Non‐steroidal anti‐inflammatory drugs increase the risk of mucosal injuries but not of overt small bowel bleeding

Since 2001, small bowel capsule endoscopy (SBCE) has been widely implemented into clinical practice as a minimal-invasive diagnostic approach for diagnosing small bowel diseases. Currently, SBCE is moreover recognized as the first-line procedure for diagnostic work-up of obscure gastrointestinal bleeding (OGIB) and for a variety of SB disorders including Crohn’s disease, inherited polyposis syndromes, suspected small bowel tumors or refractory celiac disease. In addition, capsule endoscopy is used to guide the decision as to whether device-assisted enteroscopy (i.e. balloon-assisted endoscopy, spiral enteroscopy) would be beneficial, thereby predicting the need for targeted biopsies, endoscopic therapies, and preferred insertion route (i.e. oral or retrograde approach). More recently, widespread use of endoscopic small bowel imaging has gained new insights into the field of druginduced enteropathy. Clinicians’ awareness of this relatively newly identified disease has never been so high and the list of drugs with potential SB side effects is continuously expanding. Drug-induced enteropathy is an umbrella term referring to an extremely heterogeneous family of small bowel disorders usually characterized by a variable degree and distribution of mucosal defects potentially leading to intestinal barrier impairment, malabsorption, protein-losing enteropathy, bleeding, perforation or fibrotic changes including stricture formation. Patients with druginduced enteropathy are usually oligosymptomatic and variably affected by abdominal pain, diarrhea, occult or overt SB bleeding and signs of SB malabsorption. The precise incidence of drug-induced enteropathy and its clinical complications are still unknown, as evidence from large cohort studies is still pending. In one study, the prevalence of SB erosions at SBCE was 70% among asymptomatic chronic non-steroidal anti-inflammatory drug (NSAIDs) users. Very recently, interplay of enteric dysbiosis, bile and enterohepatic drug recirculation has shown a substantial role in the pathogenesis of NSAIDs enteropathy. Additional evidence suggests that proton pump inhibitors may exacerbate NSAID-induced SB mucosal injury by inducing an enteric dysbiosis. To date, no established treatments for drug-induced enteropathy exist. However, early evidence has shown that Lactobacillus casei and rifaximin may decrease SB injury in NSAIDs users, thereby supporting the putative role of enteric microbiota for mucosal integrity. In this issue of Digestive Endoscopy, Niikura and colleagues evaluate the association between drugs and SB mucosal injury in one of the largest multicenter cohort studies published so far in the field of SBCE. In addition, they focus on the association between drug-induced SB mucosal injuries at CE and overt SB bleeding, a relevant complication that usually leads to emergency care and endoscopic interventions. The authors prospectively recorded clinical data and CE findings using the national database of the Japanese Association for Capsule Endoscopy to assess the risk of either SB mucosal injuries or overt bleeding in patients exposed to several drugs causing potential intestinal damage (e.g. NSAIDs, thienopyridines, non-aspirin antiplatelet agents, anticoagulants, acetaminophen, tramadol hydrochloride, steroids, proton pump inhibitors, histamine 2 receptor antagonists [H2RA], rebamipide, and others). Out of 1769 recorded patients, 850 were eligible for inclusion in two retrospective case– control analyses. Based on multivariate analysis, age >65 years, use of NSAIDs (mainly low-dose aspirin), and use of H2RA were significantly associated with an approximately two-fold risk of mucosal injuries at SBCE. Interestingly, these injuries did not contribute to the risk of SB overt bleeding, as no significant difference in the usage rate of any drug was observed in patients with both overt SB bleeding and SB mucosal injuries, even after adjusting for confounders (i.e., age, sex, comorbidities, smoking, alcohol consumption, use of other drugs). Only the combined use of NSAIDs with thienopyridine or steroids was associated with an increased risk of SB overt bleeding, whereas the combination of NSAIDs and anticoagulants did not achieve any significant difference. Despite these unexpected findings, they are in line with a previous large randomized trial comparing celecoxib (2238 patients) versus omeprazole and diclofenac (2246 patients) in patients with osteoarthritis and