Biologics and Small-Molecule Therapies in Netherton Syndrome: A Comprehensive Review

Netherton syndrome (NS) is a rare congenital ichthyosis caused by loss-of-function mutations in the SPINK5 gene, leading to defective expression of the serine protease inhibitor LEKTI. Dysregulated epidermal protease activity results in impaired skin barrier function and chronic inflammation, accompanied by complex immune profiles. NS patients commonly show activation of the inflammatory axis, centered on IL-17 and IL-36, in the skin and blood, and show a psoriasis-like shift to Th17. Conversely, the immune profile differs depending on the clinical type, with ichthyosis linearis circumflexa type characterized by complement activation and Th2-type allergic responses, and scaly erythroderma type characterized by a type I IFN signature and Th9-type allergic responses. While symptomatic treatments such as emollients and topical corticosteroids have been the mainstay of care, recent advances have opened new therapeutic avenues involving biologic agents and oral small-molecule immunomodulators. This review provides a comprehensive overview of the current clinical landscape and future directions of biologics (e.g., dupilumab, secukinumab, ustekinumab) and small-molecule therapies (e.g., JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib) in the treatment of NS. Though evidence remains limited to case reports and small series, preliminary data suggest that cytokine-targeted interventions-particularly those inhibiting IL-4, IL-13, IL-17, IL-36, and JAK pathways-may offer tangible clinical benefits. Well-designed clinical trials and mechanistic investigations are crucial to establishing their place in NS management.