IBD Drive Time: Dr Corey Siegel on Acute Severe Ulcerative Colitis

IBD Drive Time host Raymond Cross, MD, talks with Dr Corey Siegel about caring for patients with acute severe ulcerative colitis in the hospital and after discharge.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore, Maryland. Corey Siegel, MD, is a professor of medicine at Geisel School of Medicine at Dartmouth University and section chief of gastroenterology and hepatology at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

TRANSCRIPT:

Raymond Cross:

Welcome everyone to IBD Drive Time. I'm Raymond Cross from University of Maryland School of Medicine, and I'm delighted to have my friend and colleague, Corey Siegel from Dartmouth here today to talk about acute severe ulcerative colitis. Corey, welcome to IBD Drive Time.

Corey Siegel:

Thanks, Ray. Thanks for having me.

Raymond Cross:

So let's jump in. So, Corey, to me, these are our sickest patients that we see in practice, the ones with acute severe colitis in the hospital. So, we're going to touch on meds in a bit, but can you just summarize for our listeners the basic tenets of management of these patients?

Corey Siegel:

Yeah, sure, Ray. Thanks. You're right. These are our sickest patients. I mean, these are the patients that can really get into trouble very, very quickly. So, I think the first tenet I think about is they need a careful watch. These aren't patients that you round on once and wait until the medicine team calls you. These are patients that you really have to have higher on your radar and keep a very careful watch and make sure we don't hurt them. There are a lot of things we do in the hospital where they have pain, so we give them pain medications, which can make things worse. So, careful watch, don't hurt them, and make sure you're treating the right thing. Just because somebody has ulcerative colitis doesn't mean they can't have something else. An infection such as C. Diff, or really any GI infection, could also mimic acute severe UC. And treating the wrong thing is always going to get us in the wrong direction.

And then the parts that I also tell our trainees, and every time a patient comes in, is let's not forget about other complications that happen to people when they're in the hospital, like DVTs. And it's easily forgotten; not to want to anticoagulate somebody who has rectal bleeding, but we know it's the right thing to do in almost all circumstances. And then the last part is surgery's not a failure, it might be a great treatment. And getting your surgeons involved really early, even if they don't need surgery, get them involved so they're not meeting them when crisis occurs, but they at least know who they are and they've had the conversation.

Raymond Cross:

Yeah, I agree completely, Corey. And the only thing I'll add is I was just reviewing a case last week and it was frustrating reviewing the case that the team wasn't quantitating the bowel movement frequency, weren't giving you an idea of the severity of bleeding, they weren't doing follow up CRPs. So, for the listeners, it's really important to quantify what's happening with your patient, because otherwise how do you know that they're better? I mean, you can just say, "Do you feel better?" But that's not very specific.

Corey Siegel:

I agree completely.

Raymond Cross:

So, in the real world, all of these patients are going to be treated with intravenous steroids, and it's going to be very rare, and maybe we could touch on it at some point, when you would just skip steroids and go to a more effective agent potentially? But, so, what dose do you use, Corey? How often do you give it? And I think most importantly, how long do you wait for it to work?

Corey Siegel:

Yeah, it's funny, when you start looking at the guidelines, you immediately see discrepancies of what recommendations are. A project that I did over this past year, that you were part of as well with Parambir Dulai, trying to define what the right things to do. We did this RAND Appropriateness Panel, which is a panel of specialists really trying to determine what's most appropriate, even when we don't have great data to prove it.

And what we, together, agreed on is there are a couple options that will probably work, and that's why you see guidelines that are a little bit different, somewhere between 40 to 60 milligrams of methylprednisolone, and then 60 milligrams of methylprednisolone is equal to 300 milligrams of hydrocortisone. So methylprednisolone you give once a day, and hydrocortisone, you can do it a couple of different ways, here we do it 100 milligrams TID, and some patients who have a harder time tolerating those doses, you can give a little bit lower dose. But, that's our typical treatment dose. Lots of people for a while have looked at how long does it take to turn around, and really by day 3 is when you should start seeing something happen. And if they're completely not responding by day 3, you need to do something differently. Practically speaking, you might give it another day or two if they're starting to move in the right direction. But after 3, 4, 5 days, you're not getting many more people who turn around all of a sudden, and by day 3 is when we start planning our next move.

Raymond Cross:

I think that's really important. So, it's not 120 milligrams of methylprednisolone for 10 days. So, it's a lower dose, shorter period of time. And if they're not getting better, move on. For those that do get better, Corey, and you're transitioning them, you're prepping them to go back into the ambulatory setting. What dose are you typically giving them at the time of discharge?

Corey Siegel:

Yeah, it's a really good question, and we also had talked about this as this group, because if all it takes is a savvy medical student when you're discharging them on 40 milligrams of prednisone, which is our typical dose to say, "Wait a minute, you just gave 300 milligrams of hydrocortisone, or 60 of methylprednisolone and that's equal to 75 milligrams of prednisone," to think, "What are we doing here?" But you and I both know that after 40 milligrams, absorption doesn't really get you much more benefit; besides, you get more side effects.

So, while there are some people where I might give 60 milligrams to who really required high doses of steroids to turn around, typically it's 40 milligrams. But, you have to keep in mind that you just drop them, essentially, equivalent of 25 milligrams of steroid. So, we typically watch people for a day in the hospital to make sure that it'll bounce back in the wrong direction. You wouldn't be surprised if you dropped somebody from an equivalent of 75 to 40, and you get a call the next day that they're flaring again or their symptoms came right back because it really was a big drop off. Most people do fine with that transition once you got them better. But, 40 is typically where we start.

Raymond Cross:

And then it's a perfect segue, Corey, speaking of got them better. So, what is the Corey Siegel discharge criteria? I'm making an assumption that you're not using any of the indices for this, but maybe you are, but what are your criteria for transitioning to oral prednisone and letting them go home?

Corey Siegel:

Yeah, I mean, rectal bleeding's the first thing to watch for, and when bleeding goes away, you know you're on the right track. A little bit of bleeding might be okay, but if patients come in with significant bleeding and that hasn't gotten better, they're not ready. But once the rectal bleeding's gone, you can really start thinking about discharge. Now in an ideal world, they're having normal form stools back to baseline, but practically speaking, that doesn't always happen. We're all pushed and getting patients discharged from the hospital sooner, so, keeping them there for 7 or 10 days to watch things slowly get better becomes less realistic. So, in my mind, rectal bleeding gone, or mostly gone, and stool frequency getting better, or at least returning to baseline. I don't think you need, again, perfect form stools, but you need to see that the frequency's really gone down tremendously, and the bleedings at least mostly resolved.

Raymond Cross:

So, the Siegel rule is the same as the Cross rule. So, I'm looking for 5 stools or less, and trace to no blood. So, it sounds like we're almost perfectly aligned there. Assuming that it's abnormal at baseline, do you use CRP to help guide your decision making?

Corey Siegel:

You know, I do. I find we overrely on the quantitative value of CRP. Many of these patients come in with a CRP over 100 and then the next day it's at 50 and then the next day it's at 25, which as an outpatient, we'd still be worried about that. So, I don't know that I need complete resolution back to normal CRP, but going in the right direction, in the appropriate setting that their symptoms are better, is a useful adjunct. But, I think CRP alone doesn't get you there. And as you know, not everybody makes CRP. We have some patients come in really, really flaring with relatively normal or marginally elevated CRP.

Raymond Cross:

Right. And we chatted a little about this before the call. C. diff, and we could have an entire episode or 2 episodes on C. diff. But just really quickly, you do your GI PCR profile, or whatever you're doing at your institution, and the patient comes back positive for C. diff on the PCR, I don't know if they're doing reflex toxin testing or whatnot, but let's just say that's what you have. How long do you give vancomycin before you move on and say, "Okay, I think this is a sign of a sick colon, not active infection, now I'm going to escalate therapy." Do you have a rule of thumb for that?

Corey Siegel:

It really varies, and what often happens is they've already started on steroids on admission and that C. diff test might come back later that day or might come back the next day. It's always interesting to me when it comes back positive and just IV steroids got them significantly better, despite the teaching that staying away from steroids is the best thing while treating with antibiotics, whichever one you know choose.

So, I give it, really, just a couple days, I mean probably 2 days to see them turning around. Biologics, we've learned together as a field, are probably okay and the right thing to do to treat this. My thought on C. diff is it's rarely the only thing going on, it's C. diff on top of an inflamed colon. And in fact, I would imagine, C. diff causes more inflammation on top of their existing inflammation so that we often need to treat both. I mean, we just had a patient in the hospital who really wasn't turning around despite the fact that we thought we were treating their C. diff adequately, and gave steroids, although we always worry about this a little, and they got better in a day or 2. So, I think you have to play it very careful with steroids, give it a short period of time with antibiotics, don't hesitate to give biologics concomitantly with it, but sometimes you need to treat the peri-inflammatory process, and steroids settles that down.

Raymond Cross:

Yeah, you summarize that really beautifully, and I think we've been taught when someone with colitis is flaring, you look for infection, you either let the infection run its course or you treat the infection, they get better. So, you find something reversible, it's not to flare. But with these inpatients, it's rare, rare that you find C. Diff, start treatment, and everything just turns around. You're exactly right, it's almost always more than one thing that's going on at the same time.

Corey Siegel:

Yeah, yeah, I agree.

Raymond Cross:

All right. So, before I ask, Corey, a few more questions, I just want to remind our listeners that we are sponsored by the Gastroenterology Learning Network, and Advances in IBD, and the national in-person meeting is coming up in Orlando, Florida from December 5th to December 7th. Corey and I will both be there speaking, so, please, there's plenty of time to register and attend. So, let's talk now, Corey, about the patients that are not responding to steroids. And it's going to be nuanced, it's going to depend on what the patient's been on before, so, are you an infliximab person, are you a cyclosporine person, and if you're infliximab, are you a standard dose or elevated dose person?

Corey Siegel:

Definitely an infliximab person. Not that cyclosporine doesn't work, it's just the safety threshold is so much wider with infliximab and honestly, ease of use is so much more. So, although we occasionally have used cyclosporine, we don't use it too much. Infliximab, I feel like if you're going to use it, just use it. And I tell our trainees, if you're getting up to bat, you may as well take a full swing. So, I go right to a high dose at 10 milligrams per kilogram, and if they're not responding within a few days, or they have a minimal response, I might even give another dose a few days later. And we've all had the opportunity to check drug levels, or drug concentrations, even a few days after a big dose, and they can be zero or close to zero because so much is leaking out into the stool through essentially a colopathy, a protein wasting colopathy, with these low albumins. But, also they're metabolizing the drug very, very quickly. So, it doesn't mean they're always going to need 10 milligrams per kilogram, but to settle them down, they sometimes really require high doses, and sometimes repeated doses at that high dose.

Raymond Cross:

So, this is really interesting, Corey, at our institution, our infliximab use was being tracked, and they noticed that we were giving higher doses. So, they came to us and wanting to look at it from a quality, and perhaps a research, perspective. And I was surprised what we found, we found that our patients that got to lower dose did just as well as the higher dose, and there could be, of course, inherent confounding there. So, I've actually moved away from the high dose. But then what I've started to do, and again, I don't know if this is right, there is one study supporting giving the 3 doses in a shorter window. What I do is then I ignore the dose I gave in the hospital, try to get the next dose as an outpatient as soon as possible, and then start the 0-2-6 again. So, I'm getting those 3 doses within hopefully a 14- or a 21-day period. And that seems to be okay, but again, that's just anecdotal. And everyone I think does it a little differently.

Corey Siegel:

Yeah, I think so. I mean I've certainly thought about that, as well, and there are real cost implications. I don't think there's safety implications of giving 10 over 5. So, my belief has been there might be increased cost here, I hope that it will decrease their length of hospitalization and chance of response. But you're right, we don't really know the answer to this and it's something that we still have some room to learn, for sure.

Raymond Cross:

So, I think something we're all facing now is we have more and more weapons to treat colitis, which is great as a provider, but for most of these agents, we know that when you go from the first to the second to the third, that the chances of the next medication working are less and less and less. But, patients know that they have more options and so they're often more reluctant to go to surgery. So, when a patient doesn't respond to infliximab in the hospital, what are you doing there? I really don't like stacking immune suppression and then trying to give cyclosporine on top of just having given infliximab. So, what are you telling those patients? What's your approach there?

Corey Siegel:

Yeah, this is a tricky group and as you started with on the last question, it all depends on what they've been exposed to before, and what their thinking is. Hopefully, we've already had the patient seen by surgery, so that it's not a surprise to say, "Whoops, that didn't work. Now we need an operation." So, I think the context is we're going to try to push this through and you might need an operation. Giving more infliximab is usually my first go-to, and I realize you're trying to get me to push beyond infliximab, but we've given even higher doses than 10 milligrams per kilogram to try to get them to turn around, and some people do, they simply need higher doses. Again, their drug levels are usually close to zero in this setting when you check it in their blood. I, also, don't love the idea of giving cyclosporine afterwards, but short-acting other oral drugs might work.

And there's some emerging data, I'll say case series, and we have a lot to learn here about using the JAK inhibitors in the urgent setting. I am not a huge proponent of using these without a really carefully managed research beforehand, to understand not just the benefits of it, but the safety. But, we've used tofacitinib and upadacitinib. It does concern me stacking on top, but again, they're effective drug concentrations are often close to zero when infliximab's not working. So, I think it's reasonable to do it. In that case, we would either withdraw or turn down their steroids to really try to improve safety.

But you don't have a ton of options. We've used oral tacrolimus in some of these patients, but again, these are patients who are now being seen every day by the surgeons, and really thinking carefully about surgery. And I think we all have to remember, I said this early, but as a reminder, surgery might feel like a failure at the time, but you know, you rarely regret it with these inpatients, and are usually thanking yourself that you really help the patient make this decision, because these are patients who can get incredibly sick and patients who die these days with inflammatory bowel disease are patients with acute severe ulcerative colitis, if we don't do the right thing in time.

Raymond Cross:

Yeah, I completely agree. And I'm perhaps the bad cop in this scenario with patients, when you're going to go with infliximab or cyclosporine or if you're going to do off-label use of a JAK/STAT inhibitor, I set the stage for the patient and tell them like, "Listen, this is what we're going to try and I want you to start mentally preparing for if this doesn't work, surgery is the next best option." And then you're really a shared decision-making person and someone who's just absolutely refusing, in that situation, I'll break down and I'll try to give them a second agent. But I do try to set the stage that we're going to try one thing and not wait 14 days and have you get sicker and sicker and sicker before surgery. So, tell the listeners about hyperbaric oxygen, Corey. So, not everyone has this where their practice setting is, but you and I do in our practices and we can utilize it. So, tell them a little bit about using hyperbaric oxygen for severe colitis.

Corey Siegel:

Yeah, so this was a hypothesis just about a decade ago. I mentioned Parambir Dulai earlier where he was a resident with me here and we worked together with one of our hyperbaric physicians named Jay Buckey, and we thought there is some data to support the fact that giving hyperbaric oxygen would shut down the inflammatory cycle that happens with ulcerative colitis. And we performed a small pilot study, that was sham-controlled. So, patients actually went into the hyperbaric chamber for 90 minutes for 5-plus days at a time and weren't really getting anything other than some high flow oxygen put in in the sham group. And the treatment group got true hyperbaric oxygen for 90 minutes a session. And lo and behold, it really worked. I mean there was a real difference between these 2 groups.

We did another study and expanded it to try to understand how many days it takes and it looks like 5 days is the right amount. Patients tolerate it very, very well. There are some adverse effects to think about and talk about with patients, but in general, it's very safe. And it really does appear to work. We have data—both endoscopic-histologic data, clinical data, and now some translational work that Dr. Dulai, and others, have been gathering that really starting to show mechanism for why this works. And in fact, there's now a huge grant called a U01 grant that Parambir Dulai is leading, and many of us are taking part of, yourself included, where we'll be studying this in, really, a large essentially phase 3 trial to understand how effective it is.

We do this now routinely, Ray, and I didn't bring it up earlier as I thought we'd get to this discussion, but when patients are admitted with UC flares, until we have a clinical trial open, we're doing this routinely in our patients and the patients don't mind it at all. The hyperbaric team is thrilled to have another use of their treatment and it really has been well-tolerated and we've seen some good benefits. So, again, more data needed here, but this may end up being part of our treatment regimen with acute severe UC.

Raymond Cross:

And that's something that I'm totally comfortable stacking. So, if I give them infliximab and they don't respond, this is something that's not going to harm them from an immune suppression standpoint. And someday we may be giving both at the same time, who knows? Because it's just a bridge to get you out of the hospital. I saw a patient yesterday who was super sick in the hospital, did not respond to treatment and hyperbaric oxygen rescued her, she saved her colon, she had a healthy baby, I just saw her labs are completely normal. So, she's now on ustekinumab, doing very, very well.

Corey Siegel:

Perfect. That's great.

Raymond Cross:

All right, Corey, fun question. Tell the listeners something about yourself that they may not know, maybe something that I may not even know.

Corey Siegel:

Oh, boy. Well, let's see. You're a sports fan, so, I'll give you a fun tidbit from a few years ago, a number of years ago now, is I was at a Boston Celtics game and at halftime I came in second place in the halftime 3-point shootout with a good 20,000 spectators cheering me on.

Raymond Cross:

That's awesome. I did not know that.

Corey Siegel:

Yeah, you didn't ask me how many people were in the competition.

Raymond Cross:

It was 2.

Corey Siegel:

But it was also last place. But nonetheless, there were no air balls and it was actually an incredible experience. It was really, really fun to pretend to be a professional basketball player for about 7 minutes.

Raymond Cross:

All right, Corey, this has been wonderful. Thank you very much. I've learned a lot, I'm sure our listeners have too, and we hope to have you back here again in the future.

Corey Siegel:

I'd love to. Thanks for inviting me.