Research ArticleUrsodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis
Graphical abstract
Introduction
Primary biliary cholangitis (PBC) is a chronic and usually slowly progressive liver disease with autoimmune features, histologically characterized by destruction of the small intrahepatic bile ducts.[1], [2] The disease is primarily diagnosed based on an otherwise unexplained chronic elevation of serum alkaline phosphatase levels and the presence of anti-mitochondrial antibodies. Early identification of individuals with PBC is clinically challenging as symptoms are frequently absent. Identifying and managing patients with PBC is important, however, as the disease may silently progress towards cirrhosis and the survival of affected patients is substantially impaired.3
Ursodeoxycholic acid (UDCA) is a choleretic and hydrophilic endogenous bile acid that is considered a safe and well-tolerated drug.[4], [5], [6] Based on the cumulative experience obtained with this drug over the past decades, UDCA is recommended as the standard treatment for PBC.[4], [6] Long-term cohort studies have suggested an association between UDCA and improved liver transplant (LT)-free survival, but this was only based on the comparison of observed versus predicted LT-free survival according to the Mayo Risk Score, which estimates the prognosis when patients are left untreated.[7], [8], [9] Numerous randomized controlled trials (RCTs) have been performed as well, but all failed to show a difference in LT-free survival between placebo and UDCA-treated groups.[10], [11], [12], [13], [14], [15], [16], [17], [18], [19] As did other more extensive meta-analyses, the Cochrane hepatobiliary group recently concluded once again that there is no demonstrated benefit of UDCA on LT and/or mortality.[17], [18], [19], [20] Such positioning statements, in absence of definitive trials, have fueled the ongoing discussion about the therapeutic potential of UDCA.[21], [22], [23], [24] This might explain the observation in a well-executed national PBC registry that, until recently, as many as 20% of patients remained untreated.25 In another recent US-based cohort study the percentage of UDCA untreated patients was even as high as 30%.26 However, the meta-analyses are based on inadequate RCTs that were limited by a small number of patients, insufficient dosages of UDCA, and short follow-up. Therefore, the evaluation of the clinical efficacy of UDCA in PBC should not be based on these RCTs alone. Nonetheless, there is an understandable reluctance to initiate new long-term, placebo-controlled RCTs in which many patients would be denied UDCA therapy, because of minimal safety concerns of UDCA and practical implications.
To support current practice, alternative study designs are thus needed to assess the potential benefit of treatment with UDCA in PBC. This would be relevant both to increase awareness for timely diagnosis and referral by physicians working in other fields, and to optimize future patient management by PBC-treating physicians. A contemporary causal inference method – used to emulate a randomized controlled trial in observational data – is inverse probability of treatment weighting (IPTW). The Global PBC Study Group cohort, which includes long-term follow-up data of both UDCA-treated and untreated patients, provides the opportunity to apply this method. In our first publication, we substantiated alkaline phosphatase (ALP) and bilirubin as surrogate markers for clinical outcome in our cohort of 4,845 patients with PBC.27 In the second publication, in which only the 4,119 UDCA-treated patients were included, we developed the GLOBE score, a model that accurately predicts long-term outcome.28 In the current study performed in this cohort, we aimed to assess the effect of UDCA therapy on LT-free survival. The second objective was to evaluate the difference in LT-free survival between patients who do not meet biochemical criteria for response after 1 year of UDCA therapy and patients who remained untreated.
Section snippets
Study population and design
Patients were derived from the Global PBC Study Group database. This study group is an international collaboration between 15 liver units across 8 countries in Europe and Northern America. The database contains individual patient data from long-term follow-up cohorts. Both UDCA-treated and untreated patients with an established diagnosis of PBC in accordance with internationally accepted guidelines[4], [5], [6] were eligible for inclusion in this study. In order to be eligible, we required the
Study population
In total, 3,902 patients with PBC were included. At baseline, the mean (SD) age was 54.3 (11.9) and the vast majority of patients were female (n = 3,552, 91.0%). A total of 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated with UDCA. Table 1 shows the baseline characteristics according to treatment with UDCA. Patients treated with UDCA were younger and had higher circulating serum liver tests, while in the subgroup of patients with available baseline
Discussion
In this large, international follow-up study including both UDCA-treated and untreated patients, we report that UDCA therapy improves LT-free survival in PBC, with a dose-response relationship. Importantly, a statistically significant association between UDCA therapy and reduced all-cause mortality or LT was found in all stages of disease. These findings imply a strong recommendation for all patients with PBC to use UDCA. Even in UDCA-treated patients classified as inadequately responding to
Financial support
This investigator-initiated study was supported by an unrestricted grant from Intercept Pharmaceuticals, and was funded by the Foundation for Liver and Gastrointestinal Research (a not-for-profit foundation) in Rotterdam, the Netherlands. The supporting parties had no influence on the study design, data collection and analyses, writing of the manuscript, or on the decision to submit the manuscript for publication.
Conflict of interest
The following authors declared that they have no conflicts of interest: P.M. Battezzati, F. Nevens, M.J. Mayo. M.H. Harms reports a speaker fee from Zambon Nederland B.V. H.R. van Buuren is a consultant for Intercept Pharma Benelux and received unrestricted research grants from Intercept Pharmaceuticals and from Zambon Nederland B.V. C. Corpechot is consultant for Intercept Pharmaceuticals France. D. Thorburn reports consulting activities for Intercept Pharmaceuticals. K.D. Lindor reports that
Authors’ contributions
Maren H. Harms, Bettina E. Hansen and Adriaan J. van der Meer had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of data analyses. Study concept and design: Maren H. Harms; Henk R. van Buuren; Christophe Corpechot; Douglas Thorburn; Harry L.A. Janssen; Keith D. Lindor; Gideon M. Hirschfield; Albert Parés; Annarosa Floreani; Marlyn J. Mayo; Pietro Invernizzi; Pier M. Battezzati; Frederik Nevens; Cyriel Y. Ponsioen; Andrew L. Mason;
Acknowledgements
This study was performed on behalf of the Global PBC Study Group.
References (56)
- et al.
Primary biliary cirrhosis
Lancet
(2015) - et al.
Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years
Gastroenterology
(2002) - et al.
The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis
Gastroenterology
(2005) - et al.
Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid
Gastroenterology
(2006) - et al.
Ursodeoxycholic acid in the treatment of primary biliary cirrhosis
Gastroenterology
(1994) - et al.
Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial
Am J Gastroenterol
(2002) - et al.
A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis
Hepatology
(1995) - et al.
Is the Mayo model for predicting survival useful after the introduction of ursodeoxycholic acid treatment for primary biliary cirrhosis?
Hepatology
(1996) - et al.
Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the
Liver. J Hepatol
(2000) - et al.
Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis
Lancet
(1999)
Ursodeoxycholic acid and primary biliary cirrhosis: EASL and AASLD guidelines
J Hepatol
Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis
Gastroenterology
Ursodeoxycholic acid for primary biliary cirrhosis
Lancet
Ursodeoxycholic acid for primary biliary cirrhosis: treat early to slow progression
J Hepatol
P1184: age, bilirubin and albumin, regardless of sex, are the strongest independent predictors of biochemical response and transplantation-free survival in patients with primary biliary cirrhosis
J Hepatol
Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome
J Hepatol
The long-term effect of ursodeoxycholic acid on laboratory liver parameters in biochemically non-advanced primary biliary cirrhosis
Clin Res Hepatol Gastroenterol
Primary biliary cirrhosis
N Engl J Med
EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis
J Hepatol
Japan. Hepatol Res
Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases
Hepatology
Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients
Am J Gastroenterol
Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group
N Engl J Med
The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis
Hepatology
Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses
Am J Gastroenterol
Ursodeoxycholic acid for primary biliary cirrhosis
Cochrane Database Syst Rev
Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis
Cochrane Database Syst Rev
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