Ursodiol Plus Methotrexate Effective Long Term in Biliary Cirrhosis

Combination therapy consisting of ursodiol and either methotrexate or colchicine for primary biliary cirrhosis showed long-term effectiveness, lasting up to 20 years, wrote Dr. John Leung and his colleagues in the September issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2011.05.010).

Dr. Leung, of the department of gastroenterology at Tufts Medical Center, Boston, and his colleagues studied 29 patients with primary biliary cirrhosis, a chronic progressive disease thought to have an autoimmune etiology. The patients were originally part of an 85-patient, double-blind, prospective, randomized controlled trial comparing colchicine and methotrexate from 1988 to 2000, with ursodiol (ursodeoxycholic acid) added to that regimen 3 years after study initiation.

The patients examined in the current study had completed all 10 years of follow-up in the original trial. At completion, "the randomization code was broken and these 29 patients were treated according to their clinical response, personal preference, and tolerance to therapy."

They were then followed for an additional 9-13 years, either at the authors’ institution (21 patients) or via telephone calls and e-mail correspondence with referring physicians.

All patients except one were female, and the median age at the end of the initial 10-year randomized controlled trial (RCT) was 59 years.

According to the authors, of the 29 patients followed for 20 years, "Twenty-one patients are alive and well. Of these, 19 have normal tests of liver function and no signs of portal hypertension."

The outcomes were then analyzed by specific treatment regimen. Of the 11 patients on methotrexate plus ursodiol, "2 died of causes unrelated to liver disease at the age of 79 and 70, and 9 are alive and well," reported the authors. All nine of these patients have normal serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, and bilirubin.

Additionally, albumin levels have remained normal in eight patients; the ninth patient entered the initial trial 20 years ago with stage III biliary cirrhosis and now has a slightly decreased albumin level of 3.3 g/dL, along with portal hypertension and nonbleeding, grade 2 varices. This patient remains asymptomatic, however. Another patient receiving this regimen also developed grade 2 esophageal varices, also without bleeding.

There were 18 patients in the colchicine plus ursodiol group, and 12 were alive and well at the end of follow-up, reported the investigators. Of the remaining six, "three died of liver-unrelated causes at the age of 73, 76 and 76 respectively," wrote the authors. "They had normal biochemical tests and two had small esophageal varices at the end of the RCT."

Two patients with elevated liver enzymes at the end of the RCT underwent liver transplant; a third developed varices but was not a candidate for transplant, and died of pneumonia.

Overall, the investigators reported no treatment-related adverse events at the conclusion of follow-up.

"The results of this current study provide further evidence that combination therapy with [ursodiol], colchicine and [methotrexate] is durable and improves the natural history of primary biliary cirrhosis in a subset of primary biliary cirrhosis patients, including some who had histologically advanced liver disease at diagnosis," concluded the authors.

And while they conceded that it is impossible to determine whether the benefits were because of ursodiol, combination therapy, methotrexate, or colchicine alone, "the observations that liver function remained normal for 10 additional years and that very few patients developed portal hypertension suggests that combination therapy may have been effective."

Dr. Leung and his colleagues declared no outside funding for this study and no personal conflicts of interest.

Combination therapy consisting of ursodiol and either methotrexate or colchicine for primary biliary cirrhosis showed long-term effectiveness, lasting up to 20 years, wrote Dr. John Leung and his colleagues in the September issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2011.05.010).

Dr. Leung, of the department of gastroenterology at Tufts Medical Center, Boston, and his colleagues studied 29 patients with primary biliary cirrhosis, a chronic progressive disease thought to have an autoimmune etiology. The patients were originally part of an 85-patient, double-blind, prospective, randomized controlled trial comparing colchicine and methotrexate from 1988 to 2000, with ursodiol (ursodeoxycholic acid) added to that regimen 3 years after study initiation.

The patients examined in the current study had completed all 10 years of follow-up in the original trial. At completion, "the randomization code was broken and these 29 patients were treated according to their clinical response, personal preference, and tolerance to therapy."

They were then followed for an additional 9-13 years, either at the authors’ institution (21 patients) or via telephone calls and e-mail correspondence with referring physicians.

All patients except one were female, and the median age at the end of the initial 10-year randomized controlled trial (RCT) was 59 years.

According to the authors, of the 29 patients followed for 20 years, "Twenty-one patients are alive and well. Of these, 19 have normal tests of liver function and no signs of portal hypertension."

The outcomes were then analyzed by specific treatment regimen. Of the 11 patients on methotrexate plus ursodiol, "2 died of causes unrelated to liver disease at the age of 79 and 70, and 9 are alive and well," reported the authors. All nine of these patients have normal serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, and bilirubin.

Additionally, albumin levels have remained normal in eight patients; the ninth patient entered the initial trial 20 years ago with stage III biliary cirrhosis and now has a slightly decreased albumin level of 3.3 g/dL, along with portal hypertension and nonbleeding, grade 2 varices. This patient remains asymptomatic, however. Another patient receiving this regimen also developed grade 2 esophageal varices, also without bleeding.

There were 18 patients in the colchicine plus ursodiol group, and 12 were alive and well at the end of follow-up, reported the investigators. Of the remaining six, "three died of liver-unrelated causes at the age of 73, 76 and 76 respectively," wrote the authors. "They had normal biochemical tests and two had small esophageal varices at the end of the RCT."

Two patients with elevated liver enzymes at the end of the RCT underwent liver transplant; a third developed varices but was not a candidate for transplant, and died of pneumonia.

Overall, the investigators reported no treatment-related adverse events at the conclusion of follow-up.

"The results of this current study provide further evidence that combination therapy with [ursodiol], colchicine and [methotrexate] is durable and improves the natural history of primary biliary cirrhosis in a subset of primary biliary cirrhosis patients, including some who had histologically advanced liver disease at diagnosis," concluded the authors.

And while they conceded that it is impossible to determine whether the benefits were because of ursodiol, combination therapy, methotrexate, or colchicine alone, "the observations that liver function remained normal for 10 additional years and that very few patients developed portal hypertension suggests that combination therapy may have been effective."

Dr. Leung and his colleagues declared no outside funding for this study and no personal conflicts of interest.

Combination therapy consisting of ursodiol and either methotrexate or colchicine for primary biliary cirrhosis showed long-term effectiveness, lasting up to 20 years, wrote Dr. John Leung and his colleagues in the September issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2011.05.010).

Dr. Leung, of the department of gastroenterology at Tufts Medical Center, Boston, and his colleagues studied 29 patients with primary biliary cirrhosis, a chronic progressive disease thought to have an autoimmune etiology. The patients were originally part of an 85-patient, double-blind, prospective, randomized controlled trial comparing colchicine and methotrexate from 1988 to 2000, with ursodiol (ursodeoxycholic acid) added to that regimen 3 years after study initiation.

The patients examined in the current study had completed all 10 years of follow-up in the original trial. At completion, "the randomization code was broken and these 29 patients were treated according to their clinical response, personal preference, and tolerance to therapy."

They were then followed for an additional 9-13 years, either at the authors’ institution (21 patients) or via telephone calls and e-mail correspondence with referring physicians.

All patients except one were female, and the median age at the end of the initial 10-year randomized controlled trial (RCT) was 59 years.

According to the authors, of the 29 patients followed for 20 years, "Twenty-one patients are alive and well. Of these, 19 have normal tests of liver function and no signs of portal hypertension."

The outcomes were then analyzed by specific treatment regimen. Of the 11 patients on methotrexate plus ursodiol, "2 died of causes unrelated to liver disease at the age of 79 and 70, and 9 are alive and well," reported the authors. All nine of these patients have normal serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, and bilirubin.

Additionally, albumin levels have remained normal in eight patients; the ninth patient entered the initial trial 20 years ago with stage III biliary cirrhosis and now has a slightly decreased albumin level of 3.3 g/dL, along with portal hypertension and nonbleeding, grade 2 varices. This patient remains asymptomatic, however. Another patient receiving this regimen also developed grade 2 esophageal varices, also without bleeding.

There were 18 patients in the colchicine plus ursodiol group, and 12 were alive and well at the end of follow-up, reported the investigators. Of the remaining six, "three died of liver-unrelated causes at the age of 73, 76 and 76 respectively," wrote the authors. "They had normal biochemical tests and two had small esophageal varices at the end of the RCT."

Two patients with elevated liver enzymes at the end of the RCT underwent liver transplant; a third developed varices but was not a candidate for transplant, and died of pneumonia.

Overall, the investigators reported no treatment-related adverse events at the conclusion of follow-up.

"The results of this current study provide further evidence that combination therapy with [ursodiol], colchicine and [methotrexate] is durable and improves the natural history of primary biliary cirrhosis in a subset of primary biliary cirrhosis patients, including some who had histologically advanced liver disease at diagnosis," concluded the authors.

And while they conceded that it is impossible to determine whether the benefits were because of ursodiol, combination therapy, methotrexate, or colchicine alone, "the observations that liver function remained normal for 10 additional years and that very few patients developed portal hypertension suggests that combination therapy may have been effective."

Dr. Leung and his colleagues declared no outside funding for this study and no personal conflicts of interest.