Application of a Systems Biology Approach to Address Confounding by Indication for Immune-mediated Disorders in Spontaneous Reports Data: A Case Study of Vedolizumab-associated Pancreatitis in Inflammatory Bowel Disease

Background: Vedolizumab, an integrin receptor antagonist (IRA), is indicated for the immune-mediated disorder inflammatory bowel disease (IBD). Patients with immune disorders are at risk of acute complications such as acute pancreatitis. Pancreatitis has been reported with vedolizumab, however, it is unclear whether the signal is due to vedolizumab or an independent risk of the condition in patients with IBD.

Objectives: To investigate whether vedolizumab is associated with pancreatitis using a systems biology approach in spontaneous reports data.

Methods: The FDA Adverse Event Reporting System (FAERS) database was used to undertake a disproportionality analysis of pancreatitis adverse event reports (2015-2020). Using a systems biology approach, we compared the proportion of pancreatitis reports with vedolizumab as primary suspect, with reports for 1) all other medicines, 2) other medicines with the same structural properties (monoclonal antibodies (mAbs)), 3) similar pharmacological mechanism (other IRAs) and 4) medicines for the same indication (Crohn's disease (CD) or ulcerative colitis (UC)). Disproportionality was assessed using the Information Component (IC) from Bayesian Confidence Propagation Neural Networks (reported on the ratio scale as 2^IC). A signal was identified where 2^IC>2 and the 95% Confidence Interval (CI) lower bound >1.

Results: No signal was identified for pancreatitis with vedolizumab compared to: all other medicines (2^IC 1.96, 95% CI 1.6-2.3), other IRAs (2^IC 1.75, 95%CI 1.6-1.9), restricting to CD (2^IC 1.0, 95% CI 0.7-1.3) or UC (2^IC 1.2, 95% CI 0.9-1.5). A signal was found when compared to reports for all other mAbs (2^IC 2.2, 95% CI 1.9-2.6).

Conclusions: This analysis suggests that vedolizumab is not likely to be independently associated with the risk of pancreatitis in patients with IBD. A systems biology approach can be employed to account for potential confounding by indication when investigating signals in immune-mediated disorders.