Multiomic Analysis Reveals an IFN-driven Cellular Landscape Effectively Targeted by Ruxolitinib in Hailey-Hailey Disease

Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatosis characterized by skin blistering and erosions in intertriginous regions, frequently complicated by secondary infections leading to substantial impairment in quality of life. No targeted mechanism-based therapies are currently available. Here, we applied a multiomics approach to define the molecular and cellular landscape of HHD. Bulk transcriptomics and proteomics uncovered a striking interferon (IFN) signature in HHD skin lesions. Single cell and spatial transcriptomics analyses revealed inflammatory niches, where immune, epithelial, vascular and stromal cells create a multi-compartment IFN-driven signaling network, that sustains a feed-forward amplification loop essential for chronic inflammation. Crucially, in nine patients with refractory HHD, topical treatment with the JAK1/2 inhibitor ruxolitinib led to rapid and durable re-epithelialization with drastic reduction in pain, itching, oozing and skin inflammation, significantly improving patient quality of life. Collectively, our findings identify IFN signaling as a key pathogenic driver in HHD and support topical JAK inhibition as an effective therapy, redefining the standard of care for individuals living with HHD.