Background:Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis (SSc). To date, the progression of SSc-ILD is judged by the accrual of lung damage on computed tomography (CT) and functional decline (forced vital capacity). However, this approach does not directly assess the activity of tissue remodeling. Moreover, prediction of the course of ILD in individual SSc patients remains challenging. Fibroblast Activation Protein (FAP) is a specific, ex vivo validated marker for activated fibroblasts.Objectives:The aims of this study were: 1. To assess differences in the uptake of 68GA-FAPI 04 in SSc-ILD patients compared to controls, to analyze 2. whether 68GA-FAPI 04 uptake at baseline correlates with other risk factors of disease progression and 3. Whether 68GA-FAPI 04 uptake is associated with the course of SSc-ILD.Methods:Between September 2018 and April 2020, 21 patients with SSc-ILD confirmed by HRCT and onset of SSc-ILD within ≤ 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET/CT imaging and standard-of-care procedures including HRCT and lung function testing (PFT) at baseline. Patients with SSc-ILD patients were followed-up for 6 months with HRCT and PFT. Follow-up 68Ga-FAPI-04 PET/CT scans were obtained in a subset of patients treated with nintedanib. We compared baseline 68Ga-FAPI-04 PET/CT uptake to standard diagnostic tools and currently used predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in FVC was analyzed using mixed-effects models.Results:68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in SSc-ILD compared to controls with a median (q1-q3 interval) wlSUVmean of 0.8 (0.6 to 2.1) in the SSc-ILD group and 0.5 (0.4 to 0.5) in the control group (p<0.0001 with Mann-Whitney test) and a median whole lung maximal standardized uptake value (wlSUVmax) of 4.4 (3.05 to 5.2) in the SSc-ILD group compared to 0.7 (0.65 to 0.7) in the control group (p<0.0001). wlFAPI-MAV and wlTL-FAPI were not measurable in control subjects, as no 68Ga-FAPI-04 uptake above background level was observed. In the SSc-ILD group the median wlFAPI-MAV was 254cm3 (163.4 to 442.3) and the median wlTL-FAPI was 183.6 cm3 (98.04 to 960.7). 68Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression or high EUSTAR activity scores. Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive 68Ga-FAPI-04-PET/CTs, changes in 68Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic agent nintedanib.Conclusion:Our study presents first in human evidence that 68Ga-FAPI-04-fibroblast uptake correlates with fibrotic activity and disease progression in the lungs of SSc-ILD patients and that 68Ga-FAPI-04-PET/CT may be of potential to improve risk assessment of SSc-ILD.Figure 1.A and B:68Ga-FAPI-04 PET/CT scan from a patient with SSc-ILD with selective 68Ga-FAPI-04 uptake in fibrotic areas of the left- and right lower lung lobes (red arrows), but not in non-fibrotic areas such as the middle lobe (green arrow). B Corresponding CT component.Acknowledgements:We gratefully acknowledge Prof. Uwe Haberkorn (University Hospital Heidelberg and DKFZ, Heidelberg, Germany) and iTheranostics Inc. (Dulles, VA, USA) for providing the precursor FAPI-04.Disclosure of Interests:Christina Bergmann: None declared, Jörg H.W. Distler Speakers bureau: Actelion, Anamar, ARXX, Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Christoph Treutlein: None declared, Koray Tascilar Speakers bureau: Gilead sciences GmbH, Pfizer Turkey, UCB Turkey, Anna-Theresa Mueller: None declared, Armin Atzinger: None declared, Alexandru-Emil Matei: None declared, Johannes Knitza: None declared, Andrea-Hermina Györfi: None declared, Anja Lueck: None declared, Clara Dees: None declared, Alina Soare: None declared, Andreas Ramming: None declared, Verena Schönau: None declared, Oliver Distler Speakers bureau: Arxx Therapeutics, Baecon Discovery, Blade Therapeutics,Bayer, Böhringer Ingelheim, Catenion,Competitive Drug Development International Ltd, Corbuspharma, CSL Behring, ChemomAb, Horizon Pharmaceuticals, Ergonex, Galaapagos NV, Glenmark Pharmaceuticals,GSK, Inventiva, Italfarmaco, IQvia, Kymera, Lilly, Medac, Medscape, MSD, Novartis, Pfizer, Roche, Sanofi, Taget Bio Sciencec, UCB, Grant/research support from: Bayer,Böhringer Ingelheim, Mitsubishi Tanabe Pharma, Olaf Prante: None declared, Philipp Ritt: None declared, Theresa Ida Goetz: None declared, Markus Koehner: None declared, Michael Cordes: None declared, Tobias Baeuerle: None declared, Torsten Kuwert Speakers bureau: Honoraria for occasional lectures by Siemens Healthineers, Grant/research support from: Research grant to the Clinic of Nuclear Medicine by this entity covering projects in the field of SPECT/CT, Georg Schett: None declared, Christian Schmidkonz: None declared
Serum markers of pulmonary epithelial damage in systemic sclerosis‐associated interstitial lung disease and disease progression
