Editorial: “Stardust gastric mucosa” – A novel and consistent marker of vonoprazan safety during follow‐up?

Abstract

Real-life evaluation is of high interest to detect rare and long-term effects of medicines that cannot be observed in clinical trials. Vonoprazan, a potassium-competitive acid blocking (P-CAB) approved in Japan in 2015, has shown a satisfactory safety profile in clinical trials.1,2 A recently published article features the largest cohort study of vonoprazan users in a real-life setting. In this single-centre retrospective cohort of 19 503 patients undergoing endoscopy between 2016 and 2019, Yoshizaki et al investigated the incidence of, and aimed to identify risk factors for, a novel endoscopic lesion they named “stardust gastric mucosa”.3 This is a millimetric white protusion, occurring preferentially in the upper third of the stomach and histologically different from fundic gland polyps observed with proton pump inhibitor (PPI) therapy.4,5 Propensity matching allowed the comparison of 2516 patients exposed, and 2516 non-exposed to vonoprazan. Stardust gastric mucosa was observed in 4.9% and 0.2% of exposed and non-exposed patients, respectively. Additionally, cumulative incidence calculated according to cumulated duration or dose of treatment showed consistent resu lts. The significance, temporality, specificity and biologic plausibility favour a causal association between vonoprazan use and the occurrence of this lesion.6 Unfortunately, direct causality criteria, such as resolution of lesions after stopping vonoprazan exposure, or recurrence after resuming it, were not assessed. The prevalence of stardust gastric mucosa reported here, 4.9%, appears lower than the reported prevalence (up to 15%) for fundic gland polyps in chronic PPI users. As the use of vonoprazan is limited to Asian countries, and it has only been authorised 5 years ago, several questions remain unanswered. For example, what is the natural history of these mucosal changes, and do the prevalence and implications vary according to ethnicity? Even if this lesion is morphologically distinct from those seen with PPI therapy, stardust gastric mucosa may also be a consequence of vonoprazan-induced hypergastrinaemia, which is observed more frequently than with PPI use,2 and is a known possible risk factor of neuroendocrine tumors.7 In their discussion, Yoshizaki et al mentioned that stardust gastric mucosa was not associated with cancer. However, at this stage, this claim appears premature. This study did not conduct longitudinal follow-up of patients with stardust gastric mucosa, in order to assess risk of malignancy. In addition, the relatively short availability of P-CABs may preclude occurrence of cancerous gastric lesions. Nevertheless, the study is an interesting first description of gastric lesions associated with exposure to vonoprazan. If the consistency of this association is confirmed in further studies, this would be of importance for clinicians, as the added knowledge may avoid over-sampling during endoscopy in the future. However, as long as the natural history of stardust gastric mucosa is unknown, it is all the more relevant to perform histological sampling when it is observed. The question as to whether long-term vonoprazan users should undergo regular endoscopic monitoring remains open to debate.