Treatment Persistence, Normal Alkaline Phosphatase and Clinical Outcomes in Primary Biliary Cholangitis.

New treatments/targets for primary biliary cholangitis.

No more pilots, a phase III trial of fibrates in primary biliary cirrhosis is long overdue!

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Introduction: Numerous trials have shown that Ursodeoxycholic Acid (UDCA) is effective in improving biochemical indices, delaying progression, and improving survival in patients diagnosed with Primary Biliary Cholangitis (PBC). The alternative therapy, Obeticholic Acid (OCA), is recommended for patients who cannot tolerate UDCA or who have an inadequate response to UDCA monotherapy. Despite the efficacy of these medications, prior investigations suggest that as many as 30% of patients with PBC may have never received treatment. This study aims to characterize usage rates of UDCA and second-line therapies among patients with PBC at a large urban health system with an academic liver transplant program. Methods: This was an observational, cross-sectional study. Patients were identified according to the ICD-10 code for PBC (ICD-10-CM: K74.3). All patients with a diagnosis of PBC who had any records within the health system were included. Review of medical records was performed to confirm the diagnosis of PBC (defined by AASLD practice guidelines) and determine which medications had been prescribed for treatment of PBC, as well as candidacy for second-line therapies. Results: 495 patients met inclusion criteria for this study. Of these, 91% self-identified as female, 7% as male, and 2% did not report. 78% self-identified as white/Caucasian, 7% as black/African American, 3% as Asian, 2% as Hispanic, and 9% did not report. Results for medication candidacy and usage are shown in the attached Figure. Notably, 95% of all patients were taking UDCA for treatment of their PBC. 67% of patients had PBC that was well-controlled on UDCA monotherapy. 8% of patients were taking OCA (either as combination or monotherapy). 3% of patients had a persistently elevated alkaline phosphatase despite appropriate treatment with UDCA and would benefit from the addition of OCA but had not been offered the medication. Only 3% of patients were not on any medication for management of PBC. Conclusion: Despite prior investigations suggesting that a large proportion of PBC patients may be unmedicated for the disease, the data presented here suggest that PBC patients are generally being managed according to guidelines in our health system. The majority of patients have disease that is well-controlled with UDCA monotherapy. However, OCA remains an important adjunctive/alternative therapy in certain cases, and physicians should be aware of indications for its use.Figure 1.: Medication candidacy and usage among patients diagnosed with PBC. UDCA – Ursodeoxycholic Acid; OCA – Obeticholic Acid; ALP – Alkaline Phosphatase; ULN – Upper Limit of Normal. Shown are all patients with a diagnosis of PBC who have records within the health system. Patients were stratified on the basis of medication usage and candidacy for OCA. The number of patients in each category is displayed in parentheses. OCA candidacy is considered to be one or more of the following: failure of ALP to decrease to within 1.67 times the upper limit of normal after one year of therapy with UDCA at appropriate weight-based dosing; inability to tolerate UDCA at appropriate weight-based dosing. * Severe liver disease is defined as one or more of the following: Child-Pugh B/C categorization; presence of portal hypertension; history of liver decompensation. Severe liver disease is a contraindication to the use of OCA

Introduction: Primary biliary cholangitis (PBC) is an inflammatory disease affecting intra-lobular bile ducts. Ursodeoxycholic acid (UDCA) was the sole standard treatment for PBC for many years and is currently first line.Obeticholic acid (OCA), a farnesoid X receptor agonist, is approved as additional therapy for PBC in UDCA non-responders or as monotherapy for UDCA intolerant patients.This study reports the real world experience for the efficacy and safety of OCA from 2 large academic centers. Methods: Retrospective screening for PBC by chart review and OCA treated patients identified.Demographic information, baseline laboratory tests, clinical data were collected and patients followed for a minimum of 1 year on OCA. Statistical analysis performed using stat software SPSS IBM. Results: We identified 230 PBC and PBC-AIH overlap patients and within this group 38 patients were on treatment with OCA either because of poor response (n=37) or intolerance to UDCA (n=1).Diagnosis was based on liver biopsy [95%] and AMA serologies [86%]. Overall 30 patients had PBC alone (78%) and PBC predominant with AIH features was seen in 8 patients (22%).Majority of patients were women [n=36/38, 95%] with an age ranging between 40-74 (mean 61).Cirrhosis was noted in fifteen patients [n=15/38, 40%]. OCA was initiated with low dose 5 mg daily and titrated up to 10mg daily at 3 months if lack of response as determined by alkaline phosphatase >1.67 ULN. All patients were on Ursodiol as primary PBC treatment with (12-15 mg/kg calculated dose per weight).Results: Nineteen patients [50%] needed dose upregulation to 10 mg OCA due to lack of response in alkaline phosphatase at 6 months.Overall eighteen patients have achieved biochemical response [47%] which occurred mainly in non-cirrhosis PBC patients versus cirrhosis PBC [16/23 vs 4/15 - OR 0.159 CI 0.03-0.67]. Reasons for treatment failure were side effects in 11 patients and lack of biochemical response in 8 patients.In the biochemical treatment failure six patients were cirrhotic and mean alkaline phosphatase was 360 mg/dl in treatment failure versus 150 mg/dl in responders (p=0.0001).The commonest side effects resulting in discontinuation was pruritus Conclusion: OCA efficacy is 47% in real world PBC patients with tolerability the major issue for treatment failure and with decreased efficacy in cirrhotic patients. Careful patient selection and optimizing side effect management will be necessary to ensure improved outcomes.

Primary biliary cholangitis (PBC) is an autoimmune disease marked by destruction of small intralobular bile ducts. Without medical therapy, patients can develop cholestatic liver disease, cirrhosis, and even liver failure. First line therapy with ursodeoxycholic acid (UDCA) is often effective, but up to 35% of patients will experience a suboptimal response. Obeticholic acid (OCA) has been recently approved for use in patients with inadequate response to UDCA alone. In prior trials, the addition of OCA has been associated with significant improvement in alkaline phosphatase (ALP) but only minimal reduction in total bilirubin (Tbil). With this case, we present a patient with inadequate response to UDCA who demonstrated remarkable improvement with marked reduction in ALP and resolution of jaundice after the addition of OCA. A 62 year old female presented with jaundice and labs revealed elevated liver-associated enzymes (LAEs), notably ALP 912 and Tbil 3.9. PBC was diagnosed based on positive AMA and liver biopsy findings. Histology also noted stage 3 hepatic fibrosis. She was started on UDCA 500mg twice daily with initial improvement in ALP but not Tbil (Figure 1). MRCP revealed a questionable focal biliary stricture, although endoscopic stenting did not lead to biochemical improvement and no stricture was seen on subsequent imaging. Repeat liver biopsy confirmed PBC and excluded overlap of autoimmune hepatitis. Due to persistent jaundice, the patient was started on OCA 5mg daily in conjunction to her UDCA. After six months, ALP has slowly declined to 279, and other LAEs have normalized with Tbil 0.8. OCA is a novel agent farnesoid X receptor agonist and has direct anti-cholestatic and anti-fibrotic effects. The addition of OCA to UDCA is associated with a 20-25% reduction in ALP. While our patient had an expected decline in ALP, the more remarkable finding has been the complete resolution of her hyperbilirubinemia with the combination of UDCA and low dose OCA. Her Mayo risk score declined from intermediate to low risk of death (7.8 to 5.7). This unexpected clinical improvement has allowed us to continue medical management while deferring liver transplant evaluation. More long-term data are needed to determine whether OCA impacts overall and transplant-free survival in patients with PBC.

Summary: Primary biliary cholangitis (PBC) is a chronic, autoimmune disorder of the liver. In its long-term course, it leads to small bile ducts destruction, cholestasis, liver fibrosis, cirrhosis and chronic liver failure. PBC is much common in women, especially of middle age. Most patients are diagnosed in an asymptomatic stage. The diagnosis is based on the combination of laboratory assessments, alkaline phosphatase elevation of more than 1,5 ULN for more than 6 months, and AMA antibodies in a titre 1: 40 or higher. The typical histological finding confirms the diagnosis, but the stage of liver disease may be determined based on the non-invasive liver stiffness measurement. Ursodeoxycholic acid represents nowadays standard-of-care in PBC patients, followed by elafibranor in intolerant patients or in non-responders. Liver transplantation is indicated in those with liver failure in whom conservative therapy failed. Key words: primary biliary cholangitis – AMA antibodies – alkaline phosphatase – ursodeoxycholic acid – obeticholic acid – liver transplantation

Introduction National guidelines on the management of primary biliary cholangitis (PBC) were published by the BSG and UKPBC in 2018.1 We examined a database of all patients who had undergone anti-mitochondrial antibody (AMA) testing over a five year period in a single centre (a district general hospital serving a population of 220,000), to examine adequacy of PBC diagnosis, ursodeoxycholic acid (UDCA) dosing, biochemical response, and referral for second line therapy in cases of UDCA intolerance or failure, using the thresholds and recommendations set out in the BSG UKPBC 2018 guidelines. Methods A laboratory database search was carried out to capture all AMA test results from 01 April 2014–31 March 2019. Laboratory records for all patients with a positive AMA at any titre were cross referenced, and a registry created of all patients with positive AMA and biochemical evidence of cholestasis (elevated alkaline phosphatase (ALP) above the upper limit of normal), or a pre-existing diagnosis of PBC regardless of ALP. Medical records were examined of all patients on this registry to establish history of diagnosis of PBC, treatment history, dosing of UDCA in mg/kg, adequacy of response to UDCA, and referral for second line therapy with obeticholic acid (OCA) where relevant. Results 20783 AMA tests were carried out with positive results for AMA at any titre recorded in 155 individual patients; 45 had evidence of cholestasis at the time of index AMA testing, 23 of whom had been diagnosed with PBC by the end of the study period. A further 6 AMA positive patients had an existing diagnosis of PBC with normalised ALP on treatment, giving a total PBC population of 29 patients. 25/29 (86%) of PBC patients were treated with UDCA, which was adequately dosed in 23/25 (92%). 15/19 (79%) of patients who had completed at least one year of adequately dosed UDCA responded adequately (ALP Conclusions AMA testing was commonly carried out in a district general hospital setting, but the cohort of PBC patients identified was small. In those diagnosed with PBC, UDCA dosing was done well overall, but more than 20% of patients did not respond adequately or could not tolerate UDCA. Even in a small PBC cohort such as this, there are likely to be patients who may benefit from second line therapy with OCA. Such cases can be identified through simple audit of UDCA dosing and biochemical response. Reference Hirschfield G et al. The British Society of Gastroenterology/UKPBC primary biliary cholangitis treatment and management guidelines. Gut 2018;0:1–27

Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Efficacy and safety of obeticholic acid in liver disease—A systematic review and meta-analysis

INTRODUCTION: The currently accepted criteria to define therapeutic response to primary biliary cholangitis (PBC) consists of alkaline phosphatase (ALP) (&lt;180 U/L) and bilirubin (&lt;1.0 mg/dL). New data suggests that normalization of ALP (&lt;120 U/L) and bilirubin (&lt;0.5 mg/dL) is associated with better overall outcomes. PBC patients are usually maintained on first line therapy of ursodeoxycholic acid (UDCA), obeticholic acid (OCA) or combination of both agents. The aim of the study was to determine the percentage of PBC patients that achieve the accepted (ALP &lt; 180, bilirubin &lt; 1) and ideal (ALP &lt; 120, bilirubin &lt; 0.5) treatment responses in a real-world setting. METHODS: All adult patients in this multi-center study had a diagnosis of PBC via ICD-9 and ICD-10 codes. Other chronic liver disease cases and those with significant alcohol consumption were excluded. Baseline demographics, clinical characteristics and laboratory data were collected. Therapy starting time was noted, assessing their lab values at baseline compared to a recent workup. A two-sided t test was done to compare continuous variables and a P value &lt; 0.05 was considered statistically significant. RESULTS: 76 adult PBC patients were included in the final analysis. The mean age at the last follow up was 61.8 years (±11.3). 96% were female, 47% were White and 51% were of Hispanic ethnicity. 93% were on UDCA therapy alone with daily dosages between 750-1500 mg. Only 7% received both UDCA and OCA. The mean baseline ALP was 286 U/L and the mean follow up ALP was 172 U/L (±84.6), 52 U/L above the ideal value (P &lt; 0.05). The mean baseline bilirubin was 1.04 mg/dL and the mean follow up bilirubin was 0.8 mg/dL (±1.2), 0.3 mg/dL above the ideal value (P &lt; 0.05). 62% reached the accepted ALP value, 86% reached the accepted bilirubin value, and 57% reached the accepted level. 30% of patients achieved the ideal ALP value and 26% achieved the ideal bilirubin level with 20% reaching the ideal response. The rates for accepted and ideal responses were 80% and 40%, respectively, for those on UDCA and OCA. CONCLUSION: The majority of PBC patients in real-life settings did not achieve the ideal treatment response of ALP &lt; 120 U/L and bilirubin &lt; 0.5 mg/dL. Furthermore, a significant percentage did not achieve the accepted treatment response of ALP &lt; 180 U/L and bilirubin &lt; 1.0 mg/dL. Only a small percentage received combination therapy with UDCA/OCA. There's a need to increase awareness among healthcare providers on the optimal responses to PBC treatment.

Obeticholic acid (OCA) improves cholestasis and is generally well tolerated in patients with primary biliary cholangitis (PBC) not responding, or intolerant, to ursodeoxycholic acid (UDCA). As PBC is mainly a cholestatic disorder, less attention is paid to aminotransferase behavior in the course of treatment. In this study we evaluated, in clinical practice, the efficacy of OCA treatment on both alkaline phosphatase (ALP) and alanine aminotransferase (ALT) using updated healthy ranges for aminotransferases. Fifteen PBC patients, non-responders to UDCA, were evaluated at baseline and during OCA treatment with serial measurement of cholestasis indexes and ALT, that were also assessed using updated normal ranges (&lt;30 IU/L in males, &lt;19 IU/L in females). Median ALP and ALT decreased from 2.16 to 1.27 × upper limit of normal (p = 0.003) and from 0.93 to 0.78 × upper limit of normal (p = 0.008), respectively, in the course of OCA treatment. At treatment day-15, median ALT decreased by 29.7% and ALP by 8.8%. Bilirubin and albumin were unmodified throughout treatment. Using updated normal ranges, ALT levels were normal in 6.7% of patients at baseline and in 33.3% of patients at 18 months of treatment. OCA treatment improves cholestasis and, also, indexes of hepatocyte necrosis, with a decline in necro-inflammatory activity even predating the improvement in cholestasis. Use of recalibrated healthy ranges for aminotransferases might be a useful tool to assess hepatic histological activity and its improvement with OCA treatment.

Nearly half of the newly detected AMAs in clinical practice does not lead to a diagnosis of PBC. PBC is unrecognized in 13% of those cases. Only 1 in 6 patients with AMAs and normal ALP will develop PBC after 5 years. The mortality of AMA-positive patients without PBC is increased irrespective of the risk of PBC development. (Hepatology 2017;65:152-163).

Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis

Alkaline phosphatase and liver fibrosis at diagnosis are associated with deep response to ursodeoxycholic acid in primary biliary cholangitis