The Treat-To-Target Approach in IBD

Stephen Hanauer, MD: Once we get a patient improved, improvement in symptoms is not our ultimate goal of therapy. We’ve been talking over the past decade or two about treating-to-target strategies. What’s that mean to you?

Marla Dubinsky, MD: As you know, the target pendulum continues to swing very far. And I know, as usual, we’ll come back to the middle like we always do in IBD [inflammatory bowel disease], like with the combination/monotherapy story. We ended up somewhere a happy medium, in the middle. 

Stephen Hanauer, MD: Maybe you should explain that because everyone doesn’t really understand how with all of the biologics, combination therapy in the clinical trials with an immunosuppressive such as azathioprine didn’t make a difference. There was no difference with infliximab, with adalimumab, with ustekinumab, with vedolizumab. It didn’t matter if they were on an immunosuppressive. But you emphasize with the SONIC trial, when we look prospectively at naive patients, that’s where you can see the difference. I want to mention that there have been several network meta-analyses lately that have looked back with ustekinumab or vedolizumab in both ulcerative colitis [UC] and in Crohn disease that say, for instance, you don’t need mesalamine or you don’t need immunosuppressives. I don’t think that’s the answer. It’s a hypothesis of looking at subgroup analyses post-hoc, but I’m remarkably focused on SONIC, which is the difference between a post-hoc retrospective analysis vs looking at it prospectively.

Marla Dubinsky, MD: Yes, I remember your publication where you talked about that it didn’t have an effect on even antidrug antibodies, and we also note that in clinical trials, only about one-third of patients are on immunomodulators, maybe sometimes 45%. It’s not like SONIC where you were randomizing people.

Stephen Hanauer, MD: They were neither powered nor randomized to look at those differences. The world really does need to be aware of that as we evaluate these multiple network meta-analyses. They need to be looked at more as hypothesis generating than the truth. They are evidence and sometimes it’s the only evidence we have, but we do need to understand that they’re not necessarily the real truth in the matter for that. So, back to treat to target. What are your targets?

Marla Dubinsky, MD: I divide them up into short, medium, and long term. I’m going to give you my spectrum as I go through the journey with the patient. We know that when a patient is sitting in front of up, they’ve suffered, they want to feel better, and that’s their priority. And it is also our priority because we want people to get better quickly and get back to their lives, especially a patient with UC who’s having rectal bleeding, and urgency, and accidents. It’s very difficult. And for a patient with Crohn disease, it’s the same. If you’re in pain all the time, you’re tired, you need to get back to work. To me, that’s the urgency, to get them feeling better. And like you said, sometimes you need corticosteroids to make that happen until you get the authorization or until you get the TB [tuberculosis] test, whatever the delays are in the process. Short term, I tell them that we’re both on the same page. Medium, I’m a huge biomarker-obsessed person. I follow calprotectin crazily and CRP [C-reactive protein], and I have implemented the endoscopic healing index from Prometheus [Laboratories]. I do follow that, looking for change. It’s a sign for me that the bowel wall or the mucosa is getting better. I don’t expect perfection but….

Stephen Hanauer, MD: Let’s put some timelines into this, OK? Biomarkers, I agree with you. First and foremost, we’ve got to get the patient feeling better, and that’s, depending on how severe they are, within days, or certainly within short-term weeks. But after they’re feeling better, what’s next?

Marla Dubinsky, MD: I tell them I’m happy that they’re feeling better but that doesn’t always mean that their insides are better, which is what gets to the next concept of a more objectifying way, objectification of target is the way that I think about it. I don’t expect any huge change short term, as I noted. Then I’m looking for, and I’ll be honest, I do use fecal calprotectin. And some of the trials have shown that at 8 weeks, if you start to see a calprotectin level less than 250 [μg/g], that relates already to a better outcome after 8 weeks.

Stephen Hanauer, MD: Is that your first guidepost, about 8 weeks?

Marla Dubinsky, MD: I typically do it after induction. For ustekinumab it’s at 8 weeks; vedolizumab, it depends when I see them. I’ll tell them somewhere around 10 weeks, or if it needs to be 14, that’s fine. With anti-TNF [tumor necrosis factor] therapy it’s usually around 8 to 12 weeks. I am using it early on to look for a change.

Stephen Hanauer, MD: That’s a good question and point that you bring up. When does induction end?

Marla Dubinsky, MD: Induction ends when you go into remission. That’s my whole theory.

Stephen Hanauer, MD: Your definition of remission is?

Marla Dubinsky, MD: I’d like to see, again, in the more intermediate term, clinical [observation] plus a biomarker. I’m not expecting mucosal healing until I get into that 6 months to 12 months out from the start of therapy. Eight weeks to 6 months, and then 6 months to a year, that’s how I’m thinking, I’m progressing through my depth of remission or acceptance of it. I try to explain to patients why I’m linking biomarkers as a reflection of what’s going on in the inside. It may not correlate with your symptoms, and then say, therefore I need to look. Because, especially in patients with Crohn disease, we know from SONIC, another lesson learned, that about 50% of patients who say they’re feeling great, have ulcerations. And about 40% who say, “I don’t feel well,” have complete mucosal healing based on colonoscopy. There’s a huge disconnect. We know that in Crohn disease. With UC though, Steve, I have to say, I’m hoping you’ll agree that if you have rectal bleeding, that typically is a good surrogate for active inflammation, at least in the rectum.

Stephen Hanauer, MD: Do you need a calprotectin level in someone who’s still having rectal bleeding?

Marla Dubinsky, MD: I don’t think you need a calprotectin in someone who’s still having rectal bleeding. It’s like 10% of the time it doesn’t differentiate mucosa, but 9 out of 10 is a pretty good statistic for what we need to do. That’s how I think about the progression, my gradient of targets in terms of timeline.

Stephen Hanauer, MD: That’s relevant because in some of the recent phase 3 studies with both ustekinumab and vedolizumab, the patients who weren’t in response at the end of 8 weeks, when they had additional therapy for another 8 weeks, that captured at least 25% to 30% more patients over the second 8-week period, whether it’s after additional infusion or an additional injection in the setting of ustekinumab. The point there is, don’t give up too early on these therapies as long as the patients are having some sign of improvement.

Transcript Edited for Clarity