Methotrexate therapy for primary biliary cirrhosis

OBJECTIVE: Preliminary data suggested possible benefits of methotrexate in primary biliary cirrhosis. We assessed the effectiveness of methotrexate use in primary biliary cirrhosis and its tolerance in patients with this disease. METHODS: A total of 110 primary biliary cirrhosis patients began methotrexate 15 mg/wk; for most, ursodeoxycholic acid was added during the study. We analyzed data from patients completing 5 yr of treatment with methotrexate to assess its effect on biochemical and histologic parameters after 5 yr of therapy. Based on an intent to treat analysis, we also compared survival of our patients (n = 110) with that of patients in a previously published, placebo-controlled trial of ursodeoxycholic acid (n = 180). RESULTS: Only half of the study group completed 5 yr of methotrexate therapy. Therapy did not prevent progression of disease, as indicated by a rising Mayo risk score. Portal fibrosis tended to remain the same. Methotrexate did not diminish the risk of death or liver transplantation when compared with ursodeoxycholic acid or placebo; however, ursodeoxycholic acid use decreased the risk of death or transplant (p = 0.006). CONCLUSIONS: Methotrexate is not well tolerated in primary biliary cirrhosis. The toxicity of methotrexate and its inability to prevent complications of progressive liver disease or improve survival and the need for liver transplantation limits its utility. The benefits of ursodeoxycholic acid were again confirmed.     

Preventative therapy in primary biliary cirrhosis

Because the etiology of PBC is still unknown, therapies remain empirical. Moreover, no contributions on preventative therapy supported by evidence-based medicine have been published to date. However, there are at least two groups of subjects who might benefit from preventative therapy: (1) subjects with normal liver enzymes who are found AMA-positive during autoantibody screening and (2) subjects transplanted for PBC with no histologic or biochemical signs of disease recurrence. The key questions are whether any therapy should be proposed to these subjects, since the natural history of the disease is very long, and what kind of treatment should be prescribed. UDCA is a well-tolerated, definitely "physiologic" treatment, but it is expensive and two recent meta-analyses question its benefit on survival. Current theory considers PBC an autoimmune disease, with a genetic predisposition, possibly triggered by an infectious agent or xenobiotic. If this is so, gene therapies might be the most promising future preventative therapies. For the time being, however, the only practical preventative management is in regards to the complications of PBC, namely osteopenia and portal hypertension.     

Evidence-based therapy of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a disease which predominantly affects middle-aged women and is characterized by destruction of the interlobular bile ducts by chronic, often granulomatous, inflammation. This causes ductopenia and consequent cholestasis. Progressive fibrosis leads to cirrhosis and eventual liver failure. The frequent association of other autoimmune diseases and direct laboratory evidence of disturbed immune function suggest that PBC is an immune-mediated liver disease. Hence many clinical trials of therapy have employed immunosuppressive drugs. Another approach to therapy has been to reduce the degree of liver damage secondary to the cholestasis by altering the intra-hepatic bile acid milieu. These very different approaches to treatment of PBC are reviewed.     

Pruritus in primary biliary cirrhosis: pathogenesis and therapy

Pruritus is a symptom experienced by patients who have primary biliary cirrhosis. It seems to result from pruritogens that (as a result of cholestasis) accumulate in plasma and other tissues, and which lead to altered neurotrasnmission. Administration of medications that change opioid neurotransmission (ie, opiate antagonists) results in relief of pruritus and its behavioral manifestation, scratching. Through unknown mechanisms, other centrally acting medications, including antidepressants, may have ameliorating effects on the pruritus of cholestasis. Stimulating endogenous detoxification pathways in the liver may also lead to the amelioration of pruritus. The removal of pruritogens through administration of nonabsorbable resins, nasobiliary drainage, biliary diversion, plasmapheresis, and various dialysis procedures is reported to decrease pruritus in liver disease, although the substances that are presumably removed are unknown.     

Evaluation of colchicine therapy in primary biliary cirrhosis

We have conducted a double-blind controlled trial of colchicine in patients with primary biliary cirrhosis. Fifty-seven patients with biopsy-proven primary biliary cirrhosis were randomized to receive either 0.6 mg of colchicine twice daily or an identically appearing placebo. Patients underwent clinical and laboratory evaluation every 3 mo and liver biopsy annually. Differences in mean alkaline phosphatase and alanine aminotransferase values between the colchicine and placebo recipients were statistically significant at 4 yr. Differences in mean bilirubin and immunoglobulin M values, although lower in the colchicine group, did not reach statistical significance. In colchicine-treated patients, mean alkaline phosphatase values fell significantly compared with controls, from 281 to 112 IU/L (p less than 0.01). Similarly, mean alanine aminotransferase values fell significantly compared with controls, from 129 to 86 IU/L (p less than 0.05). Bilirubin values remained stable in drug-treated patients, even in those patients with initially elevated bilirubin values, whereas they nearly doubled in subjects receiving placebo. Although biochemical parameters of disease activity improved or stabilized in colchicine-treated subjects, no difference in histologic progression was detected between the two treatment groups. We conclude that colchicine is of clinical benefit to patients with primary biliary cirrhosis as judged by improvement in alkaline phosphatase and alanine aminotransferase activities as well as a tendency for stabilization of bilirubin values.     

Principles and perspectives of primary biliary cirrhosis therapy

A survey of existing methods of pathogenetic and symptomatic treatment of primary biliary cirrhosis has been made and it has reviewed prospective directions of its therapy. Is also presents a retrospective analysis of our own data of S-adenosylmethionine (Heptral) in 27 patients PBC receiving UDCA basic therapy. In its application intravenously of 400 mg 2 times daily for 3 weeks showed a reduction in the severity of pruritus, assessed by visual analogue scale, a subjective decrease fatigability and a decrease level of serum bilirubin.     

原发性胆汁性肝硬变的发病机制及药物治疗

原发性胆汁性肝硬变是由肝内外胆道系统长期胆汁瘀积引起的慢性进行性脂肪变性疾病.     

Antimitochondrial antibody‐negative primary biliary cirrhosis: a subset of primary biliary cirrhosis

Objective: Antimitochondrial antibodies (AMA) are the hallmark in primary biliary cirrhosis (PBC); nevertheless, it has long been recognized that 5–10% patients with typical features compatible with PBC do not have detectable AMA, and they were referred to as ‘AMA‐negative PBC’. This study aimed to evaluate whether AMA‐negative/positive PBC represents different clinical entities. Methods: We compared the clinical, laboratory, percentage of regulatory T cells (Tregs) in peripheral blood, liver biopsy features and response to treatment of the two groups of patients. The first group was comprised of 12 patients with ‘AMA‐negative PBC’. The second was made up of another 12 PBC patients with positive AMA. Results: Antimitochondrial antibodies‐negative/positive patients were remarkably similar in terms of clinical manifestations, liver biochemistries and histological findings. The frequency of anti‐nuclear antibodies, anti‐smooth‐muscle antibody, anti‐gp210 and anti‐sp100 antibody showed no significant difference between the two groups. A significantly lower mean percentage of CD4⁺CD25^high T cells was observed in peripheral blood mononuclear cells of AMA‐negative/positive PBC patients compared with that of the 12 control subjects (5.8±1.8 and 5.4±1.4% vs. 7.6±1.7% respectively; P=0.014 and 0.004). However, no difference could be found between AMA‐negative and AMA‐positive PBC patients (P=0.599). After 1 year treatment with ursodeoxycholic acid, the two groups showed similar response. Conclusion: Antimitochondrial antibody‐negative/positive PBC patients are similar in clinical, laboratory, percentage of Treg in peripheral blood, liver biopsy features and response to treatment. This suggests that AMA‐negative PBC may be a variant of AMA‐positive PBC rather than a separate clinical entity.     

B cell depletion therapy exacerbates murine primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of antimitochondrial antibodies (AMAs). Indeed, the presence of AMAs represents the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear. Therefore, although AMAs appear to interact with the biliary cell apotope and contribute to biliary pathology, there is no correlation of disease severity and titer of AMAs. The recent development of well-characterized monoclonal antibodies specific for the B cell populations, anti-CD20 and anti-CD79, and the development of a well-defined xenobiotic-induced model of autoimmune cholangitis prompted us to use these reagents and the model to address the contribution of B cells in the pathogenesis of murine PBC. Prior to the induction of autoimmune cholangitis, mice were treated with either anti-CD20, anti-CD79, or isotype-matched control monoclonal antibody and followed for B cell development, the appearance of AMAs, liver pathology, and cytokine production. Results of the studies reported herein show that the in vivo depletion of B cells using either anti-CD20 or anti-CD79 led to the development of a more severe form of cholangitis than observed in control mice, which is in contrast with results from several other autoimmune models that have documented an important therapeutic role of B cell-specific depletion. Anti-CD20/CD79-treated mice had increased liver T cell infiltrates and higher levels of proinflammatory cytokines. CONCLUSION: Our results reflect a novel disease-protective role of B cells in PBC and suggest that B cell depletion therapy in humans with PBC should be approached with caution.     

Treatment of primary biliary cirrhosis: therapy with choleretic and immunosuppressive agents

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune etiology affecting predominantly middle-aged women; it is a slowly progressive disease causing loss of intrahepatic bile ducts, resulting in advanced fibrosis, cirrhosis, and liver failure. Many drugs have been studied for treatment, including agents with choleretic and immunosuppressive properties. Ursodeoxycholic acid (UDCA) has been evaluated most widely. After liver failure, the only effective treatment is liver transplantation. Effective therapy reduces the need for transplantation and improves life expectancy. For advanced liver disease or incomplete response to UDCA, new therapies to cure or retard the progression of disease in PBC are needed.