Drs Cheifetz and Siegel discuss an abstract presented at DDW on the value of "flipping the script" from traditional step-up therapy for IBD to using advanced therapy for virtually all Crohn's disease and ulcerative colitis patients.

Corey A. Siegel, MD, MS, is the Constantine and Joyce Hampers Professor of Medicine at the Geisel School of Medicine at Dartmouth and director of the Center for Digestive Health at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. Adam S. Cheifetz, MD, is director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and professor of Medicine at Harvard Medical School in Boston, Massachusetts.

RAND panel supports default initiation of advanced therapy at diagnosis of Crohn’s disease and ulcerative colitis for most patients

• Using a RAND appropriateness panel, the Bridge Group reviewed scenarios: Advanced therapy was rated appropriate in 75% of scenarios and inappropriate in 10%, indicating that benefits outweigh risks in most early IBD presentations across symptom severity and endoscopic findings.
• The key exception was found to be among patients with ulcerative colitis scored Mayo-1; treatment-naïve mild–moderate disease: Advanced therapy was inappropriate primarily in asymptomatic or mildly symptomatic UC patients who had not yet received mesalamine; mesalamine remains appropriate first-line in this narrow subgroup. All Crohn’s disease scenarios had no inappropriate ratings, though uncertainty existed in limited cases (e.g., minimal erosions).
• Clinical strategy in the outpatient care setting is to administer modern biologics including IL-23 agents, vedolizumab, and perhaps infliximab. The abstract authors advocate a “default-to-advanced-therapy” approach at diagnosis, with no requirement to step through immunomodulators. For patients not started immediately, use close monitoring (clinical, endoscopic, biomarkers such as fecal calprotectin) and maintain a low threshold to escalate due to high risk of undertreatment and improved safety profiles of newer agents.

Dr Siegel: I'm Corey Siegel. I'm the director for digestive health at Dartmouth-Hitchcock Medical Center. 

Dr Cheifetz: And I'm Adam Cheifetz, director for the Center for IBD at Beth Israel Deaconess Medical Center. And we're very happy to be here to discuss an abstract that was done by one of my outstanding fellows, Ben Mexis-Faxon. Corey? 

Dr Siegl: Yeah, so this is part of a group that Adam and I have been part of for about 20 years now called the Bridge Group. And the abstract is called Time to Flip the Script. It's not identifying those who need advanced therapy for IBD. It's finding the few who do not. The reason we got into this is we feel like the mindset of people coming into the office and thinking about who needs advanced therapy is kind of an opt-in. We have the sense that patients have to earn needing an advanced therapy. But the way the field's going and the way that we have learned about early treatment versus later treatment is we truly like to flip the script. Let's think about... everybody should be considered for advanced therapy at diagnosis. And then let's find the few people who maybe don't need advanced therapy. And that was really the whole point of this, using a methodology that Adam will talk about and some results of where we ended up thinking. And we hope it fits in line with the way that you think we should all be practicing for the future. 

Dr Cheifetz: Yeah, I agree. I think it's very important. You know, we did our typical RAND panel where we all voted on various scenarios from Likert scale from 0 to 9 where 7 to 9 is appropriate and 0 to 3 is inappropriate. I don't want to go over all the details but we had 150 scenarios about in ulcerative colitis and Crohn's and remarkably 75% of those scenarios,
it was absolutely appropriate to start an advanced therapy in these patients with early Crohn's and ulcerative colitis. Only 10% of the scenarios was it inappropriate to start an advanced therapy in these patients. 

Dr Siegel: And the way we think about appropriate and inappropriate with these RAND appropriateness panels is, you know, do the benefits outweigh the risks of treatment? So really the thinking is, if it's appropriate, that means the benefits outweigh the risks of starting that treatment. If you're saying inappropriate, it probably isn't the right thing to do for that patient. So maybe can you give the examples of the few? And there were only a few out of all these scenarios where it was inappropriate. 

Dr Cheifetz: Yeah, in this case, and again, we broke it up between Crohn's disease and ulcerative colitis. We based it on Mayo score for UC. And in Crohn's disease, deep ulcers, shallow ulcers, or erosions. And then we broke into various asymptomatic to more moderate to severe symptoms. And it really was just those patients with ulcerative colitis, with Mayo-1 disease, were the very few scenarios where it was inappropriate. Everybody else, like I said, either appropriate or there were a few where it was still just uncertain. And, you know, certainly Crohn's, deep ulcers, Crohn's even with shallow ulcers that were
Symptomatic—absolutely appropriate.

Dr Siegel: Yeah and let me say it like from the other side of it just to re-emphasize it is out of all the scenarios of the different types of patients we see and it's not just Crohn's versus you see it's as adam said we talked about oh you know close to 150 different variations of types of patients that come into our office and out of all of those the only ones —the only ones—that we thought were inappropriate were patients who are either asymptomatic who had mild to moderate disease with ulcerative colitis, who had not been on mesalamine. So if you hadn't been on mesalamine and you have mild to moderate UC, absolutely go ahead and use mesalamine. It's a great drug for that patient population. But every other scenario, including all the scenarios in Crohn's, there were none that were inappropriate. There were some tweeners. There were some that you're not sure. Like, do you remember some that were not sure, just to give an example? 

Dr Cheifetz: Yes. So I think one of the ones that was unsure, and it's a situation that comes up, and we often talk about it, is those patients with Crohn's disease with just a few small erosions, right, either in the ileum or scattered in the colon. And in those cases we decided, again uncertain. So I think the important thing here is if we aren't going to treat with an advanced therapy we follow them very, very closely both clinically, endoscopically, using our biomarkers, fecal calpro, and then as soon we all as soon as those ulcers get larger,
become more severe…

Dr Siegel: Yeah, low threshold. 

Dr Cheifetz: Very low threshold for advanced therapy. 

Dr Siegel: And then just talking about thresholds, let's talk for a minute about why the thresholds have changed over the years. So what's changed since 1998 when infliximab was first approved? That was our first biologic. Remember, we're going back 28 years ago now. So what's changed in these 28 years? 

Dr Cheifetz: Besides our hairlines and our hair color? 

Dr Siegel: Yeah, beyond that. 

Dr Cheifetz: I would say, I mean, just go to DDW. Advanced therapies are not just infliximab, right? IL-23s, vedolizumab, right? So the safety is very different from what we're talking about, you know, just infliximab. So there's a very low threshold. So here,and I've always done this, but like I would rather over-treat a few patients as opposed to under-treating  these patients. 

Dr Siegel: Yeah we're never going to get it perfect, right? We're never going to get it perfect but the risk of under treatment of a patient is so high that we can't turn the clock back once that happens and I agree with you that you know starting an IL-23 at the time of diagnosis is very different than starting infliximab in 2002 and we know how to use these drugs, we know the safety profile, and remember appropriateness is built on the risk-benefit ratio

and when the risk is very very low, like starting an Il-23 at diagnosis, the benefit is the delta
between the benefit, is really, really high. So let me summarize where I think we ended up here—and then I'll let you throw in the last word— when you're seeing a patient in clinic based on the results of our project you should think, by default, I'm going to be starting this patient on an advanced therapy for Crohn's disease or ulcerative colitis. And there are only a few scenarios where that's inappropriate. How would you refine that a little bit? 

Dr Cheifetz: You said it beautifully. I mean, it really is like when a patient comes in, think, okay, which advanced therapy are we going to start with? And think, you know, you can backstep it. Okay, maybe this patient doesn't need it now but they may in the future. So I'm going to monitor them very, very closely. And one other thing that we voted on at the end that I also think is important, we voted that these patients with early UC and Crohn's don't need to step through an immunomodulator to sort of earn or get an advanced therapy. 

Dr Siegel: It's 2026. Let's practice like that. It's time to flip the script.