Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Peer reviewe

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.Peer reviewe

Evolution radiologique de la cholangite sclérosante primitive (étude de 289 IRM biliaires et hépatiques réalisées dans une cohorte mono-centrique de 64 patients)

I La cholangite sclérosante primitive (CSP) est une affecttion rare mais potentiellement grave pouvant se compliquer de cirrhose et de cholangiocarcinome. L'histoire naturelle de l'évolution radiologique de la CSP est mal connue. Le but de notre étude a donc été de décrire l'évolution de la CSP sur la bili-IRM, d'identifier les variables radiologiques prédictives de progression et de confronter l'évolution radiologique à l'évolution clinique.Cette étude rétrospective mono-centrique a inclus 64 patients suivis pour CSP (hommes : 59%. âge médian : 43 ans, colite inflammatoire : 70%) ayant eu au moins 2 bili-IRM, à au moins 1 an d'intervalle. Deux radiologues ont relu les bili-IRM en consensus selon une grille d'items précis. Le critère de jugement principal a été l'évolution radiologique globale, jugée sur l'ensemble des séquences disponibles. Résultats : 289 bili-IRM ont été analysées. Après un suivi médian de 3,8 ans, 58% des patients ont présenté une aggravation radiologique et 42% sont restés stables. La survie sans complication des patients présentant une aggravation radiologique était significativement inférieure à celle des patients stables. Les items IRM associés de façon indépendante à la progression radiologique étaient une dilatation des canaux secondaires (p=0,0l ), une dysmorphie (p<0,01) et des signes d'hypertension portale (p=0,05). Un score simple calculé à partir de ces 3 variables permettait de prédire la progression radiologique (p<0,0001, AUROC= 80 + 4%). Ce score était un facteur prédictif indépendant de la survie sans événement. Un score IRM simple permet de prédire révolution radiologique de la CSP.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Liver Immunology, Principles and Practice, Third Edition Chapter 24: Primary Biliary Cholangitis: Autoimmune Hepatitis Overlap Syndrome

*Some patients present with features of both primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) either simultaneously or consecutively. • The term overlap syndrome (OS) is used to describe these settings, but lack of universal agreement on what precisely constitutes an OS has generated considerable confusion. • The low prevalence of OS (roughly 10% of PBC) has made it impracticable to perform randomized controlled trials. • It remains unclear whether this syndrome forms a distinct entity or, more likely, a variant of PBC, or AIH. • Moderate-to-severe interface hepatitis is a fundamental component and histology is vital in evaluating patients with overlap presentation. Use of the International Autoimmune Hepatitis Group criteria for the diagnosis of OS is not recommended. • For PBC-AIH OS, EASL has provided diagnostic criteria and, in most cases, it is possible to define one primary disorder (“dominant” disease), usually PBC. • Patients with OS seem to have a more severe disease compared to conventional PBC. • Treatment of OS is empiric and includes ursodeoxycholic acid (UDCA) for the cholestatic component and immunosuppressive agents for the hepatitic component, either simultaneously or sequentially. Immunosuppressive treatment in addition to UDCA is recommended in patients with severe interface hepatitis and deserves consideration in those with moderate interface hepatitis. • The dominant clinical feature should be treated first and therapy adjusted according to the response. • OS is not uncommon but should not be over-diagnosed in order not to expose unnecessarily PBC patients to the risk of steroid side effects. Therapy has to be individualized and not be static

Colorectal neoplasia in PSC-IBD patients: are times changing?

International audienc

Histoire naturelle de la cholangite sclérosante primitive en France (étude prospective d'une cohorte de 174 patients)

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Overlap syndrome

Overlap syndromes (OS) between primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent rare forms of PBC, PSC and AIH, which are characterized by the presence of features of two diseases, typically PBC and AIH or PSC and AIH in the same patient. The diagnosis of OS is based on the presence or sequential development of biochemical, serological, histologic and cholangiographic features of the two diseases. Paris criteria are the recommended criteria for the diagnosis of PBC-AIH OS, whereas no strict diagnostic criteria have yet been established for the diagnosis of PSC-AIH OS. Liver biopsy is mandatory when an OS is suspected and interface hepatitis is a fundamental component for the diagnosis of OS. Patients with OS may present with one or more associated extrahepatic autoimmune disease. Treatment of OS is empiric and includes ursodeoxycholic acid (UDCA) for the cholestatic component and immunosuppressive agents for the hepatitic component, either simultaneously or sequentially. Immunosuppressive treatment in addition to UDCA is recommended in patients with severe interface hepatitis and deserves consideration in those with moderate interface hepatitis. The dominant clinical feature should be treated first and therapy adjusted according to the response. Relapse after IS agent’s withdrawal is elevated in patients with OS. Graft and patients’ survival after liver transplantation in patients with OS are comparable to that observed in patients transplanted for single autoimmune liver diseases

Disease activity and cancer risk in inflammatory bowel disease associated with primary sclerosing cholangitis

AIM: To investigate the phenotype of inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD)

Survey uncovering variations in the management of primary sclerosing cholangitis across Europe

Background & Aims: Data on the management of primary sclerosing cholangitis (PSC) in European expert centres are sparse. In this study, a PSC group from the ERN RARE-LIVER surveyed European hepatologists to uncover differences in real-life clinical practices. Methods: In April 2020 a survey questionnaire was sent to members of the International PSC Study Group and ERN RARE-LIVER. Participants were asked about the size of their PSC cohort, use of medical treatments including ursodeoxycholic acid (UDCA) and surveillance for cholangiocarcinoma, gallbladder polyps and inflammatory bowel disease (IBD). Data were presented descriptively. Results: Eighty-two of 278 members responded. Fifty percent of physicians prescribed UDCA routinely to all their patients with PSC, whereas 12% never prescribed UDCA. UDCA was used for one or more indications including: alkaline phosphatase >1.5x the upper limit of normal, severe PSC changes, pruritus, PSC-IBD or patient demand. Few physicians offered other medical treatments than UDCA. The use of medical treatments was generally comparable in small (<99 patients) and large (≥99 patients) cohorts, as well as for adult and paediatric physicians. Most physicians routinely screened for cholangiocarcinoma and the most frequent modalities used were MRI and ultrasound. At detection of a gallbladder polyp of 6 mm, 46% of physicians recommended repeated ultrasound after 3-6 months, whereas 44% of physicians recommended immediate cholecystectomy. In patients with PSC without IBD at PSC diagnosis, 68% of physicians repeated colonoscopy within 3-5 years whereas 27% referred only patients who developed symptoms of IBD. Conclusion: Substantial variations in treatment and monitoring of European patients with PSC were discovered. Harmonisation of strategies is desirable to enable improved interpretation of outcome data and to optimise clinical patient care. Lay summary: In this study, we explored how different centres in Europe manage primary sclerosing cholangitis (PSC), a rare inflammatory disease of the bile ducts. We collected information through a questionnaire sent to specialist physicians who were part of a European network for rare liver diseases. We found several differences in how patients with PSC were monitored and treated. This includes differences in surveillance for bile duct cancer, gallbladder polyps and inflammatory bowel disease. By pointing out these differences, we hope that management of PSC will be standardized, which could aid clinical research and benefit patients