Prurigo Nodularis: Review and Emerging Treatments

Maria Leis, BA; Patrick Fleming, MD, FRCPC; Charles W. Lynde, MD, FRCPC

Disclosures

Skin Therapy Letter. 2021;26(3):5-8. 

In This Article

Pathophysiology

The pathogenesis of PN is thought to be characterized by a cutaneous reaction pattern due to chronic itching and repeated scratching, otherwise termed the "itch-scratch cycle." Although the exact pathogenesis of PN is unknown, immune and neural dysregulation drive the pruritic cycle.[8]

Histopathologic studies investigating the immune response of PN have demonstrated increased infiltrate in the dermis of PN lesions consisting of increased T lymphocytes, mast cells and eosinophilic granulocytes.[8,9] The intense itch is created by an inflammatory response in the skin through mediators such as interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins and neuropeptides.[8,9] Specifically, eosinophils and IL-31 are particularly implicated in the pathogenesis of the disease through their increased expression and pathologic mechanisms in the dermis of PN lesioned skin.[8–13]

Neuronal dysregulation has also been demonstrated in PN; studies have shown differences in nerve fiber density between the dermis and epidermis in individuals with PN.[11] Further, dysregulation of neuropeptides has been implicated in the pathogenesis, with particular increases in calcitonin gene-related peptide and substance P in dermal PN skin.[8–11,14] Although these changes may be secondary to repeated mechanical scratching, they still contribute to the pruritic cycle through regulation of eosinophils, mast cells, effects on endorphins and mu- and kappa-opioid receptors.[8,9,11]

Regardless of the aforementioned potential triggering pathologies, central nervous system functioning is essential for transmitting the itch signal from the periphery. Recent seminal findings by Oetjen and colleagues have demonstrated that the IL-4 receptor is directly expressed on sensory neurons in the dorsal root ganglia of both humans and mice. This receptor is directly activated by expression of type 2 cytokines, such as IL-4, IL-13 and IL-31.[15] Most importantly, the authors demonstrated that ablating the IL-4 receptor in a mouse model significantly diminished chronic pruritus, and treating human patients with recalcitrant chronic itch that failed other immunosuppressive therapies with inhibitors of the type 2 cytokine pathway (Janus kinase – JAK – inhibitors) markedly improved their symptoms.[15] Taken together, therapeutics targeting the inhibition of this central nervous system pathway may potentially be groundbreaking in the treatment of PN.

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