Systemic Therapies for Recurrent Aphthous Stomatitis: A Systematic Review of Efficacy and Safety

OBJECTIVES: To evaluate the efficacy and safety of systemic pharmacological and nutritional interventions for recurrent aphthous stomatitis (RAS). MATERIALS AND METHODS: Following PRISMA 2020, five databases were searched for studies published from 2001 to 2026. Clinical trials and analytical observational studies of systemic treatments for RAS were included. Risk of bias was assessed using design-appropriate tools. Owing to clinical and methodological heterogeneity, findings were synthesized qualitatively. RESULTS: Twenty studies were included: 16 randomized trials, three non-randomized intervention studies, and one observational cohort. Interventions included corticosteroids, colchicine, thalidomide, levamisole, pentoxifylline, dapsone, clofazimine, sulodexide, montelukast, roflumilast, rebamipide, vitamin B12, vitamin C, multivitamins, zinc, and omega-3 fatty acids. Several therapies improved pain, ulcer burden, healing, or recurrence-related outcomes, but comparative evidence was inconsistent. Thalidomide showed potential benefit but important safety limitations and a high risk of bias. Nutritional interventions showed mixed results. CONCLUSIONS: Selected systemic therapies may benefit severe, frequent, or refractory RAS, but no intervention can be considered clearly superior. Evidence certainty is limited by heterogeneity, small samples, limited direct comparisons, and risk of bias.