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.

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.

The relationship between job tenure and work disability absence among adults: a prospective study.

Little population-based, prospective research has been conducted to examine the demographic and work-related determinants of occupational injury or illness. This study examined the relative contribution of sociodemographic characteristics and work factors to the likelihood of a work-related disability or illness. In a representative sample of adult Canadians 25-70 years old from a prospective survey, a hazard modelling approach of time to work disability absence from the start of a new job was estimated with the following predictors: age, gender, type of job (manual, non-manual, and mixed), hours worked, highest education achieved, multiple concurrent job, job tenure, school activity, union membership and living in a rural or urban area. Workers holding manual or mixed jobs and having a low education level were factors independently associated with the increased likelihood of a work disability absence. Gender was not independently associated with work disability absences. A strong job tenure gradient in the unadjusted work disability absence rates was virtually eliminated when controlling for demographic/individual and other work factors. In multivariate analyses, work-related factors remained predictors of work disability absence whereas individual characteristics such as gender did not. The exception was workers with less education who appeared to be particularly vulnerable, even after controlling of physical demands on the job. This may be due to inadequate job training or increased hazard exposure even in the same broad job category.

Work disability absence among young workers with respect to earnings losses in the following year.

OBJECTIVES: The primary objective of this study was to evaluate the earnings losses that young workers experience in the year after a work disability absence. METHODS: The sample consisted of workers aged 16 to 24 years from a longitudinal survey of a representative sample of Canadians. Young workers who lost > or =5 days of work due to work disability or illness (ie, work disability absence) were matched to uninjured controls on the basis of age, gender, preabsence earnings, and student status. This matching procedure resulted in 173 cases and 795 controls. The outcome measure was the difference in earnings the year after the work disability episode between injured cases and their uninjured controls. RESULTS: An analysis of variance indicated that young workers experiencing a work disability absence had significantly fewer earnings than their controls in the year after the absence (P<0.05). This earnings loss was not due to between-group differences in school activity or workhours in the year after the work absence. CONCLUSIONS: No study to date has estimated the impact of work-related disability on earnings trajectories among young workers. The findings of the present study indicate that earnings losses can occur among young workers even during their transition into the labor market. Documenting the economic impacts of work injuries early in one's worklife can provide information for policy debates on the allocation of resources to control workplace hazards where teenagers and young adults work and debates on the determination of fair and adequate benefits for young workers.

Association between the decline in workers' compensation claims and workforce composition and job characteristics in Ontario, Canada.

We examined associations between workforce demographics and job characteristics, grouped by industrial sector, and declines in workers' compensation claim rates in Ontario, Canada, between 1990 and 2003. Gender, age, occupation, and job tenure were predictors for claim rates in 12 industrial sectors. The decline in claims was significantly associated with a decline in the proportion of employment in occupations with high physical demands. These findings should generate interest in economic incentives and regulatory policies designed to encourage investment in safer production processes.