Miguel Regueiro, MD

 Dave, when do you decide you need to change treatments, and Ellen, what are we still missing with our UC [ulcerative colitis] therapies? Dave, let’s go to you first, how do we know when we need to change a treatment?

 I’ll break it up into 2 things. The first question, when Ellen was going over the mesalamines, one of the hardest questions for all of us is when do we pull the trigger? We have a lot of nice data in Crohn disease and some in UC showing that, bottom line, the earlier you start one of your biologics, or small molecules, the better the outcomes you’re going to have. And the better the outcomes, the lower the cost. When we’re talking about sequencing, if you start early enough, and you exclude the severe patients, you have a good shot of doing well with any of those therapies. The key is starting early and basing that decision not only on symptoms, but how the colonoscopy works, have they been on steroids, and so forth.

When they’re on a therapy, whether they’re on a biologic or small molecule, and symptoms worsen, step 1 is confirming that this is active inflammation, that it’s not an infection they picked up while traveling and ate something. We talked about quality of life, if they have underlying stress and anxiety, is this irritable bowel syndrome or bile salt diarrhea? It’s making sure there’s active inflammation, biomarkers such as fecal calprotectin, or C-reactive protein, doing a sigmoidoscopy, and seeing what’s there. Then once that’s confirmed, you can make that decision. But usually, if you have somebody who has responded well initially to a therapy, I try to optimize that therapy before moving on, versus somebody who’s maybe never had a good response, then I’ll pivot sooner. I’m sure we’ll go into more detail about which therapy to start from and which therapy to switch to.

 One thing you said and I want to emphasize is, in general, and I’m not being specific to any one person, but we burn through our therapies too quickly. The concept of, if there is a response, to optimize it. If there’s truly no response, they’re failing, that’s one thing. Some of that gets into how we monitor therapies, and some of this fits into how we assess for improvements of disease. Like you said, we’re going to come back to this in abit, but that’s such an important point.

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David P. Hudesman, MD, and expert panelists provide insight on optimizing the sequencing of therapies in ulcerative colitis and determining when a change in treatment is needed.

Switching Therapies in Ulcerative Colitis

Marla, we’re in the era of oral small molecules. We have the S1P. We have 1 S1P so far, ozanimod. I welcome you to talk about that and how we now have 2 JAK inhibitors. Talk to us about small molecules in general and those therapies specifically for ulcerative colitis [UC].

It’s crazy to think that from 1998 until 2018, we didn’t have much. Now we have more than what we had for those 20 years. It’s an incredible thing to think about, and it’s becoming more impressive over the next couple of years. In 2018, we had our first approved small molecule with advanced therapy with tofacitinib, which was the first JAK inhibitor falling under the JAK1/3 pathways, which essentially means it goes after several cytokine pathways and other immune pathways. It first came out as a reminder. For anyone with moderate to severe ulcerative colitis, you just had to not respond to or tolerate conventional therapy. Those were the days. About a year later, at DDW [Digestive Disease Week], I got a notification in 2019 that the there was concern over increased rates of pulmonary emboli and even associated mortality in a rheumatoid arthritis [RA] study. I can take 90 minutes to walk through that study because that’s how complicated and unfortunate the information was that came out and applied to UC; however, that’s for another time.

The veno-thromboembolic events led to a label change with tofacitinib. To say a few things, 1) predominantly we now have to first fail an anti–TNF [tumor necrosis factor] therapy; 2), to consider using the lowest effective dose when you think you could dose de-escalate; for example, from 10 mg in maintenance to 5 mg—it was always 10 mg twice a day in induction; 3) you need to look for veno-thromboembolic risk factors. Those were the 3 key things that changed in 2019. That was triggered by things happening in RA, not based on the data we had with the registration trials or real world on risk of veno-thromboembolic events in UC; that’s a very important distinction that I’m making.

Fast-forward, and over time the further primary outcomes of this RA—what we call ORAL Surveillance A3921133 study, whose primary outcome was not those thromboembolic events but malignancy and MACE, major adverse cardiac events. They found that tofacitinib wasn’t deemed not-not inferior—that’s a bit of a complex thing—to TNF. Therefore, there were a couple of things that resulted. One, for the malignancy, MACE wording, and thromboembolic wording, the label was changed for tofacitinib. That same label was then applied to when upadacitinib was approved in the United States on March 16. That’s a JAK1 inhibitor. It’s not a JAK1/3, so there’s a slight distinction. We call it more selective, but that’s another discussion. The idea is that you’re blocking JAK1 in this state. The same label of failing at least TNF1, maybe TNF2. For any disease state that TNF was an option, the label is recommending that these drugs—tofacitinib or upadacitinib—not be used until after you failed at least 1, along with all the safety caveats that come along with it, and it’s recommending to consider using a lower dose unless the patient is refractory. It’s complicated because we’re taking label discussions that are specifically based on a study of patients with rheumatoid arthritis and applying them.

Unfortunately, for 1 of our most effective drug classes—I’ve saved multiple colectomies by using the JAK inhibitor class—we need to be clear on the safety and efficacy in IBD [inflammatory bowel disease] specifically. I hope this discussion will help people rethink where this information came from because before these JAKs were around, patients would have gone to colectomy. This is an important statement that I’m making. In the game for who could work quickest, it’s like name those data that my rectal bleeding score and my stool frequency are going to get better. We originally had a post hoc analysis for tofacitinib by day 3, when you already saw an improvement in the key patient-reported outcomes. We presented at ECCO [European Crohn’s and Colitis Organisation] that by day 1 with tofacitinib, you’re seeing an improvement in some of these qualities, including urgency.

There’s a lot going on in the space. I don’t want it to be seen only through the lens of safety when we have these discussions with patients. You can tell I’m all over the map on this because I’m obsessed with understanding the safety and efficacy of this class. I don’t want to withhold it from patients who really need it. I know we must fail TNF; that’s not an issue. Back to ozanimod, the first S1P, which was approved in June 2021, so we’ve had it for almost a year. That was shown to be effective in biologic-naïve and biologic failure. Although if you look at the data, it works better if you use it before an entity or a biologic. I think about positioning it, which we’ll get to, but this is the first oral small molecule that doesn’t have to fail at TNF. Understanding where all these small molecules go and their positioning is going to be critical for the future.

That’s a wonderful overview of the oral small molecules. As you said, more to come on that.

Marla Dubinsky, MD, discusses the role of S1P receptor modulators and JAK inhibitors for the treatment of ulcerative colitis.

Role of JAK Inhibitors and S1P Receptor Modulators for UC Treatment

Dave, I want to move beyond anti-TNFs [tumor necrosis factor]. Can you talk to us about the anti-integrin and anti-interleukins?

With all our therapies, we have a good initial response rate. As Ellen was mentioning, it may be up to 70% in certain patient populations. But even with anti-TNF, a year later, one-third or 40% could lose response. It’s great that we have multiple options for our patients. For our anti-integrins, we have vedolizumab, which is FDA approved for moderate to severe ulcerative colitis. The way I like to explain this to patients on the mechanism is that this is very targetive; it’s gut specific.

If you imagine your white blood cells as cars on the highway, each exit off the highway is a different part of your body: brain, heart, lungs, and intestine. All vedolizumab is doing is messing with the car’s GPS [global positioning system]. The white blood cells are not getting to the intestine. Because of that, from a safety perspective, as Marla was discussing, patients are concerned if it’s a safe agent with low infection adverse effects. We don’t need to worry about malignancy. It has low rates of infusion reaction. The way I present it to patients is, the biggest risk in my mind is whether it’s going to work. Is it going to be efficacious?

Then we have ustekinumab, which is an anti–IL-12 and IL-23. It blocks the p40-subunit. Originally when the mechanism came out, we were concerned about some potential infection risk, but what we’ve seen in the data and the psoriasis literature since it’s been FDA approved for psoriasis since 2009, is that it’s a targeted agent. It has a good safety profile and low infectious complications. With malignancies, that’s not a concern. When you’re talking about efficacy, and Marla Dubinsky stated this nicely earlier, patients are concerned if it’s FDA approved and if it works. We’re seeing a 60% to 70% response rate, 30% to 40% remission rate, and somewhere in between endoscopic remission rate. Those are similar across trials. We’re going to talk about more sequencing as we dive into if these are bio-naïve patients, are they exposed, and the difference vs placebo to help us position.

 The anti-integrins in the anti-interleukins take us to the next level. Both have great safety. We’ll get into positioning and sequencing in a minute. But those were the most recent 2 monoclonal antibodies.

David P. Hudesman, MD, reviews the use of anti-integrin and anti-interleukin therapies for the management of ulcerative colitis.

UC Treatment: Anti-integrin Antibodies and Anti-interleukins

Ellen, I want to transition into specific therapies and talk about 5-ASA [5-aminosalicylic acid] and steroids. To go back to the basics of ulcerative colitis [UC], how do you use those in your practice?

 Just as a segue from the guidelines, most of us don’t practice algorithmic medicine. Even if the patients fit into the algorithms, they often don’t want to. One challenge in ulcerative colitis is that we overutilize mesalamines and steroids. We’ll talk about how we position in the first line, but I’d like to break this into the era of symptom control and then move into the era of disease modification. 5-ASAs, mesalamines, were introduced in the 1940s with sulfasalazine from our rheumatology colleagues, who said it works in rheumatoid arthritis; you may want to try it in your patient with colitis. That was the first introduction.

In the 1980s, we started to talk about sulfur pyridine free, so we could do dose escalation. For induction failures, the range is between 20% and 50% with rectal administration and up to 70% to 90% with oral; for moderate to severe, this may not be the drug of choice. For maintenance, 40% to 60% of patients fail to maintain remission in 6 months to a year…. If a patient isn’t induced and maintained in remission, they’re going to continue to flare and have progression of disease, and they’re not going to understand this. Mesalamine has a limited role in more moderate to severe patients. By using it prolonged we delay the onset and introduction of effective therapies. What’s the mechanism of action? Nobody knows. NF-kappa-B? The mechanism of action is the same. It’s the delivery system that makes the difference.

Not only is disease activity a more of a problem than active disease medications, but you want to get the active medication to the site of active disease. Yes, topicals work, but not that well. There are adverse events like nausea, diarrhea, headaches, and intolerance, where patients can get worse. What about steroids? Steroid were a big introduction as disease modification in 1950. Philip Hench got the Nobel Prize for introducing life-altering medications, mostly in rheumatoid arthritis. We jumped on the bandwagon. Ten years later, it was recognized that these medicines don’t alter. We had to come up with disease medications that are steroid-sparing, such as 6-MP [6-mercaptopurine] and the thiopurines.

Steroids are a major problem for us. The mechanism of action is the corticoid receptors, but it doesn’t matter. The adverse events are vascular necrosis, glaucoma—all the things that would never allow it to be passed by the FDA. In terms of the thiopurines, maintenance of failure rates with immunomodulators can be up to 60% in ulcerative colitis. It doesn’t change the natural progression or alter the rate of colectomy. And again, there adverse events like infection. We know from the SAPPHIRE registry and from European data that there’s an increased incidence with skin cancers and other solid tumor cancers, as well as lymphoma. Even the NF-kappa life-threatening lymphomas occur only in patients with immunomodulators with or without anti–TNF [tumor necrosis factor]. These immunomodulators, we’re beginning to recognize, are no longer where we should be. That’s the era of symptom control.

You asked me to talk about disease modification in terms of TNF. TNF changed the way we look at disease. The SONIC trial made us understand that it’s not just treating symptoms; we need to treat the disease itself. At the end of 26 weeks, I consider SONIC to be a pivotal trial, it showed that infliximab and azathioprine worked as steroid-free remission in 70%, infliximab in nearly 60%, and azathioprine vs placebo was only 28%. This spearheaded the whole concept that treating symptoms alone as not good enough because these patients had elevated CRP [C-reactive protein] or endoscopic inflammation. SONIC led to STRIDE. What about patient-reported outcomes? Do we need something more? The consensus was that you need fecal calprotectin and CRP.

Then the…trial showed that 45% of patients achieved mucosal healing if you dose escalated from adalimumab every other week to every week based on fecal current CRP, whereas only 30% had mucosal healing if you dose escalated on symptom control. TNF has been a pivotal step in understanding mucosal healing and disease progression reversal. Now we move into the era of STRIDE-II, when we talk about quality of life. Marla Dubinsky and I have talked about STRIDE-III, maybe with intestinal ultrasound. We must do better educating ourselves and our patients in terms of progression of disease. That’s where I see it.

That’s great. You took us through the first year of treatment for ulcerative colitis. To reiterate a point, 5-ASA is still in about 30% to 40% of UC, which is appropriate for milder patients who have a response. Your point is that we can’t linger on steroids, that’s not acceptable. Thiopurine data and ulcerative colitis is fairly poor, and you outline some of the adverse events and the first biologics anti-TNF. You did a great job at outlining those studies.

Ellen J. Scherl, MD, comments on the limited role of mesalamine and steroids for moderate-to-severe ulcerative colitis treatment.

Miguel Regueiro, MD

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