- 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.
We also have data with anti-TNFs,
looking in post hoc analyses from these maintenance studies,
that the shorter the time from diagnosis,
the higher the response or remission rate.
In this look at the charm data with adalimumab,
you can see that patients who had been diagnosed
less than two years before had 59% remission rate
compared to 40% in patients 2 or more years out from
their diagnosis.
And likewise, if you look in the PRECiSE 2 study,
which was Certolizumab pegol maintenance dosing,
you can see that diagnosed
less than one year have a 68% remission rate. And if you
were included in the study more than 5 years out from your
diagnosis, this dropped to 44%.
You don't see much of a change,
maybe some in the placebo response.
And this thinking led to a very important, but still,
I would say, very preliminary study looking at a
comparison of early aggressive biologic therapy
to conventional management of Crohn's Disease.
The so-called step up, top down study.
We heard about this at DDW's repeatedly
for a number of years
and finally, last year, it made it to full publication
for all of us to look at the data.
This was an open label study where patients essentially,
all of them, were within one year of diagnosis,
except for 4 patients.
But none of them had been previously been exposed to
antimetabolite therapy, to anti-TNF.
None of them had received steroids before.
And the patients assigned to conventional therapy were given
a steroid taper. If they failed this taper,
they got a second steroid taper, and then finally
failing that, they were put on a antimetabolite,
either azathioprine or methotrexate
if they didn't tolerate that. And then finally failing that,
it would eventually see infliximab.
The early aggressive arm was assigned
to get infliximab induction therapy,
just three induction doses, simultaneously
to start azathioprine, and then
they didn't get any further infliximab unless
they had a flare through their azathioprine they would get
additional episodic dosing of infliximab and failing that
they would finally get steroids.
So here are the results.
Looking at six months into twelve months.
Looking at this fairly stringent endpoint
of being in remission
without steroids and without having needed surgical
resection, there was a statistically significant difference,
and I would say a very clinically meaningful difference
in the patients who got early aggressive therapy
compared to the conventional step up therapy.
And this difference was fairly large, 25% or so.
- But first, I have to say,
their initial design of this study
one arm was placed on steroids, two courses of steroids.
- That's right.
- There's caveat data about 33% of those people
are going to be steroid dependent,
and are not going to be at the endpoint.
So you have a 33% bias against one arm.
- And that's exactly why the study was not published
for so many years, because I think, every reviewer
said the same thing, in other words,
if your primary endpoint includes the need for steroids
and you're required in one arm to have steroids, you're
really kind of biasing against one arm.
But I'll show you other data to suggest that
this is still an important result.
Now, so at one year, this was a significant difference.
But beyond one year, actually, these lines converged.
The outcomes, really, became very similar
after one year. So you could argue, well what's the use
of early aggressive therapy, early biologic therapy,
after a year they look the same anyhow?
It's important to realize that even though that this
was a step up therapy, by one year more than 70% of patients
were on an immune suppressing agent. One wonders if
you had another arm and everyone was put on azathioprine
from the get go, would the outcomes be very similar?
We don't know. I think the most impressive thing about this
study though, is this result, which shows that in a subgroup
of patients who got colonoscopies year 2, you could see
complete healing of the mucosa two years out in 73%
of the patients who got early aggressive biologic therapy
and then azathioprine, compared to only 30% who were
assigned conventional therapy. Now this is far from
saying that this will result in fewer surgeries,
but we do believe that mucosal healing will be correlated
with subsequent outcomes. This was statistically highly
significant and I think the most impressive thing is to
realize that since by 2 years, most patients were on
azathioprine, most of this effect
is probably carry over effect from the initial
induction dosing of 3 doses of infliximab.
And to get to your point, Peter, if you take out of the mix
the first 14 weeks, where everyone had to be on steroids,
and you look at it just from week 14 from 2 years, and you
say even more stringently that
patient had to been in remission not at 2 years,
but for the whole time from week 14 to 2 years,
had to discontinue steroids and infliximab
and never used these things again over 2 years and had not
had the surgeries, you still see a huge difference, 24%
difference between early aggressive and conventional.
So I think these data are very meaningful, but again,
it's an open label study.
You can understand why they did this and an open label way.
It's very difficult to randomize patients
to complicated treatment regiments
and keep everyone blinded for two years.
But it's important data nevertheless.
By comparison, a somewhat more experienced group of patients
who had been around the block with Crohn's disease
have a different look. So these are not newly diagnosed
patients who had similarly induction dosing with infliximab.
All of them were put on azathioprine of 6-MP
at the beginning of randomization. And initially
you can see that those 3 doses of infliximab do very nicely
but over a year the lines converge.
It's still statistically significant, but when you look out
more than a year everything looks the same.
So if you failed azathioprine, very likely,
just induction dosing with infliximab is not going
to be enough to maintain you over the long term.
So if early aggressive therapy, if we agree
that may be effective, it may improve the outcome,
why would we not treat every patient this way?
Well apart from the cost of treating every patient
with biologic agent, there are certainly other reasons,
and mainly it's concern over the safety anti-TNF agents.
You are probably all familiar with these warnings and data.
Hypersensitivity reactions usually are not a reason why
patients will need to stop an agent.
It's usually loss of response related to antibodies
to the drug. There are also autoimmune phenomenon,
newly positive ANA in roughly 40% of patients
exposed to infliximab. Lower rates in patients
with certiolizumab pegol exposure.
Lupus-like reactions, however, are quite rare.
TB, serious infections, histoplasmosis.
Do you see histoplasmosis in Michigan?
- [Peter] Fortunately, no.
- [Speaker] You don't. We don't see it either,
but there are places very close to both of where we live,
where this is a problem. Hematologic toxicity is uncommon
if a patient has moderate CHF, this is a relatively strong
contraindication to anti-TNF agent where you do see
an increased mortality rate. But I think the things
that really concern us are malignancy, especially lymphoma,
including hepatosplenic T cell lymphoma, which is very rare,
Eighteen reported cases with anti-TNF antibody use
of various sorts. And we worry about infections.
There is also rare demyelenating disorder,
a multiple sclerosis like illness, peripheral neuropathies,
liver failure, and so on.
But again, the main concerns are malignancy,
especially lymphoma, and infection risks.
So what are the date there? We do have data
from a prospective registry called the TREAT registry.
This was sort of a cohort of convenience.
These were not consecutive patients.
We don't know how exactly the patients were selected.
These were combinations of academic medical centers
and community practices enrolling patients who were
either exposed or not exposed to infliximab.
And in multi-varied analyses the things that predicted
serious infection and mortality were not
exposure to infliximab, not exposure to immune modulators,
but rather the current use of corticosteroids
and interestingly current use of narcotic analgesics.
I'm not entirely sure how to understand this one,
except that this is a marker
for more severe disease, more symptomatic disease.