Citations

Abstract The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single‐arm open‐label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months. The study was undertaken at two sites, Mayo Clinic, Rochester, MN, and Mayo Clinic, Phoenix, AZ. The primary endpoint of the study was improvement of serum alkaline phosphatase (ALP) at the end of the study. Secondary endpoints included assessment of other liver biomarkers (bilirubin, alanine aminotransferase, and aspartate aminotransferase). Of 18 patients enrolled, 11 completed the 6 months of study treatment. Patients who completed treatment versus those who did not were similar other than a significantly higher direct bilirubin at baseline in the group that completed treatment (mean ± SD, 0.4 ± 0.3 versus 0.1 ± 0.1, p = 0.04). By intent to treat analysis, the primary outcome was met in 16.7% (3/18) of patients. By per‐protocol analysis, including only patients who completed treatment, normalization of ALP occurred in 27.7% (3/11) at week 24 (95% confidence interval, 6.0% to 61.0%). VC was well tolerated with no drug‐related serious adverse events. Conclusion: This proof of concept study provides support for further exploration of VC in patients with PSC.

Abstract Primary sclerosis cholangitis (PSC) predisposes individuals to liver failure, but it is challenging for radiologists examining radiologic images to predict which patients with PSC will ultimately develop liver failure. Motivated by algebraic topology, a topological data analysis - inspired framework was adopted in the study of the imaging pattern between the “Early Decompensation” and “Not Early” groups. The results demonstrate that the proposed methodology discriminates “Early Decompensation” and “Not Early” groups. Our study is the first attempt to provide a topological representation-based method into early hepatic decompensation and not early groups.

The benefit of endoscopic retrograde cholangiopancreatography (ERCP) for the treatment of primary sclerosing cholangitis (PSC) remains controversial. To identify predictors of jaundice resolution after ERCP and whether resolution is associated with improved patient outcomes, we conducted a retrospective cohort study of 124 patients with jaundice and PSC. These patients underwent endoscopic biliary balloon dilation and/or stent placement at an American tertiary center, with validation in a separate cohort of 102 patients from European centers. Jaundice resolved after ERCP in 52% of patients. Median follow‐up was 4.8 years. Independent predictors of jaundice resolution included older age (P = 0.048; odds ratio [OR], 1.03 for every 1‐year increase), shorter duration of jaundice (P = 0.059; OR, 0.59 for every 1‐year increase), lower Mayo Risk Score (MRS) (P = 0.025; OR, 0.58 for every 1‐point increase), and extrahepatic location of the most advanced biliary stricture (P = 0.011; OR, 3.13). A logistic regression model predicted jaundice resolution with area under the receiver operator characteristic curve of 0.67 (95% confidence interval, 0.5‐0.79) in the validation set. Independent predictors of death or transplant during follow‐up included higher MRS at the time of ERCP (P < 0.0001; hazard ratio [HR], 2.33 for every 1‐point increase), lower total serum bilirubin before ERCP (P = 0.031; HR, 0.91 for every 1 mg/dL increase), and persistence of jaundice after endoscopic therapy (P = 0.003; HR, 2.30). Conclusion: Resolution of jaundice after endoscopic treatment of biliary strictures is associated with longer transplant‐free survival of patients with PSC. The likelihood of resolution is affected by demographic, hepatic, and biliary variables and can be predicted using noninvasive data. These findings may refine the use of ERCP in patients with jaundice with PSC.

Herein we present a patient that underwent a liver transplant due to primary biliary cholangitis (PBC) and after 9 years developed multiple myeloma. Following the cessation of mycophenolate mofetil and 2 weeks after lenalidomide treatment was started, the patient experienced acute cellular rejection. The patient recovered after treatment with corticosteroids, resumption of mycophenolate mofetil, and cessation of lenalidomide. Lenalidomide-associated allograft rejection has been reported in other organs. However, this is the first case report of liver rejection induced by lenalidomide.

Background and Aims Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5‐year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary‐to‐secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary‐to‐secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine‐learning model, PSC‐BA profile score (concordance statistic [C‐statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C‐statistic, 0.86). Conclusions Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

Goals: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). Background: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. Materials and Methods: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. Results: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). Conclusion: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.

Background and Aims Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI‐based CCA detection. Approach and Results This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re‐examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5‐year outcomes including overall survival (82% vs. 46%, log‐rank P < 0.01) and recurrence‐free survival following liver transplant (89% vs. 65%, log‐rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01‐0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01‐0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed. Conclusions MRI is superior to ultrasound for the detection of early‐stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes.