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Part 5/7, Dr. Dubinsky discusses genetic and immune markers and IBD


– That could be a disaster for someone who underwent a pouch you could imagine. You’ve removed colon and
now you have small bowel that has CBir hanging
around and wreaking havoc and that’s basically what it does. So what this group is these
are really UC like Crohn’s, meaning they behave just
like ulcerative colitis. pANCA is a very strong
drive of a UC-like behavior. PANCA trumps CBir while
the colon is in place okay. It’s not gonna behave, it’s not gonna get
small-bowel inflammation. It’s gonna look, you can do a
capsule as long as you want, you can do whatever you want the small bowel will look fantastic. You’ll send the patient to colectomy, the patient’s sick okay, they merited, they failed therapy, I’ll show you why they’re
gonna fail therapy. They failed Remicade because of the pANCA. And basically what
you’ve got is you’ve got this UC-like Crohn’s patient. Of course you’re not gonna not operate this is a sick, you know,
it’s UC-like remember. I think one of the things
we’ve gotta get out of is pure Crohn’s, pure UC, and think about CD-like behaviors and UC-like behaviors, immunologically they
have behave differently. And this is a unique
phenotype which is this group. So you can see that in
pANCA-positive Crohn’s 44% of patients are CBir positive, but in pure UC, in the best
of our diagnostic abilities, maybe we weren’t good and we missed them and that’s a possibility, but in his best workup, and
his best definition of UC, he’s small-bowel normal,
upper-track normal, no perianal disease, no rectal
sparing, blah, blah, blah, all the list of what we define UC, less than 5% of patients
were CBir positive. So the question is what
does this mean, right? Immunologically does it mean anything? Does it impact treatment outcomes and more importantly
will it impact prognosis. So just remember that
there’s this unique pANCA CBir-like phenotype, what does it mean? All right, in 2001, before CBir was actually
introduced to our world, in 2001 Phil Fleshner actually said, if you have high pANCA before colectomy, this is serum drawn
before the colon’s out, we were blinded, you don’t
know what the pANCA was until we actually measured
as part of the study, 56% of these patients were
developing chronic pouchitis. Chronic pouchitis meaning,
antibiotic dependent, and/or antibiotic-resistant pouch. And you’re like, oh my goodness, bummer, I just took this
colon out and literally like within four weeks even patient’s could be back with 20 stools and they’re asking you, did
you not remove my colon? I could swear this scar means you did some kind of surgical intervention, but I feel like I have my UC back and they describe it
quite certainly like that. And what this is showing
you is that above a hundred you had chronic pouchitis 56%, and less than 40, 16%. So I love to send pure pANCA
CBir-negative patients, by the way, to surgery. Meaning I feel low pANCA,
I should less than 40, CBir negative I’m like
this is the perfect patient for colectomy if I need to. Immunologically to me it’s the best group to send to colectomy
and I’ll show you why. Because we then uncover,
Fleshner did three years later, or seven years later,
it’s published in 2008, and said, it wasn’t just pANCA
that was causing the problem it’s those patients who are
pANCA greater than a hundred and CBir positive. These patient’s to me
actually have Crohn’s disease, they actually don’t have chronic pouchitis they now have this new form
of Crohn’s of the pouch. We’ve not brought CBir, which
is a genetically-driven marker which is a marker of
small-bowel, Crohn’s disease, we’ve brought this ileum out to the anus, exposed it to bacteria
that it never saw before, it’s now colonized, and it’s
now taken on the role of, basically we call it pouchitis, but if you actually look
and you look up the ileum it goes up for miles potentially,
there’s inflammation. And the cool thing about it is it’s to differentiate the next group that I’m gonna show you,
is it looks like UC. It’s superficial, it’s got
a response to antibiotics, even the ileal part
responds to antibiotics. So it’s a very unique, CBir
is a bacterial-driven antigen, there is no doubt. We actually know the bacteria, we know that this is of the, all of the serology that are introduced, CBir’s probably the strongest, you know, message in terms of the
bacterial etiology of IBD. But here you have a patient
who went to colectomy ’cause their pANCA
trumped everything else. You’ve now removed the colon which was pANCA associated and now you’re small bowel
kind of Crohnsy behavior is coming out and the only
saving grace for these patients is they do typically
respond to antibiotics. However, what we do is
in a patient who is, the minute their ileostomy
is down, meaning in, they’re on antibiotics for
the first year after that, after their pouch, after
the ileostomy is taken down. Why a year, I don’t know,
Bo tells me the first year is the worst year for the pouch, that’s all I can, you
know, imagine saying, is that I feel the first year
adapting the pouch bacteria, could be wrong, a lot of them
need to stay on it forever, don’t give me wrong. You all have chronic pouchitis patients who just can’t come off of antibiotics and they’re on it. And it could be that this is the group. So the reality is, for me, what I do is I do not negate a colectomy and I don’t tell them
they need an end ileostomy if they’re this group,
right, if they’re pANCA CBir. I do tell them that there’s a good chance they’re gonna be dependent on antibiotics, but I also do tell them
the minute pouch is down they’re on antibiotics, meaning we’re not waiting for them to develop chronic pouchitis. Because most of them develop it in a very short period of time. So 50% of patients who
develop the instance of chronic pouchitis, 50% in those that are CBir and high pANCA. So why wait for your patient? I mean I know it’s 50/50, but
we’re here for prevention. We’re not here to wait for
patients to get sick, right, this is what we’ve done our entire lives as
clinicians in IBD is react. We’ve never, we are now,
but before biologics we weren’t proactive and
you know in the community they are proactive,
right, they’re reactive. So the reality is we need
to start being proactive and setting this mantra
of being proactive in IBD and this is one area you may want to think about being proactive. This is another form of Crohn’s disease. This is different than the ones that look like you see when you look in. This is a group of patients who underwent colectomy, with
ulcerative colitis diagnosis, and/or IBD unspecified indeterminant. You know, IBDU is the new term
for indeterminate colitis. IBDU is before colectomy
and we’re saving the term, indeterminate, for after the pouch, after the colon has been
examined by the pathologist. So this is the new NIDDK and all of our phenotype classifications, is IBD Unspecified. Post-op, medium followup,
four years to date, 16 patient’s developed classic Crohn’s. You look inside, fistulas,
stricturing, stellate ulcers, it looks just like the ileum would’ve in someone you newly diagnosed with bad ileal Crohn’s disease. And what we found is
that those individuals who develop in the Crohn’s patients, who had these issues, 20% compared to 4%, had an ASCA IgA that was positive. Remember, I said ASCA is
very classic Crohn’s, right? It’s the one that presents
with that stricturing, or bad inflamed small-bowel disease. So it would make sense
that ASCA is a predictor, but the most important predictor of who will get classic
Crohn’s of the pouch is just take a family history. It’s actually the strongest marker that your patient will have
a complication of the pouch that looks just like Crohn’s. Look at the hazard ratio. If you have a family history
of Crohn’s, 8.4 hazard ratio for predicting Crohn’s, classic Crohn’s of the pouch. Versus ASCA, yeah, 3.1,
you know, P-value .04, just slightly over one for
the confidence interval, but this is a very strong predictor of who will actually get. And Bo actually replicated
it ’cause he said, I need to go back and see my patients and he found the exact same thing. Family history of Crohn’s is the most important predictor of who will get classic
Crohn’s of the pouch. So when you have one of these variables, so either, a ASCA or
family history, or none, this is your prediction of getting classic Crohn’s of the pouch versus close to 75% of probabilities when you have both ASCA
and family history. So what would you do? Would you tell them no pouch, or would you do a pouch and put them on 6-MP, post-op prevention? It’s all up in the air right now no one knows, right? And everyone challenge, we give our case conferences of Wednesdays and of course I’m always the one who has this patient for some reason and so it’s a matter of communicating with the patient saying,
this is the probability, I know you just were on all
these meds and failed it. The problem is just like
a post-op Crohn’s patient. You have an anastomosis,
just like ileocecal, the same bacteria in a way, and you have a patient who’s got ASCA and a family history of Crohn’s, we should be prophylactic against the anastomotic recurrence really, or Crohn’s of the ileum.

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