Disease Subtypes and Differential Diagnosis of UC and CD

Miguel Regueiro, MD: Ellen, I’m going to include you because David mentioned the differential diagnosis of IBD [inflammatory bowel disease]. But before I get to that, what are the subtypes of the different phenotypes of ulcerative colitis?

Ellen J. Scherl, MD:If you look at ulcerative colitis as part of a spectrum—and we don’t focus on the Crohn disease colonic phenotype—we’re talking about ulcerative proctitis left-sided disease or universal colitis [UC], with separate phenotypes for ulcerative colitis. There are patients who look like classic ulcerative colitis, but over time they change to more of a Crohn phenotype, with either skip areas, perianal fistula, or even ileal disease.

The point is that we don’t have a great molecular or cellular way of classifying these diseases. But in the April issue of Gastroenterology, which is devoted to the era of disease modification, they talk about the need to reclassify colitis-associated Crohn or colitis-associated ulcerative colitis, because Crohn colitis acts more like ulcerative colitis than ileal disease–related Crohn. Until we come to what Marcus Neurath has called reframing the inflammatory immune-mediated diseases—from target organs like colon vs ileum to more specific cytokine signatures—we’re left with this differential diagnosis: is it Crohn or ulcerative colitis?

Marla knows, and I think David also knows, there’s nothing like a pouch. We’ve said this many times: there’s nothing like a pouch to bring out Crohn disease in a patient who has had a total proctocolectomy for ulcerative colitis. What happens? Is it the microbiome that somehow triggers more Crohn picture? We do the serology looking for phenotypic expression of ulcerative colitis vs Crohn before recommending a total proctocolectomy in these patients with severe ulcerative colitis. It doesn’t change our recommendation, but it does change the way we gear the patient to follow up. I hope that answers some of your questions.

Miguel Regueiro, MD:You did a nice job outlining the different subtypes of ulcerative colitis, which traditionally have been proctitis left-sided disease, and this pan or universal or extensive ulcerative colitis. There’s this concept of a differential diagnosis with Crohn and UC in this overlap. I like the way you said this. Based on the recent publications, it’s more of a colitis-type phenotype.

Marla, coming back to pediatrics, the labels in determining colitis, as Ellen said, are often hard to tell if this it’s going more toward ulcerative colitis or Crohn. Can you talk about how children present, how that looks, and how you make earlier diagnoses of ulcerative colitis?

Marla Dubinsky, MD:You bring up the point that there’s these early onset IBD, and they all have different phenotypes. In pediatric patients, we’ve seen what differentiates pediatric-onset colitis. I’m going to call it colitis instead of calling it ECL [electrochemiluminescence] Crohn because, like Ellen, I’m of the understanding that colitis is its own phenotype. That comes to pediatrics because 78% to 80% of kids who present with IBD involving a colon are pancolitis. We don’t see proctitis, but when I do I’m thinking, “What’s so rare about this presentation, particularly in pediatric onset?” Under age 10, it’s almost always presenting like colitis. Their first presentation is whether it ends up more Crohn-like and involving small bowel, but the way pediatric early onset typically presents is colon-only disease.

The terminology indeterminate, which we’ve changed many times, is more unspecified or unclassified. We reserve the term for after colectomy, with the pathology specimen saying, “I can’t tell the difference, so indeterminate.” We communicate with families by saying we’re not sure what it ends up wanting to be. But going back to Ellen’s point, I don’t think it matters because my treatment will be targeted on the location. Biologically, this concept of cytokine hubs and new taxonomy that was published in New England Journal of Medicine is that there’s a completely different biology in the colon than there is a small bowel. The good news is that a lot of our newer therapies in the biologic space are focused on these pathways that are heavily Th17, IL-23, and all these different biologic strategies. It’s exciting to understand this, and in pediatrics even more so because it may be more unspecified the earlier they are.

We’ve also shown that postcolectomy, if you do operate, they have a much higher rate of developing this Crohn disease–like feature of the pouch because it wasn’t that we got it wrong. That’s always the biggest nightmare and fear for patients is, before they get the colon out: what if you were wrong and it was Crohn disease. Now we have an ability to say that we’re trying to look for biologic expression and markers that may tell us before you go colectomy whether you’re at risk of that phenomena. Understanding biology is the future to be able to communicate, particularly to kids.

Ellen J. Scherl, MD:It’s important to recognize the Th17 story, which brings us to the point that extraintestinal manifestations are a way of classifying IBD: the IBD positive extraintestinal vs nonpositive. IL-17 is fascinating because some of the anti–IL-17 drugs work better for the extraintestinal manifestations but may flare the colitis, whereas IL-23 is the reverse. We’re moving toward a molecular or cellular classification that will define how we treat with all these new therapies coming down the pike.

Miguel Regueiro, MD:Absolutely. This concept of precision medicine is something we keep throwing around, that maybe 1 day we’ll have a molecular signal or a blood test that tells us the patient’s phenotype based on molecules and treatment that then gets to that. I also heard the earlier diagnosis is important in IBD. Often patients are labeled as irritable bowel if they come in with bleeding, weight loss, and other inflammatory signs, but we should check early fecal calprotectin. I tell the primary care if they’re not sure to send that off, if that comes back very high, it could be an infection. At the same time, we must look at that.

Transcript Edited for Clarity