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Cluster Analysis Characterizes 2 Distinct Subsets of Prurigo Nodularis


Using a clustering algorithm, researchers were able to identify inflammatory and noninflammatory subsets of the disease, which may account for varying responses to certain treatments.

A group of researchers have characterized 2 neuroimmune-biased endotypes of prurigo nodularis (PN) they say can guide help guide management of patients not responding to traditional treatment.

Findings were published in Journal of the American Academy of Dermatology.

Using a clustering algorithm, the researchers of the cross-sectional study were able to identify inflammatory and noninflammatory subsets of the disease, which may account for varying responses to certain treatments, including off-label use of methotrexate or dupilumab.

“The findings of this study reveal neuroimmune-biased endotypes in the pathophysiology of PN. Dermatologists should be aware of the presence of these endotypes in PN,” commented the researchers. “Bedside investigations helpful in identifying PN patients with type 2 inflammation include increased blood eosinophils and immunoglobulin E, which have also been observed to be biomarkers of type 2 inflammation and predictors of response to immunomodulatory therapy in other chronic pruritic conditions, such as chronic pruritus of unknown origin.”

As a whole, patients with PN had increased levels of 8 circulation biomarkers compared with 18 controls, including tumor necrosis factor (TNF), C-X-C motif chemokine ligand 9, interleukin (IL)-12B, IL-18, monocyte chemotactic protein-3, CUB domain-containing protein 1, and TNF receptor superfamily member 9. The researchers used Olink proteomic analysis to compare patient and control samples.

Among the 29 patient samples, the researchers identified the distinct groups of patients using partition around medoids clustering, which showed that mean silhouette width was optimized at 2 clusters.

Although the 13 patients in cluster 1 had no upregulated or downregulated proteins compared with controls, the 16 patients in cluster 2 were more inflammatory and had significantly higher expression of 31 proteins with no downregulation.

“The inflammatory cluster 2 demonstrated dysregulation of numerous immune components, including innate and adaptive immunity components,” noted the researchers. “Disrupted innate immunity in cluster 2 was identified by aberrations in macrophage biology, including MCP-1, MCP-3, IL-8, and CCL25, which are mediators that induce macrophage production, recruitment, and polarization. This is in line with findings of increased macrophages in the skin of PN patients.”

Patients in cluster 2 also showed aberrations in multiple immune axes, with cytokine and chemokine involvement of the Th1, Th2, and Th22 immune axes.

Patients in cluster 1 were slightly younger (49 vs 58 years), with the difference between the 2 groups trending toward significance, and had higher rates of history of myelopathy (69% vs 25%). More patients in cluster 2 had atopic history (38% vs 8%), with the difference approaching significance. Based on these findings, the researchers suggest screening for history of atopy, spinal disc disease, and myelopathy.

There were no significant differences in sex (85% female vs 63% female), race (72% African American vs 69% African American), Worst Itching Intensity Numerical Rating Scale score (8.69 vs 9.06), or Investigator’s Global Assessment scores (3.31 vs 3.25) between cluster 1 and cluster 2, respectively.


Parthasarathy V, Cravero K, Xu L, et al. The blood proteomic signature of prurigo nodularis (PN) reveals distinct inflammatory and neuropathic endotypes: a cluster analysis. J Am Acad Dermatol. Published online February 15, 2023. doi:10.1016/j.jaad.2023.01.042

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