May 28, 2025 • 35 mins
Dr. Michael Bernhardt, a dermatologist and clinical researcher, joins Dr. Erich Schramm to discuss the revolutionary advancements in psoriasis treatment over the past two decades. The doctors discuss how psoriasis is an inflammatory disease more than an autoimmune disease. They discuss what inflammation is, the inflammation pathway in the body, and how different medications can help suppress the body's out-of-control inflammatory response. They go over the history of psoriasis medications, which ones may be appropriate for different severities of the disease, and what's on the cutting edge of psoriasis treatment.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Announcer (00:00):
Welcome to MedEvidence!, where we help you
navigate the truth behindmedical research with unbiased,
evidence-proven facts Hosted bycardiologist and top medical
researcher, Dr.
Michael Koren.
Dr. Erich Schramm (00:11):
Hello and welcome back to the MedEvidence!
podcast.
I'm your host, Dr.
Eric Schramm, sitting in for Dr.
Michael Koren.
Today he's out on
Dr. Michael Bernhardt (00:20):
Maternity leave.
Dr. Erich Schramm (00:21):
Maternity- leave.
That's right.
It's my pleasure to be herewith you.
Just a little background formyself for those who don't know
me I'm a long-term clinicalresearch investigator and have
been with the ENCORE ResearchGroup for more than 20 years.
My training and background isin family medicine.
I'm a board-certified familyphysician and have been in
primary care practice for morethan 20 years, though more
(00:44):
recently I'm specializing incannabis health, so I help
patients, guiding them on theirjourney for healing in the
medical marijuana space.
I'm very excited to be herewith longtime clinical research
colleague and one of my favoritedermatologists, Dr.
Michael Bernhardt.
Dr. Michael Bernhardt (01:04):
Thank you .
Dr. Erich Schramm (01:05):
So Dr.
Bernhardt and I go back a longways.
I recall the time that back inmy residency training he took me
under his wing, had a greatrotation as a family medicine
resident in his clinicaldermatologist office and came
away with a lot of practicepearls from that that I still
(01:27):
find useful today when I'mseeing patients.
So that is greatly appreciated.
Thank you so much.
Mike has a great background inclinical medicine probably three
or four decades at this point,I think and as well as thinking
about his background inacademics recently teaching at
Florida State University, theresidents and the med students
(01:50):
there Is that right?
Dr. Michael Bernhardt (01:51):
Correct.
Dr. Erich Schramm (01:51):
Yes, sir
Dr. Michael Bernhardt (01:52):
Helped run a residency program for
three and a half years.
Dr. Erich Schramm (01:55):
That's right.
And also touching base onlong-term clinical research
experiences and background inclinical research, and I think
that was going back to 2010.
Is that right?
Dr. Michael Bernhardt (02:09):
I've been here since, I think, 2008 or
2009.
I remember we started doingsome of the early phase three
clinical trials for drugs whichare now almost fading out of the
market Things like Taltz,Cosentyx, Siliq, and some of the
topicals.
So we've been at this for awhile.
Dr. Erich Schramm (02:26):
Yeah, and that's actually.
You know, we'll be talkingtoday, we'll sit down, we'll
kind of do a psoriasis 101discussion, really kind of drill
down on some of those things,and we can talk about the
treatments and kind of theevolution of those treatments
because, you know, 25 years agoin my training in your office,
(02:50):
we really weren't talking aboutthose kind of therapies because
they didn't really exist at thattime.
So that's going to be kind ofan exciting topic to get into.
Anytime, I'm sitting across thetable from a clinical
researcher.
You know, one of the firstthings I want to know is hey,
what got you interested in thisand got you wanting to pursue
research?
You know, it's really kind ofan interesting evolution,
because I started doing this, Ithink, in 2008, 2009.
(03:12):
And a couple of things.
I mean back then, really upuntil the early 2000s, I used to
call it institutionalizedmediocrity in terms of how we
treated our patients, becausethe therapies that we had were
institutionalized mediocrity interms of how we treated our
patients, because the therapiesthat we had were
institutionalized standard ofcare.
They were garbage.
I mean literally garbage.
All we had back then were drugslike methotrexate or
(03:35):
cyclosporine, which are greatdrugs they have the use, but in
psoriasis they were reallysuboptimal.
And then around 1999, 2002, adrug called Amevive came about
and it was the first injectabledrug for psoriasis and in the
15% of patients that it worked,it was a home run.
(03:57):
People got clear.
The problem was the other 85%didn't really do much.
And then around 2004, somewherearound that time, Embryol came
along and Enbrel was a gamechanger.
Enbrel and Remicade wereabsolute game changers.
They blocked an inflammatorymolecule called tumor necrosis
factor, TNF1.
And at that time we all thoughtTNF1 was the central hub that
(04:23):
drove all the inflammation inpsoriasis, which of now we know
is not true.
And then when, around 2008, 2009, when we had the big recession,
I had people coming into myoffice who were literally facing
foreclosure of their house,repossession of their cars, and
when I started talking to themabout some of these drugs, like
(04:44):
Humira and Remicade and Enbrel,their eyes would glaze over
because they lost theirinsurance, they didn't have
money.
And then, by coincidence or outof serendipity, I was contacted
here to become part of theresearch team.
And you talk about a benefit,an amazing benefit for patients.
We were able to give themstate-of-the-art drugs.
I mean, at that time, Taltz andCosentyx were were
(05:07):
state-of-the-art drugs and therewas no out-of-pocket cost to
patients.
So not only were we able to usedrugs that really delivered on
the promise, I mean, people gotclear, their skin became
uninflamed, their joints becameuninflamed, side effects were
absolutely minimal and theydidn't have to pay any money for
(05:30):
it.
So we really accomplished a lotof good, and that's what really
kind of was the hook line thatgot me into clinical trials.
That's a great story and some really
important examples to talk about.
Now let's unpack some of thatand let's talk.
Tell me, give me, a gooddefinition for psoriasis, so we
know what we're dealing withhere.
Dr. Michael Bernhardt (05:50):
So you know psoriasis comes from the
Greek word psoare P-S-O-A-R-E,which means to itch, and that's
about the extent of Greek that Iactually know.
I don't even know how to saywhere's the bathroom in Greek,
so it's challenging if I everwent there.
But that comes from the Greekword psoare, which means to itch
, and the irony is only about20% of people with it actually
(06:11):
itch.
So we now know that, unlike inthe early 1980s, late 70s, when
I was in training, where theyused to teach us that psoriasis
was a condition from rapidlyproliferating keratinocytes Skin
cells were growing too fast,which we now know as codswallop.
It's an inflammatory disease andit's really part of the whole
(06:33):
metabolic syndrome associatedwith things like cardiovascular
disease, non-alcoholic fattyliver disease, non-alcoholic
steatohepatitis.
They're all kind of integratedwith each other Psoriatic
arthritis, so we know that.
So all the people that I usedto teach when I was teaching the
(06:55):
residency program, they allknow that I'm kind of what they
call a cytokine geek.
I like to really dive down andsee what the primordial step is.
And we're getting close.
We don't really know what theprimordial step is in psoriasis,
but we know that it's aconsequence of inflammation.
There are cells that are innateto the skin and that also
circulate in the blood, calleddendritic cells, and they
(07:17):
release a molecule, apro-inflammatory molecule,
called interleukin-23.
And interleukin-23 has afeedback loop relationship with
other inflammatory cells andother keratinocytes and it
stimulates the release ofinterleukin-17, which really is
like the analogy would beputting the key in the ignition
(07:37):
and turning the switch.
Or, for those of you who havecars newer than that and don't
understand about putting a keyin and turning a switch, putting
your thumb on the start buttonand pressing it, and that starts
the whole inflammatory cascadewhich leads to skin
proliferation.
And since the skin isproliferating so fast and piling
up if you visualize a big moundof seashells when you get to
(08:00):
the top of that mound it's gotto go somewhere and it peels off
his scalp.
Dr. Erich Schramm (08:03):
Right.
So that's very interestingbecause a lot of times people
have that kind of question abouthow a condition that is
systemic manifests itself at thelevel of the skin.
So we're talking aboutautoimmune diseases and
abnormalities, immunesystem-related abnormalities
(08:27):
that result in a process thatends up relating to the skin
conditions, right?
So, getting back tounderstanding and you were
saying at the top of thediscussion, you mentioned a lot
of the biologics involved, ,this kind of early development
(08:49):
of the biologics and how theycame in and why they ended up
being real game changers in this, and so you've mentioned
interleukin-23, interleukin-17as important precipitators for
this and ultimately, as they umfrom that level in the dermis to
the epidermis and you end upwith um with the.
Dr. Michael Bernhardt (09:11):
It's hard to keep both these and all
those multi-syllable words there, Erich, it's Friday.
Dr. Erich Schramm (09:14):
I know this is you know you know, uh, it's
so interesting because right,and so you know, truth is uh
about.
Every friday we work together.
I have an opportunity to pickyour brain and be like Mike.
Tell me a little bit more aboutIL-23 and IL-17 and interferon
(09:35):
1, tumor necrosis factor, and totry to bring this down to.
I always joke with him.
I say, hey look, you've got todummy it down for me.
I'm a family practice doctor.
Dr. Michael Bernhardt (09:45):
One of the smartest I ever met and one
of the smartest I ever trainedby.
Dr. Erich Schramm (09:49):
Ok, thank you .
So that's, we have mutualadmiration society going, thank
you.
So you know, I'm always tryingto kind of think of this in
terms of really kind of thebasic premises.
Here We've got a, we have avery important immune system
functions.
But now we see what's I thinkfascinating about psoriasis is
(10:12):
if you look at the approvedtherapies out there, they're
hitting so many differentpathways and whether it's
interleukin or TNF, you havephosphodiesterase inhibitors,
and so it's such a diversecascade of these inflammatory
(10:33):
processes.
And so you, as you alluded toyou, had been involved in some
of those clinical researchtrials you mentioned.
Taltz was kind of veryimportant and pivotal.
And the other thing that'sinteresting, I think, in these
medications you start to seethis evolution.
They went from injectables andthen at some point maybe you
(10:58):
could talk about some of theJAK-STAT inhibitors out there
and understanding, hey, you know, these treatments went from
injectables to orals.
That was a big leap in, youknow, being able to offer oral
medications to patients.
So maybe you could touch alittle bit on that,
Dr. Michael Bernhardt (11:18):
Yeah, I mean, you know it's funny, Erich
.
Everything goes in cycles, youknow, and prior to the onset of
the biologic age, you know whichthe primordial era was Enbrel
and Humira.
But the modern era probablystarted with Taltz, and you know
our site.
We had like 40 patients in thestudy.
So I had hands-on experiencewith over 40 patients on Taltz
(11:41):
before the drug ever came tomarket, so I was always very
comfortable with it.
But now we are.
We're gravitating back into anoral realm.
You know there's an oral IL-23inhibitor in development.
Phase II studies have beenpublished by Johnson Johnson
which looks like it's going tobe an amazing drug.
(12:01):
The JAK inhibitors are anamazing drug.
So one of the things that I tryto impress upon people like
there's a difference betweenautoimmune and autoinflammatory,
and I think psoriasis isprobably more accurately
conceptualized asautoinflammatory rather than
autoimmune
Dr. Erich Schramm (12:20):
Can you tell me a little bit how you define
that difference?
Dr. Michael Bernhardt (12:23):
In other words you get inflammation
rather than autocraticdestruction.
So in psoriasis you'reupregulating a huge inflammatory
cascade rather thantissue-targeted destruction.
So that's why I tend to thinkof it as autoinflammatory.
One of the ways I try to teachwhen I'm teaching residents
either dermatology residents orinternal medicine or family
(12:44):
medicine residents is whenyou're thinking about the immune
response or the inflammatorycascade.
You know all the things thatyou see, everything is done to
linear.
You know 23 leads to 17 leadsto this.
I tend to think of it as aseries of interlocking gears
where one primes the pump forthe other and allows other
(13:04):
processes to turn on.
And I think that you know, Ithink, some of that.
The linear aspect of thinkingabout this is just.
I think, part of a fundamentallimitation of human thinking
that we can only think of onething at a time.
But with autoinflammationyou've got to think of
interlinking parallel gears anda lot of these.
(13:25):
I call these autoinflammatorycytokines.
I call them the usual suspectsBecause if you look at a lot of
diseases, a lot of diseases areusing the same pathomechanism
in different body parts, right?
So there's data that shows thatulcerative colitis and Crohn's
(13:47):
disease is driven by aninterleukin-17-23 cascade.
There's data that shows thatmultiple sclerosis, you know, is
driven the experimental modelfor that is driven by
interleukin-23.
There's some data that I readin one of the throwaways where
terrible diseases like ALS mayhave an IL-17 derivative to it.
So a lot of these usualsuspects, these evil suspects
(14:10):
not really evil, but the effectsthat they do are evil pop up in
different areas because thesewere originally designed to
fight certain things off andwhat happens is there's either a
genetic or an environmentalmiscue that ramps this system up
.
So if you think about theinflammatory process I used to
use the analogy it's likethinking about NATO and the
(14:30):
Warsaw Pact.
You have two armies head to headand on one side you have the
interleukin 17 AF derivative,which is designed to cause
inflammation, and then on theother side you have interleukin
10, which I always say is kindof like Snoop Dogg.
You know, give them a joint,cool them out, chill them down,
let them go to sleep and letthem stop being inflamed.
(14:51):
So these two are butting headsand when there's active
inflammation, 17 AF wins, il-10loses.
When that inflammation's dampeddown, il-10 wins, 17 AF loses.
So there's always that kind ofpush pull going on in the body
and the question is what'sdriving it?
Why does it happen?
We don't know why it happens inpsoriasis.
(15:12):
We do know that psoriasis is agenetic condition.
It can run in families.
Two of my brothers had it, mymom had it.
What can set it off?
A lot of things.
Stress, alcohol consumption,certain medications,
particularly beta blockers, cantrigger it.
Trauma, injury and sometimesrule 17, which is stuff happens.
(15:36):
And it just kind of happens.
And back in the old days beforein the modern era, you know,
counseling someone withpsoriasis was very discouraging
because all we had was topicalsteroids and maybe methotrexate
Cyclosporine you couldn't useforever because you had to watch
blood pressure and kidneys, asyou know from being an internist
, um.
So we had limits on what wecould do and and it was very
(15:59):
frustrating as a physician to dothe best that you could and
know that you're only going toget these people marginally
better right.
And then when the Taltz and theCosentyx phase three pivotal
trials came out, they were hugebecause for the first time ever
we were getting PASI 100s.
And for those of you who don'tknow what a PASI is, pasi stands
for psoriasis area severityindex and what we do is, through
(16:21):
a very tedious process, wequantify how much of the body
surface area is involved withpsoriasis, how thick the plaque
is, how severe the scaling is,and we kind of cook that up and
boil that into a number.
So a PASI of 2 or 1 is good, aPASI of 20 is very bad.
And in the old days when peoplehad these high PASI scores,
(16:44):
topical steroids would only goso far.
Now with these injectablebiological drugs, whether it's
Taltz or Cosentyx or some of the23 inhibitors, the norm is to
see people clear or almost clear.
That's the norm, and the beautyof it is that that visit has
been reduced from a 30 to a45-minute visit that mostly
consisted of hand-holding to gee, you're great.
Are your labs up to date?
(17:04):
See you in six months.
Any problems from the drug?
No, see you in six months, wow.
Dr. Erich Schramm (17:08):
So they really hit a home run.
Dr. Michael Bernhardt (17:10):
Yeah, it's Grand Slam Bases, loaded
bottom of the ninth Grand Slam,
Dr. Erich Schramm (17:17):
Right.
So the other day it wasinteresting, you're in the
office and you're talking to oneof the coordinators and you
were showing them your hand andsaid talking about body surface
area, so what's the significanceof the handprint?
Dr. Michael Bernhardt (17:29):
It's a peace sign.
So usually, when you usually,when you usually when I can't
split my fingers like Spock usedto do.
But no, usually you use thepatient's hand and it's not
really the whole hand, it's thepalm.
Use the patient's palm as anindicator of body surface area.
(17:50):
So one one area the size of thepatient's palm should
correspond to 1% body surfacearea as a rule and that's what
we use.
We use the palm.
Now in real practice, mostpatients' hands are about the
same size, unless you're talkingto someone you know, like maybe
one of the guys on the Jags orone of the professional
basketball players.
But for most normal people,most mere mortals like us, most
(18:13):
palms are about the same.
So we all kind of use our ownpalm in clinical practice to get
an idea of what their bodysurface area is.
Dr. Erich Schramm (18:19):
So for those patients suppose that they don't
meet the criteria to considerthe newer therapies, biologic or
one of the DMARs or somethinglike that what do you have to
offer somebody that isn't thatsevere?
So?
Dr. Michael Bernhardt (18:34):
there's gradations of severity, right,
and the standard is typicallyhow much body surface area there
is.
Now the other things that youhave to think about is areas of
involvement, not just bodysurface area.
Scalp involvement Do they havescalp involvement?
Why is that important?
Because people with scalpinvolvement have four times the
risk of developing arthritisfrom the psoriasis as people
(18:57):
without it Do.
They have little pits in thenails where it looks like
someone took a safety pin andtried to chisel a hole in their
nail.
Well, if the answer to that isyes, it means they've got what
we call a matrix disease.
And nail matrix disease isthree times more likely to
develop psoriatic arthritis asthe rest of the population.
So those are areas of specialinterest and that's the reasons
why.
(19:17):
The other area, facialinvolvement or genital
involvement.
Facial involvement people feelmarked, they feel like lepers.
Genital involvement involves,you know it impairs psychosocial
function, impairs relationshipformation So for people with
those areas, even though there'slimited body surface area, we
(19:37):
still in the AAD, they stillconsider that an escalation
basis to ramp that up as asevere disease.
And then I'd be more aggressivewith them.
People that don't have thoseareas, that maybe have 3%, 4%,
5% body surface area.
There are a couple of oraldrugs out there.
Otezla is one which is aphosphodiesterase inhibitor.
Typically, how does aphosphodiesterase inhibitor work
(19:59):
?
Long story short, it indirectlydecreases tumor necrosis factor
one.
It affects cyclic AMP and ATPformation, but the end run is
that it decreases TNF inhibitor.
Dr. Erich Schramm (20:13):
Right, and that can be combined with other
modalities right.
Dr. Michael Bernhardt (20:17):
Yeah, topicals you can use with
topical steroids.
Dr. Erich Schramm (20:19):
Whether you're inhibiting interleukin or
Dr. Michael Bernhardt (20:22):
It's a great drug, it's definitely got
its place.
I think we're looking at doinga clinical trial on a TIK2
inhibitor right, which istyrosine kinase, which is one of
the inflammatory systems, andthose work really well too.
I mean, there's one tyrosinekinase inhibitor already on the
market, but we're looking at acompetitive one for clinical
trials.
So it offers a nice alternativebecause there are some people
(20:46):
that don't want to injectthemselves.
Dr. Erich Schramm (20:48):
So, with the new drugs coming on the market,
what would you like to seebetter in terms of these new
medications?
What would you like to seeimproved upon?
Dr. Michael Bernhardt (21:07):
That's a tough question, because if you'd
asked me that 10 years ago, I'dhave given you a laundry list.
But now, I mean, if we canachieve the same thing with an
oral without having toself-inject, I think that would
be very nice, although I takeRepatha and I pinch a big roll
of fat which I have way too muchof and click it and it's really
not a big deal.
Dr. Erich Schramm (21:25):
But you're working out.
I see that.
Dr. Michael Bernhardt (21:26):
I know
Dr. Erich Schramm (21:28):
You're looking pretty good these days
Dr. Michael Bernhardt (21:30):
I work out, but it's like gee.
I worked out.
Now I can eat 10 pieces ofchocolate.
You know it's the whole cycleof balance.
But so if we can achieve thesame things orally that we do
with injections, I think thatwould be beneficial.
Now, you were talking about theJAK's before.
Dr. Erich Schramm (21:45):
Right, that was kind of where I was leading
to is what kind of issues werethere with that particular class
?
Dr. Michael Bernhardt (21:52):
I mean the way I think of JAK's.
I think of them as theprednisone of the 21st century.
They do a lot of things thatsteroids do do, JAK's.
So the intellectual basis forJAKs is every cell has a
receptor, right.
The psychographic for that is,if you think of putting a straw
(22:16):
in a cup of chocolate pudding,all right, the chocolate pudding
is the cell the straw goes in,that's the intracellular
environment.
The part sticking out acts likethe receptor and binds some of
these cytokines.
So let's say, a cell receptorbinds to a molecule of
interleukin-23.
What happens next?
Well, there's what I call aninflammatory synapse, just like
(22:40):
we have neuromuscular synapse.
This is an inflammatory synapsewhere the receptor binds.
There's like a little impulseof transmission that goes down
where the receptor binds.
There's like a little impulseof transmission that goes down
through the receptor, throughthe membrane, into the interior
of the cell, and thattransmission fires off a
stimulation of these JAK, whichis Janus kinase molecules.
They're enzymes.
Dr. Erich Schramm (23:01):
Right, so like little machinery factories
right.
Dr. Michael Bernhardt (23:05):
When those enzymes get tweaked, they
cause stimulation of the secondphase of that which is the STAT
stat complex, and when thesestats get activated they then
transmigrate to the nucleus andupregulate inflammatory genes.
So if you stop the JAK, youstop stat, you stop inflammation
(23:25):
.
Dr. Erich Schramm (23:25):
So really treating it right at the core.
Dr. Michael Bernhardt (23:28):
It's a big yeah.
The JAKs are more like ashotgun than a sniper rifle.
So the 23 and the 17 inhibitorsare more like a sniper rifle
because they're picking off thespecific cytokine.
The JAKs are a broad shotgunand they just shut down
everything.
Dr. Erich Schramm (23:47):
Well, I think , well, in terms of the you know
of the interleukin inhibitors,I think it's being a little more
downstream right Versus ifyou're arresting that at the
point from a cellular levelright, so you're just shutting
it down at the cellular level.
Dr. Michael Bernhardt (23:57):
For example, JAK1, right.
JAK1 upregulates a variety ofcytokines, right.
Things like interleukin 3,interleukin 5, interleukin 7,
interleukin-9.
So those all get upregulatedand they all have specific
functions.
Like interleukin-7 is a broad Tcell stimulator.
Right.
Interleukin-9 upregulateskiller cells.
Interleukin-15, right now I'mjust blanking on what 15 does.
(24:21):
But so you're downregregulating a huge inflammatory
cascade, right.
Right, interleukin 2 isresponsible for driving
interleukin 6, which is one ofthe main pro-inflammatory
cytokines for a lot of tissuedestructive
Dr. Erich Schramm (24:35):
right, so kind of the pros.
There are broad uh suppressantof these wide range of
inflammatory molecules right,but the downside is there could
be collateral damage in thatright.
In that immune system, orwhether it's infection, or
Dr. Michael Bernhardt (24:54):
that's why these drugs aren't on the
candy aisle.
I mean drugs are drugs and theycan cause great things.
They can do terrible things.
So I was doing a lecture lastnight to some of the doctors
that said, part of our job aslearned intermediaries is to be
able to figure out what drug isgoing to be in such a state
where we've mitigated thedownside risk and maximize the
upside potential.
(25:15):
That's our job as physiciansand that's why I don't think AI
will ever really replace a goodphysician.
You know, even though patientscome in all the time, Dr.
Google said I had to do this,this, this and this.
They said well, Dr.
google's office is right nextdoor.
Feel free to go see him there.
This is how we're going to do ithere.
That's right.
Dr. Erich Schramm (25:34):
No, I appreciate
Dr. Michael Bernhardt (25:35):
But the JAK's are great.
I mean, they're really, they'rea brave new world.
Um, a lot of people havedeveloped what I call JAKophobia
.
They're afraid of the JAK's andthat really bothers me.
And the reason for that fearwas there was a study, there was
a problem with Xeljanz aboutabout 12 or 13 years ago.
Xeljanzis a pan-JAK ,JAK one,two and three which blocks
(25:57):
everything.
It's a great drug and it hasits use.
But there was a cohort ofpatients with rheumatoid
arthritis who were on comorbidprednisone and methotrexate and
they were using a dose doublewhat we're using today and there
were some problems.
Some patients had pulmonaryemboli and deep vein thrombosis.
And then, about four years ago,there was a study where they
(26:20):
compared one of the TNFinhibitors to one of the to
Xeljanz in the same cohortpopulation.
You know, methotrexate andprednisone treated rheumatoid
arthritics and they showed thatthere was what they call not.
They were not able to establishnon-inferiority.
Okay, so they couldn't say thatthe JAK was non-inferior.
(26:42):
Granted everybody listening, Iagree it's double talk, but
that's just the way these thingsare done.
This is done via bureaucraticmethods, not our methods.
But it showed that there wasquote, unquote non-inferiority.
So now the entire class JAK'shave have this box warning about
infection, lymphoma, deep veinthrombosis and cardiovascular
(27:07):
disease.
Yet when you look at thesenewer drugs that are not panJAKs
, that are selective for justJAK1 or maybe JAK1, JAK2, the
data doesn't reflect the warning, at least not the data that
I've seen.
Okay, they reflect the warnings.
Now, if someone comes to mewho's got a history of deep vein
thrombosis, you know, or theyhave some of the metabolic
(27:30):
syndromes that predispose themto blood clot formation,
probably not a great choice,right, I'd go in a different
direction.
But for a lot of these otherdiseases, these JAK inhibitors
are going to be the cat's meow.
Dr. Erich Schramm (27:43):
That's great, yeah, and thinking about those
patients that were on prednisoneand methotrexate, which are—.
Dr. Michael Bernhardt (27:48):
Which, of course, have no side effects at
all.
Dr. Erich Schramm (27:50):
Yeah, I was going to say
Dr. Michael Bernhardt (27:51):
Totally benign drugs, totally harmless,
Nothing to worry about.
Dr. Erich Schramm (27:53):
So that puts it in the context of what we
think about.
And you know, I think it'sgreat to have someone with your
clinical experience and yourresearch experience so that you
can take and give kind of a realrisk assessment for patients
and say, and you know, in doingthe right thing for your patient
,
Dr. Michael Bernhardt (28:13):
The problem, Erich, is and you and I
have both dealt with this inour practices there's risks of
taking the drug but there'srisks of not taking the drug.
You know, I'm not arheumatologist, I don't treat
rheumatoid arthritis, but I havea lot of patients with
overlapping syndromes, you know.
And the inflammatoryenvironment is different.
In rheumatoid arthritis it'smore Interleukin-1 driven, you
(28:36):
know, rather thanInterleukin-4/13, like in atopic
dermatitis, which is where weuse most of our JAK inhibitors,
and atopic dermatitis is our biguse for that particular drug.
It's a differentpro-inflammatory environment.
have Interleukin don't have1-up regulation, they have 4/13.
(28:56):
So the risk for that populationof having a vascular event is
really pretty low, probably nomore so than the SEER data,
which is the expectedpopulation-based data, right,
Dr. Erich Schramm (29:07):
so your take on the TYK2, tyrosine kinase 2
inhibition, some of the newerproducts here being developed,
what's your comfort level withthat?
Dr. Michael Bernhardt (29:21):
Very, very comfortable.
You know there's one on themarket that I've been using in
patients.
Like I said, there are somepeople with psoriasis who don't
want to take a shot.
So there's one of the TYK2inhibitors is on the market and
I've been using that for acouple of years and it's a
little slower in onset than theshots.
I can tell people it's thetortoise, not the hare, but at
(29:44):
the end of the year you'rebasically going to be in the
same place.
You're just going to get therea little slower, knockwood.
I've not seen any significantside effects to the point where
patients would stop using themedication and it works.
Dr. Erich Schramm (29:59):
Wow, that's great.
So you know I was thinkingabout this because I'm a big
college basketball fan andwatching March Madness
oh my God Go Gators, what agreat year for them.
There you go, and what struck me—.
Dr. Michael Bernhardt (30:13):
And Auburn and Houston and Duke all
the teams I met at the FinalFour
Dr. Erich Schramm (30:17):
Give them credit for that.
They were all great, greatseries.
There are a lot of great gamesthere.
But what was really interestingwere the commercials right.
And so I was surprised at thenumber of commercials for
psoriasis and the selling pointfor this one particular drug was
(30:38):
it tackles or treats both typesof interleukin-17.
And I was like, wow, that is areally sophisticated advertising
approach to direct a consumer.
Advertising that's verysophisticated and so curious.
Do patients come in, you know,saying hey, I saw this
(31:02):
commercial on TV blocking bothtypes of interleukin-17.
Have you seen that inyour practice?
Dr. Michael Bernhardt (31:08):
I'm waiting because I want them to
give me a lecture about it andtell me that what?
actually is kind of funny is,like I said, I'm a pathways geek
, right.
So what I was doing thismorning in between surgical
patients.
There was a great articlepublished this month in the
British Journal of Dermatologywhere they did a genetic
analysis of hidradenitissuppurativa and they looked at
(31:32):
all 5,000 genes that areupregulated hidradenitis
suppurativa and they found thatthere was a notch.
You know, we've always knownthat there's more 17F both in
the lesion and perilesionalright, and F is a very powerful
driver and I'll talk about thatin a second.
But in this study they lookedat the gene sequencing and they
(31:55):
found that not only was 17Fupregulated in the follicle
itself but in the perilesionaldermis those dermal fibroblasts
were kicking out more 17F.
So 17A we already talked aboutit, it's released by dendritic
cells stimulates the whole 17Aloop amplification right.
(32:22):
17F seems to be more tied inwith upregulating other players
in hidradenitis, likeinterleukin-1, which the whole
interleukin-1 family is a verystrong pro-inflammatory cascade
upregulating interleukin-8.
Now interleukin-8's job is tocause neutrophils, or white
blood cells, to migrate into thelesion.
So they're taking the positionhidradenitis and and I think I
agree with hidradenitis is isprimarily a neutrophilic
(32:45):
dermatosis and it's a biphasicdisease, so it starts out as a
pro-inflammatory disease.
They know that there's a defectof this gene called secretase
and secretase gamma.
Secretase is important in thehair shaft and allowing the hair
to turn into hair, when it'sdefective it forms cysts and
(33:08):
that seems to be ground zero forHS.
They form these inappropriatecysts and the other thing that
they've found is through aprocess called epithelium
mesenchymal transformation,where cells go from one cell to
another type of cell, kind oflike what we see in cancer.
In hidradenitis fibroblasts willtransform into epidermal
(33:29):
keratinocytes within the dermis,which also drives inflammation.
So IL-17, A and F get massivelyupregulated in hidradenitis.
And the beauty of this new drug, by downregulating F and the AF
heterodimer, is you can drivedown that interleukin-1, tnf,
interleukin-6 cascade.
(33:51):
So that's why that particulardrug has been successful in
treating something, not justpsoriasis and psoriatic
arthritis, which it's great for,but I think also for treating a
previously very difficultdisease to treat, which
hidradenitis suppurativa.
Dr. Erich Schramm (34:06):
Well, I think I hear the topic of our next
podcast discussion coming upright, I think that's going to
be in a couple of weeks.
Dr. Michael Bernhardt (34:13):
Skin is in baby.
Dr. Erich Schramm (34:14):
Yeah, you know I never get tired of
hearing you talk about theinflammatory cascade.
Dr. Michael Bernhardt (34:21):
It's amazing.
Dr. Erich Schramm (34:24):
So, Mike, thank you so much.
You know a ton of insight there, always appreciate that and you
know whenever we can talk aboutscience and Snoop Dogg and all
of that.
I love picking your brain onthings.
My pleasure.
Any question you think I should ask you?
Dr. Michael Bernhardt (34:45):
Well, let's see.
For those of you who are reallyon the edge of your seat, I
found a great restaurant down inSt John's.
Dr. Erich Schramm (34:54):
Do tell
Dr. Michael Bernhardt (34:55):
it's called Irons and Ember.
Okay, and they do.
All their cooking is in castiron skillets.
Everything is fresh, theseafood is fresh.
The prices are reasonable.
The service was great.
We went there two weeks ago andit was the kind of place where
my wife and I looked at eachother and said when do you want
to come back?
(35:15):
And I'm like how about tomorrow?
So the big unanswered questionwhere should we go to eat this
weekend?
Dr. Erich Schramm (35:19):
Okay, that's great.
Well, no thanks for yourinsight, as always, and again
look forward to talking to youin the near future.
We'll pick up on hidradenitissuppurativa.
Dr. Michael Bernhardt (35:29):
Sounds great.
It's an amazing disease state.
Thank you,
Dr. Erich Schramm (35:32):
thank you,
Dr. Michael Bernhardt (35:32):
thank you .
Announcer (35:33):
Thanks for joining the MedEvidence podcast.
To learn more, head over toMedEvidencecom or subscribe to
our podcast on your favoritepodcast platform.
Welcome to MedEvidence!, where we help you
navigate the truth behindmedical research with unbiased,
evidence-proven facts Hosted bycardiologist and top medical
researcher, Dr.
Michael Koren.
Dr. Erich Schramm (00:11):
Hello and welcome back to the MedEvidence!
podcast.
I'm your host, Dr.
Eric Schramm, sitting in for Dr.
Michael Koren.
Today he's out on
Dr. Michael Bernhardt (00:20):
Maternity leave.
Dr. Erich Schramm (00:21):
Maternity- leave.
That's right.
It's my pleasure to be herewith you.
Just a little background formyself for those who don't know
me I'm a long-term clinicalresearch investigator and have
been with the ENCORE ResearchGroup for more than 20 years.
My training and background isin family medicine.
I'm a board-certified familyphysician and have been in
primary care practice for morethan 20 years, though more
(00:44):
recently I'm specializing incannabis health, so I help
patients, guiding them on theirjourney for healing in the
medical marijuana space.
I'm very excited to be herewith longtime clinical research
colleague and one of my favoritedermatologists, Dr.
Michael Bernhardt.
Dr. Michael Bernhardt (01:04):
Thank you .
Dr. Erich Schramm (01:05):
So Dr.
Bernhardt and I go back a longways.
I recall the time that back inmy residency training he took me
under his wing, had a greatrotation as a family medicine
resident in his clinicaldermatologist office and came
away with a lot of practicepearls from that that I still
(01:27):
find useful today when I'mseeing patients.
So that is greatly appreciated.
Thank you so much.
Mike has a great background inclinical medicine probably three
or four decades at this point,I think and as well as thinking
about his background inacademics recently teaching at
Florida State University, theresidents and the med students
(01:50):
there Is that right?
Dr. Michael Bernhardt (01:51):
Correct.
Dr. Erich Schramm (01:51):
Yes, sir
Dr. Michael Bernhardt (01:52):
Helped run a residency program for
three and a half years.
Dr. Erich Schramm (01:55):
That's right.
And also touching base onlong-term clinical research
experiences and background inclinical research, and I think
that was going back to 2010.
Is that right?
Dr. Michael Bernhardt (02:09):
I've been here since, I think, 2008 or
2009.
I remember we started doingsome of the early phase three
clinical trials for drugs whichare now almost fading out of the
market Things like Taltz,Cosentyx, Siliq, and some of the
topicals.
So we've been at this for awhile.
Dr. Erich Schramm (02:26):
Yeah, and that's actually.
You know, we'll be talkingtoday, we'll sit down, we'll
kind of do a psoriasis 101discussion, really kind of drill
down on some of those things,and we can talk about the
treatments and kind of theevolution of those treatments
because, you know, 25 years agoin my training in your office,
(02:50):
we really weren't talking aboutthose kind of therapies because
they didn't really exist at thattime.
So that's going to be kind ofan exciting topic to get into.
Anytime, I'm sitting across thetable from a clinical
researcher.
You know, one of the firstthings I want to know is hey,
what got you interested in thisand got you wanting to pursue
research?
You know, it's really kind ofan interesting evolution,
because I started doing this, Ithink, in 2008, 2009.
(03:12):
And a couple of things.
I mean back then, really upuntil the early 2000s, I used to
call it institutionalizedmediocrity in terms of how we
treated our patients, becausethe therapies that we had were
institutionalized mediocrity interms of how we treated our
patients, because the therapiesthat we had were
institutionalized standard ofcare.
They were garbage.
I mean literally garbage.
All we had back then were drugslike methotrexate or
(03:35):
cyclosporine, which are greatdrugs they have the use, but in
psoriasis they were reallysuboptimal.
And then around 1999, 2002, adrug called Amevive came about
and it was the first injectabledrug for psoriasis and in the
15% of patients that it worked,it was a home run.
(03:57):
People got clear.
The problem was the other 85%didn't really do much.
And then around 2004, somewherearound that time, Embryol came
along and Enbrel was a gamechanger.
Enbrel and Remicade wereabsolute game changers.
They blocked an inflammatorymolecule called tumor necrosis
factor, TNF1.
And at that time we all thoughtTNF1 was the central hub that
(04:23):
drove all the inflammation inpsoriasis, which of now we know
is not true.
And then when, around 2008, 2009, when we had the big recession,
I had people coming into myoffice who were literally facing
foreclosure of their house,repossession of their cars, and
when I started talking to themabout some of these drugs, like
(04:44):
Humira and Remicade and Enbrel,their eyes would glaze over
because they lost theirinsurance, they didn't have
money.
And then, by coincidence or outof serendipity, I was contacted
here to become part of theresearch team.
And you talk about a benefit,an amazing benefit for patients.
We were able to give themstate-of-the-art drugs.
I mean, at that time, Taltz andCosentyx were were
(05:07):
state-of-the-art drugs and therewas no out-of-pocket cost to
patients.
So not only were we able to usedrugs that really delivered on
the promise, I mean, people gotclear, their skin became
uninflamed, their joints becameuninflamed, side effects were
absolutely minimal and theydidn't have to pay any money for
(05:30):
it.
So we really accomplished a lotof good, and that's what really
kind of was the hook line thatgot me into clinical trials.
That's a great story and some really
important examples to talk about.
Now let's unpack some of thatand let's talk.
Tell me, give me, a gooddefinition for psoriasis, so we
know what we're dealing withhere.
Dr. Michael Bernhardt (05:50):
So you know psoriasis comes from the
Greek word psoare P-S-O-A-R-E,which means to itch, and that's
about the extent of Greek that Iactually know.
I don't even know how to saywhere's the bathroom in Greek,
so it's challenging if I everwent there.
But that comes from the Greekword psoare, which means to itch
, and the irony is only about20% of people with it actually
(06:11):
itch.
So we now know that, unlike inthe early 1980s, late 70s, when
I was in training, where theyused to teach us that psoriasis
was a condition from rapidlyproliferating keratinocytes Skin
cells were growing too fast,which we now know as codswallop.
It's an inflammatory disease andit's really part of the whole
(06:33):
metabolic syndrome associatedwith things like cardiovascular
disease, non-alcoholic fattyliver disease, non-alcoholic
steatohepatitis.
They're all kind of integratedwith each other Psoriatic
arthritis, so we know that.
So all the people that I usedto teach when I was teaching the
(06:55):
residency program, they allknow that I'm kind of what they
call a cytokine geek.
I like to really dive down andsee what the primordial step is.
And we're getting close.
We don't really know what theprimordial step is in psoriasis,
but we know that it's aconsequence of inflammation.
There are cells that are innateto the skin and that also
circulate in the blood, calleddendritic cells, and they
(07:17):
release a molecule, apro-inflammatory molecule,
called interleukin-23.
And interleukin-23 has afeedback loop relationship with
other inflammatory cells andother keratinocytes and it
stimulates the release ofinterleukin-17, which really is
like the analogy would beputting the key in the ignition
(07:37):
and turning the switch.
Or, for those of you who havecars newer than that and don't
understand about putting a keyin and turning a switch, putting
your thumb on the start buttonand pressing it, and that starts
the whole inflammatory cascadewhich leads to skin
proliferation.
And since the skin isproliferating so fast and piling
up if you visualize a big moundof seashells when you get to
(08:00):
the top of that mound it's gotto go somewhere and it peels off
his scalp.
Dr. Erich Schramm (08:03):
Right.
So that's very interestingbecause a lot of times people
have that kind of question abouthow a condition that is
systemic manifests itself at thelevel of the skin.
So we're talking aboutautoimmune diseases and
abnormalities, immunesystem-related abnormalities
(08:27):
that result in a process thatends up relating to the skin
conditions, right?
So, getting back tounderstanding and you were
saying at the top of thediscussion, you mentioned a lot
of the biologics involved, ,this kind of early development
(08:49):
of the biologics and how theycame in and why they ended up
being real game changers in this, and so you've mentioned
interleukin-23, interleukin-17as important precipitators for
this and ultimately, as they umfrom that level in the dermis to
the epidermis and you end upwith um with the.
Dr. Michael Bernhardt (09:11):
It's hard to keep both these and all
those multi-syllable words there, Erich, it's Friday.
Dr. Erich Schramm (09:14):
I know this is you know you know, uh, it's
so interesting because right,and so you know, truth is uh
about.
Every friday we work together.
I have an opportunity to pickyour brain and be like Mike.
Tell me a little bit more aboutIL-23 and IL-17 and interferon
(09:35):
1, tumor necrosis factor, and totry to bring this down to.
I always joke with him.
I say, hey look, you've got todummy it down for me.
I'm a family practice doctor.
Dr. Michael Bernhardt (09:45):
One of the smartest I ever met and one
of the smartest I ever trainedby.
Dr. Erich Schramm (09:49):
Ok, thank you .
So that's, we have mutualadmiration society going, thank
you.
So you know, I'm always tryingto kind of think of this in
terms of really kind of thebasic premises.
Here We've got a, we have avery important immune system
functions.
But now we see what's I thinkfascinating about psoriasis is
(10:12):
if you look at the approvedtherapies out there, they're
hitting so many differentpathways and whether it's
interleukin or TNF, you havephosphodiesterase inhibitors,
and so it's such a diversecascade of these inflammatory
(10:33):
processes.
And so you, as you alluded toyou, had been involved in some
of those clinical researchtrials you mentioned.
Taltz was kind of veryimportant and pivotal.
And the other thing that'sinteresting, I think, in these
medications you start to seethis evolution.
They went from injectables andthen at some point maybe you
(10:58):
could talk about some of theJAK-STAT inhibitors out there
and understanding, hey, you know, these treatments went from
injectables to orals.
That was a big leap in, youknow, being able to offer oral
medications to patients.
So maybe you could touch alittle bit on that,
Dr. Michael Bernhardt (11:18):
Yeah, I mean, you know it's funny, Erich
.
Everything goes in cycles, youknow, and prior to the onset of
the biologic age, you know whichthe primordial era was Enbrel
and Humira.
But the modern era probablystarted with Taltz, and you know
our site.
We had like 40 patients in thestudy.
So I had hands-on experiencewith over 40 patients on Taltz
(11:41):
before the drug ever came tomarket, so I was always very
comfortable with it.
But now we are.
We're gravitating back into anoral realm.
You know there's an oral IL-23inhibitor in development.
Phase II studies have beenpublished by Johnson Johnson
which looks like it's going tobe an amazing drug.
(12:01):
The JAK inhibitors are anamazing drug.
So one of the things that I tryto impress upon people like
there's a difference betweenautoimmune and autoinflammatory,
and I think psoriasis isprobably more accurately
conceptualized asautoinflammatory rather than
autoimmune
Dr. Erich Schramm (12:20):
Can you tell me a little bit how you define
that difference?
Dr. Michael Bernhardt (12:23):
In other words you get inflammation
rather than autocraticdestruction.
So in psoriasis you'reupregulating a huge inflammatory
cascade rather thantissue-targeted destruction.
So that's why I tend to thinkof it as autoinflammatory.
One of the ways I try to teachwhen I'm teaching residents
either dermatology residents orinternal medicine or family
(12:44):
medicine residents is whenyou're thinking about the immune
response or the inflammatorycascade.
You know all the things thatyou see, everything is done to
linear.
You know 23 leads to 17 leadsto this.
I tend to think of it as aseries of interlocking gears
where one primes the pump forthe other and allows other
(13:04):
processes to turn on.
And I think that you know, Ithink, some of that.
The linear aspect of thinkingabout this is just.
I think, part of a fundamentallimitation of human thinking
that we can only think of onething at a time.
But with autoinflammationyou've got to think of
interlinking parallel gears anda lot of these.
(13:25):
I call these autoinflammatorycytokines.
I call them the usual suspectsBecause if you look at a lot of
diseases, a lot of diseases areusing the same pathomechanism
in different body parts, right?
So there's data that shows thatulcerative colitis and Crohn's
(13:47):
disease is driven by aninterleukin-17-23 cascade.
There's data that shows thatmultiple sclerosis, you know, is
driven the experimental modelfor that is driven by
interleukin-23.
There's some data that I readin one of the throwaways where
terrible diseases like ALS mayhave an IL-17 derivative to it.
So a lot of these usualsuspects, these evil suspects
(14:10):
not really evil, but the effectsthat they do are evil pop up in
different areas because thesewere originally designed to
fight certain things off andwhat happens is there's either a
genetic or an environmentalmiscue that ramps this system up
.
So if you think about theinflammatory process I used to
use the analogy it's likethinking about NATO and the
(14:30):
Warsaw Pact.
You have two armies head to headand on one side you have the
interleukin 17 AF derivative,which is designed to cause
inflammation, and then on theother side you have interleukin
10, which I always say is kindof like Snoop Dogg.
You know, give them a joint,cool them out, chill them down,
let them go to sleep and letthem stop being inflamed.
(14:51):
So these two are butting headsand when there's active
inflammation, 17 AF wins, il-10loses.
When that inflammation's dampeddown, il-10 wins, 17 AF loses.
So there's always that kind ofpush pull going on in the body
and the question is what'sdriving it?
Why does it happen?
We don't know why it happens inpsoriasis.
(15:12):
We do know that psoriasis is agenetic condition.
It can run in families.
Two of my brothers had it, mymom had it.
What can set it off?
A lot of things.
Stress, alcohol consumption,certain medications,
particularly beta blockers, cantrigger it.
Trauma, injury and sometimesrule 17, which is stuff happens.
(15:36):
And it just kind of happens.
And back in the old days beforein the modern era, you know,
counseling someone withpsoriasis was very discouraging
because all we had was topicalsteroids and maybe methotrexate
Cyclosporine you couldn't useforever because you had to watch
blood pressure and kidneys, asyou know from being an internist
, um.
So we had limits on what wecould do and and it was very
(15:59):
frustrating as a physician to dothe best that you could and
know that you're only going toget these people marginally
better right.
And then when the Taltz and theCosentyx phase three pivotal
trials came out, they were hugebecause for the first time ever
we were getting PASI 100s.
And for those of you who don'tknow what a PASI is, pasi stands
for psoriasis area severityindex and what we do is, through
(16:21):
a very tedious process, wequantify how much of the body
surface area is involved withpsoriasis, how thick the plaque
is, how severe the scaling is,and we kind of cook that up and
boil that into a number.
So a PASI of 2 or 1 is good, aPASI of 20 is very bad.
And in the old days when peoplehad these high PASI scores,
(16:44):
topical steroids would only goso far.
Now with these injectablebiological drugs, whether it's
Taltz or Cosentyx or some of the23 inhibitors, the norm is to
see people clear or almost clear.
That's the norm, and the beautyof it is that that visit has
been reduced from a 30 to a45-minute visit that mostly
consisted of hand-holding to gee, you're great.
Are your labs up to date?
(17:04):
See you in six months.
Any problems from the drug?
No, see you in six months, wow.
Dr. Erich Schramm (17:08):
So they really hit a home run.
Dr. Michael Bernhardt (17:10):
Yeah, it's Grand Slam Bases, loaded
bottom of the ninth Grand Slam,
Dr. Erich Schramm (17:17):
Right.
So the other day it wasinteresting, you're in the
office and you're talking to oneof the coordinators and you
were showing them your hand andsaid talking about body surface
area, so what's the significanceof the handprint?
Dr. Michael Bernhardt (17:29):
It's a peace sign.
So usually, when you usually,when you usually when I can't
split my fingers like Spock usedto do.
But no, usually you use thepatient's hand and it's not
really the whole hand, it's thepalm.
Use the patient's palm as anindicator of body surface area.
(17:50):
So one one area the size of thepatient's palm should
correspond to 1% body surfacearea as a rule and that's what
we use.
We use the palm.
Now in real practice, mostpatients' hands are about the
same size, unless you're talkingto someone you know, like maybe
one of the guys on the Jags orone of the professional
basketball players.
But for most normal people,most mere mortals like us, most
(18:13):
palms are about the same.
So we all kind of use our ownpalm in clinical practice to get
an idea of what their bodysurface area is.
Dr. Erich Schramm (18:19):
So for those patients suppose that they don't
meet the criteria to considerthe newer therapies, biologic or
one of the DMARs or somethinglike that what do you have to
offer somebody that isn't thatsevere?
So?
Dr. Michael Bernhardt (18:34):
there's gradations of severity, right,
and the standard is typicallyhow much body surface area there
is.
Now the other things that youhave to think about is areas of
involvement, not just bodysurface area.
Scalp involvement Do they havescalp involvement?
Why is that important?
Because people with scalpinvolvement have four times the
risk of developing arthritisfrom the psoriasis as people
(18:57):
without it Do.
They have little pits in thenails where it looks like
someone took a safety pin andtried to chisel a hole in their
nail.
Well, if the answer to that isyes, it means they've got what
we call a matrix disease.
And nail matrix disease isthree times more likely to
develop psoriatic arthritis asthe rest of the population.
So those are areas of specialinterest and that's the reasons
why.
(19:17):
The other area, facialinvolvement or genital
involvement.
Facial involvement people feelmarked, they feel like lepers.
Genital involvement involves,you know it impairs psychosocial
function, impairs relationshipformation So for people with
those areas, even though there'slimited body surface area, we
(19:37):
still in the AAD, they stillconsider that an escalation
basis to ramp that up as asevere disease.
And then I'd be more aggressivewith them.
People that don't have thoseareas, that maybe have 3%, 4%,
5% body surface area.
There are a couple of oraldrugs out there.
Otezla is one which is aphosphodiesterase inhibitor.
Typically, how does aphosphodiesterase inhibitor work
(19:59):
?
Long story short, it indirectlydecreases tumor necrosis factor
one.
It affects cyclic AMP and ATPformation, but the end run is
that it decreases TNF inhibitor.
Dr. Erich Schramm (20:13):
Right, and that can be combined with other
modalities right.
Dr. Michael Bernhardt (20:17):
Yeah, topicals you can use with
topical steroids.
Dr. Erich Schramm (20:19):
Whether you're inhibiting interleukin or
Dr. Michael Bernhardt (20:22):
It's a great drug, it's definitely got
its place.
I think we're looking at doinga clinical trial on a TIK2
inhibitor right, which istyrosine kinase, which is one of
the inflammatory systems, andthose work really well too.
I mean, there's one tyrosinekinase inhibitor already on the
market, but we're looking at acompetitive one for clinical
trials.
So it offers a nice alternativebecause there are some people
(20:46):
that don't want to injectthemselves.
Dr. Erich Schramm (20:48):
So, with the new drugs coming on the market,
what would you like to seebetter in terms of these new
medications?
What would you like to seeimproved upon?
Dr. Michael Bernhardt (21:07):
That's a tough question, because if you'd
asked me that 10 years ago, I'dhave given you a laundry list.
But now, I mean, if we canachieve the same thing with an
oral without having toself-inject, I think that would
be very nice, although I takeRepatha and I pinch a big roll
of fat which I have way too muchof and click it and it's really
not a big deal.
Dr. Erich Schramm (21:25):
But you're working out.
I see that.
Dr. Michael Bernhardt (21:26):
I know
Dr. Erich Schramm (21:28):
You're looking pretty good these days
Dr. Michael Bernhardt (21:30):
I work out, but it's like gee.
I worked out.
Now I can eat 10 pieces ofchocolate.
You know it's the whole cycleof balance.
But so if we can achieve thesame things orally that we do
with injections, I think thatwould be beneficial.
Now, you were talking about theJAK's before.
Dr. Erich Schramm (21:45):
Right, that was kind of where I was leading
to is what kind of issues werethere with that particular class
?
Dr. Michael Bernhardt (21:52):
I mean the way I think of JAK's.
I think of them as theprednisone of the 21st century.
They do a lot of things thatsteroids do do, JAK's.
So the intellectual basis forJAKs is every cell has a
receptor, right.
The psychographic for that is,if you think of putting a straw
(22:16):
in a cup of chocolate pudding,all right, the chocolate pudding
is the cell the straw goes in,that's the intracellular
environment.
The part sticking out acts likethe receptor and binds some of
these cytokines.
So let's say, a cell receptorbinds to a molecule of
interleukin-23.
What happens next?
Well, there's what I call aninflammatory synapse, just like
(22:40):
we have neuromuscular synapse.
This is an inflammatory synapsewhere the receptor binds.
There's like a little impulseof transmission that goes down
where the receptor binds.
There's like a little impulseof transmission that goes down
through the receptor, throughthe membrane, into the interior
of the cell, and thattransmission fires off a
stimulation of these JAK, whichis Janus kinase molecules.
They're enzymes.
Dr. Erich Schramm (23:01):
Right, so like little machinery factories
right.
Dr. Michael Bernhardt (23:05):
When those enzymes get tweaked, they
cause stimulation of the secondphase of that which is the STAT
stat complex, and when thesestats get activated they then
transmigrate to the nucleus andupregulate inflammatory genes.
So if you stop the JAK, youstop stat, you stop inflammation
(23:25):
.
Dr. Erich Schramm (23:25):
So really treating it right at the core.
Dr. Michael Bernhardt (23:28):
It's a big yeah.
The JAKs are more like ashotgun than a sniper rifle.
So the 23 and the 17 inhibitorsare more like a sniper rifle
because they're picking off thespecific cytokine.
The JAKs are a broad shotgunand they just shut down
everything.
Dr. Erich Schramm (23:47):
Well, I think , well, in terms of the you know
of the interleukin inhibitors,I think it's being a little more
downstream right Versus ifyou're arresting that at the
point from a cellular levelright, so you're just shutting
it down at the cellular level.
Dr. Michael Bernhardt (23:57):
For example, JAK1, right.
JAK1 upregulates a variety ofcytokines, right.
Things like interleukin 3,interleukin 5, interleukin 7,
interleukin-9.
So those all get upregulatedand they all have specific
functions.
Like interleukin-7 is a broad Tcell stimulator.
Right.
Interleukin-9 upregulateskiller cells.
Interleukin-15, right now I'mjust blanking on what 15 does.
(24:21):
But so you're downregregulating a huge inflammatory
cascade, right.
Right, interleukin 2 isresponsible for driving
interleukin 6, which is one ofthe main pro-inflammatory
cytokines for a lot of tissuedestructive
Dr. Erich Schramm (24:35):
right, so kind of the pros.
There are broad uh suppressantof these wide range of
inflammatory molecules right,but the downside is there could
be collateral damage in thatright.
In that immune system, orwhether it's infection, or
Dr. Michael Bernhardt (24:54):
that's why these drugs aren't on the
candy aisle.
I mean drugs are drugs and theycan cause great things.
They can do terrible things.
So I was doing a lecture lastnight to some of the doctors
that said, part of our job aslearned intermediaries is to be
able to figure out what drug isgoing to be in such a state
where we've mitigated thedownside risk and maximize the
upside potential.
(25:15):
That's our job as physiciansand that's why I don't think AI
will ever really replace a goodphysician.
You know, even though patientscome in all the time, Dr.
Google said I had to do this,this, this and this.
They said well, Dr.
google's office is right nextdoor.
Feel free to go see him there.
This is how we're going to do ithere.
That's right.
Dr. Erich Schramm (25:34):
No, I appreciate
Dr. Michael Bernhardt (25:35):
But the JAK's are great.
I mean, they're really, they'rea brave new world.
Um, a lot of people havedeveloped what I call JAKophobia
.
They're afraid of the JAK's andthat really bothers me.
And the reason for that fearwas there was a study, there was
a problem with Xeljanz aboutabout 12 or 13 years ago.
Xeljanzis a pan-JAK ,JAK one,two and three which blocks
(25:57):
everything.
It's a great drug and it hasits use.
But there was a cohort ofpatients with rheumatoid
arthritis who were on comorbidprednisone and methotrexate and
they were using a dose doublewhat we're using today and there
were some problems.
Some patients had pulmonaryemboli and deep vein thrombosis.
And then, about four years ago,there was a study where they
(26:20):
compared one of the TNFinhibitors to one of the to
Xeljanz in the same cohortpopulation.
You know, methotrexate andprednisone treated rheumatoid
arthritics and they showed thatthere was what they call not.
They were not able to establishnon-inferiority.
Okay, so they couldn't say thatthe JAK was non-inferior.
(26:42):
Granted everybody listening, Iagree it's double talk, but
that's just the way these thingsare done.
This is done via bureaucraticmethods, not our methods.
But it showed that there wasquote, unquote non-inferiority.
So now the entire class JAK'shave have this box warning about
infection, lymphoma, deep veinthrombosis and cardiovascular
(27:07):
disease.
Yet when you look at thesenewer drugs that are not panJAKs
, that are selective for justJAK1 or maybe JAK1, JAK2, the
data doesn't reflect the warning, at least not the data that
I've seen.
Okay, they reflect the warnings.
Now, if someone comes to mewho's got a history of deep vein
thrombosis, you know, or theyhave some of the metabolic
(27:30):
syndromes that predispose themto blood clot formation,
probably not a great choice,right, I'd go in a different
direction.
But for a lot of these otherdiseases, these JAK inhibitors
are going to be the cat's meow.
Dr. Erich Schramm (27:43):
That's great, yeah, and thinking about those
patients that were on prednisoneand methotrexate, which are—.
Dr. Michael Bernhardt (27:48):
Which, of course, have no side effects at
all.
Dr. Erich Schramm (27:50):
Yeah, I was going to say
Dr. Michael Bernhardt (27:51):
Totally benign drugs, totally harmless,
Nothing to worry about.
Dr. Erich Schramm (27:53):
So that puts it in the context of what we
think about.
And you know, I think it'sgreat to have someone with your
clinical experience and yourresearch experience so that you
can take and give kind of a realrisk assessment for patients
and say, and you know, in doingthe right thing for your patient
,
Dr. Michael Bernhardt (28:13):
The problem, Erich, is and you and I
have both dealt with this inour practices there's risks of
taking the drug but there'srisks of not taking the drug.
You know, I'm not arheumatologist, I don't treat
rheumatoid arthritis, but I havea lot of patients with
overlapping syndromes, you know.
And the inflammatoryenvironment is different.
In rheumatoid arthritis it'smore Interleukin-1 driven, you
(28:36):
know, rather thanInterleukin-4/13, like in atopic
dermatitis, which is where weuse most of our JAK inhibitors,
and atopic dermatitis is our biguse for that particular drug.
It's a differentpro-inflammatory environment.
have Interleukin don't have1-up regulation, they have 4/13.
(28:56):
So the risk for that populationof having a vascular event is
really pretty low, probably nomore so than the SEER data,
which is the expectedpopulation-based data, right,
Dr. Erich Schramm (29:07):
so your take on the TYK2, tyrosine kinase 2
inhibition, some of the newerproducts here being developed,
what's your comfort level withthat?
Dr. Michael Bernhardt (29:21):
Very, very comfortable.
You know there's one on themarket that I've been using in
patients.
Like I said, there are somepeople with psoriasis who don't
want to take a shot.
So there's one of the TYK2inhibitors is on the market and
I've been using that for acouple of years and it's a
little slower in onset than theshots.
I can tell people it's thetortoise, not the hare, but at
(29:44):
the end of the year you'rebasically going to be in the
same place.
You're just going to get therea little slower, knockwood.
I've not seen any significantside effects to the point where
patients would stop using themedication and it works.
Dr. Erich Schramm (29:59):
Wow, that's great.
So you know I was thinkingabout this because I'm a big
college basketball fan andwatching March Madness
oh my God Go Gators, what agreat year for them.
There you go, and what struck me—.
Dr. Michael Bernhardt (30:13):
And Auburn and Houston and Duke all
the teams I met at the FinalFour
Dr. Erich Schramm (30:17):
Give them credit for that.
They were all great, greatseries.
There are a lot of great gamesthere.
But what was really interestingwere the commercials right.
And so I was surprised at thenumber of commercials for
psoriasis and the selling pointfor this one particular drug was
(30:38):
it tackles or treats both typesof interleukin-17.
And I was like, wow, that is areally sophisticated advertising
approach to direct a consumer.
Advertising that's verysophisticated and so curious.
Do patients come in, you know,saying hey, I saw this
(31:02):
commercial on TV blocking bothtypes of interleukin-17.
Have you seen that inyour practice?
Dr. Michael Bernhardt (31:08):
I'm waiting because I want them to
give me a lecture about it andtell me that what?
actually is kind of funny is,like I said, I'm a pathways geek
, right.
So what I was doing thismorning in between surgical
patients.
There was a great articlepublished this month in the
British Journal of Dermatologywhere they did a genetic
analysis of hidradenitissuppurativa and they looked at
(31:32):
all 5,000 genes that areupregulated hidradenitis
suppurativa and they found thatthere was a notch.
You know, we've always knownthat there's more 17F both in
the lesion and perilesionalright, and F is a very powerful
driver and I'll talk about thatin a second.
But in this study they lookedat the gene sequencing and they
(31:55):
found that not only was 17Fupregulated in the follicle
itself but in the perilesionaldermis those dermal fibroblasts
were kicking out more 17F.
So 17A we already talked aboutit, it's released by dendritic
cells stimulates the whole 17Aloop amplification right.
(32:22):
17F seems to be more tied inwith upregulating other players
in hidradenitis, likeinterleukin-1, which the whole
interleukin-1 family is a verystrong pro-inflammatory cascade
upregulating interleukin-8.
Now interleukin-8's job is tocause neutrophils, or white
blood cells, to migrate into thelesion.
So they're taking the positionhidradenitis and and I think I
agree with hidradenitis is isprimarily a neutrophilic
(32:45):
dermatosis and it's a biphasicdisease, so it starts out as a
pro-inflammatory disease.
They know that there's a defectof this gene called secretase
and secretase gamma.
Secretase is important in thehair shaft and allowing the hair
to turn into hair, when it'sdefective it forms cysts and
(33:08):
that seems to be ground zero forHS.
They form these inappropriatecysts and the other thing that
they've found is through aprocess called epithelium
mesenchymal transformation,where cells go from one cell to
another type of cell, kind oflike what we see in cancer.
In hidradenitis fibroblasts willtransform into epidermal
(33:29):
keratinocytes within the dermis,which also drives inflammation.
So IL-17, A and F get massivelyupregulated in hidradenitis.
And the beauty of this new drug, by downregulating F and the AF
heterodimer, is you can drivedown that interleukin-1, tnf,
interleukin-6 cascade.
(33:51):
So that's why that particulardrug has been successful in
treating something, not justpsoriasis and psoriatic
arthritis, which it's great for,but I think also for treating a
previously very difficultdisease to treat, which
hidradenitis suppurativa.
Dr. Erich Schramm (34:06):
Well, I think I hear the topic of our next
podcast discussion coming upright, I think that's going to
be in a couple of weeks.
Dr. Michael Bernhardt (34:13):
Skin is in baby.
Dr. Erich Schramm (34:14):
Yeah, you know I never get tired of
hearing you talk about theinflammatory cascade.
Dr. Michael Bernhardt (34:21):
It's amazing.
Dr. Erich Schramm (34:24):
So, Mike, thank you so much.
You know a ton of insight there, always appreciate that and you
know whenever we can talk aboutscience and Snoop Dogg and all
of that.
I love picking your brain onthings.
My pleasure.
Any question you think I should ask you?
Dr. Michael Bernhardt (34:45):
Well, let's see.
For those of you who are reallyon the edge of your seat, I
found a great restaurant down inSt John's.
Dr. Erich Schramm (34:54):
Do tell
Dr. Michael Bernhardt (34:55):
it's called Irons and Ember.
Okay, and they do.
All their cooking is in castiron skillets.
Everything is fresh, theseafood is fresh.
The prices are reasonable.
The service was great.
We went there two weeks ago andit was the kind of place where
my wife and I looked at eachother and said when do you want
to come back?
(35:15):
And I'm like how about tomorrow?
So the big unanswered questionwhere should we go to eat this
weekend?
Dr. Erich Schramm (35:19):
Okay, that's great.
Well, no thanks for yourinsight, as always, and again
look forward to talking to youin the near future.
We'll pick up on hidradenitissuppurativa.
Dr. Michael Bernhardt (35:29):
Sounds great.
It's an amazing disease state.
Thank you,
Dr. Erich Schramm (35:32):
thank you,
Dr. Michael Bernhardt (35:32):
thank you .
Announcer (35:33):
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