Background-Aim: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease. Epidemiological data in Italy are limited. To address this the Italian PBC Registry was established in 2019 to collect retrospective and prospective data. This study provides an overview of the Registry and its collected data.Methods: The Registry is based on a centralized database collecting demographics, biochemistry, disease stage and treatments. Tests at diagnosis were defined as those performed 3 months before to 30 days after diagnosis; tests at 1 year after UDCA were those performed 11–15 months after treatment initiation. Categorical variables are reported as frequencies (%); continuous variables are reported as mean ± SD or median and interquartile range (IQR). ALP, AST, ALT, GGT are expressed as ratios of their ULN, bilirubin as mg/dL.Results: From 2019 to 2025 enrolment increased from 128 to 3310 (37±22 patients/month). 3199 were analyzed (111 excluded for missing data). The Registry involves 69 active centers, 61 entering data, distributed across Italy (40 North, 9 Center, 20 South/Islands). 2836 (89%) were female with mean age 55.3 ± 12 years, BMI 24.96 ± 4.64, 3067 (96.7%) were Caucasian. Median follow-up was 6.9 years [3.1, 12.6]. 2018 (80.3%) reported no alcohol consumption, 456 (18.1%) consumed < 10/20 g/day (women/men) and 40 (1.6%) consumed >10/20 g/day (women/men). 1724 (70%) never smoked, 423 (17.2%) were former and 315 (12.8%) were current smokers. Optional biological samples (blood, urine, stool, liver tissue) are collected; 13 centers collect blood annually (recruitment/follow-up): 422 patients provided one sample, 116 two and 105 three or more. At diagnosis, among 1840 patients (57.5%) with available tests, the mean values were: ALP 1.59 [1.07, 2.67], AST 1.25 [0.83, 2.10], ALT 1.32 [0.80, 2.18], GGT 3.90 [1.89, 7.49], bilirubin 0.65 [0.50, 0.92] mg/dL. AMA positivity was detected in 1241 (68.5%), while 243 (13.4%) were negative and 328 (18.1%) had not been tested. Liver biopsy was performed in 666 (20.8%) patients and transient elastography in 653 (20.4%) with a median liver stiffness of 6.6 kPa [5.0, 9.1]. After one year of UDCA 809 (25.3%) patients had: ALP 1.11 [0.78, 1.64], AST 0.78 [0.59, 1.06], ALT 0.70 [0.48, 1.10], GGT 1.26 [0.70, 2.78], bilirubin 0.60 [0.44, 0.83] mg/dL. Elevated ALP (>1.67) was observed in 185 (22.9%) patients. However, considering the entire cohort, 923 (28.8%) patients initiated second-line therapy: 429 (46.5%) with Obeticholic Acid (OCA), 277 (30%) with fibrates (bezafibrate/fenofibrate), 163 (17.7%) with combination therapy (OCA and fibrate). Regarding the new PPAR-targeted therapies, 125 (13.5%) patients initiated Elafibranor and 52 (5.6%) initiated Seladelpar.Conclusions: The Italian PBC Registry provides a national picture of PBC, supporting disease monitoring and management. Continued commitment from participating centers will enhance data completeness and strengthen the reliability of future analyses.

Hepatic Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a severe complication following hematopoietic stem cell transplantation (HSCT), traditionally diagnosed based on clinical criteria. This study aimed to evaluate the diagnostic performance of liver stiffness measurement (LSM) as a non-invasive tool for non invasive diagnosis of VOD/SOS. A multicentre clinical trial was conducted in Italy from April 2018 to December 2021, screening 1089 patients across 25 centers. VOD/SOS diagnosis followed established clinical guidelines, and patients underwent comprehensive clinical, laboratory, and imaging evaluations up to +100 days post-HSCT or until VOD/SOS diagnosis. LSM was measured pre-HSCT and on specific post-transplant days (ClinicalTrials.gov: NCT03426358). The study enrolled 774 adults and 167 children. The +100-day incidence of VOD/SOS HSCT was 5.53 and 5.26 in the overall and allo-HSCT population, higher in children (14.3

Background & Aims: Several studies have assessed the short-term effectiveness and safety of obeticholic acid (OCA) in the real-world setting. We aimed to extend knowledge on the real-world effectiveness and safety of OCA treatment by expanding sample size and follow-up, and by exploring changes in liver stiffness measurement (LSM) over time. Methods: The RECAPITULATE project involves centres belonging to the “Italian PBC registry” and/or the “Club Epatologi Ospedalieri” PBC working group. Effectiveness was evaluated as biochemical response according to POISE and normal range (NR) criteria (normal alkaline phosphatase/alanine aminotransferase/bilirubin). Safety was assessed as the incidence of de novo/worsening pruritus and discontinuation rate/causes. Available LSMs were also captured. Results: We included 747 patients from 66 Italian centres: mean age 58 years; female/male 88%/14%; median follow-up 24 months [IQR 12-42]; 28% with cirrhosis, and 14% with autoimmune hepatitis (AIH)/PBC overlap syndrome. Probabilities of POISE and NR response increased from baseline to 57% and 20%, respectively, by the 42nd month. The probabilities of response were lower in patients with cirrhosis (p = 0.02 and p = 0.004 for POISE and NR), but not different between patients with AIH/PBC and pure PBC (p = 0.8). Overall, 130 patients (17%) discontinued treatment, mainly due to pruritus (36.9%), while 28.5% did so after developing hepatic events. The discontinuation rate was higher in patients with cirrhosis (p <0.001). LSM was available in 573 patients (∼77%), of whom 255 had multiple measurements. LSM variation over time differed based on the attainment of POISE biochemical response (expected mean annual variation -0.48 [-0.78, -0.19] in responders vs. +0.33 [-0.07, 0.73] in non-responders, respectively, p <0.001). Conclusions: Our findings confirm the effectiveness and safety profiles of OCA in the medium/long term and demonstrate that biochemical response is associated with the change in LSM over time. Impact and Implications: After the conditional approval of OCA for the treatment of PBC, the main confirmatory study failed to demonstrate OCA's ability to reduce liver-related events, leading the EMA to revoke the drug's marketing authorization. The ensuing scientific debate highlights an urgent need for further evidence from real-world practice. In the largest real-world series of patients treated with OCA to date, we confirm that the drug's effectiveness and safety profiles are maintained over a medium-to-long follow-up period. Valuable data for the management of the drug in relevant subgroups of patients, such as those with cirrhosis and autoimmune hepatitis/PBC overlap syndrome, are also provided. Our original results on liver stiffness measurement variation over time suggest a favourable impact of OCA on fibrosis progression, particularly in patients achieving a biochemical response to the drug. Overall, these data provide important insights for clinicians managing patients with PBC and contribute to the ongoing scientific debate about the effectiveness/safety profile of this drug.

Background & AimsObeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA.MethodsWe used data from the Italian RECAPITULATE (N 441) and the IBER-PBC (N 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS), or also after 6 months of treatment (ORS+). Multivariable Cox’s regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (ALP/ULN<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or NORMAL RANGE criteria (NR: normal ALP, ALT and bilirubin) up to 24 months.ResultsDepending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were of 0.75, 0.78 and 0.72 for POISE, ALP/ULN<1.67 and NR response, which raised to 0.83, 0.88, 0.81 with ORS+, respectively. The respective performances in validation were of 0.70, 0.72 and 0.71 for ORS, and 0.80, 0.84, 0.78 for ORS+. Results were consistent across groups with mild/severe disease.ConclusionsWe developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.

BackgroundObeticholic acid (OCA) stands as the sole approved second-line treatment for primary biliary cholangitis (PBC) patients unresponsive to ursodeoxycholic acid (UDCA). Preliminary studies suggested OCA's efficacy in reducing PBC decompensation and increasing survival. However, these studies face limitations, either due to heterogeneous cohorts (OCA registrative trial Vs real-world controls) or reliance on administrative data.AimTo compare transplant-free and liver-related event (LRE)-free survival between two large real-world cohorts of OCA-treated and untreated PBC patients.MethodsThe Italian RECAPITULATE is a multicenter real-world cohort of OCA-treated PBC patients enrolled from across Italy. An external control cohort of OCA-untreated PBC patients was derived from the GLOBAL-PBC dataset. Controls met OCA prescription criteria in Italy (ALP≥1.5/ULN and/or 1<bilirubin<2 mg/dl after ≥1 year of UDCA treatment), and a random visit in which eligibility criteria were met represented the index date. LRE (ascites with-/-out spontaneous bacterial peritonitis, hepatic encephalopathy, and upper gastrointestinal bleeding), liver transplant and liver-related death were tracked during follow-up. Weighted Cox regression method (using propensity scores) was applied for the external control group, incorporating age, ALP, AST, bilirubin, UDCA duration, cirrhosis and age at OCA start as baseline confounders.ResultsThe study included 437 RECAPITULATE patients (female: 88%; cirrhotics: 34%; on UDCA: 98%), and 831 GLOBAL-PBC controls (female: 91%; cirrhotics: 15%; on UDCA: 74%). RECAPITULATE's median follow-up was 30 months, and time was censored accordingly in the control cohort. Liver transplant/liver-related death and LRE were 4 and 16 in the RECAPITULATE cohort, and 58 and 107 in GLOBAL-PBC controls, respectively. In the weighted Cox regression analyses, patients in the RECAPITULATE cohort showed reduced risk of liver transplant/liver-related death [HR 0.318 (0.153-0.660); p<0.0001] and LRE [HR 0.327 (0.196-0.543); p<0.001] with respect to GLOBAL-PBC controls (Figure 1).ConclusionIn the comparison between two real-world cohorts, OCA-treated PBC patients show a longer transplant-free and LRE-free survival with respect to propensity-matched untreated controls.

IntroductionIn PBC, the prognostic value of alkaline phosphatase, bilirubin and liver stiffness measurements(LSM) has been well established. However, the significance of their variation during treatment with obeticholic acid (OCA) has never been investigated.AimTo describe on-treatment trajectories of LSM based on biochemical response to OCA, and to evaluate associated risk of liver-related events (LRE) in a large cohort of OCA-treated PBC patients.Materials and MethodsWe used data from the Italian RECAPITULATE cohort, including OCA-treated PBC patients from centers belonging to the Italian PBC Registry and/or the CLEO/AIGO PBC study groups. Subjects with <6 months’ observation and cirrhotics in Child-Pugh B-C classes were excluded. Biochemical response was evaluated through POISE criteria. Linear mixed models were used to describe on-treatment variation of LSM, while Cox-models to assess the impact on LRE. Joint models were applied to estimate the association between LSM changes and LRE, defined as the occurrence of liver-related death, liver transplantation, or hepatic decompensation.Results631 PBC patients (median age 58, women 89%, cirrhosis 27%) accounted for 29 LRE during 19,164 patient-months (median follow-up, 30 months). A sub-cohort of 243 patients with at least two LSMs (total, 656 LSMs) was also analysed. POISE response rates were 42% and 58% at 1 and 3 years, respectively. LSM progressively increased in POISE non-responders (slope +0.44 KPa/year, 95%CI 0.04,0.85), while decreasing over time in responders (slope -0.45 KPa/year 95%CI -0.75,-0.13; p interaction<0.001). Patients attaining 1year-POISE response showed a significantly reduced incidence of LRE during follow-up (HR 0.22, 95%CI 0.08,0.59). Any increase in LSM was associated with an increased risk of LRE, with an overall HR per 10% increase in LSM/year of 1.39 (95%CI 1.18,1.67).ConclusionsIn patients with PBC, biochemical response to OCA translates into a reduction of LSM and of LRE during follow-up, while non-response is associated with increased LSM and risk of LRE.

BACKGROUND & AIMS:Noninvasive tests (NITs) for ruling-out clinical significant portal hypertension (CSPH) and high-risk varices (HRVs) in patients with primary biliary cholangitis (PBC) and compensated advanced chronic liver disease (cACLD) are lacking. We evaluated NITs in these patients and the influence of cholestasis on their performance. METHODS:Consecutive patients from the "Italian PBC registry" and 2 United Kingdom large-volume PBC referral centers with upper endoscopy within 6 months from biochemical evaluation and transient elastography were included. Rete Sicilia Selezione Terapia (RESIST), Baveno VI (BVI), and Expanded Baveno VI (EBVI) criteria for ruling out HRV were assessed according to alkaline phosphatase (ALP) levels (< or ≥1.5 × upper limit of normal). Decision curve analysis was performed. Prevalence of any sized esophageal varices among patients fitting Baveno VII (BVII) criteria was also calculated. RESULTS:The final cohort consisted of 293 patients with cACLD. RESIST criteria were associated with the lowest rate of missed HRV (2.5% vs 9.8% for BVI and 8.9% for EBVI). In patients with ALP levels ≥1.5 × upper limit of normal, BVI and EBVI missed a higher rate of HRV (15.5% and 14.5%, respectively) than RESIST (3.1%). Decision curve analysis demonstrated the highest net benefit of RESIST criteria for ruling out HRV, regardless of ALP levels. Among 75 patients classified as low risk of CSPH according to BVII, 14 (18.7%) showed esophageal varices. CONCLUSIONS:Biochemical-based RESIST criteria demonstrate the highest net benefit compared with elastography-based criteria for ruling out HRV. The severity of cholestasis affects NITs performance to rule out HRV and CSPH in patients with PBC and cACLD.

IntroductionNon-invasive tests (NITs) to identify patients with Primary Biliary Cholangitis (PBC) and compensated Advanced Chronic Liver Disease (cACLD) who can avoid esophagogastroduodenoscopy (EGDS) are lacking. Aims of this study were to evaluate the diagnostic performance of NITs to rule out high-risk esophageal varices (HRV) in patients with PBC-related cACLD and to assess the influence of cholestasis on the NITs performance.MethodData of patients with cACLD from 24 centres participating to “Italian PBC registry”, were captured. All PBC patients who performed an EGD for evaluation of signs of portal hypertension were analyzed. Outcome was the presence of HRV at index EGD. RESIST criteria (platelets - PLT >120 × 109/L and serum albumin >3.6 g/dL) were compared with elastography-based criteria (Baveno VI, Expanded Baveno VI, and Baveno VII) in patients with Alkaline Phosphatase (ALP) < or ³ 1.67 ULN. Decision curve analysis (DCA) of NITs were calculated.ResultThe cohort consisted of 250 patients. At EGDS, 137 patients (54.8%) had no varices, 79 (31.6%) had low-risk varices and 34 (13.6%) had HRV. Liver stiffness by Fibroscan was available in 186 patients (74.%). Overall, the proportion of correctly spared endoscopies for HRV was 61.1%, 54.1%, 31.4% and 18.2% for RESIST, Expanded Baveno VI, Baveno VI and Baveno VII criteria, respectively. and RESIST criteria were associated with the lowest rate of missing HRV (2.9%). In patients with ALP ³ 1.67 ULN (101, 40.4%) the rate of missing HRV for Baveno VI and Expandend Baveno VI criteria were 23.8 and 18.9% respectively. In the same category of patients RESIST criteria false negative rate was 6%. DCA demonstrates the highest net benefit of RESIST criteria compared to elastography-based criteria for ruling out HRV both in patients with ALP < or ³ 1.67 ULN (Figure 1).ConclusionCholestasis impacts on NITs ability to rule out HRV in patients with PBC and cACLD. Biochemical-based RESIST criteria demonstrates the highest net benefit compared to elastography-based criteria for ruling out HRV.