XOmiVAE-Inspired Transcriptomic Analysis of Chronic Pruritus of Unknown Origin: A Cutaneous State Distinct from Healthy Skin but Not Robustly Separable from Atopic Dermatitis.

Background/

Objectives

Chronic pruritus of unknown origin (CPUO) is mechanistically poorly resolved, and its relationship to atopic dermatitis (AD) is unclear. We asked how much apparent separation survives removal of leakage.

Methods

Public bulk skin data (GSE237920; four healthy, four AD, four CPUO) were analyzed by differential expression and an XOmiVAE-inspired latent model, with public single-cell and atlas resources for context. Every label-dependent step was then re-executed inside each cross-validation fold, with label permutation and 1000 bootstraps. A frozen composite niche score was applied unchanged to prurigo nodularis (GSE210854) and AD (GSE174582) cohorts.

Results

Fully nested, the latent classifier separated CPUO from healthy skin (AUC 1.000; permutation p = 0.020) but not from AD (0.741; p = 0.140); randomized labels also reached 1.00. The composite score reached 0.919 against healthy skin but did not exceed its null (p = 0.086). Six genes recurred in ≥80% of bootstraps, five within the signature. Cell-type-restricted blood analysis recovered CPUO-associated monocyte CCL3 upregulation. In both validation cohorts, the frozen score was reduced, not elevated, in lesional skin.

Conclusions

CPUO skin differs from healthy skin and occupies the low-inflammatory, epidermal-stress-dominated pole opposite lesional inflammatory skin, but cannot be robustly separated from AD at twelve samples.