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.
Ceccacci, S., Pham, H. D. M., Dessaignes, M., Mirzayan, J., Roger, K., Tsoi, L. C., Harms, P. W., Gudjonsson, J. E., Puig Lombardi, M. E., Guerrera, I. C., Hovnanian, A.
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