We'll go on to the next talk, it's an update on the medical management of ulcerative colitis and Crohn's disease. It's our pleasure to invite Dr. David Rubin, Dr. Rubin is a professor of medicine and the chief of gastroenterology at the University of Chicago Medical Center. Welcome, David. Hello, everybody, it's David Rubin from the University of Chicago. I want to thank Dr. Shen, as always, for including me and I'm pleased to provide an update in the medical management of IBD for 2022. I'm very sorry that I can't be with you live. These are my disclosures, which are relevant to this presentation, but the presentation is my own. I've put it together for you, and I hope you'll find it fair balanced. At the conclusion of my presentation, I'm hopeful that you will have learned our updated goals of management. You'll appreciate our expanded armamentarium of options and some of the thoughtful approaches to using them in your practice, and you'll understand more how to incorporate treat to target and disease monitoring strategy for your patients with IBD. Let's start by reviewing our evolved goals of IBD management. They start, of course, with clarifying the diagnosis of IBD, but I want to emphasize to you that clarifying the diagnosis of IBD now must include elements of prognosis, as well as assessment of traditional and emerging extraintestinal manifestations. The traditional ones, of course, of joint, skin, and eyes, but the emerging ones that we increasingly appreciate, mental health, fatigue, pain, nutritional issues, all go along with your baseline evaluation of that patient. After clarifying all of that, we do want to induce remission. It still emphasizes making the patient feel better and having symptoms improve, but now we acknowledge that you must also make sure that there is objective evidence that the inflammation is under control, and this includes normalization of labs, growth and development, and nutritional parameters. After successful induction of remission, we should be able to move to maintenance phase of management, which is really focused on prevention of relapse and prevention of progression, and of course should be steroid-free. So maintenance is really misunderstood by many folks, where they think that you're treating active disease chronically. When you communicate to a patient that after successful induction of deep remission, maintenance is about prevention, it actually enables your patient to understand that we're actually just trying to prevent the disease from causing problems, as opposed to them being reminded that they're treating an active disease. It also helps them to know that our goal for management is, in fact, for their disease to be under stable control over time. After we do that successfully, of course, we enter the chronic phase of management of IBD, and this also includes preventing complications from the disease or the therapies and developing customized monitoring strategies. When we do all this in order and when we are successful, we actually can change the natural history of the disease. And in fact, we've entered an era of disease modification in IBD that I think is really quite important to understand. In April of this year, a special issue of Gastro will be coming out that is focused entirely on this, called Entering the Era of Disease Modification in IBD, and I encourage you to check that out when it arrives at your doorstep. So assessment of the baseline functioning of our patients with IBD should include a number of very practical points. Number one is asking the patient about how the disease has affected their ability to do the things that are important to them. Specifically, I say to patients, what has the disease taken away from you that you are no longer able to do? The second point is I always proactively ask patients about their diet, so they know that I also appreciate it's very important. It's also the opportunity to distinguish between diet, which is what they take in, and nutrition, which is what their body needs, so that they're clear on what we can do by modifying their diet from a symptom point of view, but that we must also pay attention to their nutrition and to their inflammation in doing so. We've come to appreciate the importance of treating and recognizing mental health disorders in our patients with IBD. The example I'm sharing here from our lab is an adaptive testing tool that we use to screen our patients. It takes 30 seconds to as long as three minutes, depending on how the questions are answered, but has been validated across numerous populations, including now IBD, and has enabled us to identify those patients who are at risk. Any screening tool you use is better than nothing, and I would encourage you to start thinking about how you can incorporate this into your practice. We've also come to appreciate that there are consequences to chronic inflammation in patients with IBD. Another way to say that is that I tell patients that it's okay that they may be getting along with their IBD active, and they've managed to figure out how to go to work or do the things they want to do, even though they have symptoms, but it's not okay to live with chronic inflammation. Increasingly, we recognize that it is associated with increased risks of morbidity and even mortality from cardiovascular disease, as summarized in the meta-analysis in the middle here. We're also, of course, recognizing that the chronic burden of inflammation is associated with increased risks of cancer, and as you can appreciate, progression of Crohn's leads to fibrosis and other complications, and the graph on the right on this slide is from our recent publication showing that there's diminished rectal compliance related to chronic activity of the disease. Interestingly, what we found in our study was that patients who normalized their histology actually had their rectal compliance similar to non-IBD controls, suggesting that the bowel may in fact remodel if we're able to control the disease better. So an emphasis on prevention and on the possibility of reversibility of some injury that may occur is important, and teaching your patients that living with active disease is not okay is an important message for our practice. When we talk about prognosis, I'm sure that this experienced audience understands some of the risk factors for bad outcomes in Crohn's and UC. Earlier diagnosis or younger age of diagnosis, more extensive bowel involvement, and then certain laboratory parameters like elevated inflammatory markers or low serum albumin, all associated with increased risk for surgery, repeat surgery, hospitalization, emergency department visits, or even disability. We also recognize increasingly that patients who have mental health disorders or those who have overlapping coexistent other immune conditions also have a worse prognosis. So in that individual patient sitting in front of you, think about what is their risk for bad outcomes? What are their other risk factors, including these other diseases you may identify, and the presence of anxiety and depression, which may lead to those worse outcomes as well. That will help you choose therapy and develop customized follow-up plans. The treatment options for IBD are increasing by the month, practically. I've summarized them on a table here for you, and I want to emphasize that I did include diet at the top, especially in children, but it's not a traditional method of managing the disease in adults, nor has it had strong evidence to support that yet. But I want to emphasize further that in addition to our three different classes of biological therapies, we now have two distinct synthetic targeted small molecules, the JAK inhibitor, tofacitinib for ulcerative colitis, and the first-in-class S1P receptor modulator, ozonamide, also for ulcerative colitis. I've included on this table the other indications for these therapies so that you can think about what treatment you might choose if you have a patient who has more than one problem. We've learned now that that's not just efficient use of your therapies. There are some clues when they have more than one diagnosis of what may actually be the dominant immune pathway, or the pathogenesis of both conditions. So if you have a patient with psoriasis and with IBD, you can pick one of the therapies that works for both. If you have a patient who has multiple sclerosis and IBD, you can think about which treatment might be appropriate for both of those conditions, etc. And we've come to appreciate that there are shared pathways, and there are some that we shouldn't be using in the IBD world. This table is summarized from a couple different sources, but I would refer you to this great review article that was in the New England Journal of Medicine recently, and it emphasizes some of the ways we might think about choosing therapies. Of course, you know some of these here, but I'll point out to you, for example, that the alpha-4 beta-7 integrin inhibitor, vitalizumab, works selectively on the gut, but wouldn't work in the extraintestinal problems. The S1P receptor modulator, ozonamide, and another drug in development, atrosimide, we know will work in the bowel. We also know they work in multiple sclerosis, but we don't know much about these other conditions yet, so it's unclear whether it might be beneficial. And IL-17 inhibition, which works really well in some of the rheumatologic and dermatologic conditions, may activate Crohn's in patients who have preexisting disease, or even those who have a family history of Crohn's, so we need to be quite careful there. The TIK2 target has been studied now, and there are some emerging data that were not as positive as we thought they should be. Works quite well in psoriasis. Remember that TIK2 is a JAK, it's one of the four JAKs. There's JAK1, 2, and 3, and then TIK2. And interestingly, TIK2 has a small molecule that targets IL-12 and 23, so we thought it might be like eustekinumab. So there's ongoing work with that therapy that will be of interest. Now to summarize how to use these new small molecules, I did want to highlight a couple things that might be good for you to use in your practice. So acidinib is a pan-JAK inhibitor that has received a couple label changes since it was approved for moderate to severe UC. First it needs to be positioned after failure of anti-TNF, and secondly you need to keep in mind that if the patient has a history of atherosclerotic heart disease, probably shouldn't use it, although we haven't seen a signal in the ulcerative colitis population, there was that problem seen in the high-risk rheumatoid patients who had preexisting heart disease. And it's also of interest that in that high-risk rheumatoid population, they had increased risks of venous thromboembolic complications or lung cancer, especially if they were smokers. So having said all that, and recognizing that's been seen in the RA population, TOFA is still an excellent option to consider for our patients with UC who may not have those risk factors and in whom, over all of our follow-up, we have yet to see any of those signals. Ozanamod is our newer drug that's available, a different mechanism. Its label allows you to use it anywhere in your management of the UC population. And the specific concern here is that a different S1P, the one that is not targeted specifically by Ozanamod, can affect cardiac conduction in a transient and usually asymptomatic way. Despite the fact that this targeted therapy doesn't affect that S1P, it is recommended that we not use this if the patient has known second-degree heart block. And of course, that's very uncommon in our patients, but a baseline EKG is necessary. So you can see some of the places where you might consider this. I think both small molecules are reasonable to consider in patients with low albumin, because they're small molecules with good absorption in the small bowel. We don't have to worry about the same protein loss of monoclonal antibody therapies in such patients. So when you choose your induction therapies, you should be thinking about how sick the patient is and what their prognosis is. You should also be thinking about whether they have that low albumin and there may be an issue with clearance of drug and rapid loss of therapy. And you should also think about organ selective treatments before we go systemically, unless they have coexisting organ system involvement of joints or skin or other problems that you want to keep in mind. Number two in Crohn's, that at the time of diagnosis, surgery is an appropriate induction therapy, not just when they're obstructed, but in some patients where there's been progression of disease before diagnosis, it might be reasonable as was seen in the Lyric study, which is summarized in that citation below. So you can think about some strategies here, but one of the main messages is to recognize a few things. In Crohn's, the earlier you treat with effective therapy, the more likely you are to have benefits. And this of course refers to the Parienti cartoon on the right that we've all looked at. And the concept that the earlier you're able to treat, the more likely you can prevent fibrosis and progression and complications. And a variety of different lines of therapy have continued to support this, including the claims database study summarized on the bottom left here, where earlier exposure to anti-TNF, regardless of disease severity, led to reduction in Crohn's related surgeries. And the post hoc analysis on the right, which showed that when you treat earlier, you also have a lower rate of loss of response to the therapy. That's from the Adalimumab maintenance study in Crohn's, where shorter disease duration resulted in more stable disease over time. We now of course have two head-to-head trials in IBD. This is the Seaview study in Crohn's comparing Eustekinumab to Adalimumab in bio-naive patients. The hypothesis was that Eustekinumab would be clinically superior to Adalimumab. But as you can see in figure one on the right, at the end of a year, the drugs were similar. However, I want to point out to you that at the end of a year, you had 61% and 65% of patients who achieved clinical remission. That's a great result and is likely a marker of the fact that these patients had short disease duration and were naive to other therapies before they were randomized in this trial. So it's a very interesting study from the standpoint of comparing head-to-head, but it's also an interesting study to appreciate how good we can get if we treat early with effective therapies. Of course, there's a difference in the number of injections patients get with Adalimumab every two weeks and Eustekinumab every eight weeks. And there were more dropouts of patients due to injection problems with Adalimumab, even though they were using citrate-free drug compared with Eustekinumab. But nonetheless, this is an important head-to-head trial that provides us some really interesting information. We also have asked, what about second-line therapy in Crohn's? And now there is actually enough studies that have tried to look at this that we even have a meta-analysis. So in a patient who has Crohn's disease who's failing anti-TNF, should you consider Eustekinumab or Vitalizumab? Well, in this meta-analysis, and now there's even another study that's been done subsequently, I want to emphasize to you that there was not a statistical difference between Eusta and Vita in the short-term, which is the top of this slide. But longer-term follow-up, Eustekinumab was superior to Vitalizumab as a second-line agent. So for your Crohn's patients who are failing anti-TNF, it seems likely that Eustekinumab would be your preferred drug over Vita. Now there are always exceptions to this, but it's important to know these data, and it might help you choose your therapies. In ulcerative colitis, of course, we do have a head-to-head study, which came out before the CBU study. This is looking at Vitalizumab compared with Adalimumab in patients with UC. They were allowed to have prior anti-TNF, as long as it wasn't Adalimumab, which is why you see the subgroup analysis on the right. But the bottom line is, if you looked at patients with moderate to severe UC, Vita was superior to Adalimumab at the end of a year, looking both at clinical remission and mucosal healing. So that might guide you in your choice of therapies. It also goes along with our principle of organ-selective therapy, before systemic treatment makes some sense. So in general now, we've adopted a treat-to-target strategy to move through therapies. So regardless of what you start with, reassessing whether you're achieving control, both with symptoms and with something objective related to how you measure inflammation, is key. I've summarized for you the consensus paper that published last year, looking at targets for Crohn's in UC. And for Crohn's, it's improvement in abdominal pain and elimination of pain and improvement in altered bowel habits, along with improvement in endoscopy or radiologic findings. In UC, it's the absence of rectal bleeding, decreased stool frequency, and endoscopic improvement. And it is recognized now that CRP and calprotectin may be used as reasonable targets, as long as you benchmark them to a baseline scope. And in children, of course, growth and development is an important target as well. So you should be using this in your practice with serial assessment of the target and adjustments of therapy until you get where you need to go. You can think about individualizing your targets and then using those for monitoring. You have your traditional patient-reported outcomes with endoscopy, as I just described. But you can be using other markers, depending on the patient and what you think is reasonable and needed for them. We even now are thinking about using mental health and other markers of inflammation as ways to monitor and as targets for effective therapy. So this is evolving. The bottom line for your individual patient is to make sure that they actually have a target and that you use it to get there as much as possible, and that you use it as a monitoring strategy for that individual patient. In Crohn's, we now have two prospective randomized trials demonstrating benefit of treat-to-target. The stronger one on the left is the CALM study, which used an added Limumab algorithm, driven either by symptoms and prednisone use, which was the standard-of-care approach, or by symptoms, prednisone use, or CRP and calprotectin, which was the treat-to-target approach. And you can see the results at the bottom left there, that the treat-to-target arm was more successful in achieving these different endpoints than the standard-of-care arm. In fact, most of the changes in management of increasing the added Limumab or adding azathioprine was driven by the CRP and the calpro, and not by symptoms. On the right is the STARDUST trial, which was a treat-to-target study with Eustachinamab that used endoscopic response as a way to adjust the interval of dosing the Eustachinamab. Similarly, in the non-responder imputation, which are the bars on the left, it didn't achieve significance. But if you looked at a variety of other endpoints, it was better in the treat-to-target arm. So you can imagine that using objective markers can drive your therapies forward. And of course, what you want to know is, does this change longer-term outcomes? And there's a variety of levels of evidence to support that, in fact, it does, not surprisingly to know that when you use objective markers of disease control, you end up with better control over time. Now, the other major message is that combination therapy has been supported by comparative effectiveness studies with infliximab in both UC and Crohn's, and I'm sure you remember the SONIC and SUCCESS trials. But actually, we have a prospective study in Japan with adalimumab that did not show that it was necessary. It's a little counterintuitive because we know adalimumab has immunogenicity similar to infliximab, but it's important to know some of those data. And I want to emphasize to you that both vitalizumab and eustekinumab have low immunogenicity, and they are now acceptable as monotherapy, even in patients who have had previous anti-drug antibodies with anti-TNF. Some of you may have heard that there was a haplotype, HLA-DQ105, identified recently that predicts immunogenicity, but it's not strong enough to necessarily change our management, so I'm not yet recommending this routinely in our practices, and I think we need to do a little more work on that. We've also learned, of course, that drug levels may help us, but I don't recommend drug levels in everybody all the time. Nonetheless, in your high-risk patients, those with high inflammatory burdens, low albumin, those who've lost response to other therapies previously, we do use infliximab and sometimes adalimumab drug levels during loading or prior to maintenance as a predictor of loss of response later and with the idea that we can then adjust dosing sooner. You can see in both Crohn's and UC that there's some benefit to knowing what your week six or week eight drug level may be in order to know whether you're going to lose response, and it can enable you to give an earlier or additional loading dose or to increase your dose or decrease your interval to try and make sure you're on top of this. I do this in my patients who are high-risk. That means they have a significant burden of inflammation or they've previously lost response to other therapies or they have a low albumin where I'm worrying about drug clearance. I'll also emphasize that with infliximab, I always use combo therapy when I'm starting the drug. I may or may not continue it long-term, and with adalimumab, I personally do still use combo therapy despite that study that I shared with you. The last point about maintenance is just to remember that we want to make sure our patients stay on their therapy. This nice study that I shared here with you was a self-management strategy, and you can actually go to the website there, constantcare.dk, to learn more about it. Not only did it improve adherence to being on therapy by reminding patients to take their five ASAs, it actually resulted in lower relapse rates. This is an effective intervention, but remember that you do need to remind your patients to stay on their therapy and that often they are staying well because of their maintenance therapy, not in spite of it. How can you incorporate some of this in your practice? Well, I think that one of the points here is that every patient should have a disease monitoring strategy, and that's what's illustrated in this nice paper from the Belgian group that I've modified a bit. The idea here is have a proactive monitoring strategy. The example I'm giving is using Calpro, but you might use CRP or some other marker. When it's less than 250, you continue going and accept that the patient's likely doing well. When Calpro becomes elevated, even before the patient feels anything, which is the ideal way to use monitoring, then it's considered that this is active disease, even if they're not feeling it, and then you can assess where's the drug, what else might be going on, and you can see the standard approach to drug level interpretation and dose optimization or swapping to a different mechanism. I think that this is a very practical approach. Every patient should have disease monitoring built into their strategy, and some patients should benefit from drug monitoring, but it's not needed for everybody. As I mentioned, given the low immunogenicity of Vito and Eusta, I don't use it in that scenario at all. Finally, how can we do all this better? Stay tuned because there's a variety of combination therapy approaches coming, one drug for induction and another for maintenance, overlapping, combining them for both phases, or even timing them differently, as we've demonstrated in some of our work at the University of Chicago. There's a lot of work going on here. Of course, everyone always asks who's going to pay for it. That's a challenge, but I think that keeping in mind the different phases of management and the fact that we might even move to microbiome-based maintenance therapies would be very interesting. I think that that's the best way to move the field forward with all the different options we currently have available and until we have some validated therapeutic biomarkers to guide us further. In summary, I hope that you found this update helpful. Remember to be thinking about those extra intestinal manifestations and prognosis in your assessment of your patient. Look for comorbid immune conditions and identify benchmark targets that you can use both to assess response to therapy, optimize therapy, and assess loss of response during the monitoring phase. Use TREAT-to-TARGET in your management strategies for your patients, and proactive disease monitoring is absolutely essential and may guide you better in how to use therapeutic drug monitoring. Overall, this is an encouraging time in IBD. Again, I apologize that I'm not with you live, but I hope that the rest of the conference is a great success. Thank you.

IBD management

remission

treat-to-target strategies

biological therapies

individual patient characteristics

maintenance therapy