A Controlled Trial of Cyclosporine in the Treatment of Primary Biliary Cirrhosis

Primary biliary cirrhosis is a progressive disease of the liver characterized by the immunologic destruction of bile ducts; effective therapy is lacking. We therefore evaluated the safety and efficacy of low-dose cyclosporine in 29 patients with primary biliary cirrhosis without evidence of damage to the lobular architecture (precirrhotic disease) or portal hypertension. The patients were randomly assigned to receive either cyclosporine (4 mg per kilogram of body weight per day) or placebo. After one year 17 of the 19 patients assigned to cyclosporine had improvement or stability in their degree of fatigue, and 18 in their degree of pruritus. In contrast, among the 10 patients assigned to placebo, fatigue increased in 4 (P<0.06) and pruritus worsened in 6 (P<0.001). Those assigned to cyclosporine also had significant decreases in serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and the titer of antimitochondrial antibodies. For the 20 patients who have completed two years in the study, liver biopsies (coded specimens) showed evidence of histologic progression in only 1 of 13 patients in the cyclosporine group, as compared with 5 of 7 in the placebo group (P<0.003). No patient has permanently discontinued cyclosporine because of side effects; however, signs of nephrotoxicity developed in 12 of 19, and 9 of 19 had increased blood pressure. We conclude that in patients with precirrhotic primary biliary cirrhosis, immunosuppressive therapy with cyclosporine is promising and deserves further evaluation. PRIMARY biliary cirrhosis is a chronic, usually progressive cholestatic liver disease that occurs predominantly in middle-aged women.^{1 2 3} Although the pathogenesis of the disease is unknown, it is becoming apparent that autoimmune mechanisms play a major part in the destruction of interlobular and septal bile ducts that leads to chronic cholestasis, cirrhosis, and liver failure.^{4 5 6} There is currently no established effective therapy.⁶ Cyclosporine is an immunosuppressive agent that inhibits predominantly T lymphocyte—dependent immune responses by interfering with the synthesis of interleukin-2.^7,8 Cyclosporine has been shown to be effective in treating and preventing the rejection of allografts and in treating autoimmune diseases…