IBD Drive Time: Sara Horst, MD, on the Best of ECCO

Host Raymond Cross, MD, talks with Dr Sara Horst from Vanderbilt University about their picks for the most interesting and important presentations on inflammatory bowel disease at ECCO 2025.

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. Sara Horst, MD, MPH, is an associate professor of medicine and assistant chief for clinical informatics in the Division of Gastroenterology, Hepatology, and Nutrition at Vanderbilt University in Nashville, Tennessee.

Welcome everyone to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center in Baltimore and I'm here with our guest host Sara Horst from Vanderbilt. We're actually recording at the AIBD regional in Nashville, which will be coverage of that will be available on the AIBD website. Sara and I were fortunate to cover ECCO as part of the IBD Education Group, which is supported by MedEd Consultants. And for those of you that have not been ECCO, it is an amazing meeting. Berlin is an amazing city. We hope that you're able to do that in the future and Sara and I thought we would do what we thought were the best of ECCO. So Sara and I each have 3 abstracts that we're going to highlight and Sara is going to go first.

Dr Horst:

So the first study that Ray I thought was really interesting that we saw at ECCO was the RESCUE study. So this is looking at ustekinumab dose optimization in patients with Crohn's disease. So it's a Belgian prospective multicenter study looking at 2 different reinduction regimens for patients who had responded to ustekinumab but actually had lost response. So they took about 108 people and they reinduced them with IV ustekinumab at 6mgs per kg times 1 dose. So the IV induction regimen again. And then they either followed them with a dose intensification, so they went to 90 milligram subq Q4 weeks or they put people back on the standard dosing, which was 90 milligrams Q8 and their endpoint was corticosteroid free clinical remission at week 48. And that was defined as the patient's feeling better abdominal pain, stool frequency, and a fecal cal less than 250 and no steroids. So basically they found no difference in the patients who did the dose intensification. So the Q4 week versus going back to the Q8 week. But what's really important about this is actually about 40% of the patients achieved clinical remission after the IV reinduction.

So to me, the point of this is if someone loses response and they're on ustekinumab, an IV reduction actually can be very helpful. You're going to recapture about 40% of your patients. Also, you probably don't need to go to that Q4 subq dosing regimen afterwards. You can kind of keep them back on that ustekinumab Q8 weeks. So we thought that was really important to me. This is practice changing sort of the way that I'm going to try to help patients who are on ustekinumab. I really do think we should really try to do that IV reduction again. Any thoughts Ray?

Dr Cross:

No, I think it's very interesting and I certainly have done IV reduction and it's typically a patient who is doing very well and then for whatever reason, whether it was a physiologic stressor, a psychological stressor or something came along antibiotics and they went out of remission. And I think it's a very, can be a very effective strategy. I think what you and I both struggle with, and we talked about this at the meeting, is in your patient on standard dosing with a novel biologic. We're not talking about we know how to optimize anti-TNFs. We became very, very good at that and squeezing every little bit of toothpaste out of the tube. But what do we do with the novel biologics? And what we did is we did what we did with anti-TNFs, we checked levels, we optimized, we tweaked, we adjusted. And this is an abstract that really calls into question, is that really worthwhile? Should we really do that or should we move to a P19 or something with a different MOA? And I think we also talked a lot about our offices and the burden that we put on staffs to try to get these 6-week and 4-week dosing approved and not only the one time but then the next year and the year after and that heavy burden and maybe what we should be doing is an IV reinduction and if it works, great. If it doesn't work, maybe we move on to something else.

Dr Horst:

Ray, so I totally agree with you. I think the other really important thing about this study is it actually is nice data to show that the IV recapture can enhance recapture of response in patients with Crohn's disease. So we need to use this in our letters. If we have to do an appeal letter for the patient to get that IV reduction, this is data that we can actually use to put in that. So I think this is really important.

Dr Cross:

Completely agree. What's the second study you want to go?

Dr Horst:

So the next study I thought again really on this idea of looking at what to do in someone who is on a newer biologic. What do we do if they lose response? So this was the LOVE CD study. So this is a really interesting study where they took patients—a lot, over 260 patients—who had moderate to severe Crohn's disease. And they actually had sort of 2 groups. They had an early diagnosis, Crohn's disease, which they had only been diagnosed for less than 24 months or a late diagnosis. They'd been diagnosed for at least 2 years and had a previous anti TNF exposure and then they put those patients on vedolizumab. And so what they did right in the middle of this study was they looked at dose intensifying. So is it helpful to dose intensify vedolizumab from Q8 weeks to Q4 weeks? This is all IV in patients who had not had endoscopic response by week 26.

So this is a different, newer biologic, different anti-, Crohn's disease nonresponders—does a dose intensification work. And really interestingly, this dose intensification really didn't seem to be very helpful in this patient population. They looked at week 52 outcomes and really found no difference between primary outcome and some of the other secondary outcomes like endoscopic remission response at about a year. So again, this is kind of practice-changing for me. I think if someone is on vedolizumab with Crohn's disease, their endoscopic nonresponders, sort of our tendency is try to dose escalate. And at least for the IV Q4, we didn't find, this study, did not find that this is effective. So for me that happens. I'll probably try to go to a new mechanism of action.

Dr Cross:

And this study really, it tells a nice story with interpret, right, when they looked at post at week 6, they looked at really dose escalating based on levels and really, really high doses, like 600 milligrams every four weeks. And they followed those patients 6 months and it really didn't make a difference. You're either going to respond or you don't respond. And I've completely changed my practice based on their studies. And I'm not saying I'm never going to try Q4 week dosing on a patient because anecdotally I think you and I both have patients that have benefitted from Q4 week dosing. But again, it causing the question is that the right approach? Is that the cost-effective approach or should you move on to something else? And I think more and more with these novel therapies, it's move on to something else.

Dr Horst:

I completely agree and I think especially for vedolizumab in Crohn's disease, to me also keeping someone who's not doing well, almost saying, oh, this is going to work and then it doesn't. You have data to show that it's not going to work, then they get frustrated. They're 6 more months in to not feeling well. This is data to really show us you got to move on. You got to go to the next step to really help that patient who's not doing well with Crohn's disease.

Dr Cross:

And we don't really know if that applies to UC, but I think that the jury's out on how we should be optimizing these drugs.

So the third one's pretty cool. It's very provocative.

Dr Horst:

This was really fun to sit and listen to at ECCO. And I don't know that this is practice-changing yet, but boy is it thought-provoking. So this is the COSTA study. So this is the study that the thing that they did was an appendectomy for remission induction for moderate to severe ulcerative colitis. So this was a Dutch prospective multicenter cohort study of patients with moderate to severe ulcerative colitis who had had active disease despite having been on a biologic or small molecule. So these patients are therapy experienced, these patients could then consider switching to a JAK inhibitor or consider an appendectomy. So this was really interesting that the idea of this was a patient preference model. So they gave the patient the option to either go on the JAK inhibitor or undergo the appendectomy, and the primary outcome was clinical remission at 12 months without therapy failure. And therapy failure meant starting steroids, switching advanced therapy, starting a new medication or undergoing colectomy.

And basically what was fascinating about this was their primary endpoint of clinical remission without therapy failure was met and it was significantly higher in the patients who had an appendectomy compared to those who went on a JAK inhibitor—30% versus 12%. Now there are some differences in the baselines of these patients. The patients who underwent the appendectomy were more likely to have just left-sided disease and they were probably just a little bit less sick, they less likely to be on steroids. But this is really fascinating and a totally new approach to think about for someone.

And the other thing that came out, and I was so glad we were able to sit through the question and answer session is that they had seen in other studies that a cecal patch might actually be prognostic for whether or not appendectomy is going to work. And they did see that in a subgroup analysis for these patients, if they had a cecal patch, they were more likely to respond to that appendectomy treatment.

So wow, I mean this is pretty interesting. I don't know that—this is still preliminary data. We need larger, probably not patient preference model to think about, but maybe a different evaluation of how to look at this in a study design itself. But it is something that pretty provocative—taking out the appendix might treat ulcerative colitis.

Dr Cross:

So my guess is that our surgeons, they're probably not going to be enthusiastic about doing an appy for refractory UC yet. But more to come. And remind me, I thought these are mostly UPA treated patients, is that right?

Dr Horst:

Most of them were on upadacitinib, yes, that's correct.

Dr Cross:

And one of the things we pointed out was the response rate we would expect with UPA was a little lower. So I think with any early phase study, we have to review the results with some skepticism. So we would expect to JAK patients to do pretty well. But hey, even if it was a tie with a JAK inhibitor, that's still useful information.

Dr Horst:

Yeah, I mean if this is going—I think about this, if this is really true that left-sided patient with a cecal patch, they may still need advanced therapy, but if this could work, would they be more likely to respond to an next advanced therapy? Again, also I think an important point is they had very low rates of adverse events, serious adverse events in the appendectomy group. Most of these patients have very low BMIs, they were a little bit younger. So is this really going to play out to a larger patient population with ulcerative colitis? Maybe not, but it's really provocative and interesting to think about.

Dr Cross:

Correct. So I just want to remind the listeners that we are sponsored by the AIBD network and we are available on Spotify and Apple podcasts. And our next AIBD regional will be in Dallas June 21st to June 22nd.

So I'm going to go over my 3 abstracts now and I'm going to give Sara a chance to weigh in on those. So the first study is really out of this world. It's called GRAVITI, which was an oral presentation and it was looking at subq guselkumab for induction of remission in moderate to severe Crohn's. So the doses used here are the FDA-approved doses. Now this was just approved for Crohn's in the US; it's 400 milligrams subq at week 0, 4, and 8. And then patients in this study were treated as treat straight through design. So what we're used to is seeing these randomized re-responder studies were after induction patients get rerandomized to either placebo or one of two doses for maintenance Here, both the treatment groups were treated either with 200 Q4 for maintenance or 100 Q8 or the placebo-treated patients if they responded, were treated straight through with placebo.

So sort of standard disease characteristics of these patients, nothing really sort of unusual. About 20% of these patients had ileal Crohn's. So a little lower maybe than what Sara and I see in clinical practice for isolated ileal disease. But otherwise pretty straightforward. And really the results were quite striking. Their primary endpoint was a coprimary of clinical remission and endoscopic response at week 12. And in the guselkumab-treated patients, this was achieved in 57% compared to 21% of placebo and endoscopic response was seen in 41% versus 21%. They looked at a number of other secondary endpoints, but I think most importantly is looking at clinical response which was achieved in 74% of patients. Now what's interesting is you can get a sense here of delayed response because you are treating straight through. That's a question we always have. What if I give this another 8 weeks, another 12 weeks? What happens?

Well at week 24 there was really incremental increase in clinical remission only to 60% and that was really preserved out to about week 48. So there was really no drop off, but there wasn't really a big gain either. However, there were higher rates of endoscopic response. It got up to about 51% at week 48. And we know the P19 inhibitor class is quite safe. And there was really no new safety signals here. The risk of serious infection throughout the 1-year study was about 1 per 100. And in fact, adverse events were actually lower in the guselkumab-treated arm probably because disease activity is better controlled. So really on groundbreaking study, I made a little joke about this is out of this world, but I'm really probably a game changer in our clinical practice. So Sara, what do you think about GRAVITI?

Dr Horst:

I loved the comment ‘out of this world,’ but it really is. To me, I have really been advocating for in patients with moderate to severe Crohn's disease, we really need to be thinking about this class of drug early. And I think this is a way for us to be able to have clinicians and patients get access to it a little bit more easily. We all know the difficulty of trying to do an IV induction to subq just in the insurance environment that we're in, trying to get approvals from a medical therapy standpoint, get the patient there and get it scheduled. I mean for our group, our target is 10 to 14 days to even get an approval and that's pretty aggressive for the IV. And then to have to go to the subq, try to ask for the pharmacy benefits to get the subq approved, it's just so much for your teams to deal with. So if you can do a subq induction off the bat for someone with Crohn's disease and they don't have, they're already sort of a little bit overwhelmed probably, and to be able to do this through one mechanism, through one insurance approval, man, it's exciting. So I'm really excited about this.

Dr Cross:

Yeah, I agree. And I think that for ustekinumab, there were questions about why aren’t providers using this more? And I think really it was the hassle factor of that dual authorization and this really allows offices to just be one authorization. So it limits the burden on staff. And it's interesting, we now have 2 different dosing strategies that we can use. And if you look at the data, if you get into the subgroups, which was not part of this abstract, but Sara and I know that data because we've seen it, is it really seems like you don't really lose much in efficacy if at all when you go to the treatment-exposed patients. But it may be that that is the group where the 200 Q4 compared to 100 Q8 is more effective. Also the group that's maybe sicker at baseline, higher endoscopic activity, more symptoms, higher biomarkers also probably benefits from the 200 Q4. So in clinical practice, now that we have this, Sara, is that how you're going to determine the maintenance dose or are you just going to give everyone 200 q4?

Dr Horst:

That's a great question and I've been thinking about this a little bit and I think phase 3 clinical trials are so super important, but they are a very particular subset of patients. They have to be a little sick but not too sick. It's sort of like Goldilocks, their porridge is just right to be able to get into this and I just end up seeing patients with Crohn's disease who just fall outside that they're just a little bit sicker. So for most of my patients, I'll probably go on that higher dosing strategy. I do think someone who is therapy-naive who maybe has a little bit lower biomarkers, who maybe has a little bit of that, a lower inflammatory threshold, I could think about that lower dose. And so I'm going to keep an open mind about that. But to start, a lot of my patients are probably on that higher dose.

Dr Cross:

Yeah, I completely agree. I think most are going to get the high dose and you can always deescalate too over time if you need to.

Dr Horst:

Absolutely.

Dr Cross:

So we always have that ability. So it's interesting. Sara had the most difficult talk at the AIBD regional. She had to summarize medical options for Crohn's and UC in 45 minutes, which she did very, very well. But one of the things we talked about was acute severe UC and the therapies that we use for that. But importantly, in those sicker UC patients, how do you optimize infliximab? And there's been discussion about using double dose, giving accelerated treatment.

So the next abstract, which was DOP 56, it was called the TRITRATE trial, addressed that. It was a prospective, open-label, multicenter randomized controlled trial where patients were randomized to either standard dosing, so they got 5 milligrams per kilogram in the hospital, and these were all steroid refractory; 90% had a Mayo endoscopic score 3. However, most of these patients were naive to advanced therapy and they could not have been on infliximab previously. So it's important that we mention that.

In the standard group, if they got the first dose in the hospital, well their second dose as an outpatient was at 2 weeks and their third dose was at 6 weeks. So standard dosing in the personalized group, what they did is they used this proprietary drug monitoring called iDose and they gave doses to ensure the patients had a level greater than 28 between baseline and 28 days. And then between days 29 to 42, they had to be higher than 15. And their primary endpoint at day 42 or 6 weeks was clinical and endoscopic response.

Now numerically in the personalized group, it was higher, it was about 57% versus 44%, and that did not meet, it was not statistically significant, although I think Sara and I would both say that that 13% delta is clinically meaningful. And if you look at just clinical response between the personalized versus standard, it was 91% versus 64% and they followed these patients out to 6 months.  And actually the clinical and endoscopic remission rates were over 60% in the personalized dosing compared to 36% in the standard. But because of the sample size, it was not significant.

So this was ended because of futility, which I don't really understand because everything was trending in the direction to favor this personalized dosing. Now what's really interesting, and I bring this up because it mirrors what I do in clinical practice and we must highlight the things we do successfully in clinical practice, but typically in the hospital for these patients, I ignore the first dose and I start 0 to 6 all over again. I don't use the levels, but I basically ignore the first dose and restart because I think the payers don't pick up on the fact that they got an inpatient dose. So guess what? The average second dose in a personalized group was at day 7 and the third infusion was at day 19. So if you just forget the levels and you just ignore the first dose and do a 0, 2, 6, that would basically on average mirror the study. And anecdotally, I do think our outcomes are a bit better. I can tell you that 5 versus 10 in our practice doesn't really make a difference. But I do think this is real and it just was an underpowered study and it really reinforces what I do in practice. But Sara, what did you think of TITRATE?

Dr Horst:

Well, this was great for us to chat through. I think initially when I looked at the study, it was really helpful for us to talk through this together because when we really dug into this data, even though they didn't meet the primary endpoint, boy, really actually digging into the data and showing that giving these doses earlier after you leave the hospital, how important that is. And at a day 42 endpoint of seeing a delta of 30% in clinical response, that's super important for your patient with acute severe UC. And I just think the primary endpoint probably wasn't necessarily the best thing to do because looking at a day, are we really endoscopically looking at people at day 42 after a hospitalization? No. And so I think that you really helped me hammer home how important this is, and this is what we've been doing.

As they get a dose in the hospital of infliximab, if they have acute severe UC and we try to get that, we start the full reinduction, we try to get that as soon as they leave the hospital. I just had this happen to somebody in the past month and she's doing great, but it's so important to keep that infliximab going for these patients because the colectomy rates for these patients after a hospitalization at 6 to 12 months is still 30%. We cannot ignore them after we give a dose. We have to watch these people so closely. So this is really important.

Dr Cross:

And that Branzi? study, which I think was Crohn's and not UC, but it just showed that these severe colitics get this protein-losing colopathy and accelerated clearance of the drug. And we all just thought, we'll give more, we'll give more. But what we also learned in clinical practice when we were using drug monitoring is that what's more effective is to give the drug more frequently, not dose escalation. And this does support that. So maybe we can keep the levels where they need to be, but do it by giving more frequent doses, not giving everyone double dose. So I think we still haven't quite figured this out, and I think that maybe JAK inhibitors will help us a little bit here because we can overcome some of that. But that's still early for JAKs.

So the third study I have was a retrospective study, but very large, nearly 500 patients. And it's a little outdated in the sense because we had more treatment options now, but it was asking a relevant question of what do you do in a patient with perianal Crohn's who are our sickest patients often, who don't respond to first line anti-TNF? What is the second drug? And what they did here, best second or third drug, what they did here is they looked at either ustekinumab, vedolizumab, or a second anti-TNF, and they looked at patients that second-line exposure and third-line exposure, and they did propensity score matching to try to make these groups equal. But unfortunately for the thir- line treatment group that propensity score matching didn't work. And we're going to focus mostly on second line; of note, about 20 to 30% of these patients had a prior fistula repair attempt, and about 36 to 46% had a seton in place.

It's also a little more complicated, not because not all of these patients had active perianal disease at baseline. Some of them were being switched for another reason. And so 181 were inactive and let's focus on that group first. The group with inactive disease at baseline, when they switched, it really didn't matter which approach you chose. The outcomes were the same. And that was true also for third line. But for the patients with active perianal disease at baseline, patients treated with ustekinumab had a clinical response for their fistulizing disease of 80% compared to 59% for VEDO and 49% for a second anti-TNF. And that was seen also for third-line use. Those same trends were there as well.

So I think it's useful. Obviously we could talk about what were the drug levels, what was the first anti-TNF? Was it adalimumab versus infliximab? There's still nuances here, but maybe this tells us that if you got good levels with an anti-TNF, you clearly should be doing a different MOA, should that be USTE or a P19 or even UPA. Now I think most of us are probably going to, would extrapolate this and use a P19 or UPA in this situation.

Dr Horst:

Yeah, I agree with that. I think this is important to sort of get to the idea of where you should go. So I've been using ustekinumab in this patient population with reasonable success already. And so I think then extrapolating that, well, these patients are anti-TNF failure and we know that a P19 probably will work better in even maybe than that anti-IL 23, 12/23. So that's really where I'm going. So if I'm going to, I think in patients with this disease process, I really will be pushing towards that. I do think upadacitinib might be another option that's outside of the scope of this study, but I think the point is we probably shouldn't stick within the anti-TNF. Don't try it again. Probably. I mean, it depends a little bit on nuance, but if they're truly nonresponding, you got to go to the next step. And at least in this study, it's probably not vedolizumab.

Dr Cross:

Yeah, I just realized you cannot do air quotes on a podcast.

Dr Horst: I know. I love an air quote.

Dr Cross: What I was thinking is that what is really refractory? And I think if you have a patient who has been seen by a good colorectal surgeon and has a seton or setons in place who's got infliximab with a drug level in the teens who's also a concurrent immunomodulator with full dose, good levels, whether you're using methotrexate or thiopurine, that patient who is not responding is completely different than a patient without a seton who's maybe on a monotherapy. And in my experience in those patients, they're very difficult to recapture no matter whether you're using a P40 or a JAK. Those are really, really sick patients that often are going to need surgery. I don't know if you've had the same experience there.

Dr Horst:

I have. And I think we should not ignore the importance of what's happening in somebody who has perianal Crohn's disease, if they have rectal inflammation or even sort of right around that anal region if there's a lot of inflammation there, if you still have inflammation going on, you really have to try to push therapy in a place where you can get that under control because I do think that really does drive the perianal disease even more. And so I'm extremely aggressive in those situations. And if there's a lot of inflammation in the track, clearly seen on an MRI, they still have, you have to control the sepsis. So you have to make sure that you're getting rid of abscess and fluid as much as you can, but just do not ignore the inflammatory component that's happening in that distal bowel.

Dr Cross:

And Tina Ha mentioned in our Q&A about the developing an anal stenosis and how much that increases the degree of difficulty of controlling these patients and getting good long-term outcomes. And you really need to be aggressive and treat those patients early to try to prevent that.

Well, Sara, this has been wonderful. We look forward to the rest of the day for the AIBD regional. And Sara is going to have an upcoming episode where she is hosting and is going to learn more about antibiotics and perineal Crohn’s.  I'm sorry, pouchitis.

Dr Horst:

That's right. Pouch, yep. Awesome. Well, thank you so much. This has been really fun to talk through this.