Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging

Christian Schmidkonz ¹, Simon Rauber ², Armin Atzinger ¹, Rahul Agarwal ², Theresa Ida Götz ¹, Alina Soare ², Michael Cordes ¹, Olaf Prante ¹, Christina Bergmann ², Arnd Kleyer ², Philipp Ritt ¹, Simone Maschauer ¹, Peter Hennig ¹, Johannes Toms ¹, Markus Köhner ¹, Bernhard Manger ², John H Stone ³, Uwe Haberkorn ⁴, Tobias Baeuerle ⁵, Jörg H W Distler ², Abbas Agaimy ⁶, Torsten Kuwert ¹, Georg Schett ², Andreas Ramming ⁷

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 IgG₄-related disease.

Methods: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG₄-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; ⁶⁸Ga-FAP inhibitor (FAPI)-04), ¹⁸F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, ¹⁸F-FDG and ⁶⁸Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data.

Results: Using combination of ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG₄-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. ¹⁸F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG₄ ⁺ cells in histology, while ⁶⁸Ga-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 IgG₄-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG₄-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.

Affiliations:

1. Department of Nuclear Medicine, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany.
2. Department of Internal Medicine 3, Rheumatology & Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany.
3. Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, Boston, Massachusetts, USA.
4. Department of Nuclear Medicine, Heidelberg University, Heidelberg, Baden-Württemberg, Germany.
5. Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.
6. Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany.
7. Department of Internal Medicine 3, Rheumatology & Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany andreas.ramming@uk-erlangen.de.