The major thrust of this randomized, double-blinded clinical trial Is to determine whether treatment of patients with Primary Biliary Cirrhosis (PBC) with Ursodiol (Ursodeoxycholic Acid-UDCA) plus methotrexate (MTX) is more effective than treatment with UDCA alone. PBC is a chronic cholestatic liver disease, predominantly of women, in which interlobular and septal bile ducts undergo inflammation and destruction. Once initiated, the disease persists and progresses at varying rates. Neither the initiating nor perpetuating mechanisms are well understood. Current concepts of pathogenesis include (1) destruction of bile ducts is maintained and perhaps initiated by autoimmune mechanisms; (2) hydrophobic bile acids which accumulate in serum and liver cause functional and cytotoxic liver injury; (3) cytokines and lymphokines released at sites of inflammation may contribute to cell damage and fibrosis. A considerable body of evidence indicates that UDCA when fed orally leads to improvement in liver tests, in pruritus and in liver histology, particularly in patients whose serum bilirubin is less than 3 mg%. It is too early to determine if development of complications of liver disease, need for transplantation or survival is affected. UDCA, a relatively non-toxic bile acid, when administered orally, alters the composition of the bile acid pool in favor of its enrichment with UDCA and appears to protect against the cytotoxic effects of endogenous bile acids that accumulate as a result of bile duct destruction. MTX is being shown to improve liver tests, symptoms and liver histology in a small number of precirrhotic patients with PBC. The mechanism of action is unknown but felt to be related to antiinflammatory-immunosuppressive effects of MTX. The current proposal will explore whether MTX improves the therapeutic effects of UDCA in PBC. Patients with PBC whose serum bilirubin is less than 3 mg%, who have been on UDCA for at least 6 months, and who satisfy a series of inclusion and exclusion criteria will be stratified into 2 groups on the basis of liver histologic stage (Ludwig classification), i.e. early (Stages I or II) versus late (Stages III or IV). They will then be randomized to receive either methotrexate or its placebo as a second drug while continuing to receive UDCA. The relative value of the two treatment arms will be assessed by comparing their effects on symptoms, results of laboratory tests, development of complications of liver disease, histologic changes in liver, need for transplantation, and on survival. Safety of each therapeutic regimen will also be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK046602-01
Application #
3248004
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1993-04-01
Project End
1998-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mayo, Marlyn J; Parkes, Julie; Adams-Huet, Beverley et al. (2008) Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 48:1549-57
Peters, Marion G; Di Bisceglie, Adrian M; Kowdley, Kris V et al. (2007) Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis in the United States. Hepatology 46:769-75
Mayo, Marlyn J; Mosby, James M; Jeyarajah, Rohan et al. (2006) The relationship between hepatic immunoglobulin production and CD154 expression in chronic liver diseases. Liver Int 26:187-96
Combes, Burton; Emerson, Scott S; Flye, Nancy L et al. (2005) Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 42:1184-93
Browning, Jeff; Combes, Burton; Mayo, Marlyn J (2003) Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 98:2736-41
Mayo, M J; Lipsky, P E; Miller, S N et al. (2001) Similar T-cell oligoclonality in antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Dig Dis Sci 46:345-51
Mayo, M J; Jenkins, R N; Combes, B et al. (1999) Association of clonally expanded T cells with the syndrome of primary biliary cirrhosis and limited scleroderma. Hepatology 29:1635-42
Mayo, M J; Combes, B; Jenkins, R N (1996) T-cell receptor Vbeta gene utilization in primary biliary cirrhosis. Hepatology 24:1148-55