Treating IBD: Induction Vs Maintenance and Combination Therapies

Stephen Hanauer, MD: When we started to write and develop guidelines for therapy for both ulcerative colitis [UC] and Crohn disease, we talked more about induction and then maintenance therapy. And while infliximab was being developed in rheumatoid arthritis, the rheumatologist didn’t look at it that way. They looked at a treat-through approach. Whereas we took patients in the studies with the biologics and looked at induction, and in the patients who had improvement, the responders, we moved them on into maintenance therapy. Is it any different in your practice now?

Marla Dubinsky, MD: There’s an urgency in pediatrics, and obviously safety does come into discussion because of the black box warning and the safety around the use of an anti-TNF [tumor necrosis factor] medication, I’ll use as an example, and its role in malignancies such as hepatosplenic T-cell lymphoma. That obviously is front and center no matter what conversation I’m having, or no matter who I’m talking to. That is front and center. A lot of it does come down to, as you noted, we have different views on combination therapy vs monotherapy, and most of it is driven by risk of malignancy. Kids are not getting more infections than adults. It comes down to, is there a better way to use, I’ll use anti-TNF, because that’s the one I would use, and we’ve discussed using combination therapy. We know based on the SONIC trial, combination therapy did do better than monotherapy TNF. There’s not even a debate.

Where the debate started to come in is that, if we would be able to optimize the dosing and use pharmacokinetics [PK] in those who might be more harmed by using a combination, and this would be a younger age group. Males maybe in particular, since that’s where the bulk of the cases were of hepatosplenic T-cell lymphoma, the role of even hemophagocytic lymphohistiocytosis in EBV [Epstein-Barr virus]-naïve patients, which more children will be EBV naïve. There’s a reason why we see things differently, and we want to use the biologics just like we would in someone who is older. It’s just a matter of, do we use it more as monotherapy? That’s where maybe there’s a separation based on age and whether treating a pediatric patient vs an adult patient.

Stephen Hanauer, MD: When you’re initiating treatment for patients who fall into the moderate to severe category, you’re looking to rapidly improve their symptoms, and then maintain it on a long-term basis. Maintain that improvement over time. Do the therapeutic options we have between steroids and immunosuppressants or TNFs, or the different mechanisms, does that impact your approach—induction then maintenance—or are you just thinking, I’ve got to get them controlled?

Marla Dubinsky, MD: Yes, you’ve taught us and spoken a lot about, whatever gets you into remission will keep you in remission. That’s in the absence of having all these new targets. Let’s put it in the context that we’re not going to have all these fancy new therapies that maybe we’ll be able to use in combination. The way I think about IBD [inflammatory bowel disease] now, as we’re starting to see small molecules permeate the market and will be for Crohn disease, as well as we have with tofacitinib in UC. But I need to get a rapid anti-inflammatory, you want a more broad-based immune anti-inflammatory effect, get them in the deepest remission you can, and then choose the therapy that’s going to keep them there for the long haul. 

The question is, when is it a sprint and when is it a marathon? That does come into play based on the different treatments because even in Crohn disease, when you look at all biologic-naïve patients and you line up the TNFs vs vedolizumab vs ustekinumab, infliximab had the best outcomes when it came to induction of remission. However, in maintenance if you look at week 52, adalimumab crept up as being more effective. Why? Because there were fewer issues with dosing and PK, let’s say, than we had with infliximab in the dosing in your trial, ACCENT. In that study, it wasn’t like we were going to every 4-week infliximab or we were going up on dosing. You could go up to 10 mg/kg if you failed 5, but that was at 8 weeks. There was no interval change, we weren’t using it the way we are now. You have to say, at least this is my opinion, I want to know what therapy is going to get my patient quick and deep and effective response, and then what’s the safest and most durable way to keep them there? I think how we do it now is going to be different than how we’re going to do it in the future. I have a vision that we’re going to be using more small molecule type, and go with a wider anti-inflammatory or an anti-TNF, which also has a wide anti-inflammatory effect. And then using a more targeted, laser missile approach, with safety being predominate. Whatever therapy we’re going to use in maintenance, we also want it to have the best safety profiles. That’s the way I’m thinking when I’m choosing therapy.

Stephen Hanauer, MD: You need a fast, effective response, and a safe long-term response. 

Transcript Edited for Clarity