Racial differences in dysregulation of the renin-angiotensin-aldosterone system in patients with prurigo nodularis.

BACKGROUND: There are limited data characterizing the association between renal disease and prurigo nodularis (PN). OBJECTIVE: To characterize the association and describe mechanistic disease linkages between PN and renal comorbidities. METHODS: We conducted a cross-sectional analysis of renal comorbidities in PN using TriNetX, a global health research network providing access to medical records. Epidemiological findings provided the basis for translational studies on plasma and skin biopsy samples from PN patients stratified by race. RESULTS: PN was associated with stages 1-5 of chronic kidney disease (CKD), end-stage renal disease, nephritic syndrome, nephrotic syndrome, glomerular disease, and tubulointerstitial disease, but the associations were significantly stronger in black patients. Compared to controls, CKD progression was faster (HR 2.88, 95% CI: 1.01-8.26) only in black PN (10-year survival: 63.5% black vs. 85.5% white). Circulating plasma angiotensinogen levels were dysregulated (P < 0.001) only in black PN patients. Cutaneous transcriptomic analysis of genes related to the renin-angiotensin-aldosterone system (RAAS) revealed considerable dysregulation in PN lesions with greater dysregulation in black patients. CONCLUSIONS: Significant dysregulation of the cutaneous and systemic RAAS in black PN patients may explain the increased incidence and severity of renal disease.

Cluster Analysis of Circulating Plasma Biomarkers in Prurigo Nodularis Reveals a Distinct Systemic Inflammatory Signature in African Americans.

Patients with prurigo nodularis (PN) suffer from intractable itch and dramatic reduction in QOL. Although there is significant clinical heterogeneity in the presentation of PN, disease endotypes remain unknown. We assayed circulating plasma cytokine concentrations in patients with PN (n = 20) along with matched healthy controls and utilized an unsupervised machine learning algorithm to identify disease endotypes. We found two distinct clusters of patients with PN with noninflammatory (cluster 1) and inflammatory (cluster 2) plasma profiles. Cluster 2 had more African Americans (82%, n = 9 vs. 33%, n = 3; P = 0.028), higher Worst Itch Numeric Rating Scale scores (9.5 ± 0.9 vs. 8.3 ± 1.2; P = 0.036), and lower QOL as reflected by higher Dermatology Life Quality Index scores (21.9 ± 6.4 vs. 13.0 ± 4.1; P = 0.015). In addition, cluster 1 had a higher rate of myelopathy (67%, n = 6 vs. 18%, n = 2; P = 0.028). Compared with cluster 1, cluster 2 had higher levels of IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, IL-25, and IFN-α. With population-level analysis, African American patients with PN had higher erythrocyte sedimentation rate, C-reactive protein, ferritin, and eosinophils and lower transferrin than Caucasian patients with PN. These findings indicate discrete clusters of patients with PN with plasma biomarker profiles corresponding to distinct demographic and clinical characteristics, potentially allowing for precision medicine approaches to treat PN.

Health-related quality of life and economic burden of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is an understudied, pruritic inflammatory skin disease. Little is known about the effect of PN on quality of life and its associated economic burden. OBJECTIVE: To quantify the impact of PN on quality of life and its economic implications. METHODS: A cohort study of PN patients (n = 36) was conducted using the Health Utilities Index Mark 3 questionnaire. Control data from US adults (n = 4187) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Quality-adjusted life year loss and economic costs were estimated by comparing the Health Utilities Index Mark 3 scores of the PN patients with those of the controls. RESULTS: The PN patients had lower overall health performance compared to the controls, (mean ± SE, 0.52 ± 0.06 vs 0.86 ± 0.003, respectively, P < .001). In multivariable regression, PN was found to be associated with worse health performance (coefficient -0.34, 95% CI [-0.46 to -0.23]), most prominent in the pain subdomain (coefficient -0.24, 95% CI [-0.35 to -0.13]). This correlated to an average of 6.5 lifetime quality-adjusted life years lost per patient, translating to an individual lifetime economic burden of $323,292 and a societal burden of $38.8 billion. CONCLUSION: These results demonstrate that PN is associated with significant quality-of-life impairment, similar to the level of other chronic systemic conditions. PN is also associated with a substantial individual economic burden, emphasizing the necessity of research on effective treatment options.

Transcriptomic analysis of atopic dermatitis in African Americans is characterized by Th2/Th17-centered cutaneous immune activation.

Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in AAs with moderate to severe pruritus, lesional and non-lesional punch biopsies were taken from AA patients along with age-, race-, and sex-matched controls. Histology of lesional skin showed psoriasiform dermatitis and spongiotic dermatitis, suggesting both Th2 and Th17 activity. Gene Set Variation Analysis showed upregulation of Th2 and Th17 pathways in both lesional versus non-lesional and lesional versus control (p < 0.01), while Th1 and Th22 upregulation were observed in lesional versus control (p < 0.05). Evidence for a broad immune signature also was supported by upregulated Th1 and Th22 pathways, and clinically may represent greater severity of AD in AA. Furthermore, population-level analysis of data from TriNetX, a global federated health research network, revealed that AA AD patients had higher values for CRP, ferritin, and blood eosinophils compared to age-, sex-, and race-matched controls as well as white AD patients, suggesting broad systemic inflammation. Therefore, AA AD patients may feature broader immune activation than previously thought and may derive benefit from systemic immunomodulating therapies that modulate key drivers of multiple immune pathways.

Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization.

Prurigo nodularis (PN) is an understudied, chronic inflammatory skin disease that disproportionately affects African Americans and presents with intensely pruritic nodules of unknown etiology. To better characterize the immune dysregulation in PN, PBMCs and skin biopsies were obtained from patients with PN and healthy subjects (majority African American) matched by age, race, and sex. Flow cytometric analysis of functional T-cell response comparing patients with PN with healthy subjects identified increased γδT cells (CD3+CD4-CD8-γδTCR+) and Vδ2+ γδT enrichment. Activated T cells demonstrated uniquely increased IL-22 cytokine expression in patients with PN compared with healthy controls. CD4+ and CD8+ T cells were identified as the source of increased circulating IL-22. Consistent with these findings, RNA sequencing of lesional PN skin compared with nonlesional PN skin and biopsy site‒matched control skin demonstrated robust upregulation of T helper (Th) 22‒related genes and signaling networks implicated in impaired epidermal differentiation. Th22‒related cytokine upregulation remained significant, with stratifications by race and biopsy site. Importantly, the expression of the IL-22 receptors IL22RA1 and IL22RA2 was significantly elevated in lesional PN skin. These results indicate that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22/IL-22 profile. PN may benefit from immunomodulatory therapies directed at Th22‒mediated inflammation.

Real-world comorbidities of atopic dermatitis in the pediatric ambulatory population in the United States.

BACKGROUND: Increasing evidence has suggested the systemic nature of atopic dermatitis (AD), a common inflammatory skin condition in children. However, comprehensive analyses of real-world comorbidities in pediatric AD are limited. OBJECTIVE: To characterize comorbidity burden in patients with AD aged <18 years old. METHODS: The MarketScan commercial claims database was queried from January 1, 2017, to December 31, 2017. Age- and sex-matched analyses were used to compare patients with AD with general population controls. RESULTS: A total of 86,969 pediatric patients with AD and 116,564 matched controls were identified. Increased anxiety (odds ratio [OR], 1.20) and attention-deficit hyperactivity disorder (OR, 1.11) were noted in patients with AD. In addition to dermatologic/allergic diseases, AD was also associated with infections, including methicillin-resistant Staphylococcus aureus (OR, 3.76), and autoimmune conditions, including vitiligo (OR, 2.98) and alopecia areata (OR, 4.32). Pediatric patients with AD had higher likelihoods of lymphoid/hematologic malignancies (OR, 1.94), ocular disorders (OR, 1.37-2.02), metabolic syndrome (OR, 1.61), and obesity (OR, 1.81). For all the ORs mentioned above, P was <.001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSIONS: AD in pediatric patients was associated with a wide range of psychologic and systemic comorbidities. Increased awareness can help minimize its negative effects on the quality of life and prevent long-term health consequences in young patients with AD.

Translational Relevance of Mouse Models of Atopic Dermatitis.

The complexity of atopic dermatitis (AD) continues to present a challenge in the appropriate selection of a mouse model because no single murine model completely recapitulates all aspects of human AD. This has been further complicated by recent evidence of the distinct AD endotypes that are dictated by unique patterns of inflammation involving Th1, Th2, Th17, and Th22 axes. A review of currently used mouse models demonstrates that while all AD mouse models consistently exhibit Th2 inflammation, only some demonstrate concomitant Th17 and/or Th22 induction. As the current understanding of the pathogenic contributions of these unique endotypes and their potential therapeutic roles expands, ongoing efforts to maximize a given mouse model's homology with human AD necessitates a close evaluation of its distinct immunological signature.