Abstract Background Lack of reliable intestinal fibrosis imaging modalities hampers the development of anti-fibrotic agents. Gallium-68 Fibroblast Activation Protein inhibitor (FAPi) PET/CT demonstrates potential for in vivo fibrosis assessment through the visualization of Fibroblast Activation Protein (FAP). We performed the first in-human study to investigate FAPi PET/CT to detect fibrosis in IBD patients using pharmacokinetic modelling. Methods Patients with active Crohn’s disease (CD) or ulcerative colitis (UC) awaiting surgical resection were included. Patients underwent a 60-minute dynamic FAPi PET/CT scan, followed by 12 minutes of static imaging within 12 weeks before surgery. Two blinded readers independently assessed the PET/CT images, which were validated by a third non-blinded reader. Bowel segment uptake was analyzed using standardized uptake values (SUV) and uptake kinetics over time using time-activity-curves (TAC). Resection specimens were selected based on high FAPi uptake bowel segments. In parallel, intestinal ultrasound (IUS) was performed to measure bowel wall thickness (BWT). To allocate samples to fibrotic, inflamed or combined phenotype, hematoxylin and eosin and Masson’s trichrome stainings were performed for inflammatory and fibrosis scoring by a blinded pathologist, as previously described.1 Results Out of 23 participants, 15 CD and 4 UC patients underwent FAPi PET/CT and IUS prior to surgery (table 1). In total, 36 bowel regions of interest were identified and 52 transmural surgical samples were acquired. FAPi tracer uptake was markedly increased in inflamed and fibrotic regions in 18/19 patients compared to non-pathologic bowel segments (reference standard) with a median SUV ratio of 3.183. TACs showed distinct phenotypes for inflamed, fibrotic or combined bowel segments. In inflamed segments, a high peak uptake of the FAPi tracer was seen followed by a decline in uptake, indicating potentially non-specific or low-binding affinity uptake. In contrast, fibrotic segments showed low peak uptake followed by a relatively stable plateau, suggesting more irreversible or higher binding affinity uptake (figure 1). SUVs were moderately correlated to BWT (r = 0.42), FAP protein expression (r = 0.55) and histological scoring for inflammation (r = 0.53) and fibrosis (r = 0.67). Conclusion FAPi uptake, detected by means of FAPi PET/CT, is associated with histological fibrosis scoring, FAP protein expression and BWT on IUS. Pharmacokinetic modelling shows different FAPi tracer uptake kinetics between predominantly fibrotic versus inflamed segments, underscoring its potential to differentiate fibrosis from inflammation in IBD patients. Reference: 1. Ke BJ, Abdurahiman S, Biscu F, et al. Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibrostenosis in Crohn’s disease. J Clin Invest 2024;134. Conflict of interest: Ms. Lartey, Dalia: No conflict of interest Van Wijnbergen, Kelly: No conflict of interest Ke, Bo-Jun: No conflict of interest Teichert, Christoph: No conflict of interest Buskens, Christianne J.: Grant: C. Buskens has received an unrestricted grant from Boehringer Ingelheim and Roche Personal Fees: C. Buskens has received consultancy fees and/or speaker’s honoraria from Tillotts, Takeda, MSD and Janssen Van Der Bilt, Jarmila: No conflict of interest Matteoli, Gianluca: Grant: We are recipient of the opnMe research grant from Boehringer Ingelheim. De Hertogh, Gert: Other: Fees to my institution KULeuven for my activities as central pathology reviewer for: Centocor and Eli Lilly Grootjans, Joep: No conflict of interest Wildenberg, Manon: Received research grant support from Hoffman-La Roche, Boehringer-Ingelheim Wiegers, Sanne: No conflict of interest Yaqub, Maqsood: No conflict of interest D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Abbvie, Alimentiv BV, Eli Lilly, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Glaxo Smith Kline, Dr Falk Pharma, Pfizer, Johnson and Johnson, Merck, Mirador, Polpharma, Procise Diagnostics, Prometheus Biosciences, Sorriso Pharma, Spyre, Takeda, Ventyx Zwezerijnen, Gerben: No conflict of interest Löwenberg, Mark: No relevant CoI to disclose
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