Now, our first speaker is a long-term friend of mine and a professor of medicine and director of the IBD Center and Vanderbilt University Medical Center, leading expert in the world in the in the scalp care management and the diagnosis, especially perianal disease, the ultrasound technique, et cetera. And David Schwartz, the platform is yours. So I'm going to talk to you today about how we use endoscopic ultrasound to really optimize outcomes for our patients with Crohn's perianal fistulas. Those of you who are not doing this, I would encourage you to try to add this to your practice, as I think it's quite easy and will add quite a bit to your care of patients, particularly with Crohn's perianal fistulas. So here are my disclosures. I'm going to talk first about how or why this is important, how we use this for initial assessment, and then spend the most of time really talking about how to use this to monitor to improve outcomes, because this is where I think you can make the most impact on the outcomes for your patients with Crohn's perianal fistulas. So just to set the stage in the background, we know that perianal fistulas for patients with Crohn's disease is very common. About 20 years ago or so, I looked at the Olmstead County population-based database. We found that about a quarter of patients with Crohn's will develop a perianal fistula at some point during their lifetime, most of which presented right around the time of diagnosis or before diagnosis. So you definitely have to have that high level of suspicion when you see someone with a fistula in clinic. A more recent update looking at that cohort in the area of biologic therapy has shown a little bit of a decrease in the incidence of perianal Crohn's disease, and it was hypothesized that that's probably because of the increased use of biologic therapy, and I definitely would support that theory as our patients who started immunomodulated therapy in the initial cohort also had a lower rate of perianal fistulas. We do know, based on the treatment that we use now, the treatment algorithm we use now, that durable fistula healing rates are really quite disappointing. So even though we've gotten a lot better medication options and a better understanding of how to do this, when we look back and see how our patients do with Crohn's perianal fistulas, they do quite poorly. So about 80% of our patients will have a complex fistula, and in those patients, only 37% of patients really had long-term fistula healing. So similar to what we saw, and I'll show you in a second, the data with anti-TNF therapy, if you had a simple fistula, the healing rates were quite a bit better, almost two-thirds or more than two-thirds of people had healing, and the proctectomy or proctocolectomy rate, even though we're using biologic therapy more frequently, has really not changed. It's about one-fifth of our patients will ultimately need a perianal fistula, or we need a proctectomy. So we definitely want to be doing better for these patients. The other thing is that even, it's bad enough that it leads to all these poor outcomes and the morbidity associated with it, but it's a tremendous cost burden for the healthcare system when this goes untreated or suboptimally treated. So this is from a claims database that we looked at about a year ago or so, and you can see that all-cause healthcare costs and GI-related healthcare costs were roughly two to two-and-a-half times higher in patients that had a Crohn's perianal fistula, and that's not just from the pharmacy costs, from the medication costs, it has to do with surgery, hospitalizations, and all the other things that go into care of these patients. So here's what we're talking about. This is obviously a very dramatic presentation of Crohn's perianal fistula. This is a gentleman that has had pneumaturia and had multiple attempts at trying to heal his perianal disease with surgery and isolation and medication in isolation. This is someone I saw before the biologic era, and really before the concept of working very closely with our surgeons was really understood and accepted. So everyone treated this patient in isolation, in a silo, and really we had suboptimal outcomes. But really the most important thing to understand, when you look at that patient's bottom, there is no way even a skilled colorectal surgeon will be able to get an accurate physical exam. There's so much scarring, so much induration, that unless you use some sort of imaging, and I'm going to advocate for EUS, there's really just no way to know exactly where all those fistulas go and to be able to control fistula healing like we want to without an imaging study. When studies have looked at this, a good digital rectal exam or exam under anesthesia by an experienced surgeon had an accuracy of only 62%. And again, that's because like that patient I just showed you, even the world's expert in rectal examination would not be able to accurately assess that. There's just so much damage that had been done in the past. And in our study that we did, which I'll show you in a second, looking at EUS and MRI and surgical exam, EOA missed about 10% of the fistulas. And so what? You'd say, why is it important to know exactly where all those fistulas go? Well, we do know from even in the non-IBD related literature, when a fistula is not appreciated at the time of exam under anesthesia, it leads to a recurrent fistula track almost 100% of the time. So this is a study from St. Mark's and they looked at primarily non-Crohn's related fistulas to see what happened when the surgical evaluation and the MRI disagreed on the perianal anatomy. And what they found was that about half the time when there was that disagreement, the patient developed a new fistula and almost all the time or 100% of the time, the MRI had predicted or had seen that fistula that wasn't recognized at the time of the EOA. So it's really important to get this very accurate evaluation and know where these fistulas are to optimize outcomes. So kind of the key take-home point of this section is the key really to successful management is to establish adequate drainage of all abscesses and to control fistula healing. And because of how the scarring and induration that can be present in imaging modality is key to provide this virtual roadmap in order for the surgeon to achieve this so that we can really optimize outcomes with our medications. Now, I started looking at EUS for this purpose because I was training in EUS and I was also training in IBD and I thought this might be a nice way to sort of marry the two interests of mine. And EUS is really ideally positioned to assess this area of the body. So this is a cartoon representation of the anal canal. You can see the dentate line is here, external sphincter, internal sphincter, and intersphincteric space. We can see all those things on EUS. Here's your EUS probe. You can see the internal sphincter here, external sphincter. This is a little bit more of a heterogeneous external sphincter in a young patient, which is very common. So we're doing this at the time of colonoscopy for our initial assessment of these patients. It's very quick and easy to do and gives you an accurate exam. And later on, we're doing it when we repeat the endoscopy for demonstration of mucosal healing. If the patient had perianal disease, we'll do this as well. Just as we're doing endoscopy, the same concept is present for perianal disease. We want to look for mucosal healing, in this case, fistula healing at the time of our EUS. So what does fistula look like at EUS? Again, just to orient you, this is the EUS probe. It's a radial probe. And this is an internal sphincter. This is an external sphincter. Generally, fistulas will appear as hypoechoic tracts. That hypoechoic echo texture represents the induration, the inflammation that's present in the tract. So this is a quite large fistula tract here. And then you'll see these beads of hypoechoic foci within that hypoechoic area. This is actually air within the fistula tract itself. So here's an EUS that we did on a patient with a perianal fistula, just before I start the video. Here is the ultrasound probe. This is a water-filled balloon, external sphincter, internal sphincter. And you're going to see a fistula tract. This is going to erect a vaginal fistula tract anteriorly, here as I start the video. So we're going to orient it at 12 o'clock. As we come back, this is the very proximal part of the sphincter complex. You can see the fistula tract here. We're going to zoom in on that right now. And you can see as I'm pushing on that tract, we get these little beads of air that I can move within the tract to sort of document the course of it. This is a little more close up. I think you can easily see those beads of air moving within the tract as I push on it. So, 20 or so years ago, we looked before at the different modalities that were available to assess Crohn's perianal fistulas to try to decide which is the most effective and accurate strategy. We took 32 consecutive patients with Crohn's perianal fistulas, and in a blinded trial, all patients underwent EUS, MRI, and an exam under anesthesia. Investigators were blinded to the results of the previous studies. And then at the end of the study, we found that all imaging and surgical modalities for evaluating the Crohn's perianal fistulas were accurate, with accuracies of anywhere from 87 to 91%. And more importantly, and maybe beyond the scope of this talk, when you combine an imaging modality with an exam under anesthesia, utilizing a surgeon that's willing to look at the imaging results to assess all the fistula tracks, you can truly achieve 100% accuracy at determining perianal anatomy. We know that we have a lot of effective tools to treat Crohn's perianal fistulas. Probably the most efficacious one to date are the anti-TNF agents, and you can see the results from the various TNFs that are approved for Crohn's disease. So, Infliximab actually did a documented study looking at the results of Infliximab and Crohn's perianal fistulas. At Ilimumab, Estrolizumab looked at fistula healing as a secondary endpoint, but you can generally see fistula healing rates at either 26 or 52 weeks of about 30 to 40%. So, much better than we had before, but if you think about it, that's still 60 to 70% of our patients that are doing suboptimally, and we really want to do a better job for them. And so that's where I started to look at using imaging to monitor fistula healing and to guide therapy as a way to maybe improve on those outcomes that we were getting in the clinical trials with the anti-TNF agents. I'll just give you a brief patient history to show you why this is important, and this is a real patient I've taken care of in clinic. It's a 45-year-old female with a five-year history of Crohn's disease. She's had a perianal fistula that has drained intermittently for four years, so I'm sure you all have patients like this. They'll come in with intermittent drainage and then the drainage will stop. It might be okay for weeks to months, and they develop new perianal pain until it starts draining again. What's happening is they're probably developing an abscess, and that abscess opens up spontaneously, then they have some relief, and this is a vicious cycle that continues. What we don't want to have happen is with that cycle, we don't want to have more damage occurring to the sphincter complex, which is commonly what's happening. This patient comes back, two-month history of perianal pain and drainage, on infliximab, and does have a little bit of active proctitis. Here's the fistula opening an exam, and here's the corresponding EUS probe again. This is that hypocoic track with the beads and hypercoic foci in the middle showing the air within the lumen. She's very concerned about this. She's frustrated and wants to know how she can break the cycle and get this fistula to close completely once and for all. This is, I think, the ideal candidate to use this approach. Just to show you why, in a cartoon manner, why this is important. If you have this fistula track with an internal opening and an external opening, sometimes these tracks can be quite long. There's purulence and inflammation within the track. Well, your body's natural tendency is to want to close off that internal opening, close off that external opening, because those are not normal connections. When we place someone on therapy, particularly biologic therapy, the healing or closure of these tracks, the openings, occur very rapidly. Typically, we'll see cessation of drainage within six weeks. Unfortunately, that middle part of that track still contains quite a bit of inflammation and quite a bit of purulence. Without CETOM placement, for instance, these patients will get a recurrent abscesses. We use the CETOMs when the surgeon uses the imaging to show them where all those fistulas are as a way to control healing, keep that track open, and prevent it from closing and causing an abscess. Then what we use imaging for after that is to leave that CETOM in until we know that fistula track is healed completely, and then pull the CETOM to make sure they don't get recurrent abscesses or fistula. One last little point before we go into the methodology. Placing CETOMs before starting biologic therapy does help improve outcomes. This is another cost study that I did for a few years back that looked at the benefit of CETOMs before biologic therapy, SPB, or the white bars, as compared to no CETOMs before biologic therapy. Having a CETOM placed before starting biologic therapy reduces the cost of care dramatically and improves outcomes and should be standard of care for patients with complex disease. We also know that one of the ways that we can help improve outcomes when we have a patient where we do imaging and we do show persistent fistula activity, one of the ways that we might sort of use imaging to change therapy and improve outcomes is to try to change the dose of our drugs, particularly in the setting of suboptimal drug levels. This is one study that looked at drug levels, in this case of infliximab, as compared to fistula healing. You can see that the higher the trough level, the higher the rate of fistula healing that occurs. Similarly, in this more recent study, both clinically and on imaging, achieving higher drug levels appears to be associated with better outcomes, both for infliximab and with adalimumab. Okay, so how do we do this in practice? This is my first initial case series that we looked at, this approach to patients, and what we do is, in this case, we studied 21 consecutive patients. I assess all our patients with colonoscopy to look for where the disease is active, particularly in the rectum, because that does affect how we approach the patient, and then we do EOS to document fistula anatomy. We send that patient to a surgeon who uses that information to perform an exam on her anesthesia, do an incision, drainage if needed, and placetons, and then we start the patient on therapy, so immunomodulator therapy with an anti-TNF and an antibiotic, and then what we normally do is continue therapy until the patient notices that the drainage dramatically slows down and becomes purulent or very mildly purulent, and then we bring them back and do an EOS, and what we're looking for, and I'll show you this in some of the slides, are for that hypococca area where there's inflammation to become more heterogeneous, suggesting a reduction in inflammation, and we also want the diameter of the inflammation to shrink dramatically to more closely approximate the diameter of the ceton, and when that happens, I feel confident that we've achieved fistula healing and can safely pull the ceton without fistula recurrence. So in this particular study, again, this is a retrospective case series, we were able to achieve long-term cessation of drainage in about three-quarters of our patients using this methodology, so about a doubling of what you were seeing in some of the clinical trials, and that led to, oh, before I get to that, one of the interesting things is that we found that the median time to cessation of drainage was about 11 weeks, so much longer than typically we would leave cetons in, and so again, using imaging, or if you don't have access to imaging, waiting a little bit longer to pull the ceton is probably a good idea. On EUS, it took us about 21 weeks to get to that evidence of fistula inactivity, so about 10 to 11 weeks after cessation of drainage occurred. So here's one of the patients from the study, and I'll show you how we kind of approach this. So this is the initial evaluation, the probe, water-filled balloon, and here you can see the fistula tract, this is the hypococcal tract with beads of air within the tract, sent him to the surgeon, ceton was placed, started him on therapy, brought him back at week 16, and now you can see that that area is very closely approximating the diameter of the ceton, and the area you're seeing in there is just the air adjacent to the actual ceton itself, so that we pulled the ceton at this exam, and then brought him back at week 30, and now all you can see, I hope you can appreciate that it's very heterogeneous, basically a scar in this location. This was done quite a while ago before we really demonstrated the importance of maintenance therapy with anti-TNF agents, and so we actually used this data, this study, to stop the anti-TNF in this patient, certainly would not do that now, but back then we were doing that, and this patient did not have any fistula recurrence out to about five years or so, and he was lost to follow-up after that. So that led to a very small prospective trial, where we used basically the same methodology, we randomized half the group to use the EOS to guide therapy, the EOS was used to initially assess and document fistula anatomy, and then surgeons used that to place cetons, we used the EOS to determine when the ceton came out, and then periodically throughout the study to reassess fistula healing, and at the end of the study four of our five that got randomized to the EOS group healed, and I'll show you that one patient that didn't in a second, and only one of the five in the control group where the surgeons placed the cetons without imaging guidance and decided when to remove the cetons, only one of those five healed, that's how we standardly practice now, and obviously led to less ideal outcomes. So here's that representative, the one EOS patient that did not do well, so here's the initial evaluation, large fistula tract with air within it, here he is brought back at the week 16 time point, and you can see that things are healing nicely, that area is kind of filling in, and this is the end of the study, you can just see scarring in that location, so this patient did well, sorry I misspoke, this is one of the representative patients that did well on the study, here is the one patient that did not do well, so the initial evaluation, again the EOS probe, anal sphincter, he had an abscess here, so he went for examiner anesthesia, had an incision and drainage, the ceton was placed and came back midpoint of the study, you can see the track, the abscess is healing and getting smaller, and he's clinically doing well, unfortunately between this exam and this exam, the ceton accidentally fell out, and he came back with a large abscess and had to go back for an EUA, so probably would have done well if that hadn't happened, but that's how the cookie crumbles I guess when it comes to the studies, it was an unfortunate event. And then we also did a much larger prospective trial, this time using Adalimumab, the blue dots are those that had EOS intervention, sorry the pink dots are those that had EOS intervention, EOS guidance to monitor fistula healing, the blue ones are ones that had standard of care or the surgical decision on when to remove cetons or change therapy, and you can see at the six-month mark, those that got randomized to the EOS arm had a much lower fistula healing rate, 78% versus 27% in those in the control arm. So in conclusion, accurate assessment of perianal anatomy is the key to optimizing medications and outcomes. I think hopefully I've shown you the benefit of EOS as a very useful tool for that initial assessment, and more importantly, really monitoring perianal disease activity and helping guide you in determining not only when to remove cetons, but whether or not you need to escalate therapy because of suboptimal outcomes, and using EOS guidance may improve outcomes for your patients with Crohn's perianal fistulas. So thank you very much again, and thank you Bo and Uday, I really appreciate the opportunity to present today.

endoscopic ultrasound

Crohn's perianal fistulas

IBD Center

Vanderbilt University Medical Center

fistula anatomy

monitoring healing