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Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging
  1. Christian Schmidkonz1,
  2. Simon Rauber2,
  3. Armin Atzinger1,
  4. Rahul Agarwal2,
  5. Theresa Ida Götz1,
  6. Alina Soare2,
  7. Michael Cordes1,
  8. Olaf Prante1,
  9. Christina Bergmann2,
  10. Arnd Kleyer2,
  11. Philipp Ritt1,
  12. Simone Maschauer1,
  13. Peter Hennig1,
  14. Johannes Toms1,
  15. Markus Köhner1,
  16. Bernhard Manger2,
  17. John H Stone3,
  18. Uwe Haberkorn4,
  19. Tobias Baeuerle5,
  20. Jörg H W Distler2,
  21. Abbas Agaimy6,
  22. Torsten Kuwert1,
  23. Georg Schett2,
  24. Andreas Ramming2
  1. 1 Department of Nuclear Medicine, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
  2. 2 Department of Internal Medicine 3, Rheumatology & Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
  3. 3 Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, Boston, Massachusetts, USA
  4. 4 Department of Nuclear Medicine, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
  5. 5 Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
  6. 6 Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bayern, Germany
  1. Correspondence to Dr Andreas Ramming, Department of Internal Medicine 3, Rheumatology & Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen 91054, Germany; andreas.ramming{at}


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.

  • fibroblasts
  • inflammation
  • outcome assessment, health care

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  • Handling editor Josef S Smolen

  • Contributors Design of the study: CS, SR, AS, GS and AR; Acquisition of data: CS, SR, AAt, RA, TIG, AS, MC, OP, CB, AK, PR, SM, PH, JT, MK, BM, UH, TB, JHWD, AAg, TK, GS and AR; Interpretation of data: CS, SR, AAt, RA, TIG, AS, OP, BM, JHS, TB, TK, GS and AR; Support of material: MC, OP, PR, SM, PH, JT, TB, AAg, UH and AR; Manuscript preparation: CS, SR, TIG, AS, JHS, GS and AR. All authors agreed to the final version of the manuscript.

  • Funding This work was supported by the Deutsche Forschungsgemeinschaft (RA 2506/4–1, RA 2506/4–2, RA 2506/6–1 to AR; SO 1735/2-1 to A.S.; DI 1537/14-1 to JHWD; SCHE 1583/7–1 to GS; and CRC1181 to GS (project A01), JHWD. (project C01) and AR (project C06)), European Research Council starting grant (853 508 BARRIER BREAK) to AR, ERC Synergy grant 4D Nanoscope (to GS), Bundesministerium für Bildung und Forschung (MASCARA to JHWD, GS, TK, AR), the Interdisciplinary Centre for Clinical Research, Erlangen (D34 to AR), the ELAN and IZKF Fonds of the Universitätsklinikum Erlangen (17-11-20-1 to AS), Wilhelm Sander-Stiftung (2017.129.1 to JHWD and AR), the development of FAPIs was funded in part by the Federal Ministry of Education and Research, grant number 13N 13341 (UH).

  • Competing interests UH has a patent for FAPI tracers.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Obtained.

  • Ethics approval The study was conducted according to the principles of the Declaration of Helsinki and approved by the ethical committee of the University of Erlangen-Nürnberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information. Data are available on reasonable request. Additional unpublished data can be obtained from the corresponding author on reasonable request.