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IBD: Treatments, Strategies and a Way Forward (Part 2)


– This was categorically a different study and had a different look at the outcomes. But if I were to summarize everything, you know, many years of research, the induction rates
with anti-TNF therapies ranging from weeks two
to six are very similar, surprisingly similar across the studies. Roughly 60% of patients will have a response
to an anti-TNF antibody regardless of which
agent you’re looking at. And if you look at the initial responders and their long-term
maintenance of response, so you could multiply these outcomes by the initial response rate to get the final overall response rate. Then what you see at,
somewhere at month six, which is where these
studies are all comparable, again, you see about 50%
to maybe as high as 60% of the initial responders still
responding out at one year. And remission rates are
roughly half that amount. So this has been a common expectation for all the anti-TNFs. And one thing that I should
point out is, of course, this leaves many patients
who don’t respond to our ultimate therapy and still suggest there is a need for additional therapies with other mechanisms. And I really won’t talk about
that at this point right now because I really believe
that we get very far with anti-TNF antibodies, but the real question
is how best to use them. Now, as I said, I’m not
going to talk very much about ulcerative colitis, but all of our basic science has suggested that TNF was not a very important cytokine in ulcerative colitis. Systemically, you find much lower levels. You do find relatively high levels of TNF in ulcerative colitis in the mucosa. But it was hotly debated
about whether this would be an effective therapy
in ulcerative colitis, as it is in Crohn’s. And I don’t think there
is any argument left after these studies, ACT 1 and ACT 2, that the response rates
and the remission rates are pretty much what you expect
to see in Crohn’s disease, albeit these are
different outcome measures for a different disease. What is really quite
different about the anti-TNFs in Crohn’s disease, as well
as in ulcerative colitis, is the capacity to heal the
mucosa really very quickly. And these were images that appeared on the cover of Gastroenterology that really kind of shocked the IBD community, seeing these long serpiginous ulcers in the pre-treatment
phase, to healing here. And it, I’m sorry, the light doesn’t make
this show up very well. But this is really complete healing of the mucosa in a four-week period, and we are not used to seeing
this with other therapies. We don’t expect to see this with, particularly with steroids, where perhaps you may see 1/3 of patients who may have mucosal healing, but, in fact, that healing
doesn’t correlate at all with the clinical outcomes
or symptoms of the patient. In addition, we have very robust evidence that, even in complicated disease, you can see marked therapeutic benefit. This is the ACCENT II study. It’s really the largest
randomized controlled trial looking at patients with
fistulizing Crohn’s disease. So, fistulas, of course,
are a dire complication of Crohn’s disease, most
often will lead to surgery if you can’t induce healing medically. And here, you can see that
69% of patients responded to induction treatment with infliximab at weeks zero, two, and six, the standard treatment, five
milligrams per kilogram. And then maintenance dosing would maintain fistula healing and clinical response over a one-year period in 36% of patients compared to 19% who got
placebo maintenance. So you can see that
there is a benefit here. It is statistically significant. I think it’s also a clinically
meaningful difference, given how refractory these patients are, but still there’s a lot
of room for improvement. And we’ve also been able to demonstrate, in these longer-term maintenance studies, that there is also an effect on decreasing the numbers of surgeries and procedures. You can see that there’s a
more than 50% in decrease over placebo maintenance in
the infliximab maintenance arm, as well, we see with anti-TNFs. And this, these are data from the CHARM study with adalimumab. You also see a decrease in
the hospitalization rates with maintenance dosing with adalimumab. There’s a relative risk
reduction of 78% at three months and at 12 months, a 57% risk reduction. We’ve known for a long time that the major cost of care is represented
by the cost of surgery and the cost of hospitalization. So these are important
outcomes not just for patients but also for the economy of care. And very recently, actually in this month’s Gastroenterology, we had evidence that, in
post-operative prevention of recurrence of Crohn’s disease, there’s at least
endoscopically apparent benefit when you put patients on infliximab after their ileal resection. You see a much lower rate
of endoscopic recurrence in patients who are
maintained on infliximab compared to placebo. So after a complication has occurred, after a surgery has occurred, you can have prevention of
recurrence of disease apparently, at least endoscopically. We need a larger study
and longer-term follow-up to know if this is really
clinically meaningful because the endoscopic
appearance is clearly just a surrogate for the
long-term outcomes, we think. So the real question is how can we best employ this
very useful set of agents in treating the disease? And what we’ve come to understand, that Crohn’s disease and
possibly also ulcerative colitis are diseases that are cumulative
in their structural damage. And what you see is the majority
of patients at diagnosis have inflammatory disease
without a penetrating or a stricturing complication. They don’t have fistulas. They don’t have strictures. These are the things that will
typically lead to a surgery. But over time, you see an
increasing number of patients who go from the inflammatory phenotype to arise one of these complications. And when you go out to 20
years, most of the patients have had at least one
complication of their disease. Also, from the same group in France, we have this interesting study where they looked historically at the use of immunosuppressives,
azathioprine, 6-MP, the things that we really had around in the two decades between 1978 and 2002. And you can see that, by 2002,
there were more than half of their patients who were
using immunosuppressives. And despite this, the rate of surgery in these patients changed not
a bit over these two decades. So these, we think of
as very potent agents. Why are they not reducing
the rate of surgery if they’re truly effective agents? Well, the question is are we using them at the optimal time in
the course of the disease? And the question then has
become, in this field, can early intervention
improve the natural history of Crohn’s disease? And if you think about this model, we start in a state of complete health, then probably there is a long or short period of
subclinical inflammation where we don’t know the
patient has the diagnosis, but the disease is sort of
grumbling beneath the surface. Eventually, they become symptomatic. Over time, many, most really, will develop one or more
complications of their disease. This will lead typically to a surgery or to disability over time. So if you think of where we intervene, we can prevent relapse or
recurrence after a surgery. That’s like the Regueiro study
that I showed you before, where infliximab was
given after a resection. We could prevent
complications, in other words, treat a patient before they’ve
had a fistula or a stricture. If we really could identify
patients very early or we knew that they were genetically or environmentally
susceptible to the disease, we could prevent it. We’re nowhere near that stage. Or we could prevent the
occurrence of symptomatic disease. But for the most part, our
treatments really focus up on this end of the arrow. Now, perhaps the earliest example of an early intervention
study in Crohn’s disease is this study by Markowitz, where they took children who
had never before been exposed to corticosteroids or
to immune modulators. They were sick enough to
require a course of steroids. All of them were treated
with a course of steroids, a steroid taper over 12 weeks. And at 12 weeks, you see that nearly 90% of
patients have a remission. But what happens over
the following 18 months? Well, you can see that only 9% of the kids who were put on 6-MP had a relapse compared to 47% of the
patients assigned to placebo. So this also correlated with a much lower cumulative dosing of corticosteroids, which is very important in
children in their growth, and is a suggestion that
you can improve the outcomes if you intervene very early
in the course of disease.

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