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

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/495051v1_fig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@101432dorg.highwire.dtl.DTLVardef@1e16d01org.highwire.dtl.DTLVardef@bb8edborg.highwire.dtl.DTLVardef@19fd785_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO 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 control C_FIG ConclusionsThis 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.