Immune Checkpoint Inhibitor–Induced Upper Gastrointestinal Tract Inflammation Shows Morphologic Similarities to, but Is Immunologically Distinct From, Helicobacter pylori Gastritis and Celiac Disease

Abstract

Context.— Immune checkpoint inhibitor (CPI) therapies are associated with multi-organ immune-related adverse events. Although colonic mucosal changes have been described, inflammatory changes incited by CPIs in the upper gastrointestinal tract have not been well characterized. Objective.— To investigate morphologic and immunologic changes incited by CPI therapy in the upper gastrointestinal tract. Design.— We compared the morphology and immune cell phenotype of gastric and duodenal biopsies from patients treated with anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or anti–programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies with biopsies from patients with Helicobacter pylori gastritis, patients with celiac disease, and normal controls. Results.— Gastric biopsies from patients on CPIs showed chronic gastritis mimicking H pylori gastritis. However, CPI gastritis demonstrated greater numbers of CD8+ intraepithelial lymphocytes, less lamina propria inflammation, fewer plasma cells and CD20+ B cells, fewer lymphoid aggregates, and reduced CD4:CD8 ratio in both the lamina propria and the epithelial layer. There were no differences between anti–CTLA-4 and anti–PD-1/PD-L1 gastritis, except for more lymphoid aggregates in anti–PD-1/PD-L1 gastritis. Duodenal biopsies from patients on CPIs revealed chronic duodenitis with villous blunting, mimicking celiac disease. Compared with celiac disease, CPI duodenitis demonstrated higher prevalence of neutrophilic infiltrates and erosions, increased lamina propria CD3 and CD8 T cells, and reduced CD4:CD8 ratio. Upper gastrointestinal biopsies were more inflamed than concomitant colonic biopsies in the majority of patients. Conclusions.— The morphologic and immunophenotypic distinctions between CPI-associated upper gastrointestinal injuries and common infectious and autoimmune diseases may provide useful discriminators when clinicians are confronted with gastric and duodenal inflammatory changes in patients receiving CPI therapy.