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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 InflammationThe 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 acneAndrogen 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 keratinisationof 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 drivesebaceous 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 levelsDrinking 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 (2.510%) 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 g or 50 g) 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, the infundibulum. Comedo formationoccurs 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.