Treatment For Rare Liver Disease Increases Mortality Risk

In five randomized controlledtrials involving 457 people, the authors report that for patientstreated with methotrexate, as a single therapy or in combination withother drug treatment, pooled data showed a tendency toward an increasedrisk of death or liver transplantation. The brand names formethotrexate are Rheumatrex and Trexall.

“ We do not advocate theuse of methotrexate for patients with primary biliary cirrhosis,”conclude lead investigator Yan Gong, M.D., of Copenhagen UniversityHospital in Denmark and colleagues.
Their review appears in thelatest issue of The Cochrane Library, a publication of the CochraneCollaboration, an international organization that evaluates medicalresearch. Systematic reviews draw evidence based conclusions aboutmedical practice after considering both the content and quality ofexisting medical trials on a topic.

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

Methotrexateworks by blocking metabolism of cells and is effective in treatingcertain diseases characterized by abnormal cell growth, like breastcancer and psoriasis. Methotrexate is also widely used to treatrheumatoid arthritis.

Many drugs have been used to treat primarybiliary cirrhosis, with ursodeoxycholic acid (a bile acid) the mostfrequently used. In contrast to methotrexate, the reviewers note thatthey saw no “significant effect of ursodeoxycholic acid on mortality orliver transplantation.”

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

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

Studiesover the past 30 years indicate an increasing prevalence of thedisease, but little progress has been made in slowing diseaseprogression. Primary biliary cirrhosis has become a frequent cause ofliver morbidity, and patients with this condition are increasinglyundergoing liver transplantation.

The Cochrane reviewers notethat their conclusions could be qualified by the size of the data pooland the mixed quality of the studies involved. “Although the majorityof the evidence did not point to a beneficial effect of methotrexatefor patients with primary biliary cirrhosis,” they write, “we were notable to exclude the possibility for a beneficial effect in certainpatient groups. We advise that any new placebo-controlled trials withmethotrexate for patients with primary biliary cirrhosis should monitorharmful effects closely.

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

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