13. Inflammatory Bowel Disease - Medical and Surgical Management

In this class, we're going to focus on inflammatory bowel disease, specifically medical and surgical management options. We'll talk about the goals of therapy for management of patients with inflammatory bowel disease. We'll have a major focus on pharmacologic options and we'll also discuss indications for surgical management of inflammatory bowel disease. So you remember that inflammatory bowel disease is a chronic relapsing condition and the etiology remains unclear. So our goals in managing these patients are to get them well, induce remission and then keep them well, prevent relapse. We can't correct the underlying cause, we can't treat the underlying cause because we really don't know what it is. So instead our goals are to control the inflammatory process, to damp it down without totally shutting down the immune response because people need their immune system to protect them against everything else. So we want to literally control and modulate the inflammatory process. And that's what all of the treatment options are designed to do. All of the medications we use in treatment of inflammatory bowel disease are designed to diminish and control the inflammatory response and the related symptoms. Now especially with ulcerative colitis, the specific options that we select are dictated by the location and the severity of the inflammation and we'll go through that in more detail. We start with pharmacologic therapy, surgery is indicated only for refractory disease or management of specific complications. Now nutrition is obviously of great importance in treating patients with inflammatory bowel disease, we want to restore and maintain their ability to digest and absorb nutrients. If any dietary factors are playing a role as a trigger to the inflammatory process, we want to identify those and have the patient avoid them. We know that nutritional deficiencies are very common and it's very understandable. First of all, for many of the patients with Crohn's and ulcerative colitis eating trigger symptomatology. So I'll tell you I eat, then I have pain, then I have diarrhea. So what do they do? They start to avoid eating or they minimize the amount of food they eat. So reduced intake is a huge issue, the inflammatory process itself can cause a hypermetabolic state so that drives up their need for chlory and protein intake but they're unable to meet those needs. Also if the inflammatory process involves the small bowel, there's compromised absorption of nutrients. So weight loss, very, very common, something that we always monitor, always ask the patient about. So we're always assessing them. How are you doing in terms of eating? How's your appetite? How's your weight? Is your weight stable? Are you losing weight unintentionally? We encourage, in general, just a balanced diet. We don't put them on a specific diet. We encourage them to eat a healthy diet because we know that contributes to a healthy microbiome, a healthy microbiome is going to make the bowel more resistant to acute inflammatory episodes. So instead of putting them on a specific diet and telling them, "Don't eat this, avoid this," whatever, we're like, "No, we want you to eat the things that you enjoy. We want you to focus on maintaining a healthy, balanced diet to keep your gut as healthy as possible." But we will tell them anytime that you develop symptomatology, we want you to look back for 12 to 24 hours and look at what you've had to eat and keep a diary. So if there are any dietary triggers, you can identify them and avoid them. But as we've said, we don't put them on strict diets. There's no data that supports dietary modifications as first-line therapy. And that's actually good news for most of our patients. They don't want to be on a restricted specific diet. Patient education is critical. One of the things they'll ask is, "What caused this? What did I do? What did I not do?" We don't really understand the causative factors clearly. We know there's a genetic component. We know that the immune system tends to over-react to triggers, but we don't know why. So we want to tell them, "This is nothing you did. This is nothing you could have prevented." Our focus is on management. We want to tell them, "There is definite inflammation involving your intestinal tract. We can see it when we do the endoscopy, when we do your colonoscopy. We can see the areas of the bowel that are inflamed." That's really important to tell them because in the past, there was a pervasive belief that IBD was kind of a stress-related disease, that it was really more in their heads than in their gut, that they were over-reacting. We know none of that is true and we want them to know that none of that is true. We can see the areas of your bowel that are very inflamed. You have a disease process going on. That's why you're having this pain. That's why you're having this diarrhea. It is not in your head and it is not a stress-related, psychogenic, psychosomatic disease. We want them to understand the goals. What we want to do is get you well, get this inflammatory process under control and then we want to keep you there. What we're going to do primarily is we're going to use medications. We want you to focus on eating a healthy diet. We want you to keep us informed. We want you to maintain all your appointments so we can do our very best to get this process under control and keep this process under control. Now, another thing that a lot of patients have heard is that almost everybody has to have surgery. Most people end up with an ostomy. We want to tell them, no, that's not true. Surgery is indicated only if you stop responding to medications or if you develop specific complications. The vast majority of patients never require surgery and certainly most people do not require an ostomy, yes, there is a minority of patients who do end up requiring surgery and may require an ostomy but that's not standard, that's not what you should expect. And as we've already said, we want to emphasize the critical importance of having them maintain follow-up with the medical program so that we can optimize their health status. Now, we want to remember that inflammatory bowel disease primarily affects teens and young adults. People in their 20s, their 30s, sometimes people in their 40s and 50s but if you look at the majority of people with inflammatory bowel disease is teens, 20s, 30s. So you can imagine that any kind of chronic, unpredictable illness with periods of relapse and then remission is going to have a major impact on their lifestyle and their quality of life. They're going to feel less able to plan activities. So think about what life is like for most people who are in that age range. They're busy with school or work. They're busy with social activities and with relationships. They're constantly planning activities but if you have a chronic, unpredictable illness, it makes it really difficult. People are saying, "Hey, you want to do this? For Thanksgiving, hey, you want to do this? For Christmas, hey, you want to plan this vacation, this trip?" And they're thinking, "Well, I want to do that. I wonder if I'll be able to. I wonder if I'll be sick. I wonder if, you know, I'll have to cancel it the last minute." Also, having any kind of chronic illness makes them different and no one wants to be different, certainly not in that way. Teens want to be like everybody else. and there you go. young adult years, they want to fit in, they want to be able to do what everyone else is doing. They don't want to be the one saying, well, I don't know, I might be in the hospital, I might not be able to go, I might be sick. I don't know if I can agree to that plan that you're making because I just don't know what's going to happen with me. So any chronic condition changes things for that person. It makes them different from their peers and it compromises their ability to plan activities. Also, a lot of people have hard things, a lot of people have concerns about the impact of IBD on sexual function and on fertility. So here are the most common questions. From women, it's very common to hear questions about, am I going to be able to get pregnant? If I do get pregnant, am I going to be able to carry that baby to term? Do women with IBD, do they have healthy babies? And the answer is yes. And the most critical thing they can do to maintain fertility and to assure a healthy pregnancy is to adhere to the management plan to keep the disease process under control. That is the single most important predictor of being able to get pregnant and being able to maintain that pregnancy, deliver a healthy baby. Men have frequently heard that some of the medications or the disease process itself can affect sperm count. And they're right if they're taking any kind of self-assalizing product. That can interfere with sperm counts. It can cause low sperm counts. So if you have a male patient with inflammatory bowel disease and he and his partner are ready to start a family, they want to get pregnant, then yes, we need to modify his medical management, get him off of any kind of self-assalizing product. You also want to alert patients to resources that are available to them because one of the most important things we can do for these individuals is connect them to other people who are dealing with similar issues. It's so helpful to talk to other people, even if it's just online. So that I know, hey, I'm not the only one going through this. There's lots of people going through this. And I can post a question and I can get responses back. I can benefit from other people's experience. Okay, so let's talk specifically about medications. Now we don't want you to get too tangled up in the details of medications because that's not your job. That's what the gastroenterologist is dealing with. That's what the internist is dealing with. But you certainly need to have a basic understanding pharmacologic management of these patients so that you can answer their questions and you can provide support. As we've said, all medications used in the management of inflammatory bowel disease are designed to kind of damp down that over the top immune response and keep it controlled. We don't want to totally shut down the immune system. We just want to keep it within the boundaries of normal. There are five major categories of anti-inflammatory medications. And the medications that are used as first-line therapy is definitely changed over the years as new medications have been developed. So that will continue to happen. You'll continue to see a shift toward newer therapies and away from older medications. But right now I'm just going to identify the most commonly used medications. We'll talk about each one briefly. We'll talk about which ones are the most commonly used. So amino salicylics. You all know aspirin is an anti-inflammatory and it can be used to reduce inflammation in the gut as well. The challenge with most of the amino salicylics is getting the active agent to the involved area in the bowel because many times it's inactivated in the proximal gut. We'll talk more about that. So amino salicylics are one, corticosteroids. Of course you know this, we use steroids for all kinds of inflammatory conditions. And we know that steroids are a very potent anti-inflammatory medication. But we also know corticosteroids have lots of side effects. We never want a patient to be on steroids long-term. And fortunately, we now have enough alternatives that we don't have to keep people on steroids long-term. In the past, we frequently did and we had to deal with lots of side effects. But now if we use steroids at all, it's typically short-term just to induce remission and then we taper off the steroids and onto another medication. Immunomodulators, they do exactly what they say. They help to modulate the immune response to control it, damp it down. So immunomodulators are frequently used as adjunctive therapy for induction. T cell inhibitors, T cells, of course, are a major component of the immune response, the inflammatory response. So by using T cell inhibitors again, what are we doing? We're controlling reducing the inflammatory response. And then definitely the stars of the pharmacotherapy lineup, all of the biologic agents which are relatively new and the fight against inflammatory bowel disease and other autoimmune conditions. And probably at this point, the most widely used. So we'll talk about each of these in a little more detail. So amino Solicilates, you're five ASA compounds. They are effective when you have a patient with mild to moderately severe inflammation. They are available both in systemic and topical form. So in addition to being able to give them orally, we can also give a suppository or a foam or an enema. So if the inflammatory process is limited to the rectum or the rectocidmoid, we can treat topically. But if the inflammation is more widespread, we can treat orally. The challenge with amino Solicilates is that they are inactivated in the stomach and the proximal small bowel. So we have to find a way to get them through that danger zone and to the area of inflammation with the anti-inflammatory component intact. And there are several ways to do that. We'll talk about that. Corticosteroids, we've already said, extremely effective with multiple side effects. We do not use them long-term anymore. And one good thing about steroids is they are available in multiple forms. So we can give steroid-based enema or a suppository. We can give oral agents. We can give steroids IV for very rapid response. Immunomodulators can be used both to promote induction and to promote maintenance. The ones that are commonly used, you've seen them as a thioprene, 6MP, methotrexate. So chemotherapy agents that work by controlling inflammation. And then T-cell inhibitors, cyclosporine and tachyrelemus primarily used to support induction. And here come the stars of the show, the new biologic agents. The advantage of the biologic agents is that they're much more targeted and their action. So as we've done more and more research, researchers have been able to identify specific components and specific agents of the inflammatory process that go awry and patients with inflammatory bowel disease. And then they have been able to develop pharmacotherapy agents that target those specific processes, those specific agents. So at present, there are two major categories of biologics. I'm sure this is going to expand. But right now, we have anti-TNF antibodies. And TNF is tumor necrosis factor. So I'll probably murder these names. But this includes influximab, etolymimab, etolymimab, and serralizimab. And then we have that anti-integrin antibodies, these molecules, vitilizimab, natalizimab, and eustachemab. Now, if we're putting patients on any biologics and almost all of our patients are now on biologics, critical to test them for TB before we initiate therapy because we are going to knock out their ability to control the TB organism. Okay, so now let's look at it from the perspective of matching the medication to the disease process and again this is not your responsibility so this is just for background information. So when you're talking ulcerative colitis, remember ulcerative colitis always starts at the rectum, always involves the rectum, proceeds proximally with no skip areas. So when you're looking to treat ulcerative colitis, the agents you select are going to be dictated by the extent of the inflammatory process how far proximally does it go and the severity. If we diagnose this patient early and the inflammation is limited to the rectum and maybe the sigmoid, you can treat topically. You can give a foam, a suppository, and in a moment. And typically we will begin with five ASA or with topical steroids and try to get the disease process under control. Now if the disease process extends more proximally if it involves the descending colon, the transverse colon, then we have to treat systemically as well. So some patients with very distal disease will be treated only with topical agents but as the disease process extends more proximally, we add systemic agents. Topical ASA, topical steroids, and systemic ASA, systemic steroids. So here we are back to our amino salicylates with the salicylate being the active anti-inflammatory component. Masalamine five ASA is the most commonly used is available both as an enema and as a suppository. So it's great for ulcerative colitis that is confined to the rectum or the recto sigmoid. If it extends more proximally as we said, we can use the systemic five ASA amino salicylate compound but we have to protect the active agent. So sulfosalazine, also known as azophadine, is the most commonly used. It's the least expensive. And what you have here is the active agent bound to a sulfur component. And the advantage of the sulfur component that gets the active agent through the proximal bowel because it's bound with this azobon that is not broken down in the proximal bowel. But it is broken down in the colon. So it gets the agent all the way to the colon which is perfect for a patient with ulcerative colitis because in the colon it becomes active. Here's the downside, sulfur, as you know, is associated with a lot of side effects. So we have to evaluate the patient's ability to tolerate this medication, a patient who has ulcerative colitis involving descending transverse and ascending colon. Yes, this would be a great option. Can they tolerate it? Do they have side effects? Again, remember that oligospermia is one of the side effects. So this would not be a good agent for a male who's when he and his partner are trying to get pregnant. Balsalazine and macellamine are two different approaches. Again, you've got the active agent, the salicylate. But with balsalazine is bound to a non-sulfur carrier. So you don't get all the side effects. Cost more. Macellamine has a coating that dissolves in the colon. So again, no sulfur, fewer side effects, but greater cost. So three ways to get salicylates to the colon. You can bind it to a sulfur agent with an azobon that's been around the longest, least costly, highest level of side effects. Or you can do balsalazine, which has a non-sulfur carrier, or you can do macellamine, which has a coating. But you pay more. What about steroids? What if you're not able to get the disease process under control with the amino salicylates? Then you can look at a modified steroid, the one that's most commonly used is buidesanide. It's a great choice because you get the benefits of the steroid, but you get many fewer side effects because it's very rapidly absorbed by the mucosa of the bowel and then very rapidly and activated by first pass in the liver. So a great choice if you're going to use the steroid. What if you have moderate to severe ulcerative colitis? So this patient is much more symptomatic. The disease process is much more extensive. Then typically you use steroids for induction. For some reason they're not a candidate for the biologics or if you need very rapid control of symptomatology, then we typically use oral or IV steroids to get the inflammation under control. And we may also use T cell inhibitors. You're cyclosporin, you're tachyrelymus. Moderate to severe ulcerative colitis, systemic therapy is going to be required as we've already said. So we've said, well, we could use steroids if the patient's not a candidate for biologics. If we need very rapid control of symptoms, if the patient's insurance doesn't cover biologics. But in general biologics are the most commonly used. So again, all of your anti-T and F drugs, all of your anti-integral drugs. You've probably worked with patients who have been on one or more of these agents and you know that some people respond extremely well to one. And there are other patients who don't respond well at all to that one, but respond to another. So it's great that we have increasing numbers of options within this category of biologics. We started out with only influxameth, Remicate. And now we have a pretty significant stable of biologic agents. Immunomodulators, you're as a thiaprin, you're 6-1p, you're methotrexate are sometimes added if needed for maintenance. I will tell you that the vast majority of patients, they use biologics for induction and for maintenance and they do very well, but these drugs are very expensive. So not all people can get them. What if they're uninsured? They're not, most people can't afford the cost if they do not have insurance coverage. So even though biologics have become the preferred and the go-to, you will still see patients who are treated with steroids for induction and then maybe amino solicylates for maintenance. What about Crohn's disease? Well, the options are pretty much the same. Biologics again are the most widely used medications for induction and for maintenance of remission and the patient with Crohn's disease. So again, your anti-T and F drugs, your anti-integrins, your immunomodulators, methotrexate being the most widely used. If you have mild disease and especially if it's confined to the colon, you might see your amino solicylates used. You do not typically see cyclosporin and tachyrelema issues because they're less effective. Now let's talk about specific subsets of patients. Patients with Crohn's disease involving the perineum and the perineal area. These patients have fistulizing disease. So what happens and you can see this in the illustration, especially on top, is you get little channels forming, little fistulist channels forming between the rectum and the skin, between the anal canal and the skin. The channels are very, very narrow. So typically you don't see stool draining through these channels. The problem is you get a lot of bacteria into these channels and you get this chronic inflammatory infectious process. How do we treat that? Well, a primary component of treatment is anaerobic antibodies like metronidazole, flageal, like cipro. Surgical drugs. drainage may be necessary, and sometimes you'll see placement of a CTON suture. So I'm going to try to walk you through a CTON suture. If you look at the illustration on bottom, you can see the CTON suture in place. They place it surgically, and then they very gradually advance it out. They pull it out a little bit at a time. So it starts out being in the anal canal and very gradually backed out. And what it does is it triggers an acute inflammatory response, collagen deposition, fibrosis, that we hope will seal that little gap and close that little fissula. And also the scar tissue can reinforce and provide support for this fainter. For patients who develop fissulas in the small bowel itself, about the only way to get those fissulas to close from a pharmacologic perspective is to put the patient on bowel rest, so very restricted oral intake and TPN. If that's ineffective, then they typically will require surgery. And that brings us to our last therapeutic option and that is surgery. So indications and options for surgery differ depending on whether or not the patient has ulcerative colitis or Crohn's disease. We're going to talk first about the patient with ulcerative colitis. One huge positive for the patient with ulcerative colitis is this. If they develop refractory disease, if we can no longer control the disease process with medications, if they develop a severe complication that requires surgery, then removing the colon and the rectum is curative. Because remember ulcerative colitis is confined to the rectum and the colon. So if we're forced to remove the rectum and the colon, the good thing is, this disease is not going to come back. Once they've had a procto, collect them, they're cured. Now when would we be pushed into doing surgery? Because no one wants to have surgery. No one wants their colon and rectum removed. Nobody wants an iliostomy or wants to undergo a continent diversion. So again, we try to manage them medically. Surgery would be indicated if they had refractory disease, persistent bleeding, persistent pain that was non-responsive to medical management. There is a complication of ulcerative colitis known as toxic mega colon. This is a fulminate variety of the basic inflammatory process, but with toxic mega colon, what happens is that the inflammation actually involves deeper layers. Typically, the inflammation and ulcerative colitis is confined to the mucosal and submucosal layers, primarily the mucosal layer, but with toxic mega colon, what happens is the inflammatory process extends to involve the muscle layers. It inactivates the inflammation shuts down the ganglion cells and all of the cells within the nerve plexuses and you literally develop an iliost. As a result, you rapid the colon rapidly distance. You have this mega colon because nothing is moving through and they are very high risk for perforation in peritonitis. So toxic mega colon is managed with urgent surgical intervention. If a patient requires steroids and you cannot get them off steroids, that's an indication for surgery. If you have a child with nutritional compromise failure to thrive, any patient who develops malignant deterioration within the mucosa, what are the surgical options? There are two primary surgical options. The one that is most commonly done is bullet point number one. As a result of the colon, remove the rectum, retain the anal canal and sphinters, create a reservoir out of the end of the ilium, connect that reservoir to the anal canal. You see that on the top illustration, the colon's gone. The end of the ilium has been turned into a reservoir and that reservoir has been connected to the anal canal. Normally this is done as a staged procedure because it's a huge operation. Many times the patient goes to surgery on steroids and so it's going to take longer for your suture lines, your staple lines to heal. We will go through this option in detail in a later class. There is another option that is very, very rarely done. That is a procto-collectomy with an internal abdominal reservoir connected to a skin level stoma. Here the patient has to pass a catheter through that skin level stoma into the reservoir to drain it multiple times a day. That's what you see in the middle, very rarely done and we will talk about it in a later class. You could elect to just remove the colon, remove the rectum and do a permanent ilostomy. If you look at the illustration on top and the illustration on bottom, those are the two surgical procedures most commonly done for a patient with ulcerative colitis who requires surgical intervention. Well the considerations are totally different. Most of all you have to remember, Crohn's disease can occur at any point along the GI tract. So surgery is never curative. Since surgery is not going to cure them and it's going to require a resection of a component of the bowel, we strictly limit physician, strictly limit surgical intervention to situations where medical management has failed and/or there is a significant complication. Go back to the fact that Crohn's disease is most likely to affect people in their teens, 20s, 30s. You have to be very careful when you're doing bowel resections for a patient with Crohn's disease because we know it can recur. And if we take out pieces of bowel every time they have a flare up, they're going to be very high risk for short bowel syndrome and for TPN dependency, which we do not want. So the goal is minimize surgical intervention, minimize bowel resections. Now there is one subset of patients with Crohn's disease where the considerations are different. But that is a patient who has Crohn's colitis, but no involvement of the small bowel. Those patients tend to have long term remission once the colon and the rectum are removed. It seems to be a sub species of Crohn's disease, Crohn's colitis. So if you have a patient with Crohn's colitis, once you remove the colon and the rectum, chances are they're going to have very long term remission. They may never have a recurrence. So given those considerations, what are the indications for surgery in a patient with Crohn's disease? We've already said if they have refractory disease, we can't get it under control with medications, they are in pain, they're having constant diarrhea, they're struggling with weight loss, major interference with their quality of life, yes. We shouldn't intervene surgically. We have to intervene if there's bowel perforation, if there's a non-healing fistula, if they develop abscesses because of the fact that the inflammatory process is transmural, then they can develop little leaks and abscess formation. We have to intervene if they develop strictures that cause obstruction. And if this does not respond to medical management, and in general, you cannot manage a stricture medically, because you can see it's going to cause recurrent obstruction, and it's going to tend to get worse with every flare up. So there's actually a procedure they can do that does not involve bowel resection. Originally, they just took out the section of the bowel with the stricture and did an intending asthmosis. Now they're much more likely to do a stricture plastic, and that's what you see on the bottom left, where they incise the bowel wall, and then they suture it in a way that opens up the strictured area. Obviously, If they develop any kind of malignant deterioration, we have to intervene and pediatric patients who are not gaining weight, not growing normally, failure to thrive in that population. What are the options? Well, if they have Crohn's colitis, again, is going to be a procto-collectomy, typically an endoleostomy. And general continent diversions are not done for patients with Crohn's disease, we'll talk more about that in later classes. If it is segmental disease, they're going to do a bowel resection and they're going to do a nastimosis of the two healthy ends of the bowel. So they're going to go in there, they're going to say, "Here's the area that is causing all the symptoms. Here's where we have acute inflammation, refractory to pharmacotherapy. We're going to remove that section and tend an nastimosis." Occasionally a diverting ostomy is required because of obstruction or because of fistula or abscess that requires bowel rest. Most of the time that is intended to be temporary. And we've already talked about stricture plastic. So here, again, talking about management of strictures is going to depend on severity. Initially, they'll see, "Well, let's see what happens when we treat the inflammatory process medically, if we can get the inflammation under control, eliminate adema in the bowel wall, controlling the infection, decompress the proximal bowel, and gradually advance the diet. Now are things okay? If not, surgical correction will be required. If you have obstructive symptoms that are unresponsive to medical management." The last thing we'll talk about is extra intestinal manifestations. You can see this with both ulcerative colitis and Crohn's disease. So even though ulcerative colitis and Crohn's disease are considered to be forms of inflammatory bowel disease, there's increasing evidence that it's really not just a bowel disease. It's a systemic disease that it can involve other organ systems as well. Now there are four organ systems commonly involved in extra intestinal manifestations. The skin, the joints, the liver, and the eyes. So skin manifestations include erythema nodosum and piodermy gangrenosum. Piodermy gangrenosum is, by far, the most significant. We will talk more about that in a later class. Joint disease, you can have just joint pain. People sometimes say, "Sometimes it's my hips, sometimes it's my knees." There's a significant subset of patients that has ankle-osin spondylitis, so that causes low back pain and arthritis. Liver complications probably the most significant. You can get sclerosin colonitis, which interferes with delivery of bile from the liver to the small bowel, you can get chronic hepatitis, and you can get cancer involving the bowel duct system. So liver disease can be very significant. Some patients where we have the underlying disease process under control, we still have progressive liver disease. So be very aware of that. That can become the most significant aspect of IBD. You can also get inflammatory changes involving the eyes. You can get UVitis, other eyes look red, you can get conjunctivitis, you can get episcleritis. They usually need to be treated with anti-inflammatory eye drops, it's very uncomfortable, and you don't want any chronic inflammation that threatens visual function. That causes extra intestinal manifestation, what makes them better, what makes them worse, we're not sure. We do know that patients who have extra intestinal manifestations are more likely to experience these symptoms during flares of the underlying disease process. So they're more likely to have abdominal pain, diarrhea, and a flare-up of their pyodermic angrenosum, or a flare-up of their joint disease, or problems with their liver. And treatment is part of the whole inflammatory process, so treatment is exactly the same. We use anti-inflammatory medications in general, our goal again, get the entire inflammatory process under control, usually with biologics, or with some combination of amino salicylate, steroids, immunomodulators. There is some increase in the risk for adenocarcinoma among patients with inflammatory bowel disease. So far we've been unable to accurately quantify that risk, but we do know that colorectal cancer occurs at an increased rate among individuals with inflammatory bowel disease. So one of the components of management is ongoing screening, that should begin 8 to 10 years following diagnosis, and anytime we start to see high grade dysplasia, we're typically looking at surgical resection. So in summary, our goals of therapy for any patient with inflammatory bowel disease get the patient well, so established remission, keep the patient well, prevent relapse. Pharmacologic therapy is the primary treatment approach for both ulcerative clitis and Crohn's disease, using some combination of biologics, immunomodulators, steroids, amino salicylates, okay. Surgery is limited to patients who fail to respond to medical management. They have refractory disease and patients who develop severe complications that cannot be managed medically. Thank you.