IBD Drive Time: Christina Ha, MD, on Positioning IBD Therapies

In the first-ever video version of the IBD Drive Time podcast, Drs Raymond Cross and Christina Ha discuss positioning IBD therapies from our Open Air Studio at the AIBD Annual Meeting.

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. 

Christina Ha, MD, is senior associate consultant in the Division of Gastroenterology and Hepatology and associate professor of medicine at Mayo Clinic Arizona in Scottsdale, Arizona.

TRANSCRIPT:

Welcome everyone to IBD DriveTime, the official podcast of the AIBD Network. I'm Raymond Cross from Mercy Medical Center in Baltimore, and I'm delighted to have my friend Tina Ha as a return guest, Tina's from Mayo Clinic, Scottsdale, and we're going to talk about positioning therapies in IBD. Tina, welcome back.

Dr Ha:

Thanks for having me.

Dr Cross:

So I thought we'd talk about 4 scenarios. I wanted to start with ulcerative colitis first, and I want you to take me through your thought process when you see a patient in the office with ulcerative colitis who is advanced therapy naive. And I've been told by Asher Kornbluth we should not say advanced therapy. We should be saying highly effective therapy. So they're naive to highly effective therapy, maxed out on 5-ASA. How are you positioning treatments for them?

Dr Ha:

Well, first things first is I want to make sure that we have an updated disease activity assessment. So I want to look to see when were their last lapse, have they had a recent fecal calprotectin or a C-reactive protein, because I want to be able to follow deltas over time, not just endoscopy. If their last scope was a while ago, I do want to just at the very least to get a sigmoidoscopy, does not have to be a full colonoscopy, so I can get an endoscopic assessment because there's certain features when we take the aggregate of the patient in front of us, their clinical symptoms, not just rectal bleeding, urgency, and their stool frequency, but their comorbidities, their lifestyle factors, other medications they're on, the endoscopic findings. Am I seeing large deep ulcers? Am I seeing denuded mucosa? Or is it mostly contact friability and absence of vascular pattern?

And then their labs, do they have a very high C-reactive protein? Do they have anemia? Do they have a lower albumin? And all of those factors in aggregate help me decide which highly effective therapy I want to talk to my patient about. Since we're lucky in 2025 that we have so many different options, the understanding is how do we best sequence these options so that we can use the right agent for the right patient right now, but also have good options later on in case our first option doesn't work. So if it's a straightforward moderate colitis, there's no large or deep ulcers, normal labs, normal albumin, C-reactive protein, the fecal calprotectin's elevated, but they're otherwise pretty functional. Any of the therapies are a reliable option. I probably, in that scenario, would not go with a JAK inhibitor first because they're advanced therapy naive, but vedolizumab, the anti-interleukins and even anti-TNFs are absolutely within the discussion.

Then the question is, do they have other factors that would influence my decision making, namely extraintestinal manifestations? If they do have extraintestinal manifestations, namely the joint manifestations, I'm going to be more inclined to use an anti-TNF because they're more effective, particularly if they have an axial spondyloarthropathy, because that's where that class is the most effective. If they have some dermatologic comorbidities, I may be leaning more towards an interleukin because they're very effective in the dermatology space. But if it's fairly straightforward, no comorbidities, and we're thinking about safety profile in addition to the effectiveness profile, vedolizumab and the S1Ps are absolutely a reasonable option as well.

Dr Cross:

So I want to ask you one question. You mentioned diagnostics and pairing those with symptoms as you're starting treatment. I'm pretty sure you have intestinal ultrasound at Mayo as well, like we do. So that's also an approach you could use as well, right? Getting a baseline IUS.

Dr Ha:

Absolutely. But in all fairness, I think intestinal ultrasound is an important and a very useful modality. I do like to pair my initial index intestinal ultrasound with a more recent objective assessment, such as a fecal calprotectin or an endoscopy, just so I can confirm that with those paired assessments that they are reliable. There's no modality that's 100% effective all the time. So once I know that the intestinal ultrasound does correlate very well with an objective assessment, then I can follow it as a delta over time.

Dr Cross:

And I want to take a quote from you that I may mess up a little bit, but I think for the listeners, understanding in your area what you can access quickly for your patient in this situation is critical, because I've heard Tina say this over and over and over again, delays in starting therapy equal steroids, hospitalization, and sometimes surgery. So when there's not a lot of differentiation among the treatments, use what you can get quickly and get a patient started. The other thing that you're starting to hear more from us is that let's think about not needing to ... You don't need to earn a highly effective treatment, right? Let's think about who shouldn't get a highly effective treatment, not necessarily who's earned it. Do you agree?

Dr Ha:

Absolutely. And also understanding that the majority of our patients do have moderate to severe ulcerative colitis, which means they fit within the category of needing an advanced therapy, which are highly effective therapies. And we do know that the uptake to starting an advanced therapy for our moderate to severe ulcerative colitis patients is lower than it should be. And I think that there's this perception that it is not as assertive of a disease or that people can live with it. We also underplay or probably under recognize the impact that active ulcerative colitis has on our patients because all you have to do is ask them, what impacts your quality of life? It's getting up at night, not knowing if they're just passing gas or they're going to be incontinent stool, constantly seeing the bleeding, that uncertainty of bowel movements, that impact on their quality of life automatically deserves attention and appropriate therapy earlier.

Dr Cross:

And I heard Asher say this yesterday, that a lot of ulcerative colitis patients will talk about their new normal, and he's very quick to discount that. I'm not talking about your new normal, I'm talking about before diagnosis. That's our goal —to have you feel completely well again.

Dr Ha:

Absolutely. And I think that that's really a key differentiation. It's not just living with your ulcerative colitis, it's living well with your ulcerative colitis, optimizing your quality. And many of our patients, they've lived with it. They deal with their current level of symptoms, they deal with a current level of inflammation because they've become accustomed to it. And sometimes we kind of turn the other cheek and say, "Well, they're doing okay. They don't look sick, so we don't need to make any changes.” Particularly if you're limited to just a quick 10 to 15 minute office visit and you say, "How are you doing?" "I'm doing okay." Continue current therapy. But you really have to do a deeper dive and understand what does okay mean to them and does that really, truly represent quiescent disease or is it smoldering disease that we're just living with?

Dr Cross:

Now you mentioned, so the scenario we just talked about was the ambulatory patient, more moderate inflammatory burden, thinking more Mayo2 endoscopic activity. What about the patient that has the deeper ulcers that maybe is anemic, more severe symptoms, they're going more than 10 times a day? How does that change your algorithm for what you're prescribing?

Dr Ha:

Yeah, and this is where understanding risk stratification is really key because that's a higher risk patient, not just higher risk for colectomy, but higher risk for developing C difficile infection, needing to go up to the hospital, needing IV steroids, missing work, impacts on quality of life. So for those patients, I not only think about which advanced therapy I would want to use, but also timing of onset of action. Those are patients where they can turn the corner real quick and go down a path towards colectomy very fast. It's sort of like when you smell gas, you don't know if your house is going to erupt in fire within the next week or within the next hour. So those are patients where I'm going to be looking more towards a treatment a, that I can access relatively quickly, and one that I can optimize relatively quickly versus one that works very quickly.

And when I'm thinking of that, I'm thinking about the anti-TNFs, namely infliximab, because with infliximab, you have the most opportunity to adjust the dose and the interval in order to combat pharmacokinetics, such as that low albumin or high C-reactive protein. But with some of the label updates with upadacitinib, those may be patients because of the quick onset of action, particularly if they're steroid dependent, steroid refractory, or there's a contraindication to using high dose steroids that we need to do something quick. And so with this thankful label update, now we have the opportunity to position upadacitinib earlier for those patients. And that class of patients, I think that's where that label update makes the greatest impact.

Dr Cross:

Yeah, you beat me to the punch. I was going to ask you about the label update because in my practice at Mercy, about two-thirds of our patients, we can get started on an infusible within two weeks, but I can literally put UPA or TOFA in their hand at that visit and get them started, and then I can avoid even a short bridge with prednisone or a long tapering course. So I think that indication label update is super important. The other point I want to make, I know that you agree with this, is that I think when you frame shift your mind about safety and recognize that uncontrolled disease, particularly in this scenario, with or without concurrent steroids, is riskier than any advanced therapy, it really helps you change and become more comfortable prescribing a JAK inhibitor and other therapies. And I think when you tell patients that, I've found that when you talk about safety, you can see some fear in their eyes. And then when you remind them, "Hey, this isn't safe, what you're doing here and the steroids are not safe and this medicine actually is going to be a net reduction in risk." I think it makes it much more palatable to them to start meds.

Dr Ha:

Absolutely. And I think that this is why it's so important to have a team-based approach when you're talking to patients who are especially having these severe active symptoms, because I think framing expectations in terms of when we're expecting to get the medications, when we're expecting to see a response, what we mean by seeing a response. Is it I'm feeling better? Is it that the number of stools have gone down? Is it less bleeding? And how we're going to continue monitor and adjust along the way? The other thing that I think is really key that's not highlighted enough in our clinical practices is that it's not just about giving the medication. Absolutely getting them on upadacitinib, infliximab, or whatever advanced therapy earlier rather than later is absolutely key, but now is a prime opportunity to optimize all these other variables. If they have an anemia, give them IV iron. They need the elevated hemoglobin to actually make themselves feel better to help with energy, fatigue, but also volume of distribution. Make sure that they're appropriately hydrated. Check vitamin and mineral levels, optimize their nutritional status, make sure they're getting enough protein, make sure they're walking around. Sarcopenia, loss of muscle mass associated with active inflammation, is associated with poorer outcomes, VTE risk. So it doesn't just live in a silo that medical therapy is all we do. It's really a team-based sport and we have to focus on the whole person, not just the colon.

Dr Cross:

Well said. How does exposure to prior highly effective therapies impact your decision-making in UC?

Dr Ha:

It really depends on what was their prior response or nonresponse and were they able to be optimized in the past? So for me, using an anti-TNF, for example, if they had an excellent response and they were actually in a deep remission and it was paused or discontinued for a variety of reasons—whether it be insurance related coverage issues, patient preference, or some sort of comorbidity or complication—I have zero problems going back to that agent because it was a highly effective therapy before. But I think one key is really to understand the difference between primary nonresponse and loss of response. If a medication never worked to begin with, using it later on and expecting a different result, especially when we have different options, shame on us.

But if a patient lost response to that agent over time, then we have to ask ourselves why. Was it because it was underdosed? Was it because we have antibodies that formed? And do I have another option within that class where I would expect if I were to use that history to make adjustments proactively in the future, would I yield a better response? With the anti-TNFs, I traditionally see that for patients who are on a subq anti-TNF, such as adalimumab, and loss response, infliximab is a very, very good option. And then I use that information to say, "Hey, this patient may be better for proactive early dose optimization or adding combination therapy." However, if that occurred with infliximab, I find that switching to an adalimumab or golimumab won't yield a better response, and then I'm more likely to switch to a different mechanism of action.

Dr Cross:

Yeah, I think we practice very similarly. In my practice, if you've been on a prior highly effective therapy and it was not an anti-TNF, particularly it wasn't infliximab, I tend to favor more infliximab or upadacitinib or even tofacitinib in that situation. Having said that, if the patient's still more of a moderate patient, more Mayo2, not horribly symptomatic, even though we know there is a drop-off with P19s and anti-integrins, S1Ps, those are still really viable options for the less sick patient.

Dr Ha:

Yeah, absolutely. And I think that this is the tricky aspect when we think about sequencing our medications because it's not just a linear algorithm. There are so many variables that we have to consider. Was it because of an adverse effect of therapy? Did they develop TNF-associated psoriasis? Or was it because their insurance no longer covered the ustekinumab and therefore that's why we have to position other medications before or after? So it's never just a black or white decision. We have to look at the aggregate.

Dr Cross:

All right, let's pivot to Crohn's. So let's take a patient with not exposed yet to highly effective therapy. Most patients with Crohn's warrant a highly effective therapy. Is it any different in Crohn's and how you think through your initial choice of treatment?

Dr Ha:

Oh, in all honesty, I view it pretty much the same because we're lucky that we have multiple classes of medications. So the first thing is risk stratification based on their endoscopic, radiographic, laboratory, and clinical presentation. Then again, you focus on their comorbidities and then patient preferences. What I will say is similarly for ulcerative colitis, if they have large or deep ulcers, extensive Crohn's disease, I'm going to favor something that has a little bit more of a rapid onset of action where I have a little bit more flexibility with dosing such as an anti-TNF that I'm using in combination most likely with an immunomodulator. Those would also be patients with perianal Crohn's disease, for example. And now that same label update with upadacitinib also carries true for Crohn's disease as well. So if they have those same factors that would influence pharmacokinetics of biologic agents, I may want to jump ahead and favor upadacitinib.

So the same approach, risk stratification, updated disease activity assessments, and looking at the labs, apply for both Crohn's disease and ulcerative colitis, with the exception of surgery. If there is stricturing disease or very obvious penetrating or fistulizing disease, oftentimes those patients are knocking on surgery's door anyway. So you have to ask yourselves, is it better to expose them to all these therapies now versus do a primary resection when you still have the window to do a primary resection and then reset the clock and then offer these agents that are more likely to be effective in the postoperative setting?

Dr Cross:

Yeah. My bias in the stricturing scenario you mentioned is I think a surgical reset is the way to go. Unfortunately, many patients and LYR!C has supported that, that's a very good option. Manasi Agarwal, some of the work she did with a European cohort database shows that surgery can be a very, very good option. But I think my guess is in your practice, it's similar. Patients aren't really considering upfront surgery before they've been on a treatment. So we're often giving them something first, but I think you agree that I usually set the tone that I'm going to give you one advanced therapy in this situation. I'm not going to cycle through multiple if you have a stricture.

Dr Ha:

Absolutely. And I use a lot of analogies in my practice, and so I equate active Crohn's disease to be like a house that's on fire. And the goal of our medications is to extinguish the fire so that the house can actually rebuild and remain livable. But if there's so much damage to the house, even if you extinguish the house and the extinguish the fire, the house is no longer livable, so you need to reset. So when I'm looking at a patient with stricturing Crohn's disease, for example, I look at the cumulative damage. If it's very clear that there's been a lot of structural damage to the house, then we have to ask ourselves, what are we gaining with constantly trying to extinguish a fire? It's not likely to be successful. And that's how I can get a lot of buy-in with our patients. Our patients want to know what does the endoscopy show and what does that mean in a context of what a normal or nonaffected Crohn's disease colon or small bowel looks like?

If you show those imaging studies where you can see the stool balls, the fecalization, or the dilated bowel loops and the fistullization that's starting to occur because of chronic dilation, it becomes very clear, wow, that's already so damaged, I'm not going to be able to fix it.

Dr Cross:

Yeah. I think when Tina and I are talking about stricturing disease to be clear, those aren't the patients with fistulas, intra-abdominal abscesses, significant prestenotic dilation. I think medical therapy in those situations is typically futile. We do also have the ability to do some endoscopic balloon dilation for short strictures. So you mentioned taking care of the whole patient, but certainly adjunctive endoscopic treatment can be another area that can be helpful. Also, I think in Crohn's, generally we deemphasize a few of the treatments like not that vedolizumab can't be effective in Crohn's disease, certainly like post-op looks like it has very good signal of efficacy, but I tend to think we de-emphasize certolizumab, vedolizumab, a little bit in a Crohn's population.

Dr Ha:

Agree. And it's not that they don't have a role. I definitely think vedolizumab has a role for Crohn's disease, but it's all about context and where do we want the understanding the effectiveness and the safety profile of vedolizumab, which is very favorable safety profile. And I think the effectiveness story is still evolving. I think that initially it was thought, well, it doesn't work as well for Crohn's disease, but at that time when it first came out, all we really had are anti- TNFs. So it's not that vedolizumab doesn't have the opportunity to work for Crohn's disease. Is it the best option for the patient in front of me compared to an anti-TNF, compared to an IL-12/23, compared to the IL-23s, or compared to the JAK inhibitors? And if it is, I'm happy to use it. If it isn't, then we may say, um,there are other options.

And we have to keep in mind when we're looking at the comparative, when we're looking at the data for the medications as a whole, we're not necessarily comparing a class classes. We're looking at that agent compared to placebo or compared to doing nothing else, standard of care. There's not really a lot of head-to-head studies comparing vedolizumab to the P19s to the P40s. There are some studies that looked at using vedolizumab with anti-TNFs in ulcerative colitis, for example, but having more of those truly comparative effectiveness studies will help us with positioning. It doesn't help us demonstrate effectiveness. We know they're all effective. We just don't know how they should be appropriately positioned.

Dr Cross:

And perianal is a whole separate topic, so I'm not going to focus on that. But I think you and I practice similarly that we're more proactive therapeutic drug monitoring advocates as opposed to combination therapy for everyone. A, is that true? But for the listeners, I think what is correct is you either have to be a proactive therapeutic drug monitoring person that gets levels above a threshold to prevent immunogenicity or you need to do combination immunomodulator with your anti-TNF.

Dr Ha:

Absolutely. And because that immunogenicity risk is real, and we do know that the immunogenicity really starts to declare itself after a hundred days of being started on treatment. So you either have to commit to a casmp—either you're going to start optimized monotherapy with an anti-TNF and commit to proactively monitor so that you can make the adjustments before that 100 days, or you're going to start combination therapy. And in truth, looking at the PANTS study, it's actually the most effective if you start the thiopurine first or right at the same time as the anti-TNFs, not afterwards. But more importantly, you have to proactively monitor your patients. So if you're starting a newly diagnosed Crohn's disease or ulcerative colitis patient, or frankly, any patient on an advanced therapy, you should be communicating with them at week 4 or week 8 and making these adjustments before you hit that window where immunogenicity can occur.

Because once they've developed antibodies, the likelihood that they're going to be able to stay on that therapy decreases and you don't want to lose the opportunity to stay on a highly effective class of medications because we did not monitor.

Dr Cross:

Yeah. There's a small study, an Israeli study, showing that you can sometimes reverse immunogenicity by adding an immunomodulator late, but that's a little harder to do. And I think that we have so many therapies now trying to do a salvage at that point, I don't think is appropriate.

Dr Ha:

And that actually, that strategy is really only effective with low levels of antibodies. And so as we're really only talking about a small fraction of patients.

Dr Cross:

Not the super high titer.

Dr Ha:

Exactly. And the problem with a lot of these dosing strategies is if you check an infliximab level, for example, at week 14, they've already gotten their first maintenance dose. So it's already beyond that window. So by the time you make an adjustment, you're already essentially at week 20 or 22, so you've already lost your stake in the game. So if you're going to be checking, you have to check well before that week 14 time period, so you can make that adjustment while you're still within the window of opportunity.

Dr Cross:

Two more questions, Tina. So first question is in Crohn's—disease location, does it impact what you're going to give a patient?

Dr Ha:

So it does in the sense that ileal disease and rectal disease are more recalcitrant to therapy. So if I see somebody who has larger or deeper ileal disease, ulcers in their ileum or in their rectum, I'm going to be more inclined to choose a therapy that I know is going to work quickly. I'm going to start them on treatment as early as I can. I'm going to be more inclined to choose an anti-TNF or an interleukin or a JAK inhibitor. Just because the stakes are higher, those sites of disease location just tend to not respond very well. Although the PROFILE study…

Dr Cross:

Do you think UPA works for small bowel disease? It's been pointed out to me and I don't think I've been thoughtful enough or been able to see this trend in my practice, but you're getting this sort of buzz that UPA isn't a really good agent for isolated ileal Crohn's. What do you think about that?

Dr Ha:

Well, I don't know if we've had the opportunity to use it in the ideal ileal patient population yet, because I think that these patients with isolated ileal disease, they need to be treated with early, pretty much at the time of diagnosis. And only recently did we have the label update for upadacitinib. So are those patients with a larger, deeper, the higher SES-CD scores of the ileum? What if we started them on upadacitinib right at that time? Do we have the opportunity to change the outcomes? Because in a lot of those studies, they've already been through a number of advanced therapies, certainly anti-TNFs.

Dr Cross:

I'm sorry, you're mentioning PROFILE and I cut you off. Go ahead. Sorry.

Dr Ha:

And I was saying, because I think that PROFILE was so impactful in that starting patients a median, I believe it was 2 weeks after their diagnosis on an advanced therapy, in that case, anti-TNFs. What was the most striking to me was not the steroid and surgical free remission, 80%, amazing, but that two-thirds had endoscopic remission. And endoscopic remission means that there's no ulcers, and that includes patients who had ileal and rectal disease. And the only modifiable variable that they accounted for was time. And that tells us for Crohn's disease how important time is when we're talking about positioning therapies. And so it's not just about positioning, it's starting therapies immediately.

Dr Cross:

And it's also yet another study confirming that top-down approaches, in this case, giving someone a highly effective therapy is way better than doing an accelerated step-up approach. It's now the third study that showed that we should not be doing that anymore.

Dr Ha:

That should not be in our vocabulary for Crohn's disease. And in all honesty, all the payers, insurers, team members, and patients should understand how high the stakes are for our Crohn's disease patients because it does impact their natural history. And with health care utilization, especially during the first year, the steroid utilization and the impact on their quality of life by simply starting patients on the right therapy early on, downstream, that's probably the biggest impact we as an IBD community can have using our current arsenal to the best of our abilities.

Dr Cross:

Identify the patient with mild Crohn's who doesn't need treatment and give everyone else a highly effective therapy.

Dr Ha:

Exactly.

Dr Cross:

And so in a patient that's been on infliximab or adalimumab, I'm just going to presume that for you, P19 inhibitor or JAK inhibitor is where you're going, that patient, it's going to depend on severity of symptoms and EIMs. It's going to help you differentiate that.

Dr Ha:

Yes. And then the main question is, what's the role of ustekinumab or the 12/23s now that we have so many P19s and some of the data, for example, the SEQUENCE study suggesting that the P19s may be a more effective strategy? Does ustekinumab still have a role? And the honest truth is we have so many options for ustekinumab. We have numerous biosimilars for ustekinumab. And I think what that'll allow is for earlier probably utilization of an agent such as ustekinumab for patients where it can be effective. Does that mean that for a patient who had prior TNF exposure, I would never use ustekinumab? Well, if it's an issue of me not being able to start a P19 for 4, 6, 8 weeks later, versus me being able to start ustekinumab within the next week, of course I'm going to give them ustekinumab because I think there's reasonable data to suggest that we can potentially use P19s after a P40 agent.

Dr Cross:

And we tend to only think of the United States, but access outside the United States with biosimilars, ustekinumab’s still a pretty good drug.

Dr Ha:

And when it first came out, it was at that time a very important agent, and it remains a very important agent for Crohn's disease. Just because we have something new and shiny doesn't mean that we have to disregard what we have previously. We have to utilize what's available to us to the best of our potential.

Dr Cross:

All right, Tina, this has been great. I want to remind the listeners that we are sponsored by the AIBD Network, and you can find this podcast on Spotify and Apple Podcast. Tina, thank you very much. I hope to have you back soon.

Dr Ha:

Well, thank you for having me. It's always fun.