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Primary Sclerosing Cholangitis: Emerging New Promising Therapies

2000; Lippincott Williams & Wilkins; Volume: 31; Issue: 4 Linguagem: Inglês

10.1097/00004836-200012000-00001

1539-2031

Paul Angulo, Keith D. Lindor,

Liver Disease Diagnosis and Treatment

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease of uncertain etiology, is frequently associated with inflammatory bowel disease and is characterized by fibrosing, inflammatory destruction of intrahepatic and/or extrahepatic bile ducts. Primary sclerosing cholangitis is usually a slowly progressive disease, even in asymptomatic patients, leading to the development of biliary cirrhosis and its complications in approximately 10 to 15 years. 1 Although initially perceived by clinicians as a rare disease, PSC is being increasingly diagnosed and, currently, is among the most common indications for liver transplantation. 2 The etiology of PSC has been poorly understood since the earliest description of the disease. Several immune and nonimmune mechanisms in the context of a genetic predisposition have been proposed. Several cellular and humoral immune alterations support an immunologic disturbance as the most attractive underlying cause of PSC. Current thinking suggests that the disease occurs as a consequence of a genetically determined dysregulated immune system, resulting in an uncontrolled inflammatory response, fibrosis, and the destruction of bile ducts, leading to biliary cirrhosis. Nevertheless, the auto-and/or alloantigen(s) triggering this inflammatory response, which is selectively restricted to the bile ducts, remains unknown. Putative agents include bacterial antigens absorbed through a diseased bowel mucosa, cytotoxic bile acids, and viral infections. Patients with PSC frequently have elevated levels of immunoglobulins, including a variety of nonorgan-specific autoantibodies, as well as increased levels of serum and biliary immune complexes, activation of the complement system, and abnormal clearance of immune complexes from the circulation. All of this evidence, albeit still circumstantial, gives strong support to an autoimmune cause of PSC. 2,3 Over the past two decades, several drugs with different mechanisms and potential benefit in PSC have been evaluated alone or in combination therapy 5–27 (Table 1). However, none of these drugs has been proven to have long-term benefits and some are associated with a significant rate of adverse events. The diversity of drugs evaluated in the treatment of PSC over time is a clear reflection of our lack of knowledge regarding the etiopathogenesis of this condition, as well as the imperative need for an effective medical treatment.TABLE 1: Drugs evaluated in the treatment of primary sclerosing cholangitisIn this issue of the Journal of Clinical Gastroenterology, Duchini et al. 4 report their experience with four patients with cholangiography-and liver biopsy-proven PSC treated with cladibrine, an antineoplastic nucleoside analogue with antilymphocytic and immunosuppressive activities. Cladibrine was given monthly in three cycles of 5 days, and patients were followed for 2 years. As expected, a significant decrease in peripheral lymphocyte cell count occurred during treatment. Improvement in the severity of pruritus was noted in two patients, although it is uncertain whether they were given any other anti-itching medications. No significant changes in liver tests were noted during treatment; although, at the end of the follow-up, serum bilirubin levels, an important prognostic marker in PSC tended to increase. The severity of inflammation on liver biopsy was reduced with therapy, but the degree of inflammation returned to pretreatment at the end of the 2 years of follow-up. The degree of fibrosis, the most worrisome feature to appear on liver biopsy in patients with PSC, increased at the end of follow-up and progression to cirrhotic stage was seen in one case. Similarly, the degree of bile duct involvement, as assessed on endoscopic cholangiographic images, remained essentially unchanged at the end of follow-up. The improvement in the degree of inflammation appearing on liver biopsy that was achieved during treatment with cladibrine was not maintained at 2 years of follow-up. Thus, it is conceivable that a longer treatment period may be necessary to see a real long-term benefit of this medication regarding the degree of inflammation. This improvement in the degree of inflammation, in theory, would improve the severity of cholestasis and perhaps slow the progression to cirrhosis. Unfortunately, given the short period of treatment with cladibrine, the potential long-term benefit of this medication in PSC could not be determined. Also, given the fact that only four patients were studied, we cannot completely exclude the possibility of sampling error on liver biopsies. Because PSC is a disease that progresses slowly over many years, regression or any impact on inhibiting inflammation and/or fibrosis may also take a number of years to show an effect. Hence, it is unlikely that the positive response obtained during treatment with a drug given for a short period of time would be maintained long enough after treatment to have an impact in arresting the natural progression of the disease. Unfortunately, given the lack of information regarding the safety of cladibrine in patients with chronic cholestatic liver diseases such as PSC, the potential toxicity of this medication may preclude researchers from its evaluation in a long-term trial, as has been the case with other drugs previously evaluated in the treatment of PSC. The drug that has received the most attention in PSC treatment is ursodeoxycholic acid (UDCA). In most trials, UDCA (at doses varying from 10 to 15 mg/kg/d) has been shown to improve liver biochemistries, at least in the short term. 5–9 In the largest randomized controlled trial of UDCA in the treatment of PSC (13–15 mg/kg/d), there was a significant improvement in liver tests relative to placebo, but this improvement was not accompanied by beneficial changes on clinically relevant outcomes after as much as 6 years of follow-up. 9 Thus, in the absence of clinical response, it is difficult to recommend the routine use of UDCA in patients with PSC. Higher dosages of UDCA (20–30 mg/kg/d) appeared to be more effective in two pilot trials. 10,11 A significantly greater improvement in liver tests and liver histology was achieved with the dose of 20 mg/kg/d in one study. 10 Another study 11 found not only a significant biochemical improvement with the dose of 25 to 30 mg/kg/d but also a significant improvement in the Mayo risk score, an accurate surrogate prognostic marker in PSC. This improvement in the Mayo risk score translates into a projected significant improvement in survival at 4 years, which was not seen with the dose of 13 to 15 mg/kg/d. 11 Thus, the potential therapeutic benefit of higher-dosage UDCA should be evaluated in a large, randomized, placebo-controlled trial. The close association between PSC and inflammatory bowel disease had led to the hypothesis that chronic portal bacteremia might cause chronic infection of bile ducts, inflammation, portal fibrosis, and ultimately, PSC. Furthermore, hepatobiliary lesions resembling PSC in humans were found in an animal model of small bowel bacterial overgrowth. 28 In this model, the absorption of peptidoglycan-polysaccharide, a bacterial wall cell product, led to Kupffer cells activation with the consequent increased production of tumor necrosis factor alpha (TNF-α). The development of hepatobiliary damage was prevented by the administration of an anti–TNF-α αrug that suppressed the release of this cytokine by Kupffer cells. 29 These findings support the theory that the absorption of bacterial endotoxins through a diseased intestinal mucosa might be a potential antigen source in genetically predisposed individuals, leading to the development of PSC. Although, the role of portal bacteremia, TNF-α and other cytokine growth factors as contributing pathogenic factors in PSC in humans remains uncertain, the potential therapeutic implications of modifying this cytokine environment in patients with PSC deserves further evaluation. The only clinical trial reported to date evaluating a drug with anti–TNF-α properties, pentoxifylline, showed no evidence of benefit. 23 However, the anti-TNF action of pentoxifylline may be too weak for patients with PSC. In this regard, other new, more potent anti-TNF drugs (e.g., monoclonal antibodies, recently approved for the treatment of inflammatory bowel disease) warrant evaluation as a therapy for PSC. As seen in Table 1, drugs other than high-dosage UDCA that may hold promise in the treatment of PSC are tacrolimus (FK506), corticosteroids, and the combination of UDCA, prednisone, and azathioprine. The positive biochemical response achieved with treatment with tacrolimus (FK506) 16 and with the combination of UDCA, prednisone, and azathioprine 27 may warrant further evaluation in a randomized, controlled trial. However, the potential therapeutic benefits from corticosteroids are usually outweighed by the high incidence of adverse events in patients with chronic cholestasis, in particular the worsening of bone disease. 19,26 Budesonide, a corticosteroid with a high first-order hepatic metabolism and theoretically minimal systemic availability, not only showed no benefit but led to a significant loss of bone mass in patients with PSC. 19 Despite the multiple methodological limitations of a small case series report, the study by Duchini et al. 4 represents another attempt to identify a drug that, based upon its mechanism(s) of action, may hold promise as a therapy for patients with PSC, who to date, are usually destined to progress and succumb from end-stage liver disease unless liver transplantation is performed. A better understanding of the molecular basis of the genetic and autoimmune milieu involved in PSC is a prerequisite to clarify the pathogenesis of PSC and to devise rational and effective medical therapies. Emerging data from clinical trials in the forthcoming years will better define the potential therapeutic benefit of promising drugs (e.g., new immunosuppressants, antioxidants, antifibrotic, and high dosage of UDCA, alone or in combination therapy) in the treatment of patients with PSC. The initial information provided by pilot studies, albeit insufficient on which to base recommendations for routine administration of a drug, will help in the design of randomized, controlled trials. As the results of these trials become available, physicians will be in a better position to determine appropriate treatment of patients with PSC.