Ryan Ungaro, MD, and Priscila Santiago, MD, on Risk Factors Predictive of Complicated IBD

In this podcast, Drs Ryan Ungaro and Priscila Santiago discuss their study of risk factors that may be predicators of complications among patients with IBD.

Ryan Ungaro, MD, is associate professor of medicine and director of Clinical Research at the Icahn School of Medicine in New York City. Priscila Santiago, MD, is an advanced IBD fellow at Mayo Clinic, in Rochester, Minnesota.

TRANSCRIPT

Welcome to this podcast from the Advances in Inflammatory Bowel Disease Network. I'm your moderator, Rebecca Mashaw. And I'm here today with Dr Ryan Ungaro, who is an associate professor of medicine and director of clinical research at the Icahn School of Medicine in New York City, and Dr. Priscila Dr Santiago, who is an advanced IBD fellow at Mayo Clinic Rochester. They're going to be talking to us about a study they did looking at the compiled risk factors from the American Gastroenterological Association that may be predictive of disease complications in both Crohn's and ulcerative colitis. But their particular aim was to evaluate the performance of these risk factors for stratification of patients with these conditions. Thank you both for joining us this morning.

Dr Ungaro:

Thank you for having us.

Rebecca Mashaw:

Dr. Ungaro, would you start us off by describing the risk factors that the AGA identified as potential potentially predictive of complications in Crohn's, in UC?

Dr Ungaro:

Sure. So the AGA number of years ago now, almost a decade ago, actually, got together to create a care pathway for treatment of patients with Crohn's and colitis. And what they did was look at all of the assembled data from prior epidemiological studies, clinical studies to guide patients and their doctors on how should we decide on which patients are at risk for complications. So typically these are the things like fistula, strictures, or needing surgery for Crohn's and an ulcerative colitis patient being hospitalized, needing steroids, or needing surgery.

And based on prior data, they propose that you should stratify patients based on their risk factors for complications. And they have a number of factors in each disease. So for example, in Crohn's disease, they said young age of diagnosis, which was age less than 30, extensive anatomic involvement—so beyond the terminal ileum—perianal disease, having more ulcers or particularly deep ulcers on your colonoscopy, having a history of surgery, having a history of strictures or having a history of fistula. So internal fistula, abdominal abscesses, they identified disease as risk factors for disease progression and all in Crohn's disease and in ulcerative colitis, the recommended risk factors to take into account were also young age diagnosis, so aged under 40, extensive colitis, so having pancolitis needing steroids, systemic steroids, having deep ulcers on your colonoscopy, personal history of hospitalization, and having a high inflammatory burden, so high C reactive protein or ESR levels. And then also in there they said if you had concomitant infection like C diff or CMV, those are a risk factors for disease progression.

And so taking these factors into account, they said, you should use these to decide on if this is a higher risk patient, you should be introducing a more targeted advanced therapy earlier. So say a biologic or small molecule therapy, you should be escalating that patient more quickly if they have risk factors. And the thing that was, I think it was a great conceptual flag to plant because it's bringing in this idea of disease severity and prognostication into our care for IBD patients.

But what was not clear from this was, so they give you this list of 5-plus risk factors, which I think are all reasonable and maks sense, but is it any individual one of these? So if you just have one of these risk factors, you should be considered high risk? Is it a specific one of these factors that you should be worried about more than others? Or is it, do you need to have a certain number of these risk factors to jump into that higher risk category and be particularly worried about these patients? And so this was the rationale for doing this study. We wanted to investigate those questions. Which of these risk factors is it a certain number of these risk factors that should make clinicians more worried about a patient or risk stratify a patient at a higher risk level? And that's where the jumping off point was for this study.

Rebecca Mashaw:

So can you tell us about the study? Where did you get the sources of information, the patient records, what kinds of endpoints did you set? What are your basic parameters?

Dr Santiago:

Yes, of course. So basically for this study we included 2 prospective cohorts of very well characterized cohorts. And one of those cohorts is the OSCAR cohort, which is the Ocean State Crohn's and Colitis area registry, which is an inception cohort and community-based cohort. And we also included the Mayo Clinic cohort, which basically included the 3 sites of Mayo Clinic, Florida, Arizona, and also Minnesota. And so we included patients from those cohorts and we subdivided those patients between those 2cohorts and also between Crohn's disease and ulcerative colitis.

So in total we had 412 patients with Crohn's disease and 265 patients with ulcerative colitis. As Dr. Ungaro mentioned, we collect baseline characteristics and demographic information, also including all those AGA clinical risk factors that the patients had at baseline. So we analyze the medical records for those risk factors. And for our endpoint, we actually utilized a combined composite endpoint that was basically looking into any IBD-related hospitalization, any IBD-related surgery in the future, and also progression of disease. Progression of disease for Crohn's disease was characterized and defined by any perianal disease, any progression to stricturing or penetrating behavior. And for ulcerative colitis, progression of disease was characterized by progression to a more extensive anatomic involvement—so any progression from proctitis to left sided-colitis or extensive colitis or left-sided colitis to extensive colitis.

Rebecca Mashaw:

What did you learn about the relationship of the risk factors and whether patients with those factors or some of those factors did in fact reach some of those endpoints? Dr Santiago?

Dr Santiago:

So basically like I said, we looked into Crohn's disease and ulcerative colitis separately. So for Crohn's disease, we did find a significant association of patients having 3 or more risk factors compared to having 0 or 1 risk factor. So those patients, we actually, we had further characterized the patients in our studies into having 0 to 1 as low risk and patients with only 2 risk factors as moderate risk and patients with 3 or more as severe risk of complications. So we did find this relationship for Crohn's disease. So actually the hazard ratio when we looked for the OSCAR cohort was 2.75 and for the Mayo Cohort was 2.05 for this association. And by contrast for ulcerative colitis, we did not find any association between number of risk factors and a prediction of a more disabling disease course or new complications. And we also didn't find any individual risk factors in ulcerative colitis that would predict a more disabling disease course.

Rebecca Mashaw:

Dr. Ungaro, did you come up with any hypothesis about why this difference between UC and Crohn's when it comes to predictive factors for complications?

Dr Ungaro:

Yeah, it's very interesting and I thought that was one of the more intriguing findings is that in Crohn's disease it's a little bit—and even there, there's still a lot of work and research to be done—but it's a little bit easier to understand who are the higher-risk patients than in ulcerative colitis, at least in a prognostic manner. So you're taking a patient now times 0, and then trying to see, okay, who's going to have complications later down the road?

And I think there's probably some potential reasons for this. Number 1 is Crohn's disease has become more appreciated over the last 5, 10-plus years as a progressive disease. And so over time patients with Crohn's are more likely to accrue bowel damage, need surgeries, have fistula, strictures, et cetera. And so there may be something just about the nature of the disease and the more common occurrences of these progression events in Crohn's patients that it's easier to predict because you have more of these events on average. That's one thing.

And so in ulcerative colitis, there is some that some research that ulcerative colitis can be a progressive disease as well. But I would say that it's less of a firm literature about ulcerative colitis as a progressive disease. I think also that it may just highlight that ulcerative colitis has a little bit more of an unpredictable disease course, and your prior history may be less predictive than of your future history in ulcerative colitis than Crohn's. It may also be that there's other clinical features that we just haven't fully delineated yet in ulcerative colitis that are more important. Our cohorts were, we didn't have a specific endoscopic score, say a Mayo score of 2 versus 3 or UCEIS score, something that's very granular and a continuous variable. And we were only able to really say if someone had an ulcer or not. So maybe something that's more of the extent of ulceration. The degree of ulceration may be more predictive in ulcerative colitis, and we weren't able to capture that in this.

But I think it may point to, 1, that the progressive nature of Crohn's as compared to ulcerative colitis is more firmly established, as I mentioned, and that the predictability is a little bit trickier in ulcerative colitis. And I think it points to the need for better prognostic markers, particularly in ulcerative colitis. And number 2, it may be that in ulcerative colitis what's most important is not necessarily your personal history as much as your current disease activity. So how inflamed you are at this moment in time and how sick you are at this moment in time. So if you're taking patients that are doing great and they had a history of hospitalization, that patient maybe you needed to treat more differently in ulcerative colitis than in Crohn's disease.

Rebecca Mashaw:

Interesting. Did you note that any of these risk factors were more predictive than others of complications in Crohn's disease? I know you said 3 or more, but were there specific risk factors that you really need to pay the most attention to?

Dr Santiago:

Yes, definitely. That's a great question. So for Crohn's disease, when we did find association of 3 or more risk factors, we did find that some individual risk factors were more productive of new onset of complications in the future. So those 3 risk factors were young age of diagnosis, so below 30, perianal disease, and also a complicated behavior, which would include penetrating or strict behavior.

Rebecca Mashaw:

That probably didn't come as a big surprise based on your own experience in working with Crohn's disease patients. Those seem to be pretty universal markers of severe disease or the potential for disease to progress even further. So what potential clinical implications do you think these findings have for clinicians who are working with patients who have IBD? Dr. Ungaro, you want to start?

Dr Ungaro:

I think the immediate take home is that I think this study helps to validate the care pathway as a tool that can be very helpful in your day-to-day care, particularly for Crohn's disease. I think it still is valuable in ulcerative colitis, but I think it's harder to predict in ulcerative colitis, as we mentioned, who's going to have that aggressive disease course. So I think taking into account the factors that they identify as more this moment in time and how active the disease is right now as opposed to their overall history, maybe more applicable. But I think number 1 is that it is validating the Crohn's care pathway at AGA, and that clinicians can go and use that and have confidence that if you're looking at these risk factors, you can say patients who have 3 or more risk factors or have 1 of these particularly high risk features—history of fistula, strictures, perianal disease, or very young age onset—those are patients who need to be more worried about and be quicker to escalate therapy as opposed to taking a more classic step up approach or just monitoring approach.

And I think on the converse, the patients who have 0 or 1 of these risk factors, that's a patient that you maybe through shared decision making with the patient, can decide to monitor more closely and decide if you need to start therapy if their disease becomes more active.

Rebecca Mashaw:

Is this a classic case of the difference between disease activity and disease severity? That severity is more important in Crohn's and disease activity is more important in UC?

Dr Ungaro:

I think it's probably that they're both important; however, in Crohn's disease severity has given a larger role and partially because it seems like we just are able to predict a little bit better in Crohn's based on these data than we are in UC. And in UC I think the severity, I think it is more activity-driven, as you mentioned. And with severity, I think it still plays a role maybe in terms of your threshold and how frequently you'll be monitoring patients, but it's just that it's harder for us to hang our hat on things and with patients to say, this is definitely going to be a predictor for you based on this study, at least.

Rebecca Mashaw:

Dr Santiago, any last thoughts about what you learned through this study that you'd like to share in any plans for expanding the study and taking a harder look at UC?

Dr Santiago:

Yeah, so I'll start with the first part of the question. So one interesting thing that we did see when we were looking into the Crohn's disease individual risk factors is that the presence of prior IBD-related surgery or bowel resection related to Crohn's disease was actually in the opposite direction of leading to complications. So it was actually a protective, we might say, factor. And that's really interesting because we do have new studies just recently published about the utility of ileocolectomy in patients with early Crohn's disease. So we did find some cues that this might be true in this population.

Dr Ungaro:

Yeah, I think that's a great point and interesting finding that is a topic of a lot of interest now. And something that I think also, this prompted one of many studies that is prompting us to think maybe we're always trying to look to predict who is going to have a complicated disease course, but maybe we also need to compliment that with understanding the reverse or the other side of the coin: Who are the patients that are going to stay mild and do well? And maybe we need to also try to understand how we can predict that group similarly as predicting the patients who are going to get sicker or more likely to get sicker. So I think it's opening up some extra avenues now, I think for follow-up studies.

Rebecca Mashaw:

So having a previous surgery may not necessarily be a predictor if you're looking at that idea of surgery as a first-line treatment for patients with Crohn's disease, which has, as you said, has gotten a lot of attention recently. Anything else either one of you would like to share about this?

Dr Santiago:

I think that it's overall very interesting conclusions and we would definitely be interested in looking at bigger databases to have the same kind of research question asked and looked into other population databases to see if the same is true and if those risk factors are predictive or more disabling disease course as well.

Rebecca Mashaw:

Well, I really appreciate both of you spending your time with us today, and this is very interesting and we'll look forward to getting back with you if and when you decide to pursue this topic a little bit further. Thanks very much.

Dr Ungaro:

Thanks for having us.

Dr Santiago:

Yes, thank you for having us.