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BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21–30 years old, 9.0 per 100 patient-years for patients 31–40 years old, 14.0 per 100 patient-years for patients 41–50 years old, 15.2 per 100 patient-years for patients 51–60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn’s disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P =.001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn’s disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients wi...

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

CA 19-9 has been used with questionable accuracy to aid diagnosis of cholangiocarcinoma complicating primary sclerosing cholangitis. We aimed to characterize the test properties of CA 19-9 and of a change in CA 19-9 over time in predicting cholangiocarcinoma. Charts of 208 patients were reviewed. Fourteen patients had cholangiocarcinoma. Median CA 19-9 was higher with cholangiocarcinoma (15 vs. 290 U/ml, p < 0.0001). A cutoff of 129 U/ml provided: sensitivity 78.6%, specificity 98.5%, adjusted positive predictive value 56.6% and negative predictive value 99.4%. The median change over time was 664 U/ml in cholangiocarcinoma compared to 6.7 U/ml in primary sclerosing cholangitis alone (p < 0.0001). A cutoff of 63.2 U/ml for change in CA 19-9 provided: sensitivity 90%, specificity 98% and positive predictive value 42%. Only 2 patients with cholangiocarcinoma were the candidates for curative therapy. In conclusion, the positive predictive value of an elevated CA 19-9 was 56.6%; only advanced cases were detected by this method.

SUMMARY BackgroundNewer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation.

We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10 −4 ) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10 −13 ), 7q12-21 (combined P = 3.50 × 10 −13 ) and MMEL1 (combined P = 3.15 × 10 −8 ) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases. Note: Supplementary information is available on the Nature Genetics website. COMPETING FINANCIAL INTERESTSThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/. Supplementary Fig. 1); for each locus, association signals at P < 1 × 10 −4 were detected for more than one SNP found in the initial GWAS, with the exception of IRF5-TNPO3, a well-recognized autoimmune disease risk locus. The combination of these replication results and our prior genome-wide association data yielded a genetic dataset derived from 1,351 PBC cases and 4,700 controls (Supplementary Methods). NIH Public AccessFifteen SNPs replicated (P < 1.39 × 10 −3 ) after Bonferroni adjustment (Table 1 and Supplementary Table 1). In addition to HLA, IL12A and IL12RB2, genes at the IRF5-TNPO3 locus, at chromosome 17q12-21 (containing IKZF3, ZPBP2, GSDMB and ORMDL3) and at MMEL1 loci showed significant association with PBC in both the replication analysis and in an analysis combining the replication and initial GWAS datasets ( Fig. 1 and Supplementary Fig. 2).Among the PBC loci confirmed by this analysis, the locus at IRF5-TNPO3 (encoding interferon regulatory factor 5 and transportin 3) is of interest because of the integral immunoregulatory roles for IRF5, the prior association of this locus with systemic lupus erythematosus (SLE) 4, 5 , systemic sclerosis 6 and Sjögrens syndrome 7 , and the strong effect of the disease-associated SNP at this locus on disease risk (rs10488631) in the replication (P = 1.13 × 10 −8 , odds ratio (OR) = 1.58) and combined datasets (P = 8.66 × 10 −13 , OR = 1.57). Association of this locus was thus explored, initially by resequencing the IRF5 locus intronic and exonic regions and the 5′ and 3′ flanking regions of IRF5 in genomic pools of 100 subjects so as to delineate the genetic variation across the locus. This analysis confirmed prior reports of 41 polymorphisms across this region, but it failed to identify any new variants. Among these 41 SNPs, two (rs3807135 and rs3834330) failed repeatedly in genotyping assays and four (rs10275092, rs12537192, rs1727172 and rs754280) showed negligible polymorphism. Thus, for finemapping studies, 1,330 cases and 1,833 controls were geno-typed for 35 SNPs across this region. Among the associations identified (Supplementary Ta...

Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC. This article is protected by copyright. All rights reserved.

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