Prurigo nodularis: new insights into pathogenesis and novel therapeutics

Abstract

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. Patients with PN 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 interleukin (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 T-helper (Th)17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibres 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 patients with PN and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centred 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 US Food and Drug Administration-approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31 receptor A inhibitor nemolizumab is in late-stage development with positive phase III data reported. In addition, the oral Janus kinase (JAK) 1 inhibitors, abrocitinib and povorcitinib, are in phase II trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase III studies.

Graphical Abstract

Figure 1

Histological findings characteristic of prurigo nodularis. (a) Elongated rete ridges, orthohyperkeratosis and hypergranulosis. (b) Dermal lymphocytic infiltrate. (c) Magnified view showing epidermal acanthosis and vertical streaking of collagen in the papillary dermis.

Figure 2

Pathogenesis of PN. The intense pruritus experienced in patients with PN is associated with both neural and immune dysregulation. Neuronal hyperplasia, likely to be driven by NGF released from mast cells and eosinophils, is found in the dermis of patients with PN. These itch-sensing neurons release SP, CGRP and CST, which activate T cells, mast cells and eosinophils. T cells release several cytokines, including IL-4, IL-13, IL-17, IL-22 and IL-31, which are all increased in PN skin and further activate inflammatory cells, fibroblasts and nerves through JAK–STAT signalling. Activated mast cells and eosinophils contribute to inflammation and pruritus through the release of NGF, ECP, EDN, EPX and other granule proteins. Activated fibroblasts further contribute to inflammation by releasing periostin, which increases activation of T cells and directly activates itch-sensing neurons. Activation of fibroblasts also allows for dermal fibrosis and epidermal hyperplasia, which are histologically characteristic of PN.

Figure 3

Racial differences in the clinical presentation of prurigo nodularis (PN). (a–d) PN in African American patients typically features firmer, nodular lesions with a fibrotic appearance. (e–h) PN in White patients typically features more shallow, ulcerative lesions.

Figure 4

Developmental phases of novel therapeutics for prurigo nodularis. JAK, Janus kinase; NK1R, neurokinin 1 receptor.

Figure 5

Novel therapeutics in development for prurigo nodularis target various aspects of itch pathogenesis. Each therapeutic in development targets a different aspect of itch pathogenesis. Dupilumab, nemolizumab and vixarelimab all target receptors that activate the JAK–STAT signalling pathway in multiple cell types, including sensory neurons, keratinocytes, macrophages, eosinophils, mast cells and T cells. Abrocitinib and povorcitinib target intracellular JAK–STAT signalling. Nalbuphine targets opioid receptors found on cutaneous nerve terminals, and barzolvolimab affects the mast cell KIT receptor, serving to block migration and activation of mast cells. Serlopitant and aprepitant target NK1Rs, acting to block activation of sensory neurons and mast cells by SP.