Drivers of Prurigo Nodularis

Itch, inflammation, altered epidermal differentiation, and fibrosis are the 4 pillars of PN 4 pillars of PN—itch 4 pillars of PN—inflammation 4 pillars of PN—altered epidermal differentiation 4 pillars of PN—fibrosis IL-31 is central to PN pathophysiology

Itch, inflammation, altered epidermal differentiation, and fibrosis are the 4 pillars of PN

Itch, inflammation, altered epidermal differentiation, and fibrosis contribute to PN.

The pathophysiology of PN involves interactions between the nervous system, immune system, and skin.^1-5

4 pillars of PN—itch

Chronic itch results from a complex interplay among T cells, mast cells, neutrophils, eosinophils, keratinocytes, and nerve cells (along with increased release of cytokines, proteases, and neuropeptides), leading to exacerbation of itch.⁶

Itch sensitization is remarkable to PN pathophysiology and is what distinguishes patients with PN.

Overactivation of the immune system induces inflammation and sensitizes sensory neurons to pruritogens.^7-12

A study of patients with chronic inflammatory skin diseases showed that the highest levels of IL-31 were located in lesions of individuals with PN (50-fold higher than in the skin of healthy individuals).¹³

In mice studies, overexpression of IL-31 was associated with sensory neuronal outgrowth, providing increased sensitivity to minimal itch-inducing stimuli.⁸

4 pillars of PN—inflammation

Inflammation contributes to PN pathophysiology.

Overactivated neurons, in turn, produce inflammatory cytokines, stimulating the recruitment of inflammatory cells^7,15-17
IL-31 contributes to neuroimmune cross talk between fibroblasts, keratinocytes, and the nervous and immune systems^17-19

4 pillars of PN—altered epidermal differentiation

Altered epidermal differentiation contributes to PN pathophysiology.

Keratinocyte differentiation and activation of fibroblasts are involved in skin integrity and tissue remodeling, respectively^19,20
IL-31 contributes to altered epidermal differentiation by inducing proinflammatory effects of keratinocytes and modulating keratinocyte differentiation ^7,18,20-27
Inhibiting IL-31 signaling results in normalized epidermal hyperproliferation and differentiation⁷

4 pillars of PN—fibrosis

Fibrosis contributes to PN pathophysiology.

Lesions associated with PN show fibrosis of the papillary dermis, hypergranulosis, irregular hyperplasia, orthohyperkeratosis, and an increased number of fibroblasts and capillaries⁷
Fibrosis is believed to play a role in the pathophysiology of PN, although other interleukins, such as IL-4, IL-17, and IL-22, may also contribute^7,14

IL-31 is central to PN pathophysiology

IL-31 acts as a bridge in PN connecting immune cells, neurons, and structural cells in the skin^15,23,29-31
PN transcriptomic analysis shows that PN is a distinct disease with a unique molecular signature⁷

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Drivers of Prurigo Nodularis - Timeline