Translational Pathophysiology and Targeted Therapies in Hidradenitis Suppurativa

Conclusions

• Hidradenitis suppurativa appears to be driven by a complex, multilayered inflammatory network rather than a single pathway, involving neutrophils, T cells, B cells, keratinocytes, cytokines, and the microbiome.
• Early HS is characterized by inflammatory nodules and abscesses, but as disease progresses it develops deep epithelialized tunnels that are central to the chronic, draining phenotype.
• Deep dermal tunnels are not just extensions of hair follicle disease; they represent a distinct epithelial structure that sustains inflammation and neutrophil recruitment.
• IL-17 signaling is highly prominent in HS lesions, perilesional skin, and especially tunnels, and blocking IL-17A/F can substantially reduce draining tunnels and induce near-complete tunnel resolution in many patients.
• TNF is a validated pathogenic target in HS, and dual-target approaches such as anti-TNF plus OX40L may improve outcomes, though the specific mechanism of added benefit remains uncertain.
• IL-23 blockade, while highly effective in psoriasis, failed in HS, suggesting that HS uses a different type 17 biology and is less IL-23 dependent.
• The data point toward an IL-1-driven axis as an important upstream contributor to HS type 17 inflammation, making IL-1α/β or IL-1 receptor targeting promising therapeutic strategies.
• B-cell–related pathways are relevant in HS, and BTK inhibition shows early evidence of clinical benefit, supporting B cells and plasma cells as potential therapeutic targets.
• JAK inhibitors may provide broader anti-inflammatory effects in HS by suppressing multiple cytokine pathways, but they are less useful for mechanistic dissection than more targeted biologics.
• Overall, translational studies suggest that measuring tissue and blood biomarkers alongside clinical endpoints is essential for identifying which inflammatory pathways are causal and for guiding the next generation of HS therapies.