Edward Barnes, MD, on Post-IPAA Complications of the Pouch

In this podcast, Dr Barnes discusses his recent research into the prevalence of pouchitis among patients who have undergone ileal pouch-anal anastamosis surgery.

Edward Barnes, MD, is an assistant professor of medicine and gastroenterologist at the University of North Carolina at Chapel Hill.

TRANSCRIPT:

Welcome to another podcast from the Gastroenterology Learning Network. I'm your moderator, Rebecca Mashaw, and I'm pleased to be joined today by Dr. Ed Barnes, who is an assistant professor of medicine and gastroenterologist at the University of North Carolina. Thank you for joining us today, Dr. Barnes.

Dr. Edward Barnes:  Thank you very much for having me. I'm excited to be here.

GLN:  We're going to be talking about some recent research that you did that was published on the incidence, risk factors, and outcomes of pouch-related complications and particularly pouchitis among patients with ulcerative colitis. To begin with, how common is pouchitis among patients with UC who have undergone the IPAA procedure?

Dr. Barnes:  That's a really excellent question and in fact, that was part of our motivation to do this particular study. Traditionally, our estimates for the incidence of pouchitis, we look at this on the first year after you get a surgery, like an ileal pouch-anal anastomosis, and then also a lifetime prevalence of pouchitis.

We've traditionally estimated this either based on what single-center studies have done or in the case of 1 well-done randomized control trial. That estimate has been about 40% of patients will develop pouchitis within the first year after having the ileal pouch-anal anastomosis surgery. Lifetime prevalence or the disease course prevalence have been estimated as high as 80% if you look at studies from the Mayo Clinic, where they followed patients up to 30 years after they have this surgery.

When we've surveyed patients looking at pouchitis symptoms in large registries such as the Crohn's & Colitis Foundation's IBD Partners online database, which is a patient-powered research network, about 80% of patients will say that they have symptoms after having an ileal pouch-anal anastomosis, symptoms of pouchitis. The lifetime prevalence can be pretty high.

What we're really looking in this study, what made it a little bit different, is that we wanted to look not just at a single center or a single population but using administrative claims to look over the entire United States population that undergo surgery in a period of time, to look at the incidence within the first 2 years. When we looked at that, we found that the incidence of pouchitis in the first 2 years was 48%, coming close to what we've traditionally estimated, which was 40% in the first year after the surgery.

GLN:  What do we know about the causes of these pouch complications?

Dr. Barnes:  Unfortunately, not as much as we would like to know. We do know that pouchitis — as you might've guessed by those numbers I was quoting you — is the most common long-term complication after this surgery, but we don't really know why this happens.

We don't have a good risk stratification and mechanism to say who's at high risk to develop pouchitis, who is at a low risk to develop pouchitis. There are some things that we know that we can put people into buckets to some degree, but we don't have a lot of actionable risk profile or actionable risk factors.

This is a little bit unfortunate, because we know that the majority of patients that undergo surgery that have a colectomy and they get an ileal pouch-anal anastomosis are doing so because they had medically refractory ulcerative colitis. Then we turn around and they develop an inflammatory condition of the pouch within the first year or a couple of years after they have surgery. This can lead to a significant burden both for the patient and then, as we showed in this paper, potentially for the health care system.

The reason that's a problem, in addition to having the patient's symptoms, is we don't have a way, as I was saying, to risk stratify them. There are some conditions that we know that there's an association, like a concomitant diagnosis of primary sclerosing cholangitis, or having a history of other extraintestinal manifestations of IBD, but those aren't things that you can act on to take away. There are other associations that have been shown, like the use of NSAIDs may increase the risk of pouchitis like we've shown in Crohn's disease and ulcerative colitis. But other than saying to stop using NSAIDs, there's not really a way we can risk stratify people at the time of surgery to then intervene and do things earlier. There's a lot of work to be done to develop better risk profiles in this area.

GLN:  That was going to be my next question. Are there things that the patient and/or the physician can do prior to the IPAA surgery to reduce the risk of pouchitis? And it sounds like your answer is not very much.

Dr. Barnes:  There's not a lot that can be done right now, but there's a lot of groups that are actively working in this area. I think this is probably one of the things that probably most needs to be done in this particular area of patient care and this area of research.

There were some earlier studies that looked at primary prophylaxis to try to prevent pouchitis. For instance, there was a particular probiotic that was studied as VSL#3 and now has been marketed in other formulations as well, but that particular probiotic showed as primary prophylaxis, perhaps, that would work.

There have been other things that have been looked at as primary prophylaxis, including antibiotics, as well, but those haven't moved forward in broader scales to show in all other follow-up studies that those would be a strategy that could be implemented on a wide scale to where every single patient that would be undergoing this surgery should get primary prophylaxis.

On the same token, we haven't been able to drill down, as I was mentioning before, who would be the patients that would benefit the most from that. Who were the patients that responded the best to those primary prophylaxis strategies that we should focus in on, and what does that risk profile look like?

There's a lot of research groups, including our own, that are trying to figure that out, and to try to figure out what should the primary prophylaxis strategy be, who would be the most appropriate to get that, and what should that intervention be?

I think that's probably one of the most exciting areas of trying to study this particular condition is that we don't want to treat pouchitis once it occurs, but can we actually prevent pouchitis from occurring, given that we know almost half of the patients are going to develop it within a short order after undergoing the surgery?

GLN:  In your latest paper, you distinguish between isolated acute pouchitis and recurrent pouchitis. Do they present differently, or is it simply a matter of one is an isolated incident and the other is a recurring problem? Are there distinguishing factors among patients that get the isolated incident versus the recurring pouchitis?

Dr. Barnes:  That's a great question. The reason that we labeled that in that particular way in this manuscript was that we were looking at administrative claims. So we had to know how many times the patient got pouchitis, but the corollary to this would be that we know, as I was quoting those numbers about patients that develop pouchitis, we know that there's a percentage of patients that will develop chronic pouchitis over the course of their lifetime. About 20% of patients will develop chronic pouchitis.

The way that we clinically define patients into acute pouchitis or into chronic pouchitis is really dependent in some ways on how your response is to antibiotics at first. Getting to your question, patients will present the same in terms of their symptoms of pouchitis, or what their pouch looks like if we did an endoscopic exam or pouchoscopy. What distinguishes them between being an acute or isolated case of pouchitis, and then being more into a recurrent or a clinical diagnosis of chronic antibiotic-dependent pouchitis, is if they have more than 4 episodes of pouchitis within a year and they're requiring antibiotics, as long as they continue to respond to antibiotics, they fall into this category of chronic antibiotic-dependent pouchitis. If they stop responding to antibiotics, they move into a category of chronic antibiotic-refractory pouchitis.

In this particular study, we didn't have a lot of the clinical data we needed to make a diagnosis of chronic antibiotic-dependent pouchitis or chronic antibiotic-refractory pouchitis. But we realized there would be a group of patients that would require multiple different courses of antibiotics and would present multiple times with pouchitis within that first 2-year follow-up period. Our suspicion was that that group of patients would look much different than the patients that got a 1-time course of antibiotics, or had a 1-time diagnosis of pouchitis when we looked at them in administrative claims.

It turns out, they were different. They required more courses of antibiotics, as you might imagine, but they also developed pouchitis in a shorter period of time after surgery than the acute or isolated group did. My suspicion is that that phenotype, that recurrent pouchitis group, is a bit of a corollary to that chronic pouchitis group.

There may be something that's different about them, and going back to our earlier point of our conversation, maybe that's a group that we could go back to more clinical diagnosis and think about, "What's different about them?" and, "How do we intervene on them?" Maybe that's the group we start to intervene on earlier.

GLN:  What's the significance of that 2-year post-surgical cut-off that you used in your surgery? Is that a critical period following IPAA to determine who's going to be likely to have recurrent problems?

Dr. Barnes:  To answer your question, yes. It is a critical period of time, because we showed that up to almost half the patients developed pouchitis within that period of time.

But the reason that we chose a 2-year cutoff in this particular study was logistics. We have not been able to study pouchitis using administrative claims until this particular study. This has not been an area that's been well-utilized using administrative claims. Administrative claims have been well-utilized to look at efficacy of therapy, comparative efficacy in Crohn's disease and ulcerative colitis, safety of therapy, and longitudinal studies as well, but we haven't used this to study pouch-related outcomes.

In the past couple of years, we've developed an algorithm to do case-finding definitions for patients with pouchitis. Not just use an ICD-9 or ICD-10 code for pouchitis, but building on the fact that that code's not used all the time to find patients with pouchitis, but using not only that code, but also a couple of different classifications as well to better find these patients.

By using that algorithm or that case-finding definition, we were able to better find patients with pouchitis, which unlocked our ability to use administrative claims in this study.

Getting to your question about why we used a 2-year cutoff, in the United States, patients change insurance a lot of times. There's something called administrative churn or administrative claims churn. The longer we've tried to follow up a patient, we'd lose patients over time when you're looking at administrative claims. So that two-year window was a nice place where, based on prior studies, you don't lose as many patients due to administrative churn or loss to follow-up in administrative claims, and you keep a tight window.

And also, it's a clinically important window, because if half the patients are going to develop a pouchitis during that first year or first 2 years of time, that gives us some clinically important information as well without having loss to follow-up if we have an open-ended window that happens with administrative claims.

GLN:  What did you find out about the impact of the chronic or recurrent pouchitis on patients?

Dr. Barnes:  As I mentioned earlier, I think this is probably a group that's a little bit different. Without having a lot of the clinical data, because we are dealing essentially with what comes down to billing codes and what comes down to billing data, we don't have a lot of that clinical information.

But looking at the fact that these patients developed pouchitis earlier that they ended up having higher rates of emergency department use and outpatient clinic visits, this is probably a sicker group. Knowing that there's this group of patients that are going to develop recurrent pouchitis that is a corollary, as I said before, to that 20% of patients that develop chronic pouchitis, that confirms that there's a group of patients that undergo this surgery that may be set up to develop problems even very early in the process.

And so if anything, this should, in my mind, motivate us to go back to figure out if there's a different risk stratification, if there's a risk profile about who those patients are in our own clinic populations, in our own more granular populations, where we know, where we're looking at stool profiles or looking at our own clinical information. Where we have a lot more information in our own centers than administrative claims to look at who those patients are, and that should motivate us, because it looks, at least, based on these data that this may be a sicker population than the patients that had one isolated episode of pouchitis in the first 2 years.

GLN:  You also mentioned that about 9% of patients with the recurrent pouchitis are diagnosed with Crohn's disease after IPAA. What exactly does that mean?

Dr. Barnes:  Thank you for phrasing it the way that we did as well, because that's a little bit of a confusing term. The reason we phrase it that way comes back also to this idea of the fact that we had to use administrative claims for this particular study.

This also is representative of patients that had a preoperative diagnosis of ulcerative colitis, but then at some point, during that 2 years after they had surgery, they had 3 different ICD codes, 3 different billing codes for a diagnosis of Crohn's disease. It looks like their doctors, after they had surgery, changed their diagnosis to Crohn's disease.

Why this is important is because we know, even though this is a very heterogeneous group, diagnostic terms have been used for this, or terms have been used for this condition. There's a diagnosis that we use of Crohn's disease of the pouch or Crohn's-like disease of the pouch. You may see it also described as Crohn's disease after IPAA, or Crohn's-like disease affecting the pouch. There's a bunch of different terms, but this occurs approximately 105 of the time.

That 10% number that I'm giving you, which is different from the 9% that we found in the administrative claims, this was from a systematic review and meta-analysis that we did a couple of years ago looking at all the studies that had looked at single-center or multicenter populations where they published their diagnostic algorithm, what they used to make that diagnosis, and then what their incidence rate was.

This 9% that we found was pretty similar to that 10% for the Crohn's-like disease of the pouch, or Crohn's disease of the pouch. Because we were using the billing coding in Crohn's disease after IPAA, we didn't know what diagnostic criteria were used to make that change in diagnosis from a preoperative diagnosis of ulcerative colitis to a postoperative diagnosis of Crohn's disease or that change after they had an IPAA, we were very specific about how we phrased that based on those ICD coding because we know that this is a very diverse or heterogeneous area, and one that we're actively working to use more standardized diagnostic criteria.

GLN:  Why is it called Crohn's disease of the pouch? What characteristics of the pouchitis put it more in the category of Crohn's versus ulcerative colitis?

Dr. Barnes:  That's a great question. One of the most distinguishing factors when we think about this is, to stay in the pouchitis realm, most patients, either they have acute pouchitis or chronic pouchitis, any of those conditions are affecting inflammation in the pouch body itself.

The 3 distinguishing factors that were most common when we did this systematic review and meta-analysis, and one that we've worked towards standardizing in other projects that we're currently working on, focused on things that didn't fall into that inflammation of the pouch. They looked more like Crohn's disease. That's why it's Crohn's-like disease of the pouch. Those 3 criteria were either inflammation above the level of the pouch or prepouch ileitis. That is inflammation of the afferent limb above the body of the pouch itself. A stricture in the afferent limb, or a stricture somewhere else in the pouch. Not just inflammation, but stricturing disease like you would see in Crohn's disease, or also the presence of a fistula or multiple fistulae.

This needs to be separated because this patient just had surgery. The typical way to say is at least 3 months—some studies have said either 6 or 12 months after surgery—but it needs to be distinguished from a post-surgical complication. So this is not a leak that happened because the patient had some complication right after surgery, but this is a true de novo fistula that developed. This looks more like Crohn's disease, because in ulcerative colitis, it's a mucosal disease. This is not a transmural disease, so patients don't develop fistulae.

The presence of pre-pouch ileitis, or stricture, or a fistula, those are the 3 most common diagnostic criteria that we found and that we've been using for this entity of Crohn's-like diseases of the pouch, or what some people would call Crohn's disease of the pouch.

GLN:  Thank you for explaining that. What are the best ways to treat these patients?

Dr. Barnes:  For the pouchitis population, which is what we focused on in this particular study, the most common antibiotics that will be used, at least as a first course, are ciprofloxacin or metronidazole.

Sometimes, they're used in combination, but either one of those is approved or suggested as a first-line antibiotic for pouchitis. Pouchitis is a bacterial problem. Most patients, the vast majority of patients will respond to one of those antibiotics. If a patient moves into that recurrent or chronic pouchitis realm, a variety of different antibiotics have been used.

There's no algorithm to work through where you have antibiotic 3, 4, 5, 6. You find the antibiotic that the patient responds to, and that's the one that you go with. Sometimes, it requires cycling of antibiotics, because a patient will respond to one for a little while, and then you go to another antibiotic.

Because of that, we looked at the antibiotic use patterns, particularly among the recurrent pouchitis patients in this particular study. As I mentioned before, we found that the recurrent pouchitis patients used a mean of about 9 different antibiotics during that 2-year period of time. There's a lot of antibiotic use when you're treating a pouchitis.

GLN:  Does that in and of itself create problems?

Dr. Barnes:  That is a great question. This is not something that we could look at in this particular study because of the way that the study is designed, but there have been groups that have looked at this. This is an ongoing area of research. There was a nice paper that was published in Gastroenterology last year from the group out of Israel. When they looked at this, there did seem to be some evidence of some genetic changes consistent with bacterial resistance patterns. That didn't change the way that patients necessarily responded clinically to those antibiotics being used to treat for pouchitis. What that does long-term still remains a question.

Whether or not that is a reason that patients may need to cycle antibiotics or maybe that should promote cycling of antibiotics among us as gastroenterologists and to try to prevent those resistance patterns from developing is a great question.

Whether or not this also leads to the development of multidrug-resistant antibiotic organisms or Clostridium difficile infections, things like this, this hasn't really been borne out in the literature to this point.

It's something we're all concerned about, and so we want to use the minimally effective dose of antibiotics, and use the antibiotic that our patient responds to that's the safest and the one that they had to use the least dose of to try to prevent some of these complications.

To date, we have not seen major complications that have been reported, but it's always a concern for us. There are obviously side effects with any type of medication, so we counsel patients about this when we're using the antibiotics, but that's beyond the scope of your question.

GLN:  What key points from your research do you think are of the greatest importance for practicing gastroenterologists who may have patients who've had the IPAA surgery and are developing or have developed either recurrent or isolated pouchitis? What should they take away from this?

Dr. Barnes:  The major takeaways really come down to the fact that as we started the conversation, we thought traditionally, or we still think traditionally, 40% of patients are going to develop pouchitis within the first year. The numbers that we showed here didn't change that, given that 48% of patients developed pouchitis in the first 2 years that we followed them.

What was different about this study is that we showed it in a large population. Basically, it's geographically diverse, it's representative of all commercially insured patients in the United States. This more confirms what we thought about how common pouchitis is among patients undergoing this surgery.

The reason that's important to the practicing gastroenterologist is that this needs to be on our radar even from the very beginning, when patients undergo surgery. Unless the patient has a reason to suspect a postsurgical complication immediately after surgery, pouchitis is probably going to happen at some point. I think this just reinforces that.

Knowing that pouchitis is going to happen, it should be important for us, as gastroenterologists, to counsel patients about this before they go to surgery so that they know what the expectation is. As I mentioned at the very beginning, unfortunately, a lot of patients are going to surgery because they have medically refractory disease. Undergoing colectomy is not necessarily a choice that they can avoid, either because they have dysplasia, or they have colon cancer, or in the vast majority of patients they have medically refractory disease. So this is the treatment of choice for their ulcerative colitis.

Knowing that inflammatory conditions of the pouch can happen after surgery, they should be aware of that, and they should know what the treatment plan is going to be, even at the time that they're going to surgery, at least they've heard this before so that when they develop pouchitis, we can know what we're going to do about it.

Thinking long term and maybe a little bit more pie in the sky, I've harped on this already, but we need to be thinking about how we can better risk stratify people. This should motivate us to think about, should we be doing earlier intervention to try to prevent some of these complications?

As I said before, there's a lot of research groups that are looking at this, both from a research standpoint and from a clinical standpoint. This should motivate us to be excited about trying to find new solutions for our patients.

GLN:  This has been very interesting. We really thank you for your insights today on this subject. And we look forward to talking to you again in the future and see if new research has shed some light on these points you've made.

Dr. Barnes:  Thank you very much. Again, I thank you for the opportunity.