Loss of biochemical response at any time worsens outcomes in UDCA-treated patients with primary biliary cholangitis.

Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. Impact and implications: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Past, current, and future trends in the prevalence of primary sclerosing cholangitis and inflammatory bowel disease across England (2015-2027): a nationwide, population-based study.

Background: Primary sclerosing cholangitis (PSC) is one of the leading indications for liver transplantation in Europe, and a major risk factor for cancer in inflammatory bowel disease (IBD). However, it is not known how the epidemiology of PSC will change as that of IBD evolves. The aim of this study is to provide nationwide statistics on the past and current prevalence of PSC and IBD across England, and forecast how this is likely to change over time. Methods: We accessed and analysed a nationwide population-based administrative healthcare registry, which houses prospectively accrued data since April 1st 2001. In so doing, the past and current prevalence of PSC-IBD and IBD alone was determined among 18-60-year-olds in England, alongside average annual percentage change rates (AAPC), between the 1st of January 2015 and 2020. Past and current prevalence data, alongside trends in incidence and event-free survival rates, were then used to forecast future prevalence between 2021 and 2027. Findings: In 2015, the prevalence of PSC with prior IBD diagnosis was 5.0 per 100,000 population, rising to 5.7 when including those with IBD diagnosed after PSC. In 2020, prevalence increased to 7.6 (8.6 accounting for IBD developing after PSC), yielding an AAPC of 8.8. In 2027, PSC-IBD prevalence is forecast to be 11.7 (95% prediction interval [PI]: 10.8-12.7), and 13.3 when accounting for IBD developing after PSC (AAPC: 6.4; 95% PI: 5.3-7.5). Comparatively, the prevalence of IBD alone rose among 18-60-year-olds from 384.3 in 2015 to 538.7 in 2020 (AAPC 7.0), and forecast to increase to 742.5 by 2027 (95% PI: 736.4-748.0; AAPC: 4.7, 95% PI: 4.6-4.8). Interpretation: The rate of growth in PSC-IBD is predicted to exceed IBD-alone. Further research is needed to understand changes in disease epidemiology, including aetiological drivers of developing (invariably progressive) liver disease in IBD, and the implications of rising case burden on health care resources. Funding: This study was supported by an unrestricted grant provided by Gilead Sciences.

COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls.

INTRODUCTION: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in patients with PBC improve with OCA therapy. METHODS: Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database. RESULTS: In the RCT, the primary endpoint occurred in 28.6% of OCA (n = 168) and 28.9% of placebo patients (n = 166; intent-to-treat analysis hazard ratio [HR] = 1.01, 95% confidence interval = 0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting and as-treated analyses shifted the HR to favor OCA. In the EC (n = 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR = 0.39; 95% confidence interval = 0.22-0.69; P = 0.001). No new safety signals were identified in the RCT. DISCUSSION: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). METHODS AND ANALYSIS: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. ETHICS AND DISSEMINATION: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. TRIAL REGISTRATION NUMBER: 1239.

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation.

BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Quantitative MRCP and metrics of bile duct disease over time in patients with primary sclerosing cholangitis: A prospective study.

BACKGROUND: Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. METHODS: Individuals with PSC were prospectively scanned using non-contrast MRCP. Quantitative metrics were calculated using MRCP+ post-processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). RESULTS: At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p < 0.01 for all correlations). Over a median 371-day follow-up (range: 364-462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p < 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non-PSC liver disease. CONCLUSION: Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist-derived cholangiographic assessment (trial registration: ISRCTN39463479).

Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts.

Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.

Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery.

Background & Aims: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS). Methods: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK. Results: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p <0.001). Conclusions: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required. Impact and implications: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.

Role of microbiome in autoimmune liver diseases.

The microbiome plays a crucial role in integrating environmental influences into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these change during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response. METHODS: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected. RESULTS: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early. CONCLUSIONS: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Primary sclerosing cholangitis and overlap features of autoimmune hepatitis: A coming of age or an age-ist problem?

Autoimmune liver diseases are siloed into three syndromes that define clinical practice. These classifiers can, and are, challenged by variant presentations across all ages, something inevitable to disease definitions that rely on interpreting (inherently variable) semi-quantitative/qualitative clinical, laboratory, pathological or radiological findings. Furthermore this categorisation is premised on an ongoing absence of definable disease aetiologies. Clinicians thus encounter individuals with biochemical, serological, and histological manifestations that are common to both primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH), often labelled as 'PSC/AIH-overlap'. In childhood the term 'autoimmune sclerosing cholangitis (ASC)' may be used, and some propose this to be a distinct disease process. In this article we champion the concept that ASC and PSC/AIH-overlap are not distinct entities. Rather, they represent inflammatory phases of PSC frequently manifesting earlier in the disease course, most notably in younger patients. Ultimately, disease outcomes remain similar to those of a more classical PSC phenotype observed in later life. Thus, we argue that it is now time to align disease names and descriptions used by clinicians across all patient subpopulations, to help unify care. This will enhance collaborative studies and ultimately contribute to rational treatment advances.

Ursodeoxycholic Acid Treatment-Induced GLOBE Score Changes Are Associated With Liver Transplantation-Free Survival in Patients With Primary Biliary Cholangitis.

INTRODUCTION: Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)-free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA). METHODS: Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE 0-1 : during the first year of UDCA, ΔGLOBE 1-2 : during the second year) and the risk of LT or death was assessed through Cox regression analyses. RESULTS: Overall, 3,775 UDCA-treated patients were included; 3,424 (90.7%) were female, the median age was 54.0 (interquartile range [IQR] 45.9-62.4) years, and the median baseline GLOBE score was 0.25 (IQR -0.47 to 0.96). During a median follow-up of 7.2 (IQR 3.7-11.5) years, 730 patients reached the combined end point of LT or death. The median ΔGLOBE 0-1 was -0.27 (IQR -0.56 to 0.02). Cox regression analyses, adjusted for pretreatment GLOBE score and ΔGLOBE 0-12 , showed that ΔGLOBE was associated with LT or death (adjusted hazard ratio 2.28, 95% confidence interval 1.81-2.87, P < 0.001). The interaction between baseline GLOBE score and ΔGLOBE 0-1 was not statistically significant ( P = 0.296). The ΔGLOBE 1-2 was associated with LT or death (adjusted hazard ratio 2.19, 95% confidence interval 1.67-2.86, P < 0.001), independently from the baseline GLOBE score and the change in GLOBE score during the first year of UDCA. DISCUSSION: UDCA-induced changes in the GLOBE score were significantly associated with LT-free survival in patients with PBC. While the relative risk reduction of LT or death was stable, the absolute risk reduction was heavily dependent on the baseline prognosis of the patient.

Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe.

BACKGROUND AND AIMS: The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. METHODS: Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. RESULTS: One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). CONCLUSION: We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). METHODS: This was a nationwide observational cohort study conducted from August 2017 until June 2021. RESULTS: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P < .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P < .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P < .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. CONCLUSION: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.

The Inconvenient Truth of Primary Biliary Cholangitis/Autoimmune Hepatitis Overlap Syndrome.

The term 'PBC/AIH-overlap' has been applied when features of autoimmune hepatitis (AIH), be they biochemical, serological or histological, coexist with primary biliary cholangitis (PBC), either at first presentation or sequentially during disease course. Several treatment paradigms have been proposed, extrapolated from those of the primary conditions. However, there are no randomised studies showing improved survival with combination therapy compared to bile acid monotherapy. In the absence of high-quality evidence, multidisciplinary patient-specific approaches must be used to individualise treatment pathways, with appreciation that disease phenotypes are not always static, differ in treatment responses, and have the potential to evolve over time.