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.

Longitudinal Course of Sleep Disturbance and Relationship With Itch in Adult Atopic Dermatitis in Clinical Practice.

Background: Sleep disturbance (SD) is common in atopic dermatitis (AD). We examined the longitudinal course of SD and relationship with itch in AD patients. Methods: A prospective, dermatology practice-based study was performed (N = 1295) where patients were assessed at baseline and follow-up visits. Results: At baseline, 16.9% of the patients had severe SD based on Patient-Reported Outcomes Information System (PROMIS) SD T scores, 19.1% had difficulty falling asleep, 22.9% had difficulty staying asleep, and 34.2% had SD from AD. A total of 31.4% of the patients with difficulty staying asleep at baseline experienced persistent difficulties (for 3 follow-ups or more). Only 17.7% with baseline difficulty falling asleep had persistent disturbance. Despite significant fluctuation in sleep scores, SD generally improved over time. Of the patients facing baseline SD from AD, 31.5% experienced SD at the first visit, and only 12.3% experienced persistent SD at the second follow-up visit. Predictors of increased PROMIS sleep-related impairment T scores over time included baseline PROMIS sleep-related impairment T scores (0.74 [0.68-0.80]), having 3 to 6 nights of itch (2.22 [0.85-3.59]), and severe/very severe AD (4.40 [2.60-6.20]). Conclusions: A significant proportion of adult AD patients, particularly those with moderate-severe AD and frequent itch, had baseline SD. Although sleep scores generally improved over time, many patients experienced a fluctuating or persistent course.

Nivolumab-Induced de novo Discoid Lupus Erythematosus.

An increasing number of checkpoint inhibitor-induced subacute cutaneous lupus erythematosus events have been reported. We present the first case of nivolumab-induced discoid lupus erythematosus in a patient with hepatocellular carcinoma. The patient presents with violaceous hypopigmented plaques on the pinna bilaterally, hypopigmented plaques with central hyperpigmentation on the posterior neck, and other hypopigmented plaques on the face, forearms, and hands. For management, nivolumab was held for 2 months, and Plaquenil and topical steroids were added. Nivolumab was resumed with no further progression of DLE lesions and improvement of the skin. It is important to characterize cutaneous side effects to effectively manage them.

Assessing Dermatology Provider Perceptions and Attitudes About the Unique Needs of Older Adult Patients.

Geriatric dermatology is an emerging field of dermatology, focused on the unique needs of older adults with dermatological diagnoses. Previous research identified important principles to consider in older adults with skin disease, including cognition, polypharmacy, mobility, social support and sleep disturbance.

Longitudinal Course of Sleep Disturbance and Relationship With Itch in Adult Atopic Dermatitis in Clinical Practice.

BACKGROUND: Sleep disturbance (SD) is common in atopic dermatitis (AD). We examined the longitudinal course of SD and relationship with itch in AD patients. METHODS: A prospective, dermatology practice-based study was performed (N = 1295) where patients were assessed at baseline and follow-up visits. RESULTS: At baseline, 16.9% of the patients had severe SD based on Patient-Reported Outcomes Information System (PROMIS) SD T scores, 19.1% had difficulty falling asleep, 22.9% had difficulty staying asleep, and 34.2% had SD from AD. A total of 31.4% of the patients with difficulty staying asleep at baseline experienced persistent difficulties (for 3 follow-ups or more). Only 17.7% with baseline difficulty falling asleep had persistent disturbance. Despite significant fluctuation in sleep scores, SD generally improved over time. Of the patients facing baseline SD from AD, 31.5% experienced SD at the first visit, and only 12.3% experienced persistent SD at the second follow-up visit. Predictors of increased PROMIS sleep-related impairment T scores over time included baseline PROMIS sleep-related impairment T scores (0.74 [0.68-0.80]), having 3 to 6 nights of itch (2.22 [0.85-3.59]), and severe/very severe AD (4.40 [2.60-6.20]). CONCLUSIONS: A significant proportion of adult AD patients, particularly those with moderate-severe AD and frequent itch, had baseline SD. Although sleep scores generally improved over time, many patients experienced a fluctuating or persistent course.

Association of atopic dermatitis with delinquent behaviors in US children and adolescents.

Childhood atopic dermatitis (AD) is associated with chronic itch, pain and sleep disturbance, which may predispose children to high-risk behaviors in their school and home environments. We examined the association between AD and delinquent/high-risk behaviors in children and adolescents. Data were analyzed from The Fragile Families and Child Wellbeing Study, a longitudinal birth cohort study consisting of 4898 children born in urban cities between 1998 and 2000. A 1-year history of AD was associated with ≥ 75th percentile of mean delinquent behavior scores at age 9 (adjusted odds ratio (aOR) [95% confidence interval] 1.39 [1.14-1.68]), but not age 15 (1.05 [0.86-1.29]). At age 9, a 1-year history of AD was associated with a higher number of delinquent behaviors (adjusted risk ratio [95% CI] 1.12 [1.03-1.23]). AD at ages 5 (aOR [95%CI] 1.31 [1.04-1.64]) and 9 (1.38 [1.14-1.67]) was associated with the highest quartile of mean delinquent behavior scores at ages 9 or 15. Children with AD persisting at multiple age groups had significantly increased odds of ≥ 75th percentile of mean delinquent behavior scores at age 15 (aOR [95%CI] 1.41 [1.09-1.81]). AD was found to be associated with the following delinquent problems: damaging property (aOR [95%CI] 1.38 [1.08-1.77]), cheating on a test (1.62 [1.17-2.26]), fist fight involvement (1.47 [1.21-1.79]) and school suspension (1.36 [1.08-1.71]). This study suggests that childhood AD may precede the onset of delinquent and high-risk behaviors later in childhood and adolescence.

Atopic Dermatitis Is Associated With Multiple Behavioral Problems in US Children and Adolescents.

BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory skin disease associated with itch, sleep disturbance, psychosocial distress, anxiety, and depression. OBJECTIVE: We aimed to understand the association between AD and aberrant childhood behaviors. METHODS: We used data from the Fragile Families and Child Wellbeing Study, a longitudinal birth cohort study of 4898 urban children. RESULTS: Atopic dermatitis was associated with the 75th or greater percentile of mean behavioral scores at 5 years (multivariable logistic regression; adjusted odds ratio [aOR] [95% confidence interval {95% CI}] = 1.51 [1.18-1.93]), 9 years (1.62 [1.32-1.99]), and 15 years (1.44 [1.17-1.76]). There were significantly increased behavioral problems at age of 15 years when AD persisted at ages of 5, 9, and 15 years (Poisson regression; adjusted risk ratio [95% CI] = 1.17 [1.01-1.35]). Atopic dermatitis was associated with 12 aberrant behaviors, particularly fighting (repeated-measures logistic regression; aOR [95% CI] = 1.40 [1.15-1.70]), physically attacking people (1.38 [1.09-1.76]), being sullen (1.31 [1.15-1.49]), worrying (1.41 [1.23-1.61]), and threatening others (1.35 [1.08-1.70]). Significant 2-way interactions were present between AD and sleep as predictors of underactivity (4.31 [3.06-6.08]), being threatening (aOR [95% CI] = 3.42 [2.20-5.34]), being sullen (3.86 [2.74-5.43]), and nervousness (4.56 [3.29-6.32]). CONCLUSIONS: Childhood AD, particularly persistent disease with sleep disturbances, was associated with a wide range of behavioral problems in childhood and adolescence.

Atopic dermatitis is not associated with SARS-CoV-2 outcomes.

Atopic dermatitis is characterized by immune dysregulation, which may predispose toward worse COVID-19 outcomes. We conducted a retrospective cohort study to investigate the relationship of atopic dermatitis with COVID-19 symptom severity, hospitalization, length of hospital stay, requirement for oxygen therapy, long-term morbidity and mortality. Multivariable logistic regression models were constructed to examine the impact of atopic dermatitis (independent variable) on COVID-19 symptom severity, hospitalization, length of hospital stay, requirement for oxygen therapy, long-term morbidity and mortality (dependent variables). SARS-CoV-2 positive adult patients with diagnosed AD had similar odds of hospitalization (adjusted odds ratio [95% confidence interval]: 0.51 [0.20-1.35]), acute level of care at initial medical care (0.67 [0.35-1.30]), severe-critical SARS-CoV-2 (0.82 [0.29-2.30]), requirement of supplemental non-mechanical oxygen therapy (1.33 [0.50-3.58]), extended hospital stay (2.24 [0.36-13.85]), lingering COVID-19 symptoms (0.58 [0.06-5.31]) and COVID-19 death (0.002 [< 0.001- > 999]) compared to patients without AD. Our findings suggest AD is not an independent risk factor for COVID-19 severity or complications.

Associations between onychomycosis and COVID-19 clinical outcomes: a retrospective cohort study from a US metropolitan center.

Little is known about the relationship of COVID-19 outcomes with onychomycosis. We investigated the relationship of onychomycosis with COVID-19 outcomes. A retrospective cohort study was performed on SARS-CoV-2 positive adult outpatients or inpatients who had onychomycosis and other skin diseases. Overall, 430 adults were identified with SARS-CoV-2 and a skin disease, including 98 with diagnosed onychomycosis. In bivariable logistic regression models, onychomycosis was associated with increased hospitalization {odds ratio(OR) [95% confidence interval (CI)]: 3.56 [2.18-5.80]}, initial inpatient vs. outpatient visits (OR [95% CI]: 2.24 [1.35-3.74]), use of oxygen therapy (OR [95% CI]: 2.77 [1.60-4.79]), severe-critical vs. asymptomatic-mild severity (OR [95% CI]: 2.28 [1.32-3.94]), and death (OR [95% CI]: 7.48 [1.83-30.47]) from COVID-19, but not prolonged hospitalization (OR [95% CI]: 1.03 [0.47-2.25]). In multivariable models adjusting for socio-demographics, comorbidities, and immunosuppressant medication use, the associations with onychomycosis remained significant for hospitalization, inpatient visits, oxygen therapy, severe-critical COVID-19. Onychomycosis was a significant independent risk factor for COVID-19 severity, hospitalization, and receiving supplemental oxygen therapy.

Interventions against Social Isolation of Older Adults: A Systematic Review of Existing Literature and Interventions.

Social isolation is widespread among older adults, especially those confined to living in nursing homes and long-term care facilities. We completed a systematic review evaluating the effectiveness of 20 interventions used to combat social isolation in older adults. A scoring mechanism based on the Joanna Briggs Appraisal Checklist was utilized to determine the quality of the studies. Searches were conducted in "MedLine", "PubMed", "PsycINFO" and "Aging and Mental Health". Studies completed on group and person-centered interventions against social isolation were the highest quality as the social isolation experienced by older adults decreased after the intervention, and this effect continued in follow-up studies. Other interventions such as volunteering-based interventions also alleviated isolation; however, follow-up studies were not completed to determine long-term efficacy. Given the increase in social isolation faced by older persons during the pandemic, our review can be utilized to create effective interventions to reduce social isolation.