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OBJECTIVES: 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 PBC patients 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 [ITT] analysis hazard ratio [HR]=1.01, 95% CI=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 (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT. CONCLUSIONS: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT 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.
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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 patients with PBC treated with ursodeoxycholic acid and followed by vibration-controlled transient elastography 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, or death, was quantified using the hazard ratio and its confidence interval. RESULTS: A total of 6362 LSMs were performed in 3078 patients (2007 on ursodeoxycholic acid 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 1000 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 < .001). For example, the adjusted hazard ratios (95% confidence interval) 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 liver transplantation was considered. CONCLUSIONS: Tracking longitudinal changes in LSM using vibration-controlled transient elastography 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 end point in PBC clinical trials.
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BACKGROUND: Primary sclerosing cholangitis associated with inflammatory bowel disease (IBD-PSC) carries significant morbidity compared to IBD without PSC. Alterations in microbial composition and bile acid (BA) profiles have been shown to modulate chronic inflammation in IBD, but data in IBD-PSC is scarce. We aimed to assess the differences in gut microbiome composition as well as in the BA profile and BA-related microbial functions between IBD-PSC and IBD-only. METHODS: 54 IBD-PSC and 62 IBD-only subjects were enrolled from 2012 to 2021. Baseline samples were collected for fecal DNA shotgun metagenomic sequencing, fecal and serum BA quantitation using mass spectrometry and fecal calprotectin. Liver fibrosis measured by transient elastography (TE) was assessed in the IBD-PSC group. Data was analyzed using general linear regression models and Spearman rank correlation tests. RESULTS: Patients with IBD-PSC had reduced microbial gene richness (p=0.004) and significant compositional shifts (PERMANOVA: R2=0.01, p=0.03) compared to IBD-only. IBD-PSC was associated with altered microbial composition and function, including decreased abundance of Blautia obeum, increased abundance of Veillonella atypica, Veillonella dispar and Clostridium scindens (q<0.05 for all), and increased abundance of microbial genes involved in secondary BA metabolism. Decreased serum sulfated and increased serum conjugated secondary BA were associated with IBD-PSC and increased liver fibrosis. CONCLUSION: We identified differences in microbial species, functional capacity and serum BA profiles in IBD-PSC compared with IBD-only. Our findings provide insight into the pathophysiology of IBD associated with PSC and suggest possible targets for modulating the risk and course of IBD in subjects with PSC.
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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.
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Colangitis Esclerosante , Proyectos de Investigación , Humanos , Colangitis Esclerosante/terapia , Ensayos Clínicos como Asunto , Técnica Delphi , Evaluación de Resultado en la Atención de Salud , Determinación de Punto Final , Revisiones Sistemáticas como AsuntoRESUMEN
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.
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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.
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Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with autoimmune liver disease (AILD), autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. We compared the survival of patients with a potential living donor (pLDLT) on the waitlist versus no potential living donor (pDDLT) on an intention-to-treat basis. Our retrospective cohort study investigated adults with AILD listed for a liver transplant in our program between 2000 and 2021. The pLDLT group comprised recipients with a potential living donor. Otherwise, they were included in the pDDLT group. Intention-to-treat survival was assessed from the time of listing. Of the 533 patients included, 244 (43.8%) had a potential living donor. Waitlist dropout was higher for the pDDLT groups among all AILDs (pDDLT 85 [29.4%] vs. pLDLT 9 [3.7%], p < 0.001). The 1-, 3-, and 5-year intention-to-treat survival rates were higher for pLDLT versus pDDLT among all AILDs (95.7% vs. 78.1%, 89.0% vs. 70.1%, and 87.1% vs. 65.5%, p < 0.001). After adjusting for covariates, pLDLT was associated with a 38% reduction in the risk of death among the AILD cohort (HR: 0.62, 95% CI: 0.42-0.93 [ p <0.05]), and 60% among the primary sclerosing cholangitis cohort (HR: 0.40, 95% CI: 0.22-0.74 [ p <0.05]). There were no differences in the 1-, 3-, and 5-year post-transplant survival between LDLT and DDLT (AILD: 95.6% vs. 92.1%, 89.9% vs. 89.4%, and 89.1% vs. 87.1%, p =0.41). This was consistent after adjusting for covariates (HR: 0.97, 95% CI: 0.56-1.68 [ p >0.9]). Our study suggests that having a potential living donor could decrease the risk of death in patients with primary sclerosing cholangitis on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups.
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Colangitis Esclerosante , Hepatitis Autoinmune , Análisis de Intención de Tratar , Trasplante de Hígado , Donadores Vivos , Listas de Espera , Humanos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Trasplante de Hígado/estadística & datos numéricos , Femenino , Masculino , Donadores Vivos/estadística & datos numéricos , Estudios Retrospectivos , Persona de Mediana Edad , Listas de Espera/mortalidad , Adulto , Resultado del Tratamiento , Colangitis Esclerosante/cirugía , Colangitis Esclerosante/mortalidad , Colangitis Esclerosante/complicaciones , Hepatitis Autoinmune/cirugía , Hepatitis Autoinmune/mortalidad , Enfermedad Hepática en Estado Terminal/cirugía , Enfermedad Hepática en Estado Terminal/mortalidad , Enfermedad Hepática en Estado Terminal/diagnóstico , Cirrosis Hepática Biliar/cirugía , Cirrosis Hepática Biliar/mortalidad , Enfermedades Autoinmunes/cirugía , Enfermedades Autoinmunes/mortalidad , Anciano , Factores de Tiempo , Supervivencia de InjertoRESUMEN
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).
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Pancreatocolangiografía por Resonancia Magnética , Colangitis Esclerosante , Humanos , Colangitis Esclerosante/diagnóstico por imagen , Pancreatocolangiografía por Resonancia Magnética/métodos , Estudios Prospectivos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Conductos Biliares/diagnóstico por imagen , Conductos Biliares/patología , Adulto JovenRESUMEN
BACKGROUND: Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. METHODS: BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. RESULTS: Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. CONCLUSIONS: The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.
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Amina Oxidasa (conteniendo Cobre) , Moléculas de Adhesión Celular , Colangitis Esclerosante , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/sangre , Amina Oxidasa (conteniendo Cobre)/sangre , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/antagonistas & inhibidores , Estudios Prospectivos , Anciano , Resultado del Tratamiento , Adulto Joven , Fosfatasa Alcalina/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , AdolescenteRESUMEN
BACKGROUND & AIMS: Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH. METHODS: We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. RESULTS: In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. CONCLUSION: In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. IMPACT AND IMPLICATIONS: Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects.
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Alanina Transaminasa , Hepatitis Autoinmune , Humanos , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/mortalidad , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Canadá/epidemiología , Adulto , Alanina Transaminasa/sangre , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Estudios de Cohortes , Resultado del Tratamiento , Pronóstico , Bilirrubina/sangre , Estudios de Seguimiento , Modelos de Riesgos Proporcionales , Inmunoglobulina G/sangreRESUMEN
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.
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BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).
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Acetatos , Fármacos Gastrointestinales , Cirrosis Hepática Biliar , Humanos , Acetatos/administración & dosificación , Acetatos/efectos adversos , Acetatos/uso terapéutico , Fosfatasa Alcalina/sangre , Método Doble Ciego , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/tratamiento farmacológico , Prurito/etiología , Prurito/tratamiento farmacológico , Resultado del Tratamiento , Ácido Ursodesoxicólico/efectos adversos , Ácido Ursodesoxicólico/uso terapéutico , PPAR delta/agonistas , Administración Oral , Bilirrubina/sangre , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Colagogos y Coleréticos/administración & dosificación , Colagogos y Coleréticos/efectos adversos , Colagogos y Coleréticos/uso terapéuticoRESUMEN
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.
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Colangitis Esclerosante , Hepatitis Autoinmune , Cirrosis Hepática Biliar , Humanos , Colangitis Esclerosante/inmunología , Hepatitis Autoinmune/inmunología , Cirrosis Hepática Biliar/inmunología , Cirrosis Hepática Biliar/etiología , Animales , Autoinmunidad , Microbioma Gastrointestinal/inmunología , Factores de Riesgo , Predisposición Genética a la Enfermedad , Disbiosis/inmunología , Ácidos y Sales Biliares/metabolismoRESUMEN
BACKGROUND AND AIMS: The incidence of biliary tract cancers (BTC) appears to be increasing worldwide. We analyzed the characteristics of BTC-related hospitalizations under medical services across 28 hospitals in Ontario, Canada. METHODS: This study uses data collected by GEMINI, a hospital research data network. BTC-related hospitalizations from 2015 to 2021 under the Department of Medicine or intensive care unit were captured using the International Classification of Diseases, 10th revision, codes for intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, and gallbladder cancers. RESULTS: A total of 4596 BTC-related hospitalizations (2720 iCCA, 1269 extrahepatic cholangiocarcinoma, 607 gallbladder cancers) were analyzed. The number of unique patients with BTC-related hospitalizations increased over time. For iCCA-related hospitalizations, the total number of hospitalizations increased (from 385 in 2016 to 420 in 2021, p = .005), the hospital length of stay decreased over the study period (mean 10 days [SD, 12] in 2016 to 9 days [SD, 8] in 2021, p = .04), and the number of in-hospital deaths was stable (from 68 [18%] in 2016 to 55 [13%] in 2021, p = .62). Other outcomes such as 30-day readmissions, medical imaging tests, intensive care unit-specific hospitalizations, and length of stay were stable over time for all cohorts. The cost of hospitalization for the BTC cohort increased from median $8203 CAD (interquartile range, 5063-15,543) in 2017 to $8507 CAD (interquartile range, 5345-14,755) in 2021. CONCLUSIONS: This real-world data analysis showed a rising number of patients with BTC-related hospitalizations and rising number of iCCA-related hospitalizations across 28 hospitals in Ontario between 2015 and 2021.
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Neoplasias del Sistema Biliar , Hospitalización , Humanos , Ontario/epidemiología , Femenino , Masculino , Anciano , Hospitalización/estadística & datos numéricos , Neoplasias del Sistema Biliar/epidemiología , Persona de Mediana Edad , Colangiocarcinoma/epidemiología , Tiempo de Internación/estadística & datos numéricos , Incidencia , Hospitales/estadística & datos numéricos , Anciano de 80 o más Años , Mortalidad Hospitalaria , Costo de Enfermedad , Neoplasias de la Vesícula Biliar/epidemiología , Neoplasias de los Conductos Biliares/epidemiologíaAsunto(s)
Colangitis Esclerosante , Trasplante de Hígado , Trastornos Linfoproliferativos , Humanos , Colangitis Esclerosante/cirugía , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/etiología , Colangitis Esclerosante/inmunología , Trasplante de Hígado/efectos adversos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/epidemiología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/diagnóstico , Factores de Riesgo , Masculino , Femenino , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Persona de Mediana Edad , Adulto , Inmunosupresores/efectos adversosRESUMEN
Background & Aims: Long-term follow-up studies of paediatric onset autoimmune liver disease (AILD) are invaluable in helping better understand the clinical course of disease. In day-to-day practice clinicians struggle with disease definitions whilst patients and parents lack clear prognostic information. Methods: The clinical progression of 159 patients with childhood onset AILD between June 1990 and December 2013 was reviewed, capturing data up to adulthood (ending May 2021). Results: Presentation with autoimmune hepatitis (AIH) was dominant (n = 119); biliary presentations accounted for 25%. During follow up, biliary disease progression confirmed by cholangiography and/or liver histology was observed frequently: 19.8% (20/101) patients with childhood onset AIH type 1 (AIH-1) developed biliary features by adulthood and of these 50% phenotypically transitioned to primary sclerosing cholangitis (PSC); the remaining transitioned to an overlap disease phenotype. No patients with AIH type 2 developed biliary progression. Two-thirds of patients with overlap features (14/21) in childhood had phenotypically progressed to PSC by adulthood. Approximately 43% (6/14) of AIH-1 patients requiring a liver transplant in adulthood had explant evidence of biliary disease compared with 11% (1/9) in childhood, whereas 35.7% (5/14) of patients had histology diagnostic of PSC in their explant liver and 7.1% (1/14) had overlap features. All patients with biliary phenotypes (PSC, autoimmune sclerosing cholangitis, overlap) who required a transplant (n = 18) were found to have explant histology consistent with PSC. Twelve of 14 patients with biliary progression developed ulcerative colitis during follow-up with 92% progressing to PSC. Conclusions: Three decades of follow-up demonstrated how children presenting with AILD had a significant risk of clinical transformation to PSC. Biliary progression was significantly associated with the development of inflammatory bowel disease. Impact and implications: Childhood onset autoimmune liver disease remains very impactful for patients and families. Disease nomenclature can however be confusing. Long-term follow up studies as children become adults is important to help understand how and why disease behaves over time. Understanding more about the long-term course of childhood autoimmune liver disease will help patients, families and doctors striving to improve care and reduce poor clinical outcomes. We followed over 150 patients with childhood onset autoimmune liver diseases into adulthood. We found that amongst patients with classical autoimmune hepatitis, 1 in 5 developed biliary disease over time, mostly consisting of primary sclerosing cholangitis. This was associated with developing inflammatory bowel disease. Our study design was retrospective and has relevant limitations. Defining phenotypes of autoimmune liver diseases is difficult and there is insufficient consensus, especially between adult and childhood physicians. Our data confirms the critical importance of careful long-term follow-up of patients, including safe transition to adult care, as well as robustly demonstrates, using real-world data, how disease nature can change over time. Our study affirms the need for investment in prospective cohort studies.
RESUMEN
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which there is an unmet need to understand the cellular composition of the affected liver and how it underlies disease pathogenesis. We aimed to generate a comprehensive atlas of the PSC liver using multi-omic modalities and protein-based functional validation. METHODS: We employed single-cell and single-nucleus RNA sequencing (47,156 cells and 23,000 nuclei) and spatial transcriptomics (one sample by 10x Visium and five samples with Nanostring GeoMx DSP) to profile the cellular ecosystem in 10 PSC livers. Transcriptomic profiles were compared to 24 neurologically deceased donor livers (107,542 cells) and spatial transcriptomics controls, as well as 18,240 cells and 20,202 nuclei from three PBC livers. Flow cytometry was performed to validate PSC-specific differences in immune cell phenotype and function. RESULTS: PSC explants with parenchymal cirrhosis and prominent periductal fibrosis contained a population of cholangiocyte-like hepatocytes that were surrounded by diverse immune cell populations. PSC-associated biliary, mesenchymal, and endothelial populations expressed chemokine and cytokine transcripts involved in immune cell recruitment. Additionally, expanded CD4+ T cells and recruited myeloid populations in the PSC liver expressed the corresponding receptors to these chemokines and cytokines, suggesting potential recruitment. Tissue-resident macrophages, by contrast, were reduced in number and exhibited a dysfunctional and downregulated inflammatory response to lipopolysaccharide and interferon-γ stimulation. CONCLUSIONS: We present a comprehensive atlas of the PSC liver and demonstrate an exhaustion-like phenotype of myeloid cells and markers of chronic cytokine expression in late-stage PSC lesions. This atlas expands our understanding of the cellular complexity of PSC and has potential to guide the development of novel treatments. IMPACT AND IMPLICATIONS: Primary sclerosing cholangitis (PSC) is a rare liver disease characterized by chronic inflammation and irreparable damage to the bile ducts, which eventually results in liver failure. Due to a limited understanding of the underlying pathogenesis of disease, treatment options are limited. To address this, we sequenced healthy and diseased livers to compare the activity, interactions, and localization of immune and non-immune cells. This revealed that hepatocytes lining PSC scar regions co-express cholangiocyte markers, whereas immune cells infiltrate the scar lesions. Of these cells, macrophages, which typically contribute to tissue repair, were enriched in immunoregulatory genes and demonstrated a lack of responsiveness to stimulation. These cells may be involved in maintaining hepatic inflammation and could be a target for novel therapies.