Risk of Acute Pancreatitis in Users of Azathioprine: A Population-Based Case–Control Study Andrea Floyd, M.D., Lars Pedersen, Gunnar Lauge Nielsen, M.D., Ole Thorlacius-Ussing, Dr. Med. Sci., and Henrik Toft Sorensen, Dr. Med. Sci., Ph.D. Department of Clinical Epidemiology at Aalborg and Aarhus University Hospitals; Department of Gastrointestinal Surgery A, Aalborg University Hospital, Aalborg; Department of Medicine M, Aalborg University Hospital, Aalborg; and Department of Medicine V, Aarhus University Hospital, Aarhus, Denmark OBJECTIVE: Azathioprine has been linked to subsequent acute pancreatitis in several case reports and small case series. We examined the risk for acute pancreatitis in users of azathioprine in North Jutland County, Denmark, with about 490,000 inhabitants. METHODS: We identified patients with incident cases of acute pancreatitis from the Hospital Discharge Registry of the county from 1991–2000, and selected 10 controls per case, matched by age and sex, from the Central Personal Registry using incidence density sampling technique. All prescriptions of azathioprine within 90 days before admis- sion were likewise collected from the population-based North Jutland Prescription Database. Data on potential con- founders were extracted from registries. We used condi- tional logistic regression to adjust for confounding. RESULTS: A total of 1,388 patients and 13,836 controls were included in the study. We found that 1,317 persons in the entire population redeemed a total of 15,811 prescriptions of azathioprine in the county. The incidence rate for acute pancreatitis among all users of azathioprine was one per 659 treatment year. The crude OR of having redeemed prescrip- tions for azathioprine within 90 days before admission for acute pancreatitis was 7.5 (95% CI = 2.6 –21.6). After adjustment for gallstone disease, alcohol-related diseases, inflammatory bowel disease, and use of glucocorticoids, the OR increased to 8.4 (95% CI = 2.4 –29.4). The population- attributable risk, which measures the proportion of all cases of pancreatitis that are attributable to the use of azathioprine in our study population, was 0.4%. CONCLUSIONS: There was a substantially increased relative risk of acute pancreatitis in users of azathioprine. (Am J Gastroenterol 2003;98:1305–1308. © 2003 by Am. Coll. of Gastroenterology) INTRODUCTION Acute pancreatitis is a serious disease with a case fatality rate of up to 15% (1). Established risk factors include gallstones, alcohol consumption, hypercalcemia, hyper- lipidemia, trauma, ERCP, and probably certain drugs (2, 3). Azathioprine is an effective drug in maintaining remission for Crohn’s disease, with evidence for a steroid-sparing effect (4). Furthermore, it has been used in renal transplant patients, in the treatment of severe rheumatoid arthritis, and in chronic active hepatitis. Azathioprine has been linked to acute pancreatitis, but this alleged association has so far been based only on animal studies, case reports, and small case series (5–9). The mechanism of azathioprine-induced pancreatitis remains speculative. It has been attributed to a kind of hypersensitivity reaction (7) similar to that of 6-mer- captopurine-related pancreatitis (10). In an improved animal model, azathioprine causes deterioration of already compro- mized pancreatic microcirculation, thereby increasing ischemia and acinar cell injury (11). Given the morbidity and mortality associated with acute pancreatitis, estimates of its risk in patients using azathio- prine have important clinical and public health implications. We, therefore, conducted a population-based nested case– control study in Denmark to examine the risk of acute pancreatitis in patients who redeemed prescriptions for aza- thioprine, taking into account the use of other drugs and risk factors associated with acute pancreatitis. MATERIALS AND METHODS Study Population and Design We conducted this register-based nested case– control study within the population of North Jutland County, Denmark, with about 490,000 inhabitants, representing 9% of the Danish population. Cases of Acute Pancreatitis We used computerized hospital discharge data from the Hospital Discharge Registry in the county, from 1991–2000. This registry, established in 1977, includes civil registry numbers, dates of admission and discharge, surgical proce- dures performed, and up to 20 discharge diagnoses coded by medical doctors at discharge according to the Danish ver- sion of the International Classification of Diseases (ICD) (ICD-8 from 1977 to 1993 and ICD-10 from 1994; ICD-9 was never used in Denmark) (12). The following ICD-8 and ICD-10 codes were used to identify patients with acute pancreatitis: 577.00 –577.09 and K85.9. Dates of death and emigration were obtained from the Civil Registration Sys- THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 6, 2003 © 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00 Published by Elsevier Inc. doi:10.1016/S0002-9270(03)00233-8