IBD Drive Time: Frank Scott, MD, on the AGA Guidelines for Ulcerative Colitis Management

In this IBD Drive Time podcast, Dr Frank Scott and host Dr Raymond Cross discuss updates in the AGA guidelines for ulcerative colitis.

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. Frank Scott, MD, is an associate professor of medicine in Gastroenterology at the University of Colorado Anschutz Medical Campus in Denver, Colorado..

Transcript: 

Hello everyone, I'm Raymond Cross from Mercy Medical Center in Baltimore, cohost of IBD drive time, and I'm delighted to have my friend and colleague, Frank Scott from the University of Colorado here to go over the new AGA guidelines on treatment of moderate to severe UC. Frank, welcome to IBD Drive Time.

Dr Scott: Thanks for the invitation. I really look forward to you talking to you about the new guidelines.

Dr Cross: So I've been fortunate to be on a guideline committee once for mild to moderate you see, and it's definitely an interesting and unique experience. So for the listeners that may not have been involved in a guideline document, can you briefly describe the process?

Dr Scott: Sure. For us, the process began about 18 months ago with the initial formation of the committee. We had two chairs, Ashwin Ananthakrishnan and Sid Singh, and there were 5 additional members that were selected5to participate. This included Mansi Agrawal, Berkeley Limketkai, Ed Loftus, John Haydek, and myself. Then we met weekly over the course of the next 12 months or so.

The first step was to determine what questions we were going to try to answer that were clinically relevant. These questions were then submitted to the AGA governing board for approval. Once they signed off on them, then we began a literature review and it started with a systematic review of all papers, clinical trials related to the agents or questions of interest. We then extracted data elements from each of those papers and it was sort of divided up amongst the team members to extract the elements into various Excel forms so that we could conduct systematic reviews, meta-analyses and network meta-analyses where there were no head-to-head data available. These efficacy estimates were then translated to recommendations using the GRADE evidence to decision framework, which allows us to convert those numeric estimates and absolute benefit estimates into actual recommendations, balancing risks of harm, patients' values and preferences, ability and health equity.

And then lastly these recommendations are sent back to the AGA governing board for approval and then presented for an open review period to the public before being published.

Dr Cross: So a lengthy process and as you know that, as the listeners know we've had agents approved in the time that you are working on this document so is it fair to say this is a living document until you finalize it that you would include things that are being approved as you're developing the document?

Dr Scott: Yes, so we had a cutoff that agents had to have been in press with regards to their publications to be included in this version of the document. But what's unique about this version of the guideline is that it is what is termed AGA's first living guideline. This means that instead of waiting 3 to 4 years before revising and including new therapies, the committee is going to reconvene every 3 to 6 months, repeat our literature review to see if there are any new data to incorporate into our prior models, and then update our position statements on the fly.

Dr Cross: Wonderful. And can you, for the listeners, explain the strengths of the recommendation, in particular, what a conditional recommendation means?

Dr Scott: Yeah, absolutely. So within the GRADE framework, we rate the strength of the evidence based on detected minimum clinically important difference and the sample sizes and the number of absolute patients that would be benefited from that therapy over either placebo for our naïve patients or in comparison to other therapies for our PICOs where we looked at comparative analyses for the exposed population. And then use that strength of the evidence to decide whether or not things would be a strong recommendation versus a conditional recommendation.

Dr Cross: So for the listeners, just to summarize, big deltas between drug A and comparator with large sample size is going to be a strong recommendation, whereas a smaller Delta with smaller sample sizes is probably going to be conditional recommendation. That's oversimplifying it, but...

Dr Scott: Yeah, that's a great summary. For example, for our comparison of an active therapy versus nontreatment, we wanted to detect a minimal clinically important difference of at least 10% over that placebo comparator and for our active comparators we wanted to detect at least 5% and the evidence could be downgraded if those weren't there. We also downgraded for things like heterogeneity in the clinical trials or in the meta-analyses.

Dr Cross: Okay, so let's start with strategies because there was discussion about step-up versus top-down. So what do the guidelines recommend regarding those two competing strategies?

Dr Scott: Sure, the guidelines recommend that in the setting of moderate to severe UC, we consider earlier use of advanced therapies, which be consistent with the top-down strategy as opposed to a step=up therapy. The overall concerns for a strategy like stepping up from a 5-ASA to a steroid course and then resuming a 5-ASA, for example, are that it potentially delays the eventual use of advanced therapy and increases the risk for reduced quality of life and increased healthcare utilization.

I do think it's important to take a step back with regards to how we define moderate to severe UC for the guidelines in general, because that's really important with regards to who this applies to. We use the PRO-2 base definition, which is the stool frequency score of 2, which is 3 or more bowel movements above normal or rectal bleeding score of 2, which is obvious blood with most bowel movements, to define our at least moderate population.

Dr Cross: So do you think there's a difference there between maybe the outpatient that's fairly sick that doesn't respond completely to mesalamine and gets a tapering course of steroids and responds pretty quickly and maybe considering maintaining high-dose mesalamine for maintenance and that patient versus a patient who got sick enough to be admitted to the hospital? Do you think there's a difference there between those 2 groups pragmatically?

Dr Scott: I think pragmatically, yes. I think the challenge when you're building a sort of a position statement or a guideline statement like this is that there is no relevant clinical trial data to drive a decision framework to discern between those 2. I think with each of our guideline statements, though, there are what we what we call implementation considerations that allow a little bit more nuance with regards to how you might manage a specific individual. And of course, this is taking into account clinical decision-making at the population level, and you should always use these guidelines or any guideline as one piece of the puzzle when facing an individual patient one-on-one and trying to decide what's right for them.

Dr Cross: Great. Why don't we start with the bio-naive patient? I'm sorry, let me rephrase that—advanced therapy-naive patient. So what do the guidelines say about that group?

Dr Scott: First, the guidelines note that the use of any advanced therapy is superior to no advanced therapy, which would seem like a no brainer. There was some heterogeneity in the certainty of evidence for various therapies though, particularly when we're thinking about that 10% minimally clinically important benefit over no treatment. And that created some stratification with regards to how we group our agents. And that stratification is the sort of the beginnings of how we ended up with sort of the bucketed approach that we eventually ended up with with regards to our guideline recommendations.

From a strength of evidence standpoint, there was moderate to high certainty of evidence supporting upadacitinib, infliximab, golimumab, vedolizumab, ozanimod, etrasimod, ustekinumab, risankizumab, guselkumab, and tofacitinib, and a lower certainty of evidence for adalimumab and mirikizumab and filgotinib.

However, we then wanted to take this certainty of evidence and transition it, like I said, using the GRADE framework into actual guidance on positioning these therapies amongst each other, and this incorporated not only the phase 3 clinical trial data, the results of our meta-analyses and network meta-analyses, but also we wanted to ensure that there was heterogeneity with regards to routes of administration, mechanisms of action, and factor in safety. And to do that, we created 3 buckets—a higher efficacy bucket, an intermediate efficacy bucket, and a lower efficacy bucket. I don't want to get hung up too much on this stratification between higher and intermediate because we recommend that clinicians could choose from either of those, depending on patient factors, and that it's preferred that they choose one of those over the lower efficacy buckets. In the higher to intermediate efficacy bucket was infliximab, vedolizumab, ozanimod, etrasimod, risankizumab, guselkumab, golimumab, and mirikizumab. Adalimumab was the only agent that was in that lower efficacy bucket. Notably, in those efficacy buckets, we did not include the JAKs And the reason why they weren't in this particular recommendation is because of the FDA labeling in the United States.

Dr Cross: Yeah, it's super interesting because I think when you go to meetings and advisory boards and so forth, like we all acknowledge that adalimumab is a fine agent for Crohn's disease, but in ulcerative, it just doesn't work as well. And even when you push the drug levels up like in the SERENE UC study, it's beyond drug levels. It's just not a really effective agent. Despite that, it's still widely used and my argument has always been, it's access, access, access. Providers can get it fairly easily and there's a struggle to get the other things.

Now, this is probably a trick question, but do you think that this guideline is going to influence payers to allow us to bypass adalimumab for UC?

Dr Scott: I hope so. You know, I agree with you that there's now a sort of robust body of evidence and these guidelines that would suggest that it shouldn't be our first-line therapy or any line therapy, in ulcerative colitis. How that's going to impact payers over time, I think remains to be seen. You know, there are contractual that are beyond our scope of control that sometimes result in these medications being positioned before the drugs that we want to use. But I do think it'll be important to monitor over time if there's any changes in adalimumab use based on the publication of this guideline and others.

Dr Cross: So let's transition to the advanced therapy-exposed patients. So what do the guidelines say about that difficult to treat population?

Dr Scott: Yeah, fortunately, most of the modern clinical trial data that we extracted from phase 3 studies has some stratified point estimates based on prior advanced therapy exposure. I think that there are some caveats. We don't usually have granular enough data with regards to classes of exposure to say when somebody's been exposed to X, we should use Y. But we can make some recommendations based on these data and work meta-analytic approaches with regards to any exposure. I do think it's important to note that we used a different minimally clinically important difference here of 5% because we're going to assume that placebo is not an option after somebody has failed in advanced therapy already and that patients would accept a smaller margin of benefit.

And then we again created the same sort of bucketed approach that we used for our naive population. For the higher or intermediate groups, those drugs included upadacitinib, tofacitinib, ustekinumab, mirikizumab, risankizumab, guselkumab, and filgotinib; for those that were advanced therapy-exposed, that included adalimumab, vedolizumab, ozanimod, and etrasimod. As with the naive population, it's again important to emphasize that these tiers were constructed not only with the results of the NMA and the phase 3 randomized control trial data, but to try to incorporate different routes of administration and classes of therapies within each bucket, and that intermediate and higher efficacy buckets are both acceptable selections.

Dr Cross: You can't really comment on infliximab here because you don't have really data on advanced therapy exposed patients with infliximab, correct?

Dr Scott: That's correct. You know, we think it potentially would be reasonable, but there is a paucity of evidence in that regard right now, for sure.

Dr Cross: And I think as a provider, it'd be interesting to see if you practice similarly. The way I think about this in the bio, the advanced therapy exposed patients is, if you're sick and I'm thinking about prednisone, and you haven't been on infliximab, I'm thinking about infliximab or UPA or TOFA, if you can access TOFA easier in your area. And for the less sick patients, some of those maybe intermediate agents, I'm still considering is reasonable for them if they're not that sick.

Dr Scott: I fully agree. And I think that's a reasonable sort of interpretation. You know, I view it as the leukocyte trafficking agents are probably not my first choice when you need something that's going to work fast for somebody who's perihospitalization, which is sort of what you are describing as well.

Dr Cross: All right, before we go to the last few questions, I just want to remind the listeners that IBD Drive Time is sponsored by the AIBD Network and that we are on Spotify and Apple podcasts, so please subscribe so that you can hear our twice-monthly Drive Time podcast. So Frank, for the patient that's progressing to an advanced therapy because nonresponse, loss of response, or incomplete response to 5-ASA, did the guidelines talk about what to do with the 5-ASA when you're going to move on to something else?

Dr Scott: They do, and I think that's a great question because it really gives us the opportunity to not only sort of improve the quality of care that we provide, but also potentially impact costs of care and inflammatory bowel disease.

Since the publication of the last guideline for moderate to severe UC, there's not really been additional literature to make us modify our recommendation from the 2020 guidelines. And in that guideline, we stated that in individuals who had moved on to an advanced therapy, they should consider withdrawing the 5-ASA, and that's still our recommendation. This is based on one study that looked at mesalamine continuation in individuals who have been advanced to azathioprine, so it's important to take that into consideration as a limited data source. But I also think it's important to consider some patient-specific factors as well, and we consider these implementation considerations in our guideline. One example would be there may be an individual that has a significant clinical response to an advanced therapy, but for instance, still has pretty significant proctitis that's symptomatic, even though they've had a robust response, and maybe they get better with rectal mesalamine. We're not saying you have to withdraw rectal mesalamine, you still get to individualize your decision in those instances.

Dr Cross: There, in fact, I looked at these about a week ago; if I remember, you guys also commented on the dubious impact for chemo prevention with these agents. We used to keep people on low dose in definitely like 1.2 grams a day and I think the trials have mostly debunked that effect. Yes, we do comment on that and specifically comment that we can't comment. So if a patient wants to stay on a low dose because they like the idea it may be helpful in cancer prevention, it's fine. And I still have some people that like that, they like that reassurance perhaps, and it's low risk, low harm, relatively low cost.

Dr Scott: And conversely for the individual who really wants to cut back on costs and stop it, we should feel reassured that that's a very viable and recommended option.

Dr Cross: Agreed. And what about, you know, my former partner used to always say that for our therapies, want to squeeze every little bit of toothpaste out of the tube. And so we all have patients that we've escalated their dosing shortened their interval, etc. What are the guidelines say about de-escalation?

Dr Scott: That's a great question. You know, I think that there are several important trials that are out there regarding de-escalation at this point. And it's something that all of our patients ask about when they started advanced therapy or in particular start combination therapy. I think the challenge is that there really is a lot of heterogeneity with regards to the literature base at this point, and the studies that have looked at forms of de-escalation have a preponderance of Crohn's patients at this point, so it really makes it difficult to

make firm recommendations on a strong literature base in ulcerative colitis right now. One example would be we specifically address the concept of withdrawing an immunomodulator and somebody who's in clinical remission off steroids for at least 6 months with combination therapy. And we decided that based on the evidence while the relative risk of withdrawing the immunomodulator appeared in our meta-analyses to notbe at, not portend any increased risk, that because there was so much heterogeneity with the literature that we couldn't make a firm recommendation in that regard. I think alternatively with regards to that patient on combination anti-TNF plus thiopurine, there are some reasonable evidence with regards to withdrawing the anti-TNF. And if you look across studies in that specific question, there's at least a 2-fold increased risk of a flare over time in those cohorts. And so we felt that given that size of that effect estimate that we could recommend against withdrawing anti-TNF in individuals on combination therapy, which is different from what we said with regards to the immunomodulator.

Dr Cross: I think for the novel biologics, I go with the philosophy, you dance with the girl that you brought to the dance and if I get you there, I tend not to move it. But I think particularly with infliximab, those patients can be really sick and then once you control that inflammatory burden, their levels seem to improve and you can sort of slowly tweak and adjust it and maybe space the interval. But I think that's very case by case and clearly there's not enough data to support that approach that some of us do in practice.

Anything else, Frank, do you want to highlight from the guidelines that I may have forgot to ask you?

Dr Scott: I think this has been a great summary of the high points. You know, I just want to emphasize that the novel format, the living guidelines that the AGA is moving to in a number of different disease spaces, the fact that you should read this guideline and incorporate it into your practice, but keep in mind that 3, 6 months from now, it can update online and we'll be keeping live notifications when that happens as well and we're planning on we're currently working on a very similar living guideline for Crohn's disease as well so so stay tuned for that next year.

Dr Cross: Great and thanks for you and other authors for the great work you did here it's really really practical and helpful to focus our conversations with our patient.

All right the fun question, Frank. Tell the audience something about yourself that they may not know or I may not know.

Dr Cross: Let's see. That's always a good one. So I think it's important to, you know, have some interests outside of work. I personally have been a fan of electronic music since the ‘90s. My freshman year at college I took some of the money that I'd saved up for textbooks and instead bought a pair of turntables and have been a DJ since then. I played a lot in college and med school, but residency, fellowship, career, and whatnot have reduced it to generally a few times a month, but I still dust them off for our annual holiday party for the CUGI division.

Dr Cross: Oh my gosh, we have so many musicians that have been guests on IBD Drive Time. We definitely need to get a, have an episode so we have all the musicians together to do something. That'll be super cool.

Dr Scott: That would be a lot of fun.

Dr Cross: All right, Frank, thanks. This has been great. Hopefully we'll have you back soon. Hopefully your Eagles and my Steelers will meet in the Super Bowl for a rematch. That would be awesome. And we can maybe debate that sometime.

Dr Scott: Yeah, I would love to see that—go birds? Thanks for inviting me and it was really great talking to you about the new guidelines.

Dr Cross: Great, thanks Frank.