies for systemic juvenile idiopathic arthritis (sJIA). First-line options for sJIA treatment (FROST) was a prospective observational study to assess CTP outcomes using the CARRA Registry. METHODS: Patients with new-onset sJIA were enrolled if they received initial treatment according to the biologic CTPs (IL-1 or IL-6 inhibitor) or non-biologic CTPs (glucocorticoid (GC) monotherapy or methotrexate). CTPs could be used with or without systemic GC. Primary outcome was achievement of clinical inactive disease (CID) at 9 months without current use of GC. Due to the small numbers of patients in the non-biologic CTPs, no statistical comparisons were made between the CTPs. RESULTS: Seventy-three patients were enrolled: 63 (86%) in the biologic CTPs and 10 (14%) in the non-biologic CTPs. CTP choice appeared to be strongly influenced by physician preference. During the first month of follow-up, oral GC use was observed in 54% of biologic CTP patients and 90% of non-biologic CTPs patients. Five (50%) non-biologic CTP patients subsequently received biologics within 4 months of follow-up. Overall, 30/53 (57%) of patients achieved CID at 9 months without current GC use. CONCLUSION: Nearly all patients received treatment with biologics during the study period, and 46% of biologic CTP patients did not receive oral GC within the first month of treatment. The majority of patients had favorable short-term clinical outcomes. Increased use of biologics and decreased use of GC may lead to improved outcomes in sJIA.

CARRA: The Childhood Arthritis and Rheumatology Research Alliance.

The Childhood Arthritis & Rheumatology Research Alliance (CARRA) launched in 2000 as a small network of pediatric rheumatologists and investigators dedicated to promoting collaborative research to improve the care and outcomes of childhood-onset rheumatic diseases. Over the past 2 decades, CARRA has grown to become a major driver of advances in evidence-based medicine and career development in pediatric rheumatology. Its research approach has transformed pediatric rheumatology. CARRA is a vibrant organization that will continue to facilitate impactful research in the care of children, adolescents, and young adults with rheumatic disease in the years to come.

Delivering clinical trials at home: protocol, design and implementation of a direct-to-family paediatric lupus trial.

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).

Improved Disease Course Associated With Early Initiation of Biologics in Polyarticular Juvenile Idiopathic Arthritis: Trajectory Analysis of a Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans Study.

OBJECTIVE: To investigate the effects of early introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) on the disease course in untreated polyarticular juvenile idiopathic arthritis (JIA). METHODS: We analyzed data on patients with polyarticular JIA participating in the Start Time Optimization of Biologics in Polyarticular JIA (STOP-JIA) study (n = 400) and a comparator cohort (n = 248) from the Childhood Arthritis and Rheumatology Research Alliance Registry. Latent class trajectory modeling (LCTM) was applied to identify subgroups of patients with distinct disease courses based on disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints) over 12 months from baseline. RESULTS: In the STOP-JIA study, 198 subjects (49.5%) received bDMARDs within 3 months of baseline assessment. LCTM analyses generated 3 latent classes representing 3 distinct disease trajectories, characterized by slow, moderate, or rapid disease activity improvement over time. Subjects in the rapid improvement trajectory attained inactive disease within 6 months from baseline. Odds of being in the rapid improvement trajectory versus the slow improvement trajectory were 3.6 times as high (95% confidence interval 1.32-10.0; P = 0.013) for those treated with bDMARDs ≤3 months from baseline compared with subjects who started bDMARDs >3 months after baseline, after adjusting for demographic characteristics, clinical attributes, and baseline disease activity. Shorter disease duration at first rheumatology visit approached statistical significance as a predictor of favorable trajectory without bDMARD treatment. CONCLUSION: Starting bDMARDs within 3 months of baseline assessment is associated with more rapid achievement of inactive disease in subjects with untreated polyarticular JIA. These results demonstrate the utility of trajectory analysis of disease course as a method for determining treatment efficacy.

Optimizing the Start Time of Biologics in Polyarticular Juvenile Idiopathic Arthritis: A Comparative Effectiveness Study of Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans.

OBJECTIVE: The optimal time to start biologics in polyarticular juvenile idiopathic arthritis (JIA) remains uncertain. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed 3 consensus treatment plans (CTPs) for untreated polyarticular JIA to compare strategies for starting biologics. METHODS: Start Time Optimization of Biologics in Polyarticular JIA (STOP-JIA) was a prospective, observational, CARRA Registry study comparing the effectiveness of 3 CTPs: 1) the step-up plan (initial nonbiologic disease-modifying antirheumatic drug [DMARD] monotherapy, adding a biologic if needed, 2) the early combination plan (DMARD and biologic started together), and 3) the biologic first plan (biologic monotherapy). The primary outcome measure was clinically inactive disease according to the provisional American College of Rheumatology (ACR) criteria, without glucocorticoids, at 12 months. Secondary outcome measures included Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and mobility scores, inactive disease as defined by the clinical Juvenile Arthritis Disease Activity Score in 10 joints (JADAS-10), and the ACR Pediatric 70 criteria (Pedi 70). RESULTS: Of 400 patients enrolled, 257 (64%) began the step-up plan, 100 (25%) the early combination plan, and 43 (11%) the biologic first plan. After propensity score weighting and multiple imputation, clinically inactive disease according to the ACR criteria was achieved in 37% of those on the early combination plan, 32% on the step-up plan, and 24% on the biologic first plan (P = 0.17). Inactive disease according to the clinical JADAS-10 (score ≤2.5) was also achieved in more patients on the early combination plan than the step-up plan (59% versus 43%; P = 0.03), as was ACR Pedi 70 (81% versus 62%; P = 0.008), but generalizability was limited by missing data. PROMIS measures improved in all groups, but without significant differences. Twenty serious adverse events were reported (mostly infections). CONCLUSION: Achievement of clinically inactive disease without glucocorticoids did not significantly differ between groups at 12 months. While there was a significantly higher likelihood of early combination therapy achieving inactive disease according to the clinical JADAS-10 and ACR Pedi 70, these results require further exploration.

Juvenile Spondyloarthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry: High Biologic Use, Low Prevalence of HLA-B27, and Equal Sex Representation in Sacroiliitis.

OBJECTIVE: To describe characteristics of children with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (PsA) who were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. METHODS: All children with ERA and those with juvenile PsA were identified. Demographic characteristics, clinical characteristics, and treatments were described. The children with sacroiliitis and those without sacroiliitis were compared. In the children with sacroiliitis, the first visit with clinically active sacroiliitis (which came first in 72% of cases) was compared to the first visit without clinically active sacroiliitis. RESULTS: A total of 902 children with ERA or juvenile PsA were identified. Children with ERA were older at diagnosis (ages 10.8 years versus 8.2 years; P < 0.01) and were more likely to be male (56% versus 38%; P < 0.01). Polyarticular involvement was reported in 57% of children with ERA and in 72% of those with juvenile PsA. Of the children tested, HLA-B27 was positive in 38% of those in the ERA group and in 12% of those in the juvenile PsA group. At least 1 biologic was taken by 72% of those with ERA and 64% of those with juvenile PsA. Sacroiliitis (diagnosed clinically and/or by imaging) was reported in 28% of the children (40% of those with ERA and 12% of those with juvenile PsA). Of these, 54% of the children were female, 36% were HLA-B27 positive, and 81% took at least 1 biologic. In children with sacroiliitis, scores according to the physician global assessment of disease activity, parent/patient global assessment of well-being, and clinical Juvenile Arthritis Disease Activity Score 10 were all significantly worse at the first visit with clinically active sacroiliitis versus the first visit without active sacroiliitis. CONCLUSION: In this registry, there are more than 900 children with ERA or juvenile PsA. There was high biologic use in this population, especially in those with sacroiliitis. Further, there was equal sex representation in those children with sacroiliitis.