Beyond Eczema Control: Long-Term Outcomes of Dupilumab Therapy in Six Patients with Netherton Syndrome

Abstract: Netherton syndrome is a rare and severe genodermatosis caused by pathogenic variants in SPINK 5, leading to epidermal barrier dysfunction, immune dysregulation, and prominent atopic manifestations. Therapeutic options remain limited, and long-term real-world data on biologic treatment are scarce. We report a retrospective two-center real-world case series of six patients with Netherton syndrome treated with dupilumab, with emphasis on long-term outcomes, safety, and clinical effects beyond eczema control. Five patients were managed at one dermatology referral center and one patient at a second center. Clinical data were collected retrospectively from medical records, including disease severity scores, pruritus, quality of life, genetic findings, comorbidities, treatment duration, adverse events, and additional clinically relevant observations. Dupilumab was initiated because of severe, chronic, and refractory inflammatory skin disease with intense pruritus and impaired quality of life. Follow-up ranged from 13 to 34 months. All patients achieved sustained, clinically meaningful improvement in inflammatory skin lesions, pruritus, and quality of life, although complete remission was not observed. Treatment was well tolerated, including in patients with recurrent infections, immunodeficiency-like features, severe food allergy, and a history of acute lymphoblastic leukemia. Additional observations included improvement in hair abnormalities and sweating in selected patients, reduced infectious burden, improved growth parameters, and absence of further anaphylactic episodes in one patient. These findings suggest that dupilumab may represent a valuable long-term therapeutic option for Netherton syndrome with prominent type 2 inflammatory features. Potential benefits beyond eczema control should be regarded as hypothesis-generating and require confirmation in larger multicenter studies. Keywords: Netherton syndrome, dupilumab, SPINK 5, trichorrhexis invaginata, ichthyosiform erythroderma, biologic therapy, atopic dermatitis