Andres Yarur, MD, Medical College of Wisconsin 

 There are several important things that we usually advise gastroenterologists to do when treating patients with ulcerative colitis [UC]. We have several options to treat moderate to severe ulcerative colitis. But it’s also important to mention that we need to approach treatment in a better fashion with the drugs we already have. For example, we know that we should aim to treat earlier, with more efficacious therapies, and not wait until someone has a complication to introduce a biologic or a new-generation small molecule. For example, a patient on mesalamine who’s symptomatic and requires multiple courses of steroids should likely be started on another drug. Another important piece of advice is to remember that we’ll have newer therapies in the future. It’s important to discuss these other options with the patient, because it’s a combined or shared decision with the patient about the best option for them. Some patients may be uncomfortable getting injections or infusions, and they’d prefer an oral therapy. Also, some patients may feel uncomfortable with the potential adverse events.

 The advice I would give a gastroenterologist is not to be afraid of our new-generation therapies—to treat our patients with ulcerative colitis—when it’s clear that mesalamine isn’t controlling their symptoms. Also, be aware of patients who are steroid dependent. Too often you see a patient who can’t get below 15 mg of prednisone. They come in, their faces are round, they’ve gained weight, and they have horrible acne. There’s damage that has been done that’s undoable. Patients scare themselves by reading things on the internet. When they approach the doctor and say, “I’d rather be on steroids because I know the risks of steroids,” as gastroenterologists, we need to speak with confidence that steroids are the “bad guys” and other medications that we’ve been talking about are safer than steroids, both short term and long term. Therefore, we need to speak with confidence and not wait years for these people to be melted away by steroids before we do something about it.

 The treatment of UC is a dialogue between you and the patients. The best advice I could give is that you need to sit down with the patient early on in their disease and define targets and goals so the patient is onboard with treatment of the disease. Once you define the targets, you treat to the target and reassess. OK isn’t good enough. You need to get these patients into remission. Once in remission, it’s important to consistently monitor these patients, whether it’s fecal calprotectin, periodic endoscopy, or whatever you and the patient agree on. It’s important to continually monitor these patients to keep them in remission and to keep the inflammatory burden down to improve their symptoms, their quality of life, and hopefully to decrease the risk of complications progressing. It’s a matter of persistence and using the right medication at the right time.

It’s also important to not undertreat patients. There’s a trend among a lot of folks to start patients on mesalamine so they get a little better, but that’s good enough. Until you’ve assessed their inflammation, endoscopy, and histology, you need to consider moving forward if you’re not meeting the targets that you set.

 In general, how we approach the treatment of ulcerative colitis has dramatically changed. We should not classify patients as mild to moderate or moderate to severe. Many patients, now classified as mild to moderate, need newer therapies, or as gastroenterologists, we should approach these patients differently. It’s important to mention that there are several new drugs coming in the next year or 2, and it’s important to be updated on the benefits and risks of each drug.

 As far as I’m concerned, the way the future is looking for people with IBD [inflammatory bowel disease] is using most of the medications we have in rational combinations. These combinations of medications will complement one another. Obviously, the reason it’s a bit pie-in-the-sky is because of finances. Because we use biosimilars and, presumably, some of the medications we have in clinical trials, the only way we’re going to have a higher response rate and remission rate, especially in the more difficult patients, will be by using combination therapies.

 Thank you for allowing me to participate. It was a pleasure to be at DDW [Digestive Disease Week] this year. It was very exciting. Every year, as we go to these conferences, the information gets better and better.

We’re constantly learning about new mechanisms, how to properly use these medications—in the right patients—and how to assess patients and get them a better quality of life and long-term remission. It’s a very exciting time to be practicing medicine.

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Advice for community physicians and gastroenterologists to help manage patients with ulcerative colitis. 

Tips to Optimize Care for Patients With Ulcerative Colitis 

 There are a lot of unmet needs in the management of ulcerative colitis. None of the medications that we have works all the time or maintains remission a significant amount of the time. We’re constantly trying to manage patients as they go through flares and changes in disease activity. Sometimes it can take a lot of time to find out what the best regimen is for your patients. One of the things we’re really lacking, 1 unmet need, is precision medicine. We need a tool that allows us to assess a patient that’s looking at their disease activity, their histology, their genetics, or some biomarker. We need a tool that allows us to get the right medicine the first time, which they’re doing for a lot of cancers these days. That’s coming around the course. The idea of precision medicine for inflammatory bowel disease is an unmet need.

The other thing is that we don’t have good ways to address some complications of inflammatory bowel disease. We don’t have anything we can offer patients who develop primary sclerosing cholangitis. This is a significant comorbidity in many patients. That’s also an unmet need. We need more mechanisms of actions for patients who fail current therapies. Those mechanisms, fortunately, are under development and on the way.

 Some of the things exciting me, in terms of mechanism of action, are 2 big buckets that we’ve left on the table untouched. One big bucket, of course, is the microbiome. There’s a publication in the January 

 issue on the Seres Therapeutics product, which is a clostridial species, in spore form, in a capsule. In theory, these spores survive the acid in the GI [gastrointestinal] tract and then sporulate, or start germinating, in the colon of a person with—in this case—ulcerative colitis. The study was a phase 1/2 study that was published. It’s a small study, but it has a signal. My own feeling—the FDA doesn’t ask me about my own feeling—is that some of these medications, like microbial therapy, shouldn’t necessarily be tested alone. I’d be delighted to layer microbiome therapy—with all the things you and I have discussed—as mechanisms of action because they’re going to be safe. They’re going to be safe and are going to be a fantastic addition to available treatments.

As Seres is ahead of the pack, others are going to be on their heels. For example, the epithelial barrier is another big thing that we leave up for grabs. We know that the epithelial barrier, in particular in ulcerative colitis, have holes [fenestrations] in the picket fence that contribute to the vicious cycle of inflammation. This agent is a recombinant interleukin-22. It’s an agonist. Interleukin-22 has beneficial effects on barrier function. We’ll have to wait and see because I have no intel on how well that’s doing as it winds its way in clinical trials. I suspect, and I would hope, that it’s going to be safe. Those are at least 2 things I’m excited about.

Drs Maria T. Abreu and Timothy Ritter comment on limitations faced by providers who treat patients with ulcerative colitis and highlight strategies under investigation that can improve how the disease is managed. 

Treatment Advances in Ulcerative Colitis 

There are several novel compounds, with different mechanisms of action, that are being investigated for the treatment of ulcerative colitis [UC]. A very important group is the sphingosine-1-phosphate receptor modulators, or S1Ps. We have several S1Ps that have been developed. The original S1P modulators were nonselective. An example of this is fingolimod [Gilenya], which has been approved for multiple sclerosis. However, newer generations of selective S1Ps are being developed to targets that we really want to block. Ozanimod [Zeposia] already has reported phase 3 results for an ulcerative colitis trial. Etrasimod is currently under a phase 3 trial. Etrasimod specifically targets S1P1, 4, and 5. The goal is to offer high efficacy, but also have a good safety profile. So far we haven’t seen any major adverse events or signals with selective S1P agonists.

These are very exciting medications. It’s a whole new pathway for us to explore. The S1P modulators work by blocking the receptor on activated lymphocytes which allow lymphocytes to follow the gradient of S1P from the lymph node to the site of inflammation. When you have inflammation occur in the colon, it generates S1P and then the pathway of these lymphocytes follow. The S1P receptors block the ability of the lymphocytes to follow that pathway. The receptors internalize so that the T cells can’t get to where they need to go. This lymphocyte tracking prevents the inflammation from occurring at the colon and traps lymphocytes high in the lymph nodes. There are several S1P modulators out there. The S1P receptor is like the JAK [Janus kinase] receptor because there are several different specific receptors. We’re very excited and looking forward to using ozanimod, which has just come on the market and, I believe, blocks the S1P1 and 5 receptor. Some of the newer ones, such as etrasimod, also block the S1P4, so we expect there will be some differences in how they work. The differences may not be great, but they may be as well. It’ll take some time to sort those out. Certainly, as we get multiple new generations of these medications, we’re hopefully going to see a refined approach to treatment with better results and better safety.

The ELEVATE UC 52 trial is a 52-week treat-through study. The main outcomes are clinical remission at week 12 and week 52. Patients are included if they have moderate to severe active ulcerative colitis. About 50% of the patients may have been exposed to a biologic or JAK inhibitor, while the rest of the 50% are naïve to these drugs. The trial is looking at clinical outcomes and endoscopic outcomes, which as we know, is a very important goal of treatment.

 I think we will be looking at these things as potential first-line agents. They have a very nice efficacy and safety profile. They’re oral, which patients are going to prefer. They have very few adverse effects. I think, in the end, there will be a significant drive of both patients and physicians to use these medications very early on in the disease course. Oral medications have many advantages. One advantage is that you often have samples in the office, so you can get a patient started right away and circumvent some of the delays we face in getting medications approved by insurance companies. That’s always a benefit for oral medication. A lot of it is going to come down to coverage. Certainly, we can’t use the medications if we can’t get them covered by insurance. But hopefully that’s something that’s going to be worked out. Aside from the financial aspect of it, I think these are potentially first-line agents.

Implications for treating patients with ulcerative colitis with novel S1P receptor modulators based on data revealed by the phase 2 OASIS trial, which has now led to a phase 3 study, ELEVATE UC 52. 

S1P Receptor Modulators for Ulcerative Colitis 

Some of the issues the treating physician and the patient face, with respect to choosing a mechanism of action, even in 2021, we don’t have good predictors yet to say, “Aha! You’re a person who’s going to respond to a JAK[Janus kinase] inhibitor,” or “You’re a person who’s going to respond to an anti-homing strategy.” I think, like I mentioned, the only comparative effect of this data that we have is vedolizumab [Entyvio] vs adalimumab [Humira]. OK, fine. But within that, I think there are nuances of picking. Sometimes they’re based on the patient profile—How risk averse are they? What age are they? Have they had other comorbidities? Have they had recurring infections?—and you might choose something, not an anti-TNF [tumor necrosis factor], for someone who’s having recurring infections. As an example, you might rethink whether you’d use tofacitinib [Xeljanz] in that scenario. But I think for medications like vedolizumab and ustekinumab [Stelara], it’s very clear that these are very safe. What about someone who has ankylosing spondylitis or other rheumatologic manifestations of their IBD [inflammatory bowel disease]? We think, in general, that when we shut off the intestinal inflammation, it’ll make the other stuff go away. But, of course, we’ve had the privilege of having something like the anti-TNFs that clearly have a salutary effect on joints and on the axial arthritidy. I think, in those scenarios, again, I might lean towards a tofa [tofacitinib] or an anti-TNF. I think that if I thought through it, these are the mechanisms that I have available. Is there something in this patient that would lead me down 1 path or when I’m making that decision?

Overall, patients and physicians have several limitations when treating ulcerative colitis and these limitations have to do with the fact that even though we have many drugs available right now, a good number of patients do not respond to therapy. Also, we need to have safer medications. Even though the ones that we have right now are considered safe and we use them all the time, having an ideal adverse event profile is still far from reality. In general, improving the rate of efficacy is important not only for patients that haven’t received treatment for ulcerative colitis, but also for those that have had exposure to other biologics. An important limitation that both physicians and patients face is how we administer these drugs. Most of the drugs that are approved for ulcerative colitis require an infusion or an injection. Obviously, this is a barrier to access these drugs, especially in remote areas, and for patients who are afraid of needles and don’t want to use needles. Biologics pose other limitations, too. For example, the development of immunogenicity against the drug—in other words, the development of antibodies against the drug—especially with the anti-TNF agents. When developing immunogenicity, patients can have reactions, and the drug stops working.

Even though patients with biologics may not develop immunogenicity against the drug, many of these patients lose response to treatment and that isn’t necessarily explained by the development of antibodies.

Certainly, we’re better off now than we were several years ago when we only had 1 mechanism of action. There are several barriers to selecting treatment. Obviously, 1 of the main things that we must work with when selecting treatment is the payers. What medications are covered by insurance, and in what order. Many payers will have step-therapy. We must use the drugs in a particular order to get them approved. That is a challenge when the order is not always in-line with what you think is the best care for the patient. The drugs that we use right now, except for tofacitinib, are all perennial. They’re either infused, such as vedolizumab or infliximab [Remicade], or are subq [subcutaneous] injections, such as adalimumab or ustekinumab. Oftentimes, there are barriers to getting patients to buy into those therapies. They perceive them as invasive or scary. They worry about those, so it would be nice to have a broader armamentarium of medications with different mechanisms—many of which would be oral—that we can use to address this. Currently, there are several different mechanisms in studies that will be coming out in the future, so hopefully we’ll be able to have a lot of new options in the future for these patients.

Limitations that physicians and patients face when selecting therapy for ulcerative colitis. 

Andres Yarur, MD, Medical College of Wisconsin

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