Prurigo nodularis is a Th-2-mediated immune disease

Abstract

Prurigo nodularis (PN), being a subtype of chronic prurigo, is defined as a chronic skin disorder characterized by the presence of highly pruritic, hyperkeratotic nodules that occur due to neuronal sensitization to itch and the development of an itch-scratch-itch cycle.¹ The pathogenesis of PN remains unclear, but the involvement of T-helper (Th) 1, Th2, Th17 and Th22 pathways has been implicated.^{2, 3} Data from clinical trials on the efficacy of biological drugs blocking interleukin (IL) 4, IL-13 and IL-31,⁴ that is, cytokines associated with the Th2 axis, strengthens the role of Th2-related inflammation as a key factor in evoking itch, pruriginous skin lesions and maintaining the vicious itch-scratch cycle.

To further elaborate the role of Th2-related cytokines in the pathogenesis of PN, Ständer et al.⁵ conducted a longitudinal, observational study across multiple international centres to provide an in-depth analysis of gene expression profiles of PN patients in relation to histological features and clinical parameters. The core scientific advance of this study is the subdivision of PN into two Th2-skewed immune signature groups.

The study identifies elevated expression of IL-31, IL-31 receptor A (IL-31RA), oncostatin M (OSM) and OSMRß in lesional PN skin compared to non-lesional and healthy controls, both at the mRNA and protein levels. Importantly, two Th2 subclusters were revealed: cluster 1 contained IL4R, CCL17, CCL22 and was associated with barrier-related and regulatory genes (e.g. FOXP3, LOR), while cluster 2 contained IL13, IL10 and CCL18, associated with markers of general inflammation and Th17/Th22 pathways.⁵ This bifurcation suggests distinct immunopathogenic mechanisms within PN and could help tailor biologic therapies to each immune signature group. The study by Stander et al.⁵ reinforces the role of the IL-31/OSM axis as key mediators of pruritus in PN. While the correlation between IL-31 expression and itch severity was modest, the finding is still important. It points to a complex regulatory role for IL-31, not limited to direct pruritogenic activity but possibly involving neuronal sensitization and neuroinflammation. The authors propose that OSM, derived not only from T cells but also monocytes (a novel observation), contributes to both neuroimmune signalling and dermal remodelling. The distinction between the two Th2 immune signatures has immediate translational potential. Therapies targeting IL-4/IL-13 (e.g. dupilumab) or IL-31 (e.g. nemolizumab) may benefit different patient subsets.

Interestingly, Parthasarathy et al.³ also found that PN is not a uniform disease but is comprised of distinct immunologic endotypes, with practical implications for precision medicine in the era of targeted biologics. They further supported the concept of heterogeneous type 2 inflammation in PN, highlighting IL-13 and periostin as promising systemic biomarkers. The clear clustering into inflammatory and non-inflammatory endotypes indicates stratified, biomarker-guided treatment such as IL-13 or IL-31 targeting biologics for the inflammatory PN subset.³ In addition, elevated Th17/22 markers in PN, despite being less pronounced than Th2 markers, highlight alternative future targets for patients unresponsive to current biologics.²

Despite some limitations (e.g. small number of studied patients, the exploratory nature and cohort heterogeneity and lack of the assessment of longitudinal immune changes and treatment responses), the current study by Ständer et al.⁵ convincingly demonstrates that PN encompasses at least two immunologically distinct subtypes within the Th2 axis, with interlinked roles for barrier dysfunction and neuroinflammation. These insights build on the growing recognition of PN as a neuroimmune disorder and pave the way for precision medicine approaches in dermatology. Future studies should validate these immune subgroups in larger, longitudinal cohorts, explore whether specific biomarkers predict response to targeted treatments and investigate the functional roles of identified cytokines and their cellular sources in PN pathogenesis. Overall, this article⁵ is a significant contribution to the understanding of chronic prurigo and reinforces the importance of immune phenotyping in dermatological diseases.

AR has served as a consultant, speaker or investigator for AbbVie, Almirall, Alumis Inc., Alvotech, Amgen, AnaptysBio, Arcutis Biotherapeutics, Argenx, AstraZeneca, Bioderma, Bausch Health, Celgene, Celltrion, Chema-Elektromet, Drug Delivery Solutions Ltd., Eli Lilly, Galderma, Genentech, Incyte, Janssen, Kymab Limited, LEO Pharma, Medac, Menlo Therapeutics, MetrioPharm, MSD, Novartis, OM Pharma SA, Pfizer, Pierre Fabre, Regeneron, Sandoz, Sanofi-Aventis and Trevi. AK declares no conflict of interest.