In this video, Dr Dubinsky discusses how to use the professional society guidelines as a framework for choosing therapeutics for patients with ulcerative colitis, while considering each patient's individual characteristics and preferences.

Marla Dubinsky, MD, is chief of pediatric gastroenterology and nutrition and codirector of the Susan and Leonard Feinstein IBD Center at the Icahn School of Medicine at Mount Sinai in New York.

TRANSCRIPT

Hello, I'm Dr. Marla Dubinsky. I'm delighted to be reviewing my talk that I gave this year at the ACG postgraduate course entitled "Positioning of Therapies in Ulcerative Colitis."

What I wanted to highlight this year was really the idea that we need to start thinking about, when a patient presents to us, what is the therapy we're going to choose first in the management of this patient? If that therapy doesn't work, what should I use second, and what is the data to support my therapeutic choices?

I actually first started by highlighting what are the fundamental issues we need to think about when we're choosing therapies in ulcerative colitis. I wanted to highlight that I do believe that we need to move towards therapeutic choices, not just based on how a patient is presenting to you today—meaning how many bowels moves they're having, whether they have rectal bleeding, whether they have abdominal pain. Very symptom-based, what we call disease activity-driving therapeutic choices, as compared to the concept of disease severity.

Before I started talking about updates and therapies, I really wanted to frame the fact that we should be thinking about therapeutic choices based on the longitudinal history, or what happened in the patient's history before they actually arrived and sitting in your clinic, and whether or not they actually have any prognostic factors which elevates their risk to say, "This patient is at high risk of colectomy," for example—meaning we're taking the totality of the course of this patient, both where they've come from and predictors of the natural history, and trying to decide whether or not where we should start our therapy. Should we start with patients with 5-ASAs, steroids, and then maybe waiting for them to declare steroid-dependent?

Then moving up maybe to an immunomodulator. Or should we just start classifying and segmenting patients into how much of a risk they are for bad prognosis and matching our therapeutic choice for going this step-up concept and more going directly to perhaps a biologic or a small molecule, making a more effective intervention early on in the course of the disease?

One reason why I was excited about both highlighting the ACG 2019 guidelines and the AGA 2020 guidelines is they both made reference to the concept that we should use predictors or disease severity markers in addition to, for example, their endoscopic score, integrating urgency into a patient-reported outcome that may declare severity, adding fecal biomarkers such as calprotectin to help declare whether the patient is active and/or at risk of not responding or responding to therapies.

I really enjoyed the fact that the authors of the ACG guidance in 2019 did implement and start to educate around the role of prognosis and matching therapies to risk. What's interesting is in the AGA guidance, they also made reference to that, which was also a great thing to see.

I do want to highlight a few differences between the ACG 2019 guideline and the AGA 2020 guideline in that they both focused on moderate to severely active UC. However, the ACG guidance also added guidelines as it related to mild to moderate.

I'm not going to focus on the mild to moderate guidance, because I do want to talk about the differences in the moderate to severely active ulcerative colitis patient guidance.

In 2019, the ACG guidance noted that, for example, tofacitinib, which at that time was approved for use in bionaive patients can be used in bionaive patients based on the label, which suggested that it was effective, approved for, and indicated for moderate to severely active ulcerative colitis.

There was no ustekinumab approval for the 2019 guidelines. That's where we change and look at what the 2020 guidance showed that the '19 didn't. That was really the fact that there was a label change for tofacitinib, in that the label was changed to be approved for patients who have failed or intolerant to anti-TNF therapies.

The other label change for us to use lowest effective dose after induction with 10 milligrams PO BID, was to try and deescalate to 5 milligrams PO BID, and to see whether or not you can actually maintain a state of remission on the lower dose.

The reason for that was really driven by safety, a couple of key safety parameters to watch for. One is that the rates of herpes zoster were indeed elevated in patients on 10 milligrams PO BID, prolonged exposure. That was one of them, but that wasn't what drove the label change.

It was really driven by the risk of thromboembolic disease noted in patients with rheumatoid arthritis above of the age of 50 who are also on concomitant methotrexate and had at least one, what we call, MACE risk factor, or one cardiac risk factor.

One goal was to see whether or not there are increased risk cardiovascular events in patients with rheumatoid arthritis exposed to tofacitinib 10 milligrams PO BID instead of the approved dose of 5 milligrams PO BID.

What I do want to highlight is, in the actual ulcerative colitis program using 10 milligrams PO BID, there actually were only four cases out as you follow out in the long-term extension safety review of the program, and there were only four cases of venothromboembolic events in that UC program, which is a rate that's very different from the rheumatoid arthritis program.

For now, this is where we stand until we get more data as it relates to the risk of staying on 10 milligrams PO BID after induction or in patients who've had prolonged exposure to the higher dose. There was at UEGW the RIVETING study, which is actually part of a postmarketing commitment from Pfizer to look at deescalating patients from 10 milligrams PO BID to 5 to see if they were able to maintain their remission at the end of a year of being on 10 milligrams PO BID.

I think that data will shed some light on whether or not what is the correct long-term dose with tofacitinib. Now, the other change was that, as I noted, ustekinumab was not approved in 2019, but was in the AGA guidelines with regards to both ustekinumab as induction and as a maintenance therapy for ulcerative colitis.

One of the other key points that I did highlight is that I do believe that sequence of therapies matters. I really made a point of us understanding how patients would get from, if they failed one therapy, what does the second therapy look like? That's what I mean by sequencing.

I really framed it against what happens when a patient is failing anti-TNF therapy, specifically infliximab, for example. Every study, both in adalimumab, in vedolizumab... particularly adalimumab, obviously, it was infliximab failure. With vedolizumab, it was both infliximab and/or adalimumab failure.

Then for the tofacitinib trial, it was also either adalimumab or infliximab failure. Then with ustekinumab, the term changed to biologic failure, because there could have been failure to both anti-TNF or vedolizumab.

Again, it frames what I use next after a patient presents, and I'm going to stick with anti-TNF failure. These are the key things to remember. That based on the clinical trial, the induction data for vedolizumab does appear to be less effective in patients who were exposed to TNF or failed TNF than those who were naive to TNF.

Secondly, when it came to tofacitinib or ustekinumab, it does not look like prior exposure to an anti-TNF — and in the case of ustekinumab, more than anti-TNF failure, the biologic failure —it actually did not impact the induction outcomes, suggesting that, if you had a patient with anti-TNF, who had failed anti-TNF, it does appear that tofacitinib and/or ustekinumab were actually superior to vedolizumab, or adalimumab, or golimumab, to be fair, in patients who were anti-TNF-exposed.

I think we need to start thinking about and understanding that sequence does matter. One thing I do want to leave you with as well is that there was a study that looked at what do patients most prioritize as importance when choosing therapies, and how does that compare to what physicians actually view as important?

One thing that both patients and physicians did indeed agree upon, that was that we both agreed that patients at a year from starting of therapy should have a significant benefit. That is where we were both aligned.

Then things started to change, because the second-most important thing that patients noted that they wanted to prioritize in their choice of treatment was actually malignancy risk. The physicians were not as concerned about 5-year malignancy risks when making treatment decisions.

I found that interesting that we're both focused on the efficacy outcomes, but things start to separate when it comes to priorities as it relates to the next level or layer of decision-making that comes into play. I think, if we can help address for patients their concerns about safety while emphasizing we're both aligned on the efficacy outcome, and then integrate special circumstances...

For example, guidelines are great as a starting point, but then you have the patient sitting in front of you who wants to get pregnant, who has extraintestinal manifestations, who's had a psoriasiform rash to anti-TNF, who has prior history of malignancy above the age of 60, then things really start to change.

Your guidelines don't take into consideration all of these different segments of patients. I'd like to conclude that I do believe that the guidance has elevated our ability to understand where treatments fall in. Then some of the network meta-analysis data suggests that we should start thinking about how we actually frame our therapies and sequence our therapies.

We cannot forget special populations and really what the patients are most concerned about. If we can elevate both our games and understanding what goes into decision on treatment, I think we will forever change the lives of patients as we think about positioning therapies in patients with IBD, particularly ulcerative colitis. Thank you for your time.