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Primary sclerosing cholangitis (PSC), a serious, rare, progressive cholestatic liver disease, is becoming more prevalent in Europe, the 2019 ISG Winter Meeting heard.
PSC expert Dr Roger Chapman, Group Head/PI Consultant Physician, John Radcliffe Hospital, Oxford, UK, gave a comprehensive overview of PSC, and explained that it is a complex premalignant autoimmune disease with a high prevalence of hepatobiliary and colonic malignancy. Mortality rates are high though variable (10-to-12 years survival in one study and over 21 years in another) but are improving, with the majority of deaths (44 per cent) due to cancer and just over a third due to liver failure.
PSC is characterised by inflammation, stricturing, and concentric, obliterative fibrosis of the biliary system, ultimately leading to biliary cirrhosis, portal hypertension, and eventually hepatic failure in the majority of patients.
It is a male‐predominant disease, with a male/female ratio of around 2:1. Although the disease can present at any age, the mean age of presentation is 40 years. Prevalence rates are higher than previously realised, with an increasing prevalence in Northern Europe, he said.
PSC is very strongly associated with IBD, particularly ulcerative colitis, and not smoking and coffee-drinking appear to be protective, Dr Chapman noted.
Current evidence confirms that PSC is a complex polygenic autoimmune disease and that PSC/IBD is genetically and phenotypically distinct from UC or Crohn’s disease without PSC, he added. Studies have shown that PSC patients have distinct gut microbial profiles (reduced biodiversity but enriched Veillonella species) compared to healthy controls or UC patients without PSC, and that ursodeoxycholic acid treatment did not alter gut microbiota.
Risk stratification for regular cancer surveillance in PSC is important but guidelines differ and there is a significant workload involved, with a need for better biomarkers, Dr Chapman said. Those who do best tend to have small-duct disease, are female, without IBD (though if they have IBD they do better with Crohn’s rather than UC), and have normal IgG4 and Alk Phos.
Treatment-wise, Dr Chapman noted “results have been disappointing” with standard therapies including immunosuppressants, antifibrotics and antibiotics, and there remains inadequate trial data for these patients. While ursodeoxycholic acid use is controversial and not supported by the guidelines, it does have some useful data and elicits a response in certain patients at particular doses, while newer bile acid nor-ursodeoxycholic acid holds more promise, with further data on the way, he told the meeting. Thus, combination therapy with bile acids and other agents may be the future, “though there is unlikely to be one ‘magic bullet’.”
The use of vancomycin is also being increasingly investigated for its impact on the intestinal bacterial flora in PSC, particularly in the US, with good results from small studies to date. “Clearly, there is a need for a large, randomised, phase 3 controlled trial, which is underway, but at that moment I think vancomycin looks very interesting as an agent,” Dr Chapman commented.
Faecal microbiota transplantation is also being investigated, he said, with small-scale early results showing improvement in faecal diversity and a significant decrease in serum ALP, with a large-scale trial currently underway, Dr Chapman confirmed. While liver transplant is necessary for some patients and is still the only proven treatment, with good survival (75-to-80 per cent at five years), recurrence of PSC is about 30 per cent at five years, and colitis may worsen in about half of transplant patients, with other complications too, he noted.
Looking to the future, Dr Chapman said there are currently 16 new compounds being trialled for PSC, in the areas of anti-fibrotics, bile acid therapy, microbiome manipulation, and immune modulation, “and so it is a very exciting time in terms of treatment and understanding this disease with hopefully better results to come in the next decade.”
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