IBD Drive Time: Edward Barnes, MD, on Pouch Complications

Guest host Sara Horst, MD, and Dr Edward Barnes discuss complications of ileal pouch-anal anastamosis surgery and whether recent use of antibiotics puts patients at risk of pouchitis.

Sara Horst, MD, MPH, is an associate professor of medicine and assistant chief for clinical informatics in the Division of Gastroenterology, Hepatology, and Nutrition at Vanderbilt University in Nashville, Tennessee. Edward Barnes, MD, is an assistant professor of medicine and associate director of the Gastroenterology and Hepatology Fellowship Program at the University of North Carolina School of Medicine at Chapel Hill, North Carolina.

TRANSCRIPT:

Welcome to IBD Drive Time. I am Sara Horst, a gastroenterologist at Vanderbilt University Medical Center and I get to guest host today. So I'm really excited and I'm very excited to have my partner in crime today on IBD Drive Time. And that is Dr. Ed Barnes. Dr Ed Barnes is the associate professor of clinical medicine and the codirector of the Inflammatory Bowel Disease Program, as well as the research program for UNC Chapel Hill. He's done extensive work in clinical research around postoperative inflammatory bowel disease, specifically around patients who've had an ileal pouch-anal anastomosis or IPAA. He's been really active in research and publishing recently around new topics in this area. So I really was excited to have him on and talk about some of these new studies and research that he's been involved in. So let's get into it. Thanks Ed, for coming. Yeah,

Dr Barnes:

Thanks so much, Sara, for having me and this is really a pleasure and always really nice to talk with you.

Dr Horst:

Great. Alright, so let's dig in. So first I want to talk about a paper that you published this year in Clinical Gastro and Hepatology and it was looking at patients who'd had an ileal pouch-anal anastomosis. And so interestingly you found that patients who'd used antibiotics in the 12 months prior to their surgery actually had increased risk of subsequent pouchitis. Could you tell us a little bit more about the cohort you were looking at and your findings?

Dr Barnes:

Yeah, so this is a really interesting work that we've been doing for the past couple of years, looking at a population-based cohort from Denmark, and I'm working with the Center for Molecular Prediction of the IBD or PREDICT, which is run by TDS in Copenhagen, Denmark. And essentially if you're not familiar with these Danish population-based cohorts, you can look at the epidemiology or natural history of patients across their lifetime. So before they have a diagnosis of inflammatory bowel disease or specific ulcerative colitis in this case, but then among those patients who have a colectomy, those who get an ileal pouch-anal anastomosis and then those who do or do not go on to develop a complication like pouchitis. So you can look at specific risk factors for development of IBD or development of these inflammatory conditions of the pouch. And in this particular instance, what we're really interested in is why we've seen in recent studies that we've been doing perhaps an increase in the risk of development of pouchitis, particularly in recent decades and specifically in the most recent time periods like what we consider a post-biologic era.

We've been seeing these increasing risks and we're trying to figure out who's at risk. And then this particular paper we were interested in looking at maybe we are potentially shaping that risk profile for people to develop pouchitis. We know the microbiome is really involved in patients developing pouchitis. We know that dysbiosis drives pouchitis the same way that we think about dysbiosis driving ulcerative colitis and Crohn's disease. And so specifically we looked at the risk of pouchitis among patients who were treated with antibiotics and the 12 months prior to that final stage of surgery and that IPAA process and we saw that not only were patients who were treated with antibiotics at an increased risk for developing pouchitis, there was actually a stepwise phenomenon. Whereas the patients who received more antibiotics, they were the ones that were at the highest risk of developing pouchitis. Those who had sort of middle doses of antibiotics were in the middle and those who had no antibiotics were at the least risk of developing pouchitis in that first 2 years after surgery.

Dr Horst:

Wow, that's fascinating. Can you tell us a little bit about what you controlled for in this study? Because I think sometimes people worry a little bit about compounding or what might've led to the antibiotic use.

Dr Barnes:

Yeah, no, I think it's a natural question, especially when you're looking at population-based data. You want to know what else is going on with these patients. A couple of things that we definitely wanted to control for, given what I was just mentioning about an increasing risk in the biologic era we controlled for and multiple different models where we looked at this, we controlled for a year of surgery, we controlled for anti-TNF exposure prior to colectomy, getting at that signal about sicker patients going on to developing pouchitis. And then we also controlled for sex in those models because we had a signal that potentially that female patients may be at an increased risk. And this is something that's a little bit less defined I think in some of these studies.

But another thing that we were really intentional about doing is we actually looked at eliminating those periods around the stages of surgery because we know that in the current era, most patients will actually have 2 or 3, usually 3-stage approach to an IPAA. And so we didn't want to just look at those patients had the most complicated sort of series of procedures and they always had antibiotics because they had some complication with their surgery. So we eliminated 30 days around each surgery to make sure that we were not just basically finding patients that had some complication from surgery or an abscess or a leak or they were having a longer hospitalization. So we eliminated those periods and we still found the same signal among those patients who had antibiotic exposures being at the risk for development of pouchitis.

Dr Horst:

Wow, this is really novel and interesting and not something that I'd necessarily thought about before and I'm really interested in hearing why you think this might be happening.

Dr Barnes:

Well, I think there's a couple of reasons to think about this. One reason is I think in some ways we need to move away from thinking about pouchitis and this surgery, the IPAA surgery being sort of the end result of very bad ulcerative colitis, and that's what happens if you have a colectomy that being the end of your ulcerative colitis journey. Maybe we're seeing more of a continual phenotype in that patients have a really severe, bad inflammatory bowel disease course and that those are the patients that are most severe that go on to develop pouchitis within the first 2 years of surgery. And maybe that's what we're identifying with this signal of increased anti-TNF, surgery, more antibiotics prior to colectomy and maybe we're just identifying sort of this different clinical phenotype altogether. And that sort of tracks with that paper that I mentioned before that we did back in 2023 where we showed that patients that had surgery in 2018 are probably a lot different than 1996 patients at that point in time were treated with mesalamine and maybe cyclosporine if they had acute severe UC.

But that's just a different patient journey and that really is what we can do in these Danish cohorts that we can't do in the United States because we just don't have those type of nationwide resources to be able to study that. But I think that's the signal we're getting at.

Now, I do obviously, as I said before, I think the microbiome is key in why people develop pouchitis. So there's probably something about the antibiotics, but it's probably that the antibiotics are selecting for a different phenotype altogether. And that's where I think we really need to reshape as we communicate to patients as they're going through this surgery process, but also us as providers, how we think about these patients, and it's not that you get to a colectomy, you get to a pouch and then you just wait for something to happen. I don't think that's the right way to be thinking about patients, especially in 2025 when we have all these other medicines that patients are exposed to prior to colectomy, given that we have so many therapies for ulcerative colitis now.

Dr Horst:

Yeah, this is practice changing for me and so I'm really glad that you all did this study because I wasn't asking people about if they had antibiotics and whether—I agree with you, maybe it's a marker of people who are more ill and more sick— but understanding their journey the year before they go to pouch surgery I think is something that I'm really going to pay a lot more attention to. So thank you. I appreciate that.

You also did some really interesting work that you just presented as an oral at ECCO this year, which I also learned a ton about and I thought probably our listeners will want to think about this a little bit. You at that point dug in a little bit more to just when you're thinking about pouchitis, it's more than just antibiotic. I'm quoting now, you guys can't see it, but antibiotic use or no, but you actually put these patients with pouchitis into clusters. So could you talk a little bit more about that? That's something I think I learned and I think everybody could use a little bit more education around acute pouchitis, chronic pouchitis, antibiotic-refractory pouchitis, that kind of thing.

Dr Barnes:

Yeah, no, I think this project that we did that we presented at ECCO I think was something that I found to be really novel and something that I'm personally proud of for the reason I'm going to delve into in a second. But one thing that, going back to this idea about a sort of continual phenotype, we really wanted to think about a way to communicate that message and actually just to analyze it, that message was a real message. This actually stemmed from some work and some signals that we've seen here in the US. There's a really nice paper a couple of years ago from Mount Sinai that showed that patients who develop pouchitis in the first year after surgery were more likely to go on to develop chronic inflammatory conditions of the pouch. We had a similar study that sort of mirrored those findings at UNC that we had published. So we had this signal that again, patients that are really sick going into surgery, develop complications and the first year after surgery may go on a different pathway than patients that maybe don't develop pouchitis right away and that do very well.

And so what we wanted to do is look at, okay, if patients are sick and they get antibiotics in that year prior to the final stage of surgery and they go on to develop pouchitis in the first 2 years, what does that look like? Is it just one episode of antibiotics and then they do great or are there different phenotypes that are actually you can identify even in that first 2 years after surgery? And the thing—going back to talking about the epidemiology strengths of looking and working with PREDICT and looking in the population-based cohorts in Denmark—you can look at individual patients and you can see what their prescription patterns are for that first 2 years after surgery.

And so working with some of the epidemiologists at PREDICT, we actually thought about how could we actually do this? And we use something called sequence analysis. It's been used a lot in social sciences, not so much in our therapy analysis within gastroenterology or within a clinical side of medicine, but you could actually look at the intervals and divide them months of the year into 12 intervals and look at did you get antibiotics prescribed each of those 12 intervals. So each month of the year were antibiotics, yes or no. And you could basically create a heat map based on colors, yes or no, and you could look at patterns of prescriptions. and what happens is exactly those sort of characteristics that you described. There's a group of patients that get one episode of pouchitis, they get one antibiotic prescription, and they don't get any more antibiotics for the rest of the year. That's the patient that probably just flies and they do very well. And we've seen those patients in all of our clinics.

There's another group of patients, though, where they get that initial antibiotic prescription and then in that sequence analysis, the rest of their sort of cluster map is just totally what we use as a pink color, which was they got antibiotics for the rest of the year. That patient phenotype is probably totally different than that initial group that I mentioned. And actually what we did is we analyzed those patients in a similar way. We said that top group is probably the intermittent pouchitis, they don't get any more antibiotics. And that tracks with definitions that we use in practice, those that have been proposed by the AGA clinical guidelines, those that have been approached by other standardized groups as well. And the other group that gets antibiotics and they continue to get antibiotics. That's sort of our recurrent or chronic pouchitis group.

And if you do a sort of binomial grouping like that and you do a multivariable analysis, you start to see the signals that we saw in those other population-based analysis. Those people who go on to develop chronic pouchitis are those that have antibiotic exposures in the 12 months prior to surgery. Those that had anti-TNF exposures and those that have had more recent surgery in the more recent time periods. And so again, just getting back to the same idea of, is this a phenotype that's developing in the more recent time periods that we need to think about IBD in a different way and we need to think about these patients undergoing surgery in a different way. And if we identify these patients that are at risk, should we be treating them in a different way other than our reactive nature that we've been doing? Can we treat patients in a more proactive way and actually change their natural history, change their disease course, and actually decrease the burden among a patient that may be destined to go to develop recurrent or chronic pouchitis? These are sort of unknown things at this point in time.

Dr Horst:

This is so fascinating and I really loved kind of nerding out a little bit with the sequence analysis because it's what I was seeing in practice. But then to see it put together and see those heat maps and really understand that this is a phenomenon that's happening for subsets of patients was really cool to see.

So you kind of mentioned that this is a little bit unknown, but what should I do? I identify somebody who's been in anti-TNF the year before and I saw that they required antibiotics 2 or 3 times. I'm going to counsel them that they're going to get an IPAA, what should I tell them? Should I treat them a little bit differently?

Dr Barnes:

Yeah, well, I don't want to mislead our listeners and say that our work in Denmark and then what we presented at ECCO is a totally novel thought. This is something that has been actually looked at in the early 2000s, the idea of primary and secondary prevention and probiotic studies that we discussed in the AGA guidelines. There's actually strong evidence that probiotics could be used as tools for primary and secondary prevention. So if you carried that thought forward and said, you have a high risk group, your patient is high risk when you're talking to them, you could introduce the idea of primary prevention or in the idea of the sequence analysis that patient developed pouchitis in the first year. You could think about, okay, you're in a high risk group. You've had multiple biologic or advanced therapy exposures and then you've developed pouchitis in the first year.

Maybe I'm going to now treat you in some way and do secondary prevention. The problem right now is we don't know that probiotics are the best thing for primary or secondary prevention. Those studies haven't sort of been redone in the last 20 years and the follow-up data from the US wasn't as strong as the initial primary clinical trials. And so that's why we didn't make as strong of a statement in the guidelines to say that we should be doing this across the board. And right now in the current, to answer your question, in the current era, I think you could still make an argument to have that sort of conversation with a patient. These 8-strain probiotic formulations are available, they're just sort of costly for patients. And that's another sort of idea that why we didn't make a strong recommendation about this.

But I think moving forward we should do these kinds of studies. We should be looking into primary prevention, we should be looking into secondary prevention. And even in 2025, we know a group like a patient with primary sclerosing cholangitis, they're at a definitively increased risk to develop pouchitis, to develop chronic pouchitis. That's a group where primary prevention makes sense. And so in our practice at UNC, we are using primary prevention and we use either sometimes in advanced therapy from my practice, I use vancomycin to try to prevent that. And that's something we're trying to research to try to have evidence to support that rather than anecdotal because it's a hard thing to capture because PSC represents a very small proportion of the population compared to patients who have had an anti-TNF prior to colectomy. Now that's the majority of our population.

Dr Horst:

I definitely learned that from you and we got to do some research around this, but those patients with PSC who end up with a pouch, I'm being much more proactive, I think, than I had in the past. Remind me what dose of vancomycin you use.

Dr Barnes:

Yeah, so for those patients where I'm doing primary prophylaxis, I'm doing vancomycin 125 milligrams PO BID, so twice a day. So a smaller dose than what we would think about doing is a standard dose for C difficile treatment. And most patients tolerate this pretty well. It's a relatively gut limited dose of antibiotics. And again, this is not something that's been well studied. Vancomycin has been studied—again, this is not an FDA approved therapy by any means—but has been looked at for the treatment of chronic pouchitis and it works quite well. There's a signal for vancomycin in the use of PSC and other settings such as ulcerative colitis. And so that's where that sort has stemmed from. But my patients have tolerated it pretty well and I think it's something that we could study. It just is going to take a long time to study.

Dr Horst:

I'm using it. So I really appreciate learning that from you. So now while you're here, I do want to talk about a study that will be hot off the presses soon. You have an oral presentation that you'll present at DDW and I'd just love to hear what you've learned. Again, this is around patients who have ileal pouch-anal anastomosis.

Dr Barnes:

Yeah, so this is one other study that we're really excited about. This is a comparative effectiveness study where we have a prospective cohort known as PROP-RD, we've been recruiting for this in terms of prospectively following patients on advanced therapies for chronic inflammatory conditions of the pouch for several years now. But we designed this study specifically looking at new start therapies among patients treated with ustekinumab versus anti-TNF therapies. Because in the current era we don't have a lot of randomized controlled trial data for patients with chronic inflammatory conditions of the pouch. We have a landmark study in the form of EARNEST looking at vedolizumab versus a placebo, but that's really the only RCT that we have. And so what we really wanted to know is in the setting where patients have gone on to develop either chronic pouchitis or more specifically Crohn's-like disease of the pouch is one therapy better than another.

And so we compared ustekinumab versus anti-TNF therapy in this setting. And what we found is that ustekinumab, at least numerically had a statistically significant difference. There are some limitations to the study in that it was actually got harder and harder to recruit for the study the further we went along, in part because more patients were using ustekinumab prior to colectomy and then also because we had more and more new therapies that were coming available. So we saw a advent of the IL-23s, we saw the EARNEST study that was published, and so we actually stopped the study early and so we were underpowered from our initial power calculation. That being said, there's no other prospective comparative effectiveness study that has these amount of data that had been presented. So we are excited to present this at DVW.

I think this mirrors what we've been seeing in clinical practice from a practical standpoint; there have been retrospective studies that have suggested that recycling a therapy, using a therapy that was used or a class of therapy that was used precolectomy, is not as effective as using a novel therapy post-IPAA. So for patients that have been on an anti-TNF precolectomy, an anti-TNF post-IPAA may not be as an effective a strategy, it's using something new. So I think that's a really important thing to sort of message to center around. And perhaps we can continue to do these comparative effectiveness studies, pragmatic study designs to really get at improving our evidence base in the pouchitis and Crohn's-like disease of the pouch area. I think this is a really appropriate way to be studying patients and actually informing decisions for patients rather than hoping that we can enroll in a placebo-controlled trial for every new therapy that we have. I'm not sure that that's going to be a tangible goal as we see this explosion of our armamentarium, which is a good thing for patients.

Dr Horst:

Yeah, this is great and I definitely am going to take this back in clinical practice. I'm excited to see when you have it published, because I think this is going to be really helpful for us when we are trying to get these therapies approved for our patients who have Crohn's disease of the pouch to say, Hey, maybe the insurance company is saying you have to use an anti-TNF. I'm going to use this study to say, Hey, maybe actually no, I need to be using a different mechanism of action for this patient because they've already experienced the anti-TNF. So I think this is really exciting and I just really want to thank you for coming. I learned so much every time we talk.

So thank you again for coming and everyone for listening to IBD Drive Time. And just remember IBD Drive time is available on Apple and Spotify and we are sponsored by the AIBD network. So thanks everybody for listening.