Comparison of Azathioprine-Induced Pancreatitis and Gastrointestinal Intolerance in IBD: Role of Demographics, Clinical Variables, and HLA DQA1/DRB1 Alleles

<b>Background:</b> Azathioprine (AZA)-associated acute pancreatitis (AP) and gastrointestinal intolerance (GI-INT) are major causes of drug discontinuation in inflammatory bowel disease (IBD). This study compared HLA alleles, demographics, and clinical variables between AZA-AP and AZA-GI-INT. <b>Methods:</b> Data from five IBD centers included control (<i>n</i> = 88), AZA-AP (<i>n</i> = 44), and GI-INT (<i>n</i> = 44) groups. AP was defined by the Atlanta criteria, and GI-INT as acute dyspeptic symptoms related to AZA that resolved after withdrawal. Demographics, disease features, and HLA-DQA1/DRB1 alleles were assessed for associations. <b>Results:</b> Among 176 patients, female sex was more frequent in AZA-AP and GI-INT than controls (<i>p</i> = 0.018, <i>p</i> < 0.001). AZA-AP patients were older at diagnosis vs. controls (<i>p</i> = 0.016) but not vs. GI-INT (<i>p</i> = 0.15). Smoking and alcohol were more common in AZA-AP. The median onset of AP was four weeks, with 91% occurring within three months. GI-INT occurred rapidly, with a median of one day and a maximum of three days after the first dose. HLA-DQA1/DRB1 positivity was comparable in GI-INT and controls (9.2% vs. 14.8%, <i>p</i> = 0.42) but higher in AZA-AP (27.3% vs. 14.8%, <i>p</i> = 0.08). Regression identified female sex, smoking, alcohol, budesonide, and HLA-DQA1/DRB1 positivity (OR 3.01, 95% CI 1.004-9.058; <i>p</i> = 0.049) as independent risk factors for AZA-AP. <b>Conclusions:</b> AZA-AP, but not GI-INT, appears genetically influenced, with HLA-DQA1/DRB1 association extending across populations. In IBD, AZA-AP usually emerges within three months and is linked to female sex, smoking, alcohol, and budesonide. GI-INT typically develops within hours to three days of initiation. These findings support AZA-AP and GI-INT as distinct idiosyncratic entities shaped by genetic, metabolic, and sensitivity factors.