Dynamics of liver stiffness measurement and clinical course of primary biliary cholangitis.

BACKGROUND & AIMS: In primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. METHODS: We conducted an international retrospective cohort study among PBC patients treated with ursodeoxycholic acid (UDCA) and followed by vibration-controlled transient elastography (VCTE) between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation (LT) or death, was quantified using the hazard ratio (HR) and its confidence interval (CI). RESULTS: A total of 6,362 LSMs were performed in 3,078 patients (2,007 on UDCA alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1,000 person-years). LSM progressed in 59% of patients (mean 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (p<0.001). For example, the adjusted HRs (95% CI) associated with a 20% annual variation in LSM were 2.13 (1.89 - 2.45) for the increase and 0.40 (0.33 - 0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or LT was considered. CONCLUSIONS: Tracking longitudinal changes in LSM using VCTE provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate endpoint in PBC clinical trials.

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.

Identifying a therapeutic window of opportunity for people living with primary sclerosing cholangitis: Embryology and the overlap of inflammatory bowel disease with immune-mediated liver injury.

Primary sclerosing cholangitis (PSC) is a variably progressive, fibrosis-causing autoimmune disorder of the intrahepatic and extrahepatic bile ducts of unclear etiology. PSC is commonly (in 60%-90% of cases) associated with an inflammatory bowel disease (IBD) like PSC-IBD and less commonly with an autoimmune hepatitis (AIH) like PSC-AIH or AIH-overlap disorder. Hepatologists and Gastroenterologists often consider these combined conditions as distinctly different from the classical forms in isolation. Here, we review recent epidemiologic observations and highlight that PSC-IBD and PSC-AIH overlap appear to represent aspects of a common PSC clinico-pathological pathway and manifest in an age-of-presentation-dependent manner. Particularly from the pediatric experience, we hypothesize that all cases of PSC likely originate from a complex "Early PSC"-"IBD"-"AIH" overlap in which PSC defines the uniquely and variably associated "AIH" and "IBD" components along an individualized lifetime continuum. We speculate that a distinctly unique, "diverticular autoimmunity" against the embryonic cecal- and hepatic diverticulum-derived tissues may be the origin of this combined syndrome, where "AIH" and "IBD" variably commence then variably fade while PSC progresses with age. Our hypothesis provides an explanation for the age-dependent variation in the presentation and progression of PSC. This is critical for the optimal targeting of studies into PSC etiopathogenesis and emphasizes the concept of a "developmental window of opportunity for therapeutic mitigation" in what is currently recognized as an irreversible disease process. The discovery of such a window would be critically important for the targeting of interventions, both the administration of current therapies and therapeutic trial planning.

Improving predictive accuracy in primary biliary cholangitis: A new genetic risk score.

BACKGROUND AND AIMS: Genetic variants influence primary biliary cholangitis (PBC) risk. We established and tested an accurate polygenic risk score (PRS) using these variants. METHODS: Data from two Italian cohorts (OldIT 444 cases, 901 controls; NewIT 255 cases, 579 controls) were analysed. The latest international genome-wide meta-analysis provided effect size estimates. The PRS, together with human leukocyte antigen (HLA) status and sex, was included in an integrated risk model. RESULTS: Starting from 46 non-HLA genes, 22 variants were selected. PBC patients in the OldIT cohort showed a higher risk score than controls: -.014 (interquartile range, IQR, -.023, .005) versus -.022 (IQR -.030, -.013) (p < 2.2 × 10-16). For genetic-based prediction, the area under the curve (AUC) was .72; adding sex increased the AUC to .82. Validation in the NewIT cohort confirmed the model's accuracy (.71 without sex, .81 with sex). Individuals in the top group, representing the highest 25%, had a PBC risk approximately 14 times higher than that of the reference group (lowest 25%; p < 10-6). CONCLUSION: The combination of sex and a novel PRS accurately discriminated between PBC cases and controls. The model identified a subset of individuals at increased risk of PBC who might benefit from tailored monitoring.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

Is there a correlation between prepartum anaemia and an increased likelihood of developing postpartum depression? A prospective observational study.

PURPOSE: Postpartum depression (PPD) represents a significant challenge to maternal and child health. Early screening for PPD is essential to ensure appropriate treatment and support. The present study aimed to assess whether maternal prepartum anaemia influences the likelihood of developing PPD within 3 days after delivery. METHODS: In collaboration with the Department of Psychiatry, a prospective observational study was carried out at the Gynaecology and Obstetrics Department of the University of Campania "Luigi Vanvitelli" in Naples. A total of 211 full-term pregnant women were enrolled, and their predelivery haemoglobin value was recorded. Women with gestational diabetes, hypertension, pre-eclampsia, intrauterine growth restriction, intellectual disability, or pre-existing diagnosis of psychotic spectrum disorder were excluded. Participants provided written informed consent to fill out the Edinburgh Postnatal Depression Scale (EPDS) 3 days after delivery. EPDS cut-off score of ≥ 10 was used to identify women at risk of developing PPD. Statistical analysis was performed using Student's t test, the Wilcoxon Rank Sum test, and linear regression. RESULTS: The participants were categorized into 2 groups based on EPDS scores: EPDS < 10 (176 patients) or EPDS ≥ 10 (35 patients). The two groups showed homogeneity in terms of socio-demographic and clinical characteristics. The mean haemoglobin values of anaemic pregnant women in the EPDS ≤ 10 group (11.78 ± 1.39 g/dl) and the EPDS > 10 group (11.62 ± 1.27 g/dl) were not significantly different (p = 0.52). There was no significant correlation between the predelivery haemoglobin value and the EPDS postpartum score of < 10 or ≥ 10. The Wilcoxon Rank Sum test and the estimated coefficients of the linear regression model did not show any statistical relationship between continuous and binary haemoglobin values. CONCLUSIONS: Our study found that maternal prepartum anaemia did not negatively impact the likelihood of developing postpartum depressive symptoms, in the first 3 days after delivery.

Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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 ≥ 10 kPa 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. CONCLUSIONS: 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.

Promoting mental health and preventing mental health problems in child and adolescent refugees and asylum seekers: A systematic review on psychosocial interventions.

BACKGROUND: According to the United Nations Commissioner for Refugees (UNHCR), children and adolescents represent 41% of all forcibly displaced individuals. They have to deal with conflicts, violence, and the many difficulties of flight and resettlement during a critical stage of their emotional, social, cognitive, and physical development. They are more likely to experience mental health problems during migration. Despite the several known risk factors, it is frequently challenging for refugees and asylum seekers to get mental health care. In this paper we review available studies on interventions aimed at promoting mental health and at preventing common mental disorders in immigrant adolescents and children. METHODS: The relevant PubMed, Scopus, PsychINFO and Web of Science databases were searched for papers published until March 21, 2023, using ("immigrants" OR "migration" OR "asylum seekers" OR "refugees") AND ("promotion" OR "prevention") AND ("mental health" OR "mental disorders" OR "psych*") AND ("children" OR "adolescents" OR "young adults") as search string. Fourteen articles qualified for the detailed review. RESULTS AND CONCLUSIONS: The majority of available interventions, although highly heterogeneous in format and content, showed significant improvement in several psychopathological dimensions, including trauma-related symptoms, psychological stress, anxiety, depressive and cognitive symptoms. Available studies on interventions for the prevention of mental disorders and the promotion of mental health in refugees and asylum seekers children and adolescents indicate that provided interventions were associated with a global improvement for participants. Implementation strategies to improve their scalability are highly needed.

Prognostic models and autoimmune liver diseases.

Autoimmune liver diseases (AILDs) are complex diseases with unknown causes and immune-mediated pathophysiology. In primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) disease modifying drugs are available which improve patient quality and quantity of life. In primary sclerosing cholangitis (PSC) no medical therapy is available and the only accepted treatment is liver transplantation (LT). PBC, PSC and AIH possess features that describe the archetype of patients within each disorder. On the other hand, the classical disorders are not homogeneous, and patients within each diagnosis may present with a range of clinical, biochemical, serological, and histological findings. Singularly, they are considered rare diseases, but together, they account for approximately 20% of LTs in Europe and USA. Management of these patients is complex, as AILDs are relatively uncommon in clinical practice with challenges in developing expertise, disease presentation can be sneaky, clinical phenotypes and disease course are heterogeneous. Prognostic models are key tools for clinicians to assess patients' risk and to provide personalized care to patients. Aim of this review is to discuss challenges of the management of AILDs and how the available prognostic models can help. We will discuss the prognostic models developed in AILDs, with a special focus on the prognostic models that can support the clinical management of patients with AILDs: in PBC models based on ursodeoxycholic acid (UDCA) response and markers of liver fibrosis; in PSC several markers including biochemistry, disease stage and radiological semiquantitative markers; and finally in AIH, markers of disease stage and disease activity.

Intensive care management of acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by an acute deterioration of the liver function associated with extrahepatic organ failures requiring intensive care support and associated with a high short-term mortality. ACLF has emerged as a major cause of mortality in patients with cirrhosis and chronic liver disease. ACLF has a unique pathophysiology in which systemic inflammation plays a key role; this provides the basis of novel therapies, several of which are now in clinical trials. Intensive care unit (ICU) therapy parallels that applied in the general ICU population in some organ failures but has peculiar differential characteristics in others. Critical care management strategies and the option of liver transplantation (LT) should be balanced with futility considerations in those with a poor prognosis. Nowadays, LT is the only life-saving treatment that can radically improve the long-term prognosis of patients with ACLF. This narrative review will provide insights on the current understanding of ACLF with emphasis on intensive care management.

Study Confirms Safety and Effectiveness of Intra-Articular Glucocorticoids for Painful Hip Dislocation in Children and Young Adults with Neurologic Impairment.

BACKGROUND: Hip dislocation is a common source of pain in children with neurologic impairment. When medical interventions fail, orthopedic surgery does not guarantee a definitive result as the displacement may continue postoperatively and a second operation is often required. METHODS: Retrospective analysis of data regarding the safety and effectiveness of an intra-articular corticosteroid injection (IACI) in 11 patients, aged 15 ± 5 years old, collected through a telephonic questionnaire administered to parents. RESULTS: 21 IACIs were performed, a mean number of 1.9 ± 1.5 times for each patient, at a mean age (of the first IACI) of 13.5 ± 5 years. According to the parents, the IACI significantly lowered the number of participants experiencing pain (82% reduction) and using analgesics (60% reduction). There was also a significant improvement in the children's hip mobility (63% reduction in patients experiencing stiffness), decubitus (90% reduction in obligated positioning), behavior (80% reduction in lamenting or crying patients), sleep quality (87.5% reduction in patients awakening every night), and caregivers' quality of life (91% reduction in worried parents). The mean reported duration of the IACIs' benefit was 5.4 ± 2.4 months (range 1-9), with a positive correlation with the number of IACIs (r = 0.48; p-value = 0.04) and a negative correlation with the age at the first injection (r = -0.71; p-value = 0.02). The only reported adverse event was mild local swelling in one child. CONCLUSIONS: the IACI could represent a safe and effective intervention for painful hip dislocation, both before and after surgery, with a long-lasting benefit which seems to increase as multiple IACIs are performed.

Exploring the landscape of steatotic liver disease in the general US population.

BACKGROUND AND OBJECTIVE: The aim of the present study is to explore the epidemiologic impact of the definition of steatotic liver disease (SLD) proposed by a multi-society (American Association for the Study of the Liver-the European Association for the Study of Liver Diseases-Asociación Latinoamericana para el Estudio del Hígado) Delphi consensus statement. METHODS: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey who were evaluated by vibration-controlled transient elastography. Hepatic steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter and liver stiffness measurement using cut-offs of 274 dB/m and 8.0 kPa, respectively. Recently proposed criteria for metabolic dysfunction-associated steatotic liver disease (MASLD), MetALD (MASLD + significant alcohol consumption), MASLD-Viral hepatitis and cryptogenic SLD were applied. RESULTS: SLD was present in 42.1% (95% CI: 40.3-43.9) of the 3173 included participants. Among patients with SLD, 99.4% met the metabolic dysfunction definition. Moreover, 89.4%, 7.7%, 2.4%, 0.4% and 0.1% were defined as MASLD, MetALD, MASLD-Viral, alcoholic liver disease (ALD) (significant alcohol consumption without metabolic dysfunction) and cryptogenic, respectively. No patients without metabolic dysfunction had significant liver fibrosis, which was present in 15.2%, 9.5% and 19.5% of patients with MASLD, MetALD and MASLD-viral, respectively. Approximately, 90% of the overall adult US population could be diagnosed with metabolic dysfunction according to the consensus criteria. A high degree of concordance was found between MASLD and the previously proposed metabolic dysfunction-associated fatty liver disease definition. CONCLUSIONS: Metabolic dysfunction is present in almost all patients with SLD in the United States. The new change in diagnostic criteria did not significantly impact disease prevalence.

Patient-reported quality of care in primary sclerosing cholangitis.

BACKGROUND: Management and follow-up strategies for primary sclerosing cholangitis (PSC) vary. The aim of the present study was to assess patient-reported quality of care to identify the most important areas for improvement. METHODS: Data were collected via an online survey hosted on the EU Survey platform in 11 languages between October 2021 and January 2022. Questions were asked about the disease, symptoms, treatment, investigations and quality of care. RESULTS: In total, 798 nontransplanted people with PSC from 33 countries responded. Eighty-six per cent of respondents reported having had at least one symptom. Twenty-four per cent had never undergone an elastography, and 8% had not had a colonoscopy. Nearly half (49%) had never undergone a bone density scan. Ursodeoxycholic acid (UDCA) was used in 90-93% in France, Netherlands and Germany, and 49-50% in the United Kingdom and Sweden. Itch was common (60%), and 50% of those had received any medication. Antihistamines were taken by 27%, cholestyramine by 21%, rifampicin by 13% and bezafibrate by 6.5%. Forty-one per cent had been offered participation in a clinical trial or research. The majority (91%) reported that they were confident with their care although half of the individuals reported the need for more information on disease prognosis and diet. CONCLUSION: Symptom burden in PSC is high, and the most important areas of improvement are disease monitoring with more widespread use of elastography, bone density scan and appropriate treatment for itch. Personalised prognostic information should be offered to all individuals with PSC and include information on how they can improve their health.

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.

Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Primary biliary cholangitis (PBC) is a rare liver disease with significant unmet need for second-line/add-on treatments. Setanaxib, a NOX1/4 inhibitor, has shown anti-fibrotic effects in in vitro and animal studies. This phase 2, randomized, multicentre study investigated the efficacy and safety of setanaxib in patients with PBC. METHODS: Patients with ≥6 months of ursodeoxycholic acid (UDCA) treatment were randomized 1:1:1 to oral setanaxib 400 mg once daily (OD), twice daily (BID), or placebo, in addition to UDCA for 24 weeks. Other inclusion criteria included alkaline phosphatase (ALP) ≥1.5 × ULN and gamma-glutamyl transferase (GGT) ≥1.5 × ULN. The primary endpoint was percentage change from baseline in GGT at Week 24; secondary endpoints included change from baseline in ALP, liver stiffness (LS; via transient elastography), fatigue at Week 24, and safety outcomes. p values compare setanaxib 400 mg BID and placebo groups. RESULTS: Of patients randomized (setanaxib 400 mg OD and BID: 38, and 36; placebo: 37), 104/111 completed Week 24. Mean (standard deviation [SD]) change in GGT to Week 24 was -4.9% (59.6%) for setanaxib 400 mg OD, -19.0% (28.9%) for setanaxib 400 mg BID, and -8.4% (21.5%) for placebo; p = .31. Patients treated with setanaxib 400 mg OD and BID showed decreased serum ALP levels from baseline to Week 24 (p = .002: setanaxib BID versus placebo). Patients treated with setanaxib 400 mg OD and BID showed mean (SD) percentage increases in LS to Week 24 of 3.3% (35.0%) and 7.9% (43.7%), versus 10.1% (33.1%) for placebo (p = .65). Changes in mean (SD) PBC-40 fatigue domain scores to Week 24 were +0.3% (24.9%) for setanaxib 400 mg OD, -9.9% (19.8%) for setanaxib 400 mg BID and +2.4% (23.1%) for placebo, p = .027. Two patients (one placebo, one setanaxib 400 mg BID) experienced serious treatment-emergent adverse events, deemed unrelated to study drug. CONCLUSIONS: The primary endpoint was not met. However, the secondary endpoints provide preliminary evidence for potential anti-cholestatic and anti-fibrotic effects in PBC, supporting the further evaluation of setanaxib in a future phase 2b/3 trial.

Noninvasive identification of probable fibrotic nonalcoholic steatohepatitis across the spectrum of glucose tolerance in the United States.

AIM: Identifying patients with fibrotic nonalcoholic steatohepatitis (NASH) is crucial in order to refer them to specialist care as fibrotic NASH represents one of the major inclusion criteria for clinical trials. The aim of this study is to report the prevalence of fibrotic NASH in the general US population across the spectrum of glucose tolerance and evaluate the performance of the recently proposed Fibrotic NASH Index (FNI). METHODS: This is a cross-sectional study of US adults participating in the 2017-2020 cycles of the National Health and Nutrition Examination Survey. Participants with available data to calculate FNI (which is based on AST, HbA1c and HDL-cholesterol) and with a reliable vibration controlled transient elastography examination were included. We excluded participants with chronic viral hepatitis, significant alcohol consumption or other forms of liver disease. Probable fibrotic NASH was defined as a Fibroscan-AST (FAST) score ≥ 0.35. RESULTS: We included a total of 6268 participants. The overall prevalence of probable fibrotic NASH was 5.9 % (95 % CI 5.2-6.7) and it increased progressively from participants with normal glucose tolerance (3.7 %, 95 % CI 2-9-4.7) to those with diabetes (14.7 %, 95 % CI 12.1-17.8). The performance of FNI for probable fibrotic NASH was satisfactory in the overall population (area under the receiver operating characteristic curve (AUROC): 0.93, 95 % CI 0.92-0.94) and it maintained a good accuracy also in participants with diabetes (n = 1113, AUROC 0.89, 95 % CI 0.86-0.92). In all groups it outperformed Fibrosis-4. CONCLUSIONS: FNI is an easy and reliable test to screen for NASH and its performance is maintained in patients with diabetes, a condition that was shown to negatively influence the performance of several non-invasive scores.

Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial.

BACKGROUND: There is a real unmet need for primary biliary cholangitis (PBC) treatments that can improve quality of life impacting symptoms. In this post hoc analysis, we evaluated potential effects of the NADP oxidase 1/4 inhibitor, setanaxib, on patient-reported quality of life from a phase 2 trial in PBC. PATIENTS AND METHODS: The underpinning double-blind, randomized, placebo-controlled trial (NCT03226067) recruited 111 patients with PBC and inadequate response/intolerance to ursodeoxycholic acid. Patients self-administered oral placebo (n=37), setanaxib 400 mg once daily (OD; n=38), or setanaxib 400 mg twice daily (BID; n=36), in addition to ursodeoxycholic acid for 24 weeks. Quality of life outcomes were assessed using the validated PBC-40 questionnaire. Patients were stratified post hoc by baseline fatigue severity. RESULTS: At week 24, patients treated with setanaxib 400 mg BID reported greater mean (SE) absolute reductions from baseline in PBC-40 fatigue domain score [-3.6 (1.3)] versus those receiving setanaxib 400 mg OD [-0.8 (1.0)]) or placebo [0.6 (0.9)]. Similar observations were made across all PBC-40 domains except itch. In the setanaxib 400 mg BID arm, patients with moderate-to-severe fatigue at baseline had a greater reduction in mean fatigue score at week 24 [-5.8 (2.1)] versus those with mild fatigue [-0.6 (0.9)]; results were similar across all domains. Reduced fatigue was correlated with emotional, social, symptom, and cognitive improvements. CONCLUSIONS: These results support further investigation of setanaxib as a treatment for patients with PBC, particularly for those with clinically significant fatigue.