PROJECT SUMMARY Across the world, spondyloarthritis (SpA) is the most common form of juvenile arthritis, accounting for as many as one-third of all cases. Since the introduction of biologic disease modifying agents such as tumor necrosis factor inhibitors (TNFi), inactive disease is a realistic goal for children with spondyloarthritis (SpA). However, side effects of TNFi include increased risk of infection, psoriasis, demyelinating disorders, and malignancy. Additionally, TNFi are expensive and may adversely impact patient’s and caregiver’s quality of life and anxiety. Recently, the COVID-19 pandemic prompted numerous inquiries regarding whether being on a TNFi increased the risk of becoming infected, and, if infected, whether being on a TNFi increased the risk of morbidity. In the absence of definitive answers many families’ next question was, “Can we stop the medication?” We must address two critical knowledge gaps to inform strategies for TNFi de-escalation in children with SpA. First, it is unknown if subclinical imaging represents a risk for flare or whether it represents benign residual activity. Presently, clinical equipoise exists in whether subclinical inflammation on pelvic MRI should impact treatment decisions about children with SpA and axial disease because we do not know the prevalence or the clinical relevance of these MRI findings. Second, the role of cellular biomarkers to predict flare after therapy de- escalation in juvenile SpA is unknown. Prior studies in polyarticular juvenile arthritis have identified cellular populations and biomarkers that can distinguish disease states that are highly associated with relapse. Similar studies have not been done in juvenile SpA. Our objective is to test the association of immunologic, serologic and imaging biomarkers with the risk of disease flare in children with SpA by leveraging the infrastructure and resources of the parent trial, Biologic Abatement and Capturing Kids’ Outcomes and Flare Frequency in Juvenile SpA (BACK-OFF JSpA) to perform mechanistic studies to address these critical knowledge gaps. This application has 2 specific aims: 1) to test the ability of imaging biomarkers at the time of medication de- escalation to predict subsequent flare in children with axial arthritis, and 2) to test the ability of cellular biomarkers at the time of medication de-escalation to predict subsequent flare in all children with SpA. The work proposed in this application will directly impact clinical care and significantly enhance the evidence base that clinicians, families, and patients use to make decisions about whether or not to de-escalate biologic therapy.

PROJECT NARRATIVE The proposed research is relevant to public health because spondyloarthritis is the most common form of childhood arthritis in large parts of the world and although inactive disease is a realistic goal since the introduction of biologic agents we do not know if or how to de-escalate therapies with minimal morbidity. There is a critical need for imaging and serologic biomarkers to accurately predict flare after therapy de-escalation so that we can eliminate much of the guesswork associated with the current standard of care. This project is directly aligned with the program announcement (RFA-AR-20-001) as the primary goal is to leverage the infrastructure and resources of a funded parent trial to enhance its scientific content and value, improve the research community’s understanding of the clinically inactive disease state, and to test the utility of imaging and serologic biomarkers to guide treatment de-escalation decisions at point-of-care.