Trajectories of disease activity in patients with JIA in the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: To describe 2-year trajectories of the clinical Juvenile Arthritis Disease Activity Score, 10 joints (cJADAS10) and associated baseline characteristics in patients with JIA. METHODS: JIA patients in the Childhood Arthritis and Rheumatology Research Alliance Registry enrolled within 3 months of diagnosis from 15 June 2015 to 6 December 2017 with at least two cJADAS10 scores and 24 months of follow-up were included. Latent growth curve models of cJADAS10 were analysed; a combination of Bayesian information criterion, posterior probabilities and clinical judgement was used to select model of best fit. RESULTS: Five trajectories were identified among the 746 included patients: High, Rapidly Decreasing (HRD) (n = 199, 26.7%); High, Slowly Decreasing (HSD) (n = 154, 20.6%); High, Increasing (HI) (n = 39, 5.2%); Moderate, Persistent (MP) (n = 218, 29.2%); and Moderate, Decreasing (MD) (n = 136, 18.2%). Most patients spent a significant portion of time at moderate to high disease activity levels. At baseline, HSD patients were more likely to be older, have a lower physician global assessment, normal inflammatory markers, longer time to first biologic, and have taken systemic steroids compared with HRD. Those with a HI trajectory were more likely to be ANA negative, have a longer time to first biologic, and less likely to be taking a conventional synthetic DMARD compared with HRD. MP patients were more likely to be older with lower household income, longer time to diagnosis, and markers of higher disease activity than those with a MD trajectory. CONCLUSIONS: Five trajectories of JIA disease activity, and associated baseline variables, were identified.

Inflammatory arthritis in pediatric patients with morphea.

BACKGROUND: Morphea or localized scleroderma is an inflammatory disorder resulting in fibrosis of the skin and subcutaneous tissues. Joint contractures, arthralgias, and functional compromise are recognized associations of pediatric morphea. The co-existence of inflammatory arthritis and morphea is not well-described in the literature. OBJECTIVE: To investigate the relationship between pediatric morphea and inflammatory arthritis with regards to cutaneous, musculoskeletal, and laboratory findings and treatment regimens. METHODS: A systematic retrospective chart review of 53 patients with pediatric morphea was performed and analyzed for morphea subtypes, arthritic joint involvement, serum autoantibodies, and therapeutic interventions. RESULTS: Eleven out of 53 patients had polyarthritis that involved joints unrelated to the site of the cutaneous morphea. These patients were mostly girls with either the linear or generalized subtypes of morphea. Serum levels of antinuclear antibodies were more significantly elevated in patients with arthritis. All children were treated with methotrexate in addition to other systemic or topical immunosuppressive agents. LIMITATIONS: This was a small, single-center retrospective study. CONCLUSION: Pediatric morphea co-existed with inflammatory arthritis in 11 of 53 children. Further understanding and appreciation of this relationship may direct more intensive therapy and musculoskeletal screening.

Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (s-JIA) is clinically distinct from other types of JIA. It is typified by extraarticular features such as quotidian fevers, rash, splenomegaly, lymphadenopathy, laboratory abnormalities (including leukocytosis, thrombocytosis, anemia, hyperferritinemia, and elevated inflammatory markers), and a close association with the macrophage activation syndrome. Recent investigations have highlighted dysregulation of the innate immune system as the critical pathogenic driver of s-JIA. Key innate immune mediators of s-JIA are the macrophage-derived cytokines interleukin-1 (IL-1) and IL-6. Increased understanding of the roles of IL-1 and IL-6 in the pathogenesis of s-JIA has led to major changes in therapeutic options. Until recently, the most commonly used medications included corticosteroids, methotrexate, and tumor necrosis factor (TNF) inhibitors, which are incompletely effective in most cases. Newer biologic agents targeting IL-1 and IL-6 have proven very effective in treating s-JIA and in minimizing corticosteroid exposure. Here we review recent advances in the understanding of the pathogenesis of s-JIA and the recent clinical trials that have revolutionized the care of children with s-JIA.

Sustained remission of severe Multicentric Castleman disease following multiagent chemotherapy and tocilizumab maintenance.

Castleman disease is a rare lymphoproliferative disorder, which presents in a unicentric or multicentric fashion. Multicentric Castleman disease (MCD) is associated with significant systemic symptoms, in part related to the underlying role of interleukin-6 in disease pathogenesis. Treatment for MCD has not been well established and prognosis has historically been poor. We present a case of severe MCD in a pediatric patient who has shown sustained remission following multi-agent chemotherapy and targeted maintenance therapy with the interleukin-6 receptor inhibitor, tocilizumab. This represents the first case report of sustained remission of MCD in a pediatric patient following discontinuation of tocilizumab therapy.

Case Report: Contiguous presentation of anti-MDA5 juvenile dermatomyositis and anti-AQP4 neuromyelitis optica spectrum disorder in an adolescent patient.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory disorder of the central nervous system (CNS) that is known to be associated with other neurologic and organ-specific autoimmune conditions. There has been increasing recognition of the association between NMOSD and systemic autoimmune disease, most commonly systemic lupus erythematosus and Sjogren's syndrome. We report a case of an adolescent presenting with anti-melanoma differentiation-associated protein 5 juvenile dermatomyositis (anti-MDA5 JDM) and NMOSD, exhibiting clinical features of myelitis, polyarthritis, myositis, and skin involvement. Currently, only two other published cases have described NMOSD associated with anti-MDA5 dermatomyositis, both in adults. To the best of our knowledge, this is the first reported case in an adolescent patient.

Comparative Effectiveness of a Second Tumor Necrosis Factor Inhibitor Versus a Non-Tumor Necrosis Factor Biologic in the Treatment of Patients With Polyarticular-Course Juvenile Idiopathic Arthritis.

OBJECTIVE: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non-TNFi biologic following discontinuation of a TNFi for patients with polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation. RESULTS: There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non-TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non-TNFi second biologic received (9% overall, 58% of non-TNFi). There was no difference between receiving TNFi versus non-TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47-3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47-2.62) at six months. CONCLUSION: Most patients with pJIA started receiving TNFi rather than non-TNFi as their second biologic, and there were no differences in disease activity at six months.

Child Health Needs and the Pediatric Rheumatology Workforce: 2020-2040.

The Pediatric Rheumatology (PRH) workforce supply in the United States does not meet the needs of children. Lack of timely access to PRH care is associated with poor outcomes for children with rheumatic diseases. This article is part of a Pediatrics supplement focused on anticipating the future pediatric subspecialty workforce supply. It draws on information in the literature, American Board of Pediatrics data, and findings from a model that estimates the future supply of pediatric subspecialists developed by the Sheps Center for Health Services Research at the University of North Carolina at Chapel Hill, Strategic Modeling and Analysis Ltd., and the American Board of Pediatrics Foundation. PRH has a smaller workforce per capita of children than most other pediatric subspecialties. The model demonstrates that the clinical workforce equivalent of pediatric rheumatologists in 2020 was only 0.27 per 100 000 children, with a predicted increase to 0.47 by 2040. Although the model predicts a 72% increase in providers, this number remains inadequate to provide sufficient care given the number of children with rheumatic diseases, especially in the South and West regions. The likely reasons for the workforce shortage are multifactorial, including lack of awareness of the field, low salaries compared with most other medical specialties, concerns about working solo or in small group practices, and increasing provider retirement. Novel interventions are needed to increase the workforce size. The American College of Rheumatology has recognized the dire consequences of this shortage and has developed a workforce solutions initiative to tackle these problems.

Occurrence of adverse events and change in disease activity after initiation of etanercept in paediatric patients with juvenile psoriatic arthritis in the CARRA Registry.

OBJECTIVE: Etanercept is commonly used to treat juvenile idiopathic arthritis, including juvenile psoriatic arthritis (JPsA); however, information on etanercept's safety and effectiveness in clinical practice is limited. We used data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry to evaluate etanercept's safety and effectiveness in JPsA in clinical practice. METHODS: We analysed safety and effectiveness data for paediatric patients enrolled in the CARRA Registry who had a JPsA diagnosis and had used etanercept. Safety was assessed by calculating rates of prespecified adverse events of special interest (AESIs) and serious adverse events (SAEs). Effectiveness was assessed by a variety of disease activity measures. RESULTS: Overall, 226 patients had JPsA and received etanercept; 191 met criteria for safety analysis and 43 met criteria for effectiveness analysis. AESI and SAE incidence rates were low. There were five events: three uveitis, one new-onset neuropathy and one malignancy. Incidence rates were 0.55 (95% CI: 0.18, 1.69), 0.18 (95% CI: 0.03, 1.29) and 0.13 (95% CI: 0.02, 0.09) per 100 patient-years for uveitis, neuropathy and malignancy, respectively. Etanercept showed effectiveness for JPsA treatment; 7 of 15 (46.7%) had an American College of Rheumatology-Pediatric Response 90, 9 of 25 (36.0%) had a clinical Juvenile Arthritis Disease Activity Score 10-joint ≤1.1 and 14 of 27 (51.9%) had clinically inactive disease at the 6-month follow-up. CONCLUSION: Data in the CARRA Registry showed that etanercept treatment was safe in treating children with JPsA, with low AESIs and SAEs. Etanercept was also effective, even when assessed in a small sample size.

Role of Environment in Pediatric Rheumatic Diseases.

Studying environmental risk factors for pediatric rheumatic diseases (PRD) is important because the identification of these factors may lead to strategies to prevent disease, and to new insights into pathogenesis and therapeutic targets. Compared with other chronic diseases, there are few environmental epidemiology studies in PRD. Although strong risk factors common to all PRDs have not been identified, some exposures including infection, smoke exposure, and ultraviolet radiation have been associated with several of them. High-technology studies, especially of microbiomics and metabolomics, are increasing and will likely lead to new understandings of the complex interplay between environment, genetics, and disease.

2015 American College of Rheumatology Workforce Study and Demand Projections of Pediatric Rheumatology Workforce, 2015-2030.

OBJECTIVE: To describe the character and composition of the 2015 pediatric rheumatology workforce in the US, evaluate current workforce trends, and project future supply and demand of the pediatric rheumatology workforce through 2030. METHODS: The American College of Rheumatology created the workforce study group to study the rheumatology workforce. The workforce study group used primary and secondary data to create a representative workforce model. Pediatric rheumatology supply and demand was projected through 2030 using an integrated data-driven framework to capture a more realistic clinical full-time equivalent (FTE) and produce a better picture of access to care issues in pediatric rheumatology. RESULTS: The 2015 pediatric rheumatology workforce was estimated at 287 FTEs (300 providers), while the estimated excess demand was 95 (33%). The projected demand will continue to increase to almost 100% (n = 230) by 2030 if no changes occur in succession planning, new graduate entrants into the profession, and other factors associated with the workforce. CONCLUSION: This study projects that the pediatric rheumatology workforce gap will continue to worsen significantly from the 2015 baseline, and by 2030 the demand for pediatric rheumatologists will be twice the supply. Innovative strategies are needed to increase the workforce supply and to improve access to care.

Effectiveness and Safety of High-Dose Biologics in Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance.

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.

Non-criteria antiphospholipid antibodies and pediatric rheumatic disease: a case series.

BACKGROUND: Non-criteria antiphospholipid antibodies (NC-aPL) are a relatively undefined subgroup of antiphospholipid antibodies (aPL). Knowledge about NC-aPL in adults is limited and even less is known in pediatric patients. Routine tests for antiphospholipid syndrome (APS)-a clinical state marked by the presence of aPL in association with vascular thrombosis-usually include lupus anticoagulant (LAC), anti-cardiolipin (aCL) and -beta-2 glycoprotein I (aß2GPI). LAC is a functional screen for prothrombotic aPL, while the latter tests identify specific autoantibodies. Specific targets of NC-aPL include, but are not limited to, phosphatidylethanolamine, phosphatidylserine, and prothrombin. PRESENTATION OF CASES: We present single-center data from eight pediatric patients with NC-aPL identified during a three-year period. All patients had presenting features raising suspicion for APS. Most patients were female with a primary rheumatic disease. One patient had a stroke. Another patient had alveolar hemorrhage and pulmonary hypertension. Raynaud's phenomenon, rashes involving distal extremities, and headaches were common. Most patients had a positive LAC, yet their routine aPL tests were negative, prompting testing for NC-aPL. CONCLUSIONS: Our findings suggest NC-aPL are associated with typical signs and symptoms of APS in pediatric patients. Pediatricians and pediatric subspecialists should consider NC-aPL when clinical suspicion is high and routine aPL tests are negative, particularly when LAC is positive. While guidelines for NC-aPL do not yet exist for children or adults, these autoantibodies have pathogenic potential. Actionable items could include evaluation for the presence of other (primary) rheumatic diseases, and consultation with hematologists and/or obstetricians regarding anticoagulation/platelet inhibition and thrombosis education. Future guidelines regarding NC-aPL will only be generated by gathering more data, ideally prospectively.

Capturing critical data elements in Juvenile Idiopathic Arthritis: initiatives to improve data capture.

BACKGROUND: Documentation of critical data elements is a focus of the Pediatric Rheumatology Care and Outcomes Improvement Network to aid in clinical care and research for patients with juvenile idiopathic arthritis. We aimed to increase data capture for critical data elements and hypothesized that quality improvement methodology would improve data capture. We also hypothesized that data capture for all critical data elements would be lower for virtual visits compared to in-person visits. METHODS: All visits for patients with JIA between 9/14/2020 and 12/31/2021 at the University of Minnesota were included. We assessed completeness of critical data element capture. Sixteen interventions with providers were conducted, including email reminders, individual discussions, group meetings, and feedback reports. We used statistical process control charts to evaluate change over time. RESULTS: Baseline included 355 patient-visits: 221 (62%) in-person and 134 (38%) virtual with critical data elements entry ranging between 50 and 60%. Post-intervention included 1,596 patient-visits: 1,350 (85%) in-person and 246 (15%) virtual, with critical data elements entry reaching 91%. All providers improved data entry during this study. In-person visits had significantly higher data capture rates than virtual visits for all 4 critical data elements. CONCLUSION: We achieved our aim to increase critical data element documentation by focusing on provider buy-in, frequent reminders, and individualized feedback. We also found that collection of critical data elements occurred significantly less often with virtual visits than with in-person visits. Now that we improved capture of critical data elements, we can shift the focus to efforts aimed at improving outcomes for patients with juvenile arthritis.

Biologic Switching Among Nonsystemic Juvenile Idiopathic Arthritis Patients: A Cohort Study in the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: Biologic medications have significantly improved disease control and outcomes of patients with juvenile idiopathic arthritis (JIA). Current treatment recommendations suggest escalating therapy, including changing biologics if needed, when inactive or low disease activity is not attained. The patterns and reasons for switching biologics in clinical practice in North America are not well described. METHODS: We used the Childhood Arthritis and Rheumatology Research Alliance Registry and included individuals with JIA if they newly started a biologic after January 1, 2008, and had at least 12 months of subsequent observable time. Subjects with systemic JIA were excluded. We compared characteristics of switchers and nonswitchers using chi-square for categorical variables and Wilcoxon rank-sum test for continuous variables, and used linear regression for time analysis. RESULTS: Of the eligible children, 1361 with JIA in the registry started a biologic (94% tumor necrosis factor inhibitors [TNFi]). Median followup time was 30 months and 349 (26%) switched biologics. Among biologic switchers, ineffectiveness/disease flare was the most common reason for switch (202, 58%). The most common documented switch was from etanercept to another TNFi (221, 63%). The median time to switch to a second biologic decreased substantially from 55.2 months in 2008 to 7.2 months in 2016. CONCLUSION: In a multicenter cohort of patients with JIA starting a biologic, one-quarter switched to a second biologic, and the time to switching decreased in recent years. Additional studies should evaluate the outcomes and optimal timing of switching and preferred sequence of biologic use.

Using quality improvement methodology and tools to reduce patient wait time in a paediatric subspecialty rheumatology clinic.

Our paediatric rheumatology clinic has experienced inefficient patient flow. Our aim was to reduce mean wait time and minimise variation for patients. Baseline data showed that most waiting occurs after a patient has been roomed, while waiting for the physician. Wait time was not associated with a patient's age, time of day, day of the week or individual physician. We implemented a checkout sheet and staggered start times. After a series of plan-do-study-act cycles, we observed an initial 26% reduction in the variation of wait time and a final 17% reduction in the mean wait time. There was no impact on patient-physician contact time. Overall, we demonstrate how process improvement methodology and tools were used to reduce patient wait time in our clinic, adding to the body of literature on process improvement in an ambulatory setting.

Parent Perspectives on Addressing Emotional Health for Children and Young Adults With Juvenile Myositis.

OBJECTIVE: To assess parent perspectives regarding the emotional health impact of juvenile myositis (JM) on patients and families, and to assess preferences for emotional health screening and interventions. METHODS: Parents of children and young adults with JM were purposively sampled for participation in focus groups at the Cure JM Foundation National Family Conference in 2018. Groups were stratified by patient age group (6-12, 13-17, and 18-21 years), and conversations were audiorecorded, transcribed verbatim, and co-coded via content analysis, with subanalysis by age group. A brief survey assessed preferences for specific emotional health interventions. RESULTS: Forty-five parents participated in 6 focus groups. Themes emerged within 2 domains: emotional challenges, and screening and interventions. Themes for emotional challenges comprised the impact of JM on: 1) patient emotional health, particularly depression and anxiety; 2) parent emotional health characterized by sadness, grief, anger, guilt, and anxiety; and 3) family dynamics, including significant sibling distress. Subanalysis revealed similar themes across age groups, but the theme of resiliency emerged specifically for young adults. Themes for emotional health screening and interventions indicated potential issues with patient transparency, several barriers to resources, the facilitator role of rheumatology providers, and preferred intervention modalities of online and in-person resources, with survey responses most strongly supporting child/parent counseling and peer support groups. CONCLUSION: JM is associated with intense patient and family distress, although resiliency may emerge by young adulthood. Despite existing barriers, increasing access to counseling, peer support groups, and online resources with rheumatology facilitation may be effective intervention strategies.

Treatment of Childhood-Onset Lupus Erythematosus Panniculitis With Rituximab.

Importance: Childhood-onset lupus erythematosus panniculitis (LEP) is a rare and chronic disfiguring disease. A paucity of literature exists on the clinical manifestations of this disease and how best to treat it. Objectives: To describe the clinical features of childhood-onset LEP and report on the use of rituximab in treatment-refractory childhood-onset LEP. Design, Setting, and Participants: A retrospective, observational case series study was conducted of 4 patients with childhood-onset LEP who presented to a single-center, tertiary care clinic with pediatric dermatology and pediatric rheumatology clinics between July 1, 2014, and July 1, 2018, and were treated with rituximab. A literature review was conducted of the clinical features and treatment of childhood-onset LEP. Exposure: Rituximab therapy for childhood-onset LEP. Main Outcomes and Measures: Reduction in the number and size of erythematous and tender subcutaneous nodules (both visually and by palpation), reduction of facial atrophy (documented with serial photography), and tolerability of rituximab at 2 to 22 months after initiation of therapy. Results: Four patients (3 male; mean [SD] age at treatment, 15 [5.9] years) with refractory childhood-onset LEP were successfully treated with rituximab. All patients had a rapid and sustained response to therapy with rituximab. One patient (25%) had minor infusion reactions; otherwise, treatment was well tolerated. Conclusions and Relevance: This case series suggests that rituximab may hold promise as a treatment for refractory, childhood-onset LEP. Larger, prospective studies are needed to validate these findings; however, given the rarity of disease, large studies may be difficult to conduct.

Henoch-Schönlein Purpura Presenting in Association With Neuroblastoma: A Case Report.

Henoch-Schönlein purpura (HSP) is a common systemic vasculitis affecting children. It is managed in the outpatient setting and rarely associated with malignancy. We present a case of neuroblastoma in a 7-year-old boy diagnosed after suspected HSP. Our case highlights the importance of maintaining a broad differential diagnosis in children with atypical HSP and performing a skin biopsy with immunofluorescence when a rash is present.

Identifying Research Priorities among Patients and Families of Children with Rheumatic Diseases Living in the United States.

OBJECTIVE: To improve the quality and participation in pediatric rheumatology research, patient-prioritized studies should be emphasized. We collaborated with United States-based pediatric rheumatology advocacy organizations to survey patients and caregivers of children with rheumatic diseases to identify what research topics were most important to them. METHODS: We conducted Web-based surveys and focus groups (FG) of patients and caregivers of children with juvenile myositis (JM), juvenile arthritis (JA), and childhood-onset systemic lupus erythematosus (cSLE). Surveys were emailed to listservs and posted to social media sites of JM, JA, and cSLE patient advocacy organizations. An initial survey asked open-ended questions about patient/caregiver research preferences. Responses were further characterized through FG. A final ranking survey asked respondents to rank from a list of research themes the 7 most important to them. RESULTS: There were 365 JM respondents, 44 JA respondents, and 32 cSLE respondents to the final ranking survey. The top research priority for JM was finding new treatments, and for JA and cSLE, the priority was understanding genetic/environmental etiology. The 3 prioritized research themes common across all disease groups were medication side effects, disease flare, and disease etiology. CONCLUSION: Patient-centered research prioritization is recognized as valuable in conducting high-quality research, yet there is a paucity of data describing patient/family preferences, especially in pediatrics. We used multimodal methodologies to assess current patient/caregiver research priorities to help frame the agenda for the pediatric rheumatology research community. Patients and caregivers from all surveyed disease groups prioritized the study of medication side effects, disease flares, and disease etiology.