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AAD 2026 Denver Psoriasis or Dermatitis? When boundaries blur and treatments flip the script
International Eczema Council
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277 views  May 26, 2026
A joint program of the IEC and International Psoriasis Council (IPC) on Psoriasis or Dermatitis? When boundaries blur and treatments flip the script at AAD 2026 Global Education Day. Date: Thursday, March 26, 2026 | Time: 2:00 - 6:00 PM Mountain Time. Colorado Convention Center, 700 14th St, Denver, CO 80202 | Room: Bluebird Ballroom 3EF
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International Eczema Council
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0:00
Okay, good afternoon everyone and welcome. I really appreciate your support for the this joint symposium
0:07
with the IEC and the IPC. Um many thanks to the people who made it happen uh the
0:13
secretariats the in both IPC and the IEC people who've worked so hard uh to make
0:19
this happen. The um I also want to thank Amy Por who I think
0:25
is going to arrive a little later and Yel Yashim who unfortunately can't be
0:30
here just for really geopolitical kind of travel reasons unfortunately but they
0:35
had a huge uh amount of uh work and effort into designing this program and I just want to acknowledge them right up
0:41
at the front before we start so this is the QR code you can get the
0:47
uh the program speaker biographies and so on by scanning the QR code I'm going to give a few remarks about the IEC and
0:53
then Bruce is going to follow with the IPC and the code will appear again at the end of uh Bruce produces remarks.
1:00
You get a second chance if you don't have the phone ready at the moment. There's complimentary Wi-Fi as well for
1:07
anyone who um who needs it. No password required. So the this afternoon session is
1:14
psoriasis or dermatitis where boundaries blur and treatments flip the script. And you'll see what we mean by that as we go
1:20
through the program. Briefly, a welcome from the International Expo Council of which I'm
1:26
currently president. This is be recorded and and posted on both websites. Any IEC questions, you've
1:34
got the email here. If you want to join the IEC, contact the other Alan, Alan
1:39
Styles, his address. You can contact me, too. But the the IEC
1:45
is now we're we're very much um following in the footsteps of the IPC, learning a lot, and this is our 11th
1:51
year in business now. We're now in 38 countries, 187 counselors and associates
1:57
across six regions and we're looking to deepen that, you know, in areas like Africa, Eastern Europe, Asia, South
2:05
America. So, if you know talented people uh who want to be interested who are interested, please let us know. You can
2:12
apply to be a member uh as a if you're a dermatologist or an algist or a PhD.
2:18
These are our our mission, vision, anthem and values. Um I think we just read out the vision here and that's
2:25
really to transform the lives of people living with attopic dermatitis through promoting research and education.
2:33
We've been generously sponsored and the sponsorship has kept us alive for 11 years and we're super grateful to that
2:39
and dependent on it and we just want to acknowledge all of our sponsors here today.
2:45
You can connect with us on social media. Probably LinkedIn's our major um social media platform, but we also have a lot
2:52
of uh videos now on YouTube. Uh over 100 hours of content free for everybody that
2:57
you can watch and today's session will also be on that. I'm going to pass over to Bruce who's my
3:04
co-chair for today. Thank you Alan and in um it's also my pleasure to be a part of this program.
3:10
It's kind of it's kind of a natural marriage to have the IPC and the IEC do a symposium of this nature because like
3:17
Ken and I always discuss like if you treat a lot of psoriasis you treat a lot of eczema and vice versa. It's like this
3:22
is not a hard transition and in this instance uh if you treat a lot of psoriasis you might encounter some
3:28
eczema and vice versa. So it makes sense to have a discussion about these phenomena. Um I serve as the IPC
3:36
president um an institution I've been a part of for
3:42
almost two decades one way or another and we too are reliant and extremely um
3:48
thankful for our sponsors uh who are our lifeblood and allow us to have programs
3:55
of this nature. Um and really they stand at an arms length allowing us to have a
4:00
a program that is unbiased and very educational. And we have a mission and a vision. Um,
4:06
and and like the IEC, we're really about improving the health and well-being of people with psoriasis worldwide.
4:14
Um, and we do that through education, research, and advocacy. Um, and we really would like to create a
4:21
world that's free of the burden of psoriasis, where everyone has access to the best available care, the opportunity
4:28
to live a healthy, fulfilling life. um our professional uh network. When I look
4:34
at this map, I think we got all the continents except Antarctica. If you are from Antarctica, please
4:41
send an email to uh Christie um and you will then complete our geographic um
4:50
spread around the world. But uh seriously, we have 233 board members,
4:55
counselors, and junior counselors in 50 countries. Um and you know that the map
5:01
on in and of itself is quite impressive and we're always trying to grow our representation
5:08
everywhere. So again if you have any interest and you feel like you should be a part of the IPC you can email us go to
5:16
our website and these are our areas of focus. Um access, research,
5:22
collaboration, education is a big thing we do of course as evidenced by this symposium. Um
5:30
regional uh delivered education as well and programs and then expanding our global
5:37
network. Um and then uh as Alan described for IEC, we have um we we we we have a lot
5:46
of educational material on the web. Um so you could you can look on YouTube,
5:52
for example, and find a lot. I I've made videos for IPC that I don't remember,
5:57
but my my dad will say, I just watched your video on this and it was like eight years ago on YouTube. So they're there.
6:04
Um and then we have symposia that are worldwide the global symposia one
6:09
attached to the SS SID meeting, the ESDR meeting in Germany. Um the EADV that
6:16
will be in Vienna this year and you can see various topics are covered and then we have regional meetings for example
6:22
one in Buenosirus. Um and you can scan that QR code if you
6:28
would like to stay connected on all the social media um sites. Varyingly we are
6:34
um on these social media sites and always growing our our reach through social media
6:42
and then to scan the QR code to get the program guide. You get today's agenda and the biographies of the speakers.
6:51
All right. And then Allan mentioned the the chairs. We really have to u credit and and Amy for putting together the
6:58
lion share of the agenda and in the educational product you're about to get.
7:03
Um so uh we can't do it any of these things without the hard work of our counselors and and board members.
7:10
So to start we're going to have uh Dr. Jason Hawks uh come to the stage. He is
7:17
a board certified dermatologist. He's the co-owner and chief scientific officer and investigator at the Oregon
7:23
Medical Research Center in Portland, Oregon. Uh he's a counselor in the IPC.
7:29
He's on the medical board and scientific advisory committee of the MPF, National Psoriasis Foundation. Um he's also an
7:36
NIH funded investigator, nationally recognized speaker, gets a lot of teaching awards. um he uh including you
7:44
got the exceptional teacher of the year um an MPF outstanding educator in seroriatic disease. Um so Jason's going
7:51
to talk about the clinical presentation of exeminus reactions in patients receiving treatments for psoriasis.
7:59
Thank you Bruce and uh thank you for the AB IPC and the National Council for putting this together. And I'll have the
8:06
pleasure of presenting with uh Ken Gordon. We're going to kind of set up the framework for looking at this, you
8:12
know, we're going to call a switch necessarily, but this shift clinically by our eye from the psoriasis patients
8:18
receiving psoriasis therapies moving towards more of an exempt disruption. Actually, Andrew did a great job in in
8:24
setting up some of that and I won't spend time on some of that overlap. These are my disclosures here. So, what
8:31
I want to go through is a little bit of what we're seeing in the literature. So I think clinically we have a good idea
8:36
of what these cases look like. We've had some of these patients that have been challenging. But I want to go through what are what are we learning about in
8:43
terms of the literature suggesting mechanisms. Do we understand this pathway? But also some of the
8:49
confounding variables which uh Andrew did hint at. So I'll say disclaimer. I
8:55
don't have a satisfying explanation for these observations because the science isn't there yet. But we're learning from
9:00
these cases to start answering questions about how we might be able to get at the mechanisms because we do need to
9:06
understand this in terms of both diagnostic recognition but also therapeutic management. So what are we
9:13
talking about just to set the stage? We're really talking about these psoriasis patients treated for psoriasis
9:18
who then have a change in their initial morphologic features. Right? We're not going to necessarily apply a certain
9:24
terminology to that, but but the idea is that they look one way, you treat them, and it looks different after that. In
9:31
the literature, there's a lot of mixed terminology. Not surprising as this is relatively new. And I think part of this shift to being new is the fact that
9:38
we've moved from broader acting agents, cycllosporin, methtoresate, for example, phototherapy. Now we've moved into very
9:45
targeted therapies on key pathways driving diseases. So it's not surprising that this is actually coming out now as
9:51
those therapies have gotten more targeted and a little bit better. But these are the some of the the reactions you'll see PE abbreviated in the
9:57
literature. I'll use that in the presentation. So paradoxal eczema paradoxal exeus reactions biologic
10:03
induced paradoxal eczema reaction which implies the drugs definitely causing it which which I would say is is is a far
10:10
reach right now based on what we know. And then of course this phenotype or class switching. class switching. I'll
10:16
tell you some of the challenges with that terminology, but but definitely a phenotype switch, right? That's what we're seeing clinically. It looks
10:22
different. So, the observations are real. There's no doubt across the board we're seeing these observations. The
10:28
question is we is the mechanism clear? And the answer is it's not really clear yet. So, we're just barely scratching
10:34
the surface. But what we know from some of the literature is that the prevalence of this is less than 5%, somewhere in
10:40
the 2 to 4%. So, it's not a majority of p patients. It's a small number. And the question is, well, who are these
10:46
patients? It's less than 5%. And what can we learn about when they present? Are there clues that might tip us off?
10:52
And I'll give you a little bit of that. I won't spend too much time here for challenge one, the initial diagnosis, but Andrew did a great job in setting
10:59
this up. This was one of my cases sent to me from a very good academic center, seen multiple dermatologists, biopsied
11:06
multiple time, was sent to me with a diagnosis of recalcitrin plaque psoriasis. And when I talked to this
11:11
patient, the thing that was striking is he said, "No matter how long I use clbatazol on any single lesion, it
11:18
doesn't change at all." It's really interesting. But look at this up in the upper left hand corner. He's had this
11:24
central clearing which doesn't have a fe it's not really a feature we see with psoriasis, not untreated psoriasis. So
11:30
this patient ended up having a different diagnosis entirely. But the point was clinically it looked like plaques and
11:37
areas but it didn't follow the treatment response pattern at all. This patient ended up having cutaneous T- cell
11:44
lymphoma or MF. And so I think the one confounder we have to consider for these
11:50
cases is that there are probably a substantial portion of them that have been misdiagnosed from the beginning. So
11:55
here are some good examples. So this numular eczema misdiagnosis psoriasis we got MF case I showed you a CTCL. This
12:02
one on the face was basically um seerm overlap SIBO psoriasis had pretty
12:08
classic CTCL when they had the workup. This is a case on the left plaque psoriasis with a patient one of my
12:14
colleagues at the academic center who had treated this patient as eczema because of the lyenification. You can
12:21
see right there on the knee, you can see where I did the biopsy. Um, actually just had plaque psoriasis pretty through
12:27
and through. Had a strong family history. SL stasis dermatitis. So I think the point is that this is still a
12:33
clinical diagnosis and this creates some of the confounding that we might see. These patients have, as Andrew
12:40
mentioned, it's a spectrum. There's overlapping clinical features and most importantly, there's no definitive
12:45
biomarkers. We still don't have a diagnostic test or any commercially available testing that can differentiate
12:52
between these inflammatory entities. So we're really relying on the clinical skills of that practitioner to make the
12:59
initial diagnosis. And one important point is that biopsies cannot reproducibly distinguish between
13:05
psoriasis and next. I want to drive this point home was a great study done by Max Fun and and others when I was at UC
13:12
Davis looking at very clear cases of plaques rice that responded to traditional therapies but they looked at
13:18
their biopsies and what's really interesting is 76% of these specimens had spongiosis 50% had dermal
13:25
eosinaphils and they were not these are patients that weren't having observed sort of this switch this paradoxal ezeus
13:31
reaction and so the point here is that a lot of clinicians fall into the diagnostic ic trap of saying well I
13:37
biopsy it had spongiotic dermatitis with you know eosinaphils therefore was eczema and they end up putting them on
13:43
treatment. So it raises this question which is one that no one's really answered in the field yet which is what
13:49
happens when you unintentionally treat a nons psoriasis disease with a targeted
13:54
biologic and part of what you're going to see in this group is that we don't know what happens to lupus on an isle 23
14:00
what happens with you know urtdicaria on an aisle 23 or bis pimpoid like these we
14:05
haven't really done those experiments but it raises this important question that some of the reactions we may be seeing are actually misdiagnoses from
14:12
the beginning and we're starting to witness what happens to that immune response when we hit a targeted portion and then let other immune circuits start
14:19
to go in a different direction. So th this creates an important problem that has to be addressed in the field. Having
14:25
these diagnostic biomarkers is going to be important to help differentiate that we thought what they had from the
14:30
beginning is actually what they had initially otherwise we're saying oh we called it psoriasis and they had this switch when in fact they had a different
14:36
disease the whole time. But there's another subset of these patients which Andrew hinted at which is the background
14:41
of attop and secondary infections. And I'm going to give you just kind of a snippet of of some of the literature
14:47
here. So you can see this is incomplete literature but it starts to give you a little bit of insight into a theme
14:52
that's going to come across. So basically we look at different studies where they're starting to look at these
14:58
groups. So here's an observational retrospective study. 54 cases of the exe examinous eruptions and chronic plaque
15:04
psoriasis after an 17 or 23. Interesting. No big difference in male
15:09
versus female. And the mean age of onset was 52. Now I'm going to drive that point home a couple of times because all
15:15
the patients I've seen that have ever had this reaction. All of them were older patients. And it starts to raise
15:21
questions about what's happening to immune tolerance and some of the changes that happens with age. You're going to see that come out as a feature
15:26
throughout some of the literature. Um but interestingly 44% had attop as a history 30% had attopic conditions and
15:34
then 20% previously had eczema very interestingly we're learning something about these patients where the vast
15:40
majority of them have some history and a lot of patients don't recall that childhood history may have had it so
15:46
getting some of that history going back some of these patients find out oh actually for my parents I did have these rashes that would kind of come and go
15:52
and pretty typical eczema history they just didn't they weren't aware of it but interestingly for the culprit when you
15:57
look at the offending medication. What was the medication that caused this switch or was related in temporally with
16:03
this switch? And most of it's 17. You can see almost half of the cases secinab
16:09
also an is 17 receptor blocker and very low rates for the 23 medications. And
16:15
interestingly in all the patients in this this analysis, they all achieved remission this this reaction whatever
16:22
the driver actually resolved. So it's telling us something about this is 17 pathway and you'll you'll see both the
16:29
is 17s but also used tokenab come up very commonly in literature. So here's another presentation. So this is a
16:35
50-year-old female had a history of GPP. So not just plaque psoriasis but other forms of psoriasis had GPP asthma
16:42
shogrin syndrome. So we've got somebody that's got multiple conditions different pathways. And interesting in this
16:48
patient is 22 increased. They didn't measure isle 36. So the question here is
16:53
was this really a flare of their underlying eczema or their or their asthma their attopic condition or was it
17:00
really a flare of their underlying GPP? So Andrew brought up the point of of ariththrodermic psoriasis but
17:05
ariththroma in general is very difficult to pin down a diagnosis just on on a single exam and so we start to do a
17:11
workup these patients. So in this case the question is could some of the manifestations here have really just
17:16
been untreated or inadequately treated GPP. But what's interesting is in this
17:22
patient that flared, when they looked at some of the cytoines during this flare, this paradoxical shift, there's actually
17:28
no increase in the type two cytoine. So it raises the question, is this really eczema? Are we just calling it eczema?
17:34
Because we're not seeing the same immune profile that we see in these patients who have traditional eczema. And that
17:40
fits with what we know about things like paradoxical psoriasis. We know it's not really psoriasis. It's not really pusher
17:45
disease. It's kind of in the middle. So I think that gives us some insights there. But again, this is a patient with underlying type two disease. Here's
17:52
another 25 reactions in Verona, Italy. Reaction onset was between three and 24 months. Also very interesting. If this
17:59
is drugrelated, why isn't that happening within the first three to six months? What why would a patient have this
18:04
shipped after two years of being on therapy? So it raises the question about the temporal relationship with these
18:10
therapies. Diagnosis, hisytologically confirmed. already raised the the concerns around that because how do you
18:15
really confirm a diagnosis when the pathologists can't consistently do that but a strong ate history in over 60% of
18:22
patients the DRA treatments worked really well so again getting back to the point of broad spectrum in terms of
18:27
hitting multiple immune circuits might be helpful and these patients well controlled with anti 23 so again another
18:34
theme coming out from the literature another case paradoxal eczema this one I think is quite interesting I've seen
18:39
this a few times 31year-old male plaque psoriasis since age 10 not responsive to traditional therapies. It's always
18:45
interesting when these patients don't respond to cycllosporin because it raises questions about the underlying
18:51
immunology. But this patient initially had clearance on an anti 17A skin
18:57
cleared and then later had this reaction this this change in the phenotype. This
19:02
patient turned out to have a positive MRSA infection and treated uh the infection uh had was noted to have high
19:10
levels but then very interesting this patient was put back on the same is 17A inhibitor and actually had good control.
19:17
I've had this happen multiple times a patient was doing well on a stress medication turns out they had this ariththromic flare a sudden shift in
19:24
their phenotype we found an underlying infection. I've seen that a few times. So these are potential confounders that
19:30
happen. The fact that a patient could go back on the same medication after the treatment was was cleared and not have
19:35
this reaction again is is quite interesting. So there are groups that are now starting to look at this. Andrew also hinted at this. Could there be
19:43
maybe some genetic overlap uh in the genes that might drive susceptibility to ferose plaque psoriasis and eczema. So
19:50
this is a looking at again retrospective over 3,000 case controls versus 88 case
19:56
cohort control. So 4% right and we're looking at G-W was so we're trying to identify could there be some genetic
20:03
markers that might help us identify the susceptibility and they know what Andrew brought up which is that there's already
20:09
been work done showing that there are some susceptibility lossi which drive uh
20:14
risk or risk factors for both conditions so are we picking up some of these patients most of the patients that had
20:22
these reactions were either anti-TNF or is 1223 so you already heard about that within map most commonly associated. But
20:29
a couple of real interesting insights, most of these patients were female. They were typically older age by by mean age
20:36
if you looked at their years and they all almost all of them had a prior history of attopy or a diagnosis of
20:42
seriatic arthritis. So raises the question about these patients as having multiple other conditions that might be
20:48
driving some of these immune circuits. But what's really interesting from this paper is that when they started looking at the genetic uh susceptibility lossi,
20:56
you could look at patients who had described this past history phenotypically of having ezeinous
21:02
reactions or history versus those who didn't have that prior history but had
21:07
the lowi. And what was interesting is that their risk for this reaction persisted even if they had never
21:14
clinically experienced what would be classic eczema. So there's clearly some driver here in this group that whether
21:21
or not they've had manifestations clinically of of eczema or attopy in some form that that relationship um
21:28
occurred to to persist which really suggesting there may be an underlying susceptibility in terms of the genetics.
21:35
So looking at some of the other ways of trying to tease out this reaction. This is the bad beer group the national
21:40
registry sice registry in the UK also Ireland center. So 168. What's
21:46
interesting about this paper is they had data before the reactions happened. So at T1 this is getting serum before these
21:53
patients had started biologic. T2 is after they had started biologic got better for typical psoriasis. And then
22:00
T3 was after this shift this PE reaction. So that gives us a chance to say, well, what what did it look like
22:06
before? Because one of the problems with this concept of class switching is you assume that you knew what their class
22:11
was before they switched and most people don't actually determine that. So now you have a chance to say, well, what did
22:17
it look like in terms of the shift? So you have 71 PE cases, 75 controls.
22:23
There's there was one identification, so stamp B and T1 that suggest that it may correlate with with these PE reactions.
22:30
And it's sort of a a soft link between IL is1 signaling. So interestingly, because some of these paradoxical
22:36
reactions, we also see the IL1 or the IS 36 pathway come up. So there may be one
22:41
biomarker, a lot more to be done in terms of teasing out mechanisms, but but may give us some insight a little bit
22:48
into what may be driving this. But at T2, so this is when they got better on their psoriasis biologic, but they
22:54
hadn't had this reaction yet, this shift. and you look at before it, they already have these genes that are
23:01
correlated with attopic conditions. So it suggests that these patients even before they've had this exemptous
23:07
reaction have already had some of these AD related genes or signals that can drive sort of this at history and then
23:15
really interestingly at T3 after they've had the reaction you compare T2 to T3 say they were got better then they have
23:22
this reaction later what's the difference well there was no significant difference and very interestingly these
23:27
patients didn't have an increase in type two cytoine. So the question this raises is this really paradoxical eczema?
23:34
Because if they're shifting from psoriasis to eczema, why are they not getting upregulation of these signals
23:39
that are classically associated with eczema? So this starts to give us some insight that there may be a susceptibility but the underlying
23:47
pathway even though we're calling an exemptous reaction may actually not be these type two cytoines. So raised the
23:52
question on the work that we still need to do. And to end just some final thoughts here. So here is actually a
23:57
skin of color patient. the same idea that Andrew brought up that these can be very difficult in terms of phenotype.
24:03
But we have to consider the fact that some of these reports may actually be confounded by the fact that they've been
24:09
misdiagnosed from the beginning because why? We know that clinically we can't always rely on our eye and the clinical
24:15
features. We know that they can patients with inverse psoriasis often get misdiagnosed with eczema for example. So
24:21
phenotype isn't totally reliable. We still need a biioarker, diagnostic biioarker that can differentiate between
24:28
some of these inflammatory conditions. Class switching, I don't like that term because it assumes that we knew their
24:36
class before. And the problem is that nobody profiled these patients before the reaction because they didn't know
24:41
they were going to get the reaction. So, we're learning everything on the back end. So, the problem with class switching is we don't know what they had
24:48
before, but we need to start learning this. I think the the study showed the bad bear study gets closest to that and
24:54
saying we have some information before the reaction but we really need some skin data. We need biomarkers in the
24:59
skin before they have this reaction. It's hard to do because you can't predict these patients but I think what's overwhelming in these cases
25:06
through the literature and this is just a snippet of the literature but consistently most of these patients at least half of these cases have some form
25:13
of ofty. So it may be that we need to be asking about these patients and and some
25:19
of those cases, but there are true denovo presentations. The very first case I saw was a 68-year-old male that
25:26
had very classic appearance of plaque psoriasis and he totally switched. I asked him every question related at
25:32
couldn't find one single thing. Never had a rash, didn't have seasonal allergies, didn't have asthma. So we do
25:37
have some denovo presentations that we do need to tease out because I think these observations suggest that's the
25:43
case. And this idea of unmasking, I like the concept unmasking because it tells
25:48
you that something was already there. It just looked different to your eyes. So, I like this idea of unmasking or
25:54
phenotype switching because I think it best captures clinically what's happening. We're getting components of
25:59
one aspect of presentation better and we're having others that either persist or others that start to worsen. So, I
26:06
think we need to think about the the proper nomenclature for these cases. And I think the other thing that's really
26:12
needed as the final point is that we really need the mechanism that's explaining these observations. So I
26:17
think most of us in this room would agree that the clinical presentation observations is real. We just don't have
26:23
the mechanism explains why it's happening. So this is just the beginning of this work to start moving forward.
26:29
Why the IL1 17s tend to be more uh related rather than the IL 23s raised
26:36
this question that is 17 has this protective immunity. I think there's there may be this crossover with
26:41
infections as these patients on a isisle 17s have this hampered response that are we then setting off something else in
26:48
these patients uh for example and colonization bacteria infections for example so I think a lot of work to be
26:55
to be done here and thank you thank you thank you Jason
27:01
um so Ken Gordon now comes to the lectern um and and just as an introduction um Ken is a professor of
27:07
dermatology at the Medical College of Wisconsin in Milwaukee. Um, and over the past 25 years, his clinical and research
27:15
interests have focused on developing novel imunotherrapeutics for psoriasis. Um, he's been part of many, uh, clinical
27:22
trials, um, pivotal clinical trials, um, involving psoriasis medications. He's on
27:28
over 250 publications including, uh, first author publications in the New
27:34
England Journal, Lancet, and JAMAMA. Um he has served as the center as as the
27:39
center of clinical research director at Northwestern and until recently he was
27:45
the chair of dermatology at the medical college of Wisconsin. He's a longtime IPC counselor and he's going to speak
27:52
now to the clinical approach to these uh quote unquote uh paradoxical exeminist
27:59
reactions. Thanks very much Bruce. Thanks for the introduction. And you know when when we
28:04
were given this topic um Jason and I were talking about you know what do we do? We don't know exactly what's going
28:10
on. I kind of like the concept of uncovering or unmasking of lesions. Um
28:15
we've talked a lot to people over time about imologic switching which I'm not sure what we can say about that in the
28:21
patients who have attopic histories. But without even full knowledge of what's
28:26
going on with these patients we're all faced with them. we have to do something about them and we try to make them
28:32
better. And so the question I have um that I've been tasked with today is sort of trying to think of what's the best
28:39
educated technique to approach these patients. And I say an educated technique rather than a evidence-based
28:45
technique because we have so little evidence to go on. And so what I'm going to go is how I think about these
28:51
patients when I see them in my clinic. Um and try to bring in as much evidence as I possibly can, including some new
28:57
observations. um that haven't even really been published yet have been presented that might direct us in some
29:03
way of thinking about these patients. Um but first let me just give you here my conflicts of interest and there are
29:09
multiple. So the question is how do you approach these patients with a paradoxical reaction and again the the
29:15
term paradoxical is used very loosely in this case because we don't know that there is some paradox. It could be that
29:21
you're controlling one arm of the immune system and allowing another one to um show up that would have been there
29:26
anyway. We don't really know. So what are the questions? One is is there value in counseling patients before we start a
29:34
biologic therapy for psoriasis? And I think that's a really critical question because I will tell you most of these
29:40
patients that show up in my office are referrals from people who are started on an agent for psoriasis and it just isn't
29:47
working. And they come into my office and I would never have guessed they had psoriasis in the first place, but they
29:53
were diagnosed with psoriasis initially and then they weren't. So the question is is it important to talk to the
29:58
patient not only because it's a possible thing that might emerge but also because that patient might be able to recognize
30:05
what's going on where the clinician might not. Secondly, if the reaction
30:10
does occur, is there any kind of diagnostic evaluation that helps us in this case um that we should be doing it?
30:16
Um there are many dermatopathologists who I've worked with over the years who've hated me over times because I have the philosophy that I've taught
30:22
residents. When's the right time to di to biopsy psoriasis? Any thoughts?
30:28
Never. And the reasons for never is just as was pointed out, everyone has got spongiosis. Everyone has scratched their
30:35
lesions. It will get you down a pathway that's very difficult to understand. Do I change my mind with these patients?
30:42
And finally, what's the therapeutic approach? And that's really what's important in trying to figure out how do you help these patients?
30:49
So the first of all, what's the incidence of this? And we really don't have a good understanding. A lot of numbers are thrown out. Typically the
30:56
number that gets thrown out to me is 1%. And that's because of a a great uh issue
31:02
about from bad beer, which is obviously a prospect of sor ISIS registry and is
31:07
probably as good as anyone that's out there right now. And they come out with about a 1% uh 1% incident. Um there are
31:16
other reports. However, there was another report that was a retrospective analysis that was 2.3%.
31:22
What do I think when you look at this var? And there are some estimates that go up to 4%. My argument would be I
31:29
think this is probably underestimated because so many patients are switched from drug to drug to drug on psoriasis
31:35
because they are not diagnosed as having something that's different from their original psoriasis.
31:40
The rates seem to be different on different classes. And again this is from the badbeer registry that the is 17
31:46
seemed to be the most common. The anti-tenfs where this is probably the first place it was described was similar
31:53
and the anti 23 inhibitors specifically seem to be the lowest though anti 123
31:59
were sort of in between. Now the one thing I want to bring about that is it might be less common in with anti 23s
32:06
but it's not zero. It's low but it's not zero. So you have to think in terms of all of our specific medications for
32:13
psoriasis that this is a possibility. Um obviously as Jason pointed out it's
32:19
much higher in patients with a personal or family history of ATP. Um and that's going to be the m great majority of
32:25
patients that I've seen even if the patients on first glance will say no I haven't had anything. When you keep on
32:32
hammering oh yeah I do have seasonal allergies every fall or every spring. And so you pull something out when you
32:38
really start talking to these patients. So I think it is important to really take as detailed any topic history as
32:44
you possibly can for both them and their family. I had a patient um I think it
32:49
was probably about a week ago who said, "Oh, I've never had anything known in my family, but man, my kids have horrible
32:54
allergies." Well, there you go. And so I think most of these patients, you can tease something out. Um I do generally
33:02
because of this data in the low incidence don't uh counsel patients specifically on this reaction. Uh I
33:08
think it's too uncommon you get people thinking about this. However, we have a a a entry questionnaire that we have
33:15
when patients enter our clinic and if they do have a history of ATP in any form I do mention by the way if your
33:23
reaction if your skin seems to change around let me know. it's something that we might want to be considering in the
33:30
future. So I do bring it out in the patients who have a clear history of ATP.
33:36
So evaluation of the patients um it's not universal. I think it's more
33:42
universal than the data would suggest but I think it's not uh completely universal. So the biopsies that have
33:47
been studied are con consistently are spongi sori acapform dermatitis with eosinaphils and those who have had
33:54
levels measured as we've had a couple patients discussed earlier today they're generally quite high. So in some ways
34:01
the biopsies the eosinaphils and the levels seem to be consistent with a very
34:06
attopic condition. Um there's a complexity in the issue of of initial
34:12
diagnosis. I think that's what Jason really pointed out quite well. Um, and when you get a biopsy after the fact,
34:18
you don't know what you had initially. Uh, so my thought is when doing the
34:24
diagnostic workup and whether we do a biopsy, does it actually change what we're going to do for the patient? And
34:31
my argument is except for one thing, no. And that one thing is cutaneous cell
34:36
lymphoma. Uh it's always the thing that's in sitting in the back of my mind. RCTCL doc uh will talk about in
34:43
every differential at grand rounds will say, "Oh, that's CTCL like lupus that or it's lupus like CTCL or eczema like CTCL
34:51
or psoriasis like we actually now have normal skin like CTCL." Um so I think in
34:56
almost every case that's the one thing that goes through my mind that I could have missed.
35:03
Now there are a couple hints of physiology that we haven't talked about. You know immune deviation is something
35:08
that we talked about and it's really yet yet to be demonstrated. I will tell you I spent a lot of time when my posttock
35:14
um working on immune deviation in mice and different reactions to um MS in in
35:20
uh things in mice and so I believe everything's immune deviation. Um but I
35:26
don't think it's been demonstrated this at all. I think on uncovering and un masking is a much higher likelihood. But
35:33
there are other possible immunologic pathways that might be interested and I want to point out this poster that was
35:39
presented at the uh ISDS in November in New York. Now I want to say I really
35:44
wasn't prepared for this. Uh I was actually chairing the session. It was the last session of the meeting on Sunday morning. So most people had left
35:51
already and um I started listening to this presentation and I suddenly was looking for a pen trying to write down
35:58
notes on this. And so what you see in terms of the interpretation is my best recollection and the abstract. So there
36:04
were there's a lot of data in this that I'm not going to do justice to in any sort of way. However, I think it was
36:11
very fascinating. There's this TNF super family protein called tweak which I think is a great name for looking at
36:17
paradoxical reactions. Um and it can synergize with interlucan 13 to produce
36:23
a TH2 type response. Anti-TNF therapy has been demonstrated to induce tweak in
36:29
patients and the inflammation associated can be a TH2 reaction with one big
36:35
difference and there seems to be a significant type one interferon reaction. And if you look at paradoxical
36:41
reactions that we see with almost any agent, type one interferons tend to show
36:47
up. And so I just want to point out that when we think about therapeutically there might be something other than just
36:53
cheat treating TH1 and treating TH2 there might be something else another third pathway that might be very
37:00
relevant and I think the type one interferon pathway is something we should consider.
37:06
So what are the possible therapeutic approaches? Now there's a wonderful view um again from the Bad Bear and that's
37:12
the first reference um on this on this slide that looks at all the patients in
37:18
their registry that had this and basically there's no cumulative data set that's presented simply because
37:25
everything that's possible has been done and sometimes they work and sometimes it doesn't. So one of the things that
37:33
happens is you can continue with biologic just add topicals or phototherapy. You can see if they make patients better some patients get better
37:40
with that some patients don't and sometimes patients get better maintaining the original biologic. You
37:46
could change the biologic. The one report that Jason pointed out talking about going uh all the patients improve
37:52
with going to an anti-23. It's possible. Do you change class or you just change biologic? I would
37:58
generally think about changing class. um but that's not what was done with all the patients. Sometimes it was changing
38:03
within the same class. You can stop the biologic and treat topically or with phototherapy. Well, what happens in
38:10
those cases? Usually the primary disease will come back. So you go from having psoriasis to this paradoxical reaction
38:16
back to psoriasis and then you can change what most of us are doing is change to an agent has less specificity
38:22
and will diminish inflammation from both TH17 and TH2 immediate inflammation. Um,
38:27
I think that uh, Jack inhibition is really my go-to right now in the patients who are particularly severe. I
38:35
want to point out, you have to think about what Jack inhibitor you're using because if you think about using a TH2
38:41
response, hitting is 17 and potentially a type one interferon, you're going to
38:47
need to hit if you're just hitting the jacks, Jack one and Jack 2. If there's a patient who's at high risk uh and and
38:56
has a sorias from derm um phenotype at start I would actually think about using tick 2 because if everything with tweak
39:04
required the um the type one interferon reaction and blocking tick 2 will hit 7
39:09
the 17 pathway through 23 and type one interferons. something that has
39:14
absolutely no evidence but I think makes some logical sense to think about especially when we have uh the second
39:20
generation of tick 2 inhibitors obviously cycllosporin's been used quite a bit um we don't use a lot of
39:26
cycllosporin in our practice anymore um but I think this is one of the places that we have gone to it so here's our
39:33
approach um we do have a number of these patients and we are trying to figure out
39:38
a a sort of standard approach for it but this is the world according to Ken and Alan and Bruce both known me for a long
39:44
time. That doesn't necessarily mean the real world. Um we have no idea what this
39:50
what our original impress our clinical impression was correct. But if we have an idea about an initial improvement
39:56
that gives me lens credence. So a lot of these patients like some of them we've heard about have initial responses of
40:02
their primary disease and then after that response have a new onset of this
40:08
different phenotype. I actually think that that gives credence to the fact that we are treating psoriasis
40:13
initially. We will biopsy to verify but not to make sure that they have attopic
40:19
dermat or a paradoxal exemptous reaction. I just want to make sure they don't have CTCL. I've been wrong before.
40:25
Um 1977 I think was the last time. Um our initial plan is to continue the
40:32
anti-corratic biologic and add topicals or phototherapy because generally the primary disease is better in these
40:38
patients and so we try to treat them. If unsuccessful change the biologic uh most
40:43
likely changing to an anti-23 but sometimes we go to vice versa. Um but we
40:49
really do move into jack inhibitors quite quickly um with significant jack one blockade. um many of the patients
40:56
have seriatic arthritis as Jason pointed out earlier in that case cycllospor is actually a pretty poor drug for seriatic
41:02
arthritis and so for that reason the jack inhibitors really have primary uh
41:07
use so with that in conclusion um paradoxal ezeinous reactions are at low
41:14
rates but I actually believe they occur I don't know if they're paradoxical they
41:19
might be unmasking they might be some other phenotype of a primary disease But they change in phenotype clearly does
41:26
happen. We have a hint that most of these patients have some attopic prop propensity but not all. The
41:32
pathophysiology understanding biomarkers understanding what's going on imunologically will give us the best
41:37
pathway to look at um how to treat these patients. But the best signal I have
41:43
right now is both a type one interf and a TH2 pathway in these patients. So
41:49
expanding the pathway to also include psoriasis treatment is important. Uh and we don't have a treatment algorithm. We
41:55
it's not there and it's not going to be there for a while. Um but I think it's something that we're going to take a lot
42:00
of centers and a lot of people and hopefully this talk will set up a number of things to make people think of
42:07
hypotheses that can be tested to take better care of these patients over time.
42:12
And with that I say thank you very much. Okay. Okay. So, we'll uh take some
42:17
questions if anyone has any. Uh you want to go to the microphone? Joel, you're going to be the uh inaugural questioner.
42:26
Yeah. First of all, it's a great session, really necessary one. I have two sort of questions. One is there's
42:32
sort of exeous reactions that we see with biological and then there's ezeactions like severe stuff. Uh so for
42:40
this 23s where I see the eczema shift, it's usually fairly mild. sometimes a
42:45
little extensive but not like exuberant way to get rid of 17. I'm just curious if that's other people's experience or
42:51
is just unique from what I'm seeing. I would say it's probably my experience
42:56
though I have to say um I've seen it in all cases and so I've seen some quite
43:04
significant reactions with IL23s as well. Um, I do see this more frequently than I thought I should, but I think a
43:10
lot of it's referral patients, you know, since we see most of the referrals for the state of Wisconsin. Um, and so, um,
43:18
I think in a general sense, yes, but it doesn't preclude the fact that you have severe patients with anti-L23s as well.
43:25
And then I'm curious about what you guys do when they have severe sort of seic eczema presentation, really inflamed
43:32
scalp lesions that are weeping and often colonizer staff. Let's say they were on a 17, like would you put them on a 23 or
43:40
like how do you balance that situation because you want that to settle down? It's really hard to treat in the acute
43:45
setting. So Joe, I think you know you're bringing up a good point which I think raises the question about why is 17s might be a
43:53
little bit more observed with this than say the 23 class. So again going back with 17 is
44:00
creating that innate protection like that's the one drawback to that class. I've had one patient that had this exact
44:07
presentation. It's really severe. Actually did quite well on the 23. So, you know, I think it raises the
44:12
question, are we allowing some background innate protection? We know that is 23, for example, doesn't
44:20
regulate innate cells that can make 17 cytoine. So I think that idea of can the
44:26
dasis we don't see with isisle 23 blockade it raises the question if some of these patients and I brought that's
44:32
why I brought up that case on infections that some of these patients get secondary infections and in the in the
44:38
presence of these secondary infections if they have this background of attopia and flare and I've seen that now in
44:44
three patients where in each case we've either found a viral infection a bacterial infection or MRSA and so I I
44:51
have personally had success very small number. I don't think a lot of people have a ton of these cases, but switching
44:56
to Isisle 23 actually worked pretty well. Thanks.
45:02
Hi, thank you for your presentations. They were really good. Uh actually I want to ask I totally agree what you
45:10
said that it's it's it's something it's a problem related to the target therapies and and and
45:17
uh so I'm from Brazil and in in Brazil we didn't have quite the opportunity to use stick to inhibitors. It was hard to
45:24
get founded and then we we got some free samples and now we don't have them
45:30
anymore. So we have just a few patients. So I want to ask you the ones who had opportunity to use T2 inhibitors was
45:38
which is a little bit broader than than than the biologics was that a problem
45:44
too with Tik T or was not that common to see
45:50
eczema induced by by by T inhibitors but ducrait I I didn't see anything I I didn't find
45:57
any cases of this being described with dravisitanib so It's an interesting
46:03
question. Um Ken's point about a possible mechanism with type one interferons is interesting but throw a
46:10
little wrench in that idea is that remember that one of the second most common medication along with TNFs is 12
46:17
and 23 inhibitors and remember tick 2 blocks both type one interference and 12
46:24
and 23 signaling. So the problem we it's possible we could see that. But the
46:30
other biggest problem I think these patients is that tick 2 therapies are just they're pretty weak overall in
46:36
terms of psoriasis clearance and these patients that have these more severe reactions like we're seeing optimal peak
46:43
response with ducravisitib at 24 weeks right so it's a problem with these
46:48
patients not being very fast acting so it creates a practical problem that way even though it may actually hit a
46:54
cytoine that's at least contributing in part to the to the physiology but I haven't seen I didn't see any reports
47:00
where that was the primary agent that led to this shift? Ju just to add to that, we haven't
47:05
either, but we we have used it occasionally where you we've had a patient on an aisle 17 who has developed this to see if you can settle the eczema
47:13
and also keep the psoriasis calm and it hasn't on the whole been overly effective, I'm afraid. Yeah, I I actually think it's something
47:19
that's be very fascinating. I was one, you know, who theorized it might be a benefit. Um not sure about that, by the
47:25
way. Um but I think it wouldn't show up with the cravisitib. It could show up with the second generation uh take two
47:32
inhibitors because their potency is quite significantly higher in terms of their impact in gene expression. So I I
47:38
think that's a question that's still waiting for an answer. Yeah. And they work a lot faster to your point. I think that that the second gen
47:44
TIK 2 inhibitors we're seeing a really dramatic shift in terms of the the time
47:50
to clearance. So it's a really important point that may actually play more of a therapeutic role in the future.
47:56
Yeah. Uh it has I think it happens uh to also answer Joe Gin. It happens with I
48:03
have patients that started with IL17 then we change for 23 it keeps going the
48:09
the the the eczema. So you add cycllosper we take everything off use jack inhibitor you control the eczema
48:16
but the psoriis comes and so that that's the maybe I thought maybe tick 2 would be an answer
48:22
for yeah I think it's worth a try to be honest with you if you're trying a stupadib which is primarily jack one but
48:28
also impacts jack 2 you would block everything that you block with tick 2 with those two um and um you still don't
48:36
always get great responses so it's hard to say and and the the I don't want to
48:42
call it data but the case series that have all the different things that we're trying it's all over the place. There's really no pla place we can make an
48:49
algorithm for how to treat these patients. Thank you very much Luis. Thank you. I I've enjoyed all the
48:54
presentations what happens issue. Please stop talking and writing about paradoxical eczema. This might be
49:01
fluoxim eczema but never paradoxic. If you have one patient with asthma that you treat with dupilmap and the patient
49:06
develops eczema that's paradoxic eczema because dupil map improves eczema. If
49:12
you're treating one patient with an 17 inhibitor and the patient gets super infected or perhaps you you you shift
49:19
the polarization of the T response towards TH2 or interferon or whatever that's not produical exam that's a shift
49:26
or switch or whatever you want to know it to to call it but please correct this because it's not not good English.
49:35
Great. I love it and English anyway. No, I totally I totally agree. I think
49:40
there is work to be done on on the language around this. It might sound superficially like semantics, but it
49:46
really matters because it's it drives how people think about these conditions and
49:51
you need we need a different language to describe these reactions. Spanish maybe. Yes.
49:57
Catalan. Yeah. Couple more questions. Yeah. Hello, I'm Dr. Fhira from Brazil. I have
50:06
two questions. First I have patients with also two disease also autotopic
50:14
dermatites and psoriasis and I we have some problems with assess in Brazil it's
50:21
very difficult for us to use jack inhibitors and it's easier for us to use dupillum
50:30
mapap especially in older patients it's also safety for as to use dupillum map.
50:40
So I'm asking you h not only about the assess but also about the safety in
50:47
older patients. Why don't you talk about this in your session? For me I I'm a
50:56
jack lovers. I have a great experience in Jack inhibitors. But in this kind of
51:04
patients that have both conditions at dermatites and also seriatic why
51:12
don't use together a dupy and also a
51:17
biologic. Can you talk about this? Sure. So um I've had a number of
51:23
patients who were treated for psoriasis got a phenotypic alteration. Is that
51:30
good Louis? um and then uh were changed to dupilab
51:35
and they got a massive psoriasis flare. Now the question of using both we would
51:41
love to use both at least in the United States in my experience and I don't know about in the UK um but we are oftenimes
51:48
inhibited by our ability to obtain both from payers and in fact most payers specifically say you cannot use both. So
51:56
in our case we need to go on broader so single agents that have broader treatment rather than using multiple
52:02
agents. But I agree 100% with you there are going to be patients who could improve get the primary you know
52:08
phenotypic presentation better and because they have improved with the primary treatment and then use something
52:15
to treat the second treatment be an ideal I think in many cases but we just
52:20
don't have access to that. Just just to add on the the funding side, if you I
52:25
suppose it depends how you frame it because if you're saying they have two different diseases,
52:30
you you may be able to access highly targeted therapies for the individual diseases. How you use them and whether
52:36
you use them both at the same time at the same dose or whether you flip-flop depending on what the prominent phenotype is is is all about the
52:43
individual in front of you, isn't it? And Andrew, I think to your to your point as well, remember in the label you
52:48
actually have the description with dupium as being associated with um
52:53
plaque, psoriasis and also seroriatic flares. One of the risk factors as PSA
52:59
at least that's been shown in the the superficial literature that that may be a risk factor. So you run the risk of a
53:04
patient with plaque psorasis and seroriatic arthritis. And I've seen this happen in patients who are misdiagnosed, which is why I brought up this point at
53:11
the beginning. patients who who were misdiagnosed put on dupillimab that clearly had features of PSA and plax
53:19
things like dactylitis anthicitis and on dupillium they had um dramatic worsening
53:24
of their joints and so I think the practical approach of when you as Andrew brought up when you initiate therapy
53:30
because the whole idea of treating one and letting the counter regulatory mechanisms not hold back the other
53:37
pathways creates that problem. So, we'd have to think of a strategy of you might need to initiate them both at the same
53:43
time, for example. Okay. So, we're going to have to cut off here. I'm sorry we can't see can't have all
53:49
your questions because we have to move forward with the program. Thank you very much. All right. So, now um we're gonna um we're
53:56
going to bring Amy Por to the to the podium. Um Amy should be recognized uh
54:02
as a one of the co-organizers of this entire agenda and she's going to take over and um and moderate the the topic
54:09
of soracform reactions um in patients receiving treatments for
54:14
attopic dermatitis and parigon nodularis.
54:19
Thanks so much Bruce. Uh we'll move forward now and unfortunately Sean Quattra who was supposed to be here has
54:26
had some travel issues. So he has kindly recorded his talk. I'm afraid we're
54:32
going to have two talks in this session that are recorded because of travel issues. But we'll move forward and do
54:38
allow me to at least present him in absentia and then we'll go ahead and
54:44
hear from him about some clinical presentation. So Dr. Sean Quattra is the
54:49
Joseph W. Bernett endowed professor and chair of dermatology at the University of Maryland School of Medicine in
54:56
Baltimore, Maryland. That's in the United States of course. Uh his area of clinical expertise includes chronic
55:03
paritis, paragonularis, attopic dermatitis and dermatology for ethnic
55:08
skin. He's funded by the National Institutes of Health and multiple foundations. He runs a basic and
55:14
translational research laboratory along with a clinical trials unit. He's been an author or co-author of more than 250
55:21
publications. Dr. Quattra is an IEC counselor, a member of the National Eczema Association Scientific and
55:27
Medical Advisory Council, and past secretary treasure of the skin of color society. So, with that, can we now show
55:35
Dr. Quantra's presentation? Hello everyone. Uh, I'm Sean Quattra. Uh
55:41
sorry I couldn't be there in person today but I'm excited about uh being able to share uh this presentation with
55:47
you all today about clinical manifestations of story acform reactions in patients receiving treatments for
55:54
both attopic dermatitis and paragonularis. These are my disclosures.
55:59
So to start a lot of us are seeing these adverse reactions soras reactions in
56:05
patients treated with both AD who have AD and PN u duplomab is the biologic
56:11
that has been approved the longest so we have more data on that but we're also finding more data on trinium leismab
56:18
even some data on jack inhibitors that's important that we can harmonize more about this phenomenon we'll start by
56:26
jumping into attopic dermatitis so these sort Acifform reactions have been
56:31
reported about 1.8 8 to 3.3% of adults on dupilly mapap similar number for child accumulata
56:39
and we know that this may be representing a phenomena associated with
56:45
precision medicine and targeted biologic monoconal antibbody targeted therapy
56:50
because when you look at these sorio reactions with drugs like dupillimat
56:56
versus standard amunosuppressants such as corticosteroids at the trexy
57:02
cycloporin or a thioprine. We know that biologic use is in associated with an
57:07
increased risk for developing psoriasis. One study around 58% increased risk for
57:13
deployment. What kind of reactions do these patients have? And we're going to get into a number of cases. But first
57:19
off, the literature so far from smaller studies and aggregation of reports suggests about 77%
57:26
of patients develop plaque type psoriasis. And then you can see smaller numbers of patients with arythromic or
57:33
whole body psoriasis. Uh more smaller lesions consistent with gutate postular
57:39
inverse or SIBO psoriasis. And in addition to most of these lesions
57:44
falling into plaque psoriasis, most of these lesions are also uh in typical psoriasis distributions. extremities the
57:51
trunk there's no gender disturbances or distance differences as well which is reassuring
57:56
in terms of duration and appearance of this orgasm reaction uh studies have suggest usually it's on the order of
58:03
magnitude of weeks one study showed about 20 weeks average duration in adults and 32 weeks in children but it's
58:10
been reported in the literature to range from as little as one week of biologic exposure up to a few years uh 2.5 years
58:18
even even longer uh than that so you could have quite a variance in that development of these manifestations.
58:25
So let's jump into a patient case. This is a 92year-old male attopic dermatitis
58:31
uh who also had attopic dermatitis since childhood and classical ezeus peritic plaques with eroded vesicles and then
58:39
along the midarms and cubital fossa just classical area been managed with phototherapy and topical steroids. So a
58:45
great candidate for biologic therapy duplap as we all know patients duplimab got much got helped the patient's
58:52
attopic dermatitis get much better however once those attopic dermatitis plaques resolved several years later you
58:59
can also see the development of these scaly pink plaques appearing on the
59:04
thigh consistent with a sor acid form reaction. So if you look closer at this
59:11
patient, their biopsies both before and after therapy, you can see before therapy you have pretty classical
59:18
morphology histopathologically for eczema, especially that apparent spongiosis that you have um and
59:27
aftermath therapy. What's notable here is the significant achanthosis paricertosis with abundant neutrfils and
59:33
the loss of the granular cellular you know suggested of psoriasis. So you have the clinical manifestations of
59:38
psoriasis, the hystopathologic um appearance also consistent and then
59:44
uh you also have molecular confirmation on a cytoine expressional shift. So if
59:52
you look before deployab therapy you can see this staining of 13 that dissipates
59:57
on deployab therapy which you'd expect or therapy with travel and you map with lepric
1:00:02
and then 17a levels which were not high at baseline actually significantly
1:00:07
increase. You can see by this staining here. You can also see on these diagrams how that IL17A shifts and this starts
1:00:14
the conversation of well we have an impressive precision medicine revolution
1:00:20
with many of these monoconal antibodies but when you target one of these cytoine
1:00:26
uh targets then you can oftenimes have this shift in this balance that's present. So we'll get into that a little
1:00:33
bit more. This patient in particular started on micophenolate uh and then cleared both AD and psoriasis. But again
1:00:39
we don't like being on these non-specific immune suppressants. When you look overall at adverse uh events uh
1:00:47
cutaneous surasopform reactions with duplab this is from the FDA's adverse event reporting system. You can see most
1:00:53
of these cases were classical psoriasis as was shown earlier less of the postular gutate ariththodmic nail
1:01:00
paradoxical psoriasis any of those uh things and this is immune shift that
1:01:07
we're getting at. So you know once you have that dampening in particular of that I13 levels uh almost this seessaw
1:01:14
balancike interaction where you have this uh sudden upregulation of some of these soras for molecular genes is 17 in
1:01:23
particular and what's also supportive of that phenomena is that dupillium responders through all the cases they've been reported seem to be more likely to
1:01:30
have these soras aspirin reactions compared to non-responders. You don't see many reports of dupelmap non-responders
1:01:36
um having these sorioform reactions probably because I 13 levels haven't
1:01:41
successfully been um decreased or there's broader immune access involved.
1:01:46
So I have to highlight an incredible article by Dr. Thomas Bieber's group um
1:01:53
looking at some risk factors that may may predict who develops uh this flip-flopping between attopic dermatitis
1:02:00
and soracform phenotypes. So you can see here um in this study what was done uh
1:02:06
was these patients were looked at who developed these orififor reactions uh and used some machine learning to be
1:02:12
able to come up with what are some of these shared features and you can see here uh that patients who are more
1:02:18
likely to um have a different phenotype upon treatment with biologic therapy
1:02:23
oftentimes do have some medical history in the family of psoriasis or joint pain dactylitis uh and then featur patients
1:02:30
who may shift over to eczema conversely uh may also have some personal history of atropy. So patients most likely to
1:02:37
flip off do have some of these shared features of both. So let's move on. What about the joints? Also that's a big
1:02:43
question. Is the skin limited? Is the joints? Well, our second case is a patient who's had attopic dermatitis
1:02:49
since childhood and been on depab for a number of years. Developed these thoratic lesions, thick scaly papules,
1:02:56
coallescent plaques, but also complaining of nail changes and widespread joint pain. So you can see
1:03:01
the rheumatologic workup um and many of these indices were with the normal limits but the bone imaging you can see
1:03:07
that there's increased uptake uh in sacred iliac joints cerno cavvicular ankles this patient was diagnosed with
1:03:14
seriatic arthritis switched off dup onto a broader acting immune agent targeting
1:03:20
uh more of the cytoines associated with both processes you had a sitting at 30 milligrams and the patient cleared and
1:03:26
you can see this process of starting depab the onset of seriatic lesions and then
1:03:33
the rapid resolution with epettys therapy. So we know that the psoriasis
1:03:39
is slightly more common than dep versus controls looking at multic-enter data again very low and we did reach
1:03:46
significant uh looking at global multic-enter data seratic arthritis the reports are very low so you can see
1:03:52
about 13 in this study excellent study highlighted here um which didn't meet
1:03:57
significance but we know that there are these cases of it isolated and happen
1:04:03
let's move on uh to another biological This is a patient with eczema who
1:04:08
developed um who was started on trickinium and you can see again this
1:04:13
patient developed the sorio from ty lesions. Um in addition scalps psoriis uh this patient had pretty significant
1:04:20
of the frontal hairline and you can see very classical biopsy here for psoriasis
1:04:26
those subcornial monrose microabses and all that hyperimpicertosis aanthosis as
1:04:32
well. So next case patient who had itching 10 out of 10 uh itch dominant
1:04:40
perhaps um and we know that nemalismab is actually an agent that is associated
1:04:46
with exemptus reactions but was very interesting here there's probably some overlap features in this case I thought this would be interesting to highlight
1:04:52
for you because we're we're traditionally thinking of four and 13 therapies inducing psoriis and that nemalismab may shift over to examus
1:04:59
reactions in small subsets this patient also developed um some of these uh
1:05:05
plaques consistent with more of a soras process. You could argue this is more of an overlap um but this did uh improve
1:05:11
with treatment and you can see this um process here and this patient got better with theatism as well. So let's now
1:05:19
shift gears and look at sorac reactions also in pryonilleris. So in pryon
1:05:28
nagilaris of course from neimalismab we know there's some exemitus reactions and
1:05:33
from the the pitfall basis but um from depiliumab in the real world uh we're
1:05:39
also seeing some sorosform type reactions and the biology of
1:05:44
paragonularis is interesting because there's certainly type two upregulation
1:05:49
in the skin this is some gene set analysis work but in the blood there's
1:05:56
you know marked levels are increased but it's also a little bit broader. There's 22 involvement. Um you can see other
1:06:02
immune axes that are involved here and actually using a precision medicine approach for pariggo you see that
1:06:08
patients actually have variable degrees of type two and type 17 um involvement
1:06:14
uh across these axes. And so some of the slower responders to an agent like
1:06:19
playmat may actually have induction of more of this type 17 capacity which we'll get to. So let's look at a case as
1:06:25
a 68-year-old uh female pertic nodules in the buttocks. I've been checking IG
1:06:30
in everybody because to me that's now becoming one of our titis uh like tark but readily clinically available
1:06:36
biomarkers of type two inflammations. This patient had very elevated Ig start
1:06:42
therapy and look at that immune switch phenomena. In my mind, this uh elevated
1:06:48
IG says this parago patient was a very type two dominant patient. And so
1:06:54
potentially um shutting down that is 13 may have predisposed to more of this shift uh to this classical sorasapform
1:07:02
phenotype and you can see that switch happening here especially that exotic cytosis of the neutrfils
1:07:08
forming these large uh subcornial spongififor pules. So this patient uh
1:07:14
did discontinue therapy and and the follow-up had resolution of those sorac
1:07:19
form lesions. So a little bit more evidence also of this process uh being attributable to the causitive agent.
1:07:26
Let's look at another patient here. This is a 42-year-old male uh with some of
1:07:31
these itchy nodules. Caucasian male. Um you can see classically on these extremities started on nupellab and it's
1:07:39
a little bit faint here but um there's improvement again like like many of our cases I'm not aware of many cases or any
1:07:47
cases of patients who are not responding and then having immune switch phenomena. So it kind of highlights the importance
1:07:53
of target engagement. This patient actually had great resolution. Look at these nodules that are almost completely
1:07:59
and totally faded. So that's pretty significant there. Um, but they had the
1:08:05
development of more linear scaly plaques. It's a little bit harder to see in this photo, but when you zoom in, uh,
1:08:11
you can totally appreciate these whitish scales. Um, and then on the biopsy, the paricarattosis, aanthosis,
1:08:18
more dilated blood vessels, uh, papillaryism, pervascular infiltration there, at least lymphosytes as well. So,
1:08:24
more of a story acform switch. And I've had actually personally multiple patients with with such a switch who
1:08:30
were super responders. So um this patient in particular had their dosing adjusted uh and did well
1:08:38
with topicals because these are very amendable. I've actually also used some several other non-steroidal topicals um
1:08:45
that have helped a lot in some of these more mild cases. But the good thing is these patients usually have their parry
1:08:50
go much better. And then in my experience, you know, this hasn't been um a huge huge deal, especially most of
1:08:57
the time since it appears in parago um to be more of a milder phenotype and uh
1:09:03
you can see just how this uh happened. So the patient was started on on depth
1:09:08
as some eruption started after a few months and then resolved at about two and a two and a half months with no
1:09:14
episodes of recurrence. So I'm going to share another case with you all. Um uh
1:09:21
this is a long-standing patient of mine who uh has very significant parago um
1:09:28
totally um diminishing her quality of life um and uh initiated therapy with dupillimap
1:09:37
um she had a gradual improvement which I I'll get to um but she she came back
1:09:43
after she was having a treatment response of dup with the development of new paritis of the scalp and I looked
1:09:49
you see here very clearly these soracform lesions scalp psoriasis um that this patient had uh that were very
1:09:57
itchy. So this is where her itch um shifted to from the lesions to here. Um we continued to pelium mapap and
1:10:03
actually in addition the patient decided to start a primal and had a pretty good
1:10:08
response um quickly there. What I wanted to highlight with this case was that the
1:10:14
dilimab study for parago was only six months but in the real world we know that the degree of type two inflammation
1:10:20
is variable. This patient probably had more mixed type two type 22 type 17. So
1:10:27
they took longer to respond. Actually, the itch took quite a while. Um, and
1:10:35
even over 12 months, even though lesions were slightly improving, but when she started having such a great response,
1:10:41
which tells me that type 2 activity was being knocked down, that's when the scalp psoriasis um seemed to emerge,
1:10:48
probably when you had a total target blockade as well. Um so that's kind of the
1:10:55
emerging theme from a number of these cases in my own personal experience um
1:11:01
uh you know from treatment. So I'll take away a few things. So seroform reactions
1:11:06
which I'm so glad we're focusing on this joint forum may emerge in both AD and PN timeline about 20 weeks in adults with
1:11:13
deploy 32 weeks children um and reflects pathogenesis immune drip drift from type
1:11:20
two to type one and 17 uh inflammation patients with a person or family history
1:11:25
of psoriasis may be at a greater risk and again we have such an amazing amount of targeted systemic and topical
1:11:32
therapies uh that often times we can successfully manage these patients and keep them on therapy or shift to other therapies. So
1:11:40
thank you all so much uh for your attention.
1:11:49
All right. Well, thank you Sean. Um he's not really here so I think he can hear me. [laughter]
1:11:56
Uh we're going to move on to our next pre-recorded one and uh this is from Dr.
1:12:01
Yael Lashm. Now, uh, those of you who know her know that she lives in Israel and we all know what's going on there. I
1:12:07
don't even think the airport is open, so she certainly wasn't able to join us,
1:12:13
but let me tell you a little bit about her and she's going to move on to to tell us a little bit about clinical
1:12:19
approach. Now, Dr. Lashm is a dermatologist and clinician scientist who specializes in chronic inflammatory
1:12:26
skin diseases. She is the director of the attopic dermatitis clinic at the division of dermatology at the Rabine
1:12:33
Medical Center and is a clinical associate professor of dermatology at Tel Aviv University. She's dedicated to
1:12:39
high quality patient care, innovative treatments, and advancing education and research in dermatology. Her research
1:12:46
focuses on the epidemiology and outcome measurement of attopic dermatitis. She's
1:12:51
a member of the board of directors of the IEC and serves as chair of the IEC's education committee. She's also on the
1:12:58
executive committee of the harmonizing outcome measure measures for eczema home
1:13:03
initiative, both global organizations dedicated to improving research quality and patient care in attopic dermatitis.
1:13:12
I'm going to just get up and ready. Yeah. Okay. It's my pleasure now to introduce
1:13:17
our next remote speaker, Dr. Lashm. Oh, I did that already. I'm sorry.
1:13:23
You did. I did that. I'm not going to do it again. Would you just press the button and get us started?
1:13:30
Hi, everybody. Um, I truly wish I could be uh there today with all of you.
1:13:35
Unfortunately, I couldn't travel because of the current situation here. But I'm really happy I can still share this talk
1:13:42
with you during what I'm sure is a wonderful session. Um I'll be discussing the clinical approach to serasif
1:13:49
reactions in patients receiving treatments for attopic dermatitis and pureo nodularis.
1:13:54
These are my disclosures and let's begin. So this is really the patients we'll be discussing in this talk. These
1:14:01
are patients from my clinic. I'm sure you all share similar patients. Uh they all had very classic attopic dermatitis.
1:14:08
They were treated dupilab in this case and developed psoriasis. And the question we're asking ourselves today is
1:14:15
what now? What's our next step? How do we manage these patients? So when we're thinking about treatments,
1:14:21
we really have to start with pathogenesis. And the main pathophysiologic event underlying these
1:14:27
sorasififor reactions as we know today is that relative imbalance between TH7
1:14:32
and TH2 inflammation skewing towards TH7 which gives us psoriasis or psoriasis
1:14:38
reactions. And classically that's uh initiated by TH2 blockade and that does
1:14:44
make mechanistic sense because4 very prominent TH2 cytoine does have
1:14:49
regulatory functions on the TH7 axis. So there are um data to show that IL4
1:14:56
suppresses differentiation of naive tea cells into TH7 and it also suppresses 23
1:15:03
uh which is very important cytoine in maintaining the TH7 response. If we block is 4, we kind of take that
1:15:10
suppression foot off the break and we really enable differentiation and expansion into T17. And when you look at
1:15:17
skin samples from these reactions that that uh tracks because we see a strong
1:15:22
T17 signature. So mechanisms are really important um
1:15:29
and they're important when we consider treatment approaches, but they're really not the end all of our decision- making.
1:15:35
We all know that we have many considerations that factor into the way we make decisions. Um so it's not going
1:15:42
to be just about TH2 or TH7. What I've done here is broadly broadly categorize
1:15:48
the treatment approaches both that I've seen in the literature in my clinical experience and also integrating the
1:15:54
mechanism we've discussed into four broad groups. One would be a conservative approach. We could think
1:16:00
about broader immunom modulation towards both possibly TH2 and TH7 in a way. We
1:16:06
could modify the the culprit possibly the TH2 blocker or we could target the TH7 pathway which is responsible for the
1:16:13
psoriis but whatever approach we do take I want to highlight that there is really
1:16:19
no clear treatment algorithm and I think this will be very easily reflected in this talk. It's all about just case
1:16:25
reports and experiences and the mechanism. And what this means is that we really have to individualize our
1:16:32
treatment on a case-byase basis. This is always true in medicine, but I think these
1:16:39
reactions really illustrate that strongly. So this is not a one-sizefitsall
1:16:44
scenario. And I hope the next case I've se the first case I show you really will demonstrate this.
1:16:51
So this was one of the first patient I actually treated with dupillimab. This is 39year-old man and he's a very kind
1:16:57
of prototypic attopic dermatitis patient very characteristic patient he's has had
1:17:02
ADCs slaved childhood he also has asthma and allergies IG in the thousands his
1:17:08
family is at topic uh he does suffer from metabolic syndrome he has obesity type two diabetes and hyper lipidmia and
1:17:15
he thankfully was one of the dupillimap super responders he cleared zero itch
1:17:21
almost zero eczema current and he was just super super happy. But then about six to seven months into treatment, he
1:17:28
comes in with this and he tells me how happy is with the pilumab. He's super pleased and he says, "Well, but now I
1:17:35
have psoriasis." I was a bit surprised because he made a very good diagnosis
1:17:40
and then turns out that this patient as a young child had a few years of very classic chronic plaque psoriasis. We
1:17:46
actually found the documentation for that which went away and then he started on his eczema route. And this
1:17:53
predisposition to psoriasis possibly is something I'm going to touch on later as well.
1:17:59
And I really like these pictures from a clinician point of view. You can see the psoriasis here, asymptomatic, very
1:18:04
localized. And then kind of eczema remnants here. Again, psoriasis. And then I hope this you can see this well.
1:18:11
It's his ichthyosis vulgaras was kind of keerized all over. So clearly this patient now has two conditions.
1:18:19
Now this is a patient we could be thinking about you know T17 maybe a jack
1:18:24
inhibitor but the patient had very limited psoriasis and he really could not care less he couldn't be even
1:18:29
bothered to put a topical on it so this is definitely a patient to consider going with a conservative approach
1:18:36
especially considering his metabolic syndrome background maybe Jack inhibitor isn't the best choice so you can always
1:18:42
treat through you can treat through with a drug you're on the psoriasis will not necessarily go away it didn't in this
1:18:48
patient. But sometimes that's a good strategy. If the patient is happy, you can add topicals, whatever makes sense.
1:18:55
We have, you know, topical corticosteroids, calcinurine inhibitors, calcotrial. We have great topicals today
1:19:02
that target both psoriasis and attopic dermatitis. That could be a good way to go. And then phototherapy is a good
1:19:08
adjunct. So still remember the conservative approach may be appropriate for some patients.
1:19:15
Or we could go the other way around kind of the polar opposite if we have especially if we have significant uh
1:19:21
psoriasis and or still significant eczema. So we can either replace a broad
1:19:27
immunom modulator drug. Uh there's been a lot of reports on methtrixide when we think about conventional drugs as well
1:19:33
as cell and cycllosporin very variable response rates from no response to
1:19:38
partial to complete improvement. And then kind of newer reports talk about Jack inhibitors which do make
1:19:44
mechanistic sense in this scenario. Um we also know that if you have really
1:19:50
classic psoriasis develop in this patient as in in these patients like the one I showed you before,
1:19:56
there is some logic to giving a Jack one inhibitor. Jackwans are not approved for psoriasis. They're not chronic plaque
1:20:01
psoriasis drugs, but you can see kind of in a roundabout way from seroriatic arthritis trials that they do have an
1:20:08
effect that's better than placebo on psoriasis. I would not prescribe them for a patient with psoriasis as a
1:20:14
firstline drug or second, you know, at all, but they do make sense here. And there have been reports of them being su
1:20:22
successful in this scenario in treating both the psoriasis and the eczema. This is one of my patients. Not a great
1:20:28
picture. It's hard to take a picture of scalp psoriis but it was very uh very clear. Um and he developed psoriasis all
1:20:35
over cleared very nicely both psoriasis and eczema with uppatitib.
1:20:41
However, there's always a butt. Unfortunately, there are starting to be
1:20:46
some reports of paradoxical psoriasis after jacquine inhibitors both upnib and
1:20:52
abberitnib. So this may not be the solution for all patients. Another
1:20:59
way to go would be well this is a TH2 problem. Let's let's take the TH2 out of out of the equation either by increasing
1:21:07
the interval between ch um injections or discontinuing the drug altogether.
1:21:13
Now I do want to make some points about this drug discontinuation as as um the
1:21:18
only intervention right without providing something else instead. First off, if you have a patient with moderate
1:21:24
to severe eczema and you're stopping dupillimab, chances are you are going to have an eczema problem down the road. So
1:21:31
you you do have to think of something else to given that scenario. Another consideration about stopping dupilab is
1:21:38
that a lot of times um dupillab treats other type two coorbidities and we're
1:21:43
not unfortunately always even aware of that and the one I would be most concerned about is asthma. So often
1:21:49
times patients asthma get so much better they self stop medicating right they
1:21:55
stop their inhalers their preventive medicine because they don't need them anymore. If we stop the dupilluma for
1:22:01
example for psoriasis we have to be really aware that these patients could get worse could even get an asthma
1:22:07
attack. So just something to consider when stopping this drug. Another way to go was maybe if this is
1:22:13
an IL4 problem, maybe we can switch to for example anti-le 13 targeted drug
1:22:18
drugs and there definitely have been reports of improvement of arthralgias by
1:22:23
associated with dupillumab or even inflammatory arthritis with switching to these medications. So interesting way to
1:22:31
go. However, again that annoying butt, we are getting more and more reports of
1:22:37
psoriasis induced by TH13 blockers. Um, and just recently there was a very nice
1:22:44
series, a cohort, I think that came out that showed a 2% incidence of psoriasis
1:22:49
on troubab. So again, this may not be the way to go.
1:22:56
This is one of my patients and scalp psoriasis. um psoriasis in areas that
1:23:01
were not involved in in eczema and then on leisumab you there is an improvement
1:23:06
you can definitely see some improvement but it did not clear and it has not cleared since we're so that's again a
1:23:13
very moderate response I would say at best here
1:23:18
so the final approach could be to target the TH7 pathway right the the that's the
1:23:24
that's what's going on in the patient's skin right now and we have great drugs that do that
1:23:30
however uh this really is kind of a very
1:23:36
uh strong uh scenario where we concerned about a phenotype switch to
1:23:41
excesservation of eczema. Okay, we all know that if we treat psoriasis with either TNF blockers but anti-L17 and
1:23:48
anti-L23 drugs like this patient is one of my colleague Professor Pavlovski's patients you can see the switch towards
1:23:55
eczema very classic eczema the problem is that this is even more prominent in
1:24:00
patients who have a background of attop and this is exactly the patient population we're dealing with these
1:24:06
patients actually have attopic dermatitis at baseline so they really are prone to this worsening of eczema on
1:24:13
these drugs and I think this case a recent case really beautifully shows this really convoluted path that both
1:24:20
the patients and the doctors go through in these scenarios. So this is a patient with numlar type uh numlar eczema type
1:24:28
ad on the top panels you can see and he got psoriasis agillimab.
1:24:34
So the treating physician stopped the dupillimab, gave him cycllosporin, didn't take it, the eczema got worse.
1:24:39
They added the dupillimab, the psoriasis got worse. Switched to methtoresate,
1:24:45
didn't work. Triedib, the psoriasis got worse. Went back to
1:24:50
methtoresate again, didn't work. Then they tried trialab, right? Psoriasis got
1:24:56
worse. Methtoate again. And then risen kisumab, an anti 23 drug. Very good
1:25:02
drug. But I would say in a way as expected the eczema got worse and what
1:25:07
they ended up doing was actually provide dual blockade with both dupilumab and
1:25:12
risenab and we do have a couple of patients a few patients with this treatment and it works well. It's not
1:25:18
the most comfortable um treatment to prescribe I would say but it is an option. So oftentimes with
1:25:26
these patients you do get a sense like you're in an arcade playing whack-a-ole. So you're kind of whacking the TH2 and
1:25:33
then the TH7 pops up. So you whack that and you get the TH TH2 back up. And it's
1:25:39
a really, you know, that's what happens when you tinker with the immune system. That's kind of the feeling we get. And
1:25:45
it would be really nice if we could actually anticipate these reactions in advance and prevent them or at least um
1:25:54
make more um informed treatment decisions. And this is what this uh work
1:26:00
for by Thomas Bieber's group from a few years ago is about. Uh they try to develop what they call the flip-flop
1:26:05
algorithm. And that would be an algorithm based on clinical data that would predict which predict which
1:26:11
psoriasis patients are going to develop ectopic dermatitis and which AD patients are prone to develop psoriasis. And I
1:26:19
think what's interesting here is the criteria this algorithm is based on. We don't have the algorithm. It's a trade
1:26:25
secret. they do have the criteria a very you know there are things we do in our day-to-day clinic it's about a medical
1:26:32
history for both attopic dermatitis and psoriasis and then the examination also
1:26:37
includes very classic signs of both diseases and I think this is something
1:26:42
we often find ourselves doing really have to make sure we do in clinic when we get one of these patients and you're
1:26:48
not really sure is this eczema is this psoriasis which way is this patient going to go with my treatment What was
1:26:55
especially interesting to me was this family history of psoriasis which my observation in clinic was that
1:27:02
this was very common in patients who developed psoriasis but I wasn't really sure if this is just
1:27:08
you know a kind of self um fulfilling prophecy if this really is true. So we set out to to examine this in our
1:27:15
patients and this is a work done by Dr. I meet Ethon, one of our great residents, and we really looked at
1:27:21
patients who got upillumab uh and classified them based on whether they
1:27:27
did did or did not have a firstderee relative of psoriasis. So a strong um background, genetic background of
1:27:33
psoriasis. I will say we really try to take very classic eczema patients. So we
1:27:40
will be very sure that what they they developed was a different uh eruption
1:27:45
that's a different condition. So we excluded patients with these psoriasififor baseline eruptions unclear
1:27:51
psoriasis versus AD type of patients very classic eczema. You can see here
1:27:56
that the patients were very similar regarding their characteristics their baseline characteristics. Interestingly
1:28:03
they were also very similar in how attopic they were. Even though some of them also had a strong genetic
1:28:09
background of psoriasis, they had very similar personal family histories of autotop at
1:28:16
patients with psoriasis had stronger um background of IBD which does make sense.
1:28:21
But look at the result. This is just a primary outcome. Patients who had a firstderee relative
1:28:28
of psoriasis 35% of them developed psoriasis and pillum versus 2.8% 8% in
1:28:34
uninvol patients who were unexposed and that translate to relative risk of
1:28:40
12.4. So 12 times the risk if you have that strong family history.
1:28:46
So I think this is really compelling evidence to think about when we're uh um
1:28:52
um making treatment decision with patients. It can inform both our treatment choice and also thinking about
1:28:57
satro profile adverse events which we can communicate to the patients beforehand.
1:29:04
So to summarize when we're managing these patients with serasifform reactions in attopic dermatitis we have
1:29:10
to realize we have to look at you know the mechanism but look at the patient one size does not fit all here we have
1:29:16
several different treatment approaches we we've discussed today and I do urge you to consider a family history
1:29:22
especially of psoriasis but also just a composite history of uh T17 conditions
1:29:29
as a predisposing possible predisposing factors. So, I want to thank you all for your
1:29:34
attention and I hope you have a lovely uh meeting. Thank you.
1:29:42
All right. Well, thanks to Yael and I think we'll we'll keep going to our live
1:29:47
speaker for this session. Thank you so much, Killian. So, I want to welcome uh
1:29:53
Dr. uh Kiamich who is the professor and chair of
1:29:58
dermatology and veneriology at the University of Fryberg in Germany. He's
1:30:04
also a guest professor at the Karolinska Institute in Stockholm, Sweden. Uh I
1:30:10
think we all know Dr. Irish's uh huge body of contributions to our field. His
1:30:16
scientific interest is in the heterogeneity and immunity of inflammatory skin diseases and he's
1:30:21
published in uh excellent journals, science nature, science translational
1:30:26
medicine, New England Journal, and the list goes on. He's also received numerous awards for his achievements,
1:30:31
including two European research council grants. He's also a counselor of both the IEC and the IPC. and we're so glad
1:30:40
you're here in person to tell us about what is soriasopform spongiotic
1:30:45
dermatitis navigating uncertainty using advanced diagnostics.
1:30:51
Yeah, thank you uh so much dear friends and colleagues actually uh I like the
1:30:57
title Alan and I thought this would really be nice to to listen to a talk with this kind of title before I found
1:31:03
out that you want to give this to me. Um but let's see. I I really uh enjoy what
1:31:10
what we've heard right and let me take the perspective of molecular diagnostics and stratified uh medicine um which is I
1:31:18
think a really really wellestablished concept in inflammatory skin diseases and we get more and more evidence. So
1:31:25
just zoom out one moment of type two versus type three diseases and and uh
1:31:31
follow with me this this uh I think really nice concept which in the core
1:31:36
has a different signature and this signature is usually in chronic inflammatory skin diseases related to
1:31:43
the interaction of adaptive immunity. most chronic inflammatory uh diseases
1:31:48
are most likely at least autoimmune diseases and then we have the monogenetic diseases which are more rare
1:31:56
and driven um at least many of them by auto inflammation right so when it comes to te- cells we don't have that many
1:32:02
different patterns we have this type one pattern coming from cytotoxic tea cells
1:32:08
and we do know that lead cytoines here are interferon gamma and TNF alpha but
1:32:13
we would not measure them if we really want to identif identify them either in skin or circulation at a patient's
1:32:18
level. We would not measure interferon gamma because it's too lowly expressed. We can almost not detect it. What we
1:32:25
would rather measure is response genes in tissue. And this in type one diseases
1:32:30
is quite clearly chemocines that are released by one um one um transcript of
1:32:37
interferon gamma thousand times in um in keratinocytes like CXL 9, 10 or 11. And
1:32:44
then we do know if we have a very strong signature of type one diseases which may be lick and planos cutaneous lupus graft
1:32:51
versus host disease different kind of drug eruptions and we still land at jack inhibitors being the best or most
1:32:57
promising outcome. Type two diseases we all know right obviously these are the cytoines that are the drivers of the uh
1:33:04
of the disease pattern but we would rather measure against cytoines here and we have a number of different specific
1:33:10
biologics same for psoriasis which is why this um let's say opposing diseases
1:33:17
um attract so much attention also today then um here it it gets a little less
1:33:23
right these are regulatory T- cell associated diseases and we have much less Here everyone talks about fibrosis
1:33:30
these days which is rather mediated by TGFBA. Um we also know how to measure it
1:33:36
in tissue but then what do we use as a kind of treatment that is not really
1:33:41
there. There's lots to do still I would say and the autoinflammatory diseases we know as well. So this is I think a
1:33:48
promising and very nice concept. The truth is it's challenged every day by
1:33:53
our patients and in real life right um so it is just a concept and it's challenged basically by two dimensions
1:34:00
and we have heard very nice talks about the first dimension which is the dynamics dimension and this means we
1:34:07
really have a switch or flip-flop of phenotypes and I don't want to talk about this because that's not my title
1:34:13
right I just want to share with you one and I hope this works if I click in here
1:34:19
one um patient from our registry because honestly I was never 100% convinced
1:34:24
until today we saw a lot of pictures but I thought okay ah maybe it was a misdiagnosis maybe it was an overlapping
1:34:31
phenotype I don't really know right usually you see blurry pictures but this is a patient that prospectively received
1:34:37
an interlucine 13 therapy in this case you see him at the left hand side and then developed the lesions at the right
1:34:43
hand side it's it's a very very clear picture let's say of attopic dermatitis
1:34:49
and psoriasis And it is 100% at the poles of the diseases. It's not
1:34:55
something which is overlapping. Okay, but I mean this is not my topic anyway, right? My topic is the second dimension
1:35:01
that challenges their concept of stratified medicine and this is overlapping phenotypes. However you may
1:35:07
call it, but we all do know them and see them in our daily clinical practice. And I have to say um I really I'm in this
1:35:15
field for 20 years. I I see quite many patients but I would really not dare to
1:35:20
say in these palmopla diseases whether this is a dishy eczema or um poplant
1:35:29
psoriasis um sometimes you have a clue and you say okay it's more this and more that and then you ask other experts and
1:35:36
they say no these are absolutely not our clues I go for uh vesicles no if I see a
1:35:41
postule then it's absolutely clear it's sharply demarcated it's it looks a little difference right uh um whatever
1:35:49
hyperp proliferation square look different or whatever I can't do it um
1:35:54
similar here cuoriasis is a nice term which was shaped psoriasis of the scalp
1:35:59
we just heard about it ciroic eczema what is it actually if it's in the ear canal like this minimal dermatosis
1:36:06
patients have a psoriasis history or whatever and then we do have these patients this patient has a psoriasis
1:36:12
for 50 years right 50 years and now he's old and he has a diabetes. He has kidney
1:36:19
problems. His skin gets drier and drier and starts to itch. So he scratches and you see around the psoriasis plux he now
1:36:26
develops this kind of eczema lesions right. Uh, of course there are also other aspects where differential
1:36:32
diagnosis is super hard for me at least very early micosis fungitis and uh just
1:36:38
to be clear this is the micosis fungitis and this is the numular eczema right it's very hard for me to identify and
1:36:44
then this whole aspect of postular diseases with all these nice names like
1:36:49
snen Wilkinson or whatever you may call it what is it I have no clue right so
1:36:55
this is what challenges us in daily practice and now the question is How can we translate and adapt this concept of
1:37:02
molecular medicine in this context of blurry and overlapping diseases? And
1:37:07
there are basically two answers to this. This is a very nice work done by Michelle Gilier in in Loausan now a
1:37:14
little more than a year ago. And what he did was to define modules. Now you already see the problem starting. We
1:37:20
called it immune response patterns. Other call it signatures cytoine signatures haps or modules, right? But
1:37:28
whatever we talk about, it's pretty much the same. This is the type one immune response pattern. Every dot is a point.
1:37:35
And you see here that by defining by nano string a certain number of genes from leional skin, uh Michelle was able
1:37:42
to clearly separate diseases. And here we have the licken planos disease which we know is a prototypic type one
1:37:49
disease. TH2 would be autotopic dermatitis. Uh TH17 psoriasis. Nothing
1:37:55
new so far. He also defined neutrfilic dermatosis and eosinophilic ones like the world syndrome and type one
1:38:01
interferon which would be cutaneous lupus. So it is possible to measure them
1:38:06
in a nanoring basis and this is also something that now special centers in Europe started to do. Uh then the
1:38:14
alternative is my personal conflict of interest is a lab on a chip system uh which is run by by germagnostics
1:38:21
um which is not really a startup anymore but really starting up let's say uh with a fully automated test now with more
1:38:28
than 50 um customers in mostly in Germany and Europe but um soon to come
1:38:34
also um I hope at least to the US where we have um either scraping or paraffin
1:38:41
embedded skin which is inserted into this kind of disc system that you see here and the disc is inserted into um a
1:38:48
player and then fully automated you get molecular diagnosis. So you just have to press one button and then you get deep
1:38:54
paraffaraphanization, single cell suspension, isolation of RNA and real-time PCR which is then read out by
1:39:01
an optical system here in the player and you have the result of this molecular
1:39:06
analysis within at the moment two hours but potentially in the future much less
1:39:12
so. Um if you want to see how this works you are warmly invited also to watch this video. So this is a lab on a tip
1:39:18
system that already works and it's approved um in Europe at least um to
1:39:24
differentiate exactly type two from type three diseases. psoriasis like from eczema like diseases and here you see
1:39:31
some of these interesting pictures that we all know from melanoma and nevi right
1:39:37
where artificial intelligence got big and we have seen that it's better actually than um than the the individual
1:39:45
clinicians also here you see these are individual clinicians and some of them tend towards the diagnosis of eczema
1:39:52
others tend towards the diagnosis of psoriasis overall you have a pretty stable and interesting and and valid
1:39:59
robust signal uh by this test which um gives a clear improvement in specificity
1:40:05
and sensitivity. The question is then what's your readout? What's the gold standard if you claim to be better than
1:40:12
what's currently there? And um the best readout that we identified so far is actually response to a specific therapy.
1:40:19
Right? If something responds to I13 or dupilumap, we would call it eczema. And
1:40:25
if it's responding to R17 or IL23, we say the ground truth, the truth is
1:40:30
psoriasis. Now, this comes again from the dermatopathology where where there are certain tests. And now since one
1:40:37
week, this is why I'm so proud. We have this very small scraping tool 0.3
1:40:42
millimeter. We borrowed it from ofologists and we scrape a little bit. And we can
1:40:47
really do this now in private practices and offices. while the patient is in the waiting room, this test system runs and
1:40:55
we get that kind of information. The question is how useful is that kind of information? And let me go back to the
1:41:01
work of Michelle Gileier actually which has um two very diff um important
1:41:06
insights. I think the one is um what he did here was to test like 80 or 90
1:41:12
patients that came into his office with a typical disease. So the clinician said
1:41:17
in blue these are auto attopic dermatitis patients and in green these are psoriasis patients the yellow one
1:41:23
were suspicious to have lick and planoslike reaction and in all these patients he did this kind of immune
1:41:29
modules that I have shown you before and the nanoring based analysis now if that matched and that was a majority the case
1:41:36
the patients had an 81% chance to respond that means even if the molecular
1:41:41
signature matches the clinical diagnosis we do not have 100% response rate. There
1:41:48
are other factors that play in here which may be pharmaccogenetics, dynamics, whatever compliance. Uh but if
1:41:54
they didn't match then the patients did not have any chance to respond which kind of makes sense. Interesting is that
1:42:00
this was the case in almost 10% of the cases. So the clinicians were sure and they are good clinicians in Loausanne
1:42:07
right they were sure about the diagnosis molecular um modules were different and these patients did not respond but when
1:42:14
he switched them the patients had a chance to respond. Another example why we think it's
1:42:20
relevant is not only the clear patients obviously but also these overlapping phenotypes and this is a patient um from
1:42:26
our um um study in Fryborg and um patient where we had this initial
1:42:34
clinical diagnosis psoriasis did not really respond but what's more important here I think is we gave it to
1:42:40
dermatopathologists and also here if you ask dermatopathologists the way that they diagnose is pretty
1:42:46
subjective so they would not give us all the same result right in the end here it came out this is not really psoriasis in
1:42:52
the um diagnostic testing and we have a another test now uh which identified
1:42:58
this to be an early MF um and this patient really um got a severe MF nodula
1:43:03
in the um in the coming month so finally and this is the core of my presentation
1:43:09
what is about mixed phenotypes is it good to have this diagnostics or don't we need it and what are mixed phenotypes
1:43:15
and let me put you here this example of num eczema which is kind of an overlapping phenotype right you see it
1:43:21
here it's sharply demarcated mostly occurring in elderly patients it has the serum crusts but then it also comes with
1:43:28
neutrfils and stuff orioe so it's in between psoriasis and attopic dermatitis
1:43:33
and I think the main message is it's in between psoriasis and attopic dermatitis from a clinical point of view and if it
1:43:40
that is the case and I think the majority of you would agree then it's usually also the case in hystopathology
1:43:46
right also hystopath pology would not give you a very clear-cut result otherwise uh yeah it's it would be
1:43:54
strange let's say uh and the the problem is also from a molecular point of view it's the same thing that means numular
1:44:01
eczema has a lot of I13 type two signature right much more than psoriasis but it also has a lot of CXL8 and
1:44:08
interlucine 17 much more than attopic dermatitis which explains why we do see neutrfils frequently in numula eczema so
1:44:16
what we C is also seen by the dermatopathologist and relies on molecular disease but still molecular
1:44:24
diagnostics can make a difference here and if we use this dermagnostics kind of system then numula eczema is identified
1:44:30
in by far more than 95% of the patients as a clear type two signature and the
1:44:36
question is then what happens if we treat it with type two biologics and here and soon there will be um a
1:44:43
clinical study coming out but here is just one of any case reports and case published and we do know that the pelium
1:44:50
mapab works in numula eczema as good as it does in auto attopic dermatitis from these sporadic cases and the thing is if
1:44:57
we treat with dupilium mapap or i13 then also the neutrfils go down right it's um
1:45:04
clearly indicating that even in overlapping kind of phenotypes we have a dominating immune response and if that
1:45:11
dominating immune response is treated with a specific therapy then also this epi phenomenon in this case of type
1:45:17
three immunity CXL8 the neutrfils go down and the lesion clears fully and that's a clear difference to this
1:45:23
dynamic state where we have a flip-flop it's an overlapping disease and with one
1:45:29
um clearly dominating pathway and the same is true for exmatized psoriasis just the other way around here um IL17
1:45:37
plays a major role I 17C but also IL7E which gives us this typical overlap uh
1:45:44
according to is fill granolocy infiltration, right? But if we treat here with interlucan 17 or 23
1:45:50
inhibitors, the lesion fully clears away. The skin stays dry, but it's not inflamed anymore. There are no ears and
1:45:57
the filths in there anymore. So to summarize, I think this concept of stratified medicine really has
1:46:03
established quite well and we do know and we have heard that numerous times today. We will hear it numerous times in
1:46:09
the coming talks. Type two eczema, type three psoriasis. But this is challenged
1:46:14
either by this flip-flop phenomenon dynamics of the disease or by overlapping phenotypes. But if we have
1:46:22
overlapping stable phenotypes, we may identify the driving dominant immune
1:46:27
response or signature or module however you call it. And if we treat that specifically, we have a very good chance
1:46:34
that the lesion overall would improve. So there's no need at all to go back in these patients to systemic steroids or
1:46:41
cycllosporin. we have to identify and that is where molecular diagnostics is
1:46:46
really helpful the dominating underlying immune phenotype and can then treat still treat these patient patients
1:46:52
specifically. Thank you very much for your attention. [applause]
1:47:00
Thank you so much. Uh why don't you have a seat over here? Y we have a chair for you and um
1:47:05
unfortunately we only have one of the speakers for this session here to answer questions but others can also chime in.
1:47:13
So I would invite anyone who has questions for this particular session uh to come up to the mic and uh go ahead
1:47:20
and ask them to Kelly or Andy.
1:47:25
You go to the mic. You got the mic. Thank you. Yeah, unfortunately that's the case.
1:47:31
It's super frustrating. I think but then I look at oncology and I'm really happy to see that checkpoint inhibitors
1:47:36
against PD1 also work better if we have a PD1 level from the beginning right and it's just the same thing that's the only
1:47:43
reliable factors that allow us to predict is positive family history or
1:47:49
own history um in in the past um and I fully agree probably it's like it can be
1:47:55
genetics and then there is an environmental influence and the best treatment we do know of um highly active
1:48:02
psoriasis is highly active eczema and the other way around because L4 works very nicely in psoriasis interferon
1:48:09
gamma may work at least to some extent in in eczema. So yes, unfortunately that's the best um predictive model and
1:48:16
then over obviously what what happens is most likely that um memory cells are silenced in the skin. They are auto
1:48:23
antigen specific and then there comes a second hit environmental trigger and that allows then to reacabate the other
1:48:31
disease. Hi thanks Mike Jones UK. Um yeah, I
1:48:37
think I've heard you speak before actually about how we've been a bit disappointed about um the utility of
1:48:43
biomarkers in AD and probably psoriasis as well. So it's kind of slightly surprising that the molecular
1:48:49
diagnostics is so useful. Do you think that perhaps it's because of our clinical sort of determinations in terms
1:48:55
of the biomarker searching has not been perfect and that's probably why we haven't found these endotypes we've
1:49:01
known perhaps might be there? Yeah, absolutely. Um I fully agree with you. Right. I think what we did um first
1:49:09
of all was always to try to squeeze biomarkers into our way of thinking.
1:49:14
They should fit to what we think rather than identifying biomarkers that would teach us new things. Right? So that's a
1:49:20
kind of this approach. And the second thing is um I think the granularity of the clinical data that we had to train
1:49:28
algorithms to identify biomarkers are just by far not enough. So we need to get much more granular to really know
1:49:34
what we're talking about and we cannot do that using a score or easy and a py on the other way. I think we need higher
1:49:41
resolution clinical images. We need to train large vision models, use agentic AI, right? So the granularity just has
1:49:48
to get better. It's not about the algorithms, it's about how we feed them in. Well, there are people standing up
1:49:54
there. Let's let them ask their questions and then Andy, the microphone's working now. Go ahead. Uh Dr. Sri from Dubai. So uh I have seen
1:50:02
quite a few facial ariththemas in uh eight patients treated with the
1:50:08
biologics uh unlike the jack inhibitors
1:50:13
almost all of them uh I would say not just dup alone even
1:50:19
libriism I have seen. So uh my question is is this a soracififor reaction and if
1:50:25
so why is it uh specific to the head and neck area face and uh is there any
1:50:33
explanation for is it the malaia and the other demodex story only a reflection of
1:50:41
our thoughts due to the location of the condition and the arythema and which came first. So head and neck associated
1:50:49
dermatitis which worsens or denovo exists exacerbates under dupilium mapap
1:50:56
treatment. I don't know somebody else wants to answer. I mean what we know is that there is more TH22 signature right
1:51:04
this is work from Patrick Bruna and um and the Vienna group um and most likely
1:51:09
it's really associated to malaceia not to demodex but to malaceia there are
1:51:15
reports that azol under mcotics may improve that condition however this is
1:51:20
highly controversial I don't really think it's understood fully yet but I wouldn't argue that this triggers a
1:51:27
zoryazi form reaction I rather think it's really triggered by the environment and microbiome my comb
1:51:34
whatever but this is just my personal opinion I don't have a full clue here any anybody
1:51:41
start thank you David Con from New York and I
1:51:47
really want to thank the IPC for putting this together is an amazing meeting and
1:51:52
Killian you're right it was really not just being in the audience lift to the lecture right and and have you put that
1:51:58
together. I was intrigued if not confused by something you said about
1:52:03
I did you give us the impression that there was some TH17 involvement because you saw the neutrfils there and I just
1:52:10
wonder if the the amazingly exudative disrupted
1:52:16
epidermis is not responsible for that neutrfilic infiltrate rather than it being a true soracform
1:52:24
phenotype of some sort. I I couldn't agree more. And probably the mechanism here is that these TH17 cells that
1:52:32
actually really um go into the skin, they migrate there, they are most likely
1:52:37
reactive to stuff orius. So it's exactly as you say, right? And that's also why the disease gets better when we treat
1:52:44
with 13 or 413 inhibitor. Um right, that's the reason. So it's not an auto
1:52:50
antigen driven process by TH7 cells. The dominant response is the auto antigen of
1:52:56
the TH2 immune response and you have the AP phenomenon of stuff orius specific TH7 cells secondary to exactly what you
1:53:04
say scratching and exodation and stuff orius overcolonization.
1:53:10
I get asked this question a lot, but I don't know if there's data. And that is,
1:53:16
do you think that there's more psoriasis and seriatic arthritis like reactions in
1:53:22
patients treated with dupiliumab where you're blocking two TH2 cytoines versus a selective 13 blocker? Do you think do
1:53:30
you think dup is more shift compared to selective 13 blocking? From a
1:53:38
mechanistic point of view, I could not explain why honestly because I don't see
1:53:43
that 4 plays a major role in differentiating um T-C cell immune responses right I
1:53:51
think there 13 is the dominating and most important cytoine so that's the let's say mechanistic kind of
1:53:57
explanation I think when it comes to epidemiology the problem is in this case that I mean 80% is dupilium mapap right
1:54:04
so obviously we see many many more cases under dupilium mapap than under labri or
1:54:09
trilocinom but um I we do see them under i13 inhibitors also so I at least think
1:54:15
that from the mechanistic concept I13 is the relevant cytoine and I don't really
1:54:21
think that4 adds a lot to the game but again here I mean I I don't want to
1:54:27
pretend in this audience I'm the expert on this topic sounds good okay
1:54:32
I agree
1:54:37
[laughter] I I think it's how how how strongly you block T2. So, uh do more effective you
1:54:45
block more effect to more. That's my idea.
1:54:51
Well, we probably may see that with the upcoming therapies, right? And there will be quite some data shown here at
1:54:56
the AAD about this um more specific higher dosing um half lifetime extended
1:55:03
I13s for example. So if your theory is correct which is absolutely possible then we should also see this as a higher
1:55:11
rate under this uh even more efficient potentially more efficient i3 inhibitors.
1:55:17
Yeah. Okay. Well thanks everybody. I think we're going to just keep moving on to
1:55:22
the next session since we had our break already. Uh, and this next session is on
1:55:27
TNF induced skin eruptions in patients with inflammatory bowel disease. So, we're flip flopping from eczema to
1:55:36
psoriasis and the problems now that we're seeing with the anti-TNF alpha induced skin eruptions. And we're going
1:55:42
to move on unfortunately one more last pre-recorded
1:55:48
uh talk. uh once again because of issues with travel. And this is from Dr. Lev
1:55:53
Pavlovski who's a clinical associate professor of dermatology at the Sackler Faculty of Medicine in Tel Aviv
1:56:00
University. He's also director of the psoriasis treatment unit and outpatient clinics in the division of dermatology
1:56:06
at Rebane Medical Center in Pedatikva, Israel. His clinical and research expertise lies in iminobiologic
1:56:13
therapies for psoriasis and he has served as principal investigator in numerous international clinical trials
1:56:19
in this field. He's authored more than 60 scientific publications and was contributing author of the Israeli
1:56:26
clinical guidelines for psoriasis treatment. His primary research interests include inflammatory skin diseases with a focus on the
1:56:32
imopharmarmacology of psoriasis and he is an IPC counselor. So let's go ahead
1:56:38
and hear what he has to say. Hello, thank you for the kind introduction. I would also like to thank the organizers
1:56:44
from IPC and international exam council for inviting me to give this lecture very gratefully due to the current
1:56:51
situation in our area. I cannot be there in person. So you will see the lecture
1:57:00
by video. My conflicts of interest
1:57:06
in the lecture we'll cover epidemiology clinical presentation differential diagnosis and treatment approach to
1:57:11
antity and induced skin eruption in patients with inflammatory bowel disease. H the term
1:57:19
most often used in the literature is paradoxical psoriasis of psoropform regions
1:57:26
due to antitf therapy in IBD patients and this clinical phenomena is
1:57:32
relatively common observed in around six patients of patient 6% of patients
1:57:38
treated with antitf for IBD and most common
1:57:43
medications are infleximap and liimab because these are most common medications used to treat IBD.
1:57:51
There is probably a genetic susceptibility. Recently paper was published on interlocking 23 receptor
1:57:59
polymorphism as a possible genetic background for uh these rashes.
1:58:05
Interestingly, the time lag between starting antitf and developing of skin
1:58:11
disease uh vary from one month to several years with meanantime of onset
1:58:18
of 11 months. I will not go in details to mechanistic
1:58:24
approach because there is a I'm sure an excellent lecture by professor goodson
1:58:31
in the in this symposium but I would like to say that the main
1:58:37
of of a disease is type one interferon what about clinical characteristics of
1:58:44
of the disease actually most of the patient don't have not personal and not
1:58:50
family history of any dermatosis, not psoriis and not atopic dermatitis.
1:58:58
H and um distribution of the rash is as you can see on the scalp limbs but um we
1:59:07
relatively common locations like panopl disease uh face
1:59:14
and genital lesions and I will show you examples.
1:59:21
The morphology of antitfind induced skin disease is most psoriasis form
1:59:29
but also execatic form and actually
1:59:36
it is not that easy to define it as you will see in their following examples.
1:59:42
But classical rash as you can see here is a
1:59:48
rash of well definfined temus plugs with scales which actually
1:59:55
resemble sorasis but these are not lesions of classical psorasis.
2:00:02
This is example of much more dermatitis like eruption in 86 year old female
2:00:09
disease with chron disease treating with treated with inflimab. You
2:00:14
can see signs of scratching.
2:00:20
And in our patient with chron with adalimab
2:00:26
again widespread rash not it at all more resembles psoriasis but again this is
2:00:32
not a classical psoriasis. Eystopathology reflects what we see clinically as you
2:00:39
can see here. This is a prominent sorapform epidermal
2:00:44
epiperplasia with maybe some degree of spongiosis and numerous aenophiles in a
2:00:51
xenophils in in in the dermis which reflects
2:00:57
of course clinical appearance.
2:01:02
As I said before, scalp and face are relatively common. And uh here you can see
2:01:09
posterioral fee which is not characteristic for scalps
2:01:15
psoriasis. The dislocation of course is common in scapsuris but not the the
2:01:21
fissure. facial disease as you can see here in this young man with a crown on inflimab
2:01:30
with a secondary infection prominent on the face and in the external ear canal and
2:01:39
in these cases it is almost impossible to treat the infection with antibiotics without treating underlying inflammatory
2:01:46
disease. Peranologenital disease is common
2:01:53
especially in patients with frequent diarrhea and the use of
2:02:01
frequent wash of the area and use of topicals
2:02:07
and here is an example of prominent seroratic involvement of peranal area.
2:02:17
Poplant disease is common as you can see here and panoplar postular disease is
2:02:24
very common much more common than in idiopathic panoplastis which is a rare disease. Another difference is that in
2:02:33
idiopathic paroplantis most of the patients or almost all
2:02:39
patients are smokers but in these IBD patients with
2:02:44
anti-inflammatory antitinalfa induced paroplant disease
2:02:49
not all of them are smokers and there's another example of severe plantar ptolois in patient on inflexim
2:02:59
one of the most important and distinct entities in this patient is inflammatory
2:03:04
alopeesia which is very
2:03:11
unique for this disease and we we don't see it not in scalps
2:03:17
psoriasis not in attopic dermatitis involving the scalp as you can see here
2:03:23
this is a prominent inflammation of the scalp with alopeesia
2:03:30
And in these cases the opete is not permanent after discontinuation of the
2:03:36
TNF and in most cases with appropriate treatment
2:03:42
the hair will regrow. In our example, there is a inflammatory
2:03:49
alopecia with secondary infection and again the antibiotic treatment will not
2:03:56
be helpful without controlling underlying inflammation and again
2:04:02
complete regrowth of hair. In our example of scalp disease with
2:04:08
secondary infection and face environment on histopathology we can see
2:04:15
from epidermal epiplasia with peralbar chronic
2:04:21
lymphoitic infiltrate and miniaturization of hair follicles. What
2:04:26
about differential diagnosis? Well, um,
2:04:32
one of the entities that can mimic this disease or
2:04:38
disease that mimic identity is mikos from most common for anostisol lymphoma.
2:04:44
As you can see in this example, 39 year old with male patient with chron disease
2:04:49
on adimo and you can see these uh plaques with
2:04:57
follicular accentuation parlantal kertoma and implant roia and
2:05:04
on histologology epithelotropism of lymphocytes.
2:05:11
These lipos are CD4 positive, CD8 negative and CD7 negative and
2:05:18
this arrangement is polyclonal. Uh you can see that there is not
2:05:25
prominent cellular of of the lymphosy but again it may be in the case of mikos
2:05:32
fungidas but the clinical course is completely different. In this case at
2:05:39
the limo was stopped. The patient was switched to stellar which is not known to be a treatment for mik because from
2:05:47
goness with complete resolution of the r.
2:05:52
Another differential diagnosis of inflammatory opacia is lopeesia arata which is also
2:06:00
reported in patients treated with antitage but differential is easy even
2:06:06
on the clinical background because you can see there is no inflammation of the skin.
2:06:13
This is very unusual case of young female patient with chrome disease onomab inflammatory opacia and the the
2:06:23
most prominent feature was in nodules. You cannot see it good on the picture
2:06:28
but if you when we touched the the scalp it was many in inflammatory painful
2:06:36
inflammatory nodules and you can see on the right picture from scalp eruption with posterioral
2:06:43
fissure. The key for diagnosis in this case was that the the analysis that husband of
2:06:50
the patient has tenia on his face and scalp and the
2:06:56
fungal culture was positive for triopetons and she was treated
2:07:02
with antifungals with a complete remission.
2:07:07
What about treatment approach for this disease?
2:07:13
Well, discontinuation of antitf is required in around 12% of patients with TNF induced psoriiform eruption
2:07:22
and switching with wing class will be not helpful in most in most
2:07:28
cases early switch to stino and vikinum
2:07:34
for many years it was the only option to treat the chro disease and psoriasis
2:07:40
form eruption. secondary to antitnf because it was the only medication that was effective for
2:07:46
skin and registered for uh for chron disease
2:07:52
indicated for chron disease. But today there are there are other options and
2:08:01
scalp location is independently associated for less remission of skin. In other words,
2:08:08
inflammatoria is a reason to discontinue antitf and
2:08:14
usually to start another [clears throat] treatment as I will show you in two cases.
2:08:22
The first one 21-year-old female patient with Crohn disease on and she was presented to our
2:08:31
department after 9 months of on and with complete remission of chron disease and
2:08:39
um the rash as you can see here which could be let's seeupive psoriasis or
2:08:48
as I judged at that moment not very severe her sorophone eruption secondary
2:08:54
to antitnf course and because she was in remission for chron disease we tried to
2:09:00
treat her disease and continue underop so we started topical cortical steroids
2:09:07
and phototherapy unfortunately severe
2:09:12
inflammatory patient developed and of course at that moment we discontinued
2:09:18
and started to kill them up it was not helpful and as you can see
2:09:24
here it was a severe palm planter disease with a nail in moment actually
2:09:29
she was on wheelchair this visit so we added cycllosporin
2:09:35
and on combination of osteino and crosperine you can see hair grow but
2:09:42
not good enough response of panopl disease
2:09:47
so almost uh more Then
2:09:53
one year of disease we switch her to resank and as you can see it was a
2:09:58
complete remission of skin disease. Uh all the domains hair paroplantal disease
2:10:07
and again chro was in complete remission but again a year and a half of suffer.
2:10:15
Another example 23 year old female patient just postpartum and breastfeeding chron disease since age of
2:10:22
14ctomy 10 years ago two years on a limoap which
2:10:29
was discontinued due to new onepsis diagnosis which was done before we met the patient and then vendorismab with
2:10:36
inadequate response of chron disease and since 2023 in flexim
2:10:45
on fleximob. She developed terrible sorasififor
2:10:52
and examid [clears throat] skin disease with secondary infection
2:11:00
gentle involvement with you cannot see it in here but believe me.
2:11:09
So uh we stopped of course inflap and at that time we already had the kismap and
2:11:18
the reason was initiated but as you know
2:11:24
is given intravenous initially in in chron and after this IV
2:11:31
induction no improvement. So we started at the prennazone and when we tapered
2:11:37
prennazone ticosporin was initiated with some improvement but again terrible disease and secondary infection and all
2:11:43
the antibiotic trials are useless
2:11:48
and uh for that time we got reinwok and after one month on reinwok it was
2:11:56
complete remission of skin disease and chron disease was in remission all the
2:12:01
time. So we and the patient were very happy for her. But then on November she
2:12:08
was planning a new pregnancy and uh we had to discontinue with the citimp
2:12:14
and restart kism with hope that this time the skin disease will not relapse.
2:12:22
But then just one month after discontinuation of upetan of reinok new
2:12:28
seratic scalpes appeared and then uh skinner. So now she's almost 3 months
2:12:36
pregnant and treated with combination of sky and crosperine
2:12:44
to control the skin disease. So to summarize,
2:12:52
patients with mild disease can continue anti-NF therapy with appropriate dermatology management. Severe or
2:12:59
refractory disease and special inflammatory rotation require require discontinuation of antitnf and in most
2:13:06
cases uh switch to to another treatment. What treatment to switch? they I think
2:13:13
here is the main gap because we don't have the
2:13:19
at least now not standard diagnostic criteria and not
2:13:24
personalized treatment pathways which we can choose
2:13:30
right patient right treatment for the right patient and of course optimal care requires multi-disiplinary management
2:13:36
individualized risk benefit assessment and close monitoring of both disease
2:13:41
skin and IBD. So with that I would like to thank you and um you can see here
2:13:49
thank you written simultaneously in Hebrew and Arabic. I think this day this
2:13:56
is self-explanative and with this hope for better future I would like to thank you again.
2:14:10
So thank you Lev again he's not actually here but Tom the miracle of technology. So our
2:14:17
next speaker really doesn't need a lot of introduction and that's Amy Pal. She's an IPC and IC counselor. She's
2:14:24
been one of the household name dermatologist for for decades.
2:14:30
She was my mentor still is over the last 25 years or more. She's been president
2:14:36
of multiple organizations and we're delighted to have Amy here to talk about uh what else other than the clinical
2:14:43
approach in children. Thank you Amy. Thanks Alan. So we've seen lots and lots of cases today of of uh both directions
2:14:52
with the uh psoriasis developing most recently discussed from TNF alpha
2:14:59
inhibitors. uh but we haven't seen a single patient presented who's been under the age of 18 that I can remember.
2:15:07
So uh it will be my job to bring us back to the fact that this can also occur in children and I will say it can go both
2:15:13
ways. We've also seen po uh patients on dupilab uh who have developed psoriasis
2:15:20
or whose psoriasis has been unmasked but we'll focus here on the anti-tf alpha
2:15:26
induced skin eruptions. So it's really very similar to what we were just talking about. There is a variety of
2:15:34
epidemiologic studies out there. They range in uh from about 4.6 to 13.6%
2:15:41
of those with IBD, but the majority of those with inflammatory bowel disease who are children. We're talking about
2:15:47
these studies having more than 10%. So perhaps a little bit higher in children
2:15:54
with IBD than what we even see in adults. lower percentages in uh juvenile
2:16:00
idiopathic arthritis. Uh a reminder that uh seroriatic arthritis in children is
2:16:06
within the category of juvenile idiopathic arthritis. Um and then when we think about what we see in terms of
2:16:13
percentages who have certain diseases, in my experience and what's in the literature, more than 90% of what we see
2:16:20
that comes in with this disorder are children with inflammatory bowel disease and particularly Crohn's. But we do see
2:16:26
it as well not just in GIA but also chronic multif focal recurrent osteolitis. We've seen a few patients
2:16:32
with that and and other disorders that have been treated with the TNF alpha inhibitors. In pediatric patients median
2:16:40
age is about 14 years and there's a range of time from the initiation of the
2:16:46
uh inhibitor to the development of the sorasopform dermatitis of 14 to 34
2:16:52
months. But once again it does take time for this to develop. There was a study
2:16:58
several years ago suggesting that at least concurrent methatrix did not reduce the risk of occurrence and in
2:17:05
children where we have more limited armamentarium for treating in general. The most commonly associated medication
2:17:12
is infleximab and to a lesser extent adalimab. There have been rare reported cases with sort of lilyizab galimmaab
2:17:21
but these are not used as much of course in children either as has been said repeatedly these are
2:17:28
patients who tend to do very well for their underlying disease. So if we think about Crohn's they're doing really
2:17:34
beautifully with Crohn's no effective response 92% in a large study that we
2:17:40
recently completed had an excellent response for their primary disease. So that translates into the fact that
2:17:46
families do not want to stop the medication that they're on. It's the last thing they're very worried even
2:17:53
about trying to do that despite the fact that the child may have this this
2:17:59
eruption that can be quite uncomfortable. So all of these are features in children.
2:18:07
Now many children have multiple sightes but overall the experience is that it's
2:18:13
typically a more limited body surface area than what we see in traditional psoriasis. There's also tend to be less
2:18:21
distinct plaques uh certainly in my experience with children more oozing and crusting more staff orius colonization.
2:18:28
The most common site that we see is the scalp and the perry and the
2:18:33
posterricular area uh as in pediatric psoriasis a very common site. Uh we know
2:18:40
from our work with the IPC that we're seeing scalp psoriasis much more often in children than what we're seeing in
2:18:47
adults. Recent studies suggesting about 80%. Uh more inflamed, more alopecia. We
2:18:54
talked we just heard from Lev about it not usually being sickial but I have seen one case that was quite severe and
2:19:01
can scar. So we do want to be very aggressive in treating scalp involvement. I'm not going to show you
2:19:07
any case uh case series or or uh specific cases but I think you can look
2:19:13
through this series of of uh children here as I'll show you more pictures
2:19:18
showing the scalp involvement sometimes oozing crusting. There's that fissure behind the ear. We just heard very
2:19:26
frequently we'll see fissering here. We sing some fissurers. We see perorificial involvement very commonly on the face as
2:19:33
you can see in this child or these two children here. Some other clinical features. Trunk not so much. I'm going
2:19:40
to give you an example with a small pilot study we did. But um sometimes they are on the trunk and they can be
2:19:47
these smaller gutate lesions but very often on the hands on the fingers on the
2:19:53
feet on the toes involving the nails sometimes with postulosis. Some more
2:19:58
examples of this in children knees and elbows. Yes, we can see it there but
2:20:04
certainly not with the frequency that we see it in our typical plaque psoriasis
2:20:09
in children. There have been many reports of these trunkalicular or
2:20:14
sometimes postular or punctate lesions. Some examples in children shown here and
2:20:20
some other examples here both cases of teenagers. So I think one of the problems is just
2:20:28
recognition of this and I'm going to raise this in the context of the fact that psoriasis is very common in adults.
2:20:36
It's much less common in children. So primary care providers often don't
2:20:42
recognize psoriasis and similarly then are we seeing this and recognizing it
2:20:48
when it occurs with the TNF alpha inhibitor induced disease and fortunately this is now common enough
2:20:56
that our pediatric GI services our pediatric rheatologists clearly think
2:21:02
about the possibility here when they have their patients on these TNF
2:21:07
inhibitor induced uh when they have their patients on TNF inhibitors. Uh, but what they sometimes
2:21:14
can't know and that they're not confident of is is this caused by the
2:21:20
TNF inhibitor or could this be that the patients just develop psoriasis because
2:21:26
they know that there's an increased risk of developing psoriasis in children with IBD with JIA and they're not well
2:21:35
trained to really understand how to differentiate. So this has been a problem and that's of course compounded
2:21:41
by the fact that psoriasis in children doesn't always look like psoriasis in
2:21:46
adults. These can be thinner scales. They can be more indistinct plaques. There's more facial involvement. There
2:21:52
can be scalp only involvement. Sometimes patients have what looks like sorac dermatitis. We call it psoriasis without
2:21:58
these TNF inhibitors. And there are certainly many patients that we see who have classic psoriasis and classic
2:22:05
attopic dermatitis. And then of course we have to think about the differential with all of these patients and very
2:22:10
commonly what is really psoriasis is mistaken for attopic or numular
2:22:15
dermatitis for seabberic dermatitis for infections that are tenia or candidada
2:22:20
or contact dermatitis. So this becomes a problem of recognition and they'll send
2:22:27
to us because they're really not sure what's going on and nobody wants to stop that highly effective TNF inhibitor. So
2:22:35
we need better education and we need to think about are there any biomarkers that we can help with making these
2:22:42
decisions and making them quickly uh to help know do we have to stop this? How
2:22:48
do we treat this? So first of all, are there biomarkers to distinguish psoriasis in children from the TNF
2:22:57
induced TNF inhibitor induced sorry form dermatitis and there's really been very
2:23:03
very little work done in this area. There were some older studies coming out of the GI literature finding some IL23
2:23:10
receptor polymorphisms conferring an increased risk after inflammab in children. There was another
2:23:16
study looking at some uh rare alals associated with increased risk and a few
2:23:22
other genes, but it really hasn't gone very far in helping us. Now, we're going to hear very quickly more from uh Johan
2:23:31
Gansen. He's going to tell us a little bit about the landscape here molecularly. Uh and these studies have
2:23:38
come from studies in adults. They have looked at uh mRNA expression. They
2:23:44
extracted these from biopsied leional skin. Now I'm a pediatric dermatologist
2:23:50
and some of you see a lot of children. You know that I don't think there's a child alive who wants us to do a biopsy
2:23:57
on them. So to try to look at that is going to be a real problem. So I'm going to say talk a little bit about how is
2:24:04
TNF inhibitor induced sory dermatitis treated in pediatric patients. And I
2:24:10
will say it's quite similar to what we've been hearing in adults. Is the response any different? And then can we
2:24:17
use any non-invasive means to predict? So this has come out in terms of an
2:24:24
algorithm for management. And very simply, I'll just say that this is what we do. If it's a milder psoriasis, we're
2:24:31
certainly not going to say to the parents, you have to stop this TNF
2:24:36
inhibitor that's been so wonderful for your life. So we will move forward with topical steroids. We might add in
2:24:44
topical calcurine inhibitors particularly for uh facial and more sensitive regions. We might use vitamin
2:24:50
D analoges even uh topical retinoids. uh if they're eitus and weeping we might
2:24:57
think about secondary staflloccal infection and we might start something that's antistaflacal whether we're
2:25:03
talking about bupirin or or let's say in Europe fucidic acid um or even a
2:25:09
systemic antistaflloccal drug but when we look at those patients with mild or
2:25:16
moderate involvement who we've treated only with topical only 15% of them will clear with topical therapy alone 63%
2:25:24
will experience partial clearance and depending on how much of a problem this is you have to make that decision about
2:25:31
is that good enough because if not then we have to treat as we think about with
2:25:36
moderate to severe psoriasis and these soriatic involvement for example we talked about involvement on the scalp
2:25:43
being something that may be pushing you towards being more aggressive with your treatment now again the TNF inhibitor is
2:25:50
being required to control that underlying disease in most of these cases I said 92% in great control. So
2:25:57
what direction do we want to go? Well, in some cases we might start by
2:26:02
increasing the immunom modulation. We heard this already. We're going to add in and we heard this both whether we're
2:26:09
talking about getting uh more of this uh ezeus or more of the soriatic depending
2:26:15
on doesn't matter what you're on. We might just add an imunom modulator. So adding the methtrixate or the cycllospor
2:26:22
or the ustkinamab or or photootherapy or acetin but in many of these patients
2:26:28
that's really not helping them sufficiently. So we might think about switching to a different TNF alpha
2:26:35
inhibitor and in the past this is primarily what we ended up doing. And in fact in a pediatric study that we just
2:26:42
did with more than a 100 patients the percentage of of children which was about 30% who did this um showed 82% of
2:26:50
them improving by 3 months. So this is a viable option but the problem is that
2:26:57
some of these children of course were recalcitrant or their disease progressed and also that as you follow these
2:27:02
children out 31% had recurrence of the TNF inhibitor induced or dermatitis at a
2:27:09
median of six months. So maybe not the ideal direction to go. So increasingly
2:27:16
we have been instead starting um sorry
2:27:21
stopping the TNF inhibitor and starting an alternative agent and depending on what we're treating obviously we may go
2:27:29
in different directions. So as I said the vast majority of what we see is is um inflammatory bowel disease and we've
2:27:35
been um starting most of these patients on Kenya with very good results and this
2:27:43
has become the treatment of choice in in pediatric dermatology for our patients uh particularly with um Crohn's disease
2:27:50
but also for example that can work well with with junctional idiopathic arthritis. So I've listed up there some
2:27:56
of the possible agents that we can be thinking about in terms of of transitioning from the TNF alpha
2:28:04
inhibitor and that usually actually takes care of it quite well. So how good are these for treating the underlying
2:28:10
disease? We'll stick with Crohn's here and talking about that a little bit to just say that with uh alternative agents
2:28:16
and especially takenab more than 81% with Crohn's will clear or stay clear on
2:28:23
their non-TNF alpha inhibitor. This is a a study here of 40 patients previously
2:28:29
treated with TNF inhibitors and 61% achieve clinical remission um a little
2:28:35
bit harder with peranal disease. uh also it's been found that usabad reduces the pediatric Crohn's disease activity index
2:28:42
by more than 50% in patients who are resistant. So some information suggesting that this is a good direction
2:28:49
to consider and my own experience over the last year or so of working with our pediatric rheatologist and our pediatric
2:28:56
gastronurologist is that they're pretty comfortable doing this and it's been quite helpful for our patients. So this
2:29:02
is what we found just very quickly um looking at these uh volcano plots
2:29:08
looking um at psoriasis versus healthy controls in the group a lot of differently expressed proteins no
2:29:15
psorias no surprise here we've got a strong TH7 TH1 signature um somewhat
2:29:21
different proteins a lot of the again the downstream ones the chemocines being seen uh in that outer epidermal area
2:29:30
vascular remodeling represented by a lot of VEGF um and epidermal activation
2:29:36
barrier remodeling biomarkers particularly TGF alpha seen
2:29:41
here on the proteomics. Now when we look at the uh pediatric TNF uh inhibitor
2:29:49
induced disease we see uh again many differentially expressed proteins versus
2:29:55
the uh healthy controls. Interestingly, if you look at the top six
2:30:00
differentially expressed proteins, they were absolutely the same in psoriasis
2:30:06
and in the TNF uh inhibitor induced set. Um, and we also saw other proteins that
2:30:13
were very high like like your TH1 ones, CXCl9, CXCl10, also some chemocine like
2:30:20
CCL22 um and interlucan 17 was also high in this group. So, we've heard this before.
2:30:26
It's similar to the adults. They they both show a sore psoriasis type phenotype. Again, vascular remodeling
2:30:32
epidermal activation and hyperp proliferation. Same same uh biioarkers here by proteomic. But we did have 19
2:30:41
differentially expressed um in the TNF inhibitor induced versus the psoriasis.
2:30:48
And I just want to point these out because they suggest to us that maybe we could have an easy panel for these um
2:30:56
specialists in GI, our specialists in rheumatology to be able to do something to try to help um in addition to our
2:31:03
clinical expertise. So we found uh four that we were particularly interested in
2:31:08
that had the in the highest group that were differentially expressed and higher in TNF inhibitor induced and these were
2:31:16
the interferent inducible protein uh particularly HLAD a regulator of interferent expression
2:31:22
CD200 uh receptor um two markers of immune cell infiltration
2:31:29
uh LP1 and HCL1S and then on the other side we were
2:31:35
particularly interested in even though we can see it in in both groups much
2:31:40
higher uh in psoriasis was the IL17C as a marker for that. So a small sample
2:31:48
but maybe giving us the idea that we might be able to find a biomicro panel that would be very useful. So in
2:31:55
conclusion, TNF inhibitor induced raspentitis is a common complication for the uh TNF inhibitor use in inflammatory
2:32:02
bowel disease in particular in children. Non-invasive tape stripping or scraping and proteomics may distinguish a
2:32:09
psoriasis from the TNF inhibitor induced disease based on the biomarkers.
2:32:15
Children in general may respond better than adults to topical intervention, but
2:32:20
we often will need to discontinue their TNF inhibitor despite the fact that it
2:32:25
is so effective for their disease. Always a hard cell with parents. But switch to another um inhibitor often uh
2:32:34
if it's a TNF inhibitor can lead to recurrence. We talked about more than 30% with a median of six months. An
2:32:40
ustiniumab has been our new treatment of choice for switching best track record
2:32:45
of change if another biologic is required and I thank you for your attention.
2:32:52
[applause]
2:32:57
Thank you for that Amy. We're going to have some questions after the next talk. So um it's a pleasure to introduce Johan
2:33:04
Johnson for our as our next speaker. Johan's the Arthur C. Curtis professor of molecular skin molecular immunology
2:33:10
at University of Michigan. He'd be well known to everyone. He's an IEC and IPC
2:33:16
counselor. Uh he's done many he's made many uh discoveries in basic immunity
2:33:21
and genetics of psoriasis and I think of it most for synthesizing really
2:33:27
elegantly huge data sets and making sense of them and some really elegant
2:33:32
experiments. So we're going to hear from Johan now. Thank you for joining us Johan.
2:33:38
Well, thank you for that kind introduction. I'm very uh excited to be with you this afternoon. Um,
2:33:44
so my talk is going to be focused on more the mechanis mechanism aspects of paradoxical reactions and these
2:33:50
iotrogenic switches. So these are my conflicts of interest
2:33:57
and I before we kind of dive into the paradoxical reactions I just want to kind of highlight uh it's it's a
2:34:02
beautiful perspective that my uh colleague Killian actually published in the uh um the European uh
2:34:11
dural of of of dermatology minology about now what eight years ago and it was really to kind of show you the you
2:34:18
know how different inflammatory diseases really have different immune
2:34:23
polarization patterns and based on that you're going to define these four major kind of polarization pattern the pattern
2:34:29
one which is like lychenoid TH1 responses pattern two aximatus blistering TH2 responses and then
2:34:34
pattern three which was more psoriasis or TH7 responses and then pattern four which was more fibrogenical fibrosis
2:34:42
driving mechanisms and granolomatus type type inflammation and you can see that in the in the graph there in the middle
2:34:48
uh that you can really kind of group different diseases based on the different in inflammatory patterns. And
2:34:53
why is this important and helpful? It's because many of the treatments that we have actually do overlap uh or are
2:35:00
specific to specific immune and inflammatory patterns like the Jack inhibitors for the the pattern one.
2:35:06
There's more more evidence for them to be effective in diseases such as lyken planners uh the antl4 antl and the jack
2:35:14
inhibitors in the u the TH2 type immune response. You have a whole range in the
2:35:19
psoriasis kind of a spectrum and then you have much fewer still in the fibroic kind of a space but kind of growing
2:35:26
evidence for the use of like jack inhibitors in like granulometers type inflammatory patterns
2:35:32
but it's helpful to also kind of think about the immune system as kind of a balance between different arms of the
2:35:39
cytoine and the immune network. And here we have kind of these three different arms that we kind of think about the TH2
2:35:46
the type type 17 and type one inflammation. And I also want to kind of add in that also interfering type
2:35:53
response is really going to contribute and play a role in this kind of a balance between the different arms. And
2:35:59
this really is is is this kind of a baseline immune balance. We see some evidence of all these different signals
2:36:06
across multiple different inflammatory diseases. There are certainly some immune patterns that are dominant in a
2:36:11
particular data set, but there's also uh evidence of of small activation of the
2:36:16
other one. So, it's really is this this even in disease state and inflammatory disease state, you really have a very
2:36:23
delicate balance between different immunaxis in these in these disease processes. And I kind of like to kind of
2:36:30
highlight uh psoriasis as a kind of a good example of this particularly given that there's so many different and
2:36:38
diverse immune responses going on at the same time. You have on one end you have
2:36:44
the type one interference response that we have associated with both unstable psoriasis and triggering and and onset
2:36:50
of psoriasis. We also have type two responses involved around interferon
2:36:55
gamma kind of the key cytoine. And then we have isle 17 response kind of being the hallmark the bullseye of of of
2:37:02
psoriasis. And then in the epidermis you have more of that isle 36 response that is really driving the feed forward
2:37:09
amplification of inflammatory responses and psoriasis. But these immune axes and
2:37:15
and cytoine axis really exist in violence in in disease like psoriasis where 17 uh based on all the clinical
2:37:23
data that we have is the key mechanism but there's also contribution from the interferon and the 36 axis.
2:37:30
So that kind of brings us into the the paradoxical type type reaction. So what are paradoxical reactions? So a
2:37:37
definition of them it's it's a development of a cutaneous inflammatory condition usually during imunom modulatory therapy that either is
2:37:44
usually treated by the same class of therapy. Uh an example of this is um
2:37:49
like psoriasis like skin rashes that arise in patients being treated with an anti-NF agent for inflammatory bowel
2:37:56
disease that do like like Dr. Amy Polar just showed you or antitnf agents for
2:38:02
rheumatoid arthritis. And then there's another mechanism that can kind of arise through composatory immune pathway
2:38:07
activation that you're treating a certain condition and then it kind of shifts and and you kind of get a little
2:38:13
bit of a different clinical phenotype arising in the same patient that you're treating for uh an underlying disease.
2:38:20
But the significance of this is is really that paradoxical reactions really illustrate that the inflammatory skin
2:38:25
diseases are not driven by a single cytoine by really an interconnected immune network where therapeutic black
2:38:31
blockade can reveal and and and activate latent inflammatory circuits.
2:38:38
So really uh paradoxical skin reactions really reflect this immune network plasticity and that's really what we're
2:38:44
talking about. This was I would say a very important publication in the field. This was from
2:38:51
Curtain Conrad. This was published about eight years ago in nature communication. He was looking at paradoxical reaction
2:38:56
new onsetsis and patients treated for other underlying inflammatory diseases.
2:39:02
And you see some clinical images there on the left with the hisytological features. And then if you're looking at
2:39:09
the different kind of a shift in the immune response that is happening and here it's being contrasted against what you see in plexorasis you're really
2:39:16
seeing a few different mechanisms kind of getting activated. One of them is the type one interferon interferon alpha and
2:39:22
interferon beta. You're also getting 22 responses and then type two interferon
2:39:27
interferon gamma is really getting activated the more highly expressed and accompanying by this is increased
2:39:34
infiltration of plasma dendritic cell which we think of being the key and major source of type one interference in
2:39:40
inflammatory skin conditions. So if you're going to go back to the in the uh
2:39:45
the schematic that I had before in terms of u that immune balance in psoriasis
2:39:51
what you're really seeing is is both increased kind of a relevance and impact
2:39:56
of the type one interference the type two interference whereas the 17 response is kind of being practically the same.
2:40:03
So it really is an interference type type shift that is driving the phenotype
2:40:08
in that particular setting. What I think is also important to kind
2:40:13
of appreciate is that there are many different types of paradoxical reactions. Uh we have lychenoid forms of
2:40:20
paradoxical reactions. So here we have uh we see this kind of a development of these purple polygonal papules with like
2:40:27
an interface reaction and this beautiful saw to on histologology and that really
2:40:33
is that you're getting a a TH7 to a TH1 kind of an inflammatory shift. You can
2:40:39
also have these emitus like reactions where the shift is probably going the other way around. You're kind of getting
2:40:45
more of a TH2 response at the cost of of the other ones being either suppressed or less relevant. And then what we have
2:40:52
or see quite frequently in the clinic is these postural type of paradoxical reactions um where you kind of get
2:40:59
postures often superimposed on the pre-existing skin lesion and here the activity is really on the IS 36 axis uh
2:41:07
being hyperactivated.
2:41:12
So what I want to show you is it's kind of some preliminary data that we have been kind of working on also in in the
2:41:18
lab. And here we have patients that have been treated with anti-L23 and anti-L17 uh drugs for classic plaque plaque
2:41:24
psoriasis and then they develop these kind of psoriasis like um skin reactions
2:41:30
that are kind of more in keeping with like attopic ecimma or or or der or dermatitis.
2:41:36
We've been using uh single cell profiling of of of skin biopsies taken from these individuals along with
2:41:42
spatial transcripttoics and and imunos chemistry for validation and then kind of looking at the different uh
2:41:48
inflammatory subsets and the shift in the specific immune population contrasting the paradoxical reaction
2:41:54
with your classic plexorasis at and and attopic dermatitis.
2:42:00
And when you do it like this, you have, you know, these four different kind of a, you know, polarization kind of a
2:42:07
pattern. You have your your normal skin, you have your your plexorasis, you have
2:42:12
your paradoxical reaction and the attopic dermatitis. You can see the epidermal phenotype and how that's developed in these different clinical
2:42:18
phenotypes. And then you can kind of look at the overlap in the gene expression on a global level between
2:42:25
these different forms of of of skin inflammation. And when you look specifically what's happening in the
2:42:30
paradoxical reaction, you're really kind of getting activation of the innate immune system uh and and and neutrfil
2:42:36
decranulation. And if you look at the biological mechanisms that are really shifting, you
2:42:41
can see that there's actually quite dramatic shift in terms of what biological pathways and immune mechanisms are actually being activated.
2:42:48
So here we see more kind of neutrfil driven inflammation but along with a TH2 uh immune response and also activation
2:42:55
of type one interferon responses. So you're getting like a really a mixed kind of inflammatory pattern that is
2:43:01
still quite strikingly different from what you see in plaque psoriasis that is in the second uh row.
2:43:09
If you look at what's happening in the in the skin, we are looking here at at the myoid and and keratinocy kind of a
2:43:15
cross talk. And if you look at PR, we're kind of getting a shift towards keratinocy myoid interactions. Not quite to the
2:43:22
same extent that you can see in atypical dermatitis but quite significant compared to pla psoriasis. And if we
2:43:28
look at the different myoid subsets in the uh the skin uh including these different dendritic cell subsets the
2:43:34
macrofasages and the dendritic cells including plasmos dendritic cells we
2:43:39
really seeing activation of u one of the TNF super family members the the tweak
2:43:44
signaling or TNF SF12 if you see what you know what really is
2:43:49
where is the tweak kind of coming from here is like an invitro study where we took LPS to activate the dendritic cells
2:43:55
and then with or without the presence of of uh infleximap and antitnf and really
2:44:01
having an anti-TNF in that system you're really getting increased levels of of of
2:44:06
of tweak expression. So in this particular setting TNF is acting as an anti-inflammatory suppressing expression
2:44:13
of this this TNF super family members to kind of suppress inflammation. So we're seeing activation of like a myoid
2:44:21
kerotin site cross talk that is activated and increased in paradoxical psoriasis. and really kind of driving
2:44:27
some of that inflammation. And you can see that also here by looking at the expression of the tweak receptor. You
2:44:33
have the image of chemistry there in the panel on the left. Then you're looking at the positive and negative cells uh
2:44:39
kind of highlighting the expression of the receptor there in red. You can really appreciate very dense expression
2:44:44
of of the receptor in the basal layer of the epidermis. Most prominently in attopic dermatitis, but more in in in PR
2:44:51
compared to um attopic skin. And you can also appreciate the uh the density of
2:44:57
the expression. So you can kind of twe tease that out of image the chemical kind of assessments
2:45:04
and then you can kind of look at the uh the number of both the tweak or cells that actually express the tweak and the
2:45:10
four conditions against one another and also the the tweak receptors. So you can see a very dramatic shift from psoriasis
2:45:17
over to much more tweak um sometimes more or at least comparable to what you
2:45:22
can see in attopic dermatitis. And if you look at the signal itself that is being activated by um by tweak
2:45:28
particularly in combination with 13 you can really appreciate this very kind of a dramatic signal where it's actually
2:45:35
amplifying a TH2 signal uh even more so than the cytoine can do itself. So it's
2:45:41
a modulating and modifying uh inflammatory response in this particular
2:45:46
setting. And here you can see also if you add in tweak with either is 13 or is 17 you're getting a pretty dramatic
2:45:54
shift um in the um in the iminological response in keratino particularly
2:45:59
towards um in different type responses. So we're going to go on back again to
2:46:05
kind of the um the different kind of a clinical phenotype. So here we have like an aximal like paradoxical reaction but
2:46:12
probably a more complex mechanism than what I showed you before. It's not just the interference that are being
2:46:17
activated. The upstream regulator of that actually is TNF super family member in this
2:46:23
setting. Uh the tweak signaling being a key key driver. So really it's additional pathways and cytoines beyond
2:46:30
type one and type two interference that really are contributing to these paradoxical reactions. And here we have
2:46:35
identified tweas as one of the members of the artf super family of cytoines as a modulator of immune responses and a
2:46:42
key driver of eczema like paradoxical reactions in psoriasis.
2:46:48
So really kind of going back to paradoxical reactions. So the key takeaway home point is that paradoxical
2:46:55
paradoxical reactions really reflect immune network plasticity and not drug failure in these diseases.
2:47:01
um and targeted cytoine blocking whether it's TNF, IL7 or IL4 receptor can unmask
2:47:07
alternative inflammatory pathway and drive the inflammation in these decences toward to a very specific inflammatory
2:47:13
axis. Um and as I showed to you before you know
2:47:19
with the psoriasis it really sits within a dynamic immune balance centered on is 17 but also interconnected with these
2:47:25
other cytoine axis uh in in in the disease and really therapeutic
2:47:31
perturbation of this can really shift this balance allowing compensatory activation on of of parallel pathway.
2:47:38
For example, AL7 inhibition can activate the TH2 or excitus responses whereas the AL4 receptor blockade can really
2:47:44
activate psoriasis form or psoriasis like inflammation. Um, and these paradoxical phenotypes
2:47:51
really follow a predictable immune polarization patterns in these reactions. Uh, and the clinical
2:47:56
manifestation usually kind of go with it. As you're going to get more of an IL7 response in these reactions, you get
2:48:01
more of a psoriasis like phenotype. If you're getting more of a TH2 kind of response with with with or with or
2:48:07
without interfant responses, you're getting more like an eczema eczema like u manifestation and they map onto these
2:48:14
different dominant inflammatory axes. So really this these data and and and and
2:48:20
the concept of paradoxical reactions really support a unifying model of immune switching across inflammatory
2:48:26
skin diseases. So with that I I'll I'll conclude and I think we have a question
2:48:31
uh panel after this. [applause]