Prurigo Nodularis: New insights into pathogenesis and novel therapeutics.

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. PN patients suffer from an intractable itch-scratch cycle leading to impaired sleep, psychosocial distress, and a significant disruption in quality of life. The pathogenesis of PN is associated with immune and neural dysregulation, mediated by inflammatory cytokines (such as IL-4, -13, -17, -22, and -31) and neuropeptides (such as substance P and calcitonin gene-related peptide). There is a role for type 2 inflammation in PN in addition to Th17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibers that cause vasodilation and further recruitment of inflammatory cells. Inflammatory cells, particularly mast cells and eosinophils, degranulate and release neurotoxins, as well as nerve growth factor, which may contribute to the neuronal hyperplasia seen in the dermis of PN patients and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centered around degrees of Type 2 inflammation or underlying myelopathy or spinal disc disease, and significant race and ethnicity-based differences with African-Americans having densely fibrotic skin lesions. Dupilumab became the first FDA approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31RA inhibitor nemolizumab is in late stage development with positive phase 3 data reported. In addition, the oral JAK1 inhibitors, abrocitinib and povorcitinib, are in phase 2 trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase 3 studies.