IL-6R Inhibitors and Gastrointestinal Perforations: A Pharmacovigilance Study and a Predicting Nomogram

Objective IL-6R inhibitors are widely used in many inflammation-related diseases, especially so during the COVID-19 pandemic. However, their relationship with gastrointestinal perforations (GIPs) has been reported more and more. We comprehensively analyzed IL-6R inhibitors in association with GIPs from the United States FDA Adverse Event Reporting System (FAERS). Methods: A disproportionate analysis was used to quantify the signals of GIPs caused by IL-6R inhibitors using two algorithms, and we assessed the risk using logistic regression analysis. We also established a risk prediction model of GIPs. Results: We identified 994 cases with GIPs of IL-6R inhibitors (tocilizumab and sarilumab) from the FAERS database. The GIPs signals of IL-6R inhibitors were significant, including tocilizumab (reporting odds ratio [ROR] 6.86, 95%CI 6.43-7.31) and sarilumab (ROR 4.03, 95%CI 2.83-5.73). Duodenal perforation had the strongest signals of tocilizumab (n = 312; ROR 19.45, 95%CI 17.33-21.83; IC₀₂₅ 3.72) and sarilumab (n = 14; ROR 9.57, 95%CI 5.66-16.17; IC₀₂₅ 1.92). The median time to GIPs was near 60 days. In total, 71% of the cases occurred within the first six months after tocilizumab treatment. After excluding missing data, we found that independent risk factors included female (OR 1.52, 95%CI 1.16-1.98), ≥40 years (OR 5.63, 95%CI 1.78-17.78), glucocorticoids (OR 1.37, 95%CI 1.10-1.72), and nonsteroidal anti-inflammatory drugs (NSAIDs, OR 3.46, 95%CI 2.77-4.32). The risk prediction model showed good discrimination and clinical applicability in both the training (AUC, 0.73) and validation (AUC, 0.75) sets. Conclusions: IL-6R inhibitors may increase the risk of GIPs, especially female, middle-aged patients, IL-6R inhibitors, NSAIDs, and glucocorticoids. Therefore, we suggest that these factors associated with gastrointestinal reactions should be considered during treatment.