Novel methods to assess brain changes in children with systemic lupus erythematosus

Neuropsychiatric involvement with systemic lupus erythematosus (SLE) is currently difficult to diagnose given the lack of specific blood-based biomarkers, and the fact that brain involvement does not result in change on routine magnetic resonance imaging (MRI). Mainly based on murine studies, brain involvement with SLE associates with altered stability of the blood-brain barrier. In collaborative research between the Division of Rheumatology and the Imaging Research Center, this group developed a safe noninvasive MRI method to measure regional blood–brain barrier integrity and investigate its relationship with neurocognitive function and regional gray matter volume in children with SLE. Using this new imaging method we conducted a matched cross-sectional, case–control study. Research found that regional decline in the blood-brain barrier stability was negatively associated with neurocognitive performance concerning psychomotor speed with SLE. Compared with controls, children with SLE patients had significantly lower blood-brain barrier integrity involving Brodmann’s areas 19, 28, 36, and 37 and caudate structures (P< 0.05 for all). We concluded that there is imaging evidence of increased regional capillary permeability in children with SLE, even if there is grossly normal cognitive performance and that a novel completely non-invasive imaging method developed at Cincinnati Children's was suitable to capture such changes. The findings of this study are in line with our previous research where we documented abnormalities in with functional neuronal network alterations and gray matter volume loss in children with SLE, supporting the notion that blood–brain barrier integrity loss precedes the loss of cognitive ability in juvenile SLE.

The Pediatric Rheumatology Collaborative Study Group (PRCSG)

The mission of the Pediatric Rheumatology Collaborative Study Group (PRCSG) is to foster, facilitate, and conduct high quality clinical research in the field of pediatric rheumatology. The PRCSG is a network of pediatric rheumatology professionals working for the most part at academic and clinical centers. PRCSG members actively engage in the diagnosis and management of children with rheumatic and related musculoskeletal diseases. The leadership and the PRCSG Coordinating Center comes from within the Division of Rheumatology at Cincinnati Children's. Dr. Daniel Lovell serves as the chairman of the organization and Dr. Hermine Brunner serves as the scientific director. Additional information about this group is available on the PRCSG website.

Currently, the PRCSG is managing Phase III and IV trials studying the following medications for use in various forms of juvenile idiopathic arthritis (JIA): Oral JAK (Janus Kinase) inhibitor tofacitinib; subcutaneous abatacept; subcutaneous tocilizumab; subcutaneous adalimumab; subcutaneous certolizumab; intravenous golimumab; and subcutaneous secukinumab. The PRCSG involvement in Phase III trials in other pediatric rheumatic diseases includes intravenous belimumab and tofacitinib in lupus.

Interferon-Gamma Activation Characterizes Macrophage Activation Syndrome Complicating Systemic JIA

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of systemic JIA, and has striking similarity to the rare histiocytic disorder hemophagocytic lymphohistiocytosis (HLH). Interferon-gamma (IFNγ) has a central role in the pathogenesis of HLH, but its role in MAS remains unclear. In this study, together with two centers in Italy, we determined levels of inflammatory cytokines and IFN-induced chemokines in patients with HLH or with systemic JIA with and without MAS. Levels of IFNγ and IFN-induced chemokines were strikingly high in patients with both HLH and active MAS. In contrast, levels in patients with active systemic JIA but without MAS were comparable to those in patients with clinically inactive systemic JIA. Serum IFNγ and IFN-induced chemokine levels also strongly correlated with laboratory features of MAS. These findings strongly suggest that IFNγ and IFN-induced chemokines have a pivotal role in MAS, and supports the use of targeted anti- IFNγ therapy for this often fatal disorder.

Research Flow Cytometry Core Provides Novel Technologies for Cincinnati Children's Hospital Medical Center Investigators

Directed by Dr. Sherry Thornton, PhD, the Research Flow Cytometry Core (RFCC) is in the Division of Rheumatology and provides state-of-the-art equipment to over 140 research investigators to perform single cell analysis. In the last year, funding from the Research Foundation enabled the Core to upgrade instruments for increased capability and more detailed highly multi-parametric flow cytometry for both analysis and sorting of cell populations. Dr. Thornton submitted and received a NIH Shared Instrumentation Grant for a fourth cell sorter, increasing the capacity of cell sorting and allowing users access to cell sorting 24/7. Support for the Core is by two NIH Center grants, the Cincinnati Rheumatic Disease Core Center and the Digestive Health Center. To enhance the research of Cincinnati Children's investigators, the RFCC works closely with investigators and other core facilities to improve workflow. Presentation of these innovative activities of the RFCC at a workshop on cross core collaborations occurred at the 2017 Annual Meeting of the Association for Biomolecular Research Facilities in San Diego, CA.

Increasing the Impact of Patient Reported Outcomes in Pediatric Rheumatology Care

The National Institutes of Health created the Patient Reported Outcomes Measurement Information System (PROMIS®) cooperative network (2005-2015) to develop a publicly available system to measure health from the patient perspective with more efficient and precise patient reported outcome (PRO) tools than previously available. During the second phase of this project, Dr. Esi Morgan was principal investigator leading a multidisciplinary research project “Enhancing PROMIS in Pediatric Pain, Rheumatology and Rehabilitation Research” (U01AR057940). The project included longitudinal validation of PROMIS measures of self-reported health in children with juvenile idiopathic arthritis (JIA), and chronic pain, as well as development of new PROMIS item banks to assess pain behavior, pain quality and pain intensity in children with chronic painful conditions. The team published an article using application of an innovative method to determine meaning of patient reported outcome measure scores from the patient perspective, as well as the viewpoint of parents and clinical providers. Researchers documented differences in perspectives which has implications for medical decision making. Establishing clinical meaning and defining important differences for PROMIS measures in juvenile idiopathic arthritis using standard setting with patients, parents, and providers. The research team also published an article on the newly developed PROMIS Pediatric Pain Behavior Items.

Novel UNC13D Intronic Variant Disrupting a NFĸB Enhancer in a Patient with Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (SJIA), and has similarity to the rare genetic disorders hemophagocytic lymphohistiocytosis (HLH). Patients with familial HLH-3 (FHL3) have intronic variants in UNC13D, but the role of non-coding variants in MAS is unknown. In work published in Arthritis and Rheumatology, Drs. Grant Schulert and Alexei Grom, together with colleagues in human genetics and the University of Alabama, sought to identify deep intronic UNC13D variants in patients with MAS. They utilized a custom enrichment library to sequence non-coding regions of UNC13D in patients with recurrent MAS and negative prior genetic (exon/coding) testing. Through this approach, they identified a child a novel functional intronic variant in UNC13D in a child with SJIA and recurrent MAS. This variant occurs in a proposed regulatory region that drives lymphocyte specific UNC13D expression, and disrupts transcription factor binding to a functional transcriptional enhancer. Identification of an additional patient with a previously described UNC13D intronic variant left a total non-coding variant hit rate of 8.3%. Taken together, these findings highlight that intronic variants in key regulatory regions may associate with MAS in patients with SJIA, and support deep sequencing approaches when causative coding variants are not identified.

Biologic Therapy Modifies Clinical and Laboratory Features of Macrophage Activation Syndrome Associated with Systemic Juvenile Idiopathic Arthritis

While treatment with biologic agents targeting IL-1 and IL-6 has dramatically improved outcomes for patients with systemic juvenile idiopathic arthritis, these children remain at risk for life-threatening complications such as macrophage activation syndrome (MAS). It is not known how such treatment may alter the clinical presentation or outcome of MAS. In work published in Arthritis Care and Research, Drs. Grant Schulert and Alexei Grom performed a systemic literature review to assess performance of newly developed MAS classification criteria for patients treated with biologic medications. Together, this study found that MAS classification criteria were less likely to classify tocilizumab treated patients as having MAS. Patients who developed MAS while treated with canakinumab trended towards lower inflammatory markers at MAS onset, but had no differences in other cardinal clinical or laboratory features. In comparison, patients who developed MAS while treated with tocilizumab were less likely febrile and had notably lower inflammatory markers. Other features of MAS were more pronounced in patients treated with tocilizumab, including lower platelet counts, lower fibrinogen and higher aspartate aminotransferase levels. Mortality rates for patients with MAS treated with tocilizumab or canakinumab were not significantly different from the historical cohort. These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologics.

Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) Joins Arthritis Foundation and Childhood Arthritis and Rheumatology Research Alliance (CARRA) to form Learning Health System

The Patients, Advocates, and Rheumatology Teams Network for Research and Service (PARTNERS) is a Patient Powered Research Network (PPRN) comprised of the Arthritis Foundation, the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN), Childhood Arthritis and Rheumatology Research Alliance (CARRA), the Lupus Foundation, and CureJM with funding from PCORI (Patient Centered Outcomes Research Institute). PARTNERS recently received an award of one of four PCORnet pilot grants to re-design our PPRN into a Learning Health System (LHS) with initial focus on juvenile idiopathic arthritis (JIA). LHS aim is to integrate patient perspectives with research, quality improvement science, and clinical care to improve the delivery of healthcare and achieve better clinical outcomes. Dr. Esi Morgan serves as principal investigator for PR-COIN based at Cincinnati Children's. PARTNERS’ vision is that all children with rheumatic conditions will be as healthy as they can be. PARTNERS’ current aims are to: increase the proportion of JIA patients with inactive disease or low disease activity, improve patient quality of life, increase the number of patients participating in research, and expand the number of rheumatology medical centers participating in collaborative quality improvement network activities. In June 2018, representatives from PR-COIN, the Arthritis Foundation, CARRA, Institute for Healthcare Improvement, and Cincinnati Children’s James M. Anderson Center for Health Systems Excellence participated in a design meeting to provide input on PARTNERS’ vision, mission, and model of interventions that together can improve outcomes. The improvement efforts will include a treatment strategy focused on keeping patient treatment goals at the center (“treat to target”), shared decision making, and self-management support. Studying data collected from both quality improvement and clinical research efforts can lead to better care. Thus, another aim of the grant is to expand the LHS research arm by enhancing data collection systems and developing a common informed consent process across participating organizations. PARTNERS LHS is creating a new way to address gaps and opportunities in pediatric rheumatology health care.

OMERACT (Outcome Measures in Rheumatology) Gains Consensus on New Domains for Evaluation in Clinical Trials of Juvenile Idiopathic Arthritis

Since 2015, Dr. Esi Morgan has served as co-chair of an International effort to update the JIA Core Set of domains to measure drug efficacy in randomized clinical trials. Drs. Hermine Brunner and Daniel Lovell are contributing members of the OMERACT JIA Working Group. OMERACT is an independent initiative of international health professionals interested in development and use of outcome measures in rheumatology. OMERACT has a formal methodology and framework established to develop core sets and holds expect consensus conferences every two years. Publication of the current JIA Core Set (ACR Pediatric 30) to assess efficacy of medications in randomized controlled trials (RCTs) was in 1997 and developed without input of patients or caregivers. The current core set includes six variables: physician global assessment, parent/patient global assessment of overall wellbeing, physical functional ability, count of joints with active arthritis, count of joints with restricted motion, an acute phase reactant and - for systemic JIA - fever in past week. OMERACT recommends four core areas to include in RCTs and longitudinal observational studies (LOS) – 1) life impact; 2) pathophysiologic manifestations; 3) resource use; 4) adverse events – and conceptualizes domains along three levels of requirements for inclusion: inner circle – mandatory for all RCTs and LOS; middle circle - important, but optional; outer circle – research agenda. The OMERACT JIA Core Set working group obtained global stakeholder input from JIA patients, caregivers, health care providers and researchers to update the JIA core domain set. Activities included use of online discussion boards (ODBs) held with 53 JIA patients and 55 parents in the United States, Australia and Italy to generate candidate domains. Three rounds of a Delphi process to prioritize 27 domains held with over 200 stakeholders identified by patient advocacy groups, pediatric rheumatology clinical trials organizations and regulators. In the final Delphi round, rating of domains were for inclusion in inner, middle or outer circles. Presentation of results occurred at the OMERACT conference in May 2018 in Australia for consensus among participants, with level of consensus set at ≥70%. Final voting at the OMERACT 2018 conference approved a revised set of domains for JIA clinical trials and observational studies with 83% agreement. A notable change is the recommendation of pain as a core domain for all JIA RCTs, and LOS. Multiple patient reported domains were also voted as important to consider for inclusion in JIA trials, including fatigue, emotional function, and participation restriction.

Pediatric Uveitis is an Inflammatory Eye Disease That Can Lead to Ocular Complications and Vision Loss

JIA is the most common rheumatic disease and uveitis is the most common extra-articular manifestation wherein 10-25% of affected children develop ocular inflammation. Uveitis can also occur in children with sarcoidosis and Behçet’s disease, or in isolation, as in idiopathic uveitis. Through the Comprehensive Pediatric Non-Infectious Uveitis Clinic, children receive specialized expert care from both rheumatologists and ophthalmologists in a combined same day clinic, with the option to participate in research programs. Dr. Sheila Angeles-Han is the author of numerous publications on pediatric uveitis, and leads active research programs to better understand risk factors for uveitis development and a severe disease course. In collaboration with Dr. Virginia Utz, the goal of combining clinical care and research is to optimize visual outcomes by preventing sight-threatening complications.

Fibromyalgia Integrative Training for Teens FIT Teens

Juvenile Fibromyalgia (JFM) is a chronic condition of amplified widespread musculoskeletal pains associated with fatigue and often with symptoms of unrestful sleep, chronic headaches, irritable bowel symptoms, numbness/tingling, anxiety/depression, subjective swelling as well as possible pain that can worsen with weather changes, stress and/or activity. Unfortunately, treatment remains challenging for this condition. Dr. Tracy Ting, in collaboration with the lead investigator, Dr. Susmita Kashikar-Zuck, a pediatric pain psychologist, and the Division of Behavioral Medicine and Clinical Psychology at Cincinnati Children's Hospital Medical Center have been working towards finding effective treatment options for patients with JFM who suffer from significant morbidity and poor functioning in school and with peers. Our current ongoing large multisite study is evaluating the potential effects of a combined program of neuromuscular training with cognitive behavioral therapy (CBT) on reducing pain and improving function in teens with fibromyalgia. Our preliminary pilot study (N=36) indicates significant reductions in pain and disability among the treatment group as compared to a CBT alone group.