Integrated Clinical Trial and Molecular Profiling Reveals Immune Drivers of Chronic Hand Eczema

Chronic hand eczema (CHE) is a painful, itchy and inflammatory skin disease of multifactorial origin. CHE can be categorized based on etiology and/or clinical presentation, including intertwined atopic-contact eczema-psoriasis traits, making it challenging to diagnose and treat. While being the most frequent work-related dermatosis, the underlying immune mechanisms remain unclear. Here we performed a randomized controlled study comparing dupilumab and placebo and demonstrated that CHE is a type 2 immunity driven disease, regardless of etiological factors or clinical presentation. We conducted a comprehensive molecular profiling of CHE patients of all etiologies and morphologies to identify potential common features and evaluated the consequences of blocking IL-4Rα during 16 weeks. This phase 2b randomized, multicenter, double-blind, placebo-controlled clinical trial included 94 adults with moderate to severe CHE persisting for at least six months and resistant to potent topical corticosteroids. We found that CHE patients share complex transcriptomic signatures with those of atopic dermatitis and psoriasis patients, with dysregulated genes involved in skin barrier, leukocyte migration, cytotoxicity, type 1, 2 and 3 immunity. 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. These findings demonstrate that IL-4Rα signaling is a critical regulator of CHE pathological features, independent of atopic dermatitis background or environmental triggers, and propose reclassifying CHE as a type 2 immune disorder, with dupilumab or IL-4/13 targeted therapy as the mainstay treatment for moderate to severe disease.