Pathophysiology of Hidradenitis Suppurativa
Hidradenitis suppurativa is fundamentally an immune-mediated inflammatory disease that begins with follicular occlusion of the pilosebaceous-apocrine unit, followed by follicular rupture and subsequent dysregulated innate and adaptive immune responses—not a primary infectious process. 1
Primary Defect: Follicular Occlusion
The disease cascade starts with a primary abnormality in the folliculopilosebaceous unit that leads to:
- Follicular plugging and occlusion
- Formation of perifollicular cysts that trap commensal microbes
- Rupture into the dermis, triggering the inflammatory cascade 2
This is the initiating event—not infection, not apocrine gland dysfunction—but rather a structural failure of the hair follicle unit.
Genetic Susceptibility
Multiple genetic factors predispose to HS 1:
- γ-secretase/Notch pathway mutations in familial cases
- Polygenic contributions affecting inflammatory regulation 3
- Alterations in epidermal stem cell fate in the follicular unit 3
- These genetic variations explain unique features like epithelialized tunnel formation and abnormal wound healing 3
Immune Dysregulation
Innate Immunity (Primary Driver)
The ruptured follicle triggers an exaggerated innate immune response 2:
- Elevated IL-1β and TNF-α (key pro-inflammatory cytokines)
- Neutrophilic infiltration and macrophage activation
- Enhanced IL-17 expression 4
Adaptive Immunity (Secondary Amplification)
As disease progresses, adaptive immunity becomes recruited 5, 2:
- Th1 and Th17 cell activation (IFN-γ, IL-17)
- Type 1 and type 17 helper T cell dysregulation 1
- Limited Th22 activity 5
- Plasma cell involvement
Importantly, HS lesions also contain anti-inflammatory mediators like IL-10, suggesting failed regulatory mechanisms 5.
Hormonal Influences
Sex hormones play a direct pathogenic role 3:
- Trigger disease through hormone-responsive transcription factors
- Explain onset at puberty and fluctuations with menstrual cycle, pregnancy
- Directly affect monocyte development and maturation
- May explain differential patient responses to certain biologics (e.g., IL-23 antagonists) 3
Metabolic and Adipose Tissue Contribution
Adipose tissue functions as an active immunological organ in HS 3, 6:
- Systemic metabolic dysfunction (often obesity-related) synergizes with local inflammation
- Adipokines drive inflammation and tissue destruction 6
- Alters the balance between matrix metalloproteinases (MMPs) and tissue inhibitors (TIMPs)
- Creates a perpetuating cycle of inflammation and fibrosis 6
Microbial Role (Secondary, Not Primary)
Bacteria and biofilms are contributory but secondary drivers 4:
- Mixed normal flora and commensals are cultured from lesions 1
- Biofilms present in most HS samples, especially sinus tracts 1
- Gram-negative organisms abundant in some lesions
- Cutaneous and gut microbiomes activate innate immunity but are not the primary cause 3
Progressive Inflammatory Cascade
The disease follows a characteristic progression 2:
- Acute phase: Initial follicular rupture and innate immune activation
- Recurrent phase: Intermittent inflammatory nodules and dermal tunnel formation
- Chronic phase: Suppurative inflammation affecting entire anatomic regions
- Systemic recruitment: Systemic immune system perpetuates chronic cutaneous inflammation
- End-stage: Irreversible fibrosis, scarring, and tissue destruction
Clinical Implications
This pathophysiology explains why:
- HS should be classified as immune-mediated disease, not infectious 2
- Antibiotics alone rarely achieve long-term control
- Biologic therapies targeting TNF-α, IL-17, and IL-23 show efficacy
- Surgery is needed for established tunnels and fibrosis (immune therapy cannot reverse structural damage)
- Metabolic optimization may improve treatment outcomes 6
Common Pitfall
Do not treat HS as primarily infectious—cultures showing mixed flora do not indicate treatment failure or need for different antibiotics. Culture is only indicated when secondary infection (cellulitis, fever) is suspected 1.
The heterogeneity in HS presentation reflects variable contributions from genetic, hormonal, metabolic, and microbial factors in individual patients 7, which increasingly supports personalized therapeutic selection based on clinicopathological biomarkers 7, 3.