IBD Drive Time: Florian Rieder, MD, on Stricturing and Penetrating Crohn's Disease

Host Raymond Cross, MD, welcomes back Dr Florian Rieder, an internationally recognized expert in penetrating and stricturing complications of Crohn's disease, to talk about diagnosing, performing endoscopy, and treating this challenging phenotype with medication, dilation, and surgery. 

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. Florian Rieder, MD, is vice chair and cosection director for inflammatory bowel diseases in the Division of Gastroenterology, Hepatology, and Nutrition at Cleveland Clinic.

• Accurate definition and imaging interpretation are essential for therapeutic decision-making.
• Operator experience, endoscope type (pediatric vs adult), and radiologist expertise significantly influence diagnosis accuracy.
• Biologics, balloon dilation for short (<5 cm) strictures, and surgery should be tailored to phenotype to yield optimal outcomes.
• Follow algorithms for moderate-to-severe luminal Crohn’s when choosing medical therapy. 
• Future direction: Integration of antifibrotic therapies and AI-based fibrosis imaging promises to redefine treatment paradigms for stricturing Crohn’s disease.

Welcome everyone to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center in Baltimore. I'm delighted to have my friend and colleague, Flo Rieder from Cleveland Clinic as a return guest to talk about stricturing Crohn's. Flo, welcome to IBD Drive Time, or I should say, welcome back.

Dr Rieder:  Thank you, Ray, and I'm honored to be back.

Dr Cross:  So Flo, we know that the majority of our patients with Crohn's are going to develop either an internal penetrating or a structuring complication in their lifetime. And I just want to focus on strictures because I think the penetrating conversation is a different conversation, but how do you define a stricture endoscopically or radiographically? That may be a simple question, but let's start there.

Dr Rieder: Yeah, it's a very good question. In fact, not as simple as it may seem. The straightforward approach is endoscopy, where a definition for a stricture found entry into both validated scoring systems for Crohn's disease, which is the SES-CD and the CDEIS. And it's defined as a narrowing difficult or impossible to pass with an endoscope. And that is also what we're using in clinical practice for defining endoscopic strictures.

It became a bit more complex when you think about imaging because just a few years ago, there were more than a dozen different definitions on how strictures are on cross-sectional imaging and to harmonize that and allow studying stricture disease, particularly within clinical trials, we formed a global interest group that created criteria and definitions for stricture disease, the so-called CONSTRICT criteria. They're now commonly used and there's 3 components: a thickened wall, a narrow lumen, and then prestricture dilation—and prestricture dilation at least 2.5 centimeters upstream of the stricture.

Dr Cross: That's great, and I think a couple caveats to that, I'll see if you agree. One is, I interact with fellows as you do, and I remind them the importance of reducing the loop. When you get to the anastomosis or ileum, when you have a loop, it may appear that you're not able to get through the stricture, but often that can be because you're looping as well. The other thing is, as we mature as endoscopists, some of us choose the adult scope as opposed to the peds scope, and obviously the diameters of the scope are different. So failure to traverse with a pediatric scope is different than failure to traverse with the adult scope. And then the last point is that we are lucky we have expert radiologists that we get to work with. All radiologists are not created equal. So sometimes when you really want to know what's present, getting that reviewed with your local radiologist with interest and expertise in abdominal imaging and IBD is important.

Dr Rieder: 100% yes to all 3 points. And actually, the first point is important, is the expertise of the operator. And that has been shown in the data on reliability of the endoscopic narrowing subscore of the SES-CD. And the reliability to your point is, in fact, low compared to all the other items in the score, which suggests exactly what you outlined.

So experience is important and the stricture may not be passable for other reasons than this being a stricture. And then the radiologist's expertise is in fact critical and then the type of scope, the definitions say pediatric or adult endoscope cannot pass, but you're right in that not only in diameter they are different, but also in probably the technical aspects that may make it more or less difficult to pass a stricture.

Dr Cross: I think you've taught me this. And I just want to make sure I'm thinking about this correctly. Whether we're talking about intestinal ultrasound, CT enterography, MR enterography, as far as ability to detect stricture, they're essentially the same.

Dr Rieder: So they're essentially the same in accuracy if you have strictures in the terminal ileum, which is about 80% or so of the strictures. And if you have strictures in the mid-small bowel, the sensitivity of ultrasound is a bit lower. And I think operator dependence then becomes more important. But anything terminal ileum, very comparable accuracies between the 3.

Dr Cross: Great. When we think about phenotyping our patients, we talk about location, we talk about age of onset, but we also talk about the behavior. Typically, it's nonstricturing, nonpenetrating, or inflammatory stricturing and penetrating. That's for the classic 3, but it seems like over the last decade or so, there's an emerging phenotype that is called stricturing and penetrating. Can you explain that to the listeners and do you use that in clinical practice?

Dr Rieder: So I'm really happy actually you're asking me this question because this is based on what we call the Montreal classification that is believed to be a unidirectional path from inflammatory to stricturing to penetrating disease. What turns out is that penetrating disease is a heterogeneous group. If you have internal penetrating disease, in about 85% of the cases—our radiologists say in 100% of the cases— but in most instances you do have a stricture associated with the penetrating disease. So internal penetrating disease alone in the absence of a stricture is extremely rare. And with our study group we find these patients, even in a very large center like ours, very tough to identify. And then a second observation, and maybe you hinted at that, is we rarely see this progression from strictures to penetrating. So even if we follow our established stricture patients, for them to develop then later on internal penetrating disease is a very low percentage, much lower than I anticipated. But when we diagnose internal penetrating disease, it comes with a stricture. So in other words, what may morph in the future is that there are different phenotypes within the penetrating category, one that develops together, stricture and fistula, one that develop stricture only or stricture first and then internal penetrating. And I think that we need to learn a lot more about that.

Dr Cross: In clinical practice, I think I'm more simple-minded. I just do the 3 categories because to me, if you have a fistula or abscess, I still view that patient as our sickest subgroup of patient. But it is interesting how we're developing these emerging phenotypes. And I think you and I would agree there's probably 30 or 40 different phenotypes of Crohn's and how disease behaves and I'm sure in some day we're going to have molecular phenotypes and other things that are going to find them even better.

I'm a little older than you and when I was in training when we saw a stricture in a patient with Crohn's we categorized them as inflammatory or fibrotic and the way we figured this out was very, very advanced—we gave patients prednisone, and if they got better, it was inflammatory, if they didn't get better, it was fibrotic. But we know that that's not true in the vast majority of cases. In fact, most strictures are mixed with inflammation and fibrosis. So the question for you is, can we look at a stricture and either radiographically or endoscopically determine if there is enough inflammation there that it may be reversible. So what tools do you use to help determine that?

Dr Rieder: I am getting up there in age also, Ray. So this was also part of my training still, that there is an inflammatory structure and a fibrotic structure. But in reality, and I agree with you, and this is what is confirmed in resection studies, inflammation and fibrosis correlate. So they essentially always, close to always, coexist with one another. So how do you separate the two? In an imaging, we are quite good in detecting the presence and degree of inflammation and the features are the classical features for luminal inflammation, and nonstricturing disease inflammation on cross-sectional imaging. So enhancement of the wall, change in the stratification of the layers, wall thickness, and engorgement of the vasa recta as the 4 probably most prominent ones.

We are not good in detecting fibrosis or irreversible strictures on cross-sectional imaging and in fact on routine imaging we cannot. And our radiologists, who I think are among the best in the world, some of them used to say, this is a fibrotic stricture. Patient has to go to surgery. And we put it to the test and, in fact, blinded them towards what type of histology a patient had on a stricture that got resected and pulled the image prior to resection and asked them, what's the degree of fibrosis and what's the degree of inflammation? And the area under the curve for fibrosis was 0.5, which for all the listeners means it's a flip of a coin. So they are not able to determine how much fibrosis is in a stricture. And that's not because they're not good radiologists. That is because the techniques we have are not developed to show that. And there's a large area of interest. There are a lot of projects ongoing using AI, using certain contrast enhancement patterns, new MR techniques, for instance, or ultrasound techniques to detect the degree of fibrosis, but this is still ongoing.

Dr Cross: In my practice, if I see significant prestenotic dilation, whether it's 25 millimeters, 30 millimeters, whatever it is, I tend to think that there's an irreversible component of fibrosis there. Do you think that's generally correct?

Dr Rieder:  Yeah, it's also a very good comment and I want to get back to one point you made earlier about the steroid test. I actually agree with you. I think this is clinically a very clever way to determine the inflammatory component because steroids are very effective to suppress inflammation quite fast. And so if the patient doesn't respond to corticosteroids, you can assume there's a high fibrotic component, if you will, like a functional test. So I really liked your comment that you made earlier.

The comment about prestricture dilation is I do think we may be surprised how flexible prestricture dilation is because it's considered sort of an irreversible dilation of the bowel, suggesting fibrosis in the stricture. And it may be, but again, in evolving data from our consortium, we find that prestenotic dilation can completely regress and in the STENOVA study, which has the interim data presented last DDW, using an enterofibrotic stricturing disease, we see quite robust changes in the degree of prestenotic dilation. But for the time being, I agree with you that prestenotic dilation signifies more severe strictures. And if you have significant, like massive prestimulation, 5 centimeters, 6 centimeters, these patients in my book go to surgery. But this also may evolve in the future conceptually.

Dr Cross: I just want to remind our listeners that we are sponsored by the AIBD Network. And we're available on Spotify and Apple podcast, so you can find IBD Drive Time there. I also want to remind the listeners that the most fun meeting of the year —maybe ECCO rivals this—the annual AIBD meeting in Orlando, December 8th to December 10th.

Just I want to come back a little bit to Flo.

Two things, one is you know really you've made it in the IBD world when you can be recognized by your first name, so Flo, everyone knows who he is, and I really don't think I gave him enough credit. I think Flo is probably the world's expert on stricturing Crohn's, so we're really glad he's here today to talk to us about this important issue.

Let's transition to medical treatment, Flo. So you see a patient with a stricture, let's say there's, looks like having an inflammation on imaging, how do you approach giving that patient medication versus surgery? And when you do give an advanced therapy, is there a specific advanced therapy that's best for stricturing Crohn’s?

Dr Rieder:  So this is a pertinent clinical question. So from a perspective of choice of medical therapies, from all we know, we follow the algorithms and approaches that we use for patient choice of medication in luminal Crohn's disease, moderate to severe luminal Crohn's disease. And this is true when it comes to biologics. Do we use combination therapies and how to sequence therapies? It's actually quite comparable. And this is based on a data that we know anti-TNF likely works, anti-IL-23 likely works, upadacitinib likely works. We, our own group, generate data on vedolizumab, which likely works. And the choices, then, are very comparable.

How do you decide between surgery and medical therapy or balloon dilation is a very interesting topic. So any patient that has dysplasia, malignancy, goes to surgery, any patient that has associated abscess, phlegmon, fistula, fluid collections, I have a low threshold to send to surgery because if fistula is associated with a downstream stricture, they, in my experience, long -term don't go away. So you may have some success with the biologic, the fistula may look better for some time. But long term, I'm not sure if you do the patient a favor by putting them on a biologic or another biologic in that instance, rather than having surgery and starting fresh.

The data overall on medical therapy is quite limited in that space. We have cohort level data in one randomized controlled study on anti-TNF. The rest is all post hoc analysis from randomized controlled trials. But we have a global consensus that we ran in our consortium that was published last year that separately interrogated naive and anastomotic strictures, symptomatic, nonsymptomatic strictures, TNF-exposed to TNF-naive patients. And the outcome was what I started my answer with, is that the approaches at the moment are very comparable to moderate to severe luminal Crohn's disease and what the global experts feel is the right medication choice.

Dr Cross: I think that you and I practice very similarly. I think the one thing for the listeners is given the results of the LIRIC trial, which was not stricturing disease. It was inflammatory, limited, ileal disease where the outcomes with surgery are quite good. I think it is our responsibility to offer patients a surgical approach to a stricture, assuming you have surgeons in your institution or area that are willing to operate on a patient who's not in extremis with a stricture, because sometimes that's not the case where our listeners may practice.

The other thing is I'll tell a patient up front we're going to give you one good trial of an advanced therapy, optimize it if it's available to be optimized, give it a good 6 months as long as you're not going backwards, but at the end of that 6 months if we haven't achieved the outcome we want I think you should move on the surgery because looking at a 6-month window, a 12-month window, that may be great but when I'm seeing patients in the office, I'm thinking about 5 years and 10 years down the line and many times to get your most durable precious remission that happens with a surgical reset and then coming up with a monitoring plan, which may or may not include being on therapy, by the way, because a very good number, 50% or so patients, do well without therapy after surgery. So do you agree with that, Flo?

Dr Rieder: I completely agree. So the scenarios I mentioned are a rather clear indication for surgery for me; in the remaining pool, your approach is exactly what I practice for me. You offer patient surgery; if they're too advanced, too far gone, we call it, with tissue damage, biologics tend to work less in this patient population, But you can give it a try, and if it does work, you can maintain them on it. But you do not always do your patients a favor by "sparing them from surgery" because ultimately, they then may go into an inevitable surgery later in poorer condition and even more advanced.

But there are examples, if you do not have the associated features I mentioned —patients obstructed, doesn't really respond to anti-inflammatory therapy early—they go to surgery. And then we have the option of endoscopic balloon dilation. And for this, the stricture would need to be in reach of endoscopy. And so in the terminal Ileum, we usually do not dilate longer than 5-centimeter strictures. It is possible, but data shows that the risk for surgical intervention in the future goes up after if longer than 5 centimeters and with every centimeter increase, in fact. But this is an option also long -term, so you can serially dilate patients. But I completely agree with your management approach.

Dr Cross: So I want to make sure you agree with the second thing I'm going to say. The first thing for the listeners is, I think it should become your routine when you consent a patient with Crohn's disease for an endoscopy, you mentioned the possibility of balloon dilation because the complication rate with the stricture dilation universally is about 2 to 3%. It's mostly bleeding as opposed to perforation with balloons. But I'm a person who, if I see a stricture, I want to dilate it to get above it to see what's happening. It may prevent complications in the future, but that's now part of my practice where every Crohn's patient, even if I'm not suspecting it, I bring it up.

The other thing, this is what I want to see if you agree with, Flo, is I find that balloon dilations are the rule of thirds. A third of patients, you dilate them, you get them to 18, they do great. You don't need to dilate them for a long time— maybe not never, but you get a long period of time where they're well. There's a third of patients that doesn't work at all. They go to surgery. And then there's a third that respond, but they seem to be, they seem to need regular balloon dilations to stay open. Do you think that that's true?

Dr Rieder: I think that's true. And it's actually also supported by the observational data that was generated, where after one year, a third of the patients go to surgery, half of the patients need redilation and 50% of the patients are just fine. And I think these were probably the long-term 30% because obviously the time-dependent variable, but the long-term 30% do really well and then you have the patients that you redilate and the patients that go to surgery. So I agree with you, and it's also supported by data. And it is a safe procedure.

One item, Ray, that I would be interested in your opinion, is asymptomatic stricturing disease, and do we dilate it? And we do find more asymptomatic strictures than we initially anticipated. And then in the European setting, I think there's a lower threshold to dilate, whereas in the US, being afraid of litigation, if there's a complication and get asked, why did you dilate, patient is asymptomatic, I think the jury is still out there if we should do that or not. But if the patient is interested in having this dilated, then I think it's important to have a very thorough documented consent about risks and benefits of the procedure and for the patient to agree to it.

But how do you handle asymptomatic strictures in terms of dilation?

Dr Cross:  Well, I'm a believer in dilating them because I feel very comfortable with my expertise of being able to do it, not that I don't have complications. And I feel like my analogy is if we identify a triple A, we don't wait for the triple A to rupture before repairing it. So why would we wait for someone to get obstructive-type symptoms? And that's why I discuss with patients before the procedure because if they say, you know what, that sounds too risky for me, if you find that just take a picture and then we'll determine what we're going to do later— completely fine. But I agree. I think particularly in the US it's more controversial But I personally believe that you should dilate an asymptomatic structure because it will become symptomatic at some point in the future and you have an opportunity with a prepped, sedated patient to do it right then and there.

So I think, Flo, this is where it's getting really exciting because we have some novel therapies available potentially for stricturing Crohn's. Can you give the listeners like a quick synopsis of what maybe is in the near future for us?

Dr Rieder: Yeah, indeed exciting times Ray. We have 2 antifibrotics in clinical development and in fact being tested in either healthy volunteers or patients with stricturing disease. And one drug is what's called a soft ROCK inhibitor. ROCK is in the profile product kinase that has been known for decades, but we could not target it because of systemic side effects and we now have a compound that acts locally in the gut, but gets degraded so fast that it does not reach the circulation. And if it does reach the circulation, it gets immediately degraded there. And this has been tested in healthy volunteers, it's a safe drug and the target is engaged and that it is moving forward to patients.

And most exciting were the recent news from DDW, where we have an anti-TGF-beta drug, it's called an ALK5 inhibitor, it's a receptor kinase to the TGF-beta receptor that shows in preliminary observations, improvement of stricture morphology, prestricture dilation, and passability of the scope, just after 12 weeks, even though the patient number still is low, as 44 patients. But the floodgates are starting to open, and I think we will see a lot of novel antifibrotics coming in the next few years.

Dr Cross: About the anti-TL1A is there's a thought that they're both anti-inflammatory and antifibrotic. What are your thoughts on that?

Dr Rieder: Yeah, so there is preclinical data with animal models that blocking TL1A has antifibrotic effect and may directly act on fibroblasts. So there is a rationale for believing that TL1A is a profibrotic cytokine and blocking it may help stricturing disease. We have to wait for human preclinical data to a higher extent, and then particularly for clinical trials in patients with stricturing disease, because the evidence we can collect in the luminal registration programs that are currently ongoing in relation to fibrosis will be largely circumstantial.

Dr Cross: Yeah, and I think one of the challenges is sometimes the fibrotic signal doesn't shut down and I think over time a patient initially responds to therapy and then they stricture and I wonder if the anti-TL1A's alone or in combination with other therapies may prevent that, but you're going to be the follow patients for years to see that and likewise the submucosal fibrosis we see in UC where patients have significant urgency and increased frequency them with control of their mucosal inflammation you sort of wonder would that remodeling be different with a TL1A but we're it's going to take a long time for us to uncover that.

The last thing I'll mention before the fun question is we're also studying a paclitaxel-encoded balloon to see if balloon dilation would be more effective and we're enrolling in our center for that it's exciting so hopefully that'll be another advance in our mechanical disruption of structure.

So Flo, did you always want to be a doctor from the time you can remember? If so, what was the driver in that? And if not, what did you want to be before you decided to be a doctor?

Dr Rieder: So I did want to be a doctor for the longest time, but the alternative to being a gastroenterologist within the medical specialties is to be a pathologist. I'm very visual and I love drawing so the alternative job option that I was thinking about is becoming a medical artist. And we have the fortunate situation here at the Cleveland Clinic that we have a whole department of medical artists so I work a lot with them for creating presentations and illustrations for book chapters. It's an amazing creative job. So that would have been my alternative choice.

Dr Rieder: I did not know that. And the theme from our guests is a lot of people have musical backgrounds where they're interested in instruments, playing instruments or singing, but clearly including drawing is artistic. Many of our guests have an artistic background our interest as well. So Flo, that's very interesting.

This has been great. Thanks for being on and we hope to have you back soon.

Dr Rieder: Thank you, Ray. It was a pleasure again. Nice to see you.