The Use of Dupilumab in Difficult-To-Treat Areas of Atopic Dermatitis: Lessons from Real-Life

: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with a high impact on quality of life. Despite major therapeutic advances, the involvement of difficult-to-treat areas such as the head and neck, hands and feet, and genital region remains a significant clinical challenge. Dupilumab, the first biologic approved for moderate-to-severe AD, has shown remarkable efficacy in clinical trials and real-world settings, but variable outcomes have been reported across sensitive sites. This narrative review synthesizes evidence from real-world studies evaluating dupilumab in patients with AD affecting difficult-to-treat areas. Data indicate that dupilumab improves signs and symptoms in the majority of cases, with substantial benefits for quality of life and disease control. However, a subset of patients may experience suboptimal responses or paradoxical reactions, such as dupilumab-associated head and neck dermatitis (DAHND), often linked to Malassezia sensitization or alternative immune pathways. Similarly, while many studies confirm dupilumab effectiveness in chronic hand and foot eczema, therapeutic failures occur, sometimes requiring transition to JAK inhibitors. Involvement of the genital area, a frequently underrecognized manifestation, generally responds well to dupilumab, though alternative biologics or small molecules may be needed in resistant cases. Overall, real-world data highlight both the strengths and limitations of dupilumab in challenging anatomical sites, stressing the need for individualized therapeutic decisions. Awareness of variable responses, adverse event profiles, and emerging alternatives is crucial for optimizing outcomes in patients with moderate-to-severe AD.