Disease Course, Treatments, and Outcomes of Children With Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease.

OBJECTIVE: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes. METHODS: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD. RESULTS: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time. CONCLUSION: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials.

HLA-DRB1*15 and Eosinophilia Are Common Among Patients With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Concern exists that medications used to treat patients with systemic juvenile idiopathic arthritis (JIA), particularly interleukin (IL)-1 and IL-6 blocking agents, might be causing adverse drug reactions and lung disease (systemic JIA-LD). Carriage of HLA-DRB1*15 has been reported as a risk factor for adverse drug reactions among patients with systemic JIA. We performed a retrospective chart review to evaluate these factors at our center. METHODS: We reviewed the records of 86 subjects with systemic JIA followed for at least 6 months between 1996 and 2022. HLA typing was performed in 23 of the subjects. We compared characteristics of patients with or without eosinophilia. Among patients with HLA typing, we compared clinical characteristics of subjects with or without DRB1*15 and with or without systemic JIA-LD. RESULTS: Among the 23 patients with HLA typing, 74% carried DRB1*15, and 63% of patients without systemic JIA-LD carried DRB1*15. Seven subjects had systemic JIA-LD, all of whom carried DRB1*15. Patients with systemic JIA-LD were younger at the time of diagnosis and more likely to have had macrophage activation syndrome. Exposure to IL-1 and IL-6 blockers was common, occurring in 95% of patients. Eosinophilia occurred in 39% of patients with systemic JIA, often before IL-1 or IL-6 blockade. Eosinophilia was associated with adverse drug reactions and macrophage activation syndrome. There was 1 death, unrelated to active systemic JIA disease. CONCLUSION: Carriage of DRB1*15 was more common in this cohort of patients with systemic JIA than in the general population. Eosinophilia and systemic JIA-LD were more common among patients with severe systemic JIA complicated by macrophage activation syndrome.

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.

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.

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.

Learner Levels of Supervision Across the Continuum of Pediatrics Training.

PURPOSE: To describe trajectories in level of supervision ratings for linked entrustable professional activities (EPAs) among pediatric learners in medical school, residency, fellowship. METHOD: The authors performed secondary analyses of 3 linked datasets of level of supervision ratings for the Core EPAs for Entering Residency, the General Pediatrics EPAs, and the Subspecialty Pediatrics EPAs. After identifying 9 activities in common across training stages and aligning the level of entrustment-supervision scales across the datasets, piecewise ordinal and linear mixed effects models were fitted to characterize trajectories of supervision ratings. RESULTS: Within each training period, learners were rated as needing less supervision over time in each activity. When transitioning from medical school to residency or during the first year of residency, learners were rated as needing greater supervision in activities related to patient management, teamwork, emergent care, and public health/QI than in earlier periods. When transitioning from residency to fellowship, learners were always rated as needing greater supervision than they had been accorded at the end of residency and sometimes even more than they had been accorded at the start of residency. CONCLUSIONS: Although development over training is often imagined as continuous and monotonically increasing competence, this study provides empirical evidence supporting the idea that entrustment is a set of discrete decisions. The relaxation of supervision in training is not a linear process. Even with a seamless curriculum, supervision is tightly bound to the training setting. Several explanations for these findings are discussed.

The Minnesota Method: A Learner-Driven, Entrustable Professional Activity-Based Comprehensive Program of Assessment for Medical Students.

PROBLEM: Assessment has been the Achilles heel of competency-based medical education. It requires a program of assessment in which outcomes are clearly defined, students know where they are in the development of the competencies, and what the next steps are to attaining them. Achieving this goal in a feasible manner has been elusive with traditional assessment methods alone. The Education in Pediatrics Across the Continuum (EPAC) program at the University of Minnesota developed a robust program of assessment that has utility and recognizes when students are ready for the undergraduate to graduate medical education transition. APPROACH: The authors developed a learner-driven program of assessment in the foundational clinical training of medical students in the EPAC program based on the Core Entrustable Professional Activities for Entering Residency (Core EPAs). Frequent workplace-based assessments, coupled with summative assessments, informed a quarterly clinical competency committee and individualized learning plans. The data were displayed on real time dashboards for the students to review. OUTCOMES: Over 4 cohorts from 2015 to 2019, students (n = 13) averaged approximately 200 discrete Core EPA workplace-based assessments during their foundational clinical training year. Assessments were completed by an average of 9 different preceptors each month across 8 different specialties. The data were displayed in a way students and faculty could monitor development and inform a clinical competency committee's ability to determine readiness to transition to advanced clinical rotations and residency. NEXT STEPS: The next steps include continuing to scale the program of assessment to a larger cohort of students.

Validity Evidence for Assessing Entrustable Professional Activities During Undergraduate Medical Education.

PURPOSE: To explore validity evidence for the use of entrustable professional activities (EPAs) as an assessment framework in medical education. METHOD: Formative assessments on the 13 Core EPAs for entering residency were collected for 4 cohorts of students over a 9- to 12-month longitudinal integrated clerkship as part of the Education in Pediatrics Across the Continuum pilot at the University of Minnesota Medical School. The students requested assessments from clinical supervisors based on direct observation while engaging in patient care together. Based on each observation, the faculty member rated the student on a 9-point scale corresponding to levels of supervision required. Six EPAs were included in the present analyses. Student ratings were depicted as curves describing their performance over time; regression models were employed to fit the curves. The unit of analyses for the learning curves was observations rather than individual students. RESULTS: (1) Frequent assessments on EPAs provided a developmental picture of competence consistent with the negative exponential learning curve theory; (2) This finding was true across a variety of EPAs and across students; and (3) The time to attain the threshold level of performance on the EPA for entrustment varied by student and EPA. CONCLUSIONS: The results provide validity evidence for an EPA-based program of assessment. Students assessed using multiple observations performing the Core EPAs for entering residency demonstrate classic developmental progression toward the desired level of competence resulting in entrustment decisions. Future work with larger data samples will allow further psychometric analyses of assessment of EPAs.

Successful Rituximab Monotherapy in Advanced-stage, Epstein-Barr Virus-positive Diffuse Large B-Cell Lymphoma in an Adolescent With Systemic Juvenile Idiopathic Arthritis.

Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) in pediatrics most commonly occurs as an iatrogenic immunodeficiency-associated lymphoproliferative disease. We report an 18-year-old female individual with refractory systemic juvenile idiopathic arthritis, treated with multiple immunosuppressive agents, who was diagnosed with stage III, EBV+ DLBCL. The patient achieved sustained complete remission after 4 weekly doses of rituximab monotherapy and reduction of immunosuppression. This case suggests that a post-transplant lymphoproliferative disease-like treatment approach can be a safe and effective therapy in a nontransplant, yet severely immunosuppressed, patient with EBV+ DLBCL.

Rapid Infliximab Infusion in the Pediatric Population.

OBJECTIVES: To compare infusion reaction rates between rapid infliximab (REMICADE, Janssen Biotech Inc) infusions and previous standard 2- to 3-hour infusions; additionally, to assess patient satisfaction and reduction in chair time associated with rapid infliximab infusions. METHODS: Pediatric rheumatology and gastroenterology patients receiving maintenance infliximab therapy using a standard 2- to 3-hour titrated infusion had the opportunity to enroll in the non-titrated rapid 1-hour infusion protocol following tolerance of induction dosing at 0, 2, and 6 weeks. Patients were included from December 1, 2017, to March 31, 2018, via retrospective chart review and patient satisfaction surveys. RESULTS: Data were collected on 55 patients receiving a total of 160 rapid infliximab infusions. There were 2 infusion reactions during the enrollment and data collection period, resulting in an overall infusion reaction rate of 1.3%. The patient satisfaction survey results showed all patients were at minimum satisfied with the information provided regarding rapid infliximab, decreased time spent in clinic, ease of scheduling, and overall process. CONCLUSIONS: Our data suggest rapid infliximab infusions are safe in pediatric rheumatology and gastroenterology patients receiving maintenance infliximab infusion therapy. The overall infusion reaction rate of 1.3% in this study is well below the accepted infusion reaction rate of standard-length infliximab infusions of 2% to 3%.

Shared Mental Models Among Clinical Competency Committees in the Context of Time-Variable, Competency-Based Advancement to Residency.

PURPOSE: To evaluate response process validity evidence for clinical competency committee (CCC) assessments of first-year residents on a subset of General Pediatrics Entrustable Professional Activities (EPAs) and milestones in the context of a national pilot of competency-based, time-variable (CBTV) advancement from undergraduate to graduate medical education. METHOD: Assessments of 2 EPAs and 8 milestones made by the trainees' actual CCCs and 2 different blinded "virtual" CCCs for 48 first-year pediatrics residents at 4 residency programs between 2016 and 2018 were compared. Residents had 3 different training paths from medical school to residency: time-variable graduation at the same institution as their residency, time-fixed graduation at the same institution, or time-fixed graduation from a different institution. Assessments were compared using ordinal mixed-effects models. RESULTS: Actual CCCs assigned residents higher scores than virtual CCCs on milestones and one EPA's supervision levels. Residents who graduated from a different institution than their residency received lower milestone ratings than either group from the same institution; CBTV residents received higher ratings on one milestone (ICS4) and similar ratings on all others compared with non-CBTV residents who completed medical school at the same institution. CONCLUSIONS: First-year residents who graduated from CBTV medical school programs were assessed as having the same level of competence as residents who graduated from traditional medical school programs, but response process evidence suggests that members of CCCs may also draw on undocumented personal knowledge of the learner to draw conclusions about resident competence.

Pediatric Career Choice: Insights From a Novel, Medical School Pathway Program.

OBJECTIVE: Research on how medical students choose a career in pediatrics is either dated or conflated with primary care career choice. Capitalizing on student participation in an innovative, time-variable, competency based pathway program, Education in Pediatrics Across the Continuum (EPAC), the authors explored the process of career decision-making in students at 5 medical schools (including 4 EPAC sites) who begin medical school with an interest in pediatrics. METHODS: Individual, semistructured interviews were conducted with students in 5 groups: Group 1: accepted into EPAC, n = 8; Group 2: accepted into EPAC, opted-out, n = 4; Group 3 applied to EPAC, not accepted, pursued pediatrics, n = 4; Group 4: applied to EPAC, not accepted, did not pursue pediatrics, n = 3; Group 5: pursued pediatrics at a non-EPAC site, n = 6. Data collection and analysis occurred iteratively, with inductive coding of data revealing patterns in data explored in subsequent interviews and refined in the final analysis. RESULTS: All students described intrinsic guiding principles, that is, "doing what you love," that attracted them to pediatrics. They described extrinsic, phase-specific experiences before medical school, before clerkship, and in clerkship that shaped their perceptions of a career in pediatrics and shed light on collective values of different specialties. Student's assessment of how their guiding principles aligned with the collective values of pediatrics, which students encountered in the clerkship phase, was a key to making career decisions. CONCLUSIONS: Intrinsic and extrinsic factors do not act alone but interact in clerkships, and influence career choice of students who enter medical school with an interest in pediatrics.

Crossing the Gap: Using Competency-Based Assessment to Determine Whether Learners Are Ready for the Undergraduate-to-Graduate Transition.

In 2011, the Education in Pediatrics Across the Continuum (EPAC) Study Group recruited four medical schools (University of California, San Francisco; University of Colorado; University of Minnesota; and University of Utah) and their associated pediatrics clerkship and residency program directors to be part of a consortium to pilot a model designed to advance learners from undergraduate medical education (UME) to graduate medical education (GME) and then to fellowship or practice based on competence rather than time spent in training. The central design features of this pilot included predetermined expectations of performance and transition criteria to ensure readiness to progress from UME to GME, using the Core Entrustable Professional Activities for Entering Residency (Core EPAs) as a common assessment framework. Using this framework, each site team (which included, but was not limited to, the EPAC course, pediatric clerkship, and pediatric residency program directors) monitored learners' progress, with the site's clinical competency committee marking the point of readiness to transition from UME to GME (i.e., the attainment of supervision level 3a). Two of the sites implemented time-variable transition from UME to GME, based on when a learner met the performance expectations and transition criteria. In this Article, the authors describe each of the four sites' implementation of Core EPA assessment and their approach to gathering the data necessary to determine readiness for transition. They conclude by offering recommendations and lessons learned from the pilot's first seven years of development, adaptation, and implementation of assessment strategies across the sites, and discussing next steps.

Successful treatment of severe subacute cutaneous lupus erythematosus with rituximab in an adolescent.

Subacute cutaneous lupus erythematosus is rare in children. Most patients respond well to conventional therapy with prednisone, hydroxychloroquine, or both. Other case reports and small series have reported successful clearance with rituximab in adults. We report an adolescent who obtained remission with rituximab after failing conventional therapy.

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.

Rituximab treatment for isolated IgG4-related hypophysitis in a teenage female.

IgG4-related hypophysitis is an important diagnostic consideration in patients with a pituitary mass or pituitary dysfunction and can initially present with headaches, visual field deficits and/or endocrine dysfunction. Isolated IgG4-related pituitary disease is rare, with most cases of IgG4-related disease involving additional organ systems. We report the case of a teenage female patient with isolated IgG4-related hypophysitis, diagnosed after initially presenting with headaches. Our patient had no presenting endocrinologic abnormalities. She was treated with surgical resection, prednisolone and rituximab with no further progression of disease and sustained normal endocrine function. This case, the youngest described patient with isolated IgG4-related hypophysitis and uniquely lacking endocrinologic abnormalities, adds to the limited reports of isolated pituitary disease. The use of rituximab for isolated pituitary disease has never been described. While IgG4-related hypophysitis has been increasingly recognized, substantial evidence concerning the appropriate treatment and follow-up of these patients is largely lacking. Learning points: IgG4-related hypophysitis most often occurs in the setting of additional organ involvement but can be an isolated finding. This diagnosis should therefore be considered in a patient presenting with pituitary abnormalities. Most patients with IgG4-related hypophysitis will have abnormal pituitary function, but normal functioning does not exclude this diagnosis. Corticosteroids have been the mainstay of therapy for IgG4-related disease, with other immunosuppressive regimens being reserved for refractory cases. Further research is needed to understand the effectiveness of corticosteroid-sparing regimens and whether there is utility in using these agents as first-line therapies.

Fcγ receptor III and Fcγ receptor IV on macrophages drive autoimmune valvular carditis in mice.

OBJECTIVE: Arthritis and valvular carditis coexist in several human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis. T cell receptor-transgenic K/BxN mice develop spontaneous autoantibody-associated arthritis and valvular carditis. The common Fc receptor γ (FcRγ) signaling chain is required for carditis to develop in K/BxN mice. FcRγ pairs with numerous receptors in a variety of cells. The aim of this study was to identify the FcRγ-associated receptors and Fcγ receptor (FcγR)-expressing cells that mediate valvular carditis in this model. METHODS: We bred K/BxN mice lacking the genes that encode activating Fcγ receptors (FcγRI, FcγRIII, and FcγRIV), and we assessed these mice for valvular carditis. We similarly evaluated complement component C3-deficient K/BxN mice. Immunohistochemistry, bone marrow transplantation, and macrophage depletion were used to define the key FcRγ-expressing cell type. RESULTS: Genetic deficiency of only one of the activating Fcγ receptors did not prevent carditis, whereas deficiency of all 3 activating Fcγ receptors did. Further analysis demonstrated that FcγRIII and FcγRIV were the key drivers of valve inflammation; FcγRI was dispensable. C3 was not required. FcRγ expression by radioresistant cells was critical for valvular carditis to develop, and further analysis indicated that macrophages were the key candidate FcγR-expressing effectors of carditis. CONCLUSION: FcγRIII and FcγRIV act redundantly to promote valvular carditis in K/BxN mice with systemic autoantibody-associated arthritis. Macrophage depletion reduced the severity of valve inflammation. These findings suggest that pathogenic autoantibodies engage Fcγ receptors on macrophages to drive valvular carditis. Our study provides new insight into the pathogenesis of cardiovascular inflammation in the setting of autoantibody-associated chronic inflammatory diseases.

Macrophage scavenger receptor 1 (Msr1, SR-A) influences B cell autoimmunity by regulating soluble autoantigen concentration.

The class A macrophage scavenger receptor Msr1 (SR-A, CD204) has been reported to participate in the maintenance of immunological tolerance. We investigated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in K/BxN TCR transgenic mice decreased the incidence and severity of arthritis because of decreased autoantibody production. Despite normal initial activation of autoreactive CD4(+) T cells, potentially autoreactive B cells in Msr1(-/-) K/BxN mice retained a naive phenotype and did not expand. This was not due to an intrinsic B cell defect. Rather, we found that macrophages lacking Msr1 were inefficient at taking up the key autoantigen glucose-6-phosphate isomerase and that Msr1-deficient mice had elevated serum concentrations of glucose-6-phosphate isomerase. Arthritis developed normally when bone marrow from Msr1(-/-) K/BxN mice was transplanted into hosts whose macrophages did express Msr1. Thus, Msr1 can regulate the concentration of a soluble autoantigen. In this model, the absence of Msr1 led to higher levels of soluble autoantigen and protected mice from developing pathogenic autoantibodies, likely because of altered cognate interactions of autoreactive T and B cells with impaired differentiation of follicular Th cells.