Marla Dubinsky, MD, on Risk Stratification in Crohn's Disease

Dr Dubinsky opened the 2024 Advances in Inflammatory Bowel Disease conference with a firm statement that virtually all patients with Crohn's disease should be treated quickly after diagnosis with approved and effective therapies—which do not include 5-ASAs— to help prevent complications and change the natural history of their disease.

Marla Dubinsky, MD, is a professor of Pediatrics and Medicine (Gastroenterology) at the Icahn School of Medicine and chief of Division of Pediatric Gastroenterology at Mount Sinai Kravis Children's Hospital in New York, New York.

TRANSCRIPT

Hello, I'm Dr. Marla Dubinsky from the Icahn School of Medicine at Mount Sinai, New York. And I'm here at the Advances in Inflammatory Bowel Disease meeting in Orlando, Florida 2024. And I was delighted to be kicking off the meeting this year with a topic that's really important for all of us to be able to move the field forward, which is the importance of risk stratification in Crohn's disease.

At the end of the day, when we're thinking about how do we decide which patient should go on what therapy, there's been a lot of discussion, a lot of research over the last 20 years-plus around the ideas that are there certain clinical factors that my patient has in front of me, whether at presentation or over time. That sort gives me an idea that this patient is at high risk of developing a complication. And that all started really in 2015, when the AGA put out a guidance or some information around certain risk factors that an individual with Crohn's disease may have clinically that actually says if a patient has these factors, they are at highest risk of developing a complication, for example, needing surgery.

Now, it wouldn't surprise you that patients who presented with strictures or fistulas were at risk of doing that again. So I think that was sort of intuitive around the idea that when a patient already declares themselves as having a higher risk-type phenotype, that they may do it again and need surgery. But more importantly, are there nonstricturing and penetrating complications that a patient may have at the time of diagnosis, for example, that may actually predict that my patient is going to develop a complication, and if my patient is at risk for developing a complication, what would be the best therapy for that patient? Which would be more in the precision idea, and I'll get to that in a moment. But when a group out of the OSCAR cohort, which is run out of Rhode Island, looked at diagnosis, what proportion of patients in an inception cohort have these determined high risk factors?

It was about 50% of the population presented with at least 2 of this list of risk factors. And those individuals who carry those risk factors did indeed have a higher rate of complication and a higher rate of surgery and an altered natural history. So we know that these factors are important. We also have looked at over the years the role of serologies, which are some of these antimicrobial antibodies such as ASCA. And we've shown that these serological markers may actually predict complications in both adults and in pediatric cohorts. And there's even been some data to support that. These immune markers may actually predict the onset of IBD—for example, some of the US Army cohort and other cohorts. So serologies are important. Genetics not as much, not too, really hasn't proven to be the risk factor for developing complicated Crohn's disease, potentially in the face of small bowel disease, potentially predicting more stricturing disease.

That data needs to be flushed out a little bit more since most of our patients don't carry the NOD2 gene. And then the idea of disease severity was introduced. So Corey Siegel, Richard Geary, the International Organization of Inflammatory Bowel Disease, have put together something called the disease severity index, which really forces us to think that my patient in front of me, it's not just about their rectal bleeding, the number of stools they're having, how much pain it is, the totality of the severity of a patient, what happened leading up to that visit in the natural history, and what are some risk factors that we know that predict complications and their research and their validation of the Crohn's Disease Severity Index showed that if you have a score between 0 and 100 of at least 23, that was strongly predictive of developing a complication, hospitalizations, a more severe phenotype.

And finally, the idea of putting it all together. There are risk stratification tools where you can actually show a patient in your clinic what their trajectory is, and it's not about somebody they know that's on this therapy or never got surgery, et cetera. It has nothing to do with another individual. It is all about their personalized risk prediction. And so myself, Corey Siegel and his wife, Lori Siegel, had validated a tool called the Prospect Tool, which included both clinical variables, a lot of them from what we know from guidance on risk factors, as well as serologies, as well as genetics. Putting that into a model, literally printing out for that individual what their risk factors are. And right now it's renamed as CD path and it's being offered through Takeda at no cost to patients or to physicians. And Prometheus is doing the lab-based testing that then gets put into the clinical variables.

And physicians could use these tools to engage in shared decision-making. That's important because we know that when patients are informed and see themselves, what is the risk of them developing a complication? Since many of our patients don't want surgery, don't want an ostomy bag, this has allowed us to communicate to patients that their disease is at risk and we need to act early. And patients are making better decisions around what treatment to choose based on their own risk profile.

And finally, to sort of I think a more drop-the-mic moment is that there have been different tests that have been put out there as if you are positive for this gene expression marker that you were at risk of needing advanced therapy. And so the profile study, which is I think one of the studies that was most cited here at Advances in Inflammatory Bowel Disease, because it has really validated what we've all been saying for a very long time, is in the PROFILE study. They took all comers, randomized them to either step up therapy with steroids, thiopurines—reminder, steroids and thiopurines are not approved for Crohn's disease—versus using Infliximab plus thiopurine and looking at the difference at outcomes at a year, who was steroid free, who was surgery free.

And it's not shocking that individuals who within 2 weeks of a diagnosis of Crohn's disease had the least amount of complications, the best outcomes compared to those patients where we would sort of creep up and give them unapproved ineffective therapy and wait for them to declare themselves needing an effective therapy, of course, did not do as well as those patients who were given effective therapy. Again, I repeat within 2 weeks of diagnosis, and that is what makes a difference in our patient's lives. So perhaps if we don't want to do a whole bunch of risk stratification, perhaps just using effective therapy early is really the key. So it could be that we're overtreating a minority of patients, but that means we are appropriately treating the majority of Crohn's patients who are going to progress to complication. But let's remember that before 1998, when Infliximab was first introduced into the Crohn's disease space, the majority, up to 80% of Crohn's patients, went to the operating room.

So now we know what the natural history of undertreatment or ineffective treatment is, and the PROFILE study sort of, I think dropped the mic in. The idea is that if you treat early with effective, I'm actually not advocating for what treatment to choose. That's another talk, and that's another sort of understanding of the literature and what therapy is best for your patient. But I'm proposing that instead of using steroids—and we must stop using mesalamine and 5-ASAs in Crohn's disease, I really believe—and I sort of ended the talk with this notion that the delay to effective therapy and treating patients with moderate to severely active Crohn's disease with a drug that is not approved for moderate to severely active Crohn's disease. And I believe that the biggest risk factor for stratifying patients into which patients are going to be at highest risk of complication, I'd venture to tell you that the use of 5-ASAs is the number 1 risk factor for Crohn's disease complications. So it was an exciting kickoff to the meeting, and there was some incredible talks that really I'd say doubled down this notion that we need to start treating moderate to severely active disease, whether it's Crohn's or UC, with treatments that are approved for moderate to severely active Crohn's disease or ulcerative colitis. Thank you.