151 Higher doses of UDCA were then studied on the grounds that larger doses might be necessary to provide sufficient enrichment of the bile acid pool in the context of cholestasis, and that these doses might also enhance a potential immunomodulatory effect of the drug. The Scandinavian UDCA trial in a group of 219 patients with PSC using a dose of 17–23 mg/kg/day for 5 years demonstrated a trend toward increased survival in the UDCA treated group when compared with placebo,152 but despite the relatively large number of patients

recruited, the study was still insufficiently powered to produce a statistically significant result. Recently, a multicenter study using high doses of 28–30 mg/kg/day of UDCA in 150 patients with PSC over 5 years has been aborted because of an enhanced risk in the UDCA treatment group for death or liver transplantation and serious Bortezomib adverse events particularly in advanced disease whereas biochemical features improved in the whole UDCA group.153 Thus, the role for UDCA in slowing the progression of PSC-related liver disease is as yet unclear and indeed, high dose UDCA may be harmful.102 Treatment with corticosteroids and other immunosuppressant agents have not demonstrated any improvement in disease activity or in the outcome of PSC. Small randomized, placebo-controlled or pilot

trials have investigated the role of agents with immunosuppressive potency like prednisolone, budesonide, azathioprine, cyclosporin, methotrexate, mycophenolate, and MCE tacrolimus, agents with TNFα antagonizing effects like pentoxifyllin, etanercept and anti-TNF monocolonal antibodies and antifibrotic Idasanutlin order agents like colchicine, penicillamine, or pirfenidone.154 There is no evidence that any of these drugs are efficacious and, therefore, none can be recommended

for classic PSC. However, these drugs may well have a role in the context of a PSC/AIH overlap syndrome, because pediatric patients and those with evidence of a PSC/AIH overlap syndrome are more likely to respond to immunosuppressive treatment.36, 39, 155 A retrospective study in adults also suggested a beneficial role of corticosteroids in a subgroup with AIH overlap features.156 Corticosteroids may also be indicated as a therapeutic trial following thorough evaluation of suspected immunoglobulin G4-associated cholangitis (IAC)/autoimmune pancreatitis (AIP).44, 157 Recommendations: 28 In adult patients with PSC, we recommend against the use of UDCA as medical therapy (1A). Liver transplant indications for patients with PSC do not differ substantially from those with other forms of chronic liver disease and relate primarily to complications of portal hypertension, impaired quality of life, and chronic liver failure. Indeed, in the United States of America, organ allocation by the Model for End-Stage Liver Disease score is etiology independent.