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HIDRADENITIS SUPPURATIVA (HS) - ACNE INVERSA

Comprehensive Dermatology Resident Study Note

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1. DEFINITION AND NOMENCLATURE

• Acne inversa (preferred modern term)
• Verneuil disease (coined the term "hidradenitis suppurativa")
• Velpeau disease (first described in 1839 - axillary/groin recurrent abscesses)
• Apocrine acne
• Fox-den disease / Pyoderma fistulans sinifica (advanced disease)

The name "hidradenitis suppurativa" is a misnomer - derived from the historical hypothesis of sweat gland inflammation. Current evidence confirms it is a primary disorder of the hair follicle, not the apocrine gland.

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2. EPIDEMIOLOGY

• Incidence is rising - likely due to increased recognition + rising obesity/metabolic syndrome
• Onset after menopause is uncommon; prepubertal onset is rare
• Pediatric cases - hormonal workup is mandatory
• Prevalence in US: 0.1%

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3. PATHOPHYSIOLOGY

Primary Event: Follicular Occlusion

A perifollicular lymphocytic infiltrate in healthy-looking perilesional skin is found, suggesting subclinical inflammation precedes infundibular hyperkeratosis.

• Sebaceous gland atrophy is an early event, preceding lymphocytic infiltration - whether primary or secondary is unknown
• Apocrine glands are secondarily involved, NOT the primary site

Immunology

• Alterations in both innate and adaptive immunity
• Elevated: IL-1β, IL-6, IL-8 (CXCL-8), IL-10, IL-12p70, IL-17A
• IL-23/Th17 pathway is activated - enhanced expression of IL-17A, IL-12, IL-23 in HS skin
• Elevated antimicrobial peptides: human beta-defensin-2, psoriasin (S100A7), calgranulin (S100A8) from non-lesional keratinocytes
• Increased Toll-like receptor expression in lesional skin
• Elevated complement components C3a and C5a

Microbiology

• HS is a primary inflammatory disorder - not an infectious disease
• Cultures often negative or show only normal skin flora
• Common isolates: Staphylococcus epidermidis, S. aureus, Peptostreptococcus spp., Cutibacterium acnes
• Dysbiosis present - overabundance of Porphyromonas and Peptoniphilus species in lesional skin; relative deficiency of Cutibacterium
• Biofilm found in advanced lesions (not in early disease)
• Streptococcal antibodies usually absent
• Secondary infection with S. aureus, Streptococcus pyogenes, gram-negative organisms may occur

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4. GENETICS

• ~1/3 of patients have a positive family history
• Inheritance pattern: Autosomal dominant (familial form)
• Twin study: 3/4 of HS susceptibility is genetic
• Loss-of-function mutations in γ-secretase complex genes:
  • Nicastrin (NCSTN)
  • Presenilin-1 (PSEN1)
  • Presenilin enhancer-2 (PSENEN)
  • Found principally in Han Chinese patients; rare in European cohorts
• No genetic test currently available for clinical use
• γ-secretase regulates Notch signaling → plays a role in epidermal and terminal hair follicle differentiation, immune cell development
• Deficient Notch signaling in mice → conversion of hair follicles to keratin-enriched epidermal cysts (via changes to outer root sheath cells)
• Sporadic cases thought to result from defects in multiple genes

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5. RISK FACTORS AND TRIGGERING FACTORS

• No evidence that poor hygiene, routine depilatory techniques, or antiperspirant use contribute
• Heat avoidance and loose-fitting clothing are recommended

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6. HISTOPATHOLOGY

Early (preclinical) changes:

• Sparse lymphocytic infiltrate of terminal follicular unit
• Sebaceous gland atrophy

Developed lesions:

• Follicular hyperplasia
• Perifollicular lymphocytic inflammatory infiltration
• Interfollicular psoriasiform hyperplasia
• Dilation of follicular lumen
• Cysts lined by stratified squamous epithelium containing lamellated keratin and free hair shafts

During flares:

• Abscess formation and ruptured follicular units
• Dense, dermal, mixed inflammatory infiltrate including histiocytes and giant cells
• Extends to interfollicular apocrine and eccrine structures and deep subcutis
• Skin tunnel formation and fibrosis follow

Less frequent findings:

• Isolated inflammation of apocrine gland - apocrinitis (5%)
• Sebaceous gland necrosis
• Epithelioid granulomas
• B-cell pseudofollicles

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7. CLINICAL FEATURES

Typical Lesions (Rook's Diagnostic Criteria - Box 90.1 - San Francisco modification of Dessau criteria)

Lesion Progression:

1. Tenderness/pruritus
2. Tender papule or deep-rooted nodule (persist 7-15 days mean)
3. Nodule → fluctuant abscess → rupture → purulent, malodorous, often blood-stained exudate
4. Involution (7-10 days) or persistent open wound with granulation tissue
5. Recurrence → epithelial strands → skin tunnel (preferred term over "sinus tract") → foul-smelling serosanguinous/purulent drainage
6. Dense fibrotic plaques, rope-like scars, contractures

Key Lesion Types:

• Inflamed and non-inflamed dermal/subcutaneous nodules
• Rounded (not "pointing") abscesses - distinction from furuncles
• Draining or non-draining skin tunnels (non-draining recognized by palpable linear shape)
• Bridged/"rope-like" scars - hypertrophic or atrophic
• Tombstone comedones - paired, polyporous, grouped (secondary/pseudo-comedones); closed comedones are NOT seen
• Pyogenic granulomas at tunnel openings
• Epidermoid cysts on external genitalia, face, thorax (some patients)

Sites of Involvement (Prevalence by gender):

• Regional lymphadenopathy not routinely seen, but dermatopathic lymphadenopathy can occur in severe disease

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8. DISEASE COURSE AND PROGNOSIS

• Mean disease duration: 19 years
• Hurley stage distribution in secondary care:
  • Stage I: 45.5%
  • Stage II: 41.5%
  • Stage III: 13%
• Most do not progress beyond mild disease; those who do progress reach severe disease relatively rapidly (within 6 years of first symptoms)
• Disease less common after age 50; spontaneous remission may occur with increasing age
• Remission in ~40% after median 22-year follow-up

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9. DISEASE SEVERITY CLASSIFICATION

Hurley Staging System (gold standard for baseline staging)

Hurley staging is useful for initial stratification of therapy but is NOT useful for assessing response to therapy.

Dynamic Scoring Tools:

• HiSCR (Hidradenitis Suppurativa Clinical Response) - validated endpoint for treatment success
  • Definition: ≥50% reduction in inflamed lesions (abscesses + inflamed nodules) from baseline, WITHOUT increase in abscesses or draining skin tunnels
  • Developed from PIONEER trials of adalimumab
• IHS4 (International HS Severity Score System) - dynamic measure
• HASI-R (HS Area and Severity Index Revised) - dynamic measure
• HiSQOL - HS-specific quality-of-life instrument (validated)
• HISTORIC - international core domains process (6 domains: HS-specific QoL, pain, physical signs, patient/physician global assessment, disease progression, symptoms)

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10. ASSOCIATED CONDITIONS AND COMORBIDITIES

Follicular Occlusion Tetrad (Pillsbury, Shelley & Kligman, 1956 - original triad; 4th component added 1975):

1. Hidradenitis suppurativa
2. Acne conglobata
3. Dissecting cellulitis of the scalp
4. Pilonidal sinus

Cardiovascular:

• Metabolic syndrome prevalence in HS: 40% (OR 2.2 vs controls)
• Myocardial infarction incidence rate: 1.6x vs matched controls
• Ischemic stroke incidence rate: 1.3x vs matched controls
• Mean life expectancy in HS: 61 years (vs 71 years for psoriasis, 75 years for healthy controls)
• Death from CV disease risk: 2x higher than unselected controls; 1.6x higher than severe psoriasis

Inflammatory/Autoimmune:

• Crohn disease (strong association) - 17% of Crohn patients likely have coexistent HS; shares epidemiological, histological, and therapeutic features
• Ulcerative colitis (weaker association)
• HLA-B27-negative, RF-negative inflammatory spondyloarthropathy
• PCOS
• Sleep apnea (probably secondary to obesity)

Syndromic HS:

• PASH - Pyoderma gangrenosum + Acne conglobata + Suppurative Hidradenitis
• PAPASH - Pyogenic Arthritis + Pyoderma gangrenosum + Acne + Suppurative Hidradenitis
• PASS syndrome

Mental Health:

• Higher rates of depression and anxiety
• 2.4-fold higher rate of completed suicide vs controls

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11. COMPLICATIONS

Structural/Local:

• Lymphatic obstruction → lymphedema → scrotal/labial/penile elephantiasis (ano-genital sites most severely affected)
• Verrucous lymphangiomas
• Dermal contractures → limit joint mobility
• Vaginal, urethral, anal strictures → incontinence
• Urethral fistulization
• Fistula to GI tract (anal canal, rectum), genitourinary tract (urethra, bladder, vagina) - in perianal HS: triggers examination for Crohn disease

Malignant:

• Squamous cell carcinoma (SCC) - occurs in 4.6% of HS cases
  • After average 19 years of active disease
  • Predominantly perianal, perineal, or buttock regions in male patients
  • Carries poor prognosis
  • Can metastasize and cause death

Systemic:

• Anemia: normocytic/microcytic (multifactorial, 4-6%)
• Hypoalbuminemia
• Polyclonal hypergammaglobulinemia
• Elevated CRP
• Rarely: amyloidosis (renal), sacral bacterial osteomyelitis
• Sepsis (rare but fatal)

Quality of Life:

• DLQI more severely impaired in HS than alopecia, psoriatic arthritis, chronic urticaria
• Work absences in 58.1% of patients (33.6 days lost/year on average)
• 23% report hindrance of professional advancement

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12. DIFFERENTIAL DIAGNOSIS

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13. INVESTIGATIONS

• Diagnosis is clinical - biopsy rarely needed
• Microbiology (swabs, pus, tissue): for refractory/atypical cases to exclude superinfection and guide antibiotic therapy
• Histopathology: for atypical cases, to exclude malignancy
• Imaging:
  • Ultrasound: subclinical extension, preoperative planning
  • MRI: perianal region, complicated severe disease, preoperative planning
• Routine bloods (Hurley III):
  • Anemia (multifactorial)
  • Hypoalbuminemia
  • Polyclonal hypergammaglobulinemia
  • Elevated CRP
• Screen for comorbidities: HbA1c / oral glucose tolerance test, fasting lipids, blood pressure

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14. MANAGEMENT

Adjuvant/General Measures (All Stages):

• Patient education and information leaflets; local support groups
• BMI calculation → weight management referral if needed
• Smoking cessation support
• Loose-fitting clothing to minimize friction
• Wound dressings for suppurative disease
• Chlorhexidine gluconate wash or benzoyl peroxide wash daily
• Heat avoidance, topical aluminum chloride or botulinum toxin A for sweating
• Laser hair removal at unaffected sites as preventive therapy
• Analgesics: paracetamol, NSAIDs, centrally acting analgesics in selected cases; avoid chronic opioids
• Screening for and treatment of comorbidities (metabolic, CV, mental health)

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Treatment Algorithm by Hurley Stage:

Hurley I → Hurley II → Hurley III
    ↓           ↓           ↓
Topical     Oral        Clindamycin +
clindamycin tetracycline  Rifampicin
                           ↓
                       Adalimumab (biologic)
                           ↓
                       Infliximab / Other biologics

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Topical Therapies:

Intralesional:

• Triamcinolone (5-7 mg) for single inflammatory nodules - rapid symptom relief

Systemic Antibiotics:

Other Oral Agents:

Biologic Agents:

• HiSCR endpoint achieved by ~50% on adalimumab (PIONEER trials)
• Paradoxical exacerbation of HS can occur with anti-TNF therapy
• Lithium and sirolimus can exacerbate HS

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15. PROCEDURAL AND SURGICAL INTERVENTIONS

Integrating Biologic + Surgical Therapy:

• Moderate-severe HS often requires combined biologic + surgical approach
• Initial biologic therapy may delineate areas of scarring and make surgery more targeted
• Biologic treatment should be continued during and after surgery to prevent recurrence of inflammation delaying healing and to avoid postoperative relapse

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16. CLINICAL PEARLS

Pearl 1 - Diagnostic Delay is Massive Average diagnostic delay is 7 years. HS is consistently misdiagnosed as recurrent furunculosis. The key diagnostic features that distinguish HS: bilateral/symmetric distribution, apocrine-bearing sites, tunnels, tombstone comedones, no response to standard antibiotics for folliculitis. Always ask about family history.

Pearl 2 - It is NOT the Apocrine Gland Despite the name, HS is a primary follicular disorder. Apocrine glands are secondarily involved. The primary event is infundibular hyperkeratosis. This explains why anti-androgens and treatments targeting follicular occlusion work, while simple drainage fails.

Pearl 3 - Incision and Drainage = 100% Recurrence HS nodules are phlegmons, not true abscesses. They rarely contain drainable fluid. Performing I&D gives short-term relief but 100% recurrence and additional scarring. Only perform if frank fluctuation is demonstrated on palpation.

Pearl 4 - Adalimumab Dose Matters The approved HS dose of adalimumab (40 mg weekly) is different from the rheumatology dose (40 mg every 2 weeks). Loading doses: 160 mg week 0, 80 mg week 2, then 40 mg weekly. HiSCR is achieved in ~50% - counsel patients that complete clearance is uncommon.

Pearl 5 - Monitor for SCC in Chronic Perianal Disease Any thickening, ulceration, or verrucous change in longstanding perianal/perineal HS (especially in men >19 years of disease) must be biopsied to exclude SCC. It carries a poor prognosis and can metastasize.

Pearl 6 - Closed Comedones Are NOT Seen The presence of open/tombstone comedones (paired, polyporous) is characteristic of HS. Closed comedones are NOT a feature - their presence should prompt reconsideration of the diagnosis. Pseudo-comedones in HS are secondary, not the primary primary acne-type comedones.

Pearl 7 - Skin Tunnels ≠ Fistulae In HS, tunnels do NOT connect to the GI tract. If perianal tunnels connect to the bowel, think Crohn disease (though both can coexist). MRI/ultrasound can help delineate tunnel extent preoperatively.

Pearl 8 - Mental Health Is a Treatable Comorbidity Depression, anxiety, and 2.4x higher completed suicide rate make psychiatric screening mandatory. The HiSQOL is HS-specific and should be used. DLQI impairment in HS exceeds that of psoriatic arthritis, alopecia, and chronic urticaria.

Pearl 9 - Isotretinoin Has Limited Role Isotretinoin is NOT effective for HS as a primary indication. It helps concomitant acne vulgaris. Acitretin is more effective in HS (especially in men), though case-series level evidence only.

Pearl 10 - Tumor Necrosis Anti-TNF agents can paradoxically trigger or worsen HS when used for other inflammatory diseases (e.g., psoriasis, IBD). Also beware lithium and sirolimus as iatrogenic triggers.

Pearl 11 - HS Has a Metabolic Phenotype Metabolic syndrome is present in 40% of HS patients (OR 2.2). Mean life expectancy is only 61 years, lower even than severe psoriasis. Screen all HS patients for diabetes, dyslipidemia, hypertension, and cardiovascular disease.

Pearl 12 - Gamma Secretase and Notch Pathway Familial HS with early/severe onset should raise suspicion for γ-secretase gene mutations (NCSTN, PSEN1, PSENEN). More common in Han Chinese. Notch signaling dysregulation leads to follicular-to-cystic conversion.

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17. RAPID REVISION

Mnemonic: "HS - HAIR-FOLLICLE FIRST"

1. Typical lesions (nodules, abscesses, tunnels, bridged scars, tombstone comedones)
2. Typical sites (axillae, groin, perineal/perianal, buttocks, mammary folds)
3. Chronicity (≥2 flares in 6 months)

• I = No tunnels/scars
• II = Tunnels + scars, widely separated
• III = Entire anatomical region involved

• F:M = 3:1 (Europe) | 1:2 (Asia)
• Age: mean 24.2 years; 3rd decade most common
• Diagnostic delay: 7 years
• Prevalence: 1-2% (Europe); 0.1% (US)

• Follicular occlusion tetrad (HS + acne conglobata + dissecting cellulitis + pilonidal sinus)
• PASH / PAPASH syndromes
• Crohn disease (strong)
• Metabolic syndrome (40%)
• PCOS
• ↑ Suicide risk (2.4x)

• I&D: 100% recurrence - avoid unless frank fluctuation
• Deroofing: tissue-saving for tunnels
• CO₂ laser: "macroscopic Mohs" for moderate-severe
• Wide excision: Hurley III - only curative option

• Adalimumab ✓ (FDA approved; HiSCR ~50%)
• Infliximab (effective, off-label; standard RCT failed primary endpoint)
• Etanercept ✗ (no benefit)
• Secukinumab (anti-IL-17; promising)
• Ustekinumab (anti-IL-12/23; off-label)

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• Rook's Textbook of Dermatology, 10th Edition (2024), Chapter 90 - Ingram JR, van der Zee HH, Jemec GBE
• Fitzpatrick's Dermatology, 9th Edition, Chapter 84 - Okoye GA
• Andrews' Diseases of the Skin, 13th Edition, Chapter 13
• Dermatology (Bolognia), 5th Edition, Chapter on Hidradenitis Suppurativa

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From Andrews' - Clinical Features

• Primary site of inflammation is the terminal hair (not the gland); Plewig uses the term "dissecting terminal folliculitis" to unify HS, acne keloidalis nuchae, pilonidal sinus, and dissecting cellulitis of the scalp
• Axilla is the most frequently affected site
• Inguinal and submammary areas favored in women; buttock, perianal, and atypical areas more often in men
• Postpubertal process; prevalence 0.1% in the US; disproportionately affects women, African Americans, and 18-29 year olds
• Pediatric cases uncommon - hormonal investigation is essential
• Disease begins as tender, red nodules - firm then fluctuant and painful; rupture, suppuration, sinus tracts, extensive scarring are distinctive
• Chronic course: "honeycombed, fistulous tracts with chronic infection"
• When a probe is used, a burrowing sinus tract is detected that may extend for many centimeters, running horizontally just underneath the skin surface
• Severe debilitation more often in men; men also more often have acne and pilonidal cysts history

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From Andrews' - Complications Mentioned

• SCC (after average 19 years of active disease)
• Interstitial keratitis
• Spondyloarthropathy
• Urethral, vesical and rectal fistulas
• Anemia, hypoproteinemia
• Pyoderma gangrenosum (PG) - occurs median 19 years after onset; may be at sites distant from HS
• PASH / PASS syndrome mentioned under complications
• Significant lymphedema of penis and groin

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From Andrews' - Etiology

• Terminal follicle hyperkeratosis → rupture → release of keratin, sebum, bacteria, hairs into dermis → inflammation
• Microbiome is altered; secondary infection with S. aureus, Streptococcus pyogenes, gram-negative organisms
• Comorbidities listed: inflammatory joint disorders, psychological disorders, obesity, metabolic syndrome, hypertension, dyslipidemia, diabetes, IBD, PCOS
• Mechanical friction (worsened by obesity) as exacerbating factor
• Autosomal dominant inherited form; γ-secretase gene mutations (NCSTN, PSENEN, PSEN1) identified; mutation-positive patients have severe/extensive disease, may onset before age 13

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From Andrews' - Differential Diagnosis

• Differentiate from common furuncles (typically unilateral)
• Bartholin abscess, scrofuloderma, actinomycosis, granuloma inguinale, lymphogranuloma venereum

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From Andrews' - Treatment

• Daily cleansing with chlorhexidine gluconate (Hibiclens) or benzoyl peroxide wash
• Laser hair removal at unaffected sites as preventive therapy
• Loose-fitting clothing, weight loss, aluminum chloride or botulinum toxin A injections, smoking cessation, heat avoidance
• Intralesional steroid for earliest lesions, combined with topical clindamycin or oral doxycycline/minocycline
• Antibiotics: tetracyclines, amoxicillin, TMP-SMX DS, dapsone
• Clindamycin + rifampicin 300 mg BD - extensively studied in Europe, quite effective
• IV ertapenem for severe cases as bridge to oral therapy
• Incision and drainage is strongly discouraged
• Adalimumab 40 mg/week - FDA approved (PIONEER trials)
• Infliximab - quite effective; may clear condition during use
• Isotretinoin - most effective in young women with mild-moderate disease; remission seldom follows; secondary S. aureus infection often occurs
• Cyclosporine, acitretin, anakinra, ustekinumab may work in select cases
• Spironolactone and OCs in women; finasteride in men or postmenopausal women as adjuvants
• Oral prednisone in limited duration for acute flares
• PDT (methyl-aminolevulinate or 5-ALA) and lasers investigated

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