P1067 Comparison of AZA-Related Pancreatitis and AZA-Related GI Intolerance Based on Demographic Factors, Clinical Variables and HLA DQA1/DRB1 Alleles
Authors: Eskazan T , Bakkaloğlu O K , Toruner M , Kani H T , Cavus B , Yılmaz V , Ünal N G , Akyüz F , Atuğ Ö , Hatemi A İ , Yılmaz E , Dogruel M , Erzin Y , Çelik A F 
Published: January 2025

Abstract

Background
Azathioprine (AZA)-associated acute pancreatitis (AP) and gastrointestinal intolerance (GI-INT) are common causes of AZA discontinuation in IBD patients1,2. This study compares HLA alleles linked to AZA-AP3,4, along with demographic and clinical data, between AP and GI-INT patients.

Methods
Data from five IBD centers were used to form three groups: Control (n=88), AZA-AP (n=44), and GI-INT (n=44). Patients diagnosed with AP during AZA treatment per the Atlanta criteria (radiology, elevated amylase/lipase, and typical pain) were placed in the AZA-AP group. The GI-INT group included cases with pancreatitis-like symptoms lacking objective evidence, appearing within hours of AZA use and resolving very rapidly after stopping the medication. The impact of patients’ demographic data, disease characteristics, and HLA-DQA1/HLA-DRB1 allele status on AZA-AP and GI-INT were analyzed. Factors associated with AP (p&lt;0.1) were further evaluated using regression analysis.

Results
A total of 176 patients were evaluated, and their socio-demographic characteristics are summarized in Table 1. Crohn’s disease was the most common diagnosis. Female gender was more prevalent in the AZA-AP and GI-INT groups compared to controls (p=0.018 and p&lt;0.001, respectively). The AZA-AP group had a higher age at diagnosis than controls (p=0.016), but no difference was noted for the GI-INT group (p=0.15). Alcohol use and smoking were more common in the AZA-AP group. In the AZA-AP group, AP developed at a median of 4 weeks, with 91% of cases occurring within the first 3 months (AP onset occurred in one patient after 8 years and in another after 5 years). GI-INT developed at a median of 1 day, with a maximum onset time of 3 days. HLA-DQA1/DRB1 positivity was comparable between the GI-INT and control groups (9.2% vs. 14.8%; p=0.42) but was higher in the AZA-AP group (27.3% vs. 14.8%; p=0.08) (Table 1).
Regression analysis indicated that female gender, older age at diagnosis, active smoking, alcohol use, and HLA-DQA1/DRB1 positivity were independently associated with an increased AP risk (OR: 2.7, 95% CI: 1.008–7.221; p=0.048) (Table 2).
To prevent one case of pancreatitis, avoiding AZA in all individuals with the risk allele would mean that testing around 6 patients (NNTest) is necessary.

Conclusion
In IBD patients, azathioprine-associated pancreatitis most commonly occurs within the first 3 months of treatment and is independently associated with active smoking, alcohol use, female gender, and HLA-DQA1/DRB1 positivity. In contrast, GI intolerance typically begins within hours of the first dose, up to a maximum of 3 days, shows no significant demographic differences from the AZA-AP group, and is not associated with HLA-DQA1/DRB1 positivity.

References
1.Teich N, Mohl W, Bokemeyer B, et al. Azathioprine-induced Acute Pancreatitis in Patients with Inflammatory Bowel Diseases--A Prospective Study on Incidence and Severity. J Crohns Colitis. 2016;10(1):61-68. doi:10.1093/ecco-jcc/jjv188
2.Eskazan T, Bozcan S, Atay K, et al. Frequency, Predisposing Factors, and Clinical Outcome of Azathioprine-Induced Pancreatitis Among Patients With Inflammatory Bowel Disease: Results From a Tertiary Referral Center. Pancreas. 2021;50(9):1274-1280. doi:10.1097/MPA.0000000000001914
3.Wilson A, Wang Q, Choi YH, et al. Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study. Clin Transl Gastroenterol. 2021;12(4):e00332. Published 2021 Apr 5. doi:10.14309/ctg.0000000000000332
4.Heap GA, Weedon MN, Bewshea CM, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014;46(10):1131-1134. doi:10.1038/ng.3093