I want to thank the organizers for the invitation. It's a pleasure being here. These are my disclosures. And let's get started with the case. A 61-year-old Caucasian woman who presents with pruritus and fatigue. She has positive anti-mitochondrial and anti-nuclear antibodies. Her ALK-FOS is 327, and her transaminases are moderately elevated. She started on erzo and follow up. After one year, her ALK-FOS reduces to 254, which is still about 1.8 fold elevated. Her transaminase is normalized. Her bilirubin is normal, but her pruritus has not improved. So what are the key questions in such a scenario? First of all, which treatment options for second line are available? Second, how can her response to treatment be monitored? And how can her pruritus and fatigue be treated? This slide summarizes our current therapeutic approach to PBC. We start our patients on first line therapy with erzo deoxycholic acid. We monitor the biochemical response. If patients respond biochemically, they are doing fine. They will have a normal prognosis on erzo. However, 30% to 50% of patients do not respond and are candidates for second line therapy. And we here have several options, including the FXR ligands, such as obeticholic acid, as approved second line therapy, the FXR target FGF19, the PIPA ligands with fibrates and the glucocorticoid receptor ligands with budesonide, which is mainly used for overlap syndrome with autoimmune hepatitis. PBC is quite a heterogeneous disease which can take different clinical courses. It's important to be aware of baseline indicators of higher risk of disease progression. And these include demographic features, such as age, sex, and ethnicity, symptoms which, however, do not necessarily correlate with disease severity, and stand-up serum liver tests, which do not allow stratification of early-stage PBC, but are very important as biochemical treatment response criteria, as we'll hear. We have PBC-specific antinuclear antibodies. We have the noninvasive serum markers of fibrosis, the liver stiffness measurements above certain cutoffs, and, if available, liver histology with interface hepatitis and ductopenia and portal pressure measurements. In addition to these parameters, we have an emerging array of novel biomarkers, such as autotaxin and others, which, however, are not yet ready for clinical routine, and I will not go into that into further detail. Antinuclear antibodies, as seen in our patient, are present in about 30% of patients with PBC. And here it is important to be aware that there are PBC-specific antinuclear antibodies, which can be identified in immunofluorescent staining patterns, such as nuclear darts, shown here on the right, perinuclear rims, or with specific immunoassays. These antinuclear antibodies allow a firm diagnosis of PBC in AMA-negative cases and also have prognostic implication. Antichlycoprotein-210 is associated with an unfavorable course and a higher risk of disease progression, and the antirest centromeres have been linked to portal hypertension. It is important to avoid confusion with overlap with autoimmune hepatitis, which requires more stringent criteria, including an ALT above 5-fold upper limit of normal and elevated IgG above 2-fold and positive SMA or interface hepatitis on liver histology, which were all absent in our patient. So the next important step is biochemical response assessment. And here we have various opportunities. We have the qualitative binary definitions with the different criteria carrying the name of the city of discovery and a slightly overwhelming array of opportunities, mainly focused around alkaline phosphatase, ASD, and bilirubin. Among those criteria, especially in early-stage PBC, the Paris-2 criteria are the most robust criteria with an ALT and a LFAS below 1.5-fold upper limit of normal and a normal bilirubin after one year of treatment. But you also find, using the Toronto criteria, with a 1.67-fold upper limit of normal. In addition, we also have the continuous scoring systems, which have slightly better performance characteristics, such as the GLOBE score and the UK PBC score. Also here, we have clinical and biochemical routine parameters. And it's quite easy to calculate them with electronic tools, including apps for risk stratification, allowing to enter these clinical routine parameters. And this gives you a risk assessment for liver-related death and liver transplantation or comparison with the normal population. More recently, there's also been a predictive score for ERSO response, which may allow a more proactive management. Again, here, we have an Internet tool with various routine parameters, which can be entered. And here, it is possible to calculate the probability of ERSO response with reasonable performance characteristics prior to starting ERSO. So, this may be particularly important in the patients with the high-risk profile, which we have discussed earlier. So, we have now identified patients who may be at need for second-line therapy. I would like to emphasize at this point that it is important to check compliance with ERSO. Patients may have difficulties refilling their prescriptions. They may have gained weight requiring those adjustments. So, why is it so important to add second-line therapy? In our patient, who is an incomplete responder to ERSO, we still have a better prognosis than untreated patients, but we have this prognostic gap to complete responders which have normal survival, which we want to close. And this slide is summarizing the principle of therapeutic strategies. We have the nuclear receptor-targeted strategies with FXR and the downstream target FGF19. We have the PPARs, and we have the glucocorticoid receptor ligands. I should mention that biological, such as ustikinumab, reduximab, and more recently, abatacept, have actually been negative in the Phase II studies. So, basically, we are left with the nuclear receptor-targeted strategies, which are an immunometabolic approach. So, here, we not only target bile acid homeostasis, but also inflammation and immunity. With FXR, the bile acid receptor, we have both steroidal and non-steroidal FXR ligands. Orbeticolic acid, or ACO, is the first-in-class steroidal FXR ligand carrying a typical bile acid, in this case, chenodeoxycholic acid structure. This drug is approved in PBC. We also have the non-steroidals, which no longer have bile acid structure. It may have a different pharmacokinetic and perhaps also side-effect profile when it comes to pruritus and cholesterol. These non-steroidals have shown efficacy in Phase II trials in PBC, such as salifaxor and tropifexor, and there are many other examples in the pipeline. These are the top-line data for orbeticolic acid, which has been approved based on this POIS trial as second-line treatment in patients with incomplete response to erzo, or not tolerating erzo. As you can see, OCA in two different dosages results in a reduction of allogfast compared to non-responders staying on placebo. Patients later catch up when they are in the open-label phase. We have a response rate of about 50%. Also, a normal improvement of various inflammatory parameters. However, there's an increase in LDL cholesterol, and there's the issue of pruritus. In the 5 to 10 milligram titration group, which is now the recommended therapeutic approach, about 1% of patients have to discontinue the drug due to pruritus. What else can be said? Open-label extensions have shown a durable response without new safety signals, and you're going to hear some of that in the late-break abstract session of this meeting. The data from real-life registries are reassuring. It is also effective as monotherapy. There have been safety issues in the FDA warning due to deaths related to excessive off-label dosing in child's B and C serotics. There's the at least theoretical risk of Goldstone formation, which not has been observed clinically, and currently a phase 4 study demonstrating hopefully hard clinical endpoints is currently ongoing. There are encouraging results in other indications, such as PBC and NASH. Another interesting approach are the PIPA ligands. Here we have three isoforms. Alpha also impacts on biliary homeostasis, promoting phospholipid secretion and reducing bile acid synthesis, and also has anti-inflammatory effects. Fibrates target alpha, with phenofibrate being a pure alpha agonist, bezafibrate being slightly broader, and both compounds have been shown to be beneficial in PBC and PSC. We also have novel drugs targeting alpha-delta, such as elefibranol, and the pure delta ligand, selatavir. These are the top-line data from the BETS-ERSO trial, again in non-responders to ERSO, and as you can see, compared to placebo, bezafibrate in 400 milligram actually resulted in profound reduction of alkaline phosphatase. The response rate was a 30% response. Here was defined slightly more stringent than in poise, with normalization of virtually all liver parameters and liver enzymes. ALK-FOS normalized in 70%, which is a rare event seen with OCA. Liver stiffness and risk scores improved, and actually, pruritus also improved. There was a slight increase in creatinine, which is a pharmacodynamic effect. Overall, the safety was very good and not different from placebo. What else can be said? I think it's very important to point out that bezafibrate improves pruritus, and we're also going to see the FITCH trial here presented at this meeting in the plenary session. We are aware that bezafibrates are not available in the U.S. There's limited experience with phenofibrate, which seems to have similar effects. Also here, safety issues with DILI reports with phenofibrates. Recently, EMA, the European Drug Agency, affirmed safety but does not encourage the use as first-line drug in dyslipidemia except severe hypertriglyceridemia. Data from Japan suggest a reduction in liver-related mortality and need for liver transplantation. And also here, we have encouraging data and other indications such as PSC. In addition to fibrates, we also have the novel PPAR ligands. And here, actually, we have phase II data for selatilbar and elefibrinol. Selatilbar, the pure delta agonist, elefibrinol, the dual alpha delta agonist. And as you can see, there was a reduction in alkaline phosphatase in these phase II studies, importantly without the side effect of pruritus. So, what about budazonide? Here, early combination studies de novo in naive patients showed superiority to erzo. Budazonide may be more than immunosuppression. Again, we have here this dual theme. Budazonide also impacts on bicarbonate secretion and bile acid detoxification. It is contraindicated in cirrhosis and portal hypertension. The results in a recent phase III add-on, again, in erzonon responders, have been mixed. The primary endpoint, which was histology for this study, was negative. However, the secondary biochemical endpoint was positive. Actually, here, about 40% of patients on budazonide met the POIS criteria. Budazonide certainly has its place in variant syndromes and overlap with autoimmune hepatitis. And the question is whether this is a drug to target and treat patients who have interfaced activity on liver histology. This, however, would require liver histology in non-responder. And this is a paradigm change, because currently, we rarely require liver histology for the diagnosis. But maybe in non-responders, of course, the question is exclusion of overlap syndrome with autoimmune hepatitis. That may be an indication. And there may be a subgroup where we tailor immunosuppressive strategies such as budazonide based on liver biopsy. What do the current guidelines say? ASLD makes a should-be consideration for OCA. Fibrates can be considered off-label. And I think that's the important statement to discourage the use in patients with decompensated liver disease. ESL suggests considering OCA and does not make a recommendation for budazonide and pizzafibrate, because at that time, the data have not been published or presented, and the guidelines are currently undergoing a re-evaluation. How can we customize second-line treatment in PBC? And I find this approach suggested by the Paris group very useful in clinical terms. Abetacolic acid as a proof drug certainly is eligible in all patients, in particular, those without pre-existing pruritus and without dyslipidemia and cardiovascular risk factors. Fibrates may be the first choice, particularly in patients with pruritus or cardiovascular risk factors. And budazonide may be the drug for patients who have inflammatory activity or true overlap syndrome in the absence of port lab attention and, ideally, non-thrival, non-elderly younger patients without osteoporosis, diabetes, and so on. There are a lot of future developments in the pipelines. I have mentioned the non-steroidal FXR ligands, FGF19 memetics, the new PIPA ligands. We also combine erso, betzafibrate, and OCA in an ongoing study as triple therapy. There's an interesting non-anticholesthetic approach with the NOX inhibitor cetanoxib, and there's a range of novel immunomodulatory approaches such as the CheX and anti-interleukin-17 and so on. Perhaps we will see a revival of immunotherapy in PBC in the near future. So treating a PBC is much more than treating just the cholangitis. It's about symptoms. It's about cirrhosis with the complications of portal hypertension, hepatocellular cancer, and osteoporosis. And among the symptoms in PBC, fatigue and pruritus are leading the list. And here it is important to keep in mind that there's no correlation of symptom severity with disease activity, and symptoms typically do not improve with first-line and currently available second-line therapy. So what can we do about managing fatigue? It is important to consider other causes than PBC such as hypothyroidism or anemia, for example, due to celiac disease, or other contributing factors such as depression and sleep disorders. Currently, there's no recommended licensed therapy for fatigue with several negative studies, the most recent one being the negative Reduximab trial. It is important to educate and counsel our patients how to deal with these symptoms, to develop coping strategies, and to avoid social isolation. It is important to state that intractable fatigue is not a valid indication for liver transplantation since it usually persists following transplant. This approach to fatigue is best summarized as a trace approach, treating direct contributors such as pruritus, autoimmune conditions, other comorbidities, amelioration of exacerbating factors, coping strategies, and certainly the empathy of us as physicians since fatigue frequently matters more to our patients than disease severity. What can we do about pruritus? It is important to exclude dermatological causes including allergies and atopy, general measures such as avoiding tight or itchy clothing and application of moisturizers or cold water and cooling packs is considered to be helpful. The first-line treatment in terms of drugs are the end-in-exchange resins such as colostyramine. You're all aware of the side effects. It's important to space it from other medications and other resins such as colestibol and colicevolan are also available as pills and preferred by some patients. In patients refractory to end-in-exchange resins, we have a step-up strategy best summarized in this slide. So we have first-line resins. We have second-line rifampicin, third-line opiate antagonists such as naltrexone, then fourth-line sertralin and SSRE and several experimental approaches including plasmapheresis, albumin dialysis, and nasobiliary drainage. And certainly intractable pruritus can be a valid indication for liver transplantation. As you see, the evidence and actually tolerability of many of these approaches is quite low. And actually the best evidence exists for rifampicin and actually the safety may be much better than perceived with less than 5% of delays in cholestatic patients. In addition, we have other novel approaches such as fibrates and ototoxin inhibitors. And it's critical to manage pruritus before starting second-line therapy. Also, pruritus may impact significantly the choice of second-line therapy. And here, pizzafibrate comes into play, which has been shown to improve pruritus in various clinical trials. And we are going to hear more about that from the Amsterdam group, I think, in the plenary session on Monday. So, in summary, respected chairs, ladies and gentlemen, PBC is a heterogeneous disease which requires a tailored approach. Biochemical response to ERSA at 12 months after treatment initiation is the best predictor to determine whether patients may require second-line therapy. The choice of the most appropriate second-line therapy should be based on individual patient risk profiles. And importantly, the evaluation and management of symptoms, particularly pruritus and fatigue, has an important impact on the quality of life of our patients. Thank you very much for your attention.

primary biliary cholangitis

treatment journey

FXR ligands

biochemical response assessment

antinuclear antibodies