A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial.
In primary biliary cirrhosis the hepatic lesions may result, at least in part, from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid), a hydrophilic bile acid without hepatotoxicity, leads to improvement in the condition of patients with primary biliary cirrhosis.
                We conducted a two-year, multicenter, double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 mumol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction.
                Treatment failed in 6 patients in the ursodiol group, as compared with 13 in the placebo group (P less than 0.01 by Cox regression model). A single patient in each group withdrew because of minor adverse effects. After two years of treatment, the proportion of patients with clinically overt disease decreased only in the ursodiol group (P less than 0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, cholesterol, and IgM (all P less than 0.001); the antimitochondrial-antibody titer (P less than 0.01); and the Mayo risk score (P less than 0.001). Follow-up analysis of 95 liver-biopsy specimens showed a significant improvement in the mean histologic score (P less than 0.002) and in all the characteristic histologic features except fibrosis only in the group given ursodiol.
                Ursodiol is a safe and effective treatment for primary biliary cirrhosis. New treatments for primary biliary cirrhosis (PBC) need to be evaluated. We conducted a single-center double-blind, randomized trial of methotrexate, 7.5 mg/wk (n = 30), vs. placebo (n = 30) for up to 6 years in PBC.
                Methods included three monthly symptom assessment and liver function tests and liver biopsy and gastroscopy at baseline, after 2 years, and after 4-6 years.
                Patients randomized to methotrexate had, compared with patients randomized to placebo, (1) significantly lower on-treatment serum alkaline phosphatase, gamma-glutamyltransferase, immunoglobulin (Ig) M, IgG, and (after 24 months) aspartate aminotransferase and alanine aminotransferase levels (P < 0.02-0.001 by analysis of covariance to adjust for baseline differences); (2) a nonsignificant trend toward lower on-treatment pruritus scores; (3) similar on-treatment Knodell inflammatory scores but nonsignificant trends toward lower Knodell fibrosis score and less ductopenia; (4) a trend toward greater increases in serum bilirubin level and Mayo score with time (both significant after 5 years of follow-up); and (5) a 2.9-fold (95% confidence interval, 0.85-10.25-fold) increase the rate of death or liver transplantation as a result of liver disease during or after the trial (P = 0.09) in a Cox multivariate regression analysis compared with patients randomized to placebo.
                These results do not support the clinical use of low-dose methotrexate in PBC.
There is insufficient data to support or reject the use of glucocorticosteroids for patients with primary biliary cirrhosis. It may be appropriate to consider a large prospective randomised clinical trial on this topic.