Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Clinical and Pathological Spectrum of Prurigo Pigmentosa in Central European Individuals.

Importance: Based on early studies, prurigo pigmentosa (PP) was considered a rare inflammatory dermatosis affecting primarily Asian individuals. However, several case reports subsequently showed that the disease is not restricted to those of Asian origin. Large studies on PP in central European individuals, on the other hand, are missing. Objective: To increase awareness of PP by describing the clinical, histopathological, and immunohistochemical features in central European individuals. Design, Setting, and Participants: This observational, retrospective case series analyzed clinicopathological features of 20 central European patients diagnosed with PP. Data collection was performed by means of archive material, including physician's letters, clinical photographs, and histopathological records, at the Department of Dermatology at the Medical University of Graz in Austria from January 1998 to January 2022. Main Outcomes and Measures: Demographic, clinical, histopathological, and immunohistochemical characteristics for patients diagnosed with PP were recorded. Results: Of the 20 patients included, 15 (75%) were female, and the mean (range) age was 24.1 (15-51) years. The study cohort consisted entirely of European patients. The most common site of involvement of PP was the breast, followed by the neck and back. Other involved clinical sites were the abdomen, shoulders, face, head, axillae, arms, and genital region and groin. Clinically, lesions were characterized by a symmetric pattern in 90% (n = 18) of all cases. Marked hyperpigmentation was observed only in 25% (n = 5) of patients. In some cases, triggers such as malnutrition, long-term pressure, and friction were noted. Histologic findings revealed presence of neutrophils in all cases and necrotic keratinocytes in 67% (n = 16) of cases. Immunohistochemistry results showed predominance of CD8+ lymphocytes in the epidermis, as well as the presence of plasmacytoid dendritic cells and myeloid cell nuclear differentiation antigen-positive neutrophil precursors. Conclusions and Relevance: This case series found that most clinical features observed in Asian patients were also observed in central European patients, but hyperpigmentation was primarily mild to moderate. Histopathological features were similar to those reported in the literature with the additional presence of myeloid cell nuclear differentiation antigen-positive precursor neutrophils. These results expand previous knowledge about PP in central European individuals.

RNA sequencing reveals the transcriptome profile of the atopic prurigo nodularis with severe itching.

Prurigo nodularis (PN), characterized by inevitable chronicity and severe pruritus, is most frequently associated with atopy compared with other origins. However, the skin transcriptomic profiling of PN arising from atopic dermatitis (AD), so-called atopic PN (APN), remains unclear. We sought to explore the cutaneous transcriptome of APN with severe pruritus and compare it with classic AD. RNA sequencing was performed on the lesional skin from 13 APN to 11 AD patients with severe pruritus (itch numerical rating scale score ≥ 7) and normal skin from 11 healthy subjects. Quantitative real-time polymerase chain reaction and immunochemistry were used for validation. We detected 1085 and 1984 differentially expressed genes (DEGs) in lesional APN skin and lesional AD skin versus normal skin, respectively. In total, 142 itch/inflammation-related DEGs were identified. Itch/inflammation-related DEGs, such as IL-6, IL-10, IL-13, oncostatin M, and IL-4 receptor, had elevated gene transcript levels in both diseases. The itch/inflammation-related DEGs that increased only in APN were mainly neuroactive molecules, while many inflammatory mediators such as T helper 22-related genes were found to be increased only in AD. Both disorders showed mixed Th1/Th2/Th17 polarisation and impaired skin barrier. In contrast to AD, M1/M2 macrophage activation, tumor necrosis factor production, fibrosis, revascularization and neural dysregulation are unique features of APN. The study findings broaden our understanding of the pathogenesis underlying APN, which provides insights into novel pathogenesis with potential therapeutic implications.

[Eosinophilic dermatoses]. / Eosinophile Dermatosen.

Eosinophilic dermatoses are a heterogeneous group of rare diseases that histopathologically display the defining pattern of an eosinophil-rich dermal infiltrate. In these eosinophilic dermatoses, a histopathologic pattern called flame figures, which result from degranulation of eosinophils in the tissue, can be observed. Although eosinophil granulocytes can also be detected in other dermatoses such as atopic dermatitis, urticaria, prurigo and bullous pemphigoid, the eosinophil-rich infiltrate is decisive for classic eosinophilic dermatoses. Accordingly, eosinophilic dermatoses include hypereosinophilic syndrome, eosinophilic fasciitis, granuloma faciale, pustular sterile eosinophilia, and angiolymphoid hyperplasia with eosinophilia. These eosinophilic dermatoses display clinical different patterns and are discussed in this article, as well as the interesting eosinophils and novel therapeutic options.

Prurigo nodular crónico / Chronic nodular prurigo

El prurigo nodular crónico se caracteriza por un ciclo de prurito y excoriación en el que intervienen mecanismos neurodérmicos, asociado a diversas enfermedades. Se manifiesta con placas o nódulos hiperqueratósicos cupuliformes. El tratamiento, enfocado en reducir el prurito, representa un desafío por la frecuente resistencia a las terapéuticas habituales. Se describe el caso de un hombre de 72 años, con antecedentes psiquiátricos, que presentó una dermatosis pruriginosa recalcitrante refractaria a múltiples esquemas de tratamiento.

Chronic prurigo nodularis is characterized by a cycle of itching and excoriation involving neurodermal mechanisms, associated with various diseases. It manifests with cupuliform hyperkeratotic plaques or nodules. Treatment is focused on reducing itching and is a challengue due to the frequent resistance to the usual therapies. We present the case of a 72-year-old man with a psychiatric history, who presented a recalcitrant pruritic dermatosis refractory to multiple treatment regimens.

Application of least absolute shrinkage and selection operator logistic regression for the histopathological comparison of chondrodermatitis nodularis helicis and hyperplastic actinic keratosis.

BACKGROUND: The distinction between chondrodermatitis nodularis helicis (CNH) and hyperplastic actinic keratosis (HAK) on the ear can pose a diagnostic challenge. We aimed to identify histopathological characteristics that could distinguish between CNH and HAK on routine sections using penalized least absolute shrinkage and selection operator (LASSO) logistic regression analysis. METHODS: Cases of CNH (n = 80) and HAK (n = 28) were analyzed for selected histopathological characteristics. Fisher's exact test and LASSO regression were performed. RESULTS: In univariate analyses, the following were significantly associated with CNH: ulceration, acanthosis, granular layer in the majority of the lesion, hypergranulosis at the periphery of the lesion, hyperkeratosis at the periphery of the lesion, hyperparakeratosis at the periphery of the lesion, fibrosis, increased blood vessels, vertically oriented blood vessels, and fibrin. A LASSO model excluding atypia found that fibrin, fibrosis, presence of granular layer, ulceration, and vertically oriented blood vessels were most predictive of CNH. Keratinized strap cells were not a significant predictor. CONCLUSION: We have identified features that may aid in differentiating these entities and demonstrated that a LASSO regression model can identify predictors that may improve diagnostic accuracy. Our results indicate that the highest diagnostic accuracy in this dilemma is dependent on obtaining biopsy specimens with visible dermis.

Nevus sebaceus with syringocystadenoma papilliferum, prurigo nodularis, apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma: case report and review of nevus sebaceus-associated conditions.

Nevus sebaceus is a benign skin hamartoma of congenital onset that grows during puberty, and in adulthood can develop secondary benign and malignant neoplasms. The most common benign neoplasms occurring in nevus sebaceus are believed to be syringocystadenoma papilliferum, trichilemmoma, and trichoblastoma. A patient with nevus sebaceus developed not only syringocystadenoma papilliferum but also prurigo nodularis within her hamartomatous lesion; multiple biopsies were necessary to establish the diagnoses. Excision of the residual nevus sebaceus also revealed an apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma. Also, it is important to select the appropriate biopsy site and size when evaluating a patient for secondary neoplasms within their nevus sebaceous. Indeed, more than one biopsy may be required if additional diagnoses are suspected.

Promyelocytic Differentiation in Infiltrates of Prurigo Pigmentosa: An Analogy to Histiocytoid Sweet Syndrome.

Prurigo pigmentosa (PP) is a rare inflammatory dermatosis of unknown etiology. Young women are affected most commonly. Clinically, heavily itchy papules erupt mainly on the trunk healing with residual reticulate pigmentation. Histopathologic descriptions of PP are somewhat controversial. First, PP was reported as lichenoid-interface dermatitis, and later, neutrophils were recognized as the characteristic feature, and the variation in histopathologic patterns was interpreted as a time-dependent phenomenon. Immunohistochemical studies on PP are rare. Biopsies of 5 patients with clinically typical PP were examined histopathologically, and infiltrates were characterized immunohistochemically: myeloperoxidase, CD11c, CD68, CD4, CD8, tryptase, and langerin. In all cases, myeloperoxidase-positive cells with band forms of nuclei and with histiocytoid cytomorphology were identified. They were seen in the epidermis (4/5) and in the dermal infiltrate (5/5). On staining with CD11c, myeloid dendritic cells could be demonstrated in the infiltrate (5/5). In conclusion, myeloid progenitor cells are part of the infiltrate in PP, and they may sometimes be more numerous than mature neutrophils, akin to the situation in histiocytoid Sweet syndrome. This supports the classification of PP as a "neutrophilic dermatosis." In biopsies of suspected PP in which mature neutrophils are sparse, the section should be searched for neutrophilic band forms and histiocytoid promyelocytic cells. Immunohistochemical staining with myeloperoxidase helps to identify such cells and may enable a diagnosis of PP even when mature neutrophils are few.

Twenty-five year-old female with sudden onset itchy skin eruption over her upper back and chest three weeks after starting a ketogenic diet.

Prurigo pigmentosa is a rare pruritic inflammatory dermatosis with a unique staged clinicopathological presentation. It was first reported by Nagashima in 1971, and recently, more cases have been reported We introduce a case of a young Saudi female who developed biopsy proved prurigo pigmentosa after she followed strict ketogenic diet. Her condition resolved after she resumed a regular diet.

Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.

Prurigo pigmentosa following laparoscopic gastric sleeve.

Prurigo pigmentosa is an uncommon inflammatory skin disease predominately affecting young women. Clinically the disease presents with erythematous and urticarial papules arranged in a reticular pattern. Lesions heal with reticulated hyperpigmentation. Strict ketogenic diet is one of many factors that might trigger the disease. In this article, we present a case of prurigo pigmentosa following a complicated laparoscopic gastric sleeve with the resolution of the rash after improvement of the patient's diet.

Idiopathic Papular Dermatitis in the Spectrum of Chronic Papular Eruptions (Subacute Prurigo): Reappraisal and Diagnostic Algorithm.

BACKGROUND: The clinical diagnosis of papular eruptions is common but poorly characterized in the literature and the etiology is often unknown. OBJECTIVE: To characterize the entity of idiopathic papular dermatitis in the spectrum of chronic papular eruptions. METHODS: The cohort consisted of patients who presented at a tertiary medical center in 2005-2014 with a papular eruption of at least 4 months' duration. Findings on histological analysis and thorough clinical investigation, performed in all cases, were collected. The patients completed a questionnaire on disease course and outcome. RESULTS: Sixty-five patients were included. Sixteen patients showed morphological changes over time and were excluded. Investigations in the remaining 49 patients with a consistent papular morphology yielded a well-defined diagnosis in 23 (46%). Twenty-six patients (54%; 14 male) were diagnosed with idiopathic papular dermatitis. Their mean age at onset was 61.6 ± 14.4 years and the mean duration of disease 3.11 ± 2.726 years. In 60%, the rash resolved with conservative treatment during follow-up (mean 4.35 ± 2.53 years). CONCLUSIONS: Chronic papular eruptions encompass a wide range of skin diseases. In more than half of the cases, the etiopathogenesis remains unclear. On the basis of our results, we propose a diagnostic algorithm for idiopathic papular dermatitis.

Xerosis cutis and associated co-factors in women with prurigo nodularis

Abstract: Background: Current data regarding the associated factors of prurigo nodularis are still uncertain, except for atopic predisposition. Objectives: The purposes of this study were to (1) determine the frequencies of xerosis and other accompanying diseases of female patients with prurigo nodularis; (2) compare the demographic, clinical and accompanying disease characteristics by grouping these patients according to whether they have associated xerosis (who were subsequently subgrouped as atopic or non-atopic) or not. Methods: In this retrospective descriptive study, 80 females with PN were categorized according to the accompanying diseases (dermatological, systemic, neurological, psychogenic, mixed, or undetermined origin). Results: A total of 45 associated co-factors including dermatological in 63 (78.8%), systemic in 57 (71.3%), psychological in 33 (41.3%) and neurological co-factors in 14 (17.5%) of all patients with prurigo nodularis were detected. Xerosis was observed in 48 (60%) patients (non-atopic co-factors in 66.7% of them). The ratio of patients with mixed co-factors, dermatological+systemic co-factors and dermatological+systemic+psychological co-factors were found to be significantly higher in patients with xerosis compared to those without xerosis. Study limitations: Our study has certain limitations such as the absence of an age-matched control group, absence of follow-up data and the fact that the diagnosis of xerosis has not been based on objective methods. Conclusions: Xerosis has been identified in more than half of the patients with PN and it has been determined that in most patients xerosis is associated especially with diabetes mellitus and other conditions related to prurigo nodularis.

Thalidomide for the treatment of chronic refractory prurigo nodularis.

Prurigo nodularis (PN) is a highly pruritic skin condition that is caused by chronic scratching. It occurs in patients with chronic itch and is characterized by multiple hyperkeratotic papules and nodules. The pathogenesis of PN is unclear, but involves a complex interplay of numerous pathways including neurogenic and inflammatory factors. As such, PN is very difficult to treat and patients are often refractory to multiple medications before finding a treatment that is effective. We present a woman with a 20-year history of exuberant prurigo nodularis who failed multiple therapies, including dapsone, azathioprine, mycophenolic acid, prednisone, topical steroids, and phototherapy. She only obtained significant relief of chronic pruritus and lesion flattening with thalidomide 100mg daily. Thalidomide is an antipruritic and anti-inflammatory agent that has shown to be very effective in treating a variety of dermatologic conditions. However, its use today is limited by concerns for its teratogenic and neuropathic side effects. With strict adherence to medication protocols, these adverse effects can be minimized. As such, thalidomide should be considered for patients with refractory dermatologic conditions.