Therapeutic Optimization in Crohn's Disease - Episode 2

Understanding the Pathophysiology of Crohn's Disease

Bruce E. Sands, MD: The pathogenesis of Crohn’s disease is not fully elucidated at this point, but we do have a clear understanding that there’s a contribution of both genetics and environmental factors. The genetics are quite complex. It’s a disease that involves over 200 risk loci, each of which contributes in a small way to the risk of Crohn’s disease. But we’ve known for a long time that there are large families, and oftentimes there will be more than 1 person in a family affected by Crohn’s disease. That has been known for quite a while. The environmental factors are harder to sort out, but through the genetic risk loci, we’ve come to understand that the intestinal microbiome plays a key role. What shapes the intestinal microbiome are all sorts of environmental exposures in utero and in early childhood through diet and other exposures.

William J. Sandborn, MD: Crohn’s disease is still idiopathic from the standpoint that we don’t know exactly what causes it, and other speakers will be addressing the genetics and the other factors that play a role. But 1 thing we know is that there is an increase in proinflammatory cytokines, and those include tumor necrosis factor alpha, interleukin-12, interleukin-23, interleukin-6, and interleukin-1. Many of these proinflammatory cytokines end up being targets for therapy.

Marla Dubinsky, MD: In terms of thinking about why Crohn’s disease happens, we think, “What are the elements that need to be in place for a patient to present with inflammatory bowel disease (IBD)?” We do know that genetics play a major role, meaning IBD won’t happen in the absence of a genetic susceptibility. So, it is a hereditary disease in the sense that there are genes that are passed down. We first learned about the genetic implications back in 2001, when the first ever Crohn’s gene was discovered. It was presented at our national meeting, actually, in San Diego as a big, late-breaking media event, because this was the first time a gene was uncovered.

What we learned about it is the NOD2 gene, or what we call the CARD15 gene, happens to be at this point probably the most important gene-defining susceptibility. A lot of other genes since 2001 have been discovered because we’ve had the Genome-Wide Association Studies. We’ve had mapping of the human genome, so we’ve had an explosion of genetic research. But interestingly enough, the NOD2 gene appears to be probably one of the strongest susceptibility genes despite all these advances in technology.

A gene has to be there. It doesn’t mean that the patient has a family history. That’s also important to distinguish. Just because it’s a genetic predisposition, a patient may not have a family history of IBD in their immediate family, it may occur in distant relatives, or they may have a family history of other autoimmune conditions such as cirrhosis or rheumatoid arthritis. So, these immune genes intermingle. Therefore, it’s not always a family history specific to Crohn’s.

We know you need a genetic background. But what happens after that? If I’m NOD2 positive, I may not get Crohn’s disease. I need some kind of environmental hit. Meaning there has to be some kind of trigger, which we don’t know yet what that is. We believe that this external or environmental trigger—maybe it’s food, it’s unclear—actually changes the microbiome environment in an individual’s intestinal tract such that we believe the gene regards these new or existing microbial profiles as foreign, and it causes an inflammatory response in the lining of the intestine that, because of the genetic susceptibility, can no longer be controlled. So, it’s this perpetual inflammatory cascade in the face of a genetic susceptibility triggered by some kind of unknown environmental factor.

Transcript edited for clarity.