By

Prof. Magdy Ragab M.D

Key features 
A multifactorial disorder of the pilosebaceous unit.  A significant psychologic and economic impact.  Clincally characterized by comedones, papules,

pustules, cysts and scarring.

Introduction 
Acne vulgaris is a multifactorial disorder of the pilosebaceous unit. The clinical picture can vary significantly, from mild comedonal acne to fulminant systemic disease. It is primarily a disorder of adolescence. The economic as well as the psychosocial impact of acne is undeniable, creating selfconsciousness and social isolation in those affected.

Epidemiology 
Acne vulgaris affects approximately 40-50 million

individuals each year in the US alone. The peak incidence occurs during adolescence, affecting approximately 85% of young people between 12 and 24 years of age, making it a physiologic occurrence in this group. 12% of women and 3% of men will continue to have clinical acne until 44 years of age.

Key points in acne pathogenesis 
Androgens  o Sebum  Propionebacterium acnes  Inflammation
The pathophysiology of acne involves a complex interaction of multiple factors.

‡ The pathogenesis of acne, the most common skin disease, which manifests in the pilosebaceous follicle, is currently attributed to multiple factors. ‡ Increased sebum production, alteration of the quality of sebum lipids ‡ Regulation of cutaneous steroidogenesis, androgen activity. ‡ Interaction with NPs, exhibition of pro-and antiinflammatory properties. ‡ Follicular hyperkeratinization. ‡ Proliferation of P. acnes within the follicle.
The increased sebum excretion is a major concurrent event associated with the development of acne.

Proposed scheme for the pathogenesis of acne
Androgen production Sebum production P. Acnes proliferation

Sebocytes

Chemotactic factors Lymphocyte & neutrophil attraction Inflammation

?

Interleukin-1E Expression from follicular keratinocytes

Hypercornification & comedogenesis

Microcomedo formation

Comedones

Papules, pustules, nodules

Key points in acne pathogenesis

Androgens play an essential role in acne pathogenesis. It is postulated that androgens may play only a permissive role in priming or initiating acne develop- ment, or

it may be the local overproduction of androgens in the skin and/or the high expression and responsiveness of androgen receptors that determines the formation of acne lesions.

Key points in acne pathogenesis

The sebaceous gland has been shown to express all the necessary enzymes for the biosynthesis of testosterone:

De novo from cholesterol. 5E-reduced substances ingested in dairy products. A shortcut from circulating dehydroepiandrosterone.

Key points in acne pathogenesis

The main influence of

androgen on acne pathogenesis

concerns the proliferation/differentiation of sebocytes and infrainfundibular keratinocytes.

1 Sebocyte proliferation 2 Sebocyte differentiation and lipogenesis 3 Comedogenesis: Formation of microcomedones is caused by hyperproliferation/hyperkeratinization

Key points in acne pathogenesis

Hyperkeratosis in the follicular infundibulum and Sebaceous duct resulting in microcomedones

retention hyperkeratosis with increased number and size of keratohyaline granules and

accumulation of lipid droplets.

Key points in acne pathogenesis

IL-1E

has

been

reported

to

induce

hyperkeratinization in follicular infundibulum. Expression of the hyperproliferative markers

keratin (K) 6 and K16 is also evident. Relative deficiency of linoleic acid and peroxides in sebum may trigger follicular hyperkeratinization.

Key points in acne pathogenesis

Terminal

differentiation

in

the

follicular

infundibulum may play a role in closed comedo formation, and fibroblast growth factor receptor

(FGFR)2 signalling also seems to be involved.

Key points in acne pathogenesis

Increased sebum production is a characteristic of acne patients even if it does not strictly correlate with the development of the lesions.

Seborrhoea is,
condition for the

indeed, not a sufficient

development of the pathology. Variations in lipid metabolism have been described in acne patients, including a decreased amount of

linoleic acid and desaturation of sebaceous fatty acids may contribute to acne development.

Sebum changes effects

squalenesqualene-wax linoleic acid

Ratio

Increase of keratinisation
of infra infundibulum area

= keratotic plug Fluidity decrease
= viscosity increase = less easy elimination
*SqmOOH - squalene mono-hydro-peroxyde

SqmOOH*

Sebum changes

Sebum composition changes

Hyperkeratinisation

Sebum retention

propro-inflammatory Subsatnces released by the keratinocyte (IL-1) (IL*SqmOOH - squalene mono-hydro-peroxyde

IL-1 ILSqmOOH*

Key points in acne pathogenesis

The significance of the involvement of

P. acnes

in

acne pathogenesis is still controversial, mainly due to the fact that it belongs to the resident microbiota.

P. acnes peptides

induces the expression of and

antimicrobial cytokines/

pro-inflammatory

chemokines and inducible enzymes.

Key points in acne pathogenesis

Acne is driven by hormones and growth factors [particularly

insulin-like

growth

factor

(IGF-1)] acting on the sebaceous

glands and the keratinocytes lining the pilary canal. Dairy products (and perhaps some other foods)

steroid hormones and other steroid precursors of DHT that drive
sebaceous gland (and likely pilar keratinocyte) function.

contain 5E-reduced

Key points in acne pathogenesis

Vitamin A. Linoleic acid. Iodine although not comedogenic, may enhance inflammation.

Key points in acne pathogenesis

IGF-1 through a disproportionate elevation in blood sugar and serum insulin levels. High glycemic load foods also cause IGF1-mediated elevations in DHT. IGF-1 levels
Drinking milk causes a direct rise in during teenage years closely parallel acne activity and are likely synergistic with the steroid hormones.

Key points in acne pathogenesis

Toll-like

receptors that

are

proteins

are crucial

transmembrane players in the innate

immune response to microbial and other invaders. Ten TLRs have recently been described in humans.
TLRs are mainly expressed on immune cells, such as

monocytes, macrophages, cells and granulocytes.

dendritic

Key points in acne pathogenesis

TLR stimulation mimics the action of IL-1E and

promotes the production of proinflammatory cytokines, prostaglandins, leukotrienes (LT), chemokines, antimicrobial peptides and inducible enzymes.

Key points in acne pathogenesis

Inflammatory events have been found to precede hyperkeratinization.
P acnes contributes to inflammation via activation of tolllike receptor (TLR) on the membranes of inflammatory cells Peroxisome proliferator-activated receptors partly regulate sebum production. Nutrition has impact on acne pathogenesis. Matrix metalloproteinases (MMPs) occur in sebum and diminish with treatment-related resolution of acne lesions. 

Non-inflammatory acne is

characterized by both open and closed comedo formation. Closed comedones, or whiteheads, are typically small-approximately 1mmskin-colored papules with no apparent follicular opening. 

Open comedones, or blackeads, are dome-shaped

papules with a conspicuous dilated follicular outlet. This opening is filled with an inspissated core of shed keratin. Melanin deposition and lipid oxidation within the debris may be responsible for the black coloration. Ice-pick-type scarring may result from comedones alone. 

The inflammatory lesions of acne originate with comedo formation but then expand to form papules, pustules, nodules and cysts of varying severity. Erythematous papules range from 1 to 5mm in diameter. Pustules tend to be approximately equal in size and are filled with sterile, white pus. As the severity of lesions progresses, nodules form and become markedly inflamed, indurated and tender. 

The cysts of acne are deeper and filled with a combination of pus and serosanguineous fluid. In patients with severe nodulocystic acne, these lesions frequently coalesce to form massively inflamed complex plaques that can include sinus tracts (conglobate lesions). 

Early treatment of acne

is

essential of

for

the

prevention cosmetic

lasting

disfigurement

associated with scarring. Postinflammatory hyperpigmentaiton (PIH). 

Pitted

or

nodular

hypertrophic scars are the often unfortunate

sequelae of both nodular and cystic acne and on the upper trunk soft,

hypopigmented, anetoderma-like lesions can be seen.

Acne fulminans 
Acne fulminans is the most severe form of cystic acne and is characterized by the abrupt onset of nodular and suppurative acne in association with variable systemic manifestations.  Osteolytic bone lesions may accompany the cutaneous findings: Systemic manifestations include fever, arthralgias, myalgias, hepatosplenomegaly prostration. and severe 

Treatment depends on clinical severity and includes

topical, intra-lesional or oral corticosteroids, oral isotretinoin conjunction beneficial. and with oral antibiotics. Dapsone in

isotretinoin

was

reportedly

Acne conglobata 
Severe eruptive nodulocystic acne without systemic manifestations is termed acne conglobata.

Acne mechanica 
Acne mechanica occurs

secondary to repeated mechanical and frictional obstruction of the pilosebaceous outlet. Comedo formation is the result. Welldescribed mechanical factors include rubbing by helmets, chin straps, suspenders and collars and scarfs.

Acne excoriee 
Acne excoriee, occurs primarily in young women.

Typical comedones and inflammatory papules are neurotically excoriated, leaving crusted erosions that may scar. Linear erosions suggest self-

mutilation, and underlying psychiatric component should be suspected. Patients with an anxiety disorder, obsessive-compulsive disorder or

personality disorder are particularly at risk.

Drug-induced acne 
Acne lesions or eruptive acneiform lesions can be seen as a side effect of a number of medications, including anabolic steroids (e.g. danazol, testosterone), corticosteroids, corticotropin, phenytoin, lithium, isoniazid, iodides, bromides, azathioprine, PUVA, monomorphous eruption of inflammatory papules and pustules is often observed in drug-induced acne.

Occupational acne 
Cutting oils, petroleum-based products, and coal tar derivatives. Comedones dominate the clinical picture, with varying numbers of papules, pustules and cystic lesions distributed in exposed as well as typically covered areas.

Chloracne 
Chloracne, the term used to define occupational acne chlorinated aromatic caused by exposure to hydrocarbons.  The following agents, found in electrical conductors and insulators, insecticides, fungicides, herbicides and wood preservatives.

Neonatal acne  Neonatal acne occurs in more than 20% of healthy newborns. Lesions appear at about 2 weeks of age and generally resolve within the first 3 months of life. Typically, small inflamed papules arise on the cheeks and across the nasal bridge.

Infantile acne  If acne presents at 3-6 months of age, it is classified as infantile. Clinically, comedo formation is much more prominent than in the neonatal from and may lead to pitted scarring. The pathogenesis of infantile acne reflects the hormonal imbalances.

I- Topical treatment 
Tretinoin (all-trans-retinoic acid) was the first topical

comedolytic agent used for the treatment of acne. Its mechanism of action involves normalizing follicular keratinization, it aids in the expulsion of existing comedones and prevents the formation of new ones. Tretinoin has been shown to have significant antiinflammatory properties. 

Benzoyl peroxide (2.5±10%) is a potent bacteriocidal

agent that reduces P. acnes within the follicle. It is particularly effective when used in combination with other therapies. In contrast to topical antibiotics, microbial resistance to benzoyl peroxide has not been reported. 
Topical antibiotics, clindamycin and erythromycin

represent

the

two

most

commonly

utilized

antibiotics and the formulations vary from creams and gels to solutions and pledgets. 

Salicylic acid is a widely used comedolytic and mild

anti-inflammatory agent. 
Azelaic acid is a naturally occurring dicarboxylic

acid found in cereal grains. It is available as a topical cream, which has been shown to be effective in inflammatory and comedonal acne. By inhibiting the growth of P. acnes, azelaic acid reduces

inflammatory acne. Azelaic acid is applied twice daily. In addition, it may help to lightened

postinflammatory hyperpigmentation.

II-Oral treatments Antibiotics 
Oral erythromycin and tetracycline, or its derivatives

doxycycline and minocycline, are usually prescribed for moderate to to severe topical inflammatory acne

unresponsive

combinations,

primary

mechanism of action of these agents is suppression of the growth of P.acnes, thereby reducing bacterial production of inflammatory factors.

Hormonal 
Hormonal

therapy

is

an

established

second-line

treatment for female patients with acne.
a) The progestational antiandrogen cyproterone acetate is currently used. The standard formulation combines

cyproterone acetate 12 mg with ethinyl estradiol (35 µg or 50 µg) in an oral contraceptive formulation. b) Spironolactone functions as both an androgen receptor blocker and an inhibitor of 5E-reductase. In doses of 50-100 mg twice daily. Side effects are dose-related and include potential hyperkalemia, irregular menstrual periods, breast tenderness, headache and fatigue.

Isotretinoin 
Since 1971, isotretinoin (13-cis-retinoic acid), for patients with severe, nodulocystic acne refractory to treatment, including oral antibiotics.  Isotretinoin is best absorbed from the gastrointestinal tract when it is taken with a fatty meal.  The oral retinoid acts upon the sebaceous gland, prohibiting maturation of the basal cells leads to sebaceous gland atrophy. It reduces sebum production by up to 90%. As a result, P. acnes, which are dependent on the glycerol resulting from the hydrolysis of sebum triglycerides, are unable to thrive. Normalization of follicular of follicular keratinization also occurs, and this initial step in acnegenesis is significantly inhibited. 

Dosing of isotretinoin 0.5-2.0 mg/kg/day for 16-20 weeks is recommended., with a total cumulative dose of 120-150 mg/kg, have been shown to reduce the risk of relapse.  The side effects of isotretinoin are numerous. These include cheilitis, dryness of the oral and nasal mucosa, generalized xerosis, and skin fragility. Alopecia. Xerophthalmia is common.  Teratogenicity is a serious potential complication when isotretinoin is used in women of childbearing age.  Elevated serum triglyceride levels. Increased levels of transaminases.

Surgical treatment 
Comedo

extraction

can

improve

the

cosmetic

appearance. 
For deep and inflamed cystic lesions, intralesional

injection of corricosteroid. Larger nodulocystic lesions may require incision and drainage prior. 
Low-concentration chemical peels are also beneficial for

the reduction of comedones. The E-hydroxy acids (including glycolic acid), salicylic acid and trichoroacetic acid are the most common peeling agents. 

One of the most distressing consequences of acne

vulgaris is scaring. Surgical treatment should be aimed at the type of scarring present. Dermabrasion, laser resurfacing and deeper chemical peels. 

Filler substances used include bovine and human

collagen hyaluronic acid and autologous fat. Punch grafting is an option for patients with "ice-pick" scaring.

I-The role of genetic predisposition in the development of acne is uncertain. 
Evidences: It is known that the number and size of

sebaceous glands and their subsequent activity is inherited. 
It

is

also

widely

held

that

acne,

including

nodulocystic acne, runs in families.

II-Follicular keratinization 
One of the first steps in the production of acne is the

formation of the microcomedo. This begins in the keratinized lining of the upper portion of the

follicle, ³the infundibulum´. Comedo formation
occurs when the corneocytes, which are normally shed into the lumen of the follicle and extruded through the follicular ostium, are retaind and

accumulate, leading to hyperkeratosis. 

Increased cellular cohesion and proliferation occurs

in the proximal portion of the infundibulum and the infra-infundibulum, and it creates a microcomedo formation. 
With expansion of the comedo, the contents become

closely

packed,

creating

whorled

lamellar

concretions. As the forces increase, rupture of the comedo wall with extrusion of the immunogenic keratin and sebum occurs with resultant

inflammation.

III- Inflammation 
Is not only the result of comedo rupture seen early in acne lesion formation. For example, CD4 cell number and IL-1 activity have been shown to increase prior to hyperkeratinization in acneprone areas. The type of inflammatory response determines the clinical lesion seen. If neutrophils predominate (typical of early lesions), a suppurative pustule is formed. Influx of predominately T-helper lymphocytes, foreign body type giant cells, and neutrophils results in inflamed papules, nodules and cysts. The type of inflammatory response also plays a role in the development of scarring. Early, nonspecific inflammation results in less scarring than does a delayed, specific inflammatory response. 

Propionibacterium acnes contributes significantly to

the production of acne. 

The pathogenicity of these microorganisms stems

from several of their properties, including the production of lipases, enzymes contributing to comedo rupture, and several proinflammatory

mediators.

One mechanism is via toll-like receptors 
P.acnes has been shown to release pro-inflammatory

mediators (IL-1E, IL-8 and TNF-E) through this ILR2 pathway. The increase in IL-8, in particular results in neutrophil recruitment, the release of lysosomal enzymes and subsequent disruption of the follicular epithelium. 

Hormonal effects, Androgens are produced both outside

the sebaceous unit, primarily from the gonads and adrenal glands, and locally within the sebaceous gland via the action of androgen-metabolizing enzymes such as 5E-reductase.

Common therapies for acne vulgaris. 1, Double-blind study; 2, clinical series; 3, anecdotal.

Topical retinoid preparations used for acne vulgaris. Preparations that are currently available.

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