Proceedings of the 2024 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Annual Scientific Meeting

Pediatric Rheumatology 2024, 22(S1):A1

Background: Chronic Nonbacterial Osteomyelitis (CNO) is characterized by sterile inflammatory bone lesions and most commonly affects skeletally immature children. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment, but in some cases second-line treatments including methotrexate, TNF-alpha inhibitors, and bisphosphonates are required. It remains unclear which patients are most likely to respond to NSAIDs or require a second-line treatment based on their initial presentation. In this study, we sought to describe our CNO cohort and to determine which clinical variables are associated with response to NSAID monotherapy versus requiring a second-line medication.

Methods : A retrospective chart review of patients with a diagnosis of CNO made before 18 years of age who attended the CNO clinic at Children’s Hospital Colorado between 1/1/05 and 1/31/22 was performed. The standardized treatment approach involved 6 months of NSAIDs, followed by a trial of discontinuation in responders. Patients who failed the discontinuation trial were given a longer NSAID course. Patients with spinal involvement, patients with comorbidities such as psoriasis or inflammatory bowel disease, and NSAID-non-responders were treated with second-line therapies. Clinical characteristics were recorded, including which of 6 regions (head and face, neck and back, upper torso, upper extremities, lower torso, lower extremities) were affected by CNO. Patients were divided into three groups: NSAID-short (NSAID monotherapy for 3 to < 7 months), NSAID-long (NSAID monotherapy for ≥7 months), or second-line treatment. A multiple linear regression model was constructed to determine the relationship between total NSAID monotherapy days and relevant predictors. Multiple logistic regression was used to determine the odds of needing second-line treatment when considering those same predictors. Both models contained combinations of variables which minimized the Akaike Information Criteria (AIC), resulting in models with low multicollinearity and high predictive power.

Results : 164 patients fulfilled inclusion criteria and 70 patients were excluded. Cohort characteristics overall and for each of the 3 treatment groups are presented in Table 1. Comparison between the NSAID-short and NSAID-long groups showed that patients with unifocal disease at diagnosis required 47% less days of NSAID treatment than those with multifocal disease at diagnosis (Table 2). Comparison of the NSAID monotherapy groups to the second-line treatment group showed that patients with 2 or more regions affected by CNO were 1.94 times more likely to require a second-line treatment (p < 0.05) and that patients with symmetric bone lesions were 6.86 times more likely to require a second-line treatment (p< 0.0001) (Table 3).

Conclusions : Our cohort is similar to other reported CNO cohorts in terms of clinical characteristics. Patients with unifocal CNO involvement at diagnosis are more likely to require shorter NSAID treatment courses. Patients with 2 or more regions affected by CNO and those with symmetric bone lesions are more likely to require a second-line treatment. These findings may inform treatment choices for patients with CNO.

IRB Statement : This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of record of records, the Colorado Multiple Institutional Review Board (COMIRB) approved this study. Informed consent and assent were obtained from all individual participants enrolled in this study after January 1, 2018 as data was collected prospectively, but consent was waived for those patients enrolled prior to January 1, 2018 given the retrospective nature of data collection for these patients.

Pediatric Rheumatology 2024, 22(S1):A2

Background: Juvenile idiopathic arthritis (JIA) carries a risk of permanent joint damage and disability in children [1]. In adult rheumatoid arthritis (RA), early aggressive treatment can lead to remission. Treatment paradigms in JIA remain reactive rather than proactive due to lack of reliable methods to predict extension to a polyarticular course. Our objective was to validate cell subpopulations using flow cytometry to predict which patients have a high likelihood of extending.

Methods: JIA FLS cell lines from oligoarticular (oligo), extended-to-be (ETB), and polyarticular (poly) types were cultured. Flow cytometry was performed by Raybiotech, Inc. scRNA-seq was performed by Genewiz using 10x Genomics Chromium protocols. SeuratR package was used for data analysis.

Results: Our scRNA-seq data showed that fibroblast-like synoviocytes (FLS) are heterogeneous [2]. Prominent subpopulations were FLS, smooth muscle cell-like cells (SMC), and chondrocyte-like cells (CH) (Figure 1). We performed flow cytometry on normal cell lines to determine if traditional markers for FLS, SMC, and CH can distinguish these cell types from one another. These markers did not confidently isolate these cell types (Table 1). We further analyzed our scRNA-seq data for markers that could distinguish JIA subtypes via flow cytometry (CH – SMOC2, SOX9; FLS – IGFBP4, VCAN; SMC – CD309). These markers could not distinguish FLS from CH using flow. We revisited Seurat single analysis data and identified the top genes of each cell type for each subtype. Genes that contribute the most variation among cells within oligo and ETB JIA subtypes and encode secreted proteins are as follows: oligo - COL1A1, ACAN, and IFI27, ETB - SERPINE1, COL3A1, and VCAM (Figure 2).

Conclusions: While flow cytometry has proven unable to distinguish between cell subpopulations within FLS cultures, these cell subpopulations have unique genetic fingerprints with transcript expression levels that can be used to distinguish JIA subtypes.

IRB Statement : Synovial fluid and fibroblast-like synoviocyte samples were obtained from the Nemours BioMedical Institutional Review Board-approved repository (IRB#84709-32). This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. Patients who underwent clinically indicated arthrocentesis were offered inclusion into the repository and informed consent was obtained. There is no identifying information in this publication.

Acknowledgements : This study was funded by a CARRA-Arthritis Foundation Large grant. The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA.

Reference

Pediatric Rheumatology 2024, 22(S1):A3

Background : Lupus nephritis (LN) is associated with significant morbidity and mortality. The 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification criteria and the NIH chronicity activity indices are used for LN classification. Some adult studies report tubulointerstitial (TI) inflammation is an independent predictor of renal outcomes in LN, however its impact in pediatric LN remains unexplored.

Methods : We conducted a retrospective, observational cohort study utilizing a subgroup analysis of patients with biopsy-confirmed LN. Inclusion criteria encompassed all patients with biopsy-confirmed lupus nephritis, where the renal biopsies were performed at the University of Chicago between January 1, 2006, and September 6, 2022. Patients were required to be ≤ 21 years of age at the time of their initial kidney biopsy. Exclusion criteria consisted of a follow-up duration of ≤ 3 months and an age ≥ 16 years at the time of initial lupus diagnosis. Non-native renal biopsies were also excluded. The primary outcome measure was end-stage renal disease (ESRD).

Results : Out of 99 identified biopsies, 42 were excluded, leaving 57 patients for analysis (see figure 1). The mean follow-up duration was 74 months (SD 26, max 210). Tubulointerstitial (TI) inflammation demonstrated a significant association with ESRD, with a hazard ratio of 6.7 (95% CI 1.8 – 24.7). Patients with TI inflammation experienced a shorter time to ESRD (mean 21.51 months, SD 20.32) compared to those without TI inflammation (mean 64.33 months, SD 37.65; see figure 2). Single variable analysis showed ESRD was also correlated with the NIH activity index (HR 1.17, 95% CI 1.06 – 1.3), the NIH chronicity index (HR 2.7, 95% CI 1.57 – 4.65), GFR (HR 6.7, 95% CI 2.7-17), and ISN class IV nephritis on biopsy (HR 6.7, 95% CI 2.15 – 21.4). However, ESRD was not correlated with race, sex, Hispanic ethnicity, or SLEDAI (see table 1). This retrospective study had a limited number of ESRD events.

Conclusions : Our findings indicate a significant association between tubulointerstitial (TI) inflammation, baseline activity / chronicity indices, initial GFR stage, ISN Class IV and the primary endpoint of ESRD in our pediatric lupus nephritis cohort. The presence of TI inflammation was also associated with a shorter time to ESRD. We are performing ongoing renal biopsy analysis to assess the impact of TI injury as measured by the NIH chronicity index to better understand the impact of TI involvement and renal outcomes.

IRB Statement : This research involved human materials and data. It was performed in accordance with the Declaration of Helsinki and has been approved by the local Institutional Review Board (ID: IRB22-1421).

Pediatric Rheumatology 2024, 22(S1):A4

Background : Down syndrome (DS) is one of the most common chromosomal conditions that affects approximately 1 in 1000 live births globally. Triplication of chromosome 21 seen in DS is associated with a four-to-six-fold higher risk of autoimmunity compared to the general population. Individuals with DS have a significantly higher prevalence of inflammatory arthritis, termed Down Syndrome-associated arthritis (DA), compared to the general population. Historically, when compared to juvenile idiopathic arthritis (JIA), the most common pediatric rheumatic disease, there has been a delay in diagnosis of DA. Additional research is needed to better elucidate the similarities and differences between DA and JIA, to improve the care of individuals with DA, and allow for earlier diagnosis and treatment. The objective of this study was to compare the clinical presentation and outcomes between DA and JIA in the Pediatric Rheumatology Care & Outcomes Improvement Network (PR-COIN) registry.

Methods : The PR-COIN registry was used to perform a retrospective case-control study that compared patients with DA matched to patients with JIA. Patients were matched on age, gender, arthritis subtype, and medication exposure. Pain rating and clinical juvenile arthritis disease activity scores ([cJADAS], which is a composite measure of active joint count, physician and patient global assessments [MD-global, Pt-global]), were compared between DA and JIA groups.

Results : Twenty patients with DA and 100 with JIA were identified. The mean days between first and last visits were 1157 for patients with JIA and 1664 for DA. Patients mostly had polyarticular arthritis subtype (70%), and those with DA had more comorbid autoimmune conditions, but less uveitis compared to the JIA group (Table 1). At the last visit those with DA had lower cJADAS scores compared to the JIA group. All measures of the cJADAS were decreased with the largest decrease in Pt-global scores when comparing between DA and JIA groups. The DA group had an average pain score that improved over time and trended with MD-global score; whereas the JIA group had a pain score that increased over time and did not trend with MD-global score (Table 2). The medication distribution and exposure were the same between groups (Table 3).

Conclusions: While a delay in diagnosis of DA is not uncommon, this study suggests that with appropriate treatment patients with DA can have similar clinical outcomes compared to those with JIA. Additionally, those with DA report less pain compared to those with JIA, and reported pain tracked with active disease for those with DA, but not JIA. This suggests that with appropriate treatment patients with DA demonstrate good resilience and improved clinical outcomes. Further, pain rating may be a poor outcome measure for active disease in patients with JIA and may represent a larger impact of central nervous system sensitization and mental health comorbidities compared to patients with DA. Here we illustrate the importance of early disease recognition and treatment, which can improve outcomes for those with DA. More research is needed to determine differences and impact of pain perception between those with JIA and DA.

IRB Statement : This study has been granted an exemption from IRB by the Children’s Mercy Research Institute IRB. The study meets criteria for Exemption Determination under Code of Federal Regulations 45 CFR 46.106 (d) category 4 (iii). Approval for exemption was effective as of 5/8/2023. CM IRB number STUDY00002736 entitled “Arthritis Outcomes for Those with Down Syndrome in the PR-COIN Registry”

Acknowledgements : We would like to acknowledge the contributions of Jade Singleton, PhD and Xing Wang, PhD, biostatisticians for the Pediatric Rheumatology Care & Outcomes Improvement Network (PR-COIN) registry. Dr. Singleton and Dr. Wang provided significant assistance in analyzing the data on this project; however, were not involved in the conceptualization of the project nor the drafting or revision of the final abstract. We will be disclosing their involvement to the learner in written form at any presentation of this study.

Pediatric Rheumatology 2024, 22(S1):A5

Background : Exercise can improve general health and, in patients with juvenile idiopathic arthritis (JIA), it helps with common problems such as fatigue, weakness, and pain, increasing quality of life. However, there are barriers to exercising regularly when facing JIA, and commonly, these patients do not complete the minimum daily exercise requirements and maintain a sedentary lifestyle.

Methods : An observational, cross-sectional, prospective, descriptive study, with a mixed and sequential evaluative study design, including qualitative techniques, was carried out. The population included patients with JIA and their caregivers; pediatric rheumatologists; and sports coaches or physical education teachers. A semi-structured interview guide was created by a group of experts (3 pediatric rheumatologists, 1 physiotherapist, 1 methodologist/anthropologist, 1 patient, 1 caregiver, and 1 Physical Medicine and Rehabilitation physician), and it was evaluated in a pilot study to confirm its relevance and understanding. The interviews aimed to assess the perspectives and attitudes about physical activity (PA) and exercise, including their knowledge, adherence, motivations, preferences, barriers, and facilitators to do it.

Results : We included 20 patients with a median age of 12 (9-15), 11 (55%) were men. The most common JIA subtype was enthesitis-related arthritis (7, 35%). Nine patients (45%) had high disease activity at the time of the interview and 7 (35%) had inactive disease. Most patients (12, 60%) did not exercise regularly, the main reasons and barriers were disease activity, pain, and concerns about being injured. Of the patients who exercised regularly (8, 40%), half reported doing so for pleasure and the other half to improve disease symptoms. Twelve patients (60%) exercised before the onset of the disease, however, half stopped due to disease activity, and those who did exercise regularly reported emotional and physical benefits. Fourteen (70%) patients reported that they had received information about the importance of exercise, in most cases given by the doctors. There was observed confusion about the differences between PA and exercise in most of the participants, independently of the group.

Conclusions : We observed confusion about the differences between PA and exercise, and myths and fears about the risks of performing it while having JIA. Most of the patients do not exercise regularly, with pain and high disease activity being the main barriers. On the other hand, those who did exercise regularly reported emotional and physical benefits.

IRB Statement : The study complies with the ethical guidelines of the Declaration of Helsinki and local regulations. This is a minimal-risk study since it only involves the application of interview guides to the participants and does not require biological sampling, or invasive procedures to the participants. An institutional review board approved the protocol and other written information provided to patients and their legal representatives.

Pediatric Rheumatology 2024, 22(S1):A6

Background : Methotrexate (MTX) is commonly utilized for treating JIA. Despite its longstanding clinical use, we are unable to predict responders in advance. Identifying clinical factors predictive of response to MTX would optimize patient care and reduce morbidity. We aimed to identify clinical characteristics predictive of MTX response in patients with JIA.

Results : There were 589 patients identified across 3674 encounters started on MTX within the study period. There were 401 females (68%), with a median age of 11 years [IQR 6, 14], symptom duration prior to JIA diagnosis of 16 months [8, 46], and disease duration of 63 days [0, 297] at initiation of MTX therapy. Discontinuation rate of MTX due to side effects was 36%. ANA positivity and disease duration had significantly lower hazards or discontinuing MTX therapy on univariate analysis. Symptom duration greater than 6 months, morning stiffness, poor physical function, increased pain, increased patient and provider global scores, increased active joint count, increased disease activity score, and higher baseline patient-reported outcomes had higher hazards of discontinuing MTX therapy (Table 1, figure). Rheumatoid factor negative and positive polyarthritis, enthesitis related arthritis, and psoriatic arthritis were associated with significantly higher hazards of stopping MTX in univariate analysis. In multivariate analysis, no variables were associated with discontinuation of MTX therapy (Table 2).

Conclusions : It remains challenging to model MTX response based solely on clinical factors. This highlights the need for further research looking into artificial intelligence, pharmacogenomic biomarkers, and incorporation of genomic data into predictive modeling.

IRB Statement : This study was approved by the Nationwide Childrens Hospital IRB on 3/3/23 under IRB study ID STUDY00003136.

Pediatric Rheumatology 2024, 22(S1):A7

Background : Childhood rheumatologic and musculoskeletal diseases (cRMDs) can cause significant morbidity and mortality, especially if not diagnosed and treated promptly. 33% of medical schools and 36% of pediatric residency programs have no affiliated pediatric rheumatologist, and many centers have a single provider covering a large catchment area. This can result in delayed patient care and inadequate clinical rheumatology education for pediatric trainees. Only 2% of the American Board of Pediatrics (ABP) content specifications pertain to cRMDs, which further decreases the likelihood that pediatric residents will allocate their studying time to these conditions. We believe that all trainees should graduate with practical knowledge about the presentation and initial management of cRMDs to optimize pediatric patient outcomes. The purpose of this study was to define essential knowledge areas in pediatric rheumatology for graduating pediatric residents.

Methods : We performed an extensive literature search of resources describing topics pertinent to pediatric rheumatology and considered potentially important for resident education. These findings were compiled into a survey that asked respondents, “How important is it for graduating pediatric residents to demonstrate competency in each of these rheumatology-related activities?” An expert focus group refined proposed items for the initial survey, and subsequent surveys were created iteratively based on the responses to prior surveys. Surveys were created in Qualtrics (Qualtrics, Provo, UT) and sent to invited participants between April 2023 and July 2023. Voting panel members were invited to participate in a modified Delphi process via email. Data was analyzed in Excel (Microsoft, Redmond, WA).

Results : Panelists were recruited as stakeholders in rheumatology-related pediatric resident education; the group represented diverse geographic and specialty backgrounds with a broad range of clinical experience. A total of 21 panelists completed two rounds of surveys with a 100% completion rate. Our analysis yielded a total of 107 items: those rated by >70% of respondents as “Very Important” were categorized as Essential (n = 52, 49.6%), and those rated by >70% of respondents as either “Very Important” or “Somewhat Important” categorized as Recommended (n = 55, 51.4%). The final list of items was organized into groups based on specific disease relevance and general principles of communication and patient management.

Conclusions : The current ABP content specifications are insufficient to prepare graduating pediatric residents to contend with cRMDs commonly encountered in the pediatric population. As we face a pediatric rheumatology workface shortage, having access to an expanded, standardized list of important rheumatology-related competencies might better prepare graduating pediatric residents to both serve patients with cRMDs and avoid unnecessary specialty referrals. The creation and distribution of these Delphi survey results with our shared opinion on the most appropriate pediatric rheumatology competencies will enhance critical education for the pediatric resident.

IRB Statement : This study was approved by the Johns Hopkins School of Medicine Institutional Review Board IRB00323040

Acknowledgements : On behalf of the CARRA Medical Education Workgroup. The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA.

Pediatric Rheumatology 2024, 22(S1):A8

Background : Involvement of the TMJ in JIA is a risk factor for poor prognosis due to its potential impact on mandibular growth, functional impairment, and associated comorbidities. Early diagnosis and treatment of TMJ arthritis is critical in preventing long-term complications. This study aims to evaluate the characteristics and therapeutic interventions of JIA patients with confirmed TMJ involvement.

Methods : In this retrospective cross-sectional study, data was abstracted from the electronic medical records of JIA patients with TMJ involvement confirmed by MRI from 2013 and 2023. Descriptive statistics were used to summarize patient characteristics, clinical features, radiographic findings, and therapeutic treatments.

Results : A total of 54 patients were included (see Table 1). The majority were female (87%), White (89%), and non-Hispanic (80%). The average age of JIA diagnosis was 7 years (SD ± 5.2), and the mean age at TMJ arthritis diagnosis was 12 years (SD ± 3.7). The most frequent JIA subtype was polyarticular (54%). ANA was positive in 65%, HLA-B27 in 9%, RF in 6%, and CCP in 6%. Thirty-six (67%) of the patients reported TMJ-related symptoms. Four of the symptomatic patients had an unremarkable clinical exam and were diagnosed based on MRI findings. Eighty percent experienced bilateral TMJ arthritis. On clinical exam, asymmetric mouth opening was the most common feature (54%), followed by reduced maximal mouth opening (43%), and mandibular growth disturbance (37%). Of the 54 patients, 41% had otherwise normal joint exams with no other active or limited joints indicating they had isolated TMJ arthritis. In initial MRI findings, 83% displayed active arthritis, 89% displayed chronic arthritis, and 72% displayed either active or inactive erosions. Recognition of active TMJ arthritis led to significant changes in management. Prior to TMJ involvement, most patients were on NSAIDs (63%), but less than half were treated with DMARDs (41%) or TNF inhibitors (39%). Only one patient was receiving oral steroids. Prior to TMJ involvement, most patients were on NSAIDs (63%), but less than half were treated with DMARDs (41%) or TNF inhibitors (39%). Only one patient was receiving oral steroids. Notably, there was significant increase in the use of NSAIDs (p=0.0019), steroids (p=0.0055), and TNF inhibitors (p< 0.0001) after TMJ involvement was recognized. Prior to their TMJ involvement, only half of polyarticular JIA patients were on TNF inhibition. This increased to 96% after diagnosis. Due to failed conservative treatment and advanced joint degeneration, 3 patients required bilateral TMJ replacement.

Conclusions : We observed TMJ arthritis in several subtypes of JIA with the majority of patients having bilateral involvement. Importantly, the findings demonstrate a significant increase in the utilization of NSAIDs, steroids, and TNF inhibition after the diagnosis of TMJ arthritis. At the time of TMJ arthritis diagnosis, the majority had evidence of chronic disease and erosions, suggesting a potential opportunity for earlier recognition of TMJ involvement. These results underscore the importance of timely recognition and appropriate management of TMJ involvement in JIA patients, aiming to optimize patient outcomes and quality of life.

IRB Statement : This study has been granted an exemption from requiring ethics approval by UT Southwestern IRB because this was a retrospective chart review of existing medical records. All data was recorded in an anonymous manner such that subjects cannot be identified directly or through identifiers linked to the subject.

Pediatric Rheumatology 2024, 22(S1):A9

Background : Secondary hemophagocytic lymphohistiocytosis (sHLH), a rare, life-threatening, hyperinflammatory syndrome, occurs in the context of an underlying disease (rheumatologic, malignancy, etc) and/or infectious trigger. sHLH is caused by the overproduction of proinflammatory cytokines, eg, interferon gamma (IFNγ). The REAL-HLH study assessed clinical and demographic characteristics and real-world treatment patterns and outcomes in patients with hemophagocytic lymphohistiocytosis (HLH) treated with emapalumab, a fully human anti-IFNγ monoclonal antibody indicated for adults and children with primary HLH with refractory, recurrent, or progressive disease, or intolerance to conventional HLH therapy.

Methods : A retrospective medical chart review across 33 US hospitals identified patients treated with ≥1 dose of emapalumab between November 20, 2018, and October 31, 2021. Data extracted on the subset of patients with rheumatologic disease-associated HLH (sHLH/macrophage activation syndrome [MAS]) from time of emapalumab initiation to end of data availability, death, or study end (December 31, 2021) are presented.

Results : Fifteen of 105 (14.3%) study patients had HLH associated with an underlying rheumatologic disease; most (10/15; 66.7%) had Still’s disease (systemic juvenile idiopathic arthritis [sJIA] = 9; adult-onset Still’s disease [AOSD] = 1). Median (range) age at HLH diagnosis was 5 (0.9–39) years, and most patients (9/15; 60.0%) initiated emapalumab treatment in an intensive care unit (Table 1). Emapalumab was most frequently initiated for the treatment of refractory (5/15; 33.3%), recurrent (5/15; 33.3%), and progressive (4/15; 26.7%) disease. Most patients received HLH-related therapies prior to (10/15; 66.7%) and concurrently (15/15; 100.0%) with emapalumab, mostly corticosteroids (15/15; 100%) and anakinra (9/15; 60.0%). Median (range) time from HLH diagnosis to emapalumab initiation and overall treatment duration was 21.0 (1–988) and 63 (3–397) days, respectively. Median (range) emapalumab starting and cumulative treatment doses were 3.1 (0.8–5.9) and 29.7 (4.0–223.6) mg/kg, respectively (Figure 1). Following treatment with emapalumab-containing regimens, key laboratory parameters were normalized in most patients (Table 2). Overall survival and 12-month survival probability from emapalumab initiation was 86.7%. There were 2 deaths; 1 patient had rheumatoid arthritis and was deemed unresponsive to treatment, whereas the other with sJIA died due to uncontrolled disseminated adenoviremia, unrelated to the clinical condition for which emapalumab was used (investigator-determined).

Conclusions : This study reported real-world treatment patterns and outcomes with emapalumab across a diverse patient population with rheumatologic disease–associated HLH. Following treatment with emapalumab-containing regimens, most laboratory parameters were normalized, and the overall survival rate was 86.7%. A pivotal clinical trial of emapalumab in patients with sHLH and underlying rheumatologic disease is ongoing (NCT05001737).

IRB Statement : The protocol and data collection forms were reviewed by the Western Institutional Review-Copernicus Group Institutional Review Board (WCG IRB) and local IRBs, where required. There was no direct patient involvement in the study and anonymized data collection was conducted in compliance with US Health Insurance Portability and Accountability Act (HIPAA) policies.

Acknowledgements : The authors thank Sajjad Raza and Alice Pressman (PRECISIONheor) and Corey Best (Sobi, Inc.) for their support. Editorial and medical writing support was provided by Aparna Nori, PhD, CMPP, of rareLife solutions, Westport, Connecticut, USA, and funded by Sobi, Inc.

Pediatric Rheumatology 2024, 22(S1):A10

Background : As of April 2021, the 21st Century Cures Act requires that patients have immediate access to their electronic health information (EHI) (https://www.healthit.gov/topic/oncs-cures-act-final-rule). This study seeks to understand pediatric rheumatology patients’ and caregivers’ perceptions of the increased data accessibility.

Results : The survey received 325 initial responses; 23 responses were incomplete, 34 listed countries of residence outside the United States, 14 did not or were unsure if they had EHI access, and 1 participant did not confirm a diagnosis by a pediatric rheumatologist. Table 1 contains demographics and diagnoses of the remaining 253 eligible responses. Nearly 48% of participants reported accessing their electronic patient portal > 12 times in the last year and only 8% reported accessing it 1-2 times. Forty-five percent reported accessing their portal the same day as their appointment, 36% only when they get an alert for new results, and 0.8% only when a healthcare provider messages. Ninety-eight percent use the patient portal to access lab results, 80% healthcare provider messages, 64% imaging results, 53% appointments, and 28% medications. Free-text questions solicited respondent likes/dislikes of increased access to EHI, including “It’s data about ME; it is only fitting that I should know it.” Table 2 and Figure 1 contain additional summary data for survey questions using 4 or 5-point Likert scales. There were no significant differences in responses by diagnosis (JIA versus systemic connective tissue disease), however, respondents diagnosed ≤ 5 years ago were more likely to prefer immediate access to EHI, rather than waiting for a provider.

Conclusions : Respondents reported overwhelmingly positive feedback regarding immediate access to EHI through the patient portal. Though some did report that electronic access to labs increases their worry, families largely expect access to this data. This study is limited by the fact that it targeted an already engaged, English-speaking population with digital literacy, access to their patient portal, and patient engagement in disease-specific social media sites.

IRB Statement : This study was granted exemption by Duke’s Internal Review Board (Pro00113906).

Acknowledgements : The authors would like to thank the patients and families who participated in this study and completed the survey. They also wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA.

Pediatric Rheumatology 2024, 22(S1):A11

Background : Craniofacial Scleroderma (CS) is a rare autoimmune disorder characterized by progressive atrophy of the skin and underlying soft tissue. Changes in facial asymmetry as a result of disease activity have aesthetic and functional ramifications that can affect quality of life. This study assesses the functional and psychosocial impacts of CS in children and adolescents through Patient Reported Outcomes (PROs).

Methods : This is a prospective study of PROs completed by children and adolescents with clinically stable CS during intake and follow-up visits between 2019-2023. Patients completed 10 functional and psychosocial domains of the validated FACE-Q Craniofacial Module (1) along with the capture of 3-dimensional (3D) photographs to document disease status. FACE-Q scores were analyzed to 1) calculate median scores for each domain, 2) evaluate differences between younger (7-14 years) and older (15+ years) age groups, 3) compare our cohort to the FACE-Q validation cohort (1), 4) document frequency/types of adverse effects, 5) measure variation in domain scores for individuals completing multiple surveys, 6) perform regression analyses between psychosocial domains, and 7) compare PROs based on severity of disease.

Results : FACE-Q surveys from 24 patients (aged 7-23 years; 18 females) were collected. Median scores were highest in Jaw Appearance (96.0) and lowest in Appearance Distress (50.0). Younger patients (n=12) reported significantly lower median scores in four psychosocial domains (p< 0.05, all). Significant differences in five domains (p< 0.05, all) were identified between our cohort and the validation group. Adverse effects were reported in 21 patients (87.5%), most commonly identified as firmness of the face (n=16). Patients completing surveys at 3+ time points (n=9) showed slight improvement in scores across all domains over time. Regression analyses found Facial Appearance domain scores predictive of scores in the Psychological domain (R2 =0.623, p< 0.001) but not in the Appearance Distress domain (R2=0.0711, p=0.208). On average, region-specific scores were similar for Minor and Moderate atrophy, but worse in severe disease which had the lowest average scores across all domains.

Conclusions : FACE-Q outcomes in patients with CS indicate a complex interaction of facial appearance satisfaction, scholastic and social quality of life, supporting the need for psychosocial support. Further studies may be useful in assessing satisfaction following treatment, including reconstructive procedures. 1. Klassen AF, Rae C, Wong Riff KW, et al. FACE-Q Craniofacial Module: Part 1 validation of CLEFT-Q scales for use in children and young adults with facial conditions. J Plast Reconstr Aesthetic Surg JPRAS. 2021;74(9):2319-2329. doi:10.1016/j.bjps.2021.05.040

IRB Statement : This study was approved by the Institutional Review Board at Boston Children’s Hospital (IRB-P00029401), and all research activities were conducted in accordance with the Declaration of Helsinki.

Pediatric Rheumatology 2024, 22(S1):A12

Background : Patients with juvenile-onset systemic lupus erythematosus (JSLE, onset < 18 years) have more severe disease and relatively higher cardiovascular disease (CVD) and mortality risk compared to adult-onset patients. This could be associated with more predominant type I interferon (IFN) signalling. We investigated a more efficient method to assess the heterogeneity of type I IFN signatures in JSLE patients and their relationship with CVD using multi-omics.

Methods : RNA-sequencing (UCL-Genomics) was used to assess differentially expressed genes (DEGs) in peripheral blood mononuclear cells between JSLE patients with inactive disease (n=29, mean age=19) and healthy controls (HCs, n=8, mean age=18). Data was analysed by gene ontology pathway enrichment, weighted gene co-expression network analysis (WGCNA), hierarchical clustering, and receiver operating characteristic (ROC) analysis. BST2 expression was quantified by spectral flow cytometry on peripheral blood mononuclear cell (PBMC) subsets. Proteomics (Olink) and Metabolomics (Nightingale) assessed serum proteins (detection validated by ELISA) and metabolites associated with inflammation and CVD in matched patients. Patient clinical data was analysed by trajectory analysis with mean follow up of 4.9 years and 17 clinical encounters.

Results : JSLE patients had significantly enriched type I IFN signalling pathways compared to HCs (p< 0.0001), despite inactive disease, validated by unbiased WGCNA, where type I IFN signalling was the most significantly upregulated network module in JSLE patients, followed by T-cell activation and cytotoxicity modules. Despite the pathway dominance of type I IFN signalling, patients clustered heterogeneously into a high (H-IFN, 66%, ROC: p< 0.0001, AUC=1.00 vs HCs) and low (L-IFN, 34%, ROC: p=0.53, AUC=0.59 vs HCs) transcriptomic type I IFN signature group using normalised gene counts, validated by IFN-scores (p< 0.0001). 281 DEGs were upregulated in the H-IFN (vs L-IFN) group, with notable enrichment of cell cycle pathways. Serum protein levels of LAMP3 correlated most significantly (p=0.0018, r=0.67) with transcriptomic IFN-scores in patients (ROC: p=0.0069, AUC=0.95 for H-IFN vs L-IFN) from a panel of >280 proteins, highlighting a novel biomarker of H-IFN with translational potential for patient stratification; this was supported by fast and cost-effective biomarker quantification/validation by ELISA. This biomarker accuracy was not replicated by the IFN-induced cell surface marker, BST2, supporting serum protein quantification. No difference in clinical serology or disease activity trajectory was observed between type I IFN groups. However, transcriptomic IFN-scores correlated positively with proteomic (including ICAM1/VCAM1) and metabolic (including glycoprotein acetyls and ApoB:ApoA1 ratios) biomarkers known to reflect CVD-risk.

Conclusions : JSLE patients can be stratified by type I IFN signatures associated with CVD-risk and upregulated cell cycle pathways even in low disease activity states. Serum LAMP3 measurement could be used as a cost-effective method to stratify patients for therapeutic intervention to improve outcomes.

IRB Statement : This study was approved by the London-Harrow Research Ethics Committee, reference 11/LO/0330. Written informed consent was acquired from patients and healthy controls.

Pediatric Rheumatology 2024, 22(S1):A13

Background : The ChRonic nonbacterial Osteomyelitis Magnetic Resonance Imaging Scoring (CROMRIS) tool was developed to assess specific characteristics of bone and soft tissue inflammation in MRI of patients with CNO, but was labor intensive to utilize. Primary objectives of this study are: 1) to adapt the CROMRIS tool to a web-based platform and 2) assess the usability of this web-based CROMRIS system among radiologists.

Results : A clickable-schematic-based CROMRIS was developed to include all body regions: head (skull/mandible), spine, torso (clavicle, sternum, ribs), pelvis, hands, feet, arms and legs [Figure 1]. Notable features are the ability to immediately highlight a schematic region upon selection to directly input scores. Suggested changes included labeling of individual spine and rib segments, insertion of scoring legend on each tab for reference and creation of a summary page with a composite diagram where one can visualize the location and size of lesions by color as well as a numerical CROMRIS activity index [Figure 2]. The general scoring on the portal is indicated by clicking on a bone unit to indicate the presence of bone marrow hyperintensity consistent with an active CNO lesion, which is qualified by other lesion parameters [Figure 3]. A video tutorial and MRI Atlas is on the platform for training (https://www.carearthritis.com/mriportal/crmo/index/). Visual factors and anatomical diagrams were among the features “liked best” by the survey respondents. Mean SUS scores increased from 64.5 (below average) to 75 (above average). All respondents agreed that the final version of the web-based CROMRIS was “easy to learn” and found that the “various functions of the web-based CROMRIS were well integrated, and “would like to use the web-based CROMRIS in future clinical trials.”

Conclusions : The web-based CROMRIS portal shows good usability amongst radiologists. Studies of interrater reliability among experienced pediatric radiologists are underway. Once validated, this tool can be used as a semi-quantitative MRI scoring tool to allow for standardization of reporting output of radiological interpretations of MRI in CNO.

IRB Statement : IRB approval Stony Brook University #IRB2021-00033).

Acknowledgements : This project is supported by a CARRA-Arthritis Foundation Small Grant. The authors wish to acknowledge the ongoing Arthritis Foundation financial support of CARRA.

Pediatric Rheumatology 2024, 22(S1):A14

Background : Brain tissue atrophy and ventricular enlargement are characteristic imaging biomarkers of systemic lupus erythematosus (SLE) that have been observed in children (cSLE) with and without a neuropsychiatric (NPSLE) diagnosis. However, these brain features are not commonly quantified in conventional Magnetic Resonance Imaging (MRI) evaluations of cSLE. Brain volumes obtained from clinical control data can facilitate baseline and longitudinal evaluations of cSLE populations; yet, neuroimaging work is limited by small cSLE cohorts. This study aimed to leverage the value of structural MRI data obtained in clinical settings over a decade and to investigate the impact of brain volumes on the diagnosis and evaluation of cSLE.

Methods : T1-weighted brain MRI data were acquired from retrospective clinical samples of 133 patients with cSLE (4-18 years) and 132 controls that were scanned from 2010 to 2021 on 1.5T or 3T scanners (Table 1). Structural metrics included total grey matter (GM) cortex, subcortical GM, white matter (WM), and lateral ventricles volumes, mean cortical thickness and WM surface area (Figure 1A). Group differences between NPSLE and non-NPSLE subgroups and controls were examined with analysis of covariance (ANCOVA), including age, sex, and total intracranial volume as covariates. Age associations and age and group (cSLE versus controls) interaction effects were explored with linear regression in brain metrics that displayed group differences. Cortical GM volume/thickness and lateral ventricles volumes were tested as predictors of group classification in cSLE patients and healthy controls with logistic regression and receiver operating characteristic analyses.

Results : ANCOVA group analyses revealed lower cortical volume (F=32.9), thinner cortex (F=27.4), and greater lateral ventricles volumes (F=21.0) in both NPSLE and non-NPSLE groups compared to healthy controls (p< 0.001), but no differences within cSLE subgroups or between NPSLE subgroup and controls for WM surface area (Figure 1B-E). Regression analyses showed an interaction effect between age and group with GM thickness that was driven by the cSLE group (t=-3.04, p=0.003; Figure 1D). Together, lower cortical tissue volume and higher lateral ventricle volume predicted cSLE diagnosis with a sensitivity of 75.9% and specificity of 73.5% when compared to healthy controls (Figure 2).

Conclusions : Cortical atrophy and thinning, and enlarged lateral ventricles were frequently observed in patients with cSLE. Cortical thinning at a faster rate in cSLE than in healthy controls indicated changes in GM morphology that are specific to this pathology. These structural MRI metrics may aid in assessing early brain atrophy and in evaluating the magnitude of these deviations with age in cSLE when compared to neuroimaging brain data from age and sex comparable healthy populations. Additionally, evaluations of cSLE against healthy brain MRI data might increase diagnostic precision in cSLE, even when retrospectively acquired.

IRB Statement : I certify that this study has received the appropriate IRB approval by an appropriate ethics committee (The Research Ethics Board established by the SickKids Board of Directors). The IRB number is 1000079127 and the official title is “Identifying Neuroimaging Biomarkers of Neuropsychiatric Childhood-Onset Systemic Lupus Erythematosus Artificial Intelligence and Machine Learning”.

Pediatric Rheumatology 2024, 22(S1):A15

Background : Many study teams spend hours reviewing the electronic health record (EHR) to identify possible research subjects. The EHR is a rich data source, but manual review can be time consuming and burdensome. This study aims to validate a predictive electronic algorithm to identify children with rheumatic disease using on-demand self-service EHR reporting functionality.

Methods : Four diverse study sites using the same EHR (Epic Systems Corporation) created SlicerDicer reports. Queries included search terms for diagnosis (juvenile arthritis (ICD10-CM M08.*, M40.5), lupus and associated conditions (M32.*, L93.*, H01.12, M35.*), and dermatomyositis (M33.*)), department (pediatric rheumatology), and encounter type (office visit). Clinic schedules were manually reviewed both prospectively and retrospectively over a 2 week period to determine the diagnosis. SlicerDicer queries were run prospectively and retrospectively over the same two week period. Clinic schedules were compared to the SlicerDicer reports. Descriptive statistics, and logistic regression with clustering by site are reported.

Results : Of the total 674 patient visits evaluated throughout the study at four clinic sites, there were 589 (88%) patient visits prospectively evaluated, and 517 (77%) patient visits retrospectively evaluated. In total, there were 433 (64%) of patient visits included in both the prospective and retrospective queries. There were 85 visits added onto clinic schedules after prospective queries were completed, and 194 (29%) visits either cancelled or no-showed. Four patients who were added on after prospective queries were completed did not show to their appointments. Prospective queries had a sensitivity of 86%, specificity of 96%, PPV of 92%, and NPV of 92%, with an AUC of 0.92 (Figure 1A). Retrospective queries had a sensitivity of 80%, specificity of 97%, PPV of 95%, and NPV of 87%, with an AUC of 0.91 (Figure 1B). Age and return visit type were statistically associated with having a diagnosis and being present on both the prospective and retrospective queries in univariate analysis (Table 1). Of the 433 patients included in both the prospective and retrospective queries, 33 (8%) changed status between queries. Change of diagnosis status was not associated with age, sex, or visit type in univariate analysis (Table 2).

Conclusions : We were able to develop a successful query to identify subjects both prospectively and retrospectively with rheumatic conditions. Further integration of predictive algorithms into standard research screening workflows is a potential way to improve subject identification and recruitment.

IRB Statement : The study was approved by Nationwide Children’s Internal Review Board, STUDY00002524, and other study sites as necessary.

Acknowledgements : This work was funded by a CARRA-Arthritis Foundation Small Grant. The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA.

Pediatric Rheumatology 2024, 22(S1):A16

Background : Yoga shows effectiveness in young adults with arthritis but has not been studied in adolescents with juvenile idiopathic arthritis (JIA). Unique challenges arise for this population, including decreased activity level and different psychosocial challenges than healthy peers. However, exercise and stress management are beneficial for JIA management. Yoga combines adaptable movement with tools for self-regulation. This project aimed to determine the feasibility and acceptability of an 8-week group yoga intervention for adolescents with JIA.

Methods : Of the 79 rheumatology clinic patients screened, 25 consented to participate in 2 cohorts (16 and 9). Participants were ages 14-18 years with a JIA diagnosis, spoke and understood English, and could get on and off the floor independently. All participants were cleared by a rheumatologist. Each 75-minute group session included breathing techniques, relaxation, mindfulness, and modified classical yoga postures, using various props and a yoga rope wall. An online yoga video was available for home practice. Outcomes measured at baseline and 8 weeks included physician global assessment with joint count, visual assessment with a joint damage assessment index, the Pediatric Quality of Life Arthritis Module 3.0 (Peds QL) and the Visual Analog Scale for pain. An anonymous satisfaction survey was administered after week 8 (5-point Likert scale). Descriptive statistics were used to summarize patient characteristics and outcomes. Wilcoxon signed-rank tests were used to assess difference in outcome measures before and after the intervention. Spearman correlation was used to assess correlations of global assessment and joint count with sessions attended.

Conclusions : Adolescents with JIA who attended an 8-week yoga program reported enjoyment, pain reduction, and interest in continued practice. No adverse events were reported. This suggests yoga may be safe and acceptable for this population. A trend toward reduction in Pain and Hurt suggests possible effectiveness for improving these symptoms. These findings must be interpreted with great caution due to the very low enrollment and attendance, indicating barriers to feasibility such as scheduling and distance. Future studies should consider stakeholder engagement to understand and reduce barriers to participation, along with larger sample sizes to test intervention effectiveness.

IRB Statement : This project was approved by the Institutional Review Board of Children’s Hospital of Los Angeles, #CHLA-17-00037-CR001.

Pediatric Rheumatology 2024, 22(S1):A17

Background : Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. With the current workforce shortage, wait times for initial consultation with pediatric rheumatology is lengthy. Providers are overwhelmed with referrals for non-specific joint complaints that infrequently result in an arthritis diagnosis. This study aims to develop a predictive algorithm for diagnosis of arthritis based on initial consultation visits using patient-reported, historical, and referral data.

Results : There were 2054 subjects; 1360 (66%) female, with a median age of 13 [IQR 8,16], and 197 (10%) were diagnosed with arthritis. Common reasons for referrals include pain (33%), swelling (12%), antinuclear antibody testing (11%), and fever (6%) (Table 1). Common patient-reported symptoms include joint complaints (71%), psychological symptoms (57%), muscle complaints (56%), gastrointestinal symptoms (52%), and neurological symptoms (52%). The PROs of patient global, pain, and physical function, as well as joint pain and morning stiffness, were higher or more commonly present, respectively, in children with arthritis (all p< 0.05). Positive constitutional, cardiac, and neurologic ROS domains were negatively associated with arthritis diagnosis whereas joint symptoms were positively associated with an arthritis diagnosis (all p< 0.05) (Table 2). A final predictive model had an area under the curve (AUC), sensitivity, and specificity of 0.83, 23%, and 99% (Table 3).

Conclusions : We were able to successfully build a predictive algorithm for diagnosis of arthritis by leveraging data potentially available before a consultative visit. Our data suggests that such models could be integrated into clinical referral pathways to assist with expedited access to pediatric rheumatology.

IRB Statement : The study was approved by Nationwide Children’s Hospital Institutional Review Board, approval number STUDY00003317.

Acknowledgements : None.

Pediatric Rheumatology 2024, 22(S1):A18

Background : Childhood Sjögren’s disease (cSjD) is a rare condition, and its diagnosis is challenging due to a lack of pediatric-specific diagnostic criteria. In this project, we aimed to understand the current clinical trend for obtaining MSG biopsy in Childhood Sjogren’s followed by determining the characteristic pathology features and focus score cut-off for Childhood Sjogren’s Disease.

Methods : For aim 1, we analyzed data from the retrospective international cohort of 300 patients collected by the Childhood Sjögren’s Disease Workgroup. We compared the use of MSG biopsy in the evaluation of cSjD in the retrospective cohort according to the clinicians who submitted the cases, demographics, clinical manifestations, disease features, and other diagnostic testing. For aims 2 & 3, we have selected 50 age and sex-matched MSG biopsy from patients with Childhood Sjogren’s and controls. Pathologists are queried on the presence of small cellular aggregates, glandular fibrosis, acinar atrophy, fatty infiltration, granulomas in the biopsies along with determining focus scores. Digitalization and pathology review are currently underway.

Results : In the retrospective cohort, minor salivary gland (MSG) biopsy was performed as part of the evaluation for cSjD in 44% of patients. Among 26 clinicians who contributed cases of cSjD, no patterns in the use of MSG biopsy were observed. SSA and SSB were performed in 97% of patients, while ocular stain (18%), Schirmer test (45%), unstimulated salivary flow (15%), parotid sialography (12%), and salivary ultrasound (40%), were performed less frequently. Patients who had undergone MSG biopsy had significantly greater odds of having additional testing performed. Age less than 9 years (p=0.0003, OR 2.9), male biologic sex (p=0.005, OR 2.4), parotitis (p< 0.001, OR 2.8), and dry mouth (p=0.01, OR 1.8) were associated with a higher odds of MSG biopsy. Hypergammaglobulinemia (p=0.0001, OR 0.36) and serologies positive for SSA (p < 0.0001, OR 0.14), SSB (p< 0.0001, OR 0.30), RF (p=0.04, OR 0.59), or ANA (p=0.002, OR 0.33) were associated with a lower odds of MSG biopsy.

Conclusions : Use of MSG biopsy in the evaluation of cSjD was heterogeneous. While SSA and SSB were routinely performed in the evaluation of cSjD, additional tests, including MSG biopsy, appeared to be reserved for patients with atypical features such as young age, male biologic sex, and negative serologies. These observations suggest a framework for standardizing the evaluation of cSjD to improve diagnosis.

IRB Statement : This study was considered Exempt Certified by IRB at Children’s National Hospital. IRB # Pro00012976.

Acknowledgements : CARRA-Arthritis Foundation Small Grant. The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA Childhood Arthritis and Rheumatology Research Alliance and the International Childhood Sjögren Syndrome Workgroup NIAMS, NIH

Pediatric Rheumatology 2024, 22(S1):A19

Background : Tumor necrosis factor inhibitors (TNFi) are effective in children with juvenile spondyloarthritis (JSpA) and generally represent the first-line choice for biologic therapy. However, not all JSpA patients respond well to TNFi initially (primary non-response) or respond well but lose efficacy over time (secondary non-response). Children who do not respond to initial TNF inhibition are left with limited options. We aimed to identify the clinical characteristics associated with TNFi nonresponse in JSpA patients.

Methods : Retrospective analysis of JSpA patients and their response to first TNFi agent enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between July 2015 - January 2019. JSpA population included enthesitis-related arthritis, psoriatic arthritis, and undifferentiated spondyloarthritis subtypes. Primary non-response defined as discontinuation of TNFi within the first 3 months of starting due to ineffectiveness and absence of other causes. Secondary non-response defined as 1) stopping TNFi AND 2) switching to another biologic or addition of a disease-modifying anti-rheumatic drug (DMARD) after 3 months OR for specific reason other than ineffectiveness if less than 3 month. Responders were defined as those continuing the 1st TNFi for duration of study. Demographic and disease characteristics were compared at 1) baseline visits prior to TNFi start and 2) time of initial TNFi non-response or visit at least 4 months following TNFi start for the responders.​

Results : Total of 286 patients met inclusion criteria; 168 TNFi responders and 118 TNFi non-responders. The median duration prior to initial TNFi non-response for the non-responders was 268 days (IQR:159.5, 426.5). Demographics are shown in Table 1. Mean age at TNFi start was 12.1y for non-responders (SD 4.0y) and 12.1y for responders (SD 4.1y). Non-responders were more likely to be female compared to responders, 60.5% vs 48.5% (p=0.04). BMI was higher in non-responders compared to responders, 22.5 vs 21 (p=0.01). Non-responders had more arthritis, enthesitis and sacroiliitis at their baseline visit prior to TNFi start and a post-TNFi start visit compared to responders shown in Table 2. The majority of non-responders were secondary non-responders (N=113/118; 96%) shown in Figure 1. Following initial TNFi therapy for all the non-responders, most patients switched to 2nd TNFi (60.2%), followed by DMARD (35.2%) then another biologic (4.6%).

Conclusions : JSpA patients who did not respond to initial TNFi had more active disease and more axial involvement at baseline prior to starting therapy. The majority of patients who failed TNFi were due to secondary non-response. Additionally, JSpA patients with a higher BMI at baseline may be a risk factor for TNFi non-response

IRB Statement : The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Indiana University (protocol #: 1812741336).

Acknowledgements : The authors wish to acknowledge the support from Arthritis Foundation and CARRA. This project is funded by a CARRA-Arthritis Foundation small grant. This work could not have been accomplished without the aid of the following organizations: The NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) & the Arthritis Foundation. We would also like to thank all participants and hospital sites that recruited patients for the CARRA Registry. The authors thank the following CARRA Registry site principal investigators: K. Abulaban, C. Aguiar Lapsia, S. Ardoin, L. Barillas-Arias, M. Basiaga, K. Baszis, H. Brunner, H. Bukulmez, E. Chalom, J. Chang, D. Co, K. Cook, A. Cooper, C. Correll, T. Davis, F. Dedeoglu, M. DeGuzman, A. Dhanrajani, K. Ede, B. Edelheit, B. Feldman, I. Ferguson, D. Glaser, D. Goldsmith, B. Gottlieb, T. Graham, T. Griffin, T. Hahn, L. Harel, O. Harry, M. Hollander, S. Hong, M. Horwitz, J. Hsu, A. Huber, L. Imundo, C. Inman, P. Kahn, S. Kim, D. Kingsbury, M. Klein-Gitelman, L. Lim, M. Mannion, D. McCurdy, D. Milojevic, S. Mohan, T. Moore, K. Moore, L. Moorthy, S. Nativ, M. Natter, K. Onel, J. Patel, S. Prahalad, C. Rabinovich, A. Robinson, T. Ronis, M. Rosenkranz, N. Ruth, S. Sabbagh, K. Schikler, C. Schutt, E. Sloan, J. Spitznagle, Y. Sterba Rakovchik, K. Stewart, G. Syverson, S. Tarvin, M. Tesher, D. Toib, M. Toth, M. Twilt, H. Van Mater, D. Wahezi, P. Weiss, J. Weiss, L. Woolnough, E. Wu, A. Yalcindag, Y. Zhao

Pediatric Rheumatology 2024, 22(S1):A20

Background : Syndrome of Undifferentiated Recurrent Fevers (SURF) is an understudied and poorly defined disease entity. It causes significant financial and emotional burden to patients and their families and is difficult to diagnose and manage. Our preliminary data suggest that at least two distinct groups exist within SURF with unique cytokine profiles. The goal of this study is to group patients diagnosed with SURF by endotype, identify candidate driving forces behind each group, and determine best treatment practices for SURF patients. Our hypothesis is that distinct groups exist within SURF, and that each group has unique clinical and cytokine characteristics, as well as different responses to treatment. The first specific aim of this study is to group SURF patients according to endotype using their clinical symptoms and cytokine findings. The second specific aim is to determine the characteristics and variables of SURF patients likely to benefit from early biologic initiation. Secondary outcomes from this aim will be to identify characteristics and variables of patients who experience disease control with on-demand steroids, colchicine, or cimetidine alone.

Methods : Patients diagnosed with SURF after March 2018 are being enrolled into this study at Cincinnati Children’s, Texas Children’s, Boston Children’s, and University of Michigan. Inclusion criteria for SURF includes: 1) age between 0-18, 2) history of recurrent fevers, defined as at least 3 episodes in the past that cannot be attributed to infection or other disease, 3) fever episodes are stereotypical, 4) not consistent with PFAPA or a hereditary fever syndrome based on the 2019 Eurofever/PRINTO criteria, and 4) negative genetic testing if symptoms are consistent with an HRF. Demographics, clinical course, and treatment responses will be recorded in REDCap, and some patients will provide biosamples for multiplex cytokine analysis, which will be performed at CCHMC.

Results : Preliminary results from the CCHMC cohort show that SURF is heterogeneous in presentation and treatment response. Hierarchical cluster analysis of peripheral cytokine analysis shows that a subset of SURF patients cluster together with higher levels of IL-12p70, IL-23, and IFNγ compared to the rest of SURF and all PFAPA patients. Lastly, the CCHMC cohort also showed that many SURF patients had variants of unknown clinical significance in genes implicated in B cell development, immunodeficiencies, granulocyte/monocyte development, and inflammatory bowel disease risk. The heterogeneity, clustering, and genetic findings led to the hypothesis of the existence of endotypes within SURF. This study is a step to identify these endotypes. This multi-institutional study is ongoing, with data currently still being collected.

Conclusions : Preliminary data from CCHMC suggest that different endotypes exist within SURF. This multi-institutional study will further evaluate whether there exist distinct SURF endotypes, what drives the disorder and each of its endotypes, and how physicians can better predict which treatment will be most successful for each patient.

IRB Statement : This study was approved by the Institutional Review Board of Cincinnati Children’s Hospital Medical Center (CCHMC IRB), and written informed consent was obtained from all patients and/or their legal guardians.

Acknowledgements : The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA. The authors would like to thank the CARRA-Arthritis Foundation grant for funding this project, the Lellen Family Foundation for supporting the Pediatric Autoinflammatory Disease registry at CCHMC, the CARRA Autoinflammatory and Rare disease workgroup for all of their support, and the patients and families who participate in this study.

Pediatric Rheumatology 2024, 22(S1):A21

Background : Juvenile dermatomyositis (JDM) is an autoimmune disease that causes skin and muscle inflammation. Why patients develop JDM is not well understood. We sought to investigate the relationship between genetic risk factors, including C4 GCN, autoantibodies, and clinical features in JDM.

Methods : Subjects were recruited from 2 pediatric institutions (n=61). C4 GCN was determined by Southern blot. NovaSeq6000 S2 PE150bp whole exome sequencing (WES) provided 100x median coverage (n=45). Comparative analyses were performed via the student’s t test (parametric) and via the Mann Whitney U test (non-parametric). Correlation was assessed via linear regression. Contingency analyses were performed via Fisher’s exact test.

Results : C4 GCN was associated with muscle pathology and extra-muscular disease at diagnosis. Lower C4A and C4L GCN but higher C4B and C4S GCN were associated with a higher number of abnormal muscle enzymes (p=0.034, p=0.020, 0.026, and p=0.010, respectively). Higher C4S GCN also correlated with lower muscle strength (p=0.039) and lower C4L with abnormal MRI (p= 0.039). C4S GCN is one of the strongest factors in the development of disease complications. Higher GCN of C4S was a risk factor for arthritis (p=0.032), systemic symptoms (p=0.020), and dysphagia at diagnosis (p=0.0078). C4 GCN was associated with myositis-related antibodies. Patients with homozygous C4A deficiency were more likely to test positive for anti-NXP2 (OR 20.00 [2.71-261.1], p=0.011), and A higher C4B GCN correlated with development of myositis-associated antibodies (p=0.043). Patients with JDM showed increased complement activation. Levels of circulating C3a, C4a, and C5a were higher in patients with JDM (p< 0.0001, p=0.028, and p< 0.0001). Patients with JDM also showed increased deposition of complement split product C4d on RBC as measured by flow cytometry (p< 0.0001); this was most notable in patients with C4A insufficiency and higher C4B GCN (p=0.0003 and p=0.003). We performed WES and ingenuity pathway analysis to identify disease drivers. We identified genes involved in endothelial integrity (laminin 5, collagen 6A6), skin and muscle homeostasis (tyrosinase, TYR, involved in melanin biosynthesis; titin; and Fer-1 like family member 5, which may be involved in myocyte membrane repair), mitochondrial function (solute carrier protein 25, SLC25), and transcriptional regulation (zinc fingered protein 48). Many of these genes were mutated in large portions of our patients: 30% carry titin mutations and 22% SLC25.

Conclusions : Both genetic and environmental factors contribute to the development of JDM. Yet the initial trigger for JDM remains unclear. Here, we show that low GCN of C4A and C4L and high GCN of C4B and C4S correlate with muscle disease, extra-muscular pathology at diagnosis, and autoantibody production. In addition, we have identified candidate gene pathways that may be involved in disease pathogenesis. These data suggest that C4 plays a key role in the pathogenesis of JDM and that mutations in proteins involved in mucosal, skin, and muscle homeostasis may act as triggers for aberrant autoreactive immune responses that then further perpetuate autoimmunity in JDM.

IRB Statement : All studies were approved by the Nationwide Children’s Hospital and Children’s Hospital of Buffalo’s respective IRBs. Informed consent was obtained prior to each subject’s participation.

Pediatric Rheumatology 2024, 22(S1):A22

Background : Rheumatic disease disproportionately impacts certain socioeconomic, racial, and ethnic groups frequently resulting in health care inequities. Social determinants of health (SDOH) are conditions in the environment where people exist that encompass a wide range of systems, and influence quality of life, outcomes, and risks. Aligning with health equity literature, children from disadvantaged socioeconomic backgrounds experience worse outcomes and delays in care.1 In adult SLE, the negative impacts of SDOH are well described with unfavorable determinants leading to more severe disease and increased mortality.2 We aimed to identify SDOH in a cohort of children with rheumatic disease followed at a single center to begin to explore risk factors for disparities in our patient population.

Methods : Patient caregivers completed a SDOH survey prior to the start of the clinic visit. Survey results from February to May 2023 were extracted from the EMR. Patient demographics, diagnosis, and survey responses were analyzed using standard descriptive statistics.

Results : We analyzed SDOH surveys (n=861) completed during the initial survey roll out. Most patients surveyed were female (70%), and the average age was 11.7 years. Seventy percent reported White race, and 38% identified their ethnicity as Hispanic/Latino. Eleven percent of respondents had no high school degree, and 7.6% reported they need help with reading materials. Approximately 4% of patients reported needing help with cost of care, utilities, food, housing, or transportation. Twenty-one percent reported being often or sometimes worried about food security (Table 1). Of the patients surveyed, 66 had a diagnosis of SLE, 50 had JDM, and 371 had JIA (Table 2). In comparison with JIA and JDM families, SLE caregivers disclosed a significant higher rate of needing help with reading materials (p=0.0136) and lack of high school degree (p=0.0355).

Conclusions : Patients seen in our center come from diverse socioeconomic, racial, and ethnic backgrounds. The SDOH survey identified critical barriers to patient care including health literacy, food security, and living costs such as transportation, housing, and utilities. Health literacy may be an essential limiting factor for our families with children who have SLE. Further study is needed to understand the impact of SDOH on outcomes for children with rheumatic disease and how it varies by diagnosis. Future efforts to improve the management and outcomes of children with rheumatic disease should focus on specific SDOH that could influence health inequities. 1. Akinsete AM, Woo JMP, Rubinstein TB. Disparities in Pediatric Rheumatic Diseases. Rheum Dis Clin North Am. Feb 2022;48(1):183-198. doi:10.1016/j.rdc.2021.09.014 2. Williams JN, Drenkard C, Lim SS. The impact of social determinants of health on the presentation, management and outcomes of systemic lupus erythematosus. Rheumatology (Oxford). Mar 29 2023;62(Suppl 1):i10-i14. doi:10.1093/rheumatology/keac613

IRB Statement : This is a restrospective chart review that is under an IRB for our rheumatology department.

Pediatric Rheumatology 2024, 22(S1):A23

Background : Childhood-onset systemic lupus erythematosus (cSLE) presents enduring physical and mental health struggles, with up to 60% and 37% of patients experiencing depressive and anxiety symptoms, respectively. Despite its potential to influence mental health outcomes, resilience, defined as the ability to adapt following experiences of adversity, remains understudied in cSLE. We aimed to 1) describe individual psychological and socio-ecological resilience within a cSLE cohort, and 2) examine the relationship between resilience levels with mental health outcomes and disease characteristics (Figure 1).

Methods : We conducted a prospective cross-sectional study of youth ages 11 to 18 years, meeting ACR/SLICC classification criteria for cSLE. Participants were recruited from The Hospital for Sick Children Lupus Clinic between October 2021 and October 2023. Youth completed the Connor-Davidson Resilience Scale 10-item (CD-RISC 10) and the Child and Youth Resilience Measure Revised (CYRM-R), measuring individual psychological resilience (i.e., personal ability to recover from adversity) and socio-ecological resilience (i.e., feeling a sense of belonging within society), respectively. In both measures, higher scores indicate more resilience. Mental health outcomes included symptoms of depression (Beck Depression Inventory- Second Edition (BDI-II)) and anxiety (Screen for Child Anxiety Related Emotional Disorders (SCARED)). In both measures, higher scores indicate more severe symptoms. Disease-related outcomes were disease activity (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)) and duration. We examined associations between CD-RISC and CYRM-R scores, and depression, anxiety, disease activity and disease duration using Pearson correlations.

Results : Thirty-six youth with cSLE were recruited (Table 1); 83.3% were female and 80.6% were non-white, with mean age of 15.3 years (SD=1.9). Mean resilience scores were CD-RISC of 26.4 (SD=6.7) and CYRM-R of 74.0 (SD=7.1). Mean scores were BDI-II of 13.3 (SD=10.0) and SCARED of 24.6 (SD=13.9), for depressive and anxiety symptoms. The mean SLEDAI score was 8.8 (SD=7.7) and disease duration 2.6 years (SD=2.4). A statistically significant association was found in which lower depressive symptoms were associated with higher resilience scores on both the CD-RISC 10 (r= -0.46, p=0.02), and CYRM-R (r= -0.42, p=0.03). No statistically significant associations were found between CD-RISC 10 or CYRM-R with the outcomes of anxiety symptoms, disease activity, or disease duration (Table 2).

Conclusions : In this cSLE cohort, higher individual and socio-ecological resilience were associated with lower levels of depressive symptoms in youth with cSLE, suggesting the potential for interventions that promote resilience as a means to decrease depression symptoms. Further exploration of patient and disease-related factors contributing to resilience in cSLE is needed.

IRB Statement : This project has been approved by the Research Ethics Board at The Hospital for Sick Children (REB #1000078857).

Acknowledgements : This project is supported by funding from the Lupus Research Alliance, US Department of Defense, SickKids Garry Hurvitz Centre for Brain and Mental Health Outcomes, and a Canada Research Chair in Mental Health and Chronic Disease of Childhood (to Dr. Knight).

Pediatric Rheumatology 2024, 22(S1):A24

Background : CNO is a rare autoinflammatory bone disease characterized by sterile uni- or multifocal bone lesions that often begins in childhood. It is currently approached as a diagnosis of exclusion. Symptomatic patients undergo painful testing, often for years, to rule out disease mimickers leading to delays in treatment.

Methods : We analyzed the diagnostic course and barriers to treatment of consecutive CRMO patients seen in a Pediatric Rheumatology clinic at a tertiary hospital with a focus on bone and joints at least twice over a ten-year span between August 2011 and August 2021, including clinical signs, labs, and imaging studies. Data presented in Table 1.

Results : Of 59 patients eventually diagnosed with CRMO, the mean time from symptom onset to diagnosis was 2.1 years. Bone pain was the most common complaint, followed by bone swelling and morning stiffness. A family history of autoimmunity was common, and many children presented with or developed a related rheumatic disease including psoriasis, inflammatory bowel disease and spondylarthritis. Whole body imaging was done on all and most children had multifocal disease. Bone biopsies were commonly performed. All 18 children with unifocal lesions underwent biopsy except for one that surgeons felt would be difficult and potentially dangerous. 3 patients underwent three biopsies and several others had two. 4 patients were referred directly from pediatrics to pediatric rheumatology. More than half of the cohort saw at least two physicians in addition to their pediatrician prior to referral. Most commonly children were seen by combinations of orthopedics, sports medicine, oncology, and infectious disease specialists. Courses of antibiotics were common with several receiving 3 courses. Despite imaging and biopsy results consistent with CRMO, as well as persistent symptoms, many children (23%) received no DMARD treatments for at least one year after biopsy. Most common treatments besides NSAIDs were cDMARDs, bisphosphonates,and bDMARDs. Permanent damage including vertebral fractures secondary to delay in treatment was common. Several patients required surgery including one patient who required a limb salvage procedure. Ten of these patients have been followed for more than 5 years, 7 of whom are still receiving treatment at the time of analysis.

Conclusions : The lack of awareness about CRMO leads to enormous emotional, physical, and financial burdens on patients and their families. Persistent delays in diagnosis and treatment can lead to permanent damage. These delays are likely conservative as compared to those experienced by children living far from specialized pediatric care. Increasing disease awareness amongst general pediatricians, pediatric subspecialists, orthopedists and radiologists is critically needed.

IRB Statement : Protocol submitted to HSS IRB. As information is de-identified and data is batched, waiver of submission was granted.

Pediatric Rheumatology 2024, 22(S1):A25

Background : Methotrexate (MTX) is the disease-modifying drug of choice for most clinical forms of juvenile idiopathic arthritis (JIA). The most frequent adverse events (AEs) of MTX are gastrointestinal alterations and hepatotoxicity, which can affects adherence to treatment, leading to the activation of the disease. The SLCO1B1 gene codes for a liver protein that is responsible for drug transportation. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles. Our aim was to determine the association between Single Nucleotide Polymorphisms (SNPs) in the SLCO1B1 gene (rs4149056, rs2306283) with the presence of AEs in patients with JIA being treated with MTX.

Methods : Observational study, where polymorphisms of the SLCO1B1 gene were analyzed in 23 patients with JIA and were related to the adverse events reported in the clinical record during therapy with MTX. The SNPs were determined with Fast Real Time-PCR using TaqMan®SNP Assays. The haplotypes were conformed of the two SNPs at *1A, *1B, *5, and *15. Allele frequencies, genotypes and haplotypes were compared using the following programs: https://www.snpstats.net/ and Epi Info V7 https://www.cdc.gov/epiinfo/esp/es_index.html.

Conclusions : SLCO1B1 genotyping is a promising way to identify patients at higher risk of getting AE during treatment with MTX allowing individualization of the treatment. Due to the sample size, the results should be interpreted as preliminary and further confirmatory studies in a larger cohort are needed.

IRB Statement : The study complies with the ethical guidelines of the Declaration of Helsinki and local regulations. This is a minimal-risk study, all the procedures were revised and approved by the ethics committee of our institution (Facultad de Medicina y Hospital Universitario, Universidad Autónoma de Nuevo León).

Pediatric Rheumatology 2024, 22(S1):A26

Background : Patients with childhood onset rheumatic disease (CORD) transfer from a pediatric rheumatologist to an adult rheumatologist. Health care transition (HCT) prepares these patients for transfer. At the University of Utah, a rheumatology transition clinic serves patients who need to prepare for transfer. In transition clinic we address transition readiness. However, comorbidity with mental health disease is common in this patient population. There is a gap in understanding how depression might affect transition readiness. In this research we ask whether depression is correlated with transition readiness or transition readiness over time in our transition clinic patient population.

Results : The mean TRA score for Module 2 was 16.9 (SD 4.6), range (4 - 23). The mean TRA score for Module 5 was 18.9 (SD 4.3), range (7 - 23). The mean difference in TRA from Module 2 to Module 5 was 2.2 (SD 3.6), range (-5 - 16). The mean PHQ9 score was 7.2 (SD 6.7), range (0 - 27) (Table 1). Between Module 2 TRA and PHQ9 the correlation coefficient was -0.0975 (95% CI: -0.2856 to 0.0979), with a p-value of 0.3272 (Figure 1). This suggests a weak, non-significant negative correlation. Between Module 5 TRA and PHQ9 the correlation coefficient was -0.0872 (95% CI: -0.3811 to 0.2226) with a p-value of 0.5828 (Figure 2). This implies a weak, non-significant negative correlation. The correlation between changes in TRA and PHQ9 was -0.0493 (95% CI: -0.3481 to 0.2585) with a p-value of 0.7563. This indicates a weak, non-significant negative correlation. There was no statistically significant relationship between demographic values and Module 2 TRA (p = 0.6199) or PHQ9 (p = 0.5277). This analysis indicates weak and non-significant correlations between TRA, PHQ9, and demographic factors.

Conclusions : This is a negative study. No statistically significant correlations were identified. However, our analysis shows consistent negative correlations between higher TRA scores (greater transition readiness) and lower PHQ9 scores (less symptoms of depression). Additionally, the mean PHQ9 score for all participants was 7.2, interpreted as a provisional diagnosis of mild depression. While not causative, this data suggests that addressing depression simultaneously to transition readiness may be a critical component to HCT in adolescent and young adult patients with CORD.

IRB Statement : This research involved human participants and was performed in accordance with the Declaration of Helsinki. It was reviewed and approved by the University of Utah Institutional Review Board (IRB).

Acknowledgements : This investigation was supported by the University of Utah Study Design and Biostatistics Center, with funding in part from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR002538 (formerly 5UL1TR001067-05, 8UL1TR000105 and UL1RR025764).

Pediatric Rheumatology 2024, 22(S1):A27

Background : Childhood-onset systemic lupus erythematosus (cSLE) occurs in approximately 20% of all SLE cases. cSLE has a worse prognosis than adult-onset SLE, often requiring more aggressive therapy. CARRA coordinates a collaborative cSLE registry for patients in the US and Canada, while additional registries capture cSLE data in the United Kingdom (UK JSLE Registry) and across Europe (JIR Registry). To date, differences in data fields and collection methodology have been barriers to collaborative inter-registry research, which could enhance patient numbers and improve research quality. Through collaborative efforts between CARRA and the Paediatric Rheumatology European Society (PReS), key “Core” and “Expanded” datasets have been developed through consensus with a focus on feasibility to conduct SLE research.

Methods : SLE experts (15 pediatric rheumatologists, 4 combined pediatric and adult rheumatologists, 2 pediatric nephrologists) with international representation (10 countries; 5 continents) participated in multiple rounds of Delphi questionnaires, topic-specific taskforce meetings, and 3 virtual consensus meetings. Four patients/caregivers also attended each taskforce and consensus meeting, with votes given equal weight. Final data elements for the core and expanded datasets were determined using adapted nominal group technique and voting, with consensus requiring ≥ 80% agreement.

Results : The group achieved consensus for Core (Table 1) and Expanded (Table 2) Datasets, inclusive of the following: demographics, SLE history, co-morbidities, family history, SLE classification criteria, visit data, laboratory testing, kidney biopsy data, disease activity measurements, damage, medications, and serious adverse events. In addition, consensus was achieved regarding patient reported outcomes (PROMs) for the Expanded Dataset (Table 3) to capture fatigue, depression, anxiety, physical functioning (all using PROMIS measures) and discrimination (using the Everyday Discrimination Scale). Finally, consensus was achieved regarding frequency of data collection for each data item (baseline, 3 months + flare visits and annual timepoints).

Conclusions : Standardized Core and Expanded Datasets for registry-based international cSLE research were defined by global expert consensus. These datasets consider unique aspects of children with SLE in a range of geographic and resourced settings. The core and expanded datasets will facilitate international collaborative research for children and adolescents with SLE worldwide, inclusive of patient-oriented outcomes.

IRB Statement : This study was granted an exemption by the Duke University IRB.

Acknowledgements : The authors wish to acknowledge the CARRA-PReS Collaborative Research Award, which funded this project, as well as the ongoing support of the CARRA and PReS organizations. In addition, we wish to acknowledge the many physicians, researchers, patients, parents, and registry database managers who helped make this work possible.

Pediatric Rheumatology 2024, 22(S1):A28

Background : Juvenile localized scleroderma (jLS) is a rare condition that impairs health-related quality of life (HRQoL) through inflammation and fibrosis of the skin and underlying tissues as well as extracutaneous sites. Recent studies demonstrate extracutaneous manifestations (ECMs) occur in over half of jLS patients and are associated with poorer HRQoL, but current measures fail to capture this complexity, limiting our understanding of the full impact on individuals with jLS. Thus, there is a critical need for coordinated, international partnerships to effectively validate and implement these novel measures.

Methods : Our overall objective is to advance global collaborations between the Childhood Rheumatology Research Alliance (CARRA), Paediatric Rheumatology European Society (PReS), and Paediatric Rheumatology INternational Trials Organisation (PRINTO) to improve jLS outcomes via 3 aims. AIM 1: Internationally validate the Localized Scleroderma Quality of Life Instrument (LoSQI), a jLS-specific patient-reported HRQoL measure. AIM 2: Refine weighting of items in two of the Localized scleroderma Total Severity Score (LoTSS) modules with an international group of jLS experts. AIM 3: Generate the first prospective global jLS dataset in order to evaluate the psychometric properties of outcome measures for use in jlS (LoSQI, LoTSS, and the Patient Reported Outcomes Measurement Information System (PROMIS®)).

Results : An update on all 3 aims can be found in Table 1. We anticipate the project will be completed by the end of the project period, March 1, 2024.

Conclusions : Upon completion of the project, the expected outcomes will be: 1) validity evidence supporting the use of multilingual versions of the LoSQI and PROMIS® measures for assessing disease-specific and generic HRQoL in individuals with jLS; 2) refined weighting of two LoTSS module items allowing for improved standardized scoring of ECMs; and 3) an integrated international collaborative research network with the first combined dataset spanning CARRA, PReS, and PRINTO. These efforts will support future studies that assess the effectiveness of treatments on the full spectrum of disease impact, in keeping with CARRA’s mission and vision to conduct collaborative research and work towards a world free of limitations from pediatric rheumatic diseases.

IRB Statement : All study procedures were performed in accordance of the Declaration of Helsinki; aims 1 and 3 were determined exempt, while study procedures in Aim 2 were approved by the Duke University IRB (Pro00108843).

Acknowledgements : The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA. This work is supported by a CARRA-Arthritis Foundation Large Grant (project period 03/01/2021 – 02/28/2023). We would like to thank PReS/PRINTO for their collaboration and input into this work and the investigators who volunteered to participate in the Delphi process (Aim 2).

Pediatric Rheumatology 2024, 22(S1):A29

Background : Arthritis of the TM joint is a frequent finding in patients with JIA.2 Orofacial examination enables early detection of TM joint involvement. The TM Joint Juvenile Arthritis Work Group published a standardized physical exam (article) to assess for JIA-induced orofacial manifestations.2 The aim of the study was to demonstrate the effectiveness of a novel e-learning module in teaching the physical exam of the TM joint in JIA.

Methods : A 20-minute e-learning module consisting of videos and interactive questions was created. Pediatric rheumatology fellows were randomized, and fellows were stratified by post-graduate year. One group received the article while the second group received both the article and access to the e-learning module. All participants completed a written pre-test before the learning intervention and then underwent both: an in-person objective structured clinical examination (OSCE) during the Childhood Arthritis and Rheumatology Research Alliance Scientific Meeting in March 2023; and a written post-test. The maximum OSCE score was 18. Crosstab tables and Chi-squared tests were used to assess categorical variables across groups. Wilcoxon Rank Sum tests were used for continuous measures due to the small sample size.

Results : Twenty-two pediatric rheumatology fellows enrolled, with 11 in each group. Both reported an equal amount of time spent preparing for the OSCE. Written test: The two groups performed equally. There was a trend toward significance in defining maximal incisal opening (MIO) on the written test in the module group. Both groups had a trend towards improvement in recognition of patient profiles and facial asymmetry. OSCE: The mean OSCE score was 11.1 (SD 3.3) in the article group and 13.5 (SD 1.9) in the module group, with a trend towards significance (p=0.059). Significant differences were seen on the OSCE in learning domains related to measuring MIO, calculating maximal unassisted mouth opening (MUMO), and assessment of facial symmetry. There were no differences in other domains (see Table 1). Confidence in TM joint exam skills was increased with no difference between groups (Figure 1). Enjoyment scores in the module group were higher than in the article group (mean 7.7/10 vs 5.9/10, p=0.017) (Figure 2). Follow up: Three months later, the TM joint exam was performed “often” or “most of the time” in 27% in the article only group and 45.5% in the module group, although this difference was not statistically significant. All participants in the module group were moderately or very satisfied with the learning intervention compared with 73% in the article group.

Conclusions : This study demonstrated effectiveness of a novel e-learning module in teaching the physical exam of the TM joint in JIA. Learners who viewed the module were more adept at obtaining quantitative TM joint measurements than those who read the article. Both groups showed improvement in overall skill and confidence level, although the module group enjoyed the learning experience more.

IRB Statement : Exemption was obtained from the Children’s National Hospital IRB.

Acknowledgements : This project is supported by both a George Washington University SMHS Education Research Grant as well as a CARRA-Arthritis Foundation small grant. The authors wish to acknowledge the Arthritis Foundation for their ongoing financial support of CARRA.

Pediatric Rheumatology 2024, 22(S1):A30

Background : A 3D skeletal muscle model is useful to investigate pathogenic theories for juvenile dermatomyositis (JDM), a condition associated with upregulated type I interferon [1, 2] and mitochondrial dysfunction [3]. Using human-derived pediatric bioengineered muscle (myobundles), we examined the effects of the following compounds on muscle function: antimycin A (AMA), mitotempo (mitoT), and polyinosinic:polycytidylic acid (poly I:C). AMA is an electron transport chain complex III inhibitor that favors reactive oxygen species production, whereas mitoT is a mitochondrially targeted antioxidant that scavenges superoxide. Poly I:C is a TLR3 ligand, synthetic double-stranded RNA that mimics viral infection and driver of type I interferon. Hypothesis: AMA and poly I:C have a detrimental effect on myobundle contractile force, yet mitoT ameliorates AMA effects.

Methods : Myogenic cells isolated from three healthy pediatric donors were cultured and used to create myobundles based on established protocols [4] (Fig. 1). After maturation, myobundles were exposed to 0 (control condition), 5 nM AMA, 10 uM MitoT, 5 nM AMA plus 10 uM MitoT, or 10 ug/mL poly I:C in differentiation media every other day for 7 days. Contractile force and kinetics of myobundles were measured after electrical stimulation (Twitch: 1 stimulation at 1 Hz for 10 ms; Tetanus: 20 stimulations at 20 Hz for 1 s; Fatigue: 600 stimulations at 20 Hz for 30 s). Data across treatment groups was analyzed using one-way ANOVA with multiple post hoc comparisons.

Results : AMA and mitotempo alone decreased twitch and tetanus force. MitoT alone also decreased twitch time to half-relax. Combination AMA and mitoT enhanced the effects of each compound alone, decreasing twitch and tetanus force further and decreasing time to half-relax. Combination treatment also increased fatigue. Poly I:C decreased twitch and tetanus force in myobundles in 2 out of 3 donors and decreased fatigue across all donors. (Fig. 2)

Conclusions : AMA and mitotempo independently decrease contractile muscle force, indicating the importance of cellular respiration and ROS in muscle function, respectively. When in combination, AMA and mitotempo have an additive detrimental effect on muscle contractile force and fatigue. Poly I:C leads to donor-dependent skeletal muscle response, yet may be associated with decreased force production and increased muscle fatigue. Bioengineered pediatric muscle can elucidate pathways of muscle weakness in JDM.

IRB Statement : Sample collection occurred under Duke University IRB approved protocols (00009025).

References

Pediatric Rheumatology 2024, 22(S1):A31

Background : Most patients with juvenile idiopathic arthritis (JIA) require scheduled anti-inflammatory and immunosuppressive medications to treat their disease. Patient-reported barriers have been shown to directly correlate with treatment adherence rates. Identification of treatment barriers offers a valuable opportunity for providers to implement patient-specific self-management support.

Methods : Our site routinely offers a treatment barriers assessment form as part of our self-management support. Initially, patients/parents completed a paper form at their clinic visit, but in August 2023, an electronic version was implemented. A chart review of follow-up patients with JIA was performed in August and September 2023 to identify use of the barriers assessment form, detect which form was utilized, determine percent of visits with a treatment barrier present, and identify which treatment barriers were selected.

Results : There were 265 charts reviewed over the 2-month period, and 81.5% (n=216) of patients with JIA were on scheduled anti-inflammatory and/or immunosuppressive medication (Figure 1). The barriers assessment form was completed in 47.7% (n=103) of the visits; of those visits, 64.1% (n=66) of the forms were completed electronically. Of those who completed a barriers assessment form, 40.8% (n=42) identified at least 1 barrier with a total of 121 barriers. Of the visits with barriers identified, most (73.8%) reported barriers to injectable medication, 47.6% had barriers to oral medication, and none (0.0%) reported barriers to infusion medication. Table 1 highlights the individual treatment barriers noted. The most common treatment barriers included treatment is painful (n=17), dislike side effects (n=14), and forget to do treatment (n=14).

Conclusions : Assessing for treatment barriers is an important first step in providing tailored self-management support for patients with JIA. Treatment barriers are common in patients with JIA on injectable and oral anti-inflammatory and/or immunosuppressive medications. There was a wide variety of reported barriers. Our next steps include a quality improvement project to improve consistent use of the treatment barriers assessment form and standardization of the implementation of adherence solution tools.

IRB Statement : Per hospital policy, quality improvement projects do not require review by the institutional review board as they are not considered human subjects research.

Pediatric Rheumatology 2024, 22(S1):A32

Background : Clinical registries are typically envisioned to be representative of a target patient population and reflective of health care delivery practices for said population. Variation in clinical practices by different sites and concerns related to recruitment/retention can have profound implications for the validity of data collected and extent to which it may be impacted by selection bias. Thus, the objective of this study is to assess the role of patient- and site-level factors associated with research attrition in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.

Methods : Patients enrolled in the CARRA Registry from 2015 to 2019 were eligible. The effects of patient (level 1) and site (level 2) factors on lost to follow-up were assessed using a 2-level logistic model, followed by empirical Bayes estimation to investigate cross-center variation. Sites classify patients as inactive if they are referred elsewhere, move to a non-CARRA site, transition to adult rheumatology, achieve remission, or are lost to follow-up. We defined our outcome of interest as patients lost to follow-up (= 1) versus all other patients (=0), who may be active or inactive due to other reasons. The empirical Bayes estimates are used to graphically illustrate variation in lost to follow-up rates between unadjusted and adjusted models (Figure 1).

Results : The final analytic sample contained 9,730 patients nested within 69 sites (Table 1). Most of the sample was female (n=6,481, 72%), White (n=6,403, 64%), and privately insured (n=5,559, 62%). Overall, 728 (7.5%) patients in the cohort were lost to follow-up. The intra-class correlation coefficient (ICC) from null model signified that 20.3% of the variance in lost to follow-up is at the registry site level. Percent of missed Registry visits (OR 1.09, 95% CI: 1.086, 1.12), non-Medicaid state insurance (OR 1.95, 95% CI: 1.15, 3.12), and an income between $25,000 and $49,999 (OR 1.52, 95% CI: 1.003, 2.31) were significantly associated with higher odds of lost to follow-up (Figure 2).

Conclusions : Significant variation in research participant lost to follow-up exists at the site level. Moreover, individual-level characteristics such as visit history, insurance status, and household socioeconomic status were associated with the likelihood of being lost to follow-up. This non-random attrition may also highlight concerns related to patient retention in clinical practice.

IRB Statement : This study was approved by the University of Alabama at Birmingham Institutional Review Board (IRB-170112004).

Acknowledgements : This study was supported by a CARRA-Arthritis Foundation Health Equity Research Grant. This work could not have been accomplished without the aid of the following organizations: The NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) & the Arthritis Foundation. We would also like to thank all participants and hospital sites that recruited patients for the CARRA Registry. The authors thank the following CARRA Registry site principal investigators: K. Abulaban, C. Aguiar Lapsia, S. Ardoin, L. Barillas-Arias, M. Basiaga, K. Baszis, H. Brunner, H. Bukulmez, E. Chalom, J. Chang, D. Co, K. Cook, A. Cooper, C. Correll, T. Davis, F. Dedeoglu, M. DeGuzman, A. Dhanrajani, K. Ede, B. Edelheit, B. Feldman, I. Ferguson, D. Glaser, D. Goldsmith, B. Gottlieb, T. Graham, T. Griffin, T. Hahn, L. Harel, O. Harry, M. Hollander, S. Hong, M. Horwitz, J. Hsu, A. Huber, L. Imundo, C. Inman, P. Kahn, S. Kim, D. Kingsbury, M. Klein-Gitelman, L. Lim, M. Mannion, D. McCurdy, D. Milojevic, S. Mohan, T. Moore, K. Moore, L. Moorthy, S. Nativ, M. Natter, K. Onel, J. Patel, S. Prahalad, C. Rabinovich, A. Robinson, T. Ronis, M. Rosenkranz, N. Ruth, S. Sabbagh, K. Schikler, C. Schutt, E. Sloan, J. Spitznagle, Y. Sterba Rakovchik, K. Stewart, G. Syverson, S. Tarvin, M. Tesher, D. Toib, M. Toth, M. Twilt, H. Van Mater, D. Wahezi, P. Weiss, J. Weiss, L. Woolnough, E. Wu, A. Yalcindag, Y. Zhao