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

Sutaria, Nishadh; Alphonse, Martin P.; Marani, Melika; Parthasarathy, V.; Deng, Junwen; Wongvibulsin, Shannon; Williams, Kyle; Roh, Youkyung S.; Choi, Justin; Bordeaux, Zachary A.; Pritchard, Thomas; Dillen, Carly; Semenov, Yevgeniy R.; Kwatra, Madan M.; Archer, Nathan K.; Garza, Luis A.; Dong, Xinzhong; Kang, Sewon; Kwatra, Shawn G.

doi:10.1016/j.jid.2021.10.011

Cited by 32 publications

(33 citation statements)

References 44 publications

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“…6 Previous studies have also found that there are endotypes in PN, represented by varying degrees of circulating inflammatory biomarkers across varying immune axes, including IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, IL-25, and IFN-α. 7,8 Our findings support distinct endotypes in PN with respect to type 2 inflammation, with one cluster consisting solely of PN patients with elevated IL-13 compared to another less inflammatory cluster, which showed no significant differences between PN and control patients with respect to T h 2 biomarkers. This supports clinical observations of heterogeneity in response to T h 2-modulating therapies in PN patients.…”

supporting

confidence: 62%

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: a cluster analysis

Parthasarathy¹,

Cravero²,

Deng³

et al. 2022

Preprint

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BackgroundPrurigo nodularis (PN) is a chronic inflammatory skin disease characterized by severe pruritus and notable disease heterogeneity. There is evidence of systemic inflammation in PN, including dysregulation observed in type 2 inflammation in subsets of patients. We aimed to elucidate which components of type 2 inflammation are dysregulated in PN patients using plasma immunoassay cytokine profiling.Materials and MethodsWhole blood was obtained from PN patients with uncontrolled disease and control patients without pruritus. Plasma samples were isolated from whole blood and assayed for IL-4, IL-5, IL-13, IgE, and periostin. For statistical analysis, ANOVA was utilized to compare PN and control patients. For multiple hypothesis, adjusted p-value was calculated with a Benjamini-Hochberg procedure with the significance threshold at 0.05. Clustering was performed using K-means clustering in R version 4.0.3.ResultsSingle-plex assays of the Th2 biomarkers demonstrated significantly elevated circulating plasma IL-13 (0.13 vs. 0.006 pg/mL, p=0.0008) and periostin (80.3 vs. 60.2 ng/mL, p=0.012) in PN patients compared to controls. IL-4 (0.11 vs. 0.02 pg/mL, p=0.30) and IL-5 (0.75 vs. 0.40 pg/mL, p=0.10) were not significantly elevated, while IgE approached significance in PN (1202.0 vs. 432.7 ng/mL, p=0.08). Clustering of PN and control patients together revealed mean silhouette maximization at two clusters. Cluster 1 (n=36) consisted of 18 PN patients and 18 controls. Cluster 2 (n=11) consisted entirely of PN patients (p<0.01) (Figure 1b). When comparing the two clusters, cluster 2 had higher levels of IL-13 (0.33 vs. 0.008 pg/mL, p=0.0001) and IL-5 (1.22 vs. 0.43 pg/mL, p=0.03) compared to cluster 1. There were no significant differences in any of the biomarkers between PN patients from cluster 1 and the healthy control patients in this cluster.Figure 1.Single-plex plasma immunoassays of prurigo nodularis vs. controls (a) Plasma single-plex immunoassays (b) Heatmap of Z-scored biomarker levels for each patient, delineated by cluster. PN, prurigo nodularis; HC, healthy controlConclusionsThis study demonstrates elevation of IL-13 and periostin in PN patients with distinct clusters with varying degrees of type 2 inflammation. Given this heterogeneity, further biomarker studies with single-cell resolution will provide better guidance towards future precision medicine approaches in the treatment of PN.

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supporting

confidence: 62%

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: a cluster analysis

Parthasarathy¹,

Cravero²,

Deng³

et al. 2022

Preprint

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“…However, PN is unique from classical type 2 inflammatory diseases, such as atopic dermatitis, because it features a novel clinical presentation and unique neurovascular and fibrotic gene dysregulation, with upregulation of axon regeneration and vascular endothelial growth factor activity ( 8 ). There is also preliminary evidence of disease heterogeneity in clinical presentation and systemic inflammation, with suggestions of neural- and immune-biased disease endotypes ( 9 ). For example, in a study of plasma biomarkers, an inflammatory subset of prurigo patients presented with higher levels of interleukin (IL)-1α, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, IL-25, and interferon (IFN)-α ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: A cluster analysis

et al. 2022

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ImportancePrurigo nodularis (PN) is a chronic heterogeneous inflammatory skin disease.ObjectiveTo elucidate which components of type 2 inflammation are dysregulated systemically in PN.DesignWhole blood was obtained from PN patients with uncontrolled disease and control patients without pruritus. Plasma was assayed for IL-4, IL-5, IL-13, IgE, and periostin. ANOVA was utilized to compare PN and control patients and multiple-hypothesis adjusted p-value was calculated with the significance threshold at 0.05. Clustering was performed using K-means clustering.ParticipantsPN patients (n = 29) and controls (n = 18) from Johns Hopkins Dermatology had similar age sex, and race distributions.ResultsSingle-plex assays of the biomarkers demonstrated elevated circulating plasma IL-13 (0.13 vs. 0.006 pg/mL, p = 0.0008) and periostin (80.3 vs. 60.2 ng/mL, p = 0.012) in PN compared to controls. IL-4 (0.11 vs. 0.02 pg/mL, p = 0.30) and IL-5 (0.75 vs. 0.40 pg/mL, p = 0.10) were not significantly elevated, while IgE approached significance (1202.0 vs. 432.7 ng/mL, p = 0.08). Clustering of PN and control patients together revealed two clusters. Cluster 1 (n = 36) consisted of 18 PN patients and 18 controls. Cluster 2 (n = 11) consisted entirely of PN patients (p < 0.01). Cluster 2 had higher levels of IL-13 (0.33 vs. 0.008 pg/mL, p = 0.0001) and IL-5 (1.22 vs. 0.43 pg/mL, p = 0.03) compared to cluster 1.Conclusion and relevanceThis study demonstrates elevation of IL-13 and periostin in the blood of PN patients, with distinct clusters with varying degrees of type 2 inflammation. Given this heterogeneity, future precision medicine approaches should be explored in the management of PN.

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“…Also, in comparison to Caucasian prurigo nodularis patients, African American prurigo nodularis patients had lower transferrin and higher acute-phase reactants [such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)], eosinophils, and ferritin. The investigators concluded that patients with prurigo nodularis could be differentiated into one of two groups—each characterized by distinctive demographic and clinical features—based on the results of a plasma biomarker profile evaluation [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Hence, it has been postulated that it may be possible to establish individualized and specifically targeted treatments for prurigo nodularis patients based upon their plasma cytokine profiles [ 35 , 37 ]. Therefore, serologic evaluation—with or without the additional observation of a clinical drug challenge—may help to differentiate subsets of prurigo nodularis patients and predict optimal therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Dermatologic Disease-Directed Targeted Therapy (D3T2): The Application of Biomarker-Based Precision Medicine for the Personalized Treatment of Skin Conditions—Precision Dermatology

Cohen

Kurzrock

2022

Dermatol Ther (Heidelb)

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Precision dermatology uses individualized dermatologic disease-directed targeted therapy (D 3 T 2 ) for the management of dermatoses and for the evaluation and therapy of cutaneous malignancies. Personalized/precision strategies are based on biomarkers that are most frequently derived from tissue transcriptomic expression or genomic sequencing or from circulating cytokines. For instance, the pathologic diagnosis of a pigmented lesion and determining the prognosis of a malignant melanocytic neoplasm can be enhanced by genomic/transcriptomic analysis. In addition to biopsy, innovative techniques have been developed for

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

Cited by 32 publications

References 44 publications

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: a cluster analysis

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: a cluster analysis

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: A cluster analysis

Dermatologic Disease-Directed Targeted Therapy (D3T2): The Application of Biomarker-Based Precision Medicine for the Personalized Treatment of Skin Conditions—Precision Dermatology

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