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What matters most in IBD?  Part 1/7


– The University of Michigan Division of Gastroenterology and the Inflammatory Bowel Disease Program host the IBD visiting
professor lecture series in Ann Arbor Michigan. The series presents the
latest in clinical research and basic science from IBD
experts from around the world. – (Professor Van Assche) Well thank you for inviting me here. It’s
both an honor and a pleasure to be here in Ann Arbor.
It’s my first time but the impression is
overwhelming to tell you. I’m meeting the people
and also the university, it’s quite a setup you have here. I did change my title a little
bit so I cheated on Peter cause he, if you look at the flyers, it says like short term outcomes in IBD. And I don’t think there’s the irrelevant. I think we should always look long term for all our patients. So, I am going to mix short
term and long term a little bit and I’ll make it clear for you. Just as a sort of introduction, you probably don’t know that, but a lot of the people
from the region where I live moved after the first
World War to this region, Michigan, and specifically to Detroit. Our country was in shatters
after the first World War, and so there is still a
Dutch-speaking gazette from Detroit that is published since 1914. – (Professor Van Assche) So,
there’s quite a few people from our region that
moved here are still here. Just evidence-based medicine, I Googled my name and Detroit. And sure enough, there’s
a Joe Assche the third, so probably his third generation. There’s some plumbers, so it runs in the family, fitting tubes. There is a Van Assche Construction, not too far away from here. And Linda sneaked into
the animal hospital, she changed her name to
stay under the radar, but, I still found her. So, there’s only my last name, and it’s not a very popular
last name in Belgium, it’s all over Michigan. These are my levels of
contamination at this time. (laughing) So, I don’t have to repeat this to you, but, I mean you all know that
IBD is, we don’t really know what’s going on, but by any means it’s an interplay between immune factors, genetic
factors, environmental factors. And what is happening in a patient is this vicious circle of
inflammation, tissue damage, loss of organ function, and surgery. And this translates for
a patient in symptoms, such as pain, diarrhea, and
a lot of other symptoms. So let’s look at those symptoms
a little bit more closely. Now, to bring you down on Earth, this would be the ideal drug for IBD. 100% induction of remission
and 100% maintenance, no laws of response. Well, keep on dreaming,
we don’t have that drug. These are steroids, too toxic,
so we’ll taper them down. Here’s (muffled speaking), 6MP, you can steroid spearing effect. And to be honest, with the
entity (muffled speaking), we’re probably in the same
ballpark at this time. So, there’s this gap, therapeutic gap, that we don’t fill for our patients. So my question to you
is the gap so wide or are the endpoints of the
clinical trial maybe not perfect? And also the selection criteria. And that’s what I am
going to talk to you about in the next 10-15 slides. This is the reality of the
the anti (muffles) agents, like the New Kids on The Block, where everyone talks about, well, if you go across the
board of all the agents that have been tested both
in UC and Crohn’s disease, you see anywhere between a 20% and 40% non-responder rate and onset. So, that’s reality. Are these all non-responders?
We don’t know. And again, to add a level of complexity, there’s a difference
between a patient you see in your office and a
patient in a clinical trial. You all know that, but I
just wanted to point out the differences again for you. In a clinical trial, there is a strict patient selection. Both for avoiding adverse effects and increasing efficacy, you know that. You do some patient
selection, to a certain extent but you can’t do the same patient selection that is being
done in clinical trials. Your patient selection
in Europe and Canada, is based on label restrictions. I know that’s a little bit less
in the U.S. and cost issues. Right, prospectively
defined efficacy end points are very important in clinical trials. But, it’s not what we’re
using in clinical practice. We use more a physician or
a patient global assessment. And, then of course, the CROs are there to have a very strict monitoring
of your trial conduct. And they always say that the
FDA is going to audit you, so please, Doctor, comply. Please, nurses, coordinators, comply. Well, what we do is our routine follow-up.
And I’m sure that the U of Michigan follow-up is different from that in the mail, or the
Toronto, or the one in Leuven. So we all have our tricks to the trade that are not in a protocol. And, of course, a study is
double blind, or should be double blind, where we are all
employing the placebo effect whether we want it or
not, we’re doing that. And of course, trials are
designed to show efficacy. While you’re a problem solver, you don’t have any privy
design for your patients. I mean, you try to tailor all
therapies to your patient, but, at post hoc, you’re solving problems. And this is a sobering
slide, but it’s very true. I mean, the Crohn’s disease
activity used in the studies by EMA and FDA to judge trials, and that is employed by companies, has a lot of subjective
components and you know that, severity of abdominal pain,
number of loose stools, general well being. It’s
all quite subjective. You see, know better. Number
of stools, rectal bleeding probably rectal bleeding is
a little bit more objective, but still, it’s reported by the patients, and a physician global assessment. What’s that? Where’s the
wind coming from today right? So, it should be objective but, we all know there’s biases in there. And, it’s no surprise that if you give if you give IBS patients the CDAI, they may have mild to
moderate Crohn’s Disease. If you just, don’t think of them as patients with irritable bowel system. And this patient, for example, they will have pain, but
what’s the cause of the pain? Sure, there’s ulcerations, you
can see the cobble stoning. But, is this the cause of the pain? You don’t know. It could be
obstructive symptoms also due to the fibrosis. It’s
really in the air there, where what your patient is suffering from. And the ancient books of the Medieval, physicians and surgeons,
had for inflammation, the characteristics of rubor,
tumor, dolor, et calor. And so the dolor is the pain.
And where does it come from? Well, we know that active
inflammation triggers afferent nerve impulses, and a lot of the motility people in
this room, write article after after article about post
inflammatory hypersensitivity and that’s probably occurring
in patients with IBD. But also, strictures
provoke obstructive pain, due to a prestenotic
increase in wall tension. And that’s not necessarily linked to inflammation, we have to be careful. So this is just a panel
of the studies that have been reported since
2004 of 2002 on patients with clinical remission IBD
having IBS type symptoms. And you see across the board for UC, there’s a 32 to 40% prevalence
of IBS type symptoms. Rome 1 or Rome 2 criteria.
Crohn’s disease even higher. The last report from the group in Cork, is 60% using the Rome 2 criteria. So, yes we are dealing with symptoms, patients in remission, on a CDAI, they’re still having
symptoms, that look like IBS. I’ll come back to that at
the end of my presentation. Is this IBS, or is it something else? If surely not IBS, we
shouldn’t call it IBS. But are these functional
symptoms due to motility or hypersensitivity, or is
something else going on. And this we should not forget. The placebo effect is there. And here, I’ll switch over from
symptoms to bio-markers. Because what we’ve learned
from the bio-markers, is that what they do is
bringing down the placebo effect (muffled speaking) First example, Opal Label Experience, Ligne, Belgium, Edward
Louis was the first author. Already, before the thing came about, he was looking in 2002, at
his patients treated with infliximab, only to show
that in patients with an increased CRP, about 5
milligrams per liter, there was a much higher
response rate than in those with a normal CRP. So first indication, do we have clinical
trial data? Yes, we do. Certolizumab-pegol. One
of their first studies reported was negative.
But, what was happening, if you increase the CRP of baseline, so you stratified post-hoc
for the patients with an increased CRP, what you saw
is that the placebo rate was going down with increasing CRP. Not so much the active drug rate.

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