ORIGINAL CONTRIBUTIONS
1
Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response Anna Reig, MD1, Pilar Sesé, RN1 and Albert Parés, MD, PhD1 OBJECTIVES:
Adding fibrates improves liver biochemistries in patients with primary biliary cholangitis (PBC) and suboptimal response to ursodeoxycholic acid (UDCA). As there are no consistent data regarding the course and outcome, we have assessed the effects of the combined treatment with UDCA and bezafibrate on a long-term basis.
METHODS:
A total of 48 patients (45 female) with PBC treated with UDCA and alkaline phosphatase (ALP) above 1.5 times upper normal levels (×UNL) were treated with bezafibrate (400 mg/day) plus UDCA (13–16 mg/kg/day). Changes in clinical features, liver biochemistries, and prognosis after therapy were assessed, as well as pruritus, using a visual analog scale (43 patients) and the 5-D descriptive pruritus scale.
RESULTS:
After a median of 38 months, 26 patients (54%) had normalized ALP. In these patients, jaundice, pruritus, and liver stiffness was lower, and age was higher than in patients who remained with elevated ALP. Biochemical improvement was less prominent in patients without ALP normalization. Five of these patients (23%) developed events of disease progression: 1 died, 3 were transplanted, and 1 developed hepatocellular carcinoma. Partial or complete itching relief was reported in all but one case with pruritus. Itching recurrence or worsening was observed after bezafibrate discontinuation.
CONCLUSIONS: The long-term treatment with UDCA and bezafibrate results in excellent response, and is associated
with a complete or partial itching relief. Incomplete ALP normalization was observed in patients with advanced disease who remained at risk for developing severe events. The combined treatment is mainly effective in patients with lower fibrosis and severity of cholestasis. Am J Gastroenterol advance online publication, 10 October 2017; doi:10.1038/ajg.2017.287
INTRODUCTION Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis (1), is a chronic cholestatic liver disease that may eventually result in severe illness, leading to death or liver transplantation (2,3). Despite the presumed autoimmune pathogenesis the effective therapies are those basically acting on improving cholestasis, mainly ursodeoxycholic acid (UDCA) (4), and more recently obeticholic acid (5). The favorable effects with a probability of survival free of transplantation have been reported with UDCA, but still a significant proportion of patients deserve further treatments addressed to improve outcome (4).
In the past two decades, fibrates, and particularly bezafibrate, commonly associated with UDCA, have demonstrated favorable effects in PBC, in terms of improving liver biochemistries with no or minor adverse effects (6–20). However, the studies lacked a significant number of patients, had low doses of UDCA, or a very short period of treatment. Moreover, a controlled study including a small number of patients indicated that long-term bezafibrate treatment may result in renal insufficiency (21). We have confirmed the encouraging effects of adding bezafibrate to UDCA for 1 year in 28 patients with PBC (20). Moreover, this report indicates that bezafibrate alleviated itching in 12 patients, an effect that resumed after bezafibrate discontinuation. Four cases
1
Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain. Correspondence: Albert Parés, MD, PhD, Liver Unit, Hospital Clínic, University of Barcelona, C/Villarroel 170, Barcelona 08036, Spain. E-mail: [email protected] Received 16 May 2017; accepted 1 August 2017
© 2017 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
LIVER
see related editorial on page x
LIVER
2
Reig et al.
with no pruritus at entry experienced pruritus within 3 months of bezafibrate discontinuation, a feature that disappeared after resuming the drug. Similar results have been observed in other studies with a very limited number of patients. Because there are no data on the long-term effects of adding bezafibrate to UDCA and no conclusive data regarding the potential consequences of bezafibrate on pruritus, we have carried out this prospective study on the one-center largest series of patients with PBC to assess changes in liver biochemistries, disease outcome, and detailed effect on pruritus.
METHODS A total of 48 patients with PBC (age 53.1; 46.3–60.8 years) treated for 8.3 (3.5–13.7) years with UDCA (13–16 mg/kg/day) who still had elevated alkaline phosphatase (ALP) and stable values during the previous 12 months were enrolled (28 of these patients participated in the previous report assessing the 1-year effect of bezafibrate (20)). All but 4 patients had antimitochondrial antibodies and 45 subjects had liver biopsy at diagnosis. No patient had simultaneous features of autoimmune hepatitis. Other causes of liver disease were excluded. This prospective study was designed to provide long-term efficacy in the use of combined treatment with UDCA and bezafibrate in patients with PBC and incomplete response to UDCA, according to the ALP levels (Barcelona criteria—normalization or 40% decrease in ALP after 1 year of treatment) (22), or patients with response but with ALP already elevated to 1.5 times upper normal values (×UNL). The study protocol complies with good clinical practice according to the Helsinki declaration and was approved by the institutional ethics committee. All study participants provided written informed consent. A single daily dosage of bezafibrate (400 mg) was added to the UDCA treatment. In 24 patients, bezafibrate was transitorily discontinued for 3 months after 1 year of therapy to assess changes in clinical and biochemical variables (reported previously) (20), and in 11 patients to assess changes in the severity of pruritus after bezafibrate discontinuation. Then, all the patients resumed bezafibrate therapy until the end of the observation period. Before adding bezafibrate (400 mg/day), a complete history and physical examination was recorded. Within the first year of bezafibrate therapy, clinical features and serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, γ -glutamyl transferase, ALP, creatinine, cholesterol, albumin, γ -globulin, and prothrombin index were measured every 3 months. Blood erythrocytes, leukocytes, and platelets were also measured. After the first year, clinical features and biochemical analyses were assessed every 6 months. In 43 patients, liver stiffness as an index of fibrosis was assessed before bezafibrate and at the end of observation. The recently developed PBC risk scores, APRI-r1 (aspartate aminotransferase/platelet ratio index at 1 year) (23), GLOBE (24), and UK-PBC (25), were calculated at baseline and at the end of the evaluation period to assess changes associated with bezafibrate therapy. The American Journal of GASTROENTEROLOGY
Presence and severity of pruritus was assessed before treatment and at the end of the observation period using a visual analog scale (VAS) (from 0 to 10) in 43 patients. Severity of pruritus was not recorded in three and two patients at entry or at the end of the observation period, respectively. The specific 5-D descriptive pruritus scale (26) and the VAS were measured in the 11 patients in whom changes in pruritus were evaluated during and after bezafibrate discontinuation. Statistical analysis
Continuous variables were expressed using the median and interquartile range. Categorical variables were expressed as numbers (percentages). As most data were nonnormally distributed, unpaired comparisons were performed using Mann–Whitney tests, and pairwise comparisons for baseline vs. posttreatment data were performed with Wilcoxon signed-rank tests. Differences in noncontinuous variables were analyzed by the χ 2 test. A two-sided P value of
1
Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response Anna Reig, MD1, Pilar Sesé, RN1 and Albert Parés, MD, PhD1 OBJECTIVES:
Adding fibrates improves liver biochemistries in patients with primary biliary cholangitis (PBC) and suboptimal response to ursodeoxycholic acid (UDCA). As there are no consistent data regarding the course and outcome, we have assessed the effects of the combined treatment with UDCA and bezafibrate on a long-term basis.
METHODS:
A total of 48 patients (45 female) with PBC treated with UDCA and alkaline phosphatase (ALP) above 1.5 times upper normal levels (×UNL) were treated with bezafibrate (400 mg/day) plus UDCA (13–16 mg/kg/day). Changes in clinical features, liver biochemistries, and prognosis after therapy were assessed, as well as pruritus, using a visual analog scale (43 patients) and the 5-D descriptive pruritus scale.
RESULTS:
After a median of 38 months, 26 patients (54%) had normalized ALP. In these patients, jaundice, pruritus, and liver stiffness was lower, and age was higher than in patients who remained with elevated ALP. Biochemical improvement was less prominent in patients without ALP normalization. Five of these patients (23%) developed events of disease progression: 1 died, 3 were transplanted, and 1 developed hepatocellular carcinoma. Partial or complete itching relief was reported in all but one case with pruritus. Itching recurrence or worsening was observed after bezafibrate discontinuation.
CONCLUSIONS: The long-term treatment with UDCA and bezafibrate results in excellent response, and is associated
with a complete or partial itching relief. Incomplete ALP normalization was observed in patients with advanced disease who remained at risk for developing severe events. The combined treatment is mainly effective in patients with lower fibrosis and severity of cholestasis. Am J Gastroenterol advance online publication, 10 October 2017; doi:10.1038/ajg.2017.287
INTRODUCTION Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis (1), is a chronic cholestatic liver disease that may eventually result in severe illness, leading to death or liver transplantation (2,3). Despite the presumed autoimmune pathogenesis the effective therapies are those basically acting on improving cholestasis, mainly ursodeoxycholic acid (UDCA) (4), and more recently obeticholic acid (5). The favorable effects with a probability of survival free of transplantation have been reported with UDCA, but still a significant proportion of patients deserve further treatments addressed to improve outcome (4).
In the past two decades, fibrates, and particularly bezafibrate, commonly associated with UDCA, have demonstrated favorable effects in PBC, in terms of improving liver biochemistries with no or minor adverse effects (6–20). However, the studies lacked a significant number of patients, had low doses of UDCA, or a very short period of treatment. Moreover, a controlled study including a small number of patients indicated that long-term bezafibrate treatment may result in renal insufficiency (21). We have confirmed the encouraging effects of adding bezafibrate to UDCA for 1 year in 28 patients with PBC (20). Moreover, this report indicates that bezafibrate alleviated itching in 12 patients, an effect that resumed after bezafibrate discontinuation. Four cases
1
Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain. Correspondence: Albert Parés, MD, PhD, Liver Unit, Hospital Clínic, University of Barcelona, C/Villarroel 170, Barcelona 08036, Spain. E-mail: [email protected] Received 16 May 2017; accepted 1 August 2017
© 2017 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
LIVER
see related editorial on page x
LIVER
2
Reig et al.
with no pruritus at entry experienced pruritus within 3 months of bezafibrate discontinuation, a feature that disappeared after resuming the drug. Similar results have been observed in other studies with a very limited number of patients. Because there are no data on the long-term effects of adding bezafibrate to UDCA and no conclusive data regarding the potential consequences of bezafibrate on pruritus, we have carried out this prospective study on the one-center largest series of patients with PBC to assess changes in liver biochemistries, disease outcome, and detailed effect on pruritus.
METHODS A total of 48 patients with PBC (age 53.1; 46.3–60.8 years) treated for 8.3 (3.5–13.7) years with UDCA (13–16 mg/kg/day) who still had elevated alkaline phosphatase (ALP) and stable values during the previous 12 months were enrolled (28 of these patients participated in the previous report assessing the 1-year effect of bezafibrate (20)). All but 4 patients had antimitochondrial antibodies and 45 subjects had liver biopsy at diagnosis. No patient had simultaneous features of autoimmune hepatitis. Other causes of liver disease were excluded. This prospective study was designed to provide long-term efficacy in the use of combined treatment with UDCA and bezafibrate in patients with PBC and incomplete response to UDCA, according to the ALP levels (Barcelona criteria—normalization or 40% decrease in ALP after 1 year of treatment) (22), or patients with response but with ALP already elevated to 1.5 times upper normal values (×UNL). The study protocol complies with good clinical practice according to the Helsinki declaration and was approved by the institutional ethics committee. All study participants provided written informed consent. A single daily dosage of bezafibrate (400 mg) was added to the UDCA treatment. In 24 patients, bezafibrate was transitorily discontinued for 3 months after 1 year of therapy to assess changes in clinical and biochemical variables (reported previously) (20), and in 11 patients to assess changes in the severity of pruritus after bezafibrate discontinuation. Then, all the patients resumed bezafibrate therapy until the end of the observation period. Before adding bezafibrate (400 mg/day), a complete history and physical examination was recorded. Within the first year of bezafibrate therapy, clinical features and serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, γ -glutamyl transferase, ALP, creatinine, cholesterol, albumin, γ -globulin, and prothrombin index were measured every 3 months. Blood erythrocytes, leukocytes, and platelets were also measured. After the first year, clinical features and biochemical analyses were assessed every 6 months. In 43 patients, liver stiffness as an index of fibrosis was assessed before bezafibrate and at the end of observation. The recently developed PBC risk scores, APRI-r1 (aspartate aminotransferase/platelet ratio index at 1 year) (23), GLOBE (24), and UK-PBC (25), were calculated at baseline and at the end of the evaluation period to assess changes associated with bezafibrate therapy. The American Journal of GASTROENTEROLOGY
Presence and severity of pruritus was assessed before treatment and at the end of the observation period using a visual analog scale (VAS) (from 0 to 10) in 43 patients. Severity of pruritus was not recorded in three and two patients at entry or at the end of the observation period, respectively. The specific 5-D descriptive pruritus scale (26) and the VAS were measured in the 11 patients in whom changes in pruritus were evaluated during and after bezafibrate discontinuation. Statistical analysis
Continuous variables were expressed using the median and interquartile range. Categorical variables were expressed as numbers (percentages). As most data were nonnormally distributed, unpaired comparisons were performed using Mann–Whitney tests, and pairwise comparisons for baseline vs. posttreatment data were performed with Wilcoxon signed-rank tests. Differences in noncontinuous variables were analyzed by the χ 2 test. A two-sided P value of
