How I Treat Ulcerative Colitis: David Rubin, MD

Dr Rubin provides an in-depth look at the treatment of ulcerative colitis, from recent advances in therapeutic agents to setting patient expectations, positioning treatments, and monitoring for disease remission or progression.

David Rubin, MD, is the Joseph B Kirsner Professor In Medicine, chief of Gastroenterology, Hepatology and Nutrition, and director of the Inflammatory Bowel Disease Center at the University of Chicago School of Medicine.

TRANSCRIPT:

Hi, my name is David Rubin. I'm a professor of medicine and director of the inflammatory bowel disease center at the University of Chicago.

Treatment of ulcerative colitis has advanced significantly in the last number of years. The good news is that we have streamlined regulatory pathways, a number of novel mechanisms of action, we have the biosimilars that are approved and hopefully saving some money, and there's an ongoing rapid pace of clinical research discoveries that have led to advances in the way we can take care of people who suffer from ulcerative colitis.

Of course, we still have a number of big challenges. First of all, we haven't figured out the cause or developed a medical cure for ulcerative colitis. Nonetheless, we certainly have developed better ways to treat this condition, and I'm going to discuss with you my approach to treating ulcerative colitis in this video.

I also want to highlight though that despite all the new therapies we have, there remains a large number of people who don't respond to our initial therapies or even to multiple treatment lines. We still need to acknowledge and use surgery in a number of people, and we should also acknowledge that there are a variety of challenges we have in communicating effective goals of management and how to raise the expectations of our patients and frankly of all of us in the way we take care of these folks.

I wanted to also add that I think that some of the direct-to-consumer advertising that's occurring has had an effect on our patients and frankly on our all of us in a way that may not be as helpful as they are meaning to be. For example, the direct-to-consumer advertising is all for the moderate to severely active patients who are available for those advanced therapies. I would say that that's important—and that of course is the group of people who have had the worst outcomes historically—but it also raises the issue of giving the perception that everyone who has ulcerative colitis suffers to that degree. And we can't forget that actually a majority of patients with ulcerative colitis may have mild to moderate disease, and of course, we don't see commercials for that and there hasn't been appropriate awareness made for that. So one of the most important things when you meet a patient with ulcerative colitis, or when you make the diagnosis of a patient with ulcerative colitis, is to explain carefully to them the range of symptoms they may have, the range of severity their disease may take, and how we are able to effectively achieve and maintain remission.

So my goal-based approach to managing ulcerative colitis always starts with first making sure that our diagnosis is accurate, that I have some sense for what the prognosis for that patient may be—in other words, what's the likelihood that you're going to be hard to treat or going to need surgery down the line? And I also include in my diagnosis a careful survey of whether they have extraintestinal manifestations. I ask about and I examine, looking for symptoms and signs of joint pain, inflammation of the joints, skin inflammation or a history of skin inflammation, and of course, eye inflammation, coexistent liver disease, and very importantly now, we are screening and thinking carefully about mental health and mood disorders, sexual dysfunction, and the ubiquitous challenge of fatigue, all when we're first trying to make a diagnosis. That's a really important point.

The second is that I spend time educating my patient on what is IBD. I have now started explaining to people that inflammatory bowel disease is actually the body's immune system of our intestines—which has evolved and been developed over many years to respond to the environment—doing what it thinks it's supposed to do. I try to explain to them that your immune system is not your enemy. We don't have good evidence that the immune system is actually attacking you.

What's happening as far as we understand is that the immune system of the bowel has been turned on and there is either continuous stimulation of that problem or it has lost the ability to regulate and shut itself down. And so by explaining to people that this is their body trying to do what it's supposed to do, but it's just out of control, it helps me get to the next part of that conversation, which is how we treat it.

I also then spend a lot of time talking to patients about our goals and expectations for them living with this condition. That includes symptomatic and deep remission, restored and maintained quality of life, and hope for the future. What I mean by this is that the patients should essentially feel perfect, and it should last forever. Now that's an oversimplification, but that's really what we're trying to do. And feeling perfect is directly related, of course, to their quality of life.

What does that mean in ulcerative colitis? No blood; no urgency; formed stools, less than 3 a day; no nocturnal symptoms; and a restored rectal sensation, or the ability to distinguish between gas and something else. I also want to emphasize that the longer somebody is in that level of symptomatic control, the more confidence they'll achieve in terms of staying there.

I also emphasize that while many patients will feel better, they may still have active inflammation, and living with the active inflammation predicts they're likely to relapse, and that's an important point. So I tell people that we want to trust their symptom improvement, but we want to verify their disease control by then looking for objective evidence, whether it's by scope, by stool, marker, by blood test, and even now increasingly, by intestinal ultrasound—some way to know that their bowel is actually healed and we've achieved the level of control that will predict ongoing stability in their disease.

I then focus on the other part of remission, which is functional remission. Have we addressed their joint pain? Have we addressed their mood or mental health disorders? Have we talked about sexual function or dysfunction and sexual health? And have we been able to focus on all the other issues that will help them get back to the life they're trying to lead?

So now let's talk a little bit more about how I treat these patients. The first point is that treatment is focused on two major phases: induction of remission —or what I say is getting control of the inflammation— and then maintenance of remission, which has a number of parts to it. But maintenance is all about prevention of relapse and prevention of progression. In the maintenance phase is also where we incorporate disease monitoring in a stable phase of the management and it’s also where we talk about prevention of complications from the disease or from the treatments.

So, let's get to the induction. The choice of your first therapy is based on the location of the disease. What's the extent of the bowel involvement? Is it isolated proctitis or more extensive colitis? It's based on how active the disease is. How sick is your patient? How symptomatic are they? It's based on the prognosis, and I mentioned that earlier. What's the likelihood they may end up meeting a hospitalization or a surgery? Patients with more extensive disease; those with more severe endoscopic findings during their assessment and initial evaluation; patients with a history of prior Clostridioides difficile infection or CMV infection; and we also started to appreciate that patients who have extraintestinal manifestations, are all at higher risk for subsequent poor outcomes. And so that helps you understand upfront whether this is somebody who will need treatment for more moderately to severely active or moderate to severe ulcerative colitis.

I emphasize to you one additional point. I do think that we should go back to a principle that was talked about in the '90s and we got away from a little bit and we recognize it still needs to be brought up. That is steroid avoidance. Now, steroid avoidance is also steroid sparing, but what I mean by steroid avoidance now is with some of our newer therapies, like our fast-acting Janus kinase inhibitors and even with our S1P receptor modulators, and frankly any of our newer therapies, you can see that a significant percentage of patients in the clinical trials were not treated with steroids.

In other words, if you know a patient's going to need an advanced therapy, don't even start prednisone. Avoid it completely, give the new therapy some time, recognize that the data support that approach, and you are now eliminating a few things. You're eliminating the potential for side effects from the prednisone. You're eliminating the confusion and frankly what we essentially arbitrarily decide, which is the tapering schedule, which often is too long in many patients, and you're also going to eliminate the theoretical possibility that steroids have some biological effect on the disease process, which limits the response to the other therapy. If you do need steroids—which we understand is still the case in some patients—I would say that you must always think ahead to a steroid-sparing strategy. And most of our advanced therapies have very clearly developed steroid-sparing endpoints, steroid-free remission, that enables you to know that this is a therapy that can do so. In my experience what I have seen is that we often taper much too long when in fact the new therapy is on board, and if it's doing its job, you should be able to get the patient off prednisone. So avoid steroids when possible and steroid-sparing strategies always.

Now, the next point is how to choose your therapy. In a patient with milder or moderate ulcerative colitis, aminosalicylic acid therapies remain the foundational therapy to try. Remember the principles that getting the drug to where the disease is with these therapies is very important. So the patient with distal colitis will have less effective delivery of oral 5-ASA, so combining it with a rectal 5-ASA makes good sense. If you're going to use a 5-ASA therapy, which of course is reasonable and the patient's appropriate for it— mild to moderate disease—remember that 3% of people may be intolerant. So they should not be getting worse on that therapy, and you should keep in mind that you may need to stop it in that case. And also remember that you should see some response within the first 4 weeks. Most of the endpoints of the 5-ASA trials were 8 weeks or 12 weeks, but at least you should know the patient's moving in the right direction.

If you're using steroids, I would say to you less than 4 weeks, and if you're going to do it once and go back to 5-ASA, that may be reasonable if the patient's mild to moderate, but if it takes more than once, you need to move on to something else. Don't keep cycling. I call this the one-and-done approach. You get one course of steroids and if it doesn't work, you move on.

Next, I want to say that you should be embracing advanced therapies. Our colleagues in other immune disease conditions and practices have done so a bit better than we have. If you know somebody has complex or moderate to severe disease, you know they're likely to need an advanced therapy. Don't make them earn it by failing other treatments and being sick longer than necessary. Have a good conversation with your patient about the goals of management, the newer targeted and safe therapies we have, the newer super-fast and steroid-avoidance therapies that we have, and get them on the right treatment.

I always tell patients we'll re-evaluate after I have you stable, safe, and healthy for 6 months or more. And then we can talk about your long-term strategy. In my experience, many patients want to stay on their advanced therapy after they see how well they're doing with it. But it also enables us to start studying the concept of giving people advanced therapies out of the gate, getting them well, and then exploring whether deintensification may be possible later. Now, that's not yet standard of practice, so don't get carried away. But I do want to bring up to you that that's something of interest.

How do you choose your advanced therapies? That might be why you logged in to see this video. There are so many new therapies to consider. We have anti-TNFs, of course. We have our anti-IL12/23 therapy, ustekinumab. We now have an ulcerative colitis and IL-23 selective therapy, a P-19 inhibitor, which is mirikizumab. We also have, of course, our anti-integrin therapy, vedolizumab.

And now we have 4 treatments that are synthetic targeted small molecules for ulcerative colitis. For moderately to severely active UC, we have tofacitinib and upadacitinib as Janus kinase inhibitors. And for moderately to severely active UC, we have two S1P receptor modulators, ozanimod and etrasimod. These are all oral therapies, and that's a nice thing to know about, but how do you pick them?

Well, a few pearls. The first thing is, think about the patient in front of you. Look for clues that they have combination immune conditions or coexisting problems that are either related to the bowel or not related. For example, the patient who has ulcerative colitis and a history of atopic dermatitis or psoriasis, I'm going to lean in there to either an IL 23-based strategy, which is a very good treatment for skin and bowel. I will also consider anti-TNF in that scenario. And once you get through one anti-TNF, you can then think about a Janus kinase inhibitor for that patient, which is a very good consideration if they have a history of atopic dermatitis. So, there's some options there that might be dictated by the individual patient.

If they have a peripheral spondyloarthopathy, so their peripheral joints hurt them and you think this is related to their bowel or not, you should be thinking about a therapy that's going to work on the bowel and may help the joints. If it's really not an inflammatory peripheral arthropathy, any treatment that fixes the bowel may work very well for those joints. But if there's concern that it's inflammatory, or if they have a central or axial spondyloarthropathy, then we need to be thinking about more systemically active therapy that'll work on the joints and the bowel. That might be your anti-TNFs first, and our JAK inhibitors are approved for ankylosing spondylitis and sacroiliitis, and they obviously work well for the peripheral joints as well.

So some ways to think about this.

Then there's other considerations for the patient in front of you—the patient who has diabetes—obviously someone we're going to try hard or very specifically to avoid steroids The patient who's over age 60— these are people who may have a higher risk of opportunistic infections, but I want to counter what many of my colleagues have said repeatedly. I don't necessarily think that we immediately go to vedolizumab or an IL-23 in that scenario. I want to emphasize to you that many of the studies we have included older patients who have done well. You should pick the therapy that that patient needs and of course protect them properly by making sure they're up to date on vaccinations and monitoring them appropriately. So I just want to emphasize that to you.

But keep in mind, I want to also emphasize to you that the S1P receptor modulators are extremely safe oral therapy and they can be used right away after a 5-ASA. So unlike the JAK inhibitors, which we have in the United States to use after anti-TNF, you can use an S1P receptor modulator after 5-ASA as your first advanced therapy for the right patients. Very safe option.

Also your patient who may be planning imminently pregnancy or who is pregnant. Now, that's a patient in whom most of our therapies are okay, but our new small molecules are not sufficiently studied or thought to be unsafe in that scenario. I wouldn't avoid one of our new small molecules in a young woman who may become pregnant later. Still getting them into remission is our primary goal before we reassess. But if you have someone in whom that's an imminent concern or consideration or who becomes pregnant, you need to have them off those small molecules.

Of course, the other point of all this is we use treating to a target. Treating to a target means you have to set up a way to measure how they respond to the therapy at some short interval to know that it's working. If you look at the clinical trials, that would tell you that you should be looking at 8 weeks or 12 weeks and then do a colonoscopy. Those were the standard end points in most of our trials. However, we now accept that a stool calprotectin might be a good way to do this. We might identify in the near future that intestinal ultrasound is a good way to do this.

In my practice, I reassess objectively how my patient's doing 6 weeks after I start a new therapy. So I think that's pretty reasonable. You might even do it sooner and we're seeing some data now to suggest that you can probably see objective improvement much sooner than we thought. What we don't know yet is if it's only partially improved and your patient's feeling better, does that predict that they're actually going to be where you need them to be at a longer end point? So there's always this balance between assessing a patient too early and underestimating the therapy that you're using or assessing them too late and having them being sick longer than necessary. So we're working on that. For me, it's usually the 6-week point where I make these decisions and do those assessments.

Now, the next point is really about maintenance. Your induction therapy usually tells you what you should be considering for maintenance. The most important conversation I have with patients is that maintenance is about a patient in remission that we're trying to prevent relapse. This is not about the patient who's still sick and who's on chronic therapy that's barely controlling their condition. This is not about the patient who's steroid-dependent, who can't get off steroids. Maintenance of remission in colitis is about prevention of relapse in the patient who's already in remission. So keep that in mind. And if you're not in remission, you've got to move the patient to get there before you can actually discuss what maintenance may mean.

We have come to appreciate that a patient in deep remission may need a lower intensity of therapy and maintenance because the burden of inflammation is lower. But that's not true in everybody and we have to be thoughtful about this. So thinking about how often did the patient need steroids or how many treatments did they not respond to before we got to this one that's working will help guide you in your choice of maintenance. therapy.

Part of the maintenance phase of management is also monitoring. What is the benchmark you have to compare to the choice of monitoring strategy? So if you know someone had a perfectly healed colon during a colonoscopy or sigmoidoscopy 6 months after a treatment, and during that time the calprotectin was 150, you're going to feel comfortable using the calpro as a way to follow up. Fecal calprotectin in ulcerative colitis is a very nice marker. Patients don't like it though, so sometimes we rely on other things. CRP, if they make CRP, may be reasonable as well.

The cadence of monitoring—when do you repeat your monitoring test—is based on how long it took the patient to get well, how long they've been well, what the last monitoring test showed, and what the therapy they're on may or may not be able to do, as well as of course, if you make a change to their therapy or the patient stops their treatment. So you can decide how often you want to do it but I want to remind you that in this day and age, you should have a monitoring strategy for every patient in your practice. For a low-risk patient, that might be once a year. Once a year, I'll see you in clinic, we'll check some labs, we'll do a calprotectin, or maybe you'll be scheduled for an appropriate surveillance scope, which can also be your monitoring. If it's a patient who’s high risk, who just got into remission after being in the hospital, and there's other challenges, of course that's somebody who you're going to monitor more closely. You might want to do quarterly for a year. You might develop some other ways, and of course, we're doing the research on a variety of biosensors and other ways to monitor people from home and long distance.

And then of course, just focus on making sure they're up to date on their vaccines. I would refer you to a nice checklist that we have at Cornerstones Health [https://cornerstoneshealth.org/ibd-checklists/]. And you can also certainly refer them to your colleagues in dermatology appropriately. And don't forget colon cancer screening. The patient in stable remission may lose track of that. You should have a callback system and know when you're supposed to do surveillance exams.

The last point I'll make is that I'm always talking to my patients about hope for the future. In other words, as I'm managing them, I'm also saying, listen, we're going to do the best we can with all these great options we have now. But I just want you to know that in the next couple of years, there's going to be a new treatment or two, we're going to have new ideas about how to do this. And I want you to be aware that we're still working towards a day when we're going to be able to cure ulcerative colitis. And I think that that's not an exaggeration. I think that that's reasonable, and every patient with a chronic condition should have that perspective on the future of their disease.

With that, I'm going to conclude. I hope that I've given you some pearls about how to think about using therapies and ulcerative colitis, and I certainly look forward to having a conversation with any and all of you in the future.