Hi, it's nice to be here. Thanks very much for the opportunity to present these guidance to you. The other members of the writing team were Chris Bolas, Jim Boyer, Cynthia Levy, and Marlon Mayo. A great team, I think, who helped us with putting this together. This was also an update from 2009, so there was a nine-year gap between the previous guideline and the new guidance. And as Dr. Heimbach pointed out, there are differences between guidelines and guidances, and this was a conscious choice by the ASLD for this to be a guidance. In part, we thought this would make the document more accessible for users, readers, and also the data sources were somewhat limited to make it difficult to be able to do the systematic reviews on all of the issues that we thought should be covered. In some cases, some of the important points about the management for these patients are being based on fewer data points than might be available for a guideline. So with this, I wanted to start by, again, emphasizing the importance of primary biliary cholangitis and showing that this curve of the increased prevalence of this condition. So it's becoming more and more common, both in men and in women. The ratio of men to women remains about the same. This is disease primarily of women. About 90% of patients with PBC will be women. If we look at prevalence, prevalence is the definition of how many people at a point in time have a disease. Prevalence can be increased because the disease is diagnosed more often. And this suggests that there's some increase in the rate of diagnosis amongst women, as shown in the upper curve, compared to men. The other reason that prevalence can change is that people who have the disease live longer with it. And I think this helps underscore, I believe, the advantages that we've recently achieved with therapy for PBC, because overall, even though the last slide I showed had the incidence going up some, we see a much more dramatic increase in the prevalence. And so I think what we're finding are there may be a few more incident cases, but those people in whom the diagnosis has been made are now living much longer. And we would posit this is due to effective therapy. The other issue that occurs is we aren't doing as great a job as we probably need to be doing. Liver transplantation, shown in the blue triangles, has dropped fairly dramatically with therapy, but it's still at a rate comparable to what we see in primary sclerosing cholangitis. So the work is not done. We haven't made the need for liver transplantation disappear. It still is a relatively common indication for liver transplantation. So improved therapies, earlier diagnosis are needed. The diagnosis of PBC has become simple. Two of the following three are necessary. There needs to be biochemical evidence of cholestasis based on alkaline phosphatase. There's either the presence of anti-mitochondrial antibodies, AMA. There are other PBC-specific autoantibodies which are emerging, including the SP100 and the GP210. These are particularly useful if the AMA is negative. Or a liver biopsy showing characteristic features of PBC will be used. We don't do liver biopsies very often because oftentimes the diagnosis is made based on other criteria, cholestasis and the autoantibodies, but we still think in terms of liver biopsy changes for PBC. So this is one staging system. There are several, but usually the staging systems look at ductular destruction, inflammation around the duct, with extension into the liver parenchyma, followed by fibrosis and then eventually scarring. We think in terms of this orderly progression, but one of the things that's been found is that oftentimes patients who have PBC may have, at a given point in time, histologic features that are characterized of various stages, sometimes all four. So it's not as linear as we like to think about it, but I think it's been a useful model for us to think about how the disease progresses over the years. At one time it was thought that the presence of an anti-mitochondrial antibody made the diagnosis of PBC, even in the absence of alkaline phosphatase elevations. And this is a recent paper that shows that in patients who are AMA positive with normal liver biochemistries, that after about five years, only about 15 to 16% of patients will have PBC, and out at 8%, it's about 1 in 5. So every positive AMA does not necessarily mean a diagnosis of PBC. So it has to be taken in the context of cholestasis, typically, or histologic features. Conversely, although we think about PBC as a straightforward, simple diagnosis, there are times when there are patients who we believe probably have PBC based on cholestasis, but their anti-mitochondrial antibody is negative. We don't necessarily need to do liver biopsies if they have other autoimmune markers. Anti-nuclear, anti-smooth muscle antibodies are present in over 90% of these patients, even if they're AMA negative, and the other more specific markers which are starting to emerge may give us even more assurance that we're dealing with AMA negative PBC. There's concerns about overlap of autoimmune hepatitis with PBC. This occurs probably in about 5% or so of cases, maybe fewer, depending upon the definition. Usually this should be considered if transaminases are greater than five-fold normal, and frequently a liver biopsy will be required to establish the true diagnosis of overlap of autoimmune hepatitis with PBC. And then the therapy may be a combination of therapies for the two conditions. Usually a choice is made based on what the predominant histologic finding is for, whether it's immunosuppression for autoimmune hepatitis or ursodeoxycholic acid for PBC. Ursodeoxycholic acid in a dose of 13 to 15 milligrams orally is recommended. It's been recommended, approved by the FDA now for 20 years, so there's lots of experience with that. One of the things to remind ourselves of is if we're using a bile acid sequestrant, say cholestyramine for itching, it needs to be separated in time from ursodeoxycholic acid, which is a bile acid. And then usually we give ourselves about 12 months. That was the recommendation to assess the effectiveness of the ursodial therapy. It's not as quick a response as we see with immunosuppression with autoimmune hepatitis, for example, in which a response can be seen in days or weeks. This oftentimes is a response that evolves over months. One of the other things we wanted to stress was the importance of earlier diagnosis. So this shows what happens when patients with PBC are treated with ursodial, and this depends. This is based on the histologic stage or the findings at the time of diagnosis. Again, we don't do so many biopsies, but for the non-serotic patients, their outcome with treatment is almost as good as the general population. The serotic patients with treatment do better than serotic PBC patients without treatment, but this slide is really meant to emphasize the value of earlier detection of the disease, initiation of treatment before a patient becomes serotic, because even when a patient does become serotic, therapy, even when used at the appropriate dose, is not nearly as effective as it will be in a non-serotic population. There are a variety of ways of predicting the response to therapy. Various cutoffs are used. I'll show you a table in a moment. This is one small study looking at clinical outcomes in the subsequent two years based on the initial response to ursodial therapy after a first year with a variety of cutoffs. So 1.5, 1.67, and two, any values less than two times the upper limit of normal had better different outcomes than those patients who had higher levels after treatment. There are a variety of, as I mentioned, a variety of ways of assessing this, and it's been difficult to come up with a consensus amongst the group as to which should be used, since these data were presented as a table in the guidance to let people choose amongst them. My bias, and based on the global PBC data, is that two times the upper limit of normal seems like a pretty reasonable cutoff, but that's not the point. Another study has used 1.67, so those are probably the two most commonly used. These are recommendations for the follow-up of PBC, so biochemistry is at every three to six months. These patients are prone to develop thyroid disorders, 25 to 30% of patients develop thyroid disorders, so TSH, thyroid-stimulating hormone, annually has been recommended. I'll show you data in a bit about bone mineral density issues, so these should be monitored. Patients who are cirrhotic, or with more advanced disease, are prone to fat-soluble vitamin deficiency, and so those should be measured if bilirubin is over two. Patients can be... The usual recommendations for surveillance for varices comes into play, the Mayo risk score, transient elastography, 17 was the cutoff value in the guidance, or a low platelet count can all raise the likelihood of finding varices on endoscopy, and then I'll show you some data also in a bit about cancer surveillance along the lines that Dr. Heimbach just described. So we're fortunate now, there's another drug as of 2016, abetacolic acid, which is approved for patients with PBC, so patients are thought to be inadequate responders, they can be considered for abetacolic acid. Just to remind all of us, though, the five milligram a day starting dose is for those patients without evidence of decompensation, because the dose for that group of patients is five milligrams a week, and so some of the deaths that were reported a couple years ago with abetacolic acid were related to inappropriate dosing with too high a dose for patients with marginally compensated disease. Because there's such a gap between when we're able to publish guidances and guidelines, nine years for ours, we wanted to try and look a little ahead at what might come down the line in the future, and fibrates seem to have been an emerging form of therapy with more and more data coming forward, and so there's a statement that they could be considered as an off-label alternative for patients with PBC with an inadequate response to UDC. I think we're starting to see more and more data, it was fun yesterday to look at the posters that have, you can just, you can see the interest and emphasis on this, so we should know a lot more about this in the next few years. And then I mentioned the issue about watching out for abetacolic acid in decompensated cirrhotic patients. These are data that show the effects of abetacolic acid. This was a trial in which patients were then allowed to cross over, and so the top line in open circles, placebo, very little effect compared to the two drug strategies, and then when they were switched over to drug, similar benefits accrued. This is looking at abesophybrate, and this is looking at normalization, which in patients who've had inadequate prior responses to ursodeoxycholic acid, and this has shown, I think, a fairly impressive rate of normalization in a group of patients who've been resistant to the effects of ursodeoxycholic acid. So this and other emerging data, I think, are starting to get people thinking about the role of abesophybrate. Abesophybrate's unavailable still in the United States. Phenophybrate is, but it has a warning on it for use in, about its use in PBC. If we use anion exchange resins for patients with pruritus, there needs to be, we need to adjust the dosing, as I had mentioned, or the timing of the dose if the patient's on ursodeoxycholic acid, and I would say probably the same is true for abetacolic acid, which has a structure of a bile acid. Other options that we can use for itching are rifampin, naltrexone, or sertraline. One of the interesting things that has emerged with abesophybrate is the effect it has on itching. So there's fairly dramatic improvement in itching. Ursodeoxycholic acid, when used to treat PBC, does not have an effect on the pruritus. Sicca syndrome can occur up to, if tested, half the patients may have evidence of keratoconjunctivitis sicca. Usually it's recommended that artificial tears be used, but there's a sequence of strategies that can be used if this becomes particularly problematic for patients, through pilocarpine or sevimlev. There's also more potent immunosuppressant oral or eye drops that can be used, but usually this should then be done in the context of help with an ophthalmologist. Serostomia, similar over-the-counter preparations for artificial saliva or other stimulants. Patients who have PBC and cirrhosis should undergo endoscopic screening, as mentioned, and also these patients should have regular screening for hepatocellular cancer at six-month intervals, particularly in men with PBC and those with cirrhosis. Even men without cirrhosis probably should be screened as well. At one time, there was the notion that patients with PBC did not develop liver cancer. I don't think that that's true, and I think that just like any other patients with chronic liver diseases, particularly if cirrhotic, these patients can develop cancers and should be screened. When we look at the risks, we can see that the presence of portal hypertension in male gender are two of the more prominent features that raise the risk, and hence the recommendations for screening in those populations in particular arise. This is looked at in a different series, looking at the risk of cancer between males and females, and again, prominent risk in cancer, particularly among the males, although over the course of time, the risk in women go up as well, and this may be for them developing cirrhosis. When we look at the underlying initial stage of a disease, this also, I think, helps make the case that the patients who have cirrhosis or advanced disease are those that are especially prone. In the early years, patients without advanced disease have little risk, but unfortunately, many of these people will probably go ahead and develop advanced disease, and hence their risk rises. This is looking at the advantages of surveillance. If we do surveillance, our ability to beneficially affect patient survival is enhanced, as shown in these data, so I think this is just to underscore the importance of and the value of surveillance in these populations of PBC men with advanced disease. Sometimes patients with PBC will develop complications related to the disease. One of the big problems is osteopenia, so recommendations for adequate calcium and vitamin D supplements are made. There's not a lot of work done on specific therapies, but there are data that suggest alendronate, and probably other bisphosphonates are effective and should be considered if patients have frank osteoporosis. This is a look at how often osteoporosis occurs. It's increased risk in patients with PBC, and I think it has mentioned one of these important things to look for, the screening every two years for osteopenia, osteoporosis is part of the guidance. This is looking at, based on age, PBC versus controls, and you can see that really at every age, but particularly around the time of diagnosis, average diagnosis about 53, the risk of osteopenia is particularly greater than it is in the control population. This is a look at changes in bone density from an old study using alendronate, and this showed that in patients with PBC who had osteopenia, the alendronate led to an increase in bone mass compared to the placebo. And then patients with PBC have a propensity to have high lipid levels. Those in and of themselves do not necessarily trigger a need for therapy, but if patients do have elevated lipid levels and other risks for cardiovascular disease, they don't necessarily, are not necessarily protected from having adverse events, and so lipid-lowering therapy could be and should be considered primarily because of the additional risks. Fat-soluble vitamin deficiencies can occur. These should be tested for. These are oftentimes more common in patients with more advanced disease. There are supplements that are available should these be found. And then for some patients with PBC who advance and meet other criteria for transplantation, this is a very good option for patients, and they should be brought to the attention of the local transplant center as they start to become closer to that time. So with that, I look forward to your questions later. Thank you.

primary biliary cholangitis

early diagnosis

treatment

ursodeoxycholic acid

monitoring

complications