Primary Biliary Cirrhosis Treatment (PBC) (cont.)
John M. Vierling, MD, FACP
John M. Vierling, MD, FACP
John M. Vierling M.D. is Professor of Medicine and Surgery at the Baylor College of Medicine in Houston, Texas, where he also serves as Director of Baylor Liver Health and Chief of Hepatology. In addition, he is the Director of Advanced Liver Therapies, a center devoted to clinical research in hepatobiliary diseases at St. Luke's Episcopal Hospital. Dr. Vierling is board certified in internal medicine and gastroenterology and a Fellow of the American College of Physicians.
Leslie J. Schoenfield, MD, PhD
Leslie J. Schoenfield, MD, PhD
Dr. Schoenfield served as associate professor of medicine and consultant in gastroenterology on the faculty of the Mayo Clinic for seven years. He became a professor of medicine in residence at UCLA from 1972 to 1999 (now emeritus). He was the director of gastroenterology at Cedars-Sinai Medical Center in Los Angeles for 25 years, where he received the chief resident's teaching award, the president's award, and the pioneer of medicine award.
In this Article
Colchicine, a drug that reduces inflammation and scarring, has been used primarily to treat arthritis caused by gout. Three randomized, controlled trials in PBC showed that colchicine, compared to placebo, modestly slowed progression of abnormal blood tests, but did not reduce symptoms or prevent progression of liver pathology (tissue abnormalities on the biopsy). One of the trials actually suggested that colchicine improved survival. This impression of better survival with colchicine, however, has not been substantiated. In fact, the seemingly improved survival appears to be due to an unexpectedly high death rate (mortality) among the patients receiving the inactive drug in that study. The benefits of colchicine are so small that it is rarely recommended.
Immunosuppressive medications (for example, corticosteroids, azathioprine, cyclosporine, and methotrexate) suppress immune reactions. These medications are theoretically attractive agents to treat PBC, based on the concept that it is an autoimmune disease. Several randomized controlled studies have tested immunosuppressive drugs in PBC. However, none of these studies has demonstrated prolonged survival of patients.
Four immunosuppressive medications -- corticosteroids, azathioprine, cyclosporine and methotrexate -- are discussed below.
Corticosteroids: Corticosteroids (prednisone, prednisolone, budesonide) inhibit the initiation of immune responses, including those initial responses required for perpetuation of autoimmunity reactions. A randomized (treatment assigned by chance) controlled trial was carried out comparing a placebo with a low dose of prednisolone over a 3-year period. This study showed that prednisolone improved liver function and did not significantly increase the rate of bone thinning or demineralization. (Osteoporosis is a potential side effect of steroids). Another randomized trial compared UDCA and placebo with UDCA and prednisolone in patients with early stages of PBC. Although improvement in liver function was similar for both groups, only the combination of UDCA and prednisolone resulted in markedly improved liver biopsies.
It is noteworthy that the principal benefits of corticosteroids were seen in patients with early stages of the disease on liver biopsy. Still, these treatments did not result in a full remission or cure. Moreover, neither the size nor duration of these trials was sufficient to determine an effect on survival without liver transplantation. Accordingly, more data are needed to confirm the benefit and safety in PBC of steroids alone or in combination with UDCA. Nevertheless, these studies disproved an earlier notion that corticosteroids would cause rapid progression of the bone disease osteoporosis in patients with PBC.
Budesonide is a steroid that is more rapidly processed (metabolized) in the liver and, therefore, presumably would be less injurious to bone than other steroids. This drug was studied in selected patients with PBC who had had suboptimal (less than favorable) responses to UDCA. Unfortunately, budesonide was ineffective in this group. In fact it significantly worsened osteoporosis and did not prevent progression of the PBC. In contrast, a randomized trial comparing UDCA and placebo with a combination of budesonide and UDCA showed the combination to be more effective, while bone thinning (loss of mineral density) was comparable in the two groups. But here again, more data are needed to confirm the benefit and safety of this combination.
Azathioprine: Azathioprine (Imuran) prevents the production of new lymphocytes (white blood cells that take part in immune responses) by blocking cell division (reproduction) of the lymphocytes. The consequence of this action is to reduce the number of new inflammatory cells entering the sites of inflammation. A large study comparing the effect of azathioprine with an inactive drug (placebo) in 248 patients with PBC, however, showed no benefit. Consequently, this drug is not currently recommended for use in PBC patients outside of research protocols.
Cyclosporine: A powerful immunosuppressive drug, cyclosporine (Sandimmune, Neoral, Gengraf) is used primarily to prevent rejection of transplanted organs. The drug prevents production of an important signal required for lymphocytes to divide (reproduce) and generate inflammation. A large study of 349 PBC patients, comparing cyclosporine with an inactive drug, showed some benefit from the cyclosporine. The frequency of the side effects of high blood pressure and decreased kidney function, however, make this drug unacceptable for long-term use.
Methotrexate: Methotrexate both suppresses the immune system and prevents cells from dividing. This drug has been used successfully in severe rheumatoid arthritis and an immunologic skin disease called psoriasis. Initial limited trials in patients with PBC did not show a benefit, and serious side effects included ulcerations of the mouth, hair loss, and pneumonia. Additionally, preliminary reports of randomized, controlled trials of methotrexate therapy of PBC in Europe noted a higher than expected rate of a form of pneumonia that scars the lungs. Moreover, a recently published randomized, controlled trial of low dose methotrexate in PBC showed serious toxicity over a six-year period. Currently, a large trial in the United States comparing UDCA alone to a combination of UDCA and methotrexate is underway. At present, it is premature to recommend the use of methotrexate to treat PBC outside of clinical trials.
Medically Reviewed by a Doctor on 4/30/2014