Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis

Burton Combes, Scott S. Emerson, Nancy L. Flye, Santiago J. Munoz, Velimir A. Luketic, Marlyn J. Mayo, Timothy M McCashland, Rowen K Zetterman, Marion G. Peters, Adrian M. Di Bisceglie, Kent G. Benner, Kris V. Kowdley, Robert L. Carithers, Leonard Rosoff, Guadalupe Garcia-Tsao, James L. Boyer, Thomas D. Boyer, Enrique J. Martinez, Nathan M. Bass, John R. Lake & 10 others David S. Barnes, Maurizio Bonacini, Karen L. Lindsay, A. Scott Mills, Rodney Smith Markin, Raphael Rubin, A. Brian West, Donald E. Wheeler, Melissa J. Contos, Alan F. Hofmann

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

This placebo-controlled, randomized, multicenter trial compared me 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 encephalopamy; 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, encephalopamy, 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.

Original languageEnglish (US)
Pages (from-to)1184-1193
Number of pages10
JournalHepatology
Volume42
Issue number5
DOIs
StatePublished - Nov 1 2005

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Ursodeoxycholic Acid
Biliary Liver Cirrhosis
Methotrexate
Treatment Failure
Therapeutics
Bilirubin
Ascites
Serum Albumin
Clinical Trials Data Monitoring Committees
Transplantation
Placebos
Medical Futility
Hemorrhage
Body Surface Area
National Institutes of Health (U.S.)
Varicose Veins
Random Allocation
Drug-Related Side Effects and Adverse Reactions
Serum
Liver Transplantation

ASJC Scopus subject areas

  • Hepatology

Cite this

Combes, B., Emerson, S. S., Flye, N. L., Munoz, S. J., Luketic, V. A., Mayo, M. J., ... Hofmann, A. F. (2005). Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology, 42(5), 1184-1193. https://doi.org/10.1002/hep.20897

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. / Combes, Burton; Emerson, Scott S.; Flye, Nancy L.; Munoz, Santiago J.; Luketic, Velimir A.; Mayo, Marlyn J.; McCashland, Timothy M; Zetterman, Rowen K; Peters, Marion G.; Di Bisceglie, Adrian M.; Benner, Kent G.; Kowdley, Kris V.; Carithers, Robert L.; Rosoff, Leonard; Garcia-Tsao, Guadalupe; Boyer, James L.; Boyer, Thomas D.; Martinez, Enrique J.; Bass, Nathan M.; Lake, John R.; Barnes, David S.; Bonacini, Maurizio; Lindsay, Karen L.; Mills, A. Scott; Markin, Rodney Smith; Rubin, Raphael; West, A. Brian; Wheeler, Donald E.; Contos, Melissa J.; Hofmann, Alan F.

In: Hepatology, Vol. 42, No. 5, 01.11.2005, p. 1184-1193.

Research output: Contribution to journalArticle

Combes, B, Emerson, SS, Flye, NL, Munoz, SJ, Luketic, VA, Mayo, MJ, McCashland, TM, Zetterman, RK, Peters, MG, Di Bisceglie, AM, Benner, KG, Kowdley, KV, Carithers, RL, Rosoff, L, Garcia-Tsao, G, Boyer, JL, Boyer, TD, Martinez, EJ, Bass, NM, Lake, JR, Barnes, DS, Bonacini, M, Lindsay, KL, Mills, AS, Markin, RS, Rubin, R, West, AB, Wheeler, DE, Contos, MJ & Hofmann, AF 2005, 'Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis', Hepatology, vol. 42, no. 5, pp. 1184-1193. https://doi.org/10.1002/hep.20897
Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology. 2005 Nov 1;42(5):1184-1193. https://doi.org/10.1002/hep.20897
Combes, Burton ; Emerson, Scott S. ; Flye, Nancy L. ; Munoz, Santiago J. ; Luketic, Velimir A. ; Mayo, Marlyn J. ; McCashland, Timothy M ; Zetterman, Rowen K ; Peters, Marion G. ; Di Bisceglie, Adrian M. ; Benner, Kent G. ; Kowdley, Kris V. ; Carithers, Robert L. ; Rosoff, Leonard ; Garcia-Tsao, Guadalupe ; Boyer, James L. ; Boyer, Thomas D. ; Martinez, Enrique J. ; Bass, Nathan M. ; Lake, John R. ; Barnes, David S. ; Bonacini, Maurizio ; Lindsay, Karen L. ; Mills, A. Scott ; Markin, Rodney Smith ; Rubin, Raphael ; West, A. Brian ; Wheeler, Donald E. ; Contos, Melissa J. ; Hofmann, Alan F. / Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. In: Hepatology. 2005 ; Vol. 42, No. 5. pp. 1184-1193.
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title = "Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis",
abstract = "This placebo-controlled, randomized, multicenter trial compared me 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 encephalopamy; 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, encephalopamy, 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.",
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AU - Mayo, Marlyn J.

AU - McCashland, Timothy M

AU - Zetterman, Rowen K

AU - Peters, Marion G.

AU - Di Bisceglie, Adrian M.

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AU - Carithers, Robert L.

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AU - Martinez, Enrique J.

AU - Bass, Nathan M.

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AU - Bonacini, Maurizio

AU - Lindsay, Karen L.

AU - Mills, A. Scott

AU - Markin, Rodney Smith

AU - Rubin, Raphael

AU - West, A. Brian

AU - Wheeler, Donald E.

AU - Contos, Melissa J.

AU - Hofmann, Alan F.

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N2 - This placebo-controlled, randomized, multicenter trial compared me 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 encephalopamy; 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, encephalopamy, 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.

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