This transcript has been edited for clarity.
Peter Higgins, MD, PhD: I'm Dr Peter Higgins, professor of gastroenterology and director of the IBD (inflammatory bowel disease) program at the University of Michigan, and chair elect of the Crohn's & Colitis Foundation National Scientific Advisory Committee. Welcome to Medscape's InDiscussion series on Crohn's disease. Today, we'll be discussing the management of Crohn's disease after surgery. First, let me introduce my guest. Dr Michael Chiorean is the co-director of IBD at Swedish Hospital in Seattle, Washington. Dr Chiorean, welcome to InDiscussion.
Michael Chiorean, MD: Good morning, Peter.
Higgins: I'd like to ask each of my guests, what it is about IBD that first drew you to this field?
Chiorean: Thinking back, it was being in the right place at the right time. By that I mean I knew I wanted to work in the GI area for a very long time. In my fellowship at the Mayo Clinic, I happened to work with outstanding mentors, great clinicians like Bill Tremaine, and real giants in this field like Ed Loftus and Bill Sandborn. I knew at that point this was what I wanted to do, and I never looked back.
Higgins: So, Michael, we frequently see patients with Crohn's disease who have high-grade small bowel obstruction that is not responsive to biologic therapy who need a resection or a strictureplasty. We often discuss with the surgeons how to manage medications in the perioperative period and discuss with the patient what to do with their medications after surgery. We know that some patients have a biologic reset and do well for a while, but we frequently have to return them to therapy, often sooner than later. So, we start with the surgical question. A lot of times you get this reset in a honeymoon period after surgery. The LIR!C trial compared surgery with no postop therapy to infliximab in patients with nonstenotic inflammatory ileal Crohn's disease who had pretty similar outcomes at 12 months and reasonable outcomes at 5 years. Do these results make surgery a reasonable first-line option for some patients with ileal Crohn's disease? And what's the risk of recurrence of Crohn's disease per year after surgery?
Chiorean: Absolutely. One of the reasons I'm very happy they did the LIR!C study is because it really put the patient's quality of life into focus. Oftentimes, as clinicians and as gastroenterologists, our onus is on fixing and improving or perhaps healing patients with IBD — and in this case specifically Crohn's disease — with medical treatment. But we forget occasionally this very important goal, which is the patient's prospective quality of life. The reason I like the LIR!C trial so much is because this was their primary endpoint. How do we do when we compare these two strategies for nonstenotic, nonstricturing, nonpenetrating small bowel Crohn's disease? How do patients do a year after intervention with medical vs surgical therapy? Now, do you really send patients with inflammatory disease to surgery without actually trying medical therapy first? Maybe not. But where the LIR!C trial brings a very important point is in terms of quality of life. The patient population we see who represent a good stratum to send to surgery first are those with irreversible structural damage — those with stricturing disease. That's where we need to think back and realize that surgery first, resetting, and then postoperative prevention is probably a very good strategy.
Higgins: It's a reasonable call in the person who presents with stricturing disease, which is probably 20%-30% of patients with Crohn's disease. I find it a little bit harder to take the LIR!C strategy, although I do meet a few patients who've read a lot about all the therapies and feel like they're more comfortable with the surgical risk than the medical therapy risk. It's not a lot of patients, but I've had a few who've been LIR!C-like; they've got inflammatory disease, they've done very well with surgery, and eventually they're going to need medical therapy, but they're very happy to put it off for 3-5 years if that's what they get out of it. They are an interesting group. But after that resection, what's the risk of recurrence per year after surgery, endoscopically vs clinically and symptomatically?
Chiorean: That has been a little bit of a moving target, as you well know. If you look back 20 years ago, we used to quote relatively high numbers, and this is thanks to another giant in the field of IBD, Paul Rutgeerts. We were quoting 80% with endoscopic recurrence and about 50%-60% with clinical recurrence at 1 year. That's perhaps because there was a bit of a selective population. If you really look at the more recent clinical trials, including PREVENT and POCER, those rates may be lower at 10%-20%. I suspect that's because we're talking about people selected from the community rather than from academic centers. Be it as it may, I think the message here is clear. The majority of patients with Crohn's disease who have one surgery will experience disease recurrence. Unfortunately, a substantial plurality, if not a majority, will experience significant disease recurrence, substantial structural damage, complications, and poor quality of life without medical treatment.
Higgins: It's clear the bottom line is that surgery is not curative for Crohn's disease, and it's a matter of time before it comes back. There's a lot of variation, and sometimes the folks we see in academic centers have disease that is much more likely to recur. When you meet somebody and you're trying to decide what to do with them after surgery, how do you risk stratify? Which risk factors matter for more early or more severe recurrence?
Chiorean: As of 2022, we have mostly clinical criteria. I'm hoping that in a few years we'll be more sophisticated in getting some cellular or molecular criteria. But right now, we're going by risk factors — young age at onset; male patients; smokers; folks who have extensive bowel disease or small bowel and colon disease; folks who have penetrating complications, both luminally or fistulas in the small bowel; those who have colon and interloop abscess; and also those with perianal disease. It's been a long time since perianal disease has been shown to be a risk factor in the general long term but specifically postoperatively. I think a very important time is from diagnosis to the first surgery. We have this population of silent killers. We used to call them the James Bond of Crohn's disease because they're very quiet and they just present with a bowel obstruction, irreversible damage, [and need for] surgery. Those patients to me are just as high risk as patients who have more symptoms throughout their disease course. This is because it's very hard to anticipate when they would need a more drastic intervention.
Higgins: It's interesting, the flip side of that — and you don't see this very often — I've seen patients with really slow disease progression who are diagnosed with Crohn's disease take 15-20 years to get to their first surgery. Generally, these are the people who are going to get the most duration of benefit from surgery.
Chiorean: I totally agree.
Higgins: They may take another 15 years to advance to their second surgery. These patients are out there. They aren't necessarily getting referred to tertiary centers, but they're definitely out there. You mentioned Paul Rutgeerts, and some of his early research on postop recurrence was using antibiotics like metronidazole and ornidazole, which showed that you could delay endoscopic recurrence and even symptomatic recurrence with 3 months or so of antibiotics after surgery. But we seem to have moved on to more biologic approaches. Do you think there's still a role for antibiotic prevention after an ileal resection?
Chiorean: That's a very interesting question. You have to appreciate the genius of Paul Rutgeerts who, 30 years ago, thought this was an issue with the microbiome, and that this had implications for disease recurrence. I personally would be happy to use antibiotics for postop prevention if we did not have to deal with poor tolerance. If you remember, in the trial by Rutgeerts and his group from Leuven, they were using 20 mg/kg of metronidazole for 3 months. In the current practice, I have a very hard time finding patients that can tolerate metronidazole for that long, especially among men in the younger population, and with 3 months of 3 times a day. Metronidazole is a very tough sell and particularly nowadays that we have simpler, better-tolerated therapies. It's almost ironic to compare this with azathioprine, but actually, azathioprine is better tolerated than metronidazole in these people. So, I have a hard time finding patients. I know there is a subpopulation where I'd use them if we had a better option than metronidazole or other nitroimidazoles. Other antibiotics don't seem to work so well. If you remember, there was a trial with ciprofloxacin by Hans Herfarth, and that did not show a spectacular benefit. So, there's got to be something to do with anaerobic coverage. Right now we don't have great choices. That's basically my answer.
Higgins: We seem to have moved on to biologics, and a lot of this was stimulated by the first infliximab trial by Regueiro and his group, and then the PREVENT trial for moderate- to high-risk patients using postop infliximab, which showed a significant reduction in endoscopic recurrence but not significance for clinical recurrence at 3 years after surgery. How do you interpret this result, and how does this result affect your approach to post-op anti-TNF therapy?
Chiorean: I'm glad you asked this because it points out how our mindset has changed from 20 years ago when we were saying that, postop, maybe we should try mesalamine. Then came azathioprine, and we said, no, let's just treat these people top down as we would do nowadays with anybody who has high-risk disease. Now, we have to acknowledge some issues with the PREVENT trial. If we redid this trial today in 2022, we clearly would fix some of the methodologic mistakes that were made in that trial specifically as far as study design. I don't have any issues with the population. Clearly, they sounded like a high-risk population. But as you know, I don't think anybody will use infliximab nowadays without standard induction; the 0, 2, and 6 weeks protocol. In my mind, one of the limitations of PREVENT is that they went straight to infliximab every 8 weeks, and a small minority was treated with combination therapy. If I were to repeat this trial in 2022, I'd probably do reinduction combination therapy. So, it would be a SONIC trial postop prevention rather than the way it was utilized in PREVENT. Then it's the matter of bad luck. The placebo recurrence rate was unusually low. This may have something to do with the patient selection. Something happened in that population that was considered to be high risk, which prevented them from disease recurrence at 1 year. If you compare this with the POCER trial, there were more community patients who appear to be lower risk, and there was a much higher recurrence rate in the placebo arm. Something happened there. Again, one of the issues was, in my mind, methodology and study design.
Higgins: Yeah. And I wonder if there might have been some recruiting selection going on where the really high-risk people didn't enroll in the trial and just went on infliximab. It might have been a kind of a funny selection there. So the POCER trial, which you mentioned, took a different approach with more endoscopic-monitoring antibiotics and step-up therapy through azathioprine, and adalimumab with active monitoring and step-up therapy. They looked more effective at reducing endoscopic recurrence, but there was less success in patients with multiple risk factors, including smoking. How does that monitoring and step-up trial influence your decisions about postop therapy?
Chiorean: Again, that was the next step in our thinking evolution about postop prevention, right? PREVENT said let's just treat with standard of care and wait and see; wait for 12 months or wait for 18 months like Paul Rutgeerts told us. You can wait for about a year, look, and then use my score to predict which patient is going to do well. Then POCER said, I think we're looking too late. Let's look a little bit earlier at 6 months. So, everybody had a colonoscopy at 6 months. I think that's where some of these standards of practice are coming from, from POCER — not necessarily what I do today. But that was the idea. Look early and adjust therapy based on what you find. If you restratify the risk at 6 months — brilliant idea. I think we can do this even earlier nowadays with intermediate targets. But that was a reasonable target at 6 months, which changed the paradigm and obviously changed the outcome. The idea here is to monitor closely and adjust your target based on risk. The risk is a continuous variable. It's not a stable variable. The risk changes over time based on what you see, biomarkers, and colonoscopy. I think that was the one of the most important things we learned from POCER.
Higgins: One of the side papers from POCER was interesting. It showed that monitoring fecal calprotectin every 3 months after resection for a level above 100 μg/g was actually very accurate, with a negative predictive value of 91% for predicting endoscopic recurrence above the anastomosis. It was actually helpful in monitoring for the next 18 months. And we've sort of thought that fecal calprotectin isn't as good for small bowel Crohn's disease. Were you surprised by this? And does this tell us something about fecal calprotectin and surgery, and whether we should be thinking about it differently in people who don't have ileocecal valves?
Chiorean: To be perfectly honest, I was not. There was an earlier study in the late 2000s early teens by a French group which showed that calprotectin was reasonably decent in predicting postoperative recurrence as early as 3 months. So when I saw the results from POCER, I was pleasantly surprised. But we were all already utilizing fecal calprotectin and postoperative monitoring in our patients in our center as early as 3 months postop. That basically became a standard algorithm. By the time POCER came out, it was just a validation of what we were doing. Now, I agree with you, calprotectin was discredited as a marker of small bowel disease — perhaps for the right reason, perhaps for the wrong reason. As you know, there is a very nice meta-analysis published about 3 or 4 years ago that shows that the accuracy of calprotectin for Crohn's disease is actually a percentage in the high 80s. We don't have anything else close to that range for accuracy, short of colonoscopy, of course. But no patient in this world is going to accept a colonoscopy every 3 months in the first year postop, especially if they don't have any symptoms. To go back to your question, I was not very surprised. I was happy. And in a way, I was happy that it validated a concept we actually put together some time ago.
Higgins: Yeah, we've been kind of doing it for a while — not feeling like we are completely supported, and having a little bit of challenge arguing with insurance companies about calprotectin back then. This really helped us a lot. Getting down to when you have a postop patient, how soon after surgery do you want to start or restart therapy, and how do you decide when to start?
Chiorean: I like to risk stratify my patients like you mentioned in the first part of our conversation, and I use some pretty hard lines in the sand. In my mind, for a person less than 40 years old when they had their first surgery with less than 10 years duration, I automatically start them on postop prevention and then substratify based on that therapeutic experience. If they really weren't treated or weren't treated very well for that very complex disease, you can talk to them about immunomodulators. Right now, we have the old classes — the antimetabolites or methotrexate, if they're willing to do that. I do still utilize thiopurines and methotrexate in postop prevention, especially with patients at moderate risk. These are patients with one surgery, perhaps limited stricturing, nonpenetrating disease, and who are nonsmokers and usually less than 40 years old. Then I have the patients who are 60 years old and older, who as you mentioned, may truly experience an immunologic reset. For those people, I just wait and see. I monitor them, but I don't necessarily treat them. We wait and see what happens, especially if they had 20 years of disease prior to their surgery. I think that's a perfect subgroup for watching to see what happens. You use calprotectin, you use colonoscopy, or you use whatever you wish, and basically tailor the therapy based on what you see. That's another form of treat-to-target — starting with nothing, so step-up therapy. Then you have the 40- to 60-year-old group; treating them is more of an art than a science. That's when I have several things to keep in mind. What type of disease behavior was there before surgery? Are these patients presenting with penetrating disease? Do they have very extensive disease, skip disease, or disease that's in a very hard area to reach? These people are very tough to monitor. We have some biomarkers that do reasonably well, but that's when the risk of recurrence is incredibly high because it happens completely off the radar. These are the people I tend to treat more aggressively. Of course you keep safety in mind, but I tend to treat them more aggressively in a top-down fashion postop, depending on their prior therapeutic experience. If I get the sense their disease has truly failed an agent, regardless of the drug class, we switch outside the class. If I'm not confident their disease truly failed the therapy — and I'm talking really about the elephant in the room — we still like anti-TNF drugs. We still believe that, as of now, they're at the top of the food chain. I like to bring them back as much as I can unless I have clear evidence in my mind through my forensic investigation that the disease has truly failed anti-TNF therapy. Then, this is the time to move on to a different mechanism of action.
Higgins: Imagine a really high-risk patient — somebody who's on their second surgery, has been through a couple of anti-TNF's, and got started on Stelara (ustekinumab) 12 weeks before they had to go to urgent surgery. How do you decide if the ustekinumab has truly failed, or would you try to treat straight through and operate in the middle between that every-8-weeks dosing? How long do you pause, and do you do a wound exam before you restart therapy?
Chiorean: I'm going to start with the second one because it's easy. I oftentimes don't wait at all. At maximum, I wait 2 weeks unless there is some kind of a wound complication or surgical complications. Typically at 2 weeks or later, we try to get those people back in, or we communicate with our surgeons very closely and let them know the patient has a green light from our standpoint. Wound infections in this day and age, unless a patient is on steroids, are really uncommon. To go back to your earlier question, my rule of thumb is 6 months, more or less. If a patient has been on the last therapeutics for more than 6 months, you can think about it as a possible failure of mechanism. But in your example, the patient was treated with ustekinumab for only 12 weeks. That is not enough to see a therapeutic response for failure and, therefore, I don't consider that as a failure of drug. I would still try postoperatively and keep the others as my wild cards. So, potentially recycle, potentially use a different mechanism, potentially [enroll the patient in] a clinical trial, or as we mentioned at the very beginning, these are the patients I sometimes push a little bit for antibiotic prophylaxis postop. That's where the stakes are very high. I try to talk these people into it by saying we have some evidence. We have to try everything we can because the situation is not very favorable.
Higgins: In terms of monitoring people, what's the role for fecal calprotectin or scoping or scanning, or do you even use capsule?
Chiorean: All of the above, but perhaps fewer radiologic investigations in the first year unless some complication is going on. We definitely have used a lot of calprotectin. Our protocol is to think about it as the baseline being the time of surgery. You think that the patient, when they're rolling out of the operating room, is disease free. Now, that may not necessarily always be the case, but the assumption is that you reset the clock. They're disease-free, healthy bowel to a healthy bowel connected. And then in 3 months, we do a baseline calprotectin, and then we monitor it every 3 months up to 9-12 months. I'm worried that if you scope too early, you're going to miss the intermediate recurrence of the 12-month recurrence. That's why I rely a lot more on calprotectin. We actually schedule clinic visits with these people every 3 months because I'm worried if I tell them they have to have their calprotectin checked every 3 months, they'll go home, feel better, and never go to the lab. We don't yet have those home-based labs so they can send them reminders, “Hey, put a dipstick in that stool sample and let me know what the result is.” One day I hope we will, but until then, we actually bring patients back every 3 months. I send a message to the surgeon. We kind of tie them in some way to refilling their medications. I see them every 3 months or our nurse practitioner sees them every 3 months, we check the calprotectin, and then we scope them around the 12-month mark.
Higgins: And we do the same. We'll trigger an earlier scope for a rising calprotectin if it goes above 100 μg/g.
Higgins: Most of them don't need it, and a few around 3 to 6 months will ping early, but most of them can make it to 12 months. We've talked a lot about deciding whether anti-inflammatory therapy is working, restarting therapy, antibiotics, biologics, and monitoring. In terms of our clinicians listening, what are the overarching concepts and take-home messages you'd tell people about perioperative care and Crohn's disease?
Chiorean: I think you should think about this as a football game or a soccer game, whichever you are a fan of. Reset your game plan at halftime. Surgery is not necessarily a failure. The game is not lost at halftime. This is when you reset your offense and your defense, and you go into the second half, and you win the game. Again, I think in a way, we were wrong for the last decade or so by thinking surgery is a failure. It is not a failure. It's another form of treating patients with severe structural damage. But it's also an opportunity for you to reset your thinking about that patient. Now, you truly have a biomarker of disease aggressiveness, right? Now we have that piece. We looked at it under a microscope and figured out how extensive it was, and what type of pathology these people had. It was multifocal strictures, severe strictures, and penetrating disease. Now you know what to expect from this team. You go into the second half with a different strategy and a different set of weapons, and you will win the game at the end.
Higgins: That big reset often helps us catch up with the disease and the bowel damage that's accumulated. Today, we've had IBD expert Dr Michael Chiorean discussing the risk stratification, monitoring, and treatment of postoperative Crohn's disease. Thank you so much for joining us.
Chiorean: Thank you, Peter.
Higgins: This is Dr Peter Higgins for InDiscussion.
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Cite this: Managing Crohn's Disease After Surgery - Medscape - Sep 22, 2022.