Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging

Objectives To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG(4)-related disease. Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG(4)-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; Ga-68-FAP inhibitor (FAPI)-04), F-18-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, F-18-FDG and Ga-68-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Results Using combination of Ga-68-FAPI-04 and F-18-FDG-PET, we demonstrate that non-invasive functional tracking of IgG 4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. F-18-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG(4)(+) cells in histology, while Ga-68-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Conclusion FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG(4)-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG(4)-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.