Strictures in Crohn’s disease – badly needed research into troublesome scarring

Around 60,000 people in the UK have Crohn’s disease.(1) This incurable illness attacks the intestine, causing debilitating and embarrassing symptoms. Many sufferers need major abdominal surgery,(2) often because of life-threatening scarring that blocks the movement of food and stool through the gut. Researchers are investigating what causes this scarring, in the hope of finding possible ways to prevent it.

What's the problem and who does it affect?

From scarring to surgery

Up to one in every 1,000 people in the UK suffers from Crohn’s disease, an incurable illness that attacks the gut, causing significant disability.(1), During flare-ups of their disease, sufferers typically endure intense abdominal pain, weight loss, exhaustion and severe diarrhoea, often passing blood. Many find their illness restricts their ability to study or work normally.

Several treatments can help manage flare-ups and keep people in remission. Most work by reducing inflammation in the gut. But up to a third of people with Crohn’s disease also develop scarring to the walls of their intestine. This can become so bad that it causes a blockage, called a stricture, which stops food and faeces from passing along the abdominal tract.

The causes of scarring are poorly understood and no treatments can prevent it. Many people with strictures have to undergo surgery to remove the damaged part of their intestine. This major operation brings serious risks.

Despite undergoing surgery, many people find their problems recur in another part of their intestine. Seventy percent of patients will have evidence of a stricture after one year and, after four years, 40% of sufferers will require a repeat operation(3),(4) – a daunting prospect for those who know from experience how slow and painful the recovery from abdominal surgery can be.

What is the project trying to achieve?

What causes excessive scarring?

Researchers are investigating what causes the excessive scarring found in the inflamed intestinal walls of people with Crohn’s disease. They are studying samples donated by at least 15 people who are undergoing surgery for Crohn’s disease and another 15 or more with colorectal cancer. They are performing detailed laboratory comparisons of the biological processes taking place within scarred and non-scarred areas of the intestinal walls.

Excessive scarring is caused by the build up of a substance called collagen, as a result of too much production or not enough removal. Researchers are focusing on the role of key molecules that affect the production or removal of collagen, namely transforming growth

factor β (TGF-β) and matrix metalloproteinases (MMP), and a new player in fibrosis -  interleukin 13 (IL-13). Recent studies have revealed that scarring in other areas of the body that have become inflamed – namely the lung, liver and kidney – may be linked to the activity of IL-13.

If IL-13, TGF-β and MMPs do play a role in excessive scarring in Crohn’s disease, the team will test several agents that seem to have the potential to block the action of these molecules. They hope this strategy might help prevent scarring.

What are the researchers' credentials?

The project team has the perfect blend of interdisciplinary expertise needed for success in this study. The Project Leader, Dr Paul Bland, is an internationally renowned researcher in the immune processes that take place within mucosal surfaces, such as the walls of the intestine, and Dr John Tarlton is a leading expert on wound healing.

Dr Christine Whiting, who will perform most of the hands-on research, is highly skilled in the laboratory techniques that are being used in this project. Dr Whiting also has extensive knowledge of both the structures that make up mucosal surfaces, such as the lining of the gut, and the immune processes that go on within them. She has published widely in this area of study.

Who stands to benefit from this research and how?

Vital information for future drug development

Researchers hope their experiments will reveal important new information about how scar tissue develops within the intestinal walls of people with Crohn’s disease, a disease process that has, so far, been very poorly understood.

If it turns out that IL-13 does play a key role in scarring, then the race will be on to develop drugs that can modify the action of IL-13 in the intestine. In theory, such drugs may be able to prevent or treat scarring, so freeing people from debilitating symptoms and reducing the need for surgery.

The project team estimates that a successful new treatment could benefit 20,000 people in the UK who are slowly developing intestinal scarring.(1),(5) It could also reduce costs to the NHS. Treating just one person with Crohn’s disease for one year costs an estimated 2,548 Euros,(6) with most of the expense being associated with surgery.(7)

It’s possible that this project might eventually touch the lives of even more people, as fibrotic disorders, where the body forms scar tissue inappropriately, are thought to account for nearly half of all deaths.(8)

References

1. Carter MJ, Lobo AJ, Travis SP; IBD Section, British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004 Sep;53 Suppl 5:V1-16.

2. Burke JP, Mulsow JJ, O’Keane C, Docherty NG, Watson RW, O’Connell PR. Fibrogenesis in Crohn’s disease. Am J Gastroenterology 2007:102(2):439-48.

3. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn's disease. Gastroenterology 1990;99:956-63.

4. Whelan G, Farmer RG, Fazio VW, Goormastic M. Recurrence after surgery in Crohn's disease: Relationship to location of disease (clinical pattern) and surgical indication. Gastroenterology 1985;88:1826-33.

5. Lahat A, Chowers Y. The patient with recurrent (sub) obstruction due to Crohn's disease. Best Pract Res Clin Gastroenterol. 2007;21(3):427-44.

6. Odes S, Vardi H, Friger M, Wolters F, Russel MG, Riis L, Munkholm P, Politi P, Tsianos E, Clofent J, Vermeire S, Monteiro E, Mouzas I, Fornaciari G, Sijbrandij J, Limonard C, Van Zeijl G, O’Morain C, Moum B, Vatn M, Stockbrugger R, European Collaborative Study on Inflammatory Bowel Disease. Cost Analysis and Cost Determinants in a European Inflammatory Bowel Disease Inception Cohort With 10 Years of Follow-up Evaluation. Gastroenterology 2006;131:719-28.

7. Cohen RD. The Cost of Crohn’s Disease: Drugs or Surgery? BioDrugs, 2000,14;331-44.

8. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nature Reviews in Immunology. 2004;4:583-94.