Original Article
A Controlled Trial of Cyclosporine in the Treatment of Primary Biliary Cirrhosis
N Engl J Med 1990; 322:1419-1424May 17, 1990
- Abstract
- Abstract
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. (N Engl J Med 1990; 322:1419–24.)
Media in This Article
Figure 1
Mean (±SEM) Changes in Serum Bilirubin, Alanine Aminotransferase (ALT), and Alkaline Phosphatase Levels.Figure 2
Mean (±SEM) Changes in Serum Gamma Globulin, IgG, and IgM Levels and the Reciprocal of the Antimitochondrial-Antibody (AMA) Titer.Article Activity
- Article
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 such as uveitis, rheumatoid arthritis, insulin-dependent diabetes mellitus, myasthenia gravis, and chronic active hepatitis.9 10 11 12 13 14 15
Preliminary studies in primary biliary cirrhosis have demonstrated that cyclosporine corrects suppressor-T-lymphocyte dysfunction and suppresses activated T lymphocytes and autoantibody levels, immunologic mechanisms whose pathogenic role in primary biliary cirrhosis has been hypothesized.16 , 17 Furthermore, clinical studies evaluating cyclosporine treatment for primary biliary cirrhosis have demonstrated short-term improvement in biochemical liver-function tests, including decreased serum levels of alkaline phosphatase and gamma-glutamyltransferase.18 , 19 In those studies, however, cyclosporine treatment was associated with significant increases in serum creatinine levels.
The aim of this study was to evaluate the efficacy and safety of low-dose cyclosporine in the treatment of primary biliary cirrhosis in patients with no evidence of portal hypertension or damage to the lobular architecture (precirrhotic disease), as assessed on peritoneoscopy and liver biopsy at study entry. Our underlying assumption was that immunosuppressive therapy would be most efficacious if administered before a critical number of interlobular and septal bile ducts had been immunologically destroyed.6
Methods
The selection criteria for enrolling patients with primary biliary cirrhosis in this study included the documentation of cholestatic biochemical abnormalities for six months, a serum alkaline phosphatase level two or more times normal, the presence of antimitochondrial antibodies, and results of liver biopsy and peritoneoscopy consistent with precirrhotic primary biliary cirrhosis.
Criteria for exclusion included evidence of esophageal varices on esophagogastroscopy, the demonstration of ascites on ultrasonography or peritoneoscopy, histologic features of cirrhosis on liver biopsy or peritoneoscopy, a serum creatinine level higher than 141 μmol per liter (1.6 mg per deciliter) or a rate of iothalamate clearance below 60 ml per minute, hypertension uncontrolled by therapy (systolic pressure higher than 160 mm Hg or diastolic pressure higher than 95 mm Hg), a history of neoplastic disease other than skin cancer, previous immunosuppressive therapy (prednisolone, chlorambucil, or azathioprine), and the presence of a coexisting liver disease documented on liver biopsy.
In our double-blind, controlled study, patients were randomly assigned to receive either cyclosporine or matching placebo. Two thirds of the patients with primary biliary cirrhosis received cyclosporine, and one third placebo.
Study Population and Dose of Cyclosporine
The study began on April 1, 1985, and patient accrual continued through February 1988. During this period 59 patients with primary biliary cirrhosis met our entry criteria, and 40 volunteered to participate. There were no differences in clinical symptoms, biochemical measures, or histologic stage between the 40 patients who participated in the study and the 19 who elected not to participate. This report describes the first 29 patients who entered the study. They have been followed for at least one year, and 20 of them have been followed for two years or more. At entry, the cyclosporine and placebo groups were very similar with regard to clinical, biochemical, and histologic indexes (Table 1Table 1
Comparison of Clinical, Biochemical, and Histologic Variables at Study Entry.*).Patients assigned to the cyclosporine group received an initial dosage of 4 mg per kilogram of body weight per day administered orally in two equal doses. In the patients who received cyclosporine, the mean maintenance dosage was 3.9 mg per kilogram per day administered orally in two equal doses. Cyclosporine trough levels in whole blood were maintained between 80 and 120 ng per milliliter, as measured by high-performance liquid chromatography.21 Cyclosporine trough levels in whole blood were monitored weekly for two months, then monthly throughout the study period in order to adjust the dosage to maintain the desired trough levels.
A physical examination was performed at entry, after 6 and 12 months, and annually thereafter. Liver-biochemistry studies were performed at entry and every three months throughout the study. Esophagogastroscopy and ultrasonography of the liver and abdomen were performed at entry and then annually for evidence of portal hypertension. Peritoneoscopy with a directed liver biopsy was performed in all the patients entering the study. Twenty patients completed two years in the study, and a protocol liver biopsy was then performed; peritoneoscopy and directed biopsy were performed in 13 of these patients, and a blind transthoracic percutaneous biopsy alone was performed in 7. Renal function was monitored by the measurement of serum creatinine levels at entry and at three-month intervals; an iothalamate-clearance study was undertaken at entry and at annual intervals.22 To monitor for hypertension, the patients were instructed to record their blood pressure on a daily basis for the first four weeks, and then three times a week for the length of the study. These results were sent to our nurse-coordinator and were reviewed by the investigators. Abnormal blood-pressure measurements were verified by the attending physician, and appropriate treatment was instituted as indicated clinically.
Each patient was questioned by the nurse-coordinator and by the attending hepatologist about symptoms of fatigue and pruritus at entry. Fatigue was graded according to the following classification: a score of 1 indicated no fatigue; 2 indicated mild fatigue that did not interfere with daily life (patient able to carry on with daily tasks); 3 indicated fatigue requiring extra rest, interfering with daily function but allowing full-time work; and 4 indicated fatigue that rendered the patient unable to work full time (eight hours a day) and that diminished the quality of life. Similarly, pruritus was graded as follows: none (scored as 1); noticeable but tolerable (2); occasionally interfering with sleep at night (3); and excoriations interfering markedly with sleep (4). Improvement was defined as a decrease of one or more grades from the level at entry. Stability was defined as no change from the level at entry, and progression as an increase of one or more grades.
All liver biopsies and peritoneoscopic examinations were performed by a single hepatologist, and liver histologic results were read by two study investigators with the clinical histories identified only by code. All liver-biopsy results were classified according to the histologic stages defined by Ludwig et al.20 Inflammation was graded on a scale of 1 to 4.
Treatment failure was defined as the documentation of cirrhosis on peritoneoscopy or liver biopsy; development of portal hypertension as evidenced by the presence of ascites on ultrasonography or peritoneoscopy; visualization of esophageal varices on esophagogastroscopy; death due to liver failure; or drug intolerance, toxicity, or both that required discontinuing the study medication.
The dosage of cyclosporine was modified according to the severity of the side effects noted. If the serum creatinine level rose above 141 μmol per liter or if blood pressure increased (a rise in systolic pressure of more than 25 mm Hg or a rise in diastolic pressure of more than 12 mm Hg), the dose of study medication was reduced by one third and the serum creatinine was measured again within seven days, the blood pressure was monitored daily, or both. If trough levels of cyclosporine were in the therapeutic range (80 to 120 ng per milliliter) and the increase in serum creatinine level or blood pressure did not correct itself after the reduction in dose, the study medication was discontinued until these values returned to pretreatment levels. Other known side effects thought to be related to cyclosporine toxicity, such as tremor, hirsutism, and gingival hyperplasia, were managed patient by patient. The study was approved by the institutional review board of the Mayo Clinic, and informed consent was given by all the patients.
Statistical Analysis
The drug and placebo regimens were compared with regard to their effects on clinical, biochemical, and histologic variables. Both parametric (Student's t-test) and nonparametric (Wilcoxon rank-sum test) methods were used to analyze differences before and after treatment between the cyclosporine and placebo groups. A two-tailed P value below 0.05 was considered to indicate a significant difference. In addition, the chi-square statistic was used to analyze differences in histologic progression between the cyclosporine and placebo groups.
Results
Clinical Symptoms
At entry, 17 of the 19 patients in the cyclosporine group and 9 of the 10 patients in the placebo group had symptoms of fatigue and pruritus. Cholestyramine therapy was administered to control pruritus in 12 of the 19 patients in the cyclosporine group and 5 of the 10 patients in the placebo group. After one year of therapy with cyclosporine, improvement or stability in the symptoms of fatigue was noted in 17 (89 percent) of the 19 patients (improvement was noted in 12) and in the symptoms of pruritus in 18 (95 percent) of the 19 patients (improvement in 16). In contrast, in the 10 patients in the placebo group fatigue and pruritus were worse after one year in 4 (40 percent; P<0.06) and 6 (60 percent; P<0.001), respectively. After one year of participation in the study, only 8 of the 19 patients in the cyclosporine group still used cholestyramine, whereas 8 of the 10 patients in the placebo group used the drug. Mean fatigue and pruritus scores decreased in the cyclosporine group, from entry scores of 1.0 and 1.2, respectively, to 0.6 and 0.4 after one year of therapy (P<0.005). In contrast, in the placebo group mean fatigue and pruritus scores increased from 1.0 and 1.1 at entry to 1.8 (P<0.02) and 1.9 (P<0.05) after one year.
Biochemical Measures
The effects of cyclosporine and placebo on biochemical liver-function and immunologic measures after one and two years are shown in Figures 1Figure 1
Mean (±SEM) Changes in Serum Bilirubin, Alanine Aminotransferase (ALT), and Alkaline Phosphatase Levels. and 2Figure 2Mean (±SEM) Changes in Serum Gamma Globulin, IgG, and IgM Levels and the Reciprocal of the Antimitochondrial-Antibody (AMA) Titer.. Mean laboratory values for both groups at entry are shown in Table 1. In the cyclosporine group as compared with the placebo group, there were significant decreases after one year in the mean (±SEM) serum levels of bilirubin (−3.42±1.71 vs. 13.68±5.13 μmol per liter; P<0.05), alanine aminotransferase (−38±11 vs. 10±6 U per liter; P<0.003), alkaline phosphatase (−438±+143 vs. 273±109 U per liter; P<0.007), gamma globulin (−5.0±1.0 vs. 1.0±1.0 g per liter; P<0.01), IgG (−2.70±1.28 vs. 2.84± 1.08 g per liter; P<0.007), and IgM (−3.24±0.99 vs. 0.84±0.40 g per liter; P<0.0002). There was also a significant decrease after two years in the antimitochondrial-antibody titer (reciprocal of the liter, −273±138 vs. 800±206; P<0.03). Furthermore, after one year the mean serum albumin level increased significantly in the cyclosporine group as compared with the placebo group (3.2±0.7 vs. 0.2±1.1 g per liter; P<0.04). The prothrombin time was normal in both groups at entry, and there were no differences between the two groups after one and two years.Histologic Assessment
Of the 20 patients followed for two years, 13 received cyclosporine, and 7 placebo. Only 1 of the 13 patients (8 percent) in the cyclosporine group had evidence of histologic progression after two years of therapy. That patient had histologic evidence of progression to cirrhosis, and treatment was therefore considered to have failed. In seven patients, the histologic stage did not change during treatment. However, evidence of histologic regression by one or more stages was found in five patients, sometimes with an appreciable decrease in inflammatory activity (Fig. 3Figure 3
Liver-Biopsy Specimens from a 52-Year-Old Woman with Primary Biliary Cirrhosis.).In contrast, five of seven patients (71 percent) in the placebo group had evidence of histologic progression by one or more stages on liver biopsy (P<0.003). Of the five who had histologic progression, four (80 percent) had evidence of progression to cirrhosis and thus met our criteria for treatment failure. The remaining two patients had no change in histologic stage; no patient in the placebo group had histologic regression.
Similarly, therapy with cyclosporine was associated with a decrease in inflammation in 10 of 13 patients (77 percent), whereas 6 of 7 patients (86 percent) in the placebo group had an increase in portal inflammation (P<0.001).
Treatment Failure
After a median follow-up of 2.7 years, seven patients met our criteria for treatment failure. Two were in the cyclosporine group, and five were in the placebo group. There have been no deaths in either group, but four patients have undergone liver transplantation for liver failure. In the cyclosporine group, portal hypertension developed in one patient in whom cirrhosis was identified on liver biopsy and esophageal varices on esophagogastroscopy. This patient had progression to liver failure and underwent liver transplantation. The second failure of treatment in the cyclosporine group involved a patient in whom uncontrolled hypertension developed after a prestudy history of essential hypertension controlled with medical therapy.
In the placebo group, five patients met the criteria for treatment failure. In four, there was histologic progression to cirrhosis; three of these patients had evidence of portal hypertension, and their condition progressed to liver failure necessitating liver transplantation. One patient in the placebo group left the study after six months because of an allergic reaction that may have been related to the placebo preparation.
Discontinuation of Therapy
In six patients the study medication had to be discontinued temporarily. Five of these patients were in the cyclosporine group. Therapy with cyclosporine was temporarily discontinued because of nephrotoxicity in three patients, in all of whom renal function returned to normal within one month. In addition, cyclosporine therapy was temporarily discontinued because of herpes stomatitis in one patient and because of the development of a pulmonary pseudolymphoma (T-cell type) in another. In the placebo group, the study medication was temporarily discontinued in one patient because of a recurrent vaginal yeast infection. In no instance was it necessary to discontinue cyclosporine therapy permanently because of toxic side effects.
Toxicity
Side effects occurred in both treatment groups, but they occurred predominantly in the patients receiving cyclosporine (Table 2Table 2
Side Effects Associated with Cyclosporine Therapy.). Nephrotoxicity occurred exclusively in the patients receiving cyclosporine. Of the 19 patients in the cyclosporine group followed for at least one year, 12 (63 percent) had serum creatinine levels above 141 μmol per liter and in 9 (47 percent) the rate of iothalamate clearance was below normal (70 ml per minute). In the cyclosporine group there was a significant decrease in the rate of iothalamate clearance after one and two years (Fig. 4Figure 4
Changes in Serum Creatinine Levels and Iothalamate Clearance.).Both the mean systolic and mean diastolic blood pressure increased significantly in the cyclosporine group from entry to one year. Mean (±SEM) systolic pressure increased from 122±3 to 133±6 mm Hg (P<0.05), and mean diastolic pressure increased from 77±4 to 84±4 mm Hg (P<0.05). In the placebo group there was no significant change in mean systolic or diastolic pressure after one and two years, as compared with levels at entry. In general, hypertension was easily controlled with medical therapy when indicated.
Other side effects that occurred more commonly in the cyclosporine group included tingling and numbness of the extremities, headache, hirsutism, and gingival hyperplasia. There were two infections. Herpes stomatitis developed in one patient taking cyclosporine and responded to treatment with acyclovir and the temporary discontinuation of cyclosporine. Recurrent vaginal yeast infections developed in one patient given placebo and rapidly responded to nystatin vaginal therapy. During the study, no bacterial or cytomegalovirus infections were noted.
Discussion
The preliminary results of our study are encouraging and suggest that low-dose cyclosporine therapy in patients with precirrhotic primary biliary cirrhosis may be clinically efficacious. Although a complete clinical, biochemical, and histologic remission was unusual in the patients with primary biliary cirrhosis who were treated with cyclosporine, symptoms of fatigue and pruritus often abated, and biochemical measures of liver function and immunologic markers of primary biliary cirrhosis frequently improved. Furthermore, follow-up liver biopsies performed in 13 patients after two years of therapy with cyclosporine demonstrated histologic stability in 7 patients and improvement in 5.
Previously evaluated immunosuppressive therapy for primary biliary cirrhosis has included azathioprine, chlorambucil, prednisolone, and more recently, methotrexate.23 24 25 26 27 Although many of these therapies have been associated with slight improvements in biochemical measures of liver function and some have been noted on liver biopsy to reduce inflammation, none of them have been associated with a sustained clinical, biochemical, and histologic remission.6 Furthermore, most immunosuppressive agents have been associated with substantial toxic side effects. For example, prednisolone therapy has been associated with the loss of bone mineral mass and the exacerbation of osteoporosis, chlorambucil therapy has been associated with bone marrow suppression, and methotrexate therapy has been associated with hepatic fibrosis and cirrhosis when used to treat psoriasis and other conditions.28
Other therapies evaluated for the treatment of primary biliary cirrhosis have included colchicine and, more recently, ursodiol.29 30 31 32 33 Colchicine therapy has improved biochemical measures of liver function, and it may prolong survival. However, colchicine therapy has not had a major effect on clinical symptoms, and it has had no effect on the histologic progression of disease. Similarly, ursodiol therapy has been associated with early improvement in pruritus and with biochemical improvement after short-term therapy. However, the effect of ursodiol on histologic progression and survival remains to be determined.
Therefore, as compared with other medical therapies for primary biliary cirrhosis, cyclosporine appears to be quite promising. However, despite the use of low doses of cyclosporine, a significant number of our patients with primary biliary cirrhosis had toxic side effects, of which nephrotoxicity and increased blood pressure were the most common. In most of these patients, reducing the dose or discontinuing cyclosporine was associated with the resolution of the side effects.
Although infection is a major side effect of cyclosporine therapy after organ transplantation, infectious complications were unusual in this study, possibly because of the low dose used.34 No cytomegalovirus infections were diagnosed in any of our patients, and only one patient had a herpes simplex infection, which resolved with the temporary discontinuation of cyclosporine. Although cyclosporine therapy appears to be promising in the treatment of precirrhotic primary biliary cirrhosis, the drug's side effects are a concern. In addition, the monitoring of drug levels and renal function that is required in patients treated with cyclosporine involves additional inconvenience and expense.
Our study is continuing in order to answer several important questions that remain with regard to cyclosporine therapy in primary biliary cirrhosis. What is its long-term efficacy? Does cyclosporine therapy over longer periods halt the histologic progression of the disease and prolong survival? What is the long-term nephrotoxicity, and will nephrotoxicity be progressive, reversible, or both? We hope that continuing this prospective clinical trial will enable us to answer these questions.
Supported by a grant from Sandoz and by the Mayo Foundation.
Presented at a meeting of the American Association for the Study of Liver Diseases, November 1 and 2, 1987, Chicago.
Source Information
From the Division of Gastroenterology and Hepatology and Section of Medical Pathology, Clinical Immunology, and Cell Kinetics, Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minn. Address reprint requests to Dr. Wiesner at the Mayo Clinic, 200 First St., S.W., Rochester, MN 55905.
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