Immune stimulus exposure as a trigger for the development of chronic pruritus and circulating blood type 2 inflammation.

Background: Chronic pruritus (CP) is a poorly characterized condition associated with intense pruritus without a primary skin eruption. This condition tends to emerge more commonly in older adults, and there is limited research on triggering factors. Objective: To explore the clinical characteristics and pathophysiology of CP following exposure to an immune stimulus. Methods: Clinical characteristics and plasma samples were collected from 15 patients who developed CP following an immune stimulus such as checkpoint inhibitors or vaccination. A multiplex panel was used to analyze plasma cytokine concentrations within these patients. Results: Most immunotherapy-treated patients experienced CP during treatment or after 21 to 60 days of receiving treatment, while vaccine-stimulated patients developed pruritus within a week of vaccination. Plasma cytokine analysis revealed elevated levels of 12 cytokines in patients with immune-stimulated CP compared to healthy controls. Notably, T helper 2 (Th2) related cytokines interleukin (IL)-5 (fold change 2.65; q < 0.25) and thymic stromal lymphopoietin (fold change 1.61 q < 0.25) were upregulated. Limitations: Limitations of this study include limited sample size, particularly in the plasma cytokine assay. Conclusions and Relevance: This study reveals triggers of CP development and describes alterations in blood Th2 markers in patients with CP, including IgE, increased blood eosinophils, and cytokines IL-5 and thymic stromal lymphopoietin.

Efficacy and Safety of Abrocitinib in Prurigo Nodularis and Chronic Pruritus of Unknown Origin: A Nonrandomized Controlled Trial.

Importance: Prurigo nodularis (PN) and chronic pruritus of unknown origin (CPUO) are chronic pruritic diseases that dramatically impair quality of life, but therapeutic options are limited. Abrocitinib, a Janus kinase 1 inhibitor, represents a promising therapy for both conditions. Objective: To assess the efficacy and safety of 200-mg oral abrocitinib administered once daily in adults with moderate to severe PN or CPUO. Design, Setting, and Participants: This phase 2, open-label, nonrandomized controlled trial conducted between September 2021 and July 2022 took place at a single center in the US. A total of 25 adult patients with moderate to severe PN or CPUO were screened. Ten patients with PN and 10 patients with CPUO were enrolled. All 20 patients completed the 12-week treatment period, 18 of whom completed the 4-week follow-up period. Intervention: Abrocitinib, 200 mg, by mouth once daily for 12 weeks. Main Outcomes and Measures: The primary efficacy end point was the percent change in weekly Peak Pruritus Numerical Rating Scale (PP-NRS) scores from baseline to week 12. Key secondary end points included the percentage of patients achieving at least a 4-point reduction in weekly PP-NRS score from baseline to week 12 and the percent change in Dermatology Life Quality Index (DLQI) scores. Results: A total of 10 patients with PN (mean [SD] age, 58.6 [13.1] years; all were female) and 10 patients with CPUO (mean [SD] age, 70.7 [5.6] years; 2 were female) enrolled in the study. The mean (SD) baseline PP-NRS score was 9.2 (1.0) for PN and 8.2 (1.2) for CPUO. PP-NRS scores decreased by 78.3% in PN (95% CI, -118.5 to -38.1; P < .001) and 53.7% in CPUO (95% CI, -98.8 to -8.6; P = .01) by week 12. From baseline to week 12, 8 of 10 patients with PN and 6 of 10 patients with CPUO achieved at least a 4-point improvement on the PP-NRS. Both groups experienced significant improvement in quality of life as demonstrated by percent change in DLQI scores (PN: -53.2% [95% CI, -75.3% to -31.1%]; P = .002; CPUO: -49.0% [95% CI, -89.6% to -8.0%]; P = .02). The most common adverse event among patients was acneiform eruption in 2 of 20 patients (10%). No serious adverse events occurred. Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that abrocitinib monotherapy may be effective and tolerated well in adults with PN or CPUO. Randomized, double-blind, placebo-controlled trials are warranted to validate these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT05038982.

Spatial Mass Cytometry-Based Single-Cell Imaging Reveals a Disrupted Epithelial-Immune Axis in Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition that disproportionately affects African Americans and features intensely pruritic, hyperkeratotic nodules on the extremities and trunk. PN is understudied compared with other inflammatory skin diseases, with the spatial organization of the cutaneous infiltrate in PN yet to be characterized. In this work, we employ spatial imaging mass cytometry to visualize PN lesional skin inflammation and architecture with single-cell resolution through an unbiased machine learning approach. PN lesional skin has increased expression of caspase 3, NF-kB, and phosphorylated signal transducer and activator of transcription 3 compared with healthy skin. Keratinocytes in lesional skin are subdivided into CD14+CD33+, CD11c+, CD63+, and caspase 3-positive innate subpopulations. CD14+ macrophage populations expressing phosphorylated extracellular signal-regulated kinase 1/2 correlate positively with patient-reported itch (P = .006). Hierarchical clustering reveals a cluster of patients with PN with greater atopy, increased NF-kB+ signal transducer and activator of transcription 3-positive phosphorylated extracellular signal-regulated kinase 1/2-positive monocyte-derived myeloid dendritic cells, and increased vimentin expression (P < .05). Neighborhood analysis finds interactions between CD14+ macrophages, CD3+ T cells, monocyte-derived myeloid dendritic cells, and keratinocytes expressing innate immune markers. These findings highlight phosphorylated extracellular signal-regulated kinase-positive CD14+ macrophages as contributors to itch and suggest an epithelial-immune axis in PN pathogenesis.

No increased risk of postoperative adverse events in total joint replacement patients with hidradenitis suppurativa.

There is concern for increased risk of adverse events, particularly periprosthetic joint infection (PJI), following total joint replacement (TJR) in patients with hidradenitis suppurativa (HS) due to compromised skin barrier and bacterial colonization of lesions. We used TriNetX health research database to identify TJR patients with (n = 1,760) and without (n = 1,760) HS matched by age, sex, race, and risk factors for PJI. Multivariate analysis was performed and revealed that 90-day risk of PJI, re-operation, wound dehiscence, delayed wound healing, emergency room visits, and readmission were not increased among HS patients who underwent TJR. Given these findings, dermatologists and orthopaedists should not defer TJR access for HS patients, as risk of postoperative complications is not prohibitive.

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.

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that disproportionately affects African Americans and is characterized by pruritic skin nodules of unknown etiology. Little is known about genetic alterations in PN pathogenesis, especially relating to somatic events which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 PN patients and 10 atopic dermatitis (AD) patients for comparison. Somatic mutational analysis revealed that PN lesional skin harbors pervasive somatic mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent in NOTCH1 and the Notch signaling pathway, a regulator of cellular proliferation and tissue fibrosis, and NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, showed that recurrently deleted and downregulated genes in PN lesional skin are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, multi-center data revealed a significantly increased risk of NOTCH1-associated diseases in PN patients. In characterizing the somatic landscape of PN, we uncover novel insights into its pathophysiology and identify a role for dysregulated Notch signaling in PN.

Clinical utility of peripheral blood laboratory testing in the diagnostic workup of prurigo nodularis: A multicenter cohort study.

Background: Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with several systemic comorbidities. However, there is lack of evidence supporting specific laboratory testing in the diagnostic workup of PN patients. Objective: To characterize the frequency and severity of clinical laboratory abnormalities in PN patients compared to controls. Methods: Cross-sectional study of adult patients between October, 2015 and August, 2021 using TriNetX, a global health records database encompassing over 74 million patients. Results: A total of 12,157 PN patients were matched to 12,157 controls. Significantly, greater proportions of PN patients had moderate-to-severely decreased hemoglobin, elevated transaminases, decreased albumin, increased bilirubin, increased serum creatinine, decreased estimated glomerular filtration rate, higher hemoglobin A1c levels, and alterations in thyroid stimulating hormone. Limitations: Our data identifies associated laboratory abnormalities in PN patients but is unable to support a causal relationship. Conclusion: PN patients are more likely to have laboratory abnormalities on renal, hepatic, hematologic, endocrine, and metabolic laboratory testing, demonstrating a role for systemic testing in the diagnostic workup of PN patients.

Risk of incident sleep disorders in patients with prurigo nodularis: A population-level analysis using The Health Improvement Network.

Background: Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by severely itchy and often painful bumps on the arms, legs, and trunk. It is unknown whether patients with PN have increased risk of developing sleep disorders. Objective: To evaluate the association of PN with sleep disorders. Methods: This retrospective, population-level, matched-cohort study was conducted using The Health Improvement Network. The study included 4193 patients with newly diagnosed PN and 4193 age, sex, and race/ethnicity-matched controls. A Cox regression model was used to assess the development of sleep disorders, including insomnia, sleep apnea, and restless legs syndrome, in patients with PN compared with control patients. Results: Compared with controls, PN was associated with insomnia (adjusted hazard ratio [aHR] = 1.77; 95% CI = 1.48-2.12) and overall sleep disorder (aHR = 1.72; 95% CI = 1.46-2.02), but not with sleep apnea (aHR = 1.51; 95% CI = 0.93-2.44) or restless legs syndrome (aHR = 1.54; 95% CI = 0.92-2.57). Limitations: As a retrospective cohort study, our analysis is subject to potential confounders not already included. Conclusions: PN was associated with subsequent development of insomnia. Thus, clinicians should consider insomnia among patients with PN and develop strategies for treatment and prevention.

Topical GZ21T Inhibits the Growth of Actinic Keratoses in a UVB-Induced Model of Skin Carcinogenesis.

Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma. There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cutaneous squamous cell carcinomas. We recently showed that GZ17-6.02, an anticancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. This study evaluated the efficacy of a topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to UVR. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (P = 0.012) and surface area occupied by tumor (P = 0.002). GZ21T also suppressed the progression of AKs to cutaneous squamous cell carcinoma by decreasing the count (P = 0.047) and surface area (P = 0.049) of lesions more likely to represent cutaneous squamous cell carcinoma. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (P = 0.025), phosphoinositide 3-kinase-protein kinase B (P = 0.04), HIF-1α (P = 0.016), Wnt (P = 0.025), insulin (P = 0.018), and ERBB (P = 0.016) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K.

Ketamine Infusions for Treatment-Resistant Neuropathic Pruritus.

This case report describes a patient in her 50s with a 4-year history of brachioradial pruritus with bilateral pruritus on her upper arms and forearms.

Modulation of Neuroimmune and Epithelial Dysregulation in Patients With Moderate to Severe Prurigo Nodularis Treated With Nemolizumab.

Importance: Prurigo nodularis (PN) is a debilitating skin disease characterized by intense pruritus and hyperkeratotic skin nodules. Nemolizumab, a monoclonal antibody targeting interleukin 31 receptor α, is a promising novel therapy for the treatment of moderate to severe PN. The biological mechanisms by which nemolizumab promotes improvement of itch and skin lesions in PN are unknown. Objective: To characterize changes in plasma protein biomarkers associated with clinical response to nemolizumab in patients with PN. Design, Setting, and Participants: This multicenter cohort study included patients recruited from Austria, France, Germany, Poland, and the US from a phase 2 clinical trial. Adults diagnosed with moderate to severe PN with severe pruritus for at least 6 months were included in the original trial. Patients in the nemolizumab group were included in the present study if they achieved at least a 4-point decrease in the Peak Pruritus Numerical Rating Scale (PP-NRS) from baseline to week 12 during nemolizumab treatment. Placebo controls did not experience a 4-point decrease in PP-NRS. Mass spectrometry with tandem mass tags to enrich skin-specific protein detection was used to characterize changes in plasma protein expression in nemolizumab and placebo groups. Data were collected from November 2, 2017, to September 26, 2018, and analyzed from December 6, 2019, to April 8, 2022. Intervention: As part of the clinical trial, patients were treated with 3 doses of nemolizumab or placebo at 0, 4, and 8 weeks. Main Outcomes and Measures: Changes in plasma and epidermal protein expression in nemolizumab-treated patients compared with the placebo group at 0, 4, and 12 weeks. Results: Among the 38 patients included in the analysis (22 women and 16 men; mean [SD] age, 55.8 [15.8] years), enrichment analysis of canonical pathways, biological functions, and upstream regulators showed downregulation of terms involving inflammation (IL-6, acute-phase response, signal transducer and activator of transcription 3, and interferon γ), neural processes (synaptogenesis signaling and neuritogenesis), tissue remodeling and fibrosis (transforming growth factor ß1 and endothelin-1), and epidermal differentiation (epithelial mesenchymal transition) in the plasma of nemolizumab group. Conclusions and Relevance: In this cohort study, differences between nemolizumab and placebo groups included modulation of inflammatory signaling, neural development, and epithelial differentiation, suggesting a promising potential approach for clinical management of PN.

Diagnosing Atopic Dermatitis in Skin of Color.

Atopic dermatitis (AD) is a pruritic inflammatory skin disease that disproportionately affects skin of color patients. African American, Asian, and Hispanic patients carry disproportionate disease burdens, with increased prevalence, disease severity, and health care utilization. AD has a unique clinical presentation in skin of color patients, often with greater extensor involvement, dyspigmentation, and papular and lichenified presentations. Erythema is also more difficult to appreciate and can result in an underappreciation of disease severity in skin of color patients. In this review, we highlight the important manifestations of AD across all skin types, including nuances in treatment.

Single-cell RNA sequencing reveals dysregulated fibroblast subclusters in prurigo nodularis.

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A+ CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multicenter PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesis/permeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.