Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275-520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.

Figures

Figure 1. Conceptual model of the “PSC-microbiota” hypothesis and natural history of PSC

Biliary epithelial cells, i.e. cholangiocytes, exist in an environment with multiple potential etiologic mediators of hepatobiliary injury. A growing body of basic, translational, and clinical evidence suggests that among these, microbially-derived molecules may be central to hepatobiliary injury in and thus the etiopathogenesis of PSC. However, while (1) increased exposure to microbial molecules (e.g. through the enterohepatic circulation, facilitated by compromised intestinal barrier function), (2) alterations in microbial diversity and/or the repertoire of microbial molecules (e.g. due to intestinal microbial dysbiosis), (3) an aberrant or exaggerated cholangiocyte response to microbial molecules (e.g. induction of cholangiocyte senescence and the senescence-associated secretory phenotype), and (4) pro-injurious effects of microbial metabolites or abnormalities on non-cholangiocyte resident and recruited hepatic cells (e.g. leukocytes) have all been proposed, their roles remain incompletely understood. In addition, host immunogenetics likely modulate the impact of any of these variables (5) and thus likely play a role in determining whether hepatobiliary injury resolves or if it persists and results in chronic disease (i.e. PSC). These variables may also determine whether PSC progresses to its associated clinical endpoints, including development of cholangiocarcinoma, liver failure, and death. Oral antibiotics are believed to exert therapeutic effects through diversity of the enteric microbiota (1) and reducing synthesis and enterohepatic circulation (2) of dysbiotic microbial metabolites. Further investigation of the cellular, molecular, and microbial interactions proposed in this figure will undoubtedly be pursued in future research and are likely to advance current understanding of the etiopathogenesis of PSC. Key: CCA, cholangiocarcinoma; HLA, human leukocyte antigen; primary sclerosing cholangitis, PSC; TLR, toll-like receptor.

Figure 2. Serum alkaline phosphatase at baseline and after 12 weeks of rifaximin therapy

Following 12 weeks of rifaximin therapy, there was no clinically or statistically significant change in the primary endpoint, serum alkaline phosphatase (p=0.47). The median serum alkaline phosphatase following 12 weeks of rifaximin therapy among individuals who completed the study (318 U/L) was also not significantly different from baseline value (i.e. per-protocol analysis, p=0.81).