Drs. Dulai and Sandborn answer questions from course participants.
So I'd like to throw out some questions and then feel free to to debate. Uh One of the questions that often comes up and dr SAn Gordon front this up as well is sort of how accurate is called protecting in uh how accurately does it correlate with the endoscopic findings? So I have a question for premier. How does your reliance on the help protect and change based on the location of Crohn's disease? Yeah, so that's a good question. Um and so I think the thought there and the sort of concept is that cal protected maybe more accurate for chronic disease um than it is for illegal disease. Um but I think it's important so I tend to use different cutoffs for both of those um you know in chronic disease sort of less than 2 50 is pretty good and illegal. You probably want to lower cut off. You know when we've looked at this in the Phase three sort of clinical trials post talk, we didn't find a difference in its prognostic values. So all the prior work with biomarkers has looked at okay, at a given time, does that help protect and tell you whether the patients and endoscopic permission or not. But when we looked at whether the cal protecting can predict their future risk of achieving endoscopic permission and probabilities, there was no difference based on location. So I think if you get to a local protecting that's very helpful for you to know that you've sort of gotten to your treatment endpoint but in terms of making decisions based on elevated values that tend to use different cut off for different locations. I kind of agree with that. But Karen berry, you're you're really knowledgeable about this and you fought through it and you're good at categorizing things and making algorithms and I think over time with the studies that you're now taking on and you're going to show us how to do that. But from a practical standpoint, you know, it's not well established in the literature yet, from my knowledge, you know what cut off you would use for small balcones versus Elio Kalanick or Kalanick grounds. And so how did the, how does the attendees today actually operationalize that in practice? One thing that I really like is the paper that you lead looking at um putting the simp the biomarker of equal protection in the context of symptoms. So looking at all sort of colitis, if you have no rectal bleeding and no diarrhea and you have a loaf equal cow protection, you have a very high likelihood of having a normal endoscopy and the work that you did showed that you probably don't need to scope in that setting. Whereas if you have a loaf equal copy protection and you have some rectal bleeding or diarrhea, the people call protected maybe um a false negative or conversely if you've been elevated fecal cow protect them and you don't have symptoms that may be a a false positive and you know, both of those would be an indication to scope and see what's going on. So I don't know if you want to comment on that, but I, you know with the debate was phrased as a binary, you know. Yes, No. Is is accurate enough, but really you have a lot more not invasive information available to you than than just the biomarker. Yeah. And I I tend to agree with you and I think um you know, the debate was phrased as do you do one or the other at the end of the day? I think you're going to do both together in some capacity, but it's more how do you maximize the value of each one? Um And I think when you're trying to maximize the value of biomarkers, um you know, there is some context specific components to it if you're feeling well and your biomarkers normal. I think you can fairly say that they clearly responded to therapy. Um and if they're not feeling well and their symptom activity indexes are very by and they have elevated cal protectant, then you're clearly not doing well and maybe you should make an adjustment that intermediate zone tends to be somewhere where you could consider endoscopy depending on where the cut offs are and hopefully we'll get some more evidence to support a clearer algorithm around that terrific. Uh So we have a question from one of our panelists what proportion of patients may never mount aquel protected or crp response. Yeah. So it's a good question. So there's this concept that floats around about biomarker producing versus non biomarker producing IBD patients during active players. You'll hear people say that there's a CRP producing a non crp producing IBD patients for these some of these players. And it's actually true about a 30% of IBD patients probably won't um mount a significant crp elevation in the setting of active disease. So cRP is really a very inaccurate um component in that setting. But when they do mount it it's very specific sort of like um you know the d timer sort of component it's always elevated. May not be very sort of sensitive. It's very sensitive and sort of identifying information may not be specific but cal protect and I think is more universally elevated when you have active disease. And if you go back to the biology of it. So the IBD is a host microbe disease meaning the immune cells are reacting to bacteria and when what you're seeing on endoscopy is actually just the presentation of that interaction. So with cal protected as dr sambar nicely outlined being a measure of neutrophils which is the most common immune cell and having antimicrobial components which is the second part of it you get a bit more of a host immune response which is pretty consistent. So I would say that can protect elevations are very common um and more consistent across uh sort of IBD, both crumbs in you see. And apparently I tend to think of physical crop protection. It's just a it's a quantitative fecal leukocyte, right? It's actually so you know when you get into this it's a little bit more than that because it's actually one of the neutrophils Granules that ends up releasing it. So it actually gives you a sense of just how activated the neutrophils are, you know, are they are they sort of taking shots? The microbes are just dropping bombs with all their Granules. Um And it is a little bit more of a sensitive marker that's supposed to whether the Lucas sites are just there or not. And then to your point with crp, we have we actually did a study on this years ago when I was a male clinics. It turns out that there is a genetic basis for whether you mounted or not. So there are polymorphisms spread through the population that uh predispose people to lower a lower ability to make crp. And so you have these people that just genetically don't make it and you can define those by calling Orpheus Yeah, traffic. Uh So we have another question from the audience. And these are related to the practical aspects of biomarker monitoring uh when should a patient uh collect their stool to check it, help protecting this time of day matter consistency. And if they do pick a way to do it, should they do it the same way every time. Yeah, so that's a very good question. So for cal protecting the studies that have been done have pretty clearly demonstrated that with the sort of commercially available essays which are Eliza based that you want the first morning sample. Um And that's going to be the most accurate and most consistent. We often forget to counsel patients on that when we asked them to collect their health protected um that they really should be taking the first morning sample to provide it. There is variability actually throughout the day and there's no good explanation for that. So I tell patients that they need to collect their first morning sample um and drop that off which is sometimes not well received. But when I tell them that avoids them having to put it in the fridge or keep it in their house overnight to drop off the next day, they tend to be more accepting of it. Remember you sound like a functional doctor, you're telling us the first tool is the best one. It is always the best one. It's a first cup of coffee and first bowel movement. It's sort of how you start your day. Does it matter if they're doing the tories at night? Nobody's looked at it. Nobody has really looked at whether the enemas would create some irritation or change the values. But it's definitely a good question. Right and how close are we to home based call protection monitoring. Very close. So in europe, the home based tests are widely available actually, Canada, they're widely available. So it's pretty it's pretty cool. So you take the swab, you swab your stool, you put it in this small container um and then it gives a color code and then you scan the QR code with your phone and the color code creates a digital QR image that then reads out on a color metric scale. How much count protecting? There isn't a feedback to your doctor to tell them what your count protecting essays. So they're using it in europe and Canada and they're working on trying to get some evidence to get approval and regulatory approval here in the US. So I'm hopeful that in the next few years that people don't even have to drop these samples off. All right. We have a question for dr sanborn. Uh how do you approach management if patients are doing well? But there's still some mild inflammation. Say small ulcers. Okay. Yeah, this is of course always the hard area. Um What small I tend to think of it as an app. This ulcer of the definition of that is? It's not more than about five. so, you know, tiny ulcers. Uh and how dense are they do you have? You know, 50 of them are in a neo terminal ilium after a search for section or you have to um So there ends up being a bit of uh subjectivity to the whole thing. But my general feeling is it's a bit like whatever you're famous spices, your favorite vices, you know it when you see it kind of thing. And so the more severe endoscopic findings I think you definitely would want to change therapy for. So let's say you've got a patient with all with all sort of colitis. You've treated them with missile amine and maybe they had a tapering course of steroids. You diligently scope them at three or four months and you see some blurring of the basketball pattern. Um are you going to escalate that? And their audience say 4.8 g of generic missile. I mean are you gonna um escalate that patient to a biologic therapy if they're asymptomatic? Probably not. On the other hand, if you see ulcers, even if there's not lots of ulcers, you're going to escalate for one ulcer and an asymptomatic patient probably not think of all sort of colitis as more of a field defect. But if you see, you know, multiple small shallow ulcers, uh you would give some thought to escalating therapy in some way. So it you know, I think you have to be thoughtful about it. Where it's going to be really interesting is the clinical trials that are going on now looking at randomly assigning patients to treating them to clinical symptoms versus endoscopic findings versus histological findings and um you know, there's some observational data from our unit and meta analyses to suggest that patients have a better outcome if you get all the way to history. Logic. Remission and resolution of neutrophils. You know, but none of us are really doing that in practice yet. That seems a bridge too far. Although it might be the right thing to do. So if it's really mild and it's going to be a big change, I probably don't necessarily act to it. Uh On the other hand, if that patient was on two point programs from the Salomon when I push them up to 4.8 sure if they're already on and look some ab would I check a drug level? And if it's a bit low what I intensified and puts them out a little bit. Sure. So it you know, I think it makes you stop and think if there's something fairly simple to do but I wouldn't make a huge change based on minimal yeah disease. Um So I guess along the lines of monitoring, we haven't talked about imaging. Um But can you both speak to the value of entire ah graffiti uh and capsules and monitoring And and would you change management based on findings? Yeah. So I can take a shot at that first. So I think in um in Crohn's disease there is actually really good evidence that the M. R. I. Or this or or an angiography study. In addition to the colonoscopy adds diagnostic value. Um there have been some studies that have looked at when you do both at the same time, about 20% of the time you can pick up complications. Um, and or increase the severity classification based on the imaging that would not have been picked up with colonoscopy. So I think having a baseline assessment and Crohn's disease patients is tremendously valuable. Um in all sort of colitis, I would say. I don't know that that's the same case. Just because sort of the fact that the endoscopy and sort of symptoms and biomarkers are much more accurate for capsule endoscopy. You know, I don't have a good position for it yet. I'm not sure that we truly sort of know how exactly to use it in terms of a treat to target or making treatment decisions capacity. So I think it will end up being context specific. But I'm curious to hell here builds thoughts around sort of imaging and capsule endoscopy to. Yeah, I mean, starting with ulcerative colitis. I just it's a mucosal disease. It's confined to the colon. I don't think that imaging uh, ctM re colon capsule is particularly useful and it's really not part of our practice for Crohn's disease. I sort of dissed distinguish between chronic Crohn's or colitis for the illegal involvement is minimal and it's mostly chronic disease. Um, and there, I think the role of CT and MRI and capsule is not really much. And those patients probably don't uh need imaging unless you're suspecting a complication of some type. Uh and often you can see structuring complications are easy to see as a starting place with colonoscopy. By contrast in the ilium, um the colonoscopy, you know, it's harder if there's significant illegal disease, it's often harder to intubate. There could be skipping of the terminal terminal ilium or you have disease up stream that you won't see. With standard endoscopy, we know that the rate of strictures and fistulas and abscesses is much higher with illegal disease than it is with chronic disease. So as parents you mentioned, you know, if you uh add and cross functional imaging procedure to the um scope, you're going to pick up quite a bit of steps. So I think that for me, significant Galileo illegal involvement in illegal colitis. And purely itis is the place where imaging adds quite a bit the capsules. An interesting study years ago when I was at the Mayo Clinic, David Schwartz and I did a study and this was, this was old enough. It was even the transition from barium to to cross sectional imaging. So we we took patients and put them who had William involvement and we put them through a capsule endoscopy a small bell series barium study, a colonoscopy with videoing uh and a ct angiography and after each modality completed their exam, they filled out a scoring system and put it in a sealed envelope and then we set together after all the modalities were completed and reached a sort of consensus standard about what the patients had and what we saw was that the capsule endoscopy picked up much more lesions than anything else. But then you could actually sit because you have the capsule endoscopy and colonoscopy and you could look at the images side by side. Uh and what you saw was that you were seeing stuff at capsule that you couldn't see with colonoscopy in exactly the same thing. It wasn't that it's upstream and you're missing upstream stuff the side by side distal ilium. The ulcers looked a lot bigger at capsule than what you saw at colonoscopy. And that always made me think that the the and then if you think back to the Cox two inhibitor days, remember those studies that where they were comparing various insets, Cox Cox two In placebo and up to 15% or so of the population had mucosal breaks. So you can see ulcers of capsule endoscopy. So my view is the capsule endoscopy is just way too sensitive. Um and the place that I generally use it is if I've got a patient with significant symptoms, they've got an elevated therapy, your child protection or some biomarker that makes me think they have uh inflammatory disease of the gut and I've done an MRI and I've done a colonoscopy and their negative. And so I mostly use capsule for kind of what I call obscure chronic disease. Terrific for patients. Just to close up the discussion on imaging for patients with terminal illegal disease that is accessible by colonoscopy. Would you ever just use and choreography? Say you've done a colonoscopy, mild inflammation. Maybe you escalate. Maybe you don't. Would you ever just use an Iraq graffiti for monitoring? So yeah, go ahead. Bill, go ahead. I was gonna say I personally wouldn't um there was a study that was published in gas or I think about three, maybe four years ago where they looked at um historiography versus double balloon endoscopy where they mapped out the entire small bowel and the angiography missed um significant Luminal narrowing and um after this ulcers about 20% of the time, if not more. Um so I think, you know, you risk missing uh important considerations. You know, if you do if you rely solely on the geography, however, it can be additive because sometimes you pick up these patients who have any biographies that are positive, but their colonoscopies are pristine and you're not even sure what to do with that at that point. So I'd be curious to hear it sort of builds thoughts, but I personally have not gotten to a point where I would use any geography and isolation for endoscopic lee accessible disease to make treatment decisions. I basically agree with that. I was just going to say from a practical standpoint, coming back to parent, there's debate. You know, patients have only so many colonoscopies in their life. And you do need to use them a little bit wisely. And and then there's just some patients, it's like, you know, doc I've just had enough and but and some of them will go for interest graffiti. There's the flip of that too though, right? There's the patient that just is claustrophobic and they would do anything not to do it and they're happy to have a propofol colonoscopy, but they do not want an autobiography. So, you know, it kind of goes both ways. Yeah. All right. Let's go back to health protection. We have a couple of questions on this. Um is help protecting best use as uh with this great cutoffs or is there a difference in a health protection of 3000 versus 1000? Yeah, so I think um so there's a few sort of things to think about about here. So yeah, you have to think about the test performance at the extremes. So when you get above 500 it becomes less sensitive. So you, you know, you can't really use 1000 versus 3000 as confidently to say that 3000 is much more severe than 1000. So, I think having some degree of use of cutoffs is important. So I treat everything above 500 is just active disease. Um Now, having said that, you know, when you think about the cutoffs for remission. Uh the com trial used to 50 a lot of studies have used to 50 is sort of an upper threshold, ideally less than 50. But if somebody's dropped their cal protected by 600 points in six weeks and they're at 300 am I going to say that they failed treatment? And we need to make adjustment note because it's a trajectory of the change that becomes important. Which I think is one of the advantages with cow protectors. You can do them a bit more often than you could with endoscopy to see how, how well they're responding and create a bit of a profile for what their trajectory looks like. So, um, you know, the upper extremes, I would not trust to distinguish severity. Um and you should use cutoffs to guide your decisions but don't ignore something that's pretty obviously getting better. Yeah. All right. I do have a sort of question on that note with built for bill. So Bill, um, what's the right time to do endoscopy? So if you do it too early, you may have missed the fact that they're actually going to get better because you just look too early and it hasn't quite changed as much. Um And if you look sort of too late, then you've lost a window of opportunity to make a treatment decision. So I'm curious what the right time is because you really only get one maybe two shots at getting somebody to come in for that colonoscopy over a year. And do you differentiate when you do the timing based on illegal versus Kalanick location. Yeah. Um So in all sort of colitis in clinical trials, you may remember like the delayed release miss Salomon trials. Some of them are even six weeks. And then we mostly, you know, we did it eventually evolved into eight weeks and then many of the biologic that we use have eight weeks, devil is ahmad was six weeks. Um and then we've gotten into 12 week trials to some degree more recently. Um And I think there's a, so you can you can definitely see a difference between an effective drug and effective dose and placebo by eight weeks. But is that the maximum effect, which is more what you're sort of looking for in clinical practice is probably not. Um So you know, I've tended to say about three months for all sort of colitis. And then in Crohn's disease we've had the sense that it feels more slowly. Um and it might take four months or more. Uh the actually in the face to study of Um you had to sit in a Jack one inhibitor in Crohn's disease. We randomly assigned The uh end of industrial production study colonoscopy. We ran the study for 16 weeks and we randomly assigned the patients to scoping at 12 weeks versus 16 weeks and the endoscopic improvement and healing rates were similar at 12 weeks and 16 weeks for whatever that's worth, I still think you get more healing later. And then if you think back to the sonic trial, we got quite good healing by six months, the combination of influx mob and so I've decided to to intend to scope the patient with all sort of colitis in about three months and Crohn's disease in about four months or so. But when if you look back at that data that we had in the treaty target studies, that's what we said we were doing in our practice. But the reality is was they were getting scoped at about six months. So you think you're going to do it three or four months and you end up doing about six months. So I think in practices it often ends up being about six months. And so I would say maybe aim for four months and realized that if you didn't effectiveness of you, you're probably going to be scoping at six months. I don't know. What do you do? Yeah, I mean I think I try to do the same thing. I think people come in early if it's december and they hit their deductibles and to come in later if it's january and they haven't met their deductible yet. So I think there's practical considerations but you can try your best for around 4 to 6 months. Perfect. Uh so we have one last question and then we're going to actually move on to our next speaker a little bit early. Um, and that will offer us some time for questions for him as well. But the last question is based on therapeutic drug monitoring and biologic trough levels. I realize that's not necessarily the focus of this talk and this will probably get addressed a little bit more later in the day. Um but if you do have a patient who's doing well, so this particular question is asking, it appears there in clinical remission there biomarkers are not elevated, but they seem to have sub therapeutic drug levels. Would you escalate? I think another way to think about that is is the drug even working or necessary, even at the slow levels. Um and then a follow up to that is target levels. So I know this is a big loaded question, but if our speakers have any feedback or if we'd also like to church some of that to the later speakers, I think that's fine. I'm gonna take 10 steps back and let bill feel this one. Um well, I think most of our data is with TNF blockers and then we tended to extrapolate that to use to kenya mob and the battle is a mob and the extrapolation may or may not be a good idea. So let's start with TNF blockers. Um we know that if you if you look at a variety of studies in the real world sort of setting that eventually at least a quarter of patients and maybe more get significant immunogenicity that abrogates the effect of the drug over time, you can block that to some degree with concomitant immunosuppressive therapy. But many practitioners and patients don't like the idea of taking a survivor and with their biologic so there remains a lot of monotherapy use. Um And then if you look at so what are the contributing factors immunogenicity? It looks like there's some underlying biology. So certain H. L. A. Subtypes make you more or less predisposed two getting immunogenicity. Um But low low low drug levels are certainly a really important contributing factor. So I think for um for anti TNF drugs if you know that the patient has a low drug level you should probably respond to it and if you're not prepared to respond to it. You could reasonably ask why did you measure it in the first place because you generally shouldn't do tests that you're not going to adapt on. So I think if it's an anti TNF and the drug levels low I would react. Now what constitutes low That's the second part of your question. Uh Citizen who's I think with us here um led a group for the A. G. A. That evaluated the literature and they ended up concluding that a constantly said you could come on if you want as I recall you guys Set a concentration for inflicts a mob of five And uh Adeline a mob of about 7.5. And there are some major enthusiasts of proactive monitoring that thought you were way off in that. But I think the literature supports that it's protective against immunogenicity and it's not clear that tried to drive to drive everybody to input Or at Islamabad concentrations of 10 or 15 or 20 and stuff which some people I want to do that you really need to do that. So I think five even maybe 7.5 at most. 10 Five for infliction. Abbott at most 7.5 or 10 for a dilemma mob is sufficient. Now, what about uh Vocalism ad and used to can you nab much less data on that. Um but the pharmacogenetics from the pivotal studies were published and you have association data is further with that. And my read of both all sort of collect this and Crohn's disease with Houston kenya mob is that concentrations of more than about 1.1 at most maybe 1 5 that you really plateau the the benefit after that. And so my personal opinion is that there's sort of an epidemic of used to Kenyan hub off label dose escalation which is not necessarily warranted. Uh and then there's a school of thought, you just do it empirically. But you know, I sort of think it's just a lot of it is not necessary that drugs really well dosed from the clinical trials with vandalism Ab for Crohn's disease. The you know, the Crp didn't change very much, which is interesting and equal protection wasn't measured and there wasn't any endoscopy. So you're purely going off clinical symptoms and that's harder to relates. So I think the blood level, You know exactly where to set the thresholds with federalism have is harder with induction. I don't think we have a very good feel for maintenance. It's probably around 20 or so. So now primer. You can take your 10 steps back. What do you actually do? Yeah, I think um, so I think there's there's two concepts to sort of make sure we touch on here. What one of the things that the question is asking about is a proactive setting. They're doing well. Everything suggesting that they're in remission. You know, I don't check the level at that point. So, you know, I'm usually not in a situation where I have to optimize them simply because I don't do necessarily proactive monitoring but the reactive setting where you have somebody who has either symptoms or active inflammation by some measures. CRP cal protector endoscopy. I agree with you. I think those those cutoffs are appropriate and you should optimize therapy at that point. And it is definitely worth checking before you empirically escalate because you will give yourself some time, you know, some people feel like the turnaround time for the drug ass a being a week is hard and then you have to wait for the next infusion to sort of make some decisions. But um, you know, for some of these drugs that are very well dosed like used to, can you add you definitely want to check before you try to empirically escalate so. Perfect. Well, I'd like to thank doctors july and Dr SAnborn, further engaging discussion on biomarkers versus endoscopy and IBD.
