1. Introduction
HS.Hidradenitis suppurativa, TNF-α, psoriasis
DISEASE, PATHOPHYSIOLOGY, PSORIASIS, SKIN CONDITION, ABSCESSES, HIDRADENITIS SUPPURATIVA, SCARRING, PATHOLOGY, PATHOGENESIS
Janus kinase (JAK)/signal transducer and activator of transcription signaling (STAT) has been implicated in the pathophysiology of hidradenitis suppurativa (HS). This study evaluated treatment-related transcriptomic and proteomic changes in patients with moderate-to-severe HS treated with the investigational oral JAK1-selective inhibitor povorcitinib (INCB054707) in two phase 2 trials. Lesional skin punch biopsies (baseline and Week 8) were taken from active HS lesions of patients receiving povorcitinib (15 or 30 mg) once daily (QD) or a placebo. RNA-seq and gene set enrichment analyses were used to evaluate the effects of povorcitinib on differential gene expression among previously reported gene signatures from HS and wounded skin. The number of differentially expressed genes was the greatest in the 30 mg povorcitinib QD dose group, consistent with the published efficacy results. Notably, the genes impacted reflected JAK/STAT signaling transcripts downstream of TNF-α signaling, or those regulated by TGF-β. Proteomic analyses were conducted on blood samples obtained at baseline and Weeks 4 and 8 from patients receiving povorcitinib (15, 30, 60, or 90 mg) QD or placebo. Povorcitinib was associated with transcriptomic downregulation of multiple HS and inflammatory signaling markers as well as the reversal of gene expression previously associated with HS lesional and wounded skin. Povorcitinib also demonstrated dose-dependent modulation of several proteins implicated in HS pathophysiology, with changes observed by Week 4. The reversal of HS lesional gene signatures and rapid, dose-dependent protein regulation highlight the potential of JAK1 inhibition to modulate underlying disease pathology in HS.Hidradenitis suppurativa (HS) is an autoinflammatory skin condition that causes recurrent painful nodules, abscesses, and tunnel formation, leading to chronic non-healing wounds and scarring [Proteomic analysis in a limited number of samples showed that patients with HS had a greater dysregulation of circulating proteins compared to patients with psoriasis, demonstrating a larger systemic burden [Previous transcriptomic analyses of HS lesional skin have identified several inflammatory pathways that may be implicated in disease pathogenesis [Several differentially expressed genes (DEGs) identified in the prior analyses are regulated to some extent by the activation of Janus kinases (JAKs) and subsequent induction of signal transducer and activator of transcription (STAT) activity. Targeting the JAK pathway in HS was investigated because the JAK/STAT signal transduction pathways are responsible for the production of numerous pro-inflammatory mediators thought to contribute to the pathology of HS [