Mayo Primary Sclerosing Cholangitis Risk Score Research Articles

OP13 Anti-integrin αvβ6 autoantibodies are increased in PSC-IBD and correlate with liver disease severity

Abstract Background Anti-integrin αvβ6 autoantibodies (anti-αvβ6) are a novel biomarker of ulcerative colitis (UC) that precede disease diagnosis by up to 10 years. Given that integrin αvβ6 is also expressed on the biliary epithelium and that primary sclerosing cholangitis (PSC) co-occurs with inflammatory bowel disease (IBD) in up to 90% of patients, we aimed to determine the prevalence of anti-αvβ6 in patients with PSC and to understand the impact of anti-αvβ6 on PSC disease course. Methods Three cohorts of pre-liver transplant patients with PSC and controls (IBD and non-IBD) were recruited from New York, Lisbon and Miami. Anti-αvβ6 levels were measured using ELISA and normalized for serum IgG concentration. Statistical analyses across groups and clinical parameters were performed using the Kruskal-Wallis and Spearman correlation test. Multivariable linear regression was conducted to assess the association between anti-αvβ6 and liver disease severity, correcting for covariates. A mixed-effects model was applied to assess change in anti-αvβ6 over time. Results In total, 94 patients with PSC (53 (56.4%) PSC-UC, 20 (21.3%) PSC-Crohn’s disease (CD) and 21 (22.3%) PSC alone) and 129 controls (74 (57.4%) IBD and 55 (42.6%) non-IBD) were enrolled; table 1 shows the baseline characteristics of the patients with PSC. Follow-up samples (n=22) were collected from 1 up to 3 years after initial baseline sampling from 17 PSC patients. Median (IQR) age was similar in PSC patients (43, 33-56 years) and controls (47, 32-62 years; p=0.59). Median (IQR) anti-αvβ6 levels were significantly higher in PSC-UC (1.07, 0.48-2.65) and UC (1.83, 1.12-3.03) compared to PSC alone (0.40, 0.23-0.63; p=0.0004 and p<0.0001 respectively) and non-IBD controls (0.39, 0.17-0.65; p<0.0001 and p<0.0001 respectively). Anti-αvβ6 levels were comparable between PSC alone and non-IBD controls (p>0.999) (figure 1A). Anti-αvβ6 levels did not increase over time (p=0.23). A positive correlation between anti-αvβ6 levels and the Mayo PSC risk score (r=0.28, p=0.008) as well as alkaline phosphatase (r=0.29, p=0.007) was observed (figure 1B). These associations remain significant after correcting for covariates including age at diagnosis of PSC, gender, race/ethnicity and IBD type in a multivariable linear regression. Conclusion Anti-αvβ6 autoantibodies are a new biomarker of PSC-IBD and are associated with liver disease severity.

Benefit of endoscopic stenting for dominant strictures in patients with primary sclerosing cholangitis.

Background and study aims Dominant strictures (DS) occur in up to 60 % of patients with primary sclerosing cholangitis (PSC). Data regarding the long-term effects of stenting vs. dilation remain limited. The aim of this study was to compare the two treatment modalities in terms of transplantation-free survival. Patients and methods This single-center, retrospective study examined patients with PSC and DS treated endoscopically with a minimum of 1 year follow-up. Patients were divided into two cohorts: 1) those who received dilation alone; and 2) those who received both dilation and stenting. The primary outcome was transplantation-free survival, defined as time after index ERCP to liver transplantation. Results In all, 169 patients (54 in dilation cohort, 115 in stenting cohort) were included. The stenting cohort had a significantly higher Mayo PSC Risk Score (1.8 ± 1.1 vs. 0.9 ± 1.2) and presented with cholangitis more frequently (22.6 % vs. 1.9 %). During a follow-up period of 1198 person-years, 69 (40.8 %) patients received transplantation at a mean of 3.4 (± 2.9) years. There was no difference in transplantation rate in the stenting cohort [68 (95 % CI 5.2–8.8) per 100 person-years] compared to the dilation cohort [3.7 (95 % CI 2.1–6.0) per 100 person-years] and no difference in risk for transplantation (dilation cohort adjusted hazards ratio 0.67, 95 % CI 0.33–1.32). Conclusions Despite a higher Mayo Risk Score in the stenting group, there was no difference in transplantation-free survival between patients managed with stenting vs. dilation alone. Stenting, therefore, may offer benefit in patients with advanced PSC and DS.

An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort.

Contemporary primary sclerosing cholangitis (PSC) population-based cohorts describing the epidemiology, natural history, and long-term fluctuations in serum alkaline phosphatase (SAP) and their prognostic relevance are lacking. Therefore, we investigated the incidence and natural history of PSC and quantified SAP fluctuations among those with PSC in Olmsted County, Minnesota over the last 41years. The Rochester Epidemiology Project was used to identify 56 subjects diagnosed with PSC between 1976 and 2017 in Olmsted County. The primary endpoint (n = 19) included liver transplantation, hepatic decompensation, and cholangiocarcinoma. The age- and sex-adjusted incidence of PSC (per 100,000 person years) nearly doubled from 2001 to 2017 compared to 1976-2000 (1.47; 95% CI 0.99-1.96 versus 0.79; 95% CI 0.42-1.16, p = 0.02). This increase paralleled a rise in patients with markers of a milder phenotype at the time of diagnosis: normal SAP (26.32% versus 0%, p < 0.01) and lower Mayo PSC risk score [0.36 (-0.57 to 1.55) versus -0.50 (-1.25 to 0.35), p = 0.03]. Intra-individual SAP fluctuates with a median coefficient of variation of 36.20%. SAP normalization and dropping below 1.5 × upper limit of normal (ULN) occurs at a rate of 5% and 10% per year, respectively. SAP less than 1.5 × ULN was associated with a lower risk of PSC-related complications (hazard ratio 0.11; 95% CI 0.03-0.42). The patients with PSC are increasingly being diagnosed with a milder phenotype. While a lower SAP is associated with improved outcomes, the high intra-individual variation of SAP levels calls into question the practice of using a single SAP value as a surrogate endpoint in clinical trials.

Changes in Liver Stiffness, Measured by Magnetic Resonance Elastography, Associated With Hepatic Decompensation in Patients With Primary Sclerosing Cholangitis

Single measurements of liver stiffness (LS) by magnetic resonance elastography (MRE) have been associated with outcomes of patients with primary sclerosing cholangitis (PSC), but the significance of changes in LS over time are unclear. We investigated associations between changes in LS measurement and progression of PSC. We performed a retrospective review of 204 patients with patients who underwent 2 MREs at a single center between January 1, 2007 and December 31, 2018. We collected laboratory data and information on revised Mayo PSC risk and model for end-stage liver disease scores, the PSC risk estimate tool, and levels of aspartate transferase at the time of each MRE. The ΔLS/time was determined by the change in LS between the second MRE compared to the first MRE divided by the time between examinations. The primary endpoint was development of hepatic decompensation (ascites, variceal hemorrhage or hepatic encephalopathy). The median LS measurement was 2.72 kPa (interquartile range, 2.32-3.44 kPa) and the overall change in LS was 0.05 kPa/y. However, ΔLS/y was 10-fold higher in patients anticipated to have cirrhosis (0.31 kPa/y) compared to patients with no fibrosis (0.03 kPa/y). The median LS increased over time in patients who ultimately developed hepatic decompensation (0.60 kPa/y; interquartile range, 0.21-1.26 kPa/y) vs but remained static in patients who did not (reduction of 0.04/y; interquartile range, reductions of 0.26 to 0.17 kPa/y) (P < .001). The ΔLS/y value associated with the highest risk of hepatic decompensation was Δ0.34 kPa/y (hazard ratio [HR], 13.29; 95% CI, 0.23-33.78). After we adjusted for baseline LS and other risk factors, including serum level of alkaline phosphatase and the Mayo PSC risk score, ΔLS/y continued to be associated with hepatic decompensation. The optimal single LS cut-off associated with the hepatic decompensation was 4.32 kPa (HR, 60.41; 95% CI, 17.85-204.47). A combination of both cut-off values was associated with risk of hepatic decompensation (concordance score, 0.93; 95% CI, 0.88-0.98) CONCLUSIONS: A single LS measurement and changes in LS over time are independently associated with hepatic decompensation in patients with PSC. However, changes in LS occur slowly in patients without advanced fibrosis or hepatic decompensation.

Effects of Antibiotic Therapy in Primary Sclerosing Cholangitis with and without Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

The authors conducted a systematic review and meta-analysis to assess the effect of antibiotic therapy in primary sclerosing cholangitis (PSC). Effect of antibiotic therapy on Mayo PSC Risk Score (MRS), serum alkaline phosphatase (ALP), total serum bilirubin (TSB), and adverse events (AEs) rates were calculated and expressed as standardized difference of means or proportions. Five studies including 124 PSC patients who received antibiotics were included. Overall, antibiotic treatment was associated with a statistically significant reduction in ALP, MRS, and TSB by 33.2, 36.1, and 28.8%, respectively. ALP reduction was greatest for vancomycin (65.6%, p < 0.002) and smallest with metronidazole (22.7%, p = 0.18). Overall, 8.9% (95% confidence interval: 3.9-13.9) of patients had AEs severe enough to discontinue antibiotic therapy. In PSC patients, antibiotic treatment results in a significant improvement in markers of cholestasis and MRS. Antibiotics, particularly vancomycin, may have a positive effect on PSC either via direct effects on the microbiome or via host-mediated mechanisms.

Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study

Goals: To assess if curcumin improves markers of cholestasis among subjects with primary sclerosing cholangitis (PSC).Background: PSC is a chronic cholestatic liver disorder for which there is no established medical therapy. Preclinical data suggest curcumin may have a beneficial effect in PSC.Study: Subjects with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal (ULN) received curcumin 750 mg orally twice daily for 12 weeks in an open-label pilot study. The primary composite endpoint was proportion of subjects who had a reduction of SAP to less than 1.5 times ULN or a 40% reduction in SAP between baseline and week 12. Secondary endpoints included changes in serum aspartate aminotransferase, total bilirubin, Mayo PSC risk score and self-reported health questionnaires.Results: Two-hundred and fifty-eight patients with PSC were screened and 15 subjects were enrolled and all completed 12 weeks of therapy. The most common reason for subject exclusion was SAP less than 1.5 times the ULN (n = 98). Curcumin did not result in a significant median (interquartile range) change in SAP times the ULN [3.43 (2.10–4.32) to 2.46 (1.89–4.41), p = .36], and only 20% (3/15) subjects achieved the primary endpoint. Similarly, there was no significant change in the secondary endpoints. There were no serious adverse events reported.Conclusion: While curcumin was well tolerated, it was not associated with significant improvements in cholestasis or symptoms. Moreover, this study also illustrates that a low SAP is common among those with PSC.AbbreviationsPSC: Primary sclerosing cholangitis; IBD: inflammatory bowel disease; CCA: cholangiocarcinoma; SAP: serum alkaline phosphatase; ULN: upper limit of normal; UDCA: ursodeoxycholic acid; CRP: c-reactive protein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; FIS: fatigue impact scale; AE: adverse events; PREsTo: PSC risk estimate tool; IQR: interquartile range; ELF: enhanced liver fibrosis

Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease.

Blocking of lymphocyte trafficking to bile ducts is a potential mechanism to alter the disease course of patients with primary sclerosing cholangitis (PSC). To describe the effect of the α4 β7 integrin antibody, vedolizumab, on liver biochemistry and disease activity in patients with PSC and inflammatory bowel disease (IBD). This is a retrospective multi-centre study of adult patients with a diagnosis of both IBD and PSC. The primary outcome was change in serum alkaline phosphatase level at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries and in clinical outcomes for the bowel disease. A safety analysis for adverse events was performed. Thirty-four patients (16 Crohn's disease, 18 ulcerative colitis) were included. Nine (26%) had a history of liver transplant. Median follow-up on vedolizumab was 9 months (IQR: 7-16). There was no overall change in serum alkaline phosphatase level with vedolizumab therapy (median 268 [IQR: 105-551] IU/L at baseline versus 249 [IQR: 183-634] IU/L, P = 0.99 at week 30). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. Clinical remission was achieved at week 30 in 55% of Crohn's disease and 29% of ulcerative colitis patients. Seven (21%) patients ceased vedolizumab; six patients stopped therapy due to persistent IBD activity and one for worsening of liver biochemistries. Vedolizumab treatment in patients with PSC and IBD did not improve liver biochemistry but was associated with improvement in bowel disease and a favourable safety profile.

P410 Vedolizumab is safe and effective for IBD, but has no effect on liver biochemistry in patients with concurrent PSC

Background: Blocking of lymphocyte trafficking is a potential mechanism to alter the disease course of primary sclerosing cholangitis (PSC). We studied the effect of the selective α4β7 integrin antibody, vedolizumab, on liver biochemistry and inflammatory bowel disease (IBD) activity in patients with IBD and PSC (IBD-PSC). Methods: We reviewed electronic medical records of adult patients who had an established diagnosis of IBD-PSC from five tertiary centers. We assessed baseline patient and disease characteristics and treatment exposures. The primary outcome was change in serum alkaline phosphatase at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries, the Mayo Risk Score for PSC and IBD clinical and endoscopic remission. We also performed a safety analysis for the development of adverse events including liver-related complications. Results: We identified 34 patients with IBD-PSC. Nine (26%) had a history of orthotopic liver transplant, 7 were on stable doses of ursodeoxycholic acid (UDCA) and 2 patients commenced UDCA during the study period. Median follow-up was 9 (IQR: 7–16) months; 28 (92%) had at least 6 months of clinical follow-up. Serum alkaline phosphatase activities did not significantly decrease with vedolizumab therapy (median 268 (IQR: 105–551) IU/L at baseline versus 249 (IQR: 183–634) IU/L, p=0.9899 at week 30). Of the 18 patients with an abnormal alkaline phosphatase at baseline (>120IU/L), 11 (61%) had improvement with treatment. In these patients, alkaline phosphatase trended down from 475 IU/L (IQR: 241–757) at baseline to 283 IU/L (IQR: 207–658), p=0.267 at week 30 but none of these normalized (Figure 1). Median alkaline phosphatase changes remained similar when patients exposed to UDCA were excluded. Of the 8 patients (31%) with normal alkaline phosphatase at baseline, 4 (50%) had a subsequent increase to abnormal levels by week 30, from a baseline median of 98 IU/L (IQR: 77–102) to 146 IU/L (IQR: 90–203), p=0.036 at week 30 (Figure 2). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. 55% of Crohn's disease and 21% of ulcerative colitis patients achieved clinical remission at week 30. Seven patients (21%) ceased vedolizumab therapy; one for a deterioration in liver biochemistry thought to be a drug reaction and six for IBD primary non-response. Two patients developed ascending cholangitis but continued vedolizumab. Conclusions: Vedolizumab therapy in patients with IBD-PSC has little overall effect on liver biochemistry, but is safe and does improve IBD clinical activity. Treatment earlier in the disease course of PSC and assessment of longer-term exposure of lymphocyte trafficking blockade in IBD-PSC remains of interest.

Su1649 Algorithmic Approach Including Bile Aspiration to Decrease ERCP Associated Adverse Events in Primary Sclerosing Cholangitis

Su1646 Endoscopic Treatment of Dominant Biliary Strictures in Primary Sclerosing Cholangitis Patients: Comparison of Adverse Events Associated With Balloon Dilation With and Without Stenting Udayakumar Navaneethan, Ramprasad Jegadeesan*, Jeffrey Hammel, Madhusudhan R. Sanaka, John J. Vargo, Mansour A. Parsi Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH; Cleveland2Center for Interventional Endoscopy, Florida Hospital Institute for Minimally Invasive Therapy, Orlando, FL Background: Dominant biliary strictures occur commonly in patients with primary sclerosing cholangitis (PSC). The optimal endoscopic management of dominant strictures remains unclear and the comparative risk of adverse events associated with balloon dilation alone versus balloon dilation and short term stenting remains unknown. Aim: Our aim was to compare the rate of adverse events associated with balloon dilation alone versus balloon dilation followed by short term stenting (! 7 days) in PSC patients with dominant strictures. Methods: In this retrospective study, 298 patients with PSC were evaluated. Among these, patients who had undergone biliary balloon dilation and/or short term stent placement (! 7 days) for endoscopic treatment of dominant strictures were identified. Adverse events associated with endoscopic biliary balloon dilatation with and without short term stenting for management of dominant strictures were determined. Results: A total of 72 PSC patients (median age 52.6 years; interquartile range 42.5-64) with dominant strictures were identified. Fifteen patients (20.8%) were treated with endoscopic balloon dilation alone and 57 patients (79.2%) were treated with balloon dilation and stent placement. Both groups had comparable baseline characteristics such as age, symptoms, bilirubin levels and severity of PSC as determined by the Mayo PSC risk score. The median duration of follow-up after intervention was similar in both groups (49 months). The overall risk of adverse events with endoscopic retrograde cholangiopancreatography (ERCP) was 15.3% (nZ11). Six patients developed cholangitis which was the most common adverse event. None of the patients in the balloon dilation alone group developed adverse events in contrast to 19.3% of patients (nZ11) who had undergone balloon dilation and short term stenting. (p! 0.01) On multivariate analysis, only stent placement increased the risk of adverse event development. (Hazard ratio 1.86; 95% confidence interval [1.3-2.2], pZ0.02). Conclusions: In this study, even short term stenting after balloon dilation appeared to increase the overall risk of adverse events associated with treatment of dominant strictures in PSC patients. Randomized controlled trials are required to clarify the appropriate management of dominant strictures in PSC patients.

Su1646 Endoscopic Treatment of Dominant Biliary Strictures in Primary Sclerosing Cholangitis Patients: Comparison of Adverse Events Associated With Balloon Dilation With and Without Stenting

Su1646 Endoscopic Treatment of Dominant Biliary Strictures in Primary Sclerosing Cholangitis Patients: Comparison of Adverse Events Associated With Balloon Dilation With and Without Stenting Udayakumar Navaneethan, Ramprasad Jegadeesan*, Jeffrey Hammel, Madhusudhan R. Sanaka, John J. Vargo, Mansour A. Parsi Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH; Cleveland2Center for Interventional Endoscopy, Florida Hospital Institute for Minimally Invasive Therapy, Orlando, FL Background: Dominant biliary strictures occur commonly in patients with primary sclerosing cholangitis (PSC). The optimal endoscopic management of dominant strictures remains unclear and the comparative risk of adverse events associated with balloon dilation alone versus balloon dilation and short term stenting remains unknown. Aim: Our aim was to compare the rate of adverse events associated with balloon dilation alone versus balloon dilation followed by short term stenting (! 7 days) in PSC patients with dominant strictures. Methods: In this retrospective study, 298 patients with PSC were evaluated. Among these, patients who had undergone biliary balloon dilation and/or short term stent placement (! 7 days) for endoscopic treatment of dominant strictures were identified. Adverse events associated with endoscopic biliary balloon dilatation with and without short term stenting for management of dominant strictures were determined. Results: A total of 72 PSC patients (median age 52.6 years; interquartile range 42.5-64) with dominant strictures were identified. Fifteen patients (20.8%) were treated with endoscopic balloon dilation alone and 57 patients (79.2%) were treated with balloon dilation and stent placement. Both groups had comparable baseline characteristics such as age, symptoms, bilirubin levels and severity of PSC as determined by the Mayo PSC risk score. The median duration of follow-up after intervention was similar in both groups (49 months). The overall risk of adverse events with endoscopic retrograde cholangiopancreatography (ERCP) was 15.3% (nZ11). Six patients developed cholangitis which was the most common adverse event. None of the patients in the balloon dilation alone group developed adverse events in contrast to 19.3% of patients (nZ11) who had undergone balloon dilation and short term stenting. (p! 0.01) On multivariate analysis, only stent placement increased the risk of adverse event development. (Hazard ratio 1.86; 95% confidence interval [1.3-2.2], pZ0.02). Conclusions: In this study, even short term stenting after balloon dilation appeared to increase the overall risk of adverse events associated with treatment of dominant strictures in PSC patients. Randomized controlled trials are required to clarify the appropriate management of dominant strictures in PSC patients.

Association between serum IgE level and adverse clinical endpoints in primary sclerosing cholangitis

Introduction. Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients.Material and methods. Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional-hazards models.Results. The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint-free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05).Conclusions. Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed.

Prognostic Implications of Elevated Serum IgE Levels in Primary Sclerosing Cholangitis

Purpose: Primary sclerosing cholangitis (PSC) is a prominent risk factor for cholangiocarcinoma (CCA), but reliable clinical biomarkers for predicting the risk of developing CCA are lacking. Recently, low serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim was to determine whether serum IgE levels predict the development of CCA and/or other adverse clinical outcomes in a United States-based cohort of PSC patients. Methods: Medical records of adult patients with well-defined PSC were retrospectively queried for serum IgE levels as well as other pertinent data, including age, sex, date of PSC diagnosis, IBD and immunosuppression status, biochemical markers of liver disease and other clinical variables and outcomes. The primary endpoint was time to developing adverse clinical endpoints including CCA, liver transplantation or death. Patients with low and high IgE (defined by sample median) were compared with respect to clinical characteristics using Mann-Whitney U and Fisher's exact test. Time to the development of adverse clinical endpoints in the low and high IgE groups was compared with Kaplan-Meier curves. The adjusted association between IgE and the primary outcome was assessed with multivariate proportional-hazards models. Results: Among the 38 patients included, the median age at PSC diagnosis was 41 years, 68% were male, 95% were non-Hispanic White and 89% had IBD. The median serum IgE was 47.6 kU/L, and median time from PSC diagnosis to IgE measurement was two weeks. The low and high IgE groups differed significantly only with respect to serum IgG levels and IgG1, IgG2 and IgG4 subclasses, all of which were higher in the high IgE group (all p<0.05). There was no significant difference in composite clinical endpoint-free (p=0.83, Figure) or CCA-free survival (p=0.20) between the low and high IgE groups. In multivariate analysis, only Mayo PSC risk score and MELD score were significant predictors of outcome (both p<0.05).Figure: Kaplan-Meier curves reveal no significant difference in the time to death, cholangiocarcinoma, or liver transplantation between the low and high IgE group (p=0.83).Conclusion: Serum IgE levels are associated with several serum IgG subclass levels, but do not appear to influence the time to development of CCA, LT or death in PSC patients from a United States-based cohort.

Su1367 Does Recurrent Bacterial Cholangitis in Primary Sclerosing Cholangitis Patients Increase the Risk of Cholangiocarcinoma

Patients with primary sclerosing cholangitis (PSC) have a significantly increased risk of developing Cholangiocarcinoma (CCA). The risk factors for the development of CCA in PSC remain unclear. Recurrent cholangitis as a risk factor for CCA in PSC patients is controversial.

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis ‐ a pilot study

Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited. To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC. Thirty-five patients with PSC were randomised in a double-blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase (ALK) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects (AEs). Nonparametric tests were used for analysis. The primary endpoint was reached in the low-dose (-43% change in ALK, P = 0.03) and high-dose (-40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low-dose metronidazole group (-20%, P = 0.03) and trended towards significance in the low-dose vancomycin group (-33%, P = 0.06). Mayo PSC risk score decreased significantly in the low-dose vancomycin (-0.55, P = 0.02) and low-dose metronidazole group (-0.16, P = 0.03). Pruritus decreased significantly in the high-dose metronidazole group (-3.4, P = 0.03). AEs led to medication discontinuation in six patients, four of whom were receiving metronidazole. Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer-term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis (clinicaltrials.gov NCT01085760).

Primary sclerosing cholangitis clinical trials: mission impossible … for now

This issue of Clinical Investigation has an excellent review of the inherent difficulties in performing clinical trials in patients with primary sclerosing cholangitis (PSC) [1]. The low number of suitable patients, need for a prolonged follow-up, and search for outcomes other than liver transplantation or death offer important challenges to investigators. These difficulties are seemingly insurmountable, but with more epidemiologic insights into the natural history of disease, these obstacles could be overcome. PSC is a chronic inflammatory disease of the bile ducts and is strongly associated with inflammatory bowel disease. The median time from diagnosis to progression to cirrhosis is between 10 and 15 years. Many patients do not progress to cirrhosis; they can be followed expectantly for their lifetime, but do not ever require therapy. Alternatively, patients who have already developed cirrhosis are not likely to benefit from innovative treatment. The ideal PSC patient to be entered into a clinical trial is one who is early in the course of their disease, but one who is likely to progress to cirrhosis. How can we identify such ‘progressors’? Histologic abnormality is a likely candidate for identifying patients. Histologic staging for PSC patients is listed in Table 1 in the artcle by Imam et al. [1]. By the time stage 3 or 4 disease is detected, it is not likely that an anti-inflammatory medication will help – these patients should be excluded from clinical trials. Patients with stage 1 disease may not be progressors and should be followed expectantly outside of a clinical trial. Stage 2 patients are ones who have progressed but are early on in the progression process. These patients may be the best candidates to be included in a clinical trial. Of course, limiting entry to only stage 2 patients limits the sample size dramatically and makes multicenter trials a necessity. Interestingly, liver biopsies are not routinely undertaken on PSC patients, may suffer from sampling error (leading to misclassification of staging), and are not included in the Mayo PSC Risk Score. While appealing, histologic staging may not be an ideal candidate to identify the appropriate patient for a clinical trial. The Mayo PSC Risk Score uses five variables (age, bilirubin, albumin, AST and variceal bleeding) to estimate survival in PSC patients [1]. Perhaps, progressors can be identified by documenting a change in Mayo PSC Risk Score over a defined period of time. Such a strategy seems very reasonable in designing trials. Are there certain populations of PSC patients that have a particularly high proportion that progress rapidly to cirrhosis? A better understanding of the natural history of the disease is needed in patients with: “The ideal PSC patient to be entered into a clinical trial is one who is early in the course of their disease, but one who is likely to progress to cirrhosis. How can we identify such ‘progressors’?”

The impact of ulcerative colitis on the long‐term outcome of patients with primary sclerosing cholangitis

The impact of ulcerative colitis (UC) on the outcome of primary sclerosing cholangitis (PSC) outcome remains unclear. To investigate whether the presence of UC is associated with a worse clinical of associated PSC. A total of 222 patients with PSC (167 with UC and 55 without UC) seen and followed at a single centre from 1985 to 2011 were included. Clinical and demographic variables were obtained and patients were followed until the date of their last clinic visit. The median age at presentation of PSC with associated UC was 38 vs. 47 years without UC (P < 0.001). At presentation, median serum bilirubin (2.1 vs. 4.5, P < 0.001) and the Mayo PSC Risk Score (0.95 vs. 1.69, P < 0.001) were lower in those with UC vs. those without UC. A total of 55 of 167 (32.9%) patients with PSC-UC developed colon neoplasia in contrast to 1 of the 55 (1.8%) patients with PSC. (P < 0.001) On proportional hazards analysis, UC (hazard ratio (HR) = 0.90 [95% confidence interval (CI): 0.60-1.34, P = 0.60] was not associated with death or orthotopic liver transplantation (OLT), when adjusting for gender, Mayo risk score and year of PSC diagnosis; whereas the revised Mayo risk score [HR = 5.08, 95% CI: (2.62-9.86), P < 0.001] was associated with a greater risk of OLT or death. Primary sclerosing cholangitis often is recognised at an early stage in patients with concurrent ulcerative colitis; ulcerative colitis has no impact on long-term prognosis in terms of liver-related outcomes when adjusted for the severity of liver disease.

The impact of severity of primary sclerosing cholangitis and clinical outcome in patients with Ulcerative Colitis

Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is associated with pancolitis and clinically mild disease. The aim of the study was to study the association between the severity of PSC and clinical outcome of UC, comparing the course of UC in patients with PSC not needing orthotopic liver transplantation (OLT) and those requiring LT. A total of 167 patients with PSC and UC seen at the Cleveland Clinic between 1985 and 2011 were included in this study. Clinical and demographic variables were obtained regarding the outcome of UC in patients with and without OLT for underlying UC. Patients were followed-up until OLT or the date of the last clinical visit. Logistic regression model was constructed by including variables known at UC or PSC diagnosis for the risk of colectomy. Patients with PSC/UC were divided into two groups: 81 did not need OLT (no-OLT) and 86 were transplanted (OLT). 81 (94.2%) of patients in the OLT group had pancolitis in contrast to 72 (88.9%) in the no-OLT group. (p=0.005) There were no significant differences concerning duration of UC between the two groups, while the duration of PSC was longer in the OLT group [median of 13.5 (interquartile range 10, 20) vs. 11(7.5, 17), p=0.01] than the no-OLT group. The median follow-up was a little higher for the OLT group (13.5 vs. 11 years, p=0.009). The OLT group had significantly more clinically quiescent UC compared with the no-OLT group. (59 (68.6%) vs. 12 (14.8%), p<0.001) The OLT group had fewer UC flare-ups [3 (2, 6) vs. 0 (0, 1), p<0.001) and required less use of azathioprine [(1 (1.2%) vs. 14 (17.3%), p=0.006]. There was an increased need for surgery in the no-OLT group [(61 (75.3%) vs. 23 (26.7%), p<0.001]. Colon carcinoma and dysplasia were also more frequent in the no-OLT group [(33 (40.7%) vs. 22 (25.6%), p=0.04]. On Cox regression analysis, OLT for PSC [Odds ratio (OR) 0.15 (95% confidence interval (C.I): 0.06 - 0.37, p<0.001] and higher Mayo risk score at diagnosis [OR 0.26, 95% CI: (0.13 - 0.52), p<0.001] independently protected against the risk of colectomy. Table 1 shows Cox regression analysis for the risk of colectomy. Cox regression analysis for the risk of colectomy Cox regression analysis for the risk of colectomy Severe PSC requiring OLT is associated with a milder course of UC (reduced disease activity and less use of azathioprine and surgery). Decreased disease activity is also associated with reduced incidence of dysplasia and colon carcinoma. The requirement for OLT and a higher Mayo PSC risk score at diagnosis appears to independently protect against colectomy.