Dr Rubin reviews his lecture on managing the complications of Crohn's disease, from strictures and fibrosis to perianal disease, from the ACG Postgraduate Course. 

David T. Rubin, MD, is the Joseph B. Kirsner Professor of Medicine, chief of the Section of Gastroenterology, Hepatology and Nutrition and director of the Inflammatory Bowel Disease Center at University of Chicago Medicine in Chicago, Illinois.

CLINICAL PRACTICE SUMMARY:

• In the PROFILE study of infliximab, initiating advanced therapy within 2 weeks of a diagnosis of Crohn’s disease achieved approximately 80% steroid-free remission and reduced the need for surgery.
• The STRIDENT trial from Australia demonstrated that patients with symptomatic strictures treated with intensified adalimumab plus a thiopurine showed significant improvement and reversal of stenosis on imaging compared with standard adalimumab monotherapy.
• Phase 2 data presented at DDW highlighted the potential of TL1A inhibitors and gut-selective oral agents as emerging antifibrotic or antistenotic therapies for Crohn’s disease.
• Antibiotics and short-term steroids may adequately treat abscesses under 3–4 cm. Larger abscesses require drainage.
• Infliximab is the only labeled therapy for perianal Crohn’s disease, but promising results are also seen with upadacitinib and anti–IL-23 agents. Ciprofloxacin during induction and collaboration with experienced colorectal surgeons were emphasized to preserve function and sustain remission.

TRANSCRIPT:

Hi, I’m Dr. David Rubin from the University of Chicago. I'm at the American College of Gastroenterology meeting in Phoenix, Arizona. I had the pleasure of presenting a few different lectures here, but the one I wanted to highlight for you was a luncheon that I was speaking at related to complications in Crohn's disease.

I started by explaining to the group what a complication is in medicine. It's a secondary effect or an unforeseen event related to an underlying condition. And obviously in Crohn's disease we understand complications occur. The most common are related to bowel obstruction or stenosis of the bowel and abscesses, whether there are abscesses inside the abdominal cavity or whether there are abscesses related to the perianal area and perineal inflammation. So when I spoke about these complications, I updated the audience on a number of things to think about, both as clinicians as well as the evolving understanding in some of the research areas for these problems.

The first thing I emphasized was that understanding complications of Crohn's disease also has to do with understanding the natural history of Crohn's disease and that in general, we think about Crohn's disease being a condition where there is chronic inflammation that progresses to cause damage to the bowel that leads to a problem subsequently. And of course the challenge is many people are diagnosed with Crohn's disease after they've already had it for quite some time, and therefore there's an accumulation of damage that has occurred before they're even diagnosed. By the time they present with symptoms—pain, cramping, diarrhea, anemia, or infection—those symptoms are related to disease that's been there for quite some time. So the challenge we have in managing such individuals is first taking care of the complication and second, understanding the natural history of Crohn's so that they don't happen again.

The other challenge to understand is when a patient presents with Crohn's disease who hasn't had a complication of a bowel obstruction or an abscess, the more usual way people present. How can you prevent that from causing a problem later?

One of the main messages that has come out of recent efforts to study Crohn's disease and to understand our new treatments is that it is essential that we treat people earlier and get them on effective therapy. If you have a patient with Crohn's disease who presents with what might be characterized as moderate to severe Crohn's disease, treat them with one of the therapies we know works effectively. I shared with the audience during my luncheon that one of our newest studies shows that within 2 weeks of being diagnosed with Crohn's, if you start a patient on an advanced therapy, and in the particular example I used, which was the PROFILE study with infliximab, you could have as high as an 80% rate of steroid-free remission and avoiding surgery. When was the last time you heard someone mention 80% remission rates in Crohn's? That's what you might be able to get when you treat earlier.

So the concept of trying to prevent bad outcomes like obstructions, abscesses, hospitalizations, repeat surgeries, has to do with first trying to treat these people earlier, gain control of the disease, and literally modify the outcomes. The second part, of course, is how do you approach the complication if it’s already occurred.

One of the emerging concepts about stenosis of the bowel is that it's not all fibrotic. It used to be that we said if someone had cramps and on imaging they had proximal dilation of the healthy bowel, it suggested there was some scar tissue and maybe they'd be better off just having surgery. What we're learning is that not all narrowing in the bowel is fibrosis. Some of it's inflammatory and some of it is reversible. So how can you figure that out as a clinician? Well, the first part is to understand whether or not the patient responds to some anti-inflammatory therapy, and that might be giving them a course of prednisone, not as a general strategy to treat them, but more as a diagnostic maneuver to see if it's somewhat reversible and if they feel much better after 1 or 2 weeks of that steroid—not longer.

The second option is of course, to think about using some of our advanced therapies. I shared a study from Australia called STRIDENT that took patients with symptomatic strictures and put them on higher dose and more intensive adalimumab with a thiopurine and compared that to patients who were randomized to monotherapy with standard dosing adalimumab. Now, the point of this is not necessarily what the doses were, but more importantly, as they followed these patients out using intestinal ultrasound every 4 months and using an MRI at baseline and at 12 months, that there was a significant number of patients who had resolution of their symptoms and resolution of their stenosis suggesting that medical therapy can work in some people. Now, I'm not here to tell you that we should avoid surgery at all costs, that surgery should be a last resort. That is not my message, but it is here to explain that we're learning more about the biology of stenosis and how we can treat some people effectively.

There's also an entire area of research that is ongoing in the preclinical area and now in clinical studies of novel mechanisms to treat fibrotic disease. There's a very great interest in TL1A inhibitors as a novel class. And because TL1A is expressed on fibroblasts among other inflammatory cells, this might be able to prevent fibrosis, maybe even treat fibrosis, and there are some novel other agents that have been studied, including some really interesting oral and gut selective agents that may have some benefits. A phase 2 study presented at DDW suggested that we might have some antifibrotic or at least antistenotic therapy. So there's some interest here in how we might move the field forward.

That doesn't change that the patient's sitting in front of you who's very symptomatic or has recurrent cramping pain or an obstruction wouldn't benefit from an early surgery and what we would now call surgical induction of remission or surgical remission, and surgical remission should be partnered by a preventive strategy afterwards, which means monitoring and medical therapy. And I think that's a very important message that came out of this presentation.

The other point that I made was about abscesses, and we've now learned that smaller abscesses, the thresholds about 3 centimeters, maybe 4 but smaller than that, you can treat with antibiotics and continue or add your immunotherapies, including steroids, short term to gain control without having to necessarily rush to surgery or to even do percutaneous drainage. Abscesses that are bigger than that in the abdominal cavity should be drained. And then based on the response to that therapy, you can decide if they need surgery or whether that patient's doing well after drainage and might respond to medical therapy. Remember that a percutaneous drain creates an enterocutaneous fistula. So when you make that decision, you also have to be thinking down the road about how you're going to keep the patient well and whether or not they really should just have surgery to clean it up after you've managed the sepsis or the abscess itself.

The separate consideration here, of course, is working with a surgeon who is experienced, whether the patient might benefit in that scenario from a temporary ostomy to gain control of the problem that occurred in the first place before they can potentially be put back together. And then again, preventive strategy.

And the last point I made during the luncheon was about perianal disease. We've been talking about perianal disease as a feature of Crohn's for many years, of course, and in some estimates it's as high as 1 out of 4 patients who have active perianal disease. Remember that perianal Crohn's as a phenotype is a complication of Crohn's by the time we diagnose it; somebody who presents with an abscess on their bottom or a draining fistula has already had a complication. What we're trying to understand, of course, is how to treat those better, but also can we prevent them in the first place.

So first, when thinking about treating perianal fistulas, we discuss the available treatment options, which of course favor anti-TNF with the best evidence. Infliximab is still the only therapy that carries its own label to treat that problem. But also now emerging data and publications supporting upadacitinib as a selective JAK1 inhibitor for perianal disease and very intriguing research that anal fistulas may express an immunotype that favors IL 23. Interleukin 23, you may understand, is related to plaque psoriasis and of course is also related to Crohn's and colitis. So it may be possible and there's more work going on that our anti-IL 23 therapies might work in perianal disease also. But one message that's being clear with the anti-TNFs, and I've extrapolated it to the JAKs or any other therapy I use in that setting, is adding an antibiotic, usually ciprofloxacin during the loading phase of the therapy, so that as the fistula tracks starts to close, the patient doesn't get an abscess as a complication of your therapy.  And that's a very important point.

And of course, working with the colorectal surgeon to make sure you understand the extent of the fistula tract, whether they need a seton to keep it open in those settings or other management strategies that may be part of this. I emphasize that we need to work with an experienced colorectal surgeon who can appreciate the different tissue planes and preserve the sphincter, so that's important as well. And then I ended with the idea that we're going to be understanding soon who is at risk for perianal disease and how we might even identify subclinical or preclinical perianal disease, meaning that the patient has inflammation in their pelvic area around their bottom when you don't even know that they're at risk for perianal disease in the first place. And that might explain who is going to develop it downstream and of course be a new target for us to make sure our patients are treated effectively.

So in conclusion, when I presented to the group and then we of course discussed their own cases, we really emphasized, number 1, how to manage a complication when it's already occurred, but number 2, how to prevent them in the first place by treating earlier and understanding the natural history of Crohn's. Having said all of that, there's a lot we still don't know, but we're making good progress. I'm sorry you weren't at ACG or if you were here and you missed that luncheon. I hope this was helpful and I would be happy to be discussing this again in the future. Thank you.