FDA approval of the first biologic medication 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. Hermine Brunner, MD, MSc, MBA, led an international randomized phase 2 clinical trial conducted with the PRCSG network in 10 countries around the world and included patients as young as 5 years of age. The objectives of this clinical trial were to test the proper medication dosing, safety and efficacy of intravenous belimumab in children with cSLE, when added to standard of care treatment. The team of researchers showed that children receiving belimumab compared to those randomized to placebo were more likely (52.8% vs. 43.6%) to achieve clinically relevant improvement of their disease by week 52. IV belimumab reduced the risk of experiencing a severe flare of lupus by 64%. Most importantly, the patient overall improved by 54% in the group of children receiving belimumab but only 24% in those randomized to placebo. Belimumab use seemed safe and did not associate with a higher percentage of adverse events or serious adverse events compared to placebo. Taken together, the study showed that the benefit–risk profile of intravenous belimumab in children with lupus is consistent with that observed in adult belimumab studies. Trial registration number NCT01649765.

Improving diagnosis and monitoring of uveitis in children with juvenile idiopathic arthritis

Juvenile idiopathic arthritis-associated uveitis (JIA-U) is a chronic inflammatory eye disease that affects 20% of children with JIA and can lead to sight-threatening complications. Regular ophthalmic screening of children with JIA is crucial because early uveitis detection can prevent visual complications and influence therapeutic management. Our long-term goal is to prevent sight-threatening ocular damage in children with JIA-U by improving uveitis detection, monitoring and treatment. Sheila Angeles-Han, MD, MSc, is the principal investigator who received a R01 from the National Eye Institute in 2019 to study tear-based biomarkers and genetic risk factors for uveitis development. “Predicting Eye Disease in children with Arthritis” or “PEDIA-U” is a multi-site longitudinal translational study that is a collaborative effort between experts in ophthalmology, rheumatology, proteomics, assay development, genetics and biostatistics. We expect that this study will improve our understanding of biological processes in JIA-U and potentially support the development of a widely applicable uveitis risk estimator for early identification of children at greatest risk for severe uveitis, which will allow for early intervention and improved vision outcomes.

Together with her collaborators, she also recently showed that inflammatory biomarkers originally studied in the aqueous humor of children with JIA-U are also detectable in tears. Increasing S100A12, IL-8, and sICAM-1 (all markers of neutrophils) in the tears of children with low-grade active JIA-U (AC cells grade 0.5+) compared to inactive JIA-U suggests a pathogenic role for neutrophils. This is advantageous since collection of tears is non-invasive and easily obtained. Tear-based biomarkers may have a role as a diagnostic tool in JIA-U and improve our understanding of the biological processes driving ocular inflammation. Further work is underway to establish tear-based biomarkers of uveitis activity for disease monitoring.

Systemic juvenile idiopathic arthritis-lung disease:  Characterization and risk factors

With a team of collaborators, Grant Schulert, MD, PhD, and Alexei Grom, MD, recently provided the first comprehensive clinical description of the new emerging life-threatening chronic pulmonary disease (SJIA-LD) in patients with SJIA that has features of alveolar proteinosis (PAP), endogenous lipoid pneumonia (ELP) and fibrosis. They also provided the first detailed mechanistic look at SJIA-LD and found that this entity has distinct clinical and immunologic features from other lung disorders, including known causes of PAP or ELP, and represents a new inflammatory ILD (SJIA-LD). Most of these patients have a history of macrophage activation syndrome, often recurrent. Furthermore, SC-RNA Seq using SJIA-LD lung biopsies revealed pathways overlapping with macrophage activation syndrome (MAS) including signs of T cell activation and strong IFN-induced signatures. Furthermore, gene expression profiling pointed to anti-IFN-gamma antibodies or Janus-kinase inhibitors as potential therapeutic agents for SJIA-LD.

Daniel J. Lovell, MD, MPH: Improved Treatment Guidelines & Classification Criteria for Children with Arthritis

Lovell participated in the ACR Treatment Guidelines Committee to develop guidelines for assessment and treatment of juvenile idiopathic arthritis (JIA) and JIA-associated uveitis and is currently participating in the current ACR Treatment Guidelines Committee to develop guidelines for assessment and treatment of oligoarticular JIA, and immunizations in JIA patients. He serves on the steering committee for the JIA Reclassification Working Group and is coordinating the effort of North American clinical sites in the longitudinal validation study for the development of new JIA classification criteria. The new classification aims at improving the prediction of the course of JIA and its response to therapy.

Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN)

Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) is a collaborative improvement learning network whose mission is to build a thriving and inclusive community of patients, families, clinical teams, and researchers that uses quality improvement science to identify and close gaps in care for children with rheumatic diseases and to bring research discovery to patients faster. Cincinnati Children’s, Esi Morgan, MD, MSCE, coordinates PR-COIN, and is the principal investigator. Janalee Taylor, MSN, APRN, CNS, CPNP, co-leads the outcomes committee. Over the past year, with funding from PCORI in conjunction with the James M. Anderson Center for Health Systems Excellence leadership, PR-COIN continued work with the advocacy organization Arthritis Foundation and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) together as the Patients, Advocates, and Rheumatology Teams Network for Research and Service (PARTNERS) Learning Health Systems (LHS).

The PR-COIN LHS registry, developed with the Division of Biomedical Informatics, enrolled 6,000 patients with juvenile idiopathic arthritis, and in 2020 put into production an interactive, on-demand reporting system including 15 quality measures, pre-visit planning, and population management reports. The registry delivered on its capacity for data upload from the electronic health record (e.g., Epic) and other databases for increased efficiency. It provides timely data useful for clinical care, quality improvement, and, ultimately, analysis of data for research. Active ongoing network projects include “Treat to Target” approach to tighten disease control, an initiative to increase patient recruitment into registries (PR-COIN jointly with CARRA), optimization of health outcomes using telehealth in response to the COVID-19 pandemic, and development of a new implementation science initiative with our research partner CARRA sponsored by the Arthritis Foundation.

Pediatric Rheumatology Collaborative Study Group (PRCSG) helps improve access to advanced medication for children with rheumatic diseases

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 while Brunner serves as the scientific director.

Currently, the PRCSG manages Phase 3 and 4 trials study of the following medications for use in various forms of JIA: Oral JAK (janus kinase) inhibitors tofacitinib and upadacitinib, subcutaneous abatacept, subcutaneous tocilizumab, subcutaneous adalimumab, subcutaneous certolizumab, intravenous golimumab, subcutaneous secukinumab, subcutaneous canakinumab, and subcutaneous sarilumab. There is additional involvement of the PRCSG in other pediatric rheumatic diseases in Phase 3 trials such as belimumab and tofacitinib in lupus.

State-of-the-art technology allows for characterization of immune cell populations key to SJIA, SJIA-LD and MAS

Systemic juvenile idiopathic arthritis (SJIA) is a chronic inflammatory disease of childhood having distinct clinical and epidemiologic characteristics. Striking features of SJIA are autoinflammation, including activation of blood monocytes and elevated inflammatory markers. Children with SJIA remain at risk for macrophage activation syndrome (MAS), a life-threatening episode of overwhelming inflammation, with fevers, cytopenias, coagulopathy, liver, and CNS dysfunction, and a systemic cytokine storm. Patients with SJIA are also at risk for developing severe lung disease (SJIA-LD). The mechanisms and cell types directing the ensuing pathology underlying these diseases are not well understood, but recent advances in cellular analysis allows for a more complete characterization of disease processes. New state-of-the-art cellular technology using spectral analysis within the Research Flow Cytometry Core at Cincinnati Children's provides the ability to assess over 35 markers on or within a cell compared to prior instrumentation that measured up to 18 markers. This capability allows a deeper dive into specific disease mechanisms involved in rheumatic disease. Researchers anticipate development of these panels will be translatable for characterization of other autoimmune or autoinflammatory diseases as well.

Towards standardization and validation of novel ultrasound scanning protocols and scoring systems for the evaluation of pediatric inflammatory arthritis

JIA, the most common chronic rheumatic disease in childhood, causes substantial morbidity worldwide. Characterized by joint inflammation or arthritis, the basis for JIA in children is on the presence of joint swelling or limited range of motion and tenderness on palpation. However, clinical detection of arthritis in the developing skeleton is difficult even if performed by an experienced clinician. This creates an imminent need for a bedside tool to objectively and accurately determine whether there is active joint inflammation or not.

Ultrasound (US) is a non-invasive, radiation-free, and accessible diagnostic modality that often is the first choice for imaging examination in pediatrics. Use of US is not systematically used to improve the diagnostic capability in JIA. The objective of this study is to develop and initially validate US scanning protocols and scoring systems for the evaluation and severity stratification of arthritis of the most common joints affected by JIA. This effort is being led by Patricia Vega-Fernandez, MD, MSc, RhMSUS, in collaboration with Tracy Ting, MD, MSc, RhMSUS, and other pediatric rheumatologists across North America. Through this work, Vega- Fernandez sees great potential for the use of ultrasound to assess arthritis in children as it is likely to offer a strong framework for the development of effective and timely strategies to identify and treat joint inflammation.