Bridging the Lab and the Bedside: The Science Behind Severe Skin Reactions

0:00Hello and welcome to Peter Purls, the podcast from the pediatric dermatology research alliance. We are a vibrant research community pursuing a mission to create, inspire, and sustain research to prevent, treat, and cure childhood skin disease. Each week we bring you inspiring stories, research updates, and practical information to advance science that improves the lives of children with skin diseases and conditions. I'm Jen Dawson, host of Peter Purls, and Peter's Director of Educational Programs. I'm so glad you're here. In this episode, I sit down with Dr. Reed Oldenberg for an in-depth conversation about his path into dermatology, his passion for translational research, and his leadership of Peter's drugs and bugs focused study group. Dr. Oldenberg shares how early experiences from field research on rare infectious diseases in West Africa to complex immunology lab work

1:03shaped his clinician scientist career. Together, we explore the origins and purpose of the drugs and bugs focused study group, the importance of clearly defining conditions like rhyme and SJS and TEN, and the major ongoing research efforts aimed at improving diagnosis, treatment, and patient support for severe cutaneous adverse reactions. So let's jump in. Welcome to Peter Purls, Dr. Oldenberg. I am so excited to be speaking with you today. So let's start with a little bit of background about you. Tell me about your journey into dermatology and research. Yeah, thanks. Thanks so much for having me. It's so cool to finally be here, and I'm so glad that I've had a chance to work on some of the projects and report back to you. So yeah, thanks again. I'm Read Oldenberg. I'm an MDPhD, so I'm a clinician scientist, and I work at UC San Diego, the VA and at Rady hospitals. My breakdown currently is, is I do about 40% of my time in the clinic,

2:07and then I've always really liked research. So I'm spending as much time as I can in the lab, and doing about 60% of my time doing research. And a lot of the research has been very translational, because I've been focused just on getting high quality patient samples, understanding the inflammation and the immunology and immunopathic mechanisms of disease in these patients. And so yeah, I really do. It's kind of a jack of all trades right now, but I really do the biggest focus of my work is in the translational science space. And was research always the career goal for you, or is that something you discovered a passion for at some point in your training? Can you talk a little bit more about that? Yeah, I definitely always knew that I wanted to do basic science research, and I wasn't sure exactly in the beginning if I wanted to do medicine, but once I got into research, I was working in a couple different labs as a research assistant. And once I started to be in the lab, I realized how much I wanted to work with people and actually see patients. And I really felt like the most

3:11interesting research really comes from things that are happening in real people, because you know, patients obviously with an inflammatory disease, there's so much to be understood about the particular patient, but then there's a huge thing that there's just so much to understand about the disease in general. And with all of the new science that we have, we have new techniques that can understand disease processes, but then we also have new drugs that are being, you know, marketed and approved so that we can combine techniques with medications to really make patients' lives better. And I think my personal journey really started with, I was doing a summer internship at the Pasteur Institute in Paris, and I got involved in a project that to me was very translational where we actually, I was sent in the field in West Africa and Ghana to study a rare dermatologic infectious disease called Borule ulcer that is caused by an actual microbacteria. And I just felt like it was so fun to be there in person meeting the patients, and it was such an understudied disease at the time that it was just to me, it was so exciting to like actually

4:16talk to patients, go visit the towns where maybe they were getting infected with the pathogen, and then actually you collect samples from the patients, get clinical data from them. So I felt like it was a very alive research project that made me really, you know, enjoy the whole process, and like it was so social, it was so fun. So that was really, I think, my initial introduction to translational research. And then during that project in the lab, I was offered a PhD spot to continue research in microbacterial infections. So microbacteria caused, you know, cancer disease or formerly known as leprosy, they caused tuberculosis. And then I ended up doing a very rigorous or more strict PhD in understanding the host pathogen interactions of how microbacteria, how they alter immune function, and how they infect people in the first place. So it was like, it went from really the patient center thing into the labs. I followed that trajectory, which was pretty much how I started in the world of research. When it comes to drugs and bugs and

5:21the work that I've been now lucky enough to be a part of pedra and work on, when it comes to drug drugs and bugs, it really started once again with the patient again, where I was a dermatology resident, and I started seeing patients with your reactive infectious microcutaneous eruptions or rhyme, being an immunologist or being a sort of, you know, aspiring immunologist, I kept wondering, you know, what is actually going on in these patients, you know, what actually causes the blistering, and after talking with, you know, my mentors like, you know, Larry, I can feel I started to learn that there were so many more questions, and that's how I ended up meeting folks in pedra and how I really found a way into my current lab and current research set up where I work. All my goodness, thank you so much for sharing that background into what inspired you to be both in the lab and working with patients. This is just really cool. I had no idea about your story and your trip to Africa, that sounds amazing. So there's a lot that I want to go in on here, but let's first, let's kind of focus on the drugs and bugs piece because you did mention

6:24drugs and bugs, and that is what we call a research focused study group here at pedra. For those listeners who are unfamiliar, pedra sort of brackets their research in these different buckets of disease-focused areas. So drugs and bugs is one of our newer focused study groups. So if you could just give our listeners like a quick definition of what that group is, I know you mentioned rhyme, but let's kind of dive into what that group is, and then we don't talk about what it does. Right, so in my understanding of the history of drugs and bugs because it predates me, is that it really was related in the beginning to understanding some of the severe cutaneous adverse reactions and really focused on pediatric dermatology patients. So drugs and bugs, I think, started off early with just trying to define some of the terms, and I think the term rhyme or reactive infectious meocuputaneous eruption essentially was in the early stages of the FST before it really formally existed. And so essentially drugs and bugs was designed to

7:28answer everything that is drugs and bugs. So of course, the major focus would be the scary things in pediatric dermatology, which are the severe cutaneous adverse reactions. So pediatric dermatology, you know, having fewer expert clinicians in the community and then having, you know, less, less research previously in the adult world, I think, for the FSG, it was really dedicated to bringing together the brightest minds in North America and internationally and really studying everything that is drugs and bugs. But of course, historically, it has been more focused on the pathogen triggered meococutaneous eruptions like rhyme. And then, of course, Stephen Johnson syndrome, toxic epidermal necrolasis, and some of these really rare and severe diseases. But in reality, drugs and bugs would cover anything that is drugs or bugs. So of course, you know, there have been other projects on, you know, tinia or ringworm. There have been projects

8:29on medications and other allergies. So it really is a wide basket. And now, you know, one of the other medications that, of course, our group is now studying our jack inhibitors and how that affects people. So really, it's a very broad FSG that covers a lot of different topics. But historically, and I think our current projects really are majorly focused on the severe cutaneous adverse reactions. And what was it about severe cutaneous adverse reactions that really attracted you and that you wanted to learn more about? I think that by definition, they're severe and they're very terrible. So I think when you're as a dermatologist, you know, these are some of the scariest things that we see in clinic or in the hospital. And these are patients that are really that are really suffering a lot. So I think just for immediately, of course, in training and then in the early years after training, it's a very easy thing to be to want to to help patients with because the patients present so dramatically, they're so sick. And then there's also so many major questions in understanding these diseases, both clinically and from a basic science perspective,

9:34that it makes it in a lot of ways. It makes it very easy to be attracted to because it's like, there's so much potential to help people, essentially. Yeah, I can definitely see why you and your colleagues who are studying these severe cutaneous adverse reactions are so passionate about it. And now you are leading the charge as the chair of this group. So give me some details and some insider information into what the group is working on, what projects are upcoming. If you need any collaborators, I just want to know what's going on in the group. Right. And there's a lot of ongoing projects and it's always a challenge because everyone has their full clinical schedule to work with. So our projects have a little bit of, it's almost like a dinosaur walking. It takes time to make progress, but we are moving. We have momentum and everything happens in time. And we have a lot of ongoing projects in terms of discussing ways to help. I'm going to share with you an electronic

10:38system that we have where we can actually track different projects. So I'll share that with you. And you can put the link in the bio as well because we're looking for ways to match people and we have chat rooms and we have ways that we can set deadlines. So I'll definitely share that with you. The group is, you know, there's a major focus, of course, as you know, in in Pedro to really bring together the minds that we have and develop consensus, you know, and it can be consensus via, you know, can we come up with consensus guidelines to better treat, to diagnose? And of course, historically, this FSG has really been dedicated to rhyme because that's where a lot of major questions still exist. So the group at large, the FSG, many of the individual members of our group are working on developing consensus guidelines. So one ongoing publication will be dedicated to to just bringing clinicians together and providing a nice roadmap for those that are maybe less expert and those that are residents that are trying to learn more about rhyme and to revise

11:41the diagnostic criteria. So there's definitely a focus to improve our outward communication on what rhyme is. And then there is an ongoing consensus really bringing the actual, the best minds of rhyme together and then identifying good treatment algorithms. So I think that's a really nice upcoming publication that I would anticipate we would be seen in the next one to two years. And I think that will be really helpful because really it's, I think it's really interesting talking to, you know, the great minds of rhyme like, you know, Ivan Chu and Michelle Rameen. There are so many things that are very intuitive to them because they have a high volume of patients that they take care of. And what we really want to do is we want to try and and transmit some of these these key knowledge points between the key opinion leaders and give it to the and give it to the public so that the or just residents and and maybe younger faculty members so that they can take this and understand some of these intuitive points and operationalize them and actually say, okay, how do I measure this? How do I understand if a patient's progressing?

12:43How do I decide to go with therapy? So I think those are, that's going to be a major. I think one of our capstone projects in the next one to two years that I'm very excited about. Well, those two projects in and of themselves sound like a massive undertaking and something that this space really, really needs, especially when you're talking about educating other providers who are going to be seeing this in their ERs or in their clinical practice. What else is going on in the group? So one of the projects that we have that's ongoing that's that's that I'm not directly involved in that I'm very excited about is Ivan Chu, Michelle Rameen and Beth Role, I think there's back in 2020 they launched a project to study rhyme patients and then do genetic sequencing of them and their parents. So the idea here is really to look for genetics susceptibility markers because maybe there's something in their actual genetic in the patient's actual genetic makeup that results in them developing rhyme. Maybe for example, when they encounter a certain pathogen like Michael Plasma pneumonia is a very common trigger for rhyme. Maybe when they encounter

13:46that there's something in their genetic makeup whether it be something like a cytokine or a protein recognition molecule that causes them to develop these things. So I'm very looking forward to they have a large team of collaborators that I can't name them all but they have folks that are doing their informatics and I'm looking forward to understanding to see if, you know, is there a genetic marker that can help us predict rhyme? But I think also it's going to be really interesting to put these genetic markers into the context of inflammation and understand, you know, maybe it's going to help us really understand what inflammatory pathways are dysregulating in these patients as well. So that's a really fun project that I'm looking forward to seeing results for. We also have a lot of other clinical research projects. So, you know, Harper Price is doing work on survey work and just getting once again bringing our FSG talent together and understanding what some of the barriers diagnostic needs are treatment and management needs are for pediatric Stephen Johnson's or

14:46toxic epidermal neck or lysis. So, so SGS and TN for those of our listeners that are not as familiar with these terms. These are our drug triggered severe trutaneous adverse reactions that do resemble rhyme. So, so the drug triggered ones will cause blistering of the mucous membranes and the skin and can be very life-threatening and very scary and they're triggered by medications. But what's really important for us to evaluate from a clinical perspective, especially in pediatric patients, is how are providers using different therapies to treat the immune system and then how are we doing the basics like wound care? And the room temperature, how are we actually doing? So really these minor details because really the importance is really in this detailed multidisciplinary care. So, so Harper Price is going to bring together some some ideas from from all over our community to really understand how how these differences exist in different centers so that we can we can learn from each other. So, that's another another really interesting clinical

15:48project. I definitely also want to highlight the work from Fiona Lynch, who is is one of our liaisons who we're hoping to bring into the leadership of this FSG in the future if she's if she's able to because she she may be recruited somewhere else. But if she's if she's able to we would love to recruit her and she's done a lot of work in terms of community engagement. So, you know, reactive infectious mucocutaneous eruptions, there essentially, you know, these pathogen triggered so people get walking pneumonia and then about a week later they develop these horrible blisters of their mouth and eyes and can get hospitalized for, you know, for weeks at a time because they're unable to even eat and this this affects, you know, children and it can happen over and over again. So, some patients will get it, you know, once a year or multiple times and it's extremely disruptive for patients, you know, they they lose a lot of weight. They can't do sports and it's a terrible disease. So, one thing that Fiona is doing is she's working to develop patient centered resources. So, how do we have a patient, a patient centered resource, you know, how do we describe what rhyme is

16:54for folks that are affected by rhyme? How do we put it into terminology that that is easy to understand for, you know, a lot of our patients are 12, 13, 14 years old. So, we're going to work in Fiona's doing some excellent work to understand, you know, different ways of conveying information to different age groups. I'm looking forward to see some of those patient facing resources because we currently have have a lack of those. She's also coordinating with Ivan Schum, she'll remain to help find patients for the genetic study. And then she is doing retrospective studies, which basically means look at all the patients that had rhyme at a center and then look back at how they did what were the triggers, what was the treatment that was used, how did the patients actually do? So, she's putting together a really nice study looking back through records at her hospital and I'm looking forward to seeing publication from her since she has the manuscripts is currently in writing there. So, I think, you know, she's been such a fun

17:55a fun member of our of our group that's been very dynamics that we're lucky to to have her input as well. And then we're also another thing we're doing is we're coordinating with another and this is one thing that we're always trying to do is talk to our how do we talk to our FSG colleagues, you know, because we have all these other FSG and there's a lot of overlapping interests and one of the recent overlapping interests that we have is Jack inhibitors are now, of course, these are systemic small molecule inhibitors that are being used to inhibit inflammation that is that is and these these medications are really helping patients who have atopic dermatitis or really bad eczema. And then it's also helping one of our non scarring hair loss disorders, alopecia areodas. So, so a lot of different patients and varying age groups are now on Jack inhibitors and we're working with an ongoing study to understand and see if Jack inhibitors are affecting certain patient outcomes, particularly their growth and how they're doing overall because, of course, you know, Jack inhibitors are a newer medication and so we're doing a lot of work with others to improve

18:59the pharmacovigilance of these medications. Oh my gosh, that is a lot happening in this focus study group. I am thrilled to see so much wonderful work coming together, especially that piece about developing content that's appropriate for different age levels of patients. That is so important. So, that's a pretty comprehensive overview of what the group is doing and if it's okay with you, I just want to pause here on the research portion because some information just finally jelled for me about the work that Drugs and Bugs is actually doing and I just want to go off on a little bit of a tangent here. So bear with me and listeners, I promise it'll be worth it. We back almost three years ago in 2023, I recorded a podcast with Dr. Michelle Rameen, Dr. Erin Mathis and Dr. Yvonne Chu where we were really talking about the differences between Rime, SJS and TEN and really kind of why the naming of these conditions matters and you really helped crystallize

20:06for me that you know, Rime is triggered by a pathogen where SJS TEN is triggered by medication or a treatment. That's not something that I think was really clear in my head, but now it is. So, I want to talk to you a little bit about like how have we evolved since just 2023 when we were talking about this sort of being a jumbled up mess and why is it important to have these specific definitions for these conditions? Oh yeah, completely. And I think this is where you know, the naming of diseases and identifying things is so important. And if I was this discussion and medicine about lumpers and splitters, the reason I think that the philosophical reason for splitting and for actually breaking down these diagnoses is because if the trigger, if the cause is different, then the actual inflammation and the actual problem that the patient is facing could be also

21:07different. So just because things look similar does not actually mean that the trigger is the same exact thing. And so it's actually pretty interesting because some patients with really bad, when they have really bad flares of lupus, their reaction can actually have some overlapping features with what we see in rhyme or ss and tn. So I really do think that of course, you know, you do have to be careful with creating all these different names because you don't want to confuse the audience and you don't want to confuse, you know, you don't want to confuse people who may not see these diagnoses frequently. I agree with the work done by other FSG members in that you really want to understand what is the trigger so that we can actually direct a workup to properly diagnose the patients. And then you do want to be able to, you know, have a clear diagnosis of pathogen triggered versus drug triggered because now we're starting to see that the pathogen triggered or rhyme cases, though the rhyme cases actually have a different clinical course, they tend to have

22:08less skin involvement. They tend to more be younger and have more eye involvement. And then they also, you want to have the appropriate diagnosis and understand rhyme because then you're going to look for that pathogen trigger, which in the case of Michael Plasma, you can direct antimicrobial therapy to treat that. And a lot of patients, you know, will have actual, you know, they'll have chest x-ray findings where they do have signs of atypical pneumonia. So I really do agree with the work done by former, you know, by former really important publications about actually splitting this. And I think this is where we're lucky to have a community like Pedro because by bringing our resources together, we're able to have publications with consensus that means that these diagnostic terms will actually get out of North America and we'll get to the rest of the world because when you explain pathogen triggered, you know, rhyme to people in other countries, they may not know that term. So sometimes you actually have to say pathogen triggered as gestine. And so your confusion around the idea and it's actually very, it's not even really a confusion.

23:12It's more just we don't have consistency, you know, internationally in terms of what the nomenclature really is. And so I think, you know, just by reaping these publications, it's really valuable. But I think even just putting a name rhyme on this, it was so valuable because it allows, you know, funding agencies like the NIH and it allows for more directed research to understand some of these questions. And so the mechanism that why does Michael Plasma pneumonia, why does it cause mucocutaneous eruptions? The mechanism has been unknown and the first cases of this have been described over a hundred years ago. So it just really goes to show that when you name something and you start to split it and really have a clear diagnostic term, it really helps. And of course, the obvious thing is that when you have a clear diagnostic term, it allows you to study individualized and molecular based therapies for that specific thing. Because as a patient, you don't want to be the one size fits all you, everyone is special.

24:16And you want the treatment that works for you. So of course, by having more individualized diagnostic and more precision in our diagnosis, it allows you to have a more precise treatment as well. That was so helpful. Thank you for allowing me that tangent. But it really illustrates why this work is so important. So let's use this time to shift into our conversation about some of the projects that you yourself are specifically working on. So I know you and several others all worked together on a recent publication that appeared in JCI Insight back in November that was supported by a 2020 PDR research grant. And the title of that project was dual dysregulation of TNF-IFN signaling and classical monocytes are implicated in reactive infectious mucocutaneous eruptions. And then you also published an abstract at the PDR 2020-24 conference titled

25:16Disciphering the immunopathogenesis of reactive infectious mucocutaneous eruption. So talk a little bit more about those projects, possibly have their linked and what you're learning. Right. And the thanks for yeah, thanks for offering the opportunity to talk about this research, because of course it's it's very exciting. And I think it's a really exciting time and it's really a good continuation on this idea of now that we have this diagnostic term. How do we how can we break it apart and how can we actually understand the pathomechanisms of what is actually happening in these patients. And the two projects are really linked because they're really just one long continuous journey. And as our research listeners know, it's such a journey. These projects always take longer. Yeah. And essentially it's collaborative in a sense where we have been working collectively with our entire pediatric dermatology faculty here at Rady Children's Hospital. And we've been working with all the residents and have been working with two different basic science labs and have also

26:21worked with collaborators that do bioinformatics at the Lehoi Institute for Immunology. So we have a pretty large group of people. And essentially what we're doing is we we're collecting samples from active rhyme patients. So when they actually are experiencing the inflammatory effects of rhyme. And we are taking their samples. We're taking their blood. And when we can, if it's if it's possible, we get blister fluid from the patients. And then what we do is we we do what we call single cell RNA sequencing, which essentially means we take each individual cell from their blood or from their blister fluid. And we put them into little microchips essentially. And then we sequence all of the RNA meaning the gene signature in each individual cell. And even with like 10,000 or 15,000 cells, you can get an unbelievable amount of information because now what you're doing is you're you're looking at not just all immune cells. You're looking at the monocytes, the T cells, the B cells. And

27:22then you can see what inflammatory pathways are upregulated in the patients. And it's very difficult research. So essentially of the hot the biggest challenge is actually getting the patients finding the patients in the emergency department early on. And then also finding them when they've recovered because what we do is we we get their sample while they're having active rhyme. And then and then we find them, you know, usually three months, six months later. And then we ask them for another sample so that we can compare their inflammation to when they're recovered. And this has been really valuable. And our first, you know, our first publication on this was a group of all comers with rhyme. So we found any patient that had rhyme. And then what we did is we took their serum and we sent it for cytokine analysis. And we looked at almost at he was 300 different cytokines. And we identified to see if there was an overlapping, you know, inflammatory signature. So like, you know, you have five different rhyme patients. Are they similar? Do they have the same

28:24inflammatory signaling? Because maybe they have different triggers. Maybe one had, you know, COVID was a trigger. One had adenovirus as a trigger. Another one had microplasma. And it's really interesting to actually look at this, this, this diverse group of patients with different triggers and see if there's actual overlapping inflammatory signaling. And this, this first initial report that we published, I think it was just two months ago now, was able to identify that there is a signature that we think links dysregulation of TNF, which is an important cytokine. And then also interferon signatures. So the TNF piece is very validating and important because currently one of the, the more accepted therapies for rhyme is a tanner stuff, which actually inhibits TNF alpha. So that TNF is, is, is an inflammatory cytokine. And, and we know extrapolating from the literature from SGS at TN, from the drug induced ones, we know that TNF is probably contributing to cell death,

29:29which is the, you know, of course, amicus membranes and the skin. And so we, we, we were able to validate that in the small series that, that there's dysregulation in these two things. It's, it's definitely a nice step. But I really think we have a ton more work to do. You know, the upcoming project now that we're doing is we've been collecting samples just of patients with microplasma pneumonia triggered rhyme. And the reason why we want to do that is because we really want to try and collect a very consolidated group of patients so that we can, we can further dig and do more of the transcriptomics. And so I'm very happy that, that Peter actually is supporting the next phase of this research. So I'm very lucky. And, and I just want to think, think, you know, Peter, of course, for, for funding the next, the next grant, which will will actually continue to do this work in these, these patient samples. Because now, of course, it's been four or five years since I've been collecting these samples. So now we have more samples that we can analyze. I'm wondering if you could comment or talk a little bit about the value of bringing in other

30:33specialties when you're working on projects like this. Like you mentioned, you're working with people in immunology. I see that Bob Ging is on your publication. So like, why is it important to bring other specialties to the table? It's, it's the, the, the potential of working interdisciplinary is really endless. And, and I think it comes from a lot of different angles. I mean, first of all, bringing people from other specialties is valuable because they have had similar questions in their field. So a good example is, is Hal Hoffman, who worked a lot with the, the periodic fever syndromes. There were so many questions that he had to answer. And so, just talking to someone like him, or talking to someone, you know, one of the Kawasaki disease experts and just saying, how did you start your work? How did you break this down? So there's just almost, you know, it's almost like an apprenticeship. It's just asking, you know, it's just asking people, well, well, how did you do it? And, and I think just through experience, through learning from others, and then, you know, rheumatology, for example, they have all these inflammatory

31:33markers. Bob Gain works in, in allergy and immunology. So, so there's this whole other experience in, you know, genes, inflammation, understanding rare diseases that comes with that. So essentially, by bringing together a large group of mentors and colleagues or whatever you want to call them, I'm able to, to get experience and learn from them directly from a pragmatic standpoint. So how did you do this? Oh, I did it this way. You know, having an IRB, you talk to the IRB. Then of course, you know, when it comes to some of the more nuts and bolts, you mentioned collaboration. So we have a key set of collaborators with bioinformatics. And so obviously, I'm not capable of, of sitting and, and, and, and, and doing all the, all the code. So, you know, the best thing that I can do is, is, from my clinical perspective, I have this perspective that I can offer. And the best thing that I'll do is, I'll sit next to the bottom from a tissue and, you know, we'll just talk, you know, over the course of a day. I'll look at the data and see what the

32:35inflammatory signaling is, is in real time, what, what the single cell RNA sequencing is showing. And then when I look at the data, I'm able to, through experience, and once again, talking to this, this collaborative network, I'm able to pick out the, the inflammatory markers that, that have a story behind them and actually make sense in the context of the patient. So the informatician is really, they're really able to, to dig deep. But then it comes to, you know, then it comes to us and it comes to me in this meeting setting. And then we're able to take everything in context and say, okay, well, what does this actually mean? Does this mean that we can use a different therapy for this? Can we analyze this? Can we analyze that? And it's really that back and forth that allows the work to go. But, but I mean, to answer your question, I mean, it's really just, there's so much benefit that you get from working with people and having, having the right people that share the motivation is so critical. Yeah, I really like how you put it, especially when you said that, you know, their questions probably aren't so different from the questions you're

33:38asking too. And so you have the chance to really work together. And then everybody brings their box of puzzle pieces. And then with everybody there, you can start putting the puzzle together. Yeah, absolutely. Yeah. And I definitely actually want to also give a shout out to Lori Broderick, who, who helped me contextualize things and understand inflammation and, and really break things down because she had a fantastic story looking at pan squadric morphia. And it was very similar. It was, it was, you know, these diseases have been understudied. And, and how do you break apart these available tools and how do you apply it to a problem? So, so yeah, I mean, completely, it's all about, it's all about that persistence, but it's all about, you know, working together. And then also just communicating clearly with, with team members. And, and just taking that time to, to, to just have patients, you know, everyone has a different skill set. So sometimes we almost need like, you know, a translator there to, to talk to each other. But, but we, we get through it. And it's really just the patience and the communication that brings, brings everything together. Yeah, it sounds like a really impressive group that you all have

34:43assembled and have going. And I know that your efforts will be rewarded certainly. We are coming to the end of our interview, which I am not happy about because I feel like there's so much more we could talk about. But I just wanted to close with a few final questions. I want to think about the future. I want to think about the future of the drugs and bugs group and of your career and your inspiration and your work and research. And where you see all of that in the next five years. Right. Yeah. Thanks for the question. It's been a such a fun discussion too. So far, I, you know, I think the, the, what will be really valuable for the FSG is, is really just continuing a lot of these projects. And I think, and I think we need to, with, and, you know, I won't be, I think, next year, I won't be president. So I think the next leadership, we're really going to have to continue to work to bring in other, other topics outside of rhyme because we've really been focused

35:44on rhyme and SGS. And then also, I didn't really mention dress syndrome, but I think there's a lot of opportunities in the world of dress syndrome. So I think, you know, the first thing we want to do is we want to continue the clinical work. We want to build more consensus. And then another thing that I think in rhyme that we have in our early phases and we're talking to different members is we're going to need to develop an activity score. Because for rhyme, it's really hard to tell in our expert clinicians certainly can. And we know they can. But it's very hard to tell for people with, with lower patient volume or residents is really hard to tell how active the patient actually is. Like, are they getting worse? Is there inflammation? How do we know that a treatment is not working? And so one thing, I'm currently in early discussion with with Ivan Xu and Michelle Rameen is we're going to try and develop a clinical activity score for rhyme. And I think an activity score will be really good because it's different from severity because activity is going to really help us in real

36:44time understand what's having with the patient. How do we, how do we proceed with treatment? So that's one thing I think is going to be valuable from the clinical perspective is an activity score. And severity scores also important as well. Rime does not have an ICD-10 code. So that's another thing that we should be working on the next once to years. There's no ICD-10 code for rhyme. And it's very hard to even identify cases. And as you know, you've talked to a lot of different clinical researchers that if you don't have good data, it's hard to actually get a good message. So I think we need to do a better job of talking to the the coders and engage with, you know, the responsible bodies like the CDC and actually have an ICD-10 code. So these are some of the short-term things. I mentioned the consensus guidelines and I think every, you know, every one to two to three years, we should probably be updating these consensus guidelines because rhyme is a very actively moving field. So in that sense, you know, I think that's going to be probably the midterm goals for Pedro as really continuing some of this work. Of course, the basic science. Thanks for giving me

37:45a chance to talk about some of the basic science work. I think the basic science work also in the midterm will be critical to continue. And I think applying for larger funds from from the NIH will really help answer some of these more mechanistic questions. The third thing is I think we we need to do more in understanding and doing group collective efforts to look back and see what's happening in the drug-induced SGS and TN. So Stephen Johnson's in toxic at the dermal necker license. And I think we need to do a better job of really looking at pediatric dermatology cases and looking retrospectively at outcomes and usage of different medications because now there's some new data from the in the adult literature. And it's a little bit complicated because some of those patients were on, you know, immunomodulatory therapies for cancer therapy. But there's new data to suggest that Jack and Heber is maybe very valuable for SGS and TN. And I think we need to start to we need to start to approach some of these questions that have been partially answered in the adult

38:49population and work to to understand in pediatrics what in in our pediatric population what is actually happening. So I think that's a major question. And then also, you know, just just bringing in more ideas, bringing in our newer members, our younger faculty, our resident residents into the group to just bring more project ideas about medications in general. You know, I think we we have more work to do in in, um, early carol dermatitis that may be triggered by medications. Some of these other drug drug reactions and there's definitely a lot of opportunity. So we definitely invite people to come to our sessions and engage with us online as well so that we can start to put put our heads together to answer more things. But yeah, good question. Um, more work is ongoing and more results to come, but we certainly have more work to do. I don't think it's I don't think it's ever gonna end. I think we have so much things to look into. You know, I think maybe I'll stop asking the the futures question because it always is more work, more things that we need to do. We have more questions that need

39:55answering. Um, but I think that the goals that you outlined there are really tremendous and highly achievable and I'm so thankful that you are in the network and and thinking about these things and getting others to think about them as well. Um, one thing that I'm just personally curious about when it comes to you is, is has there ever been like a publication or a study that you've come across that just totally flipped your thinking on something? Yeah, and I think this really links up to some of the conversations and and it's it's not going to surprise you in a lot of ways. But in 2020, there was a paper where there was a patient that had a different severe cutaneous adverse reaction that we didn't really cover in this discussion today called Dress Syndrome. And that patient was failing multiple therapies and had a very prolonged course and was on long-term systemic cortic historians like prednisone and long-term president as as many of our you know listeners know, it's not good for the body. It causes metabolic dysfunction. It's not good for bone density. It has increased risks of infection. So this patient was really suffering a lot

40:59and they did essentially, you know, what what I've been talking about and what really excites me is they did some of these transcriptomics approaches and they identified a the the inflammatory signature that was dysregulated in the patient and they ended up using an ex-feeble preparation meaning that they took the patient's cell out. They put it in a petri dish and then they treated it with a drug and the drug worked in the petri dish and then they actually, since the drug was FDA approved, they were able to use it off label of course with extensive, this was at the NIH by away. So of course with extensive, you know, discussion with the patient and making sure everything ethically was okay and they were using FDA-approved dosing, they were able to make the patient better using one of those small molecule jacken hebers. And so that's just to me that's just like very mind-boggling and that happened in 2020 and I think it was just like it really was that that sort of evidence of, you know, you can actually using these these somewhat that seem somewhat esoteric techniques. You can actually immediately turn around and and help out the patient. So that was

41:59that was probably that that was the first thing that came to my mind when you said that but there's so many studies that are that are landmark and you know groundbreaking as well. Well thank you for letting me put you on the spot with that question and I'm wondering for our listeners who are less familiar if you could just give a quick description of dress syndrome. Right so dress syndrome is is drug reaction with eosinophilia and systemic symptoms and this is another drug reaction. So typically, you know, common things that cause dress syndrome would be an antibiotic and so or or an anti epileptic something that's people are taking for seizures. So after a few weeks usually somewhere in the range of two to six maybe eight weeks patients would dress develop organ damage in a rash. So they get really get red. They get swelling of their head and neck and then in a lot of patients they develop some type of organ damage usually it's the liver or the kidneys and it's very scary and about five to ten percent but let's say five percent of patients it actually can be

43:00fatal. So it's really a scary thing in dermatology and we treat it by of course withdrawing the medication that caused it and then putting it on an an adverse reaction list. So never take it again. Some of the patients get a bracelet. Don't ever take it again just like SGS and TN don't take that medication again and then we treat it with immunomodulatory therapy with the most common one being prednisone and the patients they get interestingly enough they get very high eosinophil counts and we know that eosinophils are somewhat important because we if the biopsy is done in the skin or an organ like the heart or the liver they can see eosinophils there as well and we know that also lymphocytes such as T cells are really important as well. And so the combination of this this reaction with the medication and elevated T cells in the blood and then the tissue is causing skin but also organ damage. So it's a really scary disease in dermatology and it's another severe cutaneous adverse reaction. The human body and our immune system never ceases to amaze me.

44:01I mean it's really amazing how our immune system has evolved to really prevent us from getting infection but also the immune system is also preventing us from getting cancer. I heard recently that our immune system is maybe getting rid of one cancer a day in our body and I think it's it's really you know it's not just the immune system is not just doing infections so it's really amazing that our immune system is able in so many situations to not go completely haywire and cause a lot of inflammation and of course you know the disease is in dermatology that that we need to do better on is is really understand how the inflammation this this dysregulated inflammation that's supposed to do the right thing is not working for us in in certain disease states and and I think that's where it's it's really immunology so fascinating that way where you know that we need our immune system but sometimes it can do the wrong thing unfortunately. Yeah sometimes our immune systems just get carried away so thank goodness you and your colleagues are putting in so much time and effort to study this. Well thank you so much for joining me on Peter

45:02Pearls today Dr. Oldenberg it's always a pleasure talking with you I always learned so much I hope others in the network and those who are listening feel the same way. Thank you so much for joining me. Thank you so much yeah I was so fun to discuss with you and thanks for bringing such a fun fun you know discussion I really appreciate it. I'd like to take a moment to thank Pedro's corporate council members. Our gold level supporters are Eli Lilly and Sonofi and Regeneron pharmaceuticals. Our silver level supporters are Abvi, Abiona therapeutics, Arcutus biotherapeutics, Kiasee, Insight, Sonofi and UCB and our bronze level supporters are disc medicine, Jansen and Pfizer. We so appreciate their shared commitment to Pedro's mission as members of the Pedro corporate council. Thanks so much for listening to Peter Pearls. If you enjoyed this episode be sure to follow us or subscribe to the Peter Pearls podcast channel wherever you

46:06listen so you don't miss future conversations. To learn more about Pedro and our work to advance research in pediatric dermatology visit pedraresearch.org or follow us on social media at Pedro Research. Until next time keep listening learning and collaborating to make a difference for kids with skin disease.