Author(s): James H Tabibian [*] 1 , Keith D Lindor 2
antibacterial agents; bile duct diseases; cholangiography; cholangiopancreatography; endoscopic retrograde; enterohepatic circulation; fibrosis; genes; magnetic resonance imaging; ras; TOR serine-threonine kinases
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, cholestatic liver disease characterized by biliary inflammation, obliteration and fibrosis [1-4] . PSC generally leads to cirrhotic end-stage liver disease and represents a major risk factor for cholangiocarcinoma (CCA), which can develop prior to the onset of liver cirrhosis and is often undetectable until advanced stages [5,6] . In the USA alone, PSC affects approximately 25,000 individuals and carries a median survival time from diagnosis of only 12 years [1,2,5-8] . Although operative treatment with liver transplantation (LT) for patients with PSC is effective, it is available in very limited specialty centers and is only an option in select patients; furthermore, PSC and CCA can recur post-LT [9-11] . Thus, given the morbidity and mortality of PSC, and the challenges associated with operative treatment, safe and effective pharmacotherapy is critically needed.
Although previously believed to be an autoimmune disease, PSC is now generally accepted to be a complex, heterogeneous, likely immune-mediated disease whose clinical presentation and course are likewise variable and often unpredictable. It is believed that this mechanistic complexity and clinical heterogeneity are at the root of the disappointing results of previous therapeutic trials in PSC (Table 1). Looking forward, however, there appears to be light ahead for this obscure condition, as fundamental understanding of PSC and biliary pathobiology continues to grow and methods for translation into carefully designed clinical trials increase.
This review is organized to provide a background on the pharmacotherapies previously tested in PSC, discuss existing and emerging fundamental concepts and paradigms, and present viewpoints on how research in identifying and establishing therapies for PSC may evolve over the next 5 years.
Historical overview of pharmacotherapies evaluated in PSC
The majority of pharmacologic agents tested in PSC have been immunosuppressants or anti-inflammatory agents given the presence of a mixed (predominantly lymphocytic) inflammatory infiltrate surrounding bile ducts in liver specimens, relatively strong association with certain human leukocyte antigen (HLA) haplotypes (to be discussed later), high positivity rate for antineutrophil cytoplasmic autoantibodies  , and other immunologic alterations and associations. However, a number of other pharmacologic agents have also been studied, particularly in more recent years.
The earliest published study of pharmacotherapy for 'chronic pericholangitis associated with ulcerative colitis' (later recognized as being PSC) came in 1959  , over three decades after the first published description of 'rétrécissement du choledoque' ('stenosis of the bile duct', i.e., PSC) by the French surgeon Pierre Delbet  . In said study, the investigators described a series of five patients treated with oral tetracycline based on recent findings of portal bacteremia in these patients and the prevailing belief that the liver disease associated with ulcerative colitis was autoimmune in nature. Although the authors reported biochemical improvements, efficacy appeared to wane over time. A subsequent, more meticulous and longer-term study of tetracycline reported no effect "on the clinical course, the pathological changes...