COVID-2019 Alert

The latest information about the 2019 Novel Coronavirus, including vaccine clinics for children ages 5 years old and older.

La información más reciente sobre el nuevo Coronavirus de 2019, incluidas las clínicas de vacunación para niños de 5 años en adelante.


Tzielan Lee, MD

  • Tzielan Lee



Work and Education

Professional Education

Stanford University School of Medicine, Palo Alto, CA, 06/01/1997


Stanford Health Care at Lucile Packard Children's Hospital, Palo Alto, CA, 06/30/1998


Stanford Health Care at Lucile Packard Children's Hospital, Palo Alto, CA, 06/30/2000


Stanford University Pediatric Rheumatology Fellowship, Stanford, CA, 06/30/2003

Board Certifications

Clinical Informatics, American Board of Preventive Medicine

Pediatric Rheumatology, American Board of Pediatrics

Pediatrics, American Board of Pediatrics

All Publications

Consensus Approach to a Treat to Target Strategy in Juvenile Idiopathic Arthritis Care: Report from the 2020 PR-COIN Consensus Conference. The Journal of rheumatology El Tal, T., Ryan, M. E., Feldman, B. M., Bingham, A., Burnham, J., Batthish, M., Bullock, D., Ferraro, K., Gilbert, M., Gillispie-Taylor, M., Gottlieb, B., Harris, J. G., Hazen, M., Laxer, R. M., Lee, T. C., Lovell, D., Mannion, M., Noonan, L., Oberle, E., Taylor, J., Weiss, J. E., Yildirim Toruner, C., Morgan, E. M. 1800


OBJECTIVE: Treat to target (T2T) is a strategy of adjusting treatment until a target is reached. An international task force recommended T2T for juvenile idiopathic arthritis (JIA) treatment. Implementing T2T in a standard and reliable way in clinical practice requires agreement on critical elements of: (1) target setting, (2) T2T strategy, (3) identifying barriers to implementation, and (4) eligible patients. A consensus conference was held amongst Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) stakeholders to inform a statement of understanding regarding the PR-COIN approach to T2T.METHODS: PR-COIN stakeholders including health care providers (16) and parents (4), were invited to form a voting panel. Using the nominal group technique, two rounds of voting were held to address the above four areas to select the top 10 responses in rank order.RESULTS: Incorporation of patient goals ranked most important when setting a treatment target. Use of shared decision making (SDM), tracking measurable outcomes, and adjusting treatment to achieve goals were voted as top elements of T2T strategy. Workflow considerations, and provider buy-in were identified as key barriers to T2T implementation. Patients with JIA, with poor prognostic factors and at risk for high disease burden were leading candidates for a T2T approach.CONCLUSION: This consensus conference identified the importance of incorporating patient goals as part of target setting, and influence of patient stakeholder involvement in drafting treatment recommendations. The network approach to T2T will be modified to address the above findings including solicitation of patient goals, optimizing SDM, and better workflow integration.

View details for DOI 10.3899/jrheum.210709

View details for PubMedID 35105705

Profiling Behavioral and Psychological Symptoms in Children undergoing treatment for Spondyloarthritis and Polyarthritis. The Journal of rheumatology McHugh, A., Chan, A., Herrera, C., Park, J. M., Balboni, I., Gerstbacher, D., Hsu, J. J., Lee, T., Thienemann, M., Frankovich, J. 1800


OBJECTIVE: Few studies examine psychopathology in different juvenile idiopathic arthritis (JIA) subtypes and disease activity states. We aimed to 1) Evaluate emotional and behavioral symptoms in children with spondyloarthritis (SpA) and polyarticular arthritis (PolyA) as compared to a national normative population using the Child Behavior Checklist (CBCL), and 2) Evaluate the relationship between CBCL scores and disease activity.METHODS: JIA patients aged 6-17 years with SpA or PolyA were recruited from our Pediatric Rheumatology clinic from April 2018 to April 2019 and the CBCL and Juvenile Arthritis Disease Activity Score (cJADAS10) were completed. Primary outcome measures were CBCL total competence, internalizing, externalizing and total problems raw scores. We compared outcomes from each group to national CBCL normative data. To investigate the relationship between CBCL scores and disease activity, we ran a generalized linear regression model for all arthritis patients with cJADAS10 as the main predictor.RESULTS: There were 111 patients and 1753 healthy controls. Compared to healthy controls, SpA or PolyA patients had worse total competence and internalizing scores. Higher cJADAS10 scores were associated with worse total competence, worse internalizing, and higher total problems scores. Most of these differences reached statistical significance (p<0.01). Self-harm/ suicidality was almost four-fold higher in patients with PolyA than healthy controls (OR 3.6, 95% CI 1.3-9.6, p=0.011).CONCLUSION: Our study shows that SpA and PolyA patients with more active disease have worse psychological functioning in activities, school and social arenas and more internalized emotional disturbances suggesting the need for regular mental health screening by rheumatologists.

View details for DOI 10.3899/jrheum.210489

View details for PubMedID 35105715

Pediatric Provider Utilization of a Clinical Decision Support Alert and Association with HIV Pre-exposure Prophylaxis Prescription Rates. Applied clinical informatics Chan, C. T., Vo, M., Carlson, J., Lee, T., Chang, M., Hart-Cooper, G. 2022; 13 (1): 30-36


An electronic clinical decision support (CDS) alert can provide real-time provider support to offer pre-exposure prophylaxis (PrEP) to youth at risk for human immunodeficiency virus (HIV). The purpose of this study was to evaluate provider utilization of a PrEP CDS alert in a large academic-community pediatric network and assess the association of the alert with PrEP prescribing rates.HIV test orders were altered for patients 13 years and older to include a hard-stop prompt asking if the patient would benefit from PrEP. If providers answered "Yes" or "Not Sure," the CDS alert launched with options to open a standardized order set, refer to an internal PrEP specialist, and/or receive an education module. We analyzed provider utilization using a frequency analysis. The rate of new PrEP prescriptions for 1 year after CDS alert implementation was compared with the year prior using Fisher's exact test.Of the 56 providers exposed to the CDS alert, 70% (n=39) responded "Not sure" to the alert prompt asking if their patient would benefit from PrEP, and 54% (n=30) chose at least one clinical support tool. The PrEP prescribing rate increased from 2.3 prescriptions per 10,000 patients to 6.6 prescriptions per 10,000 patients in the year post-intervention (p=0.02).Our findings suggest a knowledge gap among pediatric providers in identifying patients who would benefit from PrEP. A hard-stop prompt within an HIV test order that offers CDS and provider education might be an effective tool to increase PrEP prescribing among pediatric providers.

View details for DOI 10.1055/s-0041-1740484

View details for PubMedID 35021253

The Emerging Telehealth Landscape in Pediatric Rheumatology. Rheumatic diseases clinics of North America Pooni, R., Lee, T. 2022; 48 (1): 259-270


This article provides an in-depth review of telemedicine and its use in pediatric rheumatology. Historical barriers to the use of telemedicine in pediatric chronic care are described, and recent policy changes that have supported the use of telemedicine are discussed. Future directions and suggestions for the evaluation of telemedicine in pediatric rheumatology care are provided with a special focus on clinical outcomes, its use in research, patient acceptability, and health equity.

View details for DOI 10.1016/j.rdc.2021.08.005

View details for PubMedID 34798951

Ensuring Adolescent Patient Portal Confidentiality in the Age of the Cures Act Final Rule. The Journal of adolescent health : official publication of the Society for Adolescent Medicine Xie, J., McPherson, T., Powell, A., Fong, P., Hogan, A., Ip, W., Morse, K., Carlson, J. L., Lee, T., Pageler, N. 2021


PURPOSE: Managing confidential adolescent health information in patient portals presents unique challenges. Adolescent patients and guardians electronically access medical records and communicate with providers via portals. In confidential matters like sexual health, ensuring confidentiality is crucial. A key aspect of confidential portals is ensuring that the account is registered to and utilized by the intended user. Inappropriately registered or guardian-accessed adolescent portal accounts may lead to confidentiality breaches.METHODS: We used a quality improvement framework to develop screening methodologies to flag guardian-accessible accounts. Accounts of patients aged 12-17 were flagged via manual review of account emails and natural language processing of portal messages. We implemented a reconciliation program to correct affected accounts' registered email. Clinics were notified about sign-up errors and educated on sign-up workflow. An electronic alert was created to check the adolescent's email prior to account activation.RESULTS: After initial screening, 2,307 of 3,701 (62%) adolescent accounts were flagged as registered with a guardian's email. Those accounts were notified to resolve their logins. After five notifications over 8 weeks, 266 of 2,307 accounts (12%) were corrected; the remaining 2,041 (88%) were deactivated.CONCLUSIONS: The finding that 62% of adolescent portal accounts were used/accessed by guardians has significant confidentiality implications. In the context of the Cures Act Final Rule and increased information sharing, our institution's experience with ensuring appropriate access to adolescent portal accounts is necessary, timely, and relevant. This study highlights ways to improve patient portal confidentiality and prompts institutions caring for adolescents to review their systems and processes.

View details for DOI 10.1016/j.jadohealth.2021.09.009

View details for PubMedID 34666956

Determinants of Tumor Necrosis Factor Inhibitor Use in Juvenile Spondyloarthropathy and Impact on Clinical Disease Outcomes. ACR open rheumatology Oliver, M., Simard, J. F., Lee, T., Gerstbacher, D., Sandborg, C. 2021


OBJECTIVE: The objectives of this study were to characterize the reasons for tumor necrosis factor inhibitor (TNFi) initiation in patients with juvenile spondyloarthropathy (JSpA) and identify clinical correlates and to assess the effect of TNFi therapy on JSpA disease activity.METHODS: We conducted a retrospective cohort study of 86 patients with JSpA with first-time use of a TNFi over a 7-year period at Stanford Children's Health. We assessed the physician's reason for TNFi initiation, disease activity at 6 months, and clinical disease status at 12 months following TNFi start. Changes in active joint count, enthesitis count, and pain were measured. Demographics, physician reasons for TNFi initiation, and clinical characteristics were summarized.RESULTS: The mean age at JSpA diagnosis was 12.4years (SD 4.0years), and the mean time from diagnosis to TNFi initiation was 1.6years (SD 2.3years). The most common reason for initiating a TNFi was active disease on physical examination (61%). At 6 months post TNFi initiation, patients on average had three fewer active joints and one fewer active enthesitis point. Patient-reported pain improved from moderate/severe to mild. After 12 months, 54% of patients had active disease.CONCLUSION: The physician's decision to initiate a TNFi relied mostly on physical examination findings. Despite improvement in arthritis, enthesitis, and patient-reported pain at 6 months post TNFi initiation, the majority of the patients still had active disease after 1 year of therapy.

View details for DOI 10.1002/acr2.11353

View details for PubMedID 34647693

Pediatric subspecialty telemedicine use from the patient and provider perspective. Pediatric research Pooni, R., Pageler, N. M., Sandborg, C., Lee, T. 2021


BACKGROUND: To characterize telemedicine use among pediatric subspecialties with respect to clinical uses of telemedicine, provider experience, and patient perceptions during the COVID-19 pandemic.METHODS: We performed a mixed-methods study of telemedicine visits across pediatric endocrinology, nephrology, orthopedic surgery, and rheumatology at a large children's hospital. We used deductive analysis to review observational data from 40 video visits. Providers and patients/caregivers were surveyed around areas of satisfaction and communication.RESULTS: We found adaptations of telemedicine including shared-screen use and provider-guided parent procedures among others. All providers felt that it was safest for their patients to conduct visits by video, and 72.7% reported completing some component of a clinical exam. Patients rated the areas of being respected by the clinical staff/provider and showing care and concern highly, and the mean overall satisfaction was 86.719.3%.CONCLUSIONS: Telemedicine has been used to deliver care to pediatric patients during the pandemic, and we found that patients were satisfied with the telemedicine visits during this stressful time and that providers were able to innovate during visits. Telemedicine is a tool that can be successfully adapted to patient and provider needs, but further studies are needed to fully explore its integration in pediatric subspecialty care.IMPACT: This study describes telemedicine use at the height of the COVID-19 pandemic from both a provider and patient perspective, in four different pediatric subspecialties. Prior to COVID-19, pediatric telehealth landscape analysis suggested that many pediatric specialty practices had pilot telehealth programs, but there are few published studies evaluating telemedicine performance through the simultaneous patient and provider experience as part of standard care. We describe novel uses and adaptations of telemedicine during a time of rapid deployment in pediatric specialty care.

View details for DOI 10.1038/s41390-021-01443-4

View details for PubMedID 33753896

The Value of OpenNotes for Pediatric Patients, Their Families and Impact on the Patient-Physician Relationship. Applied clinical informatics Sarabu, C., Lee, T., Hogan, A., Pageler, N. 2021; 12 (1): 7681


BACKGROUND: OpenNotes, the sharing of medical notes via a patient portal, has been extensively studied in adults but not in pediatric populations. This has been a contributing factor in the slower adoption of OpenNotes by children's hospitals. The 21st Century Cures Act Final Rule has mandated the sharing of clinical notes electronically to all patients and as health systems prepare to comply, some concerns remain particularly with OpenNotes for pediatric populations.OBJECTIVES: After a gradual implementation of OpenNotes at an academic pediatric center, we sought to better understand how pediatric patients and families perceived OpenNotes. This article presents the detailed steps of this informatics-led rollout and patient survey results with a focus on pediatric-specific concerns.METHODS: We adapted a previous OpenNotes survey used for adult populations to a pediatric outpatient setting (with parents of children <12 years old). The survey was sent to patients and families via a notification email sent as a standard practice after a clinic visit, in English or Spanish.RESULTS: Approximately 7% of patients/families with access to OpenNotes read the note during the study period, and 159 (20%) of those patients responded to the survey. Of the survey respondents, 141 (89%) of patients and families understood their notes; 126 (80%) found the notes always or usually accurate; 24 (15%) contacted their clinicians after reading a note; and 153 (97%) patients/families felt the same or better about their doctor after reading the note.CONCLUSION: Although limited by relatively low survey response rate, OpenNotes was well-received by parents of pediatric patients without untoward consequences. The main concerns pediatricians raise about OpenNotes proved to not be issues in the pediatric population. Our results demonstrate clear benefits to adoption of OpenNotes. This provides reassurance that the transition to sharing notes with pediatric patients can be successful and value additive.

View details for DOI 10.1055/s-0040-1721781

View details for PubMedID 33567464

Telemedicine use by pediatric rheumatologists during the COVID-19 pandemic. Pediatric rheumatology online journal Pooni, R., Ronis, T., Lee, T. 2021; 19 (1): 93


To characterize various aspects of telemedicine use by pediatric rheumatology providers during the recent pandemic including provider acceptability of telehealth practices, clinical reliability, and clinical appropriateness.An electronic survey was generated and disseminated amongst the Childhood Arthritis and Rheumatology Research Alliance (CARRA) listserv (n=547). Survey items were analyzed via descriptive statistics by question.The survey response rate was 40.8% (n=223) with the majority of respondents in an attending-level role. We observed that musculoskeletal components of the exam were rated as the most reliable components of a telemedicine exam and 86.5% of survey respondents reported engaging the patient or patient caregiver to help conduct the virtual exam. However, 65.7% of providers reported not being able to elicit the information needed from a telemedicine visit to make a complete clinical assessment. We also noted areas of disagreement regarding areas of patient engagement and confidentiality. We found that approximately one-third (35.8%) of those surveyed felt that their level of burnout was increased due to telemedicine.In general, providers found exam reliability (specifically around focused musculoskeletal elements) in telemedicine visits but overall felt that they were unable to generate the information needed to generate a complete clinical assessment. Additionally, there were suggestions that patient engagement and confidentiality varied during telemedicine visits when compared to in-person clinical visits. Further qualitative work is needed to fully explore telemedicine use in pediatric rheumatology.

View details for DOI 10.1186/s12969-021-00565-7

View details for PubMedID 34134709

Pediatric Subspecialty Adoption of Telemedicine Amidst the COVID-19 Pandemic: An Early Descriptive Analysis. Frontiers in pediatrics Xie, J., Prahalad, P., Lee, T. C., Stevens, L. A., Meister, K. D. 2021; 9: 648631


Telemedicine has rapidly expanded in many aspects of pediatric care as a result of the COVID-19 pandemic. However, little is known about what factors may make pediatric subspeciality care more apt to long-term adoption of telemedicine. To better delineate the potential patient, provider, and subspecialty factors which may influence subspecialty adoption of telemedicine, we reviewed our institutional experience. The top 36 pediatric subspecialties at Stanford Children's Health were classified into high telemedicine adopters, low telemedicine adopters, and telemedicine reverters. Distance from the patient's home, primary language, insurance type, institutional factors such as wait times, and subspecialty-specific clinical differences correlated with differing patterns of telemedicine adoption. With greater awareness of these factors, institutions and providers can better guide patients in determining which care may be best suited for telemedicine and develop sustainable long-term telemedicine programming.

View details for DOI 10.3389/fped.2021.648631

View details for PubMedID 33928058

Exploring Pediatric Tele-Rheumatology Practices During COVID-19: A Survey of the PRCOIN Network. Frontiers in pediatrics Goh, Y. I., Bullock, D. R., Taylor, J., Pooni, R., Lee, T. C., Vora, S. S., Yildirim-Toruner, C., Morgan, E. M., Pan, N., Harris, J. G., Warmin, A., Wiegand, K., Burnham, J. M., Barbar-Smiley, F. 2021; 9: 642460


Healthcare providers were rapidly forced to modify the way they practiced medicine during the coronavirus disease 2019 (COVID-19) pandemic. Many providers transitioned from seeing their patients in person to virtually using telemedicine platforms with limited training and experience using this medium. In pediatric rheumatology, this was further complicated as musculoskeletal exams typically require hands-on assessment of patients. The objective of this study was to examine the adoption of telemedicine into pediatric rheumatology practices, to assess its benefits and challenges, and to gather opinions on its continued use. A survey was sent to the lead representatives of each Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) site to collect data about their center's experience with telemedicine during the COVID-19 pandemic. Quantitative data were analyzed using descriptive statistics, and qualitative data were thematically analyzed. Responses were received from the majority [19/21 (90%)] of PR-COIN sites. All respondents reported transitioning from in-person to primarily virtual patient visits during the COVID-19 pandemic. All centers reported seeing both new consultations and follow-up patients over telemedicine. Most centers reported using both audio and video conferencing systems to conduct their telemedicine visits. The majority of respondents [13/19 (68%)] indicated that at least 50% of their site's providers consistently used pediatric Gait Arms Legs and Spine (pGALS) to perform active joint count assessments over telemedicine. Over half of the centers [11/19 (58%)] reported collecting patient-reported outcomes (PROs), but the rate of reliably documenting clinical components varied. A few sites [7/19 (37%)] reported performing research-related activity during telemedicine visits. All centers thought that telemedicine visits were able to meet providers' needs and support their continued use when the pandemic ends. Benefits reported with telemedicine visits included convenience and continuity of care for families. Conversely, challenges included limited ability to perform physical exams and varying access to technology. Pediatric rheumatology providers were able to transition to conducting virtual visits during the COVID-19 pandemic. Healthcare providers recognize how telemedicine can enhance their practice, but challenges need to be overcome in order to ensure equitable, sustainable delivery of quality and patient-centered care.

View details for DOI 10.3389/fped.2021.642460

View details for PubMedID 33748049

Telemedicine in Pediatric Rheumatology During COVID-19: The PR-COIN Experience Goh, Y., Pan, N., Harris, J., Warmin, A., Taylor, J., Vora, S., Barbar-Smiley, F., Burnham, J., Lee, T., Yildirim-Toruner, C., Wiegand, K., Morgan, E. WILEY. 2020
Comparison of Clinicopathologic and Imaging Features Between Chronic Nonbacterial Osteomyelitis and Its Mimickers: A Multi-national 450 Case-Control Study Zhao, Y., Naden, R., Oliver, M., Wang, Z., Wu, E., Aguiar, C., Akikusa, J., Basaran, O., Cain, K., Capponi, M., Donaldson, N., Fox, E., Insalaco, A., Jansson, A., Akca, U., Lee, T., Marrani, E., Mahmood, K., Murray, E., Nuruzzaman, F., Onel, K., Pardeo, M., Potts, L., Rogers, N., Schnabel, A., Simonini, G., Soep, J., Stern, S., Theos, A., Zhang, Y., Ferguson, P., Hedrich, C., Dedeoglu, F., Girschick, H., Laxer, R., Ozen, S. WILEY. 2020
New Juvenile Idiopathic Arthritis Quality Measure Set for the Pediatric Rheumatology Care and Outcomes Improvement Network Harris, J., Morgan, E., Vora, S., Gilbert, M., Yildirim-Toruner, C., Griffin, N., Ferraro, K., Loos, S., Qiu, T., Paul, A., Burnham, J., Batthish, M., Gottlieb, B., Bullock, D., Hazen, M., Laxer, R., Lee, T., Mannion, M., Olson, J., Pan, N., Shishov, M., Spencer, C., Weiss, J. E., Bingham, C. WILEY. 2020
Building a Viable Telemedicine Presence in Pediatric Rheumatology. Pediatric clinics of North America Pooni, R., Sandborg, C., Lee, T. 2020; 67 (4): 64145


This article describes the present state of telemedicine in pediatric rheumatology. Specifically, it addresses the potential use of telemedicine to increase patient-provider access as well as its potential clinical limitations. The work also briefly describes the next steps with respect to telemedicine research as well as some new research findings specifically for pediatric rheumatology.

View details for DOI 10.1016/j.pcl.2020.04.006

View details for PubMedID 32650861

Implementing Treat to Target Approach in the Care of Juvenile Idiopathic Arthritis Across a Network of Pediatric Rheumatology Centers Harris, J., Morgan, E., Taylor, J., Qiu, T., Griffin, N., Paul, A., Bingham, C., Bullock, D., Ferraro, K., Gilbert, M., Goh, Y., Halyabar, O., Jones, K., Kohlheim, M., Lovell, D. J., Smitherman, E., Vago, A., Weiss, J., Yildirim-Toruner, C., Young, A., Batthish, M., Gottlieb, B., Hazen, M., Laxer, R., Lee, T., Mannion, M., Olson, J., Shishov, M., Siddique, S., Spencer, C., Toth, M., Vora, S., Burnham, J. WILEY. 2020: 13
New Juvenile Idiopathic Arthritis Quality Measure Set for the Pediatric Rheumatology Care and Outcomes Improvement Network Harris, J., Morgan, E., Vora, S., Gilbert, M., Yildirim-Toruner, C., Griffin, N., Ferraro, K., Loos, S., Qiu, T., Paul, A., Burnham, J., Meyer, E., Batthish, M., Gottlieb, B., Bullock, D., Hazen, M., Laxer, R., Lee, T., Mannion, M., Olson, J., Shishov, M., Vehe, R., Weiss, J., Bingham, C. WILEY. 2020: 299301
Utilization of Telemedicine in Pediatric Rheumatologic Care Pooni, R., Lee, T. WILEY. 2020: 31718
Injection Fear in Juvenile Idiopathic Arthritis Patients Using Injectable Medications Collins, K., Wren, A., Lee, T. WILEY. 2019
Designing and Testing Treat to Target as a New Care Model in JIA Across a Network of Pediatric Rheumatology Centers Morgan, E., Taylor, J., Qiu, T., Griffin, N., Paul, A., Bingham, C., Bullock, D., Ferraro, K., Goh, Y., Gilbert, M., Halyabar, O., Jones, K., Kohlheim, M., Lovell, D. J., MacDonald, D., Smitherman, E., Vago, A., Weiss, J., Yildirim-Toruner, C., Young, A., Batthish, M., Gottlieb, B., Harris, J., Hazen, M., Laxer, R., Lee, T., Mannion, M., Olson, J., Shishov, M. I., Vora, S., Burnham, J. WILEY. 2019
JIA DISEASE ACTIVITY OUTCOMES ACROSS A MULTI-CENTER COHORT: ANALYSIS OF THE PEDIATRIC RHEUMATOLOGY CARE AND OUTCOMES IMPROVEMENT NETWORK (PR-COIN) REGISTRY Smitherman, E. A., Huang, B., Laxer, R., Bingham, C., Yildirim-Toruner, C., Gottlieb, B., Weiss, J. E., Lee, T., Vora, S., Burnham, J., Harris, J. G., Olson, J. C., Gilbert, M., Batthish, M., Shishov, M., Fleck, D., Morgan, E. BMJ PUBLISHING GROUP. 2019: 97071
Electronic health record (EHR) training program identifies a new tool to quantify the EHR time burden and improves providers' perceived control over their workload in the EHR. JAMIA open DiAngi, Y. T., Stevens, L. A., Halpern-Felsher, B. n., Pageler, N. M., Lee, T. C. 2019; 2 (2): 22230


To understand if providers who had additional electronic health record (EHR) training improved their satisfaction, decreased personal EHR-use time, and decreased turnaround time on tasks.This pre-post study with no controls evaluated the impact of a supplemental EHR training program on a group of academic and community practice clinicians that previously had go-live group EHR training and 20 months experience using this EHR on self-reported data, calculated EHR time, and vendor-reported metrics.Providers self-reported significant improvements in their knowledge of efficiency tools in the EHR after training and doubled (significant) their preference list entries (mean pre = 38.1 [65.88], post = 63.5 [90.47], P<.01). Of the 7 EHR satisfaction variables, only 1 self-reported variable significantly improved after training: Control over my workload in the EHR (mean pre = 2.7 [0.96], post = 3.0 [1.04], P<.01). There was no significant decrease in their calculated EHR usage outside of clinic (mean pre = 0.39 [0.77] to post = 0.37 [0.48], P=.73). No significant difference was seen in turnaround time for patient calls (mean pre=2.3 [2.06] days, post=1.9 [1.76] days, P=.08) and results (mean before = 4.0 [2.79] days, after = 3.2 [2.33] days, P=.03).Multiple sources of data provide a holistic view of the provider experience in the EHR. This study suggests that individualized EHR training can improve the knowledge of EHR tools and satisfaction with their perceived control of EHR workload, however this did not translate into less Clinician Logged-In Outside Clinic (CLOC) time, a calculated metric, nor quicker turnaround on in box tasks. CLOC time emerged as a potential less-costly surrogate metric for provider satisfaction in EHR work than surveying clinicians. Further study is required to understand the cost-benefit of various interventions to decrease CLOC time.This supplemental EHR training session, 20 months post go-live, where most participants elected to receive 2 or fewer sessions did significantly improve provider satisfaction with perceived control over their workload in the EHR, but it was not effective in decreasing EHR-use time outside of clinic. CLOC time, a calculated metric, could be a practical trackable surrogate for provider satisfaction (inverse correlation) with after-hours time spent in the EHR. Further study into interventions that decrease CLOC time and improve turnaround time to respond to inbox tasks are suggested next steps.

View details for DOI 10.1093/jamiaopen/ooz003

View details for PubMedID 31984357

View details for PubMedCentralID PMC6952029

Disease burden and social impact of pediatric chronic nonbacterial osteomyelitis from the patient and family perspective. Pediatric rheumatology online journal Oliver, M., Lee, T. C., Halpern-Felsher, B., Murray, E., Schwartz, R., Zhao, Y., CARRA SVARD CRMO/CNO workgroup, Oliver, M., Lee, T. C., Murray, E., Schwartz, R., Zhao, Y. 2018; 16 (1): 78


BACKGROUND: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that if left untreated can result in bone destruction and severe continuing pain due to persistent inflammation. The impact this chronic disease has on the daily lives of affected children and their families is not well known. The purpose of this study is to understand the disease burden and socioeconomic and psychological impact of CNO from the patients' and families' perspectives and identify areas of improvement for patient care and reduced disease burden based on patients' and families' responses.METHODS: Participants were invited through a social media platform group and at clinic visits at Stanford Children's Health. An online survey was administered to patients with a diagnosis of CNO made at <22years of age and/or the parent/guardian of a patient with CNO diagnosis made at <22years of age.RESULTS: There was a total of 284 survey participants. The median age at CNO diagnosis was 10years (range 2-22+). Median time from first CNO symptom to diagnosis was 2years. Antibiotics were used in 35% of patients prior to CNO diagnosis; of these, 24% received antibiotics for greater than 6months. Between 25 and 61% reported a negative effect of CNO on relationships, school/work performance, or finances; and 19-50% reported effects on psychosocial well-being. The majority agreed patients' performance with daily tasks and hobbies was challenged bypain, fatigue and physical limitation related to CNO.CONCLUSIONS: Patients with CNO experienced on average a 2-year delay in diagnosis and receiving effective treatments. At least 25% reported problems with relationships, school, work, finances and well-being due to CNO. Recognition of these challenges emphasizes the need to increase awareness of this disease and address the socioeconomic stressors and mental health issues in order to provide optimal care of children with CNO.

View details for PubMedID 30547806

Disease burden and social impact of pediatric chronic nonbacterial osteomyelitis from the patient and family perspective PEDIATRIC RHEUMATOLOGY Oliver, M., Lee, T. C., Halpern-Felsher, B., Murray, E., Schwartz, R., Zhao, Y., CARRA SVARD CRMO CNO Workgrp 2018; 16
Evaluating Disease Activity Outcomes for Juvenile Idiopathic Arthritis across the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) Smitherman, E. A., Huang, B., Laxer, R. M., Bingham, C., Yildirim-Toruner, C., Gottlieb, B., Weiss, J., Lee, T., Vora, S. S., Burnham, J., Harris, J., Olson, J. C., Gilbert, M., Batthish, M., Shishov, M., Fleck, D., Morgan, E. WILEY. 2018
Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions ARTHRITIS CARE & RESEARCH Zhao, Y., Wu, E. Y., Oliver, M. S., Cooper, A. M., Basiaga, M. L., Vora, S. S., Lee, T. C., Fox, E., Amarilyo, G., Stern, S. M., Dvergsten, J. A., Haines, K. A., Rouster-Stevens, K. A., Onel, K. B., Cherian, J., Hausmann, J. S., Miettunen, P., Cellucci, T., Nuruzzaman, F., Taneja, A., Barron, K. S., Hollander, M. C., Lapidus, S. K., Li, S. C., Ozen, S., Girschick, H., Laxer, R. M., Dedeoglu, F., Hedrich, C. M., Ferguson, P. J., Chronic Nonbacterial Osteomyeliti, Childhood Arthritis & Rheumatolog 2018; 70 (8): 122837


To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies.Virtual and face-to-face discussions and meetings were held within the CNO/CRMO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices. Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to nonsteroidal antiinflammatory drug (NSAID) monotherapy and/or with active spinal lesions.Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients refractory to NSAID monotherapy and/or with active spinal lesions. The 3 CTPs are methotrexate or sulfasalazine, tumor necrosis factor inhibitors with optional methotrexate, and bisphosphonates. Short courses of glucocorticoids and continuation of NSAIDs are permitted for all regimens. Consensus was achieved on these CTPs among CARRA members. Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response.Three consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions. Use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.

View details for PubMedID 29112802

View details for PubMedCentralID PMC5938153

Barriers to Adherence in Juvenile Idiopathic Arthritis: A Multicenter Collaborative Experience and Preliminary Results JOURNAL OF RHEUMATOLOGY Favier, L. A., Taylor, J., Rich, K., Jones, K. B., Vora, S. S., Harris, J. G., Gottlieb, B. S., Robbins, L., Lai, J. T., Lee, T., Kohlheim, M., Gill, J., Bouslaugh, L., Young, A., Griffin, N., Morgan, E. M., Modi, A. C. 2018; 45 (5): 69096


Nonadherence is currently an underrecognized and potentially modifiable obstacle to care in juvenile idiopathic arthritis (JIA). The purpose of our study was to design and implement a standardized approach to identifying adherence barriers for youth with JIA across 7 pediatric rheumatology clinics through the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) and to assess the frequency of adherence barriers in patients and their caregivers across treatment modalities.An iterative process using coproduction among parents and providers of patients with JIA was used to design the Barriers Assessment Tool to screen for adherence barriers across 4 treatment modalities (i.e., oral medications, injectable medications, infusions, and physical/occupational therapy). This tool was implemented in 7 rheumatology clinics across the United States and patient responses were collected for analysis.Data were collected from 578 parents and 99 patients (n = 44 parent-child dyads). Seventy-seven percent (n = 444) of caregivers and 70% (n = 69) of patients reported at least 1 adherence barrier across all treatment components. The most commonly reported adherence barriers included worry about future consequences of therapy, pain, forgetting, side effects, and embarrassment related to the therapy. There was no significant difference between endorsement of barriers between parents and adolescents.Implementing a standardized tool assessing adherence barriers in the JIA population across multiple clinical settings is feasible. Systematic screening sheds light on the factors that make adherence difficult in JIA and identifies targets for future adherence interventions in clinical practice.

View details for DOI 10.3899/jrheum.171087

View details for Web of Science ID 000431278800016

View details for PubMedID 29419467

View details for PubMedCentralID PMC5932234

Analysis of relationships between 25-hydroxyvitamin D, parathyroid hormone and cathelicidin with inflammation and cardiovascular risk in subjects with paediatric systemic lupus erythematosus: an Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) study LUPUS SCIENCE & MEDICINE Gupta, V., Tangpricha, V., Yow, E., McComsey, G. A., Schanberg, L., Robinson, A., Dewitt, E., Rabinovich, C., Ellis, J., Wootton, J., Chira, P., Hsu, J., Lee, T., Perea, J., Gottlieb, B., Irigoyen, P., Luftig, J., Siddiqi, S., Ni, Z., Orlando, M., Pagano, E., Eichenfield, A., Levy, D., Kahn, P., Batres, C., Cabral, D., Haines, K. A., Li, S. C., Weiss, J., Riordan, M., Vaidya, B., Mietus-Snyder, M., Ng, L., Ballinger, S., Klausmeier, T., Hinchman, D., Hudgins, A., Henry, S., Zhang, S., Brooks, E. B., Miner, S., Szabo, N., Scalzi, L., Dorfeld, L., Wilson, S., Tress, J., Hernandez, T., Vitale, J., Kress, A., Lowe, N., Patel, F., Hamilton, S., Caldwell, K., Kamen, D., Puplava, B., Lonchev, A., Bacani, M., Rutherford, C., Meyers-Eaton, J., Nelson, S., Grom, A., Conway, T., Frank, L., Kuss, L., Senz, H., Mason, T., Jaquith, J., Paepke-Tollefsrud, D. E., APPLE Investigators 2018; 5 (1): e000255


Previous studies demonstrated associations between reduced serum 25-hydroxyvitamin D (25OHD), inflammation and disease activity in paediatric systemic lupus erythematosus (pSLE). The goal of this study was to assess parathyroid hormone (PTH) in its relationship to vitamin D and inflammation, as well as to better understand the role of human cathelicidin (LL-37) in pSLE.Frozen serum samples collected at baseline of the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) study were assayed to determine 25OHD, PTH and LL-37 levels. Pearson's correlations and 2 tests were used to evaluate the relationships between 25OHD, PTH, LL-37, inflammation, disease activity and infection using baseline values collected as part of the APPLE study.201/221 APPLE participants had serum available for analysis. Serum 25OHD was inversely associated with serum PTH, but not LL-37. Serum PTH was not associated with high sensitivity C-reactiveprotein, carotid intima media thickness or high-density lipoprotein (HDL) or low-density lipoprotein (LDL)cholesterol, but was negatively associated with lipoprotein(a) levels. Despite no association with serum 25OHD, LL-37 was negatively associated with total cholesterol, HDL and LDLcholesterol and positively associated with age. There was no significant difference in mean LL-37 levels in participants with reported infection as an adverse event during the 3-year APPLE study.Despite links to vitamin D levels in other studies, LL-37 levels were not associated with baseline serum 25OHD concentrations in paediatricpatients with pSLE. Despite the lack of correlation with 25OHD, LL-37 levels in this study were associated with cholesterol levels. Some subjects with pSLE have significantly elevated levels of LL-37 of unknown significance. These exploratory results addressing the role of LL-37 levels in pSLE appear worthy of future study.

View details for DOI 10.1136/lupus-2017-000255

View details for Web of Science ID 000495994400008

View details for PubMedID 29955369

View details for PubMedCentralID PMC6018862

Determinants of Anti-Tumor Necrosis Factor Drug Use in Juvenile Spondyloarthropathy and Impact on Clinical Disease Outcomes Oliver, M., Simard, J. F., Gerstbacher, D., Lee, T., Sandborg, C. WILEY. 2017
Development and Implementation of a "Data-in-Once" Model for a Pediatric Rheumatology Learning Health System Lee, T., Bout-Tabaku, S., Conkle, J., Iyer, K., Servick, C., Morgan, E. WILEY. 2017
Plasma CXCL4 As a Biomarker in Juvenile Systemic Sclerosis Moore, K., Fritzler, M. J., Klein-Gitelman, M. S., Reed, A. M., Lee, T., Stevens, A. WILEY. 2017
Resilience and Transition Readiness in Pediatric SLE Patients Lai, J., Nelson, L., Balboni, I., Lee, T., Hsu, J. WILEY. 2017
Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Improvement on Quality Measures for Children with Juvenile Idiopathic Arthritis Bingham, C., Pratt, J., Yildirim-Toruner, C., Laxer, R., Gottlieb, B., Weiss, J., Lee, T., Vora, S. S., Burnham, J., Harris, J., Olson, J. C., Passo, M., Batthish, M., Shishov, M., Ferraro, K., Levy, D. M., O'Brien, C., Whitney-Mahoney, K., Griffin, N., Paul, A., Morgan, E. WILEY. 2017: 56
Disease Burden and Social Impact of Chronic Nonbacterial Osteomyelitis on Affected Children and Young Adults Oliver, M., Lee, T., Halpern-Felsher, B., Murray, E., Gholson, R., Zhao, Y. WILEY. 2017: 12325
Development and Implementation of a "Data-In-Once" Model for a Pediatric Rheumatology Learning Health System Lee, T., Bout-Tabaku, S., Conkle, J., Morgan-Dewitt, E. WILEY. 2017: 3536
Early Outcomes in Children with Antineutrophil Cytoplasmic Antibody (ANCA) Associated Vasculitis (AAV). Arthritis & rheumatology Morishita, K. A., Moorthy, L. N., Lubieniecka, J. M., Twilt, M., Yeung, R. S., Toth, M. B., Shenoi, S., Ristic, G., Nielson, S. M., Luqmani, R. A., Li, S. C., Lee, T., Lawson, E. F., Kostik, M. M., Klein-Gitelman, M., Huber, A. M., Hersh, A. O., Foell, D., Elder, M. E., Eberhard, B. A., Dancey, P., Charuvanij, S., Benseler, S. M., Cabral, D. A. 2017


To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV.Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0=no damage, score 1=one damage item present), and relapse rates at 12 months.In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had 1 PVDI damage item scored as present at 12 months.This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.

View details for DOI 10.1002/art.40112

View details for PubMedID 28371513

Designing An Individualized EHR Learning Plan For Providers APPLIED CLINICAL INFORMATICS Stevens, L. A., DiAngi, Y. T., Schremp, J. D., Martorana, M. J., Miller, R. E., Lee, T. C., Pageler, N. M. 2017; 8 (3): 92435

View details for DOI 10.4338/040054

View details for Web of Science ID 000413010400013

Novel Metrics for Improving Professional Fulfillment. Annals of internal medicine DiAngi, Y. T., Lee, T. C., Sinsky, C. A., Bohman, B. D., Sharp, C. D. 2017; 167 (10): 74041

View details for PubMedID 29052698

Brief Report: HLA-DRB1, DQA1, and DQB1 in Juvenile-Onset Systemic Sclerosis ARTHRITIS & RHEUMATOLOGY Stevens, A. M., Kanaan, S. B., Torok, K. S., Medsger, T. A., Mayes, M. D., Reveille, J. D., Klein-Gitelman, M., Reed, A. M., Lee, T., Li, S. C., Henstorf, G., Luu, C., Aydelotte, T., Nelson, J. 2016; 68 (11): 277277


Systemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc.DRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n=76) to healthy Caucasian controls (n=581).Initial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P=0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P=0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P= 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P=0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P=0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P=0.01) and in those with antibodies to topoisomerase (OR 0.14, P=0.024).Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

View details for PubMedID 27214100

Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Improvement on Quality Measures for Children with Juvenile Idiopathic Arthritis Bingham, C., Pratt, J., Yildirim-Toruner, C., Laxer, R., Gottlieb, B., Weiss, J. E., Lee, T., Vora, S. S., Burnham, J. M., Harris, J., Olson, J. C., Passo, M., Batthish, M., Shishov, M., Ferraro, K., Levy, D. M., O'Brien, C., Whitney-Mahoney, K., Griffin, N., Paul, A., Morgan, E. WILEY. 2016
Leveraging a Learning Network to Implement and Standardize Self-Management Support into Care Delivery: Experience of Pediatric Rheumatology Care and Outcomes Improvement Network Taylor, J., Modi, A., Loiselle, K., Gomez, J., Jones, K. B., Vora, S. S., Harris, J., Gottlieb, B., Robbins, L., Lee, T., Whitney-Mahoney, K., Passo, M., Kohlheim, M., Curtis, L., Vago, A., Ferraro, K., Trevey, K., Gil, J., Bouslaugh, L., Young, A., Griffin, N., Paul, A., Lannon, C. M., Morgan, E. WILEY. 2016
Effect of BMI on Symptoms and Outcomes in Juvenile Idiopathic Arthritis Patients Weiss, J. E., Andrews, T., Morgan, E., Laxer, R., Yildirim-Toruner, C., Bingham, C., Gottlieb, B., Lee, T., Vora, S. S., Burnham, J. M., Olson, J. C., Passo, M., Batthish, M., Riebschleger, M. WILEY. 2016
Association of Sex, Race and Ethnicity on Disease Outcomes in Juvenile Idiopathic Arthritis Patients Joseph, V., Andrews, T. R., Morgan, E., Laxer, R., Toruner, C., Lee, T., Gottlieb, B. S., Bingham, C., Vora, S. S., Burnham, J. M., Olson, J. C., Passo, M. H., Batthish, M., Riebschleger, M., Weiss, J. E. WILEY. 2016
Discordance Between Physician, Patient, and Parent Disease Assessment Scores in Juvenile Idiopathic Arthritis Fox, E., Hsu, J., Lee, T., Sandborg, C., Simard, J. F. WILEY. 2016
Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study ARTHRITIS & RHEUMATOLOGY Cabral, D. A., Canter, D. L., Muscal, E., Nanda, K., Wahezi, D. M., Spalding, S. J., Twilt, M., Benseler, S. M., Campillo, S., Charuvanij, S., Dancey, P., Eberhard, B. A., Elder, M. E., Hersh, A., Higgins, G. C., Huber, A. M., Khubchandani, R., Kim, S., Klein-Gitelman, M., Kostik, M. M., Lawson, E. F., Lee, T., Lubieniecka, J. M., McCurdy, D., Moorthy, L. N., Morishita, K. A., Nielsen, S. M., O'Neil, K. M., Reiff, A., Ristic, G., Robinson, A. B., Sarmiento, A., Shenoi, S., Toth, M. B., Van Mater, H. A., Wagner-Weiner, L., Weiss, J. E., White, A. J., Yeung, R. S. 2016; 68 (10): 2514-2526


To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA).The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons.In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n=48) or GPA (n=183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil.Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

View details for DOI 10.1002/art.39729

View details for PubMedID 27111558

Altered signaling in systemic juvenile idiopathic arthritis monocytes CLINICAL IMMUNOLOGY Macaubas, C., Wong, E., Zhang, Y., Nguyen, K. D., Lee, J., Milojevic, D., Shenoi, S., Stevens, A. M., Ilowite, N., Saper, V., Lee, T., Mellins, E. D. 2016; 163: 66-74


Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFN) and type II (IFN) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFN hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFN. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

View details for DOI 10.1016/j.clim.2015.12.011

View details for Web of Science ID 000370585600010

View details for PubMedID 26747737

Increasing Rates of Remission in Juvenile Idiopathic Arthritis through a Quality Improvement Learning Network - the Pediatric Rheumatology Care and Outcomes Improvement Network DeWitt, E., Ardoin, S. P., Bingham, C., Gottlieb, B. S., Laxer, R. M., Griffin, N., Pratt, J., Paul, A., Lovell, D., Olson, J. C., Passo, M. H., Weiss, J. E., Lee, T. C., Vora, S. S., Hazen, M. M., Margolis, P. WILEY-BLACKWELL. 2014: S1012
Autoantibodies in Juvenile Systemic Sclerosis Moore, K., Nelson, J., Fritzler, M. J., Klein-Gitelman, M. S., Reed, A. M., Lee, T. C., Stevens, A. M. WILEY-BLACKWELL. 2014: S136
Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for New-Onset Polyarticular Juvenile Idiopathic Arthritis ARTHRITIS CARE & RESEARCH Ringold, S., Weiss, P. F., Colbert, R. A., DeWitt, E. M., Lee, T., Onel, K., Prahalad, S., Schneider, R., Shenoi, S., Vehe, R. K., Kimura, Y. 2014; 66 (7): 1063-1072


There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies.A case-based survey was administered to CARRA members to identify the common treatment approaches for new-onset polyarticular JIA. Two face-to-face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations.The initial case-based survey identified significant variability among treatment approaches for new-onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step-up plan (nonbiologic disease-modifying antirheumatic drug [DMARD] followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face-to-face meeting.Three standardized CTPs were developed for new-onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA.

View details for DOI 10.1002/acr.22259

View details for Web of Science ID 000337976700013

View details for PubMedCentralID PMC4467832

Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Performance Improvement on Juvenile Idiopathic Arthritis Quality Measures Harris, J. G., DeWitt, E., Laxer, R. M., Ardoin, S. P., Gottlieb, B. S., Olson, J. C., Passo, M. H., Weiss, J. E., Lovell, D. J., Lee, T. C., Vora, S. S., Griffin, N., Stock, J. A., Darbie, L. M., Bingham, C. A. WILEY-BLACKWELL. 2014: S195

View details for DOI 10.1002/art.38577

View details for Web of Science ID 000349950900153

A Population Management Tool for Proactive Care of Juvenile Idiopathic Arthritis in the Pediatric Rheumatology Care and Outcomes Improvement Network Ardoin, S. P., Bingham, C., Gottlieb, B. S., Laxer, R. M., Passo, M. H., Lovell, D., Weiss, J. E., Vora, S. S., Lee, T. C., Griffith, N., DeWitt, E. WILEY-BLACKWELL. 2014: S235S236

View details for DOI 10.1002/art.38606

View details for Web of Science ID 000349950900182

Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Performance Improvement On Juvenile Idiopathic Arthritis Quality Measures Harris, J. G., DeWitt, E., Laxer, R. M., Ardoin, S. P., Gottlieb, B. S., Olson, J. C., Passo, M. H., Weiss, J. E., Lovell, D. J., Lee, T. C., Vora, S. S., Griffin, N., Stock, J. A., Darbie, L. M., Bingham, C. A. WILEY-BLACKWELL. 2013: S1194S1195
Childhood Arthritis and Rheumatology Research Alliance (CARRA) Standardized Consensus Treatment Plans for New Onset Polyarticular Juvenile Idiopathic Arthritis Ringold, S., Weiss, P. F., Colbert, R. A., DeWitt, E., Lee, T. C., Onel, K., Prahalad, S., Schneider, R., Shenoi, S., Vehe, R. K., Kimura, Y. WILEY-BLACKWELL. 2013: S116
Pulmonary Hypertension and Other Potentially Fatal Pulmonary Complications in Systemic Juvenile Idiopathic Arthritis ARTHRITIS CARE & RESEARCH Kimura, Y., Weiss, J. E., Haroldson, K. L., Lee, T., Punaro, M., Oliveira, S., Rabinovich, E., Riebschleger, M., Anton, J., Blier, P. R., Gerloni, V., Hazen, M. M., Kessler, E., Onel, K., Passo, M. H., Rennebohm, R. M., Wallace, C. A., Woo, P., Wulffraat, N. 2013; 65 (5): 745-752


Systemic juvenile idiopathic arthritis (JIA) is characterized by fevers, rash, and arthritis, for which interleukin-1 (IL-1) and IL-6 inhibitors appear to be effective treatments. Pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and alveolar proteinosis (AP) have recently been reported with increased frequency in systemic JIA patients. Our aim was to characterize and compare systemic JIA patients with these complications to a larger cohort of systemic JIA patients.Systemic JIA patients who developed PAH, ILD, and/or AP were identified through an electronic Listserv and their demographic, systemic JIA, and pulmonary disease characteristics as well as their medication exposure information were collected. Patients with these features were compared to a cohort of systemic JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry.The patients (n = 25) were significantly (P < 0.05) more likely than the CARRA registry cohort (n = 389) to be female; have more systemic features; and have been exposed to an IL-1 inhibitor, tocilizumab, corticosteroids, intravenous immunoglobulin, cyclosporine, and cyclophosphamide. Twenty patients (80%) were diagnosed with pulmonary disease after 2004. Twenty patients (80%) had macrophage activation syndrome (MAS) during their disease course and 15 patients (60%) had MAS at pulmonary diagnosis. Sixteen patients had PAH, 5 had AP, and 7 had ILD. Seventeen patients (68%) were taking or recently discontinued (<1 month) a biologic agent at pulmonary symptom onset; 12 patients (48%) were taking anti-IL-1 therapy (primarily anakinra). Seventeen patients (68%) died at a mean of 10.2 months from the diagnosis of pulmonary complications.PAH, AP, and ILD are underrecognized complications of systemic JIA that are frequently fatal. These complications may be the result of severe uncontrolled systemic disease activity and may be influenced by medication exposure.

View details for DOI 10.1002/acr.21889

View details for Web of Science ID 000318114700011

View details for PubMedID 23139240

Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis BMC MEDICINE Ling, X. B., Macaubas, C., Alexander, H. C., Wen, Q., Chen, E., Peng, S., Sun, Y., Deshpande, C., Pan, K., Lin, R., Lih, C., Chang, S. P., Lee, T., Sandborg, C., Begovich, A. B., Cohen, S. N., Mellins, E. D. 2012; 10


Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR) and number of affected joints (joint count, JC).PBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways. Pearson correlation and Student's t-test analyses were performed to identify transcripts significantly associated with clinical parameters (ESR and JC) in SJIA or POLY samples. These transcripts were used to find related biological pathways.Combining Pearson and t-test analyses, we found 91 ESR-related and 92 JC-related genes in SJIA. For POLY, 20 ESR-related and 0 JC-related genes were found. Using Ingenuity Systems Pathways Analysis, we identified SJIA ESR-related and JC-related pathways. The two sets of pathways are strongly correlated. In contrast, there is a weaker correlation between SJIA and POLY ESR-related pathways. Notably, distinct biological processes were found to correlate with JC in samples from the earlier systemic plus arthritic phase (SAF) of SJIA compared to samples from the later arthritis-predominant phase (AF). Within the SJIA SAF group, IL-10 expression was related to JC, whereas lack of IL-4 appeared to characterize the chronic arthritis (AF) subgroup.The strong correlation between pathways implicated in elevations of both ESR and JC in SJIA argues that the systemic and arthritic components of the disease are related mechanistically. Inflammatory pathways in SJIA are distinct from those in POLY course JIA, consistent with differences in clinically appreciated target organs. The limited number of ESR-related SJIA genes that also are associated with elevations of ESR in POLY implies that the SJIA associations are specific for SJIA, at least to some degree. The distinct pathways associated with arthritis in early and late SJIA raise the possibility that different immunobiology underlies arthritis over the course of SJIA.

View details for DOI 10.1186/1741-7015-10-125

View details for PubMedID 23092393

Do Adult Disease Severity Subclassifications Predict Use of Cyclophosphamide in Children with ANCA-associated Vasculitis? An Analysis of ARChiVe Study Treatment Decisions JOURNAL OF RHEUMATOLOGY Morishita, K., Guzman, J., Chira, P., Muscal, E., Zeft, A., Klein-Gitelman, M., Uribe, A. G., Abramson, L., Benseler, S. M., Eberhard, A., Ede, K., Hashkes, P. J., Hersh, A. O., Higgins, G., Imundo, L. F., Jung, L., Kim, S., Kingsbury, D. J., Lawson, E. F., Lee, T., Li, S. C., Lovell, D. J., Mason, T., McCurdy, D., O'Neil, K. M., Punaro, M., Ramsey, S. E., Reiff, A., Rosenkranz, M., Schikler, K. N., Scuccimarri, R., Singer, N. G., Stevens, A. M., Van Mater, H., Wahezi, D. M., White, A. J., Cabral, D. A. 2012; 39 (10): 2012-2020


To determine whether adult disease severity subclassification systems for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are concordant with the decision to treat pediatric patients with cyclophosphamide (CYC).We applied the European Vasculitis Study (EUVAS) and Wegener's Granulomatosis Etanercept Trial (WGET) disease severity subclassification systems to pediatric patients with AAV in A Registry for Childhood Vasculitis (ARChiVe). Modifications were made to the EUVAS and WGET systems to enable their application to this cohort of children. Treatment was categorized into 2 groups, "cyclophosphamide" and "no cyclophosphamide." Pearson's chi-square and Kendall's rank correlation coefficient statistical analyses were used to determine the relationship between disease severity subgroup and treatment at the time of diagnosis.In total, 125 children with AAV were studied. Severity subgroup was associated with treatment group in both the EUVAS (chi-square 45.14, p < 0.001, Kendall's tau-b 0.601, p < 0.001) and WGET (chi-square 59.33, p < 0.001, Kendall's tau-b 0.689, p < 0.001) systems; however, 7 children classified by both systems as having less severe disease received CYC, and 6 children classified as having severe disease by both systems did not receive CYC.In this pediatric AAV cohort, the EUVAS and WGET adult severity subclassification systems had strong correlation with physician choice of treatment. However, a proportion of patients received treatment that was not concordant with their assigned severity subclass.

View details for DOI 10.3899/jrheum.120299

View details for Web of Science ID 000310256100017

View details for PubMedID 22859342

Assessing the Performance of the Birmingham Vasculitis Activity Score at Diagnosis for Children with Antineutrophil Cytoplasmic Antibody-associated Vasculitis in A Registry for Childhood Vasculitis (ARChiVe) JOURNAL OF RHEUMATOLOGY Morishita, K., Li, S. C., Muscal, E., Spalding, S., Guzman, J., Uribe, A., Abramson, L., Baszis, K., Benseler, S., Bowyer, S., Campillo, S., Chira, P., Hersh, A. O., Higgins, G., Eberhard, A., Ede, K., Imundo, L., Jung, L., Kim, S., Kingsbury, D. J., Klein-Gitelman, M., Lawson, E. F., Lovell, D. J., Mason, T., McCurdy, D., Nanda, K., Nassi, L., O'Neil, K. M., Rabinovich, E., Ramsey, S. E., Reiff, A., Rosenkranz, M., Schikler, K., Stevens, A., Wahezi, D., Cabral, D. A. 2012; 39 (5): 1088-1094


There are no validated tools for measuring disease activity in pediatric vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is a valid disease activity tool in adult vasculitis. Version 3 (BVAS v.3) correlates well with physician's global assessment (PGA), treatment decision, and C-reactive protein in adults. The utility of BVAS v.3 in pediatric vasculitis is not known. We assessed the association of BVAS v.3 scores with PGA, treatment decision, and erythrocyte sedimentation rate (ESR) at diagnosis in pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV).Children with AAV diagnosed between 2004 and 2010 at all ARChiVe centers were eligible. BVAS v.3 scores were calculated with a standardized online tool ( Spearman's rank correlation coefficient (r(s)) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR.A total of 152 patients were included. The physician diagnosis of these patients was predominantly granulomatosis with polyangiitis (n = 99). The median BVAS v.3 score was 18.0 (range 0-40). The BVAS v.3 correlations were r(s) = 0.379 (95% CI 0.233 to 0.509) with PGA, r(s) = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and r(s) = 0.403 (95% CI 0.253 to 0.533) with ESR.Applied to children with AAV, BVAS v.3 had a weak correlation with PGA and moderate correlation with both ESR and treatment decision. Prospective evaluation of BVAS v.3 and/or pediatric-specific modifications to BVAS v.3 may be required before it can be formalized as a disease activity assessment tool in pediatric AAV.

View details for DOI 10.3899/jrheum.111030

View details for Web of Science ID 000303975300034

View details for PubMedID 22337238

Alternative activation in systemic juvenile idiopathic arthritis monocytes CLINICAL IMMUNOLOGY Macaubas, C., Nguyen, K. D., Peck, A., Buckingham, J., Deshpande, C., Wong, E., Alexander, H. C., Chang, S., Begovich, A., Sun, Y., Park, J. L., Pan, K., Lin, R., Lih, C., Augustine, E. M., Phillips, C., Hadjinicolaou, A. V., Lee, T., Mellins, E. D. 2012; 142 (3): 362-372


Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition. The association with macrophage activation syndrome, and the therapeutic efficacy of inhibiting monocyte-derived cytokines, has implicated these cells in SJIA pathogenesis. To characterize the activation state (classical/M1 vs. alternative/M2) of SJIA monocytes, we immunophenotyped monocytes using several approaches. Monocyte transcripts were analyzed by microarray and quantitative PCR. Surface proteins were measured at the single cell level using flow cytometry. Cytokine production was evaluated by intracellular staining and ELISA. CD14(++)CD16(-) and CD14(+)CD16(+) monocyte subsets are activated in SJIA. A mixed M1/M2 activation phenotype is apparent at the single cell level, especially during flare. Consistent with an M2 phenotype, SJIA monocytes produce IL-1 after LPS exposure, but do not secrete it. Despite the inflammatory nature of active SJIA, circulating monocytes demonstrate significant anti-inflammatory features. The persistence of some of these phenotypes during clinically inactive disease argues that this state reflects compensated inflammation.

View details for DOI 10.1016/j.clim.2011.12.008

View details for PubMedID 22281427

Serum amyloid A overrides T-reg anergy via monocyte-dependent and T-reg-intrinsic, SOCS3-associated pathways BLOOD Nguyen, K. D., Macaubas, C., Nadeau, K. C., Phi Truong, T., Yoon, T., Lee, T., Park, J. L., Mellins, E. D. 2011; 117 (14): 3793-3798


The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (T(reg)). Intriguingly, SAA reverses T(reg) anergy via its interaction with monocytes to activate distinct mitogenic pathways in T(reg) but not effector T cells. This selective responsiveness of T(reg) correlates with their diminished expression of SOCS3 and is antagonized by T(reg)-specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports T(reg) expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.

View details for DOI 10.1182/blood-2010-11-318832

View details for Web of Science ID 000289265500014

View details for PubMedID 21325601

View details for PubMedCentralID PMC3296631

Monocyte phenotypes in systemic juvenile idiopathic arthritis Macaubas, C., Khoa Nguyen, Peck, A., Wong, E., Buckingham, J., Goertz, Y., Deshpande, C., Alexander, H., Chang, S., Sun, Y., Park, J., Lee, T., Begovich, A., Mellins, E. AMER ASSOC IMMUNOLOGISTS. 2011
Plasma profiles in active systemic juvenile idiopathic arthritis: Biomarkers and biological implications PROTEOMICS Ling, X. B., Park, J. L., Carroll, T., Nguyen, K. D., Lau, K., Macaubas, C., Chen, E., Lee, T., Sandborg, C., Milojevic, D., Kanegaye, J. T., Gao, S., Burns, J., Schilling, J., Mellins, E. D. 2010; 10 (24): 4415-4430


Systemic juvenile idiopathic arthritis (SJIA) is a chronic arthritis of children characterized by a combination of arthritis and systemic inflammation. There is usually non-specific laboratory evidence of inflammation at diagnosis but no diagnostic test. Normalized volumes from 89/889 2-D protein spots representing 26 proteins revealed a plasma pattern that distinguishes SJIA flare from quiescence. Highly discriminating spots derived from 15 proteins constitute a robust SJIA flare signature and show specificity for SJIA flare in comparison to active polyarticular juvenile idiopathic arthritis or acute febrile illness. We used 7 available ELISA assays, including one to the complex of S100A8/S100A9, to measure levels of 8 of the15 proteins. Validating our DIGE results, this ELISA panel correctly classified independent SJIA flare samples, and distinguished them from acute febrile illness. Notably, data using the panel suggest its ability to improve on erythrocyte sedimentation rate or C-reactive protein or S100A8/S100A9, either alone or in combination in SJIA F/Q discriminations. Our results also support the panel's potential clinical utility as a predictor of incipient flare (within 9wk) in SJIA subjects with clinically inactive disease. Pathway analyses of the 15 proteins in the SJIA flare versus quiescence signature corroborate growing evidence for a key role for IL-1 at disease flare.

View details for DOI 10.1002/pmic.201000298

View details for PubMedID 21136595

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort LUPUS Ardoin, S. P., Schanberg, L. E., Sandborg, C., Yow, E., Barnhart, H. X., Mieszkalski, K. L., Ilowite, N. T., von Scheven, E., Eberhard, A., Levy, D. M., Kimura, Y., Silverman, E., Bowyer, S. L., Punaro, L., Singer, N. G., Sherry, D. D., McCurdy, D., Klein-Gitelman, M., Wallace, C., Silver, R., Wagner-Weiner, L., Higgins, G. C., Brunner, H. I., Jung, L. K., Imundo, L., Soep, J. B., Reed, A. M. 2010; 19 (11): 1315-1325


As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

View details for DOI 10.1177/0961203310373937

View details for Web of Science ID 000282090700007

View details for PubMedID 20861207

Monocytes are resistant to apoptosis in systemic juvenile idiopathic arthritis CLINICAL IMMUNOLOGY Srivastava, S., Macaubas, C., Deshpande, C., Alexander, H. C., Chang, S., Sun, Y., Park, J. L., Lee, T., Begovich, A., Mellins, E. D. 2010; 136 (2): 257-268


We investigated whether circulating monocytes from patients with systemic juvenile idiopathic arthritis (SJIA) are resistant to apoptosis and which apoptotic pathway(s) may mediate this resistance. A microarray analysis of peripheral blood mononuclear cells (PBMC) of SJIA samples and RT-PCR analysis of isolated monocytes showed that monocytes from active SJIA patients express transcripts that imply resistance to apoptosis. SJIA monocytes incubated in low serum show reduced annexin binding and diminished FasL up-regulation compared to controls. SJIA monocytes are less susceptible to anti-Fas-induced apoptosis and, upon activation of the mitochondrial pathway with staurosporine, show diminished Bid cleavage and Bcl-w down-regulation compared to controls. Exposure to SJIA plasma reduces responses to apoptotic triggers in normal monocytes. Thus, SJIA monocytes are resistant to apoptosis due to alterations in both the extrinsic and intrinsic apoptosis pathways, and circulating factors associated with active SJIA may confer this phenotype.

View details for DOI 10.1016/j.clim.2010.04.003

View details for PubMedID 20462799

Neonatal Legionellosis The Tip of the Iceberg for Pediatric Hospital-Acquired Pneumonia? PEDIATRIC INFECTIOUS DISEASE JOURNAL Yu, V. L., Lee, T. C. 2010; 29 (3): 282-284

View details for DOI 10.1097/INF.0b013e3181d1dfda

View details for Web of Science ID 000275136000024

View details for PubMedID 20190615

Distribution of circulating cells in systemic juvenile idiopathic arthritis across disease activity states CLINICAL IMMUNOLOGY Macaubas, C., Nguyen, K., Deshpande, C., Phillips, C., Peck, A., Lee, T., Park, J. L., Sandborg, C., Mellins, E. D. 2010; 134 (2): 206-216


Juvenile idiopathic arthritis (JIA) encompasses a group of chronic childhood arthritides of unknown etiology. One subtype, systemic JIA (SJIA), is characterized by a combination of arthritis and systemic inflammation. Its systemic nature suggests that clues to SJIA pathogenesis may be found in examination of peripheral blood cells. To determine the immunophenotypic profiles of circulating mononuclear cells in SJIA patients with different degrees of disease activity, we studied PBMC from 31 SJIA patients, 20 polyarticular JIA patients (similar to adult rheumatoid arthritis), and 31 age-matched controls. During SJIA disease flare, blood monocyte numbers were increased, whereas levels of myeloid dendritic cells (DC) and gammadelta T cells were reduced. At both flare and quiescence, increased levels of CD14 and CD16 were found on SJIA monocytes. Levels of CD16-DC were elevated at SJIA quiescence compared both to healthy controls and to SJIA subjects with active disease. Overall, our findings suggest dysregulation of innate immunity in SJIA and raise the possibility that quiescence represents a state of compensated inflammation.

View details for DOI 10.1016/j.clim.2009.09.010

View details for PubMedID 19879195

Classification, Presentation, and Initial Treatment of Wegener's Granulomatosis in Childhood ARTHRITIS AND RHEUMATISM Cabral, D. A., Uribe, A. G., Benseler, S., O'Neil, K. M., Hashkes, P. J., Higgins, G., Zeft, A. S., Lovell, D. J., Kingsbury, D. J., Stevens, A., McCurdy, D., Chira, P., Abramson, L., Arkachaisri, T., Campillo, S., Eberhard, A., Hersh, A. O., Huber, A. M., Kim, S., Klein-Gitelman, M., Levy, D. M., Li, S. C., Mason, T., DeWitt, E. M., Muscal, E., Nassi, L., Reiff, A., Schikler, K., Singer, N. G., Wahezi, D., Woodward, A. 2009; 60 (11): 3413-3424


To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG.Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6).The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

View details for DOI 10.1002/art.24876

View details for Web of Science ID 000271781400031

View details for PubMedID 19877069

Premature Atherosclerosis in Pediatric Systemic Lupus Erythematosus ARTHRITIS AND RHEUMATISM Schanberg, L. E., Sandborg, C., Barnhart, H. X., Ardoin, S. P., Yow, E., Evans, G. W., Mieszkalski, K. L., Ilowite, N. T., Eberhard, A., Levy, D. M., Kimura, Y., von Scheven, E., Silverman, E., Bowyer, S. L., Punaro, L., Singer, N. G., Sherry, D. D., McCurdy, D., Klein-Gitelman, M., Wallace, C., Silver, R., Wagner-Weiner, L., Higgins, G. C., Brunner, H. I., Jung, L., Soep, J. B., Reed, A. 2009; 60 (5): 1496-1507


To evaluate risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE).In a prospective multicenter study, a cohort of 221 patients underwent baseline measurements of carotid intima-media thickness (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess the thickness of the bilateral common carotid arteries and the mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT, which were examined in multivariable linear regression modeling.Based on the mean-mean common or the mean-max CIMT as the dependent variable, univariable analysis showed significant associations of the following variables with increased CIMT: increasing age, longer SLE duration, minority status, higher body mass index (BMI), male sex, increased creatinine clearance, higher lipoprotein(a) level, proteinuria, azathioprine treatment, and prednisone dose. In multivariable modeling, both azathioprine use (P=0.005 for the mean-mean model and P=0.102 for the mean-max model) and male sex (P<0.001) were associated with increases in the mean-max CIMT. A moderate dosage of prednisone (0.15-0.4 mg/kg/day) was associated with decreases in the mean-max CIMT (P=0.024), while high-dose and low-dose prednisone were associated with increases in the mean-mean common CIMT (P=0.021) and the mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031) remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing lipoprotein(a) level (P=0.005) were associated with increased mean-max CIMT.Traditional as well as nontraditional risk factors were associated with increased CIMT in this cohort of patients in the APPLE trial. Azathioprine treatment was associated with increased CIMT. The relationship between CIMT and prednisone dose may not be linear.

View details for DOI 10.1002/art.24469

View details for Web of Science ID 000266071700036

View details for PubMedID 19404953

View details for PubMedCentralID PMC2770725

Neuropsychiatric manifestations in pediatric systemic lupus erythematosus and association with antiphospholipid antibodies JOURNAL OF RHEUMATOLOGY Harel, L., Sandborg, C., Lee, T., von Scheven, E. 2006; 33 (9): 1873-1877


To determine the prevalence of neuropsychiatric (NP) manifestations in children with systemic lupus erythematosus (SLE) using the 1999 American College of Rheumatology case definitions for NP syndromes in SLE, and their association with antiphospholipid antibodies (aPL).We performed a retrospective cohort study of 106 pediatric and adolescent SLE patients at 2 academic medical centers. Clinical and laboratory data were obtained by medical record review. All aPL testing was performed in standard clinical laboratories.Twenty-five patients (23.6%) had NP manifestations, including seizures (9.4%), headaches (4.7%), mood disorders (4.7%), cognitive dysfunction (4.7%), cerebrovascular accident (CVA), psychosis and pseudotumor (2.8% each), aseptic meningitis (0.9%), acute confusional state (0.9%), anxiety (0.9%), and cranial neuropathy (0.9%). NP events were not necessarily accompanied by an SLE flare. aPL were positive in 70% of all SLE patients, including anticardiolipin antibodies (aCL) in 64%, aCL IgG in 56%, aCL IgM in 35%, rapid plasma reagin or Venereal Disease Research Laboratory test in 13%, and lupus anticoagulant (LAC) in 18%. The only significant association between NP manifestations and aPL was for CVA and IgM aCL (p=0.03). LAC was slightly more common among patients with NP events, and the finding of LAC on more than one occasion was significantly associated with developing a NP event (p = 0.01).NP manifestations occur in about one-fourth of children with SLE, are an early event in the course of the disease, and are not necessarily accompanied by an SLE flare. Seizures are the most frequent symptom. Although aPL are common, their association with NP events, unlike in adults, is weak, except for CVA, suggesting a different pathogenic mechanism for NP manifestations in pediatric SLE.

View details for Web of Science ID 000240377400030

View details for PubMedID 16845706

Problem pathogens: paediatric legionellosis - implications for improved diagnosis LANCET INFECTIOUS DISEASES Greenberg, D., Chiou, C. C., Famigilleti, R., Lee, T. C., Yu, V. L. 2006; 6 (8): 529-535


Legionnaires' disease is an established and frequent cause of pneumonia in adults but is thought to be a rare cause in children. We reviewed the medical literature for cases of Legionnaires' disease in children and analysed the epidemiology, clinical characteristics, and treatment. 76 cases of legionella infection in children were identified. In 56%, diagnosis was made with culture methodology. 46% were community-acquired infections. 51.5% were under 2 years of age. 78% of the patients had an underlying condition such as malignancy. Fever, cough, and tachypnoea were the most common symptoms. The overall mortality rate was 33% and was higher in immunosuppressed children and in children younger than the age of 1 year. Patients who were treated empirically with anti-legionella therapy had a notably lower mortality rate compared with patients on inappropriate therapy (23%vs 70%). In 88% of hospital-acquired cases, an environmental link to potable water colonised with legionella was identified. We found no clinical features unique to Legionnaires' disease in children that would allow differentiation from pneumonia due to other respiratory pathogens. Awareness of legionella as a potential cause of paediatric pneumonia is particularly important because infection can be severe and life threatening and antimicrobial therapy often used for empirical therapy in children is not effective against legionella. In any case of pneumonia unresponsive to antibiotics, Legionnaires' disease should be considered and specific diagnostic tests to verify this diagnosis should be done. As legionella diagnostic tests become more widely applied, we predict that legionellosis may appear as an emerging infectious disease in children.

View details for Web of Science ID 000239341300024

View details for PubMedID 16870531

J Rheum Sandborg, Lee 2006
Gene expression profiling of peripheral blood mononuclear cells (PBMC) from SJIA patients. 6th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Deshpande, C., Sun, Y., Mocaubas, C., Alexander, H., Pan, K., Lee, T., Chang, S., Lih, C., Lin, R., Sandborg, C., Tibshirani, R., Begovich, A. B., Cohen, S., Mellins, E. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2006: S68S68


Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) can be associated with significant morbidity in children and adolescents. Renal involvement in SLE appears to be more severe and more frequent in the pediatric age group, with the major predictors for poor outcome being the severity of histopathologic lesions, severity of renal impairment at diagnosis, and hypertension. In addition to currently recognized cardiovascular and pulmonary involvement, accelerated atherosclerosis is of increasing concern in young individuals with SLE, because of both disease effects and medication usage. Neuropsychiatric SLE seen in childhood ranges from subtle cognitive dysfunction to severe central nervous system involvement; however, there is controversy over the value of different diagnostic studies. APS in children may be associated with SLE, idiopathic, or associated with viral infections. Systemic anticoagulation is recommended for patients with thrombotic events, but long-term management has not been well studied in children.

View details for PubMedID 11604598

Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents CURRENT OPINION IN RHEUMATOLOGY Lee, T., von Scheven, E., Sandborg, C. 2001; 13 (5): 415-421