Chronic Hand Eczema is a Type 2 Disease: Evidences from Integrated Clinical Trial and Molecular Profiling

Background. Chronic hand eczema (CHE) is a debilitating skin condition characterized by pain, itch, and chronic inflammation, with a complex multifactorial origin. Its diverse presentations, including overlapping traits of atopic dermatitis, contact dermatitis, and psoriasis, make diagnosis and treatment particularly challenging. Despite being the most common occupational skin disease, the underlying immune mechanisms of CHE remain poorly understood. Methods. Here we conducted a comprehensive molecular profiling of CHE patients of all etiologies and morphologies and performed a phase 2b randomized, multicenter, double-blind, placebo-controlled clinical trial comparing dupilumab to placebo over 16 weeks. Results. We demonstrated that CHE is a type 2 immunity driven disease, regardless of etiological factors or clinical presentation. Transcriptomic profiles of CHE patients closely resemble those seen in both atopic dermatitis and psoriasis, with dysregulated genes affecting skin barrier function, leukocyte migration, cytotoxicity, and mixed type 1, 2, and 3 immunity. The clinical trial included 94 adults with moderate to severe CHE persisting for at least six months and resistant to potent topical corticosteroids. Compared to placebo control, 16-week dupilumab treatment significantly improved clinical severity and quality of life of CHE patients, while largely restoring appropriate transcriptomic and proteomic programs related to skin barrier and immune homeostasis. Conclusion. These findings demonstrate that IL-4Rα signaling is a critical regulator of CHE pathological features, independent of atopic dermatitis background or environmental triggers and support reclassifying CHE as a type 2 immune disorder, positioning dupilumab and IL-4/13 targeted therapies as leading treatments for moderate-to-severe patients.