BSG IBD Guideline - Post-op Crohn's Disease

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 gastroentrologist from King's College Hospital in London and I'm very pleased to be here with Professor Jimmy Lindy. Thank you Alex, it's a pleasure to join you here today to do this podcast with you. 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? 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. And of course there's 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? 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 the worst 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 diagnosis so under the age of 40, a shorter duration between the diagnosis of Crohn's disease and the need for the first Ileo-SQL resection, I should make it clear that what we are really referring to for most of the rest of our conversation is Ileo-SQL resection in Ileo-SQL resection in Crohn's disease. And 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 post-operative recurrence. There is also some genetics involved here and as we know the Nord 2 card 15 gene mutation has also been associated with a higher surgical risk. In fact, Alexair also surgical risk factors and it has now been known that resection of 20 to 50 centimetres of Ileo disease or even more is associated with a surgical risk recurrence risk. And more recently our surgical colleagues have taken interest in the me-centry and me-centric 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 me-centrate resection may reduce that risk. And of course that's the science and evolution and we just need to watch this space. So I suppose if we're going to summarize it, it's 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 budget 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? 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 high risk of recurrence immediately post-operatively and therefore perhaps that Ileocolonoscopy at six months may be somewhat irrelevant. And so there are a number of things that we can do to monitor our patients for post-operative recurrence and of course going back to endoscopy and the scopic recurrence can be assessed at colonoscopy at six 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 Ileocolonoscopy for whatever reason or would prefer to have imaging as their modality. Then there is of course CT entrography which is not preferred when you can have an MR entrography without ionizing radiation and in fact in the modern day and age in hospitals that can offer expertise with interstinal like to sound interstinal like to sound is a very good point of care test that can assess for post-operative recurrence with a bowel wall thickness of just over three millimeters and indeed if it's over five millimeters then that is more consistent with a 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 suggestive for a fecal calprotectin within under 50 microgramm per gram being very very reliable threshold with a high sensitivity and even predictive values for recurrence and a scopic 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 a aliocolonoscopy I should say due to a lower likelihood of recurrence in the first post-operative year. So there is biochemical markers that it's fecal calprotectin aliocolonoscopy at six months and potentially intestinal ultrasound or if you cannot have access to intestinal ultrasound then MR entrography or if necessary only perhaps a CT entrography all of these can be used to monitor patients after but going back to the beginning the BST now recognizes that people have high risk factors straight off the bat as it were which is that immediately post-operatively 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 post-operatively. 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 medications that we have been using in Crohn's disease have fortunately demonstrated efficacy in terms of reducing the risk of post-operative endoscopic recurrence and these are anti-TNF agents in fliximab and adilimumab but also more recently vedulizumab 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 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 Reguero who did the first study in 2009 with just 24 patients and followed it up with a prevent trial in the year 2016 when 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 adilimumab now and that mainly comes from the poker study which showed the reduction in endoscopic disease activity at six months for those that were randomized to receive adilimumab in the hierarchical manner that it was used in the poker study of course so adilimumab can be used and there is no difference in the public literature really between infliximab or adilimumab 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 reprieve of study which is the large randomized controlled trial that assessed adilimumab in the prevention of endoscopic post operative recurrence for after aliosecal resection so these were patients who underwent aliosecal resection and had one or more risk practice for disease recurrence which would be the ones we just mentioned and 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 adilimumab important for our listeners to remember that this was not used in the classical manner that we use infliximab with the induction at 0-2 in six weeks but in fact these patients received vedolizumab at doses of week 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 vedolizumab group versus 38% with placebo and that was a statistically significant difference of course and they showed lower God God's course which is which now led the BST also 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 the kinumab 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 aneda 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 about the role of P19 inhibitors and even small molecules and I mean Jack inhibitors that we do use in Crohn's disease so to sum it up the BST recommends the use of either anti-TNF or vedolizumab or even you stick in your map as advanced therapies for the prevention of endoscopic recurrence and subsequently hopefully any clinical recurrence of Crohn's disease postoperatively and that's great and and the guidelines have been a fantastic resource for seeing what has actually been assessed in randomized 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 vedolizumab 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 reasonable kind of assumption to make? You've summed it up very well near Alex I think it's 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 they it's it's a very very valid option and makes perfect sense because we've got to have a conscience with the health economics as well and and so if a patient can get an anti-TNF it's a very reasonable option of course with the repeatable 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 biased similar version of you stick in your map more recently for most of us almost all of us in the United Kingdom there is that added appeal to consider even using you stick in your maps although not entirely supported by robust data yet I think it makes perfect sense for clinicians to even consider using you stick in your map for the very reasons that have been explained even in the guideline and the real world studies that have supported its use so yes you stick in your map anti-TNF therapies and even wedil as you map all of them remain viable options and thing 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 Jack 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 Jack 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 yeah I yeah I mean I think we use this to kind of add because preferentially it's it's you know 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 presenting very late with quite complex terminal arterial disease and you know that advanced therapies 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 that that whatever medication you use so I think it's 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 a 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 thigh purines could be used post-operatively in Crohn's has there been any data on those that's an interesting one Alex and you and I will remember the times when people did use 5 ASA for the prevention of post-operative 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 post-operative recurrence prevention and from the Cochrane reviews that we assessed in the BSG guidelines we know that there's a very low certainty of any for a 5 ASA over a placebo in fact to prevent clinical relapse and so it is not recommended the 5 ASAs are not recommended but to your point about thigh opurines yes and I mean the topic study the trial which was done in the United Kingdom did also assess the role of thigh purines and we know that it did not demonstrate efficacy at that level but even the the network meta-analyses 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 thigh opurines are no longer recommended by the BSG as a monotherapy strategy for the prevention of endoscopic or clinical recurrence in after an ICR, ILEA, SQLA section in Crohn's disease. I think people like you and I are very likely to be using thigh opurines along with an anti-TNF agent simply to do what we do with 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 a name when using an anti-TNF so in that sense yes but as monotherapy the BSG doesn't support use of thigh opurines as monotherapy for this indication. And that's great really isn't it because it matches what we know about treatment in Crohn's as a whole we don't we really shouldn't be doing step-up treatment anymore the profile trial is 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 metronide dissolved which we at Kings have always tried to use in our patients having ILEA SQL resections although not always very well tolerated because a three-month course of metronide dissolved often comes with side effects. What says the guideline on that subject? 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 post-operative prevention of endoscopic recurrence but like you say and we do as well have used metronide dissolved supported by two studies in the main both Bipole Rodriguez group from Belgium and they had suggested that there is a lower likelihood of a clinical recurrence with the use of metronide dissolved. So we have tried to use metronide dissolved as many people especially high risk as we could over the years where we've used 400 milligrams BD actually for up to three months but as you point out metronide dissolved 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 the long-term risk of metronide dissolved and peripheral neuropathies that are something that we as clinicians will be concerned about perhaps more in other contexts that we might consider using metronide dissolved longer term or cyclically but not necessarily in this context so that and also the logistical challenges we face I think you know you and I have discussed this at other meetings that when our patient has an ICR allocical 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 you 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 nitro-emitterzoles for up to three months post-operatively 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 the regards of antibiotic therapy for three months and then wait to initiate these treatments 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 have failed that they've been on drugs for a while they've had surgery they just want to break from the world of medicine for a little 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 new risk factors you mentioned the rickus score earlier how do you use that to make decisions 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 you know advanced therapies before this perhaps for longer than necessary or long 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 a somewhat curative at least for a period of time and with our intentions with them to 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 some modality of an investigation that might prognosticate the risk of recurrence, endoscopic and clinical etc and for to that end we use aliocolonoscopy 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 a dyscopic lesion scene in the neo terminal or distal isleum and also the anastomosis into four categories so actually i0 i1 i2 and more recently this has been subclassified 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 isleum i1 is less than five half the solsars in the distal or neo terminal isleum now with i2 you have i2a where you have an astymotic ulceration and i2b is more than five half the solsars is seen in the distal isleum when it comes to i3 we are talking about diffuse after isleitis and i4 of course is large ulcers in associated with diffuse decosal 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 the bulk of the literature now suggests that if you have an i2 level lesion we sure 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 infleximab or adilimumab or vettelizumab or even you're sticking umab 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 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 report to know what you've seen and know what you're saying in terms of that patience 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 because it gives uniformity and consistency 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 and i2a or an i0 you know what i'm talking about and i know what you're talking about and i think it allows the fact that it's it's really common to have a few you know small africals as any anastomosis that's that's a common finding and what we don't want is people over calling that as being crones recurrence and not just a simple anastomotic ulcer but it's it's nicely defining when we need to start thinking about this being a bit more and not under treating the crones so i think that that that's a really nice description so we we are saying that we may have some patience where we will reassess at six months if i have a patient who i really want to put on treatment and they're saying they want a holiday i do try and bring that colonoscopy at 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 when we should get that going 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 three months so this timeline of doing an aliocolonoscopy at six months rather beats that objective anyway and therefore if we are going to start treatment soon after surgery then it really should be within the 45 days to three months at the you know which is exactly what a literature has done and supports the evidence that we have used to back these recommendations at the BST guidelines 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 no Alex I was involved with this particular section for the BST guidance as you know and I 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 BST guidance which was to remind us to assess risk factors for disease recurrence and we said this was younger age diagnosis and adverse disease phenotypes structuring 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 better lissumab or even new stachinumab data for other novel biologics is aggravated 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 BST would support that and in those who do want to take a drug holiday early risk stratification with a scolonoscopy at six months using a Rutgers score and then defining the risk of recurrence based on I2A or if not I2B level lesion scene if seen at the colonoscopy would then be the trigger to start advanced treatments in those that do not even want a cialiocolonoscopy then we might consider using non-invasive methods either such as a fecal calprotectin or maybe cross-sectional imaging MR intrography 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 their BSG we do not support the role of five ASA at all and we also now do not support thiopuring more no therapy for prevention of endoscopic or clinical recurrence and indeed even some of the other agents that have been used by people you know 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 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 our patients with Crohn's 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 thank you Alex and thanks to all our listeners for taking the time to listen to us thank you