Dear Sir,

We read with great interest the paper of Chen et al., recently published in EJNMMI [1], investigating the efficacy of 68Ga fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/CT to identify lesions in Crohn’s disease (CD) patients. CD is a chronic inflammatory disease with a relapsing-remitting course. To assess disease activity and manage anti-inflammatory treatment, non-invasive tools, evaluating the whole digestive tract, are needed. In this pilot study, Chen and colleagues showed in a group of 16 CD patients with 74 explored intestinal segments that [68Ga]Ga-FAPI-04PET/CT could detect CD lesions with very high performance, significantly superior to computed tomography enterography (CTE). FAPI expression was significantly correlated to the inflammatory burden and with the severity of the digestive lesions observed by endoscopy, as assessed by the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn Disease (SES-CD).

The chronic transmural inflammation initiates the fibrotic process, leading to fibro-inflammatory stricture formation (a frequent CD complication) and to the risk of bowel obstruction. While stricture with a predominantly inflammatory component may respond to anti-inflammatory treatments, this is not the case for stricture with a predominantly fibrotic component, which usually requires surgical resection. However, to date, there is no tool to assess the stricture’s proportion of inflammation and fibrosis and guide treatment, and it is generally the histopathological analysis of the surgical specimen that provides the answer. The advent of anti-fibrotic therapies such as FAP chimeric antigen receptor (FAPCAR) T cells [2, 3] makes the development of this tool all the more necessary. Interestingly, in the present study, strictures were the type of lesions with the highest uptake of FAPI, suggesting the ability of this marker to highlight the fibrotic component. These results are promising and correlations between stricture’s [68Ga]Ga-FAPI-04 PET/CT expression and histopathological analysis of the surgical specimen deserve to be further investigated.

Another interesting point is that some segments show FAPI uptake without any corresponding endoscopic lesions. These imaging anomalies could correspond to deeper levels of fibrosis and/or inflammation, as previously suggested in [18F]FDG PET studies performed in patients with CD [4] and ulcerative colitis [5]. This shows the possible limitations of endoscopy as gold standard and relativizes the results of PET, in particular the specificity and the rate of false positives. Moreover, endoscopy cannot reach all segments of the digestive tract because they are too proximal or due to strictures.

Since 1997, multiple studies were performed using [18F]FDG PET in CD patients and showed good performances to assess and to localize inflammation [6]. However, [18F]FDG PET is currently not a part of international guidelines for diagnosis and follow-up, in part due to the radiation exposure, while magnetic resonance imaging has taken a considerable place in routine. Fortunately, the use of new-generation PET/CT significantly decreases the injected activity and dose-length products of CT, while also adding quantitative information with dynamic acquisition. The other reasons that have hampered the implementation of [18F]FDG PET in CD management are limited body of evidence, due to the size of the studied populations, the lack of standardization (due to multiple methodologies, especially of gold-standard), lack of rigor of some studies (time interval between PET and gold-standard, treatment change, …), and mainly the absence of results validation. Finally, one of the major difficulties using [18F]FDG PET for the exploration of CD is the physiological digestive activity altering the specificity of the technique [6], which is not the case with FAPI.

In conclusion, this pilot study shows very good results and opens the doors to carrying out further studies using [68Ga]Ga-FAPI-04 PET/CT (and possibly other radiolabeled FAPI compounds) in CD, whether for the initial assessment, for the evaluation of the treatment response, and for the characterization of strictures, which probably remains the biggest challenge to date. The results of these studies, carried out while retaining the lessons of those previously performed with [18F]FDG, and the use of new-generation PET/CT devices could eventually introduce PET as a recognized tool for the CD management.