Itching for More: Improving Care of Pruritus in PBC

Start [00:05:21]

The Patient Perspective

 So for the first part, we want to ask our patient representative Pam Rivard just to start us off by describing what your personal experience has been with itch and PBC and kind of what impact on your life has had?

Pam Rivard: Thank you, Marlyn. Good afternoon everyone. It's my privilege to be here. Itching. I would have to tell you that itching is everything that you've heard your patients say that it is. It's serious. It's mind boggling. It literally turns into an issue of wound care when you're through scratching. Scratching can take place at night. Contrary to what I've heard in many places, you wake up with scratching.

My husband had told me years ago, you scratch like a dog with fleas all night long, and you don't wake up, and itch and itch and itch. So even when we're taking precautions not to break our skin, not to cause wounds, not to leave bruises, the itching is so insane. It happens even at sleep.

And I would say to not labor this point, we can come back to this at another point. In all of the assessments we’re asked to rate mild, moderate, or severe. I would suggest that in the course of a 12-month period of time, I cover all 3 categories. Sometimes it's just – I did that to you. I apologize. It's light scratching. It's something with touch. And you go on about your day. Sometimes it's moderate. It's pretty persistent. It's going on for 5, 6, 8, 12 hours. And sometimes it is wild where even as a healthcare professional, I literally sit in the evening and go, do I need to go to the emergency room? This is that bad.

So that's been my experience. The itching is real. It comes and goes. I get frustrated with some of the assessments, because I may go through a 3 or 4-month period of time where I don't – I'm not aware of. I'm not recalling itching that needed to be reported. But then other times, like a migraine, it just comes out of nowhere and hits hard for weeks on end. So that would be my summary of itching. It's real. Thanks.

[00:07:46]

The Patient Burden of PBC Pruritus

Dr Mayo: So we're going to talk just briefly about the patient burden of pruritus.

[00:07:51]

          Cholestatic Pruritus

So cholestatic pruritus. You all probably know that pruritus is the same as itching. And cholestasis just means impaired bile flow. And really you can get pruritus from any cholestatic disorder. We're focusing today on PBC, but certainly you can get it with other causes of chronic bile duct obstruction.

[00:08:15]

          PBC Pruritus Is Indiscriminate

The PBC pruritus is indiscriminate. And what do we mean by indiscriminate? It affects people regardless of their status. So here's data from a study from the UK. It almost 500 patients with PBC. And what it shows you is that it occurs pretty equally between males and females. It is present in all ages with a very broad age range. And the severity does not correlate with other disease markers that we have. It doesn't correlate with how long you've had the disease, what the lab values are, or what the degree of liver fibrosis is.

And I found it interesting, Pam, that you said some days are worse than others. That's exactly what I hear from – from my patients as well. Although in this very large UK study where they were actually grading it, the severity was similar on what was considered a normal day as opposed to – to a really bad day.

And just to highlight one patient's description, this is a quote that sounds very similar to things that I've heard before also. “Itch is more than just an itch, though. Itch is days and days of torture, thousands and thousands of ants and spiders crawling under your hands, your ears absolutely everywhere.” And that's something we hear a lot, that it's often a bug kind of crawling sensation, and that it's not on the top of the skin, it's just under the skin where they can't get at it.

[00:09:40]

          Impact of Pruritus on Day-to-Day Life

So the impact of pruritus on day-to-day life is pervasive. Itching interferes with sleep, interference with sleep worsens the fatigue that you might have from the disease to begin with. This can lead to depression. All of these can affect inability to work. And if you're not able to work, then you also can get more depressed and fatigued. And it really is a multifactorial consequences.

[00:10:07]

          Health Utility of Cholestatic Pruritus

So this is interesting data, where they assessed health utility scores of patients with cholestatic pruritus. If you're not familiar with it, that's a quality of life measurement that just assesses overall quality of life. And what you can see on the right, the PBC patients with different degrees of itch are shown in the orange bars. And if you have a PBC patient near the top there that doesn't have itching, their quality of life is similar to somebody who has hepatitis C or even someone who has hepatocellular cellular carcinoma from day to day.

But once you start to get mild or moderate pruritus, that quality of life drops significantly and is really on a par with somebody who has COPD or end stage renal disease. And for somebody who has severe pruritus, that quality of life is similar to someone who has severe Parkinson's disease.

[00:11:03]

Faculty Discussion

All right. So we're going to try some discussion. Sounds like we have some extra participants in the back there. I'm going to start with you, Stuart. We know that healthcare providers often fail to recognize the burden of pruritus. Why do you think that is? Or has that been your experience and why do you think that is?

Dr Stuart Gordon (Henry Ford Health): No, I think that's the case. Thank you, Marlyn, that was a nice overview. And I think the most obvious is the failure to ask the question, do you itch? I can't tell you how many times you say those three words and the patient's eyes light up. They've never been asked that question before.

So I think that the first and foremost is asking the question. And then the next is to sort of probe the severity of it. You were talking about bugs and fleas, and I had a patient just recently, you know, who really didn't complain about itch. But when I talked about ants crawling and that sort of a thing, she thought that her two dogs had fleas because she was feeling a crawling up and down her legs at night. And so it’s – it's not necessarily an itch per se, but it's – you know, when you describe it and probe a little bit more deeply, I think it will eventually come out.

And then, you know, the severity is another question. When you ask, do you have a back scratcher? How often do you use it? You know, you'll find out that they're actually scratching their backs all the time. And so I think it's just a matter of asking the right question and probing.

Dr Mayo: Yeah, I noticed that too, that sometimes patients, maybe because they've lived with it for so long, will sort of downplay the presence of the pruritus or attribute it, oh, my skin is just dry or I have fleas, or attribute it to some other cause when it really is coming from – from the liver disease. Why do you think patients – and this is probably more for you, Pam. Why do you think patients don't always share with the provider how bad their itching is, or what the impact of the itching is?

Pam Rivard: Probably a couple of categories. I would think sometimes we're very aware of the limited amount of time we have with the doctor, and there may be other issues like the fatigue, abdominal pain, whatever it is that you're seeing the doctor for at that visit. With patients like myself that have been dealing with it for almost 2 decades. And as I told my family doctor and my gastroenterologist, I've been telling you for 50 years something was wrong. And then all of a sudden I get the diagnosis.

But when I looked up all of the symptoms, I had had those for decades. I had been through dermatology. I had been through allergy. And I think as a patient myself, I'm speaking for, I had put many of those things to bed. I had found some alternatives, some things that helped me to some degree or another, and I just don't necessarily bring it up now. I did not actually have a first contact with a hepatologist until about 3 years ago, maybe 4 years ago.

So up until that time, it was strictly primary care who knew that I itched. And gastroenterology that just every time I said it, he just told me, learn to live with it. We have nothing for it, learn to live with it. And he just would move on. So those would be the reasons I would say that I don't bring it up.

Dr Mayo: Thanks. And before we move on to our next section, we're going to talk a little bit more about this.

[00:14:30]

          Take-home Points

I think we have audience poll questions. So these are the take-home points from the last section that cholestatic stark peritus is frequent. It's often a severe symptom, and it can dramatically impact day to day life.

[00:14:42]

          Poll 2

So here's our poll question. How do you most commonly assess pruritus. And your choices are:

1. I ask patients to rate as mild, moderate, or severe;
2. I use a visual analog scale;
3. I use a numerical rating scale;
4. I use the 5D itch scale;
5. I use the PBC 40 scale;
6. I use something else that's not on your list; and
7. I don't really assess pruritus specifically.

[00:15:28]

          Poll 2: Results

All right. so the majority of patients are asked, do they think their pruritus is mild, moderate or severe? And we have some more. But there are other. Pretty much everyone is – every response was indicated by at least 1 person.

[00:15:48]

The Patient Perspective

Okay, let's move on. Let's start, Pam, with kind of your perspective on assessing pruritus in the clinic. What's been your experience? You mentioned the one doctor said, oh, just live with it.

Pam Rivard: Deal with it. Yeah.

Dr Mayo: When you brought it up. If you don't bring it up, do the doctors ask you? I mean, what's been your experience about whether they ask you and if they – how – how much they delve into it?

Pam Rivard: They don't ask. And – and I will – with a little caveat here, as a patient, I'm sure each one of you have had a contrary patient that gives you some pushback or some itch or some – some itch. I come in with the itch. A little bit of pushback. Again myself, I – I’ve kind of settled the issue. They don't bring up the itch. I think in their mind, if I'm an established patient, they're waiting for me to bring it up.

I might get asked by the MA when I'm sitting there having my vital signs taken before the doctor walks in. I guess the question, if I'm asked, Marlyn, what is the itch like? It's – it's kind of a non-serious question. And they expect me no matter what the answer is, I'm going to get this – no matter how I answer the question, I'm going to get the same answer, right? There's nothing for you. Or here's a couple of things off label that we can try.

So I'm equal party in this not participating in bringing up the itch. I put some blame on myself as the patient.

Dr Mayo: I imagine that's not very motivating to talk about it if you're going to get the same response every time that there's something we could do.

Pam Rivard: It isn't. And I know –

Dr Mayo: That’s not true. There are things we can do right.

Pam Rivard: And I had spent 20 years with dermatology and allergy and never got to the bottom of it, and they would wring their hands. They would lament, we don't understand, we don't understand. We don't know what to tell you. So through all those different disciplines, like I said, me specific as a patient don't really go there. I had an experience. I think the last time I saw the PA last year in hepatology, I had had a horrific – I want to tell you, this was like in the top 5 itching incidences.

And it was an unusual place. It was on the back of my calves and above my knee, behind my leg. And when I had gotten up in the morning from evening scratching and evidently all night, I looked like I was ready for the hospital. I was black and blue. I was literally bleeding. I felt like the itch had come from the basement membrane and it was just a horrific mess, friction burn. And I had got asked by the PA. He's very thorough, how's the itch? And I said, it's been great for months, but you got to see this. And I pulled up my pant legs up to my thighs and he almost fell out of the chair, and he spun around and started putting labs in.

And I said, I think he's putting in a PT/INR to see if I'm bleeding. And sure enough, he was. It was that bad. I was massive, massive, massive bleeding under the skin from the itching.

Dr Mayo: That’s a good story. And it gets back to that feeling that it's under the skin. And so people just keep digging and digging and digging until they bleed.

[00:19:12]

Pruritus Evaluation: Guideline Recommendations

All right. So what are our guidelines say about assessing pruritus? The AASLD says that pruritus and the disease warrant separate evaluation and treatment. And the EASL guidelines say that evaluation of – should be done for all patients for the presence of symptoms, including pruritus.

[00:19:33]

          United Kingdom PBC Care Delivery Audit

So here's data that we don't do a good job at that. This is a survey from the UK showing that the number of patients who are actually assessed for pruritus – and this is not at a single visit, this is over a 2-year period – is kind of just over the median at about 60%. Almost 40% are never asked about it.

[00:19:58]

Patient-Reported Health Indicators and Symptoms in US Patients With PBC

And then here's another study from the US with similar results. This is the TARGET-PBC study where patients were asked to fill out questionnaires, both the 5-D itch and the PBC-40. And this categorized their itch as severe – very severe, severe, moderate, mild or not present at all.

And then they also asked the healthcare providers what they thought the patient's itch was. And the correlation was terrible. You can see on the far right, if the itch was qualified as very severe, then the providers got it right 100% of the time. But as the itching got a little bit less severe, providers almost always underestimated the severity of the itch.

[00:20:44]

Pruritus Assessment Tools: 0 to 10 Scales

There are official tools that you can use. There's several zero to 10 scales. There's the visual analogue scale where you make a hash mark on the line. There is the numerical rating scale. There's several of these that go from zero to 10. Typically on a zero to 10 scale, anything over four to six is considered moderate and seven to eight is considered severe. And I know that many of you said this is kind of the scale that you use in the clinic. And on our pretest question.

[00:21:16]

          Pruritus Assessment Tools: Detailed Scales

Some of the more detailed scales are the 5-D Itch and the PBC 40, which really delve into the impact on quality of life of the itching, not just the severity.

[00:21:27]

          Strategies to Assess PBC Pruritus

And in general a good strategy, as Stuart started us off by saying is the important part is just to ask and ask at every visit are you itching? And if the answer is yes, then following up with a question how is it affecting your day-to-day life?

And importantly, is it something you want to take medication for? Because that determines what your therapeutic discussion is going to be. Some patients will itch very severely but not want to take anything. Other patients have a mild itch and are miserable and would very much like to take something.

And then in terms of some of these more elaborate scales like the PBC 40 and the 5-D Itch, those are difficult to administer during clinic under a time restraint. But they can be administered like, for example, in the waiting room while they're waiting for their visit to start. But just keep in mind, if you do these, that how a patient reports their ich verbally might be different than what they record on a form.

[00:22:28]

          Take-home Points

So take-home points for this section are that all patients with PBC should be evaluated for pruritus. It should be evaluated separately than the underlying disease. It should be evaluated at each visit. Because as we heard from Pam, it fluctuates from time to time. And that's key to understanding how severe it is and whether the treatments are working. And there are more extensive tools available if you want to use them.

[00:22:57]

Beyond Biochemical Response: Managing Pruritus in Clinical Practice  

So now I'm going to turn it over for the second part of our program to my colleague Stuart Gordon. I'm going to hand this to you, because I think we only have one. We'll have time for questions at the end.

Dr Gordon: Yeah, sure. Okay. Thanks very much, Marlyn. That was sort of a nice – nice overview. You know, you sort of bring back all these memories of patients and their stories. And another was a patient who couldn't wear short sleeves in the summertime.

Dr Mayo: Absolutely.

Dr Gordon: Because she didn't want to show her arms and little things like that about how the itch then translates into quality of life issues.

So the next section is sort of moving on to Beyond the Biochemical Response: Managing Pruritus in Clinical Practice.

[00:23:39]

Commit to Finding a Pruritus Treatment to Provide Relief

And what do we do in the real-world setting? Well, this is a nice overview slide. It sounds good, right? We're committed to:

• Finding a pruritus treatment that can provide relief and to set appropriate patient expectations;
• Create an individual treatment plan that incorporates patient preferences;
• Modify therapy based on patient responses and tolerability; and
• Obviously, considering clinical trials.

So this is sort of a nice feel-good type of approach. Unfortunately, in the real world, we don't have a lot of options that are available to us.

[00:24:15]

Nonpharmacologic Treatments for PBC Pruritus

And this is a slide that also frequently shows up as far as nonpharmacologic treatments. And I think this is what a lot of us are left with in the clinic is:

• Topical moisturizers, which is what a lot of the dermatologists provide;
• Cool showers;
• Fragrance-free soaps and laundry detergents;
• Avoidance of irritating fabrics, you know, sticking with cottons and some of the non-irritating fabrics.

But I think this is, again, something where we would really want to hear from the patient. What – what helps you the most, you know, non-pharmacologic.

Pam Rivard: My turn?

Dr Gordon: Your turn.

Pam Rivard: My turn. Just like any other PBC in the room or in your practice, it's been decades of trying to figure out what works for me and what doesn't. Many of these things would come right out of an allergy or a dermatology flyer as well. Skin is skin.

Topical moisturizers. I have found something that's even better for me when this insane itching starts. I keep my nails short. People do tear and wound themselves terribly, and sometimes they can scratch all day and not do it. And then all of a sudden there's a wound.

I have found that when I am itching terribly, an actual lubricant, not just a moisturizer. I don't care if it's Vaseline, I don't care. Some thick, oily something or other. Most of us have some oils at home, be it – I don't care if it's olive oil out of the kitchen or coconut oil. The slicker it is, if I'm doing this, I'm not creating a friction burn. That helps me immensely with a really serious itch. I know I'm going to scratch. I know this is going to be ugly and I know it's going to endure. It's a bad spell. So beyond moisturizers, a very thick lubricant.

Cool showers. I've done both. I like to experiment on myself. What happens if I take a hot, scalding bath and Epsom salts, you know, let alone a cool shower? To each their own. I've heard people tell me that one or the other helps. Obviously, we all know with skin, heat does intensify a lot of feelings, sensitivities. So I tend to go with the cool shower.

The fragrance-free soaps and laundry detergents has been my lifetime experience, as I said, through allergy and dermatology. None of that worked for me. I never found that it was a sensitivity to any of those things, although I was very methodical and followed directions as a good patient and eliminated those things, it didn't change anything. So I can't really zero in on that other than that wasn't effective for me to avoid those things.

Irritating fabrics. I think that could have a subcategory, again, with skin, anything that has elastic in it, anything that binds the skin, underwear, socks. If your feet tend to swell and your straps on your shoes or sandals are tight, that's going to be an area where you start itching first. That's why I don't wear a watch anymore.

Many times if my hands top and palms are itching, I don't wear rings because that just seems to be a spot where it'll start. And before I know it, I'm itching all over. So myself, I have not noticed a difference between synthetics and cottons. I'll leave it at that.

Dr Gordon: Very helpful.

Pam Rivard: It has really been just a lifetime of trying to solve it on my own, because really great doctors who I trust my life with haven't been able to offer solutions, and they've been very honest that the industry hasn't caught up with products or medicines for us. And that's the best I think you can do as a practitioner. If you are not aware of or do not know, it's not out there and you tell me, that kind of leaves me up to my own devices. And I've been very creative. So I'll leave it at that.

Dr Gordon: Very nice, Pam. It's really more than – you know, it's very helpful. And it's a nice lead in to the next section, which is that hopefully there is some hope along the way.

[00:28:33]

Drug and Nondrug Management of Pruritus

So what are the current recommendations, both drug and nondrug for the management of pruritus?

Well, we turn to our guidelines and here we are at the AASLD. And what better place than to discuss the AASLD guidelines? And they have recommended that the first line of treatment should be to increase pruritogen excretion, which is in the form of bile acid resins. And it was interesting, you know, reading up on this, I saw papers from the 1960s from Sheila Sherlock. And really, things haven't changed in half a century where we're still recommending bile acid resins. And we'll talk about some of the concerns about cholestyramine in the next couple of slides.

Second-line treatment includes reduction of pruritogen production, so to speak, which would include rifampin. Rifampin has also been around for a long time. And we'll talk a little bit about the pros and cons of using it. I've used it. It's been helpful when I do use it, but we always do it with a little bit of trepidation.

And then modulation of – of the central itch pathway. And as we're hearing, it's not a typical itch. It may be mediated by other inflammatory cytokines. And so naltrexone, the opioid antagonist has been advocated in certain cases. And we'll talk about that a little bit more in the next slide, as well as sertraline, the – the SSRI and was first described here by Dr Mayo. And we'll talk a little bit about whether sertraline might be helpful in this particular setting.

And then we get into the third line, which is a whole list of – of different options that have been tried over the years. And this is by no means a complete list. The gabapentin and the phenobarbital are probably getting at some of the central mechanisms involved. Plasma exchange. Plasmapheresis have been used in some of the more severe categories.

The MARS device, the nasal biliary drainage, UV light, and as we mentioned, topical therapy. And there's a whole list of others. At one time, there was actually a potentially a role for transplant that's become much more difficult in recent times.

But it's important to mention here that UDCA is the first line treatment for PBC, but it really has no role in the reduction of pruritus in patients with PBC. And actually, there are actually some early papers early on, suggesting that some people actually get worse with their pruritus with UDCA. So it's not a treatment for the pruritus itself. Pruritus must be treated independently of the PBC.

[00:31:20]

First-line PBC Pruritus Treatment: Bile Acid Resins

So the first-line treatment of bile acid resins ideally would be cholestyramine. It can be given up to 4 times a day. It's a packet of 4 grams each. It's generally started off with 2 times a day. But you can go up to, I guess, 6. I've never gone more than 4 times a day.

And ideally when the gallbladder is in to give it 30 minutes before breakfast, 30 minutes after breakfast, 30 minutes before dinner at bedtime, just sort of work more effectively on the – on the putative bile mechanism for the cause of the pruritus. But all of the considerations and challenges in using cholestyramine include that it can interfere with the absorption of other drugs, so it must be given one hour prior or four hours after other medications to avoid inter – interference with these other meds.

It's a gritty, foul-tasting powder that's mixed up with water. It's very poorly tolerated, as you all know, nausea, bloating, constipation, and diarrhea.

There are also oral forms of the bile acid resins and including colesevelam and colestipol, both of which are in tablet forms and can be given up – given during the course of the day, BID or over the course of the day. But likewise associated with GI toxicity, including constipation and others.

[00:32:47]

          Beyond First-line Treatments for PBC Pruritus

So the second-line type therapies include rifampicin. It says 150 to 600. I personally have not gone beyond 150 a day, and we do it with a little bit of concern. So there is well-recognized hepatotoxicity in 10% to 15% with patients taking rifampicin. And that risk – and it's a cholestatic type of injury as well. And that risk is thought to increase with the severity of the underlying liver disease itself.

And often these are the people who itch the most. And it is to be avoided once the bilirubin starts rising above 2, 2.5. There are a number of drug–drug interactions, including some of the PPARs that we'll be discussing later, and we really don't want to be using it with other medications that it can be interfering with the absorption.

You'll frequently get a flag from the epic people or whatever your EMR, are you sure you want to write for rifampin? It's interacting with this or with that.

Naltrexone is an opioid antagonist, and I personally don't have a lot of experience with it. Rifampin, when it works, really works beautifully, and the patients like it and really don't want to go off of it. And the same appeared with naltrexone. But there's the concern here about withdrawal symptoms. And we don't like to use this type of medication for a prolonged period of time.

The SSRIs. Sertraline has been reported at least in one or two reports to improve the pruritus of PBC, and this benefit is felt to be independent of its improvement in depression. And fortunately, it is free of significant toxicity.

[00:34:34]

          Patient Resources

There are patient resources, and no program like this should go without discussing some of these resources. I'll frequently place my patients in touch with the PBCers, pbcers.org. And then the largest, probably in the world is out of the UK, the pbcfoundation.org. There's PBC Society in Canada and others mentioned here, including the Liver Foundation. And if you scroll down, you'll get to a lot of support in the PBC arena.

And then of course, clinicaltrials.gov. And there are ongoing clinical trials. And we'll be talking about those coming up shortly.

[00:35:12]

Panel Discussion

And so I guess the questions that I would pose to you, Marlyn, in no particular order is, one, why might there be a discrepancy between the healthcare provider assessment of itch and the patient-reported severity? We'll start off with that one.

Dr Mayo: So I think it's important to recognize that there is a difference. And I think there's probably a couple of reasons. First, what we write down is not necessarily what we say. And I think that's true for patients. We already heard that even – even the patient is – is cognizant of the limited time they have with the provider. And maybe they want to spend that time focusing on something else that's bothering them.

And whereas if they're filling out a questionnaire, then they're sitting down and exclusively focused on the pruritus. But the same is true for the healthcare providers. So they might discuss something but not necessarily write it in the note because of, again, time constraints or I know a lot of people have like note templates and so every note looks very much like the other note. And that might be part of it.

So I think – I think both parties what is – what is written is not always necessarily reflective of what is said. As a side note, I think it would be a really interesting study in the future to see if that changes with AI generated notes. And that is, you know, kind of the future, right, where you have your cell phone and you turn it on and it listens to the conversation and then translates it into a note, and maybe that would be more accurate. I don't know.

I think the studies that – that showed the difference between patient and healthcare providers and – and patients are not always, you know, perspective. I think they – they can also be subject to recall bias like you may think you talked about it but you didn't, or you know – so I think those are two of the big reasons.

And then sometimes people are talking and other people are not listening. That happens too.

Dr Gordon: Which of these scores do you use? You know, a lot of these are – are used in clinical trials, and you sort of nicely outlined the various different parameters that are used to assess severity. But what do you use, if any, in your clinical practice to assess pruritus?

Dr Mayo: Right. So we saw in the pretest question that most of the people in the audience are using the kind of like rate one to 10, mild, moderate or severe, how would you rate it? Full disclosure is that I wrote the 5-D, so I'm highly biased towards it, and I'm very well of all the work that went in to make sure that it captures the totality of the experience for – for the patient. But even for me, that – that's too long of a scale to – to do in the clinic.

The first time somebody does it, it takes them about 5 minutes. As they get used to the scale, it gets down to about 30 seconds, which is fine for a clinical trial. But, you know, my established slots are, you know, 15 to 20 minutes. And most of that is taken up by the MA getting the patient vitalized and put in the room and another five minutes for parking.

And I have precious amount of time left with the patient, and I don't want to spend it sitting there watching them, trying to interpret a question on a forum. so I also tend to just kind of do an open-ended mild, moderate severe.

I focused more on the what is the impact on your life than I do on the number?

Dr Gordon: No. And that's where we get some of these issues that you hadn't even thought about before of how the issue is actually affecting their life. And I think most of us are doing this mild, moderate to severe, 1 to 10. And I would agree with you.

Well, we talked about different treatments that are out there. None of them FDA approved for the management of pruritus. How do you discuss pharmacologic treatments, nonpharmacologic management of those that we've talked about so far, you know, which of you used? Not just first line, but also for the more severe.

Dr Mayo: Right. So you very nicely went over sort of the AASLD guidelines. And what we have as first line, second line, third line. And to be honest, I don't do it that way. I don't consider one first line, one second line and one third line. For me personally, it's more like playing a game of cards, and I have a deck of cards or, you know, a hand, and it's a very shared decision making with the patient. And I lay all the cards down and I say, these are the ones that we have.

None of them are usually going to completely obliterate the itch, but all of them have been shown to be helpful in one study or another. And then go through a detailed discussion about what it is that they're willing to accept and what their priorities are in a treatment. So there the side effects are different as you reviewed for each one. So one might have a risk of – of hepatitis. Another one might have a risk of interacting with medications. Another one might cause diarrhea. Another one might cause constipation.

And patients will have very distinct opinions about what they're willing to tolerate for – for their itch. And so we kind of go through that and – and come to a decision. And so all of those therapies – you know, I'd be willing to use any of them first line if I think that's the best fit for that patient. And it does take time to do that, but I would rather spend the time discussing that than having to fill out a questionnaire.

Dr Gordon: There's so much to discuss at each visit. We're just sort of touching on one of the manifestations of PBC.

[00:41:05]

          Take-home Points

So I think that the take-home points here then are nonpharmacologic options for mild pruritus include moisturizer use, and you sort of nicely discuss what type of moisturizers, cool showers, avoidance of irritating fabrics or soaps, guideline-based pharmacologic options for the moderate to severe pruritus currently at this stage in 2024 include bile acid resins, rifampin, naltrexone, or sertraline.

[00:41:35]

Itching for More: New and Emerging PBC Therapies           

So we're going to be moving on to some more exciting data coming up, new and emerging therapies. This is sort of the good part and the nice role that the pharmaceutical industry has played in sort of the development of some of these agents. How do I go back? Is this – no. How do we go?

[00:41:56]

          Poll 3

There we go.

Dr Mayo: Did we miss some.

Dr Gordon: Of your patients with PBC related pruritus, what percentage have significant ongoing pruritus despite the treatment with currently available agents? So you've gone through the current standard, what percent have ongoing significant pruritus?

[00:42:42]

          Poll 3: Results

There we go.

Dr Mayo: Okay.

Dr Gordon: Good. So it's really a smattering all across the board here of different degrees. So but – but still a significant proportion of patients who are sort of not responding to our current regimens. This is pretty much what we expected but really all over the map.

[00:43:03]

The Patient Perspective

So I think now it's sort of time to really ask Pam, what are the gaps in management? You know, where do we stand from the patient perspective in the management of PBC and in particular pruritus?

Dr Mayo: And how would you like providers to assess your itch also?

Pam Rivard: Good question. Let me begin with this one. As practitioners, this is a stick in my craw, if you will. It always annoys me no matter who I'm seeing if the itch issue comes up. Number 1, they tell me to use calamine lotion. Number 2, they suggest oatmeal baths. Don't do that. Because if you've got a patient who itches like this. First off, we already tried that decades ago. It doesn't work for us. So immediately it puts us – I did it again to you. I just hit this microphone.

It puts – it puts us back like, okay, here we go. And then the next question will be, do you have a lot of stress on your job? Are you depressed? Are you a high anxiety person? Unless you think I'm joking about that, the few times that I've contemplated seeking urgent emergent care because it was out of control, the itching, the number one thing that kept me from going was, I'm going to have to go through all of these Mas, all of these RNs in triage, residents, doctors coming in to see you in the ER bay, and they seem to get stuck on your psychological state of mind, why are you itching like a wild woman?

And if you get off – if I perceive that that's where you're going with this, and all you want to do is prescribe a benzodiazepine, you know, or calm me down with something and send me home, I have not communicated to you what the problem was. If I'm coming across as that hysterical, maybe the itch did that to me. I mean, I can do that with pain and a pain assessment. I can tell you that when I'm at 5 or 6, I'm a rational human being. I can talk to you and tell you what the pain is, describe it.

But once I start hitting 7, that heart rate's going up and I'm starting to get really antsy. And by the time it's 8, it's really hard for you to distract me, bringing me back to describe it. And I would say the same thing goes with itch.

So that's that piece. And I've said it. In fact, I will tell you this as a patient, the reason I have never agreed to the SSRI is 2 reasons. One, my itch is not a 365 day a year problem. When it is a problem, it's 100%. And I don't want to take a drug 365 days a year. But let's go back to seeking help, possibly at urgent care from a provider who does not know me well. I tend to stick with my doctors for years.

You don't know me well. The first thing you do, I tell you that I'm not anxious. I'm not under stress. I'm itching like a fool. And you see that I am taking an antidepressant. Again, that little decision tree goes off over here that she's really possibly got an emotional problem or a depression problem. And sometimes the wounds are so bad. If you've been itching, I don't want anybody to think I'm cutting or abusing myself. There's an issue there too.

So lest you think I'm exaggerating, I'm not, and I'll move off of that subject. But there's a question here, and it's a good one among nonpharmacological treatments. Do you ever – this would be for you, right – advise for acupuncture when your patient does not respond to drugs?

Dr Mayo: I have – I have actually never used acupuncture to treat pruritus. So -

Pam Rivard: And I've had a lot of acupuncture years ago and I never heard of it for itch.

Dr Mayo: Yeah.

Pam Rivard: Now that could be my ignorance on the subject, but I don't know anything about it. Was I to address this one? How would Pam like the provider to ask about the severity of her pruritus? Straight up, how bad is it? And don't confine me to 24 hours, 48 hours, 1 week, 1 month. I find myself very frustrated with that, especially if it ties in and it affecting the quality of your life.

Okay. I guess words have meaning and we all respond to different expressions and words. I love my life. I have a great life. I have a busy life, a creative life. I've changed my whole life to accommodate the fatigue, primarily with this disease and the itch. So just ask me straight up about it. Tell me you believe me. We're not exaggerating.

Over the years, when I've gone online to try and find more information, some things seem to disappear or become diminished in the literature, and some things become more pronounced. I think there's more, not just attention, but we're being believed more about the itch.

My gastroenterologist is brutal, as he was with me. He's a fine physician. He is. He's a fine physician. But he came right out and told me, Pam, I may not see three to five patients in my career with your diagnosis. So he really wasn't knowledgeable about a lot of things, and probably based on his training and what we knew a number of years ago, it was the truth. It's just the way he delivered it, and I'll forgive him for that.

If you're going to assess my pruritus and I tell you how severe it is, you don't have lots of options to counter with on how you can help me solve it. As Gordon and Marlyn have shared with us, there are things coming in the pipeline, and I'm really excited about that. I guess knowing – go ahead and ask it. I'm going to tell you truthfully, you'll have to address it with the tools that you have at hand.

And I want to make a little segue into this, and maybe we can come back in a few minutes. I don't know how I'm doing on time. But I really believe in the clinical trials and the privilege I've had to participate in several of them, and several of them I was kicked out of once my alkaline phosphatase was too low, and the other time it was too high. And they were both studies that I had wanted to participate in.

Offer that, say, look for it. You know, pass someone like me on to someone and get me registered for some clinical trials. There's some really good pieces and things to communicate about that probably a little bit later. But the answer to the question is, come right out and ask me and believe me when I tell you and don't quantify me to a specific period of time. Yeah.

Dr Gordon: Very nice. Thank – thank you, Pam. You know, and as you were talking about the sertraline, it was interesting to hear the patient's perspective, because when I first heard of the sertraline paper, I thought that's an interesting mechanism of action. I wonder how it's working. But I didn't really think that, you know, the patients would perceive it as, you know, a pejorative or that you're depressed. Right? And let's give you an antidepressant.

Well, let's hear from Dr Mayo, who wrote the paper.

Dr Mayo: Well, I – I think there are patients and physicians who – who wonder what the mechanism is and if it's just making people less depressed, which is why in the trial, we did depression assessments to see if it correlated. And I can't tell you for sure what the mechanism is. You know, we've done functional brain MRI studies that show that when people are itching from PBC, they get tremendous activation of – of the limbic system in the brain.

And interestingly, they do not get any sensory cortex activation. So it's not like a local sensory feeling coming from the arm or behind the knees or whatever it is that you're itching. And I suspect that that the neuromodulatory effects or downregulating that non-specifically, but don't know.

[00:51:53]

          PPAR Agonists for PBC: Effects on Pruritus          

Dr Gordon: All right. Very nice. I think we're going to move on to the next section here, which is really, I think, the most exciting that there's research into this arena, that there's interest on the part of the pharmaceuticals to come up with newer agents. And that we're really moving in a good direction here.

So over the next several minutes, we're going to be going over various agents that are being used and are showing promise in the treatment of cholestatic itch. And the first of these would be the PPAR agonist for PBC and for its effect on pruritus. And as this slide nicely outlined, there are various PPAR agonists that have different mechanisms depending on which receptor is being activated.

So there's the alpha PPAR agonist which is predominantly the fenofibrate. There's gamma. And then there's delta which is predominantly the seladelpar agent. And there's a Pan-PPAR agonists including bezafibrate and elafibranor. And what we're going to be going through here now in the next few slides include the FITCH trial, fibrates for itch, and the BEZURSO trial, which is bezafibrate and urso. We'll be talking about the phase III ELATIVE trial looking at elafibranor and the phase III RESPONSE trials for the seladelpar.

[00:53:27]

Pruritus Outcomes: Bezafibrate for People With PBC

So the BEZURSO trial was published in the New England Journal by Corpechot in 2018 and was a randomized, double-blind, placebo-controlled trial in patients with PBC who had inadequate response to ursodeoxycholic acid. So it was not predominantly looking at pruritus, but it was looking at the addition of beza with urso in the treatment of PBC.

And as you can see on the graph on the left here, specifically looking at the itch component, patients who received BEZURSO plus bezfib – the BEZURSO, the bezafibrate with urso seemed to have a reduction in their overall itch at the end of the 24-week period. So it was the beginning of – of literature that was starting to show that the bezafibrate may actually have improvements in itch.

And then the FITCH trial, which is fibrates for itch, which was a randomized, double-blind, placebo-controlled trial in patients with other forms of cholestasis, not just PBC. PBC, PSC, secondary sclerosing cholangitis. And this was published by de Vries in Gastroenterology in 2021.

And this is looking just at the PBC patients where there was 26 showing that bezafibrate for patients with PBC, 55% had a significant reduction in their visual analogue score compared to very few in the placebo group. So the emergence of literature suggesting that beza, which is not currently available in the United States, is having a favorable effect on – on itch.

[00:55:25]

ELATIVE Pruritus Outcomes: Elafibranor for 2nd Line Treatment of PBC

This is the ELATIVE trial, which was published by Kowdley in the New England Journal earlier this year. And this is, of course, the phase III elafibranor trial for second-line treatment of PBC. These are all patients who failed to respond adequately to urso. And this was a double-blind, placebo-controlled trial, phase III in PBC, who – patients who are unresponsive to urso.

And this is looking at the itch component. And as you can see, there's a separation early on in a trend toward improvement in the itch score over the course of the trial, and in particular, looking at the itch domain of the PBC 40 questionnaire, as well as the 5-D itch score, there were marked improvements on elafibranor as compared to placebo.

So the beginning of literature that suggesting now that these PPAR agonists can actually have improvement in itch, which is really not been shown before.

[00:56:27]

ENHANCE and RESPONSE Pruritus Outcomes: Seladelpar for 2nd Line Treatment of PBC

And then if you recall, there were two phase III trials for the seladelpar agent, both the ENHANCE and then the RESPONSE trial, where there were pruritus questionnaires throughout the course of the trial. All of the patients, as with elafibranor completed their itch questionnaires throughout the course of the trial.

And in addition to the benefit in the PBC and the alkaline phosphatase itself, there was marked improvement in pruritus that began about the first month and became significant by six months, and it was really maintained throughout the course of the clinical trial. So very exciting literature to suggest now that these PPAR agonists may be meaningfully helpful in the pruritus as assessed by various parameters in patients with PBC.

And again, this was stratified by patients only with NRS scores greater than 4. So these are the patients who itch the most.

[00:57:31]

PPAR Agonists for 2nd Line Treatment of PBC: FDA Approval Status

So where do we stand now with PPAR agonists for second-line treatment of PBC? Here's the current FDA approval status. Seladelpar was approved on August 14th of this year and is indicated as combination therapy with urso or as monotherapy in patients who were intolerant to the urso.

Elafibranor was approved in June of this year in combination therapy with urso or in patients who are intolerant as monotherapy. And then there's beza plus obeticholic acid. Obeticholic acid has been approved since 2016, and there's ongoing trials now looking at the combination of bezafibrate plus UDCA in a fixed dose combination for the patient population of PBC patients non-responsive to UDCA.

[00:58:24]

Ileal Bile Acid Transport Inhibitors

Well, the next interesting category is the inhibitors of bile acid transport, the so-called IBAT inhibitors. And I'm going to go through a few of them here now because this is really very exciting data. And a lot of it is just hot off the press.

We have maralixibat, which is indicated for pruritus but not in PBC, and the same with odevixibat which is – these two are indicated mostly in the pediatric population for patients with Alagille syndrome, and is also indicated in PFIC, progressive familial intrahepatic cholestasis, which is an entity that a lot of us don't necessarily think about in our AMA negative PBC patients. But it should be on our list of in the differential diagnosis to consider.

So the maralixibat is – is given at 190 micrograms per kilogram per day and is in a liquid form. Odevixibat can be available in a powder format at about 40 micrograms per kilogram per day, and both are approved for pruritus in Alagille and in PFIC.

And so there are side effects, GI toxicity side effects, but they seem to be less in the pediatric population than in the adult population, presumably related to the different gut microbiomes in the pediatric population as opposed to adults. But what I'm told from my pediatric hepatology colleagues is that it's generally very well tolerated.

And importantly, there was a nice paper by Sokol in hepatology in 2023 where the event-free survival was actually improved in these Alagille patients if they witnessed a greater than 1 point improvement in their itch scores. So very intriguing data coming out now on these two IBAT inhibitors.

There are two others that are now being looked at for the pruritus of PBC in particular. There's the linerixibat trial, which was GLIMMER, and this was published the IIb study in CGH, and we'll show that next and this study is complete. And there's also the GLISTEN trial, which is ongoing, which is the phase III trial, registration trial looking at linerixibat for the treatment of PBC pruritus.

This is perfect timing. The volixibat trial or the VANTAGE trial is presented today. So it's – the poster is out. The lead author is Kowdley. And it's a late breaker poster from today. I would encourage you to all take a look at it. Nice results. Looking at volixibat in the treatment of PPC pruritus. And so these trials are ongoing, which is really very encouraging.

[01:01:21]

GLIMMER: Linerixibat for Pruritus Associated With PBC

So this was the GLIMMER trial. The lead author was Levy, and it was in CGH last year looking at linerixibat for the pruritus associated with PBC. So this is a randomized, multicenter trial, IIb. So it was dose finding looking at patients with PBC and who had moderate to severe pruritus. Again, there were some GI toxicities that were seen.

And as you can see compared to placebo, all of the doses led to some improvement in the itch score. And in particular in the ITT analysis, none of these different doses met significance in the mean worst daily itch score here, whereas in the post-hoc analysis, looking at the worst itch score and in particular on a monthly basis, there were differences that were seen in the per protocol analysis, and in particular between placebo and the 40 milligram BID dose. And that is the dose that is moving forward in the phase III trial that is ongoing now looking at linerixibat for the treatment of pruritus in PBC. So exciting stuff coming out there. It's nice to be able to show some newer data and hopefully a preview of coming attractions.

[01:02:47]

Faculty Discussion

And so I will turn to Marlyn now and say, how do we best interpret these findings, both with the PPAR agonists in particular to start off with and the treatment of PBC-associated pruritus?

Dr Mayo: Thanks. That was a great review, by the way, of all of the – totality of pruritus data and our new agents. I think the effect of PPAR agonists on pruritus is real, because we've seen it now in multiple trials with multiple agents. Right? We've got bezafibrate, seladelpar and elafibranor, which have all demonstrated an effect on – on pruritus in one way or another.

But I think they're not the magic bullet that we are all hoping for. The data that you just showed that, you know, the average reduction in itch was about two out of 10 points for – for most of the agents. You know, one to three.

So if somebody's starting with an itch of eight out of ten, yes, it'll make them feel better, but it might just bring them down to, you know, from severe to moderate or from moderate to mild and not, like, completely abolish the itching.

I think with the PPAR agonists, they are approved as second-line therapy, and so they are given in a situation where the patients initially treated with ursodiol are attempted to be treated with ursodiol. And then you wait some period of time, you know, six months to a year, at least three months before you determine that they're not responding biochemically, and then add in that agent.

And if somebody has severe pruritus to begin with, you know, I don't think it's fair to the patient to wait that long to initiate therapy for their pruritus. Also, you know, you're going to have a lot of difficulty because these drugs are new on the market in the US and, you know, still under patent and not cheap. And insurance companies are still, you know, figuring out how they're going to handle this. It's difficult to get insurance coverage if – if the primary indication that it's a proof or is not there. Right.

So – so I think there's – there's – I think the effect is real. But I think – and I think it's helpful. But there are some stipulations such as, you know, patient access when you can treat them, how long you have to wait for them to treat them, etc..

Dr Gordon: So, you know, sort of a nice overview. And these are sort of the realities that we're putting up with in the clinics right now as we speak, in terms of indication which patients, how long, when, etc. And we have patients who itch who are not necessarily PBCers.

And what about the IBATs, Marlyn? This is a nice burgeoning field and it's very exciting. How is this, do you think going to fit into the landscape of PBC-associated pruritus?

Dr Mayo: Right. So – so – well, first of all, they're – they’re not the – the ones that are under study in PBC are not yet approved. So we're all talking hypothetically in the future. Although I have tried to get odevixibat or maralixibat for some of my adults, it's been a challenge.

Dr Gordon: Expanded access. Sometimes you can petition to get it.

Dr Mayo: Yeah, he's talking about the difficult access. But I think the IBAT inhibitors, because they are being tested explicitly with the primary indication of treating pruritus, unlike the PPAR agonists, have the potential to be a first-line therapy. So for me, I made the analogy earlier today where I said I kind of lay out the cards and say, here are choices. I think that IBAT inhibitors are going to be another card in my hand that I can use, hopefully to treat patients.

They are also not a complete magic bullet, but can improve pruritus as the data that you showed. And as I'm laying out the cards and discussing the pluses and minuses, there are, you know – pluses are that these drugs are not absorbed, so there's very little interaction with other medications. It's easy to take. Minuses would be that you're going to probably most likely have more frequent bowel movements because especially in the beginning when you're flushing all those excess bile acids out in the gut, and that may be very tolerable to some patients. But if you have somebody who has IBS-D or something that may not be tolerable.

So I think they have the potential to be a first line. It's just going to be another card in my hand to potentially play.

Dr Gordon: Very nice. I would agree with all of the assessments. They come with advantages and potential challenges and exciting times to come.

[01:07:53]

          Take-home Points

I think that the take-home points here from these last several slides is that there are additional therapeutic classes that represent promising treatment advances to help patients with pruritus, and in particular, cholestatic pruritus. Two PPAR agonists recently gained FDA approval for the second-line treatment of PBC, both seladelpar and elafibranor.

and then beza plus OCA has an orphan drug status, but is not yet FDA approved. And phase three clinical trials of linerixibat for PBC-associated pruritus are ongoing.

Did I skip something or was that it?

Dr Mayo: I don't know if you did or not.

[01:08:42]

          Posttest 1

Dr Gordon: All right.

Dr Mayo: Hard to reach.

Dr Gordon: At each visit I plant – this is the question for you guys. At each visit, I plan to specifically ask my patients with PBC whether they are experiencing pruritus and to what extent?

Dr Mayo: This is the posttest.

Dr Gordon: This is the posttest.

Dr Mayo: To see if anything has changed.

Dr Gordon: Exactly, I should have said that.

Dr Mayo: And just in case anybody is wondering, I think they're testing us with this tiny, itty bitty microscopic font for the next conference next week for the ophthalmology conference on us. This.

Dr Gordon: Yeah.

[01:09:34]

          Posttest 1: Results

Dr Mayo: I think I would have to do some statistics on that to see if it was different in the first one.

Dr Gordon: Well, at least we got you attuned to the fact that we should be asking the questions. And I think that's good news. So I think more people are going to be asking their questions and really to sort of build it into the clinical practice and not forget about it. I think a lot of us just don't think to ask or focused on the alkaline phosphatase, but I know personally I'll be asking much more frequently.

I could do this. All right. So the next one. Do I do this?

[01:10:16]

          Posttest 2

You encounter a patient who is newly diagnosed with PBC and moderate cholestatic pruritus. What is the best way to address their pruritus?

1. Treat the PBC first, then treat the pruritus if there's no improvement;
2. Treat the PBC first – treat the pruritus first, then treat the PBC;
3. Treat the PBC and the pruritus independently; or
4. Watch and wait to see if the pruritus symptoms improve independently.

[01:11:12]

          Posttest 2: Results

Great. Good. And a significant improvement. Two separate conditions also often appearing in the same patient that need to be treated independently. Great.

And I think that this is a rationale – we – did we go back. Go back. Yeah. The AASLD guidelines, specifically – and we'll go back to the previous one as well. The AASLD guidelines state that PBC-associated pruritus can significantly impair quality of life, which we've heard so eloquently this afternoon and does not typically improve with first-line PBC treatment. Therefore, pruritus warrants two separate evaluations and treatments. And did you want to go back to the previous one as well?

Dr Mayo: That was the question. Answers.

Dr Gordon: Okay. So we'll just go on to the – and that was.

[01:12:13]

          Posttest 3

So in clinical trials, all of the following agents for PBC showed promise for improvement of pruritus except:

1. Elafibranor;
2. Seladelpar;
3. Bizafibrate;
4. Linerixibat; or
5. Ursodeoxycholic acid.

[01:12:59]

          Posttest 3: Rationale

Excellent. All right. Well, most showed that answered the correct answer, which was E, all of these agents now both the PPARs and the fibrates have shown that. And the IBATs have shown – demonstrated potential to improve the pruritus in clinical trials, except for urso. Urso is not known to improve pruritus.

[01:13:36]

          Poll 4

And do you plan to make any changes in your clinical practice based on what you've learned today's program? Well that's

1. Yes;
2. No;
3. Uncertain.

[01:14:14]

          Poll 4: Results

Very nice. Okay. 90% of you answered correctly.

Dr Mayo: You just made the CME people happy.

Dr Gordon: The other 10% are already know all of this. That's great.

Any other questions? Or did you want to just –

Dr Mayo: Yes. So this – what it says on the screen is kind of the last CME question, which is please take a moment to write in one key change that you plan to make in your clinical practice.

Q&A

Dr Mayo: But I think while you're doing that we can launch into kind of a Q&A session to – to wrap things up. I think we have a few that that came in through the – through the iPad system here. Let's see. We have a couple that are about the relationship between itching and abnormal liver enzymes. Can patients experience pruritus when the liver enzymes are normal? Stuart?

Dr Gordon: No, no. I mean, absolutely they can. To my understanding, the correlation is not the best. And that you definitely can see pruritus.

Dr Mayo: So if that is true – here's the second half of the question. If that's true, should patients who have itching and normal liver enzymes have – have a biopsy to diagnose PBC? Or should we be thinking that this itch is not from the PBC?

Dr Gordon: There it gets a little dicey, you know, especially if they're AMA negative to sort of conclude that this is a cholestatic itch. I mean, I generally want some sort of corroboration that this is a cholestatic itch, and that's a difficult situation. You know, I think if there's evidence that this is AMA negative PBC or something to suggest ongoing cholestatic liver disease.

Dr Mayo: Well, I think even independent of itch, if you follow the AASLD guideline definition of diagnosing PBC, you have to have two out of three items. And if your alpha is normal, then you have to have a biopsy that shows some cholangitis itch or no itch.

And then similarly, there's a question for you, Pam. At what point in your diagnosis did your itching start? Did it correlate with bilirubin levels in you or liver enzymes?

Pam Rivard: My itching started years before diagnosis. You know, my standard thing with my primary care physician. You know, we're always chasing Pam's complaint about, is it my gallbladder? Is it my liver? And the test would always come back fine. He would, you know, order some gallbladder tests. Everything is fine. We had that ongoing discussion. And through all that time I itched to the point where when he called me one day in a panic that my routine liver labs were way out of whack. He was very upset. I was totally disrespectful and didn't mean to be. I just blew it off.

I said, what do you mean? My liver labs are bad? I've been telling you for decades my liver is bad. So the itch did not correlate previously with normal liver labs. And at the time I was diagnosed with high liver labs, I had no itch. And then it's just been kind of a mix to keep this. And we'll just kind of a mix going on.

The last two years, my liver enzymes have been high and have not come down. It's not been my norm over the last two decades. It's fluctuated. And I did not start serious itching again until about two weeks ago. I am a serious itch. And so it'd be easy to say that correlates with my high alkaline FOS[?] right now. But historically, that's not been the case. The two are unrelated in my instance.

Dr Mayo: So you – you follow what the literature would say, which is that they're not related. There are a couple of questions here that relate to some of the – the newer medications. One statement says seladelpar, elafibranor and ocaliva are all contraindicated in cirrhotic patients.

That is not necessarily true. They are not approved for use in decompensated cirrhosis, but somebody who has a child's ACE cirrhosis is – is able to take those drugs. The question just disappeared. Maybe the AV people hit it.

All right. So thank you for bringing it back. No. I will – I didn't get to the second half of the question, but it says – and then another question says, what about itching in cirrhotic patients? How should we handle those? Like I said, the PPAR agonists can be used in the earlier people. The – the treatments that we have that are off-label but suggested in the guidelines such as rifampin, etc, and bile acid binding resins are also not contraindicated in cirrhotic patients.

What do you do with someone who has decompensated cirrhosis who itches a lot?

Dr Gordon: Yeah. I mean, I stay far away from rifampin. I stick with the cholestyramine. We're really in an off-label arena here. I think we're sort of nervous about fibrates and this type of a situation. If they're decompensated, they're generally listed for transplant. But what do you do?

Dr Mayo: I also tend to like to stick to bile acid binding in – in that group. But like I said they're not absolutely contraindicated. So someone who's uncomfortable I'm – I’m willing to – to try it as long as the patient understands the risk and we monitor carefully.

There's a couple of questions about itching in non-PBC, like other cirrhotics, non-PBC liver disease. How do we handle those? Do you want to tackle that?

Dr Gordon: No, I think we're just going by the guidelines on – on bile acid binding resins. I mean this is a very real issue. I mean, a lot of our fatty liver patients itch. Some of our alcoholic liver disease patients itch. It's not unique to cholestatic liver disease. And I think it's an important arena. Hopefully when some of these IBATs come out there or, you know, whether there may be a role for some of the PPARs in this type of a situation, it would again be off-label. But it's a very debilitating symptom. And it's not limited to cholestatic liver disease.

But I would probably stick with the bile acid binding resin.

Stop [1:21:00]