An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Backgrounds & Aims Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC

MKS3/TMEM67 mutations are a major cause of COACH syndrome, a joubert syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/ aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs

Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis:an international follow-up study

Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P 1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment. Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trial

L'Italia come modello per l'Europa e per il mondo nelle politiche sanitarie per il trattamento dell'epatite cronica da HCV

The World Health Organization foresees the elimination of HCV infection by 2030. In light of this and the curre nt, nearly worldwide, restriction in direct-acting agents (DAA) accessibility due to their high price, we aimed to evaluate the cost-effectiveness of two alternative DAA treatment policies: Policy 1 (universal): treat all patients, regardless of the fibrosis stage; Policy 2 (prioritized): treat only priori tized patients and delay treatment of the remaining patients until reaching stage F3. T he model was based on patient’s data from the PITER cohort. We demonstrated that extending HC V treatment of patients in any fibrosis stage improves health outcomes and is cost-effective

Economic consequences of investing in anti-HCV antiviral treatment from the Italian NHS perspective : a real-world-based analysis of PITER data

OBJECTIVE: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. METHODS: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. RESULTS: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. CONCLUSIONS: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV

Retreatment of patients with chronic hepatitis C relapsers to a previous antiviral treatment.

Background: The efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin for patients relapsing after a previous treatment remains to be fully elucidated, although extended treatment seems to be the best option in such cases. Aim: To evaluate the efficacy of two extended protocols in patients with genotypes 1 or 4, or those with genotypes 2 or 3. Methods: A total of 181 patients who had relapsed after a previous antiviral treatment with PEG-IFN[alpha]2a plus weight-based ribavirin were offered retreatment with the same dose of both PEG-IFN plus ribavirin, to be continued for 48 weeks in those with genotypes 2 or 3 (group 1), and for 72 weeks in those with genotypes 1 or 4 (group 2). Results: A total of 59 patients (32.5%) refused the retreatment, while 122 (78 men, 44 women) patients were enrolled in the study: 41 were allocated in group 1 and 81 in group 2. Cirrhosis at baseline (staging 5/6 according to Ishak's score was recorded in 11 patients, six in group 1 and five in group 2). Nine patients (7.3%) in group 2 discontinued the treatment (due to lack of response). The remaining patients completed the treatment and were followed-up for at least 12 months after the treatment. Sustained virological response (SVR) rate was 82.9% in group 1 and 50.6% in group 2. Conclusion: Patients with chronic hepatitis C with \u2018easy genotypes\u2019 relapsers to a previous antiviral treatment have more than 80% probability of achieving a SVR with a 48-week retreatment. Patients with \u2018difficult genotypes\u2019 have more than 50% chance of a SVR after a 72-week extended treatment

Extrahepatic Autoimmune Conditions Associated with Primary Biliary Cirrhosis.

There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8\u2009\ub1\u20096.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan-Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991-2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p\u2009=\u20090.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival

INCIDENCE AND RISK FACTORS FOR EXTRA-HEPATIC MALIGNANCIES (EM) IN PRIMARY BILIARY CIRRHOSIS: A COMPARATIVE STUDY FROM TWO EUROPEAN REFERRAL CENTERS

Background and Aims: There is limited information on the prevalence/incidence, survival, and risk factors for developing EM in PBC. Aim: To analyze the incidence/prevalence, risk factors and survival for EM in patients with PBC in two European centers. Methods: The study was carried out in two series of PBC patients (361 of Padova, Italy and 397 of Barcelona, Spain) followed-up for a mean period of 7.7\ub17 and 12.2\ub17 years respectively. The incidence of EM was compared to the estimated incidence data from IARC. Demographic features and factors associated with tumor development were recorded. Survival analysis was compared with the expected survival predicted by the Mayo model. Results: 72 patients developed EM. The prevalence of cancer was similar in Padova (9.7%) and Barcelona (9.4%). The incidence of EM was also similar (855.01 vs 652.86, p=n.s.). The overall incidence of EM in the study population was similar to the expected incidence in the same geographical area (observed/expected ratio = 1.18). Older age was the only factor associated with the development of EM. Familial predisposition was associated with higher likelihood of EM in Padova series. Observed survival of patients was similar in those with either or without EM (29.2 and 33.4 years, p=n.s.) and wa similar to that predicted by the Mayo model. Conclusions: The prevalence/incidence of EM is similar in Italy and Spain and not different from the general population. Older age is the only risk factor associated with EM. The occurrence of cancer during the follow-up does not influence the natural history of liver disease

Incidence and risk factors for extra-hepatic malignancies in primary biliary cirrhosis: A comparative study from two European referral centers

Introduction: There are limited information and divergent results on the prevalence/incidence, survival, and risk factors for developing EM in PBC. Aim: To analyze the incidence/prevalence, risk factors and survival for EM in PBC patients from two European centers. Methods: The study was carried out in two series of PBC patients from two European centers (361 of Padova, Italy and 397 of Barcelona, Spain) followed-up for a mean period of 7.7\ub17 years and 12.2\ub17 years respectively. The incidence of EM was compared to the estimated incidence data from IARC (International Agency for Research on Cancer). Demographic features and factors associated with tumor development (gender, age, alcohol consumption, smoking habit, familial predisposition) were recorded. Survival analysis was compared with the expected survival predicted by the Mayo model. Results: 72 patients (35 from Padova and 37 from Barcelona) developed EM. The prevalence of cancer was similar in Padova (9.7%) and Barcelona (9.4%). The incidence of EM was also similar (855.01 vs 652.86 per 100,000 patient-year respectively, p = n.s. [95% CI 120.002 to 0.006]). The overall incidence of EM in the study population was similar to the expected incidence in the same geographical area (observed/expected ratio = 1.18 [95% CI 1.0\u20131.2]). Older age was the only factor associated with the development of EM. When analyzing the two series separately, familial predisposition was associated with higher likelihood of EM in Padova. Survival was similar in those with either or without EM (29.2 and 33.4 years respectively, p = n.s.). The actual survival was similar to that predicted by the Mayo model. Conclusions: The prevalence/incidence of EM is similar in Italy and Spain and is not different from the general population. Older age is the only risk factor associated with EM in PBC. The occurrence of cancer during the follow-up does not influence the natural history of liver disease