Children and teens with ulcerative colitis have many more treatment options than a decade ago, thanks to the invention of several new medications for this form of inflammatory bowel disease. But not all drugs work for every patient, meaning it can take weeks or months of trial and error to bring someone's symptoms under control.
Pediatric gastroenterologist Michael Rosen, MD, and his colleagues are studying how to speed up the process. Rosen, who arrived at Stanford Children's Health in 2021 to become the inaugural director of the institution's Center for Pediatric Inflammatory Bowel Disease and Celiac Disease, 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 gut. They also conduct research to understand the biology of these conditions, devise better treatments and advance precision medicine for these diseases.
People with ulcerative colitis experience unpleasant symptoms, such as intestinal pain, frequent bloody diarrhea, weight loss, anemia and fatigue. Multiple parts of the bowel, including the epithelial barrier -- the cells that line the bowel -- are impaired, and the immune response becomes overzealous, likely more in response to changes in the bacteria populating the colon than to patients' own cells. The bowel lining becomes inflamed and ulcerated, leading to blood loss.
We know all of this is triggered by factors in the environment -- factors we don't entirely understand -- in people with genetic risk for the disease, Rosen said. "It's a complex interaction of genes and environment that leads to impaired function of the colon barrier lining, an unhealthy microbiome and an overactive immune response."
Recently, Rosen and his colleagues have been devising a way to predict, at diagnosis, how individual patients will fare in the long run. He is the senior author of a new scientific study, recently published online in the Journal of Crohn's and Colitis, which assessed gene expression -- when and how much genes are turned on -- in rectal tissue samples from 428 newly diagnosed pediatric ulcerative colitis patients from 29 institutions across North America.
The study showed that the activity of two specific genes predicted patients' disease outcomes a 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.
I spoke with Rosen to learn more about his research, how he works with families to treat ulcerative colitis in kids and how this study could inform future treatment strategies.
Why isn't treating ulcerative colitis straightforward?
We generally start treatment with medicines that have been around for a long time, typically 5-aminosalicilate drugs which are taken orally and are quite safe overall. Depending on the initial disease severity, we might add corticosteroids.
Those aren't a good long-term option, due to their adverse effects, but they put out the fires of inflammation. We try to wean patients off the steroids slowly, in the hope that the 5-ASA drug will keep inflammation from flaring up again.
If that doesn't work, the next step is to try IV biologics, such as antibodies that counter the actions of an inflammatory substance called tumor necrosis factor.
A recent study showed that only about one-third of patients achieve long-term clinical remission on the traditional oral medication alone. We still think it's worth going for; we see it as the ideal outcome because it's an oral medication, taken once or twice a day.
But for patients who don't respond well to this class of drugs, trying this treatment prolongs getting their symptoms under control. It would be wonderful if we could identify these patients at the time of diagnosis, because then we could get an earlier start on therapies that are more likely to help them.
Why was your new study important?
We looked at the pattern of gene activity at diagnosis in the tissue of patients with ulcerative colitis. We focused on genes involved in the immune response in the lining of colon and tried to use that information to predict who will respond to 5-aminosalicilate medication.
We found that when we combine patients' gene-expression information and clinical measurements, such as their hemoglobin level, which measures anemia, as well as their symptom severity at diagnosis, we better predict who will need escalated therapy. This improves on our current method of identifying who needs more intense therapy, which requires waiting four weeks after diagnosis to see how a patient is doing.
How would kids and families benefit from such a prediction?
Families may feel discouraged by the idea of trying a medicine with only a 30% to 40% chance of being effective. If we could say, "For your child, there is a 60% chance this will work," that would be huge. Alternatively, if we know that a patient has only a 10% chance of succeeding on a particular medication, we probably would try something different.
We need to further validate the study results, but once do, we think this will spare patients from longer or repeated courses of corticosteroids, which have more toxicity the longer we use them, and help them get back to normal life sooner.
Ultimately, we need better tools to select from a growing list of effective therapies, so we understand not what's effective for 50% of patients, but what's going to be effective for the patient in front of me. That gets us closer to precision medicine.
You measured activity levels of specific genes linked to patients' disease outcomes. What insights did you gain about the biology of ulcerative colitis?
One gene that helped us predict outcomes, called IL13RA2, has increased activity in more severe cases of ulcerative colitis. The data from our pediatric cohort supports what had been seen in adult studies of the same gene. This gene seems to be active in cells called fibroblasts, which may interact with immune cells lining the intestine. We have a lot more work to do to understand how that interaction drives disease refractoriness, which is poor response to treatment.
We're even more excited about new findings related to another gene, RORC, which we expected to have higher activity in ulcerative colitis because of its role in immune responses in the disease. Surprisingly, we found its levels were lower in patients with poorer outcomes, including the poorest outcome of surgically removing their colon. This was really puzzling.
With techniques that allow us to look at specific tissues and individual cells, we found that this low RORC signal was not coming from immune cells, where we typically think the gene is working, but from epithelial cells lining the bowel. This is very surprising to us, and it opens the door to a future line of investigation.
All our treatments for ulcerative colitis are directed at the immune response; no existing treatment aims to improve the health of the cells lining the colon. But for a colon affected by ulcerative colitis to heal, those cells need to repopulate. Our next goal is to understand how to maintain healing of the lining of the bowel, then develop therapies to support that process.
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