Project Summary SAPHO syndrome and chronic nonbacterial osteomyelitis (SAPHO-CNO) is a painful and disabling autoinflammatory disease primarily targeting bones and joints, with no FDA-approved therapies. Severe sterile inflammation of multiple bones (osteitis), driven by the interleukin-1 (IL-1) pathway, leads to irreversible bone damage, chronic pain and disability in adult patients. Critical knowledge gaps remain about disease activity assessments, risk factors for severe outcomes, and influence of variants in IL-1 pathway genes on clinical phenotypes in adults. This K23 proposal will propel our understanding of the longitudinal course of SAPHO- CNO in adults, garnering generalizable knowledge about this understudied and disabling autoinflammatory disease. The proposed project will investigate clinician, patient and MRI-assessed disease activity in a large SAPHO-CNO cohort (Aim 1), identify risk factors for bone damage in SAPHO-CNO patients (Aim 2), and discover IL-1 signaling pathway gene variants and explore their correlation with clinical phenotypes in adults with SAPHO-CNO (Aim 3). The science resulting from this K23 award will lay the groundwork for a future R01 application. Dr. Aleksander Lenert is spearheading a unique prospective observational study in adult SAPHO- CNO (the SCS study) designed to address these knowledge gaps. His long-term career goal is to develop into an independent clinical investigator focused on patient-oriented clinical and translational research in adults with SAPHO-CNO. Under direct mentorship from Dr. Polly Ferguson (world-leading expert in CNO) and his experienced mentoring team, Dr. Lenert will build on his foundational research skills to gain critical training and hands-on experience in agreement and psychometric analyses, latent trajectory modeling, genetic sequencing analysis and interpretation, and prospective observational cohort study management. In addition to Dr. Ferguson, his mentoring team includes Dr. Robyn T. Domsic (clinical investigator and observational cohort study guru in systemic sclerosis), Dr. Daniel H. Solomon (leader in clinical science research in rheumatic diseases), Dr. Mary Vaughan-Sarrazin (experienced clinical outcomes researcher), and Dr. Jonathan Templin (measurement science and applied psychometrics researcher). To further guide this scientific proposal, develop focused training and aid his career development, Dr. Lenert has garnered the support of content area experts in advanced imaging (Dr. T. Shawn Sato), and genetics and bioinformatics (Drs. Hatem El-Shanti and Benjamin Darbro). This proposal benefits from an exceptional scientific environment and established infrastructure at the University of Iowa, including Dr. Polly Ferguson’s world-renown center for the management of patients with SAPHO-CNO, and for clinical and translational research. Accomplishment of the proposed Aims for this K23 award will directly benefit adults w...