Managing Acute Severe UC: Emerging Strategies

This transcript has been edited for clarity. 
Hi. I’m Ed Barnes from the University of North Carolina at Chapel Hill. It’s a pleasure to be able to talk with you today about a topic of real interest: acute severe ulcerative colitis (UC). 
When we think about acute severe UC, I think one of the critical things to remember is that these are some of the sickest patients and the sickest presentations that we’re going to be managing in the disease course of a patient with UC. Up to 25% of patients with UC will present with acute severe UC at some point during their disease course. 
As I mentioned, this is a critical presentation for that patient with acute severe UC because they’re at high risk for colectomy during that initial hospital admission. Up to 1 out of 5 patients will be at risk for colectomy at or during initial admission, but that risk doesn’t go away once they leave the hospital. It may actually stay at an increased risk up to 90 or even 180 days after that initial admission, so this is a critical assessment that we need to make, and we need to think about being very proactive and aggressive about treating patients with acute severe UC. 
When I think about our basic approach, initially, when that patient presents with acute severe UC, my first thought is about figuring out what’s not going on — that is, what’s not UC that’s causing this patient to present? Is there a concomitant infection, something like Clostridioides difficile colitis or cytomegalovirus (CMV) colitis? 
Often, we can assess that with a stool test for C difficile colitis or by biopsy during the initial flexible sigmoidoscopy that’s often done within the first 24 hours of that patient presenting, to look for things like CMV colitis. Once we’ve assessed for those infections, then the next step that we could do is initial treatment for that patient’s presentation of acute severe UC. This is going to be in the form of intravenous (IV) corticosteroids, which have been the backbone treatment for acute severe UC for more than 50 years. 
We have many different scoring systems that have been presented to guide the management of acute severe UC, including some new ones that have come out in the past several years. All of these are based on, first, putting that patient on IV corticosteroid treatment and then making a timely decision to decide if that patient is either responding to steroids, often within 48 to 72 hours after initial treatment, or transitioning that person to a rescue therapy.
Currently, for our main rescue therapies, we are deciding between three different classes of therapies: an anti–tumor necrosis factor (TNF) agent, which is infliximab as a main anti-TNF therapy; cyclosporine, a calcineurin inhibitor; or Janus kinase (JAK) inhibitors, about which there has been a large amount of emerging data within the past couple of years owing to both their effectiveness, which we know from the management of outpatient UC, and their rapidity of onset of action. 
If we think about infliximab, one of the key designations that we want to think about is that, as an outpatient, we’re often starting that patient on the standard dosing of 5 mg/kg with an induction dose at week 0, and then again at week 2, and then week 6, and then every 8 weeks thereafter.
If you contrast that to how we use infliximab often as an inpatient, much of the literature has been written about using a more accelerated dosing mechanism. When we think about an accelerated dosing mechanism, often we’re thinking about higher doses, something like 10 mg/kg. We’re also thinking about using that drug in a much more rapid onset — that is not waiting the standard 2 weeks between doses as is indicated when we’re thinking about induction, but often increasing the frequency within days.
When we think about how we make that decision of when we would re-dose someone with acute severe UC and that accelerated frequency dosing strategy, it’s driven by that patient’s clinical presentation. If you have a very sick patient with acute severe UC who has a decrease in the number of bowel movements with the initial dose of infliximab, and that starts to go back up, and there is an increase in their C-reactive protein levels or an increase in their abdominal pain, all of those would be triggers to re-dose that patient with a high dose, maybe 10 mg/kg, at the time of that “repeat” increase in their symptoms. 
You might wonder why an accelerated dosing strategy would work in the management of acute severe UC, specifically when using infliximab. If you think about the patients that you’ve seen with acute severe UC, or you think about that initial sigmoidoscopy or colonoscopy that might be done within the first 24 hours of presentation, you’re going to see a really sick colon. You’re going to see a patient, probably with a Mayo Score of 3 for UC, lots of edema, and lots of deep ulcers, all of which are going to lead to protein loss at the level of the mucosa. 
Remember, TNF itself is a protein. The anti-TNF, the infliximab therapy that’s going to be used to try to treat the acute severe UC, is a protein as well. All of those potentially are going to be lost across the level of that leaky mucosa.
This has been studied in a couple of different ways to show that some patients actually have massive amounts of infliximab lost in the stool within the first 24 hours of dosing. Subsequently, those are the patients who are at higher risk to be nonresponders in the use of infliximab in the treatment of acute severe UC. It stands to reason that more infliximab up front might be a better strategy. 
Now, I must tell you that, although this is theoretically a better approach, there are mixed data out there comparing these standard dosing regimens with the accelerated dosing regimen.
Another of our therapy choices for the management of acute severe UC is cyclosporine. Much of cyclosporine’s use for acute severe UC has been focused on the initial induction therapy and then as a bridge to another maintenance therapy, which was often thiopurines.
In the past couple of years, we’ve seen the emergence of cyclosporine as a bridge to our novel biologics, such as vedolizumab or ustekinumab. This has opened up the patient population where we would use cyclosporine — particularly in our center, which is one where we use a lot of cyclosporine, including in patients with lower albumin or the sicker patients whom we think have had a lot of protein loss and in whom we might not want to use infliximab, for the reasons I mentioned. 
You certainly want to be aware of the toxicities of cyclosporine. You want to be aware of how to dose it and monitor your trough levels. This is definitely something where you want to have some expertise or work with someone that has some expertise to use cyclosporine. I would encourage you to not shy away from the use of cyclosporine in the management of acute severe UC, because it can be a very effective strategy. 
We have also seen the emergence of the use of new small molecules in the treatment of acute severe UC, specifically the JAK inhibitors. Really, our first data for the JAK inhibitors came in the form of tofacitinib. A retrospective study, from the University of Michigan, looked at the use of tofacitinib in off-label doses of 10 mg orally three times daily, which showed a higher number of patients that were colectomy-free at 90 days compared with matched controls.
I mentioned this off-label dose of 10 mg three times daily because this was also the dose that was used in a more recently published randomized controlled trial known as the TACOS trial. In this trial, patients were randomized to receive standard of care, which is IV corticosteroid therapy, or tofacitinib 10 mg orally three times daily.
In the TACOS trial, at their primary outcome of clinical response at day 7, more patients receiving 10 mg orally three times daily achieved that outcome compared with standard of care (which, again, was corticosteroid therapy), suggesting that tofacitinib at this higher dose can be quite effective as an induction therapy. 
We do have some evidence for upadacitinib as well in the treatment of acute severe UC. This has come from a multicenter, retrospective study that’s been published in the past year, where patients who were treated with upadacitinib achieved both high rates of corticosteroid-free clinical remission after presenting with acute severe UC and 90-day colectomy-free rates of over 76%. 
This includes both the index admission and following those patients postdischarge, suggesting that upadacitinib can also be a highly effective induction mechanism. That’s something that we certainly want to keep our eye on when we think about the emerging roles of JAK inhibitors for the management of acute severe UC. 
I want to wrap up with the thought that these patients are at high risk for colectomy, so you definitely want to think about a multidisciplinary approach when treating patients with acute severe UC. That includes involving your colorectal surgeon in your team discussions very early in the process. 
This should not be a surprise to patients, that they’re at high risk for colectomy. Even if a patient doesn’t go to colectomy, having conversations and involving your colorectal surgeon on that team-based approach, that multidisciplinary approach, is going to be key to the efficient and overall management of these very critically ill patients.
You want to recognize this patient early, have a multidisciplinary and aggressive approach, initiate your therapy in a timely manner, and try to find an appropriate therapy that works for you, that your patient is in agreement with, and then use that appropriate therapy to try to get the best outcome for your patient.
Thank you very much for your interest. I hope this was helpful as you think about managing your patients with acute severe UC.