The Clinical Characteristics of Hypersensitivity Reactions to NSAIDs: A Comparison between COX-1 and COX-2 Inhibitors

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common cause of drug-induced hypersensitivity reactions (HSRs). These reactions present with diverse clinical manifestations, ranging from cross-reactive responses related to cyclooxygenase-1 (COX-1) inhibition to selective immunologically mediated reactions. However, real-world comparative data on HSRs between COX-1 and COX-2 inhibitors remain limited. This study aimed to compare the clinical characteristics, severity, and seriousness of NSAID-induced HSRs between COX-1 inhibitors and COX-2 inhibitors. Methods: We conducted a retrospective case-only study at Srinagarind Hospital between 1 January 2021 and 31 December 2023. Adult patients with NSAID-related HSRs were identified using diagnostic codes and subsequently validated through detailed review of clinical documentation. Causality was assessed using the Naranjo algorithm. Patients were classified according to the type of NSAID exposure into COX-1 inhibitor and COX-2 inhibitor groups. Clinical manifestations, severity, and seriousness of HSRs were compared between groups. Multivariable log-binomial regression analysis was performed to identify factors independently associated with differences in HSR characteristics, using a complete-case approach. Results: Among 1,167 patients (COX-1: n=939; COX-2: n=228), baseline characteristics were similar, although the COX-2 inhibitor group was older (p<0.001). Musculoskeletal disorders were more frequent in COX-2 users, while respiratory and genitourinary diseases were more common in COX-1 users (p<0.05). Cutaneous reactions predominated in both groups. Anaphylaxis was more common with the COX-1 inhibitor (6.84% vs 3.12%, p=0.037), whereas fixed drug eruption, Stevens–Johnson syndrome, and mucositis were more frequent with the COX-2 inhibitor (p<0.05). Severity and seriousness profiles did not differ significantly. Age was significantly associated with differences in the clinical characteristics of HSRs among patients. (adjusted risk reduction (aRR) 1.01 per year; 95% CI 1.01–1.02; p<0.001). Conclusion: Cyclooxygenase-1 inhibitors and cyclooxygenase-2 inhibitors have different patterns of clinical manifestations but similar levels of severity, and age is associated with differences in the characteristics of clinical manifestations within the group of patients who develop hypersensitivity reactions.