 So, we are getting started, and we're getting started so that we can be on time. And it's my pleasure, after those wonderful ground-laying talks from this early session, we're going to have shorter talks to get a sense of what is going on around the world. Somebody asked the question about Europe. I think Ricardo asked the question, and Dr. Mückenhaupt from the University of Freiburg is going to talk to us about Europe. Thank you very much for this kind introduction, Mr. Chairman and colleagues. I'm happy to have the chance to talk about this topic today and present you a little bit of the European experience. That lasts, I would say, 25 years, but more for some of my colleagues 30, 40 years back, and I can only just briefly touch some of the issues and not go into too much detail. I thought, I'd start with what were our aims and what were the approaches that we took. The first question that we had in the 1980s and 90s was, what is the incidence, the frequency, demographic data? We started a case registry in Germany on a population-based level that is still in place, and then we also thought we should look at etiology, risk estimation, exposure times, and we performed two case-control studies using the cases of SGS and TNS, one group and healthy controls as the other and compared the exposure to drugs. We had a number of requirements such as the initiation, organization of a network, the definition of clinical entities, a clear diagnosis, what you call phenotypes, a systematic case ascertainment, standardized case validation done independently, still to date, and professional data management and statistical analysis. Now, you've seen these conditions that we were talking about in the various amount of skin detachment, and in the beginning, you do not necessarily know how far this will go. Now, case ascertainment is one of our major issues that I want to point out a little bit more in detail. It's trained investigator, healthcare professional, it can be a pharmacist, a physician, a study nurse, and each national center, because we are now operating on an international level, uses the same standardized questionnaire, the same remote data entry system to enter the data, and the interview is done directly with a patient. So we go and see the patient in the hospital where the patient is treated, and sometimes the patient is so sick, you have to use other sources to get back to the medication history, and sometimes the patient has been transferred several times, so you have to go back and make sure you capture everything completely. Now, after review of the cases, whether they were validated as a possible probable or definite, we came up with these incidence rates that were already mentioned before, and some colleagues were so kind to point out some of our data in the previous talks. We came up with a high mortality, and what we could also see that the more skin is detached and the older the patient is, the higher the mortality is, up to 70% no matter what we do in all these clinical settings. And we could also see with the population-based data that in terms of age, here's a period of seven years, you see these two columns, and they represent the patient's 65 and older, and they have the highest incidence. So that is something we have to consider because we are having more and more older populations in western countries. Now, the case control studies. The first one called SCAR study was mentioned already by Neil Scheer before, and we had a number of publications by two relevant ones like an overall drug risk paper and one on non-drug risk factors, and the other study was called EUROSCAR. They were both done in Europe, but the first one had the database in Boston, and the second one had the database and the data management in Europe as well. And one of the results here was that we definitely could make the difference between erythema-multiforma, which is usually induced by infections, 99.9%, I would say, mainly mycoplasma in children, more herpes in adults, and that can occur repeatedly. So there's a certain way of recurrence, what you usually do not have in SJSTN. That is mainly drug-induced, but not only, and we will come to that later. Now, the achievements we also had were identifying high-risk drugs, and these are the ones that can explain more than 60% of the cases, and they were seen in both studies. And one other thing was important, that we saw a certain timeframe. So it's not the first drug, it's not the repeated use, and sometimes it's confused, re-challenged and re-exposure to a drug. Usually the drug causing SJSTN is used for the first continuous period of time. So that means not the first tablet, but the first clinical or the treatment course, and usually this is one to four weeks as we had heard before. Now, other medications were shown to have a moderate risk, but not as high as the other one, and most important for all these drugs. No risk could be found, could be detected in both case-control studies to induce SJSTN. And this is a number of drugs that even have it in the label, at least in Europe, but we've never seen a case. Now, the early events are very important in the disease, and that was mentioned already before. So the beginning of drug use, let's say about 14 days before the first symptoms, that may be prodromal symptoms like fever, flu-like things for a day or two, and then the diagnosis is made, and then it takes a bit till the patient comes to the hospital, but the disease already takes its course, and then a few days later you have the maximal detachment. This was done on the validated euros car cases. Now, most often you have things like that. This is the medication history of a patient, and especially in those 30 or 35% of the patients who developed the disease during hospitalization for other conditions. And even if you mark here your index-day line and you certainly do not consider a drug once taken here, a long time before to be culprit, it's difficult. And we heard already about Alden that was developed in Europe, and that algorithm can help taking into account the relevant exposure times, the recent start of a drug, the notoriety, all based on these study results. Now, somebody, I think Elizabeth Phillips already mentioned the problem of protopathic bias in TN, and that's a huge problem because it causes a lot of lawsuits, especially in the United States, because a lot of people think there must be a drug. So if someone has taken for the first symptoms one of these medications, whether it has been tolerated before or not, whether it's the first time of use, there was a drug, that must be the cause. And we think this is an important error because very often this is not. Now, these are the typical examples to cure or to work against fever or secretolytics, and they cannot be blamed in our opinion from the data we have if they have been tolerated multiple times before, if they were taken very shortly before the first objective sign to treat the protromos. Now, there's some critical thoughts also because I mentioned that not all of the cases are drug-induced. In the two case control studies, we could see that about 55% of the patients had taken a highly suspected drug, that of the first list I showed with a high risk. Another 10% were added with patients that had a suspected drug, plus highly suspected. So 65% could be clearly explained by drugs. Now, we looked at the current study, the registrar study, and we applied the Alden algorithm to all of the cases because this is not a case control study anymore. And we could see that in 68% of the cases, we had a probable or very probable drug course. We had almost 20% of possible courses, but the others were unlikely or no drug at all. Now, based on those data, we could say about 68, 65, close to 70% are certainly drug-induced. But what about these other 30 or more percent of the cases where we cannot identify a drug? Some may be drug-induced, there's possible ones, others are certainly not. So we have a potential, but up to 30, 32% of the cases are often called idiopathic, meaning we do not know what it is. We have heard that there have been other courses identified, but they are very few. We know about acute GVHD, we know a few cases with microplasma, but microplasma usually is the cause in erythema multiforma. I've only seen very few cases with TN and microplasma, or other overdose issues. But what we see is infectious condition, all types of viruses, many of them are perhaps not tested at the right time or cannot be tested at all. And so there is a lot of work to do, and I think it's probably also genetically mediated. I just wanna briefly point out some pathomechanism work and outcome work we've done. We heard a lot about the HLA studies, and somebody asked before, was there anything done in Europe? Yes, we did more than just carbamazepine and allopurinol. We looked for the HLA types of all high-risk drugs, but there was no clear sign. The clearest we had with the Europeans in 55% positive for the HLA allele for allopurinol. We also did a print, a genome-wide association study, together with a research center in France, and here you see what we found the threshold for the chromosome six. And for the specialists of you, I don't want to go into detail with that. Now, one point I would like to mention is the cohort study. Our aim was, in the beginning of Registrar, to have at least 300 patients to follow for more than a year. And this is the data, those who consented to be part of the cohort, but you see a high number of deaths here, especially after a longer period of time. And when we looked at outcome and severity, we could see that the death rate is, of course, higher in those patients who had the more severe disease compared to the overlap and SJS. What was more striking was that the death rate increased in the time period up to a year, so from six weeks in the acute phase of the disease to one year. And we wondered why is that? And the acute phase we know is the amount of skin detachment severity. But in later stages, obviously underlying conditions are leading to death that perhaps may not have occurred without the reaction. Now, the follow-up data then, we had 170 patients to look at, acute stage a few weeks later, and I just want to point out the ocular sequelae, because they are really a problem. More than 70% of the patients were suffering from that. And here you see the problem that is difficult even in surgical terms. And if you ask the patient in terms of impact of sequelae on daily life, you see the eyes have a serious impact in that. So we are now in the state of analyzing a five-year follow-up questionnaire on these patients. And my last thing I would like to point out is the treatment because we were discussing that before. You see again this curve and we saw when is the treatment usually administered? When the disease is already kind of full blown, rather late, and you wonder why should it help? And we doubt that. And in the observational study we did, we could see somewhat a little bit of a beneficial effect for steroids and not the same in contrast for IVIG. So we did a systematic review now that was just published as an abstract and it's based on the Cochrane rules and we try to look what is published and do this analysis. Now to summarize, I think we have the word largest database with at least validated cases of SCAR in all these topics. There's a comprised knowledge and large expertise in Europe in different fields because there's experts in clinical setting and treatment, pharmacovigilance and pharmacogenetics. And I think besides some new findings, we were able to elucidate and exclude some of the old errors and hopefully can avoid them in the future. And I thank you for your attention. Thank you very much. Your talk generated lots of questions. I'm sure amongst a lot of people we have just a few minutes for questions. Yes. Mark Williams, guys here, just very quickly. How much suicide was there that accounted for late mortality? Pardon? Suicide, accounting for late mortality in the group? We have not observed that, I have to say. Maybe for some patients, we are not 100% sure. But there was no clear suicide that we are aware of, at least not in Germany and in France. Next question. Could you tell me what percentage of the cohort is pediatric defined as under 18? And could you elaborate on the delayed tooth growth that you showed flash by on one of the slides? Yeah. Please. Fortunately, the percentage of children is lower than that of adults. So under 18, maybe 25%. And the tooth growth was observed in two or three children. We had not been expecting that. And talking to specialists in the field, we assume that it's due to kind of a breakdown of the mucus glands of the mucosa. So the saliva is different. And that has an effect on that. Similar as it is sometimes with epidermal lusus pulosa. And could I ask, what, do you have any idea of how many people you missed? In other words, this is not necessarily reportable disease. So in terms of coming to prevalence. Yeah. How do you know what your catchment is? Yeah, that's a good point. Actually, for the incidence or prevalence data, we just used the data from Germany. And we compared them with a certain area of France around Paris, Île-de-France, where we think we capture all cases. In Germany, we have a system in place that we have contact to all the departments that are able to treat these patients, including pediatrics, burn units, and so forth. And we contact them on a regular basis to make sure we haven't missed anything. So this is like every three months. They get a letter and then we check after one year if those departments that are most likely to treat the patient, so intensive care, burn, and so forth, and dermatology, that we give them a call. And we kind of do that on a regular basis, which does not mean we do not miss anyone, but one thing is for sure that these people are all hospitalized. Thank you. Thank you very much. And there was a recent paper, I think, in November from Canada, sort of poo-pooing the idea of IVIG in favor of cyclosporine. How good it was, it was not a big paper, but there was a lot of enthusiasm at first because of that science paper. But I think some of that enthusiasm has been lost with regard to the IVIG. Thank you very, very much. Our next speaker is Dr. Hung, who is Associate Professor at the Institute of Department of Pharmacology at the National Yangming University. Also in Taiwan.