Photo Credit: ALIOUI Mohammed Elamine
A review of more than 75 studies outlines the pathogenesis of strictures and fibrosis in Crohn’s disease and ulcerative colitis and prevention.
A narrative review published in Expert Review of Clinical Immunology highlighted recent progress in identifying factors related to the development of fibrosis in Crohn’s disease and ulcerative colitis. The review also examined the need for biomarkers to predict patients’ risk for developing and treating fibrosis once it develops.
“In this area, what has been lacking is the translation of basic mechanisms into clinical trials,” Florian Rieder, MD, says. “What held progress back has been difficulties in studying it. In the lab, with cultured cells and animal models, we’ve made a lot of progress, but then we don’t understand which patients develop this complication and which patients do not, which is important for clinical trials, and there is a lack of clinical trial endpoints.”
With these challenges, therapies to prevent fibrosis in patients with IBD have only recently begun to be tested. Dr. Rieder and colleagues reviewed 77 studies examining the pathogenesis of fibrosis in these patients, including findings of new cell clusters, the involvement of microbiota, proteins, cytokines, and creeping fat, and a review of developing anti-fibrosis treatments.
Pathogenesis of Fibrosis
Intestinal mesenchymal cells, namely fibroblasts, myofibroblasts, and smooth muscle cells, are primarily responsible for the development of fibrosis, Dr. Rieder and colleagues reported. These cells interact with others to produce the extracellular matrix, which leads to the presence of scar tissue. Recent research on samples from patients and control participants indicates that mast cells are also involved, whereas RNA sequencing has suggested the involvement of types of intestinal macrophages. Fibrocytes have been found to relate to fibrosis in patients with IBD, and the evidence suggests that these cells may be valuable predictors in determining the need for surgery or escalation of therapy.
“We delineate in the article that a variety of factors contribute to stricture formation and fibrosis and scar tissue formation, which is chronic inflammation, and then the mediators that are associated with it, such as cytokines, growth factors, and microbiome,” Dr. Rieder explains. “But this obstruction not only comes from the scar tissue buildup but also from a thickening of the intestinal muscle layer that surrounds the gut, called the muscularis propria, which contributes to the luminal narrowing.”
Therapeutic Options and Further Study
As work continues, Dr. Rieder says, researchers need predictive biomarkers and treatment targets for clinical studies.
“We have a list of drugs [we can study] or mechanisms we can interfere with,” Dr. Rieder says. “What was missing were clinical trial endpoints.”
As part of their work with the Stenosis Therapy and Anti-Fibrotic Research Consortium, Dr. Rieder and his colleagues developed a patient-reported outcome tool to give researchers a yardstick for measuring improvement. He says the tool is now being used in an ongoing clinical trial.
As these targets develop, researchers are exploring possible therapies to treat fibrosis. One possible option is inhibiting the cytokine transforming growth factor-beta, or TGF-β. This is now being studied in a clinical trial.
“If you block [TGF-β] systemically, you have risks for autoimmune autoimmunity, skin cancer, and heart valve abnormalities,” Dr. Rieder says. “But then, in the gut, you have a way to deliver it to the area of the stricture. … It doesn’t end up in circulation.”
Other research is evaluating the use of Rho-kinase inhibition and targeting fibroblasts, the cells that comprise scar tissue.
Moving forward, Dr. Rieder says that research from various disciplines will be needed to help patients with IBD who have fibrosis.
“This is a big problem we need to solve. You can’t solve it alone. It needs to be a big group of radiologists, surgeons, gastroenterologists, and pathologists and will require clinical trials. This is underway. We now have a path from the bench to the bedside to test these drugs, and a lot will happen in the next few years.”
Key Takeaways
- Intestinal mesenchymal cells, namely fibroblasts, myofibroblasts, and smooth muscle cells, are primarily responsible for fibrosis in Crohn’s disease and ulcerative colitis.
- Unmet needs include predictive biomarkers for developing fibrosis and treatment targets for clinical studies.
- A multidisciplinary approach that includes radiologists, surgeons, gastroenterologists, and pathologists will be needed to more effectively manage fibrosis in Crohn’s disease and ulcerative colitis.
