Pathogenesis of Inflammatory Bowel Disease

Transcript: Miguel Regueiro, MD: Hello, and welcome to this HCPLive® Peer Exchange: “Advances in the Management of Inflammatory Bowel Diseases.” I'm Dr Miguel Regueiro from the Cleveland Clinic. Joining me today in this discussion are my colleagues, Dr Jessica Allegretti from Brigham and Women's Hospital. Hi, Jess.

Jessica R. Allegretti, MD, MPH: Hi.

Miguel Regueiro, MD: Dr Marla Dubinsky from the Icahn School of Medicine at Mount Sinai. Hi, Marla.

Marla C. Dubinsky, MD: Hello.

Miguel Regueiro, MD: Dr David Rubin from the University of Chicago Medicine. Hey, Dave.

David T. Rubin, MD: Hey, Miguel.

Miguel Regueiro, MD: And, Dr William Sandborn from the University of California San Diego. Hi, Bill.

William J. Sandborn, MD: Hi. How are you?

Miguel Regueiro, MD: Doing well. Our discussion today will focus on the management of inflammatory bowel disease using biologics and the paradigm shift away from a therapeutic strategy that has traditionally relied on corticosteroids and immunomodulators. With that, let's go ahead and get started.

We have some different segments, and we're going to start off by talking about the pathogenesis and pathophysiology of IBD [inflammatory bowel disease]. I realize with this group that we could probably spend an entire conference on this, but we're going to distill it down to about 15 minutes. I'm going to ask each of you some questions, and then we'll have discussion along the way. If you want to chime in or add something, please feel free to do so.

Bill, I'm going to kick it off with you. When we think about the pathogenesis of inflammatory bowel disease in 2020, what are some high-level thoughts, or what would you say is the current understanding of the pathogenesis of Crohn disease and ulcerative colitis [UC]?

William J. Sandborn, MD: Well, some of the learnings we've had over the last decade are that ulcerative colitis and Crohn disease are in some ways more similar than they are different. In terms of shared genetics, there are about 250 gene associations now, and many of those are shared between the 2 diseases and many other autoimmune diseases. They have a fairly common genetic background, but they’re not identical. That's the first thing.

The second thing is that we always knew that the environment was important, and we still think that there are some very important unidentified external forces that impact the actual occurrence of IBD in the genetically susceptible person. What we've come to understand is that our microbiome external environment in the lumen is a huge aspect, and we're still in the very early days of understanding how that directly impacts individual patients, but I believe that that will be an important part of the future.

Finally, Marla can speak to very early onset [VEO] Crohn disease where we see monogenic immune deficiencies in a certain portion of patients, which seem to be quite unique.

Miguel Regueiro, MD: Yes. In the very early onset IBD, which many of us don't see aside from Marla, there is clearly a genetic factor there. So maybe, Marla, you can speak.

William J. Sandborn, MD: Although, don't forget that those patients grow up. We do see them, and there are probably some in our practices today, and we've forgotten that they had an onset when they were 5 or 6, and we haven't checked those genes.

Miguel Regueiro, MD: Yes, those are usually the patients, when we present at conferences, who are so severe, failing everything. Probably the reason, Bill, to your point, is that they're not the typical IBD patient.

Marla, if you want to talk a little bit about genetics, but let's move to the incidence and prevalence of IBD and some aspects of quality of life. What do we know about incidence and prevalence of IBD in the United States, North America? Tell us a little bit about that.

Marla C. Dubinsky, MD: Sure. It's estimated that anywhere between 1.5 million and 3 million people have inflammatory bowel disease at any given point. The reason I give such a wide range is some numbers come, for example, from the CDC [Centers for Disease Control and Prevention] estimating around 3 million, while other numbers hint that it's maybe somewhere in between. We don’t know the true reporting of patients with IBD. We do know that it's approximately 50% of these cases of UC and 50% of patients have Crohn disease. We know it's around that, which means around 700,000-750,000 patients with UC, 750,000 patients with Crohn disease.

We do see that epidemiologically, the age group that has the highest rising new cases is pediatrics, and bringing it back to the genetic comment that Bill made, the younger patients under the age of 6, the 2-6 age group, is probably the fastest growing new-onset cases of IBD, which speaks to the fact that the younger you are, genetics are playing a major role, as opposed to environment, for example, which would, for older patients, have equal influence of genetics and environment.

I want to pinpoint what you guys were saying about the VEO, or what we term very early onset, which is under the age of 6. But then infantile IBD, which is the Crohn disease-like illness between the ages of 0 and 2, and those individuals tend to have a very strong monogenic [disease], as Bill was referring to.

What's interesting is that the genetic piece may be tied to this refractory nature that you're talking about. Now that we have commercial use or widespread use of gene panels, we're able to test patients for common genetic variance like chronic granulomatous disease in patients who have recurrent perianal infections and abscesses, and we've been able to find a number of those. That's the epidemiological idea around IBD.

From a quality of life perspective, we have to recognize that this disease classically has been a relapsing and remitting disease, meaning it goes in phases. Obviously, our goal as physicians is to try and make it remit for that long, durable period, and once we get into the therapies, we'll talk about this new target of ours, which is complete deep remission. You have to understand that every time a patient flares, the anxiety around not knowing: when am I going to flare? Am I sick? If I eat something tomorrow, am I going to ignite a flare? That is very stressful and provokes a lot of anxiety for patients: the unknown about the quality of life tied to these diseases.

Miguel Regueiro, MD: Good. It's interesting, when you look at the quality of life related to IBD in many of the studies that have been done, in terms of chronic illnesses, this has one of the highest impacts, meaning poorest quality of life. I completely agree, and that's something that will be a theme throughout some of the discussions we have now in terms of treatments and looking at quality of life as an outcome.

Transcript Edited for Clarity