Efficacy and safety of immune-modulating therapy for primary sclerosing cholangitis: A systematic review and meta-analysis.

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease of unclear cause. Until now, there are no effective therapies for patients with PSC. A number of studies have evaluated the effects of immune-modulating therapies on the treatment of PSC. However, clinical benefits of these treatments in PSC patients are controversial and inconclusive. We performed a systematic review and meta-analysis to assess the efficacy and adverse effects of immunomodulators in adult patients with PSC based on prognostic markers (alkaline phosphatase (ALP) and total bilirubin), liver function marker (aspartate aminotransferase (AST)) and adverse event (AE) rates. Twenty-one studies (seven randomized controlled trials (RCT) and fourteen observational studies) involving 737 patients were included in this analysis. Immune-modulating therapies significantly reduced ALP level in PSC patients, but not to normal level. AST level was non-significantly decreased, while no effect was observed on total bilirubin level after treatments in PSC patients. In 16 studies reporting AEs, an average of 16.1% patients had severe AEs, resulting in discontinuation of therapies. Importantly, subgroup analysis further indicated that immune-modulating therapy significantly reduced ALP or AST levels in PSC patients with high baseline levels of ALP (over 420 U/L, > three times the upper limit of normal (ULN)) or AST (over 80 U/L, > two times the ULN), but had no effect in patients with low baseline levels. Compared to other immune-modulating therapies, immunosuppressants had the most significant effect on reducing ALP and AST levels in PSC patients but was associated with the highest incidence of severe AEs of 24.9%. Glucocorticoids showed a positive effect by significantly reducing ALP levels with the minimal AE rate of 6.1%. In conclusion, immune-modulating therapies could improve the prognostic marker of cholestasis (ALP level) in patients with PSC, especially in those of worse liver function. These findings suggest patients with high baseline level of ALP (>420 U/L) and AST (>80 U/L) respond better to immune-modulating therapy compared to those with low level of ALP and AST. Future RCTs would be needed to include different dosing regimens, a longer treatment duration and follow-up period, and patients stratified by liver function to obtain solid conclusion.