title: Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.
abstract: This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.
authors.affiliation: The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9151, USA. Burton.Combes@UTSouthwestern.edu
authors.forename: Burton
authors.initials: B
authors.lastname: Combes
authors.forename: Scott S
authors.initials: SS
authors.lastname: Emerson
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Flye
authors.forename: Santiago J
authors.initials: SJ
authors.lastname: Munoz
authors.forename: Velimir A
authors.initials: VA
authors.lastname: Luketic
authors.forename: Marlyn J
authors.initials: MJ
authors.lastname: Mayo
authors.forename: Timothy M
authors.initials: TM
authors.lastname: McCashland
authors.forename: Rowen K
authors.initials: RK
authors.lastname: Zetterman
authors.forename: Marion G
authors.initials: MG
authors.lastname: Peters
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.forename: Kent G
authors.initials: KG
authors.lastname: Benner
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Robert L
authors.initials: RL
authors.lastname: Carithers
authors.forename: Leonard
authors.initials: L
authors.lastname: Rosoff
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Garcia-Tsao
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Boyer
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Martinez
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Bass
authors.forename: John R
authors.initials: JR
authors.lastname: Lake
authors.forename: David S
authors.initials: DS
authors.lastname: Barnes
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bonacini
authors.forename: Karen L
authors.initials: KL
authors.lastname: Lindsay
authors.forename: A Scott
authors.initials: AS
authors.lastname: Mills
authors.forename: Rodney S
authors.initials: RS
authors.lastname: Markin
authors.forename: Raphael
authors.initials: R
authors.lastname: Rubin
authors.forename: A Brian
authors.initials: AB
authors.lastname: West
authors.forename: Donald E
authors.initials: DE
authors.lastname: Wheeler
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Contos
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
mesh_terms: D000328:Adult; D000368:Aged; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis; D002756:Cholagogues and Choleretics / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004724:Endoscopy; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D015995:Prevalence; D016019:Survival Analysis; D017211:Treatment Failure; D014580:Ursodeoxycholic Acid / Q000009:adverse effects / Q000627:therapeutic use*; D014648:Varicose Veins / Q000453:epidemiology / Q000209:etiology / Q000473:pathology
chemical_list: D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D008727:Methotrexate