Adalimumab Treatment Modulates Vascular Changes in Hidradenitis Suppurativa Lesions in a Sex-Dependent Manner

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic, immune-mediated inflammatory skin disease characterized by painful nodules, abscesses, sinus tracts, and progressive fibrosis. Vascular activation is becoming increasingly acknowledged as an important factor in HS pathogenesis; however, the effects of tumor necrosis factor alpha (TNF-α) blockade on vascular remodeling in HS remain poorly characterized. This study investigated the impact of TNF-α inhibition by adalimumab (ADA) on endothelial and fibroblast-associated markers in HS lesions. Methods: Formalin-fixed paraffin-embedded skin samples from 71 HS patients were analyzed, including treatment-naive (n = 38) and adalimumab-treated (n = 33) cases. Histopathology and immunofluorescence were performed using antibodies against CD31, von Willebrand factor (vWF), α-smooth muscle actin (αSMA), vimentin, Ki-67 (proliferation), and cleaved Caspase-3 (apoptosis). ImageJ software was used to determine the immunoexpression of selected markers and vascular density. Vascular density, assessed as vessel count per mm2, was designated as the primary endpoint. Sex-related differences were analyzed as exploratory endpoints. Results: Adalimumab-treated tissue exhibited significantly reduced vascular density (p < 0.01) compared to the treatment-naive group. Conversely, vimentin immunoexpression was significantly higher (p < 0.01) in the adalimumab-treated group. No significant differences were found in endothelial Ki-67 or cleaved Caspase-3 expression between treatment groups, indicating that the observed reduction in vascular density is not associated with direct effects on endothelial cell proliferation or apoptosis, but rather may occur indirectly through attenuation of the pro-angiogenic inflammatory milieu. Exploratory sex-stratified analysis revealed that treatment-naive males had significantly higher endothelial proliferation (Ki-67; p = 0.031) and vimentin expression (p = 0.017) compared to treatment-naive females. In the ADA-treated group, males exhibited significantly lower vascular density (p = 0.036) and higher endothelial apoptosis (p = 0.039) compared to females, whereas females showed a significant increase in vimentin expression following treatment (p = 0.008), suggesting possible sex-dependent differences in vascular remodeling. Conclusions: TNF-α blockade is associated with reduced vascular density, consistent with indirect anti-angiogenic effects, suggesting that adalimumab exerts disease-modifying effects on the microenvironment beyond inflammatory cytokine suppression. Sex-dependent differences in vascular regression underscore the importance of considering sex as a biological variable in HS pathogenesis and treatment response. These results highlight the significance of vascular interactions in HS and support adalimumab as a disease-modifying treatment. These exploratory findings require confirmation in longitudinal studies with paired biopsies.