We evaluated how HLA-DQA1-HLA-DRB1-screening can identify inflammatory bowel disease (IBD) patients at high-risk of azathioprine (AZA)-induced pancreatitis, a severe drug side effect. This has been practice-changing for our regional gastroenterologists. Our algorithm for the safe use of AZA, accounting for HLA-DQA1-HLA-DRB1, has led to the near-complete elimination of AZA-induced pancreatitis in IBD patients within our region and was identified as a “test [that is] strongly recommended in IBD clinical practice” (Therapeutic Advances in Gastroenterology). This work was published in journals, Alimentary Pharmacology & Therapeutics and Clinical & Translational Gastroenterology. Funding related to this project made testing available to IBD patients across Ontario. It is now provided to more than 200 patients per year seen at the Western University Personalized Medicine Clinic. Testing is accessible to other patient populations at London Health Sciences Centre who are prescribed AZA.

Azathioprine (AZA) is an important inflammatory bowel disease (IBD) treatment. In Ontario, health policy requires IBD patients to fail drugs, like AZA, prior to using other therapies. AZA has side effects that include acute pancreatitis that occurs in up to 7% of AZA-exposed patients. We have shown an association between the HLADQA1-HLADRB1 gene and AZA-induced pancreatitis. We aimed to evaluate whether HLADQA1-HLADRB1-screening in an IBD population to guide AZA use would result in less AZA-induced pancreatitis, without compromising other disease outcomes.

IBD patients screened for HLADQA1-HLADRB1 prior to AZA initiation were compared to an unscreened cohort. The incidence of AZA-pancreatitis as well as other treatment outcomes were assessed.

In this first prospective study of 701 participants with IBD, we showed that AZA-induced pancreatitis is significantly reduced (11-fold) when HLADQA1-HLADRB1-screening is used. Additionally, we did not see an increased use of more expensive drugs or worsening clinical outcomes in the screened population. Our study demonstrates that a simple diagnostic test can be easily used in clinical practice and reliably reduce the incidence of a serious side effect.

This project will allow leadership to disseminate a novel patient treatment strategy that is supported by clear clinical evidence. Next steps include making this testing more accessible to regional and provincial gastroenterologists as well as other specialties where AZA is used for the management of non-IBD diseases.

Wilson A, Wang Q, Choi YH, Ponich T, Gregor JC, Chande N, Yan B, Sey M, Beaton M, Kim RB. Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study. Clin Transl Gastroenterol. 2021 Apr 5;12(4):e00332. doi: 10.14309/ctg.0000000000000332. PMID: 33821842; PMCID: PMC8345912.

Wilson A, Jansen LE, Rose RV, Gregor JC, Ponich T, Chande N, Khanna R, Yan B, Jairath V, Khanna N, Sey M, Beaton M, McIntosh K, Teft WA, Kim RB. HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2018 Mar;47(5):615-620. doi: 10.1111/apt.14483. Epub 2017 Dec 22. PMID: 29270995.

Wilson A, Jansen LE, Rose RV, Gregor JC, Ponich T, Chande N, Khanna R, Yan B, Jairath V, Khanna N, Sey M, Beaton M, McIntosh K, Teft WA, Kim RB. Letter: predicting azathioprine-associated pancreatitis in IBD-phenotype or genotype? Authors’ reply. Aliment Pharmacol Ther. 2018 Apr;47(7):1044-1045. doi: 10.1111/apt.14562. PMID: 29512906.