We would like to welcome all our attendees and participants to this double SLD special interest group sponsored webinar on mechanisms and current all emerging therapies of fatigue and pruritus in cholestatic and autoimmune liver diseases. I am Mitchell Mahmood, Professor of Medicine at the Duke University School of Medicine in North Carolina. I'm joined by my co-chair, Dr. Michelle Turner, Associate Professor of Medicine at the University of California, San Francisco. We have assembled here two distinguished speakers who will speak on this important topic. They will each speak for 20 to 25 minutes, followed by a 10 to 15 minutes Q&A section at the end of both presentations. Please kindly send your questions into the chat room. Hi, everyone. Good morning. I just wanted to review the objectives of today's webinar. So they are to discuss mechanistic studies, as well as current and emerging therapies for fatigue and pruritus in cholestatic and autoimmune liver diseases. We are thrilled to have our two speakers here with us. Just as a point of housekeeping, this session is being recorded and will be available on liver learning within the next day or two. Continuing education points will also be available, though not immediately, rather through liver learning in the future. And so an email will be sent out to all registrants about how to collect those continuing education points, including mock. And for any questions that we don't get to today during the Q&A session after the second talk, we will compile answers, and those will also be emailed out separately in a subsequent email by the ASLD and our assistant today, Laura Shelters. So now it's my distinct pleasure to introduce our first speaker, Dr. Mark Swain. He is a professor of medicine and the Cal Wenzel Family Foundation Chair in Hepatology at the University of Calgary in Canada. He's also the president of the Canadian Association for the Study of the Liver. And he will be speaking about mechanisms and therapies for fatigue in autoimmune liver diseases. Thank you so much, Dr. Swain. Thank you so much, Michelle and Mitch. So as Michelle mentioned, I'm going to be talking about current and emerging therapies and mechanisms of fatigue in autoimmune liver diseases. These are my conflicts. And I'm going to start off really by putting a framework that I use to conceptualize fatigue. When I'm thinking of fatigue, I really divide it into two sort of branches, central fatigue and peripheral fatigue. I find these quite useful when I'm chatting about fatigue. And so when I'm talking about peripheral fatigue, I'm really talking about neuromuscular dysfunction. And importantly, it's typically associated with weakness. And I'm going to stress that that's not usually a classic feature of the fatigue that individuals who have liver disease and autoimmune liver disease complain of. And really, the neuromuscular dysfunction is anywhere from in the peripheral nervous system all the way into the muscles. And when you look at people that have chronic liver diseases, peripheral fatigue certainly can occur. It's most common with advanced liver disease. And so when you start to see muscle wasting, like in this picture on the left, deconditioning, sarcopenia, and of course, it's linked to frailty, which is really quite a hot area as well these days in the study of liver disease. When I turn to central fatigue, really what I'm referring to is our changes within the central nervous system, mainly the brain, which drive fatigue. And I'll refer you to this review that was in the Frontiers of Immunology in 2017. It's an excellent review. It really talks about central fatigue in chronic inflammatory diseases. And it talks about the multidimensionality of them. And so because fatigue is a symptom, it's most typically captured by using questionnaires, which are somewhat subjective in their application. And really what they're doing is they're looking at how that person describes a symptom. So in a physical symptom, they might say, I have difficulties performing physical tasks. With mental fatigue, you might say, I have difficulty concentrating or remembering. And lack of motivation is I really don't want to do anything. So these are the things that are picked up in a questionnaire. But you can also measure these objectively, so with specific tests. And so with physical fatigue, you can put someone, say, on a treadmill, and they exhibit reduced performance in a physical task. With mental fatigue, you explore a cognitive task and look at fatigue time. And then with lack of motivation, you expose them to hedonic awards, like money or things like that, or a money reward in a game, and look at their effort to explore that. It's also important to remember, though, although fatigue is the most common symptom reported by people with autoimmune liver disease, in fact, it's commonly associated with a number of other symptoms like disrupted sleep, social withdrawal, loss of motivation, cognitive impairment, which patients often call brain fog, and mood changes like depression and anxiety. This is a nice study that came out quite recently, and this is a study from China, where they looked into autoimmune liver diseases broadly, and they've categorized them broadly. And they use their chronic liver disease questionnaires as a way of measuring fatigue. There's almost 1,400 patients, and what they showed here, this is the percentage of individuals that have fatigue. And you can see that about 45% of individuals that have PSC, PBC, and autoimmune hepatitis complain of significant fatigue, which is higher than all of the other liver diseases that they examined in their population. Now, what about fatigue in PBC and PSC patients compared to community-based controls? Well, this is measurements, this is a publication that came out almost 10 years ago, but they looked at fatigue severity using the fatigue impact scale, and there's normal controls in the community PSC and PBC, and you can see in general, the scores for fatigue are higher in the PBC and PSC patients. And if you look at the percentage of patients that are experiencing significant fatigue, I put the green dot here, this is PSC and PBC, you can see it's about 40 to 45%, which is actually quite similar to what that Chinese study reported for all autoimmune liver diseases together. I'm going to turn to fatigue in PBC, and the rest of my talk is really going to be about And that's not because fatigue is not important in the other diseases, it's just that it's been best characterized in PBC, and a lot of studies have been done, and there are disease-specific questionnaires that people have used to assess it, so broadly, I think our understanding of fatigue is better in PBC than the other autoimmune liver diseases. So when you look at fatigue in PBC, just like the other autoimmune liver disease, it's the most common symptom, and it has the greatest impact on PBC patients. It's typically rated moderate to severe in 40 to 80% of PBC patients when they're given a questionnaire. I've highlighted the 40, because I think sort of 40 to 45% is probably the most common number that you'll see. And it's significantly more prevalent when it's asked on a questionnaire, compared to what's verbally reported to a physician. And so this leads to physicians often saying, well, you know, I don't see fatigue in my patients. However, that's because patients are much less likely to tell their physician as opposed to record it on a questionnaire. The fatigue scores are typically higher in women than men. It's more common in younger patients, and it's weakly associated with disease duration. It has a significant impact on quality of life, especially in those where fatigue leads to social withdrawal. It's commonly associated with altered mood, as I mentioned earlier, so depressive symptoms, although not depression when it's assessed by a psychiatrist, and anxiety, and there are similar levels of these in men and women. And PBC patients with higher fatigue scores appear to be more vulnerable to emotional stress and are more likely to worry and be anxious. And then there's the question of whether how individual coping skills, resiliency, personality, support networks, perceived loss, and fear of the future impact people's experience of fatigue and how it influences their generation of fatigue in those individuals. It's also important to recognize, I think we're all quite familiar with this, is that UDCA response or non-response does not influence fatigue and does not improve any of the symptoms, but I've just highlighted the fatigue. There's a nice study that shows it pictorially, but this has been shown in many studies. This is a patient-centric discussion, really, around fatigue that was published in BMJ almost 11 years ago now, and it really describes the experience of fatigue in a PBC patient. And I think it highlights why I view this as a central fatigue and not a peripheral fatigue. So I could stay in bed till lunchtime, I have problems with my memory, it's mind-numbing, and you feel as if you're in a fog and you can hardly lift one foot in front of the other. Everything is so difficult. In fact, it was at such a point that this individual said they would consider any treatment that might improve their fatigue. There's another nice study that's just come out from David Jones's group, but they look at overlap between PBC fatigue and cognitive dysfunction. What they found in this study was about a third of the patients did not have or experienced significant fatigue. About a third of them had fatigue without cognitive symptoms, and a third of the individuals had fatigue with cognitive symptoms. And when you look at the subgroup of individuals that had fatigue with cognitive symptoms, they were typically younger, they had worse fatigue, they had more quality of life impairment, and they were more likely to have EDCA incomplete response. So I'm going to really talk about fatigue in PBC as being central in nature. I'm going to show you some of the studies that we've been done, I think, that supports that in an objective way. So conceptually, for fatigue to occur in PBC patients, there has to be something that links the liver to the brain. And so in PBC, you have this immune-mediated destruction of small bile ducts in the liver and impaired bile flow. But in the other autoimmune diseases, again, you have an inflammatory component and you have immune-mediated injury within the liver. And the current theories suggest that there are signals that come out from the inflamed or damaged liver, carry the signal to the brain, and cytokines are the most commonly implicated IL-6, TNF-alpha, cytokines like that. And these inflammatory mediators result in changes in brain function. And it's really these changes in brain function by definition which gives rise to altered behaviors like fatigue. And so the most prevalent current theory about central fatigue is really that it reflects a balance or an imbalance between motivation and reward. And so in everything that we do in life, so not just the things we think about doing and then make a plan to do, but the things that every action that we take in our lives at a subconscious level that we experience a motivation to accomplish that task, our brain then has a perceived effort or cost associated with undertaking that task. And then we balance that within our brains very quickly in a nanosecond against the perceived reward related to undertaking the task. So it's this imbalance between fatigue and reward or reward and effort, sorry, that really drives the perception of fatigue. And it's really important to recognize that there's importance of the basal ganglia as a part of the brain and their associated connections in the genesis of central fatigue because the basal ganglia are very important in regulating motivation and reward. And the basal ganglia are shown here in the green box, as I call it, butamen. And there are close interactions between the basal ganglia and the limbic system, which is our emotional brain, like the amygdala and hippocampus, and the thalamus, which is shown here in the blue circle, and the prefrontal cortex, which is really the higher center, which regulates most of our behavior. And so the question I've been interested in for many years, are there objective changes in PBC patients in brain structure, brain regional neural activity and or brain inter-regional neural connectivity that can be linked to fatigue? So to do that, to look at this, we've been using functional MRI and we really have been using it to define objective brain changes in PBC patients and then link them to fatigue or not. When we think about MRIs, we traditionally think of something like this, when we look at it to look for a brain tumor, so we're looking at for structural changes, and certainly there are some structural changes within the brain. I'll talk about some of them today that happen in PBC patients that are that are distinct for that disease. Functional MRI, though, is different. It uses the same sort of apparatus and same MRI scanner, but what it actually looks at, it detects changes in blood oxygenation and flow that occur in response to neural activity in the brain. So when a brain area is more active, it consumes more oxygen. And because we don't obviously store oxygen in the brain, we have to increase the blood flow to reach to fulfill that oxygen demand. So really, what functional MRI is doing is looking at neural activity as a reflection and changes in blood flow. And it can be used for defining neural activity in a region of the brain, and this is called ALF, which I'll talk about. And so if I refer to ALF, it's neural activity in that brain region. And it's also useful to find it for defining connectivity strength of brain regions that are considered to be part of a neural network. So these are brain regions that talk to each other to generate behavior. So they synchronize their activity to generate behavior. So I'm talking about ALF, which I'll talk a little bit here at the beginning. So really what you're looking at is spontaneous neural activity in a specific brain region that is comparing between groups. It's important to remember when you look at functional MRI data, you're not looking at an individual patient. So this is not like a PET scan in a patient where you're looking at a color which represents that particular patient. It's actually a statistical comparison between one group and the other. And so if a disease group has, say, a higher neural activity in that brain region compared to the control group, then it'll be a color like up here, like yellow and oranges. However, if it has less neural activity in that whole group compared to the other group, then it'll have a different color. So I'm going to talk about a part of the brain now called the thalamus, which I mentioned earlier. The thalamus is a very important part of the brain in that it's really felt to be the relay station for essentially all sensory input except for smell, coming from the body to higher brain centers, including from the liver. So you can imagine inflammatory signals coming from the liver to the liver to the And they broadly show enhanced or stronger functional connectivity between the brain regions of the basal ganglia and the limbic systems compared to healthy controls. I'm not gonna show you that specific data. But what this means is that PBC patients as a group, their basal ganglia, which is very important for reward processing and movement-related activity, and their limbic systems, which are very important for processing feelings of motivation, reward, learning, and memory, are more strongly connected as a neural network than they are in healthy controls. I can't tell you what that means, but what it does tell you is that the disease is changing the brain connectivity between these regions quite objectively and reproducibly. And so are there changes in brain neural connectivity strength in PBC patients that are directly associated with fatigue? So I'm gonna turn now, get back to the thalamus. And when you look at thalamic functional neural connectivity with other brain regions, so I showed you how the thalamus is highly connected to other brain regions, it's altered. In PBC patients with fatigue compared to those without fatigue. So what these blue blobs show is that there's decreased functional connectivity of the thalamus with the cingulate cortex, which is very important for reward-based decision-making, and the prefrontal cortex, which intelligently regulates our thoughts, actions, and emotions in fatigued versus non-fatigued patients. And there's decreased functional, sorry, increased functional connectivity of the thalamus with the parietal right here, and premotor cortex areas in fatigued versus non-fatigued PBC patients. And these areas of the brain are very important for interpreting sensation from the body and preparing the limbs for movement. I'm gonna turn now to another part of the brain, which is actually part of the basal ganglia. Remember I said the basal ganglia and the limbic systems are very important in their connection with the prefrontal cortex and generating fatigue-like behavior. And the butamen plays an important role in learning and motor control, including speech articulation, language, reward, and cognitive functioning and addiction as well. And when you look at the butamen functional neural connectivity to other brain regions, it's also altered in fatigued versus non-fatigued patients. So here, what this shows is, if you look just at the green areas, there's increased functional connectivity of the butamen and the basal ganglia with the cortical areas that prepare the body for exact movements using sensory input from the body. And this is different in the fatigued compared to non-fatigued patients. I'm going to turn now after highlighting these objective changes in the brain that are linked to fatigue in PBC patients to just briefly talk about an approach to treating PBC-related fatigue. One of the most important things we can do is to rule out other causes of fatigue and treat the treatable. And then of course, general supportive measures. I want to also highlight, it's very important to regularly measure fatigue in PBC patients in the brain. And I see patients in the clinic. And there's many questionnaires that have been generated and there's the PBC-40, which can be challenging if you have a busy clinic to really implement those. I actually use a zero to 10 scale. Every time I see a patient in clinic with PBC, I ask them to rate their fatigue from zero to 10. So 10 being the, I mean, you can do it either way, but I actually do it opposite to this. I say that we have zero energy. It's actually that they can't get out of bed. They're so tired. And 10 out of 10 in my scale is that they can do whatever they want. And I use that to follow them longitudinally as well. A, it gives you a measure of how much their fatigue is impacting their lives at that time when they see you in clinic, but it also gives you a chance to follow it over time. This is a very nice sort of approach that's been championed by David Jones. It's really what's called the trace approach. And really it breaks it down into four groups. Treat the treatable. So if they have hypothyroidism or celiac disease, these are things that we can treat. Ameliorate the amelioratable. So if they're depressed, they should be treated for depression, but that usually doesn't impact their fatigue. If they have itch, which Andreas will talk about later, then controlling that can often help their fatigue a lot and avoid medications that drive fatigue. Help them cope with their fatigue so that they have ownership of the problem. Physical activity is very important, starting with graded kind of activity. Psychological help, cognitive behavioral therapy is something that can be employed. And then of course, the most important part as a physician is to empathize with their issue and show them that you understand that fatigue is part of their disease. And now hopefully I've convinced that there's objective changes in their brain as well. What about fatigue as a therapeutic target in PBC patient? I'm just gonna finish up with this. So I wanna remind you again that UDCA response does not improve fatigue in patients that are treated. And if you look at new additive therapies like albeta-tocolic acid, which is FXR agonist, it does not improve fatigue either. And in fact, you might say it even increases fatigue probably because it increases itch in some patient. What about bezefibrate, which is a pan-PPAR agonist? Well, there is the suggestion from this study from Kopersho, published about five years ago now, that the fatigue is improved or appears to be improved in the bezefibrate-treated group compared to the placebo-treated group. It's also important to remember though that bezefibrate does improve itch. And so this link between itch and fatigue definitely exists. I believe Andreas will touch on that. What about sort of newer therapies that are still in sort of phase two type of studies or later phase two studies? Like salidelpart, which is a PPAR-delta agonist. Well, there is a suggestion that it may improve fatigue in a nice paper published where Andreas is the first author. And what it shows in the higher dose, so these are people that are titrated up, but the people that are on the higher dose, 64% of those patients at a year, their fatigue score has improved. So it's suggesting that there might be a benefit for fatigue in PBC patients. However, it's important to recognize again that these improvements in fatigue, paralleled improvements in sleep and itch in those individuals who are treated with this dill. And then the cetaxanib, which is a NADPH oxidase one and four inhibitor, there is a suggestion that it may also improve fatigue. This is a publication that just came out quite recently. And then in the top as sort of an A panel, these are individuals that have a FibroScan result less than 9.6 kilopascals, the bottom of greater than 9.6 kilopascals. And you can see that they're, especially let's just, if you look in the people with the higher sort of liver stiffness, especially, but I think it's seen here a little bit as well, that there is an improvement in the fatigue scores 24 weeks. And interestingly, this improvement in fatigue in these patients was not paralleled by a significant improvement in itch. So it seems to be a fatigue and broadly a quality of life because pretty much all the domains within the PBC40 improved with this medication, except for the itch score. So I wanna finish off by just saying, patients have been told for many years that fatigue and PBC is all in their head. And it's often been treated as a symptom which is of less importance than targeting the liver disease itself. And obviously, stopping people from developing progressive liver disease is the prime objective. But I think it's quite clear that PBC causes objective changes in brain function, which are linked to the development of fatigue in these individuals. And I think on an up note is that fatigue is becoming a therapeutic target for the new PBC treatments and approaches. I think that the future is looking much brighter for our ability to treat the symptoms such as fatigue in PBC patients. Thanks so much for your attention. This is BAMF, which is near Calgary and Andreas is gonna show us Zurich shortly. So this is our competition for Zurich. Thanks so much. Thank you very much, Dr. Swain for your fantastic talk. It is now my pleasure to introduce our next speaker, Dr. Andreas Kramer, who is a physician scientist and a professor of hepatology at the University Hospital Zurich. He's also the deputy head of the department and has a lab group that focuses on autoimmune and cholestatic liver diseases. At this time, I would like to welcome Dr. Andreas Kramer to the virtual podium. Mitch and Michelle, thank you very much for this kind introduction. It's a real pleasure to give this talk in this special interest group on pruritus in liver disease. And I would like to start my presentation with my potential conflicts of interest. And before I start, I would like to give you a short introduction to the pathophysiology and clinical burden of pruritus in patients with liver disease. And I brought you two movies to illustrate to you how different pruritus can be experienced. And this first video is the jungle book and this is Baloo the bear. And you're well aware that when you have an itch somewhere, it can be very pleasurable situation to scratch that itch. And on the other hand, if you scratch your skin without an itch, it's not pleasurable at all. It is interesting to know that there are mirror neurons which have been investigated also in animal studies and they make you scratch if you see another person scratching as here Mowgli the orphan child. And if you have the tendency to scratch yourself during my talk, so don't bother. This is only a psychological phenomenon. Now to illustrate to you that pruritus can be way more bothersome, I brought a night video of a adolescent with a progressive familiar intraparticolistasis of cholestasis. And this illustrates to you how severe chronic itch can be during night. And you may imagine that pruritus may cause severe sleep disturbances, not only for the patient, but also for the parents who scratch often their children half of the night to enable them at least some sleep rest. And you may appreciate that such a strong sleep disruption may cause severe fatigue as illustrated by Mark to you. Now, how is the passive physiology or what is currently known on pruritus? Many years ago, we have sought that pruritus is the little brother of pain and that a little activation of sensory neurons which are here located in the skin may result as an itch and a stronger activation would be perceived as pain. However, this is not true. Bit more than 20 years ago, researchers, neuroscientists from Germany of the Handwerker Group could identify that there are a subset of sensory neurons here indicated in blue that respond to histamine but not to certain pain stimuli such as mechanical pain. And more recently, also non-histaminergic neurons have been identified which are capable of sensing non-histaminergic pruritic stimuli such as drugs, chloroquine, or other mediators. And once these neurons are activated, action potentials are transmitted via the dorsal root ganglia to the spinal cord. And here a complex interplay takes place. And then these stimuli are submitted via the contralateral spinothalamic train to the thalamus. This just illustrated by Mark's vein that all the input goes first to the thalamus before certain areas in the brain are activated. We have now a much better understanding that there is a close interaction between the sensory nerve endings in the epidermis with cells located here, the keratinocytes, but also immune cells, T-cells, mast cells, and others. Now, how does that relate then to the liver? We know that during liver diseases, in particular during cholestasis, various substances may accumulate. These may be bile acids, bilirubin, progesterone metabolites. They are capable of activating sensory neurons, bile acids, for example, sensory neuron-specific receptor, mass gene-related G-protein-coupled receptor, X4, MRG, X4, which is expressed on sensory neurons. And once these neurons are activated, it is the hypothesis that these cholephyllic substances may directly cause an action potential and then result in an itch. And to summarize potential mediators, there are lysophospholipids, which are likely to play a role, steroid metabolites, bile acids, but also endogenous opiates. And more recently could be shown that certain cytokines could also play a role such as interleukin-31, and I'll come back to that in a minute. Now, how does that relate now to this interaction between the liver, the gut, and the brain? It is our current understanding, this is a wonderful review of my previous mentor, Professor Boyas, that the enteropathic cycle is a very important part in the pathogenesis of coritis in liver disease. And these coritogens are somehow secreted into the bile, are taken up here, and transported back to the liver via the portal bloodstream. And certain drugs may improve coritis, for example, by influencing this, nasophilic drainage, by interrupting this enteropathic cycle, as well as albumin dialysis or plasma freezes in the systemic circulation, but also amnion exchange presence here in the intestinal lumen or ASBT inhibitors. On the other hand, rifampicin and basal fibrate may influence here the epidermal endothelial structures or the microbiome. And then we have, of course, the neuronal pathway, which may be influenced by opiate receptor agonists and antagonists or sertraline. Now, more recently, interleukin-31 has been also shown to be a pruritogen in particular in dermatological diseases, such as atopic dermatitis. And it was recently investigated also in patients with liver disease. And it could be shown that the activation of FXR in the liver results in an increased L31 production. And we could, with blood samples from a PPAR-Delta trial, show that interleukin-31 correlates with each intensity at baseline of these trials. More importantly, in this phase two open label study, we could show that L31 levels drop in those patients with improved pruritus after one year of treatment. And more intriguingly, the phase three study, which was placebo controlled, also showed this benefit, in particular, the 10 milligram group of siladelpa strongly not only reduced pruritus, but also attenuated or lowered the L31 levels. And thus, there is a nice correlation between symptom burden and the cytokine. But of course, it needs to be proven that there is also a causal relation. Now, I told you that pruritus and pain are likely to be mediated by distinct signaling pathways. However, they are closely intertwined. And I would like to illustrate that to you by this scheme. The pain signaling pathway is illustrated here in black. On the left, you have the skin. And as pain stimulus will result in activation of this neuron pathway here, activating neurons first in the periphery, and then in the central nervous system resulting in pain sensation in the brain. And in gray here, the itch signaling pathway. So what do you do when you experience an itch? You scratch that itch. And why do you do that? Because you want to activate these pain sensory neurons as they control itch signaling. There is an inhibitory control on these sensory neurons, which are under normal conditions silent. Only when you have an itch stimulus, these neurons will be activated. And once they are active, you can count them down by activating the pain network. And this can be done either by scratching, by cooling, by heating, by many options, but this will diminish itch experience. And you can also prove this inhibitory control by disinhibiting this inhibitory control, for example, by the application of myopieds or statics, in particular, very closely to the peridural or epidural compartment. And you may not feel a pain, but suddenly an itch may occur in this area. And another intriguing mode of action are kappa opiates, because they attenuate the pain signaling pathway, but keep this inhibitory control. And that's why they are currently investigated also as potential therapeutic options to treat an agonizing itch. Now, coming back to the liver, we have various hepatobiliary disorders, which are associated with pruritus, which are shown here in regard to the site of injury in the biliary tree. This may be a pure secretory failure, such as in intraventicolostasis of pregnancy, or the hereditary colostasis syndromes, benign recurrent intraventicolostasis, or the progressive forms by steroids, toxins, hormones, alcohol, but also viral hepatitis. Maybe a destruction of the small and smallest bile ducts, such as seen in primary biliary cholangitis, or a more obstructive component as seen in sclerosing cholangitis, or other benign and malignant disorders. Now, is pruritus really so severe? And to illustrate that to you, we investigated data from a phase two study using an IBIT inhibitor. And what I would like to illustrate to you here from easily abstract is that those patients suffering from severe pruritus, 35 patients, were those who reported on sleep interference, which was very severe. That was hardly observed in moderate and non-in-mouth pruritus patients. So this clearly illustrates to us the higher the severity of pruritus, the more patients suffer from sleep. And if we then ask for the quality of life, we were very much surprised that those patients with severe pruritus had the same quality of life as compared to patients with severe Parkinson's disease, which we would clearly indicate to be tremendously reduced. And so there is more and more data illustrating that moderate, in particular severe pruritus, tremendously reduces the quality of life of our patients. So how can we optimize the symptom burden in our patients? The first step is always a non-drug treatment that should be always offered to all patients. There are a lot of general measures you can offer to your patients, such as cutting the fingernails to reduce stretch lesions, explain them to use loose cotton wool clothes, keep everything cold, in particular where you sleep, cooling per se is better than warming the heat, that also holds true for taking a shower, and perform topical treatments. This is very important to keep the skin structure adequate. And what kind of topical treatment can you offer to your patients? You should look at the skin, the skin type, normal, then use rather a more emulsive, rehydrating topical therapy. If it's more dry or very dry, use a more lipid-containing treatment. And you may add a lot of substances which have additional benefits such as urea, polydocanol, menthol as a cooling agent, or a capsaicin. And on top of that, if you have patients with severe pruritus, and in particular those with secondary stretch lesions, UVB therapy should not be forgotten. And this is a nice retrospective analysis illustrating in various liver diseases that repetitive exhibition of UVB therapy three times per week resulted in tremendous benefits in the VASc score, and could be redone if pruritus came back after a second phototherapy course. So keep that in mind as a non-drug treatment for your patients. What kind of drugs can we offer? The previous guidelines recommend as a first-line treatment anion exchange resins such as cholesteramine. Keep in mind that they may bind a lot of other substances in the gut lumen, and that they have a horrible taste. However, they are the only in-label drugs for pruritus of liver disease. The second-line therapy is rifampicin in current guidelines. My point of view, it's the very thickest therapy. You may start only with 150 milligrams and titrate that slowly up. Often 150 to 300 milligrams are sufficient. Hepatotoxicity is around 5%, so please control transaminases after 2, 6, and 12 weeks, or after dose change. And be aware of the drug-drug interaction, which is caused by the cytochrome induction of PXR agonist. Third-line therapy are myopia antagonists, naltrexone. Fourth-line therapy, tertralin in the current guidelines. And then there are various experimental approaches I will come back to in a minute. If we follow this stop-bias approach, a certain percentage can be treated quite well, but there is a remaining percentage which is significant, which requires further therapies. And therefore, we are very lucky to be able to offer them novel therapeutic approaches if they suffer from this agonizing symptom. And the first one are the class of PPARs, paroxysome-proliferator-activated receptors, agonists. This is a slide illustrating the mode of action of the underlying cholestatic liver disease. It has anticholestatic and anti-inflammatory properties, improves lipid metabolism. The antifibrotic properties are less well-established. But aside these benefits of PPARs, they have antipyritic properties, as already illustrated by Mark Swain to you. And the first one I would like to show is the pan-PPAR agonist, basafibrate. The Fitch trial was a randomized controlled trial in PEC, PSC, and secondary sclerosing cholangitis patients, which were treated for three weeks with basafibrate 400 milligram versus placebo. Patients had to have a baseline pruritus in the moderate to severe range, about five, and the primary endpoint was each reduction by 50 percent. And that was achieved by almost 50 percent of the treated patients, while placebo had hardly any benefit. And when the treatment was stopped, pruritus came back in most of these patients, clearly illustrating to you that fibrates can be used in our patients as another valuable option. Be aware that hepatotoxicity may also be a problem here. The Bates-Urso trial showed six percent hepatotoxicity. Myopathia can be a problem. Do not use them in combination with statins. And nephrotoxicity is also a problem on long-term use. Be aware if kidney function is not adequate, I would not recommend to use fibrates in those patients. You've heard already about novel PPARs, which are currently investigated in phase three studies. This is data of psilodelpa PPAR delta agonist in a phase two study, illustrating to you beside the benefit on sleep and fatigue, illustrated by Mark to you, on pruritus. And intriguingly, those patients with moderate to severe pruritus, they all had a strong improvement, which was clinically significant, more than two points on a 10-point scale after one year of treatment. And also the phase three study, randomized control study, showed here clear benefit in the 10 milligram group compared to the 5 to 10 and placebo group. So this is promising data here and warrants further investigation in the ongoing phase three study. There are other PPAR agonists such as Elafibranor with smaller phase two studies. The benefits are less strong and established yet, but still there are tendency towards improvement also for sarroglitazar. And we are looking forward to the results of the phase three studies. Now what else can be offered to our patients? Anticonvulsive drugs are option, my point of view, which are worthwhile using. Gabapentin and pregabalin are established drugs to treat neuropathic pain. And interestingly, they are well-established in chronic kidney disease associated pruritus. And I recommend to use them in our patients as well. Is there now data in liver disease? There is one negative trial using pregabalin in a very small number of seven versus six patients here published by Nora Begasa more than 15 years ago. And the duration was much too short to really illustrate the benefit. Indeed, when the scratching activity was investigated, the scratching activity went up on gabapentin and went down on placebo, rather the opposite what we would expect. But if we look at retrospective data, and we have done that in our cohort, we observed a significant reduction of 5.8 on a visual analog scale, indicating a significant stronger benefit than the placebo benefit. And thus, I think these are suitable add-on therapies to other established drugs. Be aware that they are renally secreted, and you may adapt the dosing depending on the kidney function. And even in hemodialysis patients, they may be used in very low doses. Now, I told you that the enteropatic circulation plays a critical role in the onset of pruritus. And one mode of interrupting this enteropathic circulation is blocking ileal bile acid transporter, which is responsible for the uptake of bile acids back to the portal bloodstream. And there are several drugs which are currently investigated. They are not uptaken, they remain in the gut lumen, and they have a good safety profile but may cause diarrhea. And I will illustrate to you the first data on those drugs. Mirelixibat was investigated in a rare pediatric disease, the Ehlers-Danlos Syndrome, in this iconic trial. You may appreciate here the effect on an Itch-Rose score, a score on itch severity, and went down. And here was the placebo phase for weeks. The Mirelixibat group, which was put on placebo, had a strong deterioration of pruritus. And when they were put back to Mirelixibat, pruritus improved again. And there's a long-lasting benefit here on pruritus, but not only on pruritus, but also on the underlying cholestatic liver disease. And these very impressive data have resulted in approval by FDA and EMEA for Mirelixibat. There are these hereditary cholestasis syndromes, progressive familial intrepid cholestasis, and Odewixibat was analyzed for that. And you may appreciate that also in this phase three study, pruritus using two different doses resulted in a strong benefit in the pruritus score, but also bile acids also here came significantly down. And not only the symptom burden was improved in these patients, but also the underlying disease course was tremendously improved. And I personally think it's a disease modifying agent, which will result in much less development of liver cirrhosis and surgical interventions, including liver transplantations. And also here in regard to these tremendous benefits, Odewixibat was already approved to treat PFIC patients by FDA and EMEA. Though, more recently, FDA also improved this drug to be treated for patients with Ehlers-Danlos Syndrome. So now how does that relate to adult liver diseases? And here we have more diverging results. This is data on a phase two study of Mirelixibat in PBC. There was no benefit over placebo. In contrast, Linorexibat, another ibot inhibitor, showed a tremendous benefit here in PBC in a two-week trial. And the currently phase three study certainly has to prove the benefit of Linorexibat in PBC. We can discuss that later on. Now coming back to this opioid signaling, which is important in our patients, I would like to illustrate a little bit again on these kappa opiates, which inhibit pain signaling but keep this inhibitory control. And this is, of course, an intriguing target. And in reality, and this is a nice review of Giliosev-Povic from Miami, this is way more complex with various influencing factors, such as chemical, mechanical itch, scratching, and so on, and a descending inhibitory control. But still, this inhibitory control is well established. And does this also work in our patients? Nalforafin, which is a central acting kappa receptor agonist, was investigated for liver diseases. And there was only a mild benefit here after 12 weeks, eight to nine millimeters on the visual analog scale. And you may argue that this benefit is not really convincing. Still, it's licensed to treat this pruritus in Japan. FDA and EMEA were not convinced, thus this drug is not available in these countries. And we have to be aware that the adverse events are significant. However, there are more commonly developed peripheral acting kappa opiate receptor agonists, such as Difilicafilin, which was investigated to treat chronic kidney disease-associated pruritus. And this recent New England Journal paper illustrated that there is a significant benefit over placebo in a 12-week trial in hemodialysis patients. And importantly, there is a significant number of patients who experience a four-point improvement, 40%. This is really a strong benefit and burns further investigations. And there is an ongoing study in PBC with an oral dosing of this drug. And we are eager to see these results in the near future. So coming back to the guidelines recommendations, how will this change in the near future? We currently rewrite German guidelines and put next to cholesteroamine basal fibrate as first-line treatment. We also add the anti-convulsive drugs here. And further drugs are on the horizon to be potentially available in the near future. And thus, I think we have a much brighter future for our patients suffering from this symptom burden. In the very last two minutes, I would like to illustrate to you that there are also invasive procedures. I told you that these pruritusians accumulate in the systemic circulation, and we can potentially remove them, for example, by albumin dialysis in those patients being refractory to other treatments. And there indeed is a significant improvement, and this can be repetitively induced. And also plasmapheresis has been shown to have a strong benefit and, importantly, lasts for quite several months in these patients. This is an impressive benefit and should be considered before patients undergo liver transplantation. Also, the interruption of the entropenic cycle is important. Nasobiliary drainage completely interrupts this entropenic cycle and has been shown to be of significant benefit in BRIC and PBC patients. However, once the drainage has to be taken out again, pruritus comes back in days to weeks. It's much better in BRIC patients where we interrupt the cholestatic underlying disease, but for PBC, this is not convincing. And so with that, I would like to summarize. General measures should be taken in all patients and topical therapy should be the baseline therapy. There is a stepwise approach with basal fibrate or fibrates were available being as on the first line level with rifampicin and fibrates being the most thickest off-label therapies which are currently available. Combination therapy, I think the anticonvulsive drugs are suitable, but also other drugs. I didn't mention now doxepine, mirtazapine, and UVB light. If you have an incomplete response, please try to include those patients into clinical trials, which are currently ongoing. Palliative care, I didn't go into that. Naloxone, perfuser, cannabinoids can be an option here. And then we have these invasive procedures which should be used before we send patients to liver transplantation. And with that, I would like to thank you for your attention and I'm happy to take any questions. Thank you so much, Dr. Kramer, for that fascinating presentation. Now, we have time for a couple of questions and we'll go to a question from Christopher Bolus. This is directed to Dr. Swain. So fatigue is a frequent symptom in many inflammatory conditions, including RA and even more so in the post-COVID era. Do you know of any data on fMRI to suggest that the differences you found in PVC are unique or common to these other conditions? That's a great question. There isn't a lot of data. I mean, there's more and more data coming chronic COVID or long COVID. And in RA, there is some data. We've looked in IBD patients where fatigue is also a very common issue. And there are some common pathways, but there are many pathways which are not common. And I can say that the impact on the part of the brain that controls our social networks and our social engagement is quite differently impacted by those two disorders. And so I think for sure, the basal ganglia play a major role in fatigue and is impacted by pretty much everything that causes fatigue, but how that leads to changes in interactions with other parts of the brain can be quite disease, more disease specific. Great. Thank you. And this question says, why is pruritus worse at night? Yes, that's a good question. It has been clearly shown that each intensity undergoes a diurnal variation. And that's particularly in the evening and early night, our pruritus is experienced most severe. We have not fully understand why this is the case. This could be a diurnal variation of certain substances, which may have a 24 hour rhythm. However, no substance could be clearly shown to rise then in the early evening hours and drop in the early morning hours. I personally think we should always keep in mind that when we lay down at night in our bed, the sensory input goes down. We limit our sensory input and the pruritus remains. And thus you may imagine that pruritus maybe then sends more intents only due to the fact that all the other sensory input is limited. And secondly, under a blanket, we have a warmer situation than being outside and warmth is always a negative impact. These two factors could also result in this perception we have. So I think that this brings us to the end of our webinar. It was really fantastic. And Mitch and I would like to thank the speakers, Dr. Swain and Dr. Kramer for their wonderful presentations. We'd also like to extend thanks to all the participants, the cholestatic and autoimmune liver diseases special interest group, and the AASLD. As promised, any questions that we didn't get to today will be answered in the future via email. And we hope that everyone has a great day. Take good care. Thank you everybody for joining us.

fatigue

pruritus

cholestatic liver diseases

autoimmune liver diseases

central fatigue

peripheral fatigue

brain function

PBC

treatments

kappa-opioid receptor agonists