Prurigo nodularis: new insights into pathogenesis and novel therapeutics.

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.

Prurigo nodularis (PN) is a chronic skin condition featuring extremely itchy nodules on the skin of the legs, arms and trunk of the body. PN affects approximately 72 per 100 000 people and the severe itch associated with the condition can negatively impact a person's sleep, work and social life. However, the cause of PN remains unclear. Current understanding of PN is based on imbalances in the immune system leading to widespread inflammation as well as dysregulation of the nerves in the skin. Immune molecules released from T cells [such as interleukin (IL)-4, -13, -31, -17, -22 and -31] increase systemic inflammation and are elevated in people with PN. Activated inflammatory cells (such as mast cells or eosinophils) may also release factors that promote inflammation, itch and neural changes within the skin. Neural dysregulation in PN features a lower density of itch-sensing nerve fibres in the epidermis (upper layer of the skin) and a higher density of itch-sensing nerve fibres in the dermis (lower layer of the skin). Because the pathogenesis of PN is not fully understood, the therapies available for PN have had limited success in reducing itch and nodules. The only drug currently approved for PN in the USA and Europe is dupilumab, an IL-4Rα inhibitor that blocks signalling through IL-4 and IL-13, which is undergoing post-marketing surveillance. Other new drugs are being assessed in various phases of clinical trials, including nemolizumab, vixarelimab, barzolvolimab, ruxolitinib, abrocitinib, povorcitinib and nalbuphine.

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.

Dupilumab Therapy Modulates Circulating Inflammatory Mediators in Patients with Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intense pruritus and skin nodules. Beyond the skin, PN involves circulating blood inflammation that may contribute to systemic disease comorbidities. Dupilumab was recently approved for treatment of PN, but its effects on systemic inflammation are unknown. Thus, we aimed to characterize changes in plasma concentrations of inflammatory proteins after dupilumab treatment. In this exploratory study, plasma samples were collected from 3 patients with moderate-to-severe PN before and after ≥6 months of dupilumab treatment. All patients exhibited clinically significant improvements after treatment. Of the 2569 proteins tested, 186 were differentially expressed after treatment (q < 0.1, fold change > 1.3). Downregulated proteins included cytokines associated with T helper (Th) 1 (IFN-γ, TNF-α), Th2 (IL-4, IL-13), and Th17/Th22 (IL-6, IL-22) signaling. Markers of innate immunity (IL-19, toll-like receptor 1, nitric oxide synthase 2), immune cell migration (CCL20, CD177), and fibrosis (IL-11, IL-22) were also decreased (q < 0.1). Gene set variation analysis of Th2, Th17, and epithelial-mesenchymal transition gene sets showed reduced pathway expression in the post-treatment cohort (P < .05). Plasma cytokine levels of IL-11, nitric oxide synthase 2, IL-13, IL-4, and IFNG (R2 > 0.75, q < 0.10) showed the strongest correlations with pruritus severity. Dupilumab may reduce systemic inflammatory proteins associated with multiple immune and fibrosis pathways in patients with PN, potentially modulating the development of systemic disease comorbidities.

Five human pathogens detected by tick surveillance in New York City parks, 2014-2015.

A total of 2,504 ticks of 5 species (Ixodes scapularis, Dermacentor variabilis, Amblyomma americanum, Haemaphysalis leporispalustris, and H. longicornis) were collected over 2 yr (2014-2015) in New York City parks. Specimens were collected via tick-dragging, identified to species, and tested for pathogens of human diseases. The causative agents of 5 human diseases (Lyme borreliosis, ehrlichiosis, babesiosis, anaplasmosis, and Rocky Mountain spotted fever) were detected in a subset of samples. Results of this surveillance effort further illustrate that risk of tick-borne disease is considerable even in parks located adjacent to densely populated areas.

Earliest records of the Asian longhorned tick (Acari: Ixodidae) in Staten Island, New York, and subsequent population establishment, with a review of its potential medical and veterinary importance in the United States.

Three Asian longhorned ticks (Haemaphysalis longicornis) were collected on Staten Island, Richmond County, New York, in 2014-2015 as part of a tick-borne disease surveillance program conducted by the New York City Department of Health and Mental Hygiene and the Defense Centers of Public Health - Aberdeen Tick-Borne Disease Laboratory. These records mark the earliest known occurrence of H. longicornis in New York State outside of quarantine areas, predating previously reported detections by several years. Robust populations of H. longicornis were collected in subsequent years at the Staten Island site where these few ticks were found, demonstrating that small infestations have the potential to proliferate quickly. Haemaphysalis longicornis is a 3-host ixodid tick native to eastern Asia but now established in the United States, as well as Australasia and several Pacific islands. Although H. longicornis has not yet been associated with human disease transmission in the United States, it warrants attention as a potential vector, as it is demonstrated to harbor various pathogens of medical and veterinary interest across its native and introduced range.

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.

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.

Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/µL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

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.

A Review on the Safety of Using JAK Inhibitors in Dermatology: Clinical and Laboratory Monitoring.

Janus kinase (JAK) inhibitors are disease-modifying agents with efficacy in treating a spectrum of burdensome dermatologic conditions. The US Food and Drug Administration (FDA) recently placed a black box warning on this class of medications due to safety concerns based on data from studies investigating tofacitinib in patients with rheumatoid arthritis. Here we provide an overview of the timeline of FDA approval of JAK inhibitors in dermatology. We also discuss the available safety profiles of approved oral JAK1 inhibitors, namely abrocitinib and upadacitinib, oral baricitinib, a JAK1/2 inhibitor, deucravacitinib, a Tyk2 inhibitor, and the topical JAK1/2 inhibitor ruxolitinib in dermatology patients. Additionally, we offer suggestions for initial screening and laboratory monitoring for patients receiving JAK inhibitors. We found that the rates of venous thromboembolism reported in trials ranged from no events to 0.1-0.5% in dermatology-specific phase 3 clinical trials compared with no events in the placebo. The rates of cardiovascular events ranged from no events to 0.4-1.2% compared with no events to 0.5-1.2% in the placebo. The rates of serious infections were 0.4-4.8% compared with no events to 0.5-1.3% in the placebo. The rates of nonmelanoma skin cancer (NMSC) ranged from no event to 0.6-0.9% compared with no events in the placebo. The rates of non-NMSC ranged from no event to 0.2-0.7% compared with no event to 0.6% in the placebo. Most patients who developed these adverse events had risk factors for the specific event. The most common adverse events of oral JAK inhibitors included upper respiratory infections, nasopharyngitis, nausea, headache, and acne. Dermatologists should consider patients' baseline risk factors for developing serious complications when prescribing oral JAK inhibitors.

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.

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.

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.