Natural history and validation of surrogate biomarkers and patient-reported outcomes for SJIA-LD

Project Summary / Abstract Chronic lung disease in children with systemic juvenile idiopathic arthritis (SJIA-LD) is a life-threatening disorder which is increasing in incidence and for which there are no proven effective treatments. SJIA-LD manifests as interstitial lung disease (ILD) with varying degrees of pulmonary alveolar proteinosis (PAP), fibrosis, and pulmonary artery hypertension, and frequently progresses to hypoxic respiratory failure. Although research is urgently needed to define optimal treatments for SJIA-LD, key knowledge gaps remain that are barriers to future research: a case definition, prospective evaluation of clinical disease progression, surrogate biomarkers of disease activity, and LD-specific patient-reported outcomes (PROs). Our objectives are to define SJIA-LD, its clinical disease progression, and surrogate biomarkers, to accelerate future research in this disease. We have developed and published preliminary outcome measures, identified serum inflammatory mediators and markers of lung injury in SJIA-LD patients, and piloted surveys to identify SJIA-LD specific symptoms that can be measured using validated PROs. To operationalize these preliminary findings, we have launched a pilot multicenter prospective cohort study of SJIA-LD, which to date has enrolled 45 patients through the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Our central hypothesis is that this proposed SJIA-LD study will result in the ability to accurately define SJIA-LD cases and characterize disease trajectories, and validate surrogate biomarkers of clinical disease progression and LD-specific PROs. In this study, we will enroll ~80 SJIA-LD patients across the CARRA network, and prospectively collect clinical data, biosamples and PROs over 2 years of follow-up. In Aim 1, we will determine the clinical SJIA-LD characteristics and progression by collecting LD features at baseline and longitudinally, and use this to support a data-derived expert consensus definition of SJIA-LD. In Aim 2, we will validate biomarkers of inflammation and lung injury in children with SJIA-LD by determining longitudinal (baseline, 6-months, and end-of-study) levels of cytokines, chemokines and lung injury markers, their responsiveness to change, and correlating them with clinical disease activity. In Aim 3, we will utilize PRO measures that reflect quality of life and lung disease symptoms in children with SJIA-LD by tracking changes in existing measures captured through the CARRA Registry, as well as in previously-validated lung disease-specific instruments which measure patient- reported SJIA-LD symptoms. We will leverage the CARRA Registry and infrastructure to longitudinally assess clinical disease features, surrogate biomarkers of disease activity, lung damage and PROs in a prospective cohort of children with SJIA-LD. Successful completion of the proposed aims are necessary to accelerate future clinical research, including interventional studies, and advance our long-term goals to treat and prevent SJIA- LD.