DISPATCHES FROM THE GUILD CONFERENCE, SERIES #18 Uma Mahadevan MD, Series Editor guildconference.com Novel Therapies for Primary Sclerosing Cholangitis Manan A. Jhaveri Kris V. Kowdley INTRODUCTION rimary sclerosing cholangitis (PSC) is chronic, PSC patient is a male in their fourth or fifth decade cholestatic liver disease that progresses to of life presenting with a diagnosis of ulcerative advanced liver disease and cirrhosis. It is colitis (UC) or Crohn’s colitis and abnormal liver P 4,5 characterized by inflammation and fibrosis of both biochemistries. The IBD associated with PSC is intra and extra hepatic bile ducts leading to the unusual in that it is usually pancolitis with right formation of multiple bile duct strictures resulting sided predominance, backwash ileitis and rectal into chronic cholestasis. This may eventually sparing.6,7 develop into cirrhosis with subsequent portal PSC is associated with an increased risk of hypertension and hepatic decompensation.1,2 The biliary and colorectal cancer; patients with incidence and prevalence rates for PSC range from concomitant UC and PSC have a much higher 0 to 1.3 per 100,000 people per year and 0 to 16.2 risk compared with patients with UC or PSC per 100,000 people, respectively. The estimated alone.8,9 Surveillance colonoscopy, from the median survival from the time of PSC diagnosis time of diagnosis of PSC, cannot be stressed until liver transplantation or mortality related to enough. Patients with small duct PSC disease liver disease is 12 to 15 years.1 Roughly 65% of have an improved survival and lower risk of PSC patients are male. PSC is strongly associated cholangiocarcinoma as comparted to patients with inflammatory bowel disease (IBD), as the with large duct PSC.8,10 Patient who demonstrate a prevalence of IBD in PSC is 60-80%.3 The typical significant reduction in serum alkaline phosphatase (ALP) in a median time of two years following Manan A. Jhaveri MD, MPH Kris V. Kowdley MD, diagnosis have an improved transplant-free FACP, FAASLD Liver Care Network and Organ Care survival and reduced risk of cholangiocarcinoma.11 Research, Swedish Medical Center Seattle, WA PSC is also associated with increased frequencies PRACTICAL GASTROENTEROLOGY • NOVEMBER 2018 49 Novel Therapies for Primary Sclerosing Cholangitis DISPATCHES FROM THE GUILD CONFERENCE, SERIES #18 of multiple gall bladder abnormalities including diagnosis of PSC is MRCP, which has acceptable cholecystitis, cholelithiasis, benign lesions and sensitivity and specificity of 86% and 94% malignancies.12 Gallbladder lesions have been respectively. Small duct PSC is a disease variant found in about 5% of patients with PSC, with characterized by cholestasis and histological features half of these being malignant. Gallbladder polyps of PSC with normal bile ducts cholangiogram; liver are significantly associated with high risk of biopsy is required for diagnosis in these cases.17 malignancy, so cholecystectomy is recommended Secondary sclerosing cholangitis is characterized even if the lesion is less than 1 cm.13,14 by multiple biliary strictures due to recognizable causes such as infection, inflammation and long- Pathogenesis term biliary obstruction that leads to destruction of The exact pathogenesis of PSC is unknown. bile ducts. PSC overlap syndromes are conditions Multiple studies have supported an autoimmune with features of PSC and other autoimmune etiology given the presence of concurrent liver diseases such as autoimmune hepatitis autoimmune disease in up to 25% of PSC (AIH) and autoimmune pancreatitis. PSC-AIH patients as well as strong linkage of PSC to overlap syndrome is characterized by clinical, human histocompatibility complex genes.4 The biochemical, and histological features of AIH involvement of gut microbiota has been evaluated along with cholangiographic findings similar in PSC. Several in vitro studies have demonstrated to PSC. However, current understanding is that that small bowel bacterial overgrowth may cause rather than reflecting a separate entity, the observed cholangitis and liver lesions similar to those seen features of autoimmune hepatitis in PSC, including in PSC. Subsequent antimicrobial therapy leads to elevated transaminases and IgG, may also be an improvement in these lesions. The strong HLA due to biliary disease. Autoimmune pancreatitis associations suggest that adaptive innate responses (AIP) is characterized by stricturing of pancreatic are also involved in the pathogenesis of PSC. IgG4 duct, raised IgG4 level, a lymphocytic infiltrate (immunoglobulin-G4) related disease is a systemic and response to corticosteroid therapy. AIP in disease characterized by extensive IgG4 plasma association with stricturing of bile ducts similar cells and T-lymphocyte infiltration of various organs to PSC is termed as autoimmune pancreatitis – including pancreas (autoimmune pancreatitis) and sclerosing cholangitis (AIP-SC). It is important bile ducts (IgG associated cholangitis, IAC). It is to note that alkaline phosphatase levels fluctuate important to distinguish between IAC and PSC in PSC patients and may be normal or only with elevated IgG4 as cholangiographic changes of mildly elevated in a significant proportion of PSC IAC may resolve completely after corticosteroids patients.4,8,9 treatment. PSC patients with elevated IgG4 are less responsive to corticosteroids and also multiple Management studies have demonstrated that these patients Managing patients with PSC is complicated, as may progress rapidly and have more severe liver it requires management of primary disease and disease.15,16 also coexisting conditions and complications from end stage liver disease. Currently there is no Diagnosis medical therapy that will halt the progression of The diagnosis of PSC is made in patients liver disease in PSC patients, despite numerous with cholestatic liver test abnormalities and clinical trials over the past two decades. This is characteristic stricturing of the intrahepatic and/ due to uncertainty regarding the pathophysiology or extrahepatic bile ducts with segmental dilatation of PSC and also lack of reliable diagnostic markers. on cholangiography [e.g., magnetic resonance cholangiopancreatography (MRCP), endoscopic Ursodeoxycholic Acid retrograde cholangiopancreatography (ERC) or Multiple clinical trials have studied the efficacy percutaneous transhepatic cholangiography (PTC)] and safety of ursodeoxycholic acid (UDCA) after excluding secondary causes of sclerosing in PSC patients. UDCA is the most commonly 4,17 cholangitis. The preferable test for making a (continued on page 52) 50 PRACTICAL GASTROENTEROLOGY • NOVEMBER 2018 Novel Therapies for Primary Sclerosing Cholangitis DISPATCHES FROM THE GUILD CONFERENCE, SERIES #18 (continued from page 50) societies including the AASLD (American Society prescribed drug for PSC, as it is effective in other for the Study of Liver Diseases)17 and the ACG cholestatic liver diseases, specifically primary (American College of Gastroenterology)30 do not biliary cholangitis (PBC). However, the role of support the use of ursodeoxycholic acid; however UDCA in clinical improvement is questionable. the EASL (European Association for the Study UDCA reduces hydrophobicity of bile acid and also of the Liver)31 recommends the use of low dose affects adaptive immunity by inhibiting dendritic UDCA (13-15 mg / kg / day). cell response.18,19 The initial placebo controlled clinical trials of low dose UDCA conducted in Novel Treatment in PSC early 1990s demonstrated improvement in clinical symptoms, liver biochemistries and histological Farnesoid X Receptor Ligands features. However, its clinical significance was The Farnesoid X receptor (FXR) plays an important limited due to small sample size.20,21 A large, role in bile acid homeostasis. The natural ligands placebo-controlled clinical trial of low dose for FXR are bile salts. The key role of FXR is UDCA (13-15 mg/kg/day) in PSC demonstrated to down regulate the cytochrome P4507A1, the improvement in serum liver biochemistries but no rate limiting enzymes in bile acid synthesis.32 effect on patient’s clinical symptoms or time to liver Obeticholic acid (OCA), a semisynthetic analogue transplantation. 22 A large, multicenter, randomized, of chenodeoxycholic acid and an FXR agonist with placebo-controlled trial treated 219 PSC patients anti-fibrotic properties has been approved by the with moderate doses of UDCA (17-23 mg/kg/day) US Food and Drug Administration for the treatment and followed them for five years. Improvement in of primary biliary cholangitis (PBC).33 A clinical liver biochemistries with UDCA treatment was trial of obeticholic acid in patients with primary seen, but there was no statistically significant sclerosing cholangitis is underway (clinicaltrials. effect on survival, time to liver transplantation gov identifier, NCT02177136). The results from or prevention of cholangiocarcinoma.23 Pilot a phase 2 randomized, double blind, placebo clinical trials with a higher dose of UDCA (28-30 controlled trial (AESOP) evaluating the safety mg/kg/day) demonstrated clinical improvement and efficacy of OCA compared to placebo in 77 in liver biochemistries as well as Mayo risk patients with PSC were presented at the annual score.24,25 However, the largest clinical trial of meeting of the AASLD in 2017. Patients were high dose UDCA26 was terminated at five years randomized to placebo, OCA 1.5 – 3 mg, and OCA due to an increased risk of progression to liver 5 – 10 mg (with dose titration occurring at the 12