حب الشباب: الآلية المرضية وتقييم الشدة

Synonym: Neonatal acne

• Onset usually within the first 2–3 weeks of life.
• INFLAMMATORY NON-COMEDONAL pustular eruption, most commonly on the CHEEKS, less often on the forehead, chin, scalp, and chest.
• Malassezia spp. have been implicated in its pathogenesis.
• Spontaneous involution over weeks to months.

• Historically referred to as "neonatal acne", but LACKS the COMEDONES and more prolonged course that characterize infantile acne vulgaris (see Ch. 36).
• Develops within the first 2–3 weeks of life and resolves spontaneously by 3 MONTHS of age.
• Discrete papulopustules overlying variable background erythema — most commonly on the cheeks, but may also involve the forehead, chin, eyelids, neck, upper chest, and scalp.
• Some studies suggest an inflammatory response to Malassezia (Pityrosporum) spp. — M. furfur, M. sympodialis, M. globosa — may be involved.
• However, other studies found NO correlation between colonization of neonatal skin with Malassezia spp. and the presence or severity of the condition.
• These yeasts have been cultured from lesional skin, but they are part of the cutaneous MICROBIOTA in humans, so their exact role remains UNCERTAIN.
• Giemsa-stained smear of pustular contents may show yeast forms, neutrophils, and other inflammatory cells; culture of Malassezia spp. requires SPECIALIZED MEDIA.
• Can be treated with a topical imidazole or hydrocortisone, but this is not usually necessary.

• Epidemiology — NCP: COMMON, >20%–50% of term infants; male : female = 1 : 1. Infantile acne: UNCOMMON; MALES > females.
• Proposed pathogenic factors — NCP: inflammatory reaction to Malassezia spp. Infantile acne: ANDROGEN production.
• Typical age of onset — NCP: ~5 days to 3 weeks. Infantile acne: ~6 weeks to 1 year.
• Typical duration — NCP: weeks to 3 months. Infantile acne: 6 to 18 months.
• Morphology — NCP: papules and pustules on an erythematous base. Infantile acne: OPEN AND CLOSED COMEDONES, papules, pustules, occasionally nodules.
• Distribution — NCP: cheeks, forehead, eyelids, chin > neck, scalp, upper trunk. Infantile acne: primarily CHEEKS.
• Scarring — NCP: NONE. Infantile acne: OCCASIONALLY.
• Treatment — NCP: not usually necessary; topical imidazole or hydrocortisone. Infantile acne: more often necessary; topical retinoids, benzoyl peroxide, antibiotics; occasionally ORAL antibiotics or retinoids.
• Associated disease — NCP: occasionally SEBORRHEIC DERMATITIS. Infantile acne: rarely an ENDOCRINE DISORDER (consider when severe or with other signs/symptoms, e.g. virilization, abnormal growth); INCREASED LIKELIHOOD OF SEVERE ADOLESCENT ACNE.

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Synonym: Acne

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• A MULTIFACTORIAL disorder of the PILOSEBACEOUS UNIT.
• Significant PSYCHOLOGICAL and ECONOMIC impact.
• Clinically characterized by comedones, papules, pustules, and nodules.
• Potential sequelae include persistent erythema and postinflammatory hyperpigmentation as well as SCARRING.

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• Clinical picture varies significantly, from mild comedonal acne to FULMINANT SYSTEMIC DISEASE.
• All age groups may be affected, but the PEAK INCIDENCE is during ADOLESCENCE.
• Undeniable psychosocial impact: increased likelihood of self-consciousness, social isolation, anxiety disorders, depression, and even SUICIDAL IDEATION.

• Sixth century CE — the term "acne" was first used by Emperor Justinian's physician, AETIUS AMIDENUS.
• Later translated from Greek into Latin, and through these translations confusion arose regarding its original meaning.
• Debate continues whether its origin is from the Greek acme, meaning PEAK, or whether acne was actually the original term.
• Its use became OBSOLETE until the 1800s, when "acne" regained a place in medical dictionaries.
• 1842 — Erasmus Wilson separated acne simplex (acne vulgaris) from acne rosacea.

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• Affects ~40–50 MILLION individuals each year in the US alone; estimated annual US cost of at least $2.5 BILLION.
• Globally, acne accounts for ~0.3% of the TOTAL and ~15% of the DERMATOLOGIC disease burden.
• Affects ~85% of young people between 12 and 24 years of age — therefore a PHYSIOLOGIC occurrence in this group.
• With the trend toward earlier onset of puberty, PREADOLESCENT acne affecting children 7 to 11 years of age has become more common.
• Acne often continues well into adulthood. In a US survey-based study:
• 35% of WOMEN and 20% of MEN reported having acne in their 30s
• 26% of WOMEN and 12% of MEN were still affected in their 40s
• WHITE boys and men tend to have MORE SEVERE NODULOCYSTIC disease than other groups.
• Increased risk of developing acne: XYY karyotype, or endocrine disorders such as polycystic ovarian syndrome, hyperandrogenism, hypercortisolism, and precocious puberty.
• These patients tend to have more severe acne that is LESS RESPONSIVE to standard therapy.

• The precise role of genetic predisposition remains to be determined.
• The NUMBER, SIZE, and ACTIVITY of sebaceous glands is INHERITED.
• The concordance rate for prevalence AND severity of acne among IDENTICAL TWINS is EXTREMELY HIGH.
• The tendency to have substantial acne (including the nodulocystic variant) runs in families; an association between moderate-to-severe acne and a family history of acne has been observed in several studies.
• Genes possibly linked to acne via GWAS and other methods include those encoding: components of the TGF-β pathway, other inflammatory mediators, and regulators of ANDROGEN METABOLISM.

• The relationship between diet and acne remains CONTROVERSIAL.
• Several observational studies in different ethnic groups found that intake of MILK, ESPECIALLY SKIM MILK, is POSITIVELY associated with acne prevalence and severity.
• Exacerbation of acne with WHEY PROTEIN supplements for bodybuilding has been reported.
• VITAMIN B12 supplementation can potentially trigger acne or an acneiform eruption by altering the TRANSCRIPTOME of skin microbiota, leading to increased production of PROINFLAMMATORY PORPHYRINS by Cutibacterium acnes.

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• Development involves the complex interplay of FOUR MAIN FACTORS:
• (1) Follicular HYPERKERATINIZATION
• (2) HORMONAL influences on SEBUM production and composition
• (3) INFLAMMATION
• (4) C. acnes residing in the sebaceous follicle
• Genetics and exogenous factors (diet, medications, environmental exposures) also play a role.

• The MICROCOMEDO is thought to be the PRECURSOR of ALL clinically apparent acne lesions.
• It forms in the upper portion of the follicle within the LOWER portion of the infundibulum — the INFRAINFUNDIBULUM.
• Corneocytes, normally shed into the hair follicle lumen and extruded, ACCUMULATE due to increases in BOTH follicular keratinocyte PROLIFERATION AND corneocyte COHESIVENESS → hyperkeratotic plug acting as a BOTTLENECK.
• Non-invasive high-resolution imaging of facial skin confirmed that follicular dilation and accumulation of a keratotic plug PRECEDE the appearance of an inflammatory papule.
• The exact inciting event for microcomedo formation is UNKNOWN, but data support a putative role for IL-1α and INCREASES IN SKIN pH.

• The sebaceous gland expresses multiple receptors: androgen, estrogen, progesterone, retinoid, and peroxisome proliferator-activated receptors (PPARs).
• Sebum production is controlled PRIMARILY by ANDROGENS, with additional influences from other hormones and neuropeptides.
• Androgens are produced both OUTSIDE the pilosebaceous unit (mainly GONADS and ADRENAL glands) and LOCALLY within the sebaceous gland via androgen-metabolizing enzymes: 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, and 5α-reductase.
• Androgen receptors are found in cells of the BASAL LAYER of the sebaceous gland and the OUTER ROOT SHEATH of the hair follicle; responsive to testosterone and 5α-dihydrotestosterone (DHT) — the most potent androgens.
• DHT has a 5- to 10-FOLD GREATER AFFINITY than testosterone for the androgen receptor and is the PRINCIPAL androgen mediating sebum production.

Neonatal/infantile androgen physiology

• Impact of androgens on sebaceous gland activity begins during the NEONATAL period.
• From birth until ~6–12 months of age, infant BOYS have elevated LUTEINIZING HORMONE (LH), which stimulates testicular production of testosterone.
• Both male and female infants exhibit increased DHEA and DHEA sulfate (DHEAS) secondary to a large, androgen-producing "FETAL ZONE" in the ADRENAL gland that INVOLUTES during the first year of life.
• Sebaceous gland activity in infants is NOT the result of persistent MATERNAL hormonal stimulation, as was previously hypothesized.
• Both testicular and adrenal androgen production DECREASE substantially by 1 YEAR of age and remain at a STABLE NADIR until ADRENARCHE.

Adrenarche

• With the onset of adrenarche, typically at 7–8 years of age, circulating DHEAS begins to rise due to adrenal production.
• DHEAS serves as a precursor for the synthesis of MORE POTENT androgens WITHIN the sebaceous gland.
• The rise in DHEAS in prepubescent children is associated with increased sebum production and often the INITIAL development of COMEDONAL acne.

Sebum composition

• Overall composition of sebum is SIMILAR in adolescents irrespective of acne, but the sebum of those with acne tends to have:
• HIGHER levels of SQUALENE and MONOUNSATURATED FATTY ACIDS
• LESS LINOLEIC ACID
• In infants with facial acne, the skin surface lipid composition also differs from those without acne.

Estrogens and progesterone

• The physiologic role of estrogens and progesterone in modulating sebum production is NOT FULLY UNDERSTOOD.
• Estrogens, when administered SYSTEMICALLY in sufficient amounts, DECREASE sebum production, although the dose needed is GREATER than that required to suppress ovulation and increases the risk of THROMBOEMBOLIC events.
• Acne often responds to LOWER-DOSE oral contraceptives containing 20–50 mcg of ETHINYL ESTRADIOL or its esters, because suppression of ovulation itself inhibits OVARIAN androgen production.
• Postulated mechanisms of estrogen-mediated downregulation of sebogenesis:
• Direct OPPOSITION of androgens within the sebaceous gland
• A NEGATIVE FEEDBACK LOOP decreasing androgen production via inhibition of PITUITARY GONADOTROPIN release
• Regulation of genes that affect sebaceous gland activity
• Progesterone — role in human sebum production remains to be fully determined, but it CAN INCREASE sebum production in both male and female RATS, likely via modulation of the ANDROGEN RECEPTOR.

• When a follicle involved with acne RUPTURES, it exudes keratin, sebum, C. acnes, and cellular debris into the surrounding dermis, thereby intensifying inflammation.
• However, INFLAMMATION IS ALSO SEEN EARLY in acne lesion formation:
• In acne-prone sites, the number of CD4+ T cells and levels of IL-1 are INCREASED PERIFOLLICULARLY PRIOR TO HYPERKERATINIZATION.
• Insulin-like growth factor-1 increases expression of inflammatory markers and sebum production in cultured sebocytes.
• TREM2 MACROPHAGES induced by lipids such as SQUALENE promote inflammation in acne lesions and BLOCK OXIDATIVE KILLING of C. acnes.
• The TYPE of inflammatory response determines the clinical lesion observed:
• NEUTROPHILS predominate (typical of EARLY lesions) → suppuration → PUSTULE
• Neutrophils also promote inflammation by releasing LYSOSOMAL ENZYMES and generating REACTIVE OXYGEN SPECIES; levels of ROS in skin and plasma may CORRELATE WITH ACNE SEVERITY
• Influx of LYMPHOCYTES (predominantly T HELPER cells), FOREIGN BODY-TYPE GIANT CELLS, and neutrophils → inflamed papules, nodules, and cysts
• The type of inflammatory response also plays a role in SCARRING: EARLY, NONSPECIFIC inflammation results in LESS scarring than a DELAYED, SPECIFIC inflammatory response.

• C. acnes (previously Propionibacterium acnes) is a GRAM-POSITIVE, ANAEROBIC/MICROAEROPHILIC ROD found on the skin surface and within the sebaceous follicle, often together with smaller numbers of C. granulosum.
• In adults, C. acnes is the PREDOMINANT organism in the microbiome of FACIAL and other SEBACEOUS skin.
• C. acnes produces PORPHYRINS (primarily COPROPORPHYRIN III) that FLUORESCE with WOOD'S LAMP illumination.
• C. acnes is considered a COMMENSAL organism of the skin rather than a PATHOGEN PER SE.
• Although studies document increased levels of C. acnes on the facial skin of acne patients, the C. acnes DENSITY does NOT CORRELATE with clinical severity.
• RIBOTYPES 4 and 5 were more frequently found in acne patients — suggesting these strains are either more capable of inducing acne or better suited to survive in an acne environment.
• Acne-associated C. acnes PHYLOTYPES (IA-2, IB-1, IC) stimulated peripheral blood monocytes to produce the proinflammatory cytokines IL-17 and IFN-γ.
• Phylotypes found in HEALTHY skin (II [RT6], III) preferentially induced monocytes to secrete the anti-inflammatory cytokine IL-10.
• However, another study found that while monocytes from acne patients released MORE inflammatory cytokines in response to C. acnes than monocytes from unaffected individuals, NO differences were observed when C. acnes strains from acne lesions were compared with strains from normal skin of unaffected adults.

Pathogenic mechanisms of C. acnes

• Direct release of LIPASES, CHEMOTACTIC FACTORS, and ENZYMES that contribute to COMEDO RUPTURE.
• Stimulation of inflammatory cells and keratinocytes to produce proinflammatory mediators and reactive oxygen species.
• Toll-like receptors (TLRs) — transmembrane receptors mediating recognition of microbial pathogens by immune cells (monocytes, macrophages, neutrophils) and keratinocytes (see Ch. 4).
• TLR2 recognizes lipoproteins and peptidoglycans, as well as CAMP FACTOR 1 produced by inflammatory strains of C. acnes; found on the surface of MACROPHAGES surrounding acne follicles.
• C. acnes increases expression of TLR2 AND TLR4 by keratinocytes.
• Through TLR2 pathway activation, C. acnes stimulates release of IL-1α, IL-8, IL-12, TNF, and MATRIX METALLOPROTEINASES.
• IL-8 → NEUTROPHIL RECRUITMENT, release of lysosomal enzymes, and subsequent DISRUPTION OF THE FOLLICULAR EPITHELIUM.
• IL-12 → promotes Th1 responses.
• C. acnes ACTIVATES NLRP3 INFLAMMASOMES in neutrophils and monocytes → release of proinflammatory IL-1β.
• C. acnes also stimulates Th17 responses within acne lesions.
• C. acnes can induce monocytes to differentiate into TWO distinct innate immune cell subsets:
• (1) CD209+ MACROPHAGES — more effectively phagocytose and kill C. acnes; development promoted by TRETINOIN
• (2) CD1b+ DENDRITIC CELLS — activate T cells and release proinflammatory cytokines

• EARLY COMEDO: hyperkeratosis and ↑ corneocyte cohesiveness in the upper sebaceous follicle → microcomedo formation; androgen stimulation of sebum production.
• LATER COMEDO: accumulation of shed keratin and sebum; formation of WHORLED LAMELLAR CONCRETIONS; comedo may be CLOSED (no obvious follicular opening) or OPEN (dilated follicular opening; keratin plug DARKENS due to OXIDIZED LIPIDS & MELANIN).
• INFLAMMATORY PAPULE/PUSTULE: C. acnes proliferation upregulating innate immune responses (e.g. via TLRs); mild inflammation (primarily NEUTROPHILS), which increases upon RUPTURE of the comedo wall; SEBACEOUS LOBULE REGRESSION.
• NODULE/CYST: marked inflammation (primarily T CELLS); may lead to SCARRING.

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• Typically found in sites with well-developed sebaceous glands — most often the FACE and UPPER TRUNK.
• Despite evidence that inflammation is present even in the EARLIEST comedones, lesions are divided into non-inflammatory and inflammatory groups based on clinical appearance.

• Characterized by OPEN and CLOSED COMEDONES.
• CLOSED comedones (WHITEHEADS): generally small (~1 mm), SKIN-COLORED papules with NO apparent follicular opening or associated erythema.
• May be subtle — better appreciated upon PALPATION, STRETCHING, or SIDE-LIGHTING of the skin.
• OPEN comedones (BLACKHEADS): conspicuous DILATED follicular opening filled with an INSPISSATED CORE of shed keratin.
• MELANIN DEPOSITION and LIPID OXIDATION within the debris may be responsible for the BLACK COLOR.
• Larger MACROCOMEDONES are DEEP-SEATED and may be CYSTIC.

• Characterized by papules, pustules, and nodules of varying severity.
• Erythematous papules typically range from 1 to 5 mm in diameter.
• Pustules tend to be approximately equal in size and are filled with white purulent material and NORMAL MICROBIOTA, including C. acnes.
• As severity progresses, NODULES form and become markedly inflamed, indurated, and TENDER.
• The PSEUDOCYSTS of acne are DEEPER and filled with a combination of PUS and SEROSANGUINEOUS FLUID.
• In severe nodulocystic acne, lesions frequently COALESCE to form LARGE, COMPLEX, INFLAMED PLAQUES that can include SINUS TRACTS.

• EARLY TREATMENT IS ESSENTIAL for prevention of lasting cosmetic disfigurement due to scarring.
• Erythema and postinflammatory hyperpigmentation often persist after resolution of inflammatory lesions.
• Pigmentary changes usually FADE OVER MANY MONTHS if acne is brought under control, but occasionally can be PERMANENT.
• PITTED scars or HYPERTROPHIC scars (most commonly on the TRUNK) are often sequelae of nodulocystic acne.
• Skin-colored, DOME-SHAPED PAPULES on the NOSE and CHIN with histopathologic features INDISTINGUISHABLE FROM ANGIOFIBROMAS represent an additional form of acne scarring, with a predilection for MALE patients with DARKLY PIGMENTED skin.

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• Histopathologic examination demonstrates stages of acnegenesis paralleling the clinical findings.
• EARLY lesions — MICROCOMEDONES: a mildly distended follicle with a NARROWED follicular opening impacted by shed keratinocytes; the GRANULAR LAYER at this stage is PROMINENT.
• CLOSED comedones: the degree of follicular distension is INCREASED and a COMPACT CYSTIC STRUCTURE forms; within the cystic space are eosinophilic keratinaceous debris, hair, and NUMEROUS BACTERIA.
• OPEN comedones: BROAD, EXPANDED follicular ostia and GREATER OVERALL follicular distension; the SEBACEOUS GLANDS are typically ATROPHIC or ABSENT.
• A MILD PERIVASCULAR MONONUCLEAR CELL infiltrate encircles the expanding follicle.
• As the follicular epithelium distends, the cystic contents INEVITABLY begin to RUPTURE into the DERMIS.
• The HIGHLY IMMUNOGENIC cystic contents (KERATIN, HAIR, and BACTERIA) induce a MARKED INFLAMMATORY RESPONSE.
• NEUTROPHILS FIRST APPEAR, creating a PUSTULE.
• As the lesion matures, FOREIGN BODY GRANULOMATOUS INFLAMMATION ENGULFS the follicle and END-STAGE SCARRING can result.
• In ACNE FULMINANS: MASSIVE inflammation with varying degrees of OVERLYING NECROSIS; COMEDONES ARE RARELY OBSERVED; severe scarring may be seen in resolving lesions.

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• Classic acne vulgaris is usually easily recognized clinically, but the DDx of acneiform eruptions is broad, depending on age of onset, lesional morphology, and location.
• NEONATAL period:
• SEBACEOUS HYPERPLASIA — occurs in the MAJORITY of healthy neonates; transient YELLOWISH papules on the cheeks, nose, and forehead.
• MILIARIA RUBRA — very common; overheating and bundling cause TEMPORARY ECCRINE DUCT OBSTRUCTION → small inflammatory papulopustules.
• MILIA — small, white; often on the cheeks and nose; generally resolve within a few months.
• Predominantly COMEDONAL acne must be differentiated from comedonal eruptions caused by follicular occlusion or friction — acne mechanica, acne cosmetica, pomade acne, and occupational acne ("CONTACT ACNE"); history and location help.
• Sebaceous hyperplasia — very common in ADULTS, relatively uncommon in adolescents; YELLOWISH, LOBULATED papules primarily on the forehead and cheeks.
• A SOLITARY enlarged comedo is better classified as a DILATED PORE OF WINER; such lesions RARELY represent a LARGE-PORE BASAL CELL CARCINOMA.
• Multiple open comedones CLUSTERED in the LATERAL MALAR region → FAVRE–RACOUCHOT SYNDROME (Ch. 87); in a LINEAR array → NEVUS COMEDONICUS (Chs 62 & 109).
• Multiple VELLUS HAIRS arising from a dilated follicular orifice with keratinous debris → TRICHOSTASIS SPINULOSA; most common location is the NOSE.
• Angiofibromas and appendageal tumors of follicular origin (e.g. trichoepitheliomas, trichodiscomas, fibrofolliculomas) often present as multiple facial papules (Ch. 111); typically NON-INFLAMMATORY; trichoepitheliomas are concentrated in the NASOLABIAL FOLDS.
• STEATOCYSTOMA MULTIPLEX — non-inflammatory, CLOSED CYSTIC papules and nodules on the CENTRAL CHEST and BACK; AUTOSOMAL DOMINANT; must be differentiated from ERUPTIVE VELLUS HAIR CYSTS — smaller cysts that may become inflamed and contain MULTIPLE VELLUS HAIRS easily visualized microscopically.
• Folliculitis — lesions are relatively MONOMORPHOUS and COMEDONES ARE NOT PRESENT:
• GRAM-NEGATIVE folliculitis can complicate acne treated with oral antibiotics for a prolonged period; inflammatory lesions typically on the CENTRAL FACE, including the UPPER LIP, and CHEEKS.
• Pseudomonas ("HOT TUB") folliculitis favors the LOWER TRUNK and other sites covered by a BATHING SUIT.
• Malassezia (Pityrosporum) folliculitis — may develop in acne patients receiving antibiotic therapy; fine papules and pustules favoring the FOREHEAD and UPPER TRUNK.
• EOSINOPHILIC folliculitis — usually in the setting of IMMUNOSUPPRESSION (e.g. HIV infection); markedly PRURITIC.
• PSEUDOFOLLICULITIS BARBAE and ACNE KELOIDALIS NUCHAE most often affect men with Afro-textured hair (Ch. 38).
• ROSACEA — papular component favors the MALAR region, CHIN, and FOREHEAD; presence of TELANGIECTASIAS, ABSENCE of COMEDONES, and a history of EASY FLUSHING aid diagnosis; typically occurs at a LATER AGE than acne, but BOTH can develop in a single individual.
• Prolonged use of TOPICAL corticosteroids on the face may lead to rosacea-like lesions or PERIORIFICIAL DERMATITIS; ORAL corticosteroids → eruption of monomorphous papulopustules favoring the TRUNK ("STEROID FOLLICULITIS"); can occur at any age and resolves upon discontinuation.
• PSYCHOGENIC (NEUROTIC) EXCORIATIONS and FACTITIAL DERMATITIS concentrated on the face, chest, and back can mimic acne, particularly acne excoriée; LINEARITY and LACK of clinically detectable PRIMARY LESIONS are clues.

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• Milia • Osteoma cutis • Sebaceous hyperplasia • Pseudoacne of the nasal crease • Syringomas • Trichoepitheliomas\* (\early or small-sized) • Trichodiscomas, fibrofolliculomas • Eruptive vellus hair cysts†, steatocystoma multiplex† (†in the DDx of cystic lesions of the TRUNK) • Colloid milium • Acne exacerbated by systemic corticosteroids‡ or anabolic steroids (‡can also lead to a rosacea-like picture, Ch. 37*) • Contact acne (occupational, pomade, cosmetica, mechanica; chloracne) • Follicular keratosis of the chin/face • Follicular mucinosis • Follicular mycosis fungoides • Comedonal Darier disease

• Contact acne (see Closed) • Acne exacerbated by systemic corticosteroids‡ or anabolic steroids • Trichostasis spinulosa • Favre–Racouchot syndrome • Pseudoacne of the nasal crease • Nevus comedonicus • Basaloid follicular hamartoma syndrome • Familial dyskeratotic comedones • Comedonal Darier disease • Dowling–Degos disease • Radiation-induced comedones • Molluscum-induced comedones • Childhood flexural comedones (often a single DOUBLE-ORIFICE lesion) • Dilated pore of Winer (single lesion) • Trichofolliculoma (usually a single lesion) • Follicular spines — in settings such as viral-associated trichodysplasia¶, type VI pityriasis rubra pilaris¶, multiple myeloma, demodicosis¶, follicular mucinosis, follicular porokeratosis, and drug-induced (e.g. BRAF inhibitors, cyclosporine¶, acitretin)
• (¶often in the setting of HIV infection or other immunocompromised states)

• Rosacea • Perioral/periorificial dermatitis • Demodicosis (adults > children¶) • Folliculitis — culture-negative, staphylococcal, Gram-negative, eosinophilic¶, Malassezia • Acne/acneiform eruptions due to topical or systemic corticosteroids‡, anabolic steroids, or other medications (e.g. lithium, EGFR inhibitors) • Pseudofolliculitis barbae, acne keloidalis nuchae • Pseudoacne of the nasal crease • Furuncle/carbuncle • Idiopathic aseptic facial granuloma (in children) • Papulopustular eruption of Behçet disease • Neutrophilic dermatoses, neutrophilic eccrine hidradenitis, and neutrophilic sebaceous adenitis • Keratosis pilaris • Follicular keratosis of the chin/face • Viral-associated trichodysplasia (trichodysplasia spinulosa)¶ • Lupus miliaris disseminatus faciei • Psychogenic (neurotic) excoriations, factitial lesions • Follicular mucinosis • Follicular mycosis fungoides • Tinea faciei • Molluscum contagiosum (especially inflamed lesions) • Angiofibromas • Angiofibroma-like papules of the nose and chin • Dowling–Degos disease (especially the HABER SYNDROME variant) • Follicular porokeratosis • Cutaneous Rosai–Dorfman disease • Granulomatosis with polyangiitis • Syndromes associated with acne — e.g. PAPA, (PA)PASH, SAPHO, Apert syndrome

• Sebaceous hyperplasia • Milia • Miliaria rubra (especially pustular variant) • Candidal infection • Papulopustular eruption of hyper-IgE syndrome • Vesiculopustular eruption of transient myeloproliferative disorder

• Solid facial edema secondary to ROSACEA • Melkersson–Rosenthal syndrome, sarcoidosis (e.g. HEERFORDT syndrome), lepromatous leprosy • Lymphoma (B or T cell), leukemia cutis, angiosarcoma • Scleromyxedema, myxedema, self-healing (juvenile) cutaneous mucinosis • Autoimmune connective tissue disease (e.g. dermatomyositis, lupus erythematosus, Still disease) • Angioedema (lasts <24–72 hours), C1 esterase inhibitor deficiency (lasts 2–3 days), blepharochalasis/Ascher syndrome • Sweet syndrome or cellulitis — MORE ABRUPT onset • Superior vena caval obstruction • Lymphatic malformation • Pachydermoperiostosis and other genetic disorders with coarse facies • Other — trichinosis, primary systemic amyloidosis

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• Chronic inflammatory disease of the pilosebaceous unit.
• Clinical lesions: closed and open comedones and/or papules, pustules, nodules and cysts of varying degrees of inflammation and depth.
• Face, back and/or chest = most frequently affected sites.
• Complications: inflammatory macules, pigment changes, scarring, psychological distress.

Synonyms and inclusions

• Acne (acne vulgaris)
• Comedonal acne (acne comedonica)
• Prepubertal acne
• Nodulocystic acne (acne conglobata, conglobate acne)
• Acne fulminans

• One of the most common skin diseases worldwide, affecting all ethnicities and races.
• Highest prevalence in adolescence: ~85% of young adults aged 12–25 years.
• Brazilian cross-sectional study: prevalence as high as 96%; most prevalent form comedonal (61.1%), then mild (30.6%) and moderate (7.6%) papulopustular.
• Lower rates: 4.6% in children aged 0–12 and 23.4% in adults with Fitzpatrick type V–VI skin in Angola.
• Age of onset has changed over time, paralleling earlier onset of puberty.
• Prolonged course with acute or insidious relapse/recurrence; persistent papulopustular acne in 68.3% of acne patients (Shah et al. prospective observational study).
• Presentation: comedonal and/or inflammatory lesions over face and/or trunk; discomfort may be significant.
• Seborrhoea is integral to acne: higher sebum excretion → more severe acne; degree of sebum correlates with more inflammatory lesions.
• Combined impacts → psychosocial morbidity; successful treatment correlates with psychological improvement.
• Scarring more likely if treatment delayed → early treatment advocated.
• Burden is significant; remains high in adults despite lower prevalence; prevalence appears to be increasing globally — unclear whether due to western diet, earlier puberty, genetic drift or other environmental factors.

Age and sex

• Acne now presents earlier and lasts longer; may develop de novo in adulthood.
• Earlier development linked to earlier puberty (diet/obesity, lifestyle); earlier recognition may also lead to earlier presentation.
• Most commonly presents between ages 10 and 13 years in both sexes.
• Begins at a younger age in girls than boys (earlier puberty).
• Adolescent acne more common in males; postadolescent acne more common in females.
• Comedonal acne detectable in some children before any overt signs of puberty — consistent with rising adrenal DHEAS output triggering sebum production by androgen-susceptible follicles in both girls and boys.
• Early adrenarche in girls = risk factor for metabolic syndrome, PCOS and insulin resistance; early comedonal acne in girls may predict more severe disease later.
• Postadolescent acne (persistent and late-onset) more common in women:
• Observational study of patients >25 years: 31.7% had late-onset acne, of which 95% were female (acne tarda).
• Large multinational study: 26% of women aged 31–40 and 12% of women aged 41–50 had clinical acne (range 7–22% depending on ethnicity).
• International study of facial distribution of adult female acne: in almost 90% the distribution is similar to adolescent acne — the stereotype of hormonal mandibular-only inflammatory acne was NOT found in the majority.
• Case–control associations with female adult acne: personal/family history of acne in first-degree relatives, no previous pregnancies, hirsutism, working as an office worker, higher psychological stress, low consumption of vegetables/fruit and fish.
• Peak prevalence 15–20 years in all ethnic groups; lower prevalence of postadolescent acne 40 years ago is striking.
• Males have more severe acne in late adolescence than females.
• Risk factors for higher-grade acne scarring: being male, being underweight, current asthma; consumption of cereals and milk most/every day of the week reduces risk of higher-grade scarring.
• Age distribution of acne is widening in both sexes, more prominently in women over 40 years.

Ethnicity

• Acne among the 10 most common diseases worldwide.
• Ethnic variation in prevalence appears to exist even when socioeconomic/cultural differences accounted for.
• USA (NAMCS data): acne is the commonest or second most common reason for dermatologist visits in all racial groups including Asian Pacific islanders.
• Prevalence lower and rising more slowly in developing vs developed countries (DALY ratios for 15–19-year-olds by region, 1985–2015).
• Mainland China systematic review: pooled prevalence 39.2% (95% CI 0.310–0.479); south 46.3% (95% CI 0.374–0.555) higher than north 34.2% (95% CI 0.242–0.458; Z = 2.498, P = 0.012) — attributed to humidity, climate, dietary differences.
• Prevalent in all skin phototypes; phototype reported as a risk factor and may affect lesion type:
• Brazilian study: inflammatory lesions more common in light phototype; non-inflammatory in dark phototype.
• Postinflammatory hyperpigmentation more common in darker phototypes — key concern in skin of colour.
• Cultural skin/hair care practices: e.g. cocoa butter (highly comedogenic) often used within the black population.

Associated diseases

• Acne may be associated with conditions predisposing to inflammation or metabolic disturbance involving androgenic steroids, insulin resistance and increased FGFR2 signalling.
• Most acne patients have NO underlying endocrinological abnormality; the term 'endocrine acne' reserved for clear signs of endocrine disturbance (PCOS, late-onset congenital adrenogenital syndrome, Cushing disease).
• PCOS = by far the commonest endocrine disorder associated with acne.
• Female-to-male transgender patients on masculinising testosterone: elevated androgens associated with increased acne incidence.

Medical conditions that may predispose to acne or in which prevalence is reduced

Polycystic ovary syndrome

• Diagnosed by Rotterdam criteria — two of:
• Overt androgen excess (hirsutism, acne and/or alopecia).
• Ovulatory dysfunction (irregular or prolonged cycles).
• Polycystic ovaries.
• NIH criteria used in the USA:
• Rotterdam: two of (1) oligo-/anovulation, (2) clinical/biochemical hyperandrogenism, (3) polycystic ovaries; plus exclusion of other aetiologies (CAH, androgen-secreting tumours, Cushing).
• NIH: both (1) oligo-/anovulation and (2) clinical/biochemical hyperandrogenism; plus exclusion of hyperthyroidism, hypoprolactinaemia, CAH, androgen-secreting tumours, Cushing.
• Using Rotterdam criteria, 5–10% of adult women classified as PCOS.
• PCOS subtypes:
• Type I classic: hyperandrogenism present; oligomenorrhoea; cysts present; high CV risk — metabolic syndrome 3× higher; relatively higher BMI; insulin resistance; dyslipidaemia with increased small dense LDL and lipoprotein.
• Type II: hyperandrogenism present; irregular menses; no cysts; lowest CV risk (may be similar to no PCOS); lower BMI.
• Type III: hyperandrogenism normal; irregular menses; cysts present; lesser hyperandrogenism; mildest metabolic syndrome.
• Type IV: hyperandrogenism present; regular menses; cysts present; still higher CVD risk than non-PCOS.
• PCOS women frequently (not always) overweight, raised androgens or free androgen index, insulin resistant; PCOS ovaries more insulin sensitive → excess androgen; hyperinsulinaemia → excess adrenal androgen.
• Systematic review of acne prevalence in PCOS: 76% (NIH definition), 36% (Rotterdam); highest in East Asia — 3.5-fold higher than non-PCOS.
• Striking exception: adult Pacific Island women with PCOS have little or no acne (consistent with absence of acne in island population).
• PCOS increasingly diagnosed in adolescents; linked to obesity epidemic; transient insulin resistance in puberty makes attribution difficult.
• Higher prevalence of cystic ovaries in female acne patients.
• Adult women with PCOS often show peripheral hyperandrogenism: androgenic alopecia, hirsutism.

Prevalence of acne among women with PCOS (selected studies)

• 87 British (47 South Asian, 40 white): Asian 26 ± 4 y, white 30.1 ± 5 y — 66% Asian, 30% white.
• 716 Mexican, 27.7 ± 7.3 y — 15% (very low; acne not defined).
• 316 American, three groups 26.3 ± 6.9; 27.3 ± 6.9; 30 ± 7.8 — 19%.
• German, age 28 — 50% (vs 33% without PCOS).
• 273 Chinese, 24.83 ± 5.31 — 45%.
• 295 Taiwanese, 14–40 (26.7 ± 5.4) — 48% (vs 18% age-matched non-PCOS).
• 32 Tanzanian, 29.3 ± 4.5 — 41% (vs 17.6 for 68 non-PCOS).
• 103 American, 13–20 — 33%.
• 70 American, 11–22 (16.2) — 70%.
• 49 Indian, 12–19 — 67%.
• 51 Indian, 15–32 (22.2 ± 5.4) — 55%.
• 42 Indian, 17–31 (22.4 ± 5.53) — 54%.
• 62 Saudi Arabian, 29–43 — 39%.
• 115 Turkish, 15–41 — 53% (35% had seborrhoea).
• 210 Iranian, 17–18 — 27% (severe acne only).
• 58 American, 9–18 — 74% (five girls premenarchal).
• 318 Taiwanese, 24.5 ± 5.0 — 39%.
• 74 Greek — (no figure).
• 365 Croatian, 26.1 ± 5.9 — 50%.
• 136 Indian girls (49 PCOS, 87 without): PCOS 18.8 ± 8.5; non-PCOS 19.8 ± 0.67 — 33% vs 14.9%.
• 100 Indian, 20–38 — 13% (very low).
• 133 Turkish, 17–36 — 26% moderate/severe; 65% mild (GAGS used).
• 196 American, 11–20 (15.7 ± 1.7) — 18% moderate/severe; 53% mild.
• 10 Palestinian, 18–24 — 80% (vs 37.2% non-PCOS).
• 149 American (121 white, 28 Asian), 28 ± 5.4 white; 29.6 ± 5.9 Asian — 68% white vs 74% Asian (NS).
• 40 Korean, two groups 24.7 ± 5.1; 25.7 ± 8.2 — 95% (seborrhoea in 45%).
• 254 American, two groups 28.8 ± 5.67; 27.8 ± 6.10 — 61%.
• 59 Turkish, 21.49 ± 4.18 — 46%.

Late-onset (non-classic) congenital adrenal hyperplasia

• Relatively common autosomal recessive; incidence 1 : 500 to 1 : 1000 in white populations.
• Mutations in CYP21A2 gene at chromosome 6p21 → 21-hydroxylase deficiency (key enzyme in mineralocorticoid/glucocorticoid synthesis from progesterone and 17-OHP).
• Intermediates accumulate: elevated 17-OHP, progesterone, androstenedione (adrenal steroidogenesis pathway).
• Raised serum 17-OHP (basal or after ACTH stimulation) = diagnostic marker, but NOT 100% sensitive for CYP21A2 mutation carriers.
• Table 88.5 clinical features: Adulthood — short stature, hirsutism, acne, testicular enlargement in boys, oligospermia, menstrual irregularities, infertility both sexes. Childhood — tall stature, pseudoprecocious puberty, cystic acne, premature pubarche.
• Acne NOT a consistent feature; prevalence in women with androgen excess 0.6% to 9%; higher in some Jewish, Mediterranean, Middle Eastern and Indian populations.
• Most often diagnosed late childhood/early adulthood; can present as precocious puberty.
• Severe, refractory or atypical acne may represent late-onset CAH (16-year-old with oligomenorrhoea, post-therapy with 2 mg oral prednisolone daily).
• Widely underdiagnosed, particularly in males.
• Assessment of male acne patients for CAH:
• History: acne/infertility.
• Examination: testicular examination.
• Biochemistry: basal 17-OHP (>6.1 nmol/L screens for non-classic CAH); ACTH-stimulated 17-OHP (elevated basal or stimulated >260 ng/dL); LH, FSH; testosterone, DHEAS, androstenedione, 21-desoxycortisol.
• Testicular ultrasound; semen analysis.
• Treatment of acne with late-onset CAH in males: oral glucocorticoids — low-dose prednisolone 2.5–5 mg/day or dexamethasone 0.25–0.75 mg/day (the latter has higher risk of adrenal suppression).

Hypercortisolism / Cushing disease

• Hypercortisolism: signs/symptoms of prolonged inappropriately high cortisol or Cushing disease.
• Cushing disease = hypercortisolism from excess ACTH from a corticopituitary adenoma; ACTH levels often lower in Cushing syndrome.
• CUSHING mnemonic:
• C – central obesity, collagen fibre weakness, comedones (acne)
• U – urinary free cortisol and glucose intolerance
• S – striae, suppressed immunity
• H – hypercortisolism, hypertension, hyperglycaemia, hypercholesterolaemia
• I – iatrogenic (increased corticosteroid administration)
• N – non-iatrogenic (neoplasms)
• G – glucose intolerance, growth retardation

Acromegaly

• Excess growth hormone associated with acne; GH and excess IGF-1 stimulate sebaceous gland differentiation and androgen-induced lipogenesis; increased sebum; acne may be the only presenting symptom.

SAPHO syndrome

• Acronym first described 1987: synovitis, acne, pustulosis, hyperostosis, osteitis — pustular dermatoses + aseptic osteoarticular lesions.
• Classic: sudden-onset haemorrhagic and ulcerative acne on face and trunk, sterile palmoplantar pustules, pain esp. anterior chest wall.
• Underdiagnosed in mild cases; skin manifestations commoner in adults; severe acneform disease (acne fulminans, conglobata, HS) predominantly in males.
• May be immune reaction to unspecified antigen; C. acnes isolated from osteitic bone in some cases; bony lesions fail to respond to antibiotics (not primary haematogenous spread).
• Bisphosphonates improve bony lesions but not skin.
• Increased TNF-α; benefit from infliximab and ustekinumab in isolated cases.
• Opposing effects: TNF-α antibodies — articular improvement/cutaneous deterioration; isotretinoin — cutaneous improvement/articular deterioration.

HAIR-AN syndrome

• Hyperandrogenism, insulin resistance, acanthosis nigricans.
• Signs: hyperseborrhoea, hirsutism, acne, menstrual irregularity, androgenetic alopecia; also deepening voice, clitoromegaly, increased muscle mass.
• Associated: Graves disease, Hashimoto thyroiditis, Cushing syndrome, Cohen syndrome, acromegaly, CAH, insulinoma.
• Primary abnormality = hyperinsulinaemia; elevated/upper-limit testosterone and androstenedione; insulin excess correlates directly with androgen levels.
• Reduced insulin receptors and/or receptor gene mutations in some; insulin binding to IGF/insulin receptors on keratinocytes and fibroblasts → epidermal thickness → acanthosis nigricans.

SAHA syndrome

• Defined 1982: seborrhoea, acne, hirsutism and/or androgenetic alopecia in females.
• Types: idiopathic, ovarian, adrenal, hyperprolactinaemic.
• All four signs present in only ~20%; seborrhoea consistent; acne in ~10%.

PAPA syndrome and PAPA spectrum disorders

• First described 1997; rare autosomal dominant autoinflammatory disease; mutations in PSTPIP1 (proline/serine/threonine phosphatase interacting protein 1; also CD2BP1) — cytoskeleton-associated adaptor in haematopoietic cells modulating T-cell activation and IL-1β release.
• PAPA spectrum:
• PAPA — PSTPIP1; pyogenic sterile arthritis, PG, acne conglobata; arthritis predominant, juvenile onset, destructive.
• PASH — PSTPIP1, NCSTN, MEFV, NOD2, NLRP3; PG, acne, HS; absence of pyogenic sterile arthritis distinguishes from PAPASH/PAPA.
• PASS — unknown gene; PG, acne, HS, spondylarthritis.
• PAPASH — PSTPIP1, IL1RN, MEFV; PAPA + HS.
• PsAPASH — unknown; PG, acne, HS, psoriatic arthritis.
• PAC — PSTPIP1; PG, acne, ulcerative colitis.
• PAMI — PSTPIP1; PSTPIP1-associated myeloid-related proteinaemia inflammatory syndrome: hypercalprotectinaemia, hyperzincaemia, raised myeloid-related protein, hepatosplenomegaly, arthritis, pancytopenia, failure to thrive.
• PAPA: recurrent sterile erosive arthritis in childhood after minor trauma (may destroy joints); joint disease subsides by puberty → transition to skin disease: pathergy (abscesses at injection sites), severe nodulocystic acne in adolescence, recurrent sterile ulcers (PG).
• Review of PAPA spectrum: acne in 37 of 49 cases; severe-or-worse phenotype in 83%; topography of acne vulgaris (face, trunk), four cases with scalp involvement; PG and acne may persist for decades.
• Treatment: systemic/local glucocorticosteroids for inflammation; TNF-α blockade, IL-1 receptor antagonists (anakinra, canakinumab) improved acne in case reports.

Apert syndrome

• Acrocephalosyndactyly; first described 1906; prevalence 15/1 000 000 births.
• Craniosynostosis, early epiphyseal closure → skull/hand/foot deformities; hypertelorism, flattened occiput, proptosis, prognathism, parrot-beaked nose, fused shortened digits; delayed tooth eruption, shovel-shaped incisors, malocclusion; cleft soft palate, bifid uvula.
• Moderate to severe acne early in puberty is characteristic; trunk and face plus unusual sites — forearms and buttocks.
• Early epiphyseal closure is androgen-mediated; no difference in androgen receptor expression → abnormal sensitivity to normal androgen levels.
• Other skin: seborrhoea, hyperhidrosis, nail dystrophy, plantar hyperkeratosis, ocular/cutaneous hypopigmentation.
• Autosomal dominant or new paternal-origin mutation; two heterozygous missense FGFR2 mutations — S252W or P253R — in linker region between D2 and D3 immunoglobulin-like domains.
• Isoforms: FGFR2b (epithelial only), FGFR2c (dermal/mesenchymal only); signalling affects follicular keratinocyte proliferation, sebaceous lipogenesis, inflammatory cytokines.
• Acne frequently requires oral isotretinoin; etretinate effective in refractory cases.

Drug-induced acne

• Acneform reactions ≈ 1% of all drug-induced skin eruptions.
• Monomorphic inflammatory lesions, absence of comedones, often acute, at sites not commonly affected; face and upper trunk most frequent; interval depends on agent.
• drugs that may exacerbate or cause acne:
• Corticosteroid: topical (betamethasone), oral (prednisolone), inhaled (budesonide).
• ACTH: ACTH, synthetic ACTH.
• Anabolic steroid/synthetic androgen: danazol, nandrolone, stanozolol.
• Anticonvulsant: carbamazepine, phenytoin, phenobarbitone, troxidone, gabapentin, topiramate.
• Antidepressant: lithium, sertraline, vortioxetine.
• Other neuroleptic/antipsychotic: pimozide, risperidone.
• Antitubercular: isoniazid, pyrazinamide.
• Antineoplastic/EGFR antagonists: dactinomycin, pentostatin, cetuximab.
• Antiviral: ritonavir, ganciclovir.
• Calcium antagonist: nilvadipine, nimodipine.
• Halogen: sodium fluoride, potassium iodine.
• Human growth hormone: genetically engineered hGH.
• Vitamins: vitamin B12, possibly other B vitamins.
• Miscellaneous: buserelin, cabergoline, ciclosporin, sirolimus, tacrolimus, clofazimine, dantrolene, disulfiram, famotidine, follitropin alfa, isosorbide mononitrate, medroxyprogesterone, mesalazine, quinine, ramipril, sulphur, thiouracil, thiourea.
• Corticosteroids: acneform reaction regardless of route; mechanism uncertain; more monomorphic than acne vulgaris but both inflammatory and comedonal lesions may be present on face, back, chest.
• Anabolic androgenic steroids (testosterone derivatives/salts): exacerbate acne vulgaris (body builder), induce acne fulminans or conglobata; androgen receptor binding → sebaceous hypertrophy, increased sebum and C. acnes density; not all bind AR → other mechanisms; up to 43% of users have acne.
• Amino acid supplements: branched-chain amino acids (leucine, isoleucine, valine); leucine stimulates mTORC1-SREBP signalling, converted by sebocytes into fatty acids/sterols → promotes acne.
• DHEA supplements: increase lean mass, decrease fat; in adrenal insufficiency reduce cholesterol, improve well-being, insulin sensitivity, bone density ('antiaging superhormone'); side effects hair loss and acne (DHEA is major androgen driving sebum).
• Immunosuppressive drugs: ciclosporin → comedonal lesions 2–3 months after initiation, dose-independent; acne-like eruption in up to 25% of transplant patients; may extend beyond face/trunk, nodular component common; sirolimus — scalp folliculitis within a few weeks; impacts QoL/adherence esp. adolescent females; oral tacrolimus less likely (low skin accumulation); localised acne with topical tacrolimus for vitiligo after 3 months; conventional therapy, modify immunosuppressant if severe/refractory.
• Psychotropic drugs: lithium (lesions beyond seborrhoeic areas, monomorphic), amineptine, vortioxetine.
• Lithium acne presents 2–3 months after start; acne conglobata described; males more susceptible; mechanism: neutrophil chemotaxis/degranulation + direct follicular keratinocyte effect → plugging; discontinue if possible; tetracyclines increase lithium levels.
• Amineptine: mostly adult females; comedonal lesions predominant, sparse inflammatory; mechanism: decreased dopamine uptake → elevated dopamine inhibits prolactin → increased testosterone; withdraw drug; variable response; may need systemic therapy and physical comedone treatment.
• Progestins: varying androgenic effects; levonorgestrel IUS, implants, mini-pills can exacerbate acne; cause–effect hard to establish; delayed onset of acne with intrauterine progestogens.
• increasing androgenic effect: desogestrel → norgestimate → norethindrone → ethynodiol diacetate → levonorgestrel → norgestrel → norethindrone.
• Isoniazid: slow inactivators may develop acneform rash.
• Antiepileptics: reported, but hospitalised severe epilepsy study (including phenytoin) showed NO increased risk vs matched controls.
• Iodides and bromides: commonly and rapidly cause follicular pustules; iodides in non-prescription asthma preparations, expectorants, kelp, teas; bromides in sedatives and cold remedies. Chloracne = systemic poisoning, usually occupational; dioxins most potent (Viktor Yushchenko, 10 000 ppt tetrachlorodibenzodioxin).
• Vitamins B2, B6, B12: monomorphic small follicular inflammatory lesions on forehead, chin, upper arms, trunk with vitamin B12 5–10 mg/day; women almost exclusively; onset within first 2 weeks post-injection; B6 acne-inducing dose not established; B12 promotes porphyrin production by C. acnes; conventional therapy usually fails; withdrawal → resolution within 10 days.
• EGFR inhibitors: follicular acneform eruption within a few weeks in >50% of cancer patients; mechanism unknown; follicular papules and sterile pustules on face/upper trunk, limbs in severe cases; comedones NOT seen; histology: superficial dermal infiltrate around dilated follicular infundibulum; direct correlation between cancer therapy efficacy and rash severity; topical acne therapies, oral tetracyclines, topical/oral corticosteroids effective; oral isotretinoin used successfully.
• Diagnosing drug-related acneform disease:
• History: onset of drug treatment, dosage regimen, duration.
• Exacerbating factors to exclude: hormonal therapy, occupation, cosmetics, environmental factors.
• Temporal relationship: start of drug and clinical signs; improvement on withdrawal.

• Classic concept: increased sebaceous gland activity with seborrhoea + abnormal follicular differentiation with increased keratinisation + microbial hypercolonisation of the follicular canal + increased inflammation (primarily adaptive immune activation).
• Modified by newer research: genetic predisposition, androgens, pro-inflammatory lipids (ligands of sebocyte PPARs), other inflammatory pathways, neuroendocrine regulation, diet, exogenous factors (inflammatory cascades: IGF-1 → mTORC1 → SREBP-1; PPAR ligands; bacterial antigens; dietary lipids; smoking; androgen excess → hyperseborrhoea with pro-inflammatory lipids → epithelial hyperproliferation of ductus seboglandularis/acroinfundibulum; regulatory neuropeptides; genetic factors).

Inflammation

• Debate whether follicular hyperkeratinisation precedes inflammatory cell influx or vice versa; recent studies support inflammation first: increased IL-1 activity around uninvolved follicles triggers follicular keratinocyte activation/hyperproliferation.
• cDNA microarray profiling: majority of upregulated genes in inflammatory lesions are inflammatory — matrix metalloproteinases, human β-defensin 4, IL-8, granulysin.
• NF-κB activated in acne lesions; NF-κB-regulated mRNAs for TNF-α, IL-1β, IL-8, IL-10 upregulated vs uninvolved skin.
• Choi et al.: TNF-α induces lipogenesis in SZ95 sebocytes via JNK and PI3K/Akt.
• IL-1β mRNA and active IL-1β abundant in inflammatory lesions.
• IL-8 attracts inflammatory cells: early lesions (closed comedones) — marked increase in polymorphonuclear leukocytes; papules/pustules/nodules — lymphocytes prominent.
• Kelhälä et al.: IL-17A-positive T cells and Th17 cytokines activated in lesions — Th17 pathway may be pivotal; clinical relevance needs further study.
• Lipid mediators: leukotrienes, prostaglandins, 15-hydroxyeicosatetraenoic acids synthesised from arachidonic acid (AA) or linolenic acid by lipoxygenase (LOX) and cyclo-oxygenase (COX).
• Both COX-1 and COX-2 expressed in sebocytes in vitro; COX-2 selectively upregulated in acne sebaceous glands in vivo.
• Platelet-activating factor pathway (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) regulates COX-2, PGE2 and IL-8 in SZ95 sebocytes.
• Transgenic keratin 5-driven COX-2 overexpression in mouse epidermis + increased PGE2 → sebaceous hyperplasia and overshooting sebum — role of COX-2-mediated PGE2.
• PPAR-γ activation by UVB and tert-butylhydroperoxide induces COX-2 in SZ95 sebocytes — PPAR-γ/COX-2 pathway regulating sebocyte proliferation/lipogenesis.
• Leukotrienes (from AA by 5-LOX): sebocytes express 5-LOX and LTA4 hydrolase (needed for LTB4); 15-LOX weakly expressed (sebocytes don't make anti-inflammatory 15-HETE); AA stimulates 5-LOX, LTB4, IL-6 and IL-8; 5-LOX and LTA4 hydrolase stronger in acne lesions → new strategies e.g. 5-LOX inhibitor zileuton.

Neurophysiology

• Sebaceous gland expresses functional receptors for neuropeptides: corticotropin-releasing hormone (most proximal HPA element), melanocortins, β-endorphin, VIP, neuropeptide Y, CGRP — modulate cytokines, proliferation, differentiation, lipogenesis, androgen metabolism.
• Substance P (elicited by stress): promotes cytoplasmic organelles in sebaceous cells, stimulates germinative cells, increases gland area, cell size and sebum vacuoles → proliferation and differentiation.
• Acne facial skin: rich innervation, more substance P nerves and mast cells, strong neutral endopeptidase in sebaceous glands and E-selectin in venules.
• Ectopeptidases dipeptidyl peptidase IV (DP IV/CD26) and aminopeptidase N (APN/CD13) highly expressed in sebocytes; their inhibitors suppress proliferation, slightly decrease neutral lipids, enhance terminal differentiation → potential therapeutic targets.

Causative organisms

• Propionibacterium acnes — Gram-positive anaerobic rod; 2016 Scholz et al. reclassified to genus Cutibacterium; both names used interchangeably.
• Fitz-Gibbon et al.: strain/genome-level microbiome of nose pilosebaceous units in 49 acne patients vs 52 healthy; relative abundance similar but strain population structures significantly different — certain strains acne-associated, others enriched in health.
• P. acnes type III has highest pro-inflammatory potential (upregulates protease-activated receptor 2, TNF-α, MMP-13, TIMP).
• P. acnes and LPS upregulate pro-inflammatory cytokines in sebocytes; LPS stimulates CXCL8, TNF-α, IL-1α; P. acnes stimulates only CXCL8 and TNF-α — no effect on IL-1α.
• Viable (not heat-killed) P. acnes releases IL-1β, GM-CSF, IL-8.
• P. acnes induces IL-17 in PBMCs; IL-17+ cells in perifollicular comedone infiltrate → acne may be Th17-mediated; Kistowska et al.: Th1 and Th17 effectors upregulated; P. acnes induces IL-17A and IFN-γ from CD4+ T cells (mixed Th17/Th1).
• P. acnes triggers NLRP3 inflammasome in monocytes, macrophages, sebocytes; NLRP3 knockdown abolishes IL-1β; activation depends on protease activity and reactive oxygen species (effects on sebocytes: NLRP3/caspase-1, PAR-2, IL-8, IL-6, TLR2, SREBP-1 lipogenesis, hBD-2, IκB-α degradation, p38-MAPK, CREBP, STAT3).
• Keratinocytes and sebocytes activated by P. acnes via TLRs, CD14, CD1; TLR2 in basal/infundibular keratinocytes and sebaceous glands → IL-1α release; Bakry et al.: TLR2 expression significantly greater in acne-involved skin.
• Qin et al.: P. acnes → robust IL-1β from monocytes via NLRP3; perifollicular macrophage encounter → IL-1β → exacerbates inflammation.
• Antimicrobial peptides (psoriasin, β-defensins, cathelicidin) expressed in pilosebaceous units, upregulated in acne and by P. acnes; each strain influences sebocyte viability/differentiation differently (opportunistic worsening).
• MUFAs (palmitoleic acid C16:1, oleic acid C18:1) bactericidal vs Gram-positives; stearoyl CoA desaturase 1 (SCD1) produced by sebaceous glands; TLR-2 ligand macrophage-activating lipopeptide 2 stimulates SCD and fatty acid desaturase 2 mRNA.
• Lauric acid (C12:0): strong antimicrobial activity vs P. acnes; topical/intradermal lauric acid reduces P. acnes-induced inflammation and bacterial numbers; lauric, palmitic (16:0) and oleic acid enhance hBD-2 expression — sebum FFAs contribute to skin disinfection directly and via AMP induction.

Genetics

• Twin studies: inherited factors influence phenotype (monozygotic > dizygotic).
• Australian twin study: heritability 0.85 (95% CI 0.82–0.87).
• Risk in first-degree relative of affected person ≈ four to five times higher; similar OR for adult acne (≥25 years) in first-degree relatives.
• Heritability more strongly linked to maternal than paternal line; risk rises with more affected relatives; positive family history → earlier onset, affects presentation and treatment outcomes.
• Walton et al.: greater concordance of sebum excretion rate in monozygotic twins.
• Bataille et al.: 81% (95% CI 73–87%) of disease variance attributable to additive genetic effects; 19% unique environmental; of risk factors in 400 acne twins and 2414 unaffected twins, only apolipoprotein A1 serum levels significantly lower in acne twins.
• GWAS in severe acne: growing loci; variance among ethnic populations; genes affecting hair follicle development/maintenance and wound healing; recent meta-analysis identified 29 new susceptibility loci.
• Heritable traits predisposing to acne:
• Sebum excretion rate: high SER predisposes — numerous loci affecting gland size and lipogenesis.
• Sebum composition: poorly understood; may be modulated by diet.
• Innate and acquired immune responses: poorly understood; candidate genes.
• Sex: adolescent acne begins earlier in girls, more severe in males; female = risk for postadolescent acne.
• Ethnicity: poorly understood; acne may be uncommon in all racial groups not adopting western/urban lifestyle.

Environmental factors

• Lifestyle/environmental factors and strength of evidence:
• Diet: moderate for glycaemic index and milk/milk products; low for other foodstuffs.
• Body mass index: low.
• Smoking: high for comedonal acne in mature women with chronic smoking; otherwise low.
• Alcohol: low.
• Psychological stress: low.
• Cosmetics: low.
• Prescription medicines: high for some drugs, low for others.
• Anabolic and androgenic steroids: high.
• Seasonal factors: high.
• Sunlight: low.
• Lack of sleep/insomnia: low.
• Acne absent in remote communities: Kitavan Islanders (Papua New Guinea), Aché hunter-gatherers (Paraguay); Canadian Inuit developed acne only after urbanisation — attributed to diet (local production, constancy, low milk/meat/processed carbohydrate).

Diet

• Many sufferers believe diet modulates acne; some cross-sectional studies support, others find no link on multivariate analysis.
• Linked to obesity epidemic, insulin resistance, hyperinsulinaemia; Baldwin and Tan 2021 review.
• Paucity of RCTs; Table 88.11 excludes pre-1990 studies.
• Mechanism: high GI/GL → increased mTORC1 signalling → sebaceous hyperproliferation, lipid synthesis, keratinocyte hyperplasia; IGF-1 implicated; milk increases IGF-1.
• Three studies from same group: milk increased acne risk (unclear whole vs skimmed); meta-analysis of observational studies: significant increase in acne incidence in milk drinkers; moderate–severe acne linked to milk, mild acne not; systematic review of all dairy: association with yoghurt, borderline for cheese.
• Case–control (202 acne patients, matched sex/BMI): ≥3 servings cola, instant coffee with powdered milk, feta cheese, ≥1 serving peanuts significantly higher in acne; positive correlation GAGS score and cola; insulin index (not GI) suggested as cause of milk–acne link.
• Definite link with yoghurt, cheese, chocolate unproven.
• Reduced zinc, calcium, vitamin A in acne patients.
• Protective interest: Mediterranean, Paleolithic diets; fish/fish oils/PUFAs; small randomised study: Ω-3 fatty acid and γ-linoleic acid supplementation independently reduced severity and IL-8.
• Probiotics: randomised open-label trial of oral minocycline ± probiotic — significant improvement and fewer Candida infections in probiotic group; 36 patients consuming fermented dairy drink with Lactobacillus improved within 12 weeks.

Key findings from pivotal diet studies

Body mass index

• Risk and severity appear to increase with age-adjusted BMI in adolescents; paradoxically acne may be less prevalent in overweight women with postadolescent acne.
• BMI and acne studies:
• Italian dermatology out-patients 10–24 y: reduced risk of moderate–severe disease if underweight (BMI <18.5), stronger in males; risk not increased if overweight (BMI >23) [277].
• Taiwan schoolchildren 6–11 y: reduced risk with low BMI; increased if overweight [321].
• Ghana schoolchildren 9–16 y: trend reduced with low BMI; increased if overweight [322].
• Lithuanian schoolchildren 7–19 y: increased prevalence if overweight [323].
• Norway final-year 18–19 y: increased in overweight/obese girls; no BMI effect in boys [324].
• Italian males: acne men higher mean BMI [325].
• Malaysia 18–30 y: no BMI difference [280].
• Turkish women: more likely overweight/obese; positive correlation BMI–severity [326].
• Taiwanese reproductive-age women: obese lower prevalence [327]; PCOS out-patients Taiwan: lower prevalence if BMI >25 [327].
• Taiwan reproductive endocrinology clinic: PCOS without acne had higher BMI [86].
• Croatia PCOS: lower prevalence in obese [328].
• Turkish PCOS: reduced severity if BMI ≥27 [329].
• Saudi Arabia PCOS: acne strongly associated with obesity; more common in overweight [330,331].
• USA adolescent PCOS: similar prevalence normal (63%) vs overweight (73%) [94].
• Indian PCOS: trend less acne with BMI <23 (NS) and with increased BMI (NS) [332].
• Turkish pre-/postadolescent: less acne with higher BMI (P <0.001) [334].
• Kuwait schoolchildren: obese/overweight more likely acne [335].
• 484 residents Hail City, Saudi Arabia: BMI >30 in 38%; significant association (P = 0.005) [336].
• 693 elementary children 7–12 y: BMI ≥25 higher prevalence (age/sex-adjusted OR 2.7; 95% CI 1.81–3.92) [19].
• 143 Polish acne patients 12–18 y: prevalence not different by BMI, but overweight/obese more inflammatory acne (P = 0.03) [337].
• 1079 Nigerian students 9–20 y: prevalence 81.7% (BMI >25), 61.1% (18.5–24.99), 42.0% (<18.5) (P <0.001); BMI not associated with severity (P = 0.830) [338].
• 600 404 youths military service: lowest odds in severely obese (males aOR 0.53, 95% CI 0.42–0.64; females aOR 0.5, 0.37–0.62) [339].
• Chinese Han 10–25 y (364 acne, 295 controls): obesity–acne association stronger in women (OR 14.526, 95% CI 2.961–71.272, P <0.001) than men (OR 3.528, 1.553–8.014, P = 0.002); obesity associated with truncal acne (OR 4.480, 2.182–9.196, P <0.001) [340].
• Taiwanese women moderate–severe postadolescent acne: BMI negatively associated with lesion number [341].

25-Hydroxy vitamin D3

• Vitamin D reduces inflammatory biomarkers, inhibits C. acnes-induced Th17 differentiation, increases AMP production in sebocytes.
• Deficiency associated with acne prevalence but NOT severity.

Smoking

• Little if any effect on prevalence/severity in teenagers/young adults.
• Acne more common in postadolescent smokers; mature persistent smokers → comedonal acne with numerous comedones and macrocomedones.
• Large cross-sectional study: smoking reduced probability of acne by ~30%.
• Maternal smoking associated with earlier onset of acne (not puberty) in sons.

Alcohol

• No conclusions; two cross-sectional studies suggest relation; another and the Glasgow Alumni Cohort Study found no link.

Menstrual cycle

• ~70% of women report flare 2–7 days before menstruation (rising progestogen).
• premenstrual flare by nationality: American 100 (–) 72%; American 400 (12–52 y) 44%; French 3305 (25–40) 78%; Saudi-Arabian 200 (mean 14.8) 9.8%; Jordanian 83 (13–34) 98%; Indian 137 (13–45) 57.7%; (–) 35.5%; Korean (mean 24) 60.1%; French 591 (10–25) 55%; Korean 756 (10–56) 61.3%; Indian 230 (over 25) 11.7%; Thai 392 (18–41) >50%.

Stress and sleep deprivation

• Small studies: stress score changes correlate with acne frequency/severity; stress reported as aggravator; risk factor for severe acne.
• Presence of acne highly associated with stress (OR 1.975, 95% CI 1.588–2.457, P <0.0001), fatigue on waking, sleep disorders, reduced sexual activity.
• Stronger evidence from HPA axis effects on sebaceous function; substance P correlated with stress scales in small case–control; higher substance P in acne patients but no correlation with severity.
• Weak evidence for sleep deprivation/insomnia link.
• Pilot non-blinded randomised study of 30 females: Pythagorean self-awareness intervention (PSAI) → significant improvement in clinical grade, perceived stress, negative affect.

Cosmetics

• Acne cosmetica: chronic use of comedogenic cosmetics — lanolin, petrolatum, certain vegetable oils, butylstearate, lauryl alcohol, oleic acid; steroid-containing skin bleaching agents in women of colour; how preparations are used may matter more than ingredients.
• Pomade acne: greasy defrizzing preparations → comedonal acne (closed comedones/papules forehead and temples, pustules rare); restrict pomades + topical retinoids.
• Detergent acne: uncommon; washing many times daily; trauma and alkaline soap; inflammatory lesions; bacteriostatic soaps with weak acnegenic compounds e.g. hexachlorophene.

Ultraviolet radiation

• 139 people in Munich: one-third improved in summer, one-third worsened, one-third same; fewer seek treatment in summer; 64% reported no significant sun impact.
• Hot humid environments: WWII troops in South-East Asia suffered badly; heat/humidity may negate sunlight benefit.
• Acne aestivalis (Mallorca acne): small follicular papules esp. upper trunk during/after holiday in hot humid environment.
• PUVA: perioral dermatitis and/or acneform facial eruption in a few patients.
• Squalene monohydroperoxide (squalene + UVA) responsible for comedogenicity; UV alters comedone cytokines → UV may promote acne in susceptible individuals without photoprotection.

Pregnancy

• 415 Scottish women: 57.5% improved, 5.4% worsened during pregnancy; 75% improved after birth, 12% worsened.
• South Korea: 28.4% of 756 worsened in pregnancy, 10% improved.

Birth weight

• Turkish schoolgirls: acne more common with term birth weight <2500 g; low birth weight linked to insulin resistance and PCOS features.

Miscellaneous factors

• Virtually no evidence: hygiene/washing frequency, touching skin, mood, pollution, physical activity, recreational drugs, drinking water, sex.

Summary

• Not enough evidence for treatment guidelines; most guidelines support healthy balanced diet with adequate water.
• Uncertain whether overweight or alcohol affects acne; in some PCOS women overweight reduces acne risk.
• Smoking complex: comedonal variant in adult women with long habitual smoking; may be protective in early inflammatory acne.
• Stress evidence weak.
• Advice: avoid suspected lifestyle factor for a while and keep a diary over minimum several weeks; diet — eat healthily, everything in moderation.
• Reasonably good evidence: acne before puberty is a prognostic factor for more severe disease.

History

• Chronic disease of adolescence lasting on average 7 years; may present as young as 6 years (adrenarche); adults de novo or continuation.

Presentation

• Polymorphic inflammatory disease: face 99%, back 60% (sparing of central back; Sebutape), chest 15%.
• Seborrhoea, scarring, persistent macular redness and/or pigment change common.
• Ranges from mild comedonal to fulminant with systemic upset.
• Comedones earliest lesions in younger patients; open (blackheads) and closed (whiteheads).
• Open comedones in mid-facial distribution evident early → poor prognosis.
• Closed comedones ~1 mm, skin-coloured, no visible opening; >1 mm = macrocomedones; require lighting and stretching to see.
• Comedone subtypes:
• 'Sandpaper' comedones — multiple very small whiteheads on forehead, roughened gritty feel.
• Macrocomedones — whiteheads >1 mm; both macrocomedones and sandpaper comedones respond poorly to conventional topicals.
• 'Submarine' comedones — >0.5 cm, deep; associated with recurrent inflammatory nodules.
• Inflammatory lesions arise from microcomedo: papules and pustules (≤5 mm); deep pustules and nodules (>5 mm); sinus tracts between nodules/deep pustules → inevitable scarring; tender, chronic, treatment-resistant.
• Itching is rare — histamine-like compounds from C. acnes.
• Secondary lesions: inflammatory macules (regressing lesions, persist many weeks); atrophic scarring; hypertrophic/keloid scarring.

Clinical variants

• Severe forms (acne fulminans, acne conglobata).
• Drug-induced acne; cosmetic acne; occupational acne.
• Acne associated with psychological problems: acné excoriée, BDD, eating disorders.
• Granulomatous acne.
• Acne mechanica.

Acné excoriée (excoriated acne, picker's acne)

• Predominantly adolescent girls; increasing in mature females; stress-associated.
• Self-inflicted compulsive picking of real or imagined lesions on face; underlying OCD, bodily focused anxiety; BDD may contribute; linear erosions suggest self-mutilation/psychiatric disease; atopic background; exclude contact dermatitis; significant scarring.
• Treatment: treat acne (topicals irritate); break habit vs compulsive skin picking disorder needing psychological therapy/psychotropics; hypnosis, CBT with habit reversal; SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine) = treatments of choice with psychotherapy; scarring/ulceration improved with 585 nm pulsed dye laser + cognitive psychotherapy.

Body dysmorphic disorder

• Small number of BDD patients have acne as prime symptom; perceived acne out of proportion; depressed, obsessional, anxious; significant suicide risk; need dermatological and psychiatric management.
• Aggressive treatment of mild acne may relieve some; off-licence isotretinoin described but 'relapse' (real or perceived) common — not necessarily a solution (Chapter 84).

Eating disorders

• Acne in anorexia nervosa; acne may predispose to anorexia in vulnerable teens dieting to control acne; GH raised, IGF-1 low.

Granulomatous acne

• Mechanism unknown; deep well-demarcated lesions esp. cheeks; slow, unsatisfactory response; antibiotics and isotretinoin limited; oral steroids often required.

Mechanical acne (acne mechanica)

• Repeated mechanical trauma/frictional obstruction → comedo formation; 'fiddler's neck' (violin players: plaques with comedones, lichenification, pigmentation); headbands, bra straps, suspenders, collars, turtlenecks; amputees.
• Treat: eliminate causative force + manage lesions.

• Milia: intraepidermal keratin cysts, infraorbital.
• Syringomas: non-inflammatory papules around eyelids/upper cheeks; more in Japanese women; histology — dense fibrous stroma, dilated cystic spaces with comma-like 'tadpole' tails (Chapter 137).
• Fibrofolliculomas: 2–4 mm dome-shaped papules on face, neck, upper trunk; Birt–Hogg–Dubé syndrome — rare AD; fibrofolliculomas, trichodiscomas, acrochordons; risk of colon/kidney cancer, spontaneous pneumothorax (pulmonary cysts); BHD gene, chromosome 17p12-q11.2, encoding folliculin; if gene positive: renal ultrasound and/or abdominal CT/MRI, chest X-ray, colonoscopy.
• Ectopic sebaceous glands (Fordyce spots): vermilion border/oral mucosa; symmetrical discrete yellow papules; 25% of population over 35; oral isotretinoin used with some success for extensive lesions; CO2 laser; penile shaft; areola.
• Pilosebaceous naevoid disorders:
• Acneform naevi: symmetrical normal-skin areas in severe back acne, or acne localised to one side of back; reduced sebum and bacteria in normal areas.
• Comedo naevus (naevus comedonicus, naevus follicularis, naevus unilateralis comedonicus): developmental follicular defect; sebaceous glands normal/hypo-/hyperplastic; scalp, face, trunk, occasionally genitalia; keratin-filled pits, grouped or linear; present at birth, more prominent at puberty; FGFR2 mutations in naevus not adjacent skin; somatic heterozygous Ser252Trp-FGFR2 confirmed in unilateral acneform naevus; association with epidermolytic hyperkeratosis; treatment limited: topical retinoids, 12% aqueous ammonium lactate, gentle cautery.
• Familial comedones: uncommon genetic; single comedones then extensive grouped comedones and cysts; scarring; new lesions into middle age.
• Sebaceous naevus (naevus sebaceus of Jadassohn): organoid naevus (epidermis, dermis, sweat and sebaceous glands); scalp alopecia; verrucous at puberty; aplasia cutis co-occurrence; trichoepithelioma and eccrine syringoadenoma noted; haematopoietic proliferation at birth resolving at 4 months; excision recommended — SCC/BCC lifetime risk 5–22%.
• Favre–Racouchot syndrome (senile/solar comedones): periorbital and malar comedones in elderly with chronic sun exposure; UV damages supporting dermis → distended duct with impacted corneocytes; occasionally unilateral; histology — increased thickened tortuous elastic tissue upper/mid dermis; similar in pseudoxanthoma elasticum or post-radiotherapy; comedo extractor (recur), topical retinoids, electrocautery.
• Sebaceous gland hyperplasia: benign proliferation; yellow/pink 1–3 mm facial lesions; light-exposed skin of renal transplant patients on ciclosporin; treatment: gentle cautery, cryotherapy, TCA, CO2 and pulsed dye lasers; diffuse yellowish hue; off-licence oral isotretinoin; co-cyprindiol (Dianette®, Estelle-35®) ± cyproterone acetate regresses in some females; ALA-PDT.
• Adenoma sebaceum (angiofibromas): small translucent waxy papules central face; multiple → tuberous sclerosis; histology — dermal fibrosis, vascular proliferation/dilatation.
• Sebaceous gland tumours: uncommon; may associate with internal malignancy.
• Sebaceous adenoma: benign, incompletely differentiated sebaceous cells; elderly, face/scalp; waxy pink/yellow ≤10 mm; may ulcerate; excision (radiosensitive); Muir–Torré syndrome (MTS) — sebaceous neoplasm (adenoma, epithelioma, carcinoma) + ≥1 internal malignancy; visceral carcinomas present relatively early (45 years); cystic sebaceous neoplasms = specific markers; GI and GU malignancies commonest; colorectal cancers at or proximal to splenic flexure; variant of HNPCC (autosomal dominant) with microsatellite instability, germline MSH2 and MLH1 mutations; some sporadic; IHC for MSH2/MLH1 = screening test; MTS neoplasms more indolent; colonoscopy every 1–2 years from age 25 or 10 years younger than index relative; others recommend annual history/exam/skin review/urinalysis, endometrial sampling and transvaginal ultrasound in females.
• Sebaceous carcinoma: rare; men >40; firm solitary yellow-orange lesion face/scalp; ulcerates; MTS association; eyelid (Meibomian) more likely to metastasise; excision or radiotherapy; diameter ≥10 mm and/or T4 = poor prognosis.
• Sebaceous (epidermoid) cysts and steatocystoma multiplex (SM): classic 'sebaceous' cyst is epidermoid (Chapter 133); true sebaceous cysts = SM — naevoid; keratinising epithelium + sebaceous lobules attached by thin epidermal strand; 64 sporadic cases, mean onset 26 years; smooth yellow dermal swellings few mm–20 mm on arms, chest, neck, axillae, appearing/enlarging at puberty; SM suppurativa mimics acne conglobata; overlaps with eruptive vellus hair cysts (EVHCs) — all eosinophilic with no granular layer, 17–42% with vellus hair/follicles/keratin/smooth muscle; hamartomatous, both originate in pilosebaceous duct; associated with pachyonychia congenita type 2 (PC-2, Jackson–Lawler) with natal teeth; cysts in PC-2 may be steatocysts, EVHCs or keratinous; keratin 17 (K17) Ia domain mutations in all PC-2 cases and some SM families; familial SM with natal teeth without nail dystrophy; K17 mutations not found in some SM/EVHC → genetically heterogeneous. Treatment: excision of larger cysts, vein hook extraction, CO2 laser; topicals limited; systemic antibiotics reduce inflammation/suppuration; oral isotretinoin reduces inflammation but not primary process.
• Granulomatous rosacea (lupus miliaris disseminatus faciei, acne agminata) (Chapter 89).
• Keratosis pilaris: inflammatory KP may masquerade; proximal extremities; follicular keratotic papules ± redness; familial; chromosome 18p deletion syndromes; moderate–severe arm KP associated with lower acne prevalence and severity.
• Rosacea: older (30–50 years), no comedones/scarring, rarely trunk; flushing, triggers (heat, spicy food, alcohol); ocular involvement; overlap; acne may evolve into rosacea.
• Pyoderma faciale (rosacea fulminans): very acute, adult females; deeply inflamed nodules, cysts, sinus tracts; histology — mixed infiltrate upper/mid dermis, RBC extravasation, haemosiderin.
• Perioral dermatitis: papules/pustules on red/scaling base around mouth with clear zone at vermilion; itch; no comedones.
• Gram-negative folliculitis: complication of long-term oral (less often topical) antibiotics; HIV-positive; hot tub; sudden multiple small follicular pustules or nodules perioral/perinasal; Klebsiella, E. coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa replace Gram-positive flora. Treatment: discontinue antibiotic → ampicillin 250 mg four times daily or trimethoprim 400–600 mg/day; slow response, common relapse; isotretinoin (off-licence) very effective, lower relapse.
• Malassezia (pityrosporum) folliculitis: upper trunk monomorphic itchy papules/pustules; topical/oral antifungals; oral isotretinoin for seborrhoea.
• Scalp folliculitis (acne necrotica miliaris, propionibacteria folliculitis): small itchy pustules around hairline; C. acnes, S. aureus, Malassezia, Demodex folliculorum; on isotretinoin → S. aureus scalp folliculitis responds to flucloxacillin; persistent in cyclical neutropenia.
• Folliculitis keloidalis (acne cheloidalis nuchae, acne keloidalis): nape, cicatricial alopecia; black males; itchy papules occiput; S. aureus secondary infection; tufted hairs; close shaving/ingrowing hairs; obesity/metabolic syndrome association. Treatment: avoid friction/close haircuts, antimicrobial washes, topical steroids (small papules), intralesional steroids (large papules/nodules), oral tetracyclines, clindamycin + rifampicin, laser and hair removal, early treatment; surgery, laser vaporisation, excision; off-licence isotretinoin; radiotherapy.
• Folliculitis decalvans (tufted folliculitis): scarring alopecia (Chapter 87); hyperkeratosis, plugging, perifollicular inflammation; abnormal host response to S. aureus toxins; systemic antibiotics — oral clindamycin or rifampicin (tissue penetration); + topical mupirocin; clindamycin + isotretinoin + steroids (case report); topical fusidic acid + oral zinc; radiotherapy, dapsone isolated cases.
• Dissecting cellulitis of the scalp (perifolliculitis capitis abscedens et suffodiens): black males 2nd–4th decades; follicular occlusion tetrad (with acne conglobata, HS, pilonidal cysts); tender nodules/abscesses vertex and occiput, sinus tracts, scarring alopecia; follicular hyperkeratosis primary, secondary infection; histology — neutrophilic perifolliculitis, follicular destruction, granulomas, fibrosis; marginal keratitis; SCC in chronic cases; three cases with KID syndrome. Treatment: poor response; minocycline 100 mg BD or trimethoprim 300 mg BD; oral zinc sulphate 135 mg TDS; topical isotretinoin; oral isotretinoin most effective; potent topical/intralesional/systemic steroids; wide excision with grafting; alitretinoin in KID-associated case.
• Hidradenitis suppurativa (Chapter 90): with severe nodular/conglobate acne; family history; late adolescence onset, declines with age; axillae, breasts, genital, perianal, buttocks, lower back; polyporous open comedones, deep nodules, abscesses, sinus tracts, scarring; follicular occlusion disorder; obesity, smoking, local irritation aggravate.
• Miscellaneous papular facial rashes: dermatitis herpetiformis (very itchy), linear IgA disease (biopsy + immunofluorescence essential), micropapular sarcoid (monomorphic skin-coloured/brownish; Chapter 96), dental sinus, inflamed epidermoid cysts, zinc deficiency papulopustular eruption (after prolonged IV feeding without zinc).
• Mimics of acne scarring: hydroa vacciniforme (Ch 126), ulerythema ophryogenes (Ch 87), folliculitis keloidalis (Ch 91), varioliform atrophy, porphyria cutanea tarda (Ch 58); acne necrotica varioliformis (necrotising lymphocytic folliculitis; Ch 91) — itching, smallpox-like scars around scalp margin; mimics severe acné excoriée; excellent response to isotretinoin.

• Outcome assessment challenging; few validated tools.
• Clinical practice: visual assessment by extent, number and lesion type → mild, moderate, severe.
• Assessments = grading or counting; (i) global; (ii) individual lesions; (iii) predominant lesion type.
• Multimodal imaging being evaluated; patient-reported outcomes and poor prognostic factors important.
• Acne Core Outcome Research Network (ACORN): Delphi consensus → seven core domains.
• Comprehensive Acne Severity System (CASS) — six-category facial IGA extended to chest and back; validated:
• Clear: no lesions to barely noticeable; very few scattered comedones and papules.
• Almost clear: hardly visible from 2.5 m; few scattered comedones, few small papules, very few pustules.
• Mild: easily recognisable; <half affected area; many comedones, papules, pustules.
• Moderate: >half affected area; numerous comedones, papules, pustules.
• Severe: entire area; covered with comedones, papules, pustules, a few nodules and cysts.
• Very severe: highly inflammatory covering area, with nodules and cysts.
• Lesion counts essential for trials (reliability) but impractical in clinic.
• Other factors: extent/sites, seborrhoea, demographics/family history, sequelae (scarring, pigmentation), satisfaction, adherence, speed of action, tolerability, adverse effects, QoL impact.
• QoL measures:
• Generic: Euro-QoL (EQ-5D), SF-36, General health questionnaire (GHQ), UK sickness impact profile (UK SIP), preference-based utility measures.
• Dermatology-specific: DLQI, Skindex, DQOLS, DSQL, CDLQI.
• Acne-specific: Acne/Cardiff acne disability index (CADI), Acne-QoL, Acne quality of life scale, Acne-QOLI, APSEA, CompAQ, Acne-Q.
• Combined QoL + psychosocial questionnaires essential; scarring and pigment should be included — no single reproducible tool for scar volume or pigment extent.

• Main: psychosocial and physical scarring; persistent redness/pigment; rarely solid facial oedema, osteoma cutis; pyogenic granulomas (severe disease or isotretinoin); seborrhoea.

Psychosocial effects

• Systematic review: >408 studies, 138 questionnaires.
• Shame 70%, embarrassment/anxiety 63%, lack of confidence 67%, impaired social contact 57%, unemployment problems; severe acne → anger and anxiety.
• SF-36 impact vs other conditions (social functioning / role–emotional / mental health / energy–vitality): Acne 11.1 / 7.4 / 13.4 / 7.0; Asthma 5.9/6.3/4.2/6.0; Diabetes 8.7/9.5/5.9/9.1; Back pain 8.9/6.9/4.1/8.5; Epilepsy 7.4/5.3/3.4/5.9.
• Attractive strangers attributed more positive qualities; photographs of acne/scarring/pigment perceived more negatively.
• Anxiety, depression, suicide: depression does not necessarily correlate with severity; suicide reported — assess depressed patient for suicide risk; depression levels may reach those of hospitalised psoriasis patients; higher STAI anxiety.

Acne scarring

• Up to 90% of patients (mild in most); duration of inflammation relates to scarring → delay → significant scarring.
• Holland et al.: non-scarrers — type IV delayed hypersensitivity time course, resolution by innate and adaptive; scarrers — predominantly adaptive, persistent and upregulated in resolving lesions; managing inflammation during development and resolution may control scarring.
• Keloids extend beyond original inflammation, most prevalent on trunk; hypertrophic scars do not extend beyond; atrophic = collagen loss.
• Poor consensus on classification; significant inter-assessor variation; FASET tool for atrophic scars; atrophic scars soft/distensible or fibrotic; vascular hue for months; perifollicular elastolysis on trunk (sometimes without acne); calcification rare.
• Persistent hyperpigmentation (Fitzpatrick IV) and macular redness; Asian Acne Board: pigment change for 5 years or longer in many.

Solid facial oedema (Morbihan disease)

• Rare, disfiguring; twins; also rosacea and Melkersson–Rosenthal; thickened woody oedema of midline face/cheeks; pre-existing hypoplastic lymphatics; progressive; treat acne aggressively; oral isotretinoin alone or with clofazimine or ketotifen; short/intermittent oral steroids.

Osteoma cutis

• Focal ossification subcutaneous/dermal; women with longstanding inflammatory acne; 2–4 mm firm papules; histology — calcified trabecular bone with perivascular proliferation/fibrosis; usually no treatment; topical tretinoin for transepidermal elimination of small superficial lesions; surgical ablation most effective (dermabrasion + punch biopsy, scalpel incision/curettage, microdissection, lasers); Er:YAG better cosmesis than CO2.

Pyogenic granulomas

• Trunk in very severe acne; rarely (<1 : 10 000) with oral isotretinoin; feature of acne fulminans; clobetasol propionate cream BD for 2–3 weeks.

Seborrhoea

• May persist after acne regresses; consider acromegaly, parkinsonism; isotretinoin/antiandrogens for seborrhoea alone are outside product licence.

• WHO criteria: acne = chronic disease.
• Factors associated with severity and relapse:
• Positive family history: earlier occurrence, increased retentional lesions, increased relapses.
• Early onset: infantile acne → resurgence, more severe and more frequent relapse in teenage years; mid-facial prepubertal comedones → more severe; earlier onset relative to menarche → more severe.
• Duration: prolonged duration → reduced efficacy; family history of acne >25 years → more adult acne in relatives.
• Seborrhoea: high sebum → more severe; reduced response to systemic antibiotics.
• Extent/location: truncal acne → reduced efficacy of systemic therapy vs facial.

• For monitoring or to exclude endocrinopathy.
• Signs suggesting endocrinopathy:
• Hyperandrogenism with acne: seborrhoea, hirsutism, androgenic alopecia, Cushingoid features, increased libido, deepening voice, clitoromegaly, acanthosis nigricans.
• Acne: therapy-resistant, rapidly relapsing, very severe, marked seborrhoea, sudden onset esp. with other hyperandrogenism signs.
• Hormonal investigations: PCOS — LH, FSH, total free testosterone, prolactin; CAH — DHEAS, 17-hydroxyprogesterone, ACTH stimulation test; NCAH — TSH; ovarian tumour — free testosterone; adrenal tumour — DHEAS.
• Sebum quantification (not routine): higher sebum → poorer antibiotic response; correlates with severity.
• Sebufix®/Sebutape® (microporous hydrophobic polymer film): Sebutape shows active follicle distribution (not amount); Sebufix with UV camera calculates sebum secretion area; gravimetric methods labour intensive.
• Investigating for antibiotic-resistant C. acnes may be of interest (correlates with poor response).
• Other investigations relate to prescribed treatment.

• Acne Vulgaris: Pleomorphic, self-limited disorder of the pilosebaceous unit occurring predominantly in adolescents (prevalence >85%)
• Genetics: Twin studies demonstrate that 81% of population variance in acne is due to genetic factors
• Four Core Pathogenetic Drivers:

1. Follicular epidermal hyperproliferation (microcomedo formation)
2. Excess sebum production (androgen-driven)
3. Inflammation (pre-comedonal cytokine activation & follicle rupture)
4. Propionibacterium acnes (Cutibacterium acnes) proliferation & innate immune activation

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`

[Androgens & FGFR-2] ──► Follicular Hyperkeratinization ──► Microcomedo Formation

│

[Androgens / 5α-Reductase] ──► Excess Sebum Production ───────────┤

▼

[P. acnes (TLR-2 / Lipases)] ──► Intrafollicular Proliferation ──► Follicular Rupture ──► Dermal Inflammation

`

• Hyperkeratosis + increased cohesion of infundibular corneocytes forms a keratin plug at the follicular ostium
• Modulating factors:
• Androgens: Follicular keratinocytes possess elevated 5α-reductase and 17β-HSD, converting DHEA-S into Dihydrotestosterone (DHT)
• Linoleic Acid: Subnormal levels in sebum induce infundibular hyperkeratosis and IL-1α release (diluted by high sebum volume)
• Interleukin-1α (IL-1α): Directly drives microcomedone formation
• FGFR-2 Mutations: Somatic/germline mutations in FGFR2 drive hyperkeratinization (e.g., Apert Syndrome)

• Driven by DHT binding to sebocyte androgen receptors (5α-reductase activity is highest on face/chest/back)
• Lipid Composition: Triglycerides, wax esters, squalene, and free fatty acids
• P. acnes lipases hydrolyze triglycerides into proinflammatory free fatty acids that promote bacterial clumping and comedogenesis
• Corticotropin-releasing hormone (CRH) receptors on sebocytes upregulate sebum during stress

• Inflammatory Sequence: Perifollicular CD4+ T-cell infiltration occurs prior to microcomedo formation; neutrophils infiltrate post-follicular rupture
• TLR-2 Activation: P. acnes cell wall carbohydrates bind Toll-Like Receptor 2 (TLR-2) on monocytes/macrophages → triggers release of IL-1α, IL-8, IL-12, and TNF-α
• Antimicrobial peptides (cathelicidin, histone H4, β-defensins) and lysosomal enzymes are released into surrounding dermis

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• Non-Inflammatory Lesions:
• Closed Comedones (Whiteheads): 1–3 mm pale, smooth, non-pigmented papules with microscopic ostia (high risk of rupture)
• Open Comedones (Blackheads): Flat or raised papules with a wide, patulous ostium packed with dark-pigmented oxidized keratin, lipid, and melanin
• Inflammatory Lesions:
• Papules & Pustules: Superficial 1–5 mm erythematous lesions
• Nodules: Deep, painful, suppurative lesions >5 mm (formerly misnamed "cysts"; true epithelial cysts do not occur)

• Ice Pick Scars: Narrow (<2 mm), deep, V-shaped tracts extending into deep dermis/subcutis
• Boxcar Scars: Round/oval sharp-edged depression with vertical side walls (wide base)
• Rolling Scars: Superficial dermal-subdermal fibrous tethering creating an undulating wave-like appearance
• Hypertrophic / Keloidal Scars: Exuberant collagen deposition on trunk/chest

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• Indications for Lab Testing: Severe nodular acne, sudden onset in adults, or systemic hyperandrogenism in females (hirsutism, oligomenorrhea, clitoromegaly, androgenic alopecia)
• Laboratory Panel: Total & Free Testosterone, DHEA-S, 17-hydroxyprogesterone, LH/FSH ratio (draw fasting in early follicular phase)
• Diagnostic Thresholds:
• DHEA-S 4,000–8,000 ng/mL: Non-classic Congenital Adrenal Hyperplasia (21-hydroxylase deficiency)
• DHEA-S >8,000 ng/mL: Adrenal carcinoma
• Total Testosterone 150–200 ng/dL OR LH/FSH ratio >2.0: Polycystic Ovary Syndrome (PCOS) / HAIR-AN
• Total Testosterone >200 ng/dL: Ovarian neoplasm

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• Chronic inflammatory pilosebaceous follicle disease: comedones, papules, pustules, nodules, often scars.
• Comedo = primary lesion. Open comedo (blackhead): flat/slightly elevated papule, dilated central opening with blackened keratin. Closed comedo (whitehead): ~1mm yellowish papule (may need skin stretching to see). Macrocomedones (uncommon): 3-4mm.
• Papules/pustules 1-5mm; larger → nodules. Cysts: softer, discharge pus. Coalescence → indurated/fluctuant plaques with sinus tracts, serosanguineous/yellowish pus discharge. Redness harder to appreciate in darker skin → risk of undertreating inflammation.
• Various lesion stages simultaneously. Light skin: resolves with short-lived reddish-purple macule. Dark skin: macular hyperpigmentation, may last months.
• Scar morphologies: deep narrow ice pick scars (temples/cheeks), canyon-type atrophic (face), whitish-yellow papular scars (trunk/chin), anetoderma-type (trunk), hypertrophic/keloidal (jawline/neck/trunk).
• Sites: face (cheeks most, then nose/forehead/chin), neck, upper trunk, upper arms. Ears: large concha comedones, lobe cysts, preauricular/retroauricular comedones/cysts. Neck (nuchal area): large cystic lesions may predominate.
• Typically begins at puberty — first sign of rising sex hormones. Onset ages 7-12: usually comedonal, forehead/cheeks, may stay mild. Rising hormones into mid-teens → more severe inflammatory pustules/nodules, spreads.
• Young men: oilier complexion, more severe/widespread disease than young women. Women: flare ~1 week premenstrual. Acne may begin in women ages 20-35 without prior teenage acne — papules, pustules, deep painful persistent nodules on jawline/chin/upper neck.
• 85% of teenagers affected to some degree; greatest frequency ages 15-18. Usually involutes before 25 (great variability). 35% of women and 20% of men continue into 30s; 26% of women and 12% of men into 40s.

Age-Specific Forms

• Neonatal acne: common, days after birth, male preponderance, transient facial papules/pustules, clears spontaneously in days-weeks. = "neonatal cephalic pustulosis" (no comedones); responds to topical ketoconazole cream. Pathogenesis: likely immune response to Malassezia.
• Infantile acne: begins age 1-12 months; explained by infantile androgen production waning at 6-12 months. Comedones present. Most remit by age 1 (occasionally extends into childhood/puberty). Prolonged cases: topical benzoyl peroxide, erythromycin, or retinoids; inflammatory disease: add oral erythromycin 125mg BID or trimethoprim 100mg BID. Oral isotretinoin effective if needed.
• Midchildhood acne: evolves from infantile acne or begins after age 1; uncommon, male predominance. Grouped comedones/papules/pustules/nodules, usually face-limited. Duration weeks to years; may extend into pubertal acne. Often strong family history.
• Acne onset ages 1-7: refer to pediatric endocrinologist (as should earlier-onset with sexual precocity/virilization/growth abnormality signs). Ages 7-12 (preadolescent, adrenarche time): no workup needed unless androgen excess signs.

• Exclusively follicular disease; principal abnormality = comedo formation from impaction/distention of follicles with keratinous plug in lower infundibulum (from keratinocyte hyperproliferation/abnormal differentiation).
• Androgens, altered lipid composition, abnormal local cytokine response all causally important. Androgen stimulation of sebaceous glands critical — acne begins after sebum secretion increases; hyperandrogenic women often show acne + hirsutism + menstrual abnormalities. Sebum-reducing treatment (isotretinoin, estrogens, antiandrogens) effective.
• Retained cells block follicular opening → lower follicle dilates with entrapped sebum → epithelial disruption → follicular content discharge into dermis. Keratin + sebum + microorganisms (particularly Cutibacterium acnes) → proinflammatory mediator release → lymphocyte/neutrophil/foreign body giant cell accumulation → inflammatory papules/pustules/nodulocystic lesions.
• Comedogenic greasy/occlusive products (hair pomades) → closed comedones ± inflammatory lesions; acne cosmetica uncommon (most cosmetics tested for comedogenicity).
• Mechanical/frictional acne: key feature = unusual distribution. Triggers: chin straps, violins, hats, helmets, tight spandex/gym clothing, masks ("maskne"), collars, surgical tape, orthopedic casts, chairs/seats.
• Diet: high-glycemic diet, skim milk, whey protein may negatively influence acne (therapeutic dietary regimens not yet defined).

Hyperandrogenism Workup

• Consider in all women/children with acne. Suggestive: irregular menses, hirsutism, seborrhea, acanthosis nigricans, androgenic alopecia. Endocrine evaluation indicated for: resistant acne, quick relapse after isotretinoin, sudden severe onset.
• Screening: serum DHEAS and testosterone, obtained 2 weeks before menses onset. DHEAS >800 μg/dL: suggests adrenal tumor; 400-800 μg/dL: less dramatic, suggests congenital adrenal hyperplasia. Testosterone >200 ng/dL: suggests ovarian tumor.
• Late-onset 21-hydroxylase deficiency CAH: many have normal DHEAS. 17-OHP + ACTH stimulation testing used but baseline 17-OHP may be normal and ACTH stim may overdiagnose. Screening for adult-onset 21-hydroxylase deficiency: unclear if it improves outcomes. Also consider Cushing syndrome.
• PCOS diagnosis: needs 2 of 3: oligo/anovulation, biochemical/clinical hyperandrogenism, echographic polycystic ovaries. Clinically: anovulation (<9 periods/year or periods >40 days apart) + hyperandrogenism signs (acne, hirsutism). ~15% of women of childbearing age meet PCOS criteria.
• PCOS implications: insulin resistance (may show as acanthosis nigricans), obesity, cardiovascular disease, OSA, NASH, endometrial cancer, infertility; nearly half have metabolic syndrome. Chest hirsutism + axillary acanthosis nigricans → frequently PCOS. Best screening labs: free testosterone and DHEAS. Refer for ovarian cyst investigation, abnormal result interpretation, TSH/prolactin testing, associated disorder management (see Ch. 19).

• Comedones: thinned epithelium, dilated follicular canal with lamellar lipid-impregnated keratinous material. Pustular cases: folliculocentric abscesses with dense lymphocyte/PMN infiltrate. Indolent nodules: plasma cells, foreign body giant cells, fibroblast proliferation; epithelial-lined sinus tracts may form.

Four Key Pathophysiologic Pillars

1. Follicular Hyperkeratinization: Altered desquamation of follicular keratinocytes → microcomedo formation (the precursor lesion of all acne).
2. Androgen-Driven Sebum Production: Circulating androgens (DHT) stimulate sebaceous gland hypertrophy and excessive sebum secretion.
3. Prokaryotic Proliferation: Cutaneous colonization by Cutibacterium acnes (C. acnes, formerly P. acnes) inside sebum-rich follicles.
4. Inflammation: C. acnes activates Toll-Like Receptor 2 (TLR2) → release of pro-inflammatory cytokines (IL-1α, IL-8, TNF-α), neutrophil recruitment, and follicular wall rupture.

Classification of Acne Lesions

• Non-Inflammatory Lesions:
• Open Comedones (Blackheads): Dilated follicular orifice packed with keratin, lipids, and oxidized melanin.
• Closed Comedones (Whiteheads): Microscopic orifice; flesh-colored small cystic papules.
• Inflammatory Lesions: Papules, Pustules, Nodules, Cysts, Sinus tracts.

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