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Sunanda Kane, MD, MSPH: Hello. I'm Dr Sunanda Kane. Welcome to Medscape's InDiscussion series on ulcerative colitis. Today, we'll be discussing the management of acute and severe ulcerative colitis with our guest, Dr Peter Higgins. Dr Higgins is a professor in the division of gastroenterology and the director of the Inflammatory Bowel Disease Program at the University of Michigan, where he is also chair of the Gastroenterology and Hepatology Research Advisory Committee and director of the Michigan Clinical Trial Support Unit in the Department of Internal Medicine. Welcome to InDiscussion. Hi, Peter. How's it going?
Peter D. Higgins, MD. PhD: Good. Good to join you.
Kane: We get lots of questions about patients who end up in the hospital with ulcerative colitis. I don't know about you, but it fortunately seems to not be as frequent as it used to be in this era of biologics. Would you agree?
Higgins: I think so, although I think it's hard to tell. Our numbers have been backfilled by transfers, but we get fewer local patients. I think that N is smaller.
Kane: Interesting. Do you think it's sort of a phenomenon of folks who don't have access to tertiary care for ulcerative colitis?
Higgins: That may be more of it. I do think it's shifted, and different places are more comfortable with rescue and salvage therapies. There are a fair number of patients who still say, "I don't care, you've got to try everything before I'll tolerate a colectomy."
Kane: You used two terms that I want us to chat about a little bit more. One was rescue therapy. Perhaps we talk a little bit about what that means, who should do it, and who shouldn't do it. Then we'll talk about salvage therapy and how that's different. To you, what does rescue therapy mean?
Higgins: I think of it in three lines. There's first-line therapy, which is traditionally IV steroids. There's rescue therapy, which we usually do after 72 hours of IV steroids if the steroids really aren't working. Typically, our traditional choices are cyclosporine or infliximab. Salvage therapy is after the rescue therapy doesn't work. If a patient's really refusing a colectomy, which is still standard of care at that point, salvage therapy is thinking about if there is anything else we can or should do, sometimes at the patient's insistence.
Kane: I like how you walk through that trajectory and that spectrum. Where should salvage therapy be done? Is it something that can be done at the local hospital? I'll pick the geography of Michigan. Should this be done in the Upper Peninsula of Michigan at a patient's local hospital?
Higgins: In general, I hope not. We know from experience that salvage therapy is risky because we're usually layering on additional levels of immunosuppression. A while back, people were combining infliximab and cyclosporine on top of steroids and saw high infection rates and even deaths. I think it needs to be done very thoughtfully and very carefully and with the statement to the patient that this is not the standard of care. The standard of care is still colectomy, and colectomy outcomes are very good.
Kane: That's a good point. Do you make your patients sign a consent form if they're going to do salvage therapy?
Higgins: I certainly document a lot. I don't have a standard consent form, but if they really want to try something else, I talk to them about it and emphasize to them that at this point, colectomy is the standard of care. We're in a little bit of a bad spot because the steroids aren't going away. If we've tried an anti–tumor necrosis factor (anti-TNF), that's not going away. It's going to be around, and we're laying another level of immunosuppression on top of what we've already got. We don't really have a large enough N to be able to predict the infection or death rate, but it's real.
Kane: Let's backpedal, then, because I don't want people to think that salvage therapy is something they should be offering to their patients. So, we go back to rescue therapy. You did already mention the 72 hours for the IV steroids. In your mind, is the 72 hours a hard stop, and then we better have a plan B?
Higgins: I think it should be. I think we should evaluate with something like a Lichtiger index or a Travis index and ask if we are objectively making progress with the patient. If we're not sure, maybe we should take another look with the scope, but we should use objective data because most patients are going to say they're feeling better and we don't have to do anything because they're fine. They're terribly optimistic because they don't want a colectomy. We have to be the patient's best advocate by being objective about it and saying something like, "Yes, you are doing a little better from when you came in with a C-reactive protein (CRP) of 100 mg/L and 20 bowel movements a day, but you're still at a CRP of 50 with six bowel movements a day and they're all bloody. That's just not good enough, and you can't go home like that."
Kane: What if they say they just need another day of IV steroids?
Higgins: That's where we have to tell them that we have data and good objective evidence that these predictors say that one more day probably isn't going to cut it — unless they're right on the borderline of one of those indices and saying they're going to get better. Most of the time, the indices line up that the patient isn't going to make it. They need rescue therapy or a colectomy.
Kane: In those first 72 hours, what absolutely has to happen for a patient when they get admitted?
Higgins: A couple of things have to happen. Most patients need a fair amount of fluid. Most of them are dehydrated because everything they eat goes right through them. They eat and drink less, and they are dehydrated from the fluid coming out. They need DVT (deep vein thrombosis) prevention, usually with enoxaparin, in part because of the inflammation from IBD, but also in part because of the steroids we give them. Their BTU rate is quite high. And then they need education. A lot of the first 3 days is explaining what an ostomy is like, what the surgical options are, and what the medications are. We talk about the concept of steroids, our success rate of about 70%, and the options for rescue therapy. Increasingly with the patients we see, about 40% have already been through an anti-TNF therapy. So, Remicade [infliximab] is no longer an option. We need to think about the options for each patient.
Kane: How about KUB flex sig (kidney, ureter, and bladder flexible sigmoidoscopy) to rule out cytomegalovirus or C diff (Clostridioides difficile). How many times have we gotten fooled where this horrible flare that's not responding to steroids is because the patient has C diff? That's a kind of embarrassing to miss.
Higgins: We absolutely want to rule out infection. Generally, we're scoping the patient, hopefully within in the first 12-16 hours, and we are trying to establish if there is herpes simplex virus or cytomegalovirus, and if is it as severe as we think it is based on the patient's symptoms. Most of the time, the scope backs this up, and we can make sure it's not C diff alone. C diff is tricky because it can be present, but it can be a bit of a red herring because it can set off a UC flare. So we're often in that difficult spot of how long we should treat for C diff until we say it's not just C diff — it's C diff plus an IBD flare.
Kane: When does the patient meet a surgeon?
Higgins: We usually have them meet a surgeon on day two when they're no longer sedated from their flex sig, so they're not groggy. Usually late on day one we give them educational materials and videos about their surgical options. Early on day two, they meet the ostomy nurse who chooses an ostomy site, which makes it real. And then the patient meets the surgeon. Hopefully between the educational materials and the videos, they have much better questions for the surgeon and can talk about what their options are, how they are doing, and if at 72 hours they will be in the OR.
Kane: Another thing I see happen and get asked about is if a patient absolutely has to be NPO.
Higgins: Generally, not strictly. I generally tell patients to listen to their body. If patients don't want to eat and don't have any appetite on day one, that's fine. We can give them all the fluids they need. If they want to start by sipping some Boost [nutritional drink] and see how they do, that's probably pretty easy on their colon. If they feel like they can get down a can or two of the Boost and they're really hungry, we can offer them some solid food. A lot of our patients aren't that hungry, and that's okay.
Kane: Some patients are afraid to eat because it precipitates a bowel movement, so they just won't eat. I agree with you that if there's something that's palatable and something they're willing to do, that's better. If they're going 2 or 3 days without any oral intake, they're not going to starve to death, but you have to start wondering what you're going to do for their nutrition. You hate to start any kind of enteral nutrition. At The University of Chicago, we had this brilliant "all breakfast." It was protein, some carbs, and it was very low residue. It was eggs and pancakes and sausage, which sounds really good to most people, and there's nothing bad about any of that in terms of your colon. You could order breakfast three times a day and it was very well received. That was a [Dr Stephen] Hanauer trick. He got that instituted in the hospital.
So, what do you do with the patient who comes via the ER, and they give them pain medicine? Where are you with pain in all of this?
Higgins: That's really challenging. We have had many conversations with our ER. A lot of our patients get at least one dose of Dilaudid [hydromorphone] just because they're in the ER and that's what they do there. It's challenging because a lot of those patients have had this more than once, depending on how many ERs they've been to, and they want more Dilaudid. We have to reel this in and tell them that we understand they have pain, but we have a good amount of data showing that giving people a lot of narcotics slows down an inflamed colon when we want it to flush out all the bad stuff. And that we can't or shouldn't be giving them a lot of narcotics right now. Sometimes we negotiate down to a little bit of morphine, but we try to get them off it pretty fast and rely a little bit more on a couple of days of nonsteroidals, if we can, we lean on Celebrex [celecoxib] harder than the traditional nonsteroidals. Generally we're telling people the best way to control the pain is to treat the colitis, not to treat the pain.
Kane: This is another area where sitting down and having the conversation and educating a patient is so important because they use the word pain, but what they mean is cramps. When I hear the word pain in an ulcerative colitis patient, I examine them and look to see whether they may have toxic megacolon or impending perforation. If they do, they're going to the OR. If they say, "it's crampy pain, it's discomfort, I feel urpy," I can manage that with a little bit of Xanax [alprazolam] or some Valium [diazepam]. That's completely different. For anybody who's listening, it's important to understand what pain really is. That's not something you take lightly.
Higgins: You can ask them, "When do you have pain? Does it get worse with bowel movements? Is it worse right before bowel movements? Is it worse after bowel movements?" You'll see a lot of people, especially with bad left-sided disease, say they get a lot of pain right before, during, and after bowel movements, and that's okay. That's bad colitis, the pain between bowel movements — or in the worst case, rebound pain, which is a completely different ball game, and I'm not going to be that person's doctor for very long.
Kane: Right.
Higgins: We're going to find a surgeon, I hope.
Kane: If they have pain all the time, that's something we've got to figure out. What else is going on? Do they have C diff?
Higgins: Sometimes that diffuse abdominal pain all the time is C diff. That's not colitis.
Kane: You mentioned the patients who have already been on an anti-TNF therapy, maybe as an outpatient. Does your center offer cyclosporine?
Higgins: We do. We use it less than we used to. We've been using a lot of anti-TNF now for the last 8-10 years, but we have a protocol for it. We have morning levels. In general, we're very enthusiastic about the idea that when someone is very sick with a high fecal calprotectin, their gut leaks a lot of biologics, and it might not be the best time to start a biologic. That's where small molecules can get you out of the hole with a really sick patient, and you can start a biologic later.
Kane: Let's talk a little bit more about that. You were the leading author on the paper, and this research about using tofacitinib for the patient in the hospital comes out of your institution. Can you talk a little bit more about this and who should be trying it, how to do it, and when not to do it?
Higgins: We are keeping an eye out for the really sick patient. Sometimes that's a patient who's transferred after 3 or 4 days of steroids at the outset who has a high fecal calprotectin, a low albumin, and a high CRP. We can generally predict that this person isn't going to do well on IV steroids from the get-go. I came up with the question, "Why are we doing 3 days of IV steroids for this patient whom we know is very likely to fail?" Around the same time, we were doing a lot of infliximab but not getting great results in these really sick patients. Our inpatient pharmacists said, "Hey, you guys are spending a lot of money on infliximab. Is there anything else you could do?" This was shortly after Steve Hanauer's data that tofacitinib is really fast and really changes the bleeding. We got started on this early, using tofacitinib at 10 mg TID because of the short half-life, and we saw a lot of success early on. What was interesting about that is because it was approved for BID, some of our docs only did BID. We got a "natural experiment" where about half of our patients got BID and half got TID. As it turned out, the TID folks did a lot better. We learned that the small molecules are pretty good up front.
Kane: From a logistics standpoint, tofacitinib is FDA approved to treat moderate to severe outpatients with ulcerative colitis.
Higgins: What the FDA approved is 10 mg BID. What they did in the phase 2 was 15 mg BID, which actually worked quite a bit better than 10 mg BID.
Kane: Got it. Okay.
Higgins: When we looked at it, the inpatients are sicker than the outpatients, and the half-life is pretty short. We went with 10 mg BID, although we kind of got that nonrandomized experiment comparing twice a day, so TID in those very sick inpatients seemed to work better. We've actually moved to using more of upadacitinib recently, which by the network meta-analyses looks like it's more potent — about two to two-and-a-half times more potent than tofacitinib.
Kane: Is that once a day, or are you doing it in divided doses as well?
Higgins: Because of the half-life, I'm doing 30 mg BID for the first 3 days with upadacitinib, and then once they get their CRP down to 10 mg/L, trying to convert them to the usual 45 mg once-a-day induction.
Kane: Is your inpatient pharmacy supplying that?
Higgins: We got them on board early, and that was part of the discussion of how much money we're putting into infliximab. There are other alternatives, and it's also important that we're not using it as a rescue therapy. That's a first-line therapy in these really sick patients with really high CRPs and low albumins. We're trying to target the folks who are really sick or likely to fail IV steroids and giving this first line in combination with steroids.
Kane: This is not what you would have defined as rescue therapy — that they've already been through 2 or 3 days of IV steroids, and now you're going to give them a JAK inhibitor.
Higgins: We're trying to get them upfront, as that first-line therapy.
Kane: Interesting. But you're also using steroids.
Higgins: Yes. That's a conservative approach in the long run. I'm not 100% sure we need both. Maybe we only need steroids for the first 3 days, and then we can cut them off. We've been pretty conservative with saying we'll take this and layer it onto our standard of care, but there's room to pursue the question, "Could we reduce our steroid use substantially by using JAK inhibitors upfront?"
Kane: Are your patients getting a shingles vaccine ahead of time? Which patients are you choosing to do this for? Because there are folks out there who say they can't do cyclosporine, but they'll do tofacitinib if they can get it.
Higgins: Hopefully, especially for our folks over 50, they've already had their shingles vaccine. It's now, per the CDC, approved to give the shingles vaccine to anybody over 18 who is immunosuppressed, although not every insurance company agrees. If they haven't had the shingles vaccine, we try to give it to them on day one and tell them to get their second dose after they're off steroids.
Kane: Got it. Interesting. Dr David Rubin out of The University of Chicago has done oral tacrolimus as the calcineurin inhibitor as a bridge to vedolizumab instead of doing the whole cyclosporine bit. Have you done that? Where do you fall with that?
Higgins: We've done a few cases with that and had mixed results. I do like the idea of doing a small molecule up front and thinking about a biologic as maintenance therapy once you get somebody under control.
Kane: Perhaps we're starting to rethink this this whole doctrine of IV steroids. Do you agree?
Higgins: Yes. It's the original small molecule and it's fast, but I think the JAK inhibitors are somewhere in the neighborhood of as fast and have a lot fewer side effects.
Kane: And then what? When is the patient ready for discharge? Obviously, it's a quality indicator about rehospitalization rates. I don't know that they do an ICD (International Classification of Diseases) code for ulcerative colitis but they certainly do for the liver patients and then the surgical patients. When do you know that a patient's actually ready for discharge and that they won't bounce back in your ER within 24 hours?
Higgins: I'm probably a little conservative, but I generally want to see the patient on all oral meds, taking a regular diet, and moving around and doing what they would do at home.
Kane: Okay.
Higgins: I see some people say, "Okay, you're done with IV steroids. Here's your prescription for prednisone. Go home." I'm not thrilled with that because I've seen a decent number of patients bounce back. That transition from IV steroids where we typically are giving about a milligram per kilogram to even 60 mg of prednisone is a big drop in actual steroid efficacy. I want to make sure they're going to make it.
Kane: When a patient is in the hospital, all of their chores and tasks are done for them. They go home and suddenly nobody's done the laundry as when they were an inpatient. Suddenly they're having to go from lounging in a hospital bed to doing all of their chores. That's not going to help their colitis either.
Higgins: Yes, along with trying to race to the toilet because things aren't going that great.
Kane: Peter, can you believe it's been 20 minutes that we've been chatting? The key points we've brought up today are that education early on to talk about choices and candidacy for treatment options is important, and that surgeons really are our friends. With all of these fancy protocols, at the end of the day, for somebody who is not well, you take out that colon. With enhanced pathways for these surgeons, you can have a subtotal colectomy and be discharged within 48 hours.
Higgins: It's amazing.
Kane: It's absolutely amazing. I want to thank you for your time. It's been great talking to you, as always. You're a leader in the field, and I so much appreciate all of your work in this area. This has been Dr Sunanda Kane for InDiscussion.
Resources
Cyclosporine in Severe Ulcerative Colitis Refractory to Steroid Therapy
Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis
Inpatient Therapy With Calcineurin Inhibitors in Severe Ulcerative Colitis
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Cite this: First 72 Hours: Inpatient Patient Care for Patients With Ulcerative Colitis - Medscape - May 18, 2023.
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