Marla Dubinsky, MD

 Thanks, everybody, for this unbelievably rich and informative discussion. I always learn from the 3 of you, and I hope our colleagues will as well. We covered a lot in these segments, and each was important in terms of understanding how we treat IBD [inflammatory bowel disease], specifically how we got into the mechanism of action and treatments for ulcerative colitis [UC]. Before we end, I’d like to get 3 take-home points from each of you. Dave, I’ll start with you, and then Ellen and Marla. Dave, what are your 3 take-home points?

 First is to treat early. Whether it’s a biologic or a small molecule, start treatment early. The second point is that we must monitor our patients—not just symptoms but biomarkers and endoscopy as well. Then third, for our targets, if we’re monitoring, is that perfect is the enemy of good. Getting better is OK, and we want to be discussing what the patient targets are as well.

 We’re entering an era of disease modification, which means No. 1, get your patients off steroids. Think about a steroid exit as soon as you start the patient on it. A short course of steroids—don’t prolong mesalamines. Second, listen to your patients. What else are they doing? NSAIDs [nonsteroidal anti-inflammatory drugs], diet? Third, look to see that first-line treatments that do not have black-box warnings, that don’t have immunogenicity, but have both induction as well as persistence for disease modification. That would be vedolizumab, ozanimod, and ustekinumab, and don’t forget the JAK inhibitors.

 First, we must understand what are the biggest fears that patients have about effective therapy. We must address them head-on or else—no matter how good our therapies are and how good we think we’re doing communicating that—we’re not going to be moving. That’s important in this era where we’re going to have new drugs every year coming out for the next few years. No. 2, quality of life as we define it is very different from how a patient defines it, so find out what keeps them up at night, what keeps them away from doing the things they most want to do. We have incredible therapies that can achieve disease modification, as Ellen said, but the key is to start it early. If you wait for a patient to develop progressive bowel wall damage, including in UC because we don’t talk about that enough, we’re not able to alter the natural history of these diseases.

 My 3 take-home points are: get it right in induction, listen to your patients, and treat the whole patient. We have great therapies, so let’s get smarter using them, but also consider relationships, work, school, psychosocial, and diets. Those are such important points.

I want to thank all 3 of you and our viewing audience. We hope you found this 

 discussion to be useful and informative. If you enjoy the content, please subscribe to our e-newsletters to receive upcoming 

 and other great content right in your in-box. Thanks very much. Dave, Ellen, and Marla, thanks for joining me.

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Experts in gastroenterology share take-home messages for the management of ulcerative colitis.

Key Takeaways for Ulcerative Colitis Management

 Dave, we talked a lot about unmet needs, but what advice you share with physicians taking care of ulcerative colitis [UC]?

 Treat early. But when you’re treating early, it’s important to monitor your patient. Not just symptoms alone but with biomarkers, fecal calprotectin, CRP [C-reactive protein], and then repeating a colonoscopy. With that, the enemy of good is perfect. What we’re seeing now, as we’ve been talking about, is a lot of referrals where patients are cycling through therapies where the colon looked bad. From when it started to 6 months later, it looks significantly better, over 50% better, but they’re not healed. It’s not perfect. Then we switch to the next therapy. We had a nice discussion showing that we want to push that ceiling, but we’re not there.

When we’re looking at the trials, maybe half our patients hit endoscopic remission. We can do better, but that’s about right. If a patient is getting and feeling better, if their biomarkers are improving, if the colonoscopy is looking better, that’s a good thing. Maybe we optimize what we’re on, but we shouldn’t just reflexively switch because we could do a lot of harm in the short term. They might not respond to that mechanism or down the road they could lose response. Some patients respond quickly, and others take 6 months, a year, or longer to fully heal if we could get there. Be patient and monitor the patient.

 “Don’t let perfect be the enemy of good”—I like the way you said that. We must get it right in induction, but we may be OK, given a little time. It’s not opposite messages necessarily; it’s a continuum. To your point, at 6 or 9 months, if you do another colonoscopy and the patient was at Mayo [endoscopic score] 3 and now they’re at Mayo 1 and looking much better, then I don’t think that’s a time to panic and switch to another therapy. We can optimize within that group if there’s the ability to, but we also don’t want to have a patient stuck on steroids for 6 months with a Mayo 2/3 and saying they’re feeling better, but they have a lot of steroid adverse effects. It’s always that fine balance. Marla, what advice do you give physicians treating ulcerative colitis?

 It goes back to what we’ve been saying: first we need to understand the patient’s goals. We start with that. We must understand that our drugs work for symptoms. Most people respond. That’s less of our problem. It’s more the durability and sustainability, and lots of things go into that. We have the ability to say that every drug has its place in the journey. This is a long road. As Dan Present used to say, this isn’t a sprint; it’s a marathon. We can treatments to goal-orient it for the patient, but we must be able to have the right discussion: it’s to keep you out of the OR [operating room], from having a disability or progressive bowel wall damage and the repercussions from that. If we could use the right therapy to heal your lining, you’ll have not only symptomatic improvement but a durable response. You’ll be able to do everything you want to do despite this disease. That’s what we need to get better at.

We get so caught up in trying to push our narrative without making it the narrative the patient needs and wants to hear. How do we meet in the middle? That’s the biggest challenge we face. Ellen discussed that in UC, steroids and 5-ASAs [5-aminosalicylic acids] are it. Even in Crohn disease, that’s what…research showed us. There was a huge gap where there was no exit strategy, so people are free-floating in this gap, asking what’s next. We must have that discussion early to let them know we need an exit strategy.

 Ellen, what advice are you giving your physicians treating UC?

 We can’t underscore enough the importance of an exit strategy when you start steroids. We should look to the rheumatologist, 7 weeks in the best trial. Let’s shorten that when the patient needs another therapy. It’s fascinating—patient engagement. Algorithm medicine works for maybe 80% to 90%, but even the ones who fit into the algorithms don’t want to be there. For the discussion of diet and nutrition, patients often start to have increased fiber because they’re sick, so they’re going to change to a higher-fiber diet. That’s something that we can meet with our colleagues about because that’s simple. Where are the patients? What did they think about the microbiome? How much Coke, how much carbohydrates, sugars, etc? That way, we get a chance to know where the patient is. You don’t want to push our narrative. We must listen to the patient. Where are they? Are they taking NSAIDs [nonsteroidal anti-inflammatory drugs] for their extraintestinal manifestations and driving the disease? In our increasingly pressured world, we must find a time to listen to the patient and understand where they are in terms of complementary medicine while we’re developing what we think is the right approach, the right strategy, for mucosal healing and decreased progression. This is a dialogue with our patients and colleagues who are in the real world.

 The advice, thinking about our trainees or those coming out of fellowship, is exactly what you said. We’ve been saying it goes back to the basics, listen to the patient. It’s amazing that in first 5 minutes of a conversation, you can learn so much that guides your decisions on therapy.

David P. Hudesman, MD; Marla Dubinsky, MD; Ellen J. Scherl, MD; and Miguel Regueiro, MD, provide advice for physicians treating patients with ulcerative colitis.

Clinical Pearls for the Treatment of Ulcerative Colitis

 Dave, what other novel therapies, as we look to the future, hearing about all these great therapies we have today, what comes next? Where do you think the next 5 years are?

 Some of the therapies I’m excited about are the IL-23 [interleukin-23] inhibitors, which are coming for both ulcerative colitis and Crohn disease, where some of the early phase 1 and 2 data look good efficacy-wise in both disease states. The safety profile also looks good. It’s an injection every 8 weeks or so, which is convenient for the patient. Then I think a little further down the road, we have these oral small molecules, but possibly an oral anti-integrin therapy or oral IL-23. That’s further away than the next 5 years, but that’s something promising. Even in earlier phase data, there are some oral agents that are looking at the gut barrier in mild to moderate patients. Marla discussed earlier combination therapy. Hopefully we’re treating with whatever therapy earlier, and using combination therapy early. That’s how we’re going to push our remission rates as some of these new therapies come to market.

 Getting more selective therapies, the interleukin-23, maybe more JAKs, even TYK2 inhibitors. Then looking at the combination approach. Ellen, what do you see in the next 5 years as far as treatments you’re excited about?

 From a practical standpoint, I’m hoping we will all see the medical benefits make it easier to obtain some of these oral agents such as ozanimod, the JAK inhibitors, for our patients as a steroid-sparing and steroid-avoiding strategy. That’s important because only 5% of patients in that Truven [Health MarketScan] database are getting the therapy they need if they have moderate to severe disease. That is a real issue and should guide us on how we select therapies. We talked a little about the [Britta] Siegmund, MD, data with ozanimod and the rapidity of onset of action, 2 weeks vs 5 weeks for remission. But if it takes 1 to 2 months to get approved and then denials that we must battle with in tertiary and quaternary centers, in the real world, these are not going to be efficacious. But that’s an exciting thing. I’m fascinated by new targets like TL1A, anti–IL-36 as an antifibrotic agent, and the combination therapy. Hopefully, we’ll have more molecular cellular diagnostics so that we can classify these diseases appropriately and get the extraintestinal manifestations that might be more responsive to IL-17 vs the gut, more responsive to IL-23. If we can parse that out, that will be exciting.

 Ellen, there is a lot of hope on the horizon, and these new therapies as well. You mentioned the antifibrotics, this is a realm of investigation. There’s somebody I work with here at the Cleveland Clinic, but others are looking at therapies that might reduce fibrosis. We don’t think about that as much in ulcerative colitis, but we’re now realizing this can be an issue, so these therapies of the future that work on fibrosis. Marla, anything you want to add or treatments you’re looking forward to?

 Yes, what I’m looking forward to goes back to other discussions we’ve had, to understand the order or the sequence of things. Meaning, when you are early in the inflammatory process, there are particular pathways that are predominant. Understanding that all roads lead to anti-TNF [tumor necrosis factor] doesn’t mean we can’t put the roadblocks above it. Maybe there’s a certain point where TNF becomes the only and predominant pathway. But if you catch it early, going back to this IL-23 concept and understanding the different pathways, what’s upstream, and the timing of that in the era of the inflammatory process, will change everything. We know that JAK1, for example, and JAK3 don’t hit IL-12/23. Maybe we combine a JAK with a specific targeted, TYK2 for example, may be targeting IL-12,23, or combining it with an interleukin base.

I am excited about the future and to see what all these new therapies bring. But I think we must be clever and understand the era of the inflammatory pathway to know when we need to target different pathways, and when a more broad-based oral small molecule, which goes after multiple pathways, may be warranted. I think that’s what we need to getbetter at, being able to play with all these toys in our toy chest. Because otherwise we’re going to end up at the same place we are, and it would be an embarrassment of riches, and we can’t figure out how to use them. That’s what I’m excited about in the future.

 We must be smart as far as how we use these therapies. Marla, it’s interesting, when I heard you and Ellen and Dave talk, I was thinking back almost 20 years, so 2002, we had infliximab, and that was it. It was interesting to think at that time, we were hopeful we had this new treatment, but we were a little nervous. Now we have these great therapies, more on the horizon, such great hope. The bar has gotten even higher. We must, to your point, figure out what that ceiling is. I don’t think we’re close to that yet.

 I want to say, we still don’t know, 70 years out, how to use steroids in ulcerative colitis. That’s the first thing., let’s get this right. Short term, with or without a combination of some of these newer therapies. The second is the persistence, we know loss of response. We can do therapeutic drug monitoring, fecal calprotectin, but when you look at that retrospective Australian study PANIC, patients did better in ulcerative colitis with vedolizumab compared to adalimumab and the anti-TNFs. We need to look at these new therapies. As you’ve all said, get it right and get it right early, but also check the persistence, maintenance, and progression.

 Clearly an unmet need is to get it right in induction therapy. How do we use steroids? Obviously, we’d like never to use steroids, but maybe 1 course of steroids in a short period of time from an immunologic standpoint, may interestingly have some benefit in patients with certain disease states. More to come on that.

Drs David P. Hudesman, Ellen J. Scherl, Marla Dubinsky, and Miguel Regueiro, explore novel therapies in the pipeline and discuss approaches to optimizing sequencing and treatment selection for ulcerative colitis.

Future Treatment Paradigms in Ulcerative Colitis

 Dave, let’s get into how you sequence therapies, especially for safety and efficacy. How do you sequence therapies in ulcerative colitis [UC]?

 Sure, and Marla said this nicely. Patients are concerned about safety from their viewpoint, but for me, when I start, it must be about efficacy. Now we have options. It doesn’t matter how safe a drug is, if it doesn’t work, it’s irrelevant. The way I break it down is, we have the moderate to severe spectrum, ones on the more moderate end, and then we have our sicker, severe patients, who could be hospitalized, on high dose steroids. In those more severe patients, I’m using infliximab or a JAK inhibitor and likely upadacitinib. The majority of the patients we’re seeing are in this more moderate to severe end. From that point, all of our therapies are reasonable options.

Then the next thing we can talk about is safety. Why not start with something that’s more targeted, which would minimize the safety adverse effects? We talk about vedolizumab, ustekinumab, and ozanimod in my practice. We’re going to need more real-world data for ozanimod, but practically they’re all safe, and we don’t see many adverse effects with any of these agents. Then it becomes onset of action, which we talked about. Do you want an infusion every 8 weeks vs an injection every 8 weeks vs a pill once a day? That’s where that shared decision-making comes in. The only other thing to add is that extraintestinal manifestations can shift you to a more systemic therapy.

 Very nice, Dave, thanks for that. Ellen, what is your position on therapies and sequencing? Then Marla, I’m going to come with the same question, and what are the challenges that our physicians and colleagues might face in incorporating these new therapies? Ellen, how do you sequence and position in ulcerative colitis?

 The first thing is to try to get them off the mesalamines, or onto something better sooner rather than later; the same thing with steroids, limit the use. I have been using first-line vedolizumab or ustekinumab, as opposed to the anti-TNF [tumor necrosis factor therapy], with the exception of the patient who’s looking at a colectomy and hospitalization. We go for IV [intravenous] cyclophosphamide or infliximab for time of onset and dose escalation. But in the more moderate to severe, it’s going to be vedolizumab. Based on the VARSITY trial, we’re talking about superiority at week 52, 31% steroid-free compared to 22% with adalimumab. That’s the first-line discussion. Then as David alluded to, it’s a discussion about ease of use, time in an infusion suite or at home. Similarly, with ustekinumab, these don’t have black box warnings around them, so not only are they effective, at least VARSITY—more effective than adalimumab—but the safety issue. No black box around either vedolizumab, ustekinumab, or Zeposia [ozanimod]. Ustekinumab has been my second choice for first-line therapy rather than a TNF. We look at the UNIFI data long-term steroid-sparing, years out, 4-year data just being presented. It is more targeted, not all lymphocytes, just a subpopulation of lymphocytes, the dendritic cell targeting IL [interleukin]-12/23.

Ozanimod in the first line is increasingly attractive. You’ve put this on the line, that it is safer than patients’ concerns. Yes, we can get a cardiogram, but it’s in a very select group of patients. In the original trials, there was a 5-hour observation after every pill, and within months there’s no safety signal. Real-world data are also going to show no safety issues for a cardiogram. Ophthalmologic exam, it’s a subpopulation, and patients with steroids are at an increased risk for ophthalmologic glaucoma, cataracts, than patients on ozanimod. It’s very important that those are the first 3 medications. We look to JAK inhibitors, they’re not yet approved for the first line. But in select patients who are more severe, we might want to use those as first line. Again, steroid-sparing strategies is the way that I position all of this.

 Wonderful, that’s great. Marla, let’s move to you in terms of anything else with sequencing, and as you hear from colleagues who refer patients to you, what are the challenges? Are they facing challenges with prescribing some of the newer therapies?

 Yes, believe it or not, I thought we would have a much harder time prescribing some of the new oral small molecules, and I haven’t encountered such an issue as much as I thought. Maybe because, for example, ozanimod is already approved for relapsing MS [multiple sclerosis], and upadacitinib was already approved for RA [rheumatoid arthritis] and atopic dermatitis. As you see multiple indications for a certain drug, it helps us. As long as the specialty pharmacy turned on the toggle for UC, it wasn’t as much as an issue as I thought. You must also remember that when you’re switching to orals from an IV, you’re talking medical benefit vs pharmacy benefit, they are 2 different operations. It’s about understanding what these drugs are indicated for in other disease states to help you along.

 When I bring up specialty pharmacy, I realize that some of our tertiary and quaternary centers have IBD [inflammatory bowel disease] pharmacists. When we think of the challenges, especially those in the community or regional areas, sometimes it is hard to prescribe these, based on the insurance and the payer. You all mentioned with the JAK inhibitors, there must be failure of a TNF. You mentioned that we might want to use that first line, and all the reasons we outlined, but sometimes it’s difficult to get new therapies where you are regionally, based on the insurance and the payer. Hopefully, and as we evolve over time, that will get better.

Experts in gastroenterology discuss their approach to sequencing therapies in ulcerative colitis, considering safety, efficacy, and access to various treatment regimens and comment on challenges physicians may face when incorporating new therapies into clinical practice.

Marla Dubinsky, MD

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