Large‐Scale Blood Proteomic Analysis Across Different Inflammatory Skin Conditions Reveals Extensive Immune Dysregulation With Distinct Biomarker Profiles

ABSTRACT Background While significant progress has been made in understanding the molecular characteristics of inflammatory skin diseases, their systemic impact warrants further investigation. A comprehensive large‐scale study that examines systemic proteomic expression across the most common inflammatory skin diseases is currently lacking. Methods Serum from 38 alopecia areata/ AA , 41 atopic dermatitis/ AD , 21 psoriasis, 18 hidradenitis suppurativa/ HS , and 25 vitiligo patients was analyzed using OLINK high‐throughput multiplex assay explore panel and compared to 49 healthy‐matched controls. Differentially expressed proteins/ DEPs were defined using the criteria of fold change/| FCH | > 1.2, FDR < 0.1. Spearman analysis was also conducted to identify correlations between biomarkers and disease severity. Gene ontology of DEPs was performed using enrichr. Results Our results reveal both distinct and shared patterns of systemic dysregulation across the spectrum of inflammatory diseases. HS exhibited the highest level of dysregulation compared to healthy serum, followed by AA , AD , psoriasis, and vitiligo. The DEPs identified in HS showed the greatest overlap with those in psoriasis, while AA and AD also displayed significant similarity. HS and/or psoriasis primarily showed upregulation of markers belonging to T‐cell activation/migration (interleukin/ IL ‐ 2RA / CD40LG ), innate immunity ( IL ‐6/ CXCL8 / IL ‐8), Th1 ( TNF / CXCL9 / CXCL10 ), and Th17/22 ( IL ‐ 17A / IL ‐20/ CXCL1 / LCN2 ) compared to normal. AA and/or AD were characterized by upregulation of markers of general inflammation ( MMP12 ), T‐cell activation/migration ( IL ‐15/ IL ‐16), T Helper 1/Th1 ( IFNGR1 / CXCL10 ), Th2 ( IL ‐ 4R / CCL26 / CCL27 ), Th17/22 ( IL ‐19/ IL ‐20/ PI3 ) compared to controls. HS showed the largest dysregulation in cardiovascular/ CV /atherosclerosis markers ( PDGFA / SELP / MMP9 ) compared to controls (all FDR < 0.05). Spearman analysis captured multiple positive correlations between key immune markers ( IL ‐ 4R / OX40 / TNFRSF4 / IL ‐ 17A / TNF ) and respective clinical severity scores (e.g., SALT , SCORAD , IHS4 , PASI ). Conclusions Various inflammatory skin diseases show shared and distinct systemic protein immune activation. Overlap across conditions encourages the investigation of shared therapeutic approaches.