- So that's up for discussion and really,
it's an evolution, but I think if you,
again, wanna practice way in advance, right?
You wanna really be proactive with this patient.
I think there'd be very little harm,
or you wait, you scope them in six months,
just like you may do with a post-op patient,
you may choose to do nothing,
patient says "forget it, I need to detoxify,
you've had me on all these poisons,
I need at least six months to get all this out
and then re-scope me in six months,
I may not be symptomatic but look in,
if I start to have ulcers then you,
just like a Crohn's patient
and then you start the prophylaxis.
Would you ever give a biologic
to a patient who has ulcers, asymptomatic,
just like a Crohn, like a records too,
but looking at a different anastomotic area?
Maybe.
This is all for discussion.
Okay, so let's end with therapeutic outcomes
and just focus on where the second phase
of the next decade is going which is
individualized pharmacogenetics, pharmacogenomics
and starting to think about stratifying patients
into which therapy they should get.
So, I'm gonna just focus on serologies,
we have a whole, the paper was published
in IBD journal or it's on E-pub in IBD journal
where we ran the entire genome
against remicade responsiveness
and found four genes that were
actually associated with strongly with responsiveness.
But I'm gonna just focus on serologies
because that's commercially available
and/or available, it's a concept,
we've had serologies for a long time.
Running a whole genome and where are you gonna buy this
and what commercial lab is gonna run
the entire genome for you for ten dollars,
it's not happening right now.
So let's focus on serologies,
which we get for other reasons.
And so this dates back to '01,
in '01, it actually was thought
and suggested based on original data
that pANCA was a predictor of non-response
to anti-TNF therapy in Crohn's patients.
What this was, if you could believe it,
these are the original 1997 New England Journal
patients from one dose of remicade.
Two-thirds response, one third non-response
at 12 weeks, remember that, those days
when we gave one dose of remicade?
That was, however, 13 years ago
and now, these are the patients
and we wanted to know, why was there
a disparate in those patients as to
who responded and who didn't?
And my mentor, Steph Targan, really is the one
who pushed through all of these
immune reactivity markers and said
immunologically, which is how Steph,
immunologically, they must be different.
So he went back and he ran serologies
on the entire cohort from the study
and actually what it ended up being
is that the patients who accounted for
the response in the original Crohn's study
were ASCA positive, pANCA negative
and those patients who did not
mount a very strong response
were pANCA positive and ASCA negative.
So remember what I said.
pANCA's on one end, ASCA's on another,
what I can also tell you is ASCA loves anti-TNF therapy,
it's a TNF, there's something
associated with pure ASCA and TNF.
pANCA, not so much.
Isn't a player with TNF
and that's why, in your UC patients,
who are pANCA positive,
you may get an initial response,
'cause anyone with inflammation has TNF hanging around,
there's no doubt that you have TNF
even when you go to Mexico and get sick.
TNF is a player in inflammation.
But the reality is, what's the real player
in a pANCA positive patient?
What is that immune reactivity
that we need to be suppressing?
It's probably not anti-TNF.
So the reality is, what we often see
is patients get better after the first two infusions,
by the time they're coming for their week six
or maybe you can get them out to week 10,
they're back to exactly where they were
before you started the biologic.
And I would guess pANCA's a major player in that.
And what we told Abbott when they were
running their Abbott trial for UC,
which wasn't very successful,
they said why do you think people didn't respond?
I said did you do serologies?
You need to start to stratify,
whether genetic, I don't care if you do stool,
some kind of stratification,
so you could've gotten your drug to work
85% of the time, for example,
in people who are pANCA negative,
ASCA positive, or, actually that means they had Crohn's,
so take that away, but in the right,
that would be hilarious, but in the right diagnosed patient,
seronegative, for example, or low pANCA.
So this was a study from Europe
that confirmed that in early responses
as patients who come out of the gate
and at basically 10 weeks looking at early induction
and another study that showed
if you're pANCA positive, ASCA negative,
it's a 50/50 chance of you responding
in the short term, long term we don't know,
there wasn't a maintenance component.
If you're seronegative, seven out of 10 patients
had a response to the induction
and if you're ASCA positive you have Crohn's
so you have 100% response rate.
This was in their UC patients,
so this was the European cohort.
So again, hinting to the fact,
immunologically, pANCA is a unique subtype,
ASCA's a different subtype,
therefore we should stratify patients
based on their underlying immune phenotype.
So this is the paper that's in E-pub in IBD
and this is showing you our data,
showing you that 76% of patients
who did not respond to induction of infliximab
were pANCA positive versus only
a third of patients who responded.
So again, hinting to the idea
that, immunologically, there's a difference between
this patient and that patient
and maybe you should start to
individualize your treatment based on
their underlying immune response
and stop trying to classify them as UC and Crohn's
and saying, oh, we can use this in everybody,
but to start thinking one level deeper,
literally, what's going on at the mucosa?
And start to target those patients.
So the last notion, which is just
to show you the treatment impact
on the natural history, this is myself
and Corey Siegel and was actually
just accepted yesterday to IBD journal, is to,
our goal was to develop and validate
a graphically displayed patient communication tool
so you can appreciate our goals of doing this
and it really was to visualize risk to patients.
To have this as a discussion risk tool
and Dartmouth is, this is what they do,
they're very much into decision tools for patients.
And so, what this is, those 796 patients
where I showed you the surgical curves
and I showed you the six-fold increased stricture
and 9.5 increased risk of penetrating, these are them.
So, what we have is on the computer program,
you can actually alter the toggles
so you can say that this patient
was a 16-year-old female who had
both small bowel and peri-anal disease
and she was positive for all the serology.
Okay, so this is, obviously you know where
I'm getting to because I showed you all the predictors.
The only thing I needed to add was,
had very deep ulcers at diagnosis
so you can appreciate what the natural history
of this patient is.
So based on what we know, the hazard ratio, etc,
we've calculated based on this model
and if this patient walked in your room
and the patient said to you, what's my probability
of going to surgery because of a complication?
Based on our modeling, you could see
that out to two years, or even less,
a year and a half,
100% of patients would end up with a complication.
If you met this criteria, right, this is important.
Now a six-year-old boy with colon only.
Complication rate's about 25% over a long period of time.
So again, and who has very low quartiles,
very low serologies.
So it's about starting to differentiate
your patient into risk, so that when I sit
in front of a male patient who's six
and I'm telling the mom, we really need
to go on biologics, maybe I need to rethink it,
maybe that isn't necessarily what we need to go on to,
because maybe I'm not gonna change
the natural history of the disease
and I actually have that slide in a six-year-old,
but I think I only have it for, here,
this is a 16-year-old female.
This is true treatment data.
This is what we actually did,
meaning, in the patients that we had,
he actually took all of our treatment decisions
and we were blinded to it
and we actually sent it to him,
each of our different sites and then
they actually put in
treatment option one is within 90 days,
treatment option two is after 90 days.
So in those patients who got biologics within 90 days
and these are the patients who had
peri-anal, small bowel and 16-year-old,
this is what their natural history looked like.
So that's a much better way of communicating
to patients that you can actually
alter the natural history and you believe it,
we believe it, we think we can actually slow down,
didn't you show we can slow down fibrosis.
Yet, your grant will, your R01?
Okay, so you will show that we can
actually, hopefully slow it down and alter
and it's all based on early intervention,
I mean, that's what I think, even more so,
the discussion with our families and our patients
is please, use it early, right, if you're gonna use it
and we go out and give talks to community physicians.
Our message is, please don't wait five years.
This is what our message is, use it early
before you get too far gone in the process
and this was a way to communicate,
I mean it looks like an absolute reduction of 75%, right?
Maybe it is, I don't know, we're currently
validating it prospectively in our peds population
to try and see and we're also
gonna do it in an adult population to see if this is true.
So, and this is what I love.
This is the last point which we all
need to recognize is, when we use
steroids in our patients.