Dr. Lori A Zimmerman - Effect of biologics on surgical outcomes in children with IBD

you you you you you you you you you you you you you you you you you you you you you you you you and you we'll get started. today we're very excited to have Dr Zimmerman with us today. Dr Zimmerman completed her undergraduate in psychology at for fellowship in pediatric gastroenterology at Boston Children's and currently serves as instructor of pediatrics at the Harvard Medical School, director of endoscopy here at Boston Children's as well as medical director of our multidisciplinary IBD clinic or the music clinic. So we are especially lucky to have her here today to talk about a niche area of interest of hers. And so in the evolving landscape of medical therapies such as biologics for IBD, this can be quite confusing and it has a tremendous impact on the outcomes of our surgical patients. So our shared patients benefit greatly from her research experience as well as clinical expertise. And so we hope to draw from that today and we're very lucky to have her. Thank you so much for joining us. Is there a way to see the slides on here? I'm just here. Maybe I'll look at my last. I want to be able to look at you instead of your fingers there. Yeah, so the options are to either she's left in a laptop and clicks once, which is to click to do a video to do like, but she wants to. Oh, I get you that doesn't change the fact that she's not looking at us. She wants to face this way. She needs to have a. Yeah, I'll just put out of mind. I'll double click. Okay. Yeah, the only other way to join your laptop into the Zoom call is you'll be a little more. If you can click both of them once we like with right now, it's a chance you will hire you. Okay, if it doesn't work, you tell me. Thank you so much for having me. This is really a nice opportunity for me to see all of your bases and those so I can't see on Zoom. I know this is really nice. So I'm going to be talking to you about a topic that is of great interest to me, but something that we talk about all the time on the words and hope to review the most current research on the effects of biologics on surgical outcomes in our case with IBD. I have no financial disclosures. I will say the one disclosure that I have is that there's very limited pediatric data on this topic. So I'll highlight it when it exists, but this is why more collaboration between GI and surgery here is needed. So my objectives of the talk are to review advances in IBD therapy and most commonly used biologics. I'm going to focus on the ones that we're prescribing most commonly now, the TNF inhibitors and flicks a map and add a little map, that alizar map and oosterkin a map, and then I'll focus on how those therapies affect perioperative and postoperative outcomes. So I'm going to start with a case. This is a real case that we took care of on the words. 12-year-old male with Crohn's disease who presented with abdominal pain, anemia and weight loss. His colonoscopy showed severe Iliitis. He had an MRE that showed 8 centimeters of Iliol narrowing with proximal dilatation with thought to be inflammatory in nature, so he was induced with prednisone and then received an influximab loading dose. I'm going to just look back and forth. We'll be fine. Unfortunately, shortly thereafter, he presented to our emergency room with a small bowel obstruction. He was admitted to our service. Initially, we were able to decompress with a nasogastric tube, but unfortunately, we were unable to advance him even to a liquid diet and we called one of you hoping to pursue surgical therapies for this patient. So this is me calling the sod or whoever's on for the day. We think this patient needs surgery, but wait, this patient just got this huge loading dose of insulin sluximab. How does that influence outcomes? Those are conversations we have all the time. So I think this case highlights important clinical questions. What factors in general determine surgical outcomes in our patients with IBD and does the biologic itself increase risk of surgical complications? And then after surgery, how long after a reception should we be considering recerting biologics? So just to take a step back, before 2000, we really didn't have many options for IBD patients. We had these non-specific, systemic immune suppressor therapies. We had immunosilicylics like sulfosalazine, misalamine. We had steroids and we had immunomodulators like 6MP or esopin or methotrexae. And when those failed, we really had no other medical options. Fortunately, there's been a lot of work on the pathophysiology of IBD and now we understand more of the mechanism from an immunologic perspective that there's really this interplay between microbial dysbiosis and alterations of innate and adaptive immunity. And so in the last two decades, we've been able to have this explosion of these targeted therapies, the target these pathways that we know are disrupted in some of our patients with IBD. And so since 2000, we've seen, we have many more tools in our medical toolbox and that's why you're seeing all of these new therapies. So late 90s, early 2000s, we saw FDA approval of our TNF inhibitors. Influixamab is remakade or inflectra. And I'll talk about that a little more. Adelimimab is humera. Their influixamab and Adelimimab are starred because unfortunately, the only drugs on this list that are FDA approved for pediatrics are influixamab and Adelimimab. The other drugs are all approved for adults and we fight a lot. We spend a lot of time in GI fighting with insurance companies trying to get these other drugs approved off label. 2008 to 2016, we saw the Integran inhibitors, Natalizimab and Vetelizimab. Vetelizimab is Intivio and Ustakinimab is Salara. And then in the last few years, we've seen Jack inhibitors, which is a small molecule, Tophicidinab is Zeljans, who've had a sedemnab, it was Rinvo, you don't have to remember, it's very hard to say. Rizimkizimab is a selective IL-23 inhibitor, that's SkyRizzi. Probably seen a lot of commercials for these when you're watching sports. My kids know all commercials from Abby. Abby's Rinvo, etc. And Azanamad is a newer oral agent. So I'm really going to spend time focusing on the TNF inhibitors that Alizimab and Ustakinimab, because as of right now, those are the drugs that you're going to see us using most often. So TNF inhibitors are still really our best IBD therapy. Influximab is given as an IV infusion. You get it at weeks zero and then two and then six and then it's usually given every four to eight weeks as maintenance. It's a chimeric antibody. So it's mouth and humanized antibody that locks TNF alpha, one of the important inflammatory cytokines with IBD. The nice thing about influximab is you can order what dose you want to give and then give it through the IV in the infusion center. So there's been a lot of studies that have shown for certain IBD phenotypes, like perienal disease. If you're trying to close a fistula, you need to target higher levels. Then if you just have isolated ilial disease, if you have severe colonic disease, you lose a lot of the antibody and the stool. It's like a TNF sink. And so you need to target higher levels. So that's why we use influximab a lot more commonly in those scenarios. Atolimimab is humera that's given as a subcutaneous injection. It's a humanized antibody. It's nice for our college students because it doesn't tie you to an infusion center. So they're, you know, they can travel. They can bring the drug with them. The risk really is the same. There's risk of infection, drug reaction. Even though these drugs are used in a lot of other autoimmune conditions, you can see it induce autoimmunity. We've had patients that have had, you know, lupus-like reactions, psoriasis, CRIMO, etc. And there's a small risk of malignancy. About 60% of patients are TNF responders in general. The clinical trial that I have up there on the side is the sonic trial, which is the famous Crohn's adult study that looked at is a thiraprin compared to influximab monoptheropathy compared to combination therapy with influximab and is a thiraprin. The big issue with these drugs is that their antigenic uramune system can react against them. And so you have issues with loss of response. So your body builds up antibodies against them and then they stop working basically. So because it's one of our best drugs, we want to optimize it like in the beginning as much as possible. And so we think why combination therapy works better is that the immune modulator dampens your immune system just enough that you don't react against the drug. Sometimes we can do that also by targeting higher levels, but you never drop low enough that then you get antibodies basically. Vetalismab is also given via IV infusion. It's an 8th alpha-4 beta-7 integrin inhibitor and it inhibits leukocyte migration to the gut epithelium. So we think in general this drug is safer probably than the TNF inhibitors because it's gut-specific. It just doesn't let the white blood cells stick onto the GI track basically. So there's not a risk of systemic malignancy, systemic infection or malignancy we think. But it does take time to work. So most studies show that you don't really get response. Sometimes we have some patients that respond quicker, but usually it's like six to 12 weeks. So for a patient that's like really sick with colitis and you want to rescue, this is not a great drug because you just don't have the time for them to sit in hospital for three months. We know that Vetalismab efficacy varies by TNF exposure and this has been shown actually in all of the biologics. Once you fail TNF, the other drugs are less likely to work and we don't know if that's because that identifies you as having a worse phenotype or there's something that changes in your biology. Once you're exposed to TNF, we really don't know. But these are just two studies that show that. So this is a retrospective pediatric study that looked at Vetalismab in Crohn's and UC patients and the bar that's filled in. You can see, oh I can use this, right? The bars that are filled in, this is the dark bar is Crohn's disease, who's in patients that are TNF naive and this gray bar is UC patients for TNF. And you see that the histologic remission and isopic remission, seroi free clinical remission and ecosyl healing are higher in those patients that are TNF naive versus the dotted bars are those patients that have been exposed to TNF, both Crohn's patients and UC. On the left here, you'll see a study that was just recently published. It was called VetoKids. All these biologic studies have these cute names. Looking at Crohn's first UC efficacy, efficacy of Vetalismab. So for Crohn's patients, week 14 clinical remission was about 30% and UC was about 50%, but when you look at stratified by TNF exposure, the green bar are those patients that have been exposed to TNF before and the red bar are those that were TNF naive. Boosted kinemab is salara. This is a biologic that targets IL-12, IL-23. It's given as an IV dose and then subcutaneous maintenance dose. And the risks, this is also a pretty safe drug overall, but does risk systemic infection. You can get an injection site reaction. Posterior lucos at the lapathe syndrome is reversible, but it's headache, swelling, et cetera, and malignancy. This is an adult study that was just recently published looking at Vetalismab versus Usticinemab in Crohn's patients who have failed TNF inhibitors. And basically, the efficacy was very similar. Week 6 response was about 60% for both, and week 52 remission was about 30%. Most drugs actually are around 30% clinical remission after you fail TNF. We have a lot of options, but none of them are amazing. That's why we need to continue to work together. And thinking about the risk of the drug itself, we have to think about what other factors influence surgical outcomes. So our patients with IBD are unique. They have other risk factors, malnutrition, hypomanemia, cortical steroids, disability, or opioid and active inflammation, dilation of proximal small bowel, whether the surgery was emergent or planned. You guys all know this, all influence surgical outcomes. And so when you're trying to get to the true effect of the biologic itself, it can be a little bit murky. So just to kind of extrapolate their studies have shown that nutritional status influences perioperative outcomes. So preoperative hypomanemia is associated with increased septic complications, and malnutrition itself impacts postoperative morbidity and mortality. And so we know that this is really important. Our patients that need surgery with IBD should have a dietician involved who are monitoring their caloric intake, considering antirel and preential nutrition if possible. And if they're malnourished with a low albumin and they can wait, you might want to optimize that risk factor is really important. Cortical steroids is another biggie. Hidosteroids we know are associated with infection, an astymotic leakage, and poor wound healing over all complications, ETE. And so we really try to limit cortical steroid exposure prior to steroids and prior to surgery and rapidly taper. I will, you know, the studies show less than 20, but I know in our practice we try to get even lower than that less than 10 if possible. So when you're looking at studies who are trying to look, I'm going to about to show you some studies on biologic outcomes, a biologic effect on surgical outcomes. You have to know that there's really heterogeneous studies because the effect of the preoperative biologic on postoperative outcome, it may differ on how close to surgery the biologic is given and how sick the cohort is, you know, are they malnourished, are they on steroids, or do they have anemia, how bad is their disease, do they have other complicating factors, and I think that's why you see so much heterogeneity in the results. So some studies show that TNF inhibitors increase surgical complications, so just to show you a couple large adult studies, RoKET et al reported on almost 600 adults with Crohn's disease, and they found that TNF exposure within three months increased overall postoperative morbidity with an odds ratio close to two. Another study looked at just over 200 adults with perioperative and flixamap these are Crohn's patients, showed an increase in infectious complications, 36% in the TNF exposed group, first 25% in the nonbiologic exposed group. I want you to pay attention to the rate of complications because the adults have a much higher rate of complications that you guys have, so the way their studies are powered differed, and there's no difference in overall complication rate. This is a study that looked at TNF levels and whether they can influence surgical outcomes, so just over 217 IBD patients who had surgery and they drew an inflixamap level within seven days of surgery, and found that if you had an inflixamap level greater than three, you had higher postoperative morbidity, increased infections, and this was especially true for a level was greater than eight. A level may matter. So in contrast, some studies showed that TNF inhibitors had no effect on surgical complications, so this is a study that looked at almost 300 Crohn's patients, there were some pediatric patients in this cohort, showed no difference overall or infectious complications. Another study looked at 119 inflixamap exposed patients compared to 370 non-inflixamap exposed, they found no difference in total or intra-abdominal complications. Norgard used a Danish registry study to look at over 2000 patients, adults, and children with Crohn's disease requiring surgery, and they found no difference in postoperative complications, whether the inflixamap was given at 12 weeks or at 14 days, there was no difference in bacteriumus, there were two men analyses published within a year of each other that had completely opposite conclusions basically. So this is one study that included 1,600 Crohn's patients that showed increased complications related to inflixamap exposure, their infectious complications had an odd ratio of about 1.5, but you see it's pretty close to one, the confidence interval, and mostly they found infections remote from the surgical site. A contrasting metanalysis included studies with 1,159 Crohn subjects, and they reported no difference in major complications or minor complications based on TNF exposure. So there was very little pediatric data, so we actually reviewed our experience here at Children's, we retrospectively looked at 123 patients with Crohn's disease, ages 7 to 21, who underwent initial valve resection here, we went back deep into the record from 1979 to 2011 and assessed major and minor complications, you can see the actual complications listed here. And we found in our pediatric study no statistical difference in complication rate, so basically we had 21% complications and the inflixamap exposed for 11% and the non-inflixamap exposed. Our overall complication rate was only 13%, so that's much lower than the pediatric studies, so to see if that 10% difference between a inflixamap and non-inflixamap with statistically significant, we basically need a multi-center study, you need a very, very large study, you need you know over 700 patients really to see if there's a difference, so there's either no difference or a small difference and no difference in major complication rate or postoperative length of stay. Since our study, there have been a couple of other pediatric studies reported, Amy Lightner's group and Cleveland Clinic does a lot of work on biological exposures and surgical complications, so they looked back at 69 children with Crohn's underwent resection and they found that TNF exposure was not associated with 30-day infectious complications. Metsuya's group looked at 60 children with IBD, so this is both UC and Crohn's, some of the studies are one diagnosis, some of the studies are combined, stratified by biological exposure prior to surgery, they also had a very low complication rate of around 6%, and they found no difference by biological exposure. So finally we have some pediatric data, this is another cute study name, the Puccini study, is a prospective cohort of ulcerative colitis and Crohn's disease patients undergoing surgery to identify risk factors for postoperative infection, these are adults, so this is a multi-center study basically that prospectively enrolled IBD patients requiring surgery, they enrolled 955 patients who underwent intradominal surgery and they found no increase infection rate related to TNF exposure within 12 weeks of surgery, the complication rate was both around 20%, so that's pretty good. Active anti-TNF and detectable anti-TNF levels at the time of surgery was also not associated with infection in this cohort, so they were able obviously it's prospective, they were able to control more than some of those retrospective studies. So the way that I digest the CEDA, obviously I'm curious how you all think about it, is that you want to optimize the patient, but I wouldn't necessarily delay based on TNF exposure, the risk of anti-TNF on surgical complications seems to be small if any looking out of the studies, but you do want to optimize other risk factors as much as possible, nutrition, cordial steroids, etc. So just for an example, the patient I showed you received PN, wean steroids, decompress their bowel and then had a successful resection with primary and S and most is about two weeks later. So in a patient like that, the question also comes up, how soon after surgery can we restart the influxumab and should we be restarting the influxumab? So there have been a number of studies looking at postoperative recurrence for most patients with Crohn's disease, if you do a curative resection, like you take out all the inflammation, eventually it comes back. But there have been a number of studies looking at TNF inhibitors and preventing postoperative recurrence. This is one, it's called the prevent study, then enrolled 297 adults with Crohn's disease and randomized them to a NISLXMAB or placebo, and they found endoscopic recurrence at week 76 with 30% in the patients that were put on an influxumab versus 60% in patients who are on placebo. Miguel Regarro's group randomized Crohn's patients after resection to influxumab versus placebo at two to four weeks postop and then looked at complications and there was no difference in complications. So it looks like you can restart influxumab as early to two to four weeks once they're basically recovered from that initial surgery. So that was a lot mostly Crohn's patients. So now to kind of change gears and think about anti-TNF risk and UC patients prior to collecting me in IPA. This is, you can see I'm raised on 90s hip hops. I have to give a little nod to that. So obviously to this crew, I don't have to explain a two step versus a three step, but just in case there are trainees who are listening in. For our ulcerative colitis patients, there's three stages to the surgery. You remove the colon, you then take down the rectum, create a j-pouch, and then the third step is you take down the stoma, keep me honest, something, anything wrong here, guys. So you can do this potentially as a two step where you create the j-pouch and the initial surgery to basically save the patient a surgery or you can do this in three separate surgeries. So the studies show that a healthy pouch equals a healthy patient, basically. The more risky thing that you all do is create that j-pouch. So the plus of the two step is that it minimizes surgery. I mean, these are our patients are being pulled out of school, you know, their normal life, having to recover three times. It's not a small thing, more time with stoma, which, with human eye-see in our music clinic, really is a big deal for kids. But the con is that you're creating the pouch when those patients are sicker. So they've all those other risk factors. I just talked about their malnourished, they have bad disease, they're anemic, et cetera, they're on steroids, biologics. And so factors that affect the surgical decision-making, clinical severity of disease, nutritional status, condition of the rectal mucosa, and degree of immune suppression. And so studies have shown that anti-tain eff exposure may affect complications in creating the j-pouch. So this was over 2000 ulcerative colitis patients that underwent colectomy. And they reviewed post-operative complications based on anti-tain eff exposure within 90 days of surgery. And they found increased complications with j-pouch creation. So in patients getting a two step that had that pouch created at that initial surgery. But not if you had just the total colectomy with a diverting ostomy, those patients did really well. There's no studies to my mind that showed increased complication based on tain eff exposure and patients going undergoing a total colectomy. So the first part of a three step. So the Crohn's colitis foundation put out a position paper on this topic that basically concluded that sub-total colectomy or three step procedure, or the first part of a three step procedure I should say is safe in a patient that's been anti-tain eff exposed. It may increase risk of post-operative complications in the two step. And anti-tain eff therapy is an absolute contraindication to a one step procedure in which we don't do care based on complications. But I know from my residency they do do in other other spaces. Okay, so in Fluxna, remember I told you, it came out about 20 years ago. What about the newer biologic? So you have to remember that all the initial drug, these are all just getting FDA approval. All of the drug studies exclude surgical patients. So it takes time for us really to have any data about any of the newer drugs. They've all come out really within the last 10 years. And so sometimes we're learning as we're going. So this is an example of this. Jill and I took care of a patient on the wards right when Vetalismab came out. This is a sick patient who required a diverting Iliostomy and was really sick. It basically failed TNF inhibitors and all of our sort of drugs available at the time. And we said, oh, there's this new drug. Let's try Vetalismab didn't get better and ended up with a stoma. And the stoma like really never healed. She had this really severe mucosal separation. And that was just unusual. And that made us reach out to our partners across town at the Brigham. And they said they've been seeing some of that too. So that made us look back at our experience basically on Vetalismab. And so we at the time looked back, there were, there had been 13 patients that had received Vetalismab at our institution both for Crohn's disease and UC. And you see the complications were much higher like eight out of 13 is much higher than the other complication rate I showed you. The control population that we used were other patients with IBD that required a diverting Iliostomy thinking that those patients are also sick for lack of a better term. And there was a trend towards the Vetalismab, you know, having a higher complication rate. We also found that there were three patients in our cohort that had this mucocutaneous separation of the stoma. No difference in length of hospital stay. Around the same time, Amy Lightner's group had reported on 392 adult patients. 94 had received Vetalismab within 12 weeks of surgery. 126 had received TNF inhibitors. 172 had no biological exposure. Big percentage were on steroids and immune modulators in this study. And they had a really high complication rate, but the highest in the Vetalismab group. So 53% compared to 33% TNF and 28% no biological exposure. They also had higher surgical site infection in the group that were Vetalismab exposed. And interestingly, they also reported on this mucocutaneous separation of the stoma. So at the time, we didn't know much about Vetalismab, but it just come out we were using it on these sick patients. What I told you before is that now we think that Elismab is actually one of our safer drugs. And so we're starting to use it earlier on patients that are not as sick. And so how much of that risk is really the Vetalismab itself versus the fact that we had patients that were really sick and had all these risk factors. And it doesn't turn you around fast enough to influence outcomes basically. So since our studies, there have been some other studies that show that Vetalismab may not be as risky as had been originally reported. So this is case match control study looking at 95 Vetalismab exposed compared to 95 TNF exposed. And they matched them by gender, age, diagnosis, and surgery. And they found no difference in morbidity or infection based on Vetalismab exposure. There was a men and outs as excluded our pediatric data unfortunately, but they basically looked at all these small studies that have been reported. And they concluded that Vetalismab does not increase postoperative risk more than TNF inhibitors. This is a study that was just published last year. Again, it was Amy Lightner's group. They're doing a lot of work over there in Cleveland Clinic. They looked at the risk of abdominal abscess in Crohn's patients requiring resections stratified by biologic exposure. And they included 257 with exposed to TNF, about 500 that had no biologic exposure. And they had 32 patients that had been exposed to Vetalismab. And this study included Ustakinemab too. So that was just kind of coming up. And on univariate analysis, there was a higher risk of intrapdominal abscess with Vetalismab. But when they looked and did multivariate analysis, it really didn't have any effect. It was really only hypoabiminemia. So, albumin less than 3.5 that really influenced intrapdominal abscess. There was no difference in leak. There was a difference or at least a trend towards a difference of Ilius in the Vetalismab exposed patient. So I don't know if it has some issue with, you know, I guess it makes pathophysiologic sense that you need those weblet cells in your gut to kind of wake things up and heal. No difference in infection. A secondary part of the study that actually wasn't even like a key outcome, but I found really interesting because it's important for our patients. If that were, or not, you got an ostomy. Did seem to vary based on biologic exposure. So the top line are patients that had a primary anestimosis without an ostomy. So you see that patients not exposed to biologic and TNF are around 50 to 60 percent. And the Vetalismab group is like 30 percent. So if you look at an ostomy, patients that had an ostimosis with a temporary ostomy, the Vetalismab group is like 46 percent much higher than the TNF or the no biologic. And similar with the no an ostimosis primary ostomy. So there weren't enough patients for them to do multi-varied analysis in this, but it's just something that kind of raises an eyebrow. Obviously that's important for our patients. This is at the time when Veto was still really new. Like is this reflecting surgeon bias or? I mean, this is 2021. So it's a newer study, but newer like, you know, the other ones were like 2015. This was probably like 2019. So it's a few years later. But could be. Especially that the other like the abscess, they didn't see that it made a difference. It's hard to know, I think. This is the only study I could find on ostokinema. But self-compared to TNF inhibitors, a retrospective review of Crohn's patients with Iliocalonic resection, they compared ostokinema, exposure to TNF inhibitor, exposure, and they found similar surgical site infection. 13 percent in the ostokinema group compared to 20 percent in the TNF exposed group and no difference in readmission or other infections. So I'll be interesting for us to kind of talk. I'd be so curious to hear what you all think about all this data. But in my opinion, if a sick IBD patient needs surgery, I wouldn't necessarily delay for biologic exposure alone if you can. If it's elective, then that could be a risk factor and worth waiting. But if you have a sick, caulidic, for example, they're just going to rack up potentially other risk factors. So, you know, waiting. I do think it's important to know the risk so you can cancel your patients on the risk. You know, potentially there could be higher risk of infection. We're not sure, etc. And obviously, when I optimize other risk factors that are sort of more quickly, amenable to change. And so the take home points that I find or that anti-TNF exposure may be associated with a small increase in postoperative complication. We need more prospective data to get to understand more about perioperative biologics. I didn't even talk to you about the Jack and Hivinners or Skye Rizzi because there's really no data on, you know, that those just came out like we're just using them now. I have like one patient on Renvoq. Oussikinamab and Vidalizamab have some small inherent risk maybe, but it could be explained by other factors. I think the jury's still out. Hopefully we'll get some prospective data in the coming years on those therapies and we need more pediatric studies on all of this. So this is why we have this clinic here. So this is a multidisciplinary clinic. We call them Music Clinic. It meets right here actually. It's medicine united with surgery and the care of IBD Prithima. There are jills there. You see some friendly faces on the on the board. These patients with IBD that need surgery have complex needs. They need help with nutrition. They are often, you know, they have chronic issues where they've been sick for a long time. They're pulled out of school. They really need psychosocial support and they need us in a room together talking through what's best for the patient because it's murky. It's not always clear cut what the best option is. So this has been really fun experience to work with Prithima and Jill and Craig in this clinic. I'm Caitlin. I don't know if I talk fast but it's good that we'll have time for questions and I really appreciate being able to show all this data. All of you. Well, all right. I want to first thank you for coming and I can see his and mav now. I've worked for 20 years on that. You're last slide before this really the one we were showing the music clinic really makes the point. There's a summary to me. If you hadn't shown that side, I'd say, well, your last 40 minutes discussion makes the complete argument for the music clinic. For us to understand these biologics is pretty complicated and we don't write the prescriptions for them. We don't have to convince insurance companies about them. Thank you for all that work. I know how hard that is. But you also aren't in the operating room. You may be not been watching, but you're not the one answering to the family when the stomach separates or the intradomal affection and that decision about taking that risk of biologics, no biologics, when to do surgery, when to wait, when to give TPN, when to do one stage, two stage, two stage, three stage, it makes probably no two ones. It's a really complicated discussion and the families may have different views. The combination of the surgical, the medical, the social, the psychological is really key. I think it's good to theme up many of the things that we've developed as multi-sport efforts at children's and I know your leadership and making it happen along with the surgical leadership was not trivial. We appreciate how much it's coming along. That's the first question. We have lots of time for a few questions. For those of you on Zoom, Andrea has the laptop. She's going to ring in. So please type your questions into the chat and we'll be able to unpack them on. That goes 203. Yeah, but I don't know. We have access to them. We do. Okay. Type of things because we can see your questions. They're on the screen. You talk about from the surgical perspectives, like back in the dark ages. Going back. Back when we went to blockbuster. I didn't catch the hip hop rocker at home. That was funny without me. You've got it. I'm interested. Was I supposed to rip this? Yeah, that's a cheesy song. Oh, okay. It's crazy. So, it makes it. That's crazy. It's exactly right. The concept of surgical sure, right, was we were told it was real that some people with limited healing, you'll see cold disease for Crohn's disease can have a cure. But don't bother doing even I'm young enough to not have to do margin analysis on microscopic margins because it's not only positive, but sometimes you'll have long term symptomatic cure with surgery alone. I think the number you showed there was 60% recurrence versus 30% with inflexion. Influxion? With inflexion at 406, starting sometime after surgery. Does that mean that that's a 6% number that actually there are people still that don't occur after surgery alone? And do you ever try that? I mean, what if the surgeon says, or UCN is copied clear by imaging, it really seems like the disease is just right here. Do you ever try that and how long do you wait? That's a really good question. So, there are some patients that don't occur. How to identify who those patients are is sort of the tricky piece. So, I think it's a decision with the family. So, how quickly do they progress to structure? Where are they in their pubertal development? Because our pediatric patients kind of have more at stake as they're growing and developing. How extensive was their resection? We know with post-operative recurrence that you can catch it. So, there have been studies where they basically it's called the poster study where they stratified patients to early post-operative surveillance, like where they were screened with colonoscopy at like six to 12 months post-op. And you see usually inflammation come back that you can then capture before it's structuring or, you know, perforating. Usually you get mucosal disease before you get, you know, transmural disease. It's causing like a lot of issues. So, there are some patients. It's hard in a patient like a lot of our patients, especially we see in music, have failed a lot of drugs, you know, like they have failed and flicks the Mab, Stolara, Vidalismab, and they're on to, you know, who knows what. So, it's hard in those patients to not feel like you want to prevent them from needing another surgery for as long as possible. The drugs also do prevent penetrating complications, like they prevent you from getting official and an abscess. Interestingly, the natural history studies don't really show that they necessarily prevent you from stricture. That may be just like the natural history of the disease. I think that juries a little bit out on that, but it's not as robust as it is penetrating disease. It's really a conversation with the family. I would say for most patients that are sick enough to require a resection in their pediatric age, we would restart to try to prevent them from needing another surgery as long as possible. But I think if you had an older adolescent that had a pretty limited resection and they were really reliable family that was willing to kind of have repeat colonoscopy surveillance, then you could argue for watching seeing what happens. I don't think that's a wrong approach. If you have a really sick kid who's younger, who's loaned through a lot of meds, who presented with a big abscess and was really sick, I'd really err on the, or as a larger resection, you know, I would err on the side of putting them back on as soon as possible. I don't think there's a one answer. And you may get a different answer. Unlike if you ask five IBD doctors, I think that's a different part of it. All right, thanks so much. I learned a lot too. So I really appreciate you sharing all this data with us, especially because in pediatric surgery, a lot of what we do is not data driven. So it's always nice, even if it's an adult, it's nice to see it. I have two questions. One, I think some of the most challenging patients in Crohn's are the ones who have short segments of your disease within long segment disease. It's not one of those satisfying resections where you go in and there's really isolated disease and instead you're dealing with a couple of really troublesome strictures. And a common question I get from families that I've hedged, but we'd love to know if there's any data or if you have an opinion on is, after you remove the worst of the disease, do you tend to see a better response to the treatment they were on before or to new drugs or is it not predictive at all? And then just what I do, operatively, influence how they're going to respond to the medication for the residual long segment disease or are these really separate things and I can't cancel the family out. That's going to happen next. That's a really good question. I mean, I think we have some patients that have a say, Iliocalonic disease and you put them on one of these drugs and they're colon heals, but they have this like really stubborn area of Ilium that just nothing will touch it. That's different than what you're talking about, but I think in that realm, if you take out the sick disease and the same drug may keep things from coming back because you've had response. But for a patient that has these worse areas, but still severe disease in other areas, I think you taking out the worst when they're so bad that drug is probably not going to all of a sudden work better. We have a lot of options now, but we don't have a limited options. That's why on our end, it's really important to optimize each therapy as much as possible and really be sure you give it as much of a chance before you give up on it and go to the next one. There's more and more coming out all the time, but especially for a kid with a few small bowel disease, that's really tough, right? You can't remove a small bowel, obviously. So those are the patients I think we really struggle with. I would probably change to something else post-op if you were removing the bad stuff and there was still a lot of active disease if you have another option. The other question that comes up is how good does it have to be? Most IBD studies treat to mucosal healing, not histologic healing to your point seed. You can blow through all of your meds if you need it to be perfect. If you have a patient that's mostly great, but there's one aphae or they just have histologic inflammation, you would definitely call that a win. But it sounds like for your patient, there's poor, pretty extensive inflammation that you would probably want to change. The second question I have is I know you didn't plan to talk about the jack inhibitors, but with the trial that's happening here, I think we're going to see more of those kids coming through the ER. Can you talk a little bit about gel dand gel? I don't say it wrong. Gel, gel dand gel. Gel dand gel. And some of the complications that we might examine. So, gel dand gel is tophysidinum and rinvoke is opatysidinum. Gel dand gel came out first. It's a non-specific jack inhibitor, whereas rinvoke is more selective. So we think maybe rinvoke will have less side effects because when you're blocking the jack pathway, I'm going to go back. It's fun. It's like a really important pathway in immune suppression. I don't know. How do I go back without having a spade? Oh, thanks. So this is the jack pathway, jack one, jack three. And the things that we look at, so first of all, infection, things like curpy-soster, like it's important. It's recommended to get the shingles vaccine. I actually am not sure, like what age the shingles vaccine is approved to. I have to look that up. There's definitely increased risk of venous thromboembolism in adults. Like, you know, adults got like MIs and things like that. I mean, our population is a little more risk for that. In general, we have less obese patients. They're more active, etc. But that's definitely something that has given us pause. The plus is that works fast. So like I was what I was saying before is like the colitis patient who's failing, remocade, and steroids, and you know, you're considering collectimy versus like another drug. You wouldn't use that alias now, but you could consider a jack inhibitor. That's what I think most people are using as like a third-line rescue. Because if it's going to kick in, it's going to kick in within like two weeks pretty quick. It's a small molecule and it's oral, so that's nice. There's risk of like cholesterol alterations. You have to get a baseline cholesterol. I mean, a lot of these rare malignancy risks, like we've moved away from six MPNAs of thirapran because of this really rare risk of a padispline T cell lymphoma. You'll know about this. Basically, like we use six MPN in the 90s. We use six MPNAs of thirapran all the time as like basically like a steroid limiting agent and it worked really well as an oral drug. It's really cheap. But there is a higher risk of things like lymphoma and in young males specifically have had a sponic T cell lymphoma, which is potentially fatal. It is extremely rare, like one in 10,000. But you need to use it and enough people to find that rare risk. So I think the jury is still out like when you're hitting your immune system in this way. We have these studies that are like just coming out now. What's the malignancy signal going to be? We don't really know. I don't think, I mean, I think infection would be the thing I would think about, but because it's fast on, fast off, it's not a biologic. It's a small molecule. So the washout's quicker, I think too. So I think it's probably more like how we use the calcinearine inhibitors that it kind of goes on and off quicker, that it would probably is a quicker washout. I think the thrombone ballad piece is coming up a lot with families. It must be in the news or being out of those black box warning. Yeah, I mean, actually that's an important point because you guys worry about that with your surgical patients. So definitely could increase risk like that might be a reason to consider a low-vanox and a patient that's on cell jans or vynvoke. Because the vynvoke's a bit more selective, we think, but like it's too early, I think to know for sure, but we think that maybe some of these risk factors are going to be less with vynvoke. But there's not even pediatric studies ongoing in vynvoke yet because it's too new. Does that answer your question? I think it is really important to talk about a lot of what you're talking about today is about risk tolerance, right? Both on the medical side in terms of the medications you're giving and on the surgical side. As Steve said, you know, we're the ones that have to sort of say, sorry, you're just a dumbest operator about the access. There's a third piece, though, which is the patient and family. So are there data about sort of the patient's risk tolerance, what they prefer in terms of, as you mentioned, like having a stoma and all the issues around a stoma or the quality life piece that they have, are there data about that in terms of what they prefer in terms of their risk tolerance? That's a good question. And the short answer is like, no, there's not much data. I mean, I think with vynvoke and I will tell you in the music clinic, these kids have really major psychosocial issues in general. I mean, not every patient, but I think it does matter. Like we have a lot of teenagers, for example, that are when you're a teenager, you're just like kind of having getting used to your body, your sexuality, you know, you're starting to develop mentally, distance yourself from your parent. It's really hard to do all of that with a stoma, but I think that's really important work and hopefully something that we can start to kind of look at more in the music clinic. But it's really good instruments, I'm sure you guys are aware of, for those things. What's the learning from you? Honestly, I mean, the piece, QL sort of umbrella has a lot of GI specific symptom scales that are pretty well validated, even in chronic GI conditions, but it'd be interesting to look at it specifically with these kind of questions in terms of what the patient's prefer and what those outcomes are because obviously, you know, they have to be a part of that decision, especially these older adolescents that are starting to be like said. It's also hard, I think, for them to think short term and long term. Like, you know, for example, our UC patients, they need their pouch to last like forever, you know, ideally. So wanting less time with a stoma upfront, but potentially to have a better pouch outcome, that's like hard for a 16 year old to digest. That's a perfect group to look at because I observe the difference between how they feel about their stoma when we talk about it at stage one versus their rush to get rid of it after stage two is totally different. They're much more comfortable with their stoma by stage two. They're planning stoma closure around when prom is and when this is and they're, you know, it's totally different to them because I understand that. So it'd be really interesting to look at that before and after with familiarity. Yeah, and there's differences in parents as well. I mean, I've had parents when there was a choice about when to, um, like, I'm thinking about long term, hurt your patients, uh, total clogged patients I've had some experience with where, um, we've had discussions about timing of closure stoma and I had a couple of parents who were like, what I do and find, I'll just wait till they're old enough to decide for themselves. I've used that word problem. I said, well, you know, by time they have to, you know, take about going to prom, they may look at you and say, Mom, Dad, why did you make me go like this forever? Why didn't you do something for me when I was four or six or, or whatever? So there's different, kid views, different ages, but there's also different types of parents. And that's a really good point too in that like some of these kids are delaying, you know, now there's like all these other medical options. Sometimes the ratings on the wall, right? And the longer you kind of delay and try all these things, either the sicker, the patients are longer that they're sick, you know, not like living their life the way they're supposed to. Like these patients have really debilitating GI symptoms while they're sick. So sometimes making that choice earlier, um, for a surgical option is the way to go, but it's hard. It's, it's, it's almost harder now, I think, because there's more options like before we had all these options, it's like, well, this is it, you know, so there's, there's a lot more decision and like, there's a lot more unknown. So that makes art, I mean, it makes all of our jobs harder, I think, in some ways. Other questions for that measurement? I have the chat. Doesn't look like you put into a resting thing. I chat, I think I chat, please speak up. And that is 7.56 and now that we're doing things in person, we actually, a little bit of a passing period for some things. I will comment for those in the room, it really is a pleasure to be able to finally be in non-clinckly areas without a mask for those who so choose and are able to be vaccinated. And we will start having opportunities to put things that are mouth, response by the department, I think we used to do, and get back to some sense of prior normalcy. But as we had as a department to define before, there was user option. We started doing that before the pandemic. We didn't run our work soon then, but now it's a little smoother. So thank you so much for doing this and not only for the, then for educating us, but for all the contributions you've made to our patients and to the logistics of working with Jill to establish the music clinic and working with them up this brand team. It is a special sauce of how to take out these complicated patients and your involvement has been crucial. So thank you so much. Thank you. It's been really fun. I have to say, it's a great group. Thank you. Thank you. So that's going to go in the hall. We're all going to forget to do that. Med, forget my mouth. Can I close out the zoom?