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

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.

To review emerging systemic treatments for acne beyond isotretinoin, evaluating their efficacy, safety, and potential clinical applications.

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.

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.

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.