PROJECT SUMMARY Abnormal responses to inflammatory stimuli can lead to severe inflammation, acute tissue damage, and long- term scarring or fibrosis. One example is the rare disease fibrodysplasia ossificans progressiva (FOP), a congenital disease of progressive heterotopic ossification (HO) that leads to severe and irreversible loss of mobility. Patients with FOP show inflamed swellings (“flares”) that are associated with HO formation. Patients with FOP have evidence of increased immune system activity, including elevated levels of pro-inflammatory cytokines like IL1. Preliminary data from four FOP patients treated with anti-IL1 therapy showed a 60–90% decrease in flare activity. We hypothesize that blockade of IL1 signaling reduces the flare activity and subsequent new HO formation in patients with FOP. However, before we can perform a larger interventional study, several key knowledge gaps and tools need to be addressed. We address these needs via a clinical observational pre-post study on patients with severe FOP who are being recommended for rescue therapy with anti-IL1 medications. Eleven subjects, aged 6–18 years old with at least six flares/year (3 times higher than the reported average flare rate) will be enrolled when their primary medical team recommends initiating anti-IL1 therapy. Subjects will be monitored remotely to obtain pre-treatment flare rates and patient reported outcome assessments. Once anti-IL1 therapy is initiated, subjects will begin their post-treatment observational phase and have the first onsite visit for detailed assessments. Low-dose whole-body CT (WBCT) imaging, bloodwork, patient-reported outcomes, pain, and flare activity will be assessed during the subsequent year. Primary assessments: Determine if patients with FOP have decreased flare activity while on anti- IL1 therapy. We will use flare diaries and pain scale assessments to systematically determine if flare frequency and pain improve with anti-IL1 therapy. Aim 2: Secondary assessments: Determine the amount of new HO formation in FOP patients treated with anti-IL1 therapy. We will develop a “ground truth” HO segmentation that will serve as a basis for developing an automated artificial-intelligence analyses system. We will also quantitate the new HO bone formation that develops in patients with FOP who are treated with anti-IL1 therapy. Aim 3: Exploratory assessments: Determine if inflammatory cytokine measurements can be used as biomarkers for monitoring flare activity and inflammation in FOP patients treated with anti-IL-1 therapy. No effective biomarkers are available for FOP disease activity. We will determine if a commercial serum cytokine panel and thermal imaging are useful tools for assessing flare activity. These studies address urgent needs. No therapeutic options are available for FOP patients, particularly in children where intervention would have the greatest clinical benefit. The proposed studies provide critical clinical information potential...