Whole blood RNA-Seq identifies key pathways linked to TNF-α-inhibitor failure in patients with hidradenitis suppurativa

Summary: Abstract Body: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease often treated with TNF-α inhibitors. However, treatment often fails, and guidance for selecting therapies and predicting response is limited. Differentially expressed genes in the blood of HS patients compared to healthy controls have previously been identified, but the connection between the blood transcriptome and HS treatment response remains underexplored. Here, we analyzed bulk RNA sequencing data from whole blood of patients treated with adalimumab (N=15) and/or infliximab (N=10) for HS, using differential gene expression and Gene Ontology enrichment analysis. Patients who failed adalimumab showed downregulation of genes involved in regulation of the p38 MAPK cascade (p=0.02), which is crucial in Th17 cell differentiation and for the biosynthesis of IL-1β and TNF-α, key drivers of HS. Furthermore, these patients had decreased expression of genes involved in the regulation of epithelial cell proliferation (p=0.02), including NRARP, a known feedback inhibitor of Notch signaling. Notch signaling, particularly when induced by neutrophil extracellular traps (NETs), has been implicated the formation of sinus tunnels. Patients who failed infliximab had downregulation of genes involved in B cell activation (p=0.001), B cell receptor signaling pathway (p=0.002), and B cell differentiation (p=0.0049)—including MS4A1 (CD20). This observation aligns with previous findings that TNF-α inhibitors markedly decrease B cell activation with minimal effect on other inflammatory pathways, and suggests potential differences in B cell migration to skin lesions or reliance on B cell pathways in this subgroup. In summary, this study uncovered blood gene expression differences associated with treatment response in HS, offering insights into the immunopathogenesis of the disease and potential predictive biomarkers for response to TNF-α therapy. Albert Young¹, Randy Mi¹, Ping Wang¹, Anuradha Bishnoi¹, Andrea Dai¹, Kermanjot S. Sidhu¹, Suzanne Shoffner-Beck¹, Jeffrey Cruz¹, Sahil Kapur¹, Li Zhou¹, Indra Adrianto¹, Qing-Sheng Mi¹ 1. Dermatology, Henry Ford Health, Detroit, MI, United States. Clinical Research: Epidemiology and Observational Research