Old and Novel Therapies for Primary Biliary Cirrhosis

Parés, Albert

doi:10.1055/s-0034-1383733

Cited by 21 publications

(11 citation statements)

References 98 publications

(115 reference statements)

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“…In the important minority of patients with high risk, treatment unresponsive or highly symptomatic disease the need for new treatment approaches is now clear and well accepted. 149 In the setting of disease modification, evolution in our understanding of disease mechanisms is evolving rapidly into the advent of new and re-purposed therapeutics targeting key processes. Excellent opportunities are offered, in particular, by immunotherapeutic approaches targeting the upstream immune response postulated to initiate BEC injury, and by enhanced bile-acid therapies targeting the bile acid biosynthetic and feedback processes that drive 'midstream' injury to BECs.…”

Section: Targeting Pruritusmentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

113

102

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Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy-ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.

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Section: Targeting Pruritusmentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

113

102

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“…Additionally, FXR activation increases the expression of the bilirubin and phospholipid (multiple drug resistance gene-3) export pumps, and stimulates intestinal factors such as fibroblast growth factor 19, which provide a negative feedback loop from the intestine to hepatocytes, contributing to the repression of bile acid synthesis. Preclinical studies in various animal models have demonstrated that OCA has choleretic and antifibrotic properties and metabolic effects consistent with FXR agonist effects in vivo [41] . Clinical evaluation of this new agent and phase-II efficacy and safety assessment in PBC patients have been reported [51] .…”

Section: Proposals Targeted On Cholestasismentioning

confidence: 89%

“…Fibrates Promising data on the beneficial effects of fibrates in PBC have been reported in the last 15 years, particularly by adding fibrates in patients receiving UDCA [41] . These data are summarized in table 2 .…”

Section: Proposals Targeted On Cholestasismentioning

confidence: 99%

Therapy of Primary Biliary Cirrhosis: Novel Approaches for Patients with Suboptimal Response to Ursodeoxycholic Acid

Parés¹

2015

Dig Dis

Self Cite

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Primary biliary cirrhosis (PBC) is a chronic cholestatic disease of presumed autoimmune pathogenesis, characterized by the inflammation and damage of the intrahepatic intermediate and small bile ducts, which eventually results in cirrhosis. A number of randomized and observational and pilot studies using several agents were carried out in the 80s, but no clear results or even harmful effects were reported. Over the past 2 decades, increasing evidence indicates that ursodeoxycholic acid (UDCA) - 13 to 16 mg/kg/day - is the treatment of choice for patients with PBC. Biochemical response to UDCA, assessed at 1 year, clearly predicts the long-term outcome, since in UDCA, responders survival is similar to that estimated for the matched control population. However, about 40% of patients have incomplete biochemical response and increased risk of progression and decreased survival free of transplantation. Patients with suboptimal biochemical response to UDCA outline the group in whom further single or combined treatments with UDCA are needed. Accordingly, data on the effect of fibrates alone or in combination with UDCA, and budesonide in combination with UDCA have been reported. The combined treatment of UDCA and fibrates in patients without optimal biochemical response to UDCA improves the degree of cholestasis and may minimize the long-term management of these patients. The results of the combined therapy of UDCA with budesonide are appealing but they should be established in large randomized trials. The effect of new agents such obeticholic acid are promising, since the addition of this farnesoide-X-receptor agonist bile acid in patients with stable UDCA dosage and increased alkaline phosphatase levels results in an improvement of cholestasis as compared to placebo, with a parallel decrease of aminotransferases and immunoglobulin M, as well as one surrogate marker of bile acid synthesis. New molecular therapies are currently being investigated.

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“…50 A few clinical studies have suggested that dual therapy of budesonide (6-9 mg/day) with UDCA is more efficacious in improving the hepatic biochemical indices and histology than UDCA monotherapy in PBC subjects without concurrent cirrhosis. In one study, Leuschner et al performed a two-year prospective, controlled, double-blind study of 23 subjects undergoing dual treatment with UDCA/budesonide and 19 subjects given UDCA/placebo therapy.…”

Section: Immunomodulatory Agents Budesonidementioning

confidence: 99%