An integrated scalp and blood biomarker approach suggeststhe systemic nature of alopecia areata.

BACKGROUND Alopecia areata (AA) is characterized by immunedysregulation in both scalp and blood, but a largescale approach establishing biomarkersof AA incorporating both scalp tissue and serum compartments is lacking. We aimed to characterize thetranscriptomicsignature of AA lesional and nonlesional scalp compared to healthy scalp and determine its relationship with the blood proteome in the same individuals, with comparative correlations to clinical AA disease severity. METHODS We evaluated lesional and nonlesional scalp tissues and serum from patients with moderate-to-severe AA (n=18) and healthy individuals (n=8). We assessed 33,118 genes in AA scalp tissue using RNAseq transcriptomic evaluation and 340 inflammatory proteins in serum using OLINK high-throughput proteomics. Univariate and multivariate approaches were used to correlate disease biomarkers with Severity of Alopecia Tool (SALT). RESULTS 608 inflammatory genes were differentially expressed in lesional AA scalp (fold change/FCH>1.5, false-discovery-rate/FDR<0.05) including Th1 (IFNG/IL12B/CXCL11), Th2 (IL13/CCL18), and T-cell activation-related (ICOS) products. Th1/Th2-related markers were significantly correlated with AA clinical severity in lesional/nonlesional tissue, while keratins (KRT35/KRT83/KRT81) were significantly downregulated in lesional compared to healthy scalp(P<0.05). Expression of cardiovascular/atherosclerosis-related markers (MMP9/CCL2/IL1RL1/IL33R/ST2/AGER) in lesional scalp correlated with their corresponding serum expression (P<0.05). AA scalp demonstrated significantly greater biomarker dysregulationcompared to blood. An integrated multivariateapproach combining scalp and serum biomarkers improved correlations with disease severity/SALT. CONCLUSION This study contributes a unique understanding of the phenotype of moderate-to-severe AA with an integrated scalp and serum biomarker model suggesting the systemic nature of the disease, advocating for the need for immune-based systemic treatment.