IBD Drive Time: Miguel Regueiro, MD, on Post-Operative Crohn Disease

In this episode of IBD Drive Time, hosts Raymond Cross, MD, and Millie Long, MD, talk to Miguel Requeiro, MD, about the care of patients with Crohn disease following surgical treatment.

Miguel Regueiro, MD, is chair of the Division of Digestive Disease and Surgery and chair of the Division of Gastroenterology and Hepatology at the Cleveland Clinic. Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine. Millie Long, MD, is an associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill.

TRANSCRIPT:

Raymond Cross:  Welcome, everyone, to "IBD Drive Time." I'm Raymond Cross from the University of Maryland, and I'd like to introduce my colleague, Millie Long, from the University of North Carolina.

Today I'm delighted to have my good friend, Miguel Regueiro, who's going to talk to us about postoperative Crohn's. Miguel is chair of the Division of Gastroenterology and Hepatology, and chair of the Digestive Disease & Surgery Institute at Cleveland Clinic.

Miguel will correct me if I'm wrong, but he is the first nonsurgeon to hold the latter position at Cleveland Clinic. He's widely regarded as an innovator in management of postoperative Crohn's disease, as well as alternative care models like the IBD Medical Home.

Miguel is a master clinician, educator, researcher, and administrator. Additionally, I know he has for me, but for many others as well, he's served as an external mentor to countless number of junior and senior faculty. He's always the calm voice in the storm, and one of the best IBD speakers in the world. Miguel, welcome to IBD Drive Time.

Miguel Regueiro:  Ray and Millie, thank you very much for that incredibly kind introduction. I do appreciate it. You are correct. I'm humbled by being the first nonsurgeon to hold the chair position at Cleveland Clinic.

Raymond:  All right, Miguel, let's dive right in. For the trainees on the call, perhaps, and maybe the younger faculty, can you briefly summarize the natural history of postop Crohn's, particularly in the prebiologic era?

Miguel:  The natural history of postop Crohn's has been such in the prebiologic era where the majority of patients at some point would require another surgery. Prior to that point, the patients had symptomatic recurrence that by about 3 to 5 years after surgery, 50% to 60% of the patients would feel their recurrence. They would have symptomatic recurrence.

If you back up a step further, we now learned and it was primarily from — and may he rest in peace — Paul Rutgeerts, to define postop Crohn's endoscopically, up to 90% of the patients that have an endoscopic recurrence at 1 year but was usually clinically silent. They did not feel their disease.

Raymond:  Surgery, unfortunately, is not a cure for Crohn's, Miguel?

Miguel:  That is correct, Ray. Contrary to prior beliefs and discussions, it is true surgery is not a cure for Crohn's.

Raymond:  On the flip side, there are a fair number of patients who do very well after 1-time resection and don't have a surgical recurrence, so it does benefit a big subgroup of patients.

Miguel:  Absolutely. Surgery is not a failure either. We need to recognize. Sometimes we hold on or hold out for surgery too long, so the patient's losing weight, they have a complication, a stricture, an obstruction, an internal abscess, fistula. These are patients that need surgery.

To your point, Ray, there are some patients who have low risk factors, and maybe we'll get to that in a minute, for recurrence that do quite well with a single surgery and their disease progresses so slowly that they probably don't need a whole lot of treatment after that surgery.

Raymond:  You talked about endoscopy, Miguel, and most patients are going to have endoscopic recurrence within a year. How does the endoscopic appearance help you prognosticate patients that are either on therapy or not on therapy?

Miguel:  There's a scoring system, again, by Paul Rutgeerts, that was 0 to 4, and it's a pretty simple scoring system. Most gastroenterologists are used to this. We like it because it's easy.

Just to briefly define it, a 0 or a 1 is what we would consider remission, although it's not validated to define remission. It's more, to your point, to define progression towards another surgery or clinical recurrence. A 0 is no ulcerations, no inflammation at the anastomosis or above the anastomosis. Ideally, 10 centimeters of the neoterminal ileum is inspected above the anastomosis.

A 1 is less than 5 aphthous ulcers or erosions in that same segment. Then a 2, 3, and 4 are just more progressive inflammation. More than 5 ulcers are 2, deeper ulcers and inflammation are 3, and then ulcers but more narrowing nodularity complications is a 4.

Just to simply put, a patient who has a 3 or 4, that moderate to severe recurrence, is more likely not only to have clinical recurrence symptoms but also surgical recurrence requiring surgery.

Raymond:  Great. I've asked you this before over a glass of wine but in looking at various endoscopy reports, aphthous ulcers mean one thing to one provider and another thing to another provider. How do you define an aphthous ulcers? What's an aphthous ulcer, and what would be a larger ulcer?

Miguel:  We could probably spend an entire conference defining that because I don't think any of us really know. It's such a simple term and we think we know it when we see it, but it has a lot of interobserver variability. When you look at postop endoscopy or any endoscopy videos, there's a lot of discrepancy.

To simply put it, maybe for more of the trainees, the way I define it is there has to be a mucosal break. If you take the biopsy forceps, which is about 3 to 4 millimeters depending on the forceps size, and you actually look at the size of the forceps itself, and if you open the forceps and you have an ulceration that's about that size and there is depth to it, so it's not just the superficial redness, there's a depth and a mucosal break, that would be the best way to define an aphthous ulcer.

Raymond:  That's exactly what I remember you telling me. You taught me well over that glass of wine, Miguel. What about the anastomotic ring? There's a lot of controversy over, you do an endoscopy, the neoterminal ileum looks good, and you see this ring along the anastomotic line where it's eroded, incredibly friable, you just feel like you puff some air on it, it bleeds.

Is that recurrent Crohn's, is that ischemia, is that modifiable to medical treatment? What do you do with those patients, Miguel? It's a 3-part question.

Miguel:  Historically, we thought that anastomotic ring was ischemia. All of us said, "It's just surgical changes. It's from the suturing or the stapling. It's just an ischemic change." We've evolved our thinking and understanding, and that now is defined as a recurrence of Crohn's. Because many of our patients who don't have Crohn's—so cancer, surgery, familial adenomatous polyposis, other reasons for similar resections to what we do in Crohn's—don't get these anastomotic inflammatory rings.

However — and the Europeans have led the way in modifying the Rutgeerts score to i2a and i2b — simply put, if you think of i2a, A for anastomosis, that's that ring you're talking about, Ray, where you see these alterations along the anastomosis. An i2b, an inflammation at the anastomosis, but extending into the ileum.

The real difference is, and Ray, to answer your question -- and our group's going to present this actually at ACG, and other groups have shown the same thing -- if it's just confined to the anastomosis itself, the likelihood of progression is much lower and probably into itself does not require additional treatment. Except we should monitor that patient. Often, they stricture. Those will actually stricture. Very satisfyingly, we can put a balloon in when there's strictures. Those anastomotic rings do quite, quite well.

Then just not complicated further, this is my editorial comment, I always think we need a scoring system with i2a+ and i2a. What I mean by that is, there are i2a anastomotic changes that are really Crohn's disease and others that are very mild. I think we're still learning, but to simply answer your question, that is Crohn's. If it's just there alone, probably the progression rate is not as high.

Raymond:  You would bring him back in a year and look at him again and see if it's progressing or something like that?

Miguel:  I would definitely, yes, to answer your question, I'll bring them back in a year.

Raymond:  Just a follow-up question, do biopsies help you at all there to distinguish that?

Miguel:  No. We all do it, but often it will show in acute and chronic inflammatory changes, but it doesn't distinguish if you're asking ischemia versus not. I think it's Crohn's, and the biopsies will just show inflammation.

Raymond:  Then another thing that we see along the anastomosis, Miguel, typically on the ileal side, is we'll see this little opening and sometimes you think that's the lumen, and it looks inflamed. You try to go in there and you realize it's a little, I call it a dog ear. Almost imagine like a piece of the small bowel gets caught in the stapler, and it has its own false lumen. What is that? Is that related to inflammation from stasis? Is that recurrent Crohn's? How do you classify that and what do you do with that?

Miguel:  There's a whole RAND analysis in groups now looking at defining postop Crohn's, and to your point, I think they're going to be many subsets. To answer your question, the honest answer is I don't know. The answer is that I think it's an anastomotic change that often comes in from the surgical design.

You mentioned a stapled anastomosis or a handsewn, where you almost get this little dog ear, I think is a good way to put it. That in itself is not Crohn's. Now, if that dog ear has inflammation or an ulceration, that's Crohn's.

The only thing I worry about with those dog ears, and you can see them in side to side and to side, even sometimes the Crohn's or the new anastomosis, you'll see these. If you get a lot of inflammation in one of those, those can leak and those often can create a fistula, or a sinus tract, or an abscess, but into itself, it's just part of the regular surgical change.

Raymond:  Lastly, before I kick it over to Millie, how do you risk-stratify patients after surgery?

Miguel:  The low risk for recurrence is the patient who had their first surgery. Often it's more than 10 years from diagnosis, and they have a stricture or stenosis as their indication for surgery and limited disease. Not 30, 40 centimeters of bowel resection. About 10 centimeters.

That's still a percentage of our patients. That patient has Crohn's, you're right, surgery is not going to cure them, but their progression to recurrent Crohn's postoperatively, that would be meaningful and significant, or will be so slow that depending on their age, you cannot put them on any medical treatment.

High risk for recurrence patients I would consider for advanced therapy postoperatively are those patients who have penetrating complications that are not necessarily due to a stricture or tight area where you're getting penetration above a stricture, but also the most important and the number 1 risk factor for recurrence Crohn's is the number of surgeries.

If you've had a patient with 1 surgery, that might be low risk. Two, 3, 4, or 5 surgeries, the more surgeries, the more likely the risk for recurrence. That's the one that I would say absolutely is advanced therapy postop.

Raymond:  Are smokers high risk or intermediate risk?

Miguel:  Good question. Smoking is a little challenging. Smoking is a risk factor and probably the amount and quantity of smoking matters. It gets more complicated than that because actually some of the larger series, we haven't seen smoking pan out as strongly as a risk factor, but it's probably because these were not the greater than 1-pack-a-day smokers.

Absolutely still, it's the modifiable risk factor. Especially women, it seems to cause more stricture in postop Crohn's and we absolutely should tell our patients to quit. It's a difficult question to answer in terms of the grade of risk.

Millie Long:  That was great. I have already learned so much and look forward to a few more questions for Miguel. I do want to take a brief break and remind our listeners that we have a number of wonderful upcoming events that you may be interested in. In particular, Advances in IBD has 2 regional events coming up, September 11 and September 25.

The IBD event of the year, the Advances in IBD Meeting, December 9th to 11th, 2021, in Orlando—we invite you to participate in that where you can hear more from Ray, and Miguel, and myself, and more importantly, countless other wonderful faculty.

I'd like to also thank our sponsor for this IBD Drive Time, the Gastroenterology Learning Network and Advances in IBD. With that, Miguel, let me just ask you a few more questions in regards to that postop state.

First off, one of the things I'm doing in my practice is I'm learning a little bit more about how I like to use fecal cal, and in what way I can use it in my practice. Interestingly, here, it wasn't covered very well by insurance until the last couple of years, so I'm just starting to feel that out.

Let me ask you, is this a useful tool in terms of monitoring postoperative Crohn's disease? What kind of ranges do you use if you do use it in your practice?

Miguel:  I do think fecal cal is useful in a postoperative setting. Michael Kamm, right in the POCER study, looked at fecal cal as a postdoc marker, a biomarker, for recurrent Crohn's disease. Simply put, just to remember, the number is over 150. Seems to be the cut-off by which an over 150 on the fecal cal is significant in terms of inflammation.

Now, a few caveats. There are some patients with postop changes that will create a fecal cal that's elevated and always elevated. If you have a fecal cal especially less than 50, the likelihood of postop recurrence is very low.

50 to 150, to me is a gray zone, where we're not sure if there's really significant inflammation. As you get higher above 150, I think that's a patient that in your strategy should have a colonoscopy. I usually do a fecal cal at about 3 months, and then I will do a colonoscopy at 6 months.

If the fecal cal 3 months comes back high, thousands, 1, I'm worried there's something else going on, but 2, that may be a patient I'm not going to wait 6 months. I might scope them earlier, especially if they have not wanted to be on medical therapy. I would not wait longer and I would use it. I think it is very useful.

Millie:  Great. Active management in that sense. I like that cut-off too. That's helpful. I do want to ask as well, many of us, thanks to you, have known the data about anti-TNFs in terms of postoperative recurrence for some time.

Would you mind summarizing what we know about some of our other so-called newer biologics and where they might fit in in the postop protocol?

Miguel:  We don't have any large randomized controlled study on anything beyond infliximab. Some of the newer advanced therapies—and you could include in this, is ustekinumab, vedolizumab—the other small molecules have not been evaluated yet for postop, so it's really vedolizumab and ustekinumab.

There is a European study with vedolizumab, a randomized controlled study, looking at vedo. We're still waiting for the final results of that. And we have some open-label data with ustekinumab from different centers in postop Crohn's.

Here's the bottom line: my feeling is that when you do a resection and the patient has no inflammatory burden postoperatively, so essentially, they're in that curative state, if you will, for that moment of time, any of the advanced therapies in my mind are going to prevent postop recurrence.

Now I'm saying that without having any data, so if you've had a patient who's been on anti-TNF, can't tolerate, failed, whatever reason, can't be on anti-TNF, I'd be very comfortable, truly, with either ustekinumab or vedolizumab.

Millie:  Great. I practice in the same way and I look forward to seeing some of that data to help provide an evidence basis for what we think may be happening. But I do lean heavily on TNFs. I do think the data are very robust, and I will try to move in that direction for the appropriate patient.

One last question in regards to initiating a biologic postoperatively. A lot of patients are hesitant about, "Well, how long do I need to be on this therapy?" You've had a resection, they've been on a biologic therapy for X amount of time. Do you ever think about withdrawing that therapy, and in what scenarios would you do so?

Miguel:  From our early study -- and I realized that the numbers were extremely small -- but from early study when I was in Pittsburgh, we actually followed these patients up about 8 years, and there were some patients who had recurrent, I should say, were I-0 repeatedly, who stopped their infliximab.

The bottom line is what we've seen in withdrawal studies across the board, about 80% of those patients did actually have a recurrence. As Ray said earlier, surgery is not a cure for Crohn's. Unfortunately, we don't have one yet, so patient who's in remission, especially that high-risk patient we probably need to continue.

Stay tuned. Maybe we'll learn more. The microbiome is probably going to play a role in postop Crohn's. We didn't get into any of that necessarily, but I do think that there may be other modalities in the future. Especially that high-risk patient, I would treat it like a high-risk patient who doesn't have surgery. We're not necessarily recommending stopping therapy based on what we know today.

Millie:  No, absolutely. Even newer data just in the past year or so that showed similarly to the story. That we have a very high rate of recurrence with discontinuation of TNF in a randomized control trial. The writing's on the wall—that if therapy is working, we need to keep them on it.

With that, I'd just like to say thank you. We've hit the end of our IBD Drive Time, but we never let anyone out of here without having them tell us something about themselves that our audience might not know. Sorry to surprise you with this, but give us a tidbit that we all may not know about Miguel Regueiro.

Miguel:  I'm Gallegan. What does that mean?

Millie:  I have no idea.

Miguel:  There's a region in Spain called Galicia, so many of our Spanish colleagues out there. My grandfather came from a small town in the northern part of Spain on the border of Portugal. Although my father's from Argentina, my name is actually Gallegan or Galician, which is a very common name there.

When we've been there in the past, if you go, you'll see “Regueiro” is how they pronounce, we say Regueiro here, but that's very typical. It's like Smith. It's all over the place. I have pictures of my kids when they were little with signs of our last name all over the northern side of Spain. I'm Gallegan.

Millie:  That's very cool. Multi-international. That's fantastic. Thank you again for joining us. For our listeners, please stay tuned. Our next episode of IBD Drive Time will feature Uma Mahadevan talking to us about pregnancy and IBD. Lots of new data there to discuss. Thanks from Ray and me.

Raymond:  Thanks, Miguel.

Miguel:  Thank you.