I'd like to introduce the next speaker, we'd like to introduce Dr. Charles Bernstein, he's a professor of medicine and the chief gastroenterologist at the University of Manitoba Medical Center. And nobody needs an introduction like Charles because he's been publishing so much in the last 20 years in the field of IBD. He's going to talk on the role of medical therapy in management of Crohn's strictures. Welcome Charles. Thank you to the organizers and Bo again for including me in a really elegant program. And he's asked me to talk about biological therapy for Crohn's disease strictures, specifically strictures friend or foe. And maybe this title of this talk or maybe the whole theme of the talk came about from because Bo and I are both old, remembering the debate in the early 2000s after infliximab came about, that could this possibly worsen strictures? And I think that, in short, that's not an issue. We don't believe that to be an important problem. And we're not worried about using infliximab or adalimumab or even other biologic therapy when strictures are present from the perspective of it worsening disease. And one of the questions is, to what extent can it improve disease? So most of the time, it can be a friend. It's rarely a foe. So here are my financial disclosures. And let's define a stricture first. It can be defined by these echo comments of a combination of a reduction of luminal narrowing of greater than 50%, an increase in bowel wall thickness of greater than 25% relative to the non-affected bowel, and pre-stricture dilation of greater than 3 centimeters. I'm not sure that I wholly agree with the endoscopic definition. For lesions detected during an endoscopic examination, it was considered that stenosis may be defined as the inability to pass an adal colonoscope. But I'm sure that all of us have had the quite regular experience of finding a stricture that we can wiggle through. And we can pass through that without doing any dilation. And we still think that there's a stricture. We can identify a stricture. I do agree with the top definition, which probably reflects more to radiologic imaging. What we don't get out of this, and we struggle with, and this is where the art of medicine still thrives, is when we see strictures on radiologic imaging like CT and MR, to what extent there is actually active inflammation, and that we can make headway in improving the stricture with biologic therapy or even steroids, versus when it's wholly fibrotic. And at least to date, although perhaps that will change, but up till early 2022, we don't have anything that will change fibrosis. Stenosing lesions are ultimately a consequence of the rich immunoinflammatory milieu that is present in the gut, ultimately leading to muscular hypertrophy. And there's a variety of growth factors and cytokines that ultimately trigger myofibroblasts and ultimately muscle cells and fibroblast proliferation. And so it's rational to think that if you impact on this whole orchestration of immunoinflammatory response early, you could prevent stricture development. The question is, once the stricture is already developed, is there anything we can do to undo it? So this is a very lovely paper by Florian Reeder and friends, published in Gastro now five years ago, reviewing an algorithmic approach to strictures and asking the question that we don't always have the answer to, is inflammation present? Well, that's clearly a role for biologic therapy. And if we give them biologic therapy over on the far right and achieve success, then we give them maintenance therapy, and we carry on as we're used to. Now if the biologic therapy fails, or there's only a short symptom-free interval, well, now we're dealing with a more complicated situation, and we have to decide which pathway is ultimately going to be most appropriate. Are we going to go down an endoscopic pathway for possible balloon dilation? Five centimeters is the standard cut point upon which we say it's short enough to opt for balloon dilation. Angulated strictures are a problem to undertake balloon dilation and are at greater risk of perforation. If we do achieve endoscopic balloon dilation, then we have to come back to prevent further stricture development or progression and come back to our anti-inflammatory therapy. And then, of course, there's surgical options. But the two giant red arrows are where we would consider biologic therapy in the algorithm of finding people with strictures who have Crohn's disease. In JCC, the Bacardi risk score for strictures was reported, and you can see here that clinical predictive factors of a response to an anti-TNF in a patient with Crohn's and a stricture would be if they had an ileocolonic disease, if they were getting concomitant other immune therapy like steroids or thiopurines, if their obstructive symptoms were not very long-lived but rather short-lived. MRI predictors of a non-response is if the small bowel strictures are very long, 12 centimeters seems long. It was surprising to me in reading this that it was as much as 12 centimeters as opposed to less. But obviously a small stricture diameter, increased stricture bowel wall thickness could imply that there is some buried fibrosis in there, even if it's not obvious, for instance on T2 imaging. If there's ulceration in the stricture, pre-stenotic dilation, marked enhancement on the delayed phase, and if there are officials to the abdominal wall associated with the stricture, these are predictors of non-response to therapy. Now I'm going to run through a series of studies to show how biologic therapy, most particularly anti-TNF agents, have impacted on Crohn's disease where there are strictures. And this really comes from several countries in the world, including a handful of countries with large data sets. The Swiss IBD database is well known. And early treatment defined as treatment within two years. And that had a hazard ratio for the development of strictures of 50%. In other words, you could reduce the likelihood of developing strictures if you gave patients anti-TNFs early within two years of diagnosis. And those who received the anti-TNF early were more frequently free of new stenosis than those who got it later. And you can see the data there at two years versus five years versus 10 years. In this Italian study, a small number of patients, 51 patients with Crohn's disease all treated with an anti-TNF, ultimately 40% underwent surgery. And you can see some of the predictors for needing surgery, including a hazard ratio of 10 if there is non-perianal fistulas. And as we run through some of these studies, you can think of the issue of the glass being half full or half empty when you see the different rates of surgery. When we have rates of surgery, for instance, of 40%, it also tells us that 60% did not ultimately come to surgery if we think of avoiding surgery as a success. Sometimes a well-placed surgery can really be a fantastic advance for a patient who has struggled with longstanding fibrostenotic disease. This is a French study from the French group who have taught us so much from their different cohort studies. This was a two-year study from well over a decade ago, nearly 100 patients with Crohn's disease and obstructive symptoms who were treated with Adalimumab. And Adalimumab was successful in two-thirds who had a symptomatic stricture within a half a year. And the success was maintained in half of those patients after a median follow-up of four years. And so half of patients were free of surgery four years after treatment initiation. And you can see here in graphic form that half of patients had a prolonged success in avoiding surgery. So it wasn't effective in half, and it was in the other half. And I think that those aren't bad odds if the alternative is to take everyone to surgery. Predictors of good response were concomitant immunomodulatory therapy, again, a duration of obstructive symptoms of less than five weeks, length of a stricture of less than 12 centimeters, and maximal small bowel diameters of less than 3 centimeters. And you can see that a lot of these parameters have factored in to some of the ECHO guidelines. The Spanish group is another group with a large cohort of patients with IBD that they've reported on. This is 262 patients with symptomatic stricture and Crohn's disease up until 2018 treated with an anti-TNF. And the median time to loss of effectiveness was 15 months. And it was proving to be effective in only 26% of patients after follow-up of three years. So the Spanish data here were amongst the data with the lowest rates of efficacy in anti-TNF therapy for stricturing disease. These are all observational studies. They're not randomized, obviously. It's quite important to have the information as to when in the course of the onset of Crohn's disease the biologic therapy is initiated. That's going to impact on benefit. And you can see here that whether it was adalimumab or infliximab, it didn't really seem to make a whole lot of difference. About a third of patients ended up coming to surgery, maybe a little bit less with adalimumab than infliximab. And there were other outcomes as noted here. They enrolled patients with relatively early disease. So it was a little bit disappointing that their long-term outcomes of avoiding surgery weren't better than they had presented. Amongst the predictors of non-response, it's always tricky to think of the negative or especially double negatives, but predictors of non-response, having a high albumin was a predictor of response, but having left colon stricture and having lymph nodes was a predictor of non-response. I honestly am not sure what to make of the fact that concomitant use of 5-ASA was a predictor of non-response, unless maybe the implication is one was left on a 5-ASA too long before they got to very effective therapy. So I'm not really sure what to make of that. And here are some data about endoscopic balloon dilation from Japan. And I include this in this talk about biologic therapy because the Japanese segregated their patients, very large sample size, again non-randomized of 485 anti-TNF exposed patients, 854 non-exposed. And you can see here amongst the exposed patients, the recurrence rates were 23%, and amongst the non-exposed, they were 44%. Again, non-randomized, but there's perhaps a signal that being on an anti-TNF would be an adjunctive benefit if you're going to pursue endoscopic balloon dilation. And this is just looking at these data in graphic form, showing that the cumulative rate of patients without a second intestinal stricture developing was 40% in those who used an anti-TNF compared to those who didn't. And the cumulative rate of being surgery-free was about 50% in those who used an anti-TNF versus those who didn't. And getting towards the end of our cross-country checkup here, a smaller study from well over a decade ago from the UK showing that if you do endoscopic balloon dilation, often more than one dilation is required. We've all seen that. Repeat dilations occur within two years. And escalation of medical therapy was only adopted in less than half of patients. And I think that this tells us how we've evolved over time, that in the first decade of using anti-TNF therapy, in the UK at least, not everybody was getting escalated to a biologic therapy once they underwent endoscopic balloon dilation. I think we have a different sense of this now, that unless there's a very short, long-standing stricture that can be dilated and maybe recurrently dilated in a patient who doesn't need biologic therapy because there's absolutely no inflammation around, we might not introduce it. But much of the time, if somebody has strictured and is being treated with a balloon dilation, they are going to get a concurrent biologic therapy to try to prevent recurrence and progression. A brief word about intralesional steroids. This has been discussed with stricture dilation for decades, actually, and there's still no strong evidence supporting the use of it. Studies are limited by small sample size, lack of a control group, et cetera. So the bottom line for medical therapy of strictures in Crohn's disease, as alluded to in my first comments, anti-TNF does not induce bad outcomes in persons with Crohn's disease strictures. Intralesional treatment with either anti-TNF, which has been reported in case report form with or without endoscopic balloon dilation is unproven. Anti-TNF can be preventative and therapeutic. A course of systemic steroids may provide some evidence of an inflammatory component of the stricture. We've seen this. We've seen this in patients who come in with obstructions and they get steroids and they do very well. They open up quickly. And so we have a sense that there is an inflammatory component that we can treat with biologic therapy. And that's maybe a value, even if imaging doesn't clearly define inflammation. And finally, failure of anti-TNF therapy with recurrent obstructions and no response to steroids needs surgery. It doesn't need another biological. And you might consider that plugging in Stelara as an example instead of anti-TNF. I think the same principle holds true if people are getting recurrent obstructions. A final word, I had alluded to the fact that in 2022, we had not yet had a therapeutic approach to reverse fibrosis. There's some excitement about this compound that's under study, TL1A, a member of the TNF-like cytokine family that is secreted from immune cells and binds to the death domain receptor expressed on intestinal myofibroblasts. It's highly expressed in fibrotic tissue of Crohn's disease patients. And attacking this pathway may have some value in altering fibrosis. It's also being studied in lung fibrosis. So we await the clinical trials to see if this is actually an agent that may be able to do what we've never done before, use medical therapy to reverse fibrosis in Crohn's disease. And with that, I will stop.

Dr. Charles Bernstein

medical therapy

Crohn's strictures

biologic therapy

inflammation in strictures