Epidemiology of PN
PN is classified as a rare disease by the National Institutes of Health Genetic and Rare Diseases Information Center (GARD)10 and the National Organization for Rare Diseases (NORD).11 In the US, the prevalence of PN is estimated to range from 36.7 to 43.9 per 10,000 individuals.12,13 In Europe, rates of between 0.65 to 11.1 per 10,000 individuals have been cited.14-16 The estimated prevalence of PN in the United Kingdom is 3.27 per 10,000 individuals, and prevalence increases with age.17
The mean age of patients with PN at incident diagnosis is ~60 years, which has been reported in numerous studies.17-19 African American patients are approximately 3 times more likely to have PN than White patients.20,21 There is also a gender predilection for PN with females more commonly affected than males.17,19,22 Estrogen is known to modulate the immune response and has been shown to enhance the production of T helper 2 (Th2) cytokines such as interleukin (IL)-4, IL-5, and IL-13.23 The immunomodulatory function of estrogen may explain the greater burden of pruritus in females in general.24
Most common comorbidities associated with PN include atopic dermatitis (AD) and psychiatric diagnoses such as anxiety and depression.17,25,26 Other comorbidities include chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, HIV, and type 2 diabetes.27 With respect to chronic kidney disease, circulating plasma angiotensinogen levels were dysregulated only in Black patients with PN.28 Black patients with PN also had stronger associations with end-stage renal disease and faster progression of their renal disease compared to White patients with PN. Higher all-cause mortality was also observed in Black patients with PN and not in Asian patients with PN.29 Compared to the general population, patients with PN are more likely to be hospitalized, have longer inpatient stays, and experience a high infectious disease burden, which corresponds to higher healthcare utilization and spending.30-32 A retrospective study of 15,818 patients with PN showed a disproportionate burden of comorbid tuberculosis infection in patients with PN compared to the general population, which could be attributed to Th2 immune skewing.33 Lastly, PN may have an association with malignancies of the skin, hematopoietic system, and solid organs.34
Pathophysiology of PN
Immune and neural dysregulation are central to the pathogenesis of PN.35,36 The brain and skin are of the same ectodermal embryological origin. The term brain-skin axis describes the connection between our nervous/psychiatric and dermatological systems. While it is debated which aspect (immune or neural) occurs first in the initiation of PN, it is clear that both are inextricably intertwined and act in tandem (Figure 1).
Neural sensitization results in intense itching and scratching. The act of scratching causes disruption of the epidermal skin barrier resulting in the release of pro-inflammatory mediators by keratinocytes (eg, IL-1A, S100A), penetrance of allergens that activate epidermal Langerhans cells and T helper 2 (Th2) cells which secrete IL-31, and bacterial colonization with Staphylococcus aureus and other microbes that activate keratinocyte toll-like receptors (TLRs) to cause further secretion of IL-31 by keratinocytes.37,38 IL-31 interacts with IL-31 receptors on numerous cells resulting in pleiotropic effects. On nerve cells, IL-31 stimulates the sensation of itch and proliferation and regeneration of nerve endings, thus causing neural sensitization and release of substance P, which feeds back onto keratinocytes and Th2 cells causing further release of IL-31.39 IL-31 also acts on numerous immune cells causing a further inflammatory cascade; IL-31 interacts with (1) basophils to stimulate release of Th2-related cytokines IL-4 and IL-13 that then bind to Th2 lymphocytes, (2) eosinophils to release reactive oxygen species (ROS) and CCL26 which causes chemotaxis of basophils, (3) dendritic cells to release CCL17 and CCL 22 to recruit Th2 cells, and (4) macrophages to release TNF-alpha, IL-1b, and IL-6 (Figure 1).40-43
Recent gene expression and proteomic data have also identified fibroblasts as key players in PN.44-49 A single-cell RNA sequencing study comparing individuals with PN to AD and healthy controls found that PN exhibited a unique population of CXCL14-/IL-24+ papillary fibroblasts and upregulation of gene expression signatures corresponding to the activation of cellular pathways involved in fibrosis, extracellular matrix organization and collagen synthesis.45 While both PN and AD had type 2 immune skewing, PN also exhibited less activation of immune pathways relative to AD.45 Another single-cell RNA sequencing study also identified 7 unique subclusters of fibroblasts in lesional PN skin compared to non-lesional PN skin with a shift toward a cancer-associated fibroblast (CAF)-like phenotype.46 This
