Methotrexate for primary biliary cirrhosis.
BACKGROUND
Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous.


OBJECTIVE
To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis.


METHODS
Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies.


METHODS
Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status.


METHODS
Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses.


RESULTS
We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate.


CONCLUSIONS
Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.
Gong
Y
Y
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Dept. 7102, Blegdamsvej 9, H:S Rigshospitalet, Copenhagen, Denmark, DK-2100. ygong@ctu.rh.dk
Gluud
C
C
D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000401:mortality; D016031:Liver Transplantation; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
D005493:Folic Acid Antagonists; D007166:Immunosuppressive Agents; D008727:Methotrexate