So, hello, I'd like to welcome everybody to this AASLD webinar, which was put together by the cholestatic and autoimmune special interest group. The title is the 2018 Primary Biliary Cholangitis Practice Guidance Highlights. My name is Dr. Marlon Mayo, Professor of Medicine from UT Southwestern in Dallas, Texas. And my co-moderator today is going to be Dr. Cynthia Levy, Professor of Medicine from University of Miami Miller School of Medicine. Hello. So, Marlene, we noticed that 2009 PBC guidelines were called practice guidelines, but this new document, the 2018 document, is called the practice guidance document. Can you clarify to us what's the difference between a practice guidance and a practice guideline? Yeah, Cynthia, that's an excellent question. At first, it may sound like just a semantic difference, but I think it's important for our audience to understand what the difference is. So, the basic difference between a practice guidance and a practice guideline is that a guidance is really derived through an expert-driven assessment of the literature, and then those experts develop recommendations based on the quality of the literature, whereas what's called a guidelines is really driven by a systematic review, which is developed to answer specific questions. And guidelines were defined by the Institute of Medicine in 2011, and in order to qualify as an official guidelines, a document has to satisfy certain criteria. One is that the recommendations have to be driven by a systematic review. Also, the committee that derives the guidelines has to be multidisciplinary, and each member of the committee has to be vetted with respect to conflict of interest. And the ASLD adopted this format for guidelines just in 2016. So, the 2009 ASLD recommendation document, I'll call it that, that you referred to was called a guidelines at the time, but nowadays would be considered a guidance. And this new document that has just come out is also being called a guidance. Now, that doesn't mean that it lacks rigor. Each of the recommendations is still graded for the quality and the strength of evidence, but starting from 2016 forward, all of the ASLD documents that do not follow the Institute of Medicine regulations will be called guidance documents. And there are advantages and disadvantages to having a guidance versus a guidelines. A guidance can be more comprehensive because you're not limited in scope to those things that have an abundance of literature in order to do a systematic review. The disadvantage is that a guidance document is not allowed to be published in the guidelines clearinghouse per Institute of Medicine guidelines. So, what we're working with here today is technically called a practice guidance. So, some of the issues that are addressed in the document I thought, you know, you and I could talk about for our listeners. And I guess the first important issue is, according to ASLD, what's required for a diagnosis of PBC? What do you think, Cynthia? What does the guidance say? Yes. That is an important question. Very important part of management of PBC is actually making the proper diagnosis. We require two out of three criteria to be present. So, we need biochemical evidence of cholestasis with elevation of alkaline phosphatase and chronicity. So, that is determined by this elevation in alkaline phosphatase for more than six months. And the second criteria is presence of antimicrobial antibodies or, nowadays, we have very well-defined PBC-specific antinuclear antibodies. And they are not widely available, but there are certain research labs and even some commercial labs that can run them for you. So, if you're able to obtain those tests for those patients who are AMA negative, they would count as a positive criteria, right, the PBC-specific ANA. And the third criterion is histological evidence of non-supportive destructive cholangitis with destruction of interlobular bioducts. So, we need two out of three. And obviously, then, if we have this unexplained elevation of alkaline phosphatase and the presence of antimicrobial antibodies or this PBC-specific ANA, we don't necessarily need to proceed with a liver biopsy. There will be specific indications for that. I wanted to just spend a minute on this PBC-specific antinuclear antibodies. They have been demonstrated several years ago and, unfortunately, haven't made it to mainstream labs. But the nuclear rim or rim-like pattern for which the main antigen is the GP210 is one of these antibodies. So, we call it anti-GP210. The other one has a multiple nuclear dot pattern. There are three to 20 dots of variable size that are distributed throughout the nucleus sparing mitosis. And the main antigen is the SP100. These antibodies are present in 20 to 30% of all cases of PBC. And more recently, over the past couple of years, a couple other autoantibodies have been demonstrated that are also PBC-specific, like the anti-calc-like 12 and the anti-hexokinase 1. So, those are important, especially for the AMA-negative patients. With respect to the liver biopsy, as I mentioned, we don't have to biopsy everybody to make a diagnosis of PBC. The specific indications would be AMA-negative patients for whom we cannot demonstrate this PBC-specific ANA. Or if you suspect an overlapping condition with autoimmune hepatitis or a coexisting liver disease, such as non-alcoholic steatohepatitis. In the figure here, we illustrate the four stages of PBC. On panel A, it's stage 1, where you have this significant portal inflammation surrounding the bioduct and forming a granuloma-like structure and lymphocytic destruction of the bioduct. On panel B, we see starting some focal interface hepatitis, so that is stage 2. In panel C, we have bridging inflammation, and in D, we already have cirrhosis with nodule formation and octopenia. One specific question that comes up very often is how to diagnose this AMA-negative PBC patient or this overlap with primary biliary cholangitis and autoimmune hepatitis. To clarify, as the name implies, AMA-negative PBC patients will lack AMAs, but they have similar clinical presentation and histology as the AMA-positive patients. They tend to have a higher prevalence of antinuclear antibodies, antismorph muscle antibodies, and a lower level of serum IgM, although the clinical relevance of that is unclear, and a higher prevalence of extrahepatic autoimmune diseases. Regardless, they seem to have the same response to treatment. The algorithm on the right just illustrates the path to diagnosis. If a patient has intrahepatic cholestasis and we have checked the AMA and that is negative, we have the option of testing for PBC-specific AMAs. If that cannot be done, we do have to pursue liver biopsy to confirm the diagnosis. As for the overlap with PBC and autoimmune hepatitis, that is slightly more controversial. But the more currently accepted criteria would be the paired criteria, which would involve having at least two out of the three mentioned here, in addition, of course, to the findings of PBC. Those would be patients with a more prominent inflammatory infiltrate and more prominent inflammation. So, they tend to have higher transaminases and typically with ALT greater than five times upper limit of normal. Their IgG will be higher as well, and the criterion would be IgG more than two times upper limit of normal or a positive antismorph muscle antibody, which is a little bit more specific. And in the liver biopsy, we would observe more moderate to severe interfaced hepatitis because we need to remember that mild interfaced hepatitis is actually a normal, common process in primary biliary cholangitis. We see that in that stage two disease, as I mentioned previously. So, we would expect a more significant inflammatory infiltrate before we can attribute this to overlap. As far as the guidance document statements, just to summarize to the audience, the diagnosis of AMA negative PBC does not require liver biopsy if other criteria met, including the cholestatic liver test and PBC-specific autoantibodies, such as the SP100 or GP210. Liver biopsy to rule out concomitant autoimmune hepatitis or other liver disease should be considered in PBC patients when the ALT is more than five times the upper limit of normal. And in cases of suspected PBC and autoimmune hepatitis overlap, treatment should be targeted at the predominant histological pattern of injury. So, those are the guidance recommendations. Thanks, Cynthia. I think that's really helpful that the ASLD provides clear definition of how we should all be defining PBC and also when liver biopsy is indicated. So, we were thinking we could talk about therapy a little bit during this webinar. And most of our audience knows that we've been using ERSO for some time for treating PBC. So, is that still what we consider first-line therapy? Yes, definitely. It's still first-line therapy. The dosing recommendation is 13 to 15 milligrams per kilo per day. We often tell patients to start gradually so they get adjusted to possible side effects, which I'll mention next. I usually tell patients to start with one pill a day and then after about a week, go up to the recommended dose. This should be administered in two divided doses and taken with food to improve absorption. Although we must also say sometimes to improve compliance, patients do take it once a day and they still get the full benefits from the medication. But the recommended pathology is two divided doses. And it's also important to remember that if our patients have itching and they're taking cholesteramine or other bio-acid resin, the UTC should be taken separate from this. So, we recommend one hour before or four hours after. That's very important to consider so that we don't lose efficacy here. As far as side effects, UTC is a very, very safe drug. There are some reported side effects, especially GI intolerance. Some patients will have diarrhea and very rarely will have complaints of constipation, but they can most often adjust to these side effects. Dyspepsia and nausea can also be reported. Women sometimes complain of hair thinning with UDCA and weight gain has been demonstrated, but no more than a five-pound weight gain during the first year. And this is not a progressive weight gain. Occasionally, we'll have a patient who will complain of worsening of itching when they start UDCA. And again, they tend to adjust to that as well. So, Urso remains a first-line therapy. It should be used in all patients who have elevated alkaline phosphatase. And it has been demonstrated to improve biochemistries, this low progression of fibrosis, delay appearance of esophageal viruses. Urso also lowers serum levels of IgM and cholesterol. So, in combination, studies have shown now that the use of UDCA decreased death or the need for liver transplantation. On the right, I plotted a graph based on this large international meta-analysis that was published in 2014, showing the transplant-free survival of thousands of PBC patients, I think close to 4,000 patients here. And you will see that at 5, 10, and 15 years, the survival of UDCA-treated patients shown in green is better than that of untreated patients shown in orange. Our guidance document then recommends UDCA in a dose of 13 to 15 milligrams per kilo per day orally for all patients with PBC who have abnormal liver enzyme values, regardless of histologic stage. For patients requiring bioacid sequestrant, UDCA should be given at least one hour before or four hours after the bioacid sequestrant. Wonderful. So, the treatment with ERSO sounds like it has remained pretty similar since the 2009 document. There is a section in the new guidance document called Assessing Biochemical Response. Can you explain a little bit what that section is about, what that means? Thanks, Marlene. This is actually one of the most important sections of this guidance document. Over the years, we have understood, we have learned that about 40% of our patients with PBC do not respond completely to UDCA. So, that leads us to believe that risk stratification is not a good idea. So, that leads us to believe that risk stratification and evaluation of this biochemical response is important because we know that patients who don't respond are at increased risk for progression to cirrhosis and decompensation. So, now that we know that patients who don't respond poorly comparing to those who normalize their liver biochemistry, we have learned to identify patients early on. So, we have to, this is the risk assessment that we talk about or precision medicine, identifying baseline factors that hint at those patients who may not respond to drugs, so they have to be monitored more closely. Patients who are younger than 45 at the time of diagnosis, males, patients who already have elevation of bilirubin or lower albumin at baseline, those with the anti-GP2-10 or anti-centromere antibodies, those whose APRI score, the AST platelet ratio index greater than 0.54, and patients whose liver stiffness at baseline is higher than 9.6 kilopascals are at increased risk for non-response and progression. When we talk about evaluation of biochemical response, we're now talking about one year after initiating treatment with UDCA. So, regardless of how high the risk is for non-response, you're still going to start UDCA as your first line, and you're going to monitor them closely. At one year is when we're going to determine whether they're responding or not. And as the table shows, and we have that depicted in the guidance document as well, there are several different criteria that have been developed so far. And of course, we don't have to memorize all of them, but if we pay close attention, we'll see that alkaline phosphatase is central to most of these response criteria. So, for instance, the Mayo criteria or Rochester for patients whose alkaline phosphatase does not drop below two times the per limit of normal after a year of therapy, they're considered incomplete responders or non-responders. The Barcelona criteria refers to a reduction in alkaline phosphatase greater than 40% from baseline or normalization of alkaline phosphatase, and so forth. So, we can use this binary criteria, or we can use one of the newest continuous models. They're more sophisticated, and they include the UK PBC model and the Globe PBC model. They're both available online, and they will take advantage of the continuous relationship between the liver biochemistry, especially the alkaline phosphatase and bilirubin, with prognosis, as opposed to just dichotomizing the biochemistry. In case here, alkaline phosphatase, did it drop or not? We're actually going to look at the value continuously and have a more precise, more accurate prognostication. So, we should use one of these criteria at the end of the year to determine if our patient is responding or not. And this is, again, stated at the guidelines or guidance document that biochemical response to UDCA should be evaluated at 12 months after treatment initiation to determine whether patients should be considered for second-line therapy. As far as second-line therapy, that is indicated for those patients who are either intolerant to UDCA or who have incomplete response after this year of treatment with UDCA. The only FDA-approved therapy as second-line in PBC is obetecolic acid, or OCA. There are non-FDA-approved therapies that can be considered in selected cases, and those will be fibrates or budezonide. So it sounds like there are so many different criteria that can be used to assess response, but your comment that they're all very similar, I think, is a good one. And the important thing is that if people are following the guidance and just at 12 months assessing, just using any of those, if all patients are being assessed, we'll probably be able to detect the majority, if not all, of the patients who are in danger of progressing without additional therapy. And the guidance document is the first to talk about the use of obetecolic acid, which is our new FDA-approved therapy. So I was hoping you could explain for the audience just what is it, what's its role, what can you tell us about obetecolic acid? Right. So this is true. Obetecolic acid was approved in May of 2016. It is a semi-synthetic bio-acid. If you look here in the panel, in the center we have canodeoxycolic acid, which is a naturally occurring bio-acid. It's the endogenous FXR agonist. Obetecolic acid was developed as this synthetic bio-acid that has this side chain, this 6-alpha-ethyl side chain modification, which makes this drug 100 times more potent as an FXR agonist. FXR is the fornozoid X receptor that is central in bio-acid modulation, as we're going to be discussing soon. So obetecolic acid, again, it's a semi-synthetic bio-acid that is a very potent FXR agonist. Drugs that activate FXR, so once FXR is activated, what we see is inhibition of bio-acid synthesis. There's also an increase in bio-acid secretion into the biocannabicloid. There's inhibition of bio-acid uptake into the hepatocyte, and inhibition of TNF-alpha pathway, so an anti-inflammatory property as well. So in summary, with FXR activation, we have a decrease in the concentration of toxic bile. We have anti-inflammatory properties, and based on animal models and also on some evidence from small clinical studies, we see an anti-fibrotic effect as well. There is very, very important action of this drug. The approval of obetecolic acid was largely based on the results of this study that I'm showing here. This is the POIS trial. This was a randomized phase 3 study evaluating two different doses of obetecolic acid in comparison to placebo. So in white, we have the patients on placebo. In orange, we have the titration arm, patients who started on 5 mg daily and were increased to 10 mg daily after 6 months. And we have in blue, the obetecolic acid, 10 mg daily. And what this graph is showing to you is that at the end of the year, about 46-47% of patients treated with obetecolic acid met the primary endpoint of the study, comparing to only 10% of patients on placebo. So the study met its primary endpoint. After a year, patients on placebo were converted to obetecolic acid, and you can see that there is an increase in the proportion of patients meeting the primary endpoint. The effect on alkaline phosphatase and liver biochemistry was sustained for this open-label phase that lasted a year here. In the next slide, we show a more detailed view of what happened to the alkaline phosphatase in this study, since the alkaline phosphatase is such an important surrogate for us. We can see here in white is placebo, and the alkaline phosphatase didn't change for the duration of the study. Then we see in orange what happened to the titration arm with a significant decrease in alkaline phosphatase, and in blue, at the end of the year, the decrease in alkaline phosphatase was similar between the titration arm and the 10-milligram arm, although there is a slight benefit for a higher dose, and this is sustained for the open-label extension phase. Although, to this date, we haven't had a prospective study showing that obetrocholic acid can improve survival in PBC, although we haven't had a prospective study yet showing improvement in survival with obetrocholic acid, we have studies using mathematical modeling, in this case, Markov modeling, that indicate that the OCA would decrease 15-year cumulative incidence of decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related death among patients with PBC. So this is very exciting, and we're hoping that the long-term extension and phase 4 studies that are ongoing will confirm these results. So patients who are inadequate responders to UDCA should be considered for treatment with OCA, starting at 5 milligrams a day. I wanted to make a remark, Marlene, this is very important about the dosing of obetrocholic acid, because we have to pay attention to the histologic stage, especially if our patients are decompensated. So if they're not cirrhotic or child-aged cirrhosis, we start with 5 milligrams daily, and after 3 months, we can increase to 10 milligrams daily, which will be the maximum dose. However, if our patients have child B or C cirrhosis, even prior to the compensation would be considered in this group of decompensated cirrhosis, we should start at 5 milligrams a week as opposed to 5 milligrams daily. And after a few months, we could increase to 5 milligrams twice a week, at least 3 days apart between the doses, and eventually increase to 10 milligrams twice a week, which would be the maximum dose for this patient. So this distinction is very important to avoid hepatic decompensation. And as you can notice, we recommend the titration, so always starting with the lowest dose and then titrating up to minimize itching, which is the most common side effect of obetrocholic acid. OCA does have risks and side effects, and they're also outlined in our guidance document. Providers with the most common side effect noted in clinical trials in hepatic decompensation and death can occur or occurred in incorrectly dosed patients with child B or C cirrhosis. That's why we emphasize those dosing recommendations. The clinical trial has also demonstrated a mild reduction in HDL cholesterol. And I want to remind our audience that hyperlipidemia is very common in PBC. And even during the study, when we saw this reduction in HDL, the median values remained within the normal range for HDL. That's a lot of very useful information about how we should be incorporating obetrocholic acid into our practice at this time. The guidance document also has a section, I believe it's called Promising New Drugs or something like that. Can you kind of briefly summarize what's discussed in that section for the audience? Yes. So among the Promising New Drugs that we discuss in the guidance document are the fibrates. So this class of drugs, they activate the peroxisome proliferator activator receptor. So it is considered the fibrates are PPAR agonists. There are three isoforms of PPAR that we should be familiar with. The PPAR-alpha regulates primarily bioacid homeostasis and increases phospholipid secretion in the biokinetic lipid. It also downregulates the TNF-alpha pathway, so this anti-inflammatory properties as well. The PPAR-delta has more favorable effects on insulin resistance, lipid metabolism, it enhances energy use, and as the PPAR-alpha has anti-inflammatory properties. Whereas the PPAR-gamma regulates adipogenesis and has anti-inflammatory and anti-fibrotic properties. These isoforms will become more familiar to us as we hear not only the drugs we're discussing now in the guidance documents, but also drugs that are under development, undergoing clinical trials as we speak. The drugs that are currently available that are therefore reported as possible off-label use include the phenofibrate, which is a PPAR-alpha agonist, and this drug is available in the United States. And bisofibrate, which is a pan-PPAR agonist, and it's not available in the United States at this time. There have been many small clinical trials evaluating both drugs around the world, especially bisofibrate. In fact, the largest study that we have with fibrates is with bisofibrate. This is the French study, so-called the BESURSA trial. This study randomized 100 patients who were non-responders to UDCA, to one of two arms. Either they received placebo, shown in blue here, or they received bisofibrate, 400 milligrams. What the study shows here is a significant drop in alkaline phosphatase. There was also a drop in bilirubin, ALT. Importantly, the primary endpoint for this study, Marlene, was complete normalization of all liver biochemistry, not just alkaline phosphatase, all liver biochemistry. And that was achieved in 30% of the patients receiving bisofibrate, as opposed to nobody in the placebo arm. As far as normalization of alkaline phosphatase alone, this was seen in 67% of patients on bisofibrate, versus, I think, 1% or 2% in the placebo arm. So, very prominent biochemical effect. There was also improvement in liver stiffness, although this was just an exploratory endpoint for this study. In the United States, as I mentioned, we don't have bisofibrate, and we have conducted this small open-label study with phenofibrate in combination with UDCA. So, this was a Phase II study, 20 patients only. As you can see, at baseline, alkaline phosphatase was in the 400 range, and there was a very significant drop as early as six weeks after drug initiation. And that persisted for the 48-week duration of the trial, with a rebound noticed at 9 to 12 weeks after the drug withdrawal. So, phenofibrate also showed improvement in the markers of cholestasis. There was also a drop in IgM in this study. Now, as is the case with OCA and other medications discussed here, fibrates have risks and side effects that we need to consider. Myalgias are described with this class of medications. GERD is also common. It was actually the cause for drug discontinuation for a couple of patients in the phenofibrate study. Increase in creatinine, which seems to be a reversible side effect, and it's not associated with a decrease in GFR. And importantly, hepatotoxicity has been described with fibrates. Both acute and chronic hepatitis have been reported, including autoimmune hepatitis-like picture and two cases of liver failure. This has to be put in perspective with millions of prescriptions of fibrates in the United States and Canada for hyperlipidemia. Nevertheless, we should not overlook these complications. So, fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA. It's important to notice that the use of OCA and fibrates is discouraged in patients with decompensated liver disease, meaning child putrequoit B or C. But before we go on to the next section, I just wanted to comment that, well, first of all, those are some impressive results with those new drugs, so it's going to be exciting to see what happens with those. But one of the things I should have mentioned in the beginning when we were talking about practice guidelines versus practice guidance is that's one of the advantages of doing a guidance document is that the ASLD can give up-to-date information like this about things that are being used off-label or that are currently in development, because clearly those don't have enough data to be vetted yet for a guideline, so. Correct. I just wanted to add that. Thank you for that comment. So, I thought now we could switch gears and talk about extrahepatic manifestations of PBC and how to manage those. Fatigue and providers that we'll discuss later are among the most common symptoms for this patient. So, I was thinking with your experience, Marlene, can you please guide us through what the document says with respect to fatigue and how can we work it up and manage? Absolutely. These are some of my favorite topics. So, fatigue, as you say, is one of the most common symptoms in PBC and current estimates are about 50 to almost 80 percent of PBC patients will have fatigue, and it really significantly impairs their quality of life. More importantly, or just as importantly, severe fatigue is actually associated with decreased survival. We still, however, don't understand what the exact etiology of the fatigue is. The clinical course tends to be constant or slowly progressive over time. So, fatigue is a very common symptom. There are some clinical features of PBC fatigue that are relatively specific and intriguing that have been described. One is that these patients may have orthostatic hypotension. Not surprisingly, they have daytime sleepiness. They're also well demonstrated to have some cognitive defects in association with the fatigue. And it's also been shown that their muscles have impaired recovery from exercise. And understanding these features can help when counseling your patients. As far as what the guidance document says and how to manage fatigue in PBC, there really is no recommendation at this time because there is nothing that has been shown in randomized controlled clinical trials to be effective. Specifically, there have been randomized trials for undancetron, fluoxetine, and modafinil, all of which were negative studies. It's important to exclude other factors that are contributing to the fatigue, and common in this population would be hypothyroidism, which has a strong association with this disease, depression, anemia, and even sleep apnea. And one of the other important statements that the guidance offers is that fatigue alone is not a valid reason for pursuing liver transplant because the transplant doesn't necessarily cure the fatigue. Much of the fatigue persists even post-transplant. Yes, well, that's very helpful. Fatigue, as you mentioned, is very common. This brain fog is one of the most common complaints among our patients. Right. And pruritus is the other one. How common is that? Does it have any specific features in PBC or semestral history? What the guidance document says about that? Right. Well, it does. Pruritus is very common, not as common as fatigue these days. It used to be more common. So if we look at older studies, the prevalence is about 70%. But if we look at newer studies, the prevalence is about 20%. But still, in that 20%, it can be very disabling. It impairs quality of life. Particularly sleep is the most affected. The clinical course over time, one can expect fluctuating course with exacerbations and improvements. But it persists really until the very, very end stages of cirrhosis, at which time it paradoxically can disappear, and we don't really understand why it does paradoxically disappear at the very, very end stages of PBC. There are some unique clinical features that clinicians should be aware of. These can be helpful both in management and in differentiating whether the itch is coming from PBC or perhaps some other comorbid condition. First of all, the PBC itch is exacerbated by certain things, particularly tight clothing, the heat, and the state of pregnancy. The PBC itch has a circadian rhythm where it is worse in the evenings and tends to be better in the mornings and midday. The distribution can be anything from localized to involving the entire body, but it does have a specific predilection for the palms of the hands and the soles of the feet, which is a feature that you don't typically see in other dermatologic causes of itching. The pathophysiology of itching, even though we've learned more, still remains unclear. I think the main players that have been demonstrated to have a role in PBC itch are illustrated on the slide here. Probably the most recent is lysophosphatidic acid, which can cause itch, and the enzyme that is responsible for its production, namely autotaxin, is the one thing that has been shown to correlate with the severity of itch in PBC patients. Amylopioids have been shown to play an important role and are a therapeutic target in this disease. Likewise, bile acids have proven to be a useful therapeutic target, as has serotonin and levels of progesterone, which probably overlaps with the physiology of pruritus in cholestasis of pregnancy and also may be related to the worsening of the itch that we see during pregnancy. The approach to PBC pruritus that's outlined in the guidance document is really multifactorial, and each of these green boxes illustrates an option for these patients. In general, we would start with the items on the left and progress to the right, but that progression is really based mostly on safety as well as the quantity of the data. On the left, you see lifestyle modifications. It's important to realize that there are no clinical trials, but we still recommend things like loose clothing and keeping the skin cool and using moisturizers because they seem to be effective and they address those issues that contribute to the worsening of the itch. Most people for first-line therapy would start with bile acid-binding resins, and you can see the doses there. Cholestyramine, a single dose is usually four grams, and this can be given one to four times daily. Rifampicin has quite a bit of data, even though the clinical trials are small, there are quite a few of them, showing that 150 to 300 milligrams given twice a day can be effective at curtailing the pruritus in PBC, and opiate antagonists also are a possibility. Naltrexone is the easiest to use because it's oral and can be given as an outpatient. The starting dose is 12.5 milligrams a day. That's to get the patient used to blocking their endogenous opioids, which can cause some opioid withdrawal effects, but 12.5 milligrams a day may not be enough to improve their itching, so the dose is gradually titrated up by 12.5 milligrams every few days until an effect is achieved. Alternatively, patients can be brought into the hospital and given IV nalmethine and then crossed over to outpatient oral medication. Sertraline has been shown in one small study to be effective at a dose of 75 to 100 milligrams per day, and then in the right-hand box, you see a number of therapies which all have case series reported as being effective. I think you and I have both seen probably most of these at one point or another be used and be effective, but it's rare. Most of them are invasive or difficult to carry out, plasmapheresis, albumin dialysis, biliary drainage, which can be nasobiliary or even percutaneous biliary drainage, light therapy. There is literature in the dermatology body of work that this can be helpful in liver-related itch. And then unlike fatigue, pruritus does remain a valid indication for liver transplant because it does get better after transplant. Excellent. This is a great overview, Marlene. Thank you so much. That can be one of the most frustrating symptoms to care for, to treat for our patients. So here we see a wide array of options to manage them. So are there other symptoms that we have to worry about in PBC? Any additional recommendations from the guidance? Right. So yes, there are a few other symptoms that the guidance documents address. First is abdominal pain, which can be underappreciated, but really about 17% of patients will complain that they have this right upper quadrant discomfort just due to the PBC. And the clinical course of this is that patients may have an occasional exacerbation. They may show up even in the emergency room with severe pain, but these patients really should be reassured because the pain is not progressive over time. Even though we don't know what the cause is, we know that it doesn't correlate with their disease stage. If it's proposed, maybe it's from having a big liver, but studies have not been able to show that it correlates with the size of the liver. And the clinical course really is that over time, maybe over several years, it will actually just disappear. So really the management is just reassurance. Pain medication can be used for these exacerbations to control the pain. Another symptom complex that's addressed in the guidance documents is managing Zika syndrome. Dry eyes and dry mouth are extremely common. Up to 80% of these patients will present with this, so it's important to ask. For dry eyes, really the initial management is just to use moisturizing eye drops. But if that alone is not effective, cyclosporine or LiftoGrast drops can be used to decrease the inflammation. Pylocarpine or other anticholinergic agents can be used to increase fluid production. And if those aren't effective or patients don't tolerate them, then plugs can be placed into the puncta to block the exodus of tears. And then there are a number of therapies that can be pursued by the ophthalmologist. They can actually cauterize the plugs. They can give thermal therapy or light therapy. There's certain massaging of the glands that can increase the excretion of fluids. And then there are special contacts that will actually hold the moisture up against the eye. Now, if you look closely on this slide, you'll see that some of the circles are white and some of them are a light peach color. The treatments in white are, you know, very clearly things that a gastroenterologist or hepatologist could comfortably perform. Many people, once you get into the peach colored dot recommendations, would be sending the patients off to an ophthalmologist to pursue. But it's important to be able to discuss with the patient, even if you're referring them to an ophthalmologist, why you're referring them, what their options might be that they could discuss with the eye doctor. For dry mouth, most patients will start by just drinking lots of water and carrying around a water bottle, but they can be encouraged to use sugar-free gum or candy. There are now these little xylitol discs that stick to the roof of the mouth that help with moisture of the mouth, even throughout the night. There are various lines of oral care agents, mouthwashes, toothpaste sprays that have moisturizing agents in them. I think probably one of the most important things to emphasize to our patients is that they should be getting professional dental cleanings every six months, because the lack of saliva in the mouth really increases the rate of caries. Without the cleansing action of saliva in the mouth over the teeth, caries form rather quickly and patients get cavities very quickly. And the anticholinergic agents can also be used for the dry mouth. Great. Other than monitoring liver function, what are some other tests or regular scheduled procedures that we need to recommend for our patients? Right. So, the general guidance that the SLD offers is that these patients should have liver tests checked at least twice a year, every three to six months. Thyroid stimulating hormone, because of the high incidence of hypothyroidism, should be checked once a year. Because of the rate of increased osteoporosis, they should be getting bone densitometry every two years. Fat-soluble vitamins, vitamins A, D, E, and INR as a proxy for vitamin K, should be checked annually once the patient has an elevated bilirubin. And then to screen for varices, patients should be getting an endoscopy every one to three years if they are cirrhotic, if they have an elevated Mayo R-score greater than 4.1, or if their transient elastography is greater than or equal to 17 kilopascals. And those recommendations are based on, you know, PBC-specific data. And then, similar to all forms of cirrhosis, if patients are cirrhotic from PBC, they should be getting ultrasound with or without alpha-beta protein every six months, because these patients, once they're cirrhotic, are at increased risk for getting hepatocellular carcinoma. Thank you, Marlene. And are there any specific recommendations you would recommend for hyperlipidemia and osteoporosis, both of which are more common among our patients with PBC compared to the general population? Any specific management recommendations? Right. So, the ASLE does offer some guidance of how to approach hyperlipidemia and osteoporosis in PBC, even though there are not a lot of large prospective randomized trials in these areas. For the hyperlipidemia, the older studies, the large retrospective studies, show that there's no increased cardiovascular risk in PBC patients despite having very high lipids. However, there was a meta-analysis that was published in 2015 that found that there actually was a pooled relative risk of one and a half for cardiovascular events in patients who have elevated cholesterol. So, there may, in fact, be some risk for these patients, or I should say they're not completely risk-free. And there is a study showing that those that have hypertension along with their PBC are at particularly increased risk of having cardiovascular events. We know that ursodiol treatment will lower the LDL somewhat, but not very much. And also, the accumulation of data over the last 20 years has shown us that statins and fibrates appear to be safe and should be considered if the patient has other risk factors for cardiovascular disease. So, I don't know about you, Cynthia, but I often see patients who are told, well, hyperlipidemia is not a risk in PBC, so you don't need to treat it, but they have hypertension, they have diabetes, they have an enormous family history, and clearly these patients should be treated. PBC is not a pass jail, don't collect any cardiovascular events, you never have to be treated ticket. Exactly. For the osteoporosis... Yes? I was just going to say, that's exactly my approach, looking for other risk factors. And if they have other risk factors for cardiovascular disease, I will definitely treat them. All right. So, as for osteoporosis and PBC, the ASLD recommends that patients should be taking between 1,000 and 1,500 milligrams daily of calcium, depending on their menopausal status. They should be taking about 1,000 international units of vitamin D daily. Bisphosphonates can be used once the patient becomes osteoporotic, and there's data specifically for alendronate and abandronate in PBC. Calcium replacement therapy has not fallen completely out of favor because it has been shown to be well-tolerated and useful in patients with PBC. There are certain cautions with using these therapies in PBC patients. For example, the calcium can be a problem if patient has recurrent renal stones. If the patient has underlying varices or gastroesophageal reflux disease, bisphosphonates can be irritating. These are not absolute connotations. They are just cautionary notes. Similarly, for hormone replacement therapy, there is that increased risk of breast or endometrial cancer or developing venous thrombosis. So those things should be taken into consideration for each individual patient, balancing both the risk and the benefit. So that's really what the guidance covers in terms of symptomatology. We've covered a lot of ground in the last 45 minutes or so. And Cynthia, I'm going to give you the hard challenge, which I was hoping you could summarize for us. Really, for those who are familiar with the prior guidance or guidelines, what is different What are the new things in the new practice guidance compared to the old one? Thanks, Marlene. Okay. So I think this algorithm here actually summarizes the most important points. As we discussed earlier, this is not a difference from the previous guidance document, but making the proper diagnosis is of paramount importance. Understanding the role of autoantibodies, the role of liver biopsy. We talked about the PBC-specific ANAs. We have more of them available now than we had 10 years ago. So if we have a way to measure those, that can spare the patient a biopsy. So that's very important. Risk stratification is a concept that we better understand now, and that should be done both at baseline and at follow-up. At baseline, we learned that young age and the histologic stage are the strongest predictors of response and, therefore, disease progression, so we should be aware of those as we start managing our patients. And then the re-evaluation after one year of medical therapy, assessing for biochemical response using any of the response criteria we discussed earlier, even if it's simply to look at the alkaline phosphatase and bilirubin and see, okay, is the alkaline phosphatase normalized or not? Is it below 1.5 to 2 times the per limit of normal or not? But being aware of that relationship between alkaline phosphatase and prognosis is extremely important because those are the patients we need to target for adjuvant therapy. And here now is the greatest difference from the previous guideline document. Availability of FDA-approved second-line therapy, Obetucolic Acid, was approved May 2016 for patients who are intolerant to UDCA or who are incomplete or non-responders as assessed one year after treatment with UDCA is started. Availability of off-label therapies such as Defibrate and even Budezonide has also been discussed and those have been incorporated in the guidance document. This is the most important thing because we now have the second-line therapy available. It's important to identify patients who will benefit from them. So with that, we would like to conclude our webinar and thank our audience. I would like to thank my co-moderator, Marlene Mayo, as well as the ASLD staff for all the support provided to us. Thank you. Agreed.

PBC Practice Guidance

risk stratification

biochemical response

ursodeoxycholic acid

Obeticholic acid

off-label therapies

management of symptoms

regular monitoring

treatment decisions