Beyond Isotretinoin: A Narrative Review of Emerging Systemic Therapies for Moderate‐to‐Severe Acne

Background: Acne vulgaris is a common inflammatory skin disorder with significant psychosocial impact. While isotretinoin remains the gold standard for moderate-to-severe cases, its adverse effects and teratogenicity underscore the need for alternative systemic therapies. Objective: To review emerging systemic treatments for acne beyond isotretinoin, evaluating their efficacy, safety, and potential clinical applications. Methods: A narrative review was conducted through PubMed, Scopus, and Web of Science, including studies from January 2015 to June 2025. Eligible publications focused on systemic treatments for moderate-to-severe acne, excluding topical-only and non-peer-reviewed studies. Results: Promising alternatives include the narrow-spectrum antibiotic sarecycline, hormonal agents such as spironolactone and combined oral contraceptives, and metformin in patients with polycystic ovary syndrome. Biologic therapies, phosphodiesterase-4 inhibitors, oral probiotics, and novel agents like montelukast and CAMP factor vaccines are also under investigation. These treatments show varying degrees of efficacy and improved safety profiles, but most lack head-to-head comparisons with isotretinoin. Conclusion: Several systemic options beyond isotretinoin have emerged, showing potential in specific subgroups or as adjunctive therapies. However, further large-scale comparative studies are needed to define their roles within evidence-based acne management algorithms.