Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response.

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.

Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients.

UNLABELLED: Lifelong immunosuppression increases morbidity and mortality in liver transplantation. Discontinuation of immunosuppressive drugs could lessen this burden, but the safety, applicability, and clinical outcomes of this strategy need to be carefully defined. We enrolled 102 stable liver recipients at least 3 years after transplantation in a single-arm multicenter immunosuppression withdrawal trial. Drugs were gradually discontinued over a 6 to 9-month period. The primary endpoint was the development of operational tolerance, defined as successful immunosuppressive drug cessation maintained for at least 12 months with stable graft function and no histopathologic evidence of rejection. Out of the 98 recipients evaluated, 57 rejected and 41 successfully discontinued all immunosuppressive drugs. In nontolerant recipients rejection episodes were mild and resolved over 5.6 months (two nontolerant patients still exhibited mild gradually improving cholestasis at the end of follow-up). In tolerant recipients no progressive clinically significant histological damage was apparent in follow-up protocol biopsies performed up to 3 years following drug withdrawal. Tolerance was independently associated with time since transplantation (odds ratio [OR] 1.353; P = 0.0001), recipient age (OR 1.073; P = 0.009), and male gender (OR 4.657; P = 0.016). A predictive model incorporating the first two clinical variables identified subgroups of recipients with very high (79%), intermediate (30%-38%), and very low (0%) likelihood of successful withdrawal. CONCLUSION: When conducted at late timepoints after transplantation, immunosuppression withdrawal is successful in a high proportion of carefully selected liver recipients. A combination of clinical parameters could be useful to predict the success of this strategy. Additional prospective studies are now needed to confirm these results and to validate clinically applicable diagnostic biomarkers.