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In a single-center case series to evaluate the efficacy and safety of high-dose upadacitinib (Rinvoq) for the treatment of inpatients with acute severe ulcerative colitis (UC) or severe Crohn's disease, patients at high risk for failing first-line IV corticosteroids were offered off-label, high-intensity upadacitinib 30 mg twice daily in a shared decision-making process and according to a standardized inpatient protocol. The results of this study were presented during the recent Digestive Disease Week (DDW) conference.

In this third of four exclusive roundtable episodes, 名媛直播 brought together three expert leaders in the field -- moderator , of Baylor College of Medicine in Houston, is joined by , of Michigan Medicine in Ann Arbor, and , of the Yale School of Medicine in New Haven, Connecticut -- for a virtual roundtable discussion of this study.

Following is a transcript of their remarks:

Hou: All right, for our next abstract we'll be having Shirley discuss off-label high-intensity upadacitinib for hospitalized patients with a severe inflammatory bowel disease. Shirley?

Cohen-Mekelburg: So first I want to acknowledge that I am a co-author on this abstract. Managing hospitalized patients with inflammatory bowel disease is becoming more challenging as patients are exposed to a higher number of biologics and we are in need of medications that we can administer with rapid onset of action. Medical treatment failures with infliximab [Remicade] and cyclosporine in the inpatient setting do remain quite high. And so here we report our single center's real-world experience with high-dose upadacitinib, 30 mg twice a day for patients who were high risk for failing IV steroids.

This study was a case series. It included 13 patients who received upadacitinib 30 mg twice a day. Ten of the 13 patients had ulcerative colitis, and three of the 13 had Crohn's disease with perianal involvement. These patients were quite sick and most had been receiving prolonged steroids in an outpatient setting. A majority were also exposed to immune-targeted therapy in the past. And notably, over half of patients, I believe it was 61.5% avoided bowel surgery after the upadacitinib high-dose induction. And we did see improvements in C-reactive protein [CRP] and fecal calprotectin measurements.

As far as adverse effects, one patient did have a venous thromboembolism, and we did see several infections. One patient had COVID-19, one had bacteremia, there was a post-surgical infection, as well as a CMV [cytomegalovirus] Nocardia infection.

And mostly this work is really a proof of concept that patients do respond to high-dose upadacitinib with both CRP and fecal calprotectin improvements.

Gaidos: I think this was a great study and I applaud you for including the Crohn's disease patients prior to FDA approval, but really just forward thinking in that, like you said, they're not responding to steroids, they've already been on infliximab, we really don't have any other inpatient therapies that we can put our patients on. So we just tend to sort of drag out the steroids and cross our fingers and eventually just put them on TPN [total parenteral nutrition]. Because again, we don't have anything else. And so it's really nice to see new experiments, new research, testing out these therapies in the inpatient setting.

Just out of curiosity, what was the decision to use 30 mg twice daily as opposed to maybe a double induction dose of 45 mg?

Cohen-Mekelburg: It's a good question. So I think that decision was based on a few factors, but it was really an extrapolation from our tofacitinib [Xeljanz] inpatient experience where patients seem to do better on the tofacitinib TID [three times daily] dosing as compared to the standard dosing. And the idea behind that was that particularly in inpatients who have the most severe disease, that kind of having a more stable level is beneficial. And so that's, I believe, how that decision was made.

Another thing to note is that this wasn't upadacitinib as an alternative to steroids. It was concurrent with steroid use. So that's another thing to consider. And to me, one of the very interesting things as we move forward, and I think one thing that the JAK [Janus kinase] inhibitors in general are providing us with a good source for is, what is the best approach? Should upadacitinib in this acute setting be used the way we use steroids for induction with the idea of bridging to a different maintenance agent, let's say Entyvio [vedolizumab] or another drug? Or is this one of these things where we're putting patients on upadacitinib with the goal of long-term treatment?

And I've heard a lot of different ways that people are thinking about using it. And so I think it'll be interesting. What do you guys think? How have you guys been using it?

Gaidos: I've been using it as therapy because I feel like if it works, why try and switch them to something else that I'm not 100% sure is going to work? So to me it makes sense that if I get them on it and they respond, then I'd like to keep them on it. Particularly because a lot of patients would prefer to just take a pill every day than have to go in for infusion or give themselves an injection.

But also, looking at your dosing strategy, we sort of think about the tofacitinib as a 3-day therapy and if they haven't responded, then you kind of give up on it. But it looked like most of the patients in the study were on the upadacitinib high dose for about a week. So it seemed like you kind of just -- I don't know, did you have an endpoint? Were you saying, we want their fecal calprotectin to reach this level and then we know it's going to work or it's not going to work?

Cohen-Mekelburg: You know, I think since this was really like a proof of concept, a lot of it was iteration of the protocol as it was happening. And some of it, it was clinical decision making. Were patients doing better? What were patients' preferences? I believe some of the patients included, their preference was this over alternative options. So, really a heterogeneous group.

Hou: That's very exciting, Shirley. Obviously the JAK inhibitors have been really showing some nice early onset of action for some, we've seen some other studies.

I think one thing that's interesting about this, and I understand this is proof of concept, it's not a clean study, but the average duration of steroids in these patients was 70 days. A big standard deviation, 100 days. So there's a big spectrum of patients of how long they're on steroids. But it makes me think that these may not be quite, I mean, were these the true acute, severe UC patients? Some of these may be just really sick, obviously for a while coming up and how we treat those patients, how we expect them to respond may be a little different. I'm curious about, again, if you think this was truly representative, what we think of these acute inpatient severe UC patients or what the nuance might be, especially in the setting of using this high off-label dose.

Cohen-Mekelburg: I mean, it's a good question. I think that these are clearly very sick patients. As we've seen in other studies, prolonged steroid use is not uncommon, unfortunately. And so, if anything, that just demonstrates the need for new therapies that are going to be steroid sparing.

Again, I think this was a combination. It was patients who we felt were going to fail steroids alone for various reasons, whether it was really high CRP, whether it was their prior experience with biologics, whether it was their albumin. And I believe that a decision was made on a patient-by-patient basis and it was really shared decision making with the patients in this case.

Jeff Berinstein and Peter Higgins are really leading this work. And, I know that, since this abstract, they have collected a higher number of patients. And so hopefully that will provide a little bit more information and allow us to kind of look at different approaches for different types of patients.

Hou: I guess one more question for conversation is, or discussion is, how would you take a patient coming in the door now that UPA [upadacitinib] is approved for both Crohn's and UC, if you would try a standard dose of induction versus this twice-a-day, higher-dose induction?

Cohen-Mekelburg: I think that's a great question. I don't know if there is an actual answer to this yet. I think some of it is about a game of probabilities, right? Like, if someone comes in with all the clear criteria where you think the chance of this person succeeding on steroids alone, someone who's, let's say, been on high-dose steroids for a month with a low albumin. ... Is someone ready for surgery or not?

Gaidos: I think, too, it's also timing. I mean, could we start with standard dosing? And if they don't respond, then go up to sort of an accelerated dosing for those who are really sick, with the plan to eventually go back to standard dosing. But again, as these drugs come out of the market and we get the opportunity to play with them a little bit and see what our patients need, I mean, obviously the elephant in the room is the insurance coverage and what we can actually get paid for. So that's the other point here too, being able to sort of optimize boosting in a lot of our patients.

Cohen-Mekelburg: Sure. And I mean, everything has its risk and benefits. So, for me, as far as thinking about long-term maintenance for some patients, I think the barriers that come up are women of childbearing age. Are we comfortable with upadacitinib in those patients who could become pregnant? Obviously, folks who are really high risk for infections, and especially with zoster.

So, to me, those are the kinds of reasons that have come about, kind of on a case-by-case basis, to wonder could you induce somebody and switch them to vedolizumab or ustekinumab [Stelara] for example. But again, I think just the existence of these drugs that have a rapid onset of action really provides a lot of interesting opportunities to think about the approach.

Hou: Gone are the days of cyclosporine, perhaps.

One other thing, interestingly, you made a comment about this as well, is we typically when we're thinking of the high-dose TNF [tumor necrosis factor] infliximab, again, everyone quotes the Michigan protocol for that as well, albumin makes a lot of sense about why that albumin could be a predictor of low response. But I guess for the small molecules, does it make quite as much sense that it would be a reason to use a high dose? Obviously we're not worried about the protein binding to the same extent, we're not worried quite as much about losing it in the gut.

So I guess it'll be an interesting question. I know you don't have the answer to that, Shirley, but we're all directing the questions to you as if you know all the behind-the-scenes answers and the what's to come.

Cohen-Mekelburg: To give credit where it's due, I was a co-author on this, but this is really the work of Peter Higgins and Jeff Berinstein. And so I know that they've been really thinking about this day-to-day. And so I think interesting things to come.

Hou: Very interesting. So to summarize this interesting abstract, significant limitations is a single-center, 13 patients, really proof-of-concept abstract. But as you can tell from this conversation, this sparks a lot of clinical interest highlighting the big clinical need we have for these very sick UC and Crohn's patients who are in the hospital.

Again, some limitations. These patients have probably been sick for a bit and many of these patients were on steroids for a long time. But there were still some fairly significant changes, some dramatic drops in CRP and calprotectin in this population. Still a lot to be seen in terms of which patients can be started in this setting on a standard-dose JAK inhibitor versus at least considering an off-label higher dose as was used here.

So a lot of interesting conversation and a lot more excitement to see in this population to come. Thank you for the discussion.

Watch episode one: Reaction to FDA's Approval of Upadacitinib for Crohn's Disease

Watch episode two: Risankizumab Safe in Older Crohn's Disease Patients

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