In a letter to the editor in the Clinical Gastroenterology and Hepatology, the authors bring up some concerns with regard to a research article by Stokkeland et al about their study examining the association between exposure to various drugs and outcomes in patients with primary sclerosing cholangitis and inflammatory bowel disease (IBD). The authors of the letter to the editor concluded that further research on the subject matter is needed.

Stokkeland et al’s research outcomes indicated that statins and azathioprine decreased the risk for all-cause mortality and liver transplant or death in patients with primary sclerosing cholangitis and IBD. The letter authors point out some concerns and provide guidance as to what direction research should head.

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The letter authors’ first concern was how patients were identified as having primary sclerosing cholangitis. The researchers used the International Classification of Diseases code for cholangitis and IBD. The letter authors point out that based on earlier research, nearly half of the patients included in this study might not have had primary sclerosing cholangitis.

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The letter authors’ second concern was whether the statins reduced the risk for death by affecting cardiovascular diseases or primary sclerosing cholangitis itself. Data about the presence of cardiovascular disease and death would be beneficial to mention in the outcomes.

Their third concern was over a potential confounding issue — specifically, patients with milder primary sclerosing cholangitis and IBD were more likely to be prescribed statins. Patients with a mild form of the disease would have a lower risk for adverse outcomes from the start.

The fourth concern was the understated effect of azathioprine on outcomes. Azathioprine showed better hazard ratios than statins in all-cause mortality and affects T-cell signaling pathways, which potentially plays a pathogenic role in primary sclerosing cholangitis. In the article, the benefit of azathioprine was not highlighted.

The letter authors’ fifth concern was conflicting findings in regard to the relationship between acetylsalicylic acid and hepatobiliary cancer, death, and liver transplant.

The letter authors’ sixth concern was the potential for a type 1 error due to not correcting for multiplicity with 6 co-primary outcomes.

The authors concluded that “[t]his study provides a launchpad for further research evaluating the potential benefits, including repurposing, of existing drugs, and we look forward to seeing how this may take shape for this important area of need.”


  1. Fung BM, Ali AH, Tabibian JH. Associations between drug exposure and outcomes in patients with primary sclerosing cholangitis and inflammatory bowel disease [published online Oct. 5, 2019]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.09.044
  2. Stokkeland K, Höijer J, Bottai M, Söderberg-Löfdal K, Bergquist A. Statin use is associated with improved outcomes of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2019;17(9):1860-1866.