Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.
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.
Combes
Burton
B
The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9151, USA. Burton.Combes@UTSouthwestern.edu
Emerson
Scott S
SS
Flye
Nancy L
NL
Munoz
Santiago J
SJ
Luketic
Velimir A
VA
Mayo
Marlyn J
MJ
McCashland
Timothy M
TM
Zetterman
Rowen K
RK
Peters
Marion G
MG
Di Bisceglie
Adrian M
AM
Benner
Kent G
KG
Kowdley
Kris V
KV
Carithers
Robert L
RL
Rosoff
Leonard
L
Garcia-Tsao
Guadalupe
G
Boyer
James L
JL
Boyer
Thomas D
TD
Martinez
Enrique J
EJ
Bass
Nathan M
NM
Lake
John R
JR
Barnes
David S
DS
Bonacini
Maurizio
M
Lindsay
Karen L
KL
Mills
A Scott
AS
Markin
Rodney S
RS
Rubin
Raphael
R
West
A Brian
AB
Wheeler
Donald E
DE
Contos
Melissa J
MJ
Hofmann
Alan F
AF
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
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D008727:Methotrexate