Tools for increasing the pool of medications approved for children with lupus

Childhood-onset systemic lupus erythematosus (cSLE) is rare in many regions of the world, including Europe. Access to approved medications for cSLE is currently limited due to, among other reasons, a lack of high-quality evidence from clinical trials. Studying cSLE is difficult as it can affect every organ in the body and the effects of medication need to consider improvement and worsening in individual organ systems affected by the disease. Supported by funding from NIH, Hermine Brunner, MD, MSc, MBA, led an international collaboration of over 300 pediatric rheumatologists who participated in a global consensus formation project to develop highly sensitive and specific measures that capture the degree of benefits (minor, moderate, major) from therapies. Given the superior measurement properties of this newly developed Childhood Lupus Improvement Index, the American College of Rheumatology (ACR) endorsed the index. Further, using a similar methodologically stringent approach, Dr. Brunner developed a new standardized approach to capture treatment failures. Again, these Provisional Criteria of Global Flare of cSLE received endorsement by the ACR.

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 mostly at academic and clinical centers. PRCSG members are actively engaged in the diagnosis and management of children with rheumatic, and related musculoskeletal, diseases. Embedded in the Division of Rheumatology at Cincinnati Children's are both PRCSG leadership and the PRCSG Coordinating Center. Daniel Lovell, MD, MPH, serves as the chairman of the organization and Dr. Brunner serves as the scientific director.

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. There is additional involvement of the PRCSG in other pediatric rheumatic diseases in Phase III trials, such as belimumab and tofacitinib in lupus.

First guideline from the American College of Rheumatology (ACR) and Arthritis Foundation (AF) for children with juvenile idiopathic arthritis and uveitis

Uveitis, or ocular inflammation, is the most common and devastating extra-articular manifestation of juvenile idiopathic arthritis (JIA). Uncontrolled uveitis can lead to sight-threatening complications in 25-50% and vision loss in 10-20% of children with uveitis. JIA-associated uveitis is asymptomatic until ocular complications occur, thus the American Academy of Pediatrics (AAP) recommends routine ophthalmic screening. However, the base of those recommendations were on an older arthritis nomenclature with no other known risk factors. Overall, there is a lack of guidance on the ophthalmic monitoring of, or the treatment of, children with uveitis. Thus, the ACR and the Arthritis Foundation developed the first North American guideline for the screening, monitoring, and treatment of JIA-associated uveitis. Sheila Angeles-Han, MD, MSc, a pediatric rheumatologist at Cincinnati Children's and an international expert and leader in pediatric uveitis, led the development of this guideline. The guideline development teams consisted of other pediatric rheumatologists including: Dr. Lovell; Alexei Grom, MD; Grant Schulert, MD, PHD; uveitis specialists; a literature review consultant and team; an expert in the process of grading of recommendations assessment, development, and evaluation (GRADE) methodology; patients and parents. There were 19 final recommendations that focus on: 1) ophthalmic screening in children with JIA at risk of developing uveitis; 2) ophthalmic monitoring in children with JIA and controlled uveitis based on their use of topical glucocorticoids and systemic therapy; 3) treatment with glucocorticoids; 4) treatment with nonbiologic and biologic DMARDs, specifically methotrexate, infliximab, and adalimumab; 5) tapering of treatment; and 6) education and treatment of acute anterior uveitis. Few uveitis practice guidelines have a scope this broad, and this guideline fills a critical clinical gap in the care of children with JIA-associated uveitis. In addition, Dr. Angeles-Han co-led the development of a guideline that includes 39 recommendations for the approach to the treatment of children with non-systemic polyarthritis, sacroiliitis, and enthesitis.

Novel Technology Aids in Characterizing Monocyte and Macrophage Populations in Hyperinflammatory Diseases

Expression of protein markers on the surface of cells allows for characterization and identification of specific cell types that may be driving disease processes. Cellular characterization recently established analysis of mRNA encoding protein as well. Development of tools to define the specific macrophage and monocyte populations underlying the pathogenesis of diseases such as macrophage activation syndrome (MAS) and systemic juvenile idiopathic arthritis (SJIA), is a key barrier and may provide mechanisms for novel therapeutic targets. CD163 facilitates regulation and resolution of inflammation and removal of free hemoglobin and is highly expressed in myeloid cells from patients with inflammatory disorders such as SJIA and MAS. Our recent findings indicate that regulation of CD163 mRNA expression mediates at both transcriptional and post-transcriptional levels, including through a network of microRNA. In this study we demonstrated the detection of CD163 mRNA in monocyte/macrophage populations and determine a multi-parameter flow cytometry panel that includes analysis of CD163 mRNA at the single cell level for distinction of these cell types in peripheral blood mononuclear cells or bone marrow populations. Our studies indicate distinct changes in CD163 mRNA and protein expression in response to specific stimuli in a time and dose dependent manner. Finally, utilizing this mRNA probe in conjunction with other monocyte/macrophage polarization markers allows examination of distinct changes in CD163 mRNA and protein expression at a single cell level using flow cytometry, and aid in defining underlying mechanisms of disease pathogenesis in these hyperinflammatory syndromes. Further work with these innovative single cell tools will be essential to defining the role of myeloid effectors in SJIA and MAS.

Pediatric Rheumatology Care and Outcomes Improvement Network PRCOIN embarks on initiative to tighten

Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) is a collaborative improvement learning network coordinated by Cincinnati Children’s led by Esi Morgan, MD, MSCE, as the principal investigator and Janalee Taylor, MSN, APRN, CNS, CPNP, co-leads the outcomes committee. The mission of PR-COIN is to dramatically improve the outcomes of care for children with rheumatic conditions. The Patients, Advocates, and Rheumatology Teams Network for Research and Service (PARTNERS) Learning Health Systems (LHS), funded by PCORnet with the James M. Anderson Center for Health Systems Excellence leadership (PI: Peter Margolis, MD, PhD), fostered closer alignment of PR-COIN with the Arthritis Foundation and Childhood Arthritis and Rheumatology Research Alliance (CARRA). With a goal of improving patient health outcomes, PARTNERS LHS aims to: 1) expand learning network participation and use of QI methods in pediatric rheumatology; 2) increase dissemination of self-management support resources to the rheumatology patient community; and 3) increase patient enrollment in registries.

During the past year, PR-COIN launched a new registry working with Cincinnati Children's Division of Biomedical Informatics as part of PCORnet LHS, expanded learning network participation from 17 to 22 medical centers, and launched a “Treat to Target” initiative that uses standardized disease assessment, shared decision making and goal setting with patients, and a strategy of treatment adjustments for tighter disease control. Researchers will study the impact on disease outcomes based on data collected in a shared registry.

PR-COIN continues to engage in a consortium with other leading rheumatology organizations as part of PARTNERS Patient Powered Research Network (PPRN) comprised of PR-COIN, Arthritis Foundation, CARRA, the Lupus Foundation of America, and CureJM. Initially formed with funding from PCORI (Patient Centered Outcomes Research Institute), PARTNERS PPRN continues to work together on patient centered research studies including participation in a clinical trial of Mindfulness (PI: Andrew Nierenberg, MD, Massachusetts General Hospital), and a new award to facilitate patient engagement in research opportunities.