The use of dupilumab in difficult-to-treat areas of atopic dermatitis: lessons from real-world studies

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with a big 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 on sensitive areas of the body. 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 for the majority of patients, 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, although many studies confirm dupilumab effectiveness in chronic hand and foot eczema, treatments that have failed occur, sometimes requiring transition to Janus kinase inhibitors. Involvement of the genital area, a frequently underrecognized manifestation, generally responds well to dupilumab, although alternative biologics or small molecules may be needed in patients with 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.Difficult-to-treat areas of atopic dermatitis AD (head/neck, hands/feet, genitalia) profoundly impair the quality of life of patients and are often resistant to standard therapies. This narrative review synthesizes evidence from real-world studies evaluating treatment with dupilumab in patients with AD affecting difficult-to-treat areas.