- 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.