Chapters Transcript Novel Insights in PsA Pathogenesis Course: NYU Langone Seminar in Advanced Rheumatology Elliot Rosenstein from the audience is asking how many directorships do I carry. The reason for that is, um, I'm the only one around. There's not that many other people, so they give me everything at once. And I try to juggle as much as I can so I am today philosophical, um, as you know, through my title I'm chatty it's gonna take me a while to go through my slides if I'm mumbling that's customary on uh my end, but please let me know because it's hard to hear, uh. Me in general, right, disclosures, uh, people that pay the bills, some of the foundation, uh, uh, partners that we have and some of the research collaborations, um, I'll talk about, uh, um, a quite a bit and some of the National Strategies Foundation work we've been doing over the last, uh, 4 or 5 years. Outline fairly quickly I'll have 4 different stories that I wanna touch upon. Number one is new, uh, tissue based omics and uh novel cell populations that can help us understand psoriatic disease pathogenesis. Um, how do we address the possibility of rationally designing topical treatments for psoriasis. Uh, and then go through a little bit of microbiomics and barriers to improve PSA outcomes as, as we see them today. OK, so who's old enough, uh. To remember Donald Rumsfeld, you are, see we're both getting older, um. I come to this country the year 2002 and the first um. TV interview I hear is from Donald Rumsfeld who was the Secretary of Defense who said the following there are no knows these are the things we know that we know they're known unknows, uh, that is to say there are things that we know we don't know. And then there are also unknown unknowns. Which are things we don't know, we don't know. So I go, 00 I moved to the greatest country in the planet and this is what I hear, uh, and this is in the context of oh we're gonna invade Iraq because we don't know they have weapons of mass destruction. Just to put you in context that this is not I don't know where it comes from. Uh, constructs that are widely used in social psychology and analytical sciences and, and it applies to psoriatic arthritis I guess that's the point I was trying to make most of what we. Uh, have investigating psoriatic arthritis is not are not known knowns or facts. We know some things we know that psoriasis affects 3% of the population. We know that most people with psoriatic arthritis will have psoriasis first, uh, but the vast majority of, uh, aspects of psoriatic disease are mostly known unknown, that is, these are all knowledge gaps. Why is it that 20% of people with psoriasis get psoriatic arthritis? We don't know that it's a knowledge gap. Why is it that. Majority of people don't respond adequately to our currently available medications. We don't know that. And once in a while we get a an unknown known, uh, and a perfect example of that is, uh, Jan Vilcek who knew that TNF blockade would help some inflammatory conditions until we we found the right. Um Target or targets, uh, I should say, OK, so, uh. Psoriatic arthritis, we put this together with these are a lot of um known unknowns here are uh the um uh aspects of psoriatic disease that we're trying to understand. We know it's heterogeneous because it affects multiple domains. We know that the prevalence is about 25% of it or a third of those with pre-existent psoriasis. Kinda know that genes are not that important. Uh, we're doing some twins, uh, work if you look at monozygotic twins that are, uh, affected with psoriasis, the concordance rate is about 10%, so it's not that high, so they do play a role but it's not. Necessary for disease um emergence. We do know that we require inducers for psoriatic arthritis to uh progress and that is either skin inflammation, it's got this biosis, uh and also uh ob obesity in the form of adipocy uh activation or mechanic inflammation, you know, that is it true that psoriatic arthritis initiates. Pathology in the NCCL structures. So those are non unknowns. Uh, L23 is a it's a driver of the disease and then we have enhancer and effector cytokines, particularly at 17 and TNF. We know that that's the case, but we don't know what triggers this, uh, mechanisms. So we're gonna focus on, uh, skin inflammation, particularly in keratinocyte, some of the work we've been doing with. Uh, shooting Nike, some of, uh, the work we've done. As it pertains to in testing of this biosis and some of the metabolomics associated with it. OK, number one, can the skin itself immunomodulate synovianheal disease? Is it true that it all starts? In the cutaneous tissue so. Great data set just about a year or so ago, the question of what happens if you block. Certain molecules that are protected in the skin to the joint um uh pathology so this is S 1089. Uh, along with A8, there are, uh, calcium binding proteins also known as cut protectants. Uh, we'll talk about cut protectins later and they're up regulated in multiple inflammatory conditions is 189 levels in particular are increased in psoriatic plaques. We know that specifically in keratinocytes but also in neutrophils. And if you globally inactivate the genes for S1009. You can see skin and joint inflammation in a mouse model of psoriasis, that's the DKO mouse model. Now you ask a different question. If you conditionally knock out the A 9 gene in the keratinocytes alone, is that sufficient. To drive, uh, not only psoriasis but also psoriatic arthritis. This is the work that was done, uh, uh, recently by the British group and what you see is that the uh animals that got the double double knock out uh that included the psoriatic arthritis knock out but also the 1089 had worse. Pathology in both the skin but also in the synovium which is dependent on TNF IL-6 and infiltration of neutrophils, uh, and activation of those cells so. A 9 in keratinocytes is restrictive is protected not only for psoriatic skin disease but also for psoriatic joint disease, which suggests that there's an important role truly for epidermal immune homeostasis in the prevention of arthritis in the context of psoriasis. So if that's true, uh, Sonia mentioned PAA. This study and it takes a village this is with. Uh, Chris Ridgeley and Rebecca Heber and Lehi Eer, Alexis who's at at the back and a, a bunch of other people, um. We ask the following question If you now define patients with psoriasis at high risk for the development of psoriatic arthritis, and that's uh demarcated by having at least moderate if not moderate to severe psoriasis and also having ultrasound abnormalities in their musculoskeletal, um. Uh, ultrasound that we perform at baseline if that's the case, we randomized to either an IL 23 blocker or placebo for 6 weeks for 6 months, excuse me, and then we uh try to understand the first co-primary endpoint which is do we see improvement in those abnormalities at baseline. After we expose our patients to IL23 blockade, and a secondary endpoint or the or the co-primary endpoint is do we see less transitional progression on those patients that received IL 23 for a couple of years versus a third arm, which is an observational, uh, standard of care or uh the study is ongoing we're recruiting, we're recruiting well, but we have some interim data that's afraid of us. And that is a reminder these are patients that have moderate severe psoriasis they have no joint pain and yet they have an ultrasound score that's uh above the threshold of what we consider absolute normalcy. We've done about 100 of them, um, on average, uh, patients had, uh, truly almost severe disease, 9% body surface area, and what we see is that 80+% of our participants already have, uh, either inflammatory or structural abnormalities, uh, they are minor but distinguishable, uh, in, uh, ultrasound. So the question is, are these relevant? Number 12, these abnormalities or they are going to progress to clinically evident disease. We don't know the answer to that. Uh, and the third one is, can we prevent past this get better or is this something that we're gonna find in most patients with moderate severe psoriasis? Uh, stay tuned, uh, work being done on this and, OK, uh, it's been mentioned NIH, accelerated medicine partnership, um. Network we are part of this again with uh Chris Rich and, uh, Alexis Obi and Rebecca Shuina. So we're studying new onset psoria psoriatic arthritis. We're studying uh uh novel targets of psoriatic disease in both skin, uh, exclusive and, and synovianes disease through a variety of approaches. Uh, number one, we take biopsies of the skin. And we do skin swabbing to characterize the spatial transcriptomics outcomes of these additional non-dal skin and psoriatic patients. We do skin microbiomics. I'm not going to talk about skin microbiomics today, but then we do single cell. In both uh peripheral uh uh monocyte, um, and we also do that in synovial tissue alongside spatial transcript. So I'm gonna focus on the skin for the next. 8 or so minutes. Um, and this is work being done with, um, Shruti Ni, a very brilliant scientist, perhaps my greatest collaborator yet, and we have pursued this question. Uh, the original question was can you. Uh, characterize new cell populations using spatial transcriptomics, the groundbreaking methodology that captures the pos the positional context of transcriptional activity within intact tissue. What it means is that you don't need to mush up cells and then characterize a single cell transcript. What you can do here is you take full thickness biopsies you put this tissue sections on spatially barcoded, uh, microarray slides, and those bar uh barcoded microarray slides get now mapped back to the geography of the tissue at hand. So we've done this and, and, and we compare healthy no additional, additional, and as you can see, um, spatial transcription is pretty uh uh robust uh faithfully, uh, recapitulating what we see in histology. Not only that, what you can also see is that once you locate the cells at the right region you can understand gene expression from those cells in that particular site and you can see this I don't know how. This, this is pretty cool. So you see these purple dots here? Those are found in the epidermis of a healthy, uh, biopsy, and this correspond toyS and low level activity of keratinocytes. If you look at lesional skin in psoriasis, what you start finding, uh, is different types of keratinocytes. Uh, you can see them here, uh, represented in red dots, and these are clusters of keratinocytes that are found in an inflamed supra basal epidermis, and I'll explain. We take that supra basal epidermis um uh signature and we ask the question what is it that we find in those keratinocytes or at that specific tissue region so we find the usual suspects, right? We see LL 17 signaling pathway we see IL 22, uh, proliferation and keratinocytes. We see TNF, no surprise there. Surprising, uh, factor that we were able to discern using spatial toxicomics is this hip alpha signaling pathway. This is hypoxia, hypoxia induced factor, and I'll explain in a second what it means. So we corroborated this using, uh, immunofluorescence. This is the skin biopsy of a healthy individual. You see the dermis here. You see the epidermis, no. Uh, green dots which are fluorescence code for hippo and alpha, you do see red dots which are markers for keratinocytes. When you look at psoriasis, you see at the basal level of the epidermis, lots of keratinocys, same as in healthy but in a higher proportion. What you start seeing at the very top now is hip1 alpha. And so this is a hyperactivation of hip 1 alpha in psoriasis lesions at the topmost layer of the epi. OK, so I'll digress a little bit. To discuss the physiology of a boo boo. What happens when your kneesce gets into a bike accident and has a wound on that day? What, how do you resolve that? The answer is depending, depends on who you ask. If you ask my niece, she'll tell you you put a million dollars the Explorer band-aids. You keep them there for about a week and that boo boo is resolved. That's her no, no, um, a different approach is what we've been doing over the last couple of years, so. Um, should this group has discovered the physiology behind uh physiological repair. What happens in. Uh, the micro environment of a wound is that you have an acute hypoxic event, right? You have no systemic circulation, right? You break that, you, uh, uh, induce local proliferation of gamma delta T cells which are known to produce high levels of interleukin 17. When that happens, The epithelial cells at the wounded have IL-17 receptors. When you engage those receptors, there's a downstream, um, pathway that gets activated phosphorization of, uh, IRC and MTOR that now increases, uh, the translocation of hip 1 alpha into the nucleus and new transcripts and new protein now emerge from there and leads to re-epitelization of the wound. So this immune epithelial cross that was unknown and it's important for a variety of reasons, but one of the reasons it may be important, uh, relates to the hypothesis that we now pose. Posed together and that is maybe psoriasis is an over healing. What if it's true that in the acute wood micro environment you have some increment in gamma delta T cells with higher levels of IL-17 that now activates epithelial cells and increases C1 alpha to lead to a healing process that has a biological break in psoriasis we think. Uh, the same process, but in an exaggerated manner happens are way more capbata T cells with higher levels of 17 and that leads to he1 alpha overexpression and an over healing process that never stops. So if that's the case We reason, and this is Isita uh Subudi, who's a MD PhD student in, uh, in the lab. Um, she asked the question, what happens if you now block topically, uh, hip one alpha with an inhibitor. So for that, um, she came up with one of the most common psoriasis, model for psoriasis. That's Iiquimo and if you look at what happens in the healthy mice, uh, obviously you expose a healthy mice skin to a vehicle. Nothing happens even if you throw in a cream with hip alpha inhibition, nothing really happens because there was no pathology to begin with. But if you look at the immiquimo induced psoriatic like skin, you start noticing all of these green dots again, so you recapitulate hep1 alpha over expression in the in the animal model and if you treat it with the hep1 alpha inhibitor, then the epidermal thickness goes down and the hep one alpha. Um, expression is decrease. Now that's great. These are mice we cure psoriasis and a mouse, big deal. The next step is much more clinically relevant so now you take skin biopsies for patients. And you bisect them and you put them into a dish for 24 hours in culture and the conditions are as follows you either keep half of the biopsy in a vehicle and the other half goes into a dish with a H1 alpha inhibitor or standard care, which is beta methhasone in this case, and after 24 hours you perform RNA sequencing to understand what. Capability is inherent in X vivo uh from this HI1 alpha inhibitor compared to the standard of care and what you can see is that it is significantly more effective to have this H HIF1 alpha inhibition uh in the X vivo skin uh biopsy than it is. In those uh biopsies that get exposed to standard of care, so the downregulation of betamethasone is about 100 genes. In the case of HIP1 alpha inhibition is about 3000 genes. So it's much more robust compared to standard of care. What happens in real life. So now you can go into publicly available data sets. This is a clinical trial for psychoquiumab that had skin biopsies. And what you see here is that uh those participants that got placebo did not have a decrease in this gene signature. That we see that included hip one alpha, but those that actually received the coquinoma even at week 1 you saw this signature being done regulated gets better at the end of the study, week 12 you can discern who amongst those patients were actually responders to seoquinoma based on whether or not their gene signature or the differential gene expression went down or remained the same. So another one stay tuned. This is remarkable because now we go from bench to bedside and hopefully back to some form of uh therapeutics in the near future. OK, so synovial players, I'll uh give you a little bit of a um flavor of what's happening in the field. Um, Oh, this is a little bit, um, technology driven we're doing this so those of you who do uh ultrasound guided biopsies that's a little bit in the past I know I'm offending a lot of people right now, but what's happening right now is that we have nano arthroscopy and now and this is in the context of the um campaign network, uh, we have a single use chip on tip nanoscope system. What is it? A combined a 1 millimeter in diameter uh imaging sensor with a 2 millimeter nano arthroscopy instrumentation. It's pretty cool. So so why is it irrelevant because you can, uh, perform this in an a dramatic fashion. It is quite precise and I'll show you a video, a video in a in a second. And it's under local anesthesia, so you don't have to take patients to the OR and you can get the biopsy that you want for research purposes. So this is courtesy of late just we, our collaborator, and it looks like this patients in the, um, does it work? It doesn't work video. Didn't work, OK. Ha ha. All right, no video, but believe me that, oh, some are. Alright, I'm not gonna be labor the point. Alright, so the point of the video was to show you that we can be very precise, patient is in the. Be there it is. Thank you, AV folks um. So patients awake, local anesthesia you insert a camera, then you insert the instrumentation and you choose the tissue of choice that you want. You, you don't miss unlike ultrasound guided biopsies you go straight to where the inflamed tissue is you're gonna do research. You don't wanna subject our patients to. You know, oops, we missed it. Can we do it again? Um, so more to come, but part of the reason for what we wanna do this is to try and understand whether or not psoriatic arthritis synovial environment is any. Different from rheumatoid arthritis, we've heard from Dana that the uh fibroblast fibroblasts are very important. There's been a lot of work by the AMP network over the last 7 or 8 years showing that effective immune cells are really, uh, remarkably different than what we thought they were, including cells such as CD8 which we thought they were not part of the. Uh, discussion in terms of physopathology. This was done, uh, a year ago. They compared the presence of stromal cells, fibroblast thing I was talking about. Some circulating fibroblast, but if you look into the tissue, what you see is a very different phenotype in rheumatoid synovial tissue, you see an enrichment for double positive, you know, uh, fibroblast activation, protein positive type one protein fibroblast which have an immune effect or, uh, a phenotype. Look at psoriatic arthritis. You don't have this type of positives. You have only the, uh, the positive fibroblasts which are more of a destructive, uh, phenotype which essentially impacts the way we understand, uh, pathological mechanisms that are different between rheumatoid and and PSA, and then it opens up new opportunities to target these differential, uh, uh, fibroblasts at the site of pathology. This is Gchette's data. It's preliminary but it's very cool. So what did he do? He asked the question of if fibroblasts are important in the progression of uh psoriatic arthritis, then it follows that activation of uh fibroblasts in the joint. Should proceed clinically evident arthritis in a population a raise for psoriasis, OK, same, same principle. So he they took uh patients with psoriasis in this case with arthralgia but no other uh CASPA criteria for PSA. And they injected this puppy, uh, uh, radio tracer to look in vivo and in a noninvasive fashion for the visualization of fibroblast activity both at baseline and as a follow up, um, and what he is finding and I just spoke to him and this is ongoing and apparently it is true and true that all patients with synoviente C uh uptake. Progress eventually those threats and only one of those that had a negative uptake. At baseline ended up progressing to. Psoriatic arthritis, so you know it's important. It may be that this is the one biomarker that we were in search for. It may be that it's not ultrasound, maybe that we need, uh, a more functional imaging, uh, modality to understand, uh, progression in at risk psoriasis patients, OK. OK, PSA and the gut. I can't escape the gut. I'll give you. Two stories, maybe 3, in the gut quickly, right, uh, uh, clinically relevant, how many patients with spondyloarthritis are walking down. The street with IBD and they don't know it right undiagnosed IBD in a population of spondy arthritis. This is the ISA study. It's about 600 patients, half of them are PSA, half of them are axial sponid arthritis. All of them biologic, naive, and of steroids for at least 30 days. What is it that they did here, they lowered the threshold for what they consider positivity. In the use of calprotecting, so if the usual threshold for calling a positive is 160 mcg per gram, they lower it to a half, and they said if you have a higher level, then you get a colonoscopy. If a colonoscopy is normal, you get a capsule study and here's what they found about a third of patients walking down the street without knowing that they had IBD to begin with at an elevated um. Can protecting them. Here's how it went. A third of them had a higher level of carrotecting. Most of them got colonoscopies performed. A third of them, those that had a colonoscopy, had some abnormalities, and a third of those actually had a confirmed diagnosis of IV. So the take home is that. Yes, we know there are about 4 to 5% of people that are walking down the street, not knowing that they have IBD. They have it, it has clinical implications. I'm not gonna go into the details, but. It's still an unmet need. But it's also true that the fecal cut protecting as a biomarker has a quite questionable performance, right? You can't do this based solely on FIAA protecting those, even if you're lower, you're not gonna scope a third of your patients, right? I mean, yes, maybe when they're 45 and older, but not when they're younger. Number 12, they provided us with stool samples only in psoriatic arthritis. So we asked the question, is there anything better than coprotecting, uh, to try and discern IBD in this population, uh, reminder this is only the PSA cohort, so the um. Prevalence of IBD was lower, about 3% or less. So with that in mind, what we did is shotgun sequencing this is with Alba, uh, uh, Boys in the Jose Clemente lab and, uh, uh, Rebecca Black that's done quite a bit of work here. So we asked the question, are there any microbes in the population that actually has a diagnosed IBD ultimately that can differentiate from those that didn't? And in fact there are several, not an impressive amount, but at least 10 of them. Then we ask the question, you know, how is it true that some patients with no IBD have high levels of car protecting? The answer is yes, and the opposite is also true. Patients with IBD had low levels of car protecting. So it's not great again using car protecting alone we're working on the fact that it may very well be that you can combine some of these microbes that are um. Characteristic of IBD in the context of sponge so it's to add it to a fecal protecting so we can now uh uh better predict who needs a colonoscopy #1 and #2 who has an IBD to begin with, OK. That's diagnostics. Here is, uh, therapeutics. OK, many months ago we published this, the idea that if you, uh, enroll patients with psoria psoriatic arthritis at disease onset, you have not only uh microbiome gut diversity that it's significantly lower than controls but you also have. Uh, lower level of beneficial commensals in the gut. Most importantly, at least to us is the fact that, um, uh, protective fatty acids were also decreased in patients, particularly patients with psoriatic arthritis. That's not. Um Surprising, I think I showed this slide multiple times. Why? Because short stream fatty acids are incredibly relevant for gut and systemic immune health. How does that work? to consume. Dietary fibers can only metabolize those those uh uh fibers into short chain fatty acids in the presence of certain gut microbes. So in this case microbes act as a bioreactor to take Cheerios from the diet. Fiber and transform them into different types of short chain fatty. Why short chain fatty acids relevant for health? It's been shown for a decade now that regulatory T cells and many other cells in this in the periphery have receptors for this short chain fatty acid GPR 41, GPR 43. When that happens and you engage these cells and this has been shown, you can also suppress downstream pro-inflammatory. This is in this case uh was uh inflammatory bowel. In collaboration with the uh uh. Uh, Sergei Koronov, we generated this mouse model where you conditionally knock in stat 3 into CD4 cells to explain, they get transformed into TH17 cells and they produce tons of interleukin 17. That's what these mice, it's all about. You see more psoriasis, uh, uh, clinically, if you will, you see histological, uh, uh, presence of all the changes that you would see in psoriasis and, and you see. That this is a TH 17 IL-17 driven uh mode. OK. So that's why what happens in the musculoskeletal domain, uh, these animals get a little bit of erosive arthritis. I don't wanna exaggerate the phenotype, but the most striking one I'm gonna go back to. Bruisesto is that we see a very severe osteoporotic uh phenotype you see in the trabecular bone low density you see thinning of the cortical bone and we see a little bit of spondyloarthritis, not as dramatic. So then recently what we did is we look back at these uh animals and we asked the question what happens in the osteoclast precursors? So what we saw to our surprise is that the receptors for short chain fatiasis and the osteoplast precursors were up regulated, particularly GPR 41. What did we do? um. We got bashed. We gave these mice short chain fatty acids in the drinking water, and what we saw is that at least in vitro, short chain fatty acid inhibits differentiation of osteoplast number one. And in vivo what we saw is a very dramatic recovery of the osteoporosis phenotype, uh, as you can see here again. We believe it's due to the inhibition of osteo clustergenesis whether or not we can recapitulate this in humans, meaning so the obvious answer is increase the um dietary fiber uh we don't know. OK, I'll skip this and I'll finish with. Some barriers were not great. I mean, I hear the rheumatoid world and everything is easy and and you'll cues rheuma uh we're not there, OK. Um, why are we not there? Most patients don't achieve either remission or minimal disease activities. True in Scandinavia, 20% of people at their first biologic. Uh, gets into remission. 25% of people in Canada gets into minimal disease activity. Most of them fail due to residual pain, right? We've done this at NYU. We asked the question what the term means. The Uh, uh, fact that certain patients continue to have joint pain without evidence of inflammation, right? So, about half of our patients is worked by Rebecca, here I had half of our patients are in full remission. 25% of our patients are still active, and another 25% have persistent joint pain. They have no swollen joint pain, no swollen joints, and they still have tendering charges. And, and the fact is that they have higher levels of depression. They have high levels of anxiety and higher rapid 3 scores. What do we do with that? Or maybe if it's not inflammatory maybe it's central uh and this is uh Rebecca's new grant the idea of you can put these uh patients into a an an MRI scanner and look at functional brain MRI and try to discern whether or not some of those pain factors are related to central localization and in fact that seems to be true. Uh, there's an ongoing study, but the early data suggests that the higher the connectivity in certain areas of the brain, the higher. The pain in these particular questions so maybe it's not only anti-inflammatory approaches maybe it is an effective pain mitigating therapy. Meaning cognitive behavioral therapy or some others that needs to be used as a coadtruant for PSA. We can take known drugs and uh change the uh the uh way we uh give them uh to our patients. So now it's akinoma. Now the IV formulation. So the thought being that if you bypass the sub Q and the pharmacokinetics and dynamics, then you get better. The answer is like it really didn't. The IV formulation of a knoma has been approved. FDA approved. But if you look at the outcomes, it hasn't been any. Different compared to the sub Q formulation. We're doing combination studies. We finished with, uh, affinity, uh, that's uh a Johnsen driven study combining Goel QA versus Golimumab plus Gliumab versus Gosse QA done. We'll see what the data will show hopefully uh by ACR maybe we'll get some of the data and finally perhaps another solution is what Dana say. We got a grant to look at this. Can we monitor. Uh, response to biologic therapies in PSA by micro sampling a little different from what Dana is doing. Uh, and adding digital predictors so that you can characterize very early on who's going to turn out to be responder and non-responder based on uh RNAC and digital features and with that I'll finished uh summarizing NextGen tissue Omics is the name of the game. Uh, improving synovial NSCL outcomes has been really elusive. We, we don't know why 50% of patients at most respond and the others don't. Um, and then we need new approaches as discussed residual pain, modulation of the microbiome, combination demos and precision medicine stratification, and with that I'll thank everyone in the lab who's done a lot of amazing work and every single one of my collaborators. And I'll stop here before Sonya uh relinquishes her motherhood, um. Thank you. Thank you Jose. That was wonderful talk and you gave us lots of thought provoking ideas, so we have time for 1 or 2 questions. Hey, hey, two comments and a question. Comment one, I applaud your, uh, linguistic linguistic use of, uh, alliteration and semantic satiation in your title. Number 2, just to comment about adipose tissue, you touched on it on one of your terrific cartoons. Uh, fat tissue is known to have pro-inflammatory effects, downstream effects, crosstalk with bone, for example, uh, leptins, adipokines, drives liver, CRP. So my question is, um, now with the you know kind of increasingly ubiquitous use of some of the fat, you know, weight loss drugs, GLP ones, etc. has there been any thought about whether those drugs would have effects on psoriasis, psoriatic arthritis, IBD, etc. No, I have the answer. Go on. That was my question. Oh, OK. So I have the answer because we've been talking I don't have the answer. I, I, I think we have the our known and knows that's the knowledge gap. I was looking at Alexis at the very end of the. Room we're trying to do that isn't it true? So we've known this that if you lose 5% of your body mass index, you have less psoriasis, you have less need for biologics and you do better psoriatic arthritis-wise. So it follows that if you use Osamic, that's the only name I know, sorry, CME, um. Then you could do better. So we're trying to do a study with Alexis and Lehi and others to try and it's an easy one. How about now. The next question is, well, like we're in New York we have all these, you know, uh, very thin people that don't have obesity or but but nothing you're gonna do a sameic anyway because it's a, it's a non. Uh, you know, it's an off target effect of authentic, but don't know, but it's in the making. Yes, I, I think at least he's going to study that, yeah, next. All right, you have a question. 00. It's a friendly question. um, so, so many of the bugs that you, uh, that you identified, uh, uh, as being. Uh, overgrowing in, uh, psoriatic, uh, uh, patients are similar to those that, that seem to overgrow in rheumatoid patients, um, uh, you would know this better than I do, so I guess my question is, is there, uh, is there, are there changes from. I, I guess on the host side that promote the growth of, uh, uh, of those, uh, bacteria and, you know, and we see them as evidence of, uh, or playing a pathogenic role in RA, but. It's the phenomenal question and the directionality question. I don't know the answer to that. I know that in mice that if you have germ-free animals, then there's no disease. Specific microbes go in triggers disease compared to other microbes. So that's that proof of principle. Same with periodontal disease. I mean, do we have pigeon G values in every single patient that we, uh, you know, obtain periodontal we don't. We, we looked at that just not there. Um, I don't know, part of it may be epiphenomena. I mean, the question is, is that a trigger, and once you trigger, you perpetrate the disease, you can't take it back. You give antibiotics to patients, tetracycline. You don't respond, right? Um, so a long answer to say. I don't know yet. Thank you. Published March 14, 2024 Created by Related Presenters Jose Scher, MD View full profile
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