The prevalence of inflammatory bowel diseases (Crohn's disease and ulcerative colitis) is steadily increasing in all developed countries. In Israel, the problem is even more severe, as Crohn's disease is considered a "Jewish disease." Although the disease mainly affects young adults, about a quarter of patients will develop the characteristic symptoms of the disease already in childhood. The disease is chronic and can have periods of remission and periods of activity characterized by abdominal pain, diarrhea (sometimes bloody), weakness, fever, anemia, weight loss, and even rash. Additionally, the disease can sometimes lead to delayed sexual development and growth.
This chronic disease cannot be cured, but there is now a wide range of drugs available that, when used judiciously, can control and manage flare-ups and maintain long periods of remission.
While adult patients with ulcerative colitis are well treated in the community, around 15% of them will require hospitalization and treatment with systemic steroids during their lifetime. Until recently, there were very little data on severe attacks requiring hospitalization in children, even though the disease is more aggressive in children due to genetic factors.
In a groundbreaking series of articles by Professor Dan Turner, the Director of the Pediatric Gastroenterology and Nutrition Unit at Schneider Children's Medical Center of Israel, Professor Anne Griffiths from the University of Toronto, and their colleagues, important aspects of severe colitis in children were explored. The research was conducted internationally in collaboration with 11 centers for inflammatory bowel diseases worldwide. The researchers found that contrary to common belief, the hospitalization rate in children is three times higher compared to adults! In a follow-up of 233 children with severe colitis who were hospitalized and treated with steroids intravenously, it was found that more than a third of the children did not respond to steroid treatment, and their symptoms of bloody diarrhea, abdominal pain, fever, and weight loss did not improve. A crucial clinical question arises: when should steroid failure be declared, and when should a second-line treatment strategy be initiated? The researchers showed that these newer biological treatments are highly effective – over 80% of non-responders to steroids responded to biologic therapy (infliximab). However, the cost of biologic drugs is high, and they can cause side effects such as immune suppression. For patients who do not respond to second-line treatments, surgical removal of the colon is considered. While surgery removes the inflamed area, it leads to the creation of a stoma (a bag for collecting feces on the abdomen), which is associated with body image issues and other functional problems. Moreover, the attachment of the small intestine according to the second stage can cause frequent bowel movements during the day and sometimes lead to inflammation in the stoma area.
In adults, it's relatively easy to assess the response to steroid treatment through endoscopic evaluation of the colon. However, in children, this test requires anesthesia and is considered invasive. Professor Turner and his colleagues developed a simple alternative tool to assess the effectiveness of steroids in treated children. By using a disease activity questionnaire containing six clinical questions, it is possible to accurately predict whether the treatment will succeed or fail. Implementing this questionnaire, which has already become a clinical routine in various pediatric centers worldwide, allows for the initiation of second-line treatments after only 3-5 days of steroid treatment. This method shortens hospitalization, increases the success rate of biological drugs, and saves the complications of prolonged and futile treatment.
In the second phase of the research, attempts were made to understand why one-third of the children did not respond to steroid treatment, while others achieved complete relief within two to three days. Steroids affect complex metabolic and genetic processes that result in the inhibition of inflammatory cells. However, the general knowledge in this area is extremely limited, and few studies on inflammatory bowel diseases have focused on these processes.
Four factors may lead to resistance to steroids:
1. Reduced biological availability of the drug
2. Disease severity
3. Genetic predisposition
4. Temporal changes in the body, such as an increase in inflammatory cells
To establish or rule out these factors, an international study was conducted by Professor Turner and Professor Griffiths. The study examined 140 hospitalized children with severe colitis. On the third day of hospitalization for each child, blood samples, stool samples, and genetic samples were collected. Follow-up clinical monitoring was performed for two years after discharge.
The first study was conducted in collaboration with a research laboratory in Finland. The blood tests of the children revealed that the biological availability of the steroids did not predict treatment response. These findings have significant implications for determining the optimal steroid dosage in ulcerative colitis.
The second study showed a clear correlation between disease severity at admission and treatment response. Stool tests conducted in collaboration with a research laboratory in Sydney, Australia, supported this conclusion and even identified a new inflammatory marker that can be easily measured in stool samples. This marker accurately reflects the severity of inflammation in the colon without the need for endoscopy and can predict the need for second-line treatment as early as the third day of hospitalization.
The third study investigated suspected genetic mutations that might interfere with the steroid pathway, but no defective genes were found in those who did not respond to steroids. In collaboration with the University of Toronto, two attempts were made to assess the link between temporary metabolic changes and steroid response. Using advanced technology, 330,000 genetic products (RNA) that mediate between the genetic component of the cell and protein production were analyzed. Sixty-three genes were found to be significantly associated with resistance to steroid treatment, most of which were linked to inflammatory activity. This research series provides insight into how inflammation severity in the colon triggers a series of specific genes that lead to an increase in inflammatory cells in the blood, which can interfere with steroid activity.
This research is getting us closer to understanding the processes occurring in the body of a colitis patient during steroid treatment. This knowledge can be practically applied to more efficiently predict steroid resistance and thus enable more effective treatment early in the course of the disease. The proportion of patients for whom treatment fails is expected to decrease, and the need for colon removal surgery will be minimized.
The research findings were presented in June 2009 at the leading international conference in gastroenterology, Digestive Disease Week, in Chicago, USA, and were published in prominent medical journals.
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2. Gastroenterology 2009;136 (5 suppl 1):a-571.
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4. Inflamm. Bowel Dis. 2009;15:S16-S17