NSAID-induced gastrointestinal mucosal injury: Systemic and local mechanisms, risk stratification, and protective strategies

Non-steroidal anti-inflammatory drugs (NSAIDs) remain among the most widely used classes of medications in global clinical practice. However, their use is associated with a high incidence of NSAID-induced gastrointestinal (GI) mucosal injury, which is rather often asymptomatic until the onset of severe complications such as GI hemorrhage or perforation. The risk varies widely among individual NSAIDs, which is confirmed by the systematic review and meta-analysis conducted by the Safety Of nonSteroidal anti-inflammatory drugs (NSAIDs) [SOS] project. A literature review of PubMed/MEDLINE, Scopus and eLIBRARY.RU e-databases was conducted for the period up to 2026, using the following keywords: NSAID gastropathy, NSAID enteropathy, rebamipide, COX-2 inhibitors, and CYP2C9. For inclusion, priority was given to systematic reviews, meta-analyses, randomized controlled trials, and international consensus documents. The current concept of pathogenesis was based on the dual-hit model, which combined local topical epithelial injury (ion trapping, apoptosis) and a systemic deficiency of prostaglandins and nitric oxide, as well as impaired microcirculation due to leukocyte-endothelial cell adhesion. The most important key risk factors included advanced age, a history of ulcers, the concomitant use of antithrombotic agents, H. pylori infection, and CYP2C9 gene polymorphism (hemorrhage OR 1.86). The prevention and treatment strategy was based on the comprehensive GI and CV risk assessment and involved the use of selective COX-2 inhibitors, antisecretory agents (proton pump inhibitors, potassium-competitive blockers), H. pylori eradication, and gastroprotection. Rebamipide held a unique position among all the drugs. Unlike antisecretory therapy, it was effective in preventing both NSAID-induced gastropathy and enteropathy. The 2026 umbrella review synthesizing findings from three meta-analyses showed that rebamipide significantly reduced the incidence of NSAID-induced GI mucosal injury (OR 2.72), with comparable effects observed in the stomach (OR 2.44) and small intestine (OR 2.79). These findings confirmed its role as a valid component of the multimodal prevention and treatment programme.