Risk Factors Associated With Inflammatory Bowel Disease

Transcript:

Remo Panaccione, MD, FRCPC: Hello, and welcome to this HCPLive® Peer Exchange titled “Optimizing Treatment Strategies to Manage Inflammatory Bowel disease.” I’m Dr Remo Panaccione, a professor of medicine at the Cumming School of Medicine at the University of Calgary in Calgary, Canada. Joining me in this discussion are my colleagues Dr Jessica Allegretti, who is an assistant professor of medicine at Brigham and Women’s Hospital in Boston [Massachusetts]; Dr Ed Loftus, a professor of medicine at the Mayo Clinic in Rochester, Minnesota; and finally Dr Bill Sanborn, a professor of medicine at the University of California San Diego School of Medicine in La Jolla, California.

Our discussion is going to focus on the management of inflammatory bowel disease [IBD] using biologics and the paradigm shift that we’ve seen, from the strategy that traditionally relied on conventional therapies—such as corticosteroids and immunomodulators—to what we’re doing today, which is the use of advanced therapies, such as biologics and oral small molecules. We’ll also dive into various safety and efficacy data of these biologics, which were presented at the virtual DDW [Digestive Disease Week in May 2021. Welcome, everyone. Why don’t we get started? Why don’t we start with you, Jessica? Over the last decade or so, we’ve known more about the pathophysiology of inflammatory bowel disease. Can you review for the audience the risk factors associated with IBD and what we know in 2021 about the role of genetics and the environment?

Jessica Allegretti, MD, MPH: We certainly have learned quite a bit, but there are many questions to be answered within this space. We know that the pathophysiology or etiology of IBD is not 1 thing; it’s multifactorial. Generally speaking, you have a genetically susceptible host who has been exposed to several environmental triggers, and then there’s also a complex interplay of the luminal gut microbiome, as well as the host immune response. All those factors have to be at play to set off this set of diseases. We do know, with regard to genetics, that there have been several loci that have been looked at and identified. This isn’t Mendelian; it’s not 1:1 genetics. When this has been assessed, it looks to be between 8% and 13% of variants in Crohn disease and maybe 4% to 7% with ulcerative colitis, which can be explained by a known IBD risk loci.

There are certainly genes that have been linked to this, but it’s a complex series of genetic loci. With regard to risk factors or environmental triggers, many have been identified. We’ve gotten a lot of information from twin studies that have been done. We see certain factors, like NSAID [nonsteroidal anti-inflammatory drug] use or infections early in life have been found to be known risk factors. There have been some associations with breastfeeding and protective effects, as well as things that happen very early in life or even in utero. There are several factors at play. There are many pediatric studies looking at early childhood antibiotic use—just to name a few.

Remo Panaccione, MD, FRCPC: Ed, you’ve done some work in this area. Do you have anything to add?

Edward Loftus Jr., MD: The antibiotic use is intriguing and has been shown in both pediatric and adult-onset IBD studies. It’s a pretty profound effect. We found, when we looked at this in an Olmsted County, Minnesota, cohort, that any use of antibiotics in the preceding 5 years would have basically doubled or tripled your risk of getting IBD. It’s a real phenomenon. Presumably, that implies that microbiome is playing a role, and that’s probably how many of these environmental risk factors exert themselves: through changes in the microbiome.

Remo Panaccione, MD, FRCPC: I tend to agree. If we look at the different things in play, we can’t change genetics, but we’re targeting the immune system with drugs. This unknown element of the environment and how it relates to the microbiome and increases your risk and even affects therapy—this is something we’ll need to look at in the future. Bill, do you think that’s going to be part of our future, that we’re going to get into therapy a little later? Where do you see the microbiome and changes in the microbiome as part of our future treatments?

William Sandborn, MD: We went from not being able to collect cultures to having 16S, then shotgun metagenomic sequencing, and then meta-genomics to characterize patients, and we also had a gradual evolution and the computational ability to analyze large amounts of data when you get it. We have the association studies, and then the initial tipping point was seeing that equal transplant, especially considering those with multiple-donor multiple-dose fecal transplant doses, which had a modest to moderate effect in a subgroup of patients. People are looking at what characterizes the microbiome of the donor’s or donors’ stool, the recipient, and engraftment—all that stuff is evolving.

We have some publications of stool subsets, anaerobes, and spore fraction, for instance. There was an early translational medicine study that suggested some efficacy. We’re getting ready to see a large trial with several hundred patients read out about that. We’re getting ready to transition from the observational data to intervention, and it’s the intervention that would really prove the effect. We may not get it right with the first round of interventions, but people will continue to work in this area, and it’s going to refine those microbiome-focused therapies, which are likely to be part of our future armamentarium. They’ll probably mix in with the concept of precision medicine for both the host and the microbiome. That would be my guess of how fast it comes to be an approved product. It’s hard to imagine it will take less than 5 years, and it could be longer.

Remo Panaccione, MD, FRCPC: Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. I’m sure you’ll see the folks in front of you on future programs. With that, thank you very much.

Transcript edited for clarity.