Maia Kayal, MD

The future of therapy for ulcerative colitis is really about precision medicine. Right now, we haven’t cracked the code about which drug is the best for which patient. We’re increasingly understanding that the inflammation in ulcerative colitis is driven by multiple pathways, not just one inflammatory pathway. As a result, medications are not a one-size-fits-all and do not work necessarily the same for all patients. We’re increasingly understanding how we can predict which patient will be a nonresponder to which drug. Unfortunately, we’re not quite there yet, but I think with the increase in precision medicine in the next 10 to 15 years we’ll be able to meet a patient, draw a blood test or a stool test, or take a tissue sample, and be able to analyze and understand the pathophysiology of their disease, as each patient is unique with respect to their disease mechanism. I believe the future of ulcerative colitis is in personalized therapy and more selective therapies. There are exciting updates in the future for more selective agents, for example, against the p14 subunit of IL-23 [interleukin-23], more selective agents against the beta-7 subunits. In addition, I think the future of ulcerative colitis is in novel modalities of administration. For example, there are exciting updates for vedolizumab, and that it may shift from an infusion-based therapy to subcutaneous injection-based therapy, offering our patients who are in remission on vedolizumab improved quality of life and less need to be tethered to an infusion center.

One of the most anticipated developments in the field of ulcerative colitis is the use of novel noninvasive methods of monitoring. This primarily includes intestinal ultrasound, as we’re increasingly understanding that ulcerative colitis has transmural features in addition to just mucosal futures. The use of intestinal ultrasound in adjunct with fecal calprotectin and C-reactive protein is an excellent way to monitor your patients in the clinic. It’s a point-of-care test that can be done without preparation, without fasting, and can yield answers within seconds. Intestinal ultrasound will not take the place of a colonoscopy but can be used to monitor a long therapy before a colonoscopy is needed.

For patients presenting with increased stool frequency, urgency, or rectal bleeding, the biggest take-home message is to work up the symptoms quickly. It is to not delay the care or the work-up of the symptoms. Starting with stool studies, laboratory markers, and a referral to gastroenterology, or if they’re already with gastroenterology, a referral for a colonoscopy, is key. We know that a delay to diagnosis can impact long-term outcomes and increase the need for surgery. Therefore, it is important to make the diagnosis early, start the right therapy early, and then get the patient on the path to better care. It is also important to focus on improvement of quality of life and making sure the patient has the right ancillary support. This may involve referral to nutrition, psychology, and social workers to ensure that the patient’s quality of life is excellent and has improved with the therapies available.

As I mentioned, it’s an exciting time where we’ve had multiple new therapies hit the market recently for ulcerative colitis. In the next 1 to 3 years, we’re going to see more therapy, IL-23 inhibitors for ulcerative colitis, which has not yet been FDA approved, and another S1P [sphingosine-1-phosphate ] receptor modulator. If you look at some of these phase 2 trials, the next drugs we’re looking at are some oral medications that have some similar mechanisms of action to our current therapies. They are easier for a patient to take. There are some early data looking at different microbiome therapies, although we must see if that pans out.

When we’re talking about the future of therapy, there have been some interesting data at recent conferences looking at combination biologics. There was one study called VEGA, and it was presented in abstract form. It combined an anti-TNF [tumor necrosis factor] agent, golimumab, with a selective IL-23 inhibitor, guselkumab. What it saw was that this combination therapy did better than either alone, especially when you’re looking at mucosal healing or endoscopic remission. I think these are more of the studies we need to see. As new agents come to the market, we’re not really pushing that ceiling. We’re not seeing significantly higher clinical response or clinical remission rates. We’re having more options for our patients, which is critically important. But if we use some of this combination therapy up front, we might be able to push those response and remission rates. Right now, if we are using combination therapy, it’s usually in our very refractory patients, or patients with extraintestinal manifestations. I think the other focus in the future for ulcerative colitis is that true multidisciplinary approach and taking care of the entire patient, so not just symptoms, but improving the patient’s quality of life.

Treat-to-target is an important concept and something we’ve been talking about now for the past few years. What that means is that we’re not only treating to symptoms, but we also want to heal on the inside or have endoscopic remission, and ultimately in certain cases, histologic remission or true mucosal healing, meaning that on biopsies everything looks perfect. That’s our ultimate goal, but I think it’s important to realize that those targets aren’t attainable for many of our patients. When seeing a patient in the office, you need to set the specific target for that patient. Meaning if you have somebody come in with severe disease who failed multiple medications, maybe complete mucosal healing or complete endoscopic remission isn’t going to be attainable. However, if it’s patient you could put into clinical remission with significant endoscopic improvement, that’s a good target, and that’s OK. To keep pushing or switching is probably not the right thing to do. Treat-to-target is extremely important. But again, the key thing is to set a specific target for a specific patient, and discuss that target with the patient, and discuss how you‘re going to monitor and adjust to reach that target.

I would say the key take-home messages for managing ulcerative colitis, first it’s important to define the extent and the severity of disease, so then you can pick the right therapy for the right patient. Also, it is extremely important to closely monitor the patient. You want to set your target, monitor closely, and continue to monitor less frequently when you hit that target. I think just important, if not most important, is discussing with the patient what their No. 1 concern is when they come into the office. A lot of times, again, we focus on how many times they go to the bathroom, how much pain they’re having. But their No. 1 concern might be, how could they travel for work in the next 6 months? Bringing that up in the conversation, and working with a multidisciplinary team to help reach those patients’ goals and your own personal provider goals, is extremely important.

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Drs. Maia Kayal and David P. Hudesman discuss their hopes and future directions in the treatment of patients with ulcerative colitis.

Future Directions in the Management of Ulcerative Colitis

In addition to the normalization of stool frequency and a decrease in rectal bleeding, a very important metric that I look for in patients on therapy for moderate to severe ulcerative colitis, and in clinical trial data as well, is the improvement of their quality of life. The symptoms of ulcerative colitis are significant and can be quite debilitating, and it is important that our therapies improve quality of life for patients such that they can return to their baseline quality of life. An additional metric I’m interested in looking at for patients with moderate to severe ulcerative colitis, and that I am hopeful clinical trials will incorporate, is the use of intestinal ultrasound. We’re increasingly understanding that ulcerative colitis is not only a mucosal disease, but is also a transmural disease similar to Crohn disease. We are increasingly using intestinal ultrasound in the clinic as a noninvasive point-of-care diagnostic and prognostic plan. Intestinal ultrasound has been used in Europe for decades for the assessment of patients with ulcerative colitis and Crohn disease…. Incorporating intestinal ultrasound into your follow-up and monitoring of patients is adjunctive to the use of C-reactive protein and fecal calprotectin.

Increasingly, clinical trials have been using histologic healing as a metric and a treatment goal, which I think is very exciting. There have been conflicting data to suggest how far in remission we need to get our patients. Our treatment guidelines indicate that remission includes both clinical and endoscopic end points. However, histologic end points have not been fully understood or studied. Increasingly, clinical trial data are incorporating histologic healing as an end point. It’s important because it will impact treatment decisions. For example, in a patient who is in clinical and endoscopic remission, but still has histologic activity in their colon, is it worth optimizing or escalating therapy, or can we maintain the patient on the current regimen? In the future, increasing data will support either escalating therapy or maintaining the current regimen based on the disease activity on the histological level.

Over the past 7 years or so now, we’ve moved from treating just to symptom improvement or clinical remission, to making sure a patient is healed inside. Our goal of therapy is to lead to that endoscopic remission. Many of our trials, if not all of them, now have these combined end points looking at both symptoms and endoscopic activity. What our unmet need is, and what we’re starting to see in clinical trials, is that quality of life part. A lot of times we’re seeing patients in the office and I’m focusing on how many times a day they’re going to the bathroom, how much pain they’re having. But there are other factors: whether they’re making it to work, they’re going out and seeing friends and family, their energy levels and so forth, that aren’t really captured. I think some end points we’d like to see in clinical trials, and we’re starting to see them, are surveys looking at fatigue, work productivity, as well as anxiety and depression. This is how we could take that next step in our care and really improve our patients’ quality of life. We’re not only focusing on symptoms, but again work productivity, fatigue, and underlying anxiety.

Experts in gastroenterology share the clinical trial end points and metrics they use to guide their treatment of patients with ulcerative colitis.

Ulcerative Colitis Clinical Trial End Points and Metrics

Treatment guidelines published by the American Gastroenterological Association and the American College of Gastroenterology play a significant role in our treatment decisions. First, they help to standardize treatment across patient populations. Second, they provide the most up-to-date guidelines on how we should approach patients with mild, moderate, or severe ulcerative colitis. When I first meet a patient, I typically go through the guidelines with them so they understand our approach to therapy and our reason for optimization or escalation to biologic therapy when needed.

Goals of therapy for patients with moderate to severe ulcerative colitis have been published by the International Organization for the Study of Inflammatory Bowel Disease in the STRIDE-II guidelines that were updated in 2021. The treatment targets for patients with moderate to severe ulcerative colitis include a reduction in stool frequency, a reduction in rectal bleeding, normalization of endoscopy, in addition to normalization of fecal calprotectin. Long-term targets include a resolution of disability and a normalization of health-related quality of life. When we start therapy for patients with moderate to severe ulcerative colitis, we always start the conversation by saying what our treatment goals are. It’s important for patients to know what we’re working toward so that as a team we can achieve that treatment goal.

: Our goals of therapy are to put somebody into clinical remission, meaning they’re feeling great, their quality of life is significantly improved, if not great. We also want to heal them on the inside. This is endoscopic remission, meaning we do a colonoscopy and everything looks great on the inside. Once somebody is in remission, and most of this comes from our Crohn disease data, but we can’t just stop therapy. There have been a couple of trials now, the original trial was called STORI, and more recently a nice randomized study called SPARE. These were looking at patients on an anti-TNF [anti–tumor necrosis factor therapy], and an immune modulator, in remission, feeling great. Then when they stopped the anti-TNF or they stopped the biologic, within 1 to 1.5 years, about 50% of patients flared. We don’t want to withdraw therapy once we get somebody into remission. However, we may be able to deescalate. If somebody is on a combination of both a biologic and immune modulator, or in some situations 2 biologics, maybe we could pull back on the immune modulator and continue the biologic like the anti-TNF.

The other important part of caring for somebody when they’re in remission is disease monitoring, and closely monitoring these patients. Where we miss the boat is a lot of times somebody is feeling great, you do a colonoscopy and it looks great on the inside, and then the patient isn’t following up or we’re not following up with that patient, and the next time we see them is when they’re flaring. Monitoring them with blood work, CRP [C-reactive protein], a stool biomarker or fecal calprotectin every 3 to 6 months when somebody is well is critically important. The last thing is once you have ulcerative colitis for more than 8 years, so from symptom onset to present of more than 8 years, and somebody with more than their rectum involved, they have an increased risk of dysplasia, and we need to do surveillance colonoscopies as well for monitoring.

Treatment guidelines give us the roadmap on how to care for our patients, but really what goes into these treatment guidelines are large-scale randomized controlled trials that got a lot of these therapies FDA approved. There were some interesting studies looking at how many patients that you’re seeing in the office would qualify for these clinical trials, and it was less than 50%. Clinical trials give us the roadmap, but we really need to tailor our therapy for that specific patient. The way we do that is our experience plus what the real-world data show. There are a lot of nice real-world data using many of our agents in different settings. Also, real-world data help with maybe not only picking what therapy should go first, but in our patients who come to our office who failed 1 or 2 therapies, what happens next? Guidelines give us the roadmap, and we need real-world evidence plus our clinical experience to tailor those guidelines.

Maia Kayal, MD, explains how treatment guidelines can be used to direct and standardize treatment approaches in patients with ulcerative colitis.

Treatment Guidelines and Goals in the Management of Ulcerative Colitis

When starting any new therapy, it’s always important to ask yourself, how much risk am I willing to assume to balance with the efficacy of the drug? This is often an informed decision-making conversation we have with patients where we lay out the risks, the safety profiles of the medications, and the long-term efficacy. For each patient, the answer will be different because each patient is willing to assume a different risk. With the anti-TNF [tumor necrosis factor] therapies, the risk that often comes up is the long-term risk of lymphoma, which is about 0.06%. Patients are often worried about this, but without a family history or a personal history of lymphoma, and in the absence of the addition of a thiopurine agent, that risk stays baseline at about 0.06%.

What therapy should you start first? First you must look at efficacy, because whether you’re talking about safety, mode of administration, onset of action, if the drug is not going to work, all of that is irrelevant. First we are looking at efficacy, and this is when disease severity is important. For somebody with more moderate disease, probably the majority of our agents, our biologics and small molecules, will work. In more severe cases, in patients with extraintestinal manifestations, joint manifestations, skin manifestations, that’s when we’re going to want to use less selective therapies, or our anti-TNFs and our JAK inhibitors. After that efficacy mark, then you’re looking at safety and comfort, how comfortable both the provider and the patients are. What’s the disease burden, as we discussed? How quickly do we want these therapies to start working? What is the patient’s lifestyle? What’s the mode of administration? Is this somebody who’s traveling across the country, from out of the country, where an oral therapy is going to be a lot better than an infusion or an injection? Or is this somebody who has a fear of needles and needs to come in for infusion therapy? Putting that all together helps us sequence our therapies.

With the anti-TNF agents, adalimumab and infliximab, there are long-term signals for an increased risk of lymphoma. This risk, however, is only about 0.06%. When we monitor our patients with infusion laboratory tests, we are monitoring their blood counts and watching for any potential change in white count, hemoglobin, or platelet count that could portend the risk of lymphoma. With medications such as ozanimod, there is a risk of bradycardia and macular edema. Before starting ozanimod, we obtain an EKG [electrocardiogram] and an ophthalmologic assessment in certain patients who might be at risk for macular edema, such as those with diabetes. In medications such as tofacitinib or upadacitinib, the significant risk is herpes zoster. Otherwise, the medications have been shown to have a safety profile that is equivalent to other biologics. In terms of ustekinumab, the safety profile across indications and across multiple studies has been shown to be equivalent to placebo; that is very reassuring. When considering safety across all the biologics and the small molecules, we tend to think that vedolizumab and ustekinumab are the safest drugs we have on the market for patients with moderate to severe ulcerative colitis.

Maia Kayal, MD, and David P. Hudesman, MD, discuss the importance of efficacy and safety data in the management of patients with ulcerative colitis and how this impacts treatment choice.

Maia Kayal, MD

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