We Are Itching to Tell You About "Pruritus"

this program is a presentation of university of california television your support makes you see tv’s programming possible contribute online at UC TV TV slash support check out our youtube original channel you see TV prime at youtube.com slash you see TV prime subscribe today to get new programs every week you the outline for my talk is following the first I’m going to talk about a classification of itching it’s sort of how doctors who see patients who each categorize them how we think about them because the first step in sort of understanding disease is putting diseases in groups and then classifying them in a way that you can make a diagnosis based on the patient’s laboratory tests physical findings and their history where it got a little bit about you but newer approaches or new ways to think about treating itch and then I’m going to begin the discussion of chronic itching and the nervous system to just sort of from the patient side explain what’s going on and then dr. steinhoff will pick up from there and actually explain the science of the nervous system and the inflammatory system in the skin and how it results in us having itch okay so first question is it’s important well it turns out about 2% of all the visits to dermatologists are for itching that’s one out of 50 and that doesn’t count it’s you disease like hives and eczema that’s just itch and if you talk to someone who has chronic itching their quality of life is about the same as someone who’s on him Alyce’s so they have a pretty difficult time with a lot of activities quality of life is a way of measuring the impact of a disease on a person that’s comparable from one disease to another so you can do a quality of life analysis on a patient with disease a and compare it to disease B and they’re comfortable so this quality of life is important and it’s important for dermatologists because we don’t have endpoints of our diseases where people have heart attacks they have fatalities like other specialties do so we have to rely on the patient’s perception of their disease and how the disease affects them so dermatology and dermatological ends up being a very patient-centered practice okay the problem with treating itch is that we do not have any specific itch blockers that’s that’s actually our job here at UCSF over the next decade to help find these so we actually use drugs to treat itching that were made for other reasons and they kind of happen to work sometimes but often not well enough so so we’re left with no really specific drugs to treat itching none of them were made with itch pathways or the understanding of itch in mind so we’re really just piecing together things that we figure out happened to work okay I’m going to talk a little bit about how it affects people psychologically and when we see patients with chronic itching they come in with a sort of psychological profile where they’re both desperate and helpless so they’re desperate because all the treatments that have been done before have failed patients often tell us that if we can’t help them they’ll kill themselves because the itching is so tormenting I’ve had one patient commit suicide from itching that I was unable to control so so this this is this patients are incredibly desperate it bruinz their

lives and they’re helpless because doctors say well we don’t have specific agents to treat you we don’t know why you wish we don’t know how you itch and so they feel very helpless in this whole process in addition if you have chronic pain or some other kind of injury people are very sympathetic to you if you itch people kind of go like well it’s just itching you know and unless they themselves have had severe itching they really don’t appreciate the magnitude of suffering these patients have so it’s against this background that those of us who study this think about this okay the other thing that happens when you itch is you don’t sleep right and so then you don’t sleep and that creates a lot of the psychological consequences of each of itch so you don’t sleep you don’t feel good and then if you happen to have a child say who has eczema and they don’t sleep well guess what if your kid doesn’t sleep you don’t sleep and in fact a single child with eczema completely disrupts a household because if they don’t sleep mom and dad don’t sleep the other people don’t sleep it’s really very very difficult so itching by a blocking sleep or preventing you from getting quality sleep really has a negative impact on the quality of your life all right now most patients who itch as I said don’t get help from their significant support network so most patients are told by their friends or their parents or their doctors including dermatologists well just don’t scratch so to begin to visit with a patient with itching I tell them to just tell the person who tells you not to scratch okay and you just don’t breathe it’s that’s how impossible it is when you have severe itching telling someone not to scratch is like saying don’t breathe and and so this actually empowers the patient and begins a dialogue where we can help them to improve their situation okay now everybody asks about stress well to stress do this to stress do that and and stress is an important player in itch but it doesn’t cause it so I think of it like a stereo that there’s an on/off switch and stress is not the on/off switch but stress is the volume knob on the stereo and it works because when the sense of itch comes up to your brain and you have stress created from your lack of sleep from constant discomfort your nervous system also reacts going down and enhances and modifies the way you respond to itch it does two specific things it dries out your skin so under stress your skin actually can’t hold water as well and that triggers itching and then stress alters the response of your immune system to various things and tends to make your immune system more allergic so allergies are worse and many immune diseases that are allergic and bases each so that’s why the itching is worse and then if you don’t sleep of course you’re stressed so stress plays our multiple roles in itching now how does it get sensed well itch like pain is sensed in the target organ so that’s the skin and then that’s sent via the nervous system in the skin which pick up this itch stimulus and that signal is sent up through the spinal cord it goes through a place where the nerves sort of from the periphery meet the nerves that are going to go up to the brain in this area called the dorsal root ganglia this is like a big processing center and Martin is going to talk about the dorsal root ganglia because it’s a really important area in pain and itch theory and then these signals are sent up to the brain and they’re sent to various areas areas like the areas where your brain lights up when you eat a good chocolate bar you know areas of satisfaction so like when you scratch it’s like very satisfying which is not good because it keeps you scratching right okay so this is kind of a diagramming and dr. steinhoff will fill in and paint the picture of all this but this is simply to say that down here in the skin there are different kinds of receptors some for histamine some for other molecules in this in those each nerve [ __ ] those signals up and they send them up and they get processed there in that dorsal root ganglia and then from there they get projected up into the brain to various areas some of those areas are responsible to cause you to reach across and scratch the itchy spot and others of them modulate the sense of itch ok now I’m going to go through a few cases and describe you how a doctor would think about these patients with itching and how we’ve developed a classification

system that allows us to divide it into different categories so we can think about what causes it so there’s a woman who’s had eczema her whole life she’s got a new soap supposedly mild now she’s got a lot of rash and itching mostly here and the crooks of her elbows and knees in the place where patients with eczema get their pitching here and here and you can see that despite the fact that her skin is really inflamed she keeps scratching and keeps scratching and doesn’t stop so I would ask doctors what’s the most effective treatment for this kind of itching and often patients are given antihistamines they’re given point mints to work they they say well stop using the soap or maybe they give some kind of SSRI or something for the stress and anxiety and it turns out the most effective treatment here is going to be to treat the rash so this kind of rash or this kind of itching is what we call type 1 itching so this is itching where there’s disease on the skin and the treatment for this in this case the patient has itching associated with an inflammatory disease are eggs among the management is to treat the rash right so you make the rash go away the itching goes away so if the patient has itching from eczema treat the eczema now this seems incredibly simple but in fact is often not done patients come in and say I itch a lot and the doctors spend a lot of time giving them pills too in a histamines and things like that and they really don’t take care of their skin disease so while it seems really simple it’s very basic and important ok now this is a more complicated patient patient had hereditary polycystic kidney disease they’ve lost their kidneys functions or they have chronic renal either on dialysis and dialysis patients get a lot of bad itching and when they itch they scratch their skin in a very specific way that makes bumps with a little warty centers and we have a name for that disease we call it Curly’s disease and I would ask the doctors well how do you treat this here’s what it looks like there’s the perineal dialysis bag and you see these raised up bumps with a little horny Center in there and so a dermatologist should recognize that that patient has renal failure so this is what we call type two-inch and this is itching where the skin is normal so this patient has normal skins but has a lot of itching due to their metabolic disease so this is it with what we call only secondary lesions so they really don’t have a rash they’re all they’re actually got they made by scratching and if you see a patient like this and you look on the center part of their back where they can’t reach it looks normal and these are all the kinds of things that cause these kind of itches with no rash but as dr. Steinhoff will tell you each of these causes of itch may be produced by a completely different mechanism so now we have one type of itch type two of the three types many different causes many of which will be due to different pathways so this is not going to be an easy thing to completely sort apart the way we treat this is we improve their dialysis they tend to have dry skin we treat that we give them light therapy and then we give them neurontin like is used for pain as gabapentin and in fact that works really well so we think there’s an important neural component to the itch in these patients and this is a gabapentin trial before look after the gabapentin all right now this is another patient who has liver disease in Itchy and their treatment is naltrexone naltrexone is an opiate blocker so in fact in patients who have liver disease abnormal opiate metabolism your own morphine that you buy to soothe your pain is actually abnormal and blocking that stops the itching in patients with liver disease so if you have kidney failure versus liver failure your itch is by a completely different mechanism and your treatment is completely different okay so the way we deal with type 2 inches we diagnose their underlying problem and then we have to specifically pick agents that work for that underlying disease so if they have kidney disease we give them light and neuron if they have liver failure we give them opiate antagonist that they have to have a cancer because they’re rich it turns out that paroxetine or paxil works pretty well for that so we have different ways to treat different kinds of itch of this type this is the last type of patient we see this is a 33 year old man 34 year old man he’s had two years of itching in his genital area on his scrotum and he’s a martial arts instructor and on exam the scrotal skin is sort of just thick and we use a word like Kenna fight for that looks like lichen it’s all piled up and when you botch it it just shows that

it’s been rubbed and scratched really don’t see any disease there and so here’s this area that he just rubbed and rubbed and rubbed and the skin markings are more prominent the skin is really thick but when you Bob see if there’s no inflammation there at all so this is type 3 itch and we have a whole bunch of diseases that fit into this itch many of the cases of itching in the genital area are due to this cause no primary lesion and often the patients have a neurologic basis for the itching so they have some kind of back injury or injury along their spine somewhere and that abnormal nerve when inflammation occurs in the skin triggers a very heinous circuit of itch scratch itch scratch that the patient can’t break and it results in a complication we call sensitization so sensitization we’re going to talk a little bit about because it’s important and sensitization occurs in two places it occurs peripherally and centrally and sensitization is that process by which a similar stimulus creates more and more and more severe itching so your clothes rubbing you normally you’d feel your clothes rubbing you but in an area where you have eczema your clothes rubbing you will generate horrible itching so the nerves are sensitized and it works in several different ways the peripheral nerves get hypersensitive to stimuli and they react abnormally to inflammatory mediators so the researchers in dr. Steinhaus group have shown that things that should be causing pain or causing itch so patients who have eczema and scratch and scratch where they should be feeling pain it just makes them feel more and more itching and they just keep scratching and scratching and areas where the nerves are already irritated are very susceptible to getting this phenomenon of sensitization in addition remember that dorsal root ganglion we talked about once you have chronic itching anatomic changes occur in the dorsal root ganglion you actually hardwire the sense of itch into your spine so it’s kind of like the phantom limb you know you’ve got this ulcer on your leg it hurts like crazy so somebody says ok we’ll cut your leg off cut your leg off and it still hurts the same because the pain had moved from that ulcer up into your dorsal root ganglia here it got centralized and that happens with itching and that’s why managing itching is such a challenge because now you’ve got this central sensitization so we have peripheral and central sensitization so chronic itch is learned and it’s aunt homily fixed in the central nervous system specifically in the dorsal root ganglia so this is really one of the reasons that managing itch is so tough ok so how do we treat this patient well we try to stabilize this back we tell them to get a new chair maybe get some physical therapy get some acupuncture we give them some local anti-inflammatories and we use things like lidocaine or capsaicin which blocks itch signal things to locally stop the nerves over acting and we use oral agents like neurontin pregabalin that’s cymbalta which you hear advertised for fibromyalgia on TV that are normally used to treat neuropathic problems and the patients do better with this so we’re treating that sensitization that’s occurring back there in the dorsal root ganglia okay so this is now what we talked about Group one it’s group two inch group three inch or if you want to think about it graphically the skin interacting with the immune system that’s type one inch pitch on inflamed skin the skin nerves sensing something that triggers itching that’s the skin nerve axis and then lastly the nervous system and the immune system talking together making this chronic itch scratch so that’s our three groups of itch we now have a large group of medicines we can use opiate blockers central agents light therapy agents that act on the nervous system and you see antihistamines which are what everybody uses all the time they’re a small group up here in the corner that we use dr Stein up is going to go through and explain now the mediators and all the pathways here in the periphery that are that result in the sense of itch and how blockers can be designed to prevent this so we’re going to try to find the signals from the immune system to the nervous system that cause it we’re going to try to understand the molecules that bind to the nerves in the skin and trigger itch sort of the itch receptor and we’re going to try to find the signaling molecules in the central nervous system that transmit the sensation of itch from the periphery up to the brain so dr. Stein Hoffs lab has

bit off this big chunk here to try to elucidate all these aspects so we can understand how each and the periphery ends up being sensed in the brain so thank you very much that worker told you already about this patient which we see which feel very desperate because of their age and so your enough one possibility is to ask when how can I help this patient which is of course very important and you can also go into another perspective and and ask they are what brings this patient here what kind of mechanisms are behind this edge so that we can understand this itch better and then treat each subtype of itch better and more efficient and this is currently the problem which we have in which were already demonstrated that we currently have poor understanding of the different subtypes of it but why is it important to talk about it because we see very many patient which suffer from itch like chronic pain patient and it’s and has a huge impact on the quality of life in these patients and it is very difficult or difficult to treat and we have because we have a lack of understanding of the different path mechanisms why all these patients develop current chronic colitis as you can see here we see writers in in children as well as in elderly patients because of exogenous trigger factors but also systemic like tumors or cancers can develop into chronic itch and also on non inflamed skin this is a patient who just chronically scratches and end develop these skin lesions because of the itching and scratching vicious cycle without any primary skin disease which we have here and then I will also talk about that we can develop chronic itch because something happens with the nervous system inside on the dorsal root ganglia in the spinal cord or in the central nervous system for example you can after a stroke patients can develop a chronic itch because a certain area in the central nervous system and is not functioning correctly and develops chronic itch and also systemic diseases like liver or or kidney problems can develop into chronic itch and you can also have a combination of two or three factors that’s why it’s also important for the physician not only to look and to look very carefully because sometimes it also the itch can be due to two or three factors and this video would demonstrate to you and this is a patient which is video monitor during the night with atopic eczema and here I think you can by seeing this video appreciate that similar to chronic pain that chronic itch is a severe problem and in the next morning that this patient suffers from sleeplessness and lack of concentration at school and end at work so chronic itch is a severe problem for the quality of life in this patient and we need desperately better therapies first of all as dr. Berger also already demonstrated is that we have these three subtypes of aging this is very important to understand and I would to give you a little bit of background behind that first of all we have it in in the skin because of certain inflammation allergies that are alike in atopic eczema which can develop already in in children as well as in adults and while 20 years ago it was and in the textbook it was said that a topic eczema is a rarity it’s very very rare we see more and more also elderly patient we developed for first time in their life it toxic eczema in adults and this can lead to very severe forms like here into a generalized inflammation with chronic itch and even lead then because of the vicious cycle of itching and scratching in into infections and that’s why it’s important to treat this chronic itch but it can also come from the inside for example based on medic and you too so autoimmune diseases but also infections as I said renal problems liver problems and different kind of tumors can lead to generalized forms of age and the what is very specific

specific for the systemic age that it’s more symmetric than the localized age and more generalized and this gives you also a hint in the history taking whether itch is more likely coming from the inside or from the outside or based on inflammation and very important also in respect to localized ages that this is a patient for example which only develops a localized itch on the forearm or on the legs because of an impingement problem after an accident and a couple of years after this impingement and payment of the function of the bone which puts pressure on you on your nerves in the spinal cord or in the dorsal root ganglia nurse then can develop – – in itch sensation in the skin and then because of the chronic rubbing and scratching given you can see then secondarily these these skin lesions so many factors like impingement and injury and also osteoporosis in the cervical area or spinal area can can lead to these kinds of neuropathic itch how we call that and in elderly patients also very important to consider are always stroke or CNS problems for example strokes can lead to forms of of chronic itch in in certain areas another problem for with respect to chronic itch is that we that we see is that some pain to have a hypersensitive skin whether its genetic or by the environment use of certain toxins they develop as is what we call hyperkinesis which is an iterated each sensation so when you have something on it which is normally not itchy but then becomes a very itchy for example beasting for some patient it’s a two minute itch for others it lasts for hours or days so we have different kinds of skin and we develop a different responses to the skin to plants and so we have a different form of of sensing this and then we start to scratch and sometimes we start to scratch our skin off because sometimes the itch there’s it relief when we go deep enough in order to to suppress by by scratching behavior but there are also other forms which are important to know some patients have a certain sensitivity for each which so a wind blow or our wool fiber on the skin normally does not induce any itching for us but in some patient wool fibers or even a wind blow can be sufficient enough to end-use a chronic vision mm each cycle then you start to scratch and it starts in the next morning you have developed your eczema so this is important I understand because this can be also it’s important to know in order to treat and to prevent it so the end we have also x0 attic skin so we know during aging process we produce less lipids and then the these kind of crackles which then can be developed which are not always visible but can produce a severe itching so in order to to understand this we first need to ask the question why do we eat and why do not all skin diseases M itch because this is these are all kinds of inflammation diseases with inflammation but in this patient we only seen one or forty or fifty with rosacea fangs I describe chronic itching it’s more a stinging burning pain sensation but less itch so the question is why does the nerve some disease as a nervous system percept pain or stinging burning and not itch other diseases are 100% critics such as atopic dermatitis while in other disease which are also very chronic widely spread inflammatory only a certain percentage experiences parietal so there must be differences in our in our skin and in in the mediators which are released in doing this inflammatory process and we want to learn more about these mediators which are released in this area because then we can treat very specifically here the pain and and the itch in these patient maybe we need different kinds of treatment for this patient and for this

patient for it and it is also important to know and to keep under control because in the topic dermatitis for example you can see here appreciate that this patient scratched very severely his face because of the age and then developed because of and viral infection and severe eczema which is in more heart to treat so it’s important also in dermatology that we get this itch under control so this cartoon shows in overview of all the levels which are important in understanding parietals namely we have the skin which is a kind of a barrier for danger signaling from the outside like toxins from microbes you know scabies fungi bacteria from house dust mite allergens and so it keeps us the skin under control and then we have because we have the nerves here in the skin which then tell our central nervous system that there’s some danger and in the outside and that this this skin has to do something about it maybe scratching to get rid of the parasite so and this nerve signals year to the docile Ganga which dr. Berger already mentioned which is a very tiny spot here but very important because it’s the factory which produces all all the proteins which which then respond to all the trigger factors of it which can be released we all know histamine as a trigger factor of itch but I will show you that there are other many other mediators in the skin which can also as important as histamine and maybe future targets for therapy and explain why antihistamine many of the cases don’t work so these kind of mediators are important and they are responded here in the dorsal root ganglia and then transmitted to to the spinal cord and the spinal cord brings the whole information into the into our brain and tells the brain ok there’s something dangerous a chi on the skin so do something about it and the problem is that we still have a very poor understanding of all the mediators the receptors and the circuits which are going on in in the central nervous system and even this is a very practically a black box we don’t know very much about the mediators and secrets and receptors in the CNS so first of all what we have to appreciate is that probably they know histamine is not the only H mediator that that we have to understand more about the other mediators and the other pathway which are involved in itching and then we can find new therapies so this this picture shows you the distribution of the nerve in the skin and you can see that up to the upper epidermis are our skin is highly enough I ate it and these little green areas are the sensory nerves which stick into our skin and then give the information to the CNS okay there’s something actually on our skin so this is a picture of of this kind of nerve ending which we have in our skin and what we in currently scientists all over the world are trying to figure out is what leads to the itch in the skin and what kind of mediators transport the itch sensation to the brain in order to tell the brain to scratch because if we know all these mediators and receptors then we can treat our patients better so we know that already in the skin many cells can can release each mediators like keratinocytes even blood vessel cells and immune cells and they activate certain receptors here on the nerve ending and you can see in the nerve and we don’t have only the histamine receptor but many many different kind of receptors and which can be activated for example by pH changes or by formalin which is in many makeups or in and also but also that can respond for example to menthol and that’s why we use menthol is

an antipyretic because if these ion channel gets activated it shuts down our itch signal so we have receptors which are pro paretic which enhance the itch but also which can silence the edge and also very interesting is that these receptors here in the nerve endings are some kind of promiscuous because they can on the one hand they have been found because they can respond to touch and as I need to touch sensation and pain but then certain groups have found out that also certain medications can activate the same these touch receptors and then induce edge so a receptor which is originally therefore for touch our skin doesn’t can also mediate itch if it’s activated by it by another mediator like a medication for example that explains why we have probably many drug induced eruptions and itching because they can activate certain of these receptors and there are only a few receptors which we have so far understood and in many immune cells in in in the skin which are enhanced in a topic eczema in many of poetic skin diseases can induce many factors and you can see that that it’s not only histamine but many factors which can lead to the activation of a peripheral nerve ending so this is again the skin and then you can appreciate that doing this kind of inflammation you have a kind of a soup of different mediators different cells you have activated epithelial cells activated immune cells and they all release some kind of mediators and some of these mediators induce can induce pain and some can can induce the itch pathway and so it’s probably the combination of certain mediators which are activated they’re doing this inflammatory process which then activate either then signals Intel like in rosacea patients that there’s a painful stimulus and in others like atopic eczema that there’s which leads into an itch sensation and we know from from our observations in in the last year’s because for example morphine when it’s injected into the spinal cord it leads to terrible itch and you know all that morphine is a is a pain suppressor so this gives you a hint that the inhibition of pain can can intensify it so they are somehow connected and I will show you that they are connected here and the spinal cord but it’s not that as many people think that you have a small stimulus leads to edge and a large stimulus leads to pain so they are more like twin so each is an individual they are somehow connected but it’s not that the edge is only the small brother of pain and so each is individual and a very important part in India whole each process is that is it our brain because the stimulus comes to to the central nervous system and from certain MRI and CT images people have shown that that em histamine and other itch mediators can activate very specific areas in in the central nervous system first of all of course our motor cortex which leads in to the stretching process so you want to scratch when it’s itchy right that’s also what animals do and but all also we have activation of certain other centers which are involved in the emotional our intensification of it and also in the emotional part like suffering or also in with respect to compulsive stretching and that explains that when as a patient’s also behave differently that some patients are more depressive and in some ins compulsive stretching also there’s activation of a pleasure reward area where people say ok it’s so great if I just stretch my skin of it feels great so this is because in certain parts of our brain that can lead to pleasure Ness of stretching and that’s why it’s in this patient it’s much more difficult to treat and to

break this scratch cycle so the brain is a very important part in our em eating process and so far we don’t know really in which area which mediate and which receptor is important nobody has shown that so far in neither in mice or in humans and so this is still a black box we just know that certain drugs which we use which dr. Berger mentioned that they probably work either in the spinal cord or in the brain so we all know that history is a classical mediator and we know you system in one receptors blockers antihistamines to treat it but in the last few years very importantly and they have other histamine receptors have been cloned and described and have been shown that they are also involved in it and this may explain why in in certain diseases the antihistamines which you use like benadryl are not sufficient or effective because maybe histamine is important but act here in this disease a histamine for receptor is more important or histamine receptor or a combination so we are currently at the beginning of understanding ends pharmaceutical companies are currently developing drugs and in clinical trials also to block these other histamine pathways and maybe one day we have a better therapy by a combination of these receptor blockers and I already have told you that we have this kind of promiscuous receptors which are normally respond to touch and and then need to pain but the same receptors when they are activated by medication they can lead to itch and so they use a certain receptor and so far we have not learned about all the mechanisms is the only receptor which we currently know but here it’s a little bit more easy because if you skip the drugs and mostly the it resolves as it’s not the case in many of other chronic itch ‘iz and what I will show you in the next few minutes is that a very important part in our understanding of pathophysiology of histamine independent itch are a protease s and proteases make 5% of our whole genome and so they’re very abundant in from the brain to in all organs and in the skin is full of proteases and also house dust mite allergens are partly proteases couch has a lot of proteases and even animals or bacteria fungi use proteases in order to enter the skin and maybe produce the edge and there are certain receptors in our skin which can be activated by these proteases so from researcher in order to make better therapies we have to understand the path of mechanism and so how does it work and so what we did in the last few years with respect to proteases in atopic dermatitis was that for example we use micro dialyzer so this is kind of like acupuncture in the skin so you put these needles and into the skin and then can measure concentration of certain mediators like histamine or proteases and measure the concentration in this disease and say ok in this disease we have a high concentration of histamine in the other disease we have a high concentration of protease and therefore here we need to use an antihistamine and here we need to use an anti protease inhibitor so these kind of things give us a better understanding of but in order to develop new therapies and interestingly form the protease it was already described in science and nature in the 50s by author and Shelley that be using power hedge and use the speaker lay of courage that proteases are very important each mediators but that has been very forgotten for a very long time and then with years here at UCSF it was and found that there’s a receptor defined as part two which then may be activated by proteases and involved in this each process and there are companies currently which developed antagonists against this receptor in order to block these protease in usage in order to to understand the how these proteases work

and to develop these therapies one part important part in in the research is ourselves but also our mouse models in which we knock out a certain gene for example of this part two receptor or overexpress this receptor in in certain cells like the nervous system or in epithelial cells and so animals which which over expresses is reset protease receptor in in the epidermis in the keratinocytes they develop spontaneously an atopic eczema after six to eight weeks i’m showing here and they develop also dry skin and they develop very severe skin lesions so very suffer very much from this chronic agent this mimics this kind of chronic itch so it’s not pleasurable but but sometimes we need to use these kind of methods in order to to find and to understand the mechanism in to find precise and optimized therapies and here on why if you cut this into histology and and see that you can see that this is much thicker and inflamed as as compared to normal skin and resembles atopic eczema and this is just a few of the results which i want to show you here the black column shows that these animal scratch much more per hour as compared to the controls so gives it they develop a chronic itch sensation and the question is why they do it and whether we can treat it and one of the answers which is very important also for our understanding currently of of the itch process in the skin and what dr Berger meant as peripheral sensitization is that these miles develop much more nerves in the skin and in the epidermis so they develop what I said at the beginning this hyper sensitive skin which then a wind blow or fiber or a minimal stimulus can lead to chronic itching and and scratching in these mice and and they it’s hard for them to get rid of so does it so we use these animal models and it it’s true in animals but is it also true in humans and and we think yes that proteases are also very important in in chronic itch like atopic eczema here’s a protease defined as pro spacing which you see in green here in atopic dermatitis patients use you can see this green and that area of of this protein which is not in in depth in normal human beings healthy humans so and also the receptor which is in green is not so much expressed in healthy skin but severely expressed in in atopic eczema because that we have proteases and protease receptors which are upregulated and then can lead to the aggravation of itch and maybe in these patients we need protease inhibitors or blocker for for this protease receptor in order to treat pruritus so this cartoon summarizes what we think about histamine independent itch and Proteus only one example so we have proteins from house dust mite from bacteria from toxin fungi and also released upon stimulation by by epithelial cells then we have many immune cells in the skin which lead to activation of certain receptors and then we have the release of of growth factors for which and lead to nerve sprouting and then leading to a hyper sensitive skin so this is an example which shows you that there are many itch pathways and as I have shown you at the beginning that there are there’s not only one treatment for it because we have these kind of stimulators and we not only have histamine and proteases but also in many inflammatory skin diseases we have cytokines cytokines which are released by many immune cells and in the last part I want to show you that also the immune cells itself in inflammatory skin diseases can produce it and this is a cytokine which we caught they are defined as interleukin 1 2 3 we now have 36 cytokines interleukin 31 and and interleukin 31 is interesting

because in in mice when you overexpress interleukin 31 these mice develop spontaneously in a topic eczema severe parietal and so the question is is that important and we think yes because a couple of years ago it has been shown in for the first time that also that a cytokine is involved in familial related a chronic brightest so they are families who have localized apparatus and the question always was why do in this family do they have all family members this MH and scratch visual cycle because they over expressed a certain receptor which is called uncas 13m receptor and this is part of the interleukin 31 receptor complex and so this kind of cytokine receptor is the first receptor which has been demonstrated that if you overexpress have much more of this receptor activated in your skin that in these families the patients develop a chronic eczema so that tells us that this interleukin 31 cytokine may be important in in the for the development of chronic providers and as in these patients with atopic dermatitis atopic eczema we know we are to question whether this may be also important this is a mouse study which shows you that if you inject into looking thirty-one into into mice that you develop the disease might develop a severe scratching behavior and also develops UVA it and in these patients if you take patients with atopic dermatitis or different chronic diseases and compare that to a healthy skin you can see that while in healthy skin no there’s no interlocking 31 or interlocking 31 receptor while in other diseases psoriasis you have a little bit more of the receptor but in a topic eczema you have severe up regulation of interleukin 31 and its receptor so this is an example of a cytokine which is probably involved in the development of a chronic itch in a topic eczema and in chronic predict diseases and also here in other chronic itch patient this cytokine may be an important part and as dr. Vega has already Lou sedated is that these that the dorsal root ganglia and the spinal cord are important to talk to the to the CNS and for the aggravation of itch because if you up regulate in the dorsal ganglia or in the spinal cord these kind of itch mediators and the receptors you can develop a chronic itch process and intractable it em and so that you have activation in the skin but then aggravation in the spinal cord and then aggravation in the the brain which then leads to the vicious cycle of itching and scratching so the last slides I just want to emphasize what what kind of mediators what are the mediators which we know nowadays in in these areas which could be a future targets for for therapy so we know that that there are certain mediators like gas releasing peptide substance P which are here expressed and here’s a factory in in the doors of ganglia which and then transported to the spinal cord and activate these receptors in in the spinal cord accordingly and if you have up regulated an upregulation of the mediators and/or receptors you have more severe itch so understanding of the mediators and receptors which activates a peripheral nerve in the skin and then talk to all this region is important for our current development of future therapies this sensory nerve which are in our skin are the itch nerves are itch receptors are only a part of of the whole nerve which which are in the skin and so we have a part of histamine we have other cytokine receptors and protease receptors and so you can appreciate that when you activate with histamine you activate the histamine pathway or but if

you histamine is not important in this disease then the insta mean receptors are also not important and then you need to treat the other receptors as you can see only a small part of a whole nerve fiber is a niche fiber some are pain fibers and and it’s interesting part is that only a small number of these itch nerves here for example interleukin 31 is only 4% of all the it and or is sufficient enough in order to transport and to activate a severe itch and scratching vicious cycle still we don’t know many of these mediators which are involved in chronic itching so this gives you a hint that when we have these patients which I have acute atopic eczema they need by a vicious cycle of itching and scratching can also lead to the krona fication of itch because we have these different levels in the skin and the spinal cord and in the central nervous system which can aggravate this vicious cycle of itching and scratching and still we don’t understand clearly what brings this patient to Khurana fication and then to develop a better therapy some drugs I just want to show you and to emphasize why it’s important that I have told you all this and get went into to the nervous system and spinal cord and the brain is because many of the medications which we currently use and maybe also free to use for your chronic treatment of itch like nitric Zone or gabapentin pregabalin our work here M on these on these nerve M in in the spinal cord and and therefore this is a important part to study also in the future to understand better the pathophysiology of itch so why do we eat and why do we scratch you know that scratching is like in pain the pain withdrawal effects or when you have fire you make a withdrawal effect because it’s painful the scratching is also response of our central nervous system to get rid of the itch and so scratching helps because it activates so nerve fibers and in the spinal cords is north pain nerve fibers can suppress the itching that’s how it works that we can suppress the itch by the stretch the problem is that with the scratching we this is kind of a can activate a vicious cycle so then leads to more itching and then more scratching and then so it’s not a solution of a problem for the treatment of chronic agent many diseases and when we and all these molecules which I have shown to you is these are there are many molecules in this area in the skin and here in the nervous system which we currently study and which are still not completely understood and that’s why it’s important to study more it in order to help you to get rid of your itch thank you very much for your interest