Children and adolescents with ulcerative colitis have many more treatment options than they did a decade ago thanks to the invention of several new drugs for this form of inflammatory bowel disease. But not all medications work for every patient, which means it can take weeks or months of trial and error to get a person’s symptoms under control.
Pediatric gastroenterologist Michael Rosen, MD, director of the Center for Pediatric Inflammatory Bowel Disease and Celiac Disease at Stanford Children’s Health, works with a team to care for young patients with Crohn’s disease, ulcerative colitis, and celiac disease, all of which can cause inflammation in the bowels . They also conduct research to understand the biology of these diseases, develop better treatments, and advance precision medicine for these diseases.
People with ulcerative colitis experience uncomfortable symptoms such as intestinal pain, frequent bloody diarrhea, weight loss, anemia, and fatigue. Several parts of the gut, including the epithelial barrier — the cells that line the gut — are compromised, and the immune response becomes overzealous, likely in response to changes in the bacteria that populate the colon rather than the patient’s own cells. The intestinal lining becomes inflamed and ulcerated, leading to blood loss.
We know all of this is triggered by factors in the environment — factors that we don’t fully understand — in people at genetic risk for the disease, Rosen said. “It is a complex interaction of genes and environment that leads to impaired function of the colon barrier, an unhealthy microbiome and an overactive immune response.”
Recently, Rosen and his colleagues developed a way to predict how individual patients will fare in the long term at diagnosis. His latest study showed that the activity of two specific genes in the rectal tissue of newly diagnosed patients predicted the patients’ disease progression one year later. They hope to use these findings to identify patients who need more advanced treatment and match them to the right therapies more quickly.
In a recent Q&A, Rosen discusses his latest research, how he works with families to treat children’s ulcerative colitis, and how this study could inform future treatment strategies.
Why is ulcerative colitis not easy to treat?
We generally start treatment with drugs that have been around for a long time, typically 5-aminosalicylate drugs that are taken orally and are fairly safe overall. Depending on the initial severity of the condition, we can add corticosteroids. These are not a good long-term option due to their adverse effects, but they do put out inflammatory fires. We try to slowly wean patients off steroids in the hope that the 5-ASA drug will prevent the inflammation from recurring.
If that doesn’t work, the next step is to try intravenous biologics, e.g. B. Antibodies that counteract the effects of an inflammatory substance called tumor necrosis factor.
Why was your new study important?
We examined the pattern of gene activity at diagnosis in tissue from patients with ulcerative colitis. We focused on genes involved in the immune response in the colon mucosa and tried to use this information to predict who will respond to 5-aminosalicylate drugs. We have found that we can better predict who will need escalated therapy when we combine patients’ gene expression information and clinical measurements, such as: B. their hemoglobin level, which measures anemia, as well as their symptom severity at diagnosis. This improves our current method of identifying who needs more intensive therapy, which requires waiting four weeks after diagnosis to see how a patient is doing.
How would children and families benefit from such a prediction?
Families may feel discouraged at the idea of trying a drug that only has a 30 to 40 percent chance of being effective. If we could say, “There’s a 60 percent chance that this will work for your child,” that would be huge. Alternatively, if we knew a patient only had a 10 percent chance of success on a particular drug, we’d probably try something else. We need to further validate the study results, but once we do, we believe this will spare patients prolonged or repeated courses of corticosteroids, which become more toxic the longer we use them, and help them get back to normal sooner return to life.
Ultimately, we need better tools to choose from a growing list of effective therapies, so we don’t understand what works for 50% of patients, but what will work for the patient before me. This brings us closer to precision medicine.
They measured the activity levels of specific genes that are linked to the progression of the patient’s disease. What insights have you gained into the biology of ulcerative colitis?
We are excited about the new findings related to another gene, RORC, which we expected to be more active in ulcerative colitis due to its role in the immune response in the disease. Surprisingly, we found that scores were lower in patients with worse outcomes, including those who had the worst outcomes from having their colon surgically removed. That was really puzzling.
Using techniques that allow us to study specific tissues and individual cells, we found that this low RORC signal did not come from immune cells, which we normally think the gene is working, but from epithelial cells lining the gut . This is very surprising to us and opens the door to a future line of inquiry.
All of our treatments for ulcerative colitis are designed to target the immune response; No existing treatment aims to improve the health of the cells that line the colon. But for a colon affected by ulcerative colitis to heal, these cells must repopulate. Our next goal is to understand how healing of the intestinal mucosa can be maintained and then to develop therapies to support this process.
For more information on the Center for Pediatric IBD and Celiac Disease, visit: ibdceliac.stanfordchildrens.org.