Response to Cardinale et al

We appreciate the thoughtful letter by Cardinale et al (1) in response to our article, titled “Statin Use Is Associated With Protection Against Acute Cholangitis in Patients With Primary Sclerosing Cholangitis: A Multicenter Retrospective Cohort Study” (2). Our study focused on the prespecified hypothesis that statin use would reduce the risk of cholangitis among patients with primary sclerosing cholangitis (PSC). In a propensity-score matched national cohort, statins were associated with an ∼81% risk reduction in cholangitis ((hazard ratio 0.19, 95% confidence itnerval [CI] 0.03–0.64). Furthermore, statins were associated with a similar risk reduction in formation of new strictures, suggesting a biologically plausible mechanism for our findings as presented in the article. These findings were remarkably consistent in multiple secondary and sensitivity analyses. In addition to our primary and key secondary findings, we observed that bile acid sequestrants (BAS) were associated with a significantly increased risk of cholangitis (hazard ratio 2.98; 95% CI 1.77–4.87). As discussed in the article, patients receiving BAS often have cholestatic pruritus and may differ systematically from those without itching, raising the possibility of confounding by indication. We agree with Cardinale et al that further investigation of this association is warranted. Cardinale et al correctly note that we did not perform secondary analysis to examine the effect of BAS dose or duration. These analyses were outside of the scope of our prespecified primary and secondary analyses, but represent important directions for future work. Their proposed biological hypotheses, including potential effects on enterohepatic recirculation and antimicrobial defenses, are mechanistically plausible, although direct in vivo evidence remains lacking as they acknowledge. Finally, they note that the European Association for the Study of the Liver (EASL) guidelines do not recommend use of BAS and a randomized controlled trial of colesevelam in cholestatic-itching showed it was not effective (of note the trial examined only 35 patients) (3,4); notably EASL differs from the latest American Association for the Study of Liver Disease (AASLD) PSC guidelines, which still list BAS as first line in pruritic after attempting conservative measures (5). This reflects ongoing uncertainty and highlights the need, we also support, for additional data. We appreciate the thoughtful engagement and insights from Cardinale et al and we encourage further investigation into the possibility that BAS may truly increase the risk of cholangitis in patients with PSC. Given how commonly BAS are used in patients with PSC, additional investigation is of significant clinical relevance. CONFLICTS OF INTEREST Guarantor of the article: Sidhartha R. Sinha, MD. Specific author contributions: C.K.: wrote initial draft. S.S.: wrote and edited final response. Financial support: None to report. Potential competing interests: None to report.