Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study.

BACKGROUND: Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited. AIMS: To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC. METHODS: Thirty-five patients with PSC were randomised in a double-blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase (ALK) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects (AEs). Nonparametric tests were used for analysis. RESULTS: The primary endpoint was reached in the low-dose (-43% change in ALK, P = 0.03) and high-dose (-40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low-dose metronidazole group (-20%, P = 0.03) and trended towards significance in the low-dose vancomycin group (-33%, P = 0.06). Mayo PSC risk score decreased significantly in the low-dose vancomycin (-0.55, P = 0.02) and low-dose metronidazole group (-0.16, P = 0.03). Pruritus decreased significantly in the high-dose metronidazole group (-3.4, P = 0.03). AEs led to medication discontinuation in six patients, four of whom were receiving metronidazole. CONCLUSIONS: Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer-term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis (clinicaltrials.gov NCT01085760).

A paragenetic perspective on integration of RNA silencing into the epigenome and its role in the biology of higher plants.

We describe features of RNA silencing and associated epigenetic imprints that illustrate potential roles for RNA interference (RNAi) in maintenance and transmission of epigenetic states between cells, throughout a plant, and perhaps even across sexual generations. Three types of transgenes can trigger RNAi of homologous endogenous plant genes: (1) "sense" transgenes that overexpress translatable transcripts, (2) inverted repeat (IR) transgenes that produce double-stranded RNA (dsRNA), and (3) antisense transgenes. Each mode of RNAi produces a different characteristic developmental silencing pattern. Single-copy transgenes are sufficient for sense-RNAi and antisense-RNAi, but not inverted repeat-RNAi. A single premature termination codon dramatically attenuates sense-RNAi, but it has no effect on antisense or inverted repeat-RNAi. We report here that antisense transgenes altered by removal of nonsense codons generate silencing patterns characteristic of sense-RNAi. Duplication of a sense overexpression transgene results in two types of epigenetic events: (1) complete loss of silencing and (2) altered developmental pattern of silencing. We also report that duplicating only the transgene promoter results in complete loss of silencing, whereas duplicating only transcribed sequences produces the second class, which are vein-based patterns. We infer that the latter class is due to systemic RNA silencing signals that interact with certain epigenetic states of the transgene to imprint it with information generated at a distance elsewhere in the plant.

Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile?

OBJECTIVE: The aim of this study was to assess the safety and efficacy of high-dose ursodeoxycholic acid (UDCA, 28-32 mg/kg/day) in patients with primary biliary cirrhosis (PBC) who had shown an incomplete response to the standard dose (13-15 mg/kg/day). METHODS: A total of 25 patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 24-141 months and had shown persistent elevation of ALP activity at least two times the upper limit of normal were enrolled. The dose of UDCA was increased to 30 (28-32) mg/kg/day and given for 1 yr. RESULTS: A significant but marginal improvement in serum ALP activity (707+/-52 vs 571+/-32, p = 0.001) was noted at 1 yr of treatment with high-dose UDCA. However, levels of total bilirubin (1.1+/-0.2 vs 1.0+/-0.2, p = 0.1), AST (58+/-9 vs 54+/-1, p = 0.1), albumin (4.1+/-0.7 vs 4.0+/-0.08, p = 0.1), or Mayo risk score (4.13+/-0.3 vs 4.12+/-0.3, p = 0.2) remained essentially unchanged. Normalization of liver tests did not occur in any patient, and adverse events were not recorded in any case. CONCLUSIONS: Although UDCA at a dose of 28-32 mg/kg/day is well tolerated, this dosage does not seem to benefit most patients with PBC responding incompletely to a dose of 13-15 mg/kg/day. The results of this pilot study would seem to discourage further controlled trials of high-dose UDCA in suboptimal responders to the standard dose of UDCA.

Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study.

OBJECTIVES: No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH. METHODS: Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine. RESULTS: A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients. CONCLUSIONS: Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial.

High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis.

OBJECTIVES: To assess the tolerability and efficacy of high-dose (25-30 mg/kg per day) ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). METHODS: Thirty patients with PSC were enrolled in this pilot study and treated for 1 yr. Changes in the Mayo risk score at 1 yr of treatment and projected survival at 4 yr were compared with that observed in patients randomized to placebo (n = 52) or UDCA (n = 53) at a dose of 13-15 mg/kg per day. RESULTS: A marked improvement in serum alkaline phosphatase activity (1265+/-172 vs 693+/-110 U/L, p < 0.001), AST (161+/-037 vs 77+/-13 U/L, p = 0.001), albumin (4.0+/-0.1 vs 4.2+/-0.1 g/dl, p = 0.03), and total bilirubin (1.6+/-0.3 vs 1.3+/-0.2 mg/dl, p = 0.1) occurred at 1 yr of therapy with high-dose UDCA. Changes in the Mayo risk score after 1 yr of treatment were significantly different among the three groups (p < 0.001), and these changes would be translated into a significantly different expected survival at 4 yr (p = 0.05). This expected survival at 4 yr was significantly different between placebo and the dose of 25-30 mg/kg per day (p = 0.04), but not between placebo and the dose of 13-15 mg/kg per day (p = 0.4). High-dose UDCA was well tolerated. CONCLUSIONS: UDCA at a dose of 25-30 mg/kg per day may be of benefit for patients with PSC, and this regimen deserves further evaluation in a long-term, randomized, placebo-controlled trial.

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial.

BACKGROUND/AIM: Osteoporosis is a common complication of primary biliary cirrhosis but there is no accepted therapy for the osteoporosis. In this randomized controlled trial, we compared the effects of etidronate to placebo on the treatment of osteoporosis associated with primary biliary cirrhosis. METHODS: Sixty-seven patients with primary biliary cirrhosis and osteopenia, defined by bone mineral density criteria (T-score < -2.0) were enrolled. Measurements of the lumbar spine and proximal femur, as well as x-rays of the lumbar spine, were obtained. Patients received cyclical etidronate 400 mg/day for 14 days every 3 months for at least 1 year. Supplemental calcium was administered on the days patients did not receive etidronate. RESULTS: Of the 67 patients entered, 60 completed at least 1 year of therapy. There was no significant difference in changes in bone density at either the lumbar spine or femur in patients receiving etidronate when compared to placebo. Fractures occurred in eight patients, four receiving etidronate. Etidronate therapy was associated with a significant reduction in markers of bone turnover compared to placebo. These changes did not correlate with changes in bone density. CONCLUSIONS: Cyclical etidronate administered with supplemental calcium did not significantly improve bone density in patients with primary biliary cirrhosis.

Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC), but some patients show an incomplete response. Silymarin is a potent antioxidant with immunomodulatory and antifibrotic properties. The aim of this study was to evaluate the safety and assess the efficacy of silymarin in patients with PBC who had shown a suboptimal response to UDCA. Twenty-seven patients with PBC who had been on UDCA (13-15 mg/kg/day) therapy for 7 to 221 months and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal for more than 6 months were enrolled. Oral silymarin, 140 mg 3 times daily was given for 1 year, and patients continued on the same dosage of UDCA. No significant changes in serum alkaline phosphatase activity (897 +/- 84 vs. 876 +/- 95, P =.5), total bilirubin (0.9 +/- 0.1 vs. 1 +/- 0.1, P =.07), aspartate transaminase (AST) (58 +/- 5 vs. 56 +/- 6, P =.4), albumin (4.0 +/-.06 vs. 4.1 +/-.06, P =.4), or Mayo risk score (3.82 +/- 0.2 vs. 3.88 +/- 0.2, P =.4) were noted after 1 year of treatment with combination therapy. Transitory gastrointestinal adverse events occurred in 2 patients. In conclusion, although silymarin was well tolerated, this medication did not provide benefit to patients with PBC responding suboptimally to UDCA. The results of this pilot study would seem to discourage further controlled trials of silymarin in patients with PBC.

Oral budesonide in the treatment of primary sclerosing cholangitis.

OBJECTIVE: This study was designed to evaluate the safety and estimate the efficacy of oral budesonide in patients with primary sclerosing cholangitis (PSC). METHODS: Twenty-one patients with PSC were treated with 9 mg daily of oral budesonide for 1 yr. RESULTS: Significant, but marginally important, improvement in serum alkaline phosphatase (1,235 +/- 190 vs 951 +/-206 U/L, p = 0.003) and AST levels (119 +/- 14 vs 103 +/- 19 U/L, p = 0.02) was noted at the end of the treatment period. Serum bilirubin levels increased significantly in the 18 patients who completed 1 yr of treatment (1.1 +/- 0.1 vs 1.4 +/- 0.3, p = 0.01) and no significant changes in liver tests were noted 3 months after budesonide was discontinued. The Mayo risk score did not change significantly, and although a significant improvement in the degree of portal inflammation was noted at the end of the treatment period, the degree of fibrosis and stage of disease were not significantly affected. There was a marked loss of bone mass of the femoral neck (0.851 +/- 0.02 vs 0.826 +/- 0.02 g/cm2, p = 0.002) and lumbar spine (1.042 +/- 0.02 vs 1.029 +/- 0.02 g/cm2, p = 0.09) at 1 yr of treatment with budesonide. Two patients required evaluation for liver transplantation during treatment, and two patients developed cosmetic side effects. CONCLUSIONS: Oral budesonide appears to be of minimal, if any, benefit and it is associated with a significant worsening of osteoporosis in patients with PSC.

Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC). However, some patients show an incomplete response to UDCA therapy. Treatment with corticosteroids may be of benefit although at the expense of systemic side effects. Budesonide, a corticosteroid with an extensive first-pass hepatic metabolism appeared promising for the treatment of PBC. The aim of this study was to evaluate the safety and estimate the efficacy of budesonide in patients with PBC, who have shown a suboptimal response to UDCA. Twenty-two patients with PBC, 16 women, median age of 50 who had been on UDCA (13-15 mg/kg/d) for a mean of 46 months (range 6-108 months) and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal were enrolled. Oral budesonide, 9 mg daily was administered for 1 year and patients continued on the same dosage of UDCA. There was a significant, but transitory improvement in serum levels of total bilirubin (P =.001) and a significant, but marginal improvement in serum alkaline phsophatase (P =.001) with combination therapy. The Mayo risk score increased significantly (P =.02) and there was a significant loss of bone mass (P <.001) of the lumbar spine. Budesonide-induced hyperglycemia and cosmetic adverse effects were noted in 2 patients. In conclusion, oral budesonide appears to add minimal, if any, additional benefit to UDCA, and it is associated with a significant worsening of osteoporosis in patients with PBC.

Directed cell-to-cell movement of functional proteins: do transcription factors double as signal molecules in plants?

Cell fate in plants is predominantly determined by position during development. Jorgensen discusses a new mechanism by which cells can regulate gene expression in neighboring cells. Several lines of evidence suggest that transcription factors expressed in one cell can traffic through plasmodesmata to regulate gene expression in adjacent cells that are not expressing the transcription factor themselves. In plants, some transcription factors appear to be intercellular signaling molecules, as well as intracellular regulators of gene expression.

Is routine cholangiography useful in men with suspected primary biliary cirrhosis?

The aim of this study was to assess the diagnostic value of cholangiography in men with chronic cholestasis and positive antimitochondrial antibody (AMA) titers who were suspected of having primary biliary cirrhosis (PBC). The authors reviewed retrospectively the records of men who had positive AMA titers over a 16-month period to determine the results of cholangiography. They also reviewed the records of 102 patients with primary sclerosing cholangitis (PSC) from 1989 to 1995 who had undergone cholangiography and testing for AMA. Of 35 men with positive tests for serum AMA, 12 of these patients were referred for cholangiography (11 endoscopic and 1 transhepatic). All completed cholangiograms were normal. A diagnosis of PBC was made in nine patients and atypical autoimmune hepatitis in one. Conversely, only two PSC patients had positive AMA titers (1:20 and 1:80). Both of these patients had coexisting inflammatory bowel disease and cholangiograms diagnostic of PSC. Cholangiography was negative in the male patients with positive AMA titers who were suspected of having PBC. In men with cholestatic liver biochemistries and strongly positive AMA titers, especially in the absence of associated inflammatory bowel disease, routine cholangiography does not add to the diagnostic evaluation.

Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial.

BACKGROUND/AIM: Ursodeoxycholic acid in doses of 13-15 mg x kg(-1) x day(-1), is a safe and cost-effective treatment for patients with primary biliary cirrhosis. However, very limited information exists regarding the most appropriate dose of ursodeoxycholic acid. The aim of the study was to compare three dosages of ursodeoxycholic acid with respect to changes in liver biochemistries, Mayo risk score, biliary enrichment with ursodeoxycholic acid and side effects over at least a 1-year period. METHODS: A total of 155 patients were randomized to receive low- (5-7 mg x kg(-1) x day(-1)), standard-(13-15 mg x kg(-1) x day(-1)), and high- (23-25 mg x kg(-1) x day(-1)) doses of ursodeoxycholic acid. RESULTS: The improvements in alkaline phosphatase (p = 0.0001), aspartate aminotransferase (p = 0.0001), Mayo risk score (p = 0.002), and ursodeoxycholic acid enrichment (p = 0.0001) were significantly greater in the standard- and high-dose groups compared to the low-dose group, but not between the standard- and high-dose groups. Changes in serum bilirubin were similar between the three groups (p = 0.07). No significant effects on symptoms were noted with any dose. No patients discontinued ursodeoxycholic acid because of side effects or toxicity. CONCLUSIONS: Ursodeoxycholic acid in doses of 5-25 mg x kg(-1) x day(-1) is safe and well tolerated. The dose of 13-15 mg x kg(-1) x day(-1) appears to be the preferred dose for patients with primary biliary cirrhosis.

Utilization of the Mayo risk score in patients with primary biliary cirrhosis receiving ursodeoxycholic acid.

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA) is an effective therapy for most patients with primary biliary cirrhosis (PBC). During the management of these treated patients, a number of clinically important issues arose including which patients might be candidates for combined therapy, which patients require endoscopy for variceal bleeding, and how survival can be predicted during treatment. Our aims were: 1) to identify factors associated with a suboptimal response to UDCA in patients with PBC; 2) to define a simple, non-invasive method to predict those PBC patients most apt to have esophageal varices; and 3) to determine the reliability of the Mayo survival model in predicting the course of UDCA treated patients. METHODS: We analyzed the prospectively collected data of 180 patients, who we continue to follow, with PBC who participated in a randomized, placebo-controlled trial of UDCA. RESULTS: After six months of UDCA therapy, patients with serum alkaline phosphatase levels less than twice normal (p < 0.04), and/or a Mayo risk score < 4.5 (p < 0.04) were more likely to respond favorably to treatment over a two year period. The Mayo risk score was the single risk factor independently predictive of development of varices (p < 0.01); 93% of patients who developed varices had a Mayo risk score > or = 4. The Mayo survival model, recalculated after 6 months on UDCA therapy accurately predicted patient survival. CONCLUSIONS: Suboptimal responders to UDCA can be identified by assessment of serum alkaline phosphatase levels, and/or Mayo risk score. A Mayo risk score above 4 helps in selecting patients for endoscopic surveillance for varices and the Mayo survival model accurately predicts the clinical course in patients with PBC receiving UDCA.

Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease frequently leading to development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) is a beneficial medical therapy for patients with PBC. Improvement in some histological features, but not in histological stage, has been reported after 2 years of UDCA therapy. Thus, longer follow-up may be necessary to determine whether UDCA has a favorable effect on histological stage of disease and progression to cirrhosis. Our aim was to determine the long-term effects of UDCA therapy on histological stage and progression to cirrhosis in patients with PBC. Sixteen unselected patients with noncirrhotic PBC who had been on long-term UDCA therapy (13-15 mg/kg/d) for 6.6 +/- 0.4 years (range, 5-9 years) were identified and their histological finding during treatment compared with that of 51 noncirrhotic patients with PBC who had received ineffective therapy (D-penicillamine [DPCA] or placebo) for 5.6 +/- 0.07 years (range, 5-8 years). Histological stage was determined using the Ludwig classification. The rate of progression to cirrhosis (stage 4) was significantly less in the UDCA group than in the control group (13% vs. 49%; P =.009). Although the overall rate of progression of histological stage was less in the UDCA group than in the control group (50% vs. 71%), this difference was not significant (P =.1). A marked improvement in liver biochemistries and Mayo risk score was noted in all patients during UDCA therapy; however, this improvement was not significantly different between patients who progressed and those who did not. In conclusion, long-term UDCA therapy appeared to delay the development of cirrhosis in PBC.

Oral nicotine in treatment of primary sclerosing cholangitis: a pilot study.

Currently, no accepted medical therapy for patients with primary sclerosing cholangitis (PSC) is available. Case-control studies have shown an inverse association between PSC and smoking behavior, suggesting that nicotine might have a beneficial effect in PSC. The aim of this study was to evaluate the safety and estimate the efficacy of oral nicotine in the treatment of PSC. Eight PSC patients who had never smoked received oral nicotine at a maximum dose of 6 mg four times a day for up to one year. Liver biochemistries and plasma cotinine levels were determined at entry and at three-month intervals during the study duration. Five patients completed one year of treatment, but three of them had to temporarily reduce the dose due to side effects. One patient completed only four months of treatment due to dizziness and heart palpitations. Two patients completed only one month of treatment due to reactivation of colitis requiring corticosteroid therapy. No significant changes in liver biochemistries were noted during the treatment period despite a significant increase in plasma cotinine levels. In conclusion, oral nicotine seems to have no beneficial effects in the treatment of PSC, and it is frequently associated with side effects necessitating permanent drug cessation.

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis.

OBJECTIVE: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.

Adjuvant cholylsarcosine during ursodeoxycholic acid treatment of primary biliary cirrhosis.

We postulated that coadministration of cholylsarcosine with ursodeoxycholic acid might provide additional benefit to primary biliary cirrhosis patients with an incomplete response to ursodeoxycholic acid. Our aim was to test the tolerability and the effect of adjuvant cholylsarcosine on liver tests and plasma cholesterol in primary biliary cirrhosis patients receiving ursodeoxycholic acid. Four primary biliary cirrhosis patients, who, despite more than a year of ursodeoxycholic acid therapy, had one or more liver tests persistently equal to or greater than twice the upper limit of normal, received cholylsarcosine (12-15 mg/kg/day) in addition to ursodeoxycholic acid (13-15 mg/kg/day) for six weeks in an open label study. Values of liver tests and plasma cholesterol, determined every two weeks, remained unchanged. One patient discontinued cholylsarcosine at week 4 because of new-onset pruritus. Analysis of duodenal bile acids in one patient showed 52% enrichment in cholylsarcosine and hydrophilic bile acids constituted 87% of total bile acids. It is concluded that the addition of cholylsarcosine to ursodeoxycholic acid did not influence liver tests in four primary biliary cirrhosis patients who had not responded completely to ursodeoxycholic acid alone. Cholylsarcosine was absorbed and became a dominant biliary bile acid; its administration was associated with increased pruritus.

Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy.

OBJECTIVES: A variety of autoimmune conditions occur in association with primary biliary cirrhosis. Among these conditions are sicca syndrome, Raynaud's phenomenon, arthritis, and Hashimoto's thyroiditis. Information is sparse regarding the prevalence and natural history of these conditions when associated with primary biliary cirrhosis and their response to ursodeoxycholic acid treatment. We evaluated the prevalence, natural history, and response to ursodeoxycholic acid therapy of these conditions coassociated with primary biliary cirrhosis. METHODS: One hundred-eighty patients with primary biliary cirrhosis, enrolled in a prospective randomized controlled trial of ursodeoxycholic acid (13-15 mg/ kg/day), were included. Patients were assessed at study entry and annually. RESULTS: At entry, 77/180 patients (43%) had one of the four conditions, and 18/180 patients (10%) had two or more conditions. Sicca syndrome was the most common, occurring in 58/180 patients (32%). After 2 yr, there was no difference between the treatment groups with regard to resolution or spontaneous onset of these autoimmune features. Sicca syndrome was the most common spontaneously developing condition (9% per yr). Sicca syndrome was the most common associated autoimmune condition, present in one-third of our patients. The associated conditions tended to improve over time, with a low rate of spontaneously developing these conditions. Although ursodeoxycholic acid therapy leads to improvement in the underlying liver disease, it did not appear to influence either the development or resolution of these autoimmune features. CONCLUSIONS: Although ursodeoxycholic acid is beneficial in the treatment of primary biliary cirrhosis, it had no measurable effect on the autoimmune conditions coassociated with the disease.