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Know About Ulcers Blog

3/7 – Dr. Marla Dubinsky discusses role of genetic and immune markers and IBD


– So it fits with the complication risk and the surgical risk going up. So, how can we predict these patients? Okay, lets step to the clinical
forum for just a minute, since the fellows and the residents and us see patients clinically. Is there anything at the time of diagnosis that can actually help me
start to stratify my patient clinically into a high risk group? So, this was the group
published in France, Publishing gastro in 2006. The title was really
about disabling Crohn’s. Now, in America, we never use
that title “disabling” right? Our patients are already
calling us for parking passes. So, the reality is, we
really try and limit the use of ‘disabling’ so
it’s a French translation, so that’s why it actually,
I’m surprised the editors didn’t ask to change the
title, but what disabling to them meant, which is intuitive, you need amino modulator,
you needed surgery, you progressed to more aggressive disease, develop complications,
structuring penetrating disease. These were their clinical
variables at diagnosis, Which actually should
send some kind of red flag to you to say, your patient will progress to a more aggressive disease. Well, we’ve been talking
about the fact that if you need steroids at
diagnosis, your patient should be on amino
modulator forever, right? This has been an ongoing discussion, whereby in Crohn’s, not necessarily UC, but in Crohn’s disease,
if you have an individual who requires steroids up
front, what we’re saying and the teachings are is
that patient should be on an amino modulator,
because your exit strategy of just staying on mesalamine
for more complicated Crohn’s disease is an
unrealistic expectation that your patient’s going
to do fine after one course of prednisone if they’ve got
deep ileocecal Crohn’s disease. That’s probably really an
unrealistic expectation, as I say. So, we’ve now shown over and
over in multiple studies, that you need to think
about an exit strategy when you start steroids. Other things, we as
pediatricians laugh, of course, is because we think there is no difference between a 39 year old and a 41 year old in our ability to phenotype,
but I can tell you there’s a huge difference
between a nine year old and a 39 year old, right? So, we have a new classification system that’s going to be coming
out that actually is going to be less than 16 and then
less than eight, actually based on a lot of this
data that’s come out. So, in the Montreal classification, which is a phenotype classification, we’re redoing it for pediatrics, and we’ve added A-one-A, which is less
than eight years of age, so there’s going to be an even better way of phenotyping pediatrics,
and no one will dispute that Perianal disease at diagnosis is a bad prognostic indicator. And I don’t think just a simple fistula, I’m talking a complex fistulizing process, and I would even say, and
I don’t know if that’s what you guys do, is that, if you’ve got Complex Perianal disease,
do most people agree that biologics should be
the first line, right? I mean, there’s no messing– This is a, to me, Perianal
is one of the most malignant forms of Crohn’s disease. Something that’s complex, and therefore patients, to me, there’s no negotiation. They can negotiate. I had a father, just to
explain the LA culture, I have a father who is
transplant nephrologist who deals with all these amino modulators and amino suppressives. His nine year old son, has
complex fistulizing disease, where he has now three c-tons
within a three week period. Four abscesses, posterior (mumbles) anal fistulas and abcesses,
and the father asked me if I can use low-dose
naltrexone for his son because he read about the lymphoma risk associated with TNF, and I said ‘Sure, but a permanent
ileostomy is probably not what your son wants, actually. So, I’d say that maybe a biologic
would be more appropriate, and let’s resume the discussion of low-dose naltrexone in a year, right? Let’s table that for about a year. The reality as I said is that
this is the most aggressive, and in kids who get very complex Perianal, they will lose their rectum. There is no doubt. And therefore, we have
to advance pretty quickly to a biologic, and even amino modulators wasn’t going to really, we
don’t have the 12 weeks, I mean, within a three
week period, he now went to the OR three times, I mean,
it just wasn’t going to work. So, we know that (mumbles)
Perianal disease is important. And remember, Perianal
disease when I show you a little model that we’ve
come up with in terms of predicting aggressive disease outcomes at the end of the talk. So, what other variables
can we think about? Well, endoscopic ulceration. Should the depth of the mucosal lesion, when we look in at our initial diagnosis, should we be using that
to gauge how much healing we actually need to accomplish, and whether or not even
waiting with amino modulators is an appropriate timeframe when you have some with deep endoscopic ulcers. So, I always think about, you look in, and you’re like ‘Oh my
goodness, if I just push that scope just a little
bit, I may perforate’ or whatever your mindset is. That’s a patient that
probably steroids, is probably not going to be an
appropriate intervention, and you should think about biologics. So, there’s increasing data and interest in depth of mucosal ulceration
as being a predictor of when you should start
to engage biologics, and steroids would be
a negative association with outcome in this particular patient. And we’re talking about those patients where you do historically
small bowel follow through, now evolving to MRE and
CTEs is that you see those big rose-thorn ulcerations
that we used to see on small bowel follow through. That’s not a patient that
should be a corticosteroid, that’s a patient who needs to be healed, because that patient
is basically developing micro-prefs and is having, is going to perforate potentially,
and if indeed we believe the idea, that steroids
actually make things worse, and inhibit healing, you
may actually (mumbles) may be right in a certain
subset of patients that corticosteroids may
actually worsen prognosis and I’ll show you some data
to support that as well. So, this was a study
that was published in AJG that actually looked at
the presence of severe endoscopic lesions and again,
not to get into severity, but you can also imagine
that a DDW this year there was so much stuff on mucosal healing and change in the activity
index as a way of predicting outcomes in a year. So, looking at, for example,
(mumbles) trial extend which is the mucosal healing data, they looked at outcome
at 12 weeks mucosally to predict the outcome at 54 weeks. Of course, complete mucosal
healing was an unrealistic outcome and actually did
not predict 54 week outcome but we think that’s too early to actually look for
complete endoscopic healing. But a significant change in the score was very highly associated with outcome. So, endoscopic improvement is probably what we should be trying to achieve. And there’s a lot of discussion now. Do we scope all our patients
at four months, five months, six months after starting biologics? Should we be doing some
kind of MRE, pre, post, some kind of way of
measuring that we’re actually approaching an outcome
that we’d like to achieve, because depth of endoscopic
ulcerations actually led to colectomy in these patients who had severe deep colonic ulcers. So, does the idea of looking
at the endoscopic image actually help you choose
which therapy you’re going to use for your patient,
and remember, none of these are in isolation. Even when I showed you the serologies or if I show any genetics,
there’s really not one thing. So, the ideal thing to do,
which you’re going to appreciate is developing a risk model, right? Is to actually think about
putting all the pieces together and developing the strongest model of risk to actually communicate to your patient that based on all of these
variables, your risk score is A, mine is B, yours is C et cetera. And be able to communicate
why you feel that this actual pathway is the best
therapeutic pathway to go to. And I can tell you, and I don’t know if it’s the same in adults, but our whole practice has
changed regarding lymphoma. Meaning, all we do is counsel
and provide psychotherapy for our patients who
have actually been told they need biologics, and are
coming for a second, third, fourth discussion about the
risk of lymphoma and infections, particularly lymphoma in under
23 year olds, for example. The FDA did not do us a
favor in August by putting up that it kills children
and causes cancer. It wasn’t really helpful for
us, who prescribe it regularly. So, that’s been a big
struggle for us, is to try and appreciate, and try and
get the families to appreciate that the biggest risk to
their child, for example, or an IBD patient, is the disease itself. Not the therapies that I’m giving you but the actual disease itself. So, talk about serology. So, I said, endoscopic, maybe there are some clinical parameters, maybe
some radiologic parameters that we’ll be thinking about. And the next phase will be genetics. So, we’re right now
running the entire genome against natural history
so we’ll be able to share that with you probably,
I guess at DDW or if not, in a publication before,
talking about how genes interact with natural history at a
level of the whole genome as opposed to individual candidate genes, which is probably missing something if you’re just focused on already uncovered susceptibility genes. But we feel that serologies
are one step further, remember I felt, whether it’s true or not, serologies are even further
down the line towards clinical phenotype than the gene. There’s so many things
that modify genes, right? But it’s felt that the
serologies, the actual

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