The Big Four in the Pathogenesis and Pathophysiology of Prurigo Nodularis: Interplay among Type 2 Inflammation, Epidermal Hyperplasia, Dermal Fibrosis, and Itch from Neuroimmune DysregulationHashimoto, Okuno
Clin Dermatol (2025)
Abstract: Prurigo nodularis (PN) is a distinct inflammatory dermatosis. It is characterized by intensely pruritic, firm nodules, typically 1-2 cm in diameter, which usually develop on the extensor surfaces of the extremities. Histopathologically, the following characteristics are observed in PN lesions: (1) dermal cellular infiltrates composed of type 2 inflammation-associated immune cells with lesional overexpression of type 2 cytokines (including IL-4, IL-13, and IL-31); (2) dermal fibrosis; and (3) epidermal hyperplasia with hyperkeratosis. Additionally, functional and structural alterations of cutaneous sensory nerve fibers profoundly contribute to itch in cooperation with type 2 inflammation. This abnormal interaction is referred to as neuroimmune dysregulation. The scratching behavior induced by itching from neuroimmune dysregulation initiates the development of prurigo nodules. This distinctive pathogenic feature of "itch-first" in PN is distinct from "inflammation-first" in atopic dermatitis, another pruritic skin disease with type 2 inflammation. In atopic dermatitis, the skin initially exhibits type 2 inflammation, which is subsequently followed by itching. The interplay between the four elements, namely type 2 inflammation, epidermal hyperplasia, dermal fibrosis, and itch resulting from neuroimmune dysregulation, appears to be pivotal in the pathogenesis and pathophysiology of PN.Copyright © 2025. Published by Elsevier Inc.
Mechanisms of Itch in Atopic DermatitisKamata, Tominaga, Takamori
Juntendo Med J (2025) 71 (1), 43-50
Abstract: Atopic dermatitis (AD) is a common inflammatory skin disease characterized by recurrent eczematous lesions and intense itch. The pathological mechanism of AD involves a complex interaction between skin barrier dysfunction and a predominantly T helper (Th) 2-skewed immune dysregulation. The dysfunctional skin barrier in AD enhances antigen penetration, exacerbating allergic reactions. Scratching further damages the skin barrier, worsens dryness and increases the release of pro-inflammatory mediators, perpetuating the itch-scratch cycle. Breaking this cycle with appropriate treatments is vital. Th2 cells secrete interleukin (IL)-4, IL-13 and IL-31 which play keys roles in AD pathogenesis. IL-31 directly induces pruritus, while IL-4 and IL-13 enhance itching. An increased density of intraepidermal nerve fibers has been observed in AD lesions in a disease-state-dependent manner. In normal skin, both semaphorin 3A (Sema3A; a nerve repulsion factor) and nerve growth factor (NGF; a nerve elongation factor) are expressed. However, in AD lesions, Sema3A expression decreases while NGF expression increases. These findings suggest that epidermal nerve density is regulated by a fine balance between Sema3A and NGF, with Sema3A playing a key role in itch sensitivity in AD. In healthy skin, Sema3A is produced during the early-stage of differentiation of keratinocytes and moves into the upper epidermis. The levels of Sema3A and the density of epidermal nerve fibers may vary depending on the disease state of AD. Our future research will focus on the regulatory mechanisms of Sema3A in skin, and potential clinical applications.© 2025 The Juntendo Medical Society.
A Case of Erythema Multiforme Following the Administration of NemolizumabMima, Ohtsuka
Cureus (2025) 17 (2), e79070
Abstract: Prurigo nodularis (PN) is a chronic inflammatory skin disorder characterized by intensely pruritic nodules. The pathogenesis of PN involves immune dysregulation, with a predominance of T helper (Th2)-type inflammation, including interleukin (IL)-4, IL-5, IL-13, and IL-31. Nemolizumab, an IL-31 receptor A inhibitor, was newly approved for PN in 2024. We report a case of erythema multiforme (EM) that developed three weeks after the first administration of nemolizumab. Three weeks post-injection, she developed multiple targetoid edematous erythematous patches and plaques on her trunk and limbs, leading to a clinical diagnosis of EM. Since she had no new medications and no recent history of infections, we inferred that the development of EM was likely associated with the administration of nemolizumab. The pathophysiology of EM involves a predominant Th1-driven inflammatory response. Therefore, nemolizumab likely suppressed Th2 inflammation, leading to compensatory Th1 hyperactivation, which may have triggered EM. To our knowledge, this may be the first reported case of EM following nemolizumab treatment for PN. Further research is necessary to investigate its immunomodulatory effects and potential adverse events.Copyright © 2025, Mima et al.
Prurigo Nodularis and Acquired Perforating Dermatosis in Chronic Kidney Disease: Are They the Same Entity?Mahmoud, Coscarella, Kwak
et alClin Dermatol (2025)
Abstract: Prurigo nodularis (PN) has been reported in itchy chronic kidney disease (CKD) patients, in particular, in end-stage renal failure. Acquired perforating dermatitis (APD) associated with CKD and diabetes is a group of disorders where dermal materials are eliminated through the epidermis and is characterized by itchy papules and nodules. We focus on the relationship between PN and APD in CKD and provide data to support that both entities share many of the same clinical and histologic features. These cutaneous diseases often go underreported in this patient population, leading to inadequate treatment and suboptimal patient outcomes. Our review of the literature suggests a relationship between PN/APD and CKD, presumably driven by uremic pruritus, changes in the renin-angiotensin-aldosterone system, a predisposing immune dysregulation with increased IL-31 expression, and opioid system imbalances. A variety of pharmacologic therapies may be efficacious. The use of the new targeted biologics for PN and whether they are also helpful for CKD and APD are welcome..Copyright © 2025. Published by Elsevier Inc.
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