Biomarkers, Pruritus Management, and Real-World Evidence in PBC
Download MP3Welcome to Lavelinga Primary Biliary Cholangitis, optimizing biomarker surveillance addressing PBC related pruritus and application of real world evidence. My name is Doctor. Atoosa Rabbie. I'm joined today by 2 of my colleagues, Doctor. Hannah Blaney, MDMPH, Transplant Hepatology Fellow from MathStar Health Georgetown University, as well as, Doctor.
Dr.Atoosa Rabbie:Anahita Rabbie, MD MHS, who is a Transplant Hepatology, from Digestive Disease Section, Yale School of Medicine. For full, relevant financial disclosure information, please see the, iridium .com landing page for this activity. This is supported by an independent educational grant from Intercept Pharmaceutical. We would like to thank them for their support for this initiative. The learning objective for today's program are assess the role of biomarker monitoring in PBC, recognize the role of pharmacologic and non pharmacologic management strategy for PBC related pruritus.
Dr.Atoosa Rabbie:Hannah, can you give us a brief summary of the role of biomarkers in the management of, PBC? What are the most common biomarkers that are used?
Dr. Hannah Blaney:Biomarkers play a key role in the management of PBC. So we look at our liver associated enzymes primarily. We know that alkaline phosphatase and bilirubin levels are associated with deep disease progression with the ultimate goal of being a significant reduction, if not normalization, of these two indices with treatment. We specifically use these markers to assess the response to UDCA and determine eligibility for second line therapies. Transaminases should also be followed.
Dr. Hannah Blaney:While these can be mildly elevated in adequately treated PBC, if they are elevated above 5 times the upper limit of normal, this should prompt the clinician to consider a diagnosis of PBC autoimmune hepatitis overlap syndrome. Albumin should also be assessed along with platelet count as these may be signs, indicating the development of cirrhosis and portal hypertension. Sometimes, we will have a patient with a negative AMA, however, an increased alkaline phosphatase level. These patients should have their biomarkers monitored at least yearly. In patients where we have a high suspicion clinically of PBC, we can consider ordering PBC specific AMA serology including anti GP 210 and anti SP 100.
Dr. Hannah Blaney:We should order these if available, or we could consider a liver biopsy to house help us assist with a diagnosis of AMA positive AMA negative PBC. And, AMA negative PBC, really has a similar disease course as well as a response to treatment as, what we see with, AMA positive PBC. In patients with AMA positivity, however, with normal liver associated enzymes, these patients may have an increased risk of developing PBC. There's one study that showed that about 16% of these patients progress to PBC within 5 years. As such, these patients are at high risk of developing PBC, and they should be followed more closely with assessment of liver associated enzymes every 6 to 12 months.
Dr. Hannah Blaney:Anahita, how does biomarker monitoring fit into the new treatment algorithms for PBC?
Dr. Anahita Rabbie:That's a great question. So I'm gonna go over the new treatment algorithm and, we'll kind of put where biomarkers come in. Once the diagnosis of PBC is confirmed, you first wanna, stage the degree of fibrosis in these patients. And it is best done by transient elastography or, an MR elastography. Basically, you start them on treatment with UDCA.
Dr. Anahita Rabbie:It's the first line treatment. And it's usually it's weight based, 13 to 15 milligram per kilogram per day. And around at the same time, you wanna stage your fibrosis. So you either get transient elastography or MR elastography. If, the transient elastography is less than 10 or the MRE is less than 4 kilopascal, that means that the patient does not have advanced fibrosis.
Dr. Anahita Rabbie:So you have a little bit of more time to monitor the patient and see if they're responding to UDCA. However, if the patient has evidence of advanced fibrosis and, you know, with the transient osteography being 10 or above, you wanna, go back and make sure that they're responding sooner. So basically at 6 months, you wanna evaluate treatment response. And, the treatment response would be at 6 months. The alkaline phosphodies being less than 1.9 upper limit of normal, plus the, the bilirubin being less than upper limit of normal.
Dr. Anahita Rabbie:And at 12 months, it would be alkaline phosphodies being less than 1.5 upper limit of normal, plus bilirubin being less than, upper limit of normal. So if they are responding based on these criteria, you continue the same treatment and you monitor bilirubin and alkaline phosphatase every 3 to 6 months. However, if the patient is not responding to this treatment, or for whatever reason the patient is intolerant of UDCA, you wanna think about second agents. One part of the algorithm that comes into play here is if the patient has evidence of clinically significant portal hypertension or has decompensations, you wanna consider a referral for liver transplant early on. So going into, basically, second line treatments, you can start the patient on obeticholic acid.
Dr. Anahita Rabbie:Usually, it started at 5 milligram once a day, and you can increase it to 10 milligram after 3 months if the patient is able to tolerate the dose. Or you can consider off label use of Fenofibrate. Usually, it started at a low dose of, 45 milligram per day, and it can be titrated up again based on tolerance. And, you wanna assess alkaline phosphatase and bilirubin at, 3 to 6 months to see if they are responding. And response criteria would be alkaline phosphatase being less than 1.5 upper limit of normal and bilirubin being less than upper limit of normal.
Dr. Anahita Rabbie:However, if they are not responding to this treatment or specifically in the case of obeticholic acid, patient is intolerant because it can cause a lot of pruritus, you wanna consider another second line therapy. Or, so basically, you can switch or you can consider doing a triple therapy, basically, having the patient on, UDCA, obeticholic acid, and phenofibrate. The you might recognize that, elafibrinole is not included in this algorithm. This was very recently approved about a month ago. And I'm sure in, in the future, it will make its way to the algorithm.
Dr. Anahita Rabbie:But, currently, it's kind of hot off the press, so it's still not included in this algorithm as a second line therapy.
Dr.Atoosa Rabbie:So now let's talk, about PBC related pruritus. This obviously, significantly impacts, the lives of patients with PBC. To manage the symptom effectively not only means improved patient comfort, but also, it enhances patients' overall treatment adherence and quality of life. Can you give us an overview of what kind of impact can pruritus have on patients' quality of life and what it would mean, for treatment adherence? Pruritus is one of
Dr. Hannah Blaney:the most common symptoms of PBC. Up to 75 per se percent of patients with PBC will experience pruritus. So pruritus has been shown to negatively impact quality of life, including contributing to fatigue, depression, sleep disturbance, as well as social life interference. It can be really frustrating for patients and then providers alike, for for treating these patients. So, unfortunately, ursa deoxycholic acid or UDCA does not improve, pruritus and in rare incidences can actually worsen pruritus.
Dr. Hannah Blaney:Our second line agent of, obeticholic acid, while it's a great medication for the treatment of PBC, it can actually induce or intensify pruritus in about 40% of patients. There are some of the PPAR agonists, the newer medications that are being studied, including elafarbanor as well as the fibrates. And then there's some other agents that are currently under study that do seem to significantly reduce cholestatic pruritus. Hopefully, we'll have some new options, for these patients in the the near future.
Dr.Atoosa Rabbie:Thank you, Hannah. Anahita, can you provide us with, some strategy for managing pruritus, both pharmacological and nonpharmacological approaches, specifically to manage dose dependence, pruritus in patients, who are treated with alcholic acid, and, how you recommend, that the physicians adjust the dose, based on the, the patient's pruritus symptoms? Good question. So in terms of the pruritus, you know, one of the first line, medications that we use is colostiramine, and, it can be helpful in many
Dr. Anahita Rabbie:patients. Other medications that we use that are generally off label include rifampin, naltrexone, sertraline, and bisofibrate. There are also a nonpharmacological treatment such as skin care, phototherapy, and severe cases we can even think about albumin dialysis, plasmapheresis, and biliary drainage. In terms of the medication management, specifically, obeticholic acid is important because this is a medication that can result in, severe pruritus in, many patients treated with this and one of the main reasons for discontinuation of treatment. So basically, if the patient has moderate, pruritus and, you are at 5 milligram dose, you basically, wanna, you know, either still you could consider optite rating or stating staying at 5 milligram.
Dr. Anahita Rabbie:If you're already at 10 milligram, you stay at 10 milligram. And once the patient has severe pruritus, if you're at 5 milligram, you can decrease it down to 5 milligram every other day or pause treatment temporarily for 2 weeks. And after that, again, start with the lower dose of 5 milligram. If you have severe pruritus, you're at 10 milligram. You can decrease it to 5 milligram.
Dr. Anahita Rabbie:So, basically, by adjusting or trying to reduce the dose, you see if you can, have the patient be able to continue the treatment rather than completely stopping it.
Dr.Atoosa Rabbie:Thank you. So now let's, talk about the real world evidence about management of, pruritus in PBC. Can you highlight some of the key studies that have been done? And, what are some highlights of the promising treatments, for, pruritus, specifically
Dr. Hannah Blaney:in PBC patients? The target PBC trial is a large real world US cohort, that highlights the pervasive impact of pruritus in patients with PBC as well as, some of the shortcomings of the medical community's current response. So, it's a 2023 study that included 211 patients with PBC, with the overall prevalence of arthritis, pretty high in this population with 81% of respondents reporting itch of any degree and 37% reporting an itch that was at least severe enough to be deemed clinically significant using the PBC 40 scoring, which is a patient derived validated questionnaire. So patients with clinically significant pruritus were more likely to receive treatment versus patients with just a mild itch with 51% of patients with clinically significant itch receiving treatment versus 28% of those with mild itch. This shows us that only half of patients with PBC, that with clinically significant pruritus were treated.
Dr. Hannah Blaney:And it really suggests the undertreatment of patients with PBC related pruritus. Of those receiving treatment for for pruritus, antihistamines were commonly prescribed for both mild, which was 73% of all patients as well as clinically significant, including 66% of these patients, followed by acid, bile acid binding resins, such as cholestyramine. So as the pruritus of PBC is not mediated by histamine, antihistamine therapy is really not, it is not effective in these patients. Furthermore, antihistamines may exacerbate symptoms like fatigue as well as sicker symptoms such as dry mouth. So these data from the study revealed that clinicians were not complying to guideline recommendations for the management of pruritus.
Dr. Hannah Blaney:Cholestyramine is our first line therapy for pruritus, as recommended by both ASLD, and EASL. And really it was not used at a high, percentage in these patients. The undertreatment of pruritus and PBC, could be due to several reasons, including a lack of effective current treatment options, tolerate tolerability issues, as well as difficulty in dosing as well as the appropriate use of bile acid resins. It can be challenging for patients to time the dose with their other medications and with eating as well as a lack of FDA approved treatments. In another study involving 225 patients, Pruritus in PBC was under recorded in patient medical records.
Dr. Hannah Blaney:Pruritus of any severity was self reported by up to 90% of patients with PBC. However, it, only in 31% of these patients, had a recent documented pruritus in their medical record. As such, there's a big mismatch in patient reported measures and medical records suggesting that pruritus is really under recorded in medical records. The high percentage of patients reporting pruritus despite available antipyretic treatment suggests that pruritus continues to be undertreated and undermanaged. This should remind us to always ask, document, and treat symptoms associated with PBC like pruritus at every patient visit.
Dr. Hannah Blaney:There is still a need for newer therapies to address the debilitating impact of pruritus in patients with PBC with some exciting possible therapies in the pipeline. First, we have linarixibat, which is a ileal bile acid transporter, inhibitor, which is under study for cholestatic pruritus, in a GLIMR study. And the GLIMR study, which was a phase 2b trial for itching, there was a significant decrease in itch in the per protocol population. This drug is currently in the phase 3 trial. Besafibrate, which is not available in the United States, is a pan PPAR agonist.
Dr. Hannah Blaney:This medication was shown to significantly decrease pruritus in the phase 3 trial. Another medication, seladelpar with, which is a PPAR delta agonist demonstrated a significant reduction in pruritus from baseline in a recent phase 3 clinical trial. Elafrivenor, which was recently approved in June of 2024 by the FDA for treatment of PBC, is an alpha and delta PPAR agonist. Ellafibrinor also had a reduction in moderate to severe pruritus at 52 weeks, from baseline according to scores from the p PBC 40 questionnaire as well as the, 5 d itch scale.
Dr.Atoosa Rabbie:Thank you. That was great. If I may summarize, this session, we rely heavily on biomarkers to monitor progression of primary biliary cholangitis and to assess the effectiveness of treatment. Unfortunately, pruritus is common, very, troublesome, and can significantly impact patients' quality of life, but often doesn't receive adequate attention in treatment plan. This really underscores that we need newer, more effective treatments and, including dose dependent management strategies.
Dr.Atoosa Rabbie:We have reached the end of the program. I wanna thank all, my colleagues and faculty for this, engaging discussion. We would also like to thank Intercept for their support of the program. Be sure to claim your CME credit by filling out the evaluation and post this, and follow Iridium on X, Facebook and LinkedIn to see the corresponding meta threats.
