Miguel Regueiro, MD: David, I'll ask you the same question about switching. Bill mentioned using the therapeutic drug levels in terms of switching within class and switching out of class. Touch on that, and then specifically if you do switch to a second agent that's not an anti-TNF [tumor necrosis factor], Bill alluded to that, but to pin that down, what do you choose next for ulcerative colitis [UC], and what do you choose next for Crohn disease?
David T. Rubin, MD: First of all, I agree with everything Bill said, so I'll try to build on it. When a patient is on a therapy and they've lost response or even for our primary nonresponders, the question you have to ask this: is this a delivery or exposure/dose issue, or is this a mechanism issue? If you can sort that out, in some cases, it'll guide you as to whether you should stay within class in TNFs where we have options or whether you should be moving to a different mechanism. There are some considerations there.
My bias though is that if somebody is a primary nonresponder to IV [intravenous] infliximab, going to an injectable anti-TNF doesn't make good sense. I believe that that's reasonable. We have options.
I agree with the general comments that if somebody has failed TNF, whether they responded and lost or whether they never responded, with Crohn disease, I tend to favor ustekinumab, but vedolizumab for luminally active Crohn disease is completely reasonable. For both, I haven't been as impressed for perianal disease, and we have to be extra careful there. With UC, I'm happy with our options. I tend to go to tofacitinib if I have a patient with more severe disease. This is my bias. They may be clearing drug due to leakage or a heavy disease intensity where there's a lot of inflammation, and I might want to try to get to a different delivery of a small molecule and a predictable PK [pharmacokinetic] profile.
I'll add a couple of other things. When a patient with Crohn disease goes through their therapy and then ultimately needs surgery, you have to ask yourself whether they failed that therapy because it didn't work or because it was given too late. After surgery, as you know, Miguel, because you're one of the world's experts on this, you can take a step back and go to a therapy that might not have worked preoperatively. We have to remember that sometimes we're resetting the clock not just on the disease but also on the option of going to the therapy.
Similarly, I want to bring up the possibility that, and this is theoretical but in my experience we've had some good results, in a patient who loses response to a TNF, you swap to a different mechanism. They may do well with that for a while, but then they lose response to that one. As long as it wasn't due to immunogenicity when they lost response to the TNF, in cases where we don't have good other options, I've cycled back to the TNF and reloaded very carefully. We check drug level and look for antibodies early in that phase to see if we can't go back under the premise that maybe we're just tamping down one inflammatory pathway at a time and they become reactivated when we go to a different one.
There are some new concepts here that are emerging that will help us in the future. I completely agree with everything else Bill said about protecting your patient from recurring to immunogenicity.
William J. Sandborn, MD: David, what about combinations of biologics? Are you doing that, and what's the logic?
David T. Rubin, MD: There's a nice series now published from your center, [the University of California San Diego], with [the University of] Calgary. That's in AP&T [Alimentary Pharmacology and Therapeutics] that looked at your experience with that. I might throw it back at you, but I'll say that with patients who have more than 1 diagnosis, that's sometimes the easiest way to approach this challenge, which is that maybe they have IBD [inflammatory bowel disease] and they also have RA [rheumatoid arthritis], and we're trying to use vedolizumab for their bowel, but added a JAK [Janus kinase] inhibitor for their joints. We have to be thoughtful about whether this makes sense, rather than just stacking 1 treatment on top of the other and think carefully about safety. You can share with us your experience with this, too.
Miguel Regueiro, MD: Bill, I'm going to let you do that in the last segment because they're on the unmet needs. Maybe you can bring up the unmet need will be a combination biologic.
William J. Sandborn, MD: David did make 1 comment that I totally agree with, which is that, after surgery, you can rethink what you failed. There's another place where you have severe pancolitis, either Crohn disease or ulcerative colitis, and get a colectomy or subtotal colectomy, and then in Crohn disease maybe you end up with subtotal colectomy, Hartmann pouch, ileostomy, everything cools off, and they just unequivocally failed infliximab, for instance. If they haven't been immunized and you're going to go back and do an ileorectal anastomosis, those patients were probably failing for high clearance and disease burden, and we've had good luck with going back to the drug that they just failed in the post-operative setting, and they often do fine.
Then in ulcerative colitis, you do a pouch. Then there's a subset of patients who get Crohn disease of the pouch, having had a colectomy for ulcerative colitis, and you can go back to the drugs they failed, and they often work.
Miguel Regueiro, MD: It's interesting to note. Is it a sync? Is it a reset? Is there something that's going on? All good points.
William J. Sandborn, MD: I don't know the answer, but I know it sometimes works in a hard spot.
Transcript Edited for Clarity