Episode Transcript
[00:00:09] Speaker A: Welcome to this BSG podcast. We're focusing on IBD from top to bottom and I believe this is the seventh podcast covering different aspects of the newly published IBD guidelines. And today we will be focusing on the section dealing with post operative Crohn's disease. So I'm Alex Kent. I am a gastroenterologist from King's Colle Hospital in London. And I'm very pleased to be here with Professor Jimmy Lindy.
[00:00:36] Speaker B: Thank you, Alex. It's a pleasure to join you here today to do this podcast with you.
[00:00:41] Speaker A: So I'm going to go straight down to basics. So, Jimmy, how would you define recurrence? You know, how do we define that in patients who've had surgery?
[00:00:52] Speaker B: Indeed, Alex, I think that's a very important question because despite our increasing armamentarium of therapy and evolving paradigms, our patients with Crohn's disease do come to surgery.
Surgical incidence has reduced over the years from being just under 20% and 30% and 50% at 1, 5 and 10 years now, down to just under 20 and 30% at 5 and 10 years even. But despite that, people do come to surgery. So when we talk about post operative recurrence, what we are referring to really is a continuum of not just clinical recurrence, but in fact histological and endoscopic recurrence, which is known to occur as early as a week after surgery.
And then of course there is the clinical recurrence and potentially even surgical recurrence after surgery. So that's exactly the continuum we are referring to when we talk about post operative recurrence in Crohn's disease, which of.
[00:01:47] Speaker A: Course is terrifying for patients who've got to the point where they need surgery, that this is a condition that's going to come back.
Are we able to look at patients and are there patient demographics or are there risk factors that we can use to identify patients that are more likely to have disease recurrence?
[00:02:08] Speaker B: Yeah. Fortunately, not all patients come to recurrence with their Crohn's disease. But there are certain factors, patient driven, disease driven, that might warn us that someone is at a higher risk of disease related recurrence. And these, of course, among these risk factors, tobacco smoking is perhaps the most prominent because it is very strongly associated with with worse disease related outcomes, including post operative recurrence in Crohn's disease. Reassuringly, stopping smoking reduces the risk of surgical and clinical recurrence in Crohn's disease. Of course, there are patient related factors as well, and these include a young age at diagnosis. So, under the age of 40, a shorter duration between the diagnosis of Crohn's disease and the need for the first ileocecal resection. And I should make it clear that what we are really referring to for most of the rest of our conversation is ileocecal resection in ileal or seq ileocecal resection in Crohn's disease. Then other disease related factors, such as penetrating disease, perforating disease, perianal Crohn's disease, or even a preoperative stricturing disease behavior, are all associated with an adverse prognosis or postoperative recurrence. There is also some genetics involved here, and as we know, the NORD2 CARD15 gene mutation has also been associated with a higher surgical risk. In fact, Alex, there are also surgical risk factors and it has now been known that resection of 20-50 cm of eyelid disease, or even more, is associated with a surgical risk, recurrence risk. And more recently, our surgical colleagues have taken interest in the mesentery and mesenteric fat as being a pro inflammatory environment through which complex molecular interactions would occur. And there are of course, a number of studies that are ongoing that are looking at whether or not extended mesenteric resection may reduce that risk. But of course, that's the science and evolution and we just need to watch this space.
[00:04:07] Speaker A: So I suppose if we're going to summarise it in probably not very medical language, but it's going to be the patients who've got more extensive disease, those who've got more aggressive disease, and obviously the smokers who we constantly badger to stop smoking. Those are the ones that we're really going to be more concerned about having disease recurrence.
And so how would you suggest we go about monitoring? What do the guidelines tell us about monitoring patients post surgery?
[00:04:36] Speaker B: The gold standard for monitoring patients has been ileocolonoscopy at six months after surgery. But of course we know that not all patients will be willing to have ileocolonoscopy at six months. Not all patients can realistically, in a clinical environment, have their ileocolonoscopy at six months because of system related issues. And also we've learned over the years that there are these risk factors, which in fact would mean that some of our patients are already at a higher risk of recurrence immediately postoperatively, and therefore perhaps that ileocecular colonoscopy at 6 months may be somewhat irrelevant. And so there are a number of things that we can do to monitor our patients for postoperative recurrence. And of course, going back to endoscopy, endoscopic recurrence can be assessed at colonoscopy at 6 months. And that is the suggestion from BSG, but also from other societies, of course. I'll come back to our recommendations in a moment. There's also the potential for radiological recurrence and for those who cannot have an IL colonoscopy for whatever reason or would prefer to have imaging as their modality, then there is of course Connecticut enterography, which is not preferred when you can have an Mr. Enterography without ionizing radiation. And in fact, in the modern day and age in hospitals that can offer expertise with intestinal ultrasound is a very good point of care test that can assess for postoperative recurrence with a bowel wall thickness of just over 3 millimeters. And indeed if it's over 5 millimeters, then that is more consistent with higher risk of recurrence. And so taking together all of these radiological features can help. But of course we also use biomarkers, and when we talk about biomarkers, the very biomarkers that our listeners are thinking of would be appropriate. Unfortunately, CRP doesn't seem to correlate very well with endoscopic recurrence and indeed we know that it's unhelpful often in small bowel Crohn's disease in any case. But the fecal calprotectin can be helpful and various different thresholds have been suggested for a fecal calprotectin with an under 50 microgram per gram being very very reliable threshold with a high sensitivity and even predictive values for recurrence, endoscopic recurrence of disease. But in the other literature, of course, it is also suggested that a fecal calprotectin less than 150 micrograms may negate the need for a colonoscopy or ileocolonoscopy, I should say, due to a lower likelihood of recurrence in the first postoperative year. So there is biochemical markers, I.e. fecal calprotectin, ileocolonoscopy at 6 months and potentially intestinal ultrasound, or if you cannot have access to intestinal ultrasound, then Mr. Enterography, or if necessary only perhaps a CT enterography. All of these can be used to monitor patients after. But good. Going back to the beginning, the BSG now recognizes that people have high risk factors straight off the bat, as it were, which is that immediately postoperatively we know the writing is on the wall for some. And we also know, and I know we're going to discuss this later, that some of our literature in fact supports the earlier use of advanced therapies, and it may be appropriate for some not to wait that long and to have treatment immediately, almost immediately postoperatively.
[00:08:02] Speaker A: So if we've got patients who've got more aggressive disease or patients who are maybe on their second surgery, which medications have been shown to reduce the risk of disease recurrence post op, then the.
[00:08:15] Speaker B: Medications that we have been using in Crohn's disease have fortunately demonstrated efficacy in terms of reducing the risk of postoperative endoscopic recurrence. And these are anti TNF agents, infliximab and adalimumab, but also more recently vedolizumab in a randomized controlled trial.
So at the bsg, as you know, we perform network meta analyses with our able colleagues who did all the evidence synthesis for us, and they looked at for the anti TNF agents, they looked at four major studies for the infliximab group of people, and two were done, of course, by Miguel Ruggero, who did the first study in 2009 with just 24 patients and followed it up with the PREVENT trial in the year 2016, wherein they showed that although there was in fact a reduction with endoscopic recurrence, although not clinical, infliximab did stand out. And then there have been some other studies also supporting this, leading the BSG to say that infliximab may be considered, albeit with a low certainty of a moderate effect, for the prevention of endoscopic recurrence. Then we also have data for adalimumab now, and that mainly comes from the POCA study, which showed the reduction in endoscopic disease activity at six months for those that were randomized to receive adalimumab in the hierarchical manner that it was used in the Poker study, of course, so adalimumab can be used. And there is no difference in the published literature really between infliximab or adalimumab in terms of its ability to prevent endoscopic disease recurrence in Crohn's disease in recent years. Only very recently, of course, we've also had the Reprivo study, which is the large randomized controlled trial that assessed vedrolizumab in the prevention of endoscopic postoperative recurrence for after ileocecal resection. So these were patients who underwent ileocecal resection and had one or more risk factors for disease recurrence, which would be the ones we just mentioned, an adverse disease phenotype or smokers and previous exposure. Even they had to anti TNF in 50% of these patients, I should say, and they were randomized to receive bedolizumab. Important for our listeners to remember that this was not used in the classical manner that we use infliximab with a induction at 0, 2 and 6 weeks. But in fact these patients received vedolizumab at doses of weeks 0, week, 8, 16 and 24 after surgery.
And the patients who received vedolizumab had a greater chance of endoscopic remission, which was 77% with the wedulazumab group versus 38% with placebo. And that was a statistically significant difference, of course. And they showed lower Rutgert scores, which now led the BSG also. So aside from some other studies that we assessed for the guidelines to recommend vedolizumab is also a suitable treatment option to prevent endoscopic recurrence, then there, of course is istekinumab, for which there are smaller studies, but there are some studies that do support its use for prevention of endoscopic recurrence. And among them is a good study from the Eneda group from Spain. And of course there are others.
We don't yet have much data for the newer biologics, but of course time will tell and we will soon learn the role of P19 inhibitors and even small molecules and I mean JAK inhibitors that we do use in Crohn's disease. So, to sum it up, the BSG recommends the use of either anti TNF or bedrolizumab or even Ustekinumab as advanced therapies for the prevention of endoscopic recurrence and subsequently, hopefully, clinical recurrence of Crohn's disease postoperatively.
[00:11:59] Speaker A: And that's great. And the guidelines have been a fantastic resource for seeing what has actually been assessed in randomised controlled trials.
But the real world may not be quite so easy. We know that these patients may well have come to surgery already on an anti tnf, and not all regions of the UK are able to access every medication they'd like to. Vedelizumab is not always approved in all regions. So in regions where they are a bit more curtailed or they've got patients who fail drugs, it's still presumably reasonable to use advanced therapies that haven't got that trial data.
I would assume that actually the most important thing is keeping the disease under control so people will be restricted by what gets approved by their local kind of prescribing committee. Is that a reasonable kind of assumption to make?
[00:12:56] Speaker B: You've summed it up very well indeed, Alex. I think one has to be practical here. So for patients who may not have had anti TNF exposure or perhaps have had not have had a class effect in terms of mechanistic failure to anti TNF agents, it's a very, very valid option and makes perfect sense because we've got to have a conscience with health economics as well. And so if a patient can get an anti tnf, it's a very reasonable option. Of course, with the Reprievo study that we talked about, 50 were anti TNF exposed and had not responded to it. So there is that option for those that have not responded to anti tnf. And I think you also make a very good point here because with the availability of a biosimilar version of Ustekinumab more recently for most of us, almost all of us in the United Kingdom, there is that added appeal to consider even using Ustekinumab. So although not entirely supported by robust data yet, I think it makes perfect sense for clinicians to even consider using Ustekinumab for the very reasons that have been explained even in the guideline and the real world studies that have supported its use.
So yes, eustachinumab, anti TNF therapies, and even medilizumab, all of them remain viable options. I think I would perhaps finish on this segment with a comment. I think, and I'd love your comment to that as well, that there will be people who have been exposed to all of these agents and may have then come to surgery and we don't have the data for novel biologics and I mean P19 inhibitors and even JAK inhibitors. And I think that has to be a clinically driven, individualized decision between clinician experts and of course, in discussion with our patients. And we may have to. And we will be using P19 inhibitors and JAK inhibitors and that data will come when it comes. But I think we will be using. What do you think? Do you, do you use these agents?
[00:14:46] Speaker A: Yeah, I mean, I think we use histakinumab because preferentially it is likely to be more cost effective.
And I think you also have to think about the time points when patients have been treated. Sometimes you'll have patients present very late with quite complex terminal disease and you know that advanced therapy's unlikely to work. And of course, post operatively you're dealing with a patient who has often had clearance of their disease, so maintaining remission is potentially an easier job for whatever medication you use. So I think it's trying to look at the patient as a whole and not necessarily discounting drugs that haven't worked preoperatively when they were in a very different situation. So I think it is always a case by case basis at the end of the day.
And I'm interested because I thought there was a bit of data saying that thiopurines could be used postoperatively in Crohn's. Has there been any data on those?
[00:15:47] Speaker B: That's an interesting one, Alex. And you and I will remember the times when people did use 5 ASA for the prevention of postoperative recurrence. And of course now we have evidence synthesis to tell us that perhaps we were wrong in terms of a 5 ASA and its role in Crohn's disease at all. And even in, of course, in postoperative recurrence prevention. And from the Cochrane reviews that we assessed in the BSG guidelines, we know that there is a very low certainty, if any, for a 5 ASA over a placebo, in fact to prevent clinical relapse. And so it is not recommended. The five ASAs are not recommended. But to your point about thiopurines. Yes, and I mean the topic study, the trial, which was done in the United Kingdom, did also assess the role of thiopurines and we know that it did not demonstrate efficacy at that level. Level. But even the network meta analysis and the evidence synthesis from the BSG guidance has suggested that there's only a moderate certainty for fewer clinical relapses and there were wide confidence intervals associated with this.
So thiopurines are no longer recommended by the BSG as a monotherapy strategy for the prevention of endoscopic or clinical recurrence after an ICR ileocecal resection in Crohn's disease.
I think people like you and I are very likely to be using thiopyrins along with an anti TNF agent simply to do what we do in other scenarios, which is to maximize the potency of the anti TNF by giving us better and more credible trough levels and also preventing immunogenicity, which is of course always an aim when using an anti tnf. So in that sense, yes. But as monotherapy, the BSD doesn't support use of thiopurines as monotherapy for this indication.
[00:17:37] Speaker A: And that's great really, isn't it? Because it matches what we know about treatment in Crohn's as a whole.
We really shouldn't be doing step up treatment anymore. The Profile trial has very clearly told us that. So it's really about going straight in with advanced therapies and giving that patient the best chance of a good outcome.
I'm also going to go into a medication that maybe is a bit more historical and that's the use of metronidazole, which we at King's have always tried to use in our patients having ileocecal resection, although not always very well tolerated, because a three month course of metronidazole often comes with side effects. What says the guideline on that subject?
[00:18:19] Speaker B: So the guideline agrees with what you have said in terms of the fact that there is no statistical benefit of using antibiotics in the postoperative prevention of endoscopic recurrence. But like you say, and we do as well have used metronidazole, supported by two studies in the main, both by Paul Rutger's group from Belgium, and they had suggested that there is a lower likelihood of a clinical recurrence with the use of metronidazole. So we have tried to use metronidazole in as many people, especially high risk, as we could over the years, where we've used 400mg BD actually for up to three months. But as you point out, metrodazole is not a very pleasant drug to take and not for that long. So these associated side effects, such as nausea, the metallic taste and GI disturbances, will perhaps lead many people to stop taking it, even if we have started it. And then of course there is the potential, although perhaps not in three months time, but with long term risk of metronidazole and peripheral neuropathies that are something that we as clinicians will be concerned about, perhaps more in other contexts that we might consider using metronidazole longer term or cyclically, but not necessarily in this context. So that, and also the logistical challenges we face.
I think you and I have discussed this at other meetings that when our patient has an ICR ileocecal resection, we need as a team to be aware of this and then to initiate this in a timely manner if we are going to do this.
So to sum it up, yes, there is no statistical benefit in terms of the evidence, but there is an agreed expert consensus from the BSG that might support its use.
The use of nitroimidazoles for up to three months postoperatively so I think this is an individualized decision.
Am I doing it now? Increasingly I am not doing this. And that is since the BSG guidance. I think that if I can risk stratify my patients better, and I think we should all do that, and I know you do, then perhaps we might want to start advanced therapy straight off the bat for high risk patients and perhaps not put them through the rigors of antibiotic therapy for three months and then wait to initiate these treatments.
[00:20:41] Speaker A: And you did mention previously that you would. If we have patients who don't go on treatment straight after surgery, and of course there will be those patients who want to have a drug holiday as well. You know, at the end of the day we can make suggestions about what we want to do about medication, but there will be patients who feel that they've been on drugs for a while, they've had surgery, they just want a break from the world of medicine for a little while.
So if we can persuade them to have their colonoscopy at six months, which would be really important, especially if that patient has got any risk factors. You mentioned the Rutgarts score earlier.
How do you use that to make decisions?
[00:21:23] Speaker B: So that's a great point, Alex. There's no question that some people are so fed up by the time they've had their operation and may have been exposed to advanced therapies before this, perhaps for longer than necessary or as long as it was necessary to take them even. And they do want a drug holiday and just want some life back after having had that resection, wherein although it's not cured, they would view it as somewhat curative, at least for a period of time. And with our intentions with them to maintain it that way. And in order to do that or to achieve that, it makes sense then for us to offer some form of submodality of an investigation that might prognosticate the risk of recurrence, endoscopic and clinical, et cetera. And to that end we use ileocolonoscopy, ideally at at least six months after the surgery. And we should be using a scoring system which has been shown to help us prognosticate this and the score that we use, most of us use, and I hope all of us will be using when we do this is the Rutgers score, which stratifies people on the basis of endoscopic lesions seen in the neo terminal or distal ilium and also the anastomosis into four categories. So actually I0I1I2 and more recently this has been sub classified into I2A and I2B. And then you have I3 and you have I4.
Just to sum it up for some of our listeners who are probably very familiar with this already, but I0 is no lesions in the distal ileum. I1 is less than 5 aptus ulcers in the distal or neo terminal ilium. Now with I2, you have I2A where you have anastomotic ulceration. And I2B is more than 5 apthys ulcers seen in the distal ileum. When it comes to I3, we're talking about diffuse aphthus ileitis. And I4, of course, is large ulcers associated with diffuse mucosal inflammation. The important distinction in Recent years between I2A and I2B has been thought to be important with I2B lesions predicting a more adverse prognosis than just I2A. But I think think the bulk of the literature now suggests that if you have an i2 level lesion, that should be the trigger to consider starting advanced treatments. And as we discussed earlier, these could be one of the two anti TNF agents, Infliximab or adalimumab or vetlizumab or even Ustekinumab. And indeed, for those exposed to all of these drugs, either consider recycling on the basis of a thorough assessment of the response at that time or consider a newer agent.
[00:24:03] Speaker A: Excellent. And I think that I would encourage anyone listening to go and read up on the scoring system, have it stuck up in their endoscopy rooms, because it's the one thing that will help other people looking at endoscopy reports know what you've seen and know what you're saying in terms of that patient's kind of prognosis. And I think we're all pushing really hard that people use endoscopic scoring in all of their reports. It really should be a standard of care.
[00:24:29] Speaker B: You're so right there, Alex, because it gives uniformity and inconsistency with reporting. And then we are talking a common language, because if I say diffusely inflamed, I don't know what you would take from that, isn't it?
Whereas if I accurately describe a lesion, as in this instance an I2A or an I0, you know what I'm talking about and I know what you're talking about.
[00:24:50] Speaker A: And I think it allows for the fact that it's really common to have a few small APHA sulcers at any anastomosis.
That's a common finding. And what we don't want is people over calling that as being Crohn's recurrence and not just a simple anastomotic ulcer, but it's nicely defining when we need to start thinking about this being a bit more and not under treating the Crohn's. So I think that's a really nice description. So we are saying that we may have some patients where we will reassess at six months. If I have a patient who I really, really want to put on treatment and they're saying they want a holiday, I do try and bring that colonoscopy, maybe a bit less than six months, so that we're not going to miss anything.
If we are going to start medication, is there any particular time point that we suggest that started?
You know, most people, the surgeons probably are going to want us to let there be a bit of healing going on, but is there any suggestion when we should get that going?
[00:25:54] Speaker B: So this is interesting because most of the trials would have done started their patients on these advanced treatments that we discussed within either 45 days or 3 months. So this timeline of doing an ileocolonoscopy at 6 months rather beats that objective anyway. And therefore, if we are going to start treatment soon after surgery, then it really should be within 45 days to three months, which is exactly what the literature has done and supports the evidence that we have used to back these recommendations at the BSG guidelines.
[00:26:28] Speaker A: Excellent. So, look, Jimmy, I'm through all my questions. I don't know if there was anything you think I've missed in terms of going through that section of the guidelines.
[00:26:39] Speaker B: No, Alex, I was involved with this particular section for the BSG guidance, as you know and like you were with others. But so I remember you've covered everything very comprehensively and I think then perhaps for our listeners, maybe I'll take a moment to just summarize the top line information from the BSG guidance, which was to remind us to assess risk factors for disease recurrence. And we said this was younger age of diagnosis and adverse disease phenotypes, stricturing or penetrating disease or extensive disease, deep ulcers, perianal Crohn's disease, smoking being an important risk factor. So these are important clinical risk factors. And then in terms of treatment for those that have an adverse risk or a higher risk of disease recurrence, perhaps consider starting treatment as soon as possible after surgery. And these could be either an anti TNF or bedolizumab or even Ustekinumab data for other novel biologics is awaited and then if our patient does want to take a drug holiday and actually I should pause to say that if our patient wants to start treatment earlier, even that should be an individualized decision and the BSG would support and in those who do want to take a drug holiday, early risk stratification with a colonoscopy at six months using a Rutgert score and then defining the risk of recurrence based on I2a or if not I2b level lesion seen if seen at the colonoscopy would then be the trigger to start advanced treatments. In those that do not even want a kylio colonoscopy, then we might consider using non invasive method methods either such as a fecal calprotectin or maybe cross sectional imaging, Mr. Enterography or intestinal ultrasound where facilities exist. And we all hope that we will have more and more centers offering this to our patients in a non invasive manner. And in terms of other treatments, the BSG, we do not support the role of 5Asa at all. We also now do not support thiopurine monotherapy for prevention of endoscopic or clinical recurrence. And indeed even some of the other agents that have been used by people such as curcumin or vitamin D, they may have their role. Of course, vitamin D has its role elsewhere and so sure, if someone needs to be supplemented and optimized, absolutely. But not as a risk prevention strategy per se.
And I think that's what we have said in the guidance. And I do hope that this is useful not just to our listeners, but more importantly of course to the very people we are here for. Patients with Crohn's disease.
[00:29:12] Speaker A: Disease. That's an amazing summary. So thank you so much. You've done all the work for this podcast, but I think it's been really useful, certainly very useful for me and we will bring the podcast to a close. Thank you very much.
[00:29:24] Speaker B: Thank you Alex and thanks to all our listeners for taking the time to listen to us. Thank you.
