Frequency, Predisposing Factors, and Clinical Outcome of Azathioprine-Induced Pancreatitis Among Patients With Inflammatory Bowel Disease

Abstract

The aim of the study was to identify the frequency of azathioprine-induced acute pancreatitis (AZA-AP) and related factors.Methods: Seven hundred eighty-seven inflammatory bowel disease (IBD) patients on AZA therapy were retrospectively analyzed. Azathioprineinduced AP was diagnosed with positive imaging and/or an at least 3fold increased amylase level, in presence of typical abdominal pain. The AZA-AP group was compared with patients on AZA therapy with no history of pancreatitis and 4 numerical adjacent cases with the same diagnosis were selected (group B).Results: Fifty-four patients developed gastrointestinal symptoms (6.9%); however, only half of them (26 of 54) had pancreatitis, except 1, all within the first 2 months under AZA. When the AZA-AP group was compared with group B, only budesonide usage and active smoking were significantly more common in group A (46.2% vs 25%, P = 0.034, and 77% vs 51%, P = 0.017, respectively). Active smoking was the only independent risk factor for AZA-AP development (odds ratio, 3.208 [95% confidence interval, 1.192-8.632]). Conclusions:All IBD patients developed AZA-AP nearly all within the first 2 months. Azathioprine intolerance may be a hidden diagnosis in at least half of the patients with AZA-AP symptoms. All smoker IBD patients should be monitored closely for AZA-AP development.

Systematic review—pancreatic involvement in inflammatory bowel disease

“…The occurrence of AP due to thiopurines, namely azathioprine (AZA) and its active metabolite 6‐mercaptopurine has been described since the 1970s 9,25–31 . Since then, at least 16 studies explored this topic and were included in this systematic review 9,25–39 …”

“…In a prospective study, 24% presented nausea and vomiting, and 14% had fever, 43% of patients required hospitalisation with a median inpatient period of 5 days; only 10% of patients developed peripancreatic fluid collections, yet none required surgical/endoscopic intervention 28 . In a recent retrospective study on 787 IBD patients on AZA, the rate of abdominal pain was 6.9%, but only 3.3% of patients had AP, typically within the first 2 months of treatment, with active smoking being the only independent risk factor for AZA‐induced AP (OR = 3.2) 34 …”

“…9,[25][26][27][28][29][30][31] Since then, at least 16 studies explored this topic and were included in this systematic review. 9,[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] This side effect is reported in up to 7.3% of patients with IBD taking AZA in longitudinal prospective and retrospective studies, 27,28 while in a recent meta-analysis focusing on AZA and 6-mercaptopurine for maintenance of remission in ulcerative colitis a lower frequency, below 3%, was reported. 32 However, this meta-analysis was not focused on drug-induced AP, so it may underestimate its frequency; moreover, it seems that the incidence is higher in patients with CD compared to UC; the female gender is also associated with a 3.4-fold higher risk and smoking seems to be the strongest risk factor for thiopurine-induced AP.…”

Current Treatment of Myasthenia Gravis

“…Once remission is achieved, it is ideal to continue therapy for at least two to three years before attempting to taper or withdraw azathioprine with close follow-up to monitor for signs of relapse [ 70 ]. Potential adverse effects include flu-like symptoms, which may be experienced in up to 10% of patients, myelosuppression, abdominal discomfort, nausea, anorexia, hepatotoxicity, and pancreatitis [ 71 , 72 , 73 ]. Ten to 20 percent of patients may develop an idiosyncratic drug reaction, manifested by fever, malaise, and a picture reminiscent of sepsis shortly after starting azathioprine, which will necessitate immediate and permanent discontinuation of that medication [ 56 ].…”

“…As allopurinol inhibits xanthine oxidase, it increases the activity of azathioprine metabolites, which may result in severe leukopenia; therefore, the dose of azathioprine is to be reduced to 25–50% of the typical dose if patients on allopurinol [ 59 ]. Azathioprine-related pancreatitis is manifested as abdominal pain, elevated amylase levels >3 times, and positive imaging findings, and was significantly associated with smoking in a large cohort of patients with inflammatory bowel disease [ 73 ]. Biweekly monitoring of full blood count, chemistry panel, and liver function test is recommended upon starting or increasing the dose of azathioprine; after the patient is on a stable dose for 6 weeks, the frequency of monitoring can be reduced to monthly for 3 months, followed by every 3 months [ 59 , 74 ].…”