Treatment for rare liver disease increases mortality risk

Patients with primary biliary cirrhosis who are treated with methotrexate have an increased risk of death, according to a new systematic review of studies.

In five randomized controlled trials involving 457 people, the authors report that for patients treated with methotrexate, as a single therapy or in combination with other drug treatment, pooled data showed a tendency toward an increased risk of death or liver transplantation. The brand names for methotrexate are Rheumatrex and Trexall.

“ We do not advocate the use of methotrexate for patients with primary biliary cirrhosis,” conclude lead investigator Yan Gong, M.D., of Copenhagen University Hospital in Denmark and colleagues.
Their review appears in the latest issue of The Cochrane Library, a publication of the Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

The reviewers highlight the mortality and liver transplantation data from one long-term trial in which 11 of 30 patients in the methotrexate group died or underwent liver transplantation, compared with 7 of 30 patients in the placebo group. Combining data from this and another trial other showed that “…methotrexate had a significantly detrimental effect on mortality.”

Methotrexate works by blocking metabolism of cells and is effective in treating certain diseases characterized by abnormal cell growth, like breast cancer and psoriasis. Methotrexate is also widely used to treat rheumatoid arthritis.

Many drugs have been used to treat primary biliary cirrhosis, with ursodeoxycholic acid (a bile acid) the most frequently used. In contrast to methotrexate, the reviewers note that they saw no “significant effect of ursodeoxycholic acid on mortality or liver transplantation.”

Three of the trials compared the therapeutic use of ursodeoxycholic acid with and without methotrexate. One trial compared methotrexate to colchicine.

Primary biliary cirrhosis is an uncommon liver disease, and its cause is unknown, although it may be an autoimmune disease. Ninety percent of patients are women and most are diagnosed after the age of 40. It can be a precursor to cirrhosis of the liver or liver failure.

Studies over the past 30 years indicate an increasing prevalence of the disease, but little progress has been made in slowing disease progression. Primary biliary cirrhosis has become a frequent cause of liver morbidity, and patients with this condition are increasingly undergoing liver transplantation.

The Cochrane reviewers note that their conclusions could be qualified by the size of the data pool and the mixed quality of the studies involved. “Although the majority of the evidence did not point to a beneficial effect of methotrexate for patients with primary biliary cirrhosis,” they write, “we were not able to exclude the possibility for a beneficial effect in certain patient groups. We advise that any new placebo-controlled trials with methotrexate for patients with primary biliary cirrhosis should monitor harmful effects closely.

Keith Lindor, M.D., professor of medicine at the Mayo Medical School, says, “The most important finding in this review of the research is that methotrexate may indeed be harmful in the treatment of primary biliary cirrhosis. The drug should not be used outside of clinical trials, which will not likely be done with this drug because of the lack of efficacy and potential harm.”

Gong Y, Gluud C. Methotrexate for primary biliary cirrhosis. The Cochrane Database of Systematic Reviews 2005, Issue 3.