Identification of fibroblast biomarkers in immune-mediated inflammatory diseases
Fibroblast activation in response to inflammation can result in tissue damage and organ malfunction in IMIDs, including inflammatory bowel diseases (IBD), rheumatic diseases and interstitial lung diseases. There is a great need for anti-fibrotic agents, but the development is hampered by the lack of measurable indicators that can provide information about fibrosis (so-called biomarkers) and limitations of imaging techniques to identify fibrosis. Preliminary studies from our group showed that expression of fibroblast activation protein (FAP) is increased in intestinal resection specimens from IBD patients and in lung tissues obtained from patients with interstitial lung diseases, which was mainly found in fibrotic areas. We have scanned 18 IBD patients using a novel molecular imaging technique in which the presence of FAP in the intestines was confirmed, indicating the potential value of this fibrosis biomarker. Our main objective is to identify fibrosis biomarkers, including FAP, in a broad spectrum of IMIDs. To this end, we will apply total body PET/CT using a FAP tracer to detect FAP expression in different organ systems in patients with IBD, rheumatic and interstitial lung diseases. Imaging outcomes will be compared with clinical data and circulating FAP in blood samples. Intestinal tissue samples will be used for histological analyses focusing on collagen deposition, and for immunohistochemistry, PCR and RNA sequencing focusing on FAP and other fibrosis molecules of interest. Moreover, tissue samples will be analyzed by imaging mass cytometry and a panel of 40 different markers, which will provide additional information on potential fibrosis biomarkers and interactions between fibroblast subsets and immune cells. We foresee that this project will open new avenues for fibrosis detection in IMIDs and will identify fibrosis biomarkers and molecular targets for anti-fibrotic agents.
The overall goal of this disease-overarching project is to find biomarkers for fibrosis in a broad spectrum of IMIDs using a highly advanced imaging technique combined with laboratory studies. We foresee that once we find candidate fibrosis biomarkers, our industrial partner AstraZeneca, a global pharmaceutical company with expertise in inflammatory and fibrotic diseases, can accelerate translation to clinical practice to expedite and accelerate drug development.
IMIDs represent a large group of diseases with an estimated prevalence in the Western world of up to 7%. Fibrosis formation in IMIDs contributes to disease-related complications, which entails substantial socioeconomic costs. Approximately 50% of interstitial lung disease patients will develop progressive pulmonary fibrosis during their disease course, which can lead to irreversible lung function decline, respiratory failure and premature death. It is estimated that approximately 5 million patients worldwide suffer from interstitial lung diseases and up to 40% will develop progressive pulmonary fibrosis leading to organ failure. This means that around 2,000,0000 interstitial lung disease patients would qualify for anti-fibrotic treatment worldwide. In the Netherlands, a nationwide cohort study reported an interstitial lung disease prevalence of 9:100,000. Roughly 5 million patients suffer from IBD (Crohn’s disease and ulcerative colitis) worldwide. IBD prevalence in the Netherlands is estimated to be 613 per 100,000, and approximately 90,000 patients in the Netherlands suffer from IBD (around 40,000 Crohn’s disease and 50,000 ulcerative colitis). Fibrosis formation in Crohn's disease is observed in approximately one-third of patients during their disease course and in ulcerative colitis it becomes clinically apparent in 5% of patients. This means that 15-20,000 IBD patients would qualify for anti-fibrotic treatment in the Netherlands. At this moment, surgery or endoscopic balloon dilation are the only options to treat fibrostenotic complications. Although anti-fibrotic agents are urgently needed to treat fibrosis-related complications in IMIDs, only two have entered the marked so far, both for lung fibrosis. If fibrotic-related complications can be adequately detected and treated with anti-fibrotic agents, this will result in improved disease outcomes leading to increased patient participation and work-related productivity. Since fibrosis biomarkers and imaging tools to visualize fibrosis are currently lacking, it is virtually impossible to set-up prospective clinical trials with potential anti-fibrotic agents. Our goal is to find fibrosis biomarkers in a broad spectrum of IMIDs and to elucidate if FAPi PET/CT can be used as a novel imaging technique to detect fibrosis, which will result in a stronger substantiation of potential targets for therapeutic interventions.
Detecting fibrosis in IMID patients is challenging because imaging techniques are lacking that can identify fibrosis and due to the fact that diagnostic biomarkers are not available. This means that at time of diagnosis, loss of organ function due to irreversible fibrosis has often already occurred. We foresee that patients at risk for developing fibrosis might be identified earlier using FAPi PET/CT showing regions with active fibrosis. This project will aid in identifying fibrosis biomarker(s) for diagnostic purposes. Ultimately this might lead to the identification of molecular targets for the development of anti-fibrotic agents, which will not only mitigate disease progression, but will also bring precision medicine closer. Not to mention the reduction of disease burden and improved disease outcomes, thereby having a major impact on individual patients and society as a whole.
Uniform deliverables for the different work-packages include: (i) Characterization of FAP and other fibrosis biomarkers across different IMIDs; (ii) Study the effect of inflammation on in vivo FAP uptake and cellular and soluble FAP; (iii) Identify which fibroblast subsets express FAP; (iv) Define composition and spatial interaction between fibroblasts and immune cells. We anticipate that this project will identify fibrosis biomarkers and will result in implementation of a novel highly advanced molecular imaging technique to visualize fibrosis in different organ systems in patients with IMIDs. This work will provide new insights for the evaluation of fibrosis in IMIDs and may form the basis for the development of molecular agents to treat fibrosis.
